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Describe the genetic determinants of common epilepsies | Genetic determinants of common epilepsies are defined as the interaction of mutations in one of two unlinked genes, SCN1 and SCN2, which code for the proteins hamartin and epilepticin, respectively. Disruption of these genes has been found to be associated with epileptic encephalopathies, but it is not entirely clear if this translates directly to the increased risk for epilepsy or via epigenetic changes. | BACKGROUND: The epilepsies are a clinically heterogeneous group of neurological
disorders. Despite strong evidence for heritability, genome-wide association
studies have had little success in identification of risk loci associated with
epilepsy, probably because of relatively small sample sizes and insufficient
power. We aimed to identify risk loci through meta-analyses of genome-wide
association studies for all epilepsy and the two largest clinical subtypes
(genetic generalised epilepsy and focal epilepsy).
METHODS: We combined genome-wide association data from 12 cohorts of individuals
with epilepsy and controls from population-based datasets. Controls were
ethnically matched with cases. We phenotyped individuals with epilepsy into
categories of genetic generalised epilepsy, focal epilepsy, or unclassified
epilepsy. After standardised filtering for quality control and imputation to
account for different genotyping platforms across sites, investigators at each
site conducted a linear mixed-model association analysis for each dataset.
Combining summary statistics, we conducted fixed-effects meta-analyses of all
epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the
genome-wide significance threshold at p<1·66 × 10(-8).
FINDINGS: We included 8696 cases and 26 157 controls in our analysis.
Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3
(p=8·71 × 10(-10)), implicating SCN1A, and at 4p15.1 (p=5·44 × 10(-9)),
harbouring PCDH7, which encodes a protocadherin molecule not previously
implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted
a single signal at 2p16.1 (p=9·99 × 10(-9)), implicating VRK2 or FANCL. No
single nucleotide polymorphism achieved genome-wide significance for focal
epilepsy.
INTERPRETATION: This meta-analysis describes a new locus not previously
implicated in epilepsy and provides further evidence about the genetic
architecture of these disorders, with the ultimate aim of assisting in disease
classification and prognosis. The data suggest that specific loci can act
pleiotropically raising risk for epilepsy broadly, or can have effects limited
to a specific epilepsy subtype. Future genetic analyses might benefit from both
lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of
specific clinical subtypes).
FUNDING: International League Against Epilepsy and multiple governmental and
philanthropic agencies. |
Should nerinetide be used for treatment of ischaemic stroke? | Nerinetide did not improve the proportion of ischemic stroke patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo. | |
What is the role of alcohol acyl transferases in fruit aroma? | Volatile esters, a major class of compounds contributing to the aroma of many fruit, are synthesized by alcohol acyl-transferases (AAT).
The expression of all Cm-AAT genes is up-regulated during ripening and inhibited in antisense ACC oxidase melons and in fruit treated with the ethylene antagonist 1-methylcyclopropene (1-MCP), indicating a positive regulation by ethylene. | Two genes (CM-AAT1 and CM-AAT2) with strong sequence homology (87% identity at
the protein level) putatively involved in the formation of aroma volatile esters
have been isolated from Charentais melon fruit. They belong to a large and
highly divergent family of multifunctional plant acyl-transferases and show at
most 21% identity to the only other fruit acyl-transferase characterized so far
in strawberry. RT-PCR studies indicated that both genes were specifically
expressed in fruit at increasing rates in the early and mid phases of ripening.
Expression was severely reduced in ethylene-suppressed antisense ACC oxidase
(AS) fruit and in wild-type (WT) fruit treated with the ethylene antagonist
1-MCP. Cloning of the two genes in yeast revealed that the CM-AAT1 protein
exhibited alcohol acyl-transferase activity while no such activity could be
detected for CM-AAT2 despite the strong homology between the two sequences.
CM-AAT1 was capable of producing esters from a wide range of combinations of
alcohols and acyl-CoAs. The higher the carbon chain of aliphatic alcohols, the
higher the activity. Branched alcohols were esterified at differential rates
depending on the position of the methyl group and the nature of the acyl donor.
Phenyl and benzoyl alcohols were also good substrates, but activity varied with
the position and size of the aromatic residue. The cis/trans configuration
influenced activity either positively (2-hexenol) or negatively (3-hexenol).
Because ripening melons evolve the whole range of esters generated by the
recombit CM-AAT1 protein, we conclude that CM-AAT1 plays a major role in
aroma volatiles formation in the melon. The 'fruity' attributes of ripe apples (Malus × domestica) arise from our
perception of a combination of volatile ester compounds. Phenotypic variability
in ester production was investigated using a segregating population from a
'Royal Gala' (RG; high ester production) × 'Granny Smith' (GS; low ester
production) cross, as well as in transgenic RG plants in which expression of the
alcohol acyl transferase 1 (AAT1) gene was reduced. In the RG × GS population,
46 quantitative trait loci (QTLs) for the production of esters and alcohols were
identified on 15 linkage groups (LGs). The major QTL for 35 individual compounds
was positioned on LG2 and co-located with AAT1. Multiple AAT1 gene variants were
identified in RG and GS, but only two (AAT1-RGa and AAT1-GSa) were functional.
AAT1-RGa and AAT1-GSa were both highly expressed in the cortex and skin of ripe
fruit, but AAT1 protein was observed mainly in the skin. Transgenic RG
specifically reduced in AAT1 expression showed reduced levels of most key esters
in ripe fruit. Differences in the ripe fruit aroma could be perceived by sensory
analysis. The transgenic lines also showed altered ratios of biosynthetic
precursor alcohols and aldehydes, and expression of a number of ester
biosynthetic genes increased, presumably in response to the increased substrate
pool. These results indicate that the AAT1 locus is critical for the
biosynthesis of esters contributing to a 'ripe apple' flavour. |
What is Hikikomori syndrome? | The 'Hikikomori' syndrome (HS) consists of prolonged and severe social withdrawal. | A form of severe social withdrawal, called hikikomori, has been frequently
described in Japan and is characterized by adolescents and young adults who
become recluses in their parents' homes, unable to work or go to school for
months or years. The aim of this study was to review the evidence for hikikomori
as a new psychiatric disorder. Electronic and manual literature searches were
used to gather information on social withdrawal and hikikomori, including
studies examining case definitions, epidemiology, and diagnosis. A number of
recent empirical studies have emerged from Japan. The majority of such cases of
hikikomori are classifiable as a variety of existing Diagnostic and Statistical
Manual (DSM) psychiatric disorders. However, a notable subset of cases with
substantial psychopathology does not meet criteria for any existing psychiatric
disorder. We suggest hikikomori may be considered a culture-bound syndrome and
merits further international research into whether it meets accepted criteria as
a new psychiatric disorder. Research diagnostic criteria for the condition are
proposed. PURPOSE: To explore whether the 'hikikomori' syndrome (social withdrawal)
described in Japan exists in other countries, and if so, how patients with the
syndrome are diagnosed and treated.
METHODS: Two hikikomori case vignettes were sent to psychiatrists in Australia,
Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA.
Participants rated the syndrome's prevalence in their country, etiology,
diagnosis, suicide risk, and treatment.
RESULTS: Out of 247 responses to the questionnaire (123 from Japan and 124 from
other countries), 239 were enrolled in the analysis. Respondents' felt the
hikikomori syndrome is seen in all countries examined and especially in urban
areas. Biopsychosocial, cultural, and environmental factors were all listed as
probable causes of hikikomori, and differences among countries were not
significant. Japanese psychiatrists suggested treatment in outpatient wards and
some did not think that psychiatric treatment is necessary. Psychiatrists in
other countries opted for more active treatment such as hospitalization.
CONCLUSIONS: Patients with the hikikomori syndrome are perceived as occurring
across a variety of cultures by psychiatrists in multiple countries. Our results
provide a rational basis for study of the existence and epidemiology of
hikikomori in clinical or community populations in international settings. In 1998 the Japanese psychiatrist Tamaki Sait¯o invented the term hikikomori,
referring to a condition characterised by a state of social withdrawal and
avoidance (education, work, friendships) combined with a persistent isolation
and confinement in the own home for at least 6 months, due to various factors.
Initially it undoubtedly regarded a disorder related to a specific
socio-cultural context, however in the last couple of years some cases of
hikikomori behaviour have also been observed in other countries far from Japan,
both geographically and culturally. By way of hypothesis this diffusion can
probably be attributed to the cultural revolution represented by mass
communication in the internet era; in particular, it seems to be closely related
to the immediateness and diffusion of web 2.0, i.e. of social networks.
Therefore, we report a case of hikikomori behaviour, who was referred to our
ward. M. is a 28-year-old man, who has lived the last 10 years in a state of
almost complete isolation. He has maintained contacts with the outside world
almost exclusively via internet. He started several therapies with psychiatrists
and psychologists, without achieving significant results. The case of M.
represents, to our knowledge, the first case of hikikomori described in Italy. Maladaptive social interaction and its related psychopathology have been
highlighted in psychiatry especially among younger generations. In Japan, novel
expressive forms of psychiatric phenomena such as "modern-type depression" and
"hikikomori" (a syndrome of severe social withdrawal lasting for at least six
months) have been reported especially among young people. Economic games such as
the trust game have been utilized to evaluate real-world interpersonal
relationships as a novel candidate for psychiatric evaluations. To investigate
the relationship between trusting behaviors and various psychometric scales, we
conducted a trust game experiment with eighty-one Japanese university students
as a pilot study. Participants made a risky ficial decision about whether to
trust each of 40 photographed partners. Participants then answered a set of
questionnaires with seven scales including the Lubben Social Network Scale
(LSNS)-6 and the Patient Health Questionnaire (PHQ)-9. Consistent with previous
research, male participants trusted partners more than female participants.
Regression analysis revealed that LSNS-family (perceived support from family)
for male participants, and item 8 of PHQ-9 (subjective agitation and/or
retardation) for female participants were associated with participants' trusting
behaviors. Consistent with claims by social scientists, our data suggest that,
for males, support from family was negatively associated with cooperative
behavior toward non-family members. Females with higher subjective agitation
(and/or retardation) gave less money toward males and high attractive females,
but not toward low attractive females in interpersonal relationships. We believe
that our data indicate the possible impact of economic games in psychiatric
research and clinical practice, and validation in clinical samples including
modern-type depression and hikikomori should be investigated. Wet beriberi, characterized by high cardiac output with predomitly
right-sided heart failure and lactic acidosis, is a disease caused by thiamine
deficiency, and is rarely seen in modern society. However, patients with social
withdrawal syndrome, also known as hikikomori syndrome, may be a new population
at risk of thiamine deficiency. Hikikomori syndrome, first recognized in Japan,
is becoming a worldwide issue. A 39-year-old Japanese patient was brought to our
hospital, with a 3-week history of progressive shortness of breath and
generalized edema. The patient had right-sided high-output heart failure, lactic
acidosis, and Wernicke-Korsakoff syndrome. Because of his history of social
isolation, we diagnosed hikikomori syndrome according to the Japanese
government's definition, which is as follows: lifestyle centered at home; no
interest or willingness to attend school or work; persistence of symptoms beyond
6 months; and exclusion of other psychiatric and developmental disorders.
Considering his diagnosis of hikikomori syndrome and social isolation, we
suspected malnutrition, particularly thiamine deficiency, and successfully
treated him. Clinicians should be aware of the potential risk of thiamine
deficiency associated with hikikomori syndrome and initiate thiamine replacement
in cases of high-output heart failure associated with lactic acidosis. The universality of secure base construct, which suggests that one's use of an
attachment figure as a secure base from which to explore the environment is an
evolutionary outcome, is one of the core ideas of attachment theory. However,
this universality idea has been critiqued because exploration is not as valued
in Japanese culture as it is in Western cultures. Waters and Waters (2006)
hypothesized that one's experiences of secure base behaviors are stored as a
script in memory, and developed a narrative assessment called the Attachment
Script Assessment (ASA) to evaluate one's secure base script. This study
examined the validity of the ASA and the utility of secure base concept in
Japanese culture. A sample of Japanese young adults (N = 89; M = 23.46; SD =
3.20; 57% = females) completed both the ASA and self-report questionnaires. The
results revealed that the ASA score was associated with two dimensions of
self-report questionnaires assessing parent-youth attachment relationships
(trust and communication). The ASA score was not related to Japanese cultural
values (amae acceptance, interdependent self-construal, and low independent
self-construal). However, a low ASA score was related to a psychological
dysfunction in the Japanese cultural context; hikikomori symptoms, which are
defined as a desire to remain in his or her own room and his or her
understanding of this behavior in other people. We concluded that since
hikikomori can be interpreted as an extreme inhibition of exploration, the
association between low secure base script and hikikomori symptoms suggests the
utility of secure base construct in Japan. (PsycINFO Database Record Hikikomori, a severe form of social withdrawal syndrome, is a growing social
issue in Japan and internationally. The pathophysiology of hikikomori has not
yet been elucidated and an effective treatment remains to be established.
Recently, we revealed that avoidant personality disorder is the most common
comorbidity of hikikomori. Thus, we have postulated that avoidant personality is
the personality underpinning hikikomori. First, we herein show relationships
between avoidant personality traits, blood biomarkers, hikikomori-related
psychological features, and behavioural characteristics assessed by a trust game
in non-hikikomori volunteers. Avoidant personality traits were negatively
associated with high-density lipoprotein cholesterol (HDL-C) and uric acid (UA)
in men, and positively associated with fibrin degeneration products (FDP) and
high sensitivity C-reactive protein (hsCRP) in women. Next, we recruited actual
individuals with hikikomori, and compared avoidant personality traits, blood
biomarkers, and psychological features between individuals with hikikomori and
age-matched healthy controls. Individuals with hikikomori had higher avoidant
personality scores in both sexes, and showed lower serum UA levels in men and
lower HDL-C levels in women compared with healthy controls. This is the first
report showing possible blood biomarkers for hikikomori, and opens the door to
clarify the underlying biological pathophysiology of hikikomori. INTRODUCTION: The 'Hikikomori' syndrome (HS) consists of prolonged and severe
social withdrawal. It has been studied first in Japan and recently has
increasingly drawn the attention of researchers and clinicians all over the
world. It is unclear whether it exists in other cultural contexts than Asia. The
existing systematic reviews did not provide a quantitative synthesis on its
prevalence. In addition, a summary of the co-occurring rates of psychiatric
disorders is lacking. To provide a more comprehensive understanding of the
clinical picture, it seems important to investigate which psychiatric disorders
listed in the classification systems are most frequently associated with this
psychological condition affecting young people. This paper describes a
systematic review and meta-analysis protocol summarising worldwide prevalence of
the HS in general population and clinical samples with psychiatric disorders.
The review will also assess the co-occurrence between HS and each psychiatric
disorder defined by any version of the Diagnostic and Statistical Manual of
Mental Disorders (DSM) or International Classification of Diseases (ICD) in any
clinical samples with psychiatric disorders.
METHODS AND ANALYSIS: A systematic review will be conducted according to
Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)
guidelines. Studies will be included if they use youth aged 12-35 years,
recruited from general population or population with psychiatric disorders, if
they use international criteria to diagnose HS. No restriction about design or
language will be applied. The search will be conducted during the first week of
November 2019 by two independent reviewers through the databases Scopus, PubMed,
PsycINFO, Web of Science, by examining study references, by looking for
conference proceedings/dissertations/theses, by contacting study corresponding
authors. Random-effect meta-analysis will be performed by computing effect sizes
as logit event rates. Study quality will be assessed through the
Newcastle-Ottawa Scale.
ETHICS AND DISSEMINATION: The current review does not require ethics approval.
The results will be disseminated through conference presentations and
publications in peer-reviewed journals.
PROSPERO REGISTRATION NUMBER: CRD 42018098747. Psychiatry, as we know it, is at a crucial point because it needs to adapt to
the modern time and still maintain the integrity and ethic aspects of the
therapeutic alliance. Bearing in mind the rising prevalence of new addictions
like Internet and online gaming addictions, one can see that, however, disputed,
there is a whole new category of psychiatric illnesses on the rise. An example
of these kinds of illnesses is Hikikomori. Hikikomori, or severe social
withdrawal, pertains to patients who have stopped participating in everyday
routine and would spend the majority of time confined in their room for the
period of 6 months or more, with no evident psychosis. Although this syndrome
was originally described in Japan, over the course of last few years it has been
documented in several parts of the world, spreading like a silent epidemic. Our
case study, being the first documented case in Southeast Europe, according to
our experience and literature search, is a vivid example of this syndrome. In
this report we discuss differential diagnosis, show what kind of therapy was
efficient in the successful treatment of this syndrome and how it can be
prevented in the future. OBJECTIVE: Hikikomori, from the Japanese words 'hiku' (to pull) and 'komoru' (to
withdraw), is a clinical condition in which a subject locks himself/herself into
his/her own house for more than 6 months. This condition is becoming relevant in
Japan and other Asian countries, with new cases emerging in Europe and a steep
increase in its incidence.
METHODS: In this article, the various psychopathological and diagnostic
hypothesis and the different criteria proposed by the various authors have been
analysed and compared, paying attention also to the new studies conducted in
Europe and to therapeutic perspectives that are opening up for its treatment.
RESULTS: Numerous hypothesis have been put forward for the genesis of
hikikomori, in particular, the hypothesis of a behaviour seen as a dysfuncion of
the family system or as a result of our current modern society. Furthermore,
this behaviour has been compared to other conditions such as internet addiction
and a specific form of depression called Modern Type Depression (MTD).
CONCLUSIONS: Hikikomori could represent the clinical answer to a social
evolution, similarly to other phenomena such as binge behaviours and use of
psychoactive substances. Further studies are needed to clarify diffusion,
diagnosticassessment and differential diagnosis.Key pointsHikikomori is now
considered a contemporary society-bound syndrome linked to modern society
changes.Hikikomori might be a coping strategy to avoid relationships, social
judgement and possible failures.Hikikomori might represent an extreme suffering
that needs to be identified early: it is linked to severe form of modern type
depression and it is a risk factor for suicidal behaviours.It is important to
inform and sensitise communities about hikikomori to assure early
interventions.More clinical studies are needed to define a unitary and specific
model of hikikomori and to structure focussed interventions. |
Which gene is primarily associated with the Saethre-Chotzen syndrome? | Saethre-Chotzen syndrome is a craniosynostosis syndrome that is rarely diagnosed prenatally . It is caused by cytogenetic deletions or mutations of the TWIST1 gene . Of the 37 patients with classic features of the syndrome, the overall detection rate for TWIST mutations was 68% . Increased risk for developmental delay is associated with TWIST deletions . | Saethre-Chotzen syndrome is one of the most common autosomal domit disorders
of craniosynostosis in humans and is characterized by craniofacial and limb
anomalies. The locus for Saethre-Chotzen syndrome maps to chromosome 7p21-p22.
We have evaluated TWIST, a basic helix-loop-helix transcription factor, as a
candidate gene for this condition because its expression pattern and mutant
phenotypes in Drosophila and mouse are consistent with the Saethre-Chotzen
phenotype. We mapped TWIST to human chromosome 7p21-p22 and mutational analysis
reveals nonsense, missense, insertion and deletion mutations in patients. These
mutations occur within the basic DNA binding, helix I and loop domains, or
result in premature termination of the protein. Studies in Drosophila indicate
that twist may affect the transcription of fibroblast growth factor receptors
(FGFRs), another gene family implicated in human craniosynostosis. The emerging
cascade of molecular components involved in craniofacial and limb development
now includes TWIST, which may function as an upstream regulator of FGFRs. Saethre-Chotzen syndrome (acrocephalo-syndactyly type III, ACS III) is an
autosomal domit craniosynostosis with brachydactyly, soft tissue syndactyly
and facial dysmorphism including ptosis, facial asymmetry and prominent ear
crura. ACS III has been mapped to chromosome 7p21-22. Of interest, TWIST, the
human counterpart of the murine Twist gene, has been localized on chromosome
7p21 as well. The Twist gene product is a transcription factor containing a
basic helix-loop-helix (b-HLH) domain, required in head mesenchyme for cranial
neural tube morphogenesis in mice. The co-localisation of ACS III and TWIST
prompted us to screen ACS III patients for TWIST gene mutations especially as
mice heterozygous for Twist null mutations displayed skull defects and
duplication of hind leg digits. Here, we report 21-bp insertions and nonsense
mutations of the TWIST gene (S127X, E130X) in seven ACS III probands and
describe impairment of head mesenchyme induction by TWIST as a novel
pathophysiological mechanism in human craniosynostoses. Saethre-Chotzen syndrome, a common autosomal domit craniosynostosis in
humans, is characterized by brachydactyly, soft tissue syndactyly and facial
dysmorphism including ptosis, facial asymmetry, and prominent ear crura.
Previously, we identified a yeast artificial chromosome that encompassed the
breakpoint of an apparently balanced t(6;7) (q16.2;p15.3) translocation
associated with a mild form of Saethre-Chotzen syndrome. We now describe, at the
DNA sequence level, the region on chromosome 7 affected by this translocation
event. The rearrangement occurred approximately 5 kb 3' of the human TWIST locus
and deleted 518 bp of chromosome 7. The TWIST gene codes for a transcription
factor containing a basic helix-loop-helix (b-HLH) motif and has recently been
described as a candidate gene for Saethre-Chotzen syndrome, based on the
detection of mutations within the coding region. Potential exon sequences
flanking the chromosome 7 translocation breakpoint did not hit known genes in
database searches. The chromosome rearrangement downstream of TWIST is
compatible with the notion that this is a Saethre-Chotzen syndrome gene and
implies loss of function of one allele by a positional effect as a possible
mechanism of mutation to evoke the syndrome. The TWIST gene maps to 7p21 and mutations in the gene have been reported in the
Saethre-Chotzen form of craniosynostosis. The position of the Saethre-Chotzen
gene has previously been refined by FISH analysis of four patients carrying
balanced translocations involving 7p21 which suggested that it was located
between D7S488 and D7S503. We report here that the breakpoints in four
translocation patients do not interrupt the coding sequence of the TWIST gene
and thus most likely act through a positional effect. Twelve Saethre-Chotzen
cases were found to have TWIST mutations. Four of these families had been used
as part of the linkage study of the Saethre-Chotzen locus. The mutations
detected included missense and nonsense mutations and three cases of a 21 bp
duplication. Although phenotypically diagnosed as having Saethre-Chotzen
syndrome, three families were found to have a pro250arg mutation of FGFR3. Saethre-Chotzen syndrome (ACS III) is an autosomal domit craniosynostosis
syndrome recently ascribed to mutations in the TWIST gene, a basic
helix-loop-helix (b-HLH) transcription factor regulating head mesenchyme cell
development during cranial neural tube formation in mouse. Studying a series of
22 unrelated ACS III patients, we have found TWIST mutations in 16/22 cases.
Interestingly, these mutations consistently involved the b-HLH domain of the
protein. Indeed, mutant genotypes included frameshift deletions/insertions,
nonsense and missense mutations, either truncating or disrupting the b-HLH motif
of the protein. This observation gives additional support to the view that most
ACS III cases result from loss-of-function mutations at the TWIST locus. The
P250R recurrent FGFR 3 mutation was found in 2/22 cases presenting mild clinical
manifestations of the disease but 4/22 cases failed to harbour TWIST or FGFR 3
mutations. Clinical re-examination of patients carrying TWIST mutations failed
to reveal correlations between the mutant genotype and severity of the
phenotype. Finally, since no TWIST mutations were detected in 40 cases of
isolated coronal craniosynostosis, the present study suggests that TWIST
mutations are specific to Saethre-Chotzen syndrome. Saethre-Chotzen syndrome is a relatively common craniosynostosis disorder with
autosomal domit inheritance. Mutations in the TWIST gene have been identified
in patients with Saethre-Chotzen syndrome. The TWIST gene product is a
transcription factor with DNA binding and helix-loop-helix domains. Numerous
missense and nonsense mutations cluster in the functional domains, without any
apparent mutational hot spot. Two novel point mutations and one novel
polymorphism are included in this review. Large deletions including the TWIST
gene have been identified in some patients with learning disabilities or mental
retardation, which are not typically part of the Saethre-Chotzen syndrome.
Comprehensive studies in patients with the clinical diagnosis of Saethre-Chotzen
syndrome have demonstrated a TWIST gene abnormality in about 80%, up to 37% of
which may be large deletions [Johnson et al., 1998]. The gene deletions and
numerous nonsense mutations are suggestive of haploinsufficiency as the
disease-causing mechanism. No genotype phenotype correlation was apparent. Saethre-Chotzen syndrome is an autosomal acrocephalosyndactyly syndrome whose
gene has been assigned to chromosome 7p (TWIST). A case of a 13-year-old girl
with Saethre-Chotzen syndrome (ACS III) is described. The features of the
syndrome include: turriplagiocephaly with a cranial circumference of 52 cm,
facial asymmetry, low hairline, proptosis, antimongoloid slanting of palpebral
fissures, nasal deviation with high bridge, angled ears, scoliosis and
torticollis, clinodactyly of the fourth and fifth toes, large halluxes, and
neurosensorial hypoacusia. For correction of the deformity, a cranioorbital
remodeling was performed. The craniofacial approach with remodeling of the
frontal bar and reduction of the turricephaly resulted in a satisfactory
morphological and functional outcome, with complete three-dimensional reshaping
and remodeling of the frontonasoorbital area. Saethre-Chotzen syndrome is a common craniosynostosis syndrome characterized by
craniofacial and limb anomalies. Intragenic mutations of the TWIST gene within
7p21 have been identified as a cause of this disorder. There is phenotypic
overlap with other craniosynostosis syndromes, and intragenic mutations in FGFR2
(fibroblast growth factor receptor 2) and FGFR3 (fibroblast growth factor
receptor 3) have been demonstrated in the other conditions. Furthermore,
complete gene deletions of TWIST have also been found in a significant
proportion of patients with Saethre-Chotzen syndrome. We investigated 11
patients clinically identified as having the Saethre-Chotzen phenotype and 4
patients with craniosynostosis but without a clear diagnosis. Of the patients
with the Saethre-Chotzen phenotype, four were found to carry the FGFR3 P250R
mutation, three were found to be heterozygous for three different novel
mutations in the coding region of TWIST, and two were found to have a deletion
of one copy of the entire TWIST gene. Developmental delay was a distinguishing
feature of the patients with deletions, compared to patients with intragenic
mutations of TWIST, in agreement with the results of Johnson et al. [1998: Am J
Hum Genet 63:1282-1293]. No mutations were found for the four patients with
craniosynostosis without a clear diagnosis. Therefore, 9 of our 11 patients
(82%) with the Saethre-Chotzen phenotype had detectable genetic changes in FGFR3
or TWIST. We propose that initial screening for the FGFR3 P250R mutation,
followed by sequencing of TWIST and then fluorescence in situ hybridization
(FISH) for deletion detection of TWIST, is sufficient to detect mutations in >
80% of patients with the Saethre-Chotzen phenotype. Saethre-Chotzen syndrome is a common autosomal domit form of
craniosynostosis, the premature fusion of the sutures of the calvarial bones of
the skull. Most Saethre-Chotzen syndrome cases are caused by haploinsufficiency
for the TWIST gene. Mice heterozygous for a null mutation of the Twist gene
replicate certain features of Saethre-Chotzen syndrome, but have not been
reported to exhibit craniosynostosis. We demonstrate that Twist heterozygous
mice exhibit fusions of the coronal suture and other cranial suture
abnormalities, indicating that Twist heterozygous mice constitute a better
animal model for Saethre-Chotzen syndrome than was previously appreciated. Autosomal domit mutations in the gene encoding the basic helix-loop-helix
transcription factor Twist1 are associated with limb and craniofacial defects in
humans with Saethre-Chotzen syndrome. The molecular mechanism underlying these
phenotypes is poorly understood. We show that ectopic expression of the related
basic helix-loop-helix factor Hand2 phenocopies Twist1 loss of function in the
limb and that the two factors have a gene dosage-dependent antagonistic
interaction. Dimerization partner choice by Twist1 and Hand2 can be modulated by
protein kinase A- and protein phosphatase 2A-regulated phosphorylation of
conserved helix I residues. Notably, multiple Twist1 mutations associated with
Saethre-Chotzen syndrome alter protein kinase A-mediated phosphorylation of
Twist1, suggesting that misregulation of Twist1 dimerization through either
stoichiometric or post-translational mechanisms underlies phenotypes of
individuals with Saethre-Chotzen syndrome. The basic helix-loop-helix protein Twist, a transcriptional repressor, is
essential for embryogenesis in both invertebrates and vertebrates.
Haploinsufficiency of the human TWIST1 gene, which causes the craniosynostosis
disorder Saethre-Chotzen syndrome (SCS), is related to failure to repress
transcription of CDKN1A (which encodes p21/WAF1/CIP1), promoting osteoblast
differentiation. We have examined the functional significance of natural TWIST1
variants present in craniosynostosis patients and in their healthy relatives.
Both deletion and duplication variants of the glycine-rich tract Gly5AlaGly5
inhibited E2A (E12/E47)-dependent transcription of CDKN1A to a similar degree as
wild-type protein, indicating that the length of this glycine tract is not
critical for efficient transcriptional repression. We also evaluated a newly
identified heterozygous TWIST1 variant (c.115C>G, encoding p.Arg39Gly), located
within a putative nuclear localization signal (NLS), that was present in a child
with mild SCS and her clinically unaffected father and grandmother. Unlike
wild-type protein, this mutant required cotransfected E12 to localize to the
nucleus, indicating that the NLS, including amino acid 39, is essential for
nuclear localization; inhibition of E2A-dependent transcription of CDKN1A
occurred normally. This analysis further dissects the structure-function
relationships of TWIST and corroborates with phenotypic observations of disease
expressivity. BACKGROUND: Saethre-Chotzen syndrome is a craniosynostosis syndrome further
characterized by distinctive facial and limb abnormalities. It shows complete
penetrance and variable expressivity and has been linked to the TWIST gene on
chromosome 7p21; more than 80 different intragenic mutations and, recently,
large deletions have been detected in Saethre-Chotzen patients. The aim of this
study was to genetically and phenotypically characterize patients with a
clinical diagnosis of Saethre-Chotzen syndrome.
METHODS: Patients with a clinical diagnosis as well as those with a genetic
diagnosis of Saethre-Chotzen syndrome (n = 34) were included in the study.
RESULTS: The study showed that the important features of Saethre-Chotzen
syndrome are brachycephaly (occurring in 74 percent of patients), a broad,
depressed nasal bridge (65 percent), a high forehead (56 percent), ptosis (53
percent), and prominent auricular crura (56 percent). Furthermore, using
different molecular techniques, pathogenic mutations in the TWIST gene were
identified in 71 percent of patients.
CONCLUSIONS: Patients with deletions of the TWIST gene did not differ from those
with intragenic TWIST mutations in frequency or severity of craniofacial
abnormalities. However, they did distinguish themselves by the presence of many
additional anomalies and diseases and--most importantly--the high frequency of
mental retardation, which was borderline significant. The authors conclude that
when using stringent inclusion criteria for studies of Saethre-Chotzen syndrome,
patients who have a pathogenic mutation of the TWIST gene should be excluded. The Saethre-Chotzen syndrome is an autosomal, domitly inherited
craniosynostosis caused by mutations in the basic helix-loop-helix transcription
factor gene TWIST1. This syndrome has hitherto not been associated with an
increased risk of cancer. However, recent studies, using a murine breast tumor
model, have shown that Twist may act as a key regulator of metastasis and that
the gene is overexpressed in subsets of sporadic human breast cancers. Here, we
report a novel association between the Saethre-Chotzen syndrome and breast
cancer. In 15 Swedish Saethre-Chotzen families, 15 of 29 (52%) women carriers
over the age of 25 had developed breast cancer. At least four patients developed
breast cancer before 40 years of age, and five between 40 and 50 years of age.
The observed cases with breast cancer (n = 15) are significantly higher than
expected (n = 0.89), which gives a standardized incidence ratio (SIR) of 16.80
(95% CI 1.54-32.06). Our finding of a high frequency of breast cancer in women
with the Saethre-Chotzen syndrome identifies breast cancer as an important and
previously unrecognized symptom characteristic of this syndrome. The results
strongly suggest that women carriers of this syndrome would benefit from genetic
counseling and enrolment in surveillance programs including yearly mammography.
Our results also indicate that the TWIST1 gene may be a novel breast cancer
susceptibility gene. Additional studies are, however, necessary to reveal the
mechanism by which TWIST1 may predispose to early onset breast cancer in
Saethre-Chotzen patients. Twist1 is the mouse ortholog of TWIST1, the human gene mutated in
Saethre-Chotzen syndrome. Previously, a Twist1 null allele was generated by gene
targeting in mouse embryonic stem cells. Twist1 heterozygous mice develop
polydactyly and a craniofacial phenotype similar to Saethre-Chotzen patients.
Mice homozygous for the Twist1 null allele die around embryonic day 11.5 (E11.5)
with cranial neural tube closure and vascular defects, hindering in vivo studies
of Twist1 function at later stages of development. Here, we report the
generation of a Twist1 conditional null allele in mice that functions like a
wild-type allele but can be converted to a null allele upon Cre-mediated
recombination. BACKGROUND: Saethre-Chotzen syndrome is a syndromic craniosynostosis defined by
a genetic mutation affecting the TWIST1 gene on chromosome 7p21. It is typically
associated with unicoronal or bicoronal synostosis, eyelid ptosis, dysmorphic
external ears, and other variable facial and limb abnormalities. Surgical
management of the craniosynostosis addresses the calvarial deformity and may
relieve or reduce the risk of intracranial hypertension. The aim of this study
was to assess surgical intervention, with particular consideration of the
reoperation rate for intracranial hypertension, in Saethre-Chotzen syndrome
patients.
METHODS: A retrospective case note analysis was performed on all patients with a
confirmed TWIST1 gene abnormality who attended the Oxford Craniofacial Unit over
a 15-year period. Each patient's mutation and clinical features were recorded.
Surgical intervention and sequelae were examined in greater detail.
RESULTS: Thirty-four patients with genetically confirmed Saethre-Chotzen
syndrome were identified. All had craniosynostosis (bicoronal, 76 percent;
unicoronal, 18 percent; bicoronal and sagittal, 6 percent), and the majority had
eyelid ptosis, low frontal hairline, and external ear anomalies. Thirty-one
patients had received surgical intervention. Nine of 26 patients (35 percent)
with at least 12 months of follow-up after primary intervention and eight of 19
patients (42 percent) with at least 5 years of follow-up developed intracranial
hypertension necessitating secondary calvarial surgery.
CONCLUSIONS: Despite standard surgical intervention, patients with
Saethre-Chotzen syndrome have a high rate (35 to 42 percent) of recurrent
intracranial hypertension necessitating further surgical expansion. All patients
with either bicoronal synostosis or unicoronal synostosis with syndromic
features should be screened for TWIST1 mutations, as this confers a greater risk
than nonsyndromic synostosis of the same sutures. Regular follow-up throughout
the childhood years is essential. Saethre-Chotzen syndrome (acrocephalosyndactyly type III) is a craniosynostosis
syndrome inherited in an autosomal domit manner. Although similar to the
other craniosynostosis syndromes in its clinical presentation, this syndrome is
caused by a mutation in the TWIST1 gene. The TWIST1 gene product is a
transcription factor containing a basic helix-loop-helix (bHLH) domain important
in the development of the head and limbs. Clinical features of this syndrome
include unilateral or bilateral coronal synostosis, ptosis, low-set ears,
hearing loss, hypertelorism, maxillary hypoplasia, deviated nasal septum, broad
great toes, clinodactyly, and syndactyly. We report a young girl with clinical
features of Saethre-Chotzen syndrome who has a previously undescribed sequence
variant in the TWIST1 gene, corresponding to p.R191M. The location of the
altered amino acid in the Twist-box of TWIST1, the high conservation of this
amino acid between different species, and the phenotype of the child all support
a pathogenic role for this novel TWIST1 sequence alteration. Saethre-Chotzen syndrome is one of the most common craniosynostosis syndromes.
It is an autosomal domitly inherited disorder with variable expression that
is caused by germline mutations in the TWIST1 gene or more rarely in the FGFR2
or FGFR3 genes. We have previously reported that patients with Saethre-Chotzen
syndrome have an increased risk of developing breast cancer. Here we have
analysed a cohort of 26 women with BRCA1/2-negative hereditary breast cancer to
study whether a proportion of these families might have mutations in
Saethre-Chotzen-associated genes. DNA sequence analysis of TWIST1 showed no
pathogenic mutations in the coding sequence in any of the 26 patients. MLPA
(multiplex ligation-dependent probe amplification)-analysis also showed no
alterations in copy numbers in any of the craniofacial disorder genes MSX2,
ALX4, RUNX2, EFNB1, TWIST1, FGFR1, FGFR2,FGFR3, or FGFR4. Taken together, our
findings indicate that mutations in Saethre-Chotzen-associated genes are
uncommon or absent in BRCA1/2-negative patients with hereditary breast cancer. BACKGROUND: Patients with Saethre-Chotzen syndrome have a heterogeneous
phenotype. The purpose of this study was to use the genotypic diagnosis of the
authors' series of patients with TWIST1-confirmed Saethre-Chotzen syndrome to
describe their natural history and long-term surgical outcomes.
METHODS: A retrospective chart review was performed on patients treated at The
Children's Hospital of Philadelphia with TWIST1-confirmed Saethre-Chotzen
syndrome (n = 22) over 23 years (1985 to 2008). Their phenotype, need for
primary cranial vault remodeling surgery, and subsequent need for reoperation
were recorded. Genetic records were reviewed to identify each patient's TWIST1
mutation.
RESULTS: There were nine female patients and 13 male patients. Ten had bicoronal
(45 percent), six had unicoronal (27 percent), and four had multisuture (18
percent) craniosynostosis. One had metopic and another had sagittal
craniosynostosis. Average follow-up was 7.6 years (range, birth to 19.6 years).
Seventeen (77 percent) underwent initial cranial vault remodeling and 10 (59
percent) required repeat intracranial vault remodeling (Whitaker class IV). One
patient required major reoperation with bone grafting (Whitaker class III).
Three patients needed minor revision procedures (Whitaker class II). Three
patients needed no further intervention (Whitaker class I). The locations of the
TWIST1 gene mutations in this study did not correlate to a specific surgical
outcome.
CONCLUSIONS: TWIST1-confirmed Saethre-Chotzen syndrome is heterogeneous and
manifests as either mild or severe craniofacial deformities. Our patients with
TWIST1-confirmed Saethre-Chotzen syndrome had a reoperation rate of 65 percent
for Whitaker class III and IV surgical outcome, and 59 percent required a
secondary intracranial procedure for recurrent supraorbital retrusion. Rubinstein-Taybi syndrome (RSTS) is a rare autosomal domit disorder
characterised by facial dysmorphisms, growth and psychomotor development delay,
and skeletal defects. The known genetic causes are point mutations or deletions
of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal
rearrangements indicating novel positional candidate RSTS genes, we used a-CGH
to study 26 patients fulfilling the diagnostic criteria for RSTS who were
negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300
regions, and direct sequencing analyses of the CREBBP gene. We found seven
imbalances (27%): four de novo and three inherited rearrangements not reported
among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the
TWIST1 gene, a suggested candidate for RSTS that is responsible for the
Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with
RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb
2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the
Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate
genes could not be sought in the remaining pathogenetic imbalances, because of
the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the
relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the
inherited rearrangements, the 17q11.2 379Kb duplication, represents the
reciprocal event of the deletion underlying an overgrowth syndrome, both being
mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this
and the other detected CNVs to the clinical RSTS phenotype is difficult to
assess. Craniosynostosis, the premature closure of cranial suture, is a pathologic
condition that affects 1/2000 live births. Saethre-Chotzen syndrome is a genetic
condition characterized by craniosynostosis. The Saethre-Chotzen syndrome, which
is defined by loss-of-function mutations in the TWIST gene, is the second most
prevalent craniosynostosis. Although much of the genetics and phenotypes in
craniosynostosis syndromes is understood, less is known about the underlying
ossification mechanism during suture closure. We have previously demonstrated
that physiological closure of the posterior frontal suture occurs through
endochondral ossification. Moreover, we revealed that antagonizing canonical
Wnt-signaling in the sagittal suture leads to endochondral ossification of the
suture mesenchyme and sagittal synostosis, presumably by inhibiting Twist1.
Classic Saethre-Chotzen syndrome is characterized by coronal synostosis, and the
haploinsufficient Twist1(+/-) mice represents a suitable model for studying this
syndrome. Thus, we seeked to understand the underlying ossification process in
coronal craniosynostosis in Twist1(+/-) mice. Our data indicate that coronal
suture closure in Twist1(+/-) mice occurs between postnatal day 9 and 13 by
endochondral ossification, as shown by histology, gene expression analysis, and
immunohistochemistry. In conclusion, this study reveals that coronal
craniosynostosis in Twist1(+/-) mice occurs through endochondral ossification.
Moreover, it suggests that haploinsufficiency of Twist1 gene, a target of
canonical Wnt-signaling, and inhibitor of chondrogenesis, mimics conditions of
inactive canonical Wnt-signaling leading to craniosynostosis. The developmental pathways involved in horn development are complex and still
poorly understood. Here we report the description of a new domit inherited
syndrome in the bovine Charolais breed that we have named type 2 scurs. Clinical
examination revealed that, despite a strong phenotypic variability, all affected
individuals show both horn abnormalities similar to classical scurs phenotype
and skull interfrontal suture synostosis. Based on a genome-wide linkage
analysis using Illumina BovineSNP50 BeadChip genotyping data from 57 half-sib
and full-sib progeny, this locus was mapped to a 1.7 Mb interval on bovine
chromosome 4. Within this region, the TWIST1 gene encoding a transcription
factor was considered as a strong candidate gene since its haploinsufficiency is
responsible for the human Saethre-Chotzen syndrome, characterized by skull
coronal suture synostosis. Sequencing of the TWIST1 gene identified a
c.148_157dup (p.A56RfsX87) frame-shift mutation predicted to completely
inactivate this gene. Genotyping 17 scurred and 20 horned founders of our
pedigree as well as 48 unrelated horned controls revealed a perfect association
between this mutation and the type 2 scurs phenotype. Subsequent genotyping of
32 individuals born from heterozygous parents showed that homozygous mutated
progeny are completely absent, which is consistent with the embryonic lethality
reported in Drosophila and mouse suffering from TWIST1 complete insufficiency.
Finally, data from previous studies on model species and a fine description of
type 2 scurs symptoms allowed us to propose different mechanisms to explain the
features of this syndrome. In conclusion, this first report on the
identification of a potential causal mutation affecting horn development in
cattle offers a unique opportunity to better understand horn ontogenesis. Saethre-Chotzen syndrome is a craniosynostosis syndrome that is rarely diagnosed
prenatally. It is caused by cytogenetic deletions or mutations of the TWIST1
gene. We report here a de novo prenatal case with clinically and molecularly
well defined Saethre-Chotzen syndrome due to a TWIST1 deletion. This is the
first reported case of a deletion encompassing the TWIST1 gene to be diagnosed
prenatally. We recommend screening for a deletion of the TWIST1 gene if signs of
coronal craniosynostosis with no clear etiology are observed on ultrasound
examination. The authors describe on a Brazilian girl with coronal synostosis, facial
asymmetry, ptosis, brachydactyly, significant learning difficulties, recurrent
scalp infections with marked hair loss, and elevated serum immunoglobulin E.
Standard lymphocyte karyotype showed a small additional segment in
7p21[46,XX,add(7)(p21)]. Deletion of the TWIST1 gene, detected by Multiplex
Ligation Probe-dependent Amplification (MPLA) and array-CGH, was consistent with
phenotype of Saethre-Chotzen syndrome. Array CGH also showed deletion of four
other genes at 7p21.1 (SNX13, PRPS1L1, HD9C9, and FERD3L) and the deletion of
six genes (CACNA2D2, C3orf18, HEMK1, CISH, MAPKAPK3, and DOCK3) at 3p21.31. Our
case reinforces FERD3L as candidate gene for intellectual disability and
suggested that genes located in 3p21.3 can be related to hyper IgE phenotype. Craniosynostosis (CS) is a relatively common birth defect resulting from the
premature fusion of one or more cranial sutures. Human genetic studies have
identified several genes in association with CS. One such gene that has been
implicated in both syndromic (Saethre-Chotzen syndrome) and nonsyndromic forms
of CS in humans is TWIST1. In this study, a heterozygous Twist1 knock out
(Twist1(+/-) ) mouse model was used to study the craniofacial shape changes
associated with the partial loss of function. A geometric morphometric approach
was used to analyze landmark data derived from microcomputed tomography scans to
compare craniofacial shape between 17 Twist1(+/-) mice and 26 of their
Twist1(+/+) (wild type) littermate controls at 15 days of age. The results show
that despite the purported wide variation in synostotic severity, Twist1(+/-)
mice have a consistent pattern of craniofacial dysmorphology affecting all major
regions of the skull. Similar to Saethre-Chotzen, the calvarium is acrocephalic
and wide with an overall brachycephalic shape. Mutant mice also exhibited a
shortened cranial base and a wider and shorted face, consistent with coronal CS
associated phenotypes. The results suggest that these differences are at least
partially the direct result of the Twist1 haploinsufficiency on the developing
craniofacial skeleton. This study provides a quantitative phenotype complement
to the developmental and molecular genetic research previously done on Twist1.
These results can be used to generate further hypotheses about the effect of
Twist1 and premature suture fusion on the entire craniofacial skeleton. Craniosynostosis (a premature fusion of the cranial sutures) occurs with a
frequency of 1 in 2100-2500 births and in over 40% cases is caused by known
genetic factors--either single gene mutations or chromosomal rearrangements.
Cases caused by complex chromosomal abnormalities are uncommon and likely
associated with compound phenotype. Saethre-Chotzen syndrome (SCS) [#101400] is
caused by TWIST1 gene haploinsufficiency. Its phenotype includes uni- or
bicoronal synostosis, short stature, facial dysmorphism and variable anomalies
of the hands and feet. Due to its poor sonographic manifestation a prenatal
diagnosis of SCS is challenging. We report a case of a prenatally detected
craniosynostosis (compound Saethre-Chotzen syndrome phenotype) caused by a de
novo complex chromosomal rearrangement (1; 4; 7) with a microdeletion of
7p21.3-7p15.3, including TWIST1 gene. Saethre-Chotzen syndrome (SCS) is an autosomal domit craniosynostotic
disorder characterized by coronal synostosis, facial asymmetry, ptosis, and limb
abnormalities. Haploinsufficiency of TWIST1, a basic helix-loop-helix
transcription factor is responsible for SCS. Here, we report a 15-month-old male
patient with typical clinical features of SCS in addition to developmental
delay, which is a rare complication in SCS. He showed a de novo 0.9-Mb
microdeletion in 7p21, in which TWIST1, NPMIP13, FERD3L, TWISTNB, and HDAC9 were
included. In comparison with previously reported patients, HDAC9 was suggested
to contribute to developmental delay in SCS patients with 7p21 mirodeletions. BACKGROUND: The bHLH transcription factor TWIST1 plays a key role in the
embryonic development and in tumorigenesis. Some loss-of-function mutations of
the TWIST1 gene have been shown to cause an autosomal domit craniosynostosis,
known as the Saethre-Chotzen syndrome (SCS). Although the functional impacts of
many TWIST1 mutations have been experimentally reported, little is known on the
molecular mechanisms underlying their loss-of-function. In a previous study, we
highlighted the predictive value of in silico molecular dynamics (MD)
simulations in deciphering the molecular function of TWIST1 residues.
RESULTS: Here, since the substitution of the arginine 154 amino acid by a
glycine residue (R154G) is responsible for the SCS phenotype and the
substitution of arginine 154 by a proline experimentally decreases the
dimerizing ability of TWIST1, we investigated the molecular impact of this point
mutation using MD approaches. Consistently, MD simulations highlighted a clear
decrease in the stability of the α-helix during the dimerization of the mutated
R154P TWIST1/E12 dimer compared to the wild-type TE complex, which was further
confirmed in vitro using immunoassays.
CONCLUSIONS: Our study demonstrates that MD simulations provide a structural
explanation for the loss-of-function associated with the SCS TWIST1 mutation and
provides a proof of concept of the predictive value of these MD simulations.
This in silico methodology could be used to determine reliable pharmacophore
sites, leading to the application of docking approaches in order to identify
specific inhibitors of TWIST1 complexes. Saethre-Chotzen syndrome (SCS), associated with TWIST-1 mutations, is
characterized by premature fusion of cranial sutures. TWIST-1
haploinsufficiency, leads to alterations in suture mesenchyme cellular gene
expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We
analyzed the expression of the TWIST-1 target, Tyrosine kinase receptor
c-ros-oncogene 1 (C-ROS-1) in TWIST-1 haploinsufficient calvarial cells derived
from SCS patients and calvaria of Twist-1del/+ mutant mice and found it to be
highly expressed when compared to TWIST-1 wild-type controls. Knock-down of
C-ROS-1 expression in TWIST-1 haploinsufficient calvarial cells derived from SCS
patients was associated with decreased capacity for osteogenic differentiation
in vitro. Furthermore, treatment of human SCS calvarial cells with the tyrosine
kinase chemical inhibitor, Crizotinib, resulted in reduced C-ROS-1 activity and
the osteogenic potential of human SCS calvarial cells with minor effects on cell
viability or proliferation. Cultured human SCS calvarial cells treated with
Crizotinib exhibited a dose-dependent decrease in alkaline phosphatase activity
and mineral deposition, with an associated decrease in expression levels of
Runt-related transcription factor 2 and OSTEOPONTIN, with reduced PI3K/Akt
signalling in vitro. Furthermore, Crizotinib treatment resulted in reduced BMP-2
mediated bone formation potential of whole Twist-1del/+ mutant mouse calvaria
organotypic cultures. Collectively, these results suggest that C-ROS-1 promotes
osteogenic differentiation of TWIST-1 haploinsufficient calvarial osteogenic
progenitor cells. Furthermore, the aberrant osteogenic potential of these cells
is inhibited by the reduction of C-ROS-1. Therefore, targeting C-ROS-1 with a
pharmacological agent, such as Crizotinib, may serve as a novel therapeutic
strategy to alleviate craniosynostosis associated with aberrant TWIST-1
function. Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic
craniosynostosis (premature fusion of the cranial sutures), results from
haploinsufficiency of TWIST1, caused by deletions of the entire gene or
loss-of-function variants within the coding region. To determine whether
non-coding variants also contribute to SCS, we screened 14 genetically
undiagnosed SCS patients using targeted capture sequencing, and identified novel
single nucleotide variants (SNVs) in the 5' untranslated region (UTR) of TWIST1
in two unrelated SCS cases. We show experimentally that these variants, which
create translation start sites in the TWIST1 leader sequence, reduce translation
from the main open reading frame (mORF). This is the first demonstration that
non-coding SNVs of TWIST1 can cause SCS, and highlights the importance of
screening the 5' UTR in clinically diagnosed SCS patients without a coding
mutation. Similar 5' UTR variants, particularly of haploinsufficient genes, may
represent an under-ascertained cause of monogenic disease. |
List 4 targeted synthetic DMARDs that are JAK inhibitors. | Targeted synthetic (ts) DMARDs that are Janus kinase (JAK) inhibitors include tofacitinib, baricitinib, filgotinib, upadacitinib. | |
Which microRNAs are involved in targeting CYLD in triple negative breast cancer? | Mir-182 and miR-301b are involved in targeting CYLD in triple negative breast cancer. | Overexpression of microRNA-182 (miR-182) is found in multiple cancers, but the
association of miR-182 expression with the sensitivity of triple-negative breast
cancer (TNBC) cells to tumor necrosis factor-alpha (TNF-α) remains unknown. In
this study, up-regulation of miR-182 was validated in TNBC patients and cell
lines. Knockdown of miR-182 was observed to hinder the proliferation of BT-549
cells. More importantly, knockdown of miR-182 significantly promoted the
apoptosis induced by TNF-α treatment in BT-549. JC-1 staining and western blot
assays revealed that the K63-linked ubiquitin chains on receptor-interacting
protein 1 (RIP1) were removed and the outer mitochondrial membrane potential
(MMP) and permeability was altered upon combination of TNF-α with anti-miR-182.
We then demonstrated that knockdown of miR-182 up-regulated the expression of
cylindromatosis (CYLD) deubiquitinase, which promoted the formation of
death-inducing signaling complex (DISC) and subsequent caspase-8 activation in
TNF-α-treated BT-549 cells. Collectively, the results of the present study
improve our understanding of the role of miR-182 in TNBC, knockdown of which
facilitates the degradation of ubiquitin chains on RIP1, leading to the
caspase-8 activation and apoptosis in TNF-α-treated TNBC cells. This may be
valuable for the development of cancer therapy. |
Which drugs were tested in the candor trial? | CANDOR trial investigated carfilzomib, dexamethasone, and daratumumab for patients with relapsed or refractory multiple myeloma. | In this review, we summarize novel clinical data on multiple myeloma (MM) that
were presented at the 2019 annual meeting of the American Society of Hematology.
The Master trial showed that a response-adapted approach may effectively guide
therapeutic decisions in terms of treatment intensification after autologous
transplantation among patients with newly diagnosed MM. The Alcyone study
confirmed the superiority of adding daratumumab to the backbone combination of
bortezomib, melphalan, and dexamethasone among diagnosed MM patients unfit for
transplantation, which resulted in a significant overall survival benefit. The
Candor trial showed that the addition of daratumumab to carfilzomib and
dexamethasone is associated with a significant benefit in progression-free
survival among patients with relapsed/refractory MM after 1 to 3 prior lines of
therapy. Novel agents including selinexor- and venetoclax-based combinations
offer new therapeutic choices for relapsed/refractory MM. Furthermore, the
trispecific CC-93269 represents the new generation of highly active T-cell
engagers. Chimeric antigen receptor T-cell constructs show significant efficacy
among patients with heavily pretreated relapsed/refractory MM; however, the
sustainability of responses remains a challenge. BACKGROUND: Lenalidomide and bortezomib frontline exposure has raised a growing
need for novel treatments for patients with relapsed or refractory multiple
myeloma. Carfilzomib in combination with daratumumab has shown substantial
efficacy with tolerable safety in relapsed or refractory multiple myeloma in a
phase 1 study. In this study, we aimed to compare the efficacy and safety of
carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone
in patients with relapsed or refractory multiple myeloma.
METHODS: In this randomised, multicentre, open-label, phase 3 study, 466
patients recruited from 102 sites across North America, Europe, Australia, and
Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to
carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and
dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2
(20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered
intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the
remaining doses of the first two cycles, then every 2 weeks for four cycles
(cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg
dexamethasone weekly (20 mg for patients ≥75 years old starting on the second
week). The primary endpoint was progression-free survival assessed by intention
to treat. Adverse events were assessed in the safety population. This trial
(NCT03158688) is registered with ClinicalTrials.gov, and is active but not
recruiting.
FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed
for eligibility were enrolled. After median follow-up of approximately 17
months, median progression-free survival was not reached in the KdD group versus
15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027).
Median treatment duration was longer in the KdD versus the Kd group (70·1 vs
40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%)
patients in the KdD group and 113 (74%) patients in the Kd group. The frequency
of adverse events leading to treatment discontinuation was similar in both
groups (KdD, 69 [22%]; Kd, 38 [25%]).
INTERPRETATION: KdD significantly prolonged progression-free survival versus Kd
in patients with relapsed or refractory multiple myeloma and was associated with
a favourable benefit-risk profile.
FUNDING: Amgen. |
Which are the parts of a flaggelum? | The bacterial flagellum is a supramolecular motility machine consisting of the basal body, the hook, and the filament.
The axial structure of the flagellum consists of the rod, hook, junction, filament, and cap. | The bacterial flagellum is a filamentous organelle extending from the cell
surface. The axial structure of the flagellum consists of the rod, hook,
junction, filament, and cap. The axial structure is formed by axial component
proteins exported via a specific protein export apparatus in a well-regulated
manner. Although previous studies have revealed the outline of the flagellar
construction process, the mechanism of axial structure formation, including
axial protein export, is still obscure due to difficulties in direct observation
of protein export and assembly in vivo. We recently developed an in vitro
flagellar protein transport assay system using inverted membrane vesicles (IMVs)
and succeeded in reproducing the early stage of flagellar assembly. However, the
late stage of the flagellar formation process remained to be examined in the
IMVs. In this study, we showed that the filament-type proteins are transported
into the IMVs to produce the filament on the hook inside the IMVs. Furthermore,
we provide direct evidence that coordinated flagellar protein export and
assembly can occur at the post-translational level. These results indicate that
the ordered construction of the entire flagellar structure can be regulated by
only the interactions between the protein export apparatus, the export substrate
proteins, and their cognate chaperones. One of the central systems responsible for bacterial motility is the flagellum.
The bacterial flagellum is a macromolecular protein complex that is more than
five times the cell length. Flagella-driven motility is coordinated via a
chemosensory signal transduction pathway, and so bacterial cells sense changes
in the environment and migrate towards more desirable locations. The flagellum
of Salmonella enterica serovar Typhimurium is composed of a bi-directional
rotary motor, a universal joint and a helical propeller. The flagellar motor,
which structurally resembles an artificial motor, is embedded within the cell
envelop and spins at several hundred revolutions per second. In contrast to an
artificial motor, the energy utilized for high-speed flagellar motor rotation is
the inward-directed proton flow through a transmembrane proton channel of the
stator unit of the flagellar motor. The flagellar motor realizes efficient
chemotaxis while performing high-speed movement by an ingenious directional
switching mechanism of the motor rotation. To build the universal joint and
helical propeller structures outside the cell body, the flagellar motor contains
its own protein transporter called a type III protein export apparatus. In this
chapter we summarize the structure and assembly of the Salmonella flagellar
motor complex. |
Why are male calico cats rare? | The tortoiseshell coat color is characteristic to female cats, and its occurrence in tomcats is very rare and associated with the presence of an additional copy of X chromosome. | A syndrome in male cats analogous to chromatin-positive Klinefelter's syndrome
in human males has been demonstrated. The physical characteristics which
suggested an abnormality of chromosome number in cats were "calico" or
"tortoise-shell" coat colors in a male. Buccal mucosal smears were found to have
"female-type" patterns in two out of 12 such male cats screened, and these two
were found to have a diploid chromosome number of 39 rather than the normal 38.
Testicular biopsy performed on one revealed an abnormal pattern; no gonadal
tissue was found in the other cat with an abnormal chromosome number. These
findings indicate that the cat, in addition to the mouse, is available for
experimental study of chromosome number abnormalities. The tortoiseshell coat colour is characteristic to female cats, and its
occurrence in tomcats is very rare and associated with chromosome abnormalities
(additional copy of X chromosome). The aim of this study was identification of
the genetic basis of a case of tortoiseshell colour in a fertile Maine coon
tomcat. Cytogenetic and molecular genetic studies were carried out with painting
molecular probes (WCPP) specific to the X and Y sex chromosomes as well as a DNA
microsatellite panel for the parentage verification of cats. Cytogenetic
analysis revealed only a single set of sex chromosomes typical for male - 38,XY.
The results of the microsatellite polymorphism obtained from DNA showed three
alleles in locus FCA201 and four alleles in loci FCA149 and FCA441 in different
tissues (blood, hair roots and testicles). Based on these results, the case was
diagnosed as a true chimerism 38,XY/38,XY. To the best of our knowledge, this is
the first case of a 38,XY/38,XY chimera diagnosed in cats, confirmed by genetic
analysis. |
Which master regulator drives liver development? | Hepatocyte nuclear factor (HNF)4α regulates fetal liver development. | BACKGROUND: Nonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA
surveillance process that facilitates the recognition and destruction of mRNAs
bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs
may arise from different processes, including erroneous processing and
expression of pseudogenes, but also from more regulated events such as
alternative splicing coupled NMD (AS-NMD). Thus, the NMD pathway serves both as
a silencer of genomic noise and a regulator of gene expression. Given the early
embryonic lethality in NMD deficient mice, uncovering the full regulatory
potential of the NMD pathway in mammals will require the functional assessment
of NMD in different tissues.
METHODOLOGY/PRINCIPAL FINDINGS: Here we use mouse genetics to address the role
of UPF2, a core NMD component, in the development, function and regeneration of
the liver. We find that loss of NMD during fetal liver development is
incompatible with postnatal life due to failure of terminal differentiation.
Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and
disruption of liver homeostasis. Finally, NMD was found to be absolutely
required for liver regeneration.
CONCLUSION/SIGNIFICANCE: Collectively, our data demonstrate the critical role of
the NMD pathway in liver development, function and regeneration and highlights
the importance of NMD for mammalian biology. AIM: The molecular mechanisms by which hepatocyte nuclear factor (HNF)4α
regulates fetal liver development have not been fully elucidated. We screened
the downstream molecules of HNF4α during liver development and identified
sodium-coupled neutral amino acid transporter (SNAT)4. The aim of this study is
to investigate the regulation of SNAT4 by HNF4α and to clarify its roles in
differentiating hepatocytes.
METHODS: HNF4α was overexpressed in cultured liver buds using adenovirus, and
suppression subtractive hybridization screening was performed. Temporal and
spatial expression of SNAT4 during liver development was investigated.
Regulation of SNAT4 by HNF4α was examined by promoter analyses and
electrophoretic mobility shift assays (EMSA). Metabolic labeling and western
blotting were carried out using primary hepatoblasts with SNAT4 overexpression.
RESULTS: The expression of Slc38a4 encoding SNAT4 showed a marked perinatal
increase, and was predomit among system A amino acid transporters. It was
first detected in embryonic day 18.5 liver, and found in most hepatocytes after
birth. Three alternative first exons were found in the SNAT4 gene. Promoter
analyses using approximately 3-kb fragments corresponding to each first exon
(AP1, AP2, AP3) revealed that AP1 and AP2 exhibited strong promoter activity in
mouse hepatoblasts with endogenous HNF4α. Transactivation of AP2 was upregulated
by HNF4α in HeLa cells without endogenous HNF4α. EMSA has demonstrated that
HNF4α directly binds to cis-elements in AP2. Overexpression of SNAT4 facilitated
amino acid uptake and de novo protein synthesis in primary hepatoblasts.
CONCLUSION: SNAT4 functions downstream of HNF4α and plays significant roles in
liver development through mechanisms of amino acid uptake and protein synthesis. Author information:
(1)1] Massachusetts General Hospital Cancer Center, Harvard Medical School,
Boston, Massachusetts 02114, USA [2].
(2)Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston,
Massachusetts 02114, USA.
(3)Department of Medical Oncology, Dana-Farber Cancer Institute, Department of
Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
(4)1] HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer
Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain [2]
Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine.
Icahn School of Medicine at Mount Sinai, New York 10029, USA [3]
Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer
Institute, and Department of Experimental Oncology, Milan 20133, Italy.
(5)HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group,
Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Hospital Clínic, University of Barcelona, Catalonia 08036, Spain.
(6)Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of
Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA.
(7)Department of Pharmacology, Toxicology and Therapeutics, University of Kansas
Medical Center, Kansas City, Kansas 66160, USA.
(8)University of Rochester Medical Center, Rochester, New York 14642, USA.
(9)Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
(10)1] HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer
Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain [2]
Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine.
Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Institució
Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia 08010, Spain [4]
University of Barcelona, Catalonia 08036, Spain.
(11)1] Massachusetts General Hospital Cancer Center, Harvard Medical School,
Boston, Massachusetts 02114, USA [2] Broad Institute of Harvard and MIT,
Cambridge, Massachusetts 02142, USA. The liver is essential for survival due to its critical role in the regulation
of metabolic homeostasis. Metabolism of xenobiotics, such as environmental
chemicals and drugs by the liver protects us from toxic effects of these
xenobiotics, whereas metabolism of cholesterol, bile acids (BAs), lipids, and
glucose provide key building blocks and nutrients to promote the growth or
maintain the survival of the organism. As a well-established master regulator of
liver development and function, hepatocyte nuclear factor 4 alpha (HNF4α) plays
a critical role in regulating a large number of key genes essential for the
metabolism of xenobiotics, metabolic wastes, and nutrients. The expression and
activity of HNF4α is regulated by diverse hormonal and signaling pathways such
as growth hormone, glucocorticoids, thyroid hormone, insulin, transforming
growth factor-β, estrogen, and cytokines. HNF4α appears to play a central role
in orchestrating the transduction of extracellular hormonal signaling and
intracellular stress/nutritional signaling onto transcriptional changes in the
liver. There have been a few reviews on the regulation of drug metabolism, lipid
metabolism, cell proliferation, and inflammation by HNF4α. However, the
knowledge on how the expression and transcriptional activity of HNF4α is
modulated remains scattered. Herein I provide comprehensive review on the
regulation of expression and transcriptional activity of HNF4α, and how HNF4α
crosstalks with diverse extracellular and intracellular signaling pathways to
regulate genes essential in liver pathophysiology. Hepatocyte nuclear factor 4-alpha (HNF4α) is a well established master regulator
of liver development and function. We identified the in vitro presence of a
stable secondary structure, G-quadruplex (G4) in the 5' UTR of P1-HNF4A, the
predomit HNF4α isoform(s) in adult liver. Our data suggest that the
cooperation of G4 and the adjacent putative protein-binding sites within the 5'
UTR was necessary and sufficient to mediate a strong translational repression.
This was supported by analysis of deleted/mutated 5'UTRs and two native
regulatory single-nucleotide polymorphisms in the 5'UTR. Additional results
indicated that G4 motifs in the 5' UTRs of other liver-enriched transcription
factors also inhibited protein expression. Moreover, pyridostatin, a G4 ligand,
specifically potentiated the translational suppressing effect of P1-HNF4A-5'
UTR. In summary, the present study provides the first evidence of the presence
of G4 in human P1-HNF4A-5' UTR in vitro, and establishes a novel working model
of strong inhibition of protein translation via interactions of G4 with
potential RNA-binding proteins (RBPs). The protein expression of the tumor
suppressor HNF4α may be inhibited by interactions of RBPs with the G4 motif in
the 5' UTR to promote cell proliferation during liver development and
carcinogenesis. Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of development and
function of digestive tissues. The HNF4A gene uses two separate promoters P1 and
P2, with P1 products predomit in adult liver, whereas P2 products prevalent
in fetal liver, pancreas, and liver/colon cancer. To date, the mechanisms for
the regulation of HNF4A and the dynamic switch of P1-HNF4α and P2-HNF4α during
ontogenesis and carcinogenesis are still obscure. Our study validated the
previously reported self-stimulation of P1-HNF4α but invalidated the reported
synergism between HNF4α and HNF1α. HNF4A-AS1, a long noncoding RNA, is localized
between the P2 and P1 promoters of HNF4A. We identified critical roles of
P1-HNF4α in regulating the expression of HNF4A-AS1 and its mouse ortholog
Hnf4a-os. Paired box 6 (PAX6), a master regulator of pancreas development
overexpressed in colon cancer, cooperated with HNF1α to induce P2-HNF4α but
antagonized HNF4α in HNF4A-AS1 expression. Thus, PAX6 may be important in
determining ontogenic and carcinogenic changes of P2-HNF4α and HNF4A-AS1 in the
pancreas and intestine. We also interrogated transactivation activities on
multiple gene targets by multiple known and novel HNF4α mutants identified in
patients with maturity onset diabetes of the young 1 (MODY1) and liver cancer.
Particularly, HNF4α-D78A and HNF4α-G79S, two mutants found in liver cancer with
mutations in DNA-binding domain, displayed highly gene-specific transactivation
activities. Interestingly, HNF4α-Q277X, a MODY1 truncation mutant, antagonized
the transactivation activities of HNF1α and farnesoid X receptor, key regulators
of insulin secretion. Taken together, our study provides novel mechanistic
insights regarding the transcriptional regulation and transactivation activity
of HNF4α in digestive tissues. |
Are there small molecule CGRPs under development for the treatment of migraine? | Yes, there are several small molecule CGRPs under development for the treatment of migraine. | Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from
activated trigeminal sensory afferents in headache and facial pain disorders.
There are a handful of CGRP-targeted therapies currently in phase 3 studies for
migraine acute treatment or prevention. Currently, 4 monoclonal antibodies
targeting either the CGRP ligand or receptor are being studied for migraine
prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab),
and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor
antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute
treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in
clinical trials for cluster headache prevention as well. Several other
small-molecular CGRP receptor antagonists are in earlier stages of development
for acute migraine treatment or prevention. In this review, we will discuss the
growing body of clinical trials studying CGRP-targeted therapies for migraine
and cluster headache. |
Which subcortical brain structure is influenced the most by common genetic variants? | The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. Five novel genetic variants influencing the volumes of the putamen and caudate nucleus were identified. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. | Author information:
(1)Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck School
of Medicine of the University of Southern California, Los Angeles, California
90292, USA.
(2)1] Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck
School of Medicine of the University of Southern California, Los Angeles,
California 90292, USA. [2] Neurogenetics Program, Department of Neurology, UCLA
School of Medicine, Los Angeles, California 90095, USA.
(3)QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
(4)1] Department of Human Genetics, Radboud university medical center, Nijmegen
6500 HB, The Netherlands. [2] Department of Psychiatry, Radboud university
medical center, Nijmegen 6500 HB, The Netherlands. [3] Department of Cognitive
Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The
Netherlands. [4] Donders Institute for Brain, Cognition and Behaviour, Radboud
University, Nijmegen 6500 GL, The Netherlands.
(5)MRC-SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's
College London, London SE5 8AF, UK.
(6)1] Laboratory of Human Genetics and Cognitive Functions, Institut Pasteur,
Paris 75015, France. [2] Centre Nationale de Recherche Scientifique (CNRS) Unité
de Recherche Associée (URA) 2182 Genes, Synapses and Cognition, Institut
Pasteur, Paris 75015, France. [3] Université Paris Diderot, Sorbonne Paris Cité,
Paris 75015, France.
(7)1] German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald,
Greifswald 17487, Germany. [2] Department of Psychiatry, University Medicine
Greifswald, Greifswald 17489, Germany.
(8)Brain Center Rudolf Magnus, Department of Psychiatry, University Medical
Center Utrecht, Utrecht, 3584 CX, The Netherlands.
(9)Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901
87, Sweden.
(10)1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4
2XU, UK. [2] Department of Computer Science, Lagos State University, Lagos,
Nigeria. [3] Scottish Imaging Network, A Platform for Scientific Excellence
(SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of
Edinburgh, Edinburgh EH4 2XU, UK.
(11)1] Centre for Healthy Brain Ageing, School of Psychiatry, University of New
South Wales, Sydney 2052, Australia. [2] School of Mathematics and Statistics,
University of Sydney, Sydney 2006, Australia.
(12)The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8,
Canada.
(13)1] Department of Human Genetics, Radboud university medical center, Nijmegen
6500 HB, The Netherlands. [2] Department of Cognitive Neuroscience, Radboud
university medical center, Nijmegen 6500 HB, The Netherlands. [3] Donders
Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500
GL, The Netherlands.
(14)1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of
Oslo, Oslo N-0316, Norway. [2] NORMENT - KG Jebsen Centre, Division of Mental
Health and Addiction, Oslo University Hospital, Oslo 0424, Norway.
(15)1] Cerebral Imaging Centre, Douglas Mental Health University Institute,
Montreal H4H 1R3, Canada. [2] Department of Psychiatry and Biomedical
Engineering, McGill University, Montreal H3A 2B4, Canada.
(16)Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA.
(17)1] Imaging Genetics Center, Institute for Neuroimaging &Informatics, Keck
School of Medicine of the University of Southern California, Los Angeles,
California 90292, USA. [2] Interdepartmental Neuroscience Graduate Program, UCLA
School of Medicine, Los Angeles, California 90095, USA.
(18)Biological Psychology, Neuroscience Campus Amsterdam &EMGO Institute for
Health and Care Research, VU University &VU Medical Center, Amsterdam 1081 BT,
The Netherlands.
(19)1] NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical
Science, University of Bergen, 5021 Bergen, Norway. [2] Dr. Einar Martens
Research Group for Biological Psychiatry, Center for Medical Genetics and
Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway.
(20)Central Institute of Mental Health, Medical Faculty Mannheim, University
Heidelberg, Mannheim 68159, Germany.
(21)1] Language and Genetics Department, Max Planck Institute for
Psycholinguistics, Nijmegen 6525 XD, The Netherlands. [2] International Max
Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands.
(22)Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU
Dresden, Dresden 01307 Germany.
(23)Human Genetics Branch and Experimental Therapeutics and Pathophysiology
Branch, National Institute of Mental Health Intramural Research Program,
Bethesda, Maryland 20892, USA.
(24)1] Department of Psychology, Yale University, New Haven, Connecticut 06511,
USA. [2] Department of Psychiatry, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA.
(25)1] Department of Human Genetics, Radboud university medical center, Nijmegen
6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition and
Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
(26)Department of Psychiatry, University Medicine Greifswald, Greifswald 17489,
Germany.
(27)1] Center for Neuroimaging, Radiology and Imaging Sciences, Indiana
University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Center for
Computational Biology and Bioinformatics, Indiana University School of Medicine,
Indianapolis, Indiana 46202, USA. [3] Indiana Alzheimer Disease Center, Indiana
University School of Medicine, Indianapolis, Indiana 46202, USA.
(28)Center for Translational Research in Systems Neuroscience and Psychiatry,
Department of Psychiatry and Psychotherapy, University Medical Center,
Goettingen 37075, Germany.
(29)1] Department of Psychiatry, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA. [2] Psychiatric and Neurodevelopmental Genetics Unit,
Center for Human Genetic Research, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA. [3] Stanley Center for Psychiatric Research, Broad
Institute of MIT and Harvard, Boston, Massachusetts 02141, USA. [4] Department
of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA.
(30)Center for Neurobehavioral Genetics, University of California, Los Angeles,
California 90095, USA.
(31)Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology,
University of Edinburgh, Edinburgh EH8 9JZ, UK.
(32)Centre for Healthy Brain Ageing, School of Psychiatry, University of New
South Wales, Sydney 2052, Australia.
(33)1] Department of Biomedicine, Aarhus University, Aarhus DK-8000, Denmark.
[2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research,
iPSYCH, Aarhus and Copenhagen DK-8000, Denmark. [3] Center for integrated
Sequencing, iSEQ, Aarhus University, Aarhus DK-8000, Denmark.
(34)Department of Psychiatry, Neuroscience Campus Amsterdam, VU University
Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands.
(35)Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh,
Edinburgh EH10 5HF, UK.
(36)1] Department of Medical and Molecular Genetics, King's College London,
London SE1 9RT, UK. [2] Reta Lila Weston Institute and Department of Molecular
Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
(37)1] Center for Neuroimaging, Radiology and Imaging Sciences, Indiana
University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Indiana
Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis,
Indiana 46202, USA.
(38)1] Department of Psychiatry, University Hospital Marqués de Valdecilla,
School of Medicine, University of Cantabria-IDIVAL, Santander 39008, Spain. [2]
Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid 28029,
Spain.
(39)1] Neuropsychiatric Genetics Research Group and Department of Psychiatry,
Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2,
Ireland. [2] Center for Translational Research on Adversity, Neurodevelopment
and Substance Abuse (C-TRANS), Department of Psychiatry, University of Maryland
School of Medicine, Baltimore, Maryland 21045, USA.
(40)1] Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå
901 87, Sweden. [2] Aging Research Center, Karolinska Institutet and Stockholm
University, 11330 Stockholm, Sweden.
(41)Max Planck Institute of Psychiatry, Munich 80804, Germany.
(42)1] Multimodal Imaging Laboratory, Department of Neurosciences, University of
California, San Diego, California 92093, USA. [2] Department of Cognitive
Sciences, University of California, San Diego, California 92161, USA.
(43)1] QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. [2]
School of Psychology, University of Queensland, Brisbane 4072, Australia. [3]
Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia.
(44)Institute for Community Medicine, University Medicine Greifswald, Greifswald
D-17475, Germany.
(45)1] Analytic and Translational Genetics Unit, Massachusetts General Hospital,
Boston, Massachusetts 02114, USA. [2] Medical and Population Genetics Program,
Broad Institute of Harvard and MIT, Boston, Massachusetts 02142, USA.
(46)1] NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo
University Hospital, Oslo 0424, Norway. [2] Department of Psychology, University
of Oslo, Oslo 0373, Norway.
(47)1] The Oxford Centre for Functional MRI of the Brain, Nuffield Department of
Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK. [2] Department of
Psychiatry, Yale School of Medicine, New Haven, Connecticut 06511, USA.
(48)Donders Institute for Brain, Cognition and Behaviour, Radboud University,
Nijmegen 6500 GL, The Netherlands.
(49)Department of Neurology and Neurosurgery, Montreal Neurological Institute,
McGill University, Montreal H3A 2B4, Canada.
(50)1] Department of Child and Adolescent Psychiatry, Faculty of Medicine of the
TU Dresden, Dresden 01307 Germany. [2] Department of Psychiatry, Massachusetts
General Hospital, Boston, Massachusetts 02115, USA. [3] The Athinoula A.Martinos
Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown,
Massachusetts 02129, USA.
(51)1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of
Oslo, Oslo N-0316, Norway. [2] Department of Psychiatric Research and
Development, Diakonhjemmet Hospital, Oslo 0319, Norway.
(52)NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of
Oslo, Oslo N-0316, Norway.
(53)1] UCL Institute of Neurology, London, United Kingdom and Epilepsy Society,
London WC1N 3BG, UK. [2] Department of Medicine, Imperial College London, London
W12 0NN, UK.
(54)Department of Clinical and Experimental Epilepsy, UCL Institute of
Neurology, London WC1N 3BG, UK.
(55)1] Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut
06511, USA. [2] Olin Neuropsychiatric Research Center, Institute of Living,
Hartford Hospital, Hartford, Connecticut 06106, USA.
(56)Neuropsychiatric Genetics Research Group and Department of Psychiatry,
Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2,
Ireland.
(57)1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4
2XU, UK. [2] Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology,
University of Edinburgh, Edinburgh EH8 9JZ, UK. [3] Scottish Imaging Network, A
Platform for Scientific Excellence (SINAPSE) Collaboration, Department of
Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK.
(58)1] Division of Psychiatry, Royal Edinburgh Hospital, University of
Edinburgh, Edinburgh EH10 5HF, UK. [2] Department of Psychiatry, Yale School of
Medicine, New Haven, Connecticut 06511, USA. [3] Olin Neuropsychiatric Research
Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106,
USA.
(59)1] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL
Institute of Neurology, London WC1N 3BG, UK. [2] Department of Genetics, King
Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
(60)1] Texas Biomedical Research Institute, San Antonio, Texas 78245, USA. [2]
University of Texas Health Science Center, San Antonio, Texas 78229, USA.
(61)1] National Ageing Research Institute, Royal Melbourne Hospital, Melbourne
3052, Australia. [2] Academic Unit for Psychiatry of Old Age, University of
Melbourne, Melbourne 3101, Australia.
(62)Laboratory of Neurogenetics, National Institute on Aging, National
Institutes of Health, Bethesda, Maryland 20892, USA.
(63)1] Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4
2XU, UK. [2] Scottish Imaging Network, A Platform for Scientific Excellence
(SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of
Edinburgh, Edinburgh EH4 2XU, UK. [3] Centre for Cognitive Ageing and Cognitive
Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK. [4]
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU,
UK.
(64)N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences,
Moscow 119333, Russia.
(65)Texas Biomedical Research Institute, San Antonio, Texas 78245, USA.
(66)1] Division of Medical Genetics, Department of Biomedicine, University of
Basel, Basel 4055, Switzerland. [2] Institute of Human Genetics, University of
Bonn, Bonn, D-53127, Germany. [3] Institute of Neuroscience and Medicine
(INM-1), Research Centre Jülich, Jülich, D-52425, Germany. [4] Department of
Genomics, Life &Brain Center, University of Bonn, Bonn D-53127, Germany.
(67)School of Psychology, University of Queensland, Brisbane 4072, Australia.
(68)Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin
Berlin, CCM, Berlin 10117, Germany.
(69)Clinical Research Branch, National Institute on Aging, Baltimore, Maryland
20892, USA.
(70)1] Indiana Alzheimer Disease Center, Indiana University School of Medicine,
Indianapolis, Indiana 46202, USA. [2] Department of Medical and Molecular
Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202,
USA.
(71)1] University of Texas Health Science Center, San Antonio, Texas 78229, USA.
[2] South Texas Veterans Health Care System, San Antonio, Texas 78229, USA.
(72)Biofunctional Imaging, Immunology Frontier Research Center, Osaka
University, Osaka 565-0871, Japan.
(73)1] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL
Institute of Neurology, London WC1N 3BG, UK. [2] Academic Unit for Psychiatry of
Old Age, University of Melbourne, Melbourne 3101, Australia.
(74)1] Division of Genetics, Department of Medicine, Brigham and Women's
Hospital, Boston, Massachusetts 02115, USA. [2] Harvard Medical School, Boston,
Massachusetts 02115, USA.
(75)Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL
Institute of Neurology, London WC1N 3BG, UK.
(76)Department of Psychiatry, University of Groningen, University Medical Center
Groningen, 9713 GZ Groningen, The Netherlands.
(77)Institute of Diagnostic Radiology and Neuroradiology, University Medicine
Greifswald, Greifswald 17475, Germany.
(78)Department of Genomics, Life &Brain Center, University of Bonn, Bonn
D-53127, Germany.
(79)Departments of Cognitive and Clinical Neuropsychology, VU University
Amsterdam, 1081 BT Amsterdam, The Netherlands.
(80)Interfaculty Institute for Genetics and Functional Genomics, University
Medicine Greifswald, Greifswald 17489, Germany.
(81)Department of Psychiatry, Fujita Health University School of Medicine,
Toyoake 470-1192, Japan.
(82)Radiology, Mayo Clinic, Rochester, Minnesota 55905, USA.
(83)FMRIB Centre, University of Oxford, Oxford OX3 9DU, UK.
(84)NICHD Brain and Tissue Bank for Developmental Disorders, University of
Maryland Medical School, Baltimore, Maryland 21201, USA.
(85)1] School of Psychology, University of Sussex, Brighton BN1 9QH, UK. [2]
Institute of Cognitive Neuroscience, University College London, London WC1N 3AR,
UK.
(86)Department of Psychiatry, Maryland Psychiatric Research Center, University
of Maryland, Baltimore, Maryland 21201, USA.
(87)1] Neuroscience Research Australia, Sydney 2031, Australia. [2] School of
Medical Sciences, UNSW, Sydney 2052, Australia.
(88)1] Human Genetics Branch and Experimental Therapeutics and Pathophysiology
Branch, National Institute of Mental Health Intramural Research Program,
Bethesda, Maryland 20892, USA. [2] Department of Pathology and Cell Biology,
Columbia University Medical Center, New York 10032, USA.
(89)Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
(90)Centre for Advanced Imaging, University of Queensland, Brisbane 4072,
Australia.
(91)Department of Psychiatry, Ludwig-Maximilians-Universität, Munich 80336,
Germany.
(92)1] Institute of Human Genetics, University of Bonn, Bonn, D-53127, Germany.
[2] Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich,
Jülich, D-52425, Germany. [3] Department of Genomics, Life &Brain Center,
University of Bonn, Bonn D-53127, Germany.
(93)1] FMRIB Centre, University of Oxford, Oxford OX3 9DU, UK. [2] Department of
Statistics &WMG, University of Warwick, Coventry CV4 7AL, UK.
(94)1] Institute of Human Genetics, University of Bonn, Bonn, D-53127, Germany.
[2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn
D-53127, Germany.
(95)Department of Psychiatry, Osaka University Graduate School of Medicine,
Osaka 565-0871, Japan.
(96)Department of Medical and Molecular Genetics, Indiana University School of
Medicine, Indianapolis, Indiana 46202, USA.
(97)1] Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid
28029, Spain. [2] Institute of Psychiatry, King's College London, London SE5
8AF, UK.
(98)1] Department of Neurology, University of Calgary, Calgary T2N 2T9, Canada.
[2] Department of Clinical Neuroscience, University of Calgary, Calgary T2N 2T9,
Canada.
(99)Psychiatry and Human Behavior, University of California, Irvine, California
92617, USA.
(100)Department of Psychology, University of Oslo, Oslo 0373, Norway.
(101)1] Department of Neurology, Beth Israel Deaconess Medical Center, Boston,
Massachusetts 02215, USA. [2] Harvard Medical School, Boston, Massachusetts
02115, USA.
(102)Department of General Psychiatry, Heidelberg University Hospital,
Heidelberg 69115, Germany.
(103)Department of Neuropathology, MRC Sudden Death Brain Bank Project,
University of Edinburgh, Edinburgh EH8 9AG, UK.
(104)Laboratory of Neuro Imaging, Institute for Neuroimaging and Informatics,
Keck School of Medicine of the University of Southern California, Los Angeles,
California 90033, USA.
(105)Department of Pathology, Johns Hopkins University, Baltimore, Maryland
21287, USA.
(106)Psychology Department and Neuroscience Institute, Georgia State University,
Atlanta, Georgia 30302, USA.
(107)Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4
2XU, UK.
(108)Genentech, South San Francisco, California 94080, USA.
(109)Psychiatry and Leiden Institute for Brain and Cognition, Leiden University
Medical Center, Leiden 2333 ZA, The Netherlands.
(110)Neuroimaging Centre, University of Groningen, University Medical Center
Groningen, Groningen 9713 AW, The Netherlands.
(111)Department of Psychiatry, Carver College of Medicine, University of Iowa,
Iowa City, Iowa 52242, USA.
(112)Department of Neurobiology, Care Sciences and Society, Karolinska
Institutet, Stockholm SE-141 83, Sweden.
(113)Behavioral Epidemiology Section, National Institute on Aging Intramural
Research Program, Baltimore, Maryland 20892, USA.
(114)Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
(115)1] Center for Integrative and Translational Genomics, University of
Tennessee Health Science Center, Memphis, Tennessee 38163, USA. [2] Department
of Genetics, Genomics, and Informatics, University of Tennessee Health Science
Center, Memphis, Tennessee 38163, USA. [3] Jiangsu Province Key Laboratory for
Inflammation and Molecular Drug Target, Medical College of Nantong University,
Nantong 226001, China.
(116)1] Neuropsychiatric Genetics Research Group and Department of Psychiatry,
Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2,
Ireland. [2] Cognitive Genetics and Therapy Group, School of Psychology
&Discipline of Biochemistry, National University of Ireland Galway, Galway,
Ireland.
(117)1] Center for Integrative and Translational Genomics, University of
Tennessee Health Science Center, Memphis, Tennessee 38163, USA. [2] Department
of Genetics, Genomics, and Informatics, University of Tennessee Health Science
Center, Memphis, Tennessee 38163, USA.
(118)1] Department of Human Genetics, Radboud university medical center,
Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition
and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. [3]
Department of Clinical Genetics, Maastricht University Medical Center,
Maastricht 6200 MD, The Netherlands.
(119)1] Department of Psychiatry, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA. [2] Department of Psychology, Center for Brain
Science, Harvard University, Boston, Massachusetts 02138, USA.
(120)1] Department of Cognitive Neuroscience, Radboud university medical center,
Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition
and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands. [3]
Karakter Child and Adolescent Psychiatry, Radboud university medical center,
Nijmegen 6500 HB, The Netherlands.
(121)1] The Mind Research Network &LBERI, Albuquerque, New Mexico 87106, USA.
[2] Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131,
USA.
(122)1] Center for Translational Imaging and Personalized Medicine, University
of California, San Diego, California 92093, USA. [2] Departments of
Neurosciences, Radiology, Psychiatry, and Cognitive Science, University of
California, San Diego, California 92093, USA.
(123)Avera Institute for Human Genetics, Sioux Falls, South Dakota, 57108, USA.
(124)1] Molecular and Cellular Therapeutics, The Royal College of Surgeons,
Dublin 2, Ireland. [2] Neurology Division, Beaumont Hospital, Dublin 9, Ireland.
(125)Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles,
Brussels 1070, Belgium.
(126)1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University
of Oslo, Oslo N-0316, Norway. [2] Department of Medical Genetics, Oslo
University Hospital, Oslo 0450, Norway.
(127)1] Human Genetics Branch and Experimental Therapeutics and Pathophysiology
Branch, National Institute of Mental Health Intramural Research Program,
Bethesda, Maryland 20892, USA. [2] Janssen Research &Development, Johnson
&Johnson, Titusville, New Jersey 08560, USA.
(128)1] Department of Psychiatry, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA. [2] The Athinoula A.Martinos Center for Biomedical
Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
[3] Harvard Medical School, Boston, Massachusetts 02115, USA.
(129)Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA.
(130)1] German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald,
Greifswald 17487, Germany. [2] Institute for Community Medicine, University
Medicine Greifswald, Greifswald D-17475, Germany.
(131)1] Max Planck Institute of Psychiatry, Munich 80804, Germany. [2] Munich
Cluster for Systems Neurology (SyNergy), Munich 81377, Germany. [3] University
of Liverpool, Institute of Translational Medicine, Liverpool L69 3BX, UK.
(132)Institute of Clinical Chemistry and Laboratory Medicine, University
Medicine Greifswald, Greifswald 17475, Germany.
(133)Department of Psychiatry, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA.
(134)UCL Institute of Neurology, London, United Kingdom and Epilepsy Society,
London WC1N 3BG, UK.
(135)1] Department of Psychiatry, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA. [2] Psychiatric and Neurodevelopmental Genetics Unit,
Center for Human Genetic Research, Massachusetts General Hospital, Boston,
Massachusetts 02115, USA. [3] Stanley Center for Psychiatric Research, Broad
Institute of MIT and Harvard, Boston, Massachusetts 02141, USA. [4] Harvard
Medical School, Boston, Massachusetts 02115, USA.
(136)Center for Imaging of Neurodegenerative Disease, San Francisco VA Medical
Center, University of California, San Francisco, California 94121, USA.
(137)1] Department of Child and Adolescent Psychiatry, Erasmus University
Medical Centre, Rotterdam 3000 CB, The Netherlands. [2] Department of Radiology,
Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands.
(138)1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University
of Oslo, Oslo N-0316, Norway. [2] Department of Psychiatric Research and
Development, Diakonhjemmet Hospital, Oslo 0319, Norway. [3] Department of
Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm
SE-171 76, Sweden.
(139)1] Human Genetics Branch and Experimental Therapeutics and Pathophysiology
Branch, National Institute of Mental Health Intramural Research Program,
Bethesda, Maryland 20892, USA. [2] Clinical Neuroimaging Laboratory, College of
Medicine, Nursing and Health Sciences, National University of Ireland Galway,
Galway, Ireland.
(140)1] Department of Cognitive Neuroscience, Radboud university medical center,
Nijmegen 6500 HB, The Netherlands. [2] Donders Institute for Brain, Cognition
and Behaviour, Radboud University, Nijmegen 6500 GL, The Netherlands.
(141)1] Donders Institute for Brain, Cognition and Behaviour, Radboud
University, Nijmegen 6500 GL, The Netherlands. [2] Language and Genetics
Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The
Netherlands.
(142)1] Department of Psychiatry, University Medicine Greifswald, Greifswald
17489, Germany. [2] Department of Psychiatry and Psychotherapy, HELIOS Hospital
Stralsund 18435, Germany.
(143)1] Center for Translational Research in Systems Neuroscience and
Psychiatry, Department of Psychiatry and Psychotherapy, University Medical
Center, Goettingen 37075, Germany. [2] Max Planck Institute of Psychiatry,
Munich 80804, Germany.
(144)Molecular Research Center for Children's Mental Development, United
Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan.
(145)1] NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University
of Oslo, Oslo N-0316, Norway. [2] Department of Clinical Neuroscience,
Psychiatry Section, Karolinska Institutet, Stockholm SE-171 76, Sweden.
(146)Medical University of Lodz, Lodz 90-419, Poland.
(147)1] Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK. [2]
NIHR Dementia Biomedical Research Unit, King's College London, London SE5 8AF,
UK.
(148)1] Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA.
[2] Department of Neurology, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205, USA.
(149)Section of Gerontology and Geriatrics, Department of Medicine, University
of Perugia, Perugia 06156, Italy.
(150)Clinical Neuroimaging Laboratory, College of Medicine, Nursing and Health
Sciences, National University of Ireland Galway, Galway, Ireland.
(151)1] Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology,
University of Edinburgh, Edinburgh EH8 9JZ, UK. [2] Division of Psychiatry,
Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK.
(152)1] Brain Center Rudolf Magnus, Department of Psychiatry, University Medical
Center Utrecht, Utrecht, 3584 CX, The Netherlands. [2] Center for
Neurobehavioral Genetics, University of California, Los Angeles, California
90095, USA.
(153)1] Rotman Research Institute, University of Toronto, Toronto M6A 2E1,
Canada. [2] Departments of Psychology and Psychiatry, University of Toronto,
Toronto M5T 1R8, Canada.
(154)1] The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8,
Canada. [2] Departments of Physiology and Nutritional Sciences, University of
Toronto, Toronto M5S 3E2, Canada.
(155)1] Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL
Institute of Neurology, London WC1N 3BG, UK. [2] Department of Medical and
Molecular Genetics, King's College London, London SE1 9RT, UK.
(156)1] Centre for Healthy Brain Ageing, School of Psychiatry, University of New
South Wales, Sydney 2052, Australia. [2] Neuropsychiatric Institute, Prince of
Wales Hospital, Sydney 2031, Australia.
(157)1] Center for Neuroimaging, Radiology and Imaging Sciences, Indiana
University School of Medicine, Indianapolis, Indiana 46202, USA. [2] Indiana
Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis,
Indiana 46202, USA. [3] Department of Psychiatry and Psychotherapy, Charité
Universitätsmedizin Berlin, CCM, Berlin 10117, Germany.
(158)1] Department of Neuroimaging, Institute of Psychiatry, King's College
London, London SE5 8AF, UK. [2] Biomedical Research Centre for Mental Health,
King's College London, London SE5 8AF, UK. [3] Biomedical Research Unit for
Dementia, King's College London, London SE5 8AF, UK.
(159)1] Institute of Clinical Medicine, Neurology, University of Eastern
Finland, Kuopio FI-70211, Finland. [2] Neurocentre Neurology, Kuopio University
Hospital, Kuopio FI-70211, Finland.
(160)Department of Medical and Molecular Genetics, King's College London, London
SE1 9RT, UK.
(161)1] Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA.
[2] Departments of Psychiatry, Neurology, Neuroscience and the Institute of
Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205, USA.
(162)1] Department of Radiology, Erasmus University Medical Centre, Rotterdam
3015 CN, The Netherlands. [2] Department of Epidemiology, Erasmus University
Medical Centre, Rotterdam 3015 CN, The Netherlands.
(163)Laboratory of Epidemiology and Population Sciences, Intramural Research
Program, National Institute on Aging, Bethesda, Maryland 20892, USA.
(164)Department of Neurology, Clinical Division of Neurogeriatrics, Medical
University Graz, Graz 8010, Austria.
(165)INSERM U897, University of Bordeaux, Bordeaux 33076, France.
(166)1] Department of Neurology, Boston University School of Medicine, Boston,
Massachusetts 02118, USA. [2] Framingham Heart Study, Framingham, Massachusetts
01702, USA.
(167)1] Department of Neurology, School of Medicine, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, USA. [2] Department of Psychiatry, School of
Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. [3]
Department of Psychology, Dietrich School of Arts and Sciences, University of
Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
(168)General Internal Medicine, Johns Hopkins School of Medicine, Baltimore,
Maryland 21205, USA.
(169)Department of Epidemiology, Erasmus University Medical Centre, Rotterdam
3015 CN, The Netherlands.
(170)1] The Athinoula A.Martinos Center for Biomedical Imaging, Massachusetts
General Hospital, Charlestown, Massachusetts 02129, USA. [2] Department of
Radiology, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts 02114, USA.
(171)1] The Athinoula A.Martinos Center for Biomedical Imaging, Massachusetts
General Hospital, Charlestown, Massachusetts 02129, USA. [2] Department of
Radiology, Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts 02114, USA. [3] Computer Science and AI Lab, Massachusetts
Institute of Technology, Boston, Massachusetts 02141, USA.
(172)Department of Neurology University of Washington, Seattle, Washington
98195, USA.
(173)Institute of Molecular Biology and Biochemistry, Medical University Graz,
8010 Graz, Austria.
(174)Department of Neurology, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205, USA.
(175)Department of Biostatistics, Boston University School of Public Health,
Boston, Massachusetts 02118, USA.
(176)Groupe d'Imagerie Neurofonctionnelle, UMR5296 CNRS, CEA and University of
Bordeaux, Bordeaux 33076, France.
(177)Cardiovascular Health Research Unit, Department of Medicine, University of
Washington, Seattle, Washington 98101, USA.
(178)Icelandic Heart Association, University of Iceland, Faculty of Medicine,
Reykjavik 101, Iceland.
(179)1] Department of Neurology, Boston University School of Medicine, Boston,
Massachusetts 02118, USA. [2] Department of Neurology, School of Medicine,
University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
(180)1] QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. [2]
School of Psychology, University of Queensland, Brisbane 4072, Australia.
(181)1] Department of Human Genetics, Radboud university medical center,
Nijmegen 6500 HB, The Netherlands. [2] Department of Psychiatry, Radboud
university medical center, Nijmegen 6500 HB, The Netherlands. [3] Donders
Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6500
GL, The Netherlands. |
Givosiran is used for treatment of which disease? | Givosiran is approved for treatment of porphyria. | BACKGROUND: Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene
expression and accumulation of neurotoxic intermediates result in neurovisceral
attacks and disease manifestations in patients with acute intermittent
porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an
investigational RNA interference therapeutic agent that inhibits hepatic ALAS1
synthesis.
METHODS: We conducted a phase 1 trial of givosiran in patients with acute
intermittent porphyria. In part A of the trial, patients without recent
porphyria attacks (i.e., no attacks in the 6 months before baseline) were
randomly assigned to receive a single subcutaneous injection of one of five
ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of
body weight) or placebo. In part B, patients without recent attacks were
randomly assigned to receive once-monthly injections of one of two doses of
givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28
days apart). In part C, patients who had recurrent attacks were randomly
assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg
per kilogram) or placebo once monthly (total of four injections) or once
quarterly (total of two injections) during a 12-week period, starting on day 0.
Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were
evaluated.
RESULTS: A total of 23 patients in parts A and B and 17 patients in part C
underwent randomization. Common adverse events included nasopharyngitis,
abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who
received givosiran in parts A through C combined. In part C, all 6 patients who
were assigned to receive once-monthly injections of givosiran had sustained
reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and
porphobilinogen levels to near normal. These reductions were associated with a
79% lower mean annualized attack rate than that observed with placebo
(exploratory efficacy end point).
CONCLUSIONS: Once-monthly injections of givosiran in patients who had recurrent
porphyria attacks resulted in mainly low-grade adverse events, reductions in
induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic
intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack
rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals;
ClinicalTrials.gov number, NCT02452372 .). Recent advances in pathophysiological and genetic mechanisms of some
neuromuscular diseases and a rapid progress in new pharmacological technologies
led to an accelerated development of innovative treatments, generating an
unexpected therapeutic revolution. In part 1, we report already commercially
available drugs, just approved drugs and new therapeutic promises in the
treatment of peripheral neuropathies. Hereditary transthyretin amyloidosis
(hATTR) is a devastating disease due to amyloid accumulation in peripheral
nerves, heart and autonomic system. The first specific drug approved for hATTR
was tafamidis, a TTR tetramer stabilizer. In 2018, the positive results of two
phase 3 trials have been reported leading to start of regulatory approval route
for inotersen, an antisense oligonucleotide and patisiran, the first-ever RNA
interference (RNAi) therapeutic. System biology targeting approach has indicated
baclofen, naltrexone and sorbitol in combination (PXT3003) as candidate drugs
for Charcot-Marie-Tooth disease type 1A. This hypothesis was confirmed in
experimental models and in phase 2 and 3 clinical trials. Givosiran, another
RNAi therapeutic, targeting 5-aminolevulinic acid synthase, has been positively
tested in acute intermittent porphyria in phase 1/2 and ongoing phase 3 trials.
Although allogenic hematopoietic stem cell transplantation resulted recently a
long-term therapy in mitochondrial neurogastrointestinal encephalomyopathy
(MNGIE), a new strategy is liver transplantation which is able to revert the
severe biochemical and clinical imbalance of the disease. Recently, a gene
therapy has been tested in a MNGIE murine model, indicating that it may become a
new therapeutic option. In November 2019 givosiran became the second small interfering RNA (siRNA)-based
drug to receive US Food and Drug Administration (FDA) approval, it has been
developed for the treatment of acute intermittent porphyria (AIP), a disorder
characterized by life-threatening acute neurovisceral attacks. The porphyrias
are a group of disorders in which enzymatic deficiencies in heme production lead
to toxic accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen
(PBG), which are involved in the neurovisceral attacks. Givosiran acts as a
conventional siRNA to trigger RNA interference (RNAi)-mediated gene silencing on
delta-ALA synthase 1 (ALAS1), thus returning ALA and PBG metabolites to the
physiological level to attenuate further neurotoxicity. Givosiran makes use of a
new hepatic-delivery system that conjugates three GalNac (N-acetylgalactosamine)
molecules to the siRNA passenger strand. GalNac binds to the liver
asialoglycoprotein receptor, favoring the internalization of these
GalNac-conjugated siRNAs into the hepatic cells. In a phase I study,
subcutaneous monthly administration of givosiran 2.5 mg/kg reduced > 90% of ALA
and PBG content. This siRNA is being analyzed in ENVISION (NCT03338816), a phase
III, multicenter, placebo-controlled randomized controlled trial. In preliminary
results, givosiran achieved clinical endpoints for AIP, reducing urinary ALA
levels, and presented a safety profile that enabled further drug development.
The clinical performance of givosiran revealed that suppression of ALAS1 by
GalNac-decorated siRNAs represents an additional approach for the treatment of
patients with AIP that manifests recurrent acute neurovisceral attacks. Givosiran is a small interfering ribonucleic acid agent that was recently
approved in the United States for the treatment of acute hepatic porphyria
(AHP). This phase I study evaluated the safety, pharmacokinetic, and
pharmacodynamic profile of subcutaneously (SC) administered givosiran in
patients with acute intermittent porphyria, the most common AHP type. Givosiran
was rapidly absorbed from the SC injection site with peak plasma concentrations
achieved within 0.5-5 hours followed by elimination with a short half-life of
4-10 hours. Plasma exposures of AS(N-1)3' givosiran, an active metabolite with
equal potency as givosiran, was 35%-75%. Givosiran treatment resulted in a rapid
and dose-dependent reduction in urinary aminolevulinic acid (ALA) and
porphobilinogen (PBG) towards the upper limit of normal (ULN) in AHP patients.
Greater and more sustained reductions in ALA and PBG were achieved with once
monthly dosing compared with once quarterly dosing. After monthly dosing, trough
ALA levels were reduced to below the ULN, approximately 95% reduction from
baseline, at both the 2.5 and 5.0 mg/kg doses. Givosiran (Givlaari™) is an aminolevulinate synthase 1 (ALAS1)-directed small
interfering RNA (siRNA) covalently linked to a ligand to enable specific
delivery of the siRNA to hepatocytes. This results in downregulation of ALAS1
mRNA and prevents accumulation of neurotoxic δ-aminolevulinic acid and
porphobilinogen levels that are associated with acute porphyria attacks.
Givosiran is being developed by Alnylam Pharmaceuticals for the treatment of
acute hepatic porphyria (AHP). In November 2019, givosiran was approved in the
USA for the treatment of adults with AHP based on the positive results from the
multinational, phase III ENVISION trial. In the EU, givosiran received a
positive opinion in January 2020 for the treatment of AHP in adults and
adolescents aged 12 years and older. This article summarizes the milestones in
the development of givosiran leading to this first approval for the treatment of
adults with AHP. BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1
(ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and
porphobilinogen, is central to the pathogenesis of acute attacks and chronic
symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy,
inhibits ALAS1 expression.
METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly
assigned symptomatic patients with acute hepatic porphyria to receive either
subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly
for 6 months. The primary end point was the annualized rate of composite
porphyria attacks among patients with acute intermittent porphyria, the most
common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted
in hospitalization, an urgent health care visit, or intravenous administration
of hemin at home.) Key secondary end points were levels of ALA and
porphobilinogen and the annualized attack rate among patients with acute hepatic
porphyria, along with hemin use and daily worst pain scores in patients with
acute intermittent porphyria.
RESULTS: A total of 94 patients underwent randomization (48 in the givosiran
group and 46 in the placebo group). Among the 89 patients with acute
intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran
group and 12.5 in the placebo group, representing a 74% lower rate in the
givosiran group (P<0.001); the results were similar among the 94 patients with
acute hepatic porphyria. Among the patients with acute intermittent porphyria,
givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of
hemin use, and better daily scores for pain than placebo. Key adverse events
that were observed more frequently in the givosiran group were elevations in
serum aminotransferase levels, changes in serum creatinine levels and the
estimated glomerular filtration rate, and injection-site reactions.
CONCLUSIONS: Among patients with acute intermittent porphyria, those who
received givosiran had a significantly lower rate of porphyria attacks and
better results for multiple other disease manifestations than those who received
placebo. The increased efficacy was accompanied by a higher frequency of hepatic
and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION
ClinicalTrials.gov number, NCT03338816.). Targeted delivery of oligonucleotides to liver hepatocytes using
N-acetylgalactosamine (GalNAc) conjugates that bind to the asialoglycoprotein
receptor has become a breakthrough approach in the therapeutic oligonucleotide
field. This technology has led to the approval of givosiran for the treatment of
acute hepatic porphyria, and there are another seven conjugates in
registrational review or phase 3 trials and at least another 21 conjugates at
earlier stages of clinical development. This review highlights some of the
recent chemical and preclinical advances in this space, leading to a large
number of clinical candidates against a diverse range of targets in liver
hepatocytes. The review focuses on the use of this delivery system for small
interfering RNAs (siRNAs) and antisense molecules that cause downregulation of
target mRNA and protein. A number of other approaches such as anti-microRNAs and
small activating RNAs are starting to exploit the technology, broadening the
potential of this approach for therapeutic oligonucleotide intervention. OBJECTIVE: Since 1983, hemin has been FDA-approved for acute intermittent
porphyria (AIP) attacks. In 2019, FDA approved givosiran for the treatment of
adults with acute hepatic porphyria. The objective of this research was to
estimate and compare the total cost of AIP-related healthcare for patients
treated with hemin or givosiran.
METHODS: A microsimulation cost model was developed to estimate the annual
economic impact of hemin versus givosiran treatment for patients with AIP from
the U.S. healthcare payer perspective. Hemin treatment costs were calculated
from the Hemin Shipment Data in which patients were defined as receiving acute
attack treatment or prophylaxis treatment based on shipment patterns. Three
separate hemin subpopulations were considered: one attack per year, multiple
attacks per year, and hemin prophylaxis. Treatment costs for givosiran (with
hemin for acute attacks) were simulated based on Phase III trial efficacy
results applied to individual treatment histories in the Hemin Shipment Data.
Other healthcare utilization was also considered. Outcomes were annualized and
expenditures inflated to 2019.
RESULTS: For all patients with AIP, the average annual total cost of care with
hemin was 78% lower (difference = $482,113; 95% CI=$373,638-$594,778) than the
average annual total cost of care with givosiran. Average annual total cost of
care with hemin was between 46% and 92% lower than givosiran for the three hemin
subpopulations: one attack per year (difference = $545,219; 95%
CI=$436,584-$657,239), multiple attacks per year (difference = $459,366; 95%
CI=$350,291-$574,403), and hemin prophylaxis (difference = $311,950; 95%
CI=$191,898-$435,893). Cost savings with hemin were robust to one-way and
probabilistic sensitivity as well as scenario analyses.
CONCLUSIONS: Hemin is expected to provide cost savings compared to givosiran for
all AIP patients and subpopulations. Lower annual total costs of care with hemin
range from $311,950 to $545,219 less depending on whether the patient uses hemin
prophylactically or for acute treatment attacks. |
List mediators that are released from mast cells? | tryptase
histamine
heparin proteoglycan
chymase
cytokines
2,3-dinor-11β-PGF2α
leukotriene (LT)E4 | beta-Tryptase, a product of the TPSAB1 and TPSB2 genes, is a trypsin-like serine
protease that is a major and selective component of the secretory granules of
all human mast cells, accounting for as much as 25% of cell protein. Once mast
cells are activated, beta-tryptase is released along with histamine and heparin
proteoglycan. beta-Tryptase is a unique enzyme with a homotetrameric structure
in which active sites face into the central cavity of the four monomers,
stabilized by heparin-proteoglycan. This structure makes beta-tryptase resistant
to most biological inhibitors of serine proteases. Without stabilization, at
neutral pH beta-tryptase converts to inactive monomers. Tryptase levels are
elevated in bronchoalveolar lavage (BAL) fluid obtained from atopic asthmatics
and in serum during systemic anaphylactic shock. Several synthetic small
molecular weight beta-tryptase inhibitors reduced Ag-induced airway
hypersensitivity in animals, suggesting that beta-tryptase is involved in the
pathogenesis of airway inflammation. Although the major biologic substrate(s) of
beta-tryptase remain ambiguous, the protease can digest several proteins of
potential biologic importance, including fibrinogen, fibronectin, pro-urokinase,
pro-matrix metalloprotease-3 (proMMP-3), protease activated receptor-2 (PAR2)
and complement component C3. Recently, monomers of beta-tryptase with enzymatic
activity have been detected in vitro. Here we discuss how beta-tryptase monomers
with enzymatic activity were identified as well as their potential role in vivo. INTRODUCTION: Although 4 mast cell mediators can be routinely measured, the
results of initial testing to evaluate symptoms of mast cell activation have not
been widely reported.
OBJECTIVE: We examined the results of mast cell mediator tests used to assess
patients with mast cell activation symptoms during a 5-year time span.
METHODS: After excluding patients with alternative diagnoses, records of 108
patients were reviewed for initial mediator test results. Mediators included
serum tryptase plus urinary N-methyl histamine (N-MH), leukotriene (LT)E4, and
11β-prostaglandin (PG) F2α or 2,3-dinor-11β-PGF2α (BPG).
RESULTS: Most commonly, either a single measured elevation of 1 mediator (48.1%)
or elevations of 2 (33.3%) mediators was found at baseline, during symptoms or
at both time points. Elevated levels of a single mediator in order of frequency
were: BPG > tryptase > LTE4 > N-MH, and for two mediators: BPG + tryptase (n =
16 cases) > BPG + LTE4 (n = 9) > BPG + N-MH (n = 6). Elevations in 3 mediators
(n = 8) or 4 mediators (n = 2) were much less frequent. Monoclonal mast cell
activation syndrome (n = 6), and systemic and cutaneous mastocytosis (n = 4)
were also infrequent. Baseline plus symptom-associated tryptase values were
obtained in only 7 patients.
CONCLUSIONS: This survey suggests that elevations of 1 or 2 mediators are the
most common (total 81.4% of cases) findings from initial tests for mast cell
activation. Elevated levels of BPG were most commonly found both singly and in
combination with other mediators, followed by the finding of elevated levels of
tryptase. Baseline plus symptom-associated tryptase levels were measured in only
a minority of patients. |
What is Exencephaly? | Exencephaly is a type of cephalic disorder wherein the brain is located outside of the skull | Exencephaly is said to precede anencephaly resulting from failure of the rostral
neuropore closure. In order to verify if the exencephaly induced after neural
tube closure would also lead to anencephaly, exencephaly was induced in rat
fetuses by maternal administration of a single dose (15 mg/kg) of
cyclophosphamide on day 12 of gestation and pregcy was prolonged by uterine
ligation until postconception (PC) day 24. Fetal death was found to increase
with prolongation of gestation and no sign of recovery from growth retardation
was observed. Alizarin red-S-stained skeletal preparations substantiated the
persistence of skull malformations in the exencephalic fetuses. Histological
observations of the mesenchyme and the brain indicated degenerative changes that
were intensifying with time. The ventricular system expanded progressively; the
ependyma was denuded and neural mass lay free in the ventricle. The choroid
plexus appeared to be elaborate and extensive. The haemorrhagic capillary
network around the brain tissue was highly proliferative and appeared to
penetrate the former from the exterior. Tissue necrosis seemed to progress
unabated. Cystic spaces appeared beneath the base of the brain and became
progressively large and it appeared as if the brain was being pushed out of the
shallow cranial fossae. By PC day 24, most of the brain tissue had degenerated,
thus giving clearly the appearance of the anencephalic condition. Extensive histological and immunohistochemical studies were performed to
elucidate the histopathogenesis of exencephaly induced in chick embryo as an
experimental model. The findings were compared with those identified in a chick
myeloschisis experimental model and in human autopsy cases. The experimental
model of exencephaly in chick embryos was developed by induction with various
teratogens including ethylnitrosourea, salicylate, and phenytoin. None of the
cases of exencephaly was exposed to a teratogen prior to or within Hamburger and
Hamilton stage 12 (45 to 49 hours postincubation), when the anterior neuropore
closes. The process of overgrowth in development of exencephaly was identical to
that of myeloschisis, and the results suggested neuronal overmaturation in the
histological and immunohistochemical studies. Although the late-stage
degenerative change with neovascularization over the exposed neural tissue
(placode) was more severe in human exencephaly, the present experimental study
may suggest a possible common embryopathogenesis of dysraphism. Exencephaly
should be regarded as the most severe form of cranium bifidum, as myeloschisis
is in spina bifida. The antenatal sonographic diagnosis of exencephaly in four gestations is
reported. Exencephaly is an uncommon malformation of the cranium that
characteristically involves a large, disorganized mass of cerebral tissue. The
flat bones of the calvaria are absent, leaving the brain mass uncovered.
Secondarily, anencephaly may develop as a result of prolonged exposure of the
developing encephalon to amniotic fluid and trauma in utero. As in anencephaly,
facial structures and the bony base of the calvarium are often preserved in
exencephaly. Sonographically, the outstanding feature of exencephaly is the
cerebral mass, with convolutions or "pseudo" sulcal patterns present. These
findings correlate well with the pathologic examination and define a clinical
entity that is incompatible with human life. Exencephaly is a rare precursor of anencephaly in which a large amount of brain
tissue is present despite the absence of the calvaria. It was discovered
together with hydramnios in a near-term fetus. Sonographic, angiographic, and
pathologic findings are discussed. The paper deals with first trimester diagnosis of exencephaly. In association
with first trimester sonographic and cytogenetic screening of chromosomal
anomalies in 1145 examined pregcies 2 exencephalic fetuses with normal
karyotype were diagnosed. Exencephaly was characterized with the absence of
normal echoes of the exocranium, the lateral ventricles, the chorioid plexus,
the cerebral falx, and with the presence of deformed shape of the head and
irregular, lobulated cerebral material with increasing volume at follow-up
examination. Anencephalic fetuses were diagnosed subsequent to therapeutic
abortion, since the uterine and cervical wall contractions eroded the fragile
brain tissue during fetal expulsion. However, fetal brain was identified in
abortion material in both cases providing evidence that exencephaly is an
embryologic precursor of anencephaly. The authors report a case of acrania diagnosed on antenatal period in a routine
morphologic ultrasonography at 19 weeks of intra uterine gestation on a
20-year-old patient, gravida 1, para 0. Acrania associated with exencephaly is a
rare and lethal malformation characterized by a defect of development of the
flat bones of the scalp whereas cerebral tissue is present often abnormal.
Ultrasonography had allowed to find besides the cerebral malformation, spinal
and visceral fetal malformations as well as cord abnormality that included only
two vessels. |
What is the role of TNF in obesity? | The role of TNF in obesity is not fully understood, but it is thought to play a major role in adipose tissue formation and fat storage. TNF-alpha is a protein that has been shown to increase fat storage in fat cells. It is also thought to have a role in insulin resistance. | Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic
effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA
expression was observed in adipose tissue from four different rodent models of
obesity and diabetes. TNF-alpha protein was also elevated locally and
systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a
significant increase in the peripheral uptake of glucose in response to insulin.
These results indicate a role for TNF-alpha in obesity and particularly in the
insulin resistance and diabetes that often accompany obesity. Obesity is frequently associated with insulin resistance and abnormal glucose
homeostasis. Recent studies in animal models have indicated that TNF-alpha plays
an important role in mediating the insulin resistance of obesity through its
overexpression in fat tissue. However, the mechanisms linking obesity to insulin
resistance and diabetes in humans remain largely unknown. In this study we
examined the expression pattern of TNF-alpha mRNA in adipose tissues from 18
control and 19 obese premenopausal women by Northern blot analysis. TNF-alpha
protein concentrations in plasma and in conditioned medium of explanted adipose
tissue were measured by ELISA. Furthermore, the effects of weight reduction by
dietary treatment of obesity on the adipose expression of TNF-alpha mRNA were
also analyzed in nine premenopausal obese women, before and after a controlled
weight-reduction program. These studies demonstrated that obese individuals
express 2.5-fold more TNF-alpha mRNA in fat tissue relative to the lean controls
(P < 0.001). Similar increases were also observed in adipose production of
TNF-alpha protein but circulating TNF-alpha levels were extremely low or
undetectable. A strong positive correlation was observed between TNF-alpha mRNA
expression levels in fat tissue and the level of hyperinsulinemia (P < 0.001),
an indirect measure of insulin resistance. Finally, body weight reduction in
obese subjects which resulted in improved insulin sensitivity was also
associated with a decrease in TNF-alpha mRNA expression (45%, P < 0.001) in fat
tissue. These results suggest a role for the abnormal regulation of this
cytokine in the pathogenesis of obesity-related insulin resistance. Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in
the insulin resistance of obesity and non-insulin-dependent diabetes mellitus
(NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple
experimental models of obesity. Neutralization of TNF-alpha in one of these
models improves insulin sensitivity by increasing the activity of the insulin
receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular
level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine
phosphorylations on the beta-chain of the insulin receptor and insulin receptor
substrate-1, suggesting a defect at or near the tyrosine kinase activity of the
insulin receptor. Given the clear link between obesity, insulin resistance, and
diabetes, these results strongly suggest that TNF-alpha may play a crucial role
in the systemic insulin resistance of NIDDM. This may allow for new treatments
of disorders involving resistance to insulin. Tumor necrosis factor (TNF)-alpha plays a central role in the state of insulin
resistance associated with obesity. It has previously been shown that one
important mechanism by which TNF-alpha interferes with insulin signaling is
through the serine phosphorylation of insulin receptor substrate-1 (IRS-1),
which can then function as an inhibitor of the tyrosine kinase activity of the
insulin receptor (IR). However, the receptors and the signaling pathway used by
TNF-alpha that mediate the inhibition of IR activity are unknown. We show here
that human TNF-alpha, which binds only to the murine p55 TNF receptor (TNFR), is
as effective at inhibiting insulin-dependent tyrosine phosphorylation of IR and
IRS-1 in adipocytes and myeloid 32D cells as murine TNF-alpha, which binds to
both p55 TNFR and p75 TNFR. Likewise, antibodies that are specific agonists for
p55 TNFR or p75 TNFR demonstrate that stimulation of p55 TNFR is sufficient to
inhibit insulin signaling, though a small effect can also be seen with
antibodies to p75 TNFR. Exogenous sphingomyelinase and ceramides, known to be
formed by activation of p55 TNFR, inhibit IR and IRS-1 tyrosine phosphorylation
and convert IRS-1 into an inhibitor of IR tyrosine kinase in vitro. Myeloid 32D
cells expressing IR and IRS-1 are sensitive to this inhibition, but cells
expressing IR and IRS-2 are resistant, pointing to an important difference in
the biological function between IRS-1 and IRS-2. These data strongly suggest
that TNF-alpha inhibits insulin signaling via stimulation of p55 TNFR and
sphingomyelinase activity, which results in the production of an inhibitory form
of IRS-1. Obesity is highly associated with insulin resistance and is the biggest risk
factor for non-insulin-dependent diabetes mellitus. The molecular basis of this
common syndrome, however, is poorly understood. It has been suggested that
tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance
in obesity, as it is overexpressed in the adipose tissues of rodents and humans
and it blocks the action of insulin in cultured cells and whole animals. To
investigate the role of TNF-alpha in obesity and insulin resistance, we have
generated obese mice with a targeted null mutation in the gene encoding
TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of
TNF-alpha resulted in significantly improved insulin sensitivity in both
diet-induced obesity and that resulting for the ob/ob model of obesity. The
TNFalpha-deficient obese mice had lower levels of circulating free fatty acids,
and were protected from the obesity-related reduction in the insulin receptor
signalling in muscle and fat tissues. These results indicate that TNF-alpha is
an important mediator of insulin resistance in obesity through its effects on
several important sites of insulin action. Obesity is associated with an increased incidence of insulin resistance,
dyslipoproteinemia, and hypercoagulability. In a more recently established
hypothesis of body weight control and regulation of metabolism, the adipocyte
secretes leptin and locally expresses TNF-alpha, the latter being responsible
for the expression of metabolic cardiovascular risk factors. TNF-a mRNA
expression and TNF-alpha protein are greatly increased in adipose tissue from
obese animals and humans. Elevated TNF-alpha expression induces insulin
resistance by downregulating the tyrosine kinase activity of the insulin
receptor and decreasing the expression of GLUT-4 glucose transporters. TNF-alpha
also reduces lipoprotein lipase activity in white adipocytes, stimulates hepatic
lipolysis, and increases plasminogen activator inhibitor-1 content in
adipocytes. Moreover, adipocytes secrete leptin, a molecule with a secondary
cytokine structure whose concentrations correlate with the amount of fat tissue.
Increased leptin levels downregulate appetite and increase sympathetic activity
and thermogenesis in the hypothalamus. Diet-induced weight loss reduces adipose
TNF-alpha expression and serum leptin levels and is associated with improved
insulin sensitivity and lipid metabolism. Although exercise has also been shown
to reduce leptin levels, an influence on TNF-a expression in adipocytes or
muscle cells has not yet been demonstrated. Although obesity has become the most common metabolic disorder in the developed
world and is highly associated with insulin resistance and noninsulin-dependent
diabetes mellitus, the molecular mechanisms underlying these disorders are not
clearly understood. Tumor necrosis factor-alpha (TNF-alpha) is overexpressed in
obesity and is a candidate mediator of obesity-induced insulin resistance.
Complete lack of TNF-alpha function through targeted mutations in TNF-alpha gene
or both of its receptors results in significant improvement of insulin
sensitivity in dietary, chemical, or genetic models of rodent obesity. In this
study, we have analyzed the in vivo role of TNF signaling from p55 [TNF receptor
(TNFR) 1] and p75 (TNFR 2) TNFR in the development of insulin resistance by
generating genetically obese mice (ob/ob) lacking p55 or p75 TNFRs. In the ob/ob
mice, the absence of p55 caused a significant improvement in insulin
sensitivity. p75 deficiency alone did not affect insulin sensitivity but might
potentiate the effects of p55 deficiency in animals lacking both TNFRs. These
results indicate that TNF-alpha is a component of insulin resistance in the
ob/ob model of murine obesity and p55 TNFR is the predomit receptor mediating
its actions. BACKGROUND: Recent studies show an increased adipose production of tumor
necrosis factor-alpha (TNF-alpha) in human obesity. It was hypothesized from
this finding and other data, that TNF-alpha may be a mediator of obesity-linked
insulin resistance.
OBJECTIVE: The aim of this study was to measure plasma concentrations of the two
soluble TNF-alpha receptors, together with those of TNF-alpha in subjects with
severe obesity with and without type 2 diabetes mellitus, in comparison to a
lean control group, to examine whether plasma concentrations reflect an
up-regulation of the TNF system in adipose tissue.
PATIENTS AND METHODS: Plasma concentrations of the two soluble TNF-alpha
receptors were measured in 49 obese subjects (mean body mass index (BMI): 44.9
kg/m2, 95% confidence intervals (CI) 42.3-47.5 kg/m2, including 19 type 2
diabetic individuals) and 28 lean controls, by using a highly sensitive
enzyme-linked immunoassay (ELISA) technique. TNF-alpha concentrations were
determined in 28 obese (10 with diabetes) and 23 lean subjects.
RESULTS: The obese subjects showed significantly higher plasma concentrations of
the soluble p60 and p80 TNF receptor, respectively, compared to the lean control
group, independent of the presence of diabetes. Multiple regression analysis,
with the p80 TNF receptor as dependent variable, revealed that BMI and log
insulin significantly affected the plasma concentration of this soluble receptor
subtype, explaining 46% of the variance, whereas for the p60 TNF receptor, only
BMI turned out to influence plasma concentrations. TNF-alpha plasma
concentrations were not different between the three groups (Kruskal-Wallis test:
P=0.34), but due to the low power of the test, an effect of obesity on TNF-alpha
is not excluded.
CONCLUSION: These data indicate that plasma concentrations of both soluble TNF
receptors are elevated in obesity and insulin resistance, possibly as a function
of excess body fat. The reported adipose overexpression of TNF-alpha does not
seem to be reflected by elevated plasma concentrations, suggesting a primarily
local role of the cytokine. Obesity is associated with a cluster of abnormalities, including hypertension,
insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen
activator inhibitor 1 (PAI-1) and transforming growth factor beta (TGF-beta).
Although these changes may increase the risk for accelerated atherosclerosis and
fatal myocardial infarction, the underlying molecular mechanisms remain to be
defined. Although tumor necrosis factor alpha (TNF-alpha) has been implicated in
the insulin resistance associated with obesity, its role in other disorders of
obesity is largely unknown. In this report, we show that in obese (ob/ob) mice,
neutralization of TNF-alpha or deletion of both TNF receptors (TNFRs) results in
significantly reduced levels of plasma PAI-1 antigen, plasma insulin, and
adipose tissue PAI-1 and TGF-beta mRNAs. Studies in which exogenous TNF-alpha
was infused into lean mice lacking individual TNFRs indicate that TNF-alpha
signaling of PAI-1 in adipose tissue can be mediated by either the p55 or the
p75 TNFR. However, TNF-alpha signaling of TGF-beta mRNA expression in adipose
tissue is mediated exclusively via the p55 TNFR. Our results suggest that
TNF-alpha is a common link between the insulin resistance and elevated PAI-1 and
TGF-beta in obesity. The chronic elevation of TNF-alpha in obesity thus may
directly promote the development of the complex cardiovascular risk profile
associated with this condition. Tumour necrosis factor-alpha (TNF) is a pleiotropic cytokine involved in many
metabolic responses in both normal and pathophysiological states. In spite of
the fact that this cytokine (also known as "cachectin") has been related to many
of the metabolic abnormalities associated with cachexia, recent studies suggest
that TNF may also have a central role in obesity modulating energy expenditure,
fat deposition and insulin resistance. This review deals with the role of TNF in
the control of fat mass and obesity. Insulin resistance, a smaller than expected response to a given dose of insulin,
is associated with many common diseases including, ageing, polycystic ovarian
disease, syndrome X, cancer, infections, trauma and, most significantly, obesity
and type 2 diabetes mellitus. The biochemical basis of insulin resistance in
type 2 diabetes has been the subject of many studies. Earlier studies have
indicated that quantitative regulation of the insulin sensitive glucose
transporters (Glut-4) and insulin receptors themselves may contribute to this
disorder, however, these two factors are probably inadequate to explain the
extent of insulin resistance. This point also became apparent by the development
of only mild hyperinsulinaemia in mice with a targeted mutation in the Glut-4
gene. Studies on postreceptor defects in type 2 diabetes has recently focused on
the intrinsic catalytic activity of the insulin receptor and downstream
signalling events. A reduction in tyrosine phosphorylation of both the insulin
receptor (IR) and the insulin receptor substrate-1 (IRS-1) has been noted in
both animal and human type 2 diabetes. Importantly, this appears to occur in all
of the major insulin-sensitive tissues, namely the muscle, fat and liver. It is
now clear that decreased signalling capacity of the insulin receptor is an
important component of this disease. I will review some of the potential
mechanisms underlying this deficiency. Since evidence has appeared that tumor necrosis factor-alpha (TNF) is involved
in the loss of body fat in the course of wasting diseases, a large number of
studies have investigated the physiological role of this cytokine in adipose
tissue. TNF treatment of several in vitro models of adipogenesis clearly showed
that TNF is a potent inhibitor of adipose differentiation. This antiadipogenic
property is accompanied by suppression of developmental and metabolic markers of
fat cell differentiation, such as peroxisome proliferator-activated receptor
(PPAR)-gamma2, lipoprotein lipase (LPL), glycerol-3-phosphate dehydrogenase
(GPDH) and GLUT4. Moreover, TNF promotes lipolysis in mature adipocytes and,
subsequently, a reversion of the adipocyte phenotype. Recent studies
demonstrated that TNF directly interferes with the insulin signaling cascade at
early steps and, thus, impairs insulin-stimulated glucose transport. Further
progress in understanding the role of TNF in adipose tissue was made when
endogenous TNF mRNA expression was demonstrated in adipose tissue. Obesity was
found to represent a state of overexpression of the TNF system. Such findings
support the hypothesis that TNF is a mediator of obesity-linked insulin
resistance. However, this concept is mainly based on animal data and is so far
only partially supported by studies in humans. Taken together, the results of a
variety of experimental and clinical studies suggest that TNF may act as an
important auto/paracrine regulator of fat cell function which serves to limit
adipose tissue expansion, probably by inducing insulin resistance which may in
turn cause metabolic disturbances. Elucidation of the molecular mechanisms of
TNF production and action in adipose tissue may help to find new approaches for
the treatment of insulin resistance in humans. Tumor necrosis factor (TNF)-alpha is one of the candidate mediators of insulin
resistance associated with obesity, a major risk factor for the development of
type 2 diabetes. The insulin resistance induced by TNF-alpha is antagonized by
thiazolidinediones (TZDs), a new class of insulin-sensitizing drugs. The aim of
the current study was to dissect the mechanism whereby pioglitazone, one of the
TZDs, ameliorates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes.
Pioglitazone restored insulin-stimulated 2-deoxyglucose (DOG) uptake, which was
reduced by TNF-alpha, with concomitant restorations in tyrosine phosphorylation
and protein levels of insulin receptor (IR) and insulin receptor substrate
(IRS)-1, as well as association of the p85 regulatory subunit of
phosphatidylinositol (PI) 3-kinase with IRS-1 and PI 3-kinase activity.
Adenovirus-mediated gene transfer of either wild-type human peroxisome
proliferator-activated receptor (PPAR)-gamma2 or a mutant carrying a replacement
at the consensus mitogen-activated protein kinase phosphorylation site
(hPPAR-gamma2-S112A) promoted adipogenesis of 3T3-L1 fibroblasts and restored
TNF-alpha-induced decrease of triglyceride in adipocytes as effectively as
pioglitazone. Overexpression of the PPAR-gamma proteins in TNF-alpha-treated
adipocytes restored protein levels of IR/IRS-1, but did not improve
insulin-stimulated tyrosine phosphorylation of IR/IRS-1 or insulin-stimulated
2-DOG uptake. These results indicate that the ability of pioglitazone to restore
insulin-stimulated tyrosine phosphorylation of IR/IRS-1, which is necessary for
amelioration of TNF-alpha-induced insulin resistance, may be independent of the
adipogenic activity of PPAR-gamma that regulates protein levels of IR/IRS-1. OBJECTIVES: To investigate the influence of transmembrane tumor necrosis factor
(TNF)-alpha on adipose tissue development and insulin-mediated glucose
metabolism.
METHODS AND RESULTS: TNF-alpha and lymphotoxin-alpha-deficient mice expressing
non-cleavable transmembrane TNF-alpha (Tg-tmTNF-alpha) and
TNF-alpha/lymphotoxin-alpha double knockout (control) mice were kept on high-fat
diet for 15 weeks. The food intake and feeding efficiency of Tg-tmTNF-alpha mice
were significantly higher compared with control mice. At the end of the study,
Tg-tmTNF-alpha mice had a significantly higher total body weight, as well as
subcutaneous and gonadal adipose tissue mass. Histological analysis revealed
that the expression of Tg-tmTNF-alpha resulted in a significantly increased
adipocyte area and blood vessel density. Plasma leptin levels correlated
positively with adipose tissue mass. The plasma levels of total cholesterol and
HDL-cholesterol were significantly increased and LDL-cholesterol levels
significantly decreased in Tg-tmTNF-alpha mice. Fasting blood glucose and plasma
insulin levels were not different between the two genotypes and intraperitoneal
glucose and insulin tolerance tests did not show significant differences.
CONCLUSIONS: Transmembrane TNF-alpha enhances adipose tissue formation without
altering insulin-mediated glucose metabolism in mice with nutritionally induced
obesity. BACKGROUND: Recent findings have established an association between obesity and
immune dysfunction. However, most of the studies investigating the effects of
obesity on immune function have been carried out in genetically obese rodent
models. Since human obesity is mostly due to intake of a high fat diet and
decreased energy expenditure, we asked whether immunological defects also occur
in diet-induced obesity. Specifically, we focused on the function of monocytes
and macrophages, as these cells are thought to be involved in the low-grade
inflammation present in obesity. METHODS: Male Sprague-Dawley rats were fed a
high-fat or a standard chow diet for either 2 or 10 weeks. At the end of the
intervention period animals were anaesthetised, blood collected for
determination of plasma mediator concentrations and lipopolysaccharide (LPS)
stimulated production of TNF-alpha by monocytes. LPS stimulated production of
TNF-alpha in alveolar macrophages was also determined. RESULTS: High-fat feeding
for either 2 or 10 weeks resulted in significant increases in fat mass and serum
leptin. Although increased serum leptin has previously been linked to modulation
of innate immunity, we found no significant difference in the LPS stimulated
production of TNF-alpha by either blood monocytes or alveolar macrophages
between the dietary groups. Furthermore, we failed to find a significant
increase in circulating TNF-alpha concentrations in obese animals, as reported
for genetically obese animals. CONCLUSION: Our data suggest that defects in
innate immune function observed in genetically obese animals are not mimicked by
dietary obesity, and may more likely reflect the gross abnormality in leptin
function of these models. Further work is required delineate the effects of
dietary obesity on inflammatory state and immune function. OBJECTIVE: Tumor necrosis factor (TNF)-alpha is thought to mediate, in part, the
link between obesity and insulin resistance, and women with gestational diabetes
mellitus (GDM) have raised serum TNF-alpha concentrations. Our objective was to
investigate whether systemic TNF-alpha administration into gravid C57BL6/J mice
causes a GDM-like syndrome and affects growth and adipose tissue (AT)
development in the offspring.
METHODS: We assessed glucose tolerance and reproductive outcome in mice infused
with saline, or 2 mug or 4 mug recombit mouse (rm)TNF-alpha by subcutaneous
mini-osmotic pumps between days (d)11.5 and 18.5 of gestation. Subsequently, we
studied the effects of the 2-mug dose on maternal AT metabolism. Finally, the
growth of offspring exposed to 2 mug rmTNF-alpha in utero was followed until 8
weeks postnatal age. At 8 weeks, we assessed AT accumulation, as well as
adipocyte area in white AT and insulin sensitivity in males, and adipokine mRNA
levels in various AT depots in females.
RESULTS: The peak glucose response to an intraperitoneal glucose stimulus in
late-gravid mice and fetal weight were higher with 2 mug but not 4 mug
rmTNF-alpha compared with saline; however, 2 mug TNF-alpha did not affect AT
parameters. The female but not male offspring of these mice showed accelerated
growth, hyperadiposity, robustly increased leptin expression in all AT depots,
and raised fasting blood glucose.
CONCLUSIONS: TNF-alpha infusion (2 mug for 7 days) in gravid mice resulted in a
mild GDM syndrome and accelerated AT development in the offspring in a
sex-specific manner. The data suggest that TNF-alpha mediates in part the
effects of GDM on fetal growth and postnatal adiposity, and constitutes a
potential mediator of intrauterine programming. Obesity is commonly associated with development of insulin resistance and
systemic evidence of inflammation. Macrophages contribute to inflammatory
amplification in obesity and may contribute directly to insulin resistance and
the development of nonalcoholic fatty liver disease through the production of
inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. To test
this hypothesis, we transplanted male wild-type (WT) and TNF-alpha deficient
(KO) mice with either TNF-alpha-sufficient (TNF-alpha(+/+)) or
TNF-alpha-deficient (TNF-alpha(-/-)) bone marrow. After consuming a high-fat
diet for 26 wk, metabolic and morphometric characteristics of the animals were
analyzed. While there were no differences in terms of relative weight gain, body
composition analysis yielded a lower relative adipose and higher relative lean
mass in mice lacking TNF-alpha, which was partially explained by reduced
epididymal fat pad and liver weight. TNF-alpha(-/-) -->KO mice exhibited
enhanced insulin sensitivity compared with that observed in TNF-alpha(+/+)-->KO
mice; remarkably, no protection against insulin resistance was provided by
transplanting TNF-alpha(-/-) bone marrow in WT mice compared with
TNF-alpha(+/+)-->WT. The preserved insulin sensitivity seen in
TNF-alpha(-/-)-->KO mice provided protection against the development of hepatic
steatosis. Taken together, these data indicate that macrophage-derived TNF-alpha
contributes to the pattern and extent of fat accumulation and insulin resistance
in diet-induced obesity; however, this contribution is negligible in the
presence of host-derived TNF-alpha. BACKGROUND: In obesity, increased tumor necrosis factor (TNF)-alpha level is
involved in the development of insulin resistance. Toll-like receptor (TLR)-4
and TLR2 are expressed in adipose tissue, and polymorphisms of these receptors
may influence TNF-alpha secretion from adipocytes. In our study, TNF-alpha,
soluble TNF receptor 1 (sTNFR1), and soluble TNF receptor 2 (sTNFR2) levels were
determined, and any association between polymorphisms of TLR4 (D299G, T399I),
TLR2 (R753Q, R677W), and cytokine levels was assessed in obese children and
non-obese control subjects.
MATERIAL/METHODS: In a cross-sectional study, 79 obese children and 42 matched
non-obese control children were investigated. Cytokine levels were measured by
enzyme amplified sensitivity immunoassay. TLR4 and TLR2 polymorphisms were
determined using polymerase chain reaction - restriction fragment length
polymorphism technique.
RESULTS: TNF-alpha and sTNFR2 levels in obese children were significantly
(P<.01) higher than controls. Significant (P<.05), positive, linear correlations
were observed between TNF-alpha, sTNFR2 levels, and BMI. Patients carrying the
mutant alleles of TLR4 (299G and 399I) had lower TNF-alpha and sTNFR2 levels
compared to patients carrying wild-type alleles (299D and 399T) (TNF-alpha
4.4+/-0.7 pg/mL vs 5.5+/-0.9 pg/mL; sTNFR2 2.9+/-1.2 ng/mL vs 4.4+/-1.1 ng/mL;
P<.001). The R753Q polymorphism of TLR2 was not associated with altered cytokine
levels, and the R677W polymorphism was not detected in the sample population.
CONCLUSIONS: Serum levels of TNF-alpha and its soluble receptors are elevated
and associated with increasing BMI values in obese children. Serum cytokine
levels, as modifying factors of insulin resistance, may be affected by TLR4
polymorphisms in obese children. The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in
low-grade adipose tissue inflammation and development of insulin resistance
during obesity. In this context, nuclear factor κ-light-chain-enhancer of
activated B cells (NFκB) is directly involved and required for the acute
activation of the inflammatory gene program. Here, we show that the major
transactivating subunit of NFκB, v-rel avian reticuloendotheliosis viral
oncogene homolog A (RELA), is also required for acute TNF-induced suppression of
adipocyte genes. Notably, this repression does not involve RELA binding to the
associated enhancers but rather loss of cofactors and enhancer RNA (eRNA)
selectively from high-occupancy sites within super-enhancers. Based on these
data, we have developed models that, with high accuracy, predict which enhancers
and genes are repressed by TNF in adipocytes. We show that these models are
applicable to other cell types where TNF represses genes associated with
super-enhancers in a highly cell-type-specific manner. Our results propose a
novel paradigm for NFκB-mediated repression, whereby NFκB selectively
redistributes cofactors from high-occupancy enhancers, thereby specifically
repressing super-enhancer-associated cell identity genes. CONTEXT: Endothelium guarantees vascular homeostasis by the opposite action of
substances by vasodilating/antithrombogenic and vasoconstricting/prothrombotic
activities. Obesity is characterized by endothelial dysfunction associated with
a condition of vascular low-grade inflammation.
EVIDENCE ACQUISITION: Analysis of available basic or clinical papers published
in peer-reviewed international journals on microcirculation and obesity.
EVIDENCE SYNTHESIS: Vascular low-grade inflammation, which characterizes
obesity, is secondary to abnormal production of proinflammatory cytokines,
including TNF-α. TNF-α, generated either in small vessels or within the
perivascular adipose tissue (PVAT) of patients with obesity, stimulates reactive
oxygen species generation, mainly through NAD(P)H oxidase activation, which in
turn reduces nitric oxide (NO) availability. These aspects are highlighted by
the insulin resistance status and macronutrient intake that characterize the
obesity condition. Oxidant excess has also been proposed as a mechanism whereby
TNF-α interferes with the endothelin-1/NO system at the level of small vessels
from patients with obesity.
CONCLUSIONS: In obesity, microvasculature from visceral fat is an important
source of low-grade inflammation and oxidative stress that, together with the
PVAT, directly contribute to vascular changes, favoring the development and
acceleration of the vascular atherothrombotic process in this clinical
condition. Inflammation contributes to obesity-related hyperinsulinemia and insulin
resistance, which often precede type 2 diabetes. Inflammation is one way that
obesity can promote insulin resistance. It is not clear if the extent of
obesity, hyperinsulinemia, or hyperglycemia, underpins changes in cellular
immunity during diet-induced obesity. In particular, the requirement for obesity
or directionality in the relationship between insulin resistance and monocyte
characteristics is poorly defined. Inflammatory cytokines such as tumor necrosis
factor (TNF) can contribute to insulin resistance. It is unclear if TNF alters
monocytosis or specific markers of cellular immunity in the context of obesity.
We measured bone marrow and blood monocyte characteristics in WT and TNF-/- mice
that were fed obesogenic, high fat (HF) diets. We also used hyperglycemic Akita
mice and mice implanted with insulin pellets in order to determine if glucose or
insulin were sufficient to alter monocyte characteristics. We found that
diet-induced obesity in male mice increased the total number of monocytes in
blood, but not in bone marrow. Immature, inflammatory (Ly6Chigh ) monocytes
decreased within the bone marrow and increased within peripheral blood of HF-fed
mice. We found that neither hyperinsulinemia nor hyperglycemia was sufficient to
induce the observed changes in circulating monocytes in the absence of
diet-induced obesity. In obese HF-fed mice, antibiotic treatment lowered insulin
and insulin resistance, but did not alter circulating monocyte characteristics.
Fewer Ly6Chigh monocytes were present within the blood of HF-fed TNF-/- mice in
comparison to HF-fed wild-type (WT) mice. The prevalence of immature Ly6Chigh
monocytes in the blood correlated with serum insulin and insulin resistance
irrespective of the magnitude of adipocyte or adipose tissue hypertrophy in
obese mice. These data suggest that diet-induced obesity instigates a
TNF-dependent increase in circulating inflammatory monocytes, which predicts
increased blood insulin and insulin resistance independently from markers of
adiposity or adipose tissue expansion. |
Is eptinezumab a small molecule? | No, eptinezumab is a humanized monoclonal antibody. | Eptinezumab-jjmr (referred to as eptinezumab hereafter; Vyepti™) is a humanised
monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) and
blocks its binding to the receptor. CGRP is believed to play a major role in the
pathophysiology of migraine. Eptinezumab, delivered by intravenous (IV)
administration, is being developed by Lundbeck Seattle BioPharmaceuticals for
the prevention of migraine. In February 2020, eptinezumab was approved in the
USA for the preventive treatment of migraine in adults. This article summarizes
the milestones in the development of eptinezumab leading to this first approval. |
Describe the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium | The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. | Thompson PM(1), Stein JL, Medland SE, Hibar DP, Vasquez AA, Renteria ME, Toro R,
Jahanshad N, Schumann G, Franke B, Wright MJ, Martin NG, Agartz I, Alda M,
Alhusaini S, Almasy L, Almeida J, Alpert K, Andreasen NC, Andreassen OA,
Apostolova LG, Appel K, Armstrong NJ, Aribisala B, Bastin ME, Bauer M, Bearden
CE, Bergmann O, Binder EB, Blangero J, Bockholt HJ, Bøen E, Bois C, Boomsma DI,
Booth T, Bowman IJ, Bralten J, Brouwer RM, Brunner HG, Brohawn DG, Buckner RL,
Buitelaar J, Bulayeva K, Bustillo JR, Calhoun VD, Cannon DM, Cantor RM, Carless
MA, Caseras X, Cavalleri GL, Chakravarty MM, Chang KD, Ching CR, Christoforou A,
Cichon S, Clark VP, Conrod P, Coppola G, Crespo-Facorro B, Curran JE, Czisch M,
Deary IJ, de Geus EJ, den Braber A, Delvecchio G, Depondt C, de Haan L, de
Zubicaray GI, Dima D, Dimitrova R, Djurovic S, Dong H, Donohoe G, Duggirala R,
Dyer TD, Ehrlich S, Ekman CJ, Elvsåshagen T, Emsell L, Erk S, Espeseth T,
Fagerness J, Fears S, Fedko I, Fernández G, Fisher SE, Foroud T, Fox PT, Francks
C, Frangou S, Frey EM, Frodl T, Frouin V, Garavan H, Giddaluru S, Glahn DC,
Godlewska B, Goldstein RZ, Gollub RL, Grabe HJ, Grimm O, Gruber O, Guadalupe T,
Gur RE, Gur RC, Göring HH, Hagenaars S, Hajek T, Hall GB, Hall J, Hardy J,
Hartman CA, Hass J, Hatton SN, Haukvik UK, Hegenscheid K, Heinz A, Hickie IB, Ho
BC, Hoehn D, Hoekstra PJ, Hollinshead M, Holmes AJ, Homuth G, Hoogman M, Hong
LE, Hosten N, Hottenga JJ, Hulshoff Pol HE, Hwang KS, Jack CR Jr, Jenkinson M,
Johnston C, Jönsson EG, Kahn RS, Kasperaviciute D, Kelly S, Kim S, Kochunov P,
Koenders L, Krämer B, Kwok JB, Lagopoulos J, Laje G, Landen M, Landman BA,
Lauriello J, Lawrie SM, Lee PH, Le Hellard S, Lemaître H, Leonardo CD, Li CS,
Liberg B, Liewald DC, Liu X, Lopez LM, Loth E, Lourdusamy A, Luciano M,
Macciardi F, Machielsen MW, Macqueen GM, Malt UF, Mandl R, Manoach DS, Martinot
JL, Matarin M, Mather KA, Mattheisen M, Mattingsdal M, Meyer-Lindenberg A,
McDonald C, McIntosh AM, McMahon FJ, McMahon KL, Meisenzahl E, Melle I,
Milaneschi Y, Mohnke S, Montgomery GW, Morris DW, Moses EK, Mueller BA, Muñoz
Maniega S, Mühleisen TW, Müller-Myhsok B, Mwangi B, Nauck M, Nho K, Nichols TE,
Nilsson LG, Nugent AC, Nyberg L, Olvera RL, Oosterlaan J, Ophoff RA, Pandolfo M,
Papalampropoulou-Tsiridou M, Papmeyer M, Paus T, Pausova Z, Pearlson GD, Penninx
BW, Peterson CP, Pfennig A, Phillips M, Pike GB, Poline JB, Potkin SG, Pütz B,
Ramasamy A, Rasmussen J, Rietschel M, Rijpkema M, Risacher SL, Roffman JL,
Roiz-Santiañez R, Romanczuk-Seiferth N, Rose EJ, Royle NA, Rujescu D, Ryten M,
Sachdev PS, Salami A, Satterthwaite TD, Savitz J, Saykin AJ, Scanlon C, Schmaal
L, Schnack HG, Schork AJ, Schulz SC, Schür R, Seidman L, Shen L, Shoemaker JM,
Simmons A, Sisodiya SM, Smith C, Smoller JW, Soares JC, Sponheim SR, Sprooten E,
Starr JM, Steen VM, Strakowski S, Strike L, Sussmann J, Sämann PG, Teumer A,
Toga AW, Tordesillas-Gutierrez D, Trabzuni D, Trost S, Turner J, Van den Heuvel
M, van der Wee NJ, van Eijk K, van Erp TG, van Haren NE, van 't Ent D, van Tol
MJ, Valdés Hernández MC, Veltman DJ, Versace A, Völzke H, Walker R, Walter H,
Wang L, Wardlaw JM, Weale ME, Weiner MW, Wen W, Westlye LT, Whalley HC, Whelan
CD, White T, Winkler AM, Wittfeld K, Woldehawariat G, Wolf C, Zilles D, Zwiers
MP, Thalamuthu A, Schofield PR, Freimer NB, Lawrence NS, Drevets W; Alzheimer’s
Disease Neuroimaging Initiative, EPIGEN Consortium, IMAGEN Consortium, Saguenay
Youth Study (SYS) Group. The human hippocampal formation can be divided into a set of cytoarchitecturally
and functionally distinct subregions, involved in different aspects of memory
formation. Neuroanatomical disruptions within these subregions are associated
with several debilitating brain disorders including Alzheimer's disease, major
depression, schizophrenia, and bipolar disorder. Multi-center brain imaging
consortia, such as the Enhancing Neuro Imaging Genetics through Meta-Analysis
(ENIGMA) consortium, are interested in studying disease effects on these
subregions, and in the genetic factors that affect them. For large-scale
studies, automated extraction and subsequent genomic association studies of
these hippocampal subregion measures may provide additional insight. Here, we
evaluated the test-retest reliability and transplatform reliability (1.5T versus
3T) of the subregion segmentation module in the FreeSurfer software package
using three independent cohorts of healthy adults, one young (Queensland Twins
Imaging Study, N=39), another elderly (Alzheimer's Disease Neuroimaging
Initiative, ADNI-2, N=163) and another mixed cohort of healthy and depressed
participants (Max Planck Institute, MPIP, N=598). We also investigated agreement
between the most recent version of this algorithm (v6.0) and an older version
(v5.3), again using the ADNI-2 and MPIP cohorts in addition to a sample from the
Netherlands Study for Depression and Anxiety (NESDA) (N=221). Finally, we
estimated the heritability (h(2)) of the segmented subregion volumes using the
full sample of young, healthy QTIM twins (N=728). Test-retest reliability was
high for all twelve subregions in the 3T ADNI-2 sample (intraclass correlation
coefficient (ICC)=0.70-0.97) and moderate-to-high in the 4T QTIM sample
(ICC=0.5-0.89). Transplatform reliability was strong for eleven of the twelve
subregions (ICC=0.66-0.96); however, the hippocampal fissure was not
consistently reconstructed across 1.5T and 3T field strengths (ICC=0.47-0.57).
Between-version agreement was moderate for the hippocampal tail, subiculum and
presubiculum (ICC=0.78-0.84; Dice Similarity Coefficient (DSC)=0.55-0.70), and
poor for all other subregions (ICC=0.34-0.81; DSC=0.28-0.51). All hippocampal
subregion volumes were highly heritable (h(2)=0.67-0.91). Our findings indicate
that eleven of the twelve human hippocampal subregions segmented using
FreeSurfer version 6.0 may serve as reliable and informative quantitative
phenotypes for future multi-site imaging genetics initiatives such as those of
the ENIGMA consortium. BACKGROUND: Global scale brain research collaborations such as the ENIGMA
(Enhancing Neuro Imaging Genetics through Meta Analysis) consortium are
beginning to collect data in large quantity and to conduct meta-analyses using
uniformed protocols. It becomes strategically important that the results can be
communicated among brain scientists effectively. Traditional graphs and charts
failed to convey the complex shapes of brain structures which are essential to
the understanding of the result statistics from the analyses. These problems
could be addressed using interactive visualization strategies that can link
those statistics with brain structures in order to provide a better interface to
understand brain research results.
RESULTS: We present ENIGMA-Viewer, an interactive web-based visualization tool
for brain scientists to compare statistics such as effect sizes from
meta-analysis results on standardized ROIs (regions-of-interest) across multiple
studies. The tool incorporates visualization design principles such as
focus+context and visual data fusion to enable users to better understand the
statistics on brain structures. To demonstrate the usability of the tool, three
examples using recent research data are discussed via case studies.
CONCLUSIONS: ENIGMA-Viewer supports presentations and communications of brain
research results through effective visualization designs. By linking
visualizations of both statistics and structures, users can gain more insights
into the presented data that are otherwise difficult to obtain. ENIGMA-Viewer is
an open-source tool, the source code and sample data are publicly accessible
through the NITRC website ( http://www.nitrc.org/projects/enigmaviewer_20 ). The
tool can also be directly accessed online ( http://enigma-viewer.org ). Collaborators: Kong XZ, Mathias SR, Guadalupe T, Abé C, Agartz I, Akudjedu TN,
Aleman A, Alhusaini S, Allen NB, Ames D, Andreassen OA, Vasquez AA, Armstrong
NJ, Bergo F, Bastin ME, Batalla A, Bauer J, Baune BT, Baur-Streubel R, Biederman
J, Blaine SK, Boedhoe P, Bøen E, Bose A, Bralten J, Brandeis D, Brem S, Brodaty
H, Yüksel D, Brooks SJ, Buitelaar J, Bürger C, Bülow R, Calhoun V, Calvo A,
Canales-Rodríguez EJ, Canive JM, Cannon DM, Caparelli EC, Castellanos FX,
Cavalleri GL, Cendes F, Chaim-Avancini TM, Chantiluke K, Chen QL, Chen X, Cheng
Y, Christakou A, Clark VP, Coghill D, Connolly CG, Conzelmann A,
Córdova-Palomera A, Cousijn J, Crow T, Cubillo A, Dale A, Dannlowski U,
Ambrosino de Bruttopilo S, de Zeeuw P, Deary IJ, Delanty N, Demeter DV, Di
Martino A, Dickie EW, Dietsche B, Doan NT, Doherty CP, Doyle A, Durston S, Earl
E, Ehrlich S, Ekman CJ, Elvsåshagen T, Epstein JN, Fair DA, Faraone SV,
Fernández G, Filho GB, Förster K, Fouche JP, Foxe JJ, Frodl T,
Fuentes-Claramonte P, Fullerton J, Garavan H, Garcia DDS, Gotlib IH, Goudriaan
AE, Grabe HJ, Groenewold NA, Grotegerd D, Gruber O, Gurholt T, Haavik J, Hahn T,
Hansell NK, Harris MA, Hartman CA, Hernández MDCV, Heslenfeld D, Hester R, Hibar
DP, Ho BC, Ho TC, Hoekstra PJ, van Holst RJ, Hoogman M, Høvik MF, Howells FM,
Hugdahl K, Huyser C, Ingvar M, Irwin L, Ishikawa A, James A, Jahanshad N,
Jernigan TL, Jönsson EG, Kähler C, Kaleda V, Kelly C, Kerich M, Keshavan MS,
Khadka S, Kircher T, Kohls G, Konrad K, Korucuoglu O, Krämer B, Krug A, Kwon JS,
Lambregts-Rommelse N, Landén M, Lázaro L, Lebedeva I, Lenroot R, Lesch KP, Li Q,
Lim KO, Liu J, Lochner C, London ED, Lonning V, Lorenzetti V, Luciano M, Luijten
M, Lundervold AJ, Mackey S, MacMaster FP, Maingault S, Malpas CB, Malt UF,
Mataix-Cols D, Martin-Santos R, Mayer AR, McCarthy H, Mitchell PB, Mueller BA,
Maniega SM, Mazoyer B, McDonald C, McLellan Q, McMahon KL, McPhilemy G, Mome
R, Morales AM, Narayanaswamy JC, Moreira JCV, Nerland S, Nestor L, Newman E,
Nigg JT, Nordvik JE, Novotny S, Weiss EO, O'Gorman RL, Oosterlaan J, Oranje B,
Orr C, Overs B, Pauli P, Paulus M, Plessen KJ, von Polier GG, Pomarol-Clotet E,
Portella MJ, Qiu J, Radua J, Ramos-Quiroga JA, Reddy YCJ, Reif A, Roberts G,
Rosa P, Rubia K, Sacchet MD, Sachdev PS, Salvador R, Schmaal L, Schulte-Rüther
M, Schweren L, Seidman L, Seitz J, Serpa MH, Shaw P, Shumskaya E, Silk TJ,
Simmons AN, Simulionyte E, Sinha R, Sjoerds Z, Smelror RE, Soliva JC, Solowij N,
Souza-Duran FL, Sponheim SR, Stein DJ, Stein EA, Stevens M, Strike LT, Sudre G,
Sui J, Tamm L, Temmingh HS, Thoma RJ, Tomyshev A, Tronchin G, Turner J, Uhlmann
A, van Erp TGM, van den Heuvel OA, van der Meer D, van Eijk L, Vance A, Veer IM,
Veltman DJ, Venkatasubramanian G, Vilarroya O, Vives-Gilabert Y, Voineskos AN,
Völzke H, Vuletic D, Walitza S, Walter H, Walton E, Wardlaw JM, Wen W, Westlye
LT, Whelan CD, White T, Wiers RW, Wright MJ, Wittfeld K, Yang TT, Yasuda CL,
Yoncheva Y, Yücel M, Yun JY, Zanetti MV, Zhen Z, Zhu XX, Ziegler GC, Zierhut K,
de Zubicaray GI, Zwiers M, Glahn DC, Franke B, Crivello F, Tzourio-Mazoyer N,
Fisher SE, Thompson PM, Francks C, Farde L, Flyckt L, Engberg G, Erhardt S,
Fatouros-Bergman H, Cervenka S, Schwieler L, Piehl F, Agartz I, Collste K,
Victorsson P, Malmqvist A, Hedberg M, Orhan F. Author information:
(1)Department of Psychiatry and Human Behavior, University of California,
Irvine, Irvine, California. Electronic address: [email protected].
(2)Imaging Genetics and Neuroinformatics Lab, Georgia State University, Atlanta,
Georgia.
(3)Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics
Institute, Keck School of Medicine of the University of Southern California,
Marina del Rey, California; Janssen Research & Development, San Diego,
California.
(4)Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne,
Victoria, Australia; Centre for Youth Mental Health, University of Melbourne,
Melbourne, Victoria, Australia; Department of Psychiatry and Neuroscience, VU
University Medical Center, Amsterdam, The Netherlands.
(5)Department of Psychology, Georgia State University, Atlanta, Georgia.
(6)Department of Psychiatry, Yale University, New Haven, Connecticut; Olin
Neuropsychiatric Research Center, Institute of Living, Hartford Hospital,
Hartford, Connecticut.
(7)Division of Cerebral Integration, National Institute for Physiological
Sciences, Okazaki, Aichi, Japan.
(8)Molecular Research Center for Children's Mental Development, United Graduate
School of Child Development, Osaka University, Suita, Osaka, Japan; Department
of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka,
Japan.
(9)Department of Neuropsychiatry, Graduate School of Medicine, University of
Tokyo, Bunkyo-ku, Tokyo, Japan.
(10)Department of Psychiatry, Osaka University Graduate School of Medicine,
Suita, Osaka, Japan.
(11)Department of Psychiatry, University of New Mexico, Albuquerque, New Mexico.
(12)Department of Psychiatry, University of New Mexico, Albuquerque, New Mexico;
Mind Research Network, Albuquerque, New Mexico.
(13)Institute of Clinical Medicine, Norwegian Centre for Mental Disorders
Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of
Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital,
Oslo, Norway; Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden.
(14)Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota.
(15)Department of Psychiatry and Brain Center Rudolf Magnus, University Medical
Center Utrecht, Utrecht, The Netherlands.
(16)Semel Institute for Neuroscience and Human Behavior, University of
California, Los Angeles, Los Angeles, California; Department of Psychiatry and
Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The
Netherlands.
(17)Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical
Centre, Rotterdam, The Netherlands; Department of Psychiatry and Brain Center
Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
(18)Institute of Clinical Medicine, Norwegian Centre for Mental Disorders
Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of
Oslo, Oslo, Norway; Division of Mental Health and Addiction, NORMENT, K.G.
Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
(19)Center for Translational Imaging and Precision Medicine, San Diego,
California; Department of Neurosciences, University of California, San Diego, La
Jolla, California; Department of Radiology, University of California, San Diego,
La Jolla, California; Department of Psychiatry, University of California, San
Diego, La Jolla, California; Department of Cognitive Science, University of
California, San Diego, La Jolla, California.
(20)Institute of Clinical Medicine, Norwegian Centre for Mental Disorders
Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of
Oslo, Oslo, Norway.
(21)Institute of Clinical Medicine, Norwegian Centre for Mental Disorders
Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of
Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital,
Oslo, Norway.
(22)Division of Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for
Psychosis Research, Oslo University Hospital, Oslo, Norway.
(23)Department of Psychology, University of Oslo, Oslo, Norway; Division of
Mental Health and Addiction, NORMENT, K.G. Jebsen Centre for Psychosis Research,
Oslo University Hospital, Oslo, Norway.
(24)Section for Experimental Psychopathology and Neuroimaging, Department of
General Psychiatry, Heidelberg University Hospital, Heidelberg, Germany; Center
for Translational Research in Systems Neuroscience and Psychiatry, Department of
Psychiatry, Georg August University, Göttingen, Germany.
(25)Center for Translational Research in Systems Neuroscience and Psychiatry,
Department of Psychiatry, Georg August University, Göttingen, Germany;
Department of Psychiatry, University Medical Center Göttingen, Göttingen,
Germany.
(26)Department of Psychiatry, University Hospital Marqués de Valdecilla, School
of Medicine, Marqués de Valdecilla Research Institute (IDIVAL), University of
Cantabria, Santander, Spain; Centro Investigación Biomédica en Red de Salud
Mental, Santander, Spain.
(27)Department of Psychiatry, University Hospital Marqués de Valdecilla, School
of Medicine, Marqués de Valdecilla Research Institute (IDIVAL), University of
Cantabria, Santander, Spain; Neuroimaging Unit, Technological Facilities,
Valdecilla Biomedical Research Institute, Marqués de Valdecilla Research
Institute (IDIVAL), University of Cantabria, Santander, Spain; Centro
Investigación Biomédica en Red de Salud Mental, Santander, Spain.
(28)Priority Research Centre for Brain & Mental Health, University of Newcastle,
Newcastle, New South Wales, Australia; Hunter Medical Research Institute,
Newcastle, New South Wales, Australia; Hunter New England Local Health District,
Newcastle, New South Wales, Australia.
(29)Department of Psychiatry, Monash University, Melbourne, Victoria, Australia;
School of Psychiatry, University of New South Wales, New South Wales, Australia.
(30)Discipline of Psychiatry, School of Medicine, University of Queensland,
Brisbane, Queensland, Australia.
(31)Neuropsychiatry Centre, University of Melbourne, Melbourne, Victoria,
Australia.
(32)School of Medical Sciences, University of New South Wales, New South Wales,
Australia; Neuroscience Research Australia, Sydney, New South Wales, Australia.
(33)School of Psychiatry, University of New South Wales, New South Wales,
Australia; Neuroscience Research Australia, Sydney, New South Wales, Australia.
(34)Priority Research Centre for Health Behaviour, University of Newcastle,
Newcastle, New South Wales, Australia; School of Medicine and Public Health,
University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical
Research Institute, Newcastle, New South Wales, Australia.
(35)School of Psychiatry and Clinical Neurosciences, University of Western
Australia, Perth, Western Australia, Australia.
(36)Queensland Brain Institute, University of Queensland, Brisbane, Queensland,
Australia; Queensland Centre for Mental Health Research, University of
Queensland, Brisbane, Queensland, Australia.
(37)School of Psychology, University of Newcastle, Newcastle, New South Wales,
Australia.
(38)Neuropsychiatry Centre, University of Melbourne, Melbourne, Victoria,
Australia; Florey Institute of Neuroscience and Mental Health, University of
Melbourne, Melbourne, Victoria, Australia.
(39)Priority Research Centre for Brain & Mental Health, University of Newcastle,
Newcastle, New South Wales, Australia; Grow Up Well, University of Newcastle,
Newcastle, New South Wales, Australia; Hunter Medical Research Institute,
Newcastle, New South Wales, Australia.
(40)School of Biomedical Sciences and Pharmacy, University of Newcastle,
Newcastle, New South Wales, Australia; Hunter Medical Research Institute,
Newcastle, New South Wales, Australia.
(41)Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
(42)School of Biomedical Sciences and Pharmacy, University of Newcastle,
Newcastle, New South Wales, Australia; Priority Research Centre for Brain &
Mental Health, University of Newcastle, Newcastle, New South Wales, Australia;
Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
(43)Priority Research Centre for Brain & Mental Health, University of Newcastle,
Newcastle, New South Wales, Australia.
(44)Centre for Neuroimaging & Cognitive Genomics, Clinical Neuroimaging
Laboratory, National Centre for Biomedical Engineering (NCBES) Galway
Neuroscience Centre, College of Medicine Nursing and Health Sciences, National
University of Ireland Galway, Galway, Ireland; School of Psychology, and
Department of Biochemistry, National University of Ireland Galway, Galway,
Ireland; Neuropsychiatric Genetics Research Group, Department of Psychiatry and
Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
(45)Maryland Psychiatric Research Center, University of Maryland School of
Medicine, Baltimore, Maryland.
(46)Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania.
(47)Department of Psychiatry, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina; Brain Imaging and Analysis Center, Duke University
Medical Center, Durham, North Carolina.
(48)Department of Psychiatry, University of California, San Diego, La Jolla,
California.
(49)Department of Psychiatry, Weill Institute for Neurosciences, University of
California, San Francisco, California; San Francisco Veterans Affairs Medical
Center, San Francisco, California.
(50)Department of Psychiatry and Human Behavior, University of California,
Irvine, Irvine, California.
(51)Department of Psychiatry, University of Iowa, Iowa City, Iowa.
(52)Brain Imaging and Analysis Center, Duke University Medical Center, Durham,
North Carolina.
(53)Department of Psychiatry & Biobehavioral Sciences, University of California,
Los Angeles, Los Angeles, California.
(54)Psychiatry Research Center, Beijing Huilongguan Hospital, Beijing, China.
(55)Chongqing Three Gorges Central Hospital, Chongqing, China.
(56)Zhumadian Psychiatry Hospital, He Province, Zhumadian, China.
(57)Luoyang Fifth People's Hospital, He Province, Luoyang, China.
(58)Mind Research Network, Albuquerque, New Mexico; Department of Psychiatry,
University of Iowa, Iowa City, Iowa; Advanced Biomedical Informatics Group, LLC,
Iowa City, Iowa.
(59)Athinoula A. Martinos Center for Biomedical Imaging, Charlestown,
Massachusetts; Division of Psychological and Social Medicine and Developmental
Neurosciences, Faculty of Medicine, Technische Universität Dresden, Dresden,
Germany.
(60)Social Neuroscience Laboratory, Charlestown, Massachusetts; Psychiatric
Neuroimaging Research Program, Massachusetts General Hospital, Harvard Medical
School, Boston, Massachusetts; Department of Psychiatry, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts; Division of
Psychological and Social Medicine and Developmental Neurosciences, Faculty of
Medicine, Technische Universität Dresden, Dresden, Germany.
(61)Mind Research Network, Albuquerque, New Mexico.
(62)Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota;
Minneapolis VA Health Care System, Minneapolis, Minnesota.
(63)Department of Psychiatry, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands.
(64)Department of Psychiatry & Psychology, Maastricht University, Maastricht,
The Netherlands.
(65)Department of Psychiatry, Vrije Universiteit Medical Center, Amsterdam, The
Netherlands.
(66)Laboratory of Neuropsychiatry, Department of Clinical and Behavioral
Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Centro Fermi, Museo
Storico della Fisica e Centro Studi e Ricerche "Enrico Fermi", Rome, Italy.
(67)Laboratory of Neuropsychiatry, Department of Clinical and Behavioral
Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
(68)Laboratory of Neuropsychiatry, Department of Clinical and Behavioral
Neurology, IRCCS Santa Lucia Foundation, Rome, Italy; Dipartimento di
Neuroscienze, Salute Mentale e Organi di Senso (NESMOS), Faculty of Medicine and
Psychology, and Department of Neurology and Psychiatry, Sapienza University of
Rome, Rome, Italy.
(69)Beth K. and Stuart C. Yudofsky Division of Neuropsychiatry, Menninger
Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, Texas; Laboratory of Neuropsychiatry, Department of Clinical and
Behavioral Neurology, IRCCS Santa Lucia Foundation, Rome, Italy.
(70)Fundación para la Investigación y Docencia Maria Angustias Giménez (FIDMAG)
Germanes Hospitalaries Research Foundation, Barcelona, Spain; Centro
Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
(71)Neuropsychiatric Genetics Research Group, Department of Psychiatry and
Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland.
(72)Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts; Psychiatry Neuroimaging Laboratory,
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
(73)Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics
Institute, Keck School of Medicine of the University of Southern California,
Marina del Rey, California.
(74)Centre for Addiction and Mental Health, Toronto, Canada.
(75)Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London, United Kingdom.
(76)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm,
Sweden; Fundación para la Investigación y Docencia Maria Angustias Giménez
(FIDMAG) Germanes Hospitalaries Research Foundation, Barcelona, Spain; Centro
Investigación Biomédica en Red de Salud Mental, Barcelona, Spain; Department of
Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's
College London, London, United Kingdom.
(77)Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London, United Kingdom; National Institute
for Health Research Mental Health Biomedical Research Centre at South London and
Maudsley NHS Foundation Trust, London, United Kingdom.
(78)University of Basel Psychiatric Hospital, Basel, Switzerland.
(79)Department of Psychiatry and Behavioral Sciences, Northwestern University
Feinberg School of Medicine, Chicago, Illinois.
(80)Department of Psychiatry and Behavioral Sciences, Northwestern University
Feinberg School of Medicine, Chicago, Illinois; Department of Radiology,
Northwestern University Feinberg School of Medicine, Chicago, Illinois.
(81)Institute of Clinical Medicine, Norwegian Centre for Mental Disorders
Research (NORMENT), K.G. Jebsen Centre for Psychosis Research, University of
Oslo, Oslo, Norway; Department of Clinical Neuroscience, Karolinska Institutet,
Stockholm, Sweden.
(82)Department of Neuroscience, University Medical Center Groningen, Rijks
Universiteit Groningen, Groningen, The Netherlands; Department of Psychiatry,
University Medical Center Groningen, Rijks Universiteit Groningen, Groningen,
The Netherlands.
(83)Department of Basic Medical Science, Neuroscience and Sense Organs,
University of Bari "Aldo Moro," Bari, Italy.
(84)Istituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della
Sofferenza, San Giovanni Rotondo, Italy.
(85)Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
(86)Department of Psychiatry, Seoul National University College of Medicine,
Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College of
Natural Sciences, Seoul National University, Seoul, Republic of Korea.
(87)Yeongeon Student Support Center, Seoul National University College of
Medicine, Seoul, Republic of Korea; Seoul National University Hospital, Seoul,
Republic of Korea.
(88)Centre for Neuroimaging & Cognitive Genomics, Clinical Neuroimaging
Laboratory, National Centre for Biomedical Engineering (NCBES) Galway
Neuroscience Centre, College of Medicine Nursing and Health Sciences, National
University of Ireland Galway, Galway, Ireland.
(89)Mental Health Research Center, Moscow, Russia.
(90)Children's Clinical and Research Institute of Emergency Surgery and Trauma,
Moscow, Russia.
(91)Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden;
Stockholm Health Services, Stockholm County Council, Stockholm, Sweden.
(92)Laboratory of Psychiatric Neuroimaging, Laboratórios de Investigação Médica
21, Department of Psychiatry, Faculty of Medicine, and Center for
Interdisciplinary Research on Applied Neurosciences, University of São Paulo,
São Paulo, Brazil.
(93)National Institute of Mental Health, Klecany, Czech Republic.
(94)National Institute of Mental Health, Klecany, Czech Republic; MR Unit,
Department of Diagnostic and Interventional Radiology, Institute for Clinical
and Experimental Medicine, Prague, Czech Republic.
(95)National Institute of Mental Health, Klecany, Czech Republic; Institute of
Computer Science, Czech Academy of Sciences, Czech Technical University in
Prague, Prague, Czech Republic; Faculty of Electrical Engineering, Czech
Technical University in Prague, Prague, Czech Republic.
(96)Centre for Cognitive Ageing and Cognitive Epidemiology, University of
Edinburgh, Edinburgh, United Kingdom; Department of Psychology, University of
Edinburgh, Edinburgh, United Kingdom.
(97)Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom;
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh,
Edinburgh, United Kingdom.
(98)Department of Psychiatry, Psychosomatic Medicine and Psychotherapy,
University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
(99)Department of Psychiatry, Groote Schuur Hospital, University of Cape Town,
Cape Town, South Africa.
(100)Department of Psychiatry, Groote Schuur Hospital, University of Cape Town,
Cape Town, South Africa; Medical Research Council Unit on Risk & Resilience in
Mental Disorders, Department of Psychiatry, University of Cape Town, Cape Town,
South Africa.
(101)Department of Psychiatry, Groote Schuur Hospital, University of Cape Town,
Cape Town, South Africa; Medical Research Council Unit on Risk & Resilience in
Mental Disorders, Department of Psychiatry, Stellenbosch University, Cape Town,
South Africa.
(102)Research Group in Psychiatry, Department of Psychiatry, Faculty of
Medicine, Universidad de Antioquia, Medellin, Colombia.
(103)Department of Neuroimaging, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London, United Kingdom; Department of
Psychology, City, University of London, London, United Kingdom.
(104)Department of Biomedical Engineering, Illinois Institute of Technology,
Chicago, Illinois.
(105)Imaging Genetics and Neuroinformatics Lab, Georgia State University,
Atlanta, Georgia; Mind Research Network, Albuquerque, New Mexico. Author information:
(1)Department of Psychiatry, Amsterdam UMC, The Netherlands.
[email protected].
(2)Orygen, The National Centre of Excellence in Youth Mental Health, Parkville,
Australia. [email protected].
(3)Centre for Youth Mental Health, The University of Melbourne, Melbourne,
Australia. [email protected].
(4)Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA, USA.
(5)Psychiatry Neuroimaging Laboratory, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA, USA.
(6)Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics
Institute, Keck School of Medicine, University of Southern California, Marina
del Rey, CA, USA.
(7)Cognitive Neuroscience Center, University Medical Center Groningen,
University of Groningen, Groningen, The Netherlands.
(8)FSSBI "Scientific Research Institute of Physiology & Basic Medicine",
Laboratory of Affective, Cognitive & Translational Neuroscience, Novosibirsk,
Russia.
(9)Department of Neuroscience, Novosibirsk State University, Novosibirsk,
Russia.
(10)University of Münster, Institute of Clinical Radiology, Münster, Germany.
(11)Department of Psychiatry, University of Münster, Münster, Germany.
(12)Department of Psychiatry, The University of Melbourne, Melbourne, VIC,
Australia.
(13)The Florey Institute of Neuroscience and Mental Heatlh, The University of
Melbourne, Melbourne, VIC, Australia.
(14)Lab. of Experimental & Translational Neuroscience, Novosibirsk State
University, Novosibirsk, Russia.
(15)Department of Psychiatry and Trinity Institute of Neuroscience, Trinity
College Dublin, Dublin, Ireland.
(16)North Dublin Mental Health Services, Dublin, Ireland.
(17)Department of Psychiatry, University of California, San Francisco, CA, USA.
(18)Department of Biomedical Sciences, Florida State University, Tallahassee,
FL, USA.
(19)Institute for Molecular Bioscience, The University of Queensland, Brisbane,
QLD, Australia.
(20)Department of Psychiatry and Behavioral Sciences, The University of
Minnesota, Minneapolis, MN, USA.
(21)Department of Psychiatry and Psychotherapy, Otto von Guericke University,
Madgeburg, Germany.
(22)German Center for Neurodegenerative Disease, Magdeburg, Germany.
(23)Department of Psychology, Stanford University, Stanford, CA, USA.
(24)Department of Psychiatry, University of Cape Town, Cape Town, South Africa.
(25)Department of Psychiatry, Interdisciplinary Center Psychopathology and
Emotion regulation (ICPE), University Medical Center Groningen, University of
Groningen, Groningen, The Netherlands.
(26)Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
(27)Youth Mental Health Team, Brain and Mind Centre, University of Sydney,
Camperdown, Australia.
(28)Department of Psychiatry & Behavioral Sciences, Stanford University,
Stanford, CA, USA.
(29)Department of Psychiatry, University of Marburg, Marburg, Germany.
(30)Department of Psychology, The University of Minnesota, Minneapolis, MN, USA.
(31)Maryland Psychiatric Research Center, Department of Psychiatry, University
of Maryland School of Medicine, Baltimore, MD, USA.
(32)Sunshine Coast Mind and Neuroscience-Thompson Institute, Birtinya, QLD,
Australia.
(33)Research Division, Institute of Mental Health, Singapore, Singapore.
(34)Division of Mind and Brain Research, Department of Psychiatry and
Psychotherapy CCM, Charité-Universitätsmedizin Berlin, corporate member of Freie
Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of
Health, Berlin, Germany.
(35)Department of Neurology, University of Magdeburg, Magdeburg, Germany.
(36)Psychiatry and Paediatrics, University of Calgary, Calgary, Canada.
(37)Strategic Clinical Network for Addictions and Mental Health, Calgary,
Canada.
(38)QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
(39)Centre for Cognitive Ageing and Cognitive Epidemiology, University of
Edinburgh, Edinburgh, UK.
(40)Department of Neuroscience, University of Calgary, Calgary, Canada.
(41)Alberta Children's Hospital Research Institute, Calgary, Canada.
(42)Department of Psychiatry, Amsterdam UMC, The Netherlands.
(43)Department of Psychiatry, Institute of Biomedical Research Sant Pau,
Barcelona, Spain.
(44)CIBERSAM, Madrid, Spain.
(45)Universitat Autònoma de Barcelona, Barcelona, Spain.
(46)SAMRC Unit on Risk & Resilience in Mental Disorders, Department of
Psychiatry, Stellenbosch University, Cape Town, South Africa.
(47)Center for Depression, Anxiety, and Stress Research, McLean Hospital,
Harvard Medical School, Belmont, MA, USA.
(48)Max Planck Institute of Psychiatry, Munich, Germany.
(49)Department of Psychiatry, University of Heidelberg, Heidelberg, Germany.
(50)West Region and Research Division, Institute of Mental Health, Singapore,
Singapore.
(51)Yong Loo Lin School of Medicine, National University of Singapore,
Singapore, Singapore.
(52)Lee Kong Chian School of Medicine, Nanyang Technological University,
Singapore, Singapore.
(53)SAMRC Unit on Risk & Resilience in Mental Disorders, Department of
Psychiatry & Neuroscience Institute, University of Cape Town, South Africa.
(54)Mental Health Research Center, Moscow, Russia.
(55)Curium-LUMC Child and Adolescent Psychiatry, Leiden University Medical
Center, Leiden, The Netherlands.
(56)Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
(57)Institute of Psychology, Leiden University, Leiden, The Netherlands.
(58)Instituto ITACA, Universitat Politècnica de València, València, Spain.
(59)Department of Psychiatry and Psychotherapy, University of Tübingen,
Tubingen, Germany.
(60)Department of Psychiatry, Leiden University Medical Center, Leiden, The
Netherlands.
(61)Queensland Brain Institute, The University of Queensland, Brisbane, QLD,
Australia.
(62)Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD,
Australia.
(63)Amsterdam Neuroscience, Amsterdam, The Netherlands.
(64)Orygen, The National Centre of Excellence in Youth Mental Health, Parkville,
Australia.
(65)Centre for Youth Mental Health, The University of Melbourne, Melbourne,
Australia.
(#)Contributed equally Author information:
(1)Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics
Institute, Keck School of Medicine, University of Southern California, Marina
del Rey, CA, USA. [email protected].
(2)Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics
Institute, Keck School of Medicine, University of Southern California, Marina
del Rey, CA, USA.
(3)Department of Psychiatry, University of Münster, Münster, Germany.
(4)Department of Psychiatry, The University of Melbourne, Melbourne, VIC,
Australia.
(5)The Florey Institute of Neuroscience and Mental Health, The University of
Melbourne, Melbourne, VIC, Australia.
(6)Department of Psychiatry, Bellvitge University Hospital, Bellvitge Biomedical
Research Institute-IDIBELL, Barcelona, Spain.
(7)Department of Human Genetics, Radboud University Medical Center, Nijmegen,
The Netherlands.
(8)Donders Institute for Brain, Cognition and Behaviour, Radboud University,
Nijmegen, The Netherlands.
(9)Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam
Neuroscience, Amsterdam, The Netherlands.
(10)Institute for Diagnostic Radiology and Neuroradiology, University Medicine
Greifswald, Greifswald, Germany.
(11)Department of Computer Science and Engineering, The Ohio State University,
Columbus, OH, USA.
(12)Turner Institute for Brain and Mental Health, School of Psychological
Sciences, Monash University, Clayton, VIC, Australia.
(13)Biometris Wageningen University and Research, Wageningen, The Netherlands.
(14)Language & Genetics Department, Max Planck Institute for Psycholinguistics,
Nijmegen, The Netherlands.
(15)The Center for Neuroimaging and Cognitive Genomics, School of Psychology,
National University of Ireland, Galway, Ireland.
(16)Department of Psychiatry, University of California, San Diego, La Jolla, CA,
USA.
(17)Desert-Pacific Mental Illness Research, Education, and Clinical Center, VA
San Diego Healthcare System, San Diego, CA, USA.
(18)Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate
Medical University, Syracuse, NY, USA.
(19)INSERM Unit 955 Team 15 'Translational Psychiatry', Créteil, France.
(20)NeuroSpin, UNIACT Lab, Psychiatry Team, CEA Saclay, Gif-Sur-Yvette, France.
(21)National Institute of Mental Health, National of Health, Bethesda, MD, USA.
(22)Department of Psychiatry and Psychotherapy, Otto von Guericke University
Magdeburg, Magdeburg, Germany.
(23)Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
(24)German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
(25)Information Sciences Institute, University of Southern California, Marina
del Rey, CA, USA.
(26)Department of Computer Science, University of Southern California, Los
Angeles, CA, USA.
(27)Department of Psychiatry and Psychotherapy, University Medicine Greifswald,
Greifswald, Germany.
(28)German Center for Neurodegenerative Diseases (DZNE), Site
Rostock/Greifswald, Greifswald, Germany.
(29)Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane,
QLD, Australia.
(30)Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
(31)National Institute of Mental Health, Klecany, Czech Republic.
(32)Department of Psychiatry, Amsterdam University Medical Centers, VU
University Medical Center, GGZ inGeest, Amsterdam Neuroscience, Amsterdam, The
Netherlands.
(33)Center for Multimodal Imaging and Genetics, University of California, San
Diego, La Jolla, CA, USA.
(34)Brain and Mind Centre, University of Sydney, Sydney, Australia.
(35)Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
(36)Department of Psychiatry & Behavioral Sciences, Stanford University,
Stanford, CA, USA.
(37)Department of Psychiatry & Weill Institute for Neurosciences, University of
California, San Francisco, San Francisco, CA, USA.
(38)Interfaculty Institute for Genetics and Functional Genomics, University
Medicine Greifswald, Greifswald, Germany.
(39)APHP, Mondor University Hospitals, School of Medicine, DMU Impact,
Psychiatry Department, Créteil, France.
(40)Icahn School of Medicine at Mount Sinai, New York, NY, USA.
(41)Institute of Science and Technology for Brain-Inspired Intelligence, Fudan
University, Shanghai, China.
(42)MOE Key Laboratory of Computational Neuroscience and Brain-Inspired
Intelligence, Fudan University, Shanghai, China.
(43)Centre for Population Neuroscience and Precision Medicine (PONS), MRC SGDP
Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College
London, London, UK.
(44)Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA, USA.
(45)Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA.
(46)Department of Psychiatry, UMC Brain Center, University Medical Center
Utrecht, Utrecht University, Utrecht, The Netherlands.
(47)Department of Psychiatry, Seoul National University College of Medicine,
Seoul, Republic of Korea.
(48)Department of Brain and Cognitive Sciences, Seoul National University
College of Natural Sciences, Seoul, Republic of Korea.
(49)Department of Anatomy & Neurosciences, Amsterdam UMC, Location VUmc,
Amsterdam Neuroscience, Amsterdam, The Netherlands.
(50)Department of Sleep and Cognition, Netherlands Institute for Neuroscience,
Amsterdam, The Netherlands.
(51)Faculty of Computer Science, Dalhousie University, Halifax, NS, Canada.
(52)Child & Adolescent Psychiatry, University of California, Los Angeles, Los
Angeles, CA, USA.
(53)Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy.
(54)Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University
of Melbourne, Melbourne, VIC, Australia.
(55)Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne,
VIC, Australia.
(56)CIBERSAM-G17, Madrid, Spain.
(57)Department of Psychobiology and Methodology in Health Sciences, Universitat
Autònoma de Barcelona, Barcelona, Spain.
(58)Department of Psychiatry and Behavioral Sciences, Baylor College of
Medicine, Houston, TX, USA.
(59)Department of Psychiatry and Biobehavioral Sciences, Semel Institute for
Neuroscience and Human Behavior, University of California, Los Angeles, Los
Angeles, CA, USA.
(60)Department of Mental Health, Veterans Affairs Greater Los Angeles Healthcare
System, Los Angeles, CA, USA.
(61)Institute for Community Medicine, University Medicine Greifswald,
Greifswald, Germany.
(62)Stanley Center for Psychiatric Research, The Broad Institute, Cambridge, MA,
USA.
(63)Analytic and Translational Genetics Unit, Massachusetts General Hospital,
Boston, MA, USA.
(64)Psychiatry and Integrative Neurophysiology, VU University, Amsterdam UMC,
Amsterdam, The Netherlands.
(65)German Centre for Cardiovascular Research, Partner Site Greifswald,
Greifswald, Germany.
(66)Department of Psychology, University of Bath, Bath, UK.
(67)Psychiatry and Behavioral Sciences, Northwestern University Feinberg School
of Medicine, Chicago, IL, USA.
(68)Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL,
USA.
(69)Queensland Brain Institute, University of Queensland, Brisbane, QLD,
Australia.
(70)Centre for Advanced Imaging, University of Queensland, Brisbane, QLD,
Australia.
(71)Seoul National University Hospital, Seoul, Republic of Korea.
(72)Yeongeon Student Support Center, Seoul National University College of
Medicine, Seoul, Republic of Korea.
(73)Department of Computer Science and Electrical Engineering, University of
Maryland, Baltimore County, MD, USA.
(74)Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical
University, Syracuse, NY, USA.
(75)Department of Psychiatry, University of Maryland School of Medicine,
Baltimore, MD, USA.
(76)Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental
Health & Addiction, Institute of Clinical Medicine, University of Oslo, Oslo,
Norway.
(77)Department of Clinical Neuroscience, Centre for Psychiatric Research,
Karolinska Institutet, Stockholm, Sweden.
(78)Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
(79)Department of Psychiatry, Amsterdam UMC, Location VUmc, Amsterdam
Neuroscience, Amsterdam, The Netherlands.
(80)Department of Research & Innovation, GGZ InGeest, Amsterdam, The
Netherlands.
(81)University of Groningen, University Medical Center Groningen, Groningen, The
Netherlands.
(82)Psychiatry, Pediatrics, and Psychological Sciences, University of Vermont,
Burlington, VT, USA.
(83)Centre for Medical Image Computing (CMIC), Department of Medical Physics and
Biomedical Engineering, University College London, London, UK.
(84)Division of Mental Health and Addiction, Oslo University Hospital, Oslo,
Norway.
(85)Provost and Senior Vice President, Western University of Health Sciences,
Pomona, CA, USA.
(86)Department of Radiology, Loma Linda University Medical Center, Loma Linda,
CA, USA.
(87)Institute of Psychology, Leiden University, Leiden, The Netherlands.
(88)Department of Psychiatry, Leiden University Medical Center, Leiden, The
Netherlands.
(89)Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
(90)Department of Psychology, Yale University, New Haven, CT, USA.
(91)Department of Psychology, University of California, Los Angeles, CA, USA.
(92)Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition
and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
(93)Cognitive Neuroscience Unit, School of Psychology, Deakin University,
Burwood, VIC, Australia.
(94)Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical
Centre, Rotterdam, The Netherlands.
(95)Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The
Netherlands.
(96)Center for Cognitive Aging and Memory, University of Florida, Gainesville,
FL, USA.
(97)Clinical and Health Psychology, Gainesville, FL, USA.
(98)Centre for Medical Image Computing (CMIC), Department of Computer Science,
University College London, London, UK.
(99)Dementia Research Centre, Institute of Neurology, University College London,
London, UK.
(100)Universite de Montreal, Centre de Recherche CHU Ste-Justine, Montreal, QC,
Canada.
(101)School of Psychology and Centre for Human Brain Health, University of
Birmingham, Birmingham, UK.
(102)Department of Neurology, University of Utah, Salt Lake City, UT, USA.
(103)Psychiatry Neuroimaging Laboratory, Brigham & Women's Hospital, Harvard
Medical School, Boston, MA, USA.
(104)Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry,
Psychology & Neuroscience, King's College London, London, UK.
(105)Department of Psychology, School of Arts and Social Sciences, City,
University of London, London, UK.
(106)Department of Neuroimaging, Institute of Psychology, Psychiatry and
Neurosciences, King's College London, London, UK.
(107)Division of Psychological and Social Medicine and Developmental
Neurosciences, Faculty of Medicine, TU Dresden, Dresden, Germany.
(108)Department of Rehabilitation and Movement Sciences, School of Health
Professions, Rutgers Biomedical Health Sciences, Newark, NJ, USA.
(109)Department of Psychiatry and Mental Health, University of Cape Town, Cape
Town, South Africa.
(110)SU/UCT MRC Unit on Risk & Resilience in Mental Disorders, University of
Stellenbosch, Stellenbosch, South Africa.
(111)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New
York, NY, USA.
(112)University of British Columbia, Vancouver, Canada.
(113)Department of Psychiatry, Radboud University Medical Center, Nijmegen, The
Netherlands.
(114)Department of Psychiatry, University of Vermont, Burlington, VT, USA.
(115)Department of Psychiatry, Boston Children's Hospital and Harvard Medical
School, Boston, MA, USA.
(116)Olin Neuropsychiatric Research Center, Institute of Living, Hartford, CT,
USA.
(117)Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA.
(118)Institute for Information Transmission Problems, Kharkevich Institute,
Moscow, Russian Federation.
(119)Turner Institute for Brain and Mental Health & School of Psychological
Sciences, Monash University, Melbourne, VIC, Australia.
(120)Department of Psychiatry & Neuropsychology, School for Mental Health and
Neuroscience, Maastricht University, Maastricht, The Netherlands.
(121)Genentech, Inc., South San Francisco, CA, USA.
(122)Department of Psychology, Penn State University, University Park, PA, USA.
(123)Social Life and Engineering Sciences Imaging Center, University Park, PA,
USA.
(124)Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
(125)Research and Scientific Institute of Pediatrics and Child Health, CCH RAS,
Ministry of Science and Higher Education, Moscow, Russian Federation.
(126)Department of Pediatrics, Michigan State University, East Lansing, MI, USA.
(127)Institute for Quantitative Health Science and Engineering, East Lansing,
MI, USA.
(128)Department of Psychiatry, University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA.
(129)CBRAIN, Department of Child and Adolescent Psychiatry, Psychosomatics, and
Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany.
(130)Stevens Neuroimaging and Informatics Institute, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA.
(131)Chan Division of Occupational Science and Occupational Therapy, Los
Angeles, CA, USA.
(132)Center for Clinical Spectroscopy, Brigham and Women's Hospital, Boston, MA,
USA.
(133)Harvard Medical School, Boston, MA, USA.
(134)National Center for PTSD at Boston VA Healthcare System, Boston, MA, USA.
(135)Department of Psychiatry, Boston University School of Medicine, Boston, MA,
USA.
(136)Biomedical Genetics, Boston University School of Medicine, Boston, MA, USA.
(137)School of Psychology, University of Auckland, Auckland, New Zealand.
(138)Laboratory of Neuro Imaging, Mark and Mary Stevens Neuroimaging and
Informatics Institute, Keck School of Medicine, University of Southern
California, Los Angeles, CA, USA.
(139)Department of Psychiatry and Human Behavior, University of California,
Irvine, Irvine, CA, USA.
(140)Mind Research Network, Albuquerque, NM, USA.
(141)Psychiatry, San Diego, CA, USA.
(142)The Kavli Foundation, Los Angeles, CA, USA.
(143)Department of Psychosis Studies, Institute of Psychiatry, Psychology &
Neuroscience, King's College London, London, UK.
(144)Department of Psychiatry, Duke University School of Medicine, Durham, NC,
USA.
(145)Mental Illness Research Education and Clinical Center, Durham VA Medical
Center, Durham, NC, USA.
(146)Experimental Clinical & Health Psychology, Ghent University, Ghent,
Belgium.
(147)Department of Personality, Psychological Assessment and Treatment,
University of Deusto, Bilbao, Spain.
(148)Radiology and Biomedical Imaging, San Francisco, CA, USA.
(149)Department of Pediatrics, Russian National Research Medical University MoH
RF, Moscow, Russian Federation.
(150)Department of Psychology, Norwegian University of Science and Technology,
Trondheim, Norway.
(151)Department of Physical Medicine and Rehabilitation, St. Olavs Hospital,
Trondheim University Hospital, Trondheim, Norway.
(152)Biological Sciences, Purdue University, West Lafayette, IN, USA.
(153)National Institute of Mental Health Intramural Research Program, Bethesda,
MD, USA.
(154)Department of Genetics and Computational Biology, QIMR Berghofer Medical
Research Institute, Brisbane, QLD, Australia.
(155)Department of Neurodegenerative Disease, UCL Queen Square Institute of
Neurology, London, UK.
(156)Max Planck Institute of Psychiatry, Munich, Germany.
(157)Centre for Youth Mental Health, The University of Melbourne, Melbourne,
VIC, Australia.
(158)Department of Psychiatry and Psychotherapy, Charite, Humboldt University,
Berlin, Germany.
(159)Department of Radiology, Keck School of Medicine of USC, University of
Southern California, Los Angeles, CA, USA.
(160)Department of Clinical and Experimental Epilepsy, University College
London, London, UK.
(161)Chalfont Centre for Epilepsy, Chalfont St Peter, UK.
(162)Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
(163)Department of Psychiatry & Neuroscience Institute, SA MRC Unit on Risk &
Resilience in Mental Disorders, Cape Town, South Africa.
(164)Department of Genetics & UNC Neuroscience Center, University of North
Carolina at Chapel Hill, Chapel Hill, NC, USA.
(165)Institute of Medical Science and Technology, Shahid Beheshti University,
Tehran, I. R., Iran.
(166)Department of Neurology, TBI and Concussion Center, Salt Lake City, UT,
USA.
(167)Missouri Institute of Mental Health, Berkeley, MO, USA.
(168)Psychology Department & Neuroscience Institute, Georgia State University,
Atlanta, GA, USA.
(169)Clinical Translational Neuroscience Laboratory, Department of Psychiatry
and Human Behavior, University of California Irvine, Irvine, CA, USA.
(170)Center for the Neurobiology of Learning and Memory, University of
California, Irvine, Irvine, CA, USA.
(171)Donders Centre for Cognitive Neuroimaging, Radboud University Medical
Centre, Nijmegen, The Netherlands.
(172)Division of Mind and Brain Research, Department of Psychiatry and
Psychotherapy CCM, Charité - Universitätsmedizin Berlin, corporate member of
Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute
of Health, Berlin, Germany.
(173)Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland,
Dublin, Ireland.
(174)Research and Early Development, Biogen Inc, Cambridge, MA, USA.
(175)VA Salt Lake City Healthcare System, Salt Lake City, UT, USA.
(176)Department of Physical Medicine and Rehabilitation, Baylor College of
Medicine, Houston, TX, USA.
(177)Keck School of Medicine, University of Southern California, Los Angeles,
CA, USA.
(178)Skolkovo Institute of Science and Technology, Moscow, Russian Federation. Author information:
(1)Institute of Psychology, Leiden University, Leiden, The Netherlands.
(2)Leiden Institute for Brain and Cognition, Leiden, The Netherlands.
(3)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York,
New York, USA.
(4)Boys Town National Research Hospital, Omaha, Nebraska, USA.
(5)Department of Psychology, School of Arts and Social Sciences, City,
University of London, London, UK.
(6)Department of Neuroimaging, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London, UK.
(7)Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental
Health and Addiction, Institute of Clinical Medicine, University of Oslo, Oslo,
Norway.
(8)Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
(9)Centre for Psychiatry Research, Department of Clinical Neuroscience,
Karolinska Institutet, & Stockholm Health Care Services, Stockholm County
Council, Stockholm, Sweden.
(10)Department of Psychiatry, Amsterdam Neuroscience, Amsterdam UMC, Vrije
Universiteit, Amsterdam, The Netherlands.
(11)Department of Research & Innovation, GGZ inGeest, Amsterdam, The
Netherlands.
(12)Institute of Education and Child Studies, Forensic Family and Youth Care,
Leiden University, Leiden, The Netherlands.
(13)Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging
Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and
Health Sciences, National University of Ireland Galway, Galway, Ireland.
(14)Institute of Medical Imaging & Visualisation, Faculty of Health & Social
Sciences, Bournemouth University, Bournemouth, UK.
(15)FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
(16)Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid,
Spain.
(17)Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Barcelona, Spain.
(18)Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental
Health and Addiction, Oslo University Hospital, Oslo, Norway.
(19)Department of Psychiatry and Behavioral Sciences, Northwestern University
Feinberg School of Medicine, Chicago, Illinois, USA.
(20)Department of Psychiatry, Yale University, New Haven, Connecticut, USA.
(21)Social, Genetic and Developmental Psychiatry Centre, Institute of
Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
(22)Department of Child and Adolescent Psychiatry and Psychotherapy, Central
Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim,
Mannheim, Germany.
(23)Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain.
(24)Magnetic Resoce Image Core Facility, IDIBAPS, Barcelona, Spain.
(25)Department for Clinical Psychology, Würzburg University, Margetshöchheim,
Germany.
(26)Department of Basic Medical Science, Neuroscience and Sense Organs,
University of Bari Aldo Moro, Bari, Italy.
(27)Department of Biological Psychology, VU University Amsterdam, Amsterdam, The
Netherlands.
(28)Department of Psychiatry, University of Basel, Basel, Switzerland.
(29)Department of Psychiatry, University of Lübeck, Lübeck, Germany.
(30)Department of Psychiatry, University of Pennsylvania, Philadelphia,
Pennsylvania, USA.
(31)CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
(32)Alzheimer Center, Amsterdam UMC, Location VUMC, Amsterdam, The Netherlands.
(33)Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric
Hospital, University of Zurich, Zurich, Switzerland.
(34)Zurich Center for Integrative Human Physiology, University of Zurich,
Zurich, Switzerland.
(35)Neuroscience Centre Zurich, University and ETH Zurich, Zurich, Switzerland.
(36)Department of Psychiatry, Indiana University School of Medicine,
Indianapolis, Indiana, USA.
(37)Centre for Healthy Brain Ageing, School of Psychiatry, University of New
South Wales, Sydney, New South Wales, Australia.
(38)Dementia Centre for Research Collaboration, School of Psychiatry, University
of New South Wales, Sydney, New South Wales, Australia.
(39)Department of Psychiatry, University Medical Center Utrecht Brain Center,
Utrecht University, Utrecht, The Netherlands.
(40)Department of Cognitive Neuroscience, Radboud University Medical Centre,
Nijmegen, The Netherlands.
(41)Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, The
Netherlands.
(42)Laboratory of Psychiatric Neuroimaging (LIM-21), Departamento e Instituto de
Psiquiatria, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade
de São Paulo, São Paulo, Brazil.
(43)Tri-institutional Center for Translational Research in Neuroimaging and Data
Science (TReNDS), Georgia State, Georgia Tech, Atlanta, Georgia, USA.
(44)MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University,
Cardiff, UK.
(45)Department of Child and Adolescent Psychiatry, NYU Grossman School of
Medicine, New York, New York, USA.
(46)Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.
(47)Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics
Institute, Keck School of Medicine, University of Southern California, Los
Angeles, California, USA.
(48)Psychology Clinical Neuroscience Center, Department of Psychology,
University of New Mexico, Albuquerque, New Mexico, USA.
(49)Mind Research Network, Albuquerque, New Mexico, USA.
(50)Department of Psychiatry, University of Montreal, Montreal, Canada.
(51)Department of Child and Adolescent Psychiatry, Psychosomatics and
Psychotherapy, University of Tübingen, Tübingen, Germany.
(52)Department of Psychology (Clinical Psychology II), PFH - Private University
of Applied Sciences, Göttingen, Germany.
(53)Groupe d'Imagerie Neurofonctionnelle, Institut des Maladies
Neurodégénératives, Bordeaux, France.
(54)Centre for Youth Mental Health, University of Melbourne, Parkville,
Victoria, Australia.
(55)Orygen, Parkville, Victoria, Australia.
(56)Campbell Family Mental Health Institute, Centre for Addiction and Mental
Health, Department of Psychiatry, University of Toronto, Toronto, Canada.
(57)Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
(58)Division of Psychological & Social Medicine and Developmental Neurosciences;
Technische Universität Dresden, Faculty of Medicine, University Hospital C.G.
Carus, Dresden, Germany.
(59)Language and Genetics Department, Max Planck Institute for
Psycholinguistics, Nijmegen, The Netherlands.
(60)Donders Institute for Brain, Cognition and Behaviour, Radboud University,
Nijmegen, The Netherlands.
(61)Department of Psychiatry and Neuroscience Institute, University of Cape
Town, Cape Town, Western Cape, South Africa.
(62)Department of Human Genetics, Radboud University Medical Center, Nijmegen,
The Netherlands.
(63)Department of Psychiatry, Radboud University Medical Center, Nijmegen, The
Netherlands.
(64)IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
(65)Tommy Fuss Center for Neuropsychiatric Disease Research, Department of
Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston,
Massachusetts, USA.
(66)Olin Center for Neuropsychiatric Research, Institute of Living, Hartford
Hospital, Hartford, Connecticut, USA.
(67)Department of Psychology, Stanford University, Stanford, California, USA.
(68)Department of Psychiatry and Psychotherapy, University Medicine Greifswald,
Greifswald, Germany.
(69)German Center for Neurodegenerative Diseases (DZNE), Site
Rostock/Greifswald, Greifswald, Germany.
(70)Section for Experimental Psychopathology and Neuroimaging, Department of
General Psychiatry, Heidelberg University Hospital, Heidelberg, Germany.
(71)Lifespan Brain Institute, Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania, USA.
(72)Department of Early Psychosis, Amsterdam UMC, Amsterdam, The Netherlands.
(73)Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University
of Melbourne & Melbourne Health, Melbourne, Australia.
(74)Interdisciplinary Center Psychopathology and Emotion regulation, University
of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
(75)Brain and Mind Centre, University of Sydney, Sydney, New South Wales,
Australia.
(76)Department of Neurosciences, University of California San Diego, La Jolla,
California, USA.
(77)Departments of Experimental and Clinical Psychology, Vrije Universiteit
Amsterdam, Amsterdam, The Netherlands.
(78)Department of Anatomy & Neurosciences, Amsterdam Neuroscience, Amsterdam
UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
(79)Department of Psychiatry, University of Groningen, University Medical Center
Groningen, Groningen, The Netherlands.
(80)Department of Psychology, Yale University, New Haven, Connecticut, USA.
(81)Department of Psychiatry, Massachusetts General Hospital, Boston,
Massachusetts, USA.
(82)Institute of Diagnostic Radiology and Neuroradiology, University Medicine
Greifswald, Greifswald, Germany.
(83)Neuroscience Institute, University of Cape Town, Cape Town, Western Cape,
South Africa.
(84)Department of Psychiatry and Mental Health, University of Cape Town, Cape
Town, Western Cape, South Africa.
(85)De Bascule, Academic center child and adolescent psychiatry, Duivendrecht,
The Netherlands.
(86)Amsterdam UMC Department of Child and Adolescent Psychiatry, Amsterdam, The
Netherlands.
(87)Department of Psychiatry, Warneford Hospital, Oxford, UK.
(88)Highfield Unit, Warneford Hospital, Oxford, UK.
(89)Department of Radiology, The Ohio State University College of Medicine,
Columbus, Ohio, USA.
(90)Department of Psychology, University of Oslo, Oslo, Norway.
(91)Sunnaas Rehabilitation Hospital HT, Nesodden, Norway.
(92)Sunshine Coast Mind and Neuroscience Thompson Institute, Birtinya,
Queensland, Australia.
(93)University of the Sunshine Coast, Sunshine Coast, Queensland, Australia.
(94)Department of Child and Adolescent Psychiatry and Psychology, Hospital
Clínic, Barcelona, Spain.
(95)August Pi i Sunyer Biomedical Research Institut (IDIBAPS), Barcelona, Spain.
(96)Department of Medicine, University of Barcelona, Barcelona, Spain.
(97)Laboratory of Neuroimaging and Multimodal Analysis, Mental Health Research
Center, Moscow, Russia.
(98)Department of Psychiatry, Harvard Medical School, Boston, Massachusetts,
USA.
(99)SA MRC Unit on Risk and Resilience in Mental Disorders, Department of
Psychiatry, Stellenbosch University, Cape Town, Western Cape, South Africa.
(100)Department of Psychiatry, Academic Medical Center, Amsterdam, The
Netherlands.
(101)Institut des maladies neurodégénératives, Université de Bordeaux, Bordeaux,
France.
(102)Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane,
Queensland, Australia.
(103)Department of Psychiatry, Bellvitge University Hospital, Bellvitge
Biomedical Research Institute-IDIBELL, Barcelona, Spain.
(104)Department of Clinical Sciences, University of Barcelona, Barcelona, Spain.
(105)University of Bordeaux, Bordeaux, France.
(106)Bordeaux University Hospital, Bordeaux, France.
(107)Department of Radiology and Imaging Sciences, Indiana University School of
Medicine, Indianapolis, Indiana, USA.
(108)Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
(109)Herston Imaging Research Facility and School of Clinical Sciences,
Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
(110)Faculty of Health, Institute of Health and Biomedical Innovation,
Queensland University of Technology (QUT), Brisbane, Queensland, Australia.
(111)School of Mental Health and Neuroscience, Faculty of Health, Medicine and
Life Sciences, Maastricht University, Maastricht, The Netherlands.
(112)Department of Radiation Sciences, Umeå University, Umeå, Sweden.
(113)Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
(114)Emma Children's Hospital, Amsterdam UMC University of Amsterdam and Vrije
Universiteit Amsterdam, Emma Neuroscience Group, Department of Pediatrics,
Amsterdam Reproduction & Development, Amsterdam, The Netherlands.
(115)Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam,
The Netherlands.
(116)Department of Psychology, University of Würzburg, Würzburg, Germany.
(117)Centre of Mental Health, Medical Faculty, University of Würzburg, Würzburg,
Germany.
(118)Lieber Institute for Brain Development, Johns Hopkins Medical Campus,
Baltimore, Mary Land, USA.
(119)Department of Psychiatry, Institut d'Investigació Biomèdica Sant Pau,
Barcelona, Spain.
(120)Early Psychosis: Interventions and Clinical-detection (EPIC) lab,
Department of Psychosis Studies, Institute of Psychiatry, Psychology and
Neuroscience, King's College London, London, UK.
(121)Department of Psychiatry, Psychosomatic Medicine and Psychotherapy,
University Hospital Frankfurt, Frankfur am Maint, Germany.
(122)Department of Psychiatry, Massachusetts General Hospital and Harvard
Medical School, Charlestown, Massachusetts, USA.
(123)Center for Depression, Anxiety, and Stress Research, McLean Hospital,
Harvard Medical School, Belmont, Massachusetts, USA.
(124)Neuropsychiatric Institute, The Prince of Wales Hospital, Randwick, New
South Wales, Australia.
(125)Indiana Alzheimer Disease Center, Indianapolis, Indiana, USA.
(126)West Region, Institute of Mental Health, Singapore, Singapore.
(127)Yong Loo Lin School of Medicine, National University of Singapore,
Singapore.
(128)Department of Neuroimaging, Institute of Psychiatry, Psychology and
Neurology, King's College London, London, UK.
(129)Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic
Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
(130)Department of Biomedical Sciences of Cells and Systems, Rijksuniversiteit
Groningen, University Medical Center Groningen, Groningen, The Netherlands.
(131)Department of Psychobiology and Methodology in Health Sciences, Universitat
Autònoma de Barcelona, Barcelona, Spain.
(132)SAMRC Unit on Risk & Resilience in Mental Disorders, Dept of Psychiatry &
Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South
Africa.
(133)Queensland Brain Institute, University of Queensland, Brisbane, Queensland,
Australia.
(134)Mental Illness Research, Education and Clinical Center (MIRECC), James J.
Peters VA Medical Center, New York, New York, USA.
(135)Department of Child and Adolescent Psychiatry and Psychotherapy, Faculty of
Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany.
(136)Department of Psychiatry and Psychotherapy CCM, Charité -
Universitätsmedizin Berlin, corporate member of Freie Universität Berlin,
Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
(137)Department of Psychiatry & Amsterdam Neuroscience, Amsterdam UMC, location
VUMC, Amsterdam, The Netherlands.
(138)Institute for Community Medicine, University Medicine Greifswald,
Greifswald, Germany.
(139)DZHK (German Centre for Cardiovascular Research), partner site Greifswald,
Greifswald, Germany.
(140)DZD (German Center for Diabetes Research), partner site Greifswald,
Greifswald, Germany.
(141)Department of Radiology, Medical College of Wisconsin, Milwaukee,
Wisconsin, USA.
(142)Institute for Experimental Epileptology and Cognition Research, University
Hospital Bonn, Bonn, Germany.
(143)Division of Psychiatry, Royal Edinburgh Hospital, Edinburgh, UK.
(144)Department of Neuroimaging, King's College London, London, UK.
(145)Centre for Advanced Imaging, University of Queensland, Brisbane,
Queensland, Australia.
(146)Department of Child and Adolescent Psychiatry, NYU Child Study Center,
Hassenfeld Children's Hospital at NYU Langone, New York, New York, USA.
(147)Instituto de Ensino e Pesquisa, Hospital Sírio-Libanês, São Paulo, Brazil.
(148)Division of Molecular Psychiatry, Center of Mental Health, University of
Würzburg, Würzburg, Germany.
(149)Department of Psychology, Education and Child Studies (DPECS), Erasmus
School of Social and Behavioral Sciences, Erasmus University Rotterdam, The
Netherlands.
(150)Centre for Brain Health, University of British Columbia, Vancouver, British
Columbia, Canada.
(151)PROMENTA Research Center, Department of Psychology, University of Oslo,
Oslo, Norway. |
Inhaled Molgramostim can be used for treatment of which disease? | Inhaled Molgramostim was shown to be effective for Autoimmune Pulmonary Alveolar Proteinosis. | |
Which are the main functions of the annexin family? | Annexins are required for membrane organization and membrane transport events required for the establishment/maintenance of epithelial polarity.
An association of annexins with ion channels, as membrane-guiding auxiliary proteins or modulators of channel activity.
Last but not least, some annexins seem to work as extracellular autocrine modulators of receptor function under different physiological conditions. | This review article summarizes current knowledge about the locations and
possible functions of annexin family members in the kidney. Beginning with an
introduction on common structural and biochemical features as well as general
functional characteristics of annexins, the paper focuses on individual members
with documented and/or proposed physiological relevance for renal development,
structure, and functions. Three main aspects of annexin function in kidney
epithelia emerge from the available experimental data. First, annexins are
required for membrane organization and membrane transport events required for
the establishment/maintece of epithelial polarity. Second, there is
accumulating evidence of an association of annexins with ion channels, as
membrane-guiding auxiliary proteins or modulators of channel activity. Last but
not least, some annexins seem to work as extracellular autocrine modulators of
receptor function under different physiological conditions. Identification and clearance of apoptotic cells prevents the release of harmful
cell contents thereby suppressing inflammation and autoimmune reactions. Highly
conserved annexins may modulate the phagocytic cell removal by acting as
bridging molecules to phosphatidylserine, a characteristic phagocytosis signal
of dying cells. In this study five members of the structurally and functionally
related annexin family were characterized for their capacity to interact with
phosphatidylserine and dying cells. The results showed that AnxA3, AnxA4,
AnxA13, and the already described interaction partner AnxA5 can bind to
phosphatidylserine and apoptotic cells, whereas AnxA8 lacks this ability.
Sequence alignment experiments located the essential amino residues for the
recognition of surface exposed phosphatidylserine within the calcium binding
motifs common to all annexins. These amino acid residues were missing in the
evolutionary young AnxA8 and when they were reintroduced by site directed
mutagenesis AnxA8 gains the capability to interact with phosphatidylserine
containing liposomes and apoptotic cells. By defining the evolutionary conserved
amino acid residues mediating phosphatidylserine binding of annexins we show
that the recognition of dying cells represent a common feature of most annexins.
Hence, the individual annexin repertoire bound to the cell surface of dying
cells may fulfil opsonin-like function in cell death recognition. Annexins are a highly conserved protein family that bind to phospholipids in a
calcium (Ca2+) - dependent manner. Studies with purified annexins, as well as
overexpression and knockdown approaches identified multiple functions
predomitly linked to their dynamic and reversible membrane binding behavior.
However, most annexins are found at multiple locations and interact with
numerous proteins. Furthermore, similar membrane binding characteristics,
overlapping localizations and shared interaction partners have complicated
identification of their precise functions. To gain insight into annexin function
in vivo, mouse models deficient of annexin A1 (AnxA1), A2, A4, A5, A6 and A7
have been generated. Interestingly, with the exception of one study, all mice
strains lacking one or even two annexins are viable and develop normally. This
suggested redundancy within annexins, but examining these knockout (KO) strains
under stress conditions revealed striking phenotypes, identifying underlying
mechanisms specific for individual annexins, often supporting Ca2+ homeostasis
and membrane transport as central for annexin biology. Conversely, mice lacking
AnxA1 or A2 show extracellular functions relevant in health and disease that
appear independent of membrane trafficking or Ca2+ signaling. This review will
summarize the mechanistic insights gained from studies utilizing mouse models
lacking members of the annexin family. Annexins are a family of soluble proteins that bind to acidic phospholipids such
as phosphatidylserine in a calcium-dependent manner. The archetypical member of
the annexin family is annexin A5. For many years, its function remained unknown
despite the availability of a high-resolution structure. This, combined with the
observations of specific ion conductance in annexin-bound membranes, fueled
speculations about the possible membrane-spanning forms of annexins that
functioned as ion channels. The channel hypothesis remained controversial and
did not gather sufficient evidence to become accepted. Yet, it continues to draw
attention as a framework for interpreting indirect (e.g., biochemical) data. The
goal of the mini-review is to examine the data on annexin-lipid interactions
from the last ~30 years from the point of view of the controversy between the
two lines of inquiry: the well-characterized peripheral assembly of the annexins
at membranes vs. their putative transmembrane insertion. In particular, the
potential role of lipid rearrangements induced by annexin binding is
highlighted. |
Please list the 2 vaccines for herpes zoster(shingles) | live attenuated zoster vaccine (Zostavax®) and live attenuates herpes zoster (Shingles) are effective for treatment of infections with herpesZoster(shingles). | A live attenuated varicella-zoster vaccine (Zostavax--Merck) has been approved
by the FDA for prevention of herpes zoster (HZ; zoster; shingles) in persons >
or = 60 years old. Each dose of Zostavax contains about 14 times as much
varicella-zoster virus (VZV) as Varivax, which has been used in the US since
1995 to vaccinate against varicella (chicken pox). A new vaccine called Zostavax is available to reduce the risk of shingles
(herpes zoster) in people ages 60 and older. IMPORTANCE OF THE FIELD: Herpes zoster or shingles is a condition with the
potential to result in severe debilitation. It affects approximately 10 - 30% of
the population. Until recently there were only treatments to shorten the
duration and lessen the symptoms of herpes zoster, but no practical or approved
method of prevention for susceptible immunocompetent adults. The live attenuated
zoster vaccine (Zostavax, Merck & Co., Inc.) is effective in preventing shingles
in individuals 60 years of age and older and recommended by the Center for
Disease Control's (CDC) Advisory Committee for Immunization Practices (ACIP).
AREAS COVERED IN THIS REVIEW: Literature related to the live attenuated zoster
vaccine is reviewed from its beginnings in the early 1970s through to the
present.
WHAT THE READER WILL GAIN: Background information on herpes zoster and up to
date information on the live attenuated zoster vaccine including pharmacology,
efficacy and safety are covered. New areas of research in zoster vaccination are
also discussed.
TAKE HOME MESSAGE: The live attenuated zoster vaccine is an effective and
well-tolerated method of preventing zoster and the potentially debilitating
sequelae and is recommended for immunocompetent patients 60 years of age and
older. Ongoing clinical trials are investigating new means of effective
prevention. INTRODUCTION: Zostavax, a live attenuated vaccine, has been approved in the
United States for use in older individuals to reduce the risk and severity of
herpes zoster (HZ), also known as shingles. The vaccine is contraindicated in
individuals taking anti-tumor necrosis factor alpha (anti-TNF) therapies or
other biologics commonly used to treat autoimmune diseases because of the safety
concern that zoster vaccine may be associated with a short-term HZ risk. The
objective of the study was to examine the use, safety (short-term HZ risk after
vaccination), and effectiveness of zoster vaccine in individuals with rheumatoid
arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or
inflammatory bowel diseases.
METHODS: We conducted a cohort study of patients aged 50 years and older with
rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis,
and/or inflammatory bowel diseases by using administrative claims data from a
nationwide health plan from January 1, 2005, to August 31, 2009. We examined the
extent to which zoster vaccine was used; assessed factors associated with
vaccine use (Cox proportional hazards regression); and compared the incidence
rates of herpes zoster (HZ) between vaccinated and unvaccinated patients.
RESULTS: Among 44,115 patients with the autoimmune diseases, 551 (1.2%) received
zoster vaccine, and 761 developed HZ. Zoster vaccine use increased continuously
after approval in 2006. Younger and healthier patients, those who had an HZ
infection within the past 6 months, and those who were not using anti-TNF
therapies were more likely to receive the vaccine. Approximately 6% of
vaccinated patients were using anti-TNF therapies at the time of vaccination.
The incidence rates of HZ were similar in vaccinated and unvaccinated patients
(standardized incidence ratio, 0.99; 95% confidence interval, 0.29 to 3.43).
CONCLUSIONS: Use of the zoster vaccine was uncommon among older patients with
autoimmune diseases, including those not exposed to immunosuppressive
medications. The short-term risk of HZ did not appear to be increased in
vaccinated patients, even among those using immunosuppressive therapies (for
example, biologics) at the time of vaccination. However, our study was limited
by the small number of vaccinated patients, and further evidence is needed to
confirm the vaccine's safety and efficacy in this population. A live attenuated vaccine to prevent herpes zoster, or shingles (Zostavax; Merck
& Co Inc, Whitehouse Station, NJ), is approved by the US Food and Drug
Administration (FDA) for use in adults aged 50 years or older. Studies show that
this vaccine is safe when administered to immunocompetent adults. Investigations
are being conducted to evaluate the long-term safety and efficacy of the vaccine
in immunocompromised populations, including patients who are dependent on
steroids. The Advisory Committee on Immunization Practices (ACIP) of the Centers
for Disease Control and Prevention recommends that this vaccine be routinely
administered only to patients aged 60 years or older. As more data regarding
duration of immunity after vaccination become available and as concerns
regarding supply of this vaccine are adequately addressed, the ACIP plans to
reconsider its recommendations regarding its use in patients aged 50 to 59
years. The author provides an overview of the herpes zoster vaccine, focusing on
the latest extension in use approved by the FDA and the recommendations of the
ACIP. Zostavax, a live attenuated vaccine against shingles (herpes zoster) has been
available in Switzerland since 2008. In a population aged 60 and over, evidence
suggests the vaccine effectively reduces the incidence of shingles and some of
its corresponding complications. More importantly, in terms of public health,
vaccination appears to reduce the burden of illness and be pharmaco-economically
viable. Despite being part of the vaccination programmes in the United States
and several European countries, the vaccine is not yet part of the Swiss
vaccination programme. Should Switzerland follow suit by incorporating Zostavax
into their vaccination policy? Zostavax(®) is a live attenuated shingles (herpes zoster) vaccine approved in
the EU for the prevention of herpes zoster (HZ) and postherpetic neuralgia (PHN)
in adults aged ≥50 years. Zoster vaccine protected against HZ in adults aged
50-59 years (ZEST trial) and ≥60 years [Shingles Prevention Study (SPS)], and
also reduced the burden of illness associated with HZ and the risk of PHN in
adults aged ≥60 years (SPS). A large amount of real-world data also supports the
efficacy of zoster vaccine. Results of the SPS Short- and Long-Term Persistence
Substudies and real-world studies indicate that zoster vaccine provided
continued benefit in the longer term, albeit with a gradual decline in vaccine
efficacy over time; long-term effectiveness studies are ongoing. The need for a
booster dose is still unknown, but a study showed that, if necessary, a booster
dose administered to adults aged ≥70 years who received their first dose of
zoster vaccine ≥10 years previously was immunogenic. Zoster vaccine had a
favourable safety and tolerability profile, with the most commonly reported
adverse events being non-severe injection-site reactions. In conclusion, zoster
vaccine reduces the incidence of HZ and PHN, thereby reducing the burden of
illness associated with HZ; improved uptake of zoster vaccine is needed. About one-third of the US population will develop herpes zoster (HZ, commonly
known as shingles) over a lifetime, while two-thirds will not. It is not clear
exactly why certain people are susceptible to HZ; however, we may be coming
closer to an answer. In this issue of the JCI, a study by Levin et al. provides
important details concerning pathogenesis of and protection from HZ. The authors
characterized differences in the immunologic responses induced by two HZ
vaccines, the live attenuated zoster vaccine (ZV) and the more recently
developed adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit
herpes zoster vaccine (HZ/su), in vaccine-naive subjects and those previously
vaccinated with HZ. The observed differences in responses paralleled the
observed clinical protection of the two zoster vaccines, with HZ/su being
superior to HZ. Together, these results seem to explain immunologically why the
new subunit vaccine outperforms the live vaccine. These differences may also
provide clues as to why HZ develops in the first place. de Boer and colleagues present a cost-effectiveness analysis based in the
Netherlands of two vaccines available for the prevention of herpes zoster.
Zostavax® was the first vaccine available for the prevention of herpes zoster in
older adults. A live-attenuated vaccine, Zostavax is not free of limitations,
which include a relatively low efficacy that wanes over time and its
contraindication among immunocompromised individuals. The recently available
adjuvanted herpes zoster subunit vaccine Shingrix® overcomes some of these
limitations. The herpes zoster subunit vaccine is more efficacious than
Zostavax, and it can be administered to immunosuppressed individuals. However,
the herpes zoster subunit vaccine is considerably costlier and requires a
booster injection. In order to clarify the value of each vaccine, de Boer and
colleagues compare the cost-effectiveness of no vaccination, and of vaccination
with Zostavax or the herpes zoster subunit vaccine in four cohorts of older
adults from the perspective of the Netherlands. Whereas neither vaccine was
cost-effective under the willingness-to-pay threshold of €20,000 per
quality-adjusted life year, the authors find the herpes zoster subunit vaccine
to be cost-effective in some scenarios under a €50,000 per quality-adjusted life
year threshold.Please see related article:
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1213-5. BACKGROUND: Steep increases in herpes zoster (HZ) incidence, hospitalization due
to HZ and the risk of post-herpetic neuralgia as a complication of HZ occur in
people over 50 years of age. Two HZ vaccines are currently authorized for use in
those 50 years of age and older in Canada: a live attenuated zoster vaccine
(LZV) authorized in 2008; and a recombit subunit vaccine (RZV) authorized in
October 2017.
OBJECTIVES: To review current evidence and develop guidance on whether the
previously authorized LZV (Zostavax®) and/or the recently authorized RZV
(Shingrix®) vaccine should be offered to Canadians 50 years of age and older: 1)
at a population-level, in publicly funded immunization programs; and 2) at an
individual-level, to individuals wishing to prevent HZ, or by clinicians wishing
to advise individual patients about preventing HZ.
METHODS: The National Advisory Committee on Immunization (NACI) Herpes Zoster
Working Group developed a predefined search strategy to identify all eligible
studies, assessed their quality, and summarized and analyzed the findings. A
Cost Utility Analysis of LZV and RZV was also conducted from a health care
system perspective. Recommendations were proposed according to NACI's
evidence-based process. The strength of these recommendations was defined, and
the Grade of evidence supporting them was identified. In light of the evidence,
the recommendations were then considered and approved by NACI.
RESULTS: Five recommendations were developed for public health and
individual-level decision-making. 1) RZV should be offered to
populations/individuals >50 years of age without contraindications (Strong NACI
Recommendation, Grade A evidence). 2) RZV should be offered to
populations/individuals >50 years of age without contraindications who have
previously been vaccinated with LZV (Strong NACI Recommendation, Grade A
evidence). Re-immunization with two doses of RZV may be considered one year
after LZV (Discretionary NACI Recommendation, Grade I evidence). 3) RZV should
be offered to populations/individuals >50 years of age without contraindications
who have had a previous episode of HZ (Strong NACI Recommendation, Grade B
evidence). Immunization with two doses of RZV may be considered one year after
the HZ episode (Discretionary NACI Recommendation, Grade I evidence). 4) LZV may
be considered for immunocompetent populations/individuals >50 years of age
without contraindications when RZV is contraindicated, unavailable or
inaccessible (Discretionary NACI Recommendation, Grade A evidence). 5) RZV (not
LZV) may be considered in immunocompromised adults >50 years of age on a
case-by-case basis (Discretionary NACI Recommendation, Grade I evidence).
CONCLUSION: Both vaccines have been shown to be safe and immunogenic and to
reduce the incidence of HZ and post-herpetic neuralgia. Vaccine efficacy of LZV
against HZ decreases with age at, and time since vaccination. The vaccine
efficacy of RZV remains higher and appears to decline more slowly than vaccine
efficacy of LZV across all age groups. Both vaccines are cost-effective in those
50 years of age and older compared with no vaccination, especially in those
65-79 years of age. RZV is more cost-effective than LZV. Skin Therapy Letter © (ISSN 1201–5989) Copyright 2019 by SkinCareGuide.com Ltd.
Skin Therapy Letter © is published 6 times annually by SkinCareGuide.com Ltd,
1003 - 1166 Alberni Street, Vancouver, British Columbia, Canada, V6E 3Z3. All
rights reserved. Reproduction in whole or in part by any process is strictly
forbidden without prior consent of the publisher in writing. While every effort
is made to see that no inaccurate or misleading data, opinion, or statement
appears in the Skin Therapy Letter ©, the Publishers and Editorial Board wish to
make it clear that the data and opinions appearing in the articles herein are
the responsibility of the contributor. Accordingly, the Publishers, the
Editorial Committee and their respective employees, officers, and agents accept
no liability whatsoever for the consequences of any such inaccurate or
misleading data, opinion, or statement. While every effort is made to ensure
that drug doses and other quantities are presented accurately, readers are
advised that new methods and techniques involving drug usage, and described
herein, should only be followed in conjunction with the drug manufacturer’s own
published literature. BACKGROUND: Australia introduced a funded shingles vaccination program for older
adults in November 2016, administered predomitly in primary care clinics.
MedicineInsight, a nationally representative primary care database, was used to
investigate the risk of pre-specified outcomes following live attenuated herpes
zoster vaccine (ZVL) in Australia.
METHODS: Individuals aged 70-79 years who received ZVL between 1 November 2016
and 31 July 2018 were identified from MedicineInsight. The self-controlled case
series (SCCS) method was used to estimate the seasonally-adjusted relative
incidence (RI) of seven pre-specified outcome events (injection site reaction
(ISR) [positive control], burn [negative control], myocardial infarction (MI),
stroke, rash, rash with an antiviral prescription, and clinical attendance)
during a plausible post-vaccination at-risk window compared with times distant
from vaccination. Sensitivity analyses examined the effect of common concomitant
vaccinations and restriction to first outcome events.
RESULTS: A total of 332,988 vaccination encounters among 150,054 individuals
were identified during the study period; over 2 million clinical attendances
were observed. There was an increased RI of ISR in the seven days following ZVL
(RI = 77.4, 95% CI 48.1-124.6); the RI of clinical attendance (RI = 0.94, 95% CI
0.94-0.95) and stroke (RI = 0.58, 95% CI 0.44-0.78) were lower in the 42 days
following administration of ZVL compared to control periods. There was no
evidence of a change in the RI of MI (RI = 0.74, 95% CI 0.41-1.33), rash
(RI = 0.97, 95% CI 0.88-1.08), or rash with antiviral prescription (RI = 0.83,
95% CI 0.62-1.10) in the 42 days following ZVL compared to control periods.
CONCLUSION: No new safety concerns were identified for ZVL in this study based
on a novel, Australian primary care data source. An expected increased risk of
ISR was identified; findings in relation to cardiovascular disease were
reassuring but require confirmation using additional data, including hospital
records. Herpes zoster (HZ; shingles) results from reactivation of varicella-zoster virus
(VZV) after primary infection as varicella (chicken pox). It affects mainly
older adults and people with immunocompromising diseases or treatments. The most
common complication is postherpetic neuralgia (PHN), which has significant
adverse effects on quality of life and activities of daily living. Since PHN
cannot be prevented once HZ has occurred, and treatment is only modestly
successful and is associated with significant side effects, the recent
introduction of an effective vaccine is an important achievement. This new
vaccine, which combines a single VZV glycoprotein (gE) and a multicomponent
adjuvant, is superior to the previously available live attenuated VZV vaccine.
The recombit adjuvanted vaccine is remarkably effective in restoring the
protective T cell-mediated immunity required to prevent HZ. Its clinical
efficacy is much greater than that observed with other vaccines for older
individuals affected by immune senescence, and its safety profile is very
acceptable. It has been recommended in the USA and Canada for people who are 50
years of age and older. The immunogenicity and safety of this vaccine in
severely immunocompromised individuals, such as after chemotherapy for
maligcy, after solid organ or stem cell transplant, and in people with HIV
are being studied. Shingrix is a recombit adjuvant subunit vaccine. The vaccine is approved in
Germany for prevention of zoster manifestation and postherpetic neuralgia in
adults aged ≥60 years. In the case of bullous skin lesions after vaccination
with Shingrix a zoster disease should be considered. Unexpected side effects
associated with the vaccination should be reported to the Drug Commission of the
German Medical Association. |
What is a likely origin of intronless genes? | More than half of SEGs identified in most of the species have at least one ortholog multiple exon gene in the same genome, which provides insight to their possible origin by retrotransposition | In Teleost fish examined to date the ocular rod opsin gene, rho, is intronless,
unlike the rod opsin genes of other vertebrate classes which possess a five
exon/four intron structure. We have examined in silico the structure of rho
(which is expressed uniquely in the retina) and the closely related extraretinal
rod-like opsin (exo-rhodopsin) gene, errlo (which is expressed uniquely in the
pineal), in the puffer-fish, Fugu rubripes (Takifugu rubripes). Whilst the
ocular rho is intronless in common with other Teleosts, the pineal errlo has the
five exon/four intron structure common to the rod opsin gene of other
vertebraes. A comparison of the sequence surrounding the errlo and rho loci
indicates that the errlo locus is syntenic with RHO, the human rod opsin gene,
rather than rho. We suggest that the intronless rho may have arisen through an
ancient retrotransposition of a mature mRNA originating from errlo. This
duplication event has occurred early in the evolution of the Actinopterygii
(ray-finned fish) since the rho of the primitive Actinopterygians such as
sturgeon, bowfin, and gar is also intronless. Since it appears that the intron
containing errlo is the ancestral opsin gene that gave rise to the intronless
rho in the Teleostei, errlo is therefore the true orthologue of the rod opsin
gene in other vertebrate classes. We suggest that loss of expression of errlo in
the retina could be related to the metabolic and physiological advantages, such
as a reduction in splicing events during RNA processing, that may be conferred
through possession of an additional, intronless rod opsin gene in the form of
rho. Using computational approaches we have identified 2017 expressed intronless
genes in the mouse genome. Evolutionary analysis reveals that 56 intronless
genes are conserved among the three domains of life--bacteria, archea and
eukaryotes. These highly conserved intronless genes were found to be involved in
essential housekeeping functions. About 80% of expressed mouse intronless genes
have orthologs in eukaryotic genomes only, and thus are specific to eukaryotic
organisms. 608 of these genes have intronless human orthologs and 302 of these
orthologs have a match in OMIM database. Investigation into these mouse genes
will be important in generating mouse models for understanding human diseases. Intronless genes (IGs) constitute approximately 3% of the human genome. Human
IGs are essentially different in evolution and functionality from the IGs of
unicellular eukaryotes, which represent the majority in their genomes.
Functional analysis of IGs has revealed a massive over-representation of signal
transduction genes and genes encoding regulatory proteins important for growth,
proliferation, and development. IGs also often display tissue-specific
expression, usually in the nervous system and testis. These characteristics
translate into IG-associated diseases, mainly neuropathies, developmental
disorders, and cancer. IGs represent recent additions to the genome, created
mostly by retroposition of processed mRNAs with retained functionality.
Processing, nuclear export, and translation of these mRNAs should be hampered
dramatically by the lack of splice factors, which normally tightly cover mature
transcripts and govern their fate. However, natural IGs manage to maintain
satisfactory expression levels. Different mechanisms by which IGs solve the
problem of mRNA processing and nuclear export are discussed here, along with
their possible impact on reporter studies. Intronless genes, as a characteristic feature of prokaryotes, are an important
resource for the study of the evolution of gene architecture in eukaryotes. In
the study, 14,623 (36.87%) intronless genes in maize were identified and the
percentage is greater than that of other monocots and algae. The number of maize
intronless genes on each chromosome has a significant linear correlation with
the number of total genes on the chromosome and the length of the chromosomes.
Intronless genes in maize play important roles in translation and energy
metabolism. Evolutionary analysis revealed that 2601 intronless genes conserved
among the three domains of life and 2323 intronless genes that had no homology
with genes of other species. These two sets of intronless genes were distinct in
genetic features, physical locations and function. These results provided a
useful source to understand the evolutionary patterns of related genes and
genomes and some intronless genes are good candidates for subsequent functional
analyses specifically. Nucleosomes, the basic units of chromatin, are involved in transcription
regulation and DNA replication. Intronless genes, which constitute 3 percent of
the human genome, differ from intron-containing genes in evolution and function.
Our analysis reveals that nucleosome positioning shows a distinct pattern in
intronless and intron-containing genes. The nucleosome occupancy upstream of
transcription start sites of intronless genes is lower than that of
intron-containing genes. In contrast, high occupancy and well positioned
nucleosomes are observed along the gene body of intronless genes, which is
perfectly consistent with the barrier nucleosome model. Intronless genes have a
significantly lower expression level than intron-containing genes and most of
them are not expressed in CD4+ T cell lines and GM12878 cell lines, which
results from their tissue specificity. However, the highly expressed genes are
at the same expression level between the two types of genes. The highly
expressed intronless genes require a higher density of RNA Pol II in an
elongating state to compensate for the lack of introns. Additionally, 5' and 3'
nucleosome depleted regions of highly expressed intronless genes are deeper than
those of highly expressed intron-containing genes. |
Which company developed ivosidenib? | Ivosidenib has been developed by Agios Pharmaceuticals. | Isocitrate dehydrogenase (IDH) is a key enzyme involved in the conversion of
isocitrate to α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle. IDH
mutation produces a neomorphic enzyme, which can lead to the abnormal
accumulation of R-2-HG and promotes leukemogenesis. IDH mutation occurs in 20%
of acute myeloid leukemia (AML) patients, mainly including IDH1 R132, IDH2 R140,
and IDH2 R172. Different mutant isoforms have different prognostic values. In
recent years, IDH inhibitors have shown good clinical response in AML patients.
Hence, enasidenib and ivosidenib, the IDH2 and IDH1 inhibitors developed by
Agios Pharmaceuticals, have been approved by the Food and Drug Administration on
1 August 2017 and 20 July 2018 for the treatment of adult relapsed or refractory
(R/R) AML with IDH2 and IDH1 mutations, respectively. IDH inhibitor monotherapy
for R/R AML is efficacious and safe; however, there are problems, such as
primary or acquired resistance. Clinical trials of IDH inhibitors combined with
hypomethylating agents or standard chemotherapy for the treatment of R/R AML or
newly diagnosed AML, as well as in post hematopoietic stem cell transplantation
as maintece therapy, are ongoing. This article summarizes the use of IDH
inhibitors in AML with IDH mutations. |
Is the apilimod inhibitor effective against SARS-CoV-2? | To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules were profiled. In a study the identification of 30 known drugs that inhibit viral replication was reportedd. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment. | The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an
ongoing global pandemic of severe pneumonia-like disease designated as
coronavirus disease 2019 (COVID-19). To date, more than 2.1 million confirmed
cases and 139,500 deaths have been reported worldwide, and there are currently
no medical countermeasures available to prevent or treat the disease. As the
development of a vaccine could require at least 12-18 months, and the typical
timeline from hit finding to drug registration of an antiviral is >10 years,
repositioning of known drugs can significantly accelerate the development and
deployment of therapies for COVID-19. To identify therapeutics that can be
repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs
encompassing approximately 12,000 clinical-stage or FDA-approved small
molecules. Here, we report the identification of 30 known drugs that inhibit
viral replication. Of these, six were characterized for cellular dose-activity
relationships, and showed effective concentrations likely to be commensurate
with therapeutic doses in patients. These include the PIKfyve kinase inhibitor
Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO
5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have
advanced into the clinic, the known pharmacological and human safety profiles of
these compounds will accelerate their preclinical and clinical evaluation for
COVID-19 treatment. |
Is Lanabecestat effective for Alzheimer's disease? | No. Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline of Alzheimer's disease patients. | IMPORTANCE: Alzheimer disease (AD) is a neurodegenerative disorder characterized
by cognitive deterioration and impaired activities of daily living. Current
treatments provide only minor symptomatic improvements with limited benefit
duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid
precursor protein-cleaving enzyme 1 (BACE1/β-secretase), was developed to modify
the clinical course of AD by slowing disease progression.
OBJECTIVE: To assess whether lanabecestat slows the progression of AD compared
with placebo in patients with early AD (mild cognitive impairment) and mild AD
dementia.
DESIGN, SETTING, AND PARTICIPANTS: AMARANTH (first patient visit on September
30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient
visit on July 1, 2016; last patient visit on September 28, 2018) were
randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting
104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were
multicenter, global, double-blind studies conducted at 257 and 251 centers,
respectively, located in 15 and 18 countries or territories, respectively. A
population-based sample of men and women aged 55 to 85 years who met National
Institute on Aging-Alzheimer's Association criteria for early AD or mild AD
dementia was screened using cognitive assessments, and the presence of amyloid
was confirmed. Patients were excluded for unstable medical conditions or
medication use, significant cerebrovascular pathologic findings, or a history of
vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH
screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed
the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized,
and 76 patients completed the study.
INTERVENTIONS: Patients were randomized (1:1:1) to once-daily oral doses of
lanabecestat (20 mg), lanabecestat (50 mg), or placebo.
MAIN OUTCOMES AND MEASURES: The primary outcome measure was change from baseline
on the 13-item Alzheimer Disease Assessment Scale-cognitive subscale. Secondary
outcomes included Alzheimer's Disease Cooperative Study-Instrumental Activities
of Daily Living Inventory, Clinical Dementia Rating, Functional Activities
Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory.
Efficacy analyses were conducted on the intent-to-treat population.
RESULTS: Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years,
and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean
(SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies
were terminated early after futility analysis. There were no consistent,
reproducible dose-related findings on primary or secondary efficacy measures.
Psychiatric adverse events, weight loss, and hair color changes were reported in
a higher percentage of patients receiving lanabecestat than placebo.
CONCLUSIONS AND RELEVANCE: Treatment with lanabecestat was well tolerated and
did not slow cognitive or functional decline.
TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573. INTRODUCTION: The APECS and AMARANTH trials showed that beta-secretase (BACE)
inhibitors verubecestat and lanabecestat failed to slow cognitive and functional
decline in individuals with prodromal or early Alzheimer's disease. Here, the
performance on secondary and exploratory cognitive measures in both studies is
reported.
METHODS: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized,
double-blind, placebo-controlled, parallel-group, 104-week clinical trials
conducted by different sponsors. Measures included the 3-Domain Composite
Cognition Score (CCS-3D), Repeatable Battery for the Assessment of
Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol
Coding.
RESULTS: Verubecestat showed worsening on the CCS-3D Total Score, Episodic
Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on
the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional
Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and
improvements on Letter/Category Fluency.
DISCUSSION: In both studies, many measures showed treatment-associated cognitive
worsening, whereas verbal fluency tasks showed improvement. |
How is the STING protein activated? | During DNA virus infections, detection of cytosolic DNA by the cGAS-STING pathway leads to activation of IFN-β. | The innate immune response is crucial for defense against viral infections.
Cells recognize virus infection through pattern recognition receptors and induce
type I interferons as well as proinflammatory cytokines to orchestrate an innate
immune response. Herpes simplex virus 1 (HSV-1) triggers both the cyclic GMP-AMP
synthase (cGAS)-stimulator of interferon genes (STING) and Toll-like receptor 3
(TLR3) pathways. It is well known that TLR3 uses the adaptor protein
Toll/interleukin-1 receptor (IL-1R) domain-containing adaptor-inducing beta
interferon (TRIF) for signaling, but we recently reported that STING signaling
also requires TRIF. Because STING directly binds to TRIF, we identified the
STING-interacting domain of TRIF and generated STING-noninteracting mutants of
human and mouse TRIFs. The mutant TRIFs were unable to support STING signaling,
although they were fully functional in the TLR3 pathway. These mutants were used
to assess the relative contributions of the TLR3 and STING pathways to the
attenuation of HSV-1 replication in mouse and human cell lines. For this
purpose, the mouse L929 and NB41A3 cell lines and the human HT1080 and HeLa-M
cell lines, in which both the TLR3 and the STING pathways are operational, were
used. The TRIF gene was disrupted in these lines by CRISPR/Cas9, before
reconstituting them with mutant and wild-type TRIF expression vectors. Infection
of the reconstituted cells with HSV-1 revealed that both the cGAS-STING and the
TLR3 signaling pathways are required for the attenuation of virus replication,
but their relative contributions in attenuating HSV-1 replication were found to
be different in mouse versus human cell lines. Thus, our study suggests that the
relative contributions of the cGAS-STING and the TLR3 pathways in the
attenuation of viral infection may be species specific.IMPORTANCE The magnitude
of fatal infections caused by all different viruses in human and animal
populations justifies a better understanding of the host innate immune response
process that attenuates virus replication. In particular, the relative
contributions of different signaling pathways which are responsible for the
generation of the innate immune response are still largely unknown. In this
study, we used STING-noninteracting TRIF mutants to decipher the relative
contributions of the TLR3 and cGAS-STING signaling pathways to the attenuation
of HSV-1 infection. We show that the relative contributions of the two pathways
to the attenuation of viral infection are different in mouse versus human cell
lines. Together, our results provide new insights into the relative
contributions of two different signaling pathways in the attenuation of viral
infection and may lead to the development of new antiviral strategies aimed at
blocking viral infection at very early stages. During DNA virus infections, detection of cytosolic DNA by the cGAS-STING
pathway leads to activation of IFN-β. Kaposi's Sarcoma Herpesvirus (KSHV), an
oncogenic DNA virus, is the etiological agent of Kaposi's Sarcoma, an
endothelial cell (EC)-based tumor. To investigate the role of STING during KSHV
infection of primary ECs we identified a primary lymphatic EC sample that is
defective for STING activation and we also knocked out STING in blood ECs.
Ablation of STING in EC does not increase susceptibility to KSHV latent
infection nor does it increase KSHV spread after lytic reactivation indicating
STING signaling does not restrict KSHV. In contrast, STING ablation increases
Adenovirus spread at low MOI, but STING is dispensable for blocking replication.
These experiments reveal that the importance of STING depends on the DNA virus
and that STING appears more important for restricting spread to bystander cells
than for inhibition of viral replication. Several DNA viruses have evolved antagonists to inhibit the cyclic GMP-AMP
synthase (cGAS)-stimulator of interferon genes (STING) DNA-sensing immune
pathway. This includes DNA viral oncogenes that antagonize the cGAS-STING
pathway by binding STING through the LxCxE motif. The 293T human cells are
widely used in biology studies as they are highly transfectable. While parental
293 cells express high levels of STING, 293T cells lack STING and are unable to
induce interferon antiviral responses to cytosolic DNA. Additionally, 293T cells
express the SV40 polyomavirus large T antigen (LT) which enhances the
replication of transfected DNA plasmids carrying the SV40 origin of replication.
Since SV40 LT also encodes the LxCxE motif, the lack of STING expression in 293T
cells is commonly assumed to be due to SV40 large T antigen. We find that SV40
LT does not alter exogenously expressed and endogenous levels of STING protein.
We show that STING transcription is suppressed in 293T cells but is not driven
by SV40. This study also revealed that SV40 LT does indeed inhibit cGAS-STING
interferon induction, but through a mechanism distinct from other DNA virus
oncogenes. Collectively, these results indicate that while SV40 LT can inhibit
cGAS-STING interferon induction, it does so in an uticipated manner. |
Explain the use of Radio Frequency Ablation as a treatment | Radio-frequency ablation (RFA) is a promising minimal-invasive treatment option for treatment of, cancer, pain, tissue hyperplasia and cardiac arrhythmias cancer, triggering tissue necrosis and results in reduced tumor volumes. | PURPOSE: To evaluate the feasibility of a technique of MR-guided stereotactic
radio frequency ablation, which was developed as a minimally invasive treatment
for brain tumors, and to determine MR characteristics and sequential evolution
of radio frequency lesions created to ablate brain tumors.
METHODS: Fourteen lesions in 12 patients with primary and metastatic brain
tumors were treated with this technique and followed for up to 10 months. The
stereotactic coordinates of the tumor and the angle of the radio frequency probe
were calculated on MR imaging. The radio frequency lesion was generated in the
awake patient by increasing the temperature to 80 degrees C within the tumor for
1 minute. This was repeated until the entire tumor volume was destroyed. MR
imaging was performed before, during, and immediately after the radio frequency
procedure, and sequential MR was obtained during clinical follow-up.
RESULTS: MR imaging clearly showed well-defined radio frequency lesions and
provided feedback for treatment planning. The radio frequency lesion boundary
was well identified as a dark signal rim on T2-weighted images and showed ring
enhancement on contrast-enhanced T1-weighted images. The sequential MR imaging
showed the radio frequency lesions decreased in volume in all cases, suggesting
focal control.
CONCLUSION: Stereotactic MR-guided radio frequency brain tumor ablation is a
feasible and promising technique that can be an attractive brain tumor treatment
alternative. MR provided not only accurate tumor location but also visualization
of feedback of thermal tissue changes that reflected therapeutic effect. Atrial arrhythmias resistant to medical therapy are still a common indication
for ablation of the normal atrioventricular conduction pathway (Tawara node and
His Bundle). However, the development of catheter techniques of intra-atrial
ablation to destroy arrhythmogenic myocardial zones enables radical cure of the
arrhythmias with the respect of the nodo-hisian pathway. With respect to common
flutter, a number of series, including our own, show a 50 to 75% long-term
success rate. We believe that a very high success rate in the ablation of
flutter will probably be achieved in a reproducible manner but this will require
a more accurate understanding of the tachycardia circuit and technological
developments allowing controlled radio-frequency destruction of bigger atrial
myocardial zone. Experience of radio-frequency ablation atrial of atrial
extrasystoles is more limited than that of flutter and there are fewer published
series. Globally, catheter ablation of atrial tachycardia remains a more
difficult and a less well codified procedure than that of accessory pathways or
of intra-nodal reentry. Radio-frequency ablation in this indication is not
without danger in view of the thinness of the atrial wall. We believe that
radio-frequency catheter ablation for atrial arrhythmias should, for the moment,
be reserved for centres specialised in the techniques of electro-physiological
investigation and ablation. The series of five patients with symptomatic isolated right ventricular outflow
tract ectopy and no structural heart disease which were successfully treated
with radiofrequency ablation of the ectopic focus are reported in order to
discuss radio-frequency ablation as an alternative treatment in patients with
right ventricular outflow tract ectopy without ventricular tachycardia. PURPOSE: Small renal tumors are frequently detected during the screening of
patients with a hereditary type of renal cancer. The development of nonsurgical
treatment modalities would greatly improve quality of life in these patients. We
present our experience with radio frequency interstitial tissue ablation, a
heating device approved by the Food and Drug Administration for treating soft
tissue tumors.
MATERIALS AND METHODS: Patients underwent radio frequency interstitial tissue
ablation of small renal tumors just before surgical excision. Pathological
examination of the renal tumors was done to evaluate the treatment effect.
Computerized tomography and renal function testing were performed before and
after therapy to evaluate toxicity.
RESULTS: Four patients underwent treatment of a total of 14 tumors with the
radio frequency interstitial tissue ablation device just before surgical removal
of the tumors. All lesions were brown after ablation, in contrast to the normal
pink appearance of untreated lesions that were resected. On color Doppler
ultrasound blood flow to each tumor evident before was not visualized after
treatment. The Wilcoxon rank sum test demonstrated no difference preoperatively
and postoperatively in blood urea nitrogen, serum creatinine, creatinine
clearance or differential renal function. We identified no toxicity associated
with radio frequency interstitial tissue ablation. Of the excised tumors 11 were
renal cell carcinoma and 3 fibrotic hemorrhagic cysts. For renal cell carcinoma
the treatment effect involved the loss of nuclear detail and nonvisualization of
nucleoli. These changes were not observed in any tumors resected without radio
frequency interstitial tissue ablation. The treatment effect was noted in 10 of
the 11 lesions, and in 1 case the treatment effect involved 35% of the tumor.
CONCLUSIONS: No toxicity was associated with radio frequency interstitial tissue
ablation. Percutaneous treatment of renal tumors is planned to evaluate the
treatment effect better and further evaluate toxicity. Radio-frequency thermal ablation is one of the most promising minimally invasive
techniques for the treatment of nonresectable hepatic tumors. Essential
technical tips to successful radio-frequency ablation therapy were collected
from five international experts. They were organized into five categories:
understanding the mechanisms and principles of radio-frequency ablation,
modulation of tissue physiologic characteristics to increase tumor destruction,
strategies of overlapping ablations, strategies to improve ablation according to
tumor location, and imaging strategies after ablation to ensure adequate
therapy. Established factors for optimal ablation, as well as emerging technical
tips, are addressed with illustrations in each section. These essential tips
will be very helpful for physicians performing radio-frequency ablation of
hepatic tumors. Minimally invasive alternatives to surgery for the treatment of maligcy are
becoming more attractive owing to improvements in technology, reduced morbidity
and mortality, and the ability to provide treatment in an outpatient setting.
Radio-frequency (RF) ablation has become the imaging-guided ablative method of
choice because of its relatively low cost, its capability of creating large
regions of coagulative necrosis in a controlled fashion, and its relatively low
toxicity. RF ablation in the thorax involves the use of computed tomography (CT)
to localize the tumor and determine the optimal approach. The size of the tumor
determines whether a cluster of electrodes or a single electrode of a particular
length will be used to perform the ablation. CT fluoroscopy aids in guiding
placement of the electrode. In patients with non-small cell lung maligcy who
are not candidates for surgery owing to poor cardiorespiratory reserve, RF
ablation alone or followed by conventional radiation therapy with or without
chemotherapy may prove to be a treatment option. In patients with metastatic
disease, RF ablation may be suitable for treatment of a small tumor burden or
for palliation of larger tumors that cause symptoms such as cough, hemoptysis,
or pain. Patients with chest wall or osseous metastatic tumors in whom other
therapies have failed may benefit from RF ablation as an alternative to
radiation therapy. OBJECTIVE: To evaluate the feasibility of sonographically guided radio frequency
thermal ablation as a minimally invasive method for treatment of unresectable
recurrent or metastatic tumors in the retroperitoneum and the pelvis, which
often pose difficult surgical problems.
METHODS: Radio frequency thermal ablation was performed on 7 patients with
unresectable recurrent retroperitoneal or pelvic tumors from colorectal (n = 4),
renal (n = 2), and prostate (n = 1) cancers. Under sonographic guidance, a total
of 11 radio frequency thermal ablation operations were performed by a
percutaneous or transanal approach.
RESULTS: Three patients were asymptomatic, whereas 4 patients were symptomatic.
The sizes of the tumors ranged from 29 to 100 mm (mean, 50.5 mm). Radio
frequency thermal ablation was technically completed in all operations without
intraoperative complications. The ablation time ranged from 25 to 238 minutes
depending on the tumor size. There was no mortality. There were postoperative
complications in 3 operations (27.3%): an enterovesical fistula, a skin burn,
and fecal incontinence. The hospital stay was generally 0 to 1 day. Tumor marker
levels decreased after radio frequency thermal ablation in all operations.
Symptoms of 4 patients were controlled by radio frequency thermal ablation. One
patient with recurrent renal cancer and uncontrollable hypercalcemia became
asymptomatic immediately after radio frequency thermal ablation. Local
recurrence at the radio frequency thermal ablation site occurred in 2 patients
(28.6%), but these local recurrent tumors were treated effectively by additional
sonographically guided radio frequency thermal ablation.
CONCLUSIONS: Minimally invasive sonographically guided radio frequency thermal
ablation is technically feasible for local treatment of unresectable recurrent
retroperitoneal and pelvic tumors from different origins. Care should be taken
to avoid thermal injury to surrounding organs. Further study is needed to
evaluate its safety and efficacy. OBJECTIVE: Although radio-frequency ablation (RFA) has been recently applied as
a minimally invasive treatment option for renal cell carcinoma (RCC), indication
of this modality remains a critical issue due to the lack of complete tumor
destruction as well as the uncertainty of its long-term efficacy. We report the
efficacy of RFA for nine carefully selected patients with RCC who had
significant reason to avoid invasive surgical treatment under general
anesthesia.
METHODS: Radio-frequency ablation was performed under epidural or local
anesthesia by ultrasound or computed tomography (CT) guidance in nine patients
with biopsy proven RCC (mean diameter, 38 mm; range, 20-53 mm), who were at
significant operative or anesthetic risk for invasive surgery. Follow-up
enhanced CT scans or magnetic resoce images were evaluated every 3-6 months
and an evaluation of metastasis was performed every 6 months.
RESULTS: At a mean follow-up of 17 months, seven (78%) of the nine patients with
renal tumor showed no tumor enhancement. The renal function of all patients was
well preserved. All patients were able to continue undergoing their respective
treatments for active diseases in other organs in parallel to the RFA treatment.
No distant metastasis, urine leakage were reported and one case of temporary
hematuria and one case of peri-renal hemorrhage not requiring blood transfusion
were encountered. Intra-operative ultrasonography was useful in the real-time
monitoring of the minimally excessive extension of ablation into the normal
parenchyma.
CONCLUSION: Radio-frequency ablation appears to be an effective and safe
minimally invasive therapeutic option for selected patients with RCC who have
reason to avoid invasive surgery under general anesthesia. OBJECTIVE: To compare health-related quality of life (HRQoL) after bipolar radio
frequency ablation and thermal balloon ablation in women with dysfunctional
uterine bleeding.
DESIGN: Randomized clinical trial.
SETTING: Teaching hospital.
PATIENT(S): Women suffering from dysfunctional uterine bleeding.
INTERVENTION(S): Bipolar radio frequency ablation and thermal balloon ablation.
MAIN OUTCOME MEASURE(S): Patients were asked to complete HRQoL questionnaires at
baseline, and at 2 days, 2 weeks, 3 months, 6 months, and 12 months after
surgery. The questionnaires contained the medical outcomes study Short-Form 36
(SF-36), the Self-rating Depression Scale, the Rotterdam Symptom Checklist,
State-Trait Anxiety Inventory, and a structured clinical history questionnaire.
RESULT(S): Data on HRQoL were available on at least two different time points in
115 of 126 randomized patients. HRQoL improved significantly over time in both
groups, except for the domain of general health in the SF-36. None of the
dimensions showed a significant difference between both groups, neither was
there a significant interaction between time and treatment effect.
CONCLUSION(S): Both methods significantly improved HRQoL in women with
dysfunctional uterine bleeding. However, despite better amenorrhea and
satisfaction rates after bipolar radio frequency ablation, there was no
difference in HRQoL between the two groups. PURPOSE: We defined the role of radio frequency ablation in the treatment of
renal cell carcinoma.
MATERIALS AND METHODS: A total of 16 patients with biopsy proven renal cell
carcinoma were treated with radio frequency ablation in an outpatient setting
and followed for a minimum of 4 years.
RESULTS: Of the 16 patients 5 died before 4 years of followup of unrelated
causes. All except 1 tumor was successfully treated. All patients with exophytic
tumors were successfully treated.
CONCLUSIONS: Radio frequency ablation of exophytic renal cell carcinomas less
than 5 cm in diameter is effective in eradicating the tumor and comparable to
surgical extirpation at 4 years. The enhancement of immune response against tumor antigens has shown some
efficacy when used as a single mode of systemic treatment in patients with late
stage disease. Novel strategies of active immunotherapy could be more effective
in patients with less advanced disease who receive standard therapies supporting
concomitant stimulation of the immune system. Radio-Frequency Ablation (RFA) is
a minimally invasive technique which is used as standard local therapy of
primary and metastatic liver tumors. Tumor ablation by RFA induces effects
important for boosting anti-tumor immune responses. Tumor cell necrosis
generates a permanent immunogenic source of tumor antigens. These antigens can
be uptaken, processed and presented by dendritic cells for effective
immunization without requirement for ex vivo antigen loading. Further immune
activation can be originated by RFA through induction of heat shock proteins on
tumor cells, acute phase response which causes the release of pro-inflammatory
cytokines, and mobilization of antigen presenting cells and effector
lymphocytes. Thus, RFA can facilitate immune responses to tumor antigens driven
by active immunotherapy. On the other hand, immunotherapy is expected to
eradicate residual disease after RFA and prevent tumor recurrences. The
combination of RFA and active immunotherapy may well have synergistic effects
for cancer treatment. PURPOSE: Radio frequency ablation is an emerging nephron sparing treatment
option in select patients with small renal tumors. Some have questioned the
completeness of cell death and the reliability of axial imaging for radio
frequency ablation followup. We present results in patients with no evidence of
radiographic active disease who underwent biopsy more than 1 year following
ablation.
MATERIALS AND METHODS: Patients who had no clinical evidence of disease, defined
as absent lesion growth and contrast enhancement on computerized tomography, 1
year or more following radio frequency ablation underwent percutaneous renal
biopsy to evaluate cell viability in the ablative zone. A total of 19 patients
(20 lesions) were included in the study. Histological comparison of pre-ablation
and post-ablation specimens was performed using hematoxylin and eosin staining.
RESULTS: Pre-ablation biopsies confirmed that 17 of 20 tumors were renal cell
carcinoma, while the remaining 3 were oncocytoma. Following ablation at a mean
followup of 26.9 months (range 13.1 to 58.0) all 20 lesions were stable in size
without evidence of contrast enhancement on computerized tomography. At repeat
biopsy all histology specimens showed unequivocal tumor eradication with no
evidence of cellular viability. Histological changes beyond 1 year demonstrated
coagulative necrosis, hyalinization, inflammatory cell infiltration and residual
ghost cells.
CONCLUSIONS: Pathological examination of radiographically negative lesions
biopsied more than 1 year following radio frequency ablation confirmed no
evidence of disease in all specimens. Therefore, axial imaging can reliably
monitor treatment efficacy in the long term. Chronic changes after radio
frequency ablation demonstrate coagulative necrosis and nonviable cells. This
suggests an evolution of pathological changes that renders early post-ablative
biopsy unreliable. PURPOSE OF REVIEW: Localized renal cell carcinoma has an excellent 5-year
survival when treated surgically. Apart from extirpative treatment, ablative
techniques are becoming more popular to minimize patient morbidity. Clinically,
radio frequency ablation and cryoablation can be performed percutaneously or
laparoscopically. Oncological effectiveness of ablative techniques is
encouraging as 3-year data are emerging. Our review highlights the current
literature demonstrating the effectiveness of cryoablation and radio frequency
ablation performed laparoscopically or percutaneously.
RECENT FINDINGS: Cryoablation performed laparoscopically or percutaneously
offers excellent oncological outcomes with single-session therapy. With 3-year
cancer-specific survival of 98%, laparoscopic cryoablation is safe and can be
performed with minimal insult to overall renal function. Local recurrence rates
and metastatic progression also seem to favor cryoablation over radio frequency
ablation (4.6 vs. 11.7% and 1.2 vs. 2.3%, respectively). Radio frequency
ablation also offers similar survival rates; however, re-treatment rates are
higher (8.8%). Radio frequency ablation also carries a higher rate of collecting
system injuries when performed percutaneously.
SUMMARY: Cryoablation and radio frequency ablation are effective treatment
modalities for small renal masses in the infirm patient. Given patient and
technical variability, superiority of either radio frequency ablation or
cryoablation cannot be confirmed based on available literature. However, there
is a trend towards higher recurrence and re-treatment rates after radio
frequency ablation. BACKGROUND AND PURPOSE: Combining percutaneous plasma-mediated radio-frequency
(pmRF) ablation with vertebral body augmentation offers an alternative treatment
to surgical intervention options for advanced metastatic spinal lesions and is
particularly useful for cases with cortical destruction and/or epidural
extension. This study evaluates bone cement deposition patterns and
extravasation in treated vertebral bodies in relation to the metastatic lesion
after using this combined approach.
MATERIALS AND METHODS: Retrospective assessments of CT images performed
before/after the procedures were evaluated in 37 patients (44 levels) with
advanced metastatic lesions. A void was created in the anterior portion of the
tumor-infiltrated vertebral body by using a bipolar plasma-mediated
radio-frequency-based wand, followed by deposition of bone cement. Pain measured
by visual analog scale score was recorded preprocedure and 2-4 weeks afterward.
RESULTS: In 19 (43%) levels, 90%-100% of the cement was deposited in the
anterior two thirds of the vertebral body. In 34 levels (77%), 75% or more of
the cement was deposited in the anterior two thirds of the vertebral body. In
13/15 (86%) levels with posterior lesions, cement was deposited anterior to the
lesion. No extravasation was observed in 13 levels (29.5%). Two clinically
insignificant incidences of epidural extravasation were noted. Pain relief after
the procedure was reported by 25/28 (89.5%) patients with available data.
CONCLUSIONS: pmRF ablation may allow greater cement-deposition control,
increasing the likelihood of successfully stabilizing the anterior two thirds of
the vertebral body. This combined technique appeared particularly useful in
cases with posteriorly located lesions. The incidence of cement extravasation
was relatively high but clinically insignificant. PURPOSE: Patients with von Hippel-Lindau disease frequently have early, multiple
and recurrent renal cell carcinoma. Renal cell carcinoma treatment, which must
prevent metastatic disease and spare nephrons, has changed in the last 2
decades. We evaluated renal cell carcinoma treatments in the long term in a
large series of patients with von Hippel-Lindau disease.
MATERIALS AND METHODS: We retrospectively evaluated the use and results of
surgery and radio frequency ablation in patients with von Hippel-Lindau followed
at our institution between 1988 and 2009. Renal anatomical survival was analyzed
according to 3 periods, including 1) 1988 to 1994--the learning phase of nephron
sparing surgery, 2) 1995 to 2003--routine nephron sparing surgery and 3) 2004 to
2009--the emergence of radio frequency ablation.
RESULTS: A first renal cell carcinoma was treated at a mean age of 38 years
(range 15 to 67) in 113 patients with von Hippel-Lindau disease. During a median
followup of 7.2 years 251 therapeutic procedures were performed in a total of
176 kidneys. We observed a shift of first line renal cell carcinoma treatment
with time, that is nephrectomy in 52% of cases in period 1, tumorectomy in 75%
in period 2 and radio frequency ablation in 43% in period 3. The shift
paralleled improved renal survival. While nephron sparing surgery was primarily
done for lesions greater than 30 mm, radio frequency ablation was used to treat
less numerous and smaller ipsilateral lesions but they required more frequent
intervention. Radio frequency ablation became the most widely used second or
third line procedure and allowed renal salvage in 8 patients.
CONCLUSIONS: Nephron sparing surgery and more recently radio frequency ablation
enable earlier treatment of smaller tumors and are associated with a significant
improved renal prognosis in patients with von Hippel-Lindau disease. PURPOSE: Renal tumor size influences the efficacy of radio frequency ablation
but identification of confident size cutoffs has been limited by small numbers
and short followup. We evaluated tumor size related outcomes after radio
frequency ablation for patients with adequate (greater than 3 years) followup.
MATERIALS AND METHODS: We identified 159 tumors treated with radio frequency
ablation as primary treatment. Disease-free survival was defined as the time
from definitive treatment to local recurrence, detection of metastasis or the
most recent imaging showing no evidence of disease. Patients were evaluated with
contrast enhancing imaging preoperatively, and at 6 weeks, 6 months and at least
annually thereafter.
RESULTS: Median tumor size was 2.4 cm (range 0.9 to 5.4) with a median followup
of 54 months (range 1.5 to 120). Renal cell carcinoma was confirmed in 72% of
the 150 tumors that had pre-ablation biopsy (94%). The 3 and 5-year disease-free
survival was comparable at 92% and 91% overall, and was dependent on tumor size,
being 96% and 95% for tumors smaller than 3.0 cm and 79% and 79%, respectively,
for tumors 3 cm or larger (p=0.001). Most failures (14 of 18) were local, either
incomplete ablations or local recurrences. This is an intent to treat analysis
and, therefore, includes patients ultimately found to have benign tumors,
although outcomes were comparable in patients with cancer.
CONCLUSIONS: Radio frequency ablation treatment success of the small renal mass
is strongly correlated with tumor size. Radio frequency ablation provides
excellent and durable outcomes, particularly in tumors smaller than 3 cm. Of
tumors 3 cm or larger, approximately 20% will recur such that alternative
treatment techniques should be considered. However, most treatment failures are
local and are often successfully treated with another ablation session. PURPOSE: With the increased incidence of low stage renal cancers, thermal
ablation technology has emerged as a viable treatment option. Current AUA
(American Urological Association) guidelines include thermal ablation as a
treatment modality for select individuals. We compared the laparoscopic and
percutaneous approach for the radio frequency ablation of renal tumors under the
guidance of urological surgeons.
MATERIALS AND METHODS: We reviewed our radio frequency ablation database of
patients with renal masses undergoing laparoscopic or computerized tomography
guided percutaneous radio frequency ablation with simultaneous peripheral
fiberoptic thermometry from November 2001 to January 2011 at a single tertiary
care center. Data were collected on patient demographics, and surgical and
clinicopathological outcomes stratified by approach.
RESULTS: A total of 298 patients with 316 renal tumors underwent laparoscopic
(122 tumors) or computerized tomography guided (194 tumors) radio frequency
ablation. There were no statistically significant differences between the
laparoscopic and computerized tomography guided radio frequency ablation groups
with respect to patient demographics, complication rates and renal functional
outcomes (p>0.05). The 3-year Kaplan-Meier estimation of radiographic
recurrence-free probability was 95% for computerized tomography guided radio
frequency ablation and 94% for laparoscopic radio frequency ablation (p=0.84).
Subanalysis of the 212 (67%) renal cell carcinoma tumors showed a 3-year
Kaplan-Meier estimation of oncologic recurrence-free probability (post-ablation
biopsy proven viable tumor) of 94% for computerized tomography guided radio
frequency ablation and 100% for laparoscopic radio frequency ablation (p=0.16).
Median followup was 21 months for laparoscopic radio frequency ablation) and 19
months for computerized tomography guided radio frequency ablation.
CONCLUSIONS: Laparoscopic and computerized tomography guided radio frequency
ablation appear safe and effective with statistically equivalent rates of
complications and recurrence. PURPOSE: We compared outcomes in patients treated with radio frequency ablation
or partial nephrectomy for clinical cT1b renal cell carcinoma.
MATERIALS AND METHODS: We retrospectively reviewed the records of all patients
who underwent radio frequency ablation or nephrectomy between February 2006 and
December 2010. Radiographic followup with contrast imaging was performed 7 days,
3 and 6 months, and every 6 months thereafter after radio frequency ablation
sequentially. The followup protocol for partial nephrectomy was every 6 months
in the initial 3 years and annually thereafter. The Kaplan-Meier method was used
to generate survival curves, which were compared with the log rank test.
Multivariable regression analysis was done to determine predictors of survival.
RESULTS: A total of 56 patients who met selection criteria were included in
study. Patients in the radio frequency ablation group had relatively higher mean
age and a higher mean ASA® score than those in the partial nephrectomy group.
Mean tumor diameter was significantly larger in the partial nephrectomy cohort.
For radio frequency ablation vs partial nephrectomy 5-year overall, cancer
specific and disease-free survival was 85.5% (95% CI 72.2-98.8) vs 96.6% (95% CI
95.9-97.3), 92.6% (95% CI 82.4-98.1) vs 96.6% (95% CI 95.9-97.3) and 81.0% (95%
CI 66.2-95.8) vs 89.7% (95% CI 78.5-97.9), respectively. The percent decrease in
the glomerular filtration rate was significantly lower in the radio frequency
ablation group at early and last followup.
CONCLUSIONS: In appropriately selected patients with stage cT1b renal cell
carcinoma radio frequency ablation is an effective treatment option that
provides 5-year overall, cancer specific and disease-free survival comparable to
that of partial nephrectomy as well as better renal function preservation than
partial nephrectomy. Recently, Radio Frequency Ablation (RFA) is becoming a popular therapy for
various cancers such as liver, breast, or lung cancer. RFA is one kinds of
thermal therapy. However, it has been often reported about excessive ablation or
non-ablation due to difficult control of ablation energy. In order to solve
these difficulties, we have been proposed robotized RF-ablation system for
precise cancer treatment. We have been tried to control heat energy by control
of electromagnetic-wave frequency. In this paper, we reported about relation
among electrical impedance of lung, lung's internal air volumes, and heat energy
by use of electromagnetic-wave. In case of RFA for lung cancer, heat energy
depends on electrical impedance and lung's internal air volumes. Electrical
impedance has the dependence of electromagnetic-wave frequency and the
dependence of lung's internal air volumes. Therefore, firstly we considered
about fractional calculus model between lung's internal air volumes and
electrical impedance. Secondly, we measured electric impedance frequency
characteristic of lung with change of lung's internal air volumes. The measured
and modeled results showed that use of fractional calculus realized high
accurate model for electrical impedance of lung. And, from the results of
numerical analysis of heat energy, it is supposed that control of
electromagnetic-wave frequency has a small effectiveness for lung tissue
ablation even if lung includes abundant air. Esophageal adenocarcinoma has the fastest growing incidence rate of any cancer
in the United States, and currently carries a very poor prognosis with 5 years
relative survival rates of less than 15%. Current curative treatment options are
limited to esophagectomy, a procedure that suffers from high complication rates
and high mortality rates. Metaplasia of the esophageal epithelium, a condition
known as Barrett's esophagus (BE), is widely accepted as the precursor lesion
for adenocarcinoma of the esophagus. Recently, radio-frequency ablation has been
shown to be an effective method to treat BE, although there is disagreement as
to whether radio-frequency ablation should be used to treat all patients with BE
or whether treatment should be reserved for those at high risk for progressing
to esophageal adenocarcinoma while continuing to endoscopically survey those
with low risk. Recent research has been targeted towards identifying those at
greater risk for progression to esophageal adenocarcinoma so that
radio-frequency ablation therapy can be used in a more targeted manner,
decreasing the total health care cost as well as improving patient outcomes.
This review discusses the current state of the literature regarding risk factors
for progression from BE through dysplasia to esophageal adenocarcinoma, as well
as the current need for an integrated scoring tool or risk stratification system
capable of differentiating those patients at highest risk of progression in
order to target these endoluminal therapies. Minimally-invasive treatments of cardiac arrhythmias such as radio-frequency
ablation are gradually gaining importance in clinical practice but still lack a
noninvasive imaging modality which provides insight into the source or focus of
an arrhythmia. Cardiac deformations imaged at high temporal and spatial
resolution can be used to elucidate the electrical activation sequence in normal
and paced human subjects non-invasively and could potentially aid to better plan
and monitor ablation-based arrhythmia treatments. In this study, a novel
ultrasound-based method is presented that can be used to quantitatively
characterize focal and reentrant arrhythmias. Spatio-temporal maps of the
full-view of the atrial and ventricular mechanics were obtained in a single
heartbeat, revealing with otherwise unobtainable detail the electromechanical
patterns of atrial flutter, fibrillation, and tachycardia in humans. During
focal arrhythmias such as premature ventricular complex and focal atrial
tachycardia, the previously developed electromechanical wave imaging methodology
is hereby shown capable of identifying the location of the focal zone and the
subsequent propagation of cardiac activation. During reentrant arrhythmias such
as atrial flutter and fibrillation, Fourier analysis of the strains revealed
highly correlated mechanical and electrical cycle lengths and propagation
patterns. High frame rate ultrasound imaging of the heart can be used
non-invasively and in real time, to characterize the lesser-known mechanical
aspects of atrial and ventricular arrhythmias, also potentially assisting
treatment planning for intraoperative and longitudinal monitoring of
arrhythmias. PURPOSE: We evaluated the functional outcome, safety and efficacy of zero
ischemia laparoscopic radio frequency ablation assisted tumor enucleation
compared with conventional laparoscopic partial nephrectomy.
MATERIALS AND METHODS: A prospective randomized controlled trial was conducted
from April 2013 to March 2015 in patients with cT1a renal tumor scheduled for
laparoscopic nephron sparing surgery. All patients were followed for at least 12
months. Patients in the laparoscopic radio frequency ablation assisted tumor
enucleation group underwent tumor enucleation after radio frequency ablation
without hilar clamping. The primary outcome was the change in glomerular
filtration rate of the affected kidney by renal scintigraphy at 12 months.
Secondary outcomes included changes in estimated glomerular filtration rate,
estimated blood loss, operative time, hospital stay, postoperative complications
and oncologic outcomes. The Pearson chi-square or Fisher exact, Student t-test
and Wilcoxon rank sum tests were used.
RESULTS: The trial ultimately enrolled 89 patients, of whom 44 were randomized
to the laparoscopic radio frequency ablation assisted tumor enucleation group
and 45 to the laparoscopic partial nephrectomy group. In the laparoscopic
partial nephrectomy group 1 case was converted to radical nephrectomy. Compared
with the laparoscopic partial nephrectomy group, patients in the laparoscopic
radio frequency ablation assisted tumor enucleation group had a smaller decrease
in glomerular filtration rate of the affected kidney at 3 months (10.2% vs
20.5%, p=0.001) and 12 months (7.6% vs 16.2%, p=0.002). Patients in the
laparoscopic radio frequency ablation assisted tumor enucleation group had a
shorter operative time (p=0.002), lower estimated blood loss (p <0.001) and a
shorter hospital stay (p=0.029) but similar postoperative complications
(p=1.000). There were no positive margins or local recurrence in this study.
CONCLUSIONS: Zero ischemia laparoscopic radio frequency ablation assisted tumor
enucleation enables tumor excision with better renal function preservation
compared to conventional laparoscopic partial nephrectomy. Less blood loss and a
shorter operative time were achieved with similar postoperative complication
rates. PURPOSE OF REVIEW: Peripheral nerve pain is common among patients with typical
management including the use of pain medications, neuropathic agents, steroid
injections, and nerve blocks. Additionally, the use of pulsed radiofrequency
(PRF) and radiofrequency ablation (RFA) can be used in the management of chronic
peripheral nerve pain. Previous studies investigating the effectiveness of RFA
and PRF, typically case reports, have demonstrated that peripheral nerve RFA and
PRF have the potential to provide relief of chronic pain for long duration. Our
study aimed at testing efficacy of RFA/PRF for treating peripheral neuralgia.
This was a retrospective review. We identified 16 patients who received 17
RFAs/PRFs. Outcomes of interest collected included pain scores before and after
procedures, percent improvement in pain after each procedure, and duration of
improvement until the time of data collection. In addition, demographic data
including age, sex, and nerves involved were collected.
RECENT FINDINGS: Eleven patients (12 RFAs/PRFs) (80%) reported improvement after
their procedure. Pain scores improved significantly from 6.3 ± 2.3 before each
procedure to 3.6 ± 2.7 after each procedure (p = 0.003). Eleven patients (12
RFAs/PRFs) reported an average improvement of 60.8% ± 35% after their procedure
with an average duration of improvement of 128.8 ± 106.8 days. RFA and PRF can
be used to treat chronic peripheral pain after conservative methods fail to do
so. Large clinical trials are needed to confirm our finding. INTRODUCTION: Radio-frequency ablation (RFA) is a promising minimal-invasive
treatment option for early liver cancer, however monitoring or predicting the
size of the resulting tissue necrosis during the RFA-procedure is a challenging
task, potentially resulting in a significant rate of under- or over treatments.
Currently there is no reliable lesion size prediction method commercially
available.
OBJECTIVES: ClinicIMPPACT is designed as multicenter-, prospective-,
non-randomized clinical trial to evaluate the accuracy and efficiency of
innovative planning and simulation software. 60 patients with early liver cancer
will be included at four European clinical institutions and treated with the
same RFA system. The preinterventional imaging datasets will be used for
computational planning of the RFA treatment. All ablations will be simulated
simultaneously to the actual RFA procedure, using the software environment
developed in this project. The primary outcome measure is the comparison of the
simulated ablation zones with the true lesions shown in follow-up imaging after
one month, to assess accuracy of the lesion prediction.
DISCUSSION: This unique multicenter clinical trial aims at the clinical
integration of a dedicated software solution to accurately predict lesion size
and shape after radiofrequency ablation of liver tumors. Accelerated and
optimized workflow integration, and real-time intraoperative image processing,
as well as inclusion of patient specific information, e.g. organ perfusion and
registration of the real RFA needle position might make the introduced software
a powerful tool for interventional radiologists to optimize patient outcomes. Radiofrequency ablation (RFA) is an important standard therapy for cardiac
arrhythmias, but direct monitoring of tissue treatment is currently lacking. We
demonstrate an RFA catheter integrated with polarization sensitive optical
coherence tomography (PSOCT) for directly monitoring the RFA process in real
time. The integrated RFA/OCT catheter was modified from a standard clinical RFA
catheter and includes a miniature forward-viewing cone-scanning OCT probe. The
PSOCT system was validated with a quarter-wave plate while the RFA function of
the integrated catheter was validated by comparing lesion sizes with those made
with an unmodified RFA catheter. Additionally, the integrated catheter guided
catheter-tissue apposition and monitored RFA lesion formation in cardiac tissue
in real time. The results show that catheter-tissue contact can be characterized
by observing the features of the blood and tissue in the acquired OCT images and
that RFA lesion formation can be confirmed by monitoring the change in phase
retardance in the acquired PSOCT images. This system demonstrates the
feasibility of an integrated RFA/OCT catheter to deliver RF energy and image the
cardiac wall simultaneously and justifies further research into use of this
technology to aid RFA therapy for cardiac arrhythmias. Gastroesophageal Reflux Disease (GERD) is characterized by acid and bile reflux
in the distal oesophagus, and this may cause the development of reflux
esophagitis and Barrett's oesophagus (BE). The natural histological course of
untreated BE is non-dysplastic or benign BE (ND), then lowgrade (LGD) and
High-Grade Dysplastic (HGD) BE, with the expected increase in maligcy
transfer to oesophagal adenocarcinoma (EAC). The gold standard for BE
diagnostics involves high-resolution white-light endoscopy, followed by uniform
endoscopy findings description (Prague classification) with biopsy performance
according to Seattle protocol. The medical treatment of GERD and BE includes the
use of proton pump inhibitors (PPIs) regarding symptoms control. It is
noteworthy that long-term use of PPIs increases gastrin level, which can
contribute to transfer from BE to EAC, as a result of its effects on the
proliferation of BE epithelium. Endoscopy treatment includes a wide range of
resection and ablative techniques, such as radio-frequency ablation (RFA), often
concomitantly used in everyday endoscopy practice (multimodal therapy). RFA
promotes mucosal necrosis of treated oesophagal region via high-frequency
energy. Laparoscopic surgery, partial or total fundoplication, is reserved for
PPIs and endoscopy indolent patients or in those with progressive disease. This
review aims to explain distinct effects of PPIs and RFA modalities, illuminate
certain aspects of molecular mechanisms involved, as well as the effects of
their concomitant use regarding the treatment of BE and prevention of its
transfer to EAC. OBJECTIVES: Uterine fibroids are one of the most common female disorder of the
reproductive age and may cause abnormal uterine bleeding (UAB), pain or
infertility. Our aim was to evaluate the safety and efficacy of percutaneous
radio frequency ablation (RFA) in reducing clinical symptoms, fibroid volume and
improving laboratory parameters.
MATERIAL AND METHODS: Thirty-five symptomatic patients with 54 uterine fibroids
were enrolled. Preintervention evaluation was made for each participant and
included ultrasonography to assess the volume, largest diameter and location of
the fibroid and Visual Analogue Scale (VAS) for quantifying the degree of
menstrual pain. The magnitude of menstrual bleeding was scored for each patient
by using pictogram. Preprocedural laboratory assessment included hemoglobulin
and hematocrit. Treatment efficacy was evaluated at 3, 6 and 12 months after the
intervention with ultrasound (US) measurements, symptom scores and laboratory
parameters.
RESULTS: Pretreatment mean Hb was significantly lower than those at 3, 6 and 12
month post treatment visits (p < 0.001). The pretreatment median volume was
significantly higher than the median volumes measured at 3, 6 and 12 months
after RFA (p < 0.001). Visual Analogue Score (VAS) for pain was significantly
lower than baseline values at 6 and 12 month visits (p < 0.01). Pretreatment
bleeding scores and the number of patients in the predefined severe bleeding
category were significantly decreased.
CONCLUSIONS: US guided RF ablation of uterine fibroids is relatively safe and
effective procedure. It can be applied to the fibroids with varying
localizations and sizes. It reduces the fibroid volume and obviate a need for
more invasive treatment. |
What does "28" stand for in the Disease Activity Score DAS28? | It stands for the Disease Activity Score 28 Joint Index (DAS28). It’s basically a measure of how active a patient is in regards to how active they are in relation to the DAS28. The 28 joint DAS (28 joints) is a way to measure how active the patient is compared to other people with the same disease. | OBJECTIVE: To study the extent to which muscle strength and performance, pain,
and disease activity are associated with the total Health Assessment
Questionnaire (HAQ) disability index and its subdimensions in male and female
patients with rheumatoid arthritis.
METHODS: HAQ for functional capacity was completed by 135 patients with
rheumatoid arthritis referred for orthopaedic surgery (74% women; mean (SD) age
62 (10) years; disease duration 19 (13) years, 70% positive for rheumatoid
factor). Knee extension, trunk extension and flexion, grip strength, walking
speed, and sit-to-stand test were measured to mirror physical function.
Radiographs of hands and feet, pain, and the modified 28 joint disease activity
score (DAS28) were also assessed.
RESULTS: Mean total HAQ was 1.08 (0.68) in women and 0.67 (0.70) in men (p =
0.0031). Women had greater disability than men in five of the eight
subdimensions of the HAQ. Grip strength was 48%, knee extension strength 46%,
trunk extension strength 54%, and trunk flexion strength 43% lower in women than
in men. Knee extension strength was inversely correlated with walking time (r =
-0.63 (95% confidence interval, -0.73 to -0.51)) and with sit-to-stand test (r =
-0.47 (-0.60 to -0.31)). In an ordered logistic regression analysis in female
rheumatoid patients, DAS28, pain, knee extension strength, and grip strength
were associated with the total HAQ disability index.
CONCLUSIONS: Women reported greater disability than men both in the total HAQ
and in the majority of its eight subdimensions. In addition to disease activity
and pain, muscle strength has a major impact on disability especially in female
rheumatoid patients. Although there is strong evidence supporting the short-term efficacy and safety
of anti-tumour necrosis factor-alpha agents, few studies have examined the
long-term effects. We evaluated 511 patients with long-standing refractory
rheumatoid arthritis treated with intravenous infusions of infliximab 3 mg/kg at
weeks 0, 2, 6, and 14 and every 8 weeks thereafter for 4 years. Among the
initial 511 patients included in the study, 479 could be evaluated; of these,
295 (61.6%) were still receiving infliximab treatment at year 4 of follow-up.
The most common reasons for treatment discontinuation were lack of efficacy (65
patients, 13.6%), safety (81 patients, 16.9%), and elective change (38 patients,
7.9%). Analysis of disease activity scores (DAS28 [disease activity score based
on the 28-joint count]) over time showed that, after the initial rapid
improvement during the first 6 to 22 weeks of therapy, a further decrease in
disease activity of 0.2 units in the DAS28 score per year was observed. DAS28
scores, measured at week 14 or 22, were found to predict subsequent
discontinuation due to lack of efficacy. In conclusion, long-term maintece
therapy with infliximab 3 mg/kg is effective in producing further reductions in
disease activity. Disease activity measured by the DAS28 at week 14 or 22 of
infliximab therapy was the best predictor of long-term attrition. OBJECTIVE: To assess the factorial structure of the Disease Activity Score
including a 28-joint count (DAS28) if applied in patients with rheumatoid
arthritis (RA) and psoriatic arthritis (PsA).
METHODS: DAS28 values from 85 consecutive PsA outpatients and 2 RA patient
cohorts comprising 85 patients each were compared. The first RA cohort (RA1)
consisted of age- and sex-matched patients seen during the same period as the
patients with PsA. The first 85 RA outpatients from September 2003 were included
in the second cohort (RA2). Item weighting, factor loading, and internal
consistency were assessed by factor analysis, principal component analysis, and
calculation of Cronbach's alpha.
RESULTS: The mean +/- SD DAS28 scores of patients in the PsA, RA1, and RA2
cohorts were 3.2 +/- 1.31, 3.21 +/- 1.45, and 3.79 +/- 1.44, respectively. A
significant difference between the PsA and RA2 cohorts was found for DAS28 (P =
0.0063), swollen joint count (P = 0.007), and patient's global assessment (P <
0.001), but not for erythrocyte sedimentation rate. Internal consistency of the
DAS28 in patients with PsA was considerably lower, item weighting showed
remarkable differences, and factor analysis revealed that the DAS28 constitutes
a bidimensional instrument in patients with PsA, whereas in both RA cohorts it
appeared to be monodimensional.
CONCLUSION: With respect to its statistical properties, the DAS28 proved to be
considerably different in PsA compared with RA. Therefore its application for
disease activity assessment in patients with PsA cannot be recommended without a
formal validation procedure. OBJECTIVE: To examine the influence of components of the Disease Activity Score
28 (DAS28) [tender joint count (TJC), swollen joint count (SJC), patient's
general health (GH), and erythrocyte sedimentation rate (ESR)] on the total
DAS28 score, and overlapping of the 4 individual components in rheumatoid
arthritis (RA) patients with low, moderate, or high disease activity.
METHODS: The effect of each component was studied in the FIN-RACo trial patients
at 6 months and in a "theoretical model," where each component of the DAS28
ranged as follows: TJC and SJC from 0 to 28, GH from 0 to 100, and ESR from 1 to
100, while the other 3 components were 0 (ESR1). Overlapping of the components
was studied in the FIN-RACo trial patients at 6 months with low (DAS28 < or =
3.2), moderate (DAS28 > 3.2 and < or = 5.1), and high (DAS28 > 5.1) disease
activity. The higher limit for overlapping was defined as the highest SJC in the
low disease activity group, and the lower limit as the lowest SJC in the high
disease activity group; the percentage of patients who fall between these limits
represent overlapping in SJC. Overlapping was calculated similarly concerning
TJC, ESR, and GH.
RESULTS: ESR had the greatest effect on DAS28, followed by TJC, GH, and SJC,
while in the "theoretical model" TJC had the greatest effect on the DAS28,
followed by ESR, SJC, and GH. At 6 months, overlapping was present in 54%, 45%,
49%, and 31% of patients in SJC, TJC, GH, and ESR, respectively.
CONCLUSION: In real-life patients, ESR had the greatest effect of the 4
components of DAS28 on the total DAS28 score. The values of the individual
components of DAS28 overlap considerably among the 3 disease activity groups. INTRODUCTION: The aim of this study was to determine a low disease activity
threshold--a 28-joint disease activity score (DAS28) value--for the decision to
maintain unchanged disease-modifying antirheumatic drug (DMARD) treatment in
rheumatoid arthritis patients, based on expert opinion.
METHODS: Nine hundred and sixty-seven case scenarios with various levels for
each component of the DAS28 (resulting in a disease activity score between 2 and
3.2) were presented to 44 panelists. For each scenario, panelists had to decide
whether or not DMARD treatment (excluding steroids) could be maintained
unchanged. In each scenario, for decision, the participants were given the DAS28
parameters, without knowledge of the resultant DAS28. The relationship between
panelists' decision, DAS28 value, and components of the score were analysed by
multiple logistic regression analysis. Each panelist analysed 160 randomised
scenarios. Intra-rater and inter-rater reproducibility were assessed.
RESULTS: Forty-four panelists participated in the study. Inter-panelist
agreement was good (kappa = 0.63; 95% confidence interval = 0.61 to 0.65).
Intra-panelist agreement was excellent (kappa = 0.87; 95% confidence interval =
0.82 to 0.92). Quasi-perfect agreement was observed for DAS28 < or = 2.4, less
pronounced between 2.5 and 2.9, and almost no agreement for DAS28 > 3.0. For
values below 2.5, panelists agreed to maintain unchanged DMARDs; for values
above 2.5, discrepancies occurred more frequently as the DAS28 value increased.
Multivariate analysis confirmed the relationship between panelist's decision,
DAS28 value and components of the DAS28. Between DAS28 of 2.4 and 3.2, a major
determit for panelists' decision was swollen joint count. Female and public
practice physicians decided more often to maintain treatment unchanged.
CONCLUSIONS: As a conclusion, panelists suggested that in clinical practice
there is no need to change DMARD treatment in rheumatoid arthritis patients with
DAS28 < or = 2.4. INTRODUCTION: This study is based on the results from a Belgian expanded access
program in which patients with active refractory and erosive rheumatoid
arthritis (RA) were treated with intravenous infusions of infliximab in
combination with methotrexate. The objectives of this study were to evaluate the
continuation rate of infliximab and its clinical effect over a 7-year period and
to document the reasons for discontinuation.
METHODS: Between 2000 and 2001, 511 patients with severe and refractory RA were
enrolled and treated with infliximab. After 7 years, apart from routine clinical
follow-up, treating rheumatologists were asked to complete a questionnaire
designed specifically for the present study to evaluate the current therapy with
infliximab, the level of disease activity (Disease Activity Score in 28 joints
[DAS28]) and the reasons for infliximab discontinuation.
RESULTS: After 7 years, 160 of 511 patients (31%) were still on infliximab
treatment. The major reasons for infliximab discontinuation included lack of
efficacy (104 patients), adverse events (107 patients) and elective change of
therapy (70 patients). The majority of cases of treatment discontinuation for
safety reasons occurred during the first 2 years. In contrast, discontinuation
due to ineffectiveness showed a more constant rate over the 7-year period. Mean
DAS for patients still on treatment with infliximab decreased from 5.7 (standard
error [SE] 0.1) at baseline to 3.0 (SE 0.1) at year 4 and remained that low
until year 7 (3.0 [SE 0.1]). Low disease activity (defined as DAS28<3.2) was
present in 60.9% of patients, and 45.5% achieved remission (DAS28<2.6). DAS28 at
the time of treatment discontinuation due to ineffectiveness decreased over the
7-year period from 5.6 (SE 0.3) in 2001 to 4.8 (SE 0.3) in 2008.
CONCLUSIONS: This observational study revealed that patients who continue to
receive infliximab experience sustained clinical benefit. The majority of safety
issues occurred during the first 2 years of infliximab therapy. We observed that
the DAS at the time of therapy discontinuation showed a trend to decrease over
time. OBJECTIVE: The Disease Activity Score in 28 joints (DAS28) is a key measure in
clinical practice and clinical trials. There are at least five different
versions of the 'Patient Global' Visual Analogue Scale (PG-VAS) being used in
the DAS28. The developers suggested that the PG-VAS can be an assessment of
global health or disease activity, but did not specify the wording of the
question. There is no consensus on what the PG-VAS is intended to capture, and
the different words and phrases have not been evaluated. The aim of this study
was to test if phrasing affects PG-VAS scores and hence yields different results
for the DAS28.
METHODS: Fifty patients with rheumatoid arthritis taking biologic agents in a
rheumatology outpatient department completed a self-administered questionnaire
containing five versions of the 100 mm PG-VAS.
RESULTS: All PG-VAS versions correlated strongly with each other
(rho = 0.67-0.87, p < 0.0001). However, individual scores for each PG-VAS, when
compared with the comparator on a Bland-Altman chart had wide limits of
agreement--the largest being -42 mm to +45 mm. The five overall DAS28 scores
were calculated for each patient using the five different PG-VAS. The largest
difference in DAS28 scores was 0.63.
CONCLUSION: Different phrasing of the PG-VAS gives different DAS28 results. As
the DAS28 is a key outcome measure, such differences have the potential to
influence clinical decisions relating to eligibility for biologic agents and
evaluation of new therapies. We urgently need to decide on the concept to be
measured and the phrasing required to capture this. The PG-VAS phrasing should
then be standardized and validated. Collaborators: Gaston H, Mulherin D, Price T, Sheeran T, Chalam V, Baskar S,
Emery P, Morgan A, Buch M, Bingham S, O'Reilly S, Badcock L, Regan M, Ding T,
Deighton C, Summers G, Raj N, Stevens R, Cavell E, Williams N, Isaacs J, Platt
P, Walker D, Kay L, Griffiths B, Ng WF, Peterson P, Lorenzi A, Foster H,
Friswell M, Thompson B, Lee M, Griffiths I, Hassell A, Dawes P, Dowson C, Kamath
S, Packham J, Shadforth M, Brownfield A, Williams R, Mukhtyar C, Harrison B,
Snowden N, Naz S, Ledingham J, Hull R, McCrae F, Thomas A, Min S, Shaban R, Wong
E, Kelly C, Heycock C, Hamilton J, Sarava V, Wilson G, Bax D, Dunkley L, Akil
M, Tattersall R, Kilding R, Till S, Boulton J, Tait T, Bukhari M, Halsey J,
Ottewell L, Buckley C, Situnayake D, Carruthers D, Grindulis K, Khatack F,
Elamanchi S, Raza K, Filer A, Jubb R, Abernathy R, Plant M, Pathare S, Clarke F,
Tuck S, Fordham J, Paul A, Bridges M, Hakim A, Rajagopal V, Bhagat S, Edwards C,
Prouse P, Moitra R, Shawe D, Bamji A, Klimiuk P, Bowden A, Mitchell W, Bruce I,
Barton A, Gorodkin R, Ho P, Hyrich K, Dixon W, Rai A, Kitas G, Erb N, Klocke R,
Douglas K, Pace A, Sandhu R, Whallett A, Birrell F, Allen M, Chaudhuri K,
Chattopadhyay C, McHale J, Jones A, Gupta A, Pande I, Gaywood I, Lanyon P,
Courtney P, Doherty M, Chinoy H, Herrick A, Jones A, Cooper R, Bucknall R,
Marguerie C, Rigby S, Dunn N, Green S, Al-Ansari A, Webber S, Hopkinson N, Dunne
C, Quilty B, Szebenyi B, Green M, Quinn M, Isdale A, Brown A, Saleem B, Samanta
A, Sheldon P, Hassan W, Francis J, Kinder A, Neame R, Moorthy A, Al-Allaf W,
Taggart A, Fairburn K, McKenna F, Green M, Gough A, Lawson C, Piper M,
Korendowych E, Jenkinson T, Sengupta R, Bhalla A, McHugh N, Bond D, Radcliffe J,
Luqmani R, Bowness B, Wordsworth P, David J, Smith W, Mewar D, Tunn E, Nelson K,
Kennedy T, Nixon J, Woolf A, Davis M, Hutchinson D, Endean A, Coady D, Wright D,
Morley C, Raftery G, Bracewell C, Kidd L, Abbas I, Filer C, Kallarackal G. There has been continuous debate regarding the applicability of various
composite measures for the assessment of disease activity in rheumatoid
arthritis (RA). In order to further dissect this issue, we numerically and
graphically modeled 28-joint disease activity scale (DAS28), simplified disease
activity index (SDAI), and clinical disease activity index (CDAI) by
three-dimensional (3D) plotting. We wished to graphically visualize the relative
contribution of various elements in the three activity indices to each other. We
calculated DAS28 (3 variables), SDAI, and CDAI by the standard equations. We
plotted 3D "carpets" showing all combinations of the corresponding variables
yielding to DAS28 = 5.1, DAS28 = 3.2, DAS28 = 2.6, SDAI = 26, SDAI = 11, and
SDAI = 3.3. We also plotted the 3D carpet for CDAI. In patients with high or
moderate disease activity, erythrocyte sedimentation rate (ESR) or C-reactive
protein (CRP) was not a major confounding factor when calculating DAS28 and
SDAI, respectively. In contrast, ESR and CRP highly overshadowed changes in
joint counts and global assessments in patients with low disease activity (LDA)
or those in remission. No reliable assessment of LDA can be performed in cases
where ESR >54 mm/h or CRP >20 mg/dl. Similarly, remission cannot be determined
if ESR >19 mm/h or CRP >5 mg/dl. As CDAI does not include acute phase reactants,
CDAI may be a useful tool even in states of remission or LDA. Our results
suggest that acute phase reactants are indeed major confounding factors and
should be omitted when assessing RA disease activity at least in special cases. BACKGROUND: The 28-joint Disease Activity Score (DAS28) combines scores on a
28-tender and swollen joint count (TJC28 and SJC28), a patient-reported measure
for general health (GH), and an inflammatory marker (either the erythrocyte
sedimentation rate [ESR] or the C-reactive protein [CRP]) into a composite
measure of disease activity in rheumatoid arthritis (RA). This study examined
the reliability of the DAS28 in patients with early RA using principles from
generalizability theory and evaluated whether it could be increased by adjusting
individual DAS28 component weights.
METHODS: Patients were drawn from the DREAM registry and classified into a "fast
response" group (N = 466) and "slow response" group (N = 80), depending on their
pace of reaching remission. Composite reliabilities of the DAS28-ESR and
DAS28-CRP were determined with the individual components' reliability, weights,
variances, error variances, correlations and covariances. Weight optimization
was performed by minimizing the error variance of the index.
RESULTS: Composite reliabilities of 0.85 and 0.86 were found for the DAS28-ESR
and DAS28-CRP, respectively, and were approximately equal across patients
groups. Component reliabilities, however, varied widely both within and between
sub-groups, ranging from 0.614 for GH ("slow response" group) to 0.912 for ESR
("fast response" group). Weight optimization increased composite reliability
even further. In the total and "fast response" groups, this was achieved mostly
by decreasing the weight of the TJC28 and GH. In the "slow response" group,
though, the weights of the TJC28 and SJC28 were increased, while those of the
inflammatory markers and GH were substantially decreased.
CONCLUSIONS: The DAS28-ESR and the DAS28-CRP are reliable instruments for
assessing disease activity in early RA and reliability can be increased even
further by adjusting component weights. Given the low reliability and weightings
of the general health component across subgroups it is recommended to explore
alternative patient-reported outcome measures for inclusion in the DAS28. OBJECTIVE: We retrospectively investigated the inhibitory effect on radiographic
joint damage (RJD) for non-biological disease-modifying antirheumatic drug
(non-bioDMARD) monotherapy or methotrexate (MTX) combination therapy for
rheumatoid arthritis (RA) in the disease activity score with 28 joint counts
with erythrocyte sedimentation rate (DAS28) remission.
METHODS: Eighty-four patients (55 cases of monotherapy, 29 cases of
MTX-combination therapy) in DAS28 remission (DAS28 ≤ 2.6) were investigated from
538 RA patients newly registered between February 2007 and August 2010. The
patients were analyzed for radiological assessments using the modified total
Sharp score/year (mTSS/y).
RESULTS: The remission rates and ΔmTSS/y for each agent using monotherapy were
7.1% and 0.17 for sulfasalazine; 11.9% and 0.49 for bucillamine (BUC); and 23.9%
and 2.06 for MTX. Those using combination therapy were 6.8% and 1.39 for MTX +
BUC; 23.5% and -1.64 for MTX + leflunomide; and 8.0% and 0.31 for MTX +
tacrolimus. The cumulative distribution in the single and combination therapy
groups showed improvement of percentages in structural remission from baseline
to 1-year treatment, 34.1% to 60.9% (P < 0.05) and from 0% to 56.7%(P < 0.0001),
respectively. Baseline mTSS (r = 0.67, P < 0.0001), disease duration (r = 0.40,
P < 0.01), swollen joint counts (r = 0.33, P < 0.05), and anti-cyclic
citrullinated peptide antibody (r = 0.31, P < 0.05) were useful predictors of
RJD for non-bioDMARD monotherapy, but not for combination therapy.
CONCLUSION: Satisfactory inhibition of RJD was observed in the DAS28 remission
cases of monotherapy or MTX combination therapy with a non-bioDMARD. Author information:
(1)Portuguese Society of Rheumatology, Lisbon, Rheumatology Research Unit,
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de
Lisboa, Lisbon, Clínica Universitária de Reumatologia, Centro Hospitalar e
Faculdade de Medicina da Universidade de Coimbra, Rheumatology Department,
Garcia de Orta Hospital, Almada, Rheumatology Department, CHLN-Santa Maria
Hospital, CAML, Lisbon, Rheumatology Department, Centro Hospitalar e
Universitário de Coimbra, Portuguese Institute of Rheumatology, Lisbon,
Rheumatology Department, ULSAM, EPE - Unidade Local de Saúde do Alto Minho,
Ponte de Lima, CEDOC-Faculdade de Ciências Médicas da Universidade Nova de
Lisboa, Rheumatology Department, CHLO-Egas Moniz Hospital, Lisbon, Rheumatology
Department, CHBV-Infante D. Pedro Hospital, Aveiro, Rheumatology Department,
Divino Espírito Santo Hospital, Ponta Delgada, Faculdade de Ciências Médicas da
Universidade Nova de Lisboa, Lisbon, Rheumatology Department, São João
University Hospital, Porto and Clínica Reumatológica Dr Melo Gomes, Lisbon,
Portugal. Portuguese Society of Rheumatology, Lisbon, Rheumatology Research
Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de
Lisboa, Lisbon, Clínica Universitária de Reumatologia, Centro Hospitalar e
Faculdade de Medicina da Universidade de Coimbra, Rheumatology Department,
Garcia de Orta Hospital, Almada, Rheumatology Department, CHLN-Santa Maria
Hospital, CAML, Lisbon, Rheumatology Department, Centro Hospitalar e
Universitário de Coimbra, Portuguese Institute of Rheumatology, Lisbon,
Rheumatology Department, ULSAM, EPE - Unidade Local de Saúde do Alto Minho,
Ponte de Lima, CEDOC-Faculdade de Ciências Médicas da Universidade Nova de
Lisboa, Rheumatology Department, CHLO-Egas Moniz Hospital, Lisbon, Rheumatology
Department, CHBV-Infante D. Pedro Hospital, Aveiro, Rheumatology Department,
Divino Espírito Santo Hospital, Ponta Delgada, Faculdade de Ciências Médicas da
Universidade Nova de
(2)Portuguese Society of Rheumatology, Lisbon, Rheumatology Research Unit,
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de
Lisboa, Lisbon, Clínica Universitária de Reumatologia, Centro Hospitalar e
Faculdade de Medicina da Universidade de Coimbra, Rheumatology Department,
Garcia de Orta Hospital, Almada, Rheumatology Department, CHLN-Santa Maria
Hospital, CAML, Lisbon, Rheumatology Department, Centro Hospitalar e
Universitário de Coimbra, Portuguese Institute of Rheumatology, Lisbon,
Rheumatology Department, ULSAM, EPE - Unidade Local de Saúde do Alto Minho,
Ponte de Lima, CEDOC-Faculdade de Ciências Médicas da Universidade Nova de
Lisboa, Rheumatology Department, CHLO-Egas Moniz Hospital, Lisbon, Rheumatology
Department, CHBV-Infante D. Pedro Hospital, Aveiro, Rheumatology Department,
Divino Espírito Santo Hospital, Ponta Delgada, Faculdade de Ciências Médicas da
Universidade Nova de Lisboa, Lisbon, Rheumatology Department, São João
University Hospital, Porto and Clínica Reumatológica Dr Melo Gomes, Lisbon,
Portugal. INTRODUCTION: Pain remains the most important problem for people with rheumatoid
arthritis (RA). Active inflammatory disease contributes to pain, but pain due to
non-inflammatory mechanisms can confound the assessment of disease activity. We
hypothesize that augmented pain processing, fibromyalgic features, poorer mental
health, and patient-reported 28-joint disease activity score (DAS28) components
are associated in RA.
METHODS: In total, 50 people with stable, long-standing RA recruited from a
rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs)
at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and
mental health status. Multivariable analysis was performed to assess the
association between PPT and DAS28 components, DAS28-P (the proportion of DAS28
derived from the patient-reported components of visual analogue score and tender
joint count), or fibromyalgia status.
RESULTS: More-sensitive PPTs at sites over or distant from joints were each
associated with greater reported pain, higher patient-reported DAS28 components,
and poorer mental health. A high proportion of participants (48%) satisfied
classification criteria for fibromyalgia, and fibromyalgia classification or
characteristics were each associated with more sensitive PPTs, higher
patient-reported DAS28 components, and poorer mental health.
CONCLUSIONS: Widespread sensitivity to pressure-induced pain, a high prevalence
of fibromyalgic features, higher patient-reported DAS28 components, and poorer
mental health are all linked in established RA. The increased sensitivity at
nonjoint sites (sternum and anterior tibia), as well as over joints, indicates
that central mechanisms may contribute to pain sensitivity in RA. The
contribution of patient-reported components to high DAS28 should inform
decisions on disease-modifying or pain-management approaches in the treatment of
RA when inflammation may be well controlled. OBJECTIVE: Ankle joints are frequently neglected in activity scoring systems,
including the Disease Activity Score in 28 joints (DAS28). Only a few studies
have assessed pathologies detected by ultrasonography of the ankles in
symptomatic rheumatoid arthritis (RA) patients. We evaluated ankle joints in RA
patients regardless of symptomatology, using musculoskeletal ultrasound (MSUS)
as well as power Doppler ultrasound (PDUS).
METHODS: A total of 160 ankle joints of 80 RA patients were examined using MSUS
and PDUS, according to the European League Against Rheumatism MSUS guidelines.
Additionally, the talonavicular joints (TNJs) and the medial and the lateral
tendon compartments were examined. The visual analog scale (VAS) score was
recorded for each patient.
RESULTS: A total of 80 RA patients with a median age of 60 years and disease
duration of 5 years were enrolled in our study. The median DAS28 score was 5. A
total of 97 ankles were painful (VAS 1-10), whereas 63 ankles were asymptomatic
(VAS 0). Overall, the predomit pathology was arthritis of the tibiotalar
joint (TTJ) and/or TNJ in 124 ankles (77%), followed by tenosynovitis of the
medial compartment tendons in 44 ankles (28%). Arthritis of the TTJ was present
in 59% and synovitis of the TNJ in 35% of the symptomatic ankles. In
asymptomatic ankles, TTJ synovitis was detected in 35%, whereas TNJ arthritis
was observed in 18%. PDUS activity was higher in the subgroup of symptomatic
ankles.
CONCLUSION: The most frequent pathologies detected by MSUS were arthritis of the
TTJ and TNJ, followed by tenosynovitis of the medial compartment tendons.
Pathologic findings were more frequent in symptomatic but also common in
asymptomatic patients, whereas PDUS activity was generally low and mainly
observed in symptomatic patients. BACKGROUND: Disease Activity Score in 28 Joints (DAS28) is a scoring system to
evaluate disease activity and treatment response in rheumatoid arthritis (RA). A
DAS28 score of greater than 3.2 is a well-described limit for treatment
intensification; however, the reliability of DAS28 might be overestimated.
OBJECTIVE: The aim of this study was to evaluate the reliability of DAS28 in RA,
especially focusing on a subgroup of patients with a DAS28 score of greater than
3.2.
METHODS: Data from RA patients registered in the local part of Danish DANBIO
Registry were collected in May 2015. Patients were categorized into 2 groups:
First, those with DAS28 >3.2 with at least one swollen joint (SJ) or elevated
C-reactive protein (CRP) ("objective group"), and second, patients with a DAS28
>3.2 who had no SJ, and CRP values were within the reference range ("subjective
group"). Disease Activity Score in 28 Joints, Clinical Disease Activity Index,
and Health Assessment Questionnaire scores were calculated for each group. We
defined new score, DAS28 subjective, to focus on subjective parameters.
RESULTS: Two hundred thirty patients were included; 198 (86.1%) and 32 (13.9%)
patients were in the objective and subjective groups, respectively. Patients in
the subjective group had lower mean values of DAS28 (P < 0.001) and Evaluator
Global Assessment (P < 0.001) with less common immunoglobulin M rheumatoid
factor (P < 0.001) and anti-cyclic citrullinated peptide positivity (P = 0.02)
and contrarily higher mean values of tender joints (P = 0.04) and DAS28 based on
subjective parameters (P = 0.003) compared with the objective group.
CONCLUSIONS: Rheumatoid arthritis scoring systems should be used cautiously in
patients who are considered for treatment intensification. Patients with central
sensitization and psychological problems and those with false-positive diagnosis
of RA are at high risk of overtreatment. Author information:
(1)From the Departments of Rheumatology and Clinical Immunology and Oral and
Maxillofacial Surgery, University of Groningen, University Medical Center
Groningen, the Netherlands.
(2)R.V. Moerman, MD, Department of Rheumatology and Clinical Immunology,
University of Groningen, University Medical Center Groningen; S. Arends, PhD,
Department of Rheumatology and Clinical Immunology, University of Groningen,
University Medical Center Groningen; P.M. Meiners, MD, PhD, Department of Oral
and Maxillofacial Surgery, University of Groningen, University Medical Center
Groningen; A. Vissink, MD, PhD, Department of Oral and Maxillofacial Surgery,
University of Groningen, University Medical Center Groningen; F.K. Spijkervet,
MD, PhD, Department of Oral and Maxillofacial Surgery, University of Groningen,
University Medical Center Groningen; F.G. Kroese, PhD, Department of
Rheumatology and Clinical Immunology, University of Groningen, University
Medical Center Groningen; E. Brouwer, MD, PhD, Department of Rheumatology and
Clinical Immunology, University of Groningen, University Medical Center
Groningen; H. Bootsma, MD, PhD, Department of Rheumatology and Clinical
Immunology, University of Groningen, University Medical Center Groningen.
(3)From the Departments of Rheumatology and Clinical Immunology and Oral and
Maxillofacial Surgery, University of Groningen, University Medical Center
Groningen, the Netherlands. [email protected].
(4)R.V. Moerman, MD, Department of Rheumatology and Clinical Immunology,
University of Groningen, University Medical Center Groningen; S. Arends, PhD,
Department of Rheumatology and Clinical Immunology, University of Groningen,
University Medical Center Groningen; P.M. Meiners, MD, PhD, Department of Oral
and Maxillofacial Surgery, University of Groningen, University Medical Center
Groningen; A. Vissink, MD, PhD, Department of Oral and Maxillofacial Surgery,
University of Groningen, University Medical Center Groningen; F.K. Spijkervet,
MD, PhD, Department of Oral and Maxillofacial Surgery, University of Groningen,
University Medical Center Groningen; F.G. Kroese, PhD, Department of
Rheumatology and Clinical Immunology, University of Groningen, University
Medical Center Groningen; E. Brouwer, MD, PhD, Department of Rheumatology and
Clinical Immunology, University of Groningen, University Medical Center
Groningen; H. Bootsma, MD, PhD, Department of Rheumatology and Clinical
Immunology, University of Groningen, University Medical Center Groningen.
[email protected]. BACKGROUND & OBJECTIVES: In patients with rheumatoid arthritis (RA), disease
severity assessment is done using Disease Activity Score in 28 joints with ESR
(DAS28). Computing DAS28 is time-consuming, requires laboratory testing and an
online calculator. There is a need to validate rapid methods of disease severity
assessment for routine daily use. This study was conducted to compare DAS28,
Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire
Disability Index (HAQ-DI) and Routine Assessment of Patient Index Data with 3
measures (RAPID3) to assess the disease activity in patients with RA.
METHODS: We prospectively studied the utility of CDAI, HAQ-DI and RAPID3 scoring
in 100 consecutive newly diagnosed, disease modifying antirheumatic drugs
(DMARDs) naïve adult patients with RA seen during January 2013 and June 2014 at
a tertiary care teaching hospital in south India.
RESULTS: The mean age of the patients was 42.1±11.6 yr, there were 82 females.
The median [interquartile range (IQR)] symptom duration was 6 (range 4-12)
months. The median (IQR) DAS28, CDAI, HAQ-DI and RAPID3 scores at presentation
were 7 (6-7), 36 (28-43), 2 (1-2) and 17 (13-19), respectively. A significant
positive correlation was observed between DAS28 and CDAI (r=0.568; P<0.001);
DAS28 and HAQ-DI (r=0.304; P=0.002) and DAS28 and RAPID3 (r=0.404; P<0.001). A
'slight-to-fair' agreement was observed in between DAS28 and CDAI
(kappa-statistic=0.296). The agreement between DAS28 and HAQ-DI
(kappa-statistic=0.007) and RAPID3 (kappa-statistic=0.072) was less robust.
INTERPRETATION & CONCLUSIONS: In adult patients with RA, in the setting where
illiteracy is high, CDAI emerged as the preferred choice for rapid assessment of
severity of disease at the time of initial presentation. To determine the contribution of fibromyalgia (FM) to the subjective components
of the Disease Activity Score 28-joints (DAS28) in patients with rheumatoid
arthritis (RA), and to analyse the discriminatory performance of the derived
DAS28 patient-reported components (DAS28-P) to identify patients with
fibromyalgic RA. Consecutive RA patients underwent clinical and clinimetric
assessment. The DAS28-P index was derived from the components of the DAS28
scores by rearranging the DAS28-ESR formula. Patients were distinguished by the
presence of FM. Student parametric t tests or Mann-Whitney non-parametric U
tests were used to determine any between-group differences. Receiver operating
characteristic (ROC) curve analysis was used to test the ability of the DAS28-P
index to distinguish patients with RA and those with fibromyalgic RA. The study
involved 292 RA patients (80.5% females, mean age 63 years) with a mean disease
duration of 11.6 ± 8.5 years. Forty-three patients (14.7%) had concomitant FM,
and significantly higher tender joint count (p < 0.001), pain numerical rating
scale, global health status (p = 0.007), and DAS28 scores (p = 0.006) than those
without FM. The DAS28-P values were also significantly higher in the patients
with FM (0.68 ± 0.09 vs 0.58 ± 0.06; p < 0.001). The discriminatory power of the
DAS28-P was very good (area under the ROC of 0.858, optimal cut-off value of
0.631). The presence of FM strongly influences the DAS28 results. The assessment
of patient-reported components to the DAS28 through the DAS28-P can be a useful
way to identify patients with fibromyalgic RA. AIM: To investigate whether remission can be sustained for rheumatoid arthritis
(RA) patients after tapering abatacept (ABT).
METHOD: All patients were naïve to biological disease-modifying anti-rheumatic
drugs (bDMARDs) and in low or moderate Disease Activity Score of 28 joints with
C-reactive protein (DAS)28-CRP). ABT was administrated intravenously (IV) or
subcutaneously (SC) for 36 weeks to patients with RA, who had not previously
received bDMARDs. As the ABT tapering protocol, ABT was administrated SC at
125 mg every 2 weeks for 12 weeks in patients with remission. RA disease
activity was assessed by DAS28-CRP and ultrasonography. Remission was assessed
by defining it as DAS28-CRP <2.3.
RESULTS: Of the 51 patients, 84.3% were women (mean age 68.7 ± 10.2 years, mean
disease duration 7.7 ± 10.2 years). Twenty-nine patients achieved remission and
a power Doppler (PD) score ≤1 at each joint at 36 weeks, followed by tapering
ABT. Of these patients, 25 sustained DAS28-CRP remission, and DAS28-CRP was not
significantly elevated (1.62 ± 0.41 to 1.69 ± 0.49) at 48 weeks, but the total
PD score was significantly elevated (1.52 ± 1.21 to 2.59 ± 2.81 P = 0.049).
Longer disease duration, higher DAS28-CRP at 24 weeks, and higher total PD score
at 24 weeks were predictors of an elevated total PD score after tapering ABT
therapy.
CONCLUSION: These findings suggest that ABT tapering is a promising short-term
strategy to sustain remission in patients with RA, and ultrasonography is a
useful tool for monitoring disease activity after tapering ABT. The Disease Activity Score (DAS) is integral in tailoring the clinical
management of rheumatoid arthritis (RA) patients and is an important measure in
clinical research. Different versions have been developed over the years to
improve reliability and ease of use. Combining the original DAS and the newer
DAS28 data in both contemporary and historical studies is important for both
primary and secondary data analyses. As such, a methodologically robust means of
converting the old DAS to the new DAS28 measure would be invaluable. Using data
from The Early RA Study (ERAS), a sub-sample of patients with both DAS and DAS28
data were used to develop new regression imputation formulas using the total DAS
score (univariate), and using the separate components of the DAS score
(multivariate). DAS were transformed to DAS28 using an existing formula quoted
in the literature, and the newly developed formulas. Bland and Altman plots were
used to compare the transformed DAS with the recorded DAS28 to ascertain levels
of agreement. The current transformation formula tended to overestimate the true
DAS28 score, particularly at the higher end of the scale. A formula which uses
all separate components of the DAS was found to estimate the scores with a
higher level of precision. A new formula is proposed that can be used by other
early RA cohorts to convert the original DAS to DAS28. OBJECTIVES: In patients with rheumatoid arthritis (RA), remission may be
assessed by various composite measures. We assessed achievement of remission as
defined by Boolean criteria, Simplified Disease Activity Index (SDAI), Clinical
Disease Activity Index (CDAI), and 28-joint Disease Activity Score using
C-reactive protein (DAS28[CRP]) and determined the components that limit
patients in SDAI, CDAI, or DAS28(CRP) remission from achieving Boolean
remission.
METHODS: The proportions of patients achieving Boolean, SDAI, CDAI, or
DAS28(CRP) remission were calculated for 3 trials: PREMIER and OPTIMA in
patients with early RA and DE019 in patients with established RA. At the first
visit that remission was recorded during the first 52 weeks of the trial, the
following were assessed: swollen/tender joint count at 28 and 66/68 joints, CRP,
Patient's/Physician's Global Assessment (PGA/PhGA), SDAI, DAS28(CRP), and Health
Assessment Questionnaire-Disability Index.
RESULTS: The majority of patients (61-66%) who achieved SDAI or CDAI remission
also attained Boolean remission. Although DAS28(CRP) remission was most
frequently attained, 74-77% of patients in DAS28(CRP) remission did not achieve
Boolean remission. Compared with patients in Boolean remission, patients in SDAI
or CDAI remission but not Boolean remission had higher PGA scores, while
patients with DAS28(CRP) remission but not Boolean remission had higher joint
counts, and PGA and PhGA scores.
CONCLUSIONS: Differences in PGA limit patients in SDAI/CDAI remission from
meeting the Boolean remission criteria, suggesting that these criteria otherwise
can be used interchangeably. In contrast, patients in DAS28(CRP) remission are
limited by differences in multiple disease activity measures from achieving
Boolean remission. This prospective one-year follow-up study was conducted from 835 visits in 178
rheumatoid arthritis (RA) patients. Tender-/swollen-joint count, Health
Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score
28-ESR (DAS28-ESR), DAS28-CRP, Simplified Disease Activity Index (SDAI) and
DAS28-monocyte chemotactic protein-1 (DAS28-MCP-1) scores were obtained every 3
months. Radiographs of hands and feet were acquired at baseline and one year. We
evaluated the correlation and accuracy of activity scores in predicting
remission, HAQ-DI changes and radiographic changes. DAS28-MCP-1 correlated
strongly with DAS28-ESR, DAS28-CRP and SDAI scores (0.830, 0.899 and 0.931,
respectively, with all P < 0.001). Score changes of DAS28-MCP-1 were comparable
to those of DAS28-ESR, DAS28-CRP and SDAI in predicting changes in HAQ-DI and
bone erosion. DAS28-MCP-1 (<2.2) was better than DAS28-ESR (<2.6) in indicating
modified American Rheumatism Association remission and 2011 American College of
Rheumatology/European League Against Rheumatism remission (75.61% vs. 36.99% and
81.71% vs. 49.13%, respectively) with odds ratios of 5.28 and 4.62 (both
P < 0.001), respectively. We compared DAS28-MCP-1 with SDAI (≦3.3) in indicating
remission with odds ratios of 2.63 (P = 0.002) and 0.98, respectively (and
DAS28-MCP-1 with DAS28-CRP < 2.5: 1.33 and 0.92). Therefore, DAS28-MCP-1 is
useful as an alternative in assessing RA activity. OBJECTIVE: To investigate if autoimmune thyroid disease (AITD) impacts
rheumatoid arthritis (RA) disease activity or response to methotrexate.
METHODS: A nationwide register-based cohort study of 9 004 patients with
new-onset RA from the Swedish Rheumatology Quality Register year 2006-2016, with
linkage to other nationwide registers to identify comorbidity with AITD defined
as thyroxine prescription before RA diagnosis, excluding non-autoimmune causes.
We compared RA disease activity using 28-joint Disease Activity Score (DAS28)
and its components, and EULAR response, between patients with and without AITD,
using logistic regression.
RESULTS: At diagnosis, patient reported outcome measures (PROMs; patient global,
Health Assessment Questionnaire Disability Index and pain) but not objective
disease activity measures (erythrocyte sedimentation rate and swollen joint
count) were significantly higher (p<0.05 for all PROMs) among RA patients with
AITD compared with those without. The level of DAS28 was 5.2 vs 5.1. By
contrast, AITD had little influence on EULAR response to methotrexate at 3
months (OR of non/moderate response=0.95, 95% CI 0.8 to 1.1), nor at 6 months.
When stratified by age, however, AITD was more common among EULAR non/moderate
responders at 3 and 6 months in patients below 45 years resulting in ORs of
non/moderate response of 1.44 (0.76-2.76) and 2.75 (1.04-7.28).
CONCLUSION: At diagnosis, RA patients with concomitant AITD score worse on
patient reported but not on objective RA disease activity measures, while DAS28
was only marginally elevated. The overall chance of achieving a EULAR good
response at 3 or 6 months remains unaffected, although among a limited subgroup
of younger patients, AITD may be a predictor for an inferior primary response. |
What is EPICCURE? | EPICCURE is an ongoing randomized, double-blind, placebo-controlled study of the safety of AZD8601 in patients with moderately decreased left ventricular function (ejection fraction 30%-50%) undergoing elective coronary artery bypass surgery. EPICCURE combines high-efficiency delivery with quantitative targeting and follow-up for robust assessment of the safety and exploratory efficacy of VEGF-A mRNA angiogenesis (ClinicalTrials.gov: NCT03370887). | |
List updates for JASPAR 2020 | JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. | |
Was golimumab tested for diabetes? | Yes, among children and young adults with newly diagnosed overt type 1 diabetes, golimumab resulted in better endogenous insulin production and less exogenous insulin use than placebo. | BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by
progressive loss of pancreatic beta cells. Golimumab is a human monoclonal
antibody specific for tumor necrosis factor α that has already been approved for
the treatment of several autoimmune conditions in adults and children. Whether
golimumab could preserve beta-cell function in youth with newly diagnosed overt
(stage 3) type 1 diabetes is unknown.
METHODS: In this phase 2, multicenter, placebo-controlled, double-blind,
parallel-group trial, we randomly assigned, in a 2:1 ratio, children and young
adults (age range, 6 to 21 years) with newly diagnosed overt type 1 diabetes to
receive subcutaneous golimumab or placebo for 52 weeks. The primary end point
was endogenous insulin production, as assessed according to the area under the
concentration-time curve for C-peptide level in response to a 4-hour mixed-meal
tolerance test (4-hour C-peptide AUC) at week 52. Secondary and additional end
points included insulin use, the glycated hemoglobin level, the number of
hypoglycemic events, the ratio of fasting proinsulin to C-peptide over time, and
response profile.
RESULTS: A total of 84 participants underwent randomization - 56 were assigned
to the golimumab group and 28 to the placebo group. The mean (±SD) 4-hour
C-peptide AUC at week 52 differed significantly between the golimumab group and
the placebo group (0.64±0.42 pmol per milliliter vs. 0.43±0.39 pmol per
milliliter, P<0.001). A treat-to-target approach led to good glycemic control in
both groups, and there was no significant difference between the groups in
glycated hemoglobin level. Insulin use was lower with golimumab than with
placebo. A partial-remission response (defined as an insulin dose-adjusted
glycated hemoglobin level score [calculated as the glycated hemoglobin level
plus 4 times the insulin dose] of ≤9) was observed in 43% of participants in the
golimumab group and in 7% of those in the placebo group (difference, 36
percentage points; 95% CI, 22 to 55). The mean number of hypoglycemic events did
not differ between the trial groups. Hypoglycemic events that were recorded as
adverse events at the discretion of investigators were reported in 13
participants (23%) in the golimumab group and in 2 (7%) of those in the placebo
group. Antibodies to golimumab were detected in 30 participants who received the
drug; 29 had antibody titers lower than 1:1000, of whom 12 had positive results
for neutralizing antibodies.
CONCLUSIONS: Among children and young adults with newly diagnosed overt type 1
diabetes, golimumab resulted in better endogenous insulin production and less
exogenous insulin use than placebo. (Funded by Janssen Research and Development;
T1GER ClinicalTrials.gov number, NCT02846545.). |
Is G3BP1 found in stress granules? | Yes,
RAS GTPase-activating protein-binding protein (G3BP1) is an RNA-binding protein that is essential for assembling stress granules. | |
What is Progeria? | Hutchinson-Gilford progeria syndrome is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. | Progeria is a rare genetic disease with striking features that resemble
accelerated aging. The inheritance pattern, paternal age effect, and lack of
consanguinity argue that it is due to a sporadic domit mutation. We have
observed elevated levels of hyaluronic acid (HA) excretion in progeria patients.
In several progeria patients we observed normal levels of growth hormone (GH)
but very low levels of insulin-like growth factor I along with very high basal
metabolic rates (BMRs). A trial of GH treatment was begun, which resulted in a
marked increase in linear growth and a paradoxical drop in BMRs in these two
patients. We hypothesize that the failure of patients with progeria to thrive
may be due to a bioinactive form of GH and a lack of vasculogenesis caused by
excess HA. An understanding of the progeria genetic mutation may define a key
gene with a major effect on normal aging. Werner's syndrome (adult progeria) is a rare autosomal recessive condition
characterized mainly by a characteristic habitus (short stature, light body
weight) scleroderma like changes of the limbs and premature aging. Chronic leg
ulcers appears in about fifty per cent of the patients. These ulcers can be
related to the combination of mechanical factors on atrophic subcutaneous tissue
and skin of the feet and leg associated with early arteriosclerosis (20%) and
diabetes mellitus (60%). The basic genetic defect in the Hutchinson-Gilford Progeria Syndrome (progeria),
a premature aging syndrome, is unknown. To investigate possible defects in
hyaluronic acid (HA) metabolism in this disease, the urinary excretion of HA was
studied. Urine specimens from 11 patients with this disorder were examined for
HA by a novel high performance liquid chromatography (HPLC) technique. In
patients with progeria, HA excretion ranged from 169 micrograms HA/g creatinine
to 1440 micrograms HA/g creatinine. In normal age-matched controls, HA excreted
ranged from 0 to 77 micrograms HA/g creatinine. In all, a mean 17-fold increase
in HA excretion was observed in patients with progeria when compared with
age-matched normal controls. Total glycosaminoglycan (GAG) excretion was not
elevated. Amongst normal controls, a modest age-related increase in HA excretion
was observed. These results suggest that urinary HA levels are abnormally
elevated in progeria. The glycosylation of proteins in fibroblasts from people with the premature
ageing disease Hutchinson-Gilford Progeria Syndrome (progeria) was investigated.
Protein was prepared from fibroblast cell lines established from skin biopsy
taken from progeria patients and control donors. Glycoproteins were labelled by
the covalent attachment of the steroid hapten digoxygenin to the sugar group.
After separation of total protein by SDS-PAGE and electroblotting onto
Immobilon-PTM, glycoproteins were detected by enzyme immunoassay. We have
observed a glycoprotein of M(r) 200 kDa which is consistently present in protein
preparations from progeria fibroblasts and which is absent, or markedly reduced,
in preparations from control fibroblasts. This suggests that it may be useful as
a marker for progeria. Similar analysis of progeria lymphoblast and control
lymphoblast cultures did not show this altered pattern of glycosylated proteins,
indicating that it may be cell-type specific. Glycoproteins were also detected
by labelling fibroblasts in vitro with D-[6-3H]glucosamine hydrochloride
followed by SDS-PAGE of isolated protein and subsequent fluorography. Profiles
of glycoproteins from progeria and control fibroblasts were consistent with
those obtained from labelling of carbohydrate groups with digoxygenin. Protease
digestion of cell protein verified that the band at M(r) 200 kDa contains a
protein core. Characteristic features of progeria primarily involve the
connective tissue and include wrinkled and loose skin, loss of soft tissue, thin
limbs and stiff joints. Death of progeria patients is usually a result of
cardiovascular abnormalities. The most consistent manifestations thus involve
the connective tissue. The glycoprotein of M(r) 200 kDa which we have observed
in progeria fibroblasts in vitro could reflect a perturbation in glycosylation
which may underly the connective tissue defects seen in progeria. Progeria is a rare syndrome, with an estimated incidence of 1 per 250,000
births. Although children with progeria have the appearance of premature aging
or senility, the term is misleading because reported cases of progeria have not
manifested most physical or biochemical aspects of old age. Many children with
progeria appear normal at birth and then progressively, and rather rapidly,
develop the characteristic features during early childhood. Although first
described in the 1880s, only approximately 100 cases of progeria are reported in
the international literature. The single case study of hearing in progeria,
which appeared in 1965, is limited to pure-tone and speech audiometry findings.
We report the results of otolaryngologic examination and pure-tone, speech,
immittance, and auditory brainstem response (ABR) audiometry for a 5-year-old
female with progeria. The patient had a mild-to-moderate, bilateral, conductive
hearing loss. Immittance measurements were consistent with fixation of the
ossicular chain and this was confirmed surgically. Mildly prolonged ABR wave I-V
latencies suggest possible auditory central nervous system involvement. Proteomics has revealed differential protein expression and glycosylation in
membrane proteins from premature aging Hutchinson-Gilford progeria syndrome
fibroblasts (progeria). Progeria is a rare autosomal domit genetic disorder
of premature aging characterized by marked growth retardation and specific,
progressive, premature senescent changes of the skin and other tissues. Affected
children live to an average age of 13 years. The 1q20-24 region of chromosome 1
which codes for one of these proteins, lamin A/C, has previously been implicated
by Brown et al. (1990) who described identical twins with progeria, where
cytogenetic analysis showed an inverted insertion in the long arm of the
chromosome in 70% of cells. Luengo et al. (2002) similarly reported an
interstitial deletion of chromosome 1q23, in a 9-year-old patient with a classic
clinical picture of progeria. Progeria is a rare, genetically determined condition characterized by
accelerated aging in children. Its name is derived from Greek (Geron) and means
"prematurely old". The classic type is the Hutchinson-Gilford Progeria Syndrome
(HGPS), which was first described in England in 1886 by Dr. Jonathan Hutchinson
(1) and again in 1904 by Dr. Hastings Gilford (2). Since then and up to now,
very little advancement toward the understanding of this devastating disorder
has been accomplished. In early 2003 a French group succeeded in identifying
point mutations in the LMNA gene, encoding A-type lamins, as the main cause of
this disorder. These results were concomitantly confirmed by an American group,
who identified mutations in LMNA, working on a large cohort of patients (3,4).
HGPS is thus the most severe disorder added to the expanding list of
"laminopathies", diseases caused by mutations in the LMNA gene encoding A-type
lamins. To date, up to ten disorders are associated with mutations in LMNA.
These disorders are diverse, both in their symptomatology and pattern of
inheritance (see below and table 1). Due to the extremely low prevalence of
progeria and the putative functional links between progeria and other premature
aging disorders, setting-up a network about these disorders has become an
absolute necessity. A reunion of families with a child affected with progeria,
gathered within the European Progeria Family Circle, was held from September
25th to 29th 2003 in Magdeburg, Germany. In parallel to this event, a scientific
symposium centered on clinical and molecular update of HGPS and related
syndromes was organised. Several international experts, including clinical and
molecular geneticists, cell biologists involved in the field of laminopathies,
as well as paediatricians and other physicians with clinical experience in
diagnosis, treatment and research on progeria and progeria-like syndromes
presented their experience as well as their research projects and yet
unpublished results. The main discussed topics as well as the developing
research fields on progeria and related premature ageing disorders will be
presented here. Hutchinson-Gilford progeria syndrome (HGPS), a rare disease that results in what
appears to be premature aging, is caused by the production of a mutant form of
prelamin A known as progerin. Progerin retains a farnesyl lipid anchor at its
carboxyl terminus, a modification that is thought to be important in disease
pathogenesis. Inhibition of protein farnesylation improves the hallmark nuclear
shape abnormalities in HGPS cells and ameliorates disease phenotypes in mice
harboring a knockin HGPS mutation (LmnaHG/+). The amelioration of disease,
however, is incomplete, leading us to hypothesize that nonfarnesylated progerin
also might be capable of eliciting disease. To test this hypothesis, we created
knockin mice expressing nonfarnesylated progerin (LmHG/+). LmHG/+ mice
developed the same disease phenotypes observed in LmnaHG/+ mice, although the
phenotypes were milder, and mouse embryonic fibroblasts (MEFs) derived from
these mice contained fewer misshapen nuclei. The steady-state levels of progerin
in LmHG/+ MEFs and tissues were lower, suggesting a possible explanation for
the milder phenotypes. These data support the concept that inhibition of protein
farnesylation in progeria could be therapeutically useful but also suggest that
this approach may be limited, as progerin elicits disease phenotypes whether or
not it is farnesylated. Progeria is a rare and peculiar combination of dwarfism and premature aging. The
incidence is one in several million births. It occurs sporadically and is
probably an autosomal recessive syndrome. Though the clinical presentation is
usually typical, conventional radiological and biochemical investigations help
in confirming the diagnosis. We present a rare case of progeria with most of the
radiological features as a pictorial essay. Progeria, or Hutchinson-Gilford syndrome, is a rare genetic disease,
characterized by several clinical features that develop in childhood, in
particular, an accelerated aging aspect. Its incidence is 1-4 per 8 million
newborns. Children with progeria syndrome usually appear normal at birth and in
early infancy. Profound failure to thrive occurs during the 1st year.
Characteristic facies, partial alopecia progressing to total alopecia, loss of
subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of
the skin over the abdomen and upper thighs usually become apparent during the
2nd to 3rd years. Motor and mental development is normal. Patients develop
severe atherosclerosis. Death occurs as a result of complications of cardiac or
cerebrovascular disease (heart attack or stroke) generally between ages 6 and 20
years. The diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) is based on
recognition of common clinical features and the detection of the recurrent
p.Gly608Gly mutation in exon 11 of the LMNA gene, which is present in almost all
individuals with HGPS. We present here 3 patients aged 5, 11, and 12 years
referred to genetic consultation for dysmorphic facies and failure to thrive.
After careful clinical examination and paraclinical assessment, the diagnosis of
progeria syndrome was raised. We performed molecular analysis for the 3 patients
by searching for the recurrent mutation c.1824C>T (p.Gly608Gly) of the LMNA
gene, which was found only in 1 patient. We discuss the geneticist's role in the
diagnosis of rare dysmorphic syndromes and their genetic counseling. We also
analyze the clinical spectrum of HGPS by comparing the 3 patients. BACKGROUND: Progeria is a rare segmental premature aging disease with
significant skeletal abnormalities. Defining the full scope of radiologic
abnormalities requires examination of a large proportion of the world's progeria
population (estimated at 1 in 4 million). There has been no comprehensive
prospective study describing the skeletal abnormalities associated with
progeria.
OBJECTIVE: To define characteristic radiographic features of this syndrome.
MATERIALS AND METHODS: Thirty-nine children with classic progeria, ages 2-17
years, from 29 countries were studied at a single site. Comprehensive
radiographic imaging studies were performed.
RESULTS: Sample included 23 girls and 16 boys-the largest number of patients
with progeria evaluated prospectively to date. Eight new and two little known
progeria-associated radiologic findings were identified (frequencies of 3-36%).
Additionally, 23 commonly reported findings were evaluated. Of these, 2 were not
encountered and 21 were present and ranked according to their frequency. Nine
abnormalities were associated with increasing patient age (P = 0.02-0.0001).
CONCLUSION: This study considerably expands the radiographic morphological
spectrum of progeria. A better understanding of the radiologic abnormalities
associated with progeria and improved understanding of the biology of progerin
(the molecule responsible for this disease), will improve our ability to treat
the spectrum of bony abnormalities. Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused
by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C.
In HGPS and related progerias, processing of prelamin A is blocked at a critical
step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be
grouped into two classes: (1) the processing-deficient, early onset "typical"
progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria
syndromes (APS) that are later in onset. Here we describe a previously
unrecognized progeria syndrome with prominent cutaneous and cardiovascular
manifestations belonging to the second class. We suggest the name
LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder.
Affected patients are normal at birth but undergo progressive cutaneous changes
in childhood and die in middle age of cardiovascular complications, including
accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In
addition, the proband demonstrated cancer susceptibility, a phenotype rarely
described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS
in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter
the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the
proband, the processing and levels of lamin A and C are normal. However, nuclear
morphology is aberrant and rescued by treatment with farnesyltransferase
inhibitors, as is also the case for HGPS and other laminopathies. Our findings
advance knowledge of human LMNA progeria syndromes, and raise the possibility
that typical and atypical progerias may converge upon a common mechanism to
cause premature aging disease. BACKGROUND: Progeria is a rare fatal genetic condition characterized by an
appearance of accelerated aging in children. It has an incidence of 1 in 8
million and results from a mutation of the LMNA gene causing nuclear
instability. Clinical diagnosis is based on recognition of common clinical
features and definitive diagnosis is by identifying the mutation in the LMNA
gene. Affected children usually have a median life span of 13 years. There is no
known cure but research is ongoing. Currently about 80 children have had a
definitive diagnosis worldwide with the exclusion of Nigeria. There was however
a case report of 3 siblings in the University of Benin Teaching Hospital, Benin
City, Nigeria in 1990.
OBJECTIVE: To present a rare case of suspected progeria in Nigeria.
CASE REPORT: We report the case of baby IV, a 4-year old girl who presented with
clinical and radiologic features consistent with progeria.
CONCLUSION: Clinical and radiologic evidence give a high suspicion of progeria
in the index patient. Efforts are ongoing to ensure a definitive diagnosis is
made; which will be the first diagnosed case of progeria in Nigeria. The Hutchinson-Gilford syndrome or progeria is a rare autosomal domit
syndrome characterized by premature aging and involvement of internal systems,
such as the circulatory and locomotor. The diagnosis is essentially clinical and
the manifestations become more evident from the first year of life. Long term
outcome data from Progeria Research Foundation clinical trials have demonstrated
an increase in survival in recent years. Even though new trials are ongoing, the
recognition of this syndrome is essential to prevent cardiovascular and
cerebrovascular complications. A patient, initially asymptomatic, who developed
characteristic signs of the syndrome at the age of 6 months is reported. She was
referred for evaluation only when she was two years and eleven months old. The
diagnosis of Hutchinson-Gilford syndrome was suspected owing to clinical
characteristics. The diagnosis was confirmed by genetic testing. A mutation
c.1824C> T in exon 11 of the LMNA gene was detected. She was registered in the
Progeria Research Foundation and was invited to participate in the weighing and
supplementation program. She was included in the lonafarnib protocol study. This
medication is a farnesyl transferase inhibitor that prevents the production of
progerina and slows cardiovascular and neurological complications of the
syndrome. This case highlights the importance of diagnosing progeria patients
because they may be referred to the Progeria Research Foundation, which offers
genetic screening and inclusion in clinical and therapeutic follow-up protocols
without any costs. Progeria trials and research may also contribute to new drug
developments related to prevention of aging and atherosclerosis in the near
future. Werner syndrome (i.e., adult progeria) is a rare autosomal recessive disorder
caused by mutations of the WRN gene, which is characterized by the premature
appearance of features associated with normal aging and cancer predisposition.
Patients with Werner syndrome can present with musculoskeletal complaints,
associated with suggestive radiographic features with a potential prognostic or
therapeutic impact. This review illustrates the main radiographic features of
Werner syndrome, focusing on the musculoskeletal system, such as soft-tissue
calcification, muscular atrophy, osteoporosis, foot deformities, osteitis and
osteomyelitis, and bone or soft-tissues maligcies. The identification of
these features by radiologists can therefore be useful in the clinical screening
of Werner syndrome. Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare
premature aging disorder affecting children, with a disease incidence of ∼1 in
18 million individuals. HGPS is usually caused by a de novo point mutation in
exon 11 of the LMNA gene (c.1824C>T, p.G608G), resulting in the increased usage
of a cryptic splice site and production of a truncated unprocessed lamin A
protein named progerin. Since the genetic cause for HGPS was published in 2003,
numerous potential treatment options have rapidly emerged. Strategies to
interfere with the post-translational processing of lamin A, to enhance progerin
clearance, or directly target the HGPS mutation to reduce the progerin-producing
alternative splicing of the LMNA gene have been developed. Here, we give an
up-to-date resume of the contributions made by our and other research groups to
the growing list of different candidate treatment strategies that have been
tested, both in vitro, in vivo in mouse models for HGPS and in clinical trials
in HGPS patients. Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating premature aging
disease. Mouse models have been instrumental for understanding HGPS mechanisms
and for testing therapies, which to date have had only marginal benefits in mice
and patients. Barriers to developing effective therapies include the unknown
etiology of progeria mice early death, seemingly unrelated to the reported
atherosclerosis contributing to HGPS patient mortality, and mice not
recapitulating the severity of human disease. Here, we show that progeria mice
die from starvation and cachexia. Switching progeria mice approaching death from
regular diet to high-fat diet (HFD) rescues early lethality and ameliorates
morbidity. Critically, feeding the mice only HFD delays aging and nearly doubles
lifespan, which is the greatest lifespan extension recorded in progeria mice.
The extended lifespan allows for progeria mice to develop degenerative aging
pathologies of a severity that emulates the human disease. We propose that
starvation and cachexia greatly influence progeria phenotypes and that
nutritional/nutraceutical strategies might help modulate disease progression.
Importantly, progeria mice on HFD provide a more clinically relevant animal
model to study mechanisms of HGPS pathology and to test therapies. Hutchinson-Gilford progeria syndrome is a rare genetic disorder, characterized
by progressive premature aging and early death in the first or second decade of
life, usually secondary to cardiovascular events (myocardial infarction and
stroke). We report a case of a 14-year-old boy with progeria syndrome and
cardiac arrest due to myocardial infarction, who was submitted to an immediate
coronary angiography which revealed left main stem and three-vessel coronary
artery disease. A prompt double bypass coronary artery grafting surgery was
performed, and, despite successful coronary reperfusion, the patient remained in
coma and brain death was declared on fourth day after surgery. Hutchinson-Gilford Progeria Syndrome (HGPS) is a segmental premature aging
disease causing patient death by early teenage years from cardiovascular
dysfunction. Although HGPS does not totally recapitulate normal aging, it does
harbor many similarities to the normal aging process, with patients also
developing cardiovascular disease, alopecia, bone and joint abnormalities, and
adipose changes. It is unsurprising, then, that as physicians and scientists
have searched for treatments for HGPS, they have targeted many pathways known to
be involved in normal aging, including inflammation, DNA damage, epigenetic
changes, and stem cell exhaustion. Although less studied at a mechanistic level,
severe metabolic problems are observed in HGPS patients. Interestingly, new
research in animal models of HGPS has demonstrated impressive lifespan
improvements secondary to metabolic interventions. As such, further
understanding metabolism, its contribution to HGPS, and its therapeutic
potential has far-reaching ramifications for this disease still lacking a robust
treatment strategy. INTRODUCTION: Progeria also known as Hutchinson Gilford Progeria Syndrome (HGPS)
(MIM176670) is a very uncommon fatal genetic untimely aging syndrome. It is
characterized by retarded physical development, accelerated degeneration of the
skin, cardiovascular and musculoskeletal abnormalities. Other features include
prominent eyes, thin nose, small chin and thin lips. Eyebrow hair loss,
madarosis and lagopththalmos are the common ocular manifestations.
CASE: We report a case of five year old boy with complaints of discomfort in
bright light and a whitish appearance in his right eye for two months. He was
accompanied by the parents. They complained of loss of eyelashes and eyebrows.
In the developmental history he was normal at birth till the age of one year
then they noticed gradual hair fall, delayed growth, wrinkling of skin, increase
in size of head and thinning of limbs.
CONCLUSION: This is the first case report from Nepal with the ocular
presentation of progeria indicating the role of ocular senescence in patients
with Hutchinson Progeria Gilford Syndrome. Werner syndrome, also called adult progeria, is a heritable autosomal recessive
human disorder characterized by the premature onset of numerous age-related
diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM),
osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental
progeroid syndrome whose presentation resembles accelerated aging. The most
common causes of death for WS patients are atherosclerosis and cancer. A
40-year-old female presented with short stature, bird-like facies, canities with
alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The
patient reported a history of delayed puberty, abortion, hypertriglyceridemia,
and juvenile cataracts. A clinical diagnosis of WS was made and subsequently
confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was
the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9,
which caused a premature termination codon (PTC) at position 369. Variant 2 was
a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC
at position 383 and has no published reports describing. Patients with WS can
show a wide variety of clinical and biological manifestations in
endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia).
Doctors must be cognizant of early manifestations of WS and treatment options. |
Describe CrossICC | CrossICC is an R package designed for the unsupervised clustering of gene expression data from multiple datasets/platforms without the requirement of batch effect adjustment. CrossICC utilizes an iterative strategy to derive the optimal gene signature and cluster numbers from a consensus similarity matrix generated by consensus clustering. | Unsupervised clustering of high-throughput gene expression data is widely
adopted for cancer subtyping. However, cancer subtypes derived from a single
dataset are usually not applicable across multiple datasets from different
platforms. Merging different datasets is necessary to determine accurate and
applicable cancer subtypes but is still embarrassing due to the batch effect.
CrossICC is an R package designed for the unsupervised clustering of gene
expression data from multiple datasets/platforms without the requirement of
batch effect adjustment. CrossICC utilizes an iterative strategy to derive the
optimal gene signature and cluster numbers from a consensus similarity matrix
generated by consensus clustering. This package also provides abundant functions
to visualize the identified subtypes and evaluate subtyping performance. We
expected that CrossICC could be used to discover the robust cancer subtypes with
significant translational implications in personalized care for cancer patients.
AVAILABILITY AND IMPLEMENTATION: The package is implemented in R and available
at GitHub (https://github.com/bioinformatist/CrossICC) and Bioconductor
(http://bioconductor.org/packages/release/bioc/html/CrossICC.html) under the GPL
v3 License. |
Which receptor is blocked by Finerenone? | Finerenone is a nonsteroidal mineralocorticoid receptor antagonist. | INTRODUCTION: The mineralocorticoid receptor antagonists (MRAs) spironolactone
and eplerenone reduce the risk of hospitalizations and mortality in patients
with heart failure (HF) with reduced ejection fraction (HFrEF), and attenuate
progression of diabetic kidney disease. However, their use is limited by the
fear of inducing hyperkalemia, especially in patients with renal dysfunction.
Finerenone is a novel nonsteroidal MRA, with higher selectivity toward the
mineralocorticoid receptor (MR) compared to spironolactone and stronger
MR-binding affinity than eplerenone.
AREAS COVERED: This paper discusses the chemistry, pharmacokinetics, clinical
efficacy and safety of finerenone.
EXPERT OPINION: The selectivity and greater binding affinity of finerenone to
the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby
overcome the reluctance to start and uptitrate MRAs in patients with HF and
diabetic kidney disease. Studies conducted in patients with HFrEF and moderate
chronic kidney disease and diabetic kidney disease, showed promising results.
Phase III trials will have to show whether finerenone might become the
third-generation MRA for the treatment of HF and diabetic kidney disease. Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect
against organ damage caused by elevated aldosterone levels in patients
experiencing heart failure (HF), chronic kidney disease (CKD), primary
aldosteronism, and hypertension. While traditional steroid-based MR antagonists
effectively reduce mortality rates and extend patient survival, their broad
application has been limited by significant side effects, most notably
hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a
next-generation non-steroidal dihydropyridine-based MR antagonist designed to
minimize off-target effects while maintaining potent efficacy. In this review,
the outcomes of finerenone therapy in several diseases associated with MR
activity are explored. The (pre-) clinical efficacy of finerenone is compared
with that of traditional steroid-based MR antagonists. Finally, recent and
ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic
nephropathy are discussed. Taken together, pre-clinical and clinical evidence
suggests that finerenone may achieve equivalent organ-protective effects with
reduced levels of electrolyte disturbance compared with traditional
steroid-based MR antagonists. This supports further clinical development of
finerenone for the treatment of cardiovascular and renal disease. Mineralocorticoid receptor (MR) antagonists slow down the progression of heart
failure after myocardial infarction (MI), but the cell-specific role of MR in
these benefits is unclear. In this study, the role of MR expressed in vascular
smooth muscle cells (VSMCs) was investigated. Two months after coronary artery
ligation causing MI, mice with VSMC-specific MR deletion (MI-MR(SMKO)) and mice
treated with the MR antagonist finerenone (MI-fine) had improved left
ventricular compliance and elastance when compared with infarcted control mice
(MI-CTL), as well as reduced interstitial fibrosis. Importantly, the coronary
reserve assessed by magnetic resoce imaging was preserved (difference in
myocardial perfusion before and after induction of vasodilatation, mL mg(-1)
min(-1): MI-CTL: 1.1 ± 0.5, nonsignificant; MI-MR(SMKO): 4.6 ± 1.6 [P<0.05];
MI-fine: 3.6 ± 0.7 [P<0.01]). The endothelial function, tested on isolated
septal coronary arteries by analyzing the acetylcholine-induced nitric
oxide-dependent relaxation, was also improved by MR deletion in VSMCs or by
finerenone treatment (relaxation %: MI-CTL: 36 ± 5, MI-MR(SMKO): 54 ± 3, and
MI-fine: 76 ± 4; P<0.05). Such impairment of the coronary endothelial function
on MI involved an oxidative stress that was reduced when MR was deleted in VSMCs
or by finerenone treatment. Moreover, short-term incubation of coronary arteries
isolated from noninfarcted animals with low-dose angiotensin-II (10(-9) mol/L)
induced oxidative stress and impaired acetylcholine-induced relaxation in CTL
but neither in MR(SMKO) nor in mice pretreated with finerenone. In conclusion,
deletion of MR in VSMCs improved left ventricular dysfunction after MI, likely
through maintece of the coronary reserve and improvement of coronary
endothelial function. MR blockage by finerenone had similar effects. Finerenone (BAY 94-8862) is a nonsteroidal mineralocorticoid receptor antagonist
in development for the treatment of diabetic kidney disease. This observational
trial compared the pharmacokinetics of a single oral dose of finerenone 10 mg
(immediate-release tablet) in adults with mild (creatinine clearance [CLCR ]
50-80 mL/min; n = 8), moderate (CLCR 30 to < 50 mL/min; n = 8), or severe (CLCR
< 30 mL/min; n = 9) renal impairment with those in adults with normal renal
function (CLCR > 80 mL/min; n = 8) over 96 hours postdose. Exposure to
finerenone was not affected by mild renal impairment. In participants with
moderate or severe renal impairment, exposure to finerenone was increased
compared with those with normal renal function (increase in area under the curve
for unbound finerenone, 57.1% [outlier excluded] and 46.5%, respectively), with
moderate to high interindividual variability. Renal impairment had no consistent
effect on the maximum plasma concentration, Cmax (differences in Cmax for
unbound finerenone of +12% and -7% with moderate [outlier excluded] and severe
impairment vs normal renal function, respectively). Renal elimination of
finerenone is minimal. However, changes in exposure may occur because of the
effects of renal impairment on nonrenal routes of elimination. Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent
complication in hospitalized patients. Mineralocorticoid receptor antagonism has
shown to be helpful against renal IR consequences; however, the potential
benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as
finerenone has to be further explored. In this study, we evaluated the efficacy
of finerenone to prevent the acute and chronic consequences of ischemic acute
kidney injury. For the acute study (24 hours), 18 rats were divided into sham,
bilateral renal ischemia of 25 minutes, and rats that received 3 doses of
finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4
months), 23 rats were divided into sham, rats that underwent 45 minutes of
bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour
before IR. We found that after 24 hours of reperfusion, the untreated IR rats
presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and
neutrophil gelatinase associated to lipolacin mRNA levels were increased. In
contrast, the rats treated with finerenone displayed normal kidney function and
significantly lesser tubular injury and kidney injury molecule-1 and neutrophil
gelatinase associated to lipolacin levels. After 4 months, the IR rats developed
chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria
and renal vascular resistance, tubular dilation, extensive tubule-interstitial
fibrosis, and an increase in kidney transforming growth factor-β and collagen-I
mRNA. The transition from acute kidney injury to chronic kidney disease was
fully prevented by finerenone. Altogether, our data show that in the rat,
finerenone is able to prevent acute kidney injury induced by IR and the chronic
and progressive deterioration of kidney function and structure. Finerenone is a novel selective nonsteroidal mineralocorticoid receptor
antagonist. Results in preclinical studies showed that lower doses of finerenone
were needed to achieve similar cardiorenal protective effects compared to both
spironolactone and eplerenone and phase II studies in finerenone in patients
with heart failure, type-2 diabetes mellitus and/or chronic kidney disease are
encouraging as the drug is effective and safe in patients on renin-angiotensin
system inhibitors (significant reduction in albuminuria and a low rate of
hyperkalemia), but the primary end points were "soft" end points (serum
potassium, estimated glomerular filtration rate, albuminuria, N-terminal
prohormone B-type natriuretic peptide levels). Thus, further, large-scale,
long-term phase III trials are needed to confirm whether the greater affinity
and selectivity is translated into improved clinical outcomes. BACKGROUND: The novel nonsteroidal mineralocorticoid receptor (MR) antagonist
finerenone holds promise to be safe and efficient in the treatment of patients
with heart failure and/or chronic kidney disease. However, its effects on
vascular function remain elusive.
PURPOSE: The aim of this study was to determine the functional effect of
selective MR antagonism by finerenone in vascular cells in vitro and the effect
on vascular remodeling following acute vascular injury in vivo.
METHODS AND RESULTS: In vitro, finerenone dose-dependently reduced
aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by
BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC)
apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay.
In vivo, oral application of finerenone resulted in an accelerated
re-endothelialization 3 days following electric injury of the murine carotid
artery. Furthermore, finerenone treatment inhibited intimal and medial cell
proliferation following wire-induced injury of the murine femoral artery 10 days
following injury and attenuated neointimal lesion formation 21 days following
injury.
CONCLUSION: Finerenone significantly reduces apoptosis of ECs and simultaneously
attenuates SMC proliferation, resulting in accelerated endothelial healing and
reduced neointima formation of the injured vessels. Thus, finerenone appears to
provide favorable vascular effects through restoring vascular integrity and
preventing adverse vascular remodeling. Mineralocorticoid receptor antagonists (MRAs) reduce morbidity and mortality in
chronic heart failure. Novel nonsteroidal MRAs are currently developed and need
to be pharmacologically characterized in comparison to classical steroidal MRAs.
A mouse model of cardiac fibrosis induced by short-term isoproterenol injection
was used to compare the nonsteroidal MRA finerenone and the steroidal MRA
eplerenone in equi-efficient systemic MR blocking dosages. Molecular mechanisms
were studied in MR-expressing H9C2/MR+ cardiomyocytes and in MR transcriptional
cofactor binding assays. Both MRAs significantly inhibited an
isoproterenol-mediated increase of left ventricular mass. Isoproterenol-induced
cardiac fibrosis and macrophage invasion were potently blocked by finerenone,
whereas eplerenone had no significant effect. Speckle tracking echocardiography
revealed a significant improvement of global longitudinal peak strain by
finerenone, an effect less prominent with eplerenone. Antifibrotic actions of
finerenone were accompanied by a significant inhibition of profibrotic cardiac
TNX (tenascin-X) expression, a regulation absent with eplerenone. Finally, we
show a higher potency/efficacy and inverse agonism of finerenone versus
eplerenone in MR transcriptional cofactor binding assays indicating differential
MR cofactor modulation by steroidal and nonsteroidal MRAs. This study
demonstrates that the nonsteroidal MRA finerenone potently prevents cardiac
fibrosis and improves strain parameters in mice. Cardiac antifibrotic actions of
finerenone may result from the inhibition of profibrotic TNX gene expression
mediated by differential MR cofactor binding. Selective MR cofactor modulation
provides a molecular basis for distinct (pre)-clinical actions of nonsteroidal
and steroidal MRAs. BACKGROUND: The non-steroidal mineralocorticoid receptor antagonist finerenone
(BAY 94-8862) has been used to treat chronic heart failure (CHF) with reduced
ejection fraction (HFrEF). However, conflicting results were reported for its
efficacy and safety. The study aimed to compare the efficacy and safety of
finerenone versus spironolactone or eplerenone in patients with chronic heart
failure.
METHODS: Electronic databases including MEDLINE, EMBASE, and CENTRAL were
searched from inception to December 2017 for randomized controlled trials
assessing finerenone treatment in patients with chronic heart failure. Data
concerning the study's design, patients' characteristics, and outcomes were
extracted. Risk ratio (RR) and mean differences (MD) were calculated using
either fixed or random effects models.
RESULTS: Three trials with 1520 CHF patients were included in the systematic
review. In terms of anti-ventricular remodeling, we calculated the effective
number of cases with a 30% reduction in NT-proBNP. Finerenone was equivalent to
the existing steroidal mineralocorticoid antagonist (P < .05). However, the
efficacy of finerenone appeared to be dose-dependent. At a dose of 10 mg/d
finerenone was found to be marginally better than that of steroidal
mineralocorticoid receptor antagonists (MRAs) (RR = 1.18, 95% confidence
interval [CI] 0.88, 1.57, P > .05). The incidence of treatment-related adverse
events (TEAEs) of finerenone at 10 mg/d was significantly lower than 25 to
50 mg/d of steroidal MRAs (RR = 0.81, 95% CI = 0.66-0.99, P = .04). Moreover,
the serum potassium levels in the finerenone 10 mg/d group were lower than those
in the 25 to 50 mg/d steroidal MRAs group (MD = -0.14, 95% CI -0.30-0.02,
P = .09), whereas the estimated glomerular filtration rate (eGFR) was higher in
finerenone versus steroidal MRAs treated patients (MD = 2.07, 95% CI -0.04-4.17,
P = .05).
CONCLUSIONS: Finerenone reduced NT-proBNP level, urinary albumin/creatinine
ratio (UACR), and other biochemical indicators, in a dose-dependent manner. In
terms of anti-ventricular remodeling in patient with chronic heart failure,
finerenone at 10 mg/d is as effective as 20 to 50 mg/d of steroidal MRAs.
However, finerenone is much safer to patients with chronic kidney disease. BACKGROUND AND OBJECTIVES: Finerenone is a selective, non-steroidal
mineralocorticoid receptor antagonist. In vivo and in vitro studies were
performed to assess absolute bioavailability of finerenone, the effect of
metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its
metabolites, the quantitative contribution of the involved enzymes cytochrome
P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism.
METHODS: The pharmacokinetics, safety and tolerability of finerenone (1.25-10 mg
orally or 0.25-1.0 mg intravenously) were evaluated in healthy male volunteers
in four crossover studies. Absolute bioavailability was assessed in volunteers
receiving finerenone orally and by intravenous infusion (n = 15) and the effects
of erythromycin (n = 15), verapamil (n = 13) and gemfibrozil (n = 16) on
finerenone pharmacokinetics were investigated. Finerenone was also incubated
with cryopreserved human hepatocytes in vitro in the presence of erythromycin,
verapamil or gemfibrozil.
RESULTS: Finerenone absolute bioavailability was 43.5% due to first-pass
metabolism in the gut wall and liver. The geometric mean AUC0-∞ ratios of
finerenone (drug + inhibitor/drug alone) were 3.48, 2.70 and 1.10 with
erythromycin, verapamil and gemfibrozil, respectively. The contribution ratio of
CYP3A4 to the metabolic clearance of finerenone derived from these values was
0.88-0.89 and was consistent with estimations based on in vitro data, with the
remaining metabolic clearance due to CYP2C8 involvement.
CONCLUSION: Finerenone is predomitly metabolized by CYP3A4 in the gut wall
and liver. Increases in systemic exposure upon concomitant administration of
inhibitors of this isoenzyme are predictable and consistent with in vitro data.
Inhibition of CYP2C8, the second involved metabolic enzyme, has no relevant
effect on finerenone in vivo. Mass balance and biotransformation of finerenone, a nonsteroidal
mineralocorticoid receptor antagonist, were investigated in four healthy male
volunteers following a single oral administration of 10 mg (78 μCi) of
[14C]finerenone and compared with data from studies in dogs and rats. The total
recovery of the administered radioactivity was 101% in humans, 94.7% in dogs,
and 95.2% in rats. In humans, radioactivity was mainly excreted renally (80%);
in rats, it was primarily the biliary/fecal route (76%); and in dogs, excretion
was more balanced. Finerenone was extensively metabolized in all species by
oxidative biotransformation, with minor amounts of unchanged drug in excreta
(humans: 1%; dogs, rats: <9%). In vitro studies suggested cytochrome P450 3A4
was the predomit enzyme involved in finerenone metabolism in humans. Primary
metabolic transformation involved aromatization of the dihydronaphthyridine
moiety of metabolite M1 as a major clearance pathway with a second oxidative
pathway leading to M4. These were both prone to further oxidative
biotransformation reactions. Naphthyridine metabolites (M1-M3) were the domit
metabolites identified in human plasma, with no on-target pharmacological
activity. In dog plasma, finerenone and metabolite M2 constituted the major
components; finerenone accounted almost exclusively for drug-related material in
rat plasma. For metabolites M1-M3, axial chirality was observed, represented by
two atropisomers (e.g., M1a and M1b). Analysis of plasma and excreta showed one
atropisomer (a-series, >79%) of each metabolite predominated in all three
species. In summary, the present study demonstrates that finerenone is cleared
by oxidative biotransformation, mainly via naphthyridine derivatives. Albuminuria is an early marker of renovascular damage associated to an increase
in oxidative stress. The Munich Wistar Frömter (MWF) rat is a model of chronic
kidney disease (CKD), which exhibits endothelial dysfunction associated to low
nitric oxide availability. We hypothesize that the new highly selective,
non-steroidal mineralocorticoid receptor (MR) antagonist, finerenone, reverses
both endothelial dysfunction and microalbuminuria. Twelve-week-old MWF (MWF-C;
MWF-FIN) and aged-matched normoalbuminuric Wistar (W-C; W-FIN) rats were treated
with finerenone (FIN, 10 mg/kg/day p.o.) or vehicle (C) for 4-week. Systolic
blood pressure (SBP) and albuminuria were determined the last day of treatment.
Finerenone lowered albuminuria by >40% and significantly reduced SBP in MWF.
Aortic rings of MWF-C showed higher contractions to either noradrenaline (NA) or
angiotensin II (Ang II), and lower relaxation to acetylcholine (Ach) than W-C
rings. These alterations were reversed by finerenone to W-C control levels due
to an upregulation in phosphorylated Akt and eNOS, and an increase in NO
availability. Apocynin and 3-amino-1,2,4-triazole significantly reduced
contractions to NA or Ang II in MWF-C, but not in MWF-FIN rings. Accordingly, a
significant increase of Mn-superoxide dismutase (SOD) and Cu/Zn-SOD protein
levels were observed in rings of MWF-FIN, without differences in p22phox,
p47phox or catalase levels. Total SOD activity was increased in kidneys from
MWF-FIN rats. In conclusion, finerenone improves endothelial dysfunction through
an enhancement in NO bioavailability and a decrease in superoxide anion levels
due to an upregulation in SOD activity. This is associated with an increase in
renal SOD activity and a reduction of albuminuria. BACKGROUND AND OBJECTIVES: Finerenone (BAY 94-8862) is a selective, nonsteroidal
mineralocorticoid receptor antagonist. The aim of this study was to assess the
effect of mild or moderate hepatic impairment on the pharmacokinetics, safety
and tolerability of finerenone.
METHODS: The study was conducted in a single-center, nonrandomized,
noncontrolled, nonblinded observational design with group stratification. A
single oral 5-mg dose of finerenone was administered as a tablet to participants
with mild or moderate hepatic impairment (Child-Pugh A, score 5-6 [n = 9], or
Child-Pugh B, score 7-9 [n = 9], respectively) and to age-, weight- and
sex-matched healthy participants (n = 9). The pharmacokinetics of finerenone and
its metabolites were assessed in plasma and urine, and safety and tolerability
were monitored.
RESULTS: Finerenone area under the plasma concentration-time curve (AUC) and
unbound AUC were 38% and 55% greater, respectively, in participants with
moderate hepatic impairment than in healthy participants, whereas maximum plasma
concentration (Cmax) was unchanged. No clear effects on AUC or Cmax were seen in
participants with mild hepatic impairment. Finerenone was safe and well
tolerated in all participants.
CONCLUSION: The effects of mild or moderate hepatic impairment on systemic
exposure of finerenone are small, consistent with its low hepatic extraction and
preponderance of gastrointestinal over hepatic first-pass clearance. Considering
the small increases in AUC and the absence of changes in Cmax, a dose adaptation
does not appear to be warranted in patients with mild or moderate hepatic
impairment. Mineralocorticoid receptor (MR) overactivation promotes cardiac fibrosis. We
studied the ability of the non-steroidal MR antagonist finerenone to prevent
fibrotic remodeling. In neonatal rat cardiac fibroblasts, finerenone prevented
aldosterone-induced nuclear MR translocation. Treatment with finerenone
decreased the expression of connective tissue growth factor (CTGF) (74 ± 15% of
control, p = 0.005) and prevented aldosterone-induced upregulation of CTGF and
lysyl oxidase (LOX) completely. Finerenone attenuated the upregulation of
transforming growth factor ß (TGF-ß), which was induced by the Rac1 GTPase
activator l-buthionine sulfoximine. Transgenic mice with cardiac-specific
overexpression of Rac1 (RacET) showed increased left ventricular (LV)
end-diastolic (63.7 ± 8.0 vs. 93.8 ± 25.6 µl, p = 0.027) and end-systolic
(28.0 ± 4.0 vs. 49.5 ± 16.7 µl, p = 0.014) volumes compared to wild-type FVBN
control mice. Treatment of RacET mice with 100 ppm finerenone over 5 months
prevented LV dilatation. Systolic and diastolic LV function did not differ
between the three groups. RacET mice exhibited overactivation of MR and 11ß
hydroxysteroid dehydrogenase type 2. Both effects were reduced by finerenone
(reduction about 36%, p = 0.030, and 40%, p = 0.032, respectively). RacET mice
demonstrated overexpression of TGF-ß, CTGF, LOX, osteopontin as well as collagen
and myocardial fibrosis in the left ventricle. In contrast, expression of these
parameters did not differ between finerenone-treated RacET and control mice.
Finerenone prevented left atrial dilatation (6.4 ± 1.5 vs. 4.7 ± 1.4 mg,
p = 0.004) and left atrial fibrosis (17.8 ± 3.1 vs. 12.8 ± 3.1%, p = 0.046)
compared to vehicle-treated RacET mice. In summary, finerenone prevented from
MR-mediated structural remodeling in cardiac fibroblasts and in RacET mice.
These data demonstrate anti-fibrotic myocardial effects of finerenone. Collaborators: Besada D, Wassermann A, Bittar J, Elbert A, Vallejos A, Viñes G,
Sanabria H, Pérez Manghi F, Liberman A, Bartolacci I, Aizenberg D, Chahin M,
Maffei L, Gelersztein E, Ludvik B, Schmidt A, Hanusch U, Wiesholzer M, Neudorfer
P, Prischl F, Paulweber B, Mayer G, Schönherr HR, Drexel H, Preiß W, Ebenbichler
C, Prager R, Sourij H, Lhotta K, Krebs M, Schernthaner GH, Clodi M,
Fliesser-Görzer E, Stingl H, Ekinci E, MacIsaac R, Packham D, Stephenson H,
Suranyi M, Wittert G, Acharya S, Lee D, Pape A, Topliss D, Colman P, Nelson C,
Regal P, Colquhoun D, Davis T, Roger S, Mah PM, Abhayaratna W, VAN Gaal L,
Gillard P, Hougardy JM, Speeckaert M, Stas K, Engelen W, Maes B, Krzesinski JM,
Vanbelleghem H, Doubel P, Vasileva S, Rashkov R, Nonchev B,
Temelkova-Kurktschieva T, Apostolova E, Yoncheva-Mihaylova M, Rangelov R,
Klyuchkova N, Stanchev P, Tagarev Z, Boshnyashka R, Manova P, Prakova Z, Lucheva
M, Gushterova V, Farah G, Georgiev D, Pichmanova M, Dimitrova E, Minkova D,
Stoyanovska-Elencheva B, Ganeva-Todorova S, Bacheva T, Canziani ME, Hissa M,
Noronha I, Salles JE, Gomes M, Antunes D, Eliaschewitz F, Figueiredo CE, de
Paula R, Cai L, Leite M Jr, Paolino B, Rea R, Vencio S, Brito C, Paschoalin
R, Pecoits Filho R, Vasconcellos E, Paschoalin N, Forti A, Botelho R, Carmo L,
Tzanno C, Riella M, Lisboa H, Geloneze B, Precoma D, Cerqueira M, Lima E, Franco
R, Portes E, Sgarbi J, Pereira M, Jolly S, Liutkus J, O Keefe D, Tytus R,
Carlson B, Conway J, Walsh M, Wilderman I, Steele A, Tobe S, Vitou L, Tenkore
K, Martinho V, McFarlane P, Shu D, Cournoyer S, Dumas R, Mazza G, Tellier G,
Tsoukas G, Weisnagel S, Yale JF, Fikry S, Hart R, Hamet P, Madore F, Barre P,
Schwartz D, Kelly A, Teitelbaum I, Peterson S, Pesant Y, Henein S, Goluch R,
Burnier M, Ackermann D, Bilz S, Martin PY, Venzin R, Donath M, Forster C,
Kalbermatter S, Kistler A, Schultes B, Pechère-Bertschi A, Downey P, Tijerino M,
Varleta P, Godoy J, Lobos S, González F, Hidd E, Vega M, Muñoz R, Pedemonte O,
Romero C, Saavedra V, Fiedler U, Prieto JC, Reyes E, Palma JC, Cobos J, Pincetti
C, Raffo Grado C, Liu Z, Zhu D, Liu F, Wang L, Li Y, Su Q, Shi B, Yin A, Wang H,
Li Y, Niu J, Wu C, Wang X, Zhang Y, Peng A, Chen N, Ma J, Li Y, Zheng H, Lei M,
Mo Z, Tong N, Cheng J, Dong Y, Xu X, Chen Q, Guan T, Long G, Jiang Z, Xing C, Li
L, Liu Y, Zhang H, Zhong L, Li Z, Zeng L, Wei J, Cai H, Wu T, Lu W, Xu N, Lu Y,
Chen D, Bu R, Yang H, Shen J, Dong J, Luo Y, Zhao Z, Xiong F, Li M, Jiang F, Li
X, Yang J, Huang W, Luo P, Zhuang Y, Kuang J, Liang X, Lu G, Wang L, Wang Y, Yan
T, Zhang Y, Tang S, Liang B, Chen X, Wang G, Liu J, Zhu J, Fang Y, Du Y, Sun Z,
Liu Y, Zhao W, Zhong L, Li D, Li H, Zhang P, Hao C, Shen F, Li Q, Wang J, Li J,
Wang G, Malaver N, Cadena A, Yupanqui H, Hernández E, López M, Sánchez G, Vargas
R, Arcos E, Urina M, Kattah W, Durán C, Luján D, Arango C, Espinoza D, Coronel
J, Blanco G, Terront M, Guzmán G, García L, Lenis C, Jaramillo C, Liévano M,
Molina D, Benitez D, Cárdenas T, Villegas I, Cure C, Ibarra J, Manzur F, Barrera
S, González A, Jaramillo N, Beltran J, Unspecified U, Beltrán López N, Trujillo
F, Morales F, Prazny M, Hasalova Zapletalova J, Okenka L, Alferi D, Karen I,
Edelsberger T, Tomanek P, Brezina J, Hola O, Houdova J, Bucek P, Karasek D,
Kopecka S, Kovar R, Brada M, Hornova L, Krcova E, Lubanda H, Kutejova V, Kuchar
J, Hrmova H, Pumprla J, Mokrejsova M, Gulakova D, Matyasek I, Krüger T, Haller
H, Koch T, Rose L, Tschöpe D, Stemler L, Schettler V, Pfützner A, Derwahl K,
Merker L, Horacek T, Sigal H, Täschner H, Schiefke I, Hagenow A, Birkenfeld A,
Axthelm C, Pröpper F, Wanner C, Busch K, Schlichthaar H, Hasslacher C,
Degenhardt S, Mühlfeld A, van der Giet M, Strack G, Schöll N, Winkelmann BR,
Rump L, Nischik R, Schröppel B, Giebel T, Ulmer A, Bergmann A, Contzen C,
Jungmair W, Toursarkissian N, Kloos C, Müller J, Schürholz T, Schenkenberger I,
Braun H, Maxeiner S, Pistrosch F, Mondorf U, Klausmann G, Poulsen P, Bech J,
Rasmussen O, Rossing P, Faber J, Krarup T, Lindhardt M, Juhl C, Nielsen J,
Pedersen-Bjergaard UP, Schousboe K, Hangaard J, Madsbad S, Gislason G, Jaroslaw
Pacyk G, González Albarrán O, Segura de la Morena JJ, Cigarrán Guldris S,
Martínez Deben F, Pascual Izuel JM, Pascual Santos J, Calero F, Sánchez Juan C,
Soto A, Polaina Rusillo M, Ampudia FJ, Galcerán J, Mediavilla J, Martínez
Esteban MD, Michán A, de Álvaro F, Unspecified U, Cruzado Garrit J, Castro C,
Unspecified U, Santamaría Olmo R, Poch E, Martins J, Hernández Jaras J, Ibernón
M, Agraz I, Bouarich H, Troya M, Strand J, Kantola I, Nieminen S, Koistinen A,
Kaen K, Sulosaari S, Honkasalo M, Removed For Gdpr RFG, Korsoff P, Honkasalo
M, Kuitunen T, Nieminen T, Sadeharju K, Humaloja K, Lahtela J, Zaoui P, Fauvel
JP, Marre M, Penfornis A, Gouet D, Serusclat P, Clavel S, Verges B, Hourmant M,
Guerci B, Combe C, Mariat C, Moranne O, Monier A, Klein A, Vendrely B, DE Geeter
G, Hadjadj S, Chantrel F, LE Meur Y, Mesbah R, Cariou B, Guerrot D, Gallouj K,
Leduc JJ, McCafferty K, Vijayaraman A, Kon SP, AbouSaleh A, Wong YK, Zaidi R,
Rice S, Kahal H, Gibson M, Dang C, Hanna F, Mathew A, Arif I, Balasubramaniam G,
Patel D, Barratt J, Kirk A, Kilvert A, Wahba M, Unspecified U, Unspecified U,
Unspecified U, Unspecified U, Unspecified U, Stefanidis I, Passadakis P,
Papagianni A, Hatziagelaki E, Papadopoulou D, Boletis I, Makriniotou I, Kounadi
T, Ioannidis I, Lee P, Luk OYA, Yeung V, Siu SC, Wang A, Ip TP, Noori E, Fulop
T, Kiss J, Harcsa E, Szocs A, Vasas S, Wudi K, Kirschner R, Bajcsi D, Lamboy B,
Literati-Nagy B, Nyirati G, Petro G, Schneider K, Keltai K, Kalina A, Szelestei
T, Danos P, Kazup S, Zilahi Z, Bajnok L, Simon J, Kovacs L, Zsom M, Mileder M,
Nagy L, Yagil Y, Wainstein J, Wainstein J, Mosenzon O, Abramof Ness R, Ben
Chetrit S, Adawi F, Liberty I, Grossman E, Elias M, Armaly Z, Farber E, Nimer A,
Khazim K, Chernin G, Efrati S, Schwartz D, Berar Yanay N, Glandt M, Zukermann R,
Halabi M, Atar S, Darawsha M, Perico N, La Manna G, Battaglia GG, Santoro D,
Montanaro D, Piatti P, Bonora E, Maggi DC, Calabrò P, Cimino R, Cozzolino MG,
Trevisan R, Avogaro A, Fiorina P, Pisani A, Pani A, Santorelli G, Bossi CA,
Tonolo G, Fiaccadori E, Veronelli AM, Unspecified U, Ponzani P, Sciangula L,
Genovese S, Gregorini MC, Cavalot FL, Giorda CB, Giorda CB, Shibasaki T, Suzuki
H, Matsuda H, Nomiyama T, Matsubayashi S, Shinoda J, Matsumoto K, Kanehara H,
Hirohata Y, Yamada M, Nakazawa J, Yamasaki Y, Nakayama M, Furuya R, Ebisui O,
Kawasaki S, Yamada D, Noritake M, Ishiko T, Sasaki N, Suzuki D, Tanaka A, Kubota
M, Araki H, Ohashi H, Osonoi T, Yamagata K, Fujita N, Kanda D, Tanaka S, Koide
J, Ishii M, Ogiwara T, Suzuki M, Sekigami T, Higashi T, Yambe Y, Kusano Y,
Kikuchi H, Miyaoka H, Kato K, Kashima M, Yamakawa F, Horinouchi S, Yanagida T,
Sobajima H, Kanai H, Yamano G, Matsuoka N, Shibata H, Takeda A, Sugiura T,
Sugiyama T, Yanai H, Hamamoto Y, Hatazaki M, Hayashi T, Kobayashi K, Murao S,
Ujihara M, Sugitatsu K, Kawamitsu K, Yamakawa K, Watanabe N, Fujisawa K, Hata Y,
Tsunematsu I, Kikuchi F, Jinnouchi H, Imura M, Yasuda T, Nakamura K, Goto D,
Maeda H, Makiishi T, Matsuo Y, Tsuzura S, Okamoto H, Katsuki T, Noma Y, Suzuki
K, Kajimoto Y, Uenaka R, Yajima K, Tanaka H, Morita T, Inagaki M, Lee W, Park
CY, Kim H, Kim S, Kim S, Hwang Y, Kim I, Kim J, Oh KH, Lee B, Chung C, Lim S,
Sung SA, Oh JE, Oh YK, Park J, Yu JM, Choi BS, Oh DJ, Shin SJ, Lee KW, Kim TH,
Choi MG, Won JC, Kim C, Kriauciuniene D, Zabuliene L, Navickas A, Velaviciene A,
Sulcaite R, Urbanaviciene E, Urbonas G, Lasiene J, Radzeviciene L, Gansevoort R,
Kooy A, Lieverse AG, Laverman GD, Penne EL, Smak Gregoor P, van Buren M,
Boonstra AH, Bakker RC, Krekels M, Bos W, Brouwer CB, van Leendert RJM, Luik PT,
Barendregt JNM, Vogt L, Finnes T, Karlsson T, Stenehjem AE, Selsås H, Wium C,
Tafjord AB, Hagemeier R, Radtke M, Eriksen E, Risberg K, Høivik H, Khusrawi A,
Solnør L, Munk PS, Rocke J, Cutfield R, Dunn P, Krebs J, Scott R, Nirmalaraj K,
Smuts N, Baker J, Crawford V, Perez R, Villa M, Panelo A, Pamugas G, Tirador L,
Tanque M, Gumprecht J, Napora P, Franek E, Stankiewicz A, Landa K,
Tiuryn-Petrulewicz A, Ciechanowski K, Wierusz-Wysocka B, Rewerska B, Cieslik G,
Hoffmann M, Nowicki M, Krzykowska J, Mazur S, Wasilewska K, Ocicka-Kozakiewicz
A, Skokowska E, Wnetrzak-Michalska R, Ruxer J, Butrymowicz P, Madziarska K,
Kurnatowska I, Mlodawska-Choluj D, Rusicka T, Madrzejewski A, Kobielusz-Gembala
I, Gogola-Migdal B, Stompor T, Guia J, Pereira A, Melo P, Roque C, Rosario F,
Teixeira E Costa F, Nolasco F, Almeida E, Birne R, Esteves C, Palma I, Marques
O, Beirao I, Heitor S, Vila Lobos A, Ballesteros R, Silva G, Barreto C, Silva A,
Alves R, Babenko A, Klimontov V, Baranov V, Verlan N, Galyavich A, Demko A,
Vorokhobina N, Dobronravov V, Barysheva O, Sherenkov A, Gordeev I, Semenova O,
Levashov S, Marasaev V, Sardinov R, Kobalava Z, Zakharova E, Fadeev V, Kvitkova
L, Solovev O, Yakushin S, Smolyarchuk E, Zhukova L, Zhdanova E, Babkin A,
Nechaeva G, Barbarash O, Reshedko G, Rechkova E, Libis R, Kosmacheva E,
Rodionova T, Ipatko I, Dreval A, Petunina N, Tomilina N, Chernyavskaya E,
Suplotova L, Milovanova T, Zalevskaya A, Khalimov Y, Zykova T, Edin A, Mkrtumyan
A, Palyutin S, Mareev V, Strongin L, Edemskaya E, Lipatov K, Ukhanova O, Gapon
L, Antsiferov M, Shwartz Y, Yakhontov D, Pimenov L, Smolenskaya O, Khromtsova O,
Esayan A, Koziolova N, Duplyakov D, Osipova I, Nikolaev K, Sergeeva-Kondrachenko
M, Oleinikov V, Merai I, Germash E, Zanozina O, Kastanayan A, Khaisheva L,
Gaysina L, Izmozherova N, Arkhipov M, Chukaeva I, Malykh N, Rymar O, Martynenko
V, Malyutina S, Ermakova P, Kalashnikova M, Alkorbi L, Unspecified U, Al-Ghamdi
S, Hersi A, Al-Ghamdi S, Farooqui M, Kinsara A, Al Qarni A, Dammas H, Tengmark
BO, Lindholm CJ, Curiac D, Eliasson K, Rein-Hedin E, Guron G, Soveri I,
Bruchfeld A, Spaak J, Frank M, Löndahl M, Larnefeldt H, Hellgren M, Hellberg O,
Suhail SM, Sum CF, Tan RS, Atharaman V, Wong E, Kitiyakara C, Deerochanawong
C, Pongchaiyakul C, Ophascharoensuk V, Satirapoj B, Sayin B, Gul I, Sari R,
Gulel O, Turk U, Varan H, Temizhan A, Cayli M, Badak O, Ozdogan O, Tavli T, Eren
N, Oguz A, Sari I, Yilmaz H, Cayli M, Ustundag S, Yenicerioglu Y, Kocyigit I,
Kumbasar A, Kaya A, Sahin I, Lin SL, Jiang JY, Lee CT, Tarng DC, Tu ST, Wu MS,
Wu MJ, Chang CT, Hung CC, Sokolova L, Mankovsky B, Kogut D, Chernikova V, Malyar
K, Kravchun N, Botsyurko V, Maslyanko V, Martynyuk L, Serhiyenko O, Stryzhak V,
Myshanych H, Donets O, Bondarets I, Bevz V, Sorokina I, Vlasenko M, Pertseva N,
Grachova M, Pashkovska N, Polyakov A, Smirnov I, Pererva L, Kozhukhov S, Fushtey
I, Komisarenko J, Isayeva A, Zinych O, Vyshnyvetskyy I, Meisner C, Khan B,
Maletz L, Dixon B, Arif A, Jackson T, Lala V, Pritsiolas J, Ponduchi M, El
Shahawy M, Nadkarni S, Urbach D, Paoli-Bruno J, Lora H, Farooq U, Zeig S,
Rudolph L, Damle J, Andrawis N, Radhakrish J, Kaye W, Belo D, Bashir K,
Heigerick G, Smelser J, Ricardo Colomar J, Scott D, First B, Handelsman S,
Bautista J, Patel R, Minton S, Frias J, Alexander C, Ramos-Gonez L, Bertsch J,
Iranmanesh A, Fonseca V, Yuryev M, Popeil L, Cardona J, Saxena S, Sharma S,
Gonzalez E, Solomon R, Perlman A, Khan M, Iglesias R, Awad A, Fitz-Patrick D,
Linfert D, Grant D, Wynne A, Unspecified U, Fogelfeld L, Canadas R, Spinowitz B,
Pergola P, Soufer J, Patel R, Valika S, Winston J, Allison D, Caramori M, Huang
W, Koch S, Rastogi A, Judd E, Bornfreund J, Weiss R, Rocco M, Hamilton M,
Garcia-Mayol L, Unspecified U, Weissman P, Oparil S, Ruoff G, Soe K, Korff G,
Busch R, Lurie A, Hartman I, Samuels G, LeJeune D, Numrungroad V, Brietzke S,
Brusco O, Kreit C, Cruz H, Mocherla B, Prabhakar S, Fadda G, Valdes M, Soroka E,
Berenji R, Alla S, Miller S, Bansal S, Odugbesan A, Pettis K, Azizad M, Acosta
I, Kayali Z, Szerlip H, Barag S, Seco G, Vega D, Adams A, Drakakis J, Sanchez W,
Suarez R, Reisin E, Herrera C, Lee K, Kovesdy C, Whaley-Connell A, Peixoto A,
Mayfield R, Jain M, Martin E, Norwood P, Wise J, Romeu H, Halpern S, Mandviwala
M, Turk T, Burgner A, Schulman G, Kaplan J, Kaplan J, Doshi A, Diaz J, Posada J,
Leon-Forero C, Magno A, Nakhle S, Parikh S, Goldstein G, Mbogua C, McMullen D,
Ajani D, Henry A, Santos V, Kotzker W, Sam R, Rosenfeld J, Kopyt N, Treger R,
Ruhullah Y, Adler S, Ali S, Hertel J, Rendell M, Ross D, Beddhu S, Spry L,
Herdez G, Rosas S, Kirkman MS, Crawford P, El-Shahawy M, El-Meanawy A, Ranjan
P, Fried L, Rothman J, Robertson D, Barakzoy A, Tamirisa A, Benjamin S, Mohandas
R, Bahrami M, Seek M, Brosius F, Campese V, Dandillaya R, Trullenque G, Birriel
J, Flack J, Falcone R, Johnson K, Lemus B, Nosrati S, Umpierrez G, Rahman M,
Oderinde A, Maddukuri G, Jamerson K, Townsend R, Bansal V, Case C, Fluck P,
Kronfli S, Habwe V, Subramanian B, Shafi T, Raina R, Ferdo R, Kharait S,
Lucas K, Herdez-Cassis C, Satko S, Fink R, Hammoud J, Germain M,
Zaniewski-Singh M, Al-Karadsheh A, Henner D, Montero M, Fraser N, Nicol P,
Navarro J, Shanik M, Patel D, Gardner D, Din Z, Gonzalez-Abreu F, Dodd R,
Biscoveanu M, Lerman S, Galphin C, Evans J, Gore A, Alicic R, Sahani M, Pisoni
R, Tran TH, Shaw S, Ryu J, Lehrner L, McGill J, Serota H, Neyra N, O Donovan R,
Fornoni A, Mandayam S, Moustafa M, Barzilay J, Smith M, Gupta D, Krishna A,
Fadem S, Sinha A, Bhargava A, Ramanathan K, Dawoud D, Thomson S, Nica R,
Abdel-Rahman E, Gorton S, Barney M, Markell M, Smith D, Shahid N, Juang G,
Oliver D, Khanh T, Son PN, Hoang LV, Chu P, Nga NTP, Thanh HTK, Tran LP, Ahmed
F, Bhorat A, Urbach D, Jansen van Rensburg D, Podgorski G, Amod A, Bhana S,
Joshi S, Seeber M, Mitha E, Lakha D, van Zyl L, Trokis J, Ranjith N, Sarvan M,
Tayob M, Rayner B, Distiller L, Siebert H, Removed For Gdpr RFG, Joshi M,
Rheeder P, Govender V, Madero Rovalo M, Herver Cabrera M, Solache Ortiz G,
Méndez Machado G, Valdez Ortiz R, Chevaile Ramos A, Chew Wong A, Dehesa López E,
Villagordoa Mesa J, Irizar Santana S, Avila Pardo S, Correa Rotter J, Escobedo
de la Peña J, Rico Herdez R, González Gálvez G, Sauque Reyna L, Bastidas
Adrian M, Fanghänel Salmón G, Vásquez J, Hernández Gaeta D, Gutiérrez Ochoa R,
Nevarez Ruiz L, Ramos López G, Chew Wong A, Ramos Ibarra D, García Hernández P,
González González J, Alpizar Salazar M, Lazcano Soto J, Roman-Miranda A,
Cortes-Maisonet G, Cortes-Maisonet G, Turcu L, Barbonta H, Mistodie C, Vacaru G,
Popescu A, Vlad A, Catrinoiu D, Dumitrescu A, Radulian G, Paveliu S, Mindrescu
N, Albota A, Pintilei E, Pop L, Negrisanu G, Bala C, Popa A, Szilagyi I,
Constantin C, Caceaune E, Onaca A, Lee LY, Vaithilingam I, Aziz NA, Wan Mohamed
WMI, Wan Hasan WHHB, Ratnasingam J, Nik Ahmad NNF, Abd Ghani R, Mohd Ali N, Mohd
Noor N, Loh CL, Eustace J, Brown C, Holian J, Reddan D, O Meara Y, Sree S,
Hatunic M, Ochodnicka Z, Sosovec D, Benusova O, Dzupina A, Buganova I, Babikova
J, Spodniakova D. Collaborators: Besada D, Wassermann A, Bittar J, Elbert A, Vallejos A, Viñes G,
Sanabria H, Pérez Manghi F, Liberman A, Bartolacci I, Aizenberg D, Chahin M,
Maffei L, Gelersztein E, Ludvik B, Schönherr HR, Drexel H, Preiß W, Hanusch U,
Neudorfer P, Prischl F, Paulweber B, Ebenbichler C, Prager R, Sourij H,
Schernthaner GH, Clodi M, Fliesser-Görzer E, Ekinci E, MacIsaac R, Packham D,
Stephenson H, Suranyi M, Wittert G, Wynne KJ, Pape A, Topliss D, Colman P,
Nelson C, Vandeleur J, Colquhoun D, Roger S, Mah PM, Abhayaratna W, VAN Gaal L,
Gillard P, Hougardy JM, Speeckaert M, Stas K, Engelen W, Duyck F, Scheen A,
Vanbelleghem H, Doubel P, Vasileva S, Rashkov R, Nonchev B,
Temelkova-Kurktschieva T, Yoncheva-Mihaylova M, Rangelov R, Klyuchkova N,
Stanchev P, Tagarev Z, Boshnyashka R, Manova P, Prakova Z, Lucheva M, Gushterova
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O, Abramof Ness R, Ben Chetrit S, Adawi F, Liberty I, Grossman E, Elias M,
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Trevisan R, Fiorina P, Pisani A, Pani A, Santorelli G, Bossi CA, Tonolo G,
Fiaccadori E, Veronelli AM, Emdin M, Ponzani P, Gregorini MC, Cavalot FL, Giorda
CB, Shibasaki T, Hamasaki A, Nomiyama T, Matsubayashi S, Shinoda J, Matsumoto K,
Kanehara H, Hirohata Y, Yamada M, Nakazawa J, Yamasaki Y, Nakayama M, Furuya R,
Ebisui O, Kawasaki S, Yamada D, Noritake M, Ishiko T, Sasaki N, Suzuki D, Tanaka
A, Kubota M, Araki H, Ohashi H, Osonoi T, Yamagata K, Fujita N, Kanda D, Tanaka
S, Koide J, Ishii M, Ogiwara T, Suzuki M, Sekigami T, Higashi T, Yambe Y, Kusano
Y, Kikuchi H, Miyaoka H, Kato K, Kashima M, Yamakawa F, Horinouchi S, Imoto H,
Sobajima H, Kanai H, Matsuoka N, Shibata H, Inagaki A, Sugiura T, Sugiyama T,
Yanai H, Hamamoto Y, Hatazaki M, Hayashi T, Kobayashi K, Murao S, Ujihara M,
Sugitatsu K, Kawamitsu K, Yamakawa K, Tsunematsu I, Kikuchi F, Jinnouchi H,
Yasuda T, Maeda H, Matsuo Y, Okamoto H, Katsuki T, Yajima K, Morita T, Inagaki
M, Lee W, Kang J, Park CY, Kim H, Kim S, Hwang Y, Kim I, Kim J, Cho YM, Lee B,
Chung C, Lim S, Yu JM, Kriauciuniene D, Navickas A, Velaviciene A, Urbanaviciene
E, Urbonas G, Lasiene J, Radzeviciene L, Gansevoort R, Kooy A, Lieverse AG,
Penne EL, van Leendert RJM, van Buren M, Boonstra AH, Bakker RC, Krekels M,
Brouwer CB, Luik PT, Barendregt JNM, van den Born BJ, Finnes T, Karlsson T,
Selsås H, Asprusten E, Hagemeier R, Eriksen E, Risberg K, Høivik H, Solnør L,
Thorup F, Rocke J, Cutfield R, Dunn P, Krebs J, Scott R, Nirmalaraj K, Smuts N,
Baker J, Crawford V, Bautista A, Mirasol R, Catindig E, Pamugas G, Tirador L,
Tanque M, Gumprecht J, Napora P, Franek E, Stankiewicz A, Landa K,
Tiuryn-Petrulewicz A, Ciechanowski K, Wierusz-Wysocka B, Rewerska B, Cieslik G,
Hoffmann M, Nowicki M, Krzykowska J, Mazur S, Wasilewska K, Ocicka-Kozakiewicz
A, Skokowska E, Wnetrzak-Michalska R, Ruxer J, Butrymowicz P, Madziarska K,
Kurnatowska I, Rusicka T, Madrzejewski A, Stompor T, Guia J, Pereira A, Melo P,
Roque C, Rosario F, Teixeira E Costa F, Nolasco F, Almeida E, Matos P, Esteves
C, Carvalho R, Brandao I, Heitor S, Vila Lobos A, Ballesteros R, Silva G,
Barreto C, Silva A, Vorokhobina N, Sherenkov A, Gordeev I, Semenova O, Levashov
S, Marasaev V, Sardinov R, Klimontov V, Baranov V, Verlan N, Galyavich A, Demko
A, Kobalava Z, Zakharova E, Kvitkova L, Solovev O, Smolyarchuk E, Zhukova L,
Zhdanova E, Babkin A, Nechaeva G, Barbarash O, Rechkova E, Libis R, Kosmacheva
E, Rodionova T, Ipatko I, Dreval A, Petunina N, Chernyavskaya E, Zalevskaya A,
Khalimov Y, Zykova T, Edin A, Mkrtumyan A, Palyutin S, Mareev V, Strongin L,
Ukhanova O, Antsiferov M, Yakhontov D, Pimenov L, Koziolova N, Nikolaev K, Merai
I, Zanozina O, Gaysina L, Arkhipov M, Malykh N, Rymar O, Martynenko V, Malyutina
S, Ermakova P, Kalashnikova M, Tengmark BO, Lindholm CJ, Curiac D, Eliasson K,
Rein-Hedin E, Guron G, Soveri I, Bruchfeld A, Spaak J, Frank M, Löndahl M,
Larnefeldt H, Hellgren M, Hellberg O, Bee YM, Sum CF, Tan RS, Sritara P,
Deerochanawong C, Pongchaiyakul C, Kosachunha N, Satirapoj B, Temizhan A, Gul
I, Sari R, Oguz A, Tigen M, Yilmaz H, Badak O, Ozdogan O, Tavli T, Eren N, Cayli
M, Ustundag S, Yenicerioglu Y, Kocyigit I, Kumbasar A, Sahin I, Chuang LM, Jiang
JY, Lee CT, Tarng DC, Tu ST, Wu MS, Wu MJ, Chang CT, Hung CC, Sokolova L,
Mankovsky B, Kogut D, Chernikova V, Malyar K, Kravchun N, Botsyurko V, Maslyanko
V, Martynyuk L, Serhiyenko O, Stryzhak V, Myshanych H, Donets O, Bondarets I,
Vlasenko M, Pertseva N, Grachova M, Smirnov I, Pererva L, Fushtey I, Komisarenko
J, Isayeva A, Meisner C, Khan B, Maletz L, Dixon B, Arif A, Jackson T, Ponduchi
M, El Shahawy M, Nadkarni S, Urbach D, Paoli-Bruno J, Lora H, Farooq U, Zeig S,
Rudolph L, Andrawis N, Kaye W, Meyer J, Bashir K, Heigerick G, Smelser J,
Ricardo Colomar J, Scott D, First B, Handelsman S, Bautista J, Patel R, Minton
S, Frias J, Ramos-Gonez L, Bertsch J, Iranmanesh A, Fonseca V, Yuryev M, Popeil
L, Cardona J, Saxena S, Sharma S, Gonzalez E, Solomon R, Khan M, Awad A,
Fitz-Patrick D, Linfert D, Grant D, Brian S, Fogelfeld L, Canadas R, Pergola P,
Soufer J, Patel R, Valika S, Winston J, Allison D, Caramori M, Koch S, Rastogi
A, Bornfreund J, Rocco M, Hamilton M, Garcia-Mayol L, Weissman P, Oparil S,
Ruoff G, Soe K, Korff G, Busch R, Lurie A, Hartman I, Samuels G, LeJeune D,
Numrungroad V, Brietzke S, Kayali Z, Szerlip H, Barag S, Seco G, Vega D, Brusco
O, Kreit C, Cruz H, Mocherla B, Prabhakar S, Fadda G, Valdes M, Soroka E,
Berenji R, Alla S, Bansal S, Odugbesan A, Pettis K, Azizad M, Acosta I, Adams A,
Sanchez W, Suarez R, Reisin E, Herrera C, Lee K, Kovesdy C, Whaley-Connell A,
Peixoto A, Mayfield R, Jain M, Martin E, Norwood P, Wise J, Romeu H, Halpern S,
Mandviwala M, Turk T, Burgner A, Bleich D, Doshi A, Carpio J, Posada J, Magno A,
Nakhle S, Goldstein G, Mbogua C, McMullen D, Ajani D, Kotzker W, Kopyt N, Treger
R, Ruhullah Y, Adler S, Brar H, Rendell M, Ross D, Beddhu S, Herdez G, Rosas
S, Kirkman MS, El-Shahawy M, Rothman J, Barakzoy A, Tamirisa A, Benjamin S,
Bahrami M, Roy-Chaudhury P, Dandillaya R, Trullenque G, Birriel J, Flack J,
Johnson K, Lemus B, Umpierrez G, Maddukuri G, Jamerson K, Case C, Fluck P,
Kronfli S, Habwe V, Subramanian B, Shafi T, Raina R, Ferdo R, Kharait S,
Herdez-Cassis C, Fink R, Hammoud J, Al-Karadsheh A, Montero M, Nicol P,
Navarro J, Shanik M, Din Z, Gonzalez-Abreu F, Lerman S, Galphin C, Evans J, Gore
A, Alicic R, Sahani M, Pisoni R, Tran TH, Ryu J, Serota H, Neyra N, O Donovan R,
Mandayam S, Moustafa M, Smith M, Krishna A, Sinha A, Bhargava A, Ramanathan K,
Dhanireddy S, Thomson S, Nica R, Abdel-Rahman E, Barney M, Markell M, Shahid N,
Oliver D, Khanh T, Son PN, Hoang LV, Nguyen BN, Nui NM, Tran LP, Ahmed F, Urbach
D, Jansen van Rensburg D, Podgorski G, Amod A, Bhana S, Joshi S, Mitha E, Lakha
D, van Zyl L, Trokis J, Ranjith N, Seeber M, Sarvan M, Tayob M, Rayner B,
Distiller L, Siebert H, Joshi M, Rheeder P, Madero Rovalo M, Solache Ortiz G,
Méndez Machado G, Valdez Ortiz R, Villagordoa Mesa J, Irizar Santana S, Avila
Pardo S, Escobedo de la Peña J, González Gálvez G, Sauque Reyna L, Bastidas
Adrian M, Fanghänel Salmón G, Gutiérrez Ochoa R, Nevarez Ruiz L, Ramos López G,
Chew Wong A, Saldaña Mendoza A, García Hernández P, González González J, Alpizar
Salazar M, Lazcano Soto J, Roman-Miranda A, Cortes-Maisonet G, Cortes-Maisonet
G, Turcu L, Dumitrescu A, Radulian G, Barbonta H, Mistodie C, Vacaru G, Popescu
A, Vlad A, Paveliu S, Mindrescu N, Albota A, Pintilei E, Pop L, Negrisanu G,
Catrinoiu D, Bala C, Popa A, Szilagyi I, Constantin C, Caceaune E, Onaca A, Lee
LY, Aziz NA, Wan Mohamed WMI, Wan Hasan WHHB, Ratnasingam J, Nik Ahmad NNF,
Najme Khir R, Mohd Ali N, Mohamad M, Loh CL, Eustace J, Holian J, Reddan D, O
Meara Y, Hatunic M, Ochodnicka Z, Sosovec D, Dzupina A, Buganova I, Babikova J,
Spodniakova D. PURPOSE OF REVIEW: We aim to review the mechanism of action and safety profile
of mineralocorticoid receptor antagonists (MRAs) and discuss the differences
between selective and non-selective MRAs. More specifically, finerenone is a new
medication that is currently under investigation for its promising
cardiovascular and nephrological effects.
RECENT FINDINGS: MRAs are well known for their utility in treating heart
failure, refractory hypertension, and diverse nephropathies, namely, diabetic
nephropathy. As their name denotes, MRAs inhibit the action of aldosterone at
the mineralocorticoid receptor, preventing receptor activation. This prevents
remodeling, decreases inflammation, and improves proteinuria. There are not
significant differences in outcomes between selective and non-selective MRAs. A
new selective MRA named finerenone (originally BAY 94-8862) has shown promising
results in several trials (ARTS-HF and ARTS-DN) and smaller studies. Finerenone
may have a dose-dependent benefit over older MRAs, decreasing rates of
albuminuria and levels of BNP and NT-ProBNP without causing a significant
increase in serum potassium levels. This medication is not yet approved as it is
still in phase 3 clinical trials (FIGARO-DKD and FIDELIO-DKD trials). MRAs are
beneficial in several disease states. Newer medications, such as finerenone,
should be considered in patients with heart failure and diabetic nephropathy who
may benefit from a reduction in albuminuria and BNP/NT-ProBNP. Data surrounding
finerenone are limited to date. However, results from ongoing clinical trials,
as well as new trials to evaluate use in other pathologies, could validate the
implementation of this medication in daily practice. AIMS: Duchenne muscular dystrophy (DMD) is an X-linked inherited disease due to
dystrophin deficiency causing skeletal and cardiac muscle dysfunction. Affected
patients lose ambulation by age 12 and usually die in the second to third
decades of life from cardiac and respiratory failure. Symptomatic treatment
includes the use of anti-inflammatory corticosteroids, which are associated with
side effects including weight gain, osteoporosis, and increased risk of
cardiovascular disease. Novel treatment options include blockade of the
renin-angiotensin-aldosterone system, because angiotensin as well as aldosterone
contribute to persistent inflammation and fibrosis, and aldosterone blockade
represents an efficacious anti-fibrotic approach in cardiac failure. Recent
preclinical findings enabled successful clinical testing of a combination of
steroidal mineralocorticoid receptor antagonists (MRAs) and angiotensin
converting enzyme inhibitors in DMD boys. The efficacy of MRAs alone on
dystrophic skeletal muscle and heart has not been investigated. Here, we tested
efficacy of the novel non-steroidal MRA finerenone as a monotherapy in a
preclinical DMD model.
METHODS AND RESULTS: The dystrophin-deficient, utrophin haploinsufficient mouse
model of DMD was treated with finerenone and compared with untreated dystrophic
and wild-type controls. Grip strength, electrocardiography, cardiac magnetic
resoce imaging, muscle force measurements, histological quantification, and
gene expression studies were performed. Finerenone treatment alone resulted in
significant improvements in clinically relevant functional parameters in both
skeletal muscle and heart. Normalized grip strength in rested dystrophic mice
treated with finerenone (40.3 ± 1.0 mN/g) was significantly higher (P = 0.0182)
compared with untreated dystrophic mice (35.2 ± 1.5 mN/g). Fatigued
finerenone-treated dystrophic mice showed an even greater relative improvement
(P = 0.0003) in normalized grip strength (37.5 ± 1.1 mN/g) compared with
untreated mice (29.7 ± 1.1 mN/g). Finerenone treatment also led to significantly
lower (P = 0.0075) susceptibility to limb muscle damage characteristic of DMD
measured during a contraction-induced injury protocol. Normalized limb muscle
force after five lengthening contractions resulted in retention of 71 ± 7% of
baseline force in finerenone-treated compared with only 51 ± 4% in untreated
dystrophic mice. Finerenone treatment also prevented significant reductions in
myocardial strain rate (P = 0.0409), the earliest sign of DMD cardiomyopathy.
Moreover, treatment with finerenone led to very specific cardiac gene expression
changes in clock genes that might modify cardiac pathophysiology in this DMD
model.
CONCLUSIONS: Finerenone administered as a monotherapy is disease modifying for
both skeletal muscle and heart in a preclinical DMD model. These findings
support further evaluation of finerenone in DMD clinical trials. This review covers the last 80 years of remarkable progress in the development
of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the
first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear
receptor expressed in many tissues/cell types including the kidney, heart,
immune cells, and fibroblasts. The MR directly affects target gene
expression-primarily fluid, electrolyte and haemodynamic homeostasis, and also,
but less appreciated, tissue remodelling. Pathophysiological overactivation of
the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the
mechanisms of action of nonsteroidal MRAs and how they differ from steroidal
MRAs. Nonsteroidal MRAs have demonstrated important differences in their
distribution, binding mode to the MR and subsequent gene expression. For
example, the novel nonsteroidal MRA finerenone has a balanced distribution
between the heart and kidney compared with spironolactone, which is
preferentially concentrated in the kidneys. Compared with eplerenone,
equinatriuretic doses of finerenone show more potent anti-inflammatory and
anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs
appear to demonstrate a better benefit-risk ratio than steroidal MRAs, where
risk is measured as the propensity for hyperkalaemia. Among patients with Type 2
diabetes, several Phase II studies of finerenone show promising results,
supporting benefits on the heart and kidneys. Furthermore, finerenone
significantly reduced the combined primary endpoint (chronic kidney disease
progression, kidney failure, or kidney death) vs. placebo when added to the
standard of care in a large Phase III trial. BACKGROUND: Treatment with angiotensin-converting enzyme inhibitors (ACEi) and
angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the
progression of chronic kidney disease (CKD). However, resolution of proteinuria
may be incomplete with these therapies and the addition of an aldosterone
antagonist may be added to further prevent progression of CKD. This is an update
of a Cochrane review first published in 2009 and updated in 2014.
OBJECTIVES: To evaluate the effects of aldosterone antagonists (selective
(eplerenone), non-selective (spironolactone or canrenone), or non-steroidal
mineralocorticoid antagonists (finerenone)) in adults who have CKD with
proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints
including kidney failure (previously know as end-stage kidney disease (ESKD)),
major cardiovascular events, and death (any cause); kidney function
(proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum
creatinine); blood pressure; and adverse events (including hyperkalaemia, acute
kidney injury, and gynaecomastia).
SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of
Studies up to 13 January 2020 through contact with the Information Specialist
using search terms relevant to this review. Studies in the Register are
identified through searches of CENTRAL, MEDLINE, and EMBASE, conference
proceedings, the International Clinical Trials Register (ICTRP) Search Portal,
and ClinicalTrials.gov.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) and
quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB
(or both) to other anti-hypertensive strategies or placebo in participants with
proteinuric CKD.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality
and extracted data. Data were summarised using random effects meta-analysis. We
expressed summary treatment estimates as a risk ratio (RR) for dichotomous
outcomes and mean difference (MD) for continuous outcomes, or standardised mean
difference (SMD) when different scales were used together with their 95%
confidence interval (CI). Risk of bias were assessed using the Cochrane tool.
Evidence certainty was evaluated using GRADE.
MAIN RESULTS: Forty-four studies (5745 participants) were included. Risk of bias
in the evaluated methodological domains were unclear or high risk in most
studies. Adequate random sequence generation was present in 12 studies,
allocation concealment in five studies, blinding of participant and
investigators in 18 studies, blinding of outcome assessment in 15 studies, and
complete outcome reporting in 24 studies. All studies comparing aldosterone
antagonists to placebo or standard care were used in addition to an ACEi or ARB
(or both). None of the studies were powered to detect differences in
patient-level outcomes including kidney failure, major cardiovascular events or
death. Aldosterone antagonists had uncertain effects on kidney failure (2
studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low
certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to
3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies,
1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty
evidence) compared to placebo or standard care. Aldosterone antagonists may
reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82
to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165
participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low
certainty evidence) and systolic blood pressure (14 studies, 911 participants:
MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence)
compared to placebo or standard care. Aldosterone antagonists probably increase
the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47
to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies,
1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty
evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14
to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard
care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain
effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI
-3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum
potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² =
0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective
aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500
participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence)
compared ACEi or ARB (or both). There were insufficient studies to perform
meta-analyses for the comparison between non-selective aldosterone antagonists
and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB
(or both) and nitrate plus ACEi or ARB (or both), and non-steroidal
mineralocorticoid antagonists and selective aldosterone antagonists.
AUTHORS' CONCLUSIONS: The effects of aldosterone antagonists when added to ACEi
or ARB (or both) on the risks of death, major cardiovascular events, and kidney
failure in people with proteinuric CKD are uncertain. Aldosterone antagonists
may reduce proteinuria, eGFR, and systolic blood pressure in adults who have
mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney
injury and gynaecomastia when added to ACEi and/or ARB. Mineralocorticoid receptor (MR) antagonists, for example, spironolactone and
eplerenone, are in clinical use to treat hypertension. Increasing evidence
suggests that mineralocorticoid receptor activation causes the pathogenesis and
progression of chronic kidney disease. Aldosterone-induced MR activation
increases inflammation, fibrosis, and oxidative stress in the kidney. MR
antagonists (MRAs) have demonstrated therapeutic actions in chronic kidney
disease (CKD), diabetic nephropathy (DN), renal fibrosis, and drug-induced renal
injury in preclinical and clinical studies. We have summarized and discussed
these studies in this review. The nonsteroidal MRA, esaxerenone, recently
received approval for the treatment of hypertension. It has also shown a
positive therapeutic effect in phase 3 clinical trials in patients with DN.
Other nonsteroidal MRA such as apararenone, finerenone, AZD9977, and LY2623091
are in different clinical trials in patients with hypertension suffering from
renal or hepatic fibrotic diseases. Hyperkalemia associated with MRA therapy has
frequently led to the discontinuation of the treatment. The new generation
nonsteroidal MRAs like esaxerenone are less likely to cause hyperkalemia at
therapeutic doses. It appears that the nonsteroidal MRAs can provide optimum
therapeutic benefit for patients suffering from kidney diseases. |
Is colistin an antibiotic? | Yes,
colistin is an antibiotic. | BACKGROUND: Uropathogenic Escherichia coli (UPEC) is a major cause of Urinary
Tract Infections (UTIs). Due to increasing antibiotic-resistance among UPEC
bacteria, new treatment options for UTIs are urgently needed.
OBJECTIVE: To identify new agents targeting growing bacteria that may be used
for the treatment of antibiotic-resistant UTIs.
METHODS: We screened a clinical compound library consisting of 1,524 compounds
using a high throughput 96-well plate assay and ranked the activities of the
selected agents according to their MICs against the UPEC strain UTI89.
RESULTS: We identified 33 antibiotics which were active against log-phase
clinical UPEC strain UTI89. Among the selected antibiotics, there were 12
fluoroquinolone antibiotics (tosufloxacin, levofloxacin, sparfloxacin,
clinafloxacin, pazufloxacin, gatifloxacin, enrofloxacin, lomefloxacin,
norfloxacin, fleroxacin, flumequine, ciprofloxacin), 15 beta-lactam or
cephalosporin antibiotics (cefmenoxime, cefotaxime, ceftizoxime, cefotiam,
cefdinir, cefoperazone, cefpiramide, cefamandole, cefixime, ceftibuten,
cefmetazole, cephalosporin C, aztreonam, piperacillintazobactam, mezlocillin), 3
tetracycline antibiotics (meclocycline, doxycycline, tetracycline), 2
membrane-acting agents (colistin and clofoctol), and 1 protein synthesis
inhibitor (amikacin). Among them, the top 7 hits were colistin, tosufloxacin,
levofloxacin, sparfloxacin, clinafloxacin, cefmenoxime and pazufloxacin, where
clinafloxacin and pazufloxacin were the newly identified agents active against
UPEC strain UTI89. We validated the key results obtained with UTI89 on two other
UTI strains CFT073 and KTE181 and found that they all had comparable MICs for
fluoroquinolones while CFT073 and KTE181 were more susceptible to cephalosporin
antibiotics and tetracycline antibiotics but were less susceptible to colistin
than UTI89.
CONCLUSION: Our findings provide possible effective drug candidates for the more
effective treatment of antibiotic-resistant UTIs. Background: Clostridium difficile infection is the most common cause of
antimicrobial-associated diarrhea. Our aim was to introduce a novel and
efficient clinical sickness score (CSS), and to define a detailed histologic
injury score (HIS) in a murine model of C. difficile colitis. Methods: Mice
received an antibiotic cocktail (kanamycin, gentamicin, colistin, metronidazole,
and vancomycin) for 96 h. After 48 h, mice received an intraperitoneal injection
of clindamycin, followed by oral C. difficile (1.5 × 107 CFU). Signs of sickness
were scored using a novel CSS (range 0-12) with scores ≥6 consistent with C.
difficile colitis. Intestinal tissue was analyzed utilizing an adapted HIS
(range 0-9) with scores ≥4 consistent with C. difficile colitis. Stool was
analyzed for C. difficile, and survival evaluated. Results: No control mice
showed signs of sickness, whereas 23% of mice receiving antibiotics alone and
65% of mice exposed to antibiotics and subsequently C. difficile demonstrated
signs of sickness (p = 0.0134). No control mice had histologic injury, whereas
8% of mice receiving antibiotics alone and 75% of mice exposed to antibiotics
followed by C. difficile had evidence of histologic injury (p = 0.0001). Mice
exposed to C. difficile lost more weight, although not significant (p = 0.070).
Mice that received C. difficile had decreased survival compared to control mice
and mice receiving antibiotics only (p = 0.03). Conclusions: We have developed a
novel clinical scoring system, and detailed histological grading system, that
enables the objective evaluation of a murine C. difficile colitis model. This
model allows the study of this disease in a host that demonstrates clinical and
histologic signs comparable to human C. difficile infection. This will allow for
improved study of therapeutics for this disease in the future. OBJECTIVES: To reconstruct the evolutionary history of the clinical
Acinetobacter baumannii XH1056, which lacks the Oxford scheme allele gdhB.
METHODS: Susceptibility testing was performed using broth microdilution and agar
dilution. The whole-genome sequence of XH1056 was determined using the Illumina
and Oxford Nanopore platforms. MLST was performed using the Pasteur scheme and
the Oxford scheme. Antibiotic resistance genes were identified using ABRicate.
RESULTS: XH1056 was resistant to all antibiotics tested, apart from colistin,
tigecycline and eravacycline. MLST using the Pasteur scheme assigned XH1056 to
ST256. However, XH1056 could not be typed with the Oxford MLST scheme as gdhB is
not present. Comparative analyses revealed that XH1056 contains a 52 933 bp
region acquired from a global clone 2 (GC2) isolate, but is otherwise closely
related to the ST23 A. baumannii XH858. The acquired region in XH1056 also
contains a 34 932 bp resistance island that resembles AbGRI3 and contains the
armA, msrE-mphE, sul1, blaPER-1, aadA1, cmlA1, aadA2, blaCARB-2 and ere(B)
resistance genes. Comparison of the XH1056 chromosome to that of GC2 isolate
XH859 revealed that the island in XH1056 is in the same chromosomal region as
that in XH859. As this island is not in the standard AbGRI3 position, it was
named AbGRI5.
CONCLUSIONS: XH1056 is a hybrid isolate generated by the acquisition of a
chromosomal segment from a GC2 isolate that contains a resistance island in a
new location-AbGRI5. As well as generating ST256, it appears likely that a
single recombination event is also responsible for the acquisition of AbGRI5 and
its associated antibiotic resistance genes. |
Is Tocilizumab (Actemra) used to block/antagonize the IL-6 receptor? | yes, tocilizumab (actemra) is used to block/antagonize the il-6 receptor. | Roche is co-developing tocilizumab (Actemra, RoActemra), a humanized
anti-interleukin-6 receptor (IL-6R) monoclonal antibody, with Chugai
Pharmaceutical. Tocilizumab is marketed in Japan for Castleman disease and
several types of arthritis. The product is approved in the European Union for
treatment of moderate-to-severe rheumatoid arthritis, and is currently
undergoing review by the US Food and Drug Administration for this condition.
Tocilizumab has also been studied for potential use in the treatment of other
IL-6 related disorders including Crohn disease. Recent years have seen many exciting developments in the treatment of
inflammatory arthritis. Tocilizumab (TCZ) is a compound that inhibits the IL-6
receptor. Following initial studies in Japan, it has been extensively studied in
five multicenter clinical trials. This report concentrates on the Actemra Versus
Methotrexate Double-blind Investigative Trial in Monotherapy (AMBITION), which
compared TCZ monotherapy (8 mg/kg every 4 weeks) with methotrexate monotherapy
over 24 weeks. TCZ was shown to be the first biologic agent that is superior to
methotrexate across a whole range of clinical outcomes measures with a rapid
onset of effect. Significant liver toxicity was less common in the TCZ group.
However, increases in lipids and decreases in neutrophils and skin infections
were more common in the TCZ arm. Long-term efficacy and safety follow-up is
ongoing. This trial supports the use of TCZ as monotherapy and suggests it
should be regarded as a first-line biologic therapy. Tocilizumab (Actemra; Genentech, Inc) is the first biologic therapy targeting
the cytokine interleukin 6 (IL-6). It is a humanized monoclonal immunoglobulin
G1 antibody against the α-chain of the IL-6 receptor that prevents the binding
of IL-6 to membrane-bound and -soluble IL-6 receptor. It was approved by the US
Food and Drug Administration in January 2010 for rheumatoid arthritis refractory
to other approved therapies and in April 2011 for systemic juvenile idiopathic
arthritis. It has been used as an off-label treatment in many autoimmune
diseases, where IL-6 plays a major role in pathogenesis. We report a case of
refractory systemic lupus erythematosus in a 22-year-old woman with recurrent
high-grade fever, polyarthritis, diffuse rash with urticarial vasculitis, and
tumid lupus who did not respond to topical corticosteroids, photoprotection,
antimalarials, methotrexate, anakinra, mycophenolate mofetil, etanercept, and
intravenous immunoglobulin therapy. Symptoms recurred after corticosteroid
tapers below 10 mg. She was noted to have an elevated IL-6 level, and
tocilizumab was started. She responded favorably with remission of fever,
arthritis, and skin manifestations and was able to taper corticosteroid therapy
successfully. Tocilizumab (TCZ; RoActemra® or Actemra®) is a recombit humanized monoclonal
antibody that acts as an interleukin 6 (IL-6) receptor antagonist. For
rheumatoid arthritis (RA), intravenous (IV) TCZ 8 mg/kg every 4 weeks has been
approved since 2008 in Japan (where it is also approved for polyarticular
juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and
Castleman's disease), and since 2009 in Europe in combination with methotrexate
(MTX) for the treatment of moderate to severe active RA in adult patients with
inadequate response to, or intolerance of, disease-modifying antirheumatic drug
(DMARD) or tumor necrosis factor (TNF) antagonist therapy. It may also be
administered as monotherapy in the same dose regimen in patients with
methotrexate intolerance or with inadequate response to MTX. Since January 2011
in the United States, the indication for treatment with TCZ for RA patients with
an inadequate response to one or more TNF antagonists was extended to patients
with moderately to severely active RA, and the recommended starting dose is 4
mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response. All
of these approvals are based on the effectiveness and safety of the 8 mg/kg dose
regimen when administered either as monotherapy or in combination with
conventional DMARDs in well-designed clinical studies in adult patients with
moderate to severe RA. TCZ at this dose is more effective than placebo, MTX or
other DMARDs in reducing disease activity and improving health-related quality
of life (HR-QoL). Although there were fewer responses with the 4 mg/kg dose,
this dose every 4 weeks was not statistically different to 8 mg/kg when
administered in combination with MTX, and this dose is the recommended starting
dose in the US. Both doses have also been shown to inhibit structural joint
damage in patients with an inadequate response to MTX. Thus, TCZ is an important
new treatment option in patients with moderate to severe RA. Tocilizumab (RoActemra(®); Actemra(®)) is a recombit humanized monoclonal
antibody that acts as an interleukin-6 receptor antagonist. Both in the US and
EU, tocilizumab has been approved for the treatment of two subtypes of juvenile
idiopathic arthritis (JIA), namely systemic JIA (sJIA) and polyarticular JIA
(pJIA), in patients aged ≥2 years. These approvals are based on favorable
results from two randomized, double-blind, placebo-controlled, multinational,
phase III trials in which patients aged 2-17 years with active sJIA (TENDER) or
pJIA (CHERISH) received an intravenous dose of tocilizumab based on bodyweight
every 2 or 4 weeks, respectively. Tocilizumab met the primary endpoint in both
of these ongoing, multi-part studies. That is, in TENDER, significantly more
tocilizumab recipients than placebo recipients achieved a JIA American College
of Rheumatology (ACR) 30 response plus absence of fever, as assessed at the end
of a 12-week double-blind treatment period, while in CHERISH, significantly
fewer tocilizumab recipients than placebo recipients experienced a JIA ACR 30
flare during a 24-week double-blind withdrawal period (all patients had
previously received open-label tocilizumab in a 16-week lead-in phase).
Tocilizumab was generally well tolerated in the TENDER trial. Infections (e.g.
upper respiratory tract infection and pharyngitis or nasopharyngitis) accounted
for just over one-third of all reported adverse events in this trial;
tocilizumab-treated patients appeared to have an approximately 11 % risk of a
serious infection per year of treatment. Clinical laboratory abnormalities
included neutropenia and elevated aminotransferase levels. The tolerability
profile of tocilizumab in CHERISH was generally consistent with that of the drug
in TENDER. Tocilizumab (TCZ), is a recombit humanized anti-interleukin-6 receptor
(IL-6R) monoclonal antibody which has a main use in the treatment of rheumatoid
arthritis, systemic juvenile idiopathic arthritis (sJIA) and polyarticular
juvenile idiopathic arthritis (pJIA). This article provides an overview of TCZ
including looking into the past at the discovery of interleukin-6 (IL-6) as a
pro-inflammatory cytokine. It also looks at how tocilizumab was developed,
manufactured and tested to ensure both safety and efficacy in a human
population. The article then explores the advantages and disadvantages of using
TCZ when compared to other biologics approved in RA, sJIA and pJIA and finally
looks ahead to the future and the emerging role of IL-6 and its blockade by TCZ
as a treatment for giant cell arteritis (GCA), polymyalgia rheumatica (PMR) and
large vessel vasculitis (LVV). PURPOSE: To demonstrate improvement and stabilization of retinal findings,
including recalcitrant cystoid macular edema, in a patient with
nonparaneoplastic autoimmune retinopathy after treatment with tocilizumab, a
humanized monoclonal antibody against soluble and membrane-bound IL-6 receptor.
METHODS: Observational case report. A 46-year-old woman was diagnosed with
nonparaneoplastic autoimmune retinopathy and followed over 4 years on various
immunosuppressive medications with worsening disease and recalcitrant cystoid
macular edema. This report describes the rapid improvement and stabilization of
her ocular disease once tocilizumab was initiated.
RESULTS: Tocilizumab, a monoclonal antibody against the IL-6 receptor, was
initiated at a dose of 8 mg/kg every 4 weeks. Cystoid macular edema was
significantly decreased after just two infusions and nearly resolved after five
infusions. Ellipsoid zone and outer retinal integrity also improved on optical
coherence tomography. The patient tolerated the medication with limited side
effects.
CONCLUSION: Long-term immunosuppression is the cornerstone of treatment for
nonparaneoplastic autoimmune retinopathy, although success is highly variable.
We report a case treated with tocilizumab with dramatic improvement in
refractory macular edema and reconstitution of the ellipsoid zone on optical
coherence tomography in a patient with nonparaneoplastic autoimmune retinopathy.
This case highlights the potential role of treatment with an IL-6 inhibitor in
autoimmune retinopathy though further studies are needed. INTRODUCTION: Epithelial ovarian cancer (EOC) is the most lethal gynecologic
maligcy worldwide and despite an initial response to therapeutic agents, the
majority of patients have chemoresistant disease. There is no treatment strategy
with proven efficacy against chemoresistant EOC and in this setting, overcoming
therapy resistance is the key to successful treatment.
METHODS: This study aimed to investigate expression of interleukin-6 (IL-6)
(IL-6) and IL-6 receptor (IL-6R) in a panel of the EOC cell lines. To achieve
this, the expression of IL-6 and its receptor were compared in the EOC cells
using quantitative reverse transcription polymerase chain reaction. MTT assay
was performed to obtain chemosensitivity of the EOC cells.
RESULTS: In this report, we show that expressions of IL6 and IL6R are higher in
therapy-resistant EOC cells compared to sensitive ones. Higher expression of IL6
and its receptor correlated with resistance to certain chemotherapeutic agents.
Moreover, our findings showed that combination of tocilizumab (Actemra; Roche),
an anti-IL-6R monoclonal antibody, with carboplatin synergistically inhibited
growth and proliferation of the EOC cells and the most direct axis for IL-6 gene
expression was NF-κB pathway.
CONCLUSION: Collectively, our findings suggest that blockade of the IL-6
signaling pathway with anti-IL-6 receptor antibody tocilizumab might resensitize
the chemoresistant cells to the current chemotherapeutics. AIMS/HYPOTHESIS: IL-6 is a cytokine with various effects on metabolism. In mice,
IL-6 improved beta cell function and glucose homeostasis via upregulation of
glucagon-like peptide 1 (GLP-1), and IL-6 release from muscle during exercise
potentiated this beneficial increase in GLP-1. This study aimed to identify
whether exercise-induced IL-6 has a similar effect in humans.
METHODS: In a multicentre, double-blind clinical trial, we randomly assigned
patients with type 2 diabetes or obesity to intravenous tocilizumab (an IL-6
receptor antagonist) 8 mg/kg every 4 weeks, oral sitagliptin (a dipeptidyl
peptidase-4 inhibitor) 100 mg daily or double placebos (a placebo saline
infusion every 4 weeks and a placebo pill once daily) during a 12 week training
intervention. The primary endpoints were the difference in change of active
GLP-1 response to an acute exercise bout and change in the AUC for the
concentration-time curve of active GLP-1 during mixed meal tolerance tests at
baseline and after the training intervention.
RESULTS: Nineteen patients were allocated to tocilizumab, 17 to sitagliptin and
16 to placebos. During the acute exercise bout active GLP-1 levels were 26%
lower with tocilizumab (multiplicative effect: 0.74 [95% CI 0.56, 0.98],
p = 0.034) and 53% higher with sitagliptin (1.53 [1.15, 2.03], p = 0.004)
compared with placebo. After the 12 week training intervention, the active GLP-1
AUC with sitagliptin was about twofold that with placebo (2.03 [1.56, 2.62];
p < 0.001), while GLP-1 AUC values showed a small non-significant decrease of
13% at 4 weeks after the last tocilizumab infusion (0.87 [0.67, 1.12];
p = 0.261).
CONCLUSIONS/INTERPRETATION: IL-6 is implicated in the regulation of GLP-1 in
humans. IL-6 receptor blockade lowered active GLP-1 levels in response to a meal
and an acute exercise bout in a reversible manner, without lasting effects
beyond IL-6 receptor blockade.
TRIAL REGISTRATION: Clinicaltrials.gov NCT01073826.
FUNDING: Danish National Research Foundation. Danish Council for Independent
Research. Novo Nordisk Foundation. Danish Centre for Strategic Research in Type
2 Diabetes. European Foundation for the Study of Diabetes. Swiss National
Research Foundation. IL-6 is a pro-inflammatory cytokine upregulated in some autoimmune diseases. The
role of IL-6 in the development of type 1 diabetes (T1D) is unclear. Clinical
studies are investigating whether tocilizumab (anti-IL-6 receptor) can help
preserve beta cell function in patients recently diagnosed with T1D. However, in
some rodent models and isolated human islets, IL-6 has been found to have a
protective role for beta cells by reducing oxidative stress. Hence, we
systematically investigated local tissue expression of IL-6 in human pancreas
from non-diabetic, auto-antibody positive donors and donors with T1D and T2D.
IL-6 was constitutively expressed by beta and alpha cells regardless of the
disease state. However, expression of IL-6 was highly reduced in
insulin-deficient islets of donors with T1D, and the expression was then mostly
restricted to alpha cells. Our findings suggest that the implication of IL-6 in
T1D pathogenesis might be more complex than previously assumed. |
Is the process of DNA loop-extrusion independent of ATP? | The process of DNA loop-extrusion is not independent of ATP. It is dependent on the energy of ATP hydrolysis. | Type I restriction enzymes use two motors to translocate DNA before carrying out
DNA cleavage. The motor function is accomplished by amino-acid motifs typical
for superfamily 2 helicases, although DNA unwinding is not observed. Using a
combination of extensive single-molecule magnetic tweezers and stopped-flow bulk
measurements, we fully characterized the (re)initiation of DNA translocation by
EcoR124I. We found that the methyltransferase core unit of the enzyme loads the
motor subunits onto adjacent DNA by allowing them to bind and initiate
translocation. Termination of translocation occurs owing to dissociation of the
motors from the core unit. Reinitiation of translocation requires binding of new
motors from solution. The identification and quantification of further
initiation steps--ATP binding and extrusion of an initial DNA loop--allowed us
to deduce a complete kinetic reinitiation scheme. The dissociation/reassociation
of motors during translocation allows dynamic control of the restriction process
by the availability of motors. Direct evidence that this control mechanism is
relevant in vivo is provided. Topologically associating domains (TADs) are fundamental structural and
functional building blocks of human interphase chromosomes, yet the mechanisms
of TAD formation remain unclear. Here, we propose that loop extrusion underlies
TAD formation. In this process, cis-acting loop-extruding factors, likely
cohesins, form progressively larger loops but stall at TAD boundaries due to
interactions with boundary proteins, including CTCF. Using polymer simulations,
we show that this model produces TADs and finer-scale features of Hi-C data.
Each TAD emerges from multiple loops dynamically formed through extrusion,
contrary to typical illustrations of single static loops. Loop extrusion both
explains diverse experimental observations-including the preferential
orientation of CTCF motifs, enrichments of architectural proteins at TAD
boundaries, and boundary deletion experiments-and makes specific predictions for
the depletion of CTCF versus cohesin. Finally, loop extrusion has potentially
far-ranging consequences for processes such as enhancer-promoter interactions,
orientation-specific chromosomal looping, and compaction of mitotic chromosomes. Using molecular dynamics simulations, we show here that growing plectonemes
resulting from transcription-induced supercoiling have the ability to actively
push cohesin rings along chromatin fibres. The pushing direction is such that
within each topologically associating domain (TAD) cohesin rings forming
handcuffs move from the source of supercoiling, constituted by RNA polymerase
with associated DNA topoisomerase TOP1, towards borders of TADs, where
supercoiling is released by topoisomerase TOPIIB. Cohesin handcuffs are pushed
by continuous flux of supercoiling that is generated by transcription and is
then progressively released by action of TOPIIB located at TADs borders. Our
model explains what can be the driving force of chromatin loop extrusion and how
it can be ensured that loops grow quickly and in a good direction. In addition,
the supercoiling-driven loop extrusion mechanism is consistent with earlier
explanations proposing why TADs flanked by convergent CTCF binding sites form
more stable chromatin loops than TADs flanked by divergent CTCF binding sites.
We discuss the role of supercoiling in stimulating enhancer promoter contacts
and propose that transcription of eRNA sends the first wave of supercoiling that
can activate mRNA transcription in a given TAD. Chromatin loop extrusion is a popular model for the formation of CTCF loops and
topological domains. Recent HiC data have revealed a strong bias in favour of a
particular arrangement of the CTCF binding motifs that stabilize loops, and
extrusion is the only model to date which can explain this. However, the model
requires a motor to generate the loops, and although cohesin is a strong
candidate for the extruding factor, a suitable motor protein (or a motor
activity in cohesin itself) has yet to be found. Here we explore a new
hypothesis: that there is no motor, and thermal motion within the nucleus drives
extrusion. Using theoretical modelling and computer simulations we ask whether
such diffusive extrusion could feasibly generate loops. Our simulations uncover
an interesting ratchet effect (where an osmotic pressure promotes loop growth),
and suggest, by comparison to recent in vitro and in vivo measurements, that
diffusive extrusion can in principle generate loops of the size observed in the
data. Extra View on : C. A. Brackley, J. Johnson, D. Michieletto, A. N. Morozov,
M. Nicodemi, P. R. Cook, and D. Marenduzzo "Non-equilibrium chromosome looping
via molecular slip-links", Physical Review Letters 119 138101 (2017). Author information:
(1)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.
(2)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX
77030, USA; Department of Structural Biology, Stanford University School of
Medicine, Stanford, CA 94305, USA.
(3)Gene Regulation, Laboratory of Pathology, NCI, NIH, Bethesda, MD 20892, USA.
(4)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX
77030, USA.
(5)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX
77030, USA; Department of Computer Science, Stanford University, Stanford, CA
94305, USA.
(6)Laboratory of Genome Integrity, NCI, NIH, Bethesda, MD 20892, USA.
(7)The Jackson Laboratory for Genomic Medicine and Department of Genetic and
Development Biology, University of Connecticut, Farmington, CT 06030, USA.
(8)Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852, USA.
(9)Center for Theoretical Biological Physics, Rice University, Houston, TX
77030, USA.
(10)The Center for Genome Architecture, Baylor College of Medicine, Houston, TX
77030, USA; Center for Theoretical Biological Physics, Rice University, Houston,
TX 77030, USA; Shanghai Institute for Advanced Immunochemical Studies,
ShanghaiTech University, Shanghai, China. Electronic address: [email protected].
(11)Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA; Center of
Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. Electronic address:
[email protected]. As predicted by the notion that sister chromatid cohesion is mediated by
entrapment of sister DNAs inside cohesin rings, there is perfect correlation
between co-entrapment of circular minichromosomes and sister chromatid cohesion.
In most cells where cohesin loads without conferring cohesion, it does so by
entrapment of individual DNAs. However, cohesin with a hinge domain whose
positively charged lumen is neutralized loads and moves along chromatin despite
failing to entrap DNAs. Thus, cohesin engages chromatin in non-topological, as
well as topological, manners. Since hinge mutations, but not Smc-kleisin
fusions, abolish entrapment, DNAs may enter cohesin rings through hinge opening.
Mutation of three highly conserved lysine residues inside the Smc1 moiety of
Smc1/3 hinges abolishes all loading without affecting cohesin's recruitment to
CEN loading sites or its ability to hydrolyze ATP. We suggest that loading and
translocation are mediated by conformational changes in cohesin's hinge driven
by cycles of ATP hydrolysis. Structural maintece of chromosomes (SMC) complexes shape the genomes of
virtually all organisms, but how they function remains incompletely understood.
Recent studies in bacteria and eukaryotes have led to a unifying model in which
these ring-shaped ATPases act along contiguous DNA segments, processively
enlarging DNA loops. In support of this model, single-molecule imaging
experiments indicate that Saccharomyces cerevisiae condensin complexes can
extrude DNA loops in an ATP-hydrolysis-dependent manner in vitro. Here, using
time-resolved high-throughput chromosome conformation capture (Hi-C), we
investigate the interplay between ATPase activity of the Bacillus subtilis SMC
complex and loop formation in vivo. We show that point mutants in the SMC
nucleotide-binding domain that impair but do not eliminate ATPase activity not
only exhibit delays in de novo loop formation but also have reduced rates of
processive loop enlargement. These data provide in vivo evidence that SMC
complexes function as loop extruders. Eukaryotic genomes are folded into loops and topologically associating domains,
which contribute to chromatin structure, gene regulation, and gene
recombination. These structures depend on cohesin, a ring-shaped DNA-entrapping
adenosine triphosphatase (ATPase) complex that has been proposed to form loops
by extrusion. Such an activity has been observed for condensin, which forms
loops in mitosis, but not for cohesin. Using biochemical reconstitution, we
found that single human cohesin complexes form DNA loops symmetrically at rates
up to 2.1 kilo-base pairs per second. Loop formation and maintece depend on
cohesin's ATPase activity and on NIPBL-MAU2, but not on topological entrapment
of DNA by cohesin. During loop formation, cohesin and NIPBL-MAU2 reside at the
base of loops, which indicates that they generate loops by extrusion. Our
results show that cohesin and NIPBL-MAU2 form an active holoenzyme that
interacts with DNA either pseudo-topologically or non-topologically to extrude
genomic interphase DNA into loops. Cohesin is a chromosome-bound, multisubunit adenosine triphosphatase complex.
After loading onto chromosomes, it generates loops to regulate chromosome
functions. It has been suggested that cohesin organizes the genome through loop
extrusion, but direct evidence is lacking. Here, we used single-molecule imaging
to show that the recombit human cohesin-NIPBL complex compacts both naked and
nucleosome-bound DNA by extruding DNA loops. DNA compaction by cohesin requires
adenosine triphosphate (ATP) hydrolysis and is force sensitive. This compaction
is processive over tens of kilobases at an average rate of 0.5 kilobases per
second. Compaction of double-tethered DNA suggests that a cohesin dimer extrudes
DNA loops bidirectionally. Our results establish cohesin-NIPBL as an ATP-driven
molecular machine capable of loop extrusion. |
What is the effect of carbamazepine on CYP3A4? | Carbamazepine is an inducer of CYP3A4. | Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under
investigation for the treatment of peripheral neuropathic pain conditions,
including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine
diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome
P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We
conducted a double-blind, randomized, placebo-controlled, parallel-group,
single-center phase 1 study to investigate the impact of coadministering
vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in
healthy volunteers, the safety and tolerability of combined treatment, and PK
recovery of vixotrigine following carbamazepine discontinuation. Randomly
assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg
twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received
vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times,
whole-blood samples were collected for PK assessment. Statistical analyses were
performed on the log-transformed PK parameters area under the concentration-time
curve within a dosing interval (AUC0-tau ) and maximum observed concentration
(Cmax ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0-tau
and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with
carbamazepine compared with placebo. Seven days after carbamazepine
discontinuation, vixotrigine AUC0-tau and Cmax remained 24.5% and 21.4% lower
compared with placebo. Carbamazepine AUC0-tau and Cmax were <10% lower when
coadministered with vixotrigine compared on days 15 and 21.
Vixotrigine/carbamazepine coadministration was well tolerated. These results
suggest that vixotrigine does not have an effect on carbamazepine PK, and
although carbamazepine has an effect on the exposure of vixotrigine, the effect
is not considered clinically relevant. |
Is there an upper limit on the functional fraction of the human genome? | Mutational load considerations lead to the conclusion that the functional fraction within the human genome cannot exceed 25%, and is probably considerably lower. | For the human population to maintain a constant size from generation to
generation, an increase in fertility must compensate for the reduction in the
mean fitness of the population caused, among others, by deleterious mutations.
The required increase in fertility due to this mutational load depends on the
number of sites in the genome that are functional, the mutation rate, and the
fraction of deleterious mutations among all mutations in functional regions.
These dependencies and the fact that there exists a maximum tolerable
replacement level fertility can be used to put an upper limit on the fraction of
the human genome that can be functional. Mutational load considerations lead to
the conclusion that the functional fraction within the human genome cannot
exceed 25%, and is probably considerably lower. |
What is Couvelaire Uterus? | Couvelaire uterus is hematic infiltration uterine myometrium due to the formation of a massive hematoma. It is charecterised by dark purple patches with ecchymosis and indurations. | Uteroplacental apoplexy is a rare but nonfatal complication of severe forms of
placental abruption. It occurs when vascular damage within the placenta causes
hemorrhaging that progresses to and infiltrates the wall of the uterus. It is a
syndrome that can only be diagnosed by direct visualization or biopsy (or both).
For this reason, its occurrence is perhaps underreported and underestimated in
the literature. The subject of this report is a 24-year-old pregt woman who
had a placental abruption an in whom classic uteroplacental apoplexy was
diagnosed at the time of her cesarean section. Amniotic fluid (AF) embolism is a rare but catastrophic complication of
pregcy. We present the first case where the debris was seen in the maternal
uterine veins at the time of cesarean section. During a cesarean delivery
performed for deteriorating fetal status and in conjunction with massive
hydramnios; air bubbles and vernix were observed in the left uterine vein and in
an area of Couvelaire appearance of the uterine fundus. As the patient was
clinically stable and desired retained fertility, a decision was made to attempt
to contain the debris in the uterine vasculature. The infundibulopelvic ligament
and uterine arteries were ligated and the area of Couvelaire uterus was
oversewn. With the exception of a mild laboratory coagulopathy, which required
no specific treatment, the patient did well. The area of Couvelaire uterus is
the likely portal for the debris seen in this patient's vasculature. Containment
appears to have averted the AF embolism syndrome. Couvelaire uterus is rare in modern obstetrics, a state of the hematic
infiltration uterine myometrium due to the formation of a massive hematoma
retroplacental that can not be sold to the vaginal cavity through the cervical
route. In all cases described in the present there is a history of placental
abruption during labor or trauma, and drugs that affect the collapse of the
uterus-placental circulation A 32-year-old multigravid patient at 21 weeks gestation presents with major
concealed placental abruption and subsequent fetal demise. During an eventually
failed misoprostol regime aiming for vaginal delivery she develops severe
disseminated intravascular coagulopathy. Subsequent hysterotomy reveals
Couvelaire uterus with major haemorrhage and requires subtotal hysterectomy for
haemostasis. This case highlights the severity of the systemic response to
abruption and fetal demise in utero and the multifactorial nature of its
management. |
What protein is Otof gene encoding? | The OTOF gene encodes otoferlin, a critical protein at the synapse of auditory sensory cells, the inner hair cells (IHCs) | BACKGROUND: Hereditary hearing loss is characterized by a very high genetic
heterogeneity. The OTOF (Locus: DFNB9), encoding otoferlin, is reported to be
one of the major causes of non-syndromic hearing loss, and is also reported to
be the most common cause of non-syndromic recessive auditory neuropathy spectrum
disorder.
METHODS: In this study, whole exome sequencing was employed for detection of
novel pathogenic variant that segregates with autosomal recessive nonsyndromic
hearing loss in a tribal family from Rajouri, Jammu and Kashmir. Proband was a
9-year-old male born to first-cousin parents and presented with sensorineural
hearing loss since birth. Family resides in an area with high consanguinity and
lack of basic health care facilities including genetic counselling services.
RESULTS: We report a novel OTOF pathogenic variant NM_194248.2:c.4249_4250insG
(p.Ser1417CysfsTer4) co-segregating with hearing loss in this family and not
present in any public databases.
CONCLUSIONS: Our findings not only extend the geographical and mutational
spectrum of autosomal recessive nonsyndromic hearing loss but also support the
need for introducing genetic counselling services to rural and tribal areas in
India with high consanguinity. Different mutations of the OTOF gene, encoding for otoferlin protein expressed
in the cochlear inner hair cells, induces a form of deafness that is the major
cause of nonsyndromic recessive auditory neuropathy spectrum disorder in humans.
We report the generation of the first large animal model of OTOF mutations using
the CRISPR system associated with different Cas9 components (mRNA or protein)
assisted by single strand oligodeoxynucleotides (ssODN) to induce
homology-directed repair (HDR). Zygote microinjection was performed with two
sgRNA targeting exon 5 and 6 associated to Cas9 mRNA or protein (RNP) at
different concentrations in a mix with an ssODN template targeting HDR in exon 5
containing two STOP sequences. A total of 73 lambs were born, 13 showing indel
mutations (17.8%), 8 of which (61.5%) had knock-in mutations by HDR. Higher
concentrations of Cas9-RNP induced targeted mutations more effectively, but
negatively affected embryo survival and pregcy rate. This study reports by
the first time the generation of OTOF disrupted sheep, which may allow better
understanding and development of new therapies for human deafness related to
genetic disorders. These results support the use of CRISPR/Cas system assisted
by ssODN as an effective tool for gene editing in livestock. |
What is hypercapnia? | Hypercapnia is also known as High CO2 retention. | The effect of hypercapnia (an increase in CO(2) concentration in the blood) on
the functional magnetic resoce imaging (fMRI) blood oxygenation level
dependent (BOLD) haemodynamic response has been well characterised and is
commonly used for BOLD calibration. However, relatively little is known of the
effect of hypercapnia on the electrical brain processes that underlie the BOLD
response. Here, we investigate the effect of hypercapnia on resting and stimulus
induced changes in neural oscillations using a feed-forward low gas flow system
to deliver a reliable and repeatable level of hypercapnia.
Magnetoencephalography (MEG) is used in conjunction with beamformer source
localisation algorithms to non-invasively image changes in oscillatory
amplitude. At rest, we find robust oscillatory power loss in the alpha
(8Hz-13Hz), beta (13Hz-30Hz) and low gamma (30Hz-50Hz) frequency bands in
response to hypercapnia. Further, we show that the spatial signature of this
power loss differs across frequency bands, with the largest effect being
observed for the beta band in sensorimotor cortices. We also measure changes in
oscillatory activity induced by visual and motor events, and the effect of
hypercapnia on these changes; whilst the percentage change in oscillatory
activity on activation was largely unaffected by hypercapnia, the absolute
change in oscillatory amplitude differed between normocapnia and hypercapnia.
This work supports invasive recordings made in animals, and the results have
potential implications for calibrated BOLD studies. Hypercapnia, an elevation of the level of carbon dioxide (CO2) in blood and
tissues, is a marker of poor prognosis in chronic obstructive pulmonary disease
and other pulmonary disorders. We previously reported that hypercapnia inhibits
the expression of TNF and IL-6 and phagocytosis in macrophages in vitro. In the
present study, we determined the effects of normoxic hypercapnia (10% CO2, 21%
O2, and 69% N2) on outcomes of Pseudomonas aeruginosa pneumonia in BALB/c mice
and on pulmonary neutrophil function. We found that the mortality of P.
aeruginosa pneumonia was increased in 10% CO2-exposed compared with air-exposed
mice. Hypercapnia increased pneumonia mortality similarly in mice with acute and
chronic respiratory acidosis, indicating an effect unrelated to the degree of
acidosis. Exposure to 10% CO2 increased the burden of P. aeruginosa in the
lungs, spleen, and liver, but did not alter lung injury attributable to
pneumonia. Hypercapnia did not reduce pulmonary neutrophil recruitment during
infection, but alveolar neutrophils from 10% CO2-exposed mice phagocytosed fewer
bacteria and produced less H2O2 than neutrophils from air-exposed mice.
Secretion of IL-6 and TNF in the lungs of 10% CO2-exposed mice was decreased 7
hours, but not 15 hours, after the onset of pneumonia, indicating that
hypercapnia inhibited the early cytokine response to infection. The increase in
pneumonia mortality caused by elevated CO2 was reversible when hypercapnic mice
were returned to breathing air before or immediately after infection. These
results suggest that hypercapnia may increase the susceptibility to and/or
worsen the outcome of lung infections in patients with severe lung disease. Hypercapnia, the elevation of CO2 in blood and tissue, commonly develops in
patients with advanced lung disease and severe pulmonary infections, and it is
associated with high mortality. We previously reported that hypercapnia alters
expression of host defense genes, inhibits phagocytosis, and increases the
mortality of Pseudomonas pneumonia in mice. However, the effect of hypercapnia
on autophagy, a conserved process by which cells sequester and degrade proteins
and damaged organelles that also plays a key role in antimicrobial host defense
and pathogen clearance, has not previously been examined. In the present study
we show that hypercapnia inhibits autophagy induced by starvation, rapamycin,
LPS, heat-killed bacteria, and live bacteria in the human macrophage. Inhibition
of autophagy by elevated CO2 was not attributable to acidosis. Hypercapnia also
reduced macrophage killing of Pseudomonas aeruginosa. Moreover, elevated CO2
induced the expression of Bcl-2 and Bcl-xL, antiapoptotic factors that
negatively regulate autophagy by blocking Beclin 1, an essential component of
the autophagy initiation complex. Furthermore, small interfering RNA targeting
Bcl-2 and Bcl-xL and the small molecule Z36, which blocks Bcl-2 and Bcl-xL
binding to Beclin 1, prevented hypercapnic inhibition of autophagy and bacterial
killing. These results suggest that targeting the Bcl-2/Bcl-xL-Beclin 1
interaction may hold promise for ameliorating hypercapnia-induced
immunosuppression and improving resistance to infection in patients with
advanced lung disease and hypercapnia. Molecular oxygen and carbon dioxide are the primary gaseous substrate and
product of oxidative metabolism, respectively. Hypoxia (low oxygen) and
hypercapnia (high carbon dioxide) are co-incidental features of the tissue
microenvironment in a range of pathophysiologic states, including acute and
chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master
regulator of the transcriptional response to hypoxia; however, little is known
about the impact of hypercapnia on gene transcription. Because of the
relationship between hypoxia and hypercapnia, we investigated the effect of
hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability
and HIF target gene expression both in mice and cultured cells in a manner that
was at least in part independent of the canonical O2-dependent HIF degradation
pathway. The suppressive effects of hypercapnia on HIF-α protein stability could
be mimicked by reducing intracellular pH at a constant level of partial pressure
of CO2 Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase that
blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α
protein. Based on these results, we hypothesize that hypercapnia
counter-regulates activation of the HIF pathway by reducing intracellular pH and
promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may
play a key role in the pathophysiology of diseases where HIF is implicated. Carbon dioxide (CO₂) retention, or hypercapnia, is a known risk of diving that
can cause mental and physical impairments leading to life-threatening accidents.
Often, such accidents occur due to elevated inspired carbon dioxide. For
instance, in cases of CO₂ elimination system failures during rebreather dives,
elevated inspired partial pressure of carbon dioxide (PCO₂) can rapidly lead to
dangerous levels of hypercapnia. Elevations in PaCO₂ (arterial pressure of PCO₂)
can also occur in divers without a change in inspired PCO₂. In such cases,
hypercapnia occurs due to alveolar hypoventilation. Several factors of the dive
environment contribute to this effect through changes in minute ventilation and
dead space. Predomitly, minute ventilation is reduced in diving due to
changes in respiratory load and associated changes in respiratory control.
Minute ventilation is further reduced by hyperoxic attenuation of
chemosensitivity. Physiologic dead space is also increased due to elevated
breathing gas density and to hyperoxia. The Haldane effect, a reduction in CO₂
solubility in blood due to hyperoxia, may contribute indirectly to hypercapnia
through an increase in mixed venous PCO₂. In some individuals, low ventilatory
response to hypercapnia may also contribute to carbon dioxide retention. This
review outlines what is currently known about hypercapnia in diving, including
its measurement, cause, mental and physical effects, and areas for future study. Hypercapnia, the elevation of CO2 in blood and tissues, commonly occurs in
severe acute and chronic respiratory diseases, and is associated with increased
risk of mortality. Recent studies have shown that hypercapnia adversely affects
innate immunity, host defense, lung edema clearance and cell proliferation.
Airway epithelial dysfunction is a feature of advanced lung disease, but the
effect of hypercapnia on airway epithelium is unknown. Thus, in the current
study we examined the effect of normoxic hypercapnia (20% CO2 for 24 h) vs
normocapnia (5% CO2), on global gene expression in differentiated normal human
airway epithelial cells. Gene expression was assessed on Affymetrix microarrays,
and subjected to gene ontology analysis for biological process and
cluster-network representation. We found that hypercapnia downregulated the
expression of 183 genes and upregulated 126. Among these, major gene clusters
linked to immune responses and nucleosome assembly were largely downregulated,
while lipid metabolism genes were largely upregulated. The overwhelming majority
of these genes were not previously known to be regulated by CO2. These changes
in gene expression indicate the potential for hypercapnia to impact bronchial
epithelial cell function in ways that may contribute to poor clinical outcomes
in patients with severe acute or advanced chronic lung diseases. High CO2 retention, or hypercapnia, is associated with worse outcomes in
patients with chronic pulmonary diseases. Skeletal muscle wasting is also an
independent predictor of poor outcomes in patients with acute and chronic
pulmonary diseases. Although previous evidence indicates that high CO2
accelerates skeletal muscle catabolism via AMPK (AMP-activated protein
kinase)-FoxO3a-MuRF1 (E3-ubiquitin ligase muscle RING finger protein 1), little
is known about the role of high CO2 in regulating skeletal muscle anabolism. In
the present study, we investigated the potential role of high CO2 in attenuating
skeletal muscle protein synthesis. We found that locomotor muscles from patients
with chronic CO2 retention demonstrated depressed ribosomal gene expression in
comparison with locomotor muscles from non-CO2-retaining individuals, and
analysis of the muscle proteome of normo- and hypercapnic mice indicates
reduction of important components of ribosomal structure and function. Indeed,
mice chronically kept under a high-CO2 environment show evidence of skeletal
muscle downregulation of ribosomal biogenesis and decreased protein synthesis as
measured by the incorporation of puromycin into skeletal muscle. Hypercapnia did
not regulate the mTOR pathway, and rapamycin-induced deactivation of mTOR did
not cause a decrease in ribosomal gene expression. Loss-of-function studies in
cultured myotubes showed that AMPKα2 regulates CO2-mediated reductions in
ribosomal gene expression and protein synthesis. Although previous evidence has
implicated TIF1A (transcription initiation factor-1α) and KDM2A (lysine-specific
demethylase 2A) in AMPK-driven regulation of ribosomal gene expression, we found
that these mediators were not required in the high CO2-induced depressed protein
anabolism. Our research supports future studies targeting ribosomal biogenesis
and protein synthesis to alleviate the effects of high CO2 on skeletal muscle
turnover. INTRODUCTION: Chronic non-invasive ventilation (NIV) has become evidence-based
care for stable hypercapnic COPD patients. While the number of patients
increases, home initiation of NIV would greatly alleviate the healthcare burden.
We hypothesise that home initiation of NIV with the use of telemedicine in
stable hypercapnic COPD is non-inferior to in-hospital NIV initiation.
METHODS: Sixty-seven stable hypercapnic COPD patients were randomised to
initiation of NIV in the hospital or at home using telemedicine. Primary outcome
was daytime arterial carbon dioxide pressure (PaCO2) reduction after 6 months
NIV, with a non-inferiority margin of 0.4 kPa. Secondary outcomes were
health-related quality of life (HRQoL) and costs.
RESULTS: Home NIV initiation was non-inferior to in-hospital initiation
(adjusted mean difference in PaCO2 change home vs in-hospital: 0.04 kPa (95% CI
-0.31 to 0.38 kPa), with both groups showing a PaCO2 reduction at 6 months
compared with baseline (home: from 7.3±0.9 to 6.4±0.8 kPa (p<0.001) and
in-hospital: from 7.4±1.0 to 6.4±0.6 kPa (p<0.001)). In both groups, HRQoL
improved without a difference in change between groups (Clinical COPD
Questionnaire total score-adjusted mean difference 0.0 (95% CI -0.4 to 0.5)).
Furthermore, home NIV initiation was significantly cheaper (home: median €3768
(IQR €3546-€4163) vs in-hospital: median €8537 (IQR €7540-€9175); p<0.001).
DISCUSSION: This is the first study showing that home initiation of chronic NIV
in stable hypercapnic COPD patients, with the use of telemedicine, is
non-inferior to in-hospital initiation, safe and reduces costs by over 50%.
TRIAL REGISTRATION NUMBER: NCT02652559. BACKGROUND: Considerable variability exists regarding CO2 management in early
ARDS, with the impact of arterial CO2 tension on management and outcomes poorly
understood.
RESEARCH QUESTION: To determine the prevalence and impact of hypocapnia and
hypercapnia on the management and outcomes of patients with early ARDS enrolled
in the Large Observational Study to Understand the Global Impact of Severe Acute
Respiratory Failure (LUNG SAFE) study, an international multicenter
observational study.
STUDY DESIGN AND METHODS: Our primary objective was to examine the prevalence of
day 1 and sustained (day 1 and 2) hypocapnia (Paco2 < 35 mm Hg), normocapnia
(Paco2 35-45 mm Hg), and hypercapnia (Paco2 > 45 mm Hg) in patients with ARDS.
Secondary objectives included elucidating the effect of CO2 tension on
ventilatory management and examining the relationship with ARDS outcome.
RESULTS: Of 2,813 patients analyzed, 551 (19.6%; 95%CI, 18.1-21.1) were
hypocapnic, 1,018 (36.2%; 95% CI, 34.4-38.0) were normocapnic, and 1,214 (43.2%;
95% CI, 41.3-45.0) were hypercapnic, on day 1. Sustained hypocapnia was seen in
252 (9.3%; 95% CI, 8.2-10.4), sustained normocapnia in 544 (19.3%; 95% CI,
17.9-20.8), and sustained hypercapnia in 654 (24.1%; 95% CI, 22.5-25.7)
patients. Hypocapnia was more frequent and severe in patients receiving
noninvasive ventilation but also was observed in patients on controlled
mechanical ventilation. Sustained hypocapnia was more frequent in middle-income
countries, whereas sustained hypercapnia was more frequent in Europe. ARDS
severity profile was highest in sustained hypercapnia, and these patients
received more protective ventilation. No independent association was seen
between arterial CO2 and outcome. In propensity-matched analyses, the hospital
mortality rate was 36% in both sustained normocapnic and hypercapnic patients
(P = 1.0). ICU mortality was higher in patients with mild to moderate ARDS
receiving sustained hypocapnia (38.1%) compared with normocapnia (27.1%).
INTERPRETATION: No evidence was found for benefit or harm with hypercapnia. Of
concern, ICU mortality was higher with sustained hypocapnia in mild to moderate
ARDS. |
What is TSA-Seq used for? | TSA-Seq provides a "cytological ruler" for estimating mean chromosomal distances from nuclear speckles genome-wide and for predicting several Mbp chromosome trajectories between nuclear compartments without sophisticated computational modeling. | While nuclear compartmentalization is an essential feature of three-dimensional
genome organization, no genomic method exists for measuring chromosome distances
to defined nuclear structures. In this study, we describe TSA-Seq, a new mapping
method capable of providing a "cytological ruler" for estimating mean
chromosomal distances from nuclear speckles genome-wide and for predicting
several Mbp chromosome trajectories between nuclear compartments without
sophisticated computational modeling. Ensemble-averaged results in K562 cells
reveal a clear nuclear lamina to speckle axis correlated with a striking spatial
gradient in genome activity. This gradient represents a convolution of multiple
spatially separated nuclear domains including two types of transcription "hot
zones." Transcription hot zones protruding furthest into the nuclear interior
and positioning deterministically very close to nuclear speckles have higher
numbers of total genes, the most highly expressed genes, housekeeping genes,
genes with low transcriptional pausing, and super-enhancers. Our results
demonstrate the capability of TSA-Seq for genome-wide mapping of nuclear
structure and suggest a new model for spatial organization of transcription and
gene expression. |
Does the HercepTest use a polycloncal or monoclonal antibody? | The HercepTest uses a polyclonal antibody. | We compared a monoclonal antibody (SV2-61γ) and a polyclonal antibody (Dako
HercepTest) in immunohistochemical assessments of human epidermal growth factor
receptor 2 (HER2) expression in 73 samples of advanced gastric cancer. Results
were scored as 0 to 3+, and equivocal or discordant (SV2-61γ/Dako HercepTest =
0/2+, 0/3+, 1+/3+ or 2+/3+) cases were subjected to fluorescence in situ
hybridization (FISH) analysis. The frequencies of HER2 scores of 2+ or 3+ were
15.1% (11/73) using SV2-61γ and 38.4% (28/73) using Dako HercepTest. All of the
equivocal or discordant cases with a HER2 score of 3+ using Dako HercepTest
exhibited amplification of the HER2 gene regardless of the HER2 score determined
with SV2-61γ. The results of the HER2 tests differed according to the antibodies
used for immunohistochemistry that preceded FISH analysis, being 15.1% (11/73)
using SV2-61γ and 23.3% (17/73) using Dako HercepTest. Thus, therapeutic
decisions might be markedly influenced by the selection of antibody used in the
HER2 test. |
Describe participants' experiences from the 100,000 genomes project | Interviewees' decisions to participate in 100 kG P were based on interpersonal and institutional trust in the NHS, and on an investment in improving care for the future. Interviewees relied upon receiving good ongoing NHS care for managing their own or their child's rare disease, but they worried about what their relationships with NHS healthcare professionals would be like in future. A few participants worried about whether Genomics England's biorepository would remain protected and an asset of the NHS. | |
What is the role of elagolix in treatment of uterine fibroids? | Elagolix is approved for the treatment of moderate to severe pain caused by endometriosis. Elagolix is also effective for heavy bleeding caused by uterine fibroids. | OBJECTIVE: To evaluate the safety and efficacy of elagolix vs. placebo and
elagolix with low-dose E2/progestogen add-back therapy.
DESIGN: Proof-of-concept, dose-ranging, multiple-cohort study.
SETTING: Clinics.
PATIENT(S): Premenopausal women with fibroids and heavy menstrual bleeding
(menstrual blood loss [MBL] >80 mL per cycle).
INTERVENTION(S): Three months' treatment with elagolix alone: 100 mg twice daily
(BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the
600 mg QD arm were placebo controlled); or elagolix plus add-back therapy:
200 mg BID plus continuous low-dose E2 0.5 mg/norethindrone acetate 0.1 mg or
elagolix 300 mg BID plus E2 1 mg continuously and cyclical P 200 mg.
MAIN OUTCOME MEASURE(S): Least-squares mean percentage change in MBL; adverse
events (AEs).
RESULT(S): Mean age was 41.8 years; 73.8% were black; mean baseline MBL was
267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix
with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment
period. The MBL percentage change from baseline to last 28 days was
significantly greater with elagolix alone (range, -72% to -98%; dose-dependent
reduction was highest with 300 mg BID) vs. placebo (range, -8% to -41%); mean
percentage changes with add-back regimens were -80% to -85%. Overall AEs were
dose independent (elagolix alone, 70.0%-81.3%) but lower with placebo (56.0%)
and add-back regimens (55.6%-70.6%). Hot flush was the most common AE (elagolix
alone, 45.5%-62.5%; placebo, 12.0%; add-back regimens, 18.5%-26.5%).
CONCLUSION(S): Elagolix significantly reduced heavy menstrual bleeding in women
with fibroids. Low-dose add-back regimens substantially reduced flushing.
CLINICAL TRIAL REGISTRATION NUMBER: NCT01441635. Elagolix (ORILISSA™), an orally bioavailable, second-generation, non-peptide
gonadotropin-releasing hormone (GnRH) receptor antagonist, is being developed
AbbVie and Neurocrine Biosciences for the treatment of reproductive
hormone-dependent disorders in women. In July 2018, the US FDA approved elagolix
tablets for the management of moderate to severe pain associated with
endometriosis. This approval was based on positive results in two replicate
phase III trials; additional phase III trials in the USA, Canada and Puerto Rico
are currently evaluating elagolix as both monotherapy and in combination with
low-dose hormone add-back therapy in the same indication. Elagolix with and
without low-dose hormone add-back therapy is also undergoing phase III clinical
development for heavy menstrual bleeding associated with uterine fibroids in the
aforementioned locations. This article summarizes the milestones in the
development of elagolix leading to its first approval for the management of
moderate to severe pain associated with endometriosis. The aim of these studies was to assess the safety and pharmacokinetics of
elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following
oral administration in women with renal or hepatic impairment. Two phase 1
studies were conducted in adult women with normal renal function versus renal
impairment (reduced study), and normal hepatic function versus hepatic
impairment (full study design). All women received a single dose of elagolix 200
mg (renal) or 150 mg (hepatic). Intensive pharmacokinetic blood samples were
collected. Elagolix exposures were comparable in women with normal renal
function and those with moderate/severe renal impairment or end-stage renal
disease. Elagolix exposures also appeared to be similar in women with normal
hepatic function and women with mild hepatic impairment. Elagolix area under the
curve in women with moderate hepatic impairment and with severe hepatic
impairment was approximately 3-fold and 7-fold higher than in women with normal
hepatic function. The adverse event incidence was low, with the main events
being mild nausea and headache. No dosage adjustment was needed in women with
renal impairment or women with mild hepatic impairment. Although an elagolix
dose of 150 mg once daily may be used in women with moderate hepatic impairment
for up to 6 months, this elagolix dose should not be used in women with severe
hepatic impairment. CONTEXT: Elagolix is an oral gonadotropin-releasing hormone (GnRH) antagonist
recently approved for the treatment of endometriosis-associated pain and being
developed for heavy menstrual bleeding associated with uterine fibroids.
OBJECTIVE: The objective was to evaluate the effects of elagolix on ovulation
and ovarian sex hormones.
DESIGN AND SETTING: This was a randomized, open-label, multicenter study.
PARTICIPANTS: Participants were healthy ovulatory women aged 18 to 40 years.
INTERVENTIONS: Elagolix was administered orally for 3 continuous 28-day dosing
intervals at 100 to 200 mg once daily (QD), 100 to 300 mg twice daily (BID), and
300 mg BID plus estradiol/norethindrone acetate (E2/NETA) 1/0.5 mg QD.
MAIN OUTCOME MEASURES: The main outcomes measures were ovulation rates measured
by transvaginal ultrasound, progesterone concentrations, and hormone
suppression.
RESULTS: Elagolix suppressed ovulation in a dose-dependent manner. The
percentage of women who ovulated was highest at 100 mg QD (78%), intermediate at
150 and 200 mg QD and 100 mg BID (47%-57%), and lowest at 200 and 300 mg BID
(32% and 27%, respectively). Addition of E2/NETA to elagolix 300 mg BID further
suppressed the ovulation rate to 10%. Elagolix also suppressed luteinizing
hormone and follicle stimulating hormone in a dose-dependent manner, leading to
dose-dependent suppression of estradiol and progesterone. Elagolix had no effect
on serum biomarker of ovarian reserve, and reduced endometrial thickness
compared to the screening cycle.
CONCLUSION: Women being treated with elagolix may ovulate and should use
effective methods of contraception. The rate of ovulation was lowest with
elagolix 300 mg BID plus E2/NETA 1/0.5 mg QD. BACKGROUND: Uterine fibroids are one of the most common neoplasms found among
women globally, with a prevalence of approximately 11 million women in the
United States alone. The morbidity of this common disease is significant because
it is the leading cause of hysterectomy and causes significant functional
impairment for women of reproductive age. Factors including age, body mass
index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and
fibroid volume influence the incidence of fibroids and severity of symptoms.
Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that
competitively inhibits pituitary gonadotropin-releasing hormone receptor
activity and suppresses the release of gonadotropins from the pituitary gland,
resulting in dose-dependent suppression of ovarian sex hormones, follicular
growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2
replicate multicenter, double-blind, randomized, placebo-controlled, phase 3
studies, treatment of premenopausal women with elagolix with hormonal add-back
therapy demonstrated reduction in heavy menstrual bleeding associated with
uterine fibroids.
OBJECTIVE: This analysis aimed to evaluate the safety and efficacy of elagolix
(300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone
acetate once a day) in reducing heavy menstrual bleeding associated with uterine
fibroids in various subgroups of women over 6 months of treatment.
STUDY DESIGN: Data were pooled from Elaris Uterine Fibroid-1 and Uterine
Fibroid-2 studies, which evaluated premenopausal women (18-51 years) with heavy
menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin
methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups
analyzed included age, body mass index, race, ethnicity, baseline menstrual
blood loss, fibroid location, and uterine and primary fibroid volume (largest
fibroid identified by ultrasound). The primary endpoint was the proportion of
women with <80 mL menstrual blood loss during the final month and ≥50% menstrual
blood loss reduction from baseline to final month. Secondary and other efficacy
endpoints included mean change in menstrual blood loss from baseline to final
month, amenorrhea, symptom severity, and health-related quality of life. Adverse
events and other safety endpoints were monitored.
RESULTS: The overall pooled Elaris Uterine Fibroid-1 and Uterine Fibroid-2
population was typical of women with fibroids, with a mean age of 42.4 (standard
deviation, 5.4) years and a mean body mass index of 33.6 (standard deviation,
7.3) kg/m2 and 67.6% of participants being black or African American women. A
wide range of baseline uterine and fibroid volumes and menstrual blood loss were
also represented in the overall pooled study population. In all subgroups, the
proportion of responders to the primary endpoint, mean change in menstrual blood
loss, amenorrhea, reduction in symptom severity, and improvement in
health-related quality of life were clinically meaningfully greater for women
who received elagolix with add-back therapy than those who received placebo and
consistent with the overall pooled study population for the primary endpoint
(72.2% vs 9.3%), mean change in menstrual blood loss (-172.5 mL vs -0.8 mL),
amenorrhea (50.4% vs 4.5%), symptom severity (-37.1 vs -9.2), and health-related
quality of life score (39.9 vs 8.9). Adverse events by subgroup were consistent
with the overall pooled study population.
CONCLUSION: Elagolix with hormonal add-back therapy was effective in reducing
heavy menstrual bleeding associated with uterine fibroids independent of age,
body mass index, race, ethnicity, baseline menstrual blood loss, fibroid
location, and uterine and primary fibroid volume. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist indicated
for the management of endometriosis-associated pain and in combination with
estradiol/norethindrone acetate indicated for the management of heavy menstrual
bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.
Elagolix coadministered with estradiol/norethindrone acetate is in late-stage
development for the management of heavy menstrual bleeding associated with
uterine fibroids. Based on the in vitro profile of elagolix metabolism and
disposition, 9 drug-drug interaction (DDI) studies evaluating the victim and
perpetrator characteristics of elagolix were conducted in 144 healthy
volunteers. As a victim of cytochrome P450 (CYPs) and transporter-mediated DDIs,
elagolix area under the curve (AUC) increased by ∼2-fold following
coadministration with ketoconazole and by ∼5- and ∼2-fold with single and
multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased
midazolam AUC (90% confidence interval) by 54% (50%-59%) and increased digoxin
AUC by 32% (23%-41%). Elagolix decreased rosuvastatin AUC by 40% (29%-50%). No
clinically significant changes in exposure on coadministration with sertraline
or fluconazole occurred. A elagolix 150-mg once-daily regimen should be limited
to 6 months with strong CYP3A inhibitors and rifampin because of the potential
increase in bone mineral density loss, as described in the drug label. A 200-mg
twice-daily regimen is recommended for no more than 1 month with strong CYP3A
inhibitors and not recommended with rifampin. Elagolix is contraindicated with
strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and
gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when
coadministered with elagolix, and individualize therapy based on patient
response. Clinical monitoring is recommended for P-glycoprotein substrates with
a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for
sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when
coadministered. |
Where is the organ of Corti located? | The cochlea, a coiled structure located in the ventral region of the inner ear, acts as the primary structure for the perception of sound. Along the length of the cochlear spiral is the organ of Corti, a highly derived and rigorously patterned sensory epithelium that acts to convert auditory stimuli into neural impulses. | Several factors trigger apoptosis in cochlear hair cells. Previous studies have
shown that mitochondria play key roles in apoptosis, but the role of
mitochondrial deoxyribonucleic acid (mtDNA) copy number in the pathogenesis of
hair cell apoptosis remains largely unknown. We used mouse cochlear hair cells
and House Ear Institute‑Organ of Corti 1 (HEI‑OC1) cells to explore the
relationship between mtDNA copy number and cell apoptosis. We found that the
mtDNA copy number of hair cells was reduced relative to mitochondrial mass and
hypothesized that increasing it might have a protective effect. We then
increased the mtDNA copy number of the hair and HEI‑OC1 cells by transfecting
them with an adeno‑associated virus (AAV) vector containing mitochondrial
transcription factor A (TFAM). We found that the apoptosis rates decreased upon
inducing apoptosis with neomycin or cisplatin (DDP). To elucidate the
mechanisms, we analyzed the mitochondrial‑membrane permeability and
mitochondrial function of HEI‑OC1 cells. Our results suggested that the increase
in mtDNA copy number could protect hair cells and HEI‑OC1 cells against
drug‑induced apoptosis by stabilizing the permeability of the mitochondrial
membrane and mitochondrial function. We study the vibration modes of a short section in the middle turn of the gerbil
cochlea including both longitudinal and radial interstitial fluid spaces between
the pillar cells (PC) and the sensory hair cells to determine the role of the
interstitial fluid flow within the organ of corti (OoC). Three detailed finite
element (FE) models of the cochlear short section (CSS) are studied. In model 1,
the CSS is without fluids; model 2 includes the OoC fluid, but not the exterior
scalae fluids; and model 3 is the CSS with both scalae and OoC fluids. We find
that: (1) the fundamental mode shape of models 1 or 3 is similar to the
classical basilar membrane (BM) bending mode that includes pivoting of the arch
of corti, and hence determines the low frequency vibrational mode shape of the
cochlea in the presence of the cochlear wave. (2) The fundamental mode shape of
model 2 is characterized by a cross-sectional shape change similar to the
passive response of the cochlea. This mode shape includes a tilting motion of
the inner hair cell (IHC) region, a fluid motion within the tunnel of corti
(ToC) in the radial direction and along the OoC, and a bulging motion of the
reticular lamina (RL) above the outer hair cell (OHC). Each of these motions
provides a plausible mode of excitation of the sensory hair cells. (3) The
higher vibrational modes of model 1 are similar to the electrically evoked
response within the OoC and suggests that the higher vibrational modes are
responsible for the active response of the cochlea. We also observed that the
fluid flow through the OoC interstitial space is significant, and the model
comparison suggests that the OoC fluid contributes to the biphasic BM motion
seen in electrical stimulation experiments. The effect of fluid viscosity on
cilium deflection was assessed by performing a transient analysis to calculate
the cilium shearing gain. The gain values are found to be within the range of
experimentally measured values reported by Dallos et al. (1996, The Cochlea,
Springer-Verlag, New York). "Growing old" is the most common cause of hearing loss. Age-related hearing loss
(ARHL) (presbycusis) first affects the ability to understand speech in
background noise, even when auditory thresholds in quiet are normal. It has been
suggested that cochlear denervation ("synaptopathy") is an early contributor to
age-related auditory decline. In the present work, we characterized age-related
cochlear synaptic degeneration and hair cell loss in mice with enhanced α9α10
cholinergic nicotinic receptors gating kinetics ("gain of function" nAChRs).
These mediate inhibitory olivocochlear feedback through the activation of
associated calcium-gated potassium channels. Cochlear function was assessed via
distortion product otoacoustic emissions and auditory brainstem responses.
Cochlear structure was characterized in immunolabeled organ of Corti whole
mounts using confocal microscopy to quantify hair cells, auditory neurons,
presynaptic ribbons, and postsynaptic glutamate receptors. Aged wild-type mice
had elevated acoustic thresholds and synaptic loss. Afferent synapses were lost
from inner hair cells throughout the aged cochlea, together with some loss of
outer hair cells. In contrast, cochlear structure and function were preserved in
aged mice with gain-of-function nAChRs that provide enhanced olivocochlear
inhibition, suggesting that efferent feedback is important for long-term
maintece of inner ear function. Our work provides evidence that
olivocochlear-mediated resistance to presbycusis-ARHL occurs via the α9α10 nAChR
complexes on outer hair cells. Thus, enhancement of the medial olivocochlear
system could be a viable strategy to prevent age-related hearing loss. The cochlea, a coiled structure located in the ventral region of the inner ear,
acts as the primary structure for the perception of sound. Along the length of
the cochlear spiral is the organ of Corti, a highly derived and rigorously
patterned sensory epithelium that acts to convert auditory stimuli into neural
impulses. The development of the organ of Corti requires a series of inductive
events that specify unique cellular characteristics and axial identities along
its three major axes. Here, we review recent studies of the cellular and
molecular processes regulating several aspects of cochlear development, such as
axial patterning, cochlear outgrowth and cellular differentiation. We highlight
how the precise coordination of multiple signaling pathways is required for the
successful formation of a complete organ of Corti. High sensitivity and selectivity of hearing require an active cochlea. The
cochlear sensory epithelium, the organ of Corti, vibrates because of external
and internal excitations. The external stimulation is acoustic pressures
mediated by the scala fluids, whereas the internal excitation is generated by a
type of sensory receptor cells (the outer hair cells) in response to the
acoustic vibrations. The outer hair cells are cellular actuators that are
responsible for cochlear amplification. The organ of Corti is highly structured
for transmitting vibrations originating from acoustic pressure and active outer
hair cell force to the inner hair cells that synapse on afferent nerves.
Understanding how the organ of Corti vibrates because of acoustic pressure and
outer hair cell force is critical for explaining cochlear function. In this
study, cochleae were freshly isolated from young gerbils. The organ of Corti in
the excised cochlea was subjected to mechanical and electrical stimulation that
are analogous to acoustic and cellular stimulation in the natural cochlea. Organ
of Corti vibrations, including those of individual outer hair cells, were
measured using optical coherence tomography. Respective vibration patterns due
to mechanical and electrical stimulation were characterized. Interactions
between the two vibration patterns were investigated by applying the two forms
of stimulation simultaneously. Our results show that the interactions could be
either constructive or destructive, which implies that the outer hair cells can
either amplify or reduce vibrations in the organ of Corti. We discuss a
potential consequence of the two interaction modes for cochlear frequency
tuning. |
What eye disease(s) are associated with ocular toxoplasmosis? | Retinochoroiditis is the most frequent manifestation of congenital toxoplasmosis Infectious uveitis accounted for 37% of posterior uveitis cases of which toxoplasmosis was the most common cause. Toxoplasmosis was the most common cause of posterior uveitis (60%) | BACKGROUND: Retinochoroiditis is the most common ocular manifestation of
congenital toxoplasmosis, but other associated ophthalmological pathologies can
also occur. The aim of this study was to determine the nature of the latter in
treated cases of the disease and to assess their impact on visual function.
METHODS: Four hundred and thirty consecutive children with serologically
confirmed congenital toxoplasmosis were included in this study. Data were
prospectively collected using standardized ophthalmological assessment forms.
The presence of retinochoroiditis and of associated pathologies was ascertained,
and their impact on visual function was assessed.
RESULTS: After a median follow-up of 12 years [range 0.6-26 years], 130 children
manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth
and 264 additional ones during the follow-up period. Of these, 48 (17%) were
active when first diagnosed. Twenty-five of the 130 children (19%) had other
associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was
due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral
microphthalmia, and 4 (3%) with cataracts. Most of these events were detected
after the onset of retinochoroiditis. None of the children presented with ocular
involvement in the absence of chorioretinal lesions. Macular lesions occurred
more frequently in children with associated pathologies (p<0.0001), and
associated pathologies were likewise more common in individuals with macular
lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3
of these eyes it was due not to an associated pathology but to macular
retinochoroiditis.
CONCLUSIONS: At the end of the follow-up period, ocular involvement existed in
30% of the treated children with congenital toxoplasmosis. Associated eye
pathologies were manifested less frequently than anticipated. They may occur
later in life and are an indirect marker of the severity of congenital
toxoplasmosis, but they do not have a direct impact on visual acuity. The
overall functional prognosis of congenital toxoplasmosis is better than would be
expected on the basis of literature findings, with only 2 of the 130 children
suffering bilateral visual impairment. Ocular toxoplasmosis is present in 20% of infected immunocompetent individuals.
Toxoplasmosis is the most common cause of posterior uveitis in immunocompetent
subjects and congenital toxoplasmosis transmission was the first parasite to be
linked to human lesions in the eye. An experimental model for congenital ocular
toxoplasmosis was developed in C57BL/6 mice with the purpose to evaluate
Toxoplasma induced ocular pathology during fetal life. Toxoplasma gondii, ME-49
strain, was used to infect pregt females. Histological analysis of pre-natal
fetal eyes from infected female mice, did not show parasite infestation,
however, alterations were observed in the outer nuclear layer (ONL) and in the
inner nuclear layers (INL) of the retina. Edema was also observed, characterized
by the increase of interstitial spaces forming lacunae between the ONL and INL
cells and a net of vessels associated with an intense inflammatory infiltrate.
These histological observations suggest that ocular lesions are not delayed
manifestations of toxoplasmosis. The eye was affected in the initial phase of
disease, and these alterations were of similar nature as those observed in mice
at later stages of infection. Purpose: To report the epidemiology, etiology, ocular characteristics, treatment
and visual outcome of pediatric uveitis in Israel.Methods: Retrospective study
from two tertiary uveitis centers.Results: Included were 107 patients (182
eyes), 55% females. Mean age at diagnosis 8.8 years. Uveitis was predomitly
anterior, idiopathic, bilateral, and chronic. Systemic associations were seen in
36% of patients of which the most common disease was juvenile idiopathic
arthritis. Infectious uveitis accounted for 37% of posterior uveitis cases of
which toxoplasmosis was the most common cause. Anterior segment complications
were commonly observed at presentation (41%); the most predomit were
posterior synechiae, cataract, and band keratopathy. The most common posterior
segment complications were papillitis, epiretinal membrane, and macular
atrophy/scar. Ninety-three percent of eyes had visual acuity >20/40 at last
follow-up.Conclusion: The pattern of pediatric uveitis in Israel is similar to
that in the western world. Visual outcome was good in most eyes. To evaluate quality of life in patients with uveitis-related to toxoplasmosis
and its correlation with demographic, ocular involvement and psychosocial
aspects.Methods: Data were collected through standardized interviews using a
form to collect clinical and demographic data, in addition forms such as HADS,
SF-12, NEI-VFQ-25 for health-related quality of life and anxiety and depression
symptoms.Results: 81 patients were included with a mean age of 41.5 ± 14.5
years, females (50.6%) They were divided into three categories of best corrected
visual acuity in the better seeing eye: normal (0-0.4 logMAR, 60 participants),
low vision (0.48-0.9 logMAR, 9 participants) and blindness (>1 logMAR, 12
participants). The mean of VFQ-25 score was 75.5 ± 19.5 and the mean of SF-12
physical and mental components scores were 48.5 ± 7.4 and 52.4 ± 10.6 for
health-related quality of life (HRQol). Anxiety symptoms were most prevalente
than depression and were found in 38% of the subjects.Conclusions: Slightly more
than a quarter of the sample presented impaired vision. It is associated with
worsening of the quality of life since it affects mostly mental and related to
the vision domains. This affects familiar, social and in addition, labor
relations, since the majority of the subjects are in the economically active age
group. Purpose: We investigated the changes in etiology of uveitis at the Uveitis
Clinic of Tokyo Medical University Hospital in recent years.Methods: Medical
records of patients with uveitis diagnosed between 2011 and 2017 (Group A) and
between 2001 and 2007 (Group B) were reviewed.Results: 1,587 patients in group A
and 1,507 patients in group B were analyzed. For noninfectious uveitis,
frequencies of Vogt-Koyanagi-Harada disease, intraocular lymphoma (IOL) and
iridocyclitis in young girls increased, while those of sarcoidosis and Behçet's
disease decreased in the recent era. For infectious uveitis, herpetic
iridocyclitis, ocular toxoplasmosis, ocular syphilis, and bacterial
endophthalmitis increased, while acute retinal necrosis and ocular toxocariasis
decreased. Unclassified uveitis decreased, whereas infectious uveitis and IOL
increased due to the availability of new diagnostic tests.Conclusion: Etiologies
of uveitis have changed over the years. Further development of novel tests and
diagnostic criteria would increase definitive diagnosis for unclassified
uveitis. (147/150 words). BACKGROUND: Retinochoroiditis is the most frequent manifestation of congenital
toxoplasmosis. We aimed to describe the ocular outcome and factors that may
influence the visual prognosis of these patients.
METHODS: Cohort of patients with confirmed congenital toxoplasmosis seen between
1996 and 2017 in Porto Alegre, southern Brazil.
RESULTS: Seventy-seven patients were included, of which 65 (85.5%) were
identified by routine screening. Median age at the end of the follow-up was 10
years (minimum 2, maximum 25). Retinochoroiditis was present in 55 patients
(71.4%). New retinochoroidal lesions developed after the first year of life in
77.8% of the patients who began treatment after the fourth month of life,
compared with 35.2% among those treated before 4 months of life (relative
risk = 0.45, 95% confidence intervals: 0.27-0.75, P = 0.02) and 33.3% among
those treated before 2 months of life (relative risk = 0.42, 95% confidence
intervals: 0.25-0.72, P = 0.01). There was a peak incidence of new
retinochoroidal lesions between 4 and 5 years and another peak between 9 and 14
years, the latter only among girls. Thirty-four patients with retinochoroiditis
were followed up for 10 years or more, and the school performance was
appropriate in 28 (82.4%).
CONCLUSIONS: The high incidence of new retinochoroidal lesions during the
follow-up period indicates the importance of long-term follow-up of patients
with congenital toxoplasmosis. Initiating treatment within the first 4 months of
life, especially within the first 2 months, was a protective factor against the
later development of retinochoroiditis. Despite the usual favorable prognosis,
the high morbidity of congenital toxoplasmosis in Brazil was confirmed. |
Which eukaryote genomes contain operons? | Genes in nematode and ascidian genomes frequently occur in operons such genes comprise 15-20% of the coding genome for Caenorhabditis elegans and Ciona intestinalis We find that birth-death models of operon evolution reasonably describe the relative abundance of operons of different sizes in the C. elegans and Ciona genomes and generate predictions about the number of monocistronic, nonoperon genes that likely participate in the birth-death process | The nematode worm Caenorhabditis elegans and its relatives are unique among
animals in having operons. Operons are regulated multigene transcription units,
in which polycistronic pre-messenger RNA (pre-mRNA coding for multiple peptides)
is processed to monocistronic mRNAs. This occurs by 3' end formation and
trans-splicing using the specialized SL2 small nuclear ribonucleoprotein
particle for downstream mRNAs. Previously, the correlation between downstream
location in an operon and SL2 trans-splicing has been strong, but anecdotal.
Although only 28 operons have been reported, the complete sequence of the C.
elegans genome reveals numerous gene clusters. To determine how many of these
clusters represent operons, we probed full-genome microarrays for SL2-containing
mRNAs. We found significant enrichment for about 1,200 genes, including most of
a group of several hundred genes represented by complementary DNAs that contain
SL2 sequence. Analysis of their genomic arrangements indicates that >90% are
downstream genes, falling in 790 distinct operons. Our evidence indicates that
the genome contains at least 1,000 operons, 2 8 genes long, that contain about
15% of all C. elegans genes. Numerous examples of co-transcription of genes
encoding functionally related proteins are evident. Inspection of the operon
list should reveal previously unknown functional relationships. The genome of the nematode Caenorhabditis elegans is unusual among eukaryotes,
in that it contains operons. Approximately 15% of genes in the worm are
clustered into groups of between two and eight genes, which are under the
control of shared regulatory sequences. Polycistronic transcripts from such
operons are trans-spliced, during transcription, to produce mature monocistronic
messengers. The C. elegans frataxin gene, frh-1, is encoded in the operon
CEOP2232. This is one of the largest operons identified thus far in the C.
elegans genome. Here we describe in detail the structure of all of the coding
units within this operon. The operon is composed of eight genes of a diverse
nature, organized in a complex structure. We have produced transgenic strains
carrying fusions between gfp and a number of genes from the operon. These
constructs show complex differential expression patterns that suggest the
presence of internal promoters and regulatory sequences in the operon. This
organization would permit both coordinated expression and differential
expression of the components of the CEOP2232 operon. The heterogeneity of the
genes, and their complex expression patterns, suggests that the clustering of
CEOP2232 is not due to a need for synchronized expression of genes involved in
the same physiological pathway. BACKGROUND: The zinc finger (ZF) protein CTCF (CCCTC-binding factor) is highly
conserved in Drosophila and vertebrates where it has been shown to mediate
chromatin insulation at a genomewide level. A mode of genetic regulation that
involves insulators and insulator binding proteins to establish independent
transcriptional units is currently not known in nematodes including
Caenorhabditis elegans. We therefore searched in nematodes for orthologs of
proteins that are involved in chromatin insulation.
RESULTS: While orthologs for other insulator proteins were absent in all 35
analysed nematode species, we find orthologs of CTCF in a subset of nematodes.
As an example for these we cloned the Trichinella spiralis CTCF-like gene and
revealed a genomic structure very similar to the Drosophila counterpart. To
investigate the pattern of CTCF occurrence in nematodes, we performed
phylogenetic analysis with the ZF protein sets of completely sequenced
nematodes. We show that three ZF proteins from three basal nematodes cluster
together with known CTCF proteins whereas no zinc finger protein of C. elegans
and other derived nematodes does so.
CONCLUSION: Our findings show that CTCF and possibly chromatin insulation are
present in basal nematodes. We suggest that the insulator protein CTCF has been
secondarily lost in derived nematodes like C. elegans. We propose a switch in
the regulation of gene expression during nematode evolution, from the common
vertebrate and insect type involving distantly acting regulatory elements and
chromatin insulation to a so far poorly characterised mode present in more
derived nematodes. Here, all or some of these components are missing. Instead
operons, polycistronic transcriptional units common in derived nematodes,
seemingly adopted their function. The current predicted mechanisms that describe RNA polymerase II (pol II)
transcription termination downstream of protein expressing genes fail to
adequately explain, how premature termination is prevented in eukaryotes that
possess operon-like structures. Here we address this issue by analysing
transcription termination at the end of single protein expressing genes and
genes located within operons in the nematode Caenorhabditis elegans. By using a
combination of RT-PCR and ChIP analysis we found that pol II generally
transcribes up to 1 kb past the poly(A) sites into the 3' flanking regions of
the nematode genes before it terminates. We also show that pol II does not
terminate after transcription of internal poly(A) sites in operons. We provide
experimental evidence that five randomly chosen C. elegans operons are
transcribed as polycistronic pre-mRNAs. Furthermore, we show that cis-splicing
of the first intron located in downstream positioned genes in these
polycistronic pre-mRNAs is critical for their expression and may play a role in
preventing premature pol II transcription termination. Genes in nematode and ascidian genomes frequently occur in operons--multiple
genes sharing a common promoter to generate a polycistronic primary
transcript--and such genes comprise 15-20% of the coding genome for
Caenorhabditis elegans and Ciona intestinalis. Recent work in nematodes has
demonstrated that the identity of genes within operons is highly conserved among
species and that the unifying feature of genes within operons is that they are
expressed in germline tissue. However, it is generally unknown what processes
are responsible for generating the distribution of operon sizes across the
genome, which are composed of up to eight genes per operon. Here we investigate
several models for operon evolution to better understand their abundance,
distribution of sizes, and evolutionary dynamics over time. We find that
birth-death models of operon evolution reasonably describe the relative
abundance of operons of different sizes in the C. elegans and Ciona genomes and
generate predictions about the number of monocistronic, nonoperon genes that
likely participate in the birth-death process. This theory, and applications to
C. elegans and Ciona, motivates several new and testable hypotheses about
eukaryote operon evolution. Operons are primarily a bacterial phenomenon, not commonly observed in
eukaryotes. However, new research indicates that operons are found in higher
organisms as well. There are instances of operons found in C. elegans,
Drosophila melanogaster and other eukaryotic species. We developed a prototype
using positional, structural and gene expression information to identify
candidate operons. We focused our efforts on "trans-spliced" operons in which
the pre-mRNA is trans-spliced into individual transcripts and subsequently
translated, as widely observed in C. elegans and some instances in Drosophila.
We identify several candidate operons in Drosophila melanogaster of which two
have been subsequently molecularly validated. One of the most pressing challenges in the post genomic era is the
identification and characterization of protein-protein interactions (PPIs), as
these are essential in understanding the cellular physiology of health and
disease. Experimental techniques suitable for characterizing PPIs (X-ray
crystallography or nuclear magnetic resoce spectroscopy, among others) are
usually laborious, time-consuming and often difficult to apply to membrane
proteins, and therefore require accurate prediction of the candidate interacting
partners. High-throughput experimental methods (yeast two-hybrid and affinity
purification) succumb to the same shortcomings, and can also lead to high rates
of false positive and negative results. Therefore, reliable tools for predicting
PPIs are needed. The use of the operon structure in the eukaryote Caenorhabditis
elegans genome is a valuable, though underserved, tool for identifying
physically or functionally interacting proteins. Based on the concept that genes
organized in the same operon may encode physically or functionally related
proteins, this algorithm is easy to be applied and, importantly, gives a limited
number of candidate partners of a given protein, allowing for focused
experimental verification. Moreover, this approach can be successfully used to
predict PPIs in the human system, including those of membrane proteins. The organization of genes into operons, clusters of genes that are
co-transcribed to produce polycistronic pre-mRNAs, is a trait found in a wide
range of eukaryotic groups, including multiple animal phyla. Operons are present
in the class Chromadorea, one of the two main nematode classes, but their
distribution in the other class, the Enoplea, is not known. We have surveyed the
genomes of Trichinella spiralis, Trichuris muris, and Romanomermis culicivorax
and identified the first putative operons in members of the Enoplea. Consistent
with the mechanism of polycistronic RNA resolution in other nematodes, the mRNAs
produced by genes downstream of the first gene in the T. spiralis and T. muris
operons are trans-spliced to spliced leader RNAs, and we are able to detect
polycistronic RNAs derived from these operons. Importantly, a putative
intercistronic region from one of these potential enoplean operons confers
polycistronic processing activity when expressed as part of a chimeric operon in
Caenorhabditis elegans. We find that T. spiralis genes located in operons have
an increased likelihood of having operonic C. elegans homologs. However, operon
structure in terms of synteny and gene content is not tightly conserved between
the two taxa, consistent with models of operon evolution. We have nevertheless
identified putative operons conserved between Enoplea and Chromadorea. Our data
suggest that operons and "spliced leader" (SL) trans-splicing predate the
radiation of the nematode phylum, an inference which is supported by the
phylogenetic profile of proteins known to be involved in nematode SL
trans-splicing. |
What has capmatinib received FDA approval for in 2020? | In May 2020, oral capmatinib received its first global approval in the USA for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumours have a mutation that leads to MET exon 14 skipping, as detected by an FDA-approved test. | Capmatinib (Tabrecta™) is an oral, small molecule mesenchymal-epithelial
transition (MET) inhibitor being developed by Novartis Oncology, under a license
from Incyte Corporation, for the treatment of lung cancer. Capmatinib targets
and selectively binds to MET, including the mutant variant produced by exon 14
skipping, and inhibits cancer cell growth driven by the mutant MET variant. In
May 2020, oral capmatinib received its first global approval in the USA for the
treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose
tumours have a mutation that leads to MET exon 14 skipping, as detected by an
FDA-approved test. Clinical development for the treatment of glioblastoma, liver
cancer, maligt melanoma, breast cancer, colorectal cancer, head and neck
cancer and solid tumours is ongoing in several countries. This article
summarizes the milestones in the development of capmatinib leading to its first
approval. |
Is SLIC-CAGE used for quantification of translation? | No. Cap analysis of gene expression (CAGE) is a method used for single-nucleotide resolution detection of RNA polymerase II transcription start sites (TSSs). Accurate detection of TSSs enhances identification and discovery of core promoters. In addition, active enhancers can be detected through signatures of bidirectional transcription initiation. Described here is a protocol for performing super-low input carrier-CAGE (SLIC-CAGE). The SLIC adaptation of the CAGE protocol minimizes RNA losses by artificially increasing the RNA amount through use of an in vitro transcribed RNA carrier mix that is added to the sample of interest, thus enabling library preparation from nanogram-amounts of total RNA (i.e., thousands of cells). | |
Does hypofractionated radiotherapy offers any benefit for DIPG? | No. Hypofractionated radiotherapy does not offers benefit when compared to conventional fractionated radiation therapy for DIPG. | BACKGROUND: The pediatric diffuse intrinsic pontine glioma (DIPG) outcome
remains dismal despite multiple therapeutic attempts.
PURPOSE: To compare the results of treatment of pediatric diffuse intrinsic
pontine glioma (DIPG) using hypofractionated versus conventional radiotherapy.
PATIENTS AND METHODS: Seventy-one newly diagnosed DIPG children were randomized
into hypofractionated (HF) (39Gy/13 fractions in 2.6weeks) and conventional (CF)
arm (54Gy/30 fractions in 6weeks).
RESULTS: The median and one-year overall survival (OS) was 7.8months and
36.4±8.2% for the hypofractionated arm, and 9.5 and 26.2±7.4% for the
conventional arm respectively. The 18-month OS difference was 2.2%. The OS
hazard ratio (HR) was 1.14 (95% CI: 0.70-1.89) (p=0.59). The hypofractionated
arm had a median and one-year progression-free survival (PFS) of 6.6months and
22.5±7.1%, compared to 7.3 and 17.9±7.1% for the conventional arm. The PFS HR
was 1.10 (95% CI: 0.67-1.90) (p=0.71). The 18-month PFS difference was 1.1%.
These differences exceed the non-inferiority margin. The immediate and delayed
side effects were not different in the 2 arms.
CONCLUSIONS: Hypofractionated radiotherapy offers lesser burden on the patients,
their families and the treating departments, with nearly comparable results to
conventional fractionation, though not fulfilling the non-inferiority
assumption. INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is the most common form of
brainstem glioma. The present study was performed to assess if hypofractionated
radiotherapy completed in < 3 weeks with temozolomide improves survival in DIPG.
MATERIAL AND METHODS: The present study is a phase II open label randomized
trial. The study included newly diagnosed patients with DIPG. Patients in arm A
received conventional fractionated RT of 60 Gy in 30 fractions over 6 weeks
while patients in arm B received hypo-fractionated radiotherapy of 39 Gy in 13
fractions over 2.6 weeks along with concurrent Temozolomide (TMZ) 75 mg/m2 from
day 1 to day 17 followed by adjuvant TMZ for six cycles. The survival analysis
was performed with modified intention to treat analysis.
RESULTS: A total of 35 patients were randomized. 33 patients were evaluable. 93%
(n = 14) of patients in the conventional arm completed treatment while only 17%
(n = 3) of the children could complete planned course of treatment in the
experimental arm. The median overall survival (OS) was 11 months (95% CI - 7.5
to 14.5 months) in the conventional arm and 12 months (95% CI - 10.5 to
13.5 months) in the experimental arm (p = 0.208). 28% (n = 5) patients in the
experimental arm developed grade 3 or 4 hematological toxicity.
CONCLUSION: The above study shows that hypofractionated radiotherapy with
concurrent and adjuvant temozolomide does not improve OS and has higher
hematological toxicity. Conventional radiotherapy remains the standard of care. BACKGROUND: Overall survival (OS) of patients with diffuse intrinsic pontine
glioma (DIPG) is poor, with radiation therapy (RT) the only intervention that
transiently delays tumor progression. Hypofractionated RT and re-irradiation at
first progression have gained popularity in improving the quality of life of
such patients.
METHODS: We performed a retrospective review of children with DIPG treated at
Kanagawa Children's Medical Center from 2000 to 2018.
RESULTS: A total of 24 cases were reviewed. Median age at diagnosis was
6.3 years (1.6-14.0). Twenty patients received RT only once. Thirteen patients
received conventionally fractionated RT, and seven patients received
hypofractionated RT as up-front RT. Severe toxicities were not observed in
patients who received hypofractionated RT. Median OS and time to progression
were similar between conventionally fractionated and hypofractionated RT
groups.(9.7 [95% confidence interval(CI): 7.1-11.2] versus 11.0[95% CI:
5.2-13.6] months, P = 0.60; 4.2[95% CI: 1.8-8.3] versus 7.1 [95% CI:4.5-8.7]
months, P = 0.38). Four patients received re-irradiation at first progression
and all patients showed transient neurological improvement and survival more
than a year after diagnosis. A 4-year-old boy was re-irradiated 5-and-a-half
months after the first re-irradiation; following transient neurological
improvement. He survived a further 5 months.
CONCLUSION: Hypofractionated RT for children with newly diagnosed DIPG is well
tolerated and feasible from the viewpoint of reducing a patient's burden of
treatment. Re-irradiation at first progression is suggested to be beneficial. BACKGROUND: The standard treatment for diffuse intrinsic pontine glioma (DIPG)
is radiotherapy, although conventional fractionated radiotherapy (CFRT) may not
be in the best interest of the patient. Instead, hypofractionated radiotherapy
(HFRT) may shorten the treatment period and reduce related costs for this
treatment, which is typically palliative in nature.
METHODS: This systematic review and meta-analysis evaluated survival outcomes
among patients who received HFRT or CFRT for DIPG. The PubMed, Medline, EMBASE,
Cochrane Central Register, and Scopus databases were searched to identify
relevant studies. Overall survival was the primary outcome of interest and
progression-free survival was the secondary outcome of interest.
RESULTS: The search identified a total of 2376 reports, although only 4 reports
were ultimately included in the meta-analysis. The studies included 88 patients
who underwent HFRT and 96 patients who underwent CFRT. Relative to CFRT, HFRT
provided comparable outcomes in terms of overall survival (hazard ratio [HR]:
1.07, 95% confidence interval [CI]: 0.77-1.47) and progression-free survival
(HR: 1.04, 95% CI: 0.75-1.45).
CONCLUSIONS: The results of this meta-analysis suggest that CFRT and HFRT
provide similar survival outcomes for patients with DIPG. |
What is the function of the stard10 protein? | STARD10, a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) protein family, is highly expressed in the liver and has been shown to transfer phosphatidylcholine. | We originally identified StarD10 as a protein overexpressed in breast cancer
that cooperates with the ErbB family of receptor tyrosine kinases in cellular
transformation. StarD10 contains a steroidogenic acute regulatory protein
(StAR/StarD1)-related lipid transfer (START) domain that is thought to mediate
binding of lipids. We now provide evidence that StarD10 interacts with
phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by electron spin
resoce measurement. Interaction with these phospholipids was verified in a
fluorescence resoce energy transfer-based assay with
7-nitro-2,1,3-benzoxadiazol-4-yl-labeled lipids. Binding was not restricted to
lipid analogs since StarD10 selectively extracted PC and PE from small
unilamellar vesicles prepared with endogenous radiolabeled lipids from Vero
monkey kidney cells. Mass spectrometry revealed that StarD10 preferentially
selects lipid species containing a palmitoyl or stearoyl chain on the sn-1 and
an unsaturated fatty acyl chain (18:1 or 18:2) on the sn-2 position. StarD10 was
further shown to bind lipids in vivo by cross-linking of protein expressed in
transfected HEK-293T cells with photoactivable phosphatidylcholine. In addition
to a lipid binding function, StarD10 transferred PC and PE between membranes.
Interestingly, these lipid binding and transfer specificities distinguish
StarD10 from the related START domain proteins Pctp and CERT, suggesting a
distinct biological function. STARD10, a member of the steroidogenic acute regulatory protein (StAR)-related
lipid transfer (START) protein family, is highly expressed in the liver and has
been shown to transfer phosphatidylcholine. Therefore it has been assumed that
STARD10 may function in the secretion of phospholipids into the bile. To help
elucidate the physiological role of STARD10, we produced Stard10 knockout mice
(Stard10(-/-)) and studied their phenotype. Neither liver content nor biliary
secretion of phosphatidylcholine was altered in Stard10(-/-) mice. Unexpectedly,
the biliary secretion of bile acids from the liver and the level of
taurine-conjugated bile acids in the bile were significantly higher in
Stard10(-/-) mice than wild type (WT) mice. In contrast, the levels of the
secondary bile acids were lower in the liver of Stard10(-/-) mice, suggesting
that the enterohepatic cycling is impaired. STARD10 was also expressed in the
gallbladder and small intestine where the expression level of apical sodium
dependent bile acid transporter (ASBT) turned out to be markedly lower in
Stard10(-/-) mice than in WT mice when measured under fed condition. Consistent
with the above results, the fecal excretion of bile acids was significantly
increased in Stard10(-/-) mice. Interestingly, PPARα-dependent genes responsible
for the regulation of bile acid metabolism were down-regulated in the liver of
Stard10(-/-) mice. The loss of STARD10 impaired the PPARα activity and the
expression of a PPARα-target gene such as Cyp8b1 in mouse hepatoma cells. These
results indicate that STARD10 is involved in regulating bile acid metabolism
through the modulation of PPARα-mediated mechanism. |
Is progeria caused by an autosomal recessive gene? | Yes. Progeria is caused by an autosomal recessive gene. | We have studied a boy with progeria (Hutchinson Gilford) born to third cousins.
Four other individuals with progeria were born in another consanguineous sibship
in the same family. Thus, this disorder can be inherited as an autosomal
recessive trait. INTRODUCTION: Werner Syndrome, or adult progeria, is a rare autosomal recessive
disorder caused by a mutation in the Werner Syndrome Gene belonging to the
family of RecQ helicase. Maligt mesenchymal tumours and atherosclerosis are
typical causes of death. Intracranial meningiomas are frequently described in
these patients.
CLINICAL PRESENTATION: We present the case of a 46-year-old man with Werner
Syndrome and a convexity meningioma. The patient had a 2-year history of
paresthesia and paresis in his right leg, which had worsened in recent months.
He underwent surgery with Simpson grade II removal, with improvement of the
slight paresis and no other neurological defects. The patient then underwent
radiotherapy (60 Gy). Histological examination revealed an atypical meningioma.
Cytogenetic analysis showed a hypodiploid clone with a complex karyotype
characterized by monosomy 22 and deletion 1p. After 3 years' follow-up no
relapses had occurred.
CONCLUSION: 1p deletion correlates with meningioma progression and in this case
correlates with histological examination. The chromosomal instability underlying
Werner Syndrome could have fostered the complex karyotype. Hutchinson-Gilford progeria syndrome (HGPS) is a rare but well known entity
characterized by extreme short stature, low body weight, early loss of hair,
lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial
features that resemble aged persons. Cardiovascular compromise leads to early
demise. Cognitive development is normal. Data on 10 of our own cases and 132
cases from literature are presented. The incidence in the last century in the
Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were
failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy
(20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed
than growth in height, and growth delay started already prenatally. Mean height
> 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide-spread but
not expressed, except in the viscerocranium, and remained limited to membranous
formed bone. Lipodystrophy is generalized, only intra-abdominal fat depositions
remain present. Cardiovascular problems are extremely variable, both in age of
onset and nature. Stroke and coronary dysfunctioning are most frequent.
Pathologic findings in coronaries and aorta resemble sometimes the findings in
elderly persons, but can also be much more limited. Loss of smooth muscle cells
seems the most important finding. Mean age of demise was 12.6 years. Patients
can be subdivided in patients with classical HGPS, which follows an autosomal
domit pattern of inheritance, (almost) all cases representing spontaneous
mutations, and in non-classical progeria, in whom growth can be less retarded,
scalp hair remains present for a longer time, lipodystrophy is more slowly
progressive, osteolysis is more expressed except in the face, and survival well
into adulthood is not uncommon. Pattern of inheritance of non-classical progeria
is most probably autosomal recessive. The cause of HGPS is an abnormally formed
Lamin A, either directly by a mutated LMNA gene, or through abnormal
posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations
found in progeria patients, there were 26 classical p.G608G mutations (76%).
Pathogenesis is most likely to follow several different pathways. Potential
therapeutic strategies are developed along these lines and include RNA
interference techniques and inhibition of the domit-negative influence of
abnormally formed Lamin A on polymerization with normally formed Lamin A. HISTORY AND CLINICAL FINDINGS: A 49-year-old man of German parentage with
Werner's syndrome (including insulin-dependent type 2 diabetes mellitus) was
treated in our department for extensive ulcers on his lower legs.
GENETICS: Genetic analysis detected a novel compound heterozygous defect
(1396delA and 2334delAC) of the WRN gene.
TREATMENT AND FURTHER COURSE: The ulcer clearly decreased in size on local and
antibiotic treatment as well as autologous fibroplast transplantation. The most
severely affected right small finger required amputation with exarticulation.
The severe pain caused by the ulcer was successfully treated with temporary
blockage of the stellate ganglion and permanent sympathetic blockage at the
level of the 2nd thoracic and lumbar vertebrae.
CONCLUSION: Werner's syndrome is a rare form of progeria with an autosomal
recessive mode of inheritance mimicking the symptoms of accelerated aging. The
reduced life expectancy is caused by the increased incidence and early onset of
atherosclerosis and maligt tumors. The detection of underlying molecular
mechanisms will have an important impact in the field of anti-aging research. Werner's syndrome (adult onset progeria) is a rare form of autosomal recessive
genodermatosis associated in almost 80% of cases with mutation of the WRN gene.
This prototype of rapid ageing syndromes is characterized by short stature with
skin and hair anomalies (early graying of the hair, alopecia, depilation,
sclerosed skin), orthopedic complications (flat foot, hallux valgus and other
joint deformations) as well as systemic signs (early cataract, premature and
diffuse atherosclerosis, endocrinopathies) and high risk of certain types of
cancer (sarcomas, myeloid blood dyscrasias). Death occurs around the age of 40 -
50 years mainly as a result of cardiovascular accident or development of a
maligt tumour. Signs of early aging should evoke this basic diagnosis and
arrangements should be made for appropriate follow-up with screening for and
treatment of systemic complications. AIM: To describe two Chinese siblings of atypical Hutchinson-Gilford progeria
syndrome (HGPS), with genetic diagnosis and special clinical manifestation.
METHODS: We screened the LMNA gene in four members of a consanguineous family,
in which two children were suffering from atypical HGPS. Besides general HGPS
features, such as growth retardation and characteristic appearance, special
clinical phenotypes including disorders of digestive system and severe skeletal
damages were observed.
RESULTS: Homozygous mutation 1579C>T, which predicts R527C, was identified in
the exon 9 of LMNA among the affected siblings. Heterozygous carrier status
1579C>T was detected in both of the asymptomatic parents.
CONCLUSION: Homozygous mutation R527C in LMNA yields atypical HGPS, and it
suggests an autosomal recessive inheritance in this family. CONTEXT: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral
dysplasia are well-recognized allelic autosomal domit and recessive progeroid
disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous
LMNA mutations have also been reported in a small number of patients with a less
well-characterized atypical progeroid syndrome (APS).
OBJECTIVE: The objective of the study was to investigate the underlying genetic
and molecular basis of the phenotype of patients presenting with APS.
RESULTS: We report 11 patients with APS from nine families, many with novel
heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and
C588R. These and previously reported patients now reveal a spectrum of clinical
features including progeroid manifestations such as short stature, beaked nose,
premature graying, partial alopecia, high-pitched voice, skin atrophy over the
hands and feet, partial and generalized lipodystrophy with metabolic
complications, and skeletal anomalies such as mandibular hypoplasia and mild
acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C
expression using epifluorescence microscopy revealed variable nuclear
morphological abnormalities similar to those observed in patients with HGPS.
However, these nuclear abnormalities in APS patients could not be rescued with
48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase
inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of
cell lysates from fibroblasts did not reveal prelamin A accumulation in any of
these patients.
CONCLUSIONS: APS patients have a few overlapping but some distinct clinical
features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of
clinical manifestations in APS patients seems not to be related to accumulation
of mutant farnesylated prelamin A. Werner's Syndrome (WS) or adult-onset progeria is an autosomal recessive
disorder of accelerated aging caused by mutations of the DNA RecQ
helicase/exonuclease (WRN). WRN is an ATP-dependent helicase with 3' to 5' DNA
exonuclease activity that regulates the replicative potential of dividing cells,
and WRN loss-of-function mutations promote cellular senescence and neoplastic
transformation. These molecular findings translate clinically into adult-onset
progeria manifested by premature hair graying, dermal atrophy, cardiovascular
disease, and cancer predilection along with a markedly reduced life expectancy.
Recently, a patient with WS who developed pancreatic adenocarcinoma was
identified in Honolulu suggesting a significant prevalence of loss-of-function
WRN mutations in Hawaii's Japanese-American population. Based upon the
indigenous Japanese WRN loss-of-function mutation heterozygote rate of 6 per
1,000, we speculate the possibility of approximately 1,200 heterozygotes in
Hawaii. Our ongoing studies aim to evaluate Hawaii's true allelic prevalence of
WRN loss-of-function mutations in the Japanese-American population, and the role
of WRN silencing in sporadic cancers. In summary, WRN plays a nexus-like role in
the complex interplay of cellular events that regulate aging, and analysis of
WRN polymorphisms in Hawaii's population will generate novel insights to advance
care for age-related pathologies. Our life span is genetically programmed and it is possible that a defect in
produced proteins encoded by the longevity gene is a cause of aging. Progeria
which is a rare, fatal genetic condition which affects between one in four
million and one in eight million children of both sexes equally and
characterized by premature and accelerated aging. The appearance and physiology
of these children resembles to elderly people but they typically have life span
to their mid teens. It is also known as the Hutchinson-Gilford syndrome, which
was initially reported by Johnathan Hutchinson in 1886 and further described by
Hastings Gilford in 1904. It is an autosomal recessive disorder, which means an
individual has inherited a mutated gene from both parents. It is added to the
expanding catalogue of laminopathies, diseases caused by mutations affecting
nuclear lamina proteins known as lamin A (LMNA). In oral manifestation primary
finding is micrognathia with delayed tooth eruption and incomplete formation of
root of permanent tooth. Presently there are no known cures for this
abnormality. Werner syndrome (i.e., adult progeria) is a rare autosomal recessive disorder
caused by mutations of the WRN gene, which is characterized by the premature
appearance of features associated with normal aging and cancer predisposition.
Patients with Werner syndrome can present with musculoskeletal complaints,
associated with suggestive radiographic features with a potential prognostic or
therapeutic impact. This review illustrates the main radiographic features of
Werner syndrome, focusing on the musculoskeletal system, such as soft-tissue
calcification, muscular atrophy, osteoporosis, foot deformities, osteitis and
osteomyelitis, and bone or soft-tissues maligcies. The identification of
these features by radiologists can therefore be useful in the clinical screening
of Werner syndrome. Progeria is sporadic, very rare, autosomal domit, deadly childhood disorder.
It is one of the progeroid syndromes also known as Hutchinson-Gilford progeria
syndrome (HGPS). Aging is a developmental process that begins with fertilization
and ends up with death involving a lot of environmental and genetic factors. The
disease firstly involves premature aging and then death from complications of
atherosclerosis such as myocardial infarction, stroke, atherosclerosis, or heart
failure. The lifespan of the patient is normally up to teen age or early
twenties. It is usually not inherited because a patient normally dies before the
age of reproduction. The most important genetic linkage between progeria and
aging is shortening of telomere ends with each replication cycle. The patients
are normally observed to have extremely short telomeres. Currently, 90% of the
patients are said to have de novo point mutations in the LMNA gene that
substitute cytosine with thymine and have been found in individuals with HGPS.
Lmna encodes lamins A and C, and the A-type lamins have important structural
function in the nuclear envelope. The most common type of HGPS mutation is
located at codon 608 (G608G). It could not be diagnosed at birth, but after the
age of 2 years, visible, prominent symptoms can be observed. Still, lot of
research is needed to solve this mystery; hopefully, future research on HGPS
would provide important clues for progeria and other fatal age-related
disorders. BACKGROUND: Most syndromes of accelerated aging are caused by mutations
affecting the integrity of the genetic material. Among them, the most studied is
Werner's syndrome, "adult progeria", caused by a recessive autosomal mutation
with a frequency of 1 in 10 million, which affects a helicase involved in DNA
repair. In Werner syndrome, there is a loss of heterochromatin, though the
stability of heterochromatin is also affected in "normal" aging. The
Hutchinson-Gilford Progeria Syndrome (HGPS), "child progeria", has an even lower
frequency. In most cases, it is caused by a point mutation of a gene coding a
protein in the nuclear envelope, lamin A.
OBJECTIVES: HGPS may provide valuable insights into the aging process. The
symptoms of this condition do not entirely overlap with those of "normal" aging.
METHOD: A critical analysis of the accelerated aging syndromes may explain what
aging is, and also why some tissues and organs age at accelerated rates as
compared to other tissues.
RESULTS: In this article, we will discuss the implications of HGPS and other
accelerated aging syndromes in the light of the biochemical hypothesis of aging
we advanced. According to this hypothesis, some reactions are less stimulated
and diminish in time, affecting not only specific biochemical functions, but
cellular energy, and therefore its capacity for synthesis.
CONCLUSION: Besides, a new vision on aging, possible therapeutic strategies for
these conditions and others, with similar mechanisms, are also presented. Werner's syndrome (WS) or progeria adultorum is a heritable autosomal recessive
disease in which the aging process is accelerated, just after puberty. It is
caused by mutations in the WRN gene, which encodes a member of the RECQ family
of DNA helicases and has a role in DNA repair. WS is being more appropriately
recognized as a condition in which the lack of WRN protein results in an overall
decline in the normal physiological functions of various organs rather than
premature aging. Here, we describe a rare case of WS with a novel mutation from
India. Our patient was an adult male with a history of growth arrest since
puberty and other clinical features such as sclerodermatous skin changes,
premature graying and thinning of hair, bilateral cataract, a single non-healing
ulcer, hypothyroidism, underdeveloped secondary sexual characters with
hypogonadism, infertility, squeaky voice, and early signs of arteriosclerosis.
On genetic analysis, he was found to have a homozygous pathogenic variant
c.3190C>T in exon 26 of the WRN gene, which has never been reported in WS. Hutchinson-Gilford progeria syndrome (HGPS) is an autosomal-domit genetic
disease that leads to accelerated aging and often premature death caused by
cardiovascular complications. Till now clinical management of HGPS has largely
relied on the treatment of manifestations and on the prevention of secondary
complications, cure for the disease has not yet been established. Addressing
this need cannot only benefit progeria patients but may also provide insights
into intervention design for combating physiological aging. By using the
systematic review approach, this article revisits the overall progress in the
development of strategies for HGPS treatment over the last ten years, from 2010
to 2019. In total, 1,906 articles have been retrieved, of which 56 studies have
been included for further analysis. Based on the articles analyzed, the trends
in the use of different HGPS models, along with the prevalence, efficiency, and
limitations of different reported treatment strategies, have been examined.
Emerging strategies for preclinical studies, and possible targets for
intervention development, have also been presented as avenues for future
research. Werner syndrome, also called adult progeria, is a heritable autosomal recessive
human disorder characterized by the premature onset of numerous age-related
diseases including juvenile cataracts, dyslipidemia, diabetes mellitus (DM),
osteoporosis, atherosclerosis, and cancer. Werner syndrome is a segmental
progeroid syndrome whose presentation resembles accelerated aging. The most
common causes of death for WS patients are atherosclerosis and cancer. A
40-year-old female presented with short stature, bird-like facies, canities with
alopecia, scleroderma-like skin changes, and non-healing foot ulcers. The
patient reported a history of delayed puberty, abortion, hypertriglyceridemia,
and juvenile cataracts. A clinical diagnosis of WS was made and subsequently
confirmed. We discovered two WRN gene mutations in the patient, Variant 1 was
the most common WRN mutation, nonsense mutation (c.1105C>T:p.R369Ter) in exon 9,
which caused a premature termination codon (PTC) at position 369. Variant 2 was
a frameshift mutation (c.1134delA:p.E379KfsTer5) in exon 9, which caused a PTC
at position 383 and has no published reports describing. Patients with WS can
show a wide variety of clinical and biological manifestations in
endocrine-metabolic systems (DM, thyroid dysfunction, and hyperlipidemia).
Doctors must be cognizant of early manifestations of WS and treatment options. |
What is the target of adalimumab? | adalimumab is an anti-tumour necrosis factor (tf)-α antibody. | The next generation of targeted biologic therapies for psoriasis will either be
directed against new protein targets or improve on the efficacy, safety, or
convenience of medications available for an already validated area in the immune
response. Adalimumab is a fully human monoclonal antibody directed against tumor
necrosis factor-alpha, a central cytokine in the immune response in psoriasis
that has already been shown to be an effective target for therapy. This
medication is approved by the US Food and Drug Administration (USFDA) for the
treatment of rheumatoid arthritis. Early phrase II studies with adalimumab have
shown excellent efficacy for psoriasis with either weekly or every other week
subcutaneous injection. Moreover, the safety and tolerability of adalimumab in
large clinical studies of rheumatoid arthritis have shown good results. Thus,
adalimumab shows significant promise for the therapy of psoriasis in the future. Biological agents targeting on pro-inflammatory cytokines are developed, and
provide a great impact on the medical management of rheumatoid arthritis (RA).
Particularly, biologics against tumor necrosis factor(TNF) can not only induce
great clinical improvement, but also halt structural damage on the joints. Now
chimeric anti-TNFalpha monoclonal antibody, infliximab, full human anti-TNFalpha
monoclonal antibody, adalimumab, and TNF receptor II (p75) -IgGFc fusion
protein, etanercept, are widely used in the inflammatory disorders including RA.
This review article shows the characteristics of these anti-TNF biologics on RA,
and summarizes the efficacy as well as the safety of the agents. Tumour necrosis factor (TNF) has a central role in the pathogenesis of psoriatic
arthritis (PsA). Adalimumab (Humira, Abbott Laboratories) is the first fully
human, recombit IgG1 monoclonal antibody that specifically targets human TNF.
Adalimumab blocks the interaction of TNF with the p55 and p75 cell surface TNF
receptors, thereby neutralising the activity of this cytokine. In clinical
trials of patients with PsA, adalimumab significantly reduced both joint and
skin symptoms. In addition, structural changes were inhibited, and statistically
and clinically significant improvements in measures of disability and quality of
life were observed. Adalimumab was generally safe and well tolerated. Adalimumab is a fully human monoclonal antibody targeted toward tumor necrosis
factor alpha (TNF-alpha). TNF-alpha is proinflammatory cytokine involved in the
pathogenesis of many inflammatory diseases, as the psoriasis. The production
process of adalimumab is complex and it is based in the called phague display
technology. Psoriasis is a chronic inflammatory disease affecting 2% to 3% of the population
in Western countries. Psoriasis is associated with limited quality of life,
cardiovascular disease, and depression. The approval of injectable biological
agents has revolutionized the management of moderate to severe psoriasis.
Adalimumab is a human monoclonal antibody against tumor necrosis factor (TNF)
alpha approved for moderate-to-severe plaque-type psoriasis and psoriatic
arthritis (PsA). This systematic review summarizes the evidence concerning the
efficacy, clinical effectiveness, safety, and cost-effectiveness of adalimumab
in the treatment of psoriasis. Five randomized controlled trials demonstrated
the efficacy of adalimumab in moderate-to-severe plaque-type psoriasis and PsA
with PASI-75 response rates of 53% to 80% and ACR-20 response rates of 39% to
58% after 12 to 16 weeks of treatment. In clinical practice patients who have
not responded to one TNF antagonist may respond to another TNF antagonist.
Adalimumab has similar or better cost-effectiveness than other biologics, but is
less efficient than methotrexate and cyclosporine. Adalimumab is generally well
tolerated. Patients should be evaluated for active/latent tuberculosis, serious
infections, and other contraindications prior to initiation of adalimumab
therapy. Future studies should investigate the comparative efficacy of
adalimumab and other biologic and prebiologic agents. Recently established
registries will yield additional data on the effectiveness and long-term safety
of adalimumab. Psoriasis is a chronic, systemic T-cell mediated autoimmune skin disease,
potentially associated with arthritis. The new understanding of
immunopathogenesis and inflammatory cytokine pathways was actually the rationale
for developing and introducing biological drugs in the treatment of moderate to
severe psoriasis and psoriatic arthritis. Different from the traditional
systemic drugs that impact the entire immune system, bio-logics target only
specific points of the immune system. This review focuses on five biologics
which target either T-cells (alefacept) or TNF-alpha (etanercept, adalimumab and
infliximab) or interleukin IL-12/IL-23 (ustekinumab)--their efficacy, safety,
patient monitoring and recommended dosage. The purpose of the treatment
guidelines presented here is to provide a high standard of continuing care of
psoriasis and psoriatic arthritis patients. Psoriasis is a chronic inflammatory disease of the skin. The causes of psoriasis
are unknown, although family and twin studies have shown genetic factors to play
a key role in its development. The many genes associated with psoriasis and the
immune response include TNF α , IL23, and IL12. Advances in knowledge of the
pathogenesis of psoriasis have enabled the development of new drugs that target
cytokines (e.g., etanercept, adalimumab, and infliximab, which target TNF α ,
and ustekinumab, which targets the p40 subunit of IL23 and IL12). These drugs
have improved the safety and efficacy of treatment in comparison with previous
therapies. However, not all patients respond equally to treatment, possibly
owing to interindividual genetic variability. In this review, we describe the
genes associated with psoriasis and the immune response, the biological drugs
used to treat chronic severe plaque psoriasis, new drugs in phase II and III
trials, and current knowledge on the implications of pharmacogenomics in
predicting response to these treatments. Tumour necrosis factor (TNF) plays an important role in the pathogenesis of
immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in
down-regulation of abnormal and progressive inflammatory processes, resulting in
rapid and sustained clinical remission, improved quality of life and prevention
of target organ damage. Adalimumab is the first fully human monoclonal antibody
directed against TNF. In this article, we review the role and cost effectiveness
of adalimumab in the treatment of IMIDs in adults and children. The efficacy and
tolerability of adalimumab has been demonstrated in patients with a wide range
of inflammatory conditions, leading to regulatory approval in rheumatoid
arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel
diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and
intestinal Behçet's disease), ankylosing spondylitis (AS), axial
spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major
tolerability issues with adalimumab are class effects, such as injection site
reactions and increased risk of infection and lymphoma. As with all anti-TNF
agents, adalimumab is immunogenic, although less than infliximab, and some
patients receiving long-term adalimumab will develop anti-drug antibodies,
causing a loss of response. Comparisons of its clinical utility and cost
effectiveness have shown it to be a valid treatment choice in a wide range of
patients. Recent data from Italian economic studies show the cost effectiveness
of adalimumab to be below the threshold value for health care interventions for
most indications. In addition, analysis of indirect costs shows that adalimumab
significantly reduces social costs associated with RA, PsA, AS, Crohn's disease
and psoriasis. The fact that adalimumab has the widest range of approved
indications, many often presenting together in the same patient due to the
common pathogenesis, may further improve the utility of adalimumab. Current
clinical evidence shows adalimumab to be a valuable resource in the management
of IMIDs. Further research, designed to identify patients who may benefit most
from this drug, will better highlight the role and cost-effectiveness of this
versatile TNF inhibitor. As our understanding of the pathogenesis of autoimmune diseases is growing, new
therapies are being developed to target disease-specific pathways. Since the
introduction of etanercept in 1998, several biotechnological agents have been
developed, most of them indicated in the treatment of rheumatoid arthritis, but
also psoriatic arthritis. Most currently available molecules target TNF-alfa
with different strategies (i.e., etanercept, infliximab, adalimumab, golimumab,
and certolizumab pegol), IL-6 (tocilizumab), CTLA-4 (abatacept), and B cells
(rituximab, belimumab) as they are key mediators in the cascade of inflammation.
Further, small molecules have been recently developed to target intracellular
signaling, such as Janus Kinases for tofacitinib, the first FDA-approved small
molecule for rheumatoid arthritis. Most novel treatments are being developed for
arthritis with specific differences between rheumatoid and psoriatic arthritis,
as well as for systemic lupus erythematosus, following the approval of
belimumab. Finally, biologic therapies are effective also in gout, mainly
targeting interleukin-1 to block the inflammasome. This review article describes
the new and upcoming treatment options for rheumatoid arthritis, psoriatic
arthritis, systemic lupus erythematosus, and gout to dissect what we should be
aware of when discussing these new and promising molecules. OBJECTIVES: Targeted drugs against key pathogenetic molecules such as TNF-alpha
have significantly improved outcomes in rheumatoid arthritis (RA). They are
widely used in clinical practice and drug registries give us information to
support their use. Adalimumab (ADA) is able to induce a comprehensive disease
control in RA by achieving clinical, functional and radiographic control.
METHODS: By interrogating 2 Italian registries, LORHEN and GISEA, we analysed
the efficacy of ADA in first- or second-line in a total of 2262 RA patients.
RESULTS: Patients in 1st line were significantly older, with lower disease
activity and HAQ scores compared to 2nd line. In 1st line, rates of
DAS28-remission (DAS28rem) at 2 years were 34.4% while 26.5% in 2nd line
(p=0.038). A normal HAQ score (HAQ≤0.5) was achieved in 53.5% after 2 years in
1st line versus 30.1% in 2nd (p<0.0001). DAS28rem+HAQ≤0.5, a combined parameter
that we defined global clinical disease control, was reached in 20.7% in 1st
line versus 13.3% in 2nd (p<0.01). Five-year-survival on therapy was higher for
patients in 1st line (45.6% vs. 33.2%, p<0.0001). Discontinuation due to lack of
efficacy was lower in 1st line (37.4 vs. 54.4%, p<0.0001). Rates of adverse
events were similar.
CONCLUSIONS: Responses in 1st line are generally significantly better than after
a first anti-TNF-alpha failure but patients in 2nd line have a worse clinical
and functional profile. A global disease control with clinical and functional
remission is an achievable target in both lines. In psoriasis, a specific cytokine network has been described to play a central
role in the pathophysiology of the disease. Anti-cytokine therapeutic approaches
have been largely developed and TNFα constitutes the main target. Adalimumab is
a human anti-TNFα monoclonal antibody that has been reported to demonstrate
clinical efficacy and safety, resulting in reversal of epidermal hyperplasia and
cutaneous inflammation. We aimed to analyse changes in the skin inflammatory
transcriptomic profile in psoriatic patients during adalimumab therapy. In
addition, the circulating cytokine profile was analysed to define systemic
inflammation. Eighteen patients with chronic plaque psoriasis were treated with
adalimumab. After four and 16 weeks, clinical efficacy was assessed using PASI
and DLQI, and skin mRNA profiles were determined and circulating cytokines
quantified. We identified a rapid effect of adalimumab therapy on a large array
of Th17 cytokines of the skin, which may account for the modification of
keratinocyte expression profile and clinical response. In contrast, analysis of
serum cytokine concentrations was uninformative, confirming the need for
characterization of local cytokines in skin lesions. Finally, in non-responders,
local cytokine expression was shown to be unchanged. We show that TNFα
inhibition in psoriasis patients treated with adalimumab has a broad effect on
the expression profile of cytokines and keratinocyte markers of skin
inflammation, which may account for its clinical efficacy. Adalimumab is a human monoclonal antibody which targets tumor necrosis factor
(TNF)-alpha. It is produced by recombit DNA technology, using a mammalian
cell expression system and is widely-known to treat a number of immune-mediated
conditions, including psoriasis. There has been a growing concern regarding the
possible association between TNF-alpha inhibitors and maligcy. In this case
report, we describe the case of a 20-year-old woman, known to have been
suffering from chronic plaque psoriasis for 12 years, and who developed
Hodgkin's lymphoma within five weeks of beginning adalimumab treatment. |
Which gene is implicated in the metabolism of codeine, and its polymorphisms in the mother can pose a risk to breastfeeding children? | Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding, by producing more of the active metabolite, morphine. | |
Describe the role of epidermal CYLD inactivation in sebaceous and basaloid skin tumors | Epidermal CYLD inactivation sensitizes mice to the development of sebaceous and basaloid skin tumors. Epidermal cyld inactivation also inhibits the growth of epidermal cell lines, leading to development of skin tumors in the early phase of the disease. | The deubiquitinase-encoding gene Cyld displays a domit genetic linkage to a
wide spectrum of skin-appendage tumors, which could be collectively designated
as CYLD mutant-syndrome (CYLDm-syndrome). Despite recent advances, little is
understood about the molecular mechanisms responsible for this painful and
difficult-to-treat skin disease. Here, we generated a conditional mouse model
with epidermis-targeted expression of a catalytically deficient CYLDm through
K14-Cre-mediated deletion of exon 9 (hereafter refer to CyldEΔ9/Δ9 ). CyldEΔ9/Δ9
mice were born alive but developed hair and sebaceous gland abnormalities and
dental defects at 100% and 60% penetrance, respectively. Upon topical challenge
with DMBA/TPA, these animals primarily developed sebaceous and basaloid tumors
resembling human CYLDm-syndrome as opposed to papilloma, which is most commonly
induced in WT mice by this treatment. Molecular analysis revealed that
TRAF6-K63-Ubiquitination (K63-Ub), c-Myc-K63-Ub, and phospho-c-Myc (S62) were
markedly elevated in CyldEΔ9/Δ9 skin. Topical treatment with a pharmacological
c-Myc inhibitor induced sebaceous and basal cell apoptosis in CyldEΔ9/Δ9 skin.
Consistently, c-Myc activation was readily detected in human cylindroma and
sebaceous adenoma. Taken together, our findings demonstrate that CyldEΔ9/Δ9 mice
represent a disease-relevant animal model and identify TRAF6 and c-Myc as
potential therapeutic targets for CYLDm-syndrome. |
Describe the mechanism of action of Lisocabtagene maraleucel. | Lisocabtagene maraleucel is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. | Aggressive B-cell lymphomas that are primary refractory to, or relapse after,
frontline chemoimmunotherapy have a low cure rate with conventional therapies.
Although high-dose chemotherapy remains the standard of care at first relapse
for sufficiently young and fit patients, fewer than one-quarter of patients with
relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric
antigen receptor (CAR) T cells have emerged as an effective therapy in patients
with multiple relapsed/refractory disease, capable of inducing durable
remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR
T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel,
tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug
Administration approved or in late-stage development. All three CAR T cells
produce durable remissions in 33%-40% of treated patients. Differences among
these products include the specific CAR constructs, costimulatory domains,
manufacturing process, dose, and eligibility criteria for their pivotal trials.
Notable toxicities include cytokine release syndrome and neurologic toxicities,
which are usually treatable and reversible, as well as cytopenias and
hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity
differ across CAR T-cell products, related in part to the type of costimulatory
domain. Potential mechanisms of resistance include CAR T-cell exhaustion and
immune evasion, CD19 antigen loss, and a lack of persistence. Rational
combination strategies with CAR T cells are under evaluation, including immune
checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel
cell products are also being developed and include CAR T cells that target
multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T
cells, among others. Adoptive cellular immunotherapy with anti CD19 chimeric antigen receptor (CAR)-T
cell has changed the treatment landscape in relapsed/refractory B cell
lymphomas. They have emerged as effective therapy in patients with multiple
relapsed/refractory disease, capable of sustaining durable remissions. Two CAR-T
cell products (axicabtagene ciloleucel and tisagenlecleucel) are currently
approved by the United States Food and Drug Administration. A third anti CD19
CAR-T cell, lisocabtagene ciloleucel is currently being evaluated in large
clinical trials and may also be United States Food and Drug
Administration-approved soon. CAR-T cell-related toxicities, including
infections, cytokine release syndrome, and neurotoxicity are potential
complications of therapy. With increasing use of CAR-T cells, the mechanism of
toxicities and mitigation strategies needs to be developed. Additionally,
reasons for CAR-T cell failure and progression following this therapy needs to
be further studied. We describe the recent developments in this field, with
emphasis on the complications of therapy and factors contributing to toxicities,
efficacy, and resistance. We also describe the ongoing research in this field
and the newer CAR-T cell constructs that are being developed to counter the
challenges that have been identified in this field. CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor
which targets the modified T-cell against a specified cancer antigen. Anti-CD19
CAR T-cells currently represent transformational therapy for relapsed/refractory
aggressive B-cell lymphomas where durable remissions can be induced in patients
with previously incurable chemotherapy-refractory disease. Three anti-CD19 CAR
T-cells are currently Food and Drug Administration and European Medicines Agency
approved or in advanced-stage development: axicabtagene ciloleucel,
tisagenlecleucel, and lisocabtagene maraleucel. Although all targeting CD19 on
the surface of maligt (and healthy) B-cells, these products differ from one
another in multiple ways including construct, manufacturing, dose, design of
pivotal clinical trials, and toxicity profile. Efficacy and safety data for
anti-CD19 CAR T-cell therapy in aggressive B-cell lymphomas will be reviewed, as
well as novel CAR T-cell designs and strategies for overcoming treatment
resistance. Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for
patients with CD19 B-cell maligcies. Combination strategies that improve CAR
T-cell potency, limit tumor environment-mediated immune dysfunction, and
directly reduce tumor burden may increase the potential for durable clinical
benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product
therapy candidate being tested in patients with relapsed/refractory non-Hodgkin
lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and
in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of
liso-cel in combination with ibrutinib or acalabrutinib. In prolonged
stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR
T-cell effector function. RNA-Seq analysis and surface marker profiling of these
CAR T cells treated with ibrutinib but not acalabrutinib revealed gene
expression changes consistent with skewing toward a memory-like, type 1
T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved
CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in
combination with CAR T cells. A combination of the defined cell product therapy
candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach
that may potentiate the promising clinical responses already achieved in CD19
B-cell maligcies with each of these single agents. Chimeric antigen receptor-modified (CAR) T cells targeting CD19 have
revolutionized the treatment of relapsed or refractory aggressive B-cell
lymphomas, and their use has increased the cure rate for these cancers from 10
to 40%. Two second-generation anti-CD19 CAR T-cell products, axicabtagene
ciloleucel and tisagenlecleucel, have been approved for use in patients, and the
approval of a third product, lisocabtagene maraleucel, is expected in 2020. The
commercial availability of the first two products has facilitated the
development of real-world experience in treating relapsed or refractory
aggressive B-cell lymphomas, shed light on anti-CD19 CAR T-cell products'
feasibility in trial-ineligible patients, and raised the need for strategies to
mitigate the adverse effects associated with anti-CD19 CAR T-cell therapy, such
as cytokine release syndrome, neurotoxicity, and cytopenia. In addition,
promising clinical data supporting the use of anti-CD19 CAR T-cell therapy in
patients with indolent B-cell lymphomas or chronic lymphocytic leukemia have
recently become available, breaking the paradigm that these conditions are not
curable. Multiple clinical CAR T-cell therapy-based trials are ongoing. These
include studies comparing CAR T-cell therapy to autologous stem cell
transplantation or investigating their use at earlier stages of disease, novel
combinations, and novel constructs. Here we provide a thorough review on the use
of the anti-CD19 CAR T-cell products axicabtagene ciloleucel, tisagenlecleucel
and lisocabtagene maraleucel in patients with indolent or aggressive B-cell
lymphoma or with chronic lymphocytic leukemia, and present novel CAR T
cell-based approaches currently under investigation in these disease settings. |
What is the cause of the Kleefstra syndrome? | Mutations in the Euchromatic Histone Methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a rare form of intellectual disability (ID) with strong autistic traits and sensory processing deficits. | Kleefstra syndrome (chromosome 9q34.3 deletion) is a rare genetic disorder with
less than 110 patients reported till date. We report a 4-month-old Caucasian
girl with Kleefstra syndrome and Shone's complex, an association which has not
been previously reported. Surgical planning for patients with Kleefstra syndrome
and complex CHD can pose challenges due to an uncertain natural history and a
risk of post-operative pulmonary hypertension. Kleefstra syndrome is a rare neurogenetic disorder caused by a subtelomeric
9q34.3 deletion or by an intragenic mutation of the euchromatin histone methyl
transferase 1 gene (EHMT1). Approximately 20% to 30% of individuals have hearing
loss. The left temporal bone of one subject with hearing loss was studied using
light microscopy. There were several abnormalities including dysostosis of the
stapes without fixation, enlarged vestibular aqueduct, anomalies of the organ of
Corti in the basal turn, cyst formation in the stria vascularis, and dysmorphia
of the cochlear modiolus and the vestibular labyrinth. This is the first
published description of the otopathology in Kleefstra syndrome. Laryngoscope,
130:2028-2033, 2020. Kleefstra syndrome is a disorder caused by a mutation in the EHMT1 gene
characterized in humans by general developmental delay, mild to severe
intellectual disability and autism. Here, we characterized cumulative memory in
the Ehmt1+/- mouse model using the Object Space Task. We combined conventional
behavioral analysis with automated analysis by deep-learning networks, a
session-based computational learning model, and a trial-based classifier.
Ehmt1+/- mice showed more anxiety-like features and generally explored objects
less, but the difference decreased over time. Interestingly, when analyzing
memory-specific exploration, Ehmt1+/- show increased expression of cumulative
memory, but a deficit in a more simple, control memory condition. Using our
automatic classifier to differentiate between genotypes, we found that
cumulative memory features are better suited for classification than general
exploration differences. Thus, detailed behavioral classification with the
Object Space Task produced a more detailed behavioral phenotype of the Ehmt1+/-
mouse model. Kleefstra syndrome (KS) is an autosomal domit disorder caused by a
chromosomal deletion at 9q34.3 resulting in pathogenic variants of the gene that
codes for the enzyme, euchromatin histone methyltransferase 1 (EHMT1). KS is a
rare, yet clinically relevant congenital disorder for anesthesiologists because
of its potential for cardiac and craniofacial involvement. We present a
3-month-old patient with KS who required anesthetic care for diagnostic
laryngoscopy and rigid bronchoscopy. The end-organ effects of KS are reviewed
and our anesthetic care presented. Mutations in the Euchromatic Histone Methyltransferase 1 (EHMT1) gene cause
Kleefstra syndrome, a rare form of intellectual disability (ID) with strong
autistic traits and sensory processing deficits. Proper development of
inhibitory interneurons is crucial for sensory function. Here we report a
timeline of Parvalbumin-positive (PV+) interneuron development in the three most
important sensory cortical areas in the Ehmt1+/- mouse. We find a hitherto
unreported delay of PV+ neuron maturation early in sensory development, with
layer- and region-specific variability later in development. The delayed PV+
maturation is also reflected in a delayed maturation of GABAergic transmission
in Ehmt1+/- auditory cortex, where we find a reduced GABA release probability
specifically in putative PV+ synapses. Together with earlier reports of
excitatory impairments in Ehmt1+/- neurons, we propose a shift in
excitatory-inhibitory balance towards overexcitability in Ehmt1+/- sensory
cortices as a consequence of early deficits in inhibitory maturation. |
Is acupotomy used to treat muscle stiffness? | Yes. Acupotomy has been widely used to treat nerve entrapment syndrome. URL_0 | This study observed the local tissue homogenates in rabbits with third lumbar
vertebral transverse foramen syndrome and explored the mechanism of
acupotomylysis in local tissue revascularization. Thirty Japanese white rabbits
were randomly divided into the following 5 groups of 6 rabbits each: normal,
model, acupotomy, electroacupuncture (EA), and acupotomy-EA groups. All except
the normal group were comprised of animal models of third lumbar vertebral
transverse foramen syndrome prepared by embedding sponge in the left third
lumbar transverse process. The rabbits in the acupotomy and EA groups underwent
bilateral acupotomylysis intervention; those in the acupotomy-EA group underwent
acupotomylysis and EA interventions. On the 28th day after modeling, the
double-antibody ELISA was used to detect b-FGF and CD34 levels in the serum and
homogenates of a muscle tissue sample from the left side of the third lumbar
transverse process. The b-FGF levels in local muscle homogenates were
significantly higher in the modeled rabbits than in the normal rabbits (P <
0.01), and the CD34 levels in the modeled group were significantly lower than in
the normal group (P < 0.01). The b-FGF and CD34 levels in the EA, acutopomy, and
acutopomy-EA groups were significantly lower than those in the modeled group (P
< 0.01); the CD34 levels were significantly higher in the acupotomy-EA group
than in the model group (P < 0.05); and the differences among the EA, acupotomy,
and acupotomy-EA groups were not significant (P > 0.05). In conclusion,
acupotomylysis regulates the levels of b-FGF and CD34 levels in serum and muscle
tissue as well as local tissue revascularization. OBJECTIVE: To investigate the clinical efficacy of acupotomy stress position
percutaneous dynamic release for severe shoulder periarthritis.
METHODS: From April 2012 to August 2016, 160 patients with severe shoulder
periarthritis were randomly divided into treatment group and control group.
Among them, 80 patients in treatment group were treated with acupotomy stress
position percutaneous dynamic release including 32 males and 48 females with an
average of(52.47±9.04)years old ranging from 40 to 74 years old;the courses of
disease was(20.72±9.55)months on average. The other 80 patients in control group
were treated with simple joint loosening according to Maitland technique in
grade III-IV therapy, once a day, 15 to 20 min each time, and 10 d for 1 course,
for a total of 2 courses, including 33 males and 47 females with an average of
(53.19±10.18) years old ranging from 42 to 75 years old; the average course of
disease was (21.98 ±8.99) months. After operation, the shoulder muscles training
and shoulder joint activity training were routinely conducted, the treatment
lasted for 3 weeks. The visual analogue scale(VAS) and Constant-Murley shoulder
function score were observed and compared between the two groups before
treatment and 3 weeks, 3, 6 months after treatment.
RESULTS: The VAS scores of the treatment group at 3 weeks, 3 and 6 months after
treatment were all lower than those of the control group(P<0.05). The shoulder
joint function Constant-Murley scores of the treatment group at 3 weeks, 3 and 6
months after treatment were higher than those of the control group (P<0.05); the
result was excellent in 59 cases, good in 18 cases, fair in 3 cases in the
treatment group; excellent in 15 cases, good in 31 cases, fair in 23 cases, poor
in 11 cases in the control group, and the difference between the two groups was
statistically significant(P<0.01).
CONCLUSIONS: Treatment of severe shoulder periarthritis with acupotomy stress
position percutaneous dynamic release can obviously improve the shoulder joint
function and pain, according to the different parts of the shoulder joint pain
and function limitation, the corresponding shoulder stress and body position
should be designed and maintained during the treatment process, and the angle of
stress position gradually increased by loosening the adhesion, which is the key
to ensure the curative effect. BACKGROUND: In children, cerebral palsy (CP) is one of the most common causes of
irreversible neurological sequelae. Acupotomy, a modernized acupuncture form
combining the effects of microsurgery and conventional acupuncture, may show
specific benefits in the treatment of CP, especially with respect to spasticity.
The aim of this review was to evaluate the efficacy of acupotomy for CP.
METHODS: Eleven databases were comprehensively searched from their inception
dates to November 27, 2018. Randomized controlled trials (RCTs) or quasi-RCTs
evaluating acupotomy as a monotherapy or as adjunctive therapy to rehabilitation
treatment for CP were included. The methodological quality of included studies
was assessed using the risk of bias tool. The quality of evidence for each main
outcome was evaluated using the Grading of Recommendations Assessment,
Development, and Evaluation approach. Meta-analysis was performed, and the
pooled data were presented as mean difference (MD) with 95% confidence interval
(CI) for continuous outcomes and as risk ratio (RR) with 95% CI for dichotomous
outcomes.
RESULTS: Eight studies involving 530 participants were included. In 1 study,
acupotomy was associated with significantly higher total effective rate (TER)
compared with Bobath (P < .01). Acupotomy combined with rehabilitation was
associated with significantly higher TER (RR 1.24, 95% CI 1.01-1.52, I = 77%)
and gross motor function measure score (MD 12.62, 95% CI 11.75-13.49, I = 54%),
and significantly lower muscle tone of gastrocnemius measured by the Ashworth
scale or the modified Ashworth scale (MD -0.97, 95% CI -1.07 to -0.88, I = 0%)
compared with rehabilitation alone. No studies reported the incidence of adverse
events. The methodological quality of the included studies and quality of
evidence for the main finding were generally low.
CONCLUSION: Current evidence shows that acupotomy as a monotherapy or as
adjunctive therapy to rehabilitation treatment might have benefits in the
treatment of CP. However, due to the small number of studies included, the lack
of sample size, poor methodological qualities, and low quality of evidence, the
findings of this review should be interpreted with caution. Larger and more
rigorous, high-quality RCTs should be performed on this topic.
PROSPERO REGISTRATION NUMBER: CRD42018105891. OBJECTIVE: To observe the clinical efficacy of minimally invasive
acupotomy-injection technique with targeted three-point in the treatment of
frozen shoulder.
METHODS: From March 2017 to November 2018, a total of 140 patients with frozen
shoulder were randomly divided into observation group and control group. The
observation group was made up of 70 patients, including 30 males and 40 females;
the mean age was (59.2±11.5) years old; the mean duration of disease was
(6.76±4.14) months; the observed patients were treated with acupotomy-injection
technique with targeted three-point. There were also 70 patients in the control
group, made up of 29 males and 41 females; the mean age was (58.9±11.8) years
old; the mean duration of disease was (6.65±3.98) months; the control group was
treated with the small needle knife therapy. Before treatment and one month
after the treatment, the pain levels of both groups were assessed using the
short-form McGill pain questionnaire, and the shoulder function was evaluated
using the Constant-Murley Shoulder Outcome Scoring. The clinical efficacy of
between groups was compared after treatment, and finally, the improvement rate
of pain degree was used to evaluate the therapeutic effect of the patients.
RESULTS: The PRI, VAS, PPI and total pain scores of frozen shoulder patients in
both groups decreased significantly one month after the treatment compared with
those before treatment (P<0.01). Compared with the control group, the
observation group exhibited a more significant decrease in pain scores (P<0.01).
Furthermore, the shoulder pain, muscle strength, ADL, ROM and total function
scores of frozen shoulder patients in the two groups were significantly improved
one month after the treatment compared with those before treatment(P<0.01). The
inter-group comparison indicated that the pain, ADL, ROM and total function
scores were improved obviously in the observation group when compared to those
in the control group(P<0.01), but no remarkable difference was found between
muscle strength score and the control group(P>0.05). In addition, the markedly
effective rate of pain improvement was 70.0% and 45.7% in the observation group
and the control group, respectively, meanwhile, the corresponding total
effective rate was 97.1% and 84.3%, respectively.
CONCLUSIONS: The application of acupotomy-injection technique with targeted
three-point in the treatment of frozen shoulder shows definite efficacy, easy
operation, little pain and high safety. Therefore, it is an ideal method for
minimally invasive treatment. BACKGROUND AND PURPOSE: Acupotomy is a modern type of acupuncture that uses a
blade-needle combined with a flat surgical scalpel at its tip. This study was
conducted to summarize and critically evaluate the current evidence on
acupotomy.
MATERIALS AND METHODS: All relevant studies up to February 19, 2019, were
included, through comprehensive searches in 11 electronic databases without
language restrictions.
RESULTS: Eleven systematic reviews (SRs) comprising of 69 randomized controlled
trials were included, and the methodological quality was medium-to-high in
AMSTAR. All the included studies reviewed musculoskeletal disorders and reported
a significantly higher total effective and cure rates in the acupotomy group for
frozen shoulder, cervical spondylosis, third lumbar vertebrae transverse process
syndrome, trigger finger, knee osteoarthritis, and lumbar spinal stenosis,
compared to the other active control groups.
CONCLUSION: Acupotomy showed promising results for some musculoskeletal
disorders; however, additional high-quality evidence is required to make
clinical recommendations regarding this procedure. INTRODUCTION: Cervical spondylotic radiculopathy (CSR) is the most common
pattern of cervical spondylosis, which is a serious and common degenerative
disease. Both acupotomy and acupuncture have been widely used clinically to
treat CSR in China with satisfied efficacy. However, there is no systematic
review comparing the effectiveness of these two therapies. The aim of this study
is to compare the therapeutic efficacy and safety between acupotomy and
acupuncture for patients with CSR to provide evidence for clinical practice.
METHODS AND ANALYSIS: The following electronic databases will be searched: Web
of Science, PubMed, Embase, Cochrane Library, China National Knowledge
Infrastructure , China Biology Medicine disc, Wanfang Database and Chinese
Scientific Journal Database (VIP). The randomised controlled trials of acupotomy
versus acupuncture with/without additional treatment for CSR will be searched in
the databases from their inception to December 2018 by two researchers
independently. Visual analogue scale, symptom score and neck disability index
will be assessed as the primary outcomes. The total effective rate, curative
rate, adverse events and amount of rescue medication used will be assessed as
the secondary outcomes. The Review Manager 5.3 will be used for meta-analysis
and the evidence level will be assessed by using the method for Grading of
Recommendations Assessment, Development and Evaluation. Continuous outcomes will
be presented as the weighted mean difference or standardised mean difference
with 95% CI, whereas dichotomous data will be expressed as relative risk with
95% CI. If the included studies have existing heterogeneity (p<0.05), then a
random-effects model will be used. Otherwise, we will calculate using a
fixed-effects model.
ETHICS AND DISSEMINATION: Ethical approval is not required because no primary
data are collected. This review will be published in a peer-reviewed journal and
will be presented at an international academic conference for dissemination.
PROSPERO REGISTRATION NUMBER: CRD42019117348. BACKGROUND: Acupotomy has been widely used to treat nerve entrapment syndrome.
But its efficiency has not been scientifically and methodically evaluated. The
aim of this study is to evaluate the efficacy and safety of the acupotomy
treatment in patients with nerve entrapment syndrome.
METHODS: Fifteen databases will be searched from inception to Dec 2019. We will
include randomized controlled trials (RCTs) assessing acupotomy for nerve
entrapment syndrome. All RCTs on acupotomy or related interventions will be
included. Study inclusion, data extraction and quality assessment will be
performed independently by 2 reviewers. Assessment of risk of bias and data
synthesis will be performed using RevMan 5.3 software. Cochrane criteria for
risk-of-bias will be used to assess the methodological quality of the trials.
RESULTS: This study will provide a high-quality synthesis of pain VAS and
functional disability or the quality of life, the success treatment rate, the
recurrent rate and the complications rate to assess the effectiveness and safety
of acupotomy for nerve entrapment syndrome patients.
CONCLUSION: This systematic review will provide evidence to judge whether
acupotomy is an effective intervention for patients with nerve entrapment
syndrome.
PROSPERO REGISTRATION NUMBER: CRD42018109086. The aim of this study was to determine the effects of acupotomy on energy crises
in rat trigger points (TrPs) by measuring mechanical pain thresholds (MPTs) and
levels of acetylcholinesterase (AChE), free sarcoplasmic calcium (Ca2+),
adenosine 5'-triphosphate (ATP), adenosine 5'-monophosphate (AMP), substance P
(SP), and calcitonin gene-related peptide (CGRP) in rat muscle TrP tissue. Male
Sprague Dawley rats (n = 32) were randomly divided into four groups: control,
TrP, acupotomy, and lidocaine injection. Enzyme-linked immunosorbent assays were
used to measure AChE, and free sarcoplasmic Ca2+ concentrations were determined
by fluorescent staining with Fura-2 AM; high-performance liquid chromatography
was used to measure ATP and AMP, and SP and CGRP were evaluated by
immunohistochemistry. Compared with the control group, free sarcoplasmic Ca2+,
AMP, SP, and CGRP were higher in the model group, while MPT, AChE, and ATP were
lower. Treatment with acupotomy or lidocaine injection reduced free sarcoplasmic
Ca2+, SP, and CGRP and increased MPTs and AChE levels compared with the model
group. However, only acupotomy also led to decreased AMP and increased ATP
levels relative to the model group. We conclude that acupotomy can alleviate
energy crises at TrPs. BACKGROUND: Acupotomy, which involves the addition of a scalpel function to the
conventional acupuncture treatment, has recently been applied as a conservative
treatment method for lumbar disc herniation (LDH). This study investigated the
effectiveness and safety of acupotomy, compared to manual acupuncture, for the
treatment of patients with LDH.
METHODS: A total of 146 patients diagnosed with LDH were randomly assigned to
either the acupotomy group or the manual acupuncture group at a 1:1 ratio.
Participants in both groups received four sessions of each intervention over 2
weeks. Outcome assessments based on the visual analog scale (VAS), Roland Morris
Disability Questionnaire (RMDQ), Modified-Modified Schober Test (MMST), EuroQol
Five Dimensions (EQ-5D), clinically important difference (CID), and patient
global impression of change (PGIC) were conducted at baseline and at 2, 4, and 6
weeks post-randomization.
RESULTS: The acupotomy group showed significant improvement in VAS and MMST at
2, 4, and 6 weeks than did the manual acupuncture group. RMDQ was significantly
different between the two groups at 2 and 6 weeks. In EQ-5D, there was no
significant difference between the two groups. The proportion of patients with
≥15 mm decrease on the VAS (minimal CID) was significantly higher in the
acupotomy group at weeks 2 and 4. Better improvement in the PGIC at week 4 was
also observed in the acupotomy group. Post-intervention muscle pain was
reported, but there was no serious adverse event related to interventions.
CONCLUSION: In this study, four sessions of acupotomy treatment were found to be
effective in improving the pain intensity and range of motion of the lumbar
region in patients with LDH. Despite post-treatment muscle pain, acupotomy
treatment can be considered a preferred treatment method over manual
acupuncture.
TRIAL REGISTRATION: This trial has been registered 24 April 2018 in Clinical
Research Information Service of South Korea (CRIS-KCT0002824). OBJECTIVE: To evaluate the clinical efficacy and safety of acupotomy in
treatment of knee osteoarthritis (OA).
METHODS: Extensive literature searches were carried out in PubMed, EMBASE,
Cochrane Library (Issue 5, 2017), Chinese Biomedical Literature Database, China
National Knowledge Infrastructure Database, China Science and Technology Journal
Database and Wanfang Database. All databases were retrieved from their inception
until May 31, 2017. Randomized controlled trials incorporating acupotomy versus
intra-articular sodium hyaluronate for knee osteoarthritis were included.
According to Cochrane Reviews' Handbook (5.2), two reviewers screened each
article and extracted data independently and were blinded to the findings of
each reviewer. Meta-analysis was performed by the Cochrane Collaboration's
RevMan 5.3 software.
RESULTS: We identified 12 studies involving 1150 patients aged between 40 and 78
years old. The pooled analysis indicated that acupotomy showed a significant
improvement for short-term effect [cure rate: odds ratio (OR) = 2.04, 95%
confidence interval (CI) (1.46, 2.85), P < 0.01; total effective rate: OR =
2.25, 95% CI (1.55, 3.28), P < 0.01; pain score: standard mean difference (SMD)
= －1.02; 95% CI (－1.72, －0.31); P = 0.005; Western Ontario and McMaster
Universities Questionnaire (WOMAC) score: SMD = －0.74; 95% CI (－1.11, －0.37); P
< 0.01]; and also for long-term effect [total effective rate: OR = 2.99, 95%CI
(1.88, 4.76), Z = 4.64, P < 0.01; pain score: SMD = －1.68; 95% CI (－2.14,
－1.22); P < 0.001; WOMAC score: SMD = －0.91; 95% CI (－1.40, －0.41); P < 0.001].
In addition, there was no obvious difference between acupotomy group and control
group in adverse events [OR = 2.13, 95%CI (0.14, 32.28), P = 0.58].
CONCLUSION: Acupotomy is a safe and effective treatment for KOA. However, due to
the methodological deficiency of the included studies, well-designed randomized
controlled trials are required to further confirm the findings. METHODS: We performed a comprehensive search on PubMed, the Cochrane Library,
EMBASE, and four Chinese databases for articles published prior to June 2020. We
included only randomized controlled trials (RCTs) that used acupotomy therapy as
the major intervention in adults with knee OA, were published in either Chinese
and English, included more than 20 subjects in each group, and included pain and
function in the outcome measures. Knee OA was defined by the American College of
Rheumatology or Chinese Orthopedic Association criteria in all studies. We
extracted the visual analogue scale (VAS) pain score, the Western Ontario and
McMaster Universities Osteoarthritis Index (WOMAC) pain score, the total
effectiveness rate, the modified Japanese Orthopedic Association (JOA)
activities of daily living score, and Lysholm's score. We calculated the mean
difference (MD) or risk ratio (RR) for all relevant outcomes. Meta-analyses were
conducted using random-effects models when appropriate.
RESULTS: We identified 1317 potentially relevant studies, thirty-two of which
met the eligibility criteria and were conducted in China between 2007 and 2020.
A total of 3021 knee OA patients (62.96% female, median age: 57 years, and
median disease duration: 33 months) were included. The treatment duration ranged
from 1 week to 5 weeks (median: 3 weeks). The typical acupotomy treatment
involved releasing soft tissue adhesions and was performed once a week for 1-5
weeks until the pain was relieved. The control group treatments included
acupuncture (8 studies), electroacupuncture (10 studies), sodium hyaluronate (8
studies), radiofrequency electrotherapy (1 study), and nonsteroidal
anti-inflammatory drugs (NSAIDs, 5 studies). The results from the meta-analysis
showed that acupotomy led to superior improvements in the VAS pain score
(MD = -1.11; 95% confidence interval (CI), -1.51 to -0.71; p < 0.00001) and
WOMAC pain score (MD = -2.32; 95% CI, -2.94 to -1.69; p < 0.00001), a higher
total effectiveness rate (RR = 1.15; 95% CI, 1.09-1.21; p < 0.00001), and
superior improvements in the JOA score (MD = 6.39; 95% CI, 4.11-9.76;
p < 0.00001) and Lysholm's score (MD = 12.75; 95% CI, 2.61-22.89; p = 0.01) for
overall pain and function. No serious adverse events were reported.
CONCLUSION: Chinese acupotomy therapy may relieve pain and improve function in
patients with knee OA. Furthermore, rigorously designed and well-controlled RCTs
are warranted. |
Which is the role of mediator in genome organization? | Mediator binds to boundaries of chromosomal interaction domains and to proteins involved in DNA looping, RNA metabolism, chromatin remodeling, and actin assembly. | Homologous recombination is crucial for genome stability and for genetic
exchange. Although our knowledge of the principle steps in recombination and its
machinery is well advanced, homology search, the critical step of exploring the
genome for homologous sequences to enable recombination, has remained mostly
enigmatic. However, recent methodological advances have provided considerable
new insights into this fundamental step in recombination that can be integrated
into a mechanistic model. These advances emphasize the importance of genomic
proximity and nuclear organization for homology search and the critical role of
homology search mediators in this process. They also aid our understanding of
how homology search might lead to unwanted and potentially disease-promoting
recombination events. Mediator is a large multiprotein complex conserved in all eukaryotes, which has
a crucial coregulator function in transcription by RNA polymerase II (Pol II).
However, the molecular mechanisms of its action in vivo remain to be understood.
Med17 is an essential and central component of the Mediator head module. In this
work, we utilised our large collection of conditional temperature-sensitive
med17 mutants to investigate Mediator's role in coordinating preinitiation
complex (PIC) formation in vivo at the genome level after a transfer to a
non-permissive temperature for 45 minutes. The effect of a yeast mutation
proposed to be equivalent to the human Med17-L371P responsible for infantile
cerebral atrophy was also analyzed. The ChIP-seq results demonstrate that med17
mutations differentially affected the global presence of several PIC components
including Mediator, TBP, TFIIH modules and Pol II. Our data show that Mediator
stabilizes TFIIK kinase and TFIIH core modules independently, suggesting that
the recruitment or the stability of TFIIH modules is regulated independently on
yeast genome. We demonstrate that Mediator selectively contributes to TBP
recruitment or stabilization to chromatin. This study provides an extensive
genome-wide view of Mediator's role in PIC formation, suggesting that Mediator
coordinates multiple steps of a PIC assembly pathway. Cohesin is a large ring-shaped protein complex, conserved from yeast to human,
which participates in most DNA transactions that take place in the nucleus. It
mediates sister chromatid cohesion, which is essential for chromosome
segregation and homologous recombination (HR)-mediated DNA repair. Together with
architectural proteins and transcriptional regulators, such as CTCF and
Mediator, respectively, it contributes to genome organization at different
scales and thereby affects transcription, DNA replication, and locus
rearrangement. Although cohesin is essential for cell viability, partial loss of
function can affect these processes differently in distinct cell types.
Mutations in genes encoding cohesin subunits and regulators of the complex have
been identified in several cancers. Understanding the functional significance of
these alterations may have relevant implications for patient classification,
risk prediction, and choice of treatment. Moreover, identification of
vulnerabilities in cancer cells harboring cohesin mutations may provide new
therapeutic opportunities and guide the design of personalized treatments. Mediator is a multi-unit molecular complex that plays a key role in transferring
signals from transcriptional regulators to RNA polymerase II in eukaryotes. We
have combined biochemical purification of the Saccharomyces cerevisiae Mediator
from chromatin with chromatin immunoprecipitation in order to reveal Mediator
occupancy on DNA genome-wide, and to identify proteins interacting specifically
with Mediator on the chromatin template. Tandem mass spectrometry of proteins in
immunoprecipitates of mediator complexes revealed specific interactions between
Mediator and the RSC, Arp2/Arp3, CPF, CF 1A and Lsm complexes in chromatin.
These factors are primarily involved in chromatin remodeling, actin assembly,
mRNA 3'-end processing, gene looping and mRNA decay, but they have also been
shown to enter the nucleus and participate in Pol II transcription. Moreover, we
have found that Mediator, in addition to binding Pol II promoters, occupies
chromosomal interacting domain (CID) boundaries and that Mediator in chromatin
associates with proteins that have been shown to interact with CID boundaries,
such as Sth1, Ssu72 and histone H4. This suggests that Mediator plays a
significant role in higher-order genome organization. Mediator is a conserved, multi-subunit macromolecular machine divided
structurally into head, middle, and tail modules, along with a transiently
associating kinase module. Mediator functions as an integrator of
transcriptional regulatory activity by interacting with DNA-bound transcription
factors and with RNA polymerase II (Pol II) to both activate and repress gene
expression. Mediator has been shown to affect multiple steps in transcription,
including chromatin looping between enhancers and promoters, pre-initiation
complex formation, transcriptional elongation, and mRNA splicing. Individual
Mediator subunits participate in regulation of gene expression by the estrogen
and androgen receptors and are altered in a number of endocrine cancers,
including breast and prostate cancer. In addition to its role in genomic
signaling, MED12 has been implicated in non-genomic signaling by interacting
with and activating TGF-beta receptor 2 in the cytoplasm. Recent structural
studies have revealed extensive inter-domain interactions and complex
architecture of the Mediator-Pol II complex, suggesting that Mediator is capable
of reorganizing its conformation and composition to fit cellular needs. We
propose that alterations in Mediator subunit expression that occur in various
cancers could impact the organization and function of Mediator, resulting in
changes in gene expression that promote maligcy. A better understanding of
the role of Mediator in cancer could reveal new approaches to the diagnosis and
treatment of Mediator-dependent endocrine cancers, especially in settings of
therapy resistance. The Mediator complex regulates transcription by connecting enhancers to
promoters. High Mediator binding density defines super enhancers, which regulate
cell-identity genes and oncogenes. Protein interactions of Mediator may explain
its role in these processes but have not been identified comprehensively. Here,
we purify Mediator from neural stem cells (NSCs) and identify 75 protein-protein
interaction partners. We identify super enhancers in NSCs and show that
Mediator-interacting chromatin modifiers colocalize with Mediator at enhancers
and super enhancers. Transcription factor families with high affinity for
Mediator dominate enhancers and super enhancers and can explain genome-wide
Mediator localization. We identify E-box transcription factor Tcf4 as a key
regulator of NSCs. Tcf4 interacts with Mediator, colocalizes with Mediator at
super enhancers and regulates neurogenic transcription factor genes with super
enhancers and broad H3K4me3 domains. Our data suggest that high binding-affinity
for Mediator is an important organizing feature in the transcriptional network
that determines NSC identity. Loss of nuclear pore complex (NPC) proteins, transcription factors (TFs),
histone modification enzymes, Mediator, and factors involved in mRNA export
disrupts the physical interaction of chromosomal sites with NPCs. Conditional
inactivation and ectopic tethering experiments support a direct role for the TFs
Gcn4 and Nup2 in mediating interaction with the NPC but suggest an indirect role
for factors involved in mRNA export or transcription. A conserved "positioning
domain" within Gcn4 controls interaction with the NPC and inter-chromosomal
clustering and promotes transcription of target genes. Such a function may be
quite common; a comprehensive screen reveals that tethering of most yeast TFs is
sufficient to promote targeting to the NPC. While some TFs require Nup100,
others do not, suggesting two distinct targeting mechanisms. These results
highlight an important and underappreciated function of TFs in controlling the
spatial organization of the yeast genome through interaction with the NPC. Cohesin, a critical mediator of genome organization including sister chromatid
cohesion, is a ring-shaped multi-subunit ATPase that topologically embraces DNA.
Its loading and function on chromosomes require the Scc2-Scc4 loader. Using
biochemical reconstitution, we show here that the ability of the loader to bind
DNA plays a critical role in promoting cohesin loading. Two distinct sites
within the Mis4Scc2 subunit are found to cooperatively bind DNA. Mis4Scc2
initially forms a tertiary complex with cohesin on DNA and promotes subsequent
topological DNA entrapment by cohesin through its DNA binding activity, a
process that requires an additional DNA binding surface provided by Psm3Smc3,
the ATPase domain of cohesin. Furthermore, we show that mutations in the two DNA
binding sites of Mis4 impair the chromosomal loading of cohesin. These
observations demonstrate the physiological importance of DNA binding by the
loader and provide mechanistic insights into the process of topological cohesin
loading. |
Which two antibodies directed towards the CGRP ligand, were approved by the FDA in September 2018. | Two antibodies, fremanezumab and galcanezumab, directed towards the CGRP ligand, were approved by the FDA in September 2018. | Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its
receptor (CLR + RAMP1) offer considerable improvements over existing drugs in
migraine prophylaxis and are the first designed to act on the trigeminal pain
system. Erenumab is approved by the FDA and EMA and has reached the market since
May 2018. Two antibodies, fremanezumab and galcanezumab, directed towards the
CGRP ligand, were approved by the FDA in September 2018. To view this Bench to
Bedside, open or download the PDF. |
Describe LowMACA | LowMACA (Low frequency Mutations Analysis via Consensus Alignment) is a method that combines the mutations of various proteins sharing the same functional domains to identify conserved residues that harbor clustered mutations in multiple sequence alignments. LowMACA is designed to visualize and statistically assess potential driver mutations through the identification of their mutational hotspots. Low MACA is an R package available at http://www.bioconductor.org/packages/release/bioc/html/LowMCCC.html. | |
Is ofatumumab effective for multiple sclerosis? | Ofatumumab, a fully human anti-CD20 monoclonal antibody, is effective for relapsing forms of multiple sclerosis. | OBJECTIVES: We present the first study to explore safety and efficacy of the
human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple
sclerosis (RRMS).
METHODS: In this randomized, double-blind, placebo-controlled study, patients
received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks
apart. At week 24, patients received alternate treatment. Safety and efficacy
were assessed.
RESULTS: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26;
placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients
in the 300-mg group withdrew from the study because of adverse events. No
unexpected safety signals emerged. Infusion-related reactions were common on the
first infusion day but not observed on the second infusion day. None of the
patients developed human anti-human antibodies. Ofatumumab was associated with
profound selective reduction of B cells as measured by CD19(+) expression. New
brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after
ofatumumab administration (all doses), with statistically significant reductions
(p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions,
total enhancing T1 lesions, and new and/or enlarging T2 lesions.
CONCLUSIONS: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated
with any unexpected safety concerns and was well tolerated in patients with
RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all
doses studied. Results warrant further exploration of ofatumumab in RRMS.
CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in
patients with RRMS, ofatumumab compared with placebo does not increase the
number of serious adverse events and decreases the number of new MRI lesions. Author information:
(1)From the Department of Neurology (A.B.-O.), Perelman School of Medicine,
University of Pennsylvania, Philadelphia; Neuroimmunology Unit (A.B.-O.),
Montreal Neurological Institute and Hospital, McGill University and McGill
University Health Center, Quebec, Canada; Neurosciences Clinical Statistics
(R.A.G.), Clinical Pharmacology (R.A.G., D.J.A.), and Modeling and Simulation
(D.J.A.), GlaxoSmithKline, Uxbridge, Middlesex, UK; Neurosciences Therapy Area
Unit (J.M.T., S.A.V., E.W.L., F.J.D., M.C.L., S.T.K.), SAVM (F.J.D., M.C.L.),
Global Clinical Safety and Pharmacovigilance (E.W.L.), and Neurosciences
Clinical Statistics (SecTK), GlaxoSmithKline, Research Triangle Park, NC;
Department of Neurology (A.E.M.), Corinne Goldsmith Dickinson Center for
Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY; and
Danish Multiple Sclerosis Center (P.S.S.), Department of Neurology, University
of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Dr. Derosier is now at
Clinical Development, Isis Pharmaceutical, Carlsbad, CA. [email protected].
(2)From the Department of Neurology (A.B.-O.), Perelman School of Medicine,
University of Pennsylvania, Philadelphia; Neuroimmunology Unit (A.B.-O.),
Montreal Neurological Institute and Hospital, McGill University and McGill
University Health Center, Quebec, Canada; Neurosciences Clinical Statistics
(R.A.G.), Clinical Pharmacology (R.A.G., D.J.A.), and Modeling and Simulation
(D.J.A.), GlaxoSmithKline, Uxbridge, Middlesex, UK; Neurosciences Therapy Area
Unit (J.M.T., S.A.V., E.W.L., F.J.D., M.C.L., S.T.K.), SAVM (F.J.D., M.C.L.),
Global Clinical Safety and Pharmacovigilance (E.W.L.), and Neurosciences
Clinical Statistics (SecTK), GlaxoSmithKline, Research Triangle Park, NC;
Department of Neurology (A.E.M.), Corinne Goldsmith Dickinson Center for
Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY; and
Danish Multiple Sclerosis Center (P.S.S.), Department of Neurology, University
of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Dr. Derosier is now at
Clinical Development, Isis Pharmaceutical, Carlsbad, CA. Multiple sclerosis (MS) is a disease of the central nervous system characterized
by inflammation, demyelination, and neuronal damage. Environmental and genetic
factors are associated with the risk of developing MS, but the exact cause still
remains unidentified. Epstein-Barr virus (EBV), vitamin D, and smoking are among
the most well-established environmental risk factors in MS. Infectious
mononucleosis, which is caused by delayed primary EBV infection, increases the
risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by
activating silent human endogenous retrovirus-W. The emerging B-cell depleting
therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well
as the fully human ofatumumab, have shown promising clinical and magnetic
resoce imaging benefit. One potential effect of these therapies is the
depletion of memory B-cells, the primary reservoir site where EBV latency
occurs. In addition, EBV potentially interacts with both genetic and other
environmental factors to increase susceptibility and disease severity of MS.
This review examines the role of EBV in MS pathophysiology and summarizes the
recent clinical and radiological findings, with a focus on B-cells and in vivo
imaging. Addressing the potential link between EBV and MS allows the better
understanding of MS pathogenesis and helps to identify additional disease
biomarkers that may be responsive to B-cell depleting intervention. The use of monoclonal antibodies in multiple sclerosis (MS) patients is in a
transitional period. Studies regarding well-established, effective antibodies
such as natalizumab and alemtuzumab focus more and more on long-term efficacy
and safety, risk management, and treating complications. Primary progressive MS,
a disease that was long considered to be unmodifiable, is currently in focus
following ocrelizumab being approved as the first drug with a proven beneficial
effect on the disease course. Conversely, post-marketing safety mechanisms have
also proven to function as daclizumab has been suspended after a series of
relevant serious adverse events. Currently, new therapies are emerging that
promise more convenience and an improved safety profile (ofatumumab) or
remyelinating potential with clinical improvement (opicinumab). While it is very
unlikely that monoclonal antibodies will ever cure MS, they have become very
valuable therapeutic tools to better patient outcomes. This review focuses on
developments of monoclonal antibodies used in the past, present, and near future
in MS patients. PURPOSE OF REVIEW: To critically assess the current landscape of
disease-modifying agents for multiple sclerosis (MS). Treatment algorithms will
be discussed and studies for new agents in late development or recently approved
are analyzed in terms of their impact on current treatment strategies.
RECENT FINDINGS: A real-world study from Wales suggests that early initiation of
highly effective therapy may provide more benefit that an escalation approach in
relapsing MS. A study from the MSBase dataset found evidence that early
treatment with highly effective therapies decreased the risk of developing
secondary progressive MS. Ocrelizumab is highly efficacious in relapsing MS and
in a group of patients with primary progressive MS. Another CD20 directed mAb,
ofatumumab, is in phase 3. A large study examining extended interval dosing of
natalizumab in an attempt to decrease the risk of developing progressive
multifocal leukoencephalopathy is underway. Cladribine and alemtuzumab may work
by immune reconstitution. Siponimod was recently approved by United States
Federal Drug Administration for relapsing MS and active secondary progressive
MS. Other S1P receptor modulators are being studied in phase 3 trials for
relapsing MS. Cladribine received FDA approval as treatment for relapsing and
active secondary progressive MS. Autologous hematopoetic stem-cell
transplantation may be an option for treatment-refractory MS.
SUMMARY: Development of disease-modifying agents in MS continues to be
successful. Treatment algorithms need to take new developments into account. Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies
(DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network
meta-analysis was conducted to determine the relative effect of ofatumumab on
annualized relapse rate and confirmed disability progression at 3 months and
6 months. Results: For each outcome, ofatumumab was as effective as other highly
efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and
ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by
reducing relapse and disability progression risk. Until recently, in the pathogenesis of Multiple Sclerosis (MS), the contribution
of B cells has been largely underestimated, and the disease was considered a
T-cell-mediated disorder. However, newer evidence shows that B cells play a
crucial role in the pathogenesis of MS via antigen-driven autoantibody responses
and through the cross regulation of T-helper cells. As B cells express the
surface molecule CD20 at all points of differentiation, it provides a specific
target for monoclonal antibodies, and the development and clinical testing of
anti-CD20 antibody treatments for MS have been successful. After some
observations, some small clinical trials found positive effects for the first
anti-CD20 therapeutic rituximab in MS; newer agents have been specifically
evaluated, resulting in the development of ocrelizumab and ofatumumab.
Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was approved in March
2017 by the Food and Drug Administration (FDA) and is also the first proven
therapy to reduce disability progression in primary progressive MS. This is
particularly significant considering that disease-modifying treatment options
are few for both primary and secondary progressive MS. Ofatumumab, a fully human
anti-CD20 monoclonal antibody, that binds a distinct epitope, has been further
investigated in phase 3 trials for relapsing forms of MS. In this review, we
discuss in detail these two anti-CD20 agents and their advent for treatment of
MS. The remarkable success of anti-CD20 B cell depletion therapies in reducing the
burden of multiple sclerosis (MS) disease has prompted significant interest in
how B cells contribute to neuroinflammation. Most focus has been on identifying
pathogenic CD20+ B cells. However, an increasing number of studies have also
identified regulatory functions of B lineage cells, particularly the production
of IL-10, as being associated with disease remission in anti-CD20-treated MS
patients. Moreover, IL-10-producing B cells have been linked to the attenuation
of inflammation in experimental autoimmune encephalomyelitis (EAE), the animal
model of MS. In addition to IL-10-producing B cells, antibody-producing plasma
cells (PCs) have also been implicated in suppressing neuroinflammation. This
review will examine regulatory roles for B cells and PCs in MS and EAE. In
addition, we speculate on the involvement of regulatory PCs and the cytokine
BAFF in the context of anti-CD20 treatment. Lastly, we explore how the
microbiota could influence anti-inflammatory B cell behavior. A better
understanding of the contributions of different B cell subsets to the regulation
of neuroinflammation, and factors that impact the development, maintece, and
migration of such subsets, will be important for rationalizing next-generation B
cell-directed therapies for the treatment of MS. |
List proteins that promotes calcification. | tissue nonspecific alkaline phosphatase (TNAP)
matrix Gla protein (MGP)
fibroblast growth factor-23 (FGF-23)
matrix metalloproteinases | Patients undergoing long-term hemodialysis (HD) are known to have abnormal blood
concentrations of antioxidant minerals; concurrent oxidative stress can
contribute to increased vascular calcification. This study aims to evaluate the
associations between circulating antioxidant minerals and clinical biomarkers of
vascular calcification in HD patients. Blood biochemical parameters, antioxidant
minerals (selenium (Se), zinc (Zn), copper (Cu), and magnesium (Mg)), and
several promoters and inhibitors of calcification (matrix Gla protein (MGP),
fibroblast growth factor-23 (FGF-23), matrix metalloproteinases (MMP-2 and -9),
and tissue inhibitors of metalloproteinase (TIMP-1 and -2)) were determined in
HD patients (n = 62) and age- and sex-matched healthy individuals (n = 30).
Compared with healthy subjects, HD patients had significantly lower plasma
concentrations of Se and Zn, increased Cu and Mg, and higher levels of oxidative
stress and inflammatory markers (Cu/Zn ratios, malondialdehyde (MDA), advanced
glycation end products (AGEs), and C-reactive protein (CRP)). We observed that
HD patients had significantly lower concentrations of MGP and higher levels of
FGF-23, MMP-2 and -9, TIMP-1 and -2, and MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios.
We also observed significant relationships between the concentrations of these
minerals and calcification biomarkers in HD patients. These results suggest that
changes in the homeostasis of antioxidant minerals (Se, Zn, Cu, and Mg) may
contribute to the effects of oxidative stress and inflammatory status, thereby
participating in the mechanism for accelerated vascular calcification in
patients undergoing long-term HD. Primary familial brain calcification (PFBC), widely known as Fahr's disease, is
a rare disorder caused by pathogenic variants in SLC20A2, PDGFB, PDGFRB, XPR1,
or MYORG genes. It is characterized by ectopic brain calcification, mostly
affecting basal ganglia, thalamus, and cerebellum. PFBC patients can present a
wide spectrum of symptoms including cognitive, neuropsychiatric, and motor
alterations. However, it is well established that PFBC individuals also present
high clinical heterogeneity, though the genetic cause of this phenotypic is not
understood. Recently, Wang et al. (Front Cell Neurosci.
https://doi.org/10.3389/fncel.2019.00250, 2019) reported on the role of MEA6
gene in cerebellar development and motor performance, also citing that MEA6
might be linked to PFBC. A MEA6 variant was described in 2007 as a PFBC
candidate gene in an American family. However, this family was later linked to
the SLC20A2 gene discarding the MEA6 as a PFBC-gene and also some members were
confirmed as phenocopy. Additionally, five independent studies have been shown
that variants in a second gene, not related to PFBC, were identified in PFBC
patients, promoting a complex and heterogeneous phenotype. Thus, further
investigation is required to explain whether and how MEA6 contributes to the
clinical presentation in this American family. Finally, this letter highlights
the possible digenic influence on clinical heterogeneity of PFBC patients, and
such a possibility might advance our understanding of PFBC phenotypes. OBJECTIVE: Retinoic acid (RA) is a ligand for nuclear receptors that modulate
gene transcription and cell differentiation. Whether RA controls ectopic
calcification in humans is unknown. We tested the hypothesis that RA regulates
osteogenic differentiation of human arterial smooth muscle cells and aortic
valvular interstitial cells that participate in atherosclerosis and heart valve
disease, respectively. Approach and Results: Human cardiovascular tissue
contains immunoreactive RAR (RA receptor)-a retinoid-activated nuclear receptor
directing multiple transcriptional programs. RA stimulation suppressed primary
human cardiovascular cell calcification while treatment with the RAR inhibitor
AGN 193109 or RARα siRNA increased calcification. RA attenuated calcification in
a coordinated manner, increasing levels of the calcification inhibitor MGP
(matrix Gla protein) while decreasing calcification-promoting TNAP (tissue
nonspecific alkaline phosphatase) activity. Given that nuclear receptor action
varies as a function of distinct ligand structures, we compared calcification
responses to cyclic retinoids and the acyclic retinoid peretinoin. Peretinoin
suppressed human cardiovascular cell calcification without inducing either
secretion of APOC3 (apolipoprotein-CIII), which promotes atherogenesis, or
reducing CYP7A1 (cytochrome P450 family 7 subfamily A member 1) expression,
which occurred with cyclic retinoids all-trans RA, 9-cis RA, and 13-cis RA.
Additionally, peretinoin did not suppress human femur osteoblast mineralization,
whereas all-trans RA inhibited osteoblast mineralization.
CONCLUSIONS: These results establish retinoid regulation of human cardiovascular
calcification, provide new insight into mechanisms involved in these responses,
and suggest selective retinoid modulators, like acyclic retinoids may allow for
treating cardiovascular calcification without the adverse effects associated
with cyclic retinoids. |
Please list 3 small molecule CGRP-Receptor antagonists for migraine | Rimegepant and ubrogepant have been developed for acute migraine treatment, while atogepant is studied for migraine prophylaxis. | BACKGROUND: Migraine is a debilitating headache disorder which affects
approximately 12% of the general population and is the cause of significant loss
of productivity (i.e., lost time from work or school) for those afflicted. The
current standard of care, the 5-HT(1B/1D) agonists known as triptans, is
contraindicated in patients with cardiovascular disease due to their inherent
vasoconstrictive activity; thus, there is a need to develop an alternative
therapy for the treatment of the disorder.
OBJECTIVE: This article reviews patent publications related to the use of small
molecule calcitonin gene-related peptide (CGRP) receptor antagonists for the
treatment of migraine that have appeared in the literature within the past
decade. The commentary is supplemented by information presented in journal
articles and focuses on the activity of several major pharmaceutical companies
in the field.
CONCLUSION: Two small molecule CGRP receptor antagonists, olcegepant and
telcagepant, have been shown to be clinically efficacious in the treatment of
migraine, and thus provide validation of this novel therapeutic mechanism. Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from
activated trigeminal sensory afferents in headache and facial pain disorders.
There are a handful of CGRP-targeted therapies currently in phase 3 studies for
migraine acute treatment or prevention. Currently, 4 monoclonal antibodies
targeting either the CGRP ligand or receptor are being studied for migraine
prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab),
and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor
antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute
treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in
clinical trials for cluster headache prevention as well. Several other
small-molecular CGRP receptor antagonists are in earlier stages of development
for acute migraine treatment or prevention. In this review, we will discuss the
growing body of clinical trials studying CGRP-targeted therapies for migraine
and cluster headache. Migraine is a common neurological disorder that afflicts up to 15% of the adult
population in most countries, with predomice in females. It is characterized
by episodic, often disabling headache, photophobia and phonophobia, autonomic
symptoms (nausea and vomiting), and in a subgroup an aura in the beginning of
the attack. Although still debated, many researchers consider migraine to be a
disorder in which CNS dysfunction plays a pivotal role while various parts of
the trigeminal system are necessary for the expression of associated
symptoms.Treatment of migraine has in recent years seen the development of drugs
that target the trigeminal sensory neuropeptide calcitonin gene-related peptide
(CGRP) or its receptor. Several of these drugs are now approved for use in
frequent episodic and in chronic migraine. CGRP-related therapies offer
considerable improvements over existing drugs, as they are the first to be
designed specifically to act on the trigeminal pain system: they are more
specific and have little or no adverse effects. Small molecule CGRP receptor
antagonists, gepants, are effective for acute relief of migraine headache,
whereas monoclonal antibodies against CGRP (Eptinezumab, Fremanezumab, and
Galcanezumab) or the CGRP receptor (Erenumab) effectively prevent migraine
attacks. The neurobiology of CGRP signaling is briefly summarized together with
key clinical evidence for the role of CGRP in migraine headache, including the
efficacy of CGRP-targeted treatments. Several lines of evidence pointed to an important role for CGRP in migraine.
These included the anatomic colocalization of CGRP and its receptor in sensory
fibers innervating pain-producing meningeal blood vessels, its release by
trigeminal stimulation, the observation of elevated CGRP in the cranial
circulation during migraine with normalization concomitant with headache relief
by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked
migraine only in migraineurs. The development of small molecule CGRP receptor
antagonists (CGRP-RAs) that showed clinical antimigraine efficacy acutely and
prophylactically in randomized placebo-controlled clinical trials subsequently
gave definitive pharmacological proof of the importance of CGRP in migraine.
More recently, CGRP target engagement imaging studies using a CGRP receptor PET
ligand [11 C]MK-4232 demonstrated that there was no brain CGRP receptor
occupancy at clinically effective antimigraine doses of telcagepant, a
prototypic CGRP-RA. Taken together, these data indicated that (1) the
therapeutic site of action of the CGRP-RAs was peripheral not central; (2) that
IV CGRP had most likely evoked migraine through an action at sites outside the
blood-brain barrier; and (3) that migraine pain was therefore, at least in part,
peripheral in origin. The evolution of CGRP migraine science gave impetus to the
development of peripherally acting drugs that could modulate CGRP chronically to
prevent frequent episodic and chronic migraine. Large molecule biologic antibody
(mAb) approaches that are given subcutaneously to neutralize circulating CGRP
peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have
shown consistent efficacy and tolerability in multicenter migraine prevention
trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing
antibody given IV, shows promise in late stage clinical development. Recently,
orally administered next-generation small molecule CGRP-RAs have been shown to
have safety and efficacy in acute treatment (ubrogepant and rimegepant) and
prevention (atogepant) of migraine, giving additional CGRP-based therapeutic
options for migraine patients. BACKGROUND: The treatment of migraine is impeded by several difficulties, among
which insufficient headache relief, side effects, and risk for developing
medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs
are currently being developed, among which the small molecule CGRP receptor
antagonists, gepants, and the 5-HT1F receptor agonist lasmiditan. Whether
treatment with these drugs carries the same risk for developing MOH is currently
unknown.
MAIN BODY: Pathophysiological studies on MOH in animal models have suggested
that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased
calcitonin-gene related peptide (CGRP) expression and changes in 5-HT receptor
expression (lower 5-HT1B/D and higher 5-HT2A expression) may be involved in MOH.
The decreased 5-HT may increase cortical spreading depression frequency and
induce central sensitization in the cerebral cortex and caudal nucleus of the
trigeminal tract. Additionally, low concentrations of 5-HT, a feature often
observed in MOH patients, could increase CGRP expression. This provides a
possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and
gepants, respectively. Since lasmiditan is a 5-HT1F receptor agonist and gepants
are CGRP receptor antagonists, they could have different risks for developing
MOH because of the different (over) compensation mechanisms following prolonged
agonist versus antagonist treatment.
CONCLUSION: The acute treatment of migraine will certainly improve with the
advent of two novel classes of drugs, i.e., the 5-HT1F receptor agonists
(lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on
the effects of 5-HT1F receptor agonism in relation to MOH, as well as the
effects of chronic CGRP receptor blockade, are awaited with interest. OBJECTIVE: To provide the first clinical report that 2 calcitonin gene-related
peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an
anti-CGRP receptor antibody, can be used concomitantly to treat refractory
migraine.
METHODS: Case reports are presented of 2 patients participating in a long-term
safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588).
After Food and Drug Administration approval of erenumab, both patients started
subcutaneous erenumab monthly as allowed per protocol.
RESULTS: Patients were women 44 and 36 years of age with ≥2 decades of
self-reported suboptimal response to multiple migraine medications. Patient 1
used rimegepant for 6 months and then started erenumab 70 mg subcutaneous
monthly. Despite a response to preventive treatment with erenumab, she
experienced substantial relief treating 7 of 7 acute attacks with rimegepant and
eliminated regular, frequent use of ibuprofen and a caffeinated analgesic.
Patient 2 used rimegepant for 60 days before starting erenumab 140 mg
subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with
rimegepant responded. She stopped near-daily use of injectable ketorolac and
diphenhydramine. While using rimegepant alone or together with erenumab,
patients reported no related adverse events.
CONCLUSIONS: Rimegepant 75 mg may be effective for acute treatment during
concomitant erenumab preventive administration. The mechanism underlying the
benefits of concomitant use of a small molecule CGRP receptor antagonist and an
anti-CGRP receptor antibody is unknown and requires further study.
CLINICALTRIALSGOV IDENTIFIER: NCT03266588.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for
patients with migraine using erenumab, rimegepant is effective for acute
treatment. Ubrogepant (Ubrelvy™) is an orally administered, small molecule,
highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was
developed by Allergan under license to Merck & Co. as an acute treatment for
migraine. In December 2019, ubrogepant received its first global approval in the
USA for the acute treatment of migraine (± aura) in adults. This article
summarizes the milestones in the development of ubrogepant leading to its first
global approval for the acute treatment of migraine (± aura) in adults. The pivotal role of calcitonin gene-related peptide (CGRP) in migraine
pathophysiology was identified over 30 years ago, but the successful clinical
development of targeted therapies has only recently been realized. This
Perspective traces the decades long evolution of medicinal chemistry required to
advance small molecule CGRP receptor antagonists, also called gepants, including
the current clinical agents rimegepant, vazegepant, ubrogepant, and atogepant.
Providing clinically effective blockade of CGRP signaling required surmounting
multiple challenging hurdles, including defeating a sizable ligand with
subomolar affinity for its receptor, designing antagonists with an extended
confirmation and multiple pharmacophores while retaining solubility and oral
bioavailability, and achieving circulating free plasma levels that provided near
maximal CGRP receptor coverage. The clinical efficacy of oral and intranasal
gepants and the injectable CGRP monoclonal antibodies (mAbs) are described, as
are recent synthetic developments that have benefited from new structural
biology data. The first oral gepant was recently approved and heralds a new era
in the treatment of migraine. Migraine is a highly disabling neurovascular disorder characterized by a severe
headache (associated with nausea, photophobia and/or phonophobia), and
trigeminovascular system activation involving the release of calcitonin-gene
related peptide (CGRP). Novel anti-migraine drugs target CGRP signaling through
either stimulation of 5-HT1F receptors on trigeminovascular nerves (resulting in
inhibition of CGRP release) or direct blockade of CGRP or its receptor.
Lasmiditan is a highly selective 5-HT1F receptor agonist and, unlike the
triptans, is devoid of vasoconstrictive properties, allowing its use in patients
with cardiovascular risk. Since lasmiditan can actively penetrate the
blood-brain barrier, central therapeutic as well as side effects mediated by
5-HT1F receptor activation should be further investigated. Other novel
anti-migraine drugs target CGRP signaling directly. This neuropeptide can be
targeted by the monoclonal antibodies eptinezumab, fremanezumab and
galcanezumab, or by CGRP-neutralizing L-aptamers called Spiegelmers. The CGRP
receptor can be targeted by the monoclonal antibody erenumab, or by
small-molecule antagonists called gepants. Currently, rimegepant and ubrogepant
have been developed for acute migraine treatment, while atogepant is studied for
migraine prophylaxis. Of these drugs targeting CGRP signaling directly,
eptinezumab, erenumab, fremanezumab, galcanezumab, rimegepant and ubrogepant
have been approved for clinical use, while atogepant is in the last stage before
approval. Although all of these drugs seem highly promising for migraine
treatment, their safety should be investigated in the long-term. Moreover, the
exact mechanism(s) of action of these drugs need to be elucidated further, to
increase both safety and efficacy and to increase the number of responders to
the different treatments, so that all migraine patients can satisfactorily be
treated. OBJECTIVE: Evaluate the safety and tolerability of oral rimegepant when used for
acute treatment concomitantly with a monoclonal antibody (mAb) targeting the
calcitonin gene-related peptide (CGRP) ligand or receptor (CGRP mAb) for the
preventive treatment of migraine.
BACKGROUND: The efficacy of CGRP mAbs for the preventive treatment of migraine
and the small molecule CGRP receptor antagonist rimegepant for acute treatment
has been demonstrated in randomized controlled clinical trials. Over the past
few years, the US Food and Drug Administration has approved 4 CGRP mAbs for the
preventive treatment of migraine and 2 small molecule CGRP receptor antagonists
for the acute treatment of migraine. A previous case report of 2 patients
receiving concomitant treatment with rimegepant and erenumab suggested that
rimegepant may be safely used as acute treatment in patients who are also
receiving a preventive regimen involving CGRP mAbs. We report here 13 additional
patients with migraine who simultaneously used rimegepant and either erenumab,
fremanezumab, or galcanezumab and assess the rate of on-treatment adverse events
(AEs).
METHODS: This was a substudy nested within a multicenter, open-label, long-term
safety study in adults with 2-14 monthly migraine attacks of moderate to severe
pain intensity. A subgroup experiencing 2-8 monthly attacks and taking a stable
dose of a CGRP mAb also took rimegepant 75 mg as needed up to once daily for
acute treatment for 12 weeks.
RESULTS: The 13 patients (11 women [85%]; mean age 49.9 years) enrolled in the
substudy were being treated with CGRP mAbs (erenumab [n = 7], fremanezumab
[n = 4], or galcanezumab [n = 2]). Mean (SD) time in the rimegepant treatment
period was 9.6 (4.6) weeks. Mean (SD) 4-week rimegepant exposure was 7.8 (5.5)
doses; a total of 224 doses were taken. Five (38%) patients reported ≥1
on-treatment AE. Of these, 2 (15%) patients had mild or moderate
nasopharyngitis; no other AEs occurred in ≥2 patients. Three patients had AEs of
mild or moderate severity that were considered potentially treatment-related. No
patients had serious AEs, AEs leading to discontinuation, or aminotransferase
levels >3× the upper limit of normal.
CONCLUSION: Rimegepant, when used as an oral acute treatment in patients
receiving CGRP mAbs as preventive treatment, was well tolerated; no safety
issues were identified. Studies involving larger patient populations are needed
to confirm these findings. |
What are the two types of duplicated genes in the yeast S. cerevisiae? | Yeast genes are duplicated both via the whole genome duplication and via smaller scale duplications. The genome of the budding yeast contains 50% of protein-coding genes that are paralogs, including 457 pairs of duplicated genes coming probably from an ancient whole genome duplication. | Gene redundancy has been observed in yeast, plant and human genomes, and is
thought to be a consequence of whole-genome duplications. Baker's yeast,
Saccharomyces cerevisiae, contains several hundred duplicated genes.
Duplication(s) could have occurred before or after a given speciation. To
understand the evolution of the yeast genome, we analysed orthologues of some of
these genes in several related yeast species. On the basis of the inferred
phylogeny of each set of genes, we were able to deduce whether the gene
duplicated and/or specialized before or after the divergence of two yeast
lineages. Here we show that the gene duplications might have occurred as a
single event, and that it probably took place before the Saccharomyces and
Kluyveromyces lineages diverged from each other. Further evolution of each
duplicated gene pair-such as specialization or differentiation of the two
copies, or deletion of a single copy--has taken place independently throughout
the evolution of these species. An increasing number of studies report that functional divergence in duplicated
genes is accompanied by gene expression changes, although the evolutionary
mechanism behind this process remains unclear. Our genomic analysis on the yeast
Saccharomyces cerevisiae shows that the number of shared regulatory motifs in
the duplicates decreases with evolutionary time, whereas the total number of
regulatory motifs remains unchanged. Moreover, genes with numerous paralogs in
the yeast genome do not have especially low number of regulatory motifs. These
findings indicate that degenerative complementation is not the sole mechanism
behind expression divergence in yeast. Moreover, we found some evidence for the
action of positive selection on cis-regulatory motifs after gene duplication.
These results suggest that the evolution of functional novelty has a substantial
role in yeast duplicate gene evolution. Gene duplication with subsequent divergence plays a central role in the
acquisition of genes with novel function and complexity during the course of
evolution. With reduced functional constraints or through positive selection,
these duplicated genes may experience accelerated evolution. Under the model of
subfunctionalization, loss of subfunctions leads to complementary acceleration
at sites with two copies, and the difference in average rate between the
sequences may not be obvious. On the other hand, the classical model of
neofunctionalization predicts that the evolutionary rate in one of the two
duplicates is accelerated. However, the classical model does not tell which of
the duplicates experiences the acceleration in evolutionary rate. Here, we
present evidence from the Saccharomyces cerevisiae genome that a duplicate
located in a genomic region with a low-recombination rate is likely to evolve
faster than a duplicate in an area of high recombination. This observation is
consistent with population genetics theory that predicts that purifying
selection is less effective in genomic regions of low recombination
(Hill-Robertson effect). Together with previous studies, our results suggest the
genomic background (e.g., local recombination rate) as a potential force to
drive the divergence between nontandemly duplicated genes. This implies the
importance of structure and complexity of genomes in the diversification of
organisms via gene duplications. BACKGROUND: The direct examination of large, unbiased samples of young gene
duplicates in their early stages of evolution is crucial to understanding the
origin, divergence and preservation of new genes. Furthermore, comparative
analysis of multiple genomes is necessary to determine whether patterns of gene
duplication can be generalized across diverse lineages or are species-specific.
Here we present results from an analysis comprising 68 duplication events in the
Saccharomyces cerevisiae genome. We partition the yeast duplicates into ohnologs
(generated by a whole-genome duplication) and non-ohnologs (from small-scale
duplication events) to determine whether their disparate origins commit them to
divergent evolutionary trajectories and genomic attributes.
RESULTS: We conclude that, for the most part, ohnologs tend to appear remarkably
similar to non-ohnologs in their structural attributes (specifically the
relative composition frequencies of complete, partial and chimeric duplicates),
the discernible length of the duplicated region (duplication span) as well as
genomic location. Furthermore, we find notable differences in the features of S.
cerevisiae gene duplicates relative to those of another eukaryote,
Caenorhabditis elegans, with respect to chromosomal location, extent of
duplication and the relative frequencies of complete, partial and chimeric
duplications.
CONCLUSIONS: We conclude that the variation between yeast and worm duplicates
can be attributed to differing mechanisms of duplication in conjunction with the
varying efficacy of natural selection in these two genomes as dictated by their
disparate effective population sizes. Whole-genome duplications (WGDs) have contributed to gene-repertoire enrichment
in many eukaryotic lineages. However, most duplicated genes are eventually lost
and it is still unclear why some duplicated genes are evolutionary successful
whereas others quickly turn to pseudogenes. Here, we show that dosage
constraints are major factors opposing post-WGD gene loss in several Paramecium
species that share a common ancestral WGD. We propose a model where a majority
of WGD-derived duplicates preserve their ancestral function and are retained to
produce enough of the proteins performing this same ancestral function. Under
this model, the expression level of individual duplicated genes can evolve
neutrally as long as they maintain a roughly constant summed expression, and
this allows random genetic drift toward uneven contributions of the two copies
to total expression. Our analysis suggests that once a high level of imbalance
is reached, which can require substantial lengths of time, the copy with the
lowest expression level contributes a small enough fraction of the total
expression that selection no longer opposes its loss. Extension of our analysis
to yeast species sharing a common ancestral WGD yields similar results,
suggesting that duplicated-gene retention for dosage constraints followed by
divergence in expression level and eventual deterministic gene loss might be a
universal feature of post-WGD evolution. Gene and genome duplication are the major sources of biological innovations in
plants and animals. Functional and transcriptional divergence between the copies
after gene duplication has been considered the main driver of innovations .
However, here we show that increased phenotypic plasticity after duplication
plays a more major role than thought before in the origin of adaptations. We
perform an exhaustive analysis of the transcriptional alterations of duplicated
genes in the unicellular eukaryote Saccharomyces cerevisiae when challenged with
five different environmental stresses. Analysis of the transcriptomes of yeast
shows that gene duplication increases the transcriptional response to
environmental changes, with duplicated genes exhibiting signatures of adaptive
transcriptional patterns in response to stress. The mechanism of duplication
matters, with whole-genome duplicates being more transcriptionally altered than
small-scale duplicates. The predomit transcriptional pattern follows the
classic theory of evolution by gene duplication; with one gene copy remaining
unaltered under stress, while its sister copy presents large transcriptional
plasticity and a prominent role in adaptation. Moreover, we find additional
transcriptional profiles that are suggestive of neo- and subfunctionalization of
duplicate gene copies. These patterns are strongly correlated with the
functional dependencies and sequence divergence profiles of gene copies. We show
that, unlike singletons, duplicates respond more specifically to stress,
supporting the role of natural selection in the transcriptional plasticity of
duplicates. Our results reveal the underlying transcriptional complexity of
duplicated genes and its role in the origin of adaptations. Gene duplication generates new genetic material, which has been shown to lead to
major innovations in unicellular and multicellular organisms. A whole-genome
duplication occurred in the ancestor of Saccharomyces yeast species but 92% of
duplicates returned to single-copy genes shortly after duplication. The
persisting duplicated genes in Saccharomyces led to the origin of major
metabolic innovations, which have been the source of the unique biotechnological
capabilities in the Baker's yeast Saccharomyces cerevisiae. What factors have
determined the fate of duplicated genes remains unknown. Here, we report the
first demonstration that the local genome mutation and transcription rates
determine the fate of duplicates. We show, for the first time, a preferential
location of duplicated genes in the mutational and transcriptional hotspots of
S. cerevisiae genome. The mechanism of duplication matters, with whole-genome
duplicates exhibiting different preservation trends compared to small-scale
duplicates. Genome mutational and transcriptional hotspots are rich in
duplicates with large repetitive promoter elements. Saccharomyces cerevisiae
shows more tolerance to deleterious mutations in duplicates with repetitive
promoter elements, which in turn exhibit higher transcriptional plasticity
against environmental perturbations. Our data demonstrate that the genome traps
duplicates through the accelerated regulatory and functional divergence of their
gene copies providing a source of novel adaptations in yeast. |
Why is fingolimod considered a prodrug? | FTY720/fingolimod, is considered a prodrug because it requires in vivo phosphorylation to its active phosphorylated form. | Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver dysfunction,
is a metabolic disease that begins with steatosis. Sphingolipid metabolites,
particularly ceramide and sphingosine-1-phosphate (S1P), have recently received
attention for their potential roles in insulin resistance and hepatic steatosis.
FTY720/fingolimod, a prodrug for the treatment of multiple sclerosis, is
phosphorylated in vivo to its active phosphorylated form by sphingosine kinase 2
and has been shown to interfere with the actions of S1P and to inhibit ceramide
biosynthesis. Therefore, in this study we investigated the effects of FTY720 in
a diet-induced animal model of NAFLD (DIAMOND) that recapitulates the hallmarks
of the human disease. The oral administration of FTY720 to these mice fed a
high-fat diet and sugar water improved glucose tolerance and reduced steatosis.
In addition to decreasing liver triglycerides, FTY720 also reduced hepatic
sphingolipid levels, including ceramides, monohexosylceramides, and
sphingomyelins, particularly the C16:0 and C24:1 species, as well as S1P and
dihydro-S1P. FTY720 administration decreased diet-induced fatty acid synthase
(FASN) expression in DIAMOND mice without affecting other key enzymes in
lipogenesis. FTY720 had no effect on the expression of SREBP-1c, which
transcriptionally activates FASN. However, in agreement with the notion that the
active phosphorylated form of FTY720 is an inhibitor of histone deacetylases,
FTY720-P accumulated in the liver, and histone H3K9 acetylation was markedly
increased in these mice. Hence, FTY720 might be useful for attenuating FASN
expression and triglyceride accumulation associated with steatosis. |
Is there a role for Dickkopf-1 (DKK1) in prostate cancer? | Yes. Dickkopf-1 (DKK1) expression is increased in double-negative prostate cancer (DNPC) relative to prostate-specific antigen (PSA)-expressing Metastatic castration-resistant prostate cancer (mCRPC). | In addition to new tumour antigens, new prognostic and diagnostic markers are
needed for common cancers. In this study, we report the expression of Dickkopf-1
(DKK1) in multiple common cancers. This constitutes a comprehensive analysis of
the DKK1 expression profile. Dickkopf-1 expression was evaluated by classical
and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and
enzyme-linked immunosorbant assay for protein determination, in cancer lines and
clinical specimens of several cancer origins. For breast cancer, expression was
correlated with clinicopathological parameters. Dickkopf-1 expression was
confirmed in several cancer cell lines derived from breast and other common
cancers. Dickkopf-1 protein secretion was documented in breast, prostate and
lung cancer lines, but was negligible in melanoma. Analysis of DKK1 expression
in human cancer specimens revealed DKK1 expression in breast (21 out of 73),
lung (11 out of 23) and kidney cancers (six out of 20). Interestingly, DKK1 was
preferentially expressed in oestrogen and progesterone receptor-negative tumours
(ER(-)/PR(-); P=0.005) and in tumours from women with a family history of breast
cancer (P=0.024). Importantly, DKK1 protein production was confirmed in multiple
breast cancer specimens that were positive by RT-PCR. This work establishes DKK1
as a potential prognostic and diagnostic marker for cohorts of breast cancer
patients with poor prognosis. Dickkopf-1 may also become a relevant candidate
target for immunotherapy of different cancers. Wnt/beta-catenin signaling is central to bone development and homeostasis in
adulthood and its deregulation is associated with bone pathologies. Dickkopf-1
(DKK1), a soluble inhibitor of Wnt/beta-catenin signaling required for embryonic
head development, regulates Wnt signaling by binding to the Wnt coreceptor
lipoprotein-related protein-5 (LRP5)/Arrow. LRP5 mutations causing high bone
mass syndromes disrupt DKK1-mediated regulation of LRP5. Forced overexpression
of Dkk1 in osteoblasts causes osteopenia, disruption of the hematopoietic stem
cell (HSC) niche, and defects in HSC function. Dkk1 also inhibits fracture
repair. Studies suggest that DKK1 activation in osteoblasts is the underlying
cause of glucocorticoid- and estrogen deficiency-mediated osteoporosis, and at
least partially underlies the teratogenic effects of thalidomide on limb
development. DKK1 induces proliferation of mesenchymal stem cells (MSC) in vitro
and may play a role in the development of high-grade undifferentiated
pleomorphic sarcomas derived from MSC and osteosarcomas. DKK1 has been
implicated in causing erosive arthritis, the osteolytic phenotypes of multiple
myeloma and metastatic breast cancer, and osteoblastic metastases of prostate
cancer. Preclinical studies have shown that neutralizing DKK1/Dkk1 and/or
enhancing Wnt/beta-catenin signaling may prove effective in treating bone
pathologies. Here, we review the rapidly growing body of literature defining a
pivotal role for DKK1 in bone health and disease. The Wnt inhibitor Dickkopf-1 (DKK-1) has been associated with the occurrence of
bone metastases in osteotropic prostate cancer by inhibiting osteoblastogenesis.
P38 mitogen-activated protein kinase (MAPK) activity is also dysregulated in
advanced prostate cancer. However, the impact of p38 MAPK signaling on DKK-1
remains unknown. Inhibition of p38 MAPK signaling in osteolytic PC3 cells by
small molecule inhibitors (doramapimod, LY2228820 and SB202190) suppressed DKK-1
expression, whereas activation of p38 MAPK by anisomycin increased DKK-1.
Further dissection by targeting individual p38 MAPK isoforms with siRNA revealed
a stronger role for MAPK11 than MAPK14 and MAPK12 in the regulation of DKK-1.
Moreover, prostate cancer cells with a predomitly osteolytic phenotype
produced sufficient amounts of DKK-1 to inhibit Wnt3a-induced osteoblastic
differentiation in C2C12 cells. This inhibition was blocked directly by
neutralizing DKK-1 using a specific antibody and also indirectly by blocking p38
MAPK. Furthermore, tissue expression in human prostate cancer revealed a
correlation between p38 MAPK and DKK-1 expression with higher expression in
tumor compared with normal tissues. These results reveal that p38 MAPK regulates
DKK-1 in prostate cancer and may present a potential target in osteolytic
prostate cancers. |
What is Hemophilic Pseudotumor? | Hemophilic Pseudotumor is a rare complication of hemophilia. It is an encapsulated haematoma in patients with haemophilia which has a tendency to progress and produce clinical symptoms related to its anatomical location. The lesion most frequently occurs in the long bones, pelvis, small bones of the hands and feet, or rarely in the maxillofacial region. | The iliac hemophilic pseudotumor is a rare complication of hemophilia occurring
in 1-2% of patients with Factor VIII or Factor IX deficiency. It is frequently
disabling and life threatening. This report presents a comparative study of
postoperative results of two cases of hemophilic pseudotumor of ilium. One
patient undergoing partial resection showed a favorable postoperative course,
whereas the patient with complete resection of the pseudotumor died of
postoperative bleeding and sepsis. Studies on the postoperative results of these
two cases indicate that careful preoperative consideration of tumor size and
degree of infiltration is of the utmost importance in operative management.
Early excision of tumors eliminates the possibility of endogenous infection.
Even partial resection of huge tumors, leaving the lateral wall intact for
compression, can promote recovery of functions. Hemophilic pseudotumor is one of the most serious complications of hemophilia
and is usually treated with extensive surgery. A new treatment approach is
radiotherapy. Patients with long-bone pseudotumors are usually treated with high
doses of radiotherapy greater than 1500 cGy. We treated a 13-year-old hemophilic
boy who had a pseudotumor of the tibia with low-dose radiotherapy (600 cGy).
There was no complication during the two-and-a-half-year follow-up. Improvement
of both the clinical and radiological status of the patient was noteworthy. We
would like to suggest the use of low-dose radiotherapy in patients with
hemophilic pseudotumors. OBJECTIVE AND IMPORTANCE: Hemophilic pseudotumor is a rare complication of
hemophilia, occurring in 1 to 2% of patients with severe hemophilia. Its
principal sites of occurrence are the long bones and the pelvis. Only one case
of this tumor occurring in the cranium has been previously reported.
CLINICAL PRESENTATION: We report a case of cranial hemophilic pseudotumor
involving the diploe of the right parietal vault. A 29-year-old man with severe
hemophilia (Factor VIII, 0.8% of normal activity) presented with an unsightly
scalp protrusion measuring 5 x 5 x 2 cm and tingling discomfort in the left arm.
About 5 years before admission, he noted a walnut-sized, nontender mass in the
right parietal area that had enlarged slightly after minor head trauma. Tingling
discomfort developed as the manifestation of the compression of the parietal
lobe in the 2 to 3 months after the head trauma.
INTERVENTION: Under proper factor replacement therapy, surgery was undertaken
for excision and tissue diagnosis. Histological examination of the content in
the diploe revealed old blood coagulum.
CONCLUSION: Postoperatively, the tingling discomfort in the arm resolved
completely. To our knowledge, this is the second case of the cranial hemophilic
pseudotumor in the English literature. Diagnosis and management of cranial
hemophilic pseudotumor are presented with a review of the literature. Hemophilic pseudotumor is a rare, but well-known, complication of hemophilia. We
describe a 50-year-old man with mild hemophilia A, but with no previous need for
Factor VIII supplementation, who presented with a pathologic fracture of the
right femoral neck and shaft caused by a large hemophilic pseudotumor. Initial
nonoperative therapy with factor replacement and skeletal traction resulted in
radiographic evidence of fracture healing, but the patient's pain persisted.
Therefore, he had a radical resection of his hemophilic pseudotumor (soft tissue
component and entire femur), and reconstruction with a custom total femoral
replacement. Six months after resection, the patient returned to full-time
employment. Although pseudotumor formation is a well-recognized complication of
hemophilia, the pseudotumor in our study is one of the largest yet described.
More importantly, to our knowledge this is the first report of a pseudotumor
treated by radical resection and reconstruction with a custom femoral
prosthesis. We think that radical resection and reconstruction with a custom
total femoral prosthesis is a valuable alternative to amputation in massive
pseudotumors of the femur and soft tissues of the thigh. Bleeding diatheses are a hallmark of hemophilia. Hemophilic pseudotumor results
from multiple episodes of hemorrhage into bones or soft tissue spaces. It is
uncommon and is seen in severe cases of hemophilia only 1-2% of the time.
Complications and symptoms arise due to pain and/or compression of surrounding
structures. Pathologic fractures can be associated with intraosseous lesions and
can result from bone destruction or resorption due to the chronic pressure of an
osseous hemorrhage. Radiographs may demonstrate expansile lesions of the bones
or increased soft tissue density that may be associated with extra osseous
lesions. Bleeding may also occur within the joint space. These intra-articular
hemorrhages can, over time, result in hemophilic arthropathy. The following case
report demonstrates both an expansile lesion of a metacarpal as well as
hemophilic knee arthropathy in an 11 year old. The haemophilic pseudotumor is defined as an encased hematoma that increases of
volume progressively by episodes of recurrent hemorrhage. It is a rare
complication of haemophilia occurring in 1-2% of patients with moderate or
severe factor VIII or IX deficiency. Its more frequent location is in the long
bones of low extremities and pelvis. We report a case of a 21-year-old man with
moderate deficiency of factor VIII (19% of normal factor VIII activity) that
developed a pseudotumor in the cranium. To our knowledge, this is the third case
of the cranial hemophilic pseudotumor in medical literature. Surgery in hemophilic patients is a challenge for the general surgeon.
Hemophilic pseudotumor is a rare complication occurring in 1-2% of hemophiliacs
and affecting mainly patients with severe disease or those who have developed
antibodies to factor VIII or IX. A number of alternatives are available for the
management of these tumors, including conservative treatment, surgical removal,
percutaneous drainage, embolization, and external radiation. The only definitive
treatment is surgical excision. We report a case of hemophilic pseudotumor of
the pelvic bone. Treatment consisted of surgical resection after arterial
embolization using factor replacement to achieve hemostasis. Hemophilic pseudotumor is a rare complication of hemophilia. We describe a
14-year-old young male with hemophilic pseudotumor in the second and fifth
fingers of the left hand. We treated him only with radiotherapy. A total dose of
2000 cGy in 10 fractions was administered in 2 weeks. Factor VIII was not given.
After 4 months, complete healing was seen. The patient was followed up at 24
months, and there was no evidence of recurrence and no bone growth disturbance.
Based on our experience and a review of the literature, radiotherapy can be an
effective alternative modality in treating hemophilic pseudotumor. Hemophilic pseudotumor is an uncommon complication seen in approximately 1-2% of
patients with severe hemophilia. Hemophilic pseudotumors are distinguished into
two subdivisions based on location, proximal or distal. Plain x-rays and CT are
useful in diagnosis, but MR imaging is the diagnostic test of choice because of
its sensitivity to the various blood products. The choice of therapy depends on
many parameters, such as the size of the tumor, the age of the patient, and the
relation with underlying organs. In most cases of asymptomatic hemophilic
pseudotumor, conservative treatment with administration of missing factor as
well as immobilization is recommended. The authors describe a 13-year-old boy
with severe hemophilia A, who presented with a tibial pseudotumor a few months
after an injury. He was conservatively treated for a long period, with daily
administration of recombit factor VIII. His clinical condition improved
shortly after therapy induction, but radiological improvement has been moderate.
Case history, imaging findings, and therapeutic options are discussed. BACKGROUND: Hemophilic pseudotumor is an unusual complication occurring in only
1% to 2% of patients with severe factor VIII or IX deficiency, and manifests as
a progressive enlargement of hematoma by recurrent hemorrhage, often resulting
in bone destruction or resorption due to the chronic pressure of osseous
hemorrhage. Cranial hemophilic pseudotumors are extremely rare, with only 4
previous cases associated with mild or moderate factor XIII deficiency.
CASE DESCRIPTION: A 24-year-old man with moderate deficiency of factor IX
developed a cranial pseudotumor as a swelling in the frontal scalp. Blood
coagulation profile revealed extended activated partial thromboplastin time
(58.2 seconds). Factor IX analysis showed 3% of normal activity. Computed
tomography and magnetic resoce imaging demonstrated an extra-axial lesion
with bone destruction, enhanced rim, and signal changes consistent with chronic
hemorrhage. Surgical removal was performed. Histologic examination disclosed old
blood coagulum.
CONCLUSIONS: This case of cranial hemophilic pseudotumor in a patient with
moderate factor IX deficiency suggests that cranial pseudotumor should be
considered in the differential diagnosis of cranial lesion in a patient with
hemophilia, and adequate replacement therapy in the perioperative period is
essential to achieve safe surgical removal. Hemophilic pseudotumors are rare, but well known complications of severe
hemophilia A, which most frequently develops at the femur, tibia, pelvic bones,
iliac bones, or rarely in the cranium or gnathic bones. This report describes a
case of hemophilic pseudotumor of the maxillary alveolar ridge that occurred in
a boy with mild hemophilia A (14% factor VIII activity). The lesion, which
presented as an alveolar mucosal swelling, responded well to enucleation,
curettage, and intralesional fibrin glue injection. Pseudotumor is an uncommon but severe complication in patients with hemophilia.
To our knowledge, although China has large population of persons with
hemophilia, there is rare information on the incidence, clinical feature, image
finding, and management of pseudotumor among Chinese patients. This study aimed
at improving our knowledge on clinical diagnosis and management of hemophiliac
pseudotumor. In this retrospective study, the medical records of 1248 patients
with hemophilia diagnosed between January 1983 and October 2004 at our hospital
were reviewed. The clinical feature, imaging finding, management, and outcome of
14 patients with pseudotumor among these patients with hemophilia were analyzed.
All patients have hemophilia A (8 severe cases and 6 moderate cases). Eight
patients sustained an injury prior to the development of pseudotumor. Main image
findings included osteolysis lesion, soft tissue swelling, or lump. Surgical
therapy was carried out in 7 patients and 6 achieved remission, with fistula
formation remaining in 1. One patient underwent radiotherapy together with
replacement therapy achieved remission. Three patients accepted replacement
therapy as only management and only 1 patient achieved improvement of swelling.
Our study showed that the incidence of pseudotumor in our enrolled patients with
hemophilia is 1.12%. Hemophilic history of patients can contribute to the right
diagnosis of pseudotumor. Surgical therapy together with sufficient replacement
therapy is safe and effective. Hemophilic pseudotumor is a rare lesion that is essentially a progressive,
slowly expanding, encapsulated hematoma. It is estimated to affect 1% to 2% of
severe hemophiliacs. The majority of hemophilic pseudotumors occur within soft
tissues (intramuscular) and long bones of adult males. Fewer than 20 cases have
been reported in the maxillofacial region. We report a rare case occurring in
the mandible of a 14-year-old boy who presented with considerable expansion and
displacement of teeth. A 46-year-old man with factor VIII deficiency presented with a rare case of
hemophilic pseudotumor in the temporal bone manifesting as severe conductive
hearing loss and external ear bleeding. The pseudotumor expanded and destroyed
the temporal bone and skin of the external ear over the course of 8 years. The
pseudotumor was surgically excised, and the patient's symptoms improved.
Histological examination of a specimen collected from inside the pseudotumor
demonstrated blood products in various stages of evolution and showed that the
outer membrane consisted of a collagen layer. Hemophilic pseudotumors are rare
complications occurring in 1-2% of patients with mild or severe hemophilia.
Pseudotumors are chronic, slowly expanding, encapsulated cystic masses, and most
are located in the long bones and pelvis. The present case suggests that cranial
pseudotumor should be considered in the differential diagnosis of cranial lesion
in a patient with hemophilia. Hemophilic pseudotumor is a rare complication of hemophilia. We present the case
of a male toddler with moderate hemophilia A and cranial hemophilic pseudotumor
managed with factor VIII infusions. We also provide a review of the literature.
Recognition of this rare manifestation of this complication of hemophilia is
important to provide correct treatment and avoid unnecessary investigations,
particularly biopsy, which is contraindicated in this condition. Hemophilic pseudotumor is a rare, but well-known, complication of hemophilia
occurring in 1-2 % of individuals with a severe factor VIII or IX deficiency.
The hemophilic pseudotumor is defined as an encapsulated hematoma that increases
of volume progressively by episodes of recurrent hemorrhage; usually originate
in soft tissues or in subperiosteal or intraosseous areas. Very seldom, patient
with mild form of hemophilia present with intraosseous pseudotumor. This report
describe an 11-year-old boy with mild factor IX deficiency (17 % of normal
factor IX activity), who developed a pseudotumor of the femur. Hemophilic pseudotumor gradually erodes bone and induces fracture or deformity,
causing joint dysfunction or destructive osteoarthropathy. Reports about surgery
for hemophilic pseudotumor complicated by destructive osteoarthropathy are
scarce. The object of this study was to evaluate the results and complications
of surgical management for patients of pseudotumor complicated by destructive
osteoarthropathy. We retrospectively reviewed records from July 1996 to July
2013, and found eight patients with pseudotumor complicated by destructive
osteoarthropathy. We recorded their demographic data, time of surgery, amount of
blood loss and transfusion, bone union, and complications. Seven patients were
diagnosed with hemophilia A and one with hemophilia B. The mean age at surgery
was 31.9 ± 8.3 years. Two of the eight underwent excision of the pseudotumor and
metallic fixation, one had amputation, and five underwent autogenous or
exogenous bone grafting and fixation with an absorbable screw. The median
operating time was 170 min (135-315 min). The median amount of intraoperative
blood loss was 1350 ml (100-4000 ml). The amount of red blood cells, plasma, and
whole blood transfusion after surgery were 0-24 units, 0-2000 ml, and 0-4600 ml,
respectively. After a median follow-up of 75 months, the numbers of pseudotumor
recurrence, fracture nonunion, coagulation factor inhibitor formation, and wound
complications were one, one, two, and four, respectively. Surgery is an
effective treatment for hemophilic pseudotumor complicated by destructive
osteoarthropathy. However, the incidences of wound infection, coagulation factor
inhibitor formation, hemophilic pseudotumor recurrence, and fracture nonunion
are high. Hemophilic pseudotumor is a rare complication of hemophilia, occurring in 1 to 2
percent of individuals with severe factor VIII or factor IX deficiency. A
35-year-old male presented with a swelling in the right lower abdomen for 3
months. There was no history of trauma. Examination revealed a swelling over the
right iliac fossa. Right hip showed 30° flexion deformity. Blood investigations
like complete blood count, APTT, PT, bleeding and clotting time, and fibrinogen
were all normal. Plain radiograph and MRI showed a lytic lesion in the right
iliac wing. Excision biopsy of the swelling showed organized hematoma with a
fibrous capsule suggestive of a pseudotumor. Further haematological workup like
factors VIII and IX was normal. At 2 years follow-up, there was no recurrence.
We report this case of pseudotumour in patient without any bleeding disorder.
Such case has not been reported in literature to the best of our knowledge. INTRODUCTION: Hemophilic pseudotumor is a rare but well documented complication
seen in approximately 1-2% of patients with hemophilia. The incidence continues
to decrease, likely because of increasingly sophisticated techniques in managing
factor deficiency. We present a case of hemophilic pseudotumor in a patient
without hemophilia, an exceptionally rare entity, and outline a hybrid approach
to treatment.
PRESENTATION OF CASE: The patient presented with a left sided iliopsoas mass and
associated radiculopathy, with a history of a poorly characterized bleeding
diathesis and Noo's syndrome. He had no history of trauma and was not being
treated with anti-coagulation. Of note, factors VIII, IX and XI were normal. An
open biopsy was consistent with hemophilic pseudotumor. The patient underwent a
hybrid procedure of preoperative embolization of the left internal iliac and
left deep circumflex arteries followed by surgical debridement and resection,
with an excellent outcome.
DISCUSSION: Hemophilic pseudotumor is rarely seen in patients with hemophilia,
and even less frequently in patients without. Trauma is often the inciting
event. A high index of clinical suspicion is required in order to secure the
diagnosis, as the radiographic appearance is non-specific. Our patient had no
history of trauma, although we question whether his underlying bleeding
diathesis may have predisposed him to developing the pseudotumor. Surgery
remains the cornerstone of management in these cases.
CONCLUSION: Within the literature, there are only two other cases of hemophilic
pseudotumor occurring in a non-hemophiliac patient, highlighting the rarity of
this case and the associated diagnostic dilemma. Hemophilic pseudotumor is a rare complication, even in patients with severe
hemophilia. Herein we report on a case of hemophilic pseudotumor in a patient
with mild hemophilia A and allergic rhinitis, initially suspected to be a nasal
tumor. The pseudotumor was cured by supplementation with recombit factor VIII
concentrates, and medication for allergic rhinitis. Pseudotumor should always be
considered in hemophiliac patients, even in those with only mild deficiency of
coagulation factors. BACKGROUND: Hemophilic pseudotumor (HPT) is a rare disease with many challenges.
Only a few reports on surgical treatment for HPT have been published.
METHODS: The cases of 23 patients with HPT who had surgical treatment from July
1996 to December 2014 were retrospectively reviewed. Demographic data, blood
loss and transfusion during surgery, outcomes, and complications after surgery
were analyzed.
RESULTS: Eleven patients underwent HPT resection; 4 underwent HPT excision,
allograft transplantation, and absorbable screw fixation; 3 had HPT resection
and metallic internal fixation; 2 had HPT resection, autogenous fibular
grafting, and absorbable screw fixation; 2 underwent curettage and
bone-grafting; and 1 patient received above-the-knee amputation. The average age
(and standard deviation) of the patients at the time of surgery was 31.9 ± 12.8
years (range, 6 to 54 years) with an average follow-up of 5.3 ± 4.7 years
(range, 1.1 to 19.6 years). The median duration of the surgery was 157 minutes
(range, 90 to 315 minutes). The median amount of blood loss during surgery was
800 mL (range, 100 to 4,000 mL). Three patients (13%) had a postoperative
infection, 2 (8.7%) had recurrence of HPT, and another 2 patients had fracture
nonunion.
CONCLUSIONS: Surgical treatment of HPT with a modified protocol of coagulation
factor replacement is safe and effective. It should be recommended for patients
with HPT who have progressive enlargement of the mass, recurrent and massive
bleeding, spontaneous perforation, bone erosion, or compression of surrounding
tissues or who have had failure of conservative treatment.
LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a
complete description of levels of evidence. INTRODUCTION: Hemophilic pseudotumor is a rare complication occurring in
patients with hemophilia, frequently seen in the femur, tibia, pelvic bones,
iliac bones, or rarely in the maxillofacial region.
CASE REPORT: A 7-year-old male reported with a spontaneous extra-oral swelling
that was managed with pre-operative transfusion of factor IX along with
curettage of the lesion. Our report presents only the fourth case in literature
wherein this tumor presented in a patient with hemophilia B.
FINDING: Hemophilic pseudotumor is a rare entity in the maxillofacial region.
High degree of suspicion is required for diagnosis, and close coordination
between the medical and surgical teams aids in management. Giant abdominal hemophilic pseudotumor is exceedingly rare, thus may bring great
challenges to the timely and proper diagnosis and treatment of clinicians. The
only definitive management is complete removal of the abdominal hemophilic
pseudotumor. The objective of this article is to report surgical treatment and
follow-up outcomes of three unusual cases with giant abdominal hemophilic
pseudotumor.We describe 3 patients with giant hemophilic pseudotumor involving
the abdomen who were successfully treated with tumor resection. On presentation
to our institution, the patients all had signs of giant cystic lesions in
abdomen, and the patients' most outstanding complaints were aggravated abdominal
pain. All of three patients underwent complete excision of abdominal hemophilic
pseudotumor. The patients showed adequate pain relief compared with the previous
status.Surgical resection is the most effective treatment option for patients
with giant abdominal hemophilic pseudotumor who can undergo appropriate surgical
treatment. This represents a safe and reasonable approach to sustainably relieve
pain and other symptoms with giant hemophilic pseudotumor in the abdomen.
Perioperative coagulation factor replacement therapy is also of great
significance in reducing the risks and complications. INTRODUCTION: Haemophilic pseudotumour (HP) is an encapsulated haematoma in
patients with haemophilia (PWH) which has a tendency to progress and produce
clinical symptoms related to its anatomical location.
AIM: To show the experience of one surgeon who has been using mini-invasive
technique to treat pseudotumours of limbs in PWH with and without inhibitors at
one centre for 28 years.
MATERIALS AND METHODS: Thirty-three patients with 39 HP were treated. All
patients had haemophilia A. Twenty-four patients had no inhibitors (72.8%), and
9 had inhibitors (27.2%). The mean follow-up was 16 years (1-25). All patients
had x-rays and MRIs. All of them received Buenos Aires protocol as conservative
treatment for 6 weeks. MRIs were repeated after 6 weeks' treatment to assess
response to treatment. Surgery was performed in patients who did not respond to
conservative treatment.
RESULTS: After Buenos Aires protocol, four pseudotumours did not shrink
(10.24%), 33 (84.61%) shrank, and two (5.12%) healed. Thirty-seven pseudotumours
had surgery, 35 pseudotumours (94.59%) healed with minimally invasive treatment,
and two did not heal (5.41%). No infection was observed with this treatment. The
mortality rate for the series was 0%.
CONCLUSION: The minimally invasive treatment of pseudotumours was effective in
95% of the cases and resulted in no mortality in this series after 28 years. AIMS: Haemophilic pseudotumor (HPT) is a rare but challenging complication of
haemophilia. This study was intended to provide our experience about clinical
characteristics and surgical treatment of HPT.
METHODS: Clinical medical records were retrieved from the Hemophilia Center,
Nanfang Hospital, to identify the patients who had been surgically treated from
1 January 2006 to 31 December 2017 with a definite diagnosis of HPT. Their
clinical features, surgical management, outcomes and complications after surgery
were analysed.
RESULTS: We identified 34 patients with HPT who had surgical treatment over a
12-year period and five of them had multiple HPTs. The incidence of HPT at this
centre was 2.3% over the dozen years. A previous trauma leading to the
development of HPT was reported in 18 cases (52.9%). The HPT affected only soft
tissue in 7 patients, bone and soft tissue in 25 ones and joint in 2 ones.
Preoperative infection and fistula formation happened in ten patients, two of
whom were related to abdominal HPTs. Enterococcus faecalis was cultured in five
cases with fistula formation. HPT associated with pathological fracture was
observed in five cases, two of whom were treated by external fixation and 3 by
HPT resection and metallic internal fixation. Amputation was performed for nine
patients, 6 of whom had preoperative infection and fistula formation. Their
follow-up duration averaged 4.2 ± 2.9 years (range, from 1 to 13.5 years) after
surgery. Of all our cases, three suffered from postoperative infection, five
from recurrence of HPT and two with external fixation from fracture non-union.
CONCLUSIONS: HPT patients with preoperative infection had worse prognosis than
those without. Surgical treatment plus intensive replacement therapy was
effective for HPT but with a high rate of complications. HPT resection and
metallic internal fixation rather than external fixation should be recommended
for HPT patients with pathological fracture. BACKGROUND: Hemophilic pseudotumor (HP) is a rare complication in patients with
hemophilia. The lesion most frequently occurs in the long bones, pelvis, small
bones of the hands and feet, or rarely in the maxillofacial region.
Postoperative changes in HP are seldom arrested, whereas angiogenesis
characterized by disturbed wound healing in HP may cause vascular malformations.
CASE SUMMARY: We report the case of an 11-year-old boy who was affected by
maxillary intraosseous venous malformation. Enucleation of an HP without factor
replacement was performed initially on the right side of the maxilla 3 years
ago. The patient was referred to us because of painless swelling in the same
location. Factor replacement and subtotal maxillectomy were performed.
Pathological examinations revealed intraosseous venous malformation.
CONCLUSION: This study is the first to document the development of intraosseous
venous malformation after enucleation of an HP in the maxillofacial region.
Angiogenesis characterized by disturbed wound healing in patients with
hemophilia may be pivotal in the pathogenesis of this condition. |
What is the aim of the TRAP method? | The translating ribosome affinity purification (TRAP) method is used to obtain obtain translatome data. | Organs and specific cell types execute specialized functions in multicellular
organisms, in large part through customized gene expression signatures. Thus,
profiling the transcriptomes of specific cell and tissue types remains an
important tool for understanding how cells become specialized. Methodological
approaches to detect gene expression differences have utilized samples from
whole animals, dissected tissues, and more recently single cells. Despite these
advances, there is still a challenge and a need in most laboratories to
implement less invasive yet powerful cell-type specific transcriptome profiling
methods. Here, we describe the use of the Translating Ribosome Affinity
Purification (TRAP) method for C. elegans to detect cell type-specific gene
expression patterns at the level of translating mRNAs. In TRAP, a ribosomal
protein is fused to a tag (GFP) and is expressed under cell type-specific
promoters to mark genetically defined cell types in vivo. Affinity purification
of lysates of animals expressing the tag enriches for ribosome-associated mRNAs
of the targeted tissue. The purified mRNAs are used for making cDNA libraries
subjected to high-throughput sequencing to obtain genome-wide profiles of
transcripts from the targeted cell type. The ease of exposing C. elegans to
diverse stimuli, coupled with available cell type specific promoters, makes TRAP
a useful approach to enable the discovery of molecular components in response to
external or genetic perturbations. Early life experiences program brain structure and function and contribute to
behavioral endophenotypes in adulthood. Epigenetic control of gene expression by
those experiences affect discrete brain regions involved in mood, cognitive
function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In
rodents, acute restraint stress increases the expression of the repressive
histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including
the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive
function and mood regulation as well as activation of glucocorticoid (CORT)
secretion. CA3 neurons also exhibit structural and functional changes after
early-life stress (ELS) as well as after chronic stress in adulthood. Using a
protocol of chronic ELS induced by limited bedding and nesting material followed
by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS
display a blunted CORT response to AS, despite exhibiting activation of
immediate early genes after stress similar to that found in control mice. We
find that ELS induced persistently increased expression of the repressive
H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently
decreased following AS. In contrast, AS induced a transient increase of this
mark in control mice. Using translating ribosome affinity purification (TRAP)
method to isolate CA3 translating mRNAs, we found that expression of genes of
the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors
binding genes were decreased transiently in control mice by AS and showed a
persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce
gene expression changes. A stringent filtering of genes affected by AS in
control and ELS mice revealed a noteworthy decrease in gene expression change in
ELS mice compared to control. Only 18 genes were selectively regulated by AS in
ELS mice and encompassed pathways such as circadian rhythm, inflammatory
response, opioid receptors, and more genes included in the glucocorticoid
receptor binding family. Thus, ELS programs a restricted translational response
to stress in stress-sensitive CA3 neurons leading to persistent changes in gene
expression, some of which mimic the transient effects of AS in control mice,
while leaving in operation the immediate early gene response to AS. |
The Shingrix vaccine is used to prevent what disease? | Shingrix is a 4-component vaccine against capsular herpes zoster (4CZV), which has recently been licensed in Europe, Canada and Australia. | Conflict of interest statement: Disclosure: The authors report no commercial or
ficial interest in regard to this article. BACKGROUND: The adjuvanted recombit zoster vaccine (Shingrix) can prevent
herpes zoster in older adults and autologous haemopoietic stem cell transplant
recipients. We evaluated the safety and immunogenicity of this vaccine in adults
with haematological maligcies receiving immunosuppressive cancer treatments.
METHODS: In this phase 3, randomised, observer-blind, placebo-controlled study,
done at 77 centres worldwide, we randomly assigned (1:1) patients with
haematological maligcies aged 18 years and older to receive two doses of the
adjuvanted recombit zoster vaccine or placebo 1-2 months apart during or
after immunosuppressive cancer treatments, and stratified participants according
to their underlying diseases. The co-primary objectives of the study were the
evaluation of safety and reactogenicity of the adjuvanted recombit zoster
vaccine compared with placebo from the first vaccination up to 30 days after
last vaccination in all participants; evaluation of the proportion of
participants with a vaccine response in terms of anti-glycoprotein E humoral
immune response to the adjuvanted recombit zoster vaccine at month 2 in all
participants, excluding those with non-Hodgkin B-cell lymphoma and chronic
lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune
responses to the vaccine compared with placebo at month 2 in all participants,
excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic
leukaemia. We assessed immunogenicity in the per-protocol cohort for
immunogenicity and safety in the total vaccinated cohort. The study is
registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical
Trials Register, number 2012-003438-18.
FINDINGS: Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286
participants to adjuvanted recombit zoster vaccine and 283 to placebo. 283 in
the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119
(80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to
adjuvanted recombit zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130
participants in the placebo group, and the adjusted geometric mean
anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI
16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the
placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p<0·0001) in
all patients, excluding those with non-Hodgkin B-cell lymphoma and chronic
lymphocytic leukaemia. Humoral and cell-mediated immune responses persisted
above baseline until month 13 in all strata and, as expected, vaccine was more
reactogenic than placebo (within 7 days after vaccination pain was reported by
221 [79·5%] of 278 vaccine group participants and 45 [16·4%] of 274 placebo
group participants; fatigue was reported by 162 [58·3%] of 278 vaccine group
participants and 102 [37·2%] of 274 placebo group participants). Incidences of
unsolicited or serious adverse events, potential immune-mediated diseases,
disease-related events, and fatal serious adverse events were similar between
the groups.
INTERPRETATION: The immunocompromised adult population with haematological
maligcies is at high risk for herpes zoster. The adjuvanted recombit
zoster vaccine, which is currently licensed in certain countries for adults aged
50 years and older, is likely to benefit this population.
FUNDING: GlaxoSmithKline Biologicals SA. Author information:
(1)National Center for Immunization and Respiratory Diseases, Centers for
Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, United
States. Electronic address: [email protected].
(2)National Center for Immunization and Respiratory Diseases, Centers for
Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, United
States.
(3)Adult and Child Consortium for Health Outcomes Research and Delivery Science,
University of Colorado Anschutz Medical Campus and Children's Hospital Colorado,
13001 E 17th Pl, Aurora, CO, United States; Division of General Internal
Medicine, 777 Bannock St, Denver, CO 80204, United States.
(4)Office of the Associate Director for Communication, Centers for Disease
Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30333, United States.
(5)Adult and Child Consortium for Health Outcomes Research and Delivery Science,
University of Colorado Anschutz Medical Campus and Children's Hospital Colorado,
13001 E 17th Pl, Aurora, CO, United States; Department of Pediatrics, Colorado
School of Public Health, University of Colorado Anschutz Medical Campus, 13001 E
17th Pl, Aurora, CO, United States.
(6)Department of Pediatrics, Colorado School of Public Health, University of
Colorado Anschutz Medical Campus, 13001 E 17th Pl, Aurora, CO, United States.
(7)Adult and Child Consortium for Health Outcomes Research and Delivery Science,
University of Colorado Anschutz Medical Campus and Children's Hospital Colorado,
13001 E 17th Pl, Aurora, CO, United States; Department of Community and
Behavioral Health, Colorado School of Public Health, University of Colorado
Anschutz Medical Campus, 13001 E 17th Pl, Aurora, CO, United States.
(8)Adult and Child Consortium for Health Outcomes Research and Delivery Science,
University of Colorado Anschutz Medical Campus and Children's Hospital Colorado,
13001 E 17th Pl, Aurora, CO, United States. Patients with inflammatory bowel disease, especially those on immunosuppressive
therapy, are at higher risk of acquiring infectious diseases (Reich et al.,
2016). For this reason, immunizations are routinely recommended in comprehensive
inflammatory bowel disease care. SHINGRIX, a non-live recombit herpes zoster
vaccine, was approved by the Food and Drug Administration in 2017. Adults aged
50 and over are recommended to receive two doses of SHINGRIX. Unlike ZOSTAVAX®
which is a live zoster vaccine that has been in use since 2006, SHINGRIX is safe
for those on immunosuppression (Reich et al., 2016). The offside effects of
SHINGRIX include injection-site erythema, tenderness, fatigue, and
gastrointestinal upset. To our knowledge, blistering autoimmune skin disorders
following SHINGRIX administration have not been reported. Here we discuss a case
of a 74-year-old female patient with a history of ulcerative proctosigmoiditis
on mesalamine who presented with a blistering skin disease after each SHINGRIX
vaccination. PURPOSE: Previously, secondary prevention of herpes zoster required
live-attenuated vaccination, which is contraindicated in immunocompromised
populations. More recently, a recombit subunit vaccine (Shingrix,
GlaxoSmithKline, Research Triangle Park, North Carolina) was approved by the
Food and Drug Administration. Iatrogenic varicella-zoster virus (VZV) infection
is theoretically impossible as it does not contain a live virus. We present a
case of acute retinal necrosis (ARN) and disseminated zoster after receiving the
recombit subunit vaccine.
OBSERVATIONS: A 65-year-old woman with past medical history of multiple myeloma
treated with a previous autologous hematopoietic stem cell transplant and now
with daratumumab and pomalidomide developed disseminated zoster and subsequently
acute retinal necrosis weeks after receiving the zoster subunit vaccine.
Molecular testing confirmed the presence of VZV, and the absence of herpes
simplex virus, cytomegalovirus, and toxoplasmosis. The VZV was found to be
genotypically wildtype and not related to the Oka strain used in the
live-attenuated zoster vaccine. She was treated with systemic valacyclovir and
intravitreal foscarnet.
CONCLUSIONS AND IMPORTANCE: This is the first report of VZV infection following
the zoster subunit vaccine. The Advisory Committee on Immunization Practices
(ACIP) has recommended the recombit subunit vaccine over the live-attenuated
vaccine due to its superior efficacy. The off-label use of the subunit vaccine
in immunocompromised populations has been supported up to this point by studies
demonstrating its relative safety. Though post-vaccination VZV infection or
reactivation appears to be rare, clinicians should be aware of this potential
complication to the recombit subunit vaccine. |
What is the function of HP1a in the nucleus? | Heterochromatin protein 1 (HP1) is an abundant component of heterochromatin, a highly condensed compartment of the nucleus that comprises a major fraction of complex genomes. | Heterochromatin Protein 1 (HP1a) is a well-known conserved protein involved in
heterochromatin formation and gene silencing in different species including
humans. A general model has been proposed for heterochromatin formation and
epigenetic gene silencing in different species that implies an essential role
for HP1a. According to the model, histone methyltransferase enzymes (HMTases)
methylate the histone H3 at lysine 9 (H3K9me), creating selective binding sites
for itself and the chromodomain of HP1a. This complex is thought to form a
higher order chromatin state that represses gene activity. It has also been
found that HP1a plays a role in telomere capping. Surprisingly, recent studies
have shown that HP1a is present at many euchromatic sites along polytene
chromosomes of Drosophila melanogaster, including the developmental and
heat-shock-induced puffs, and that this protein can be removed from these sites
by in vivo RNase treatment, thus suggesting an association of HP1a with the
transcripts of many active genes. To test this suggestion, we performed an
extensive screening by RIP-chip assay (RNA-immunoprecipitation on microarrays),
and we found that HP1a is associated with transcripts of more than one hundred
euchromatic genes. An expression analysis in HP1a mutants shows that HP1a is
required for positive regulation of these genes. Cytogenetic and molecular
assays show that HP1a also interacts with the well known proteins DDP1, HRB87F,
and PEP, which belong to different classes of heterogeneous nuclear
ribonucleoproteins (hnRNPs) involved in RNA processing. Surprisingly, we found
that all these hnRNP proteins also bind heterochromatin and are domit
suppressors of position effect variegation. Together, our data show novel and
unexpected functions for HP1a and hnRNPs proteins. All these proteins are in
fact involved both in RNA transcript processing and in heterochromatin
formation. This suggests that, in general, similar epigenetic mechanisms have a
significant role on both RNA and heterochromatin metabolisms. The eyegone (eyg) gene encodes Eyg, a transcription factor of the Pax family
with multiple roles during Drosophila development. Although Eyg has been shown
to act as a repressor, nothing is known about the mechanism by which it
represses its target genes. Here, we show that Eyg forms a protein complex with
heterochromatin protein 1a (HP1a). Both proteins bind to the same chromatin
regions on polytene chromosomes and act cooperatively to suppress variegation
and mediate gene silencing. In addition, Eyg binds to a wingless (wg) enhancer
region, recruiting HP1a to assemble a closed, heterochromatin-like conformation
that represses transcription of the wg gene. We describe here the evidence that
suggests that Eyg, encoded by eyegone (eyg), represses wingless (wg) during eye
development by association with HP1a. We show that Eyg forms a protein complex
with HP1a and both proteins colocalize on salivary gland polytene chromosomes.
Using position effect variegation (PEV) experiments, we demonstrated that eyg
has a dose-dependent effect on heterochromatin gene silencing and identified a
genetic interaction with HP1a in this process. We further demonstrated that HP1a
binds to the same wg enhancer element as Eyg. DNase I sensitivity assays
indicated that this enhancer region has a closed heterochromatin-like
conformation, which becomes open in eyg mutants. In these mutants, much less
HP1a binds to the wg enhancer region, as shown by ChIP experiments. Furthermore,
as previously described for Eyg, a reduction in the amount of HP1a in the eye
imaginal disc derepresses wg. Together, our results suggest a model in which Eyg
specifically binds to the wg enhancer region, recruiting HP1a to that site. The
recruitment of HP1a prevents transcription by favoring a closed,
heterochromatin-like structure. Thus, for the first time, we show that HP1a
plays a direct role in the repression of a developmentally regulated gene, wg,
during Drosophila eye development. Heterochromatin protein 1a (HP1a) is a chromatin-associated protein important
for the formation and maintece of heterochromatin. In Drosophila, the two
histone methyltransferases SETDB1 and Su(var)3-9 mediate H3K9 methylation marks
that initiates the establishment and spreading of HP1a-enriched chromatin.
Although HP1a is generally regarded as a factor that represses gene
transcription, several reports have linked HP1a binding to active genes, and in
some cases, it has been shown to stimulate transcriptional activity. To clarify
the function of HP1a in transcription regulation and its association with
Su(var)3-9, SETDB1 and the chromosome 4-specific protein POF, we conducted
genome-wide expression studies and combined the results with available binding
data in Drosophila melanogaster. The results suggest that HP1a, SETDB1 and
Su(var)3-9 repress genes on chromosome 4, where non-ubiquitously expressed genes
are preferentially targeted, and stimulate genes in pericentromeric regions.
Further, we showed that on chromosome 4, Su(var)3-9, SETDB1 and HP1a target the
same genes. In addition, we found that transposons are repressed by HP1a and
Su(var)3-9 and that the binding level and expression effects of HP1a are
affected by gene length. Our results indicate that genes have adapted to be
properly expressed in their local chromatin environment. Histone H3-lysine(9) (H3K9) trimethyltransferase gene Su(var) 3-9 was cloned and
identified in three Spodoptera insects, Spodopterafrugiperda (S. frugiperda), S.
exigua and S. litura. Sequence analysis showed that Spodoptera Su(var) 3-9 is
highly conserved evolutionarily. Su(var) 3-9 protein was found to be localized
in the nucleus in Sf9 cells, and interact with histone H3, and the
heterochromatin protein 1a (HP1a) and HP1b. A dose-dependent enzymatic activity
was found at both 27 °C and 37 °C in vitro, with higher activity at 27 °C.
Addition of specific inhibitor chaetocin resulted in decreased histone
methylation level and host chromatin relaxation. In contrast, overexpression of
Su(var) 3-9 caused increased histone methylation level and cellular genome
compaction. In AcMNV-infected Sf9 cells, the transcription of Su(var) 3-9
increased at late time of infection, although the mRNA levels of most cellular
genes decreased. Pre-treatment of Sf9 cells with chaetocin speeded up viral DNA
replication, and increased the transcription level of a variety of virus genes,
whereas in Sf9 cells pre-transformed with Su(var) 3-9 expression vector, viral
DNA replication slow down slightly. These findings suggest that Su(var) 3-9
might participate in the viral genes expression an genome replication repression
during AcMNPV infection. It provided a new insight for the understanding
virus-host interaction mechanism. Heterochromatin protein 1 (HP1a in Drosophila) is a conserved eukaryotic
chromosomal protein that is prominently associated with pericentric
heterochromatin and mediates the concomitant gene silencing. Mechanistic studies
implicate HP1 family proteins as 'hub proteins,' able to interact with a variety
of chromosomal proteins through the chromo-shadow domain (CSD), as well as to
recognize key histone modification sites [primarily histone H3 di/trimethyl Lys9
(H3K9me2/3)] through the chromodomain (CD). Consequently, HP1 has many important
roles in chromatin architecture and impacts both gene expression and gene
silencing, utilizing a variety of mechanisms. Clearly, HP1 function is altered
by context, and potentially by post-translational modifications (PTMs). Here, we
report on recent ideas as to how this versatile protein accomplishes its diverse
functions. Heterochromatin protein 1 (HP1) was first described in Drosophila melanogaster
as a heterochromatin associated protein required for epigenetic gene silencing.
Most eukaryotes have at least three HP1 homologs that play differential roles in
heterochromatin and euchromatin. However, despite the fact that the three HP1
proteins bind to different regions of the genome, several studies show that most
of the interactions occur in a manner specific to HP1a. In addition, little is
known about the overall interaction network of the three Drosophila HP1
homologs, HP1a, HP1b, and HP1c. Here, we performed the first comprehensive
proteomic analysis of Drosophila HP1 homologs by coupling a double-affinity
purification approach with MudPIT analysis to identify interacting proteins of
Drosophila HP1. We discovered 160-310 proteins co-eluted with HP1, including a
number of novel HP1-binding partners along with the previously identified HP1
binding proteins. Finally, we showed that slight and unique binding preferences
might exist between the three HP1 proteins in Drosophila. These studies are the
first to systematically analyze the interactome of HP1 paralogs and provide the
basic clues as to the molecular mechanism by which HP1 might control cellular
processes.
BIOLOGICAL SIGNIFICANCE: Most eukaryotes have at least three HP1 homologs with
similar domain structures but with differential roles in heterochromatin and
euchromatin. However, little is known about the overall interactome of the three
Drosophila HP1 homologs, HP1a, HP1b, and HP1c. The present study compared
interacting proteins of three HP1 homologs in Drosophila. To better understand
the underlying mechanisms for gene regulation of HP1, a double-affinity
purification and MudPIT mass spectrometry were employed to identify differential
proteins as well as common binding proteins of HP1. Therefore, this study
provides not only the comparative proteomic analysis but also molecular
mechanism underlying the HP1 homolog-specific function. The Piwi-interacting RNA (piRNA)-interacting Piwi protein is involved in
transcriptional silencing of transposable elements in ovaries of Drosophila
melanogaster. Here we characterized the genome-wide effect of nuclear Piwi
elimination on the presence of the heterochromatic H3K9me3 mark and HP1a, as
well as on the transcription-associated mark H3K4me2. Our results demonstrate
that a significant increase in the H3K4me2 level upon nuclear Piwi loss is not
accompanied by the alterations in H3K9me3 and HP1a levels for several
germline-expressed transposons, suggesting that in this case Piwi prevents
transcription by a mechanism distinct from H3K9 methylation. We found that the
targets of Piwi-dependent chromatin repression are mainly related to the
elements that display a higher level of H3K4me2 modification in the absence of
silencing, i.e. most actively transcribed elements. We also show that
Piwi-guided silencing does not significantly influence the chromatin state of
dual-strand piRNA-producing clusters. In addition, host protein-coding gene
expression is essentially not affected due to the nuclear Piwi elimination, but
we noted an increase in small nuclear spliceosomal RNAs abundance and propose
Piwi involvement in their post-transcriptional regulation. Our work reveals new
aspects of transposon silencing in Drosophila, indicating that transcription of
transposons can underpin their Piwi dependent silencing, while canonical
heterochromatin marks are not obligatory for their repression. Constitutive heterochromatin is an important component of eukaryotic genomes
that has essential roles in nuclear architecture, DNA repair and genome
stability, and silencing of transposon and gene expression. Heterochromatin is
highly enriched for repetitive sequences, and is defined epigenetically by
methylation of histone H3 at lysine 9 and recruitment of its binding partner
heterochromatin protein 1 (HP1). A prevalent view of heterochromatic silencing
is that these and associated factors lead to chromatin compaction, resulting in
steric exclusion of regulatory proteins such as RNA polymerase from the
underlying DNA. However, compaction alone does not account for the formation of
distinct, multi-chromosomal, membrane-less heterochromatin domains within the
nucleus, fast diffusion of proteins inside the domain, and other dynamic
features of heterochromatin. Here we present data that support an alternative
hypothesis: that the formation of heterochromatin domains is mediated by phase
separation, a phenomenon that gives rise to diverse non-membrane-bound nuclear,
cytoplasmic and extracellular compartments. We show that Drosophila HP1a protein
undergoes liquid-liquid demixing in vitro, and nucleates into foci that display
liquid properties during the first stages of heterochromatin domain formation in
early Drosophila embryos. Furthermore, in both Drosophila and mammalian cells,
heterochromatin domains exhibit dynamics that are characteristic of liquid
phase-separation, including sensitivity to the disruption of weak hydrophobic
interactions, and reduced diffusion, increased coordinated movement and inert
probe exclusion at the domain boundary. We conclude that heterochromatic domains
form via phase separation, and mature into a structure that includes liquid and
stable compartments. We propose that emergent biophysical properties associated
with phase-separated systems are critical to understanding the unusual
behaviours of heterochromatin, and how chromatin domains in general regulate
essential nuclear functions. Heterochromatin protein 1a (HP1a) is a highly conserved and versatile epigenetic
factor that can both silence and activate transcription. However, the function
of HP1a in development has been underinvestigated. Here, we report the role of
maternal HP1a in producing maternal transcripts that drive early Drosophila
embryogenesis. Maternal HP1a upregulates genes involved in translation, mRNA
splicing, and cell division, but downregulates genes involved in neurogenesis,
organogenesis, and germline development, which all occur later in development.
Our study reveals the earliest contribution of HP1a during oogenesis in
regulating the production of maternal transcripts that drive early Drosophila
embryogenesis. |
Has AZD9668 been tested in clinical trials? | Yes, AZD9668 has been tested in clinical trials. | AZD9668 is a fully reversible, selective, oral inhibitor of neutrophil elastase,
a protease implicated in chronic obstructive pulmonary disease (COPD). Efficacy,
safety and tolerability of AZD9668 (5, 20 and 60 mg bid) were compared with
placebo in a randomised, double-blind, placebo-controlled, 12-week, Phase IIb
trial (NCT00949975: approved by an Investigational Review Board), in patients
with symptomatic COPD receiving maintece tiotropium. The primary endpoint was
pre-bronchodilator forced expiratory volume in 1 second (FEV₁). Secondary
endpoints included forced vital capacity and inspiratory capacity, peak
expiratory flow, Breathlessness, Cough and Sputum Scale score, exercise
capacity, quality of life (QoL), exacerbation assessments, safety and
pharmacokinetics. Exploratory endpoints included inflammatory and tissue
degradation biomarkers. A total of 838 patients were randomised to AZD9668 5 mg
bid (212 patients), 20 mg bid (206 patients), 60 mg bid (202 patients) or
placebo (218 patients). AZD9668 showed no effect on lung function, respiratory
signs and symptoms, QoL or biomarkers. At end of treatment, the change in mean
pre-bronchodilator FEV₁ for AZD9668 60 mg bid compared with placebo was 0.00L
(95% confidence interval: -0.05, 0.04; p = 0.873). Overall, AZD9668 was well
tolerated; the numbers of patients with adverse events (AEs), serious AEs and
AEs leading to discontinuation were similar in each of the four study groups.
AZD9668 60 mg bid showed no clinical benefit and no effect on biomarkers of
inflammation or tissue degradation when added to tiotropium in patients with
COPD. These results raise important questions for future investigation of
anti-inflammatory and disease-modifying agents in patients with COPD. INTRODUCTION: The aim of this study was to establish the feasibility of using
computed tomography (CT) in a multicenter setting to assess structural airway
changes.
METHODS: This was a 12-week, randomized, double-blind, placebo-controlled, Phase
IIb trial using CT to investigate the effect of a novel, oral, reversible
neutrophil elastase inhibitor, AZD9668 60 mg twice daily (BID), on structural
airway changes in patients aged 50-80 years with chronic obstructive pulmonary
disease (COPD) (ex-smokers).
PRIMARY OUTCOME VARIABLE: airway wall thickness at an extrapolated interior
perimeter of 10 mm (AWT-Pi10). Secondary outcome variables: fifth-generation
wall area %; air trapping index; pre- and post-bronchodilator forced expiratory
volume in 1 s (FEV1); morning and evening peak expiratory flow and FEV1; body
plethysmography; EXAcerbations of Chronic pulmonary disease Tool (EXACT);
Breathlessness, Cough, and Sputum Scale (BCSS); St George's Respiratory
Questionnaire for COPD; and proportion of reliever-medication-free trial days.
Safety variables were also assessed.
RESULTS: There was no difference between placebo (n = 19) and AZD9668 (n = 17)
for AWT-Pi10 at treatment end. This was consistent with results for most
secondary variables. However, patients randomized to AZD9668 experienced an
improvement versus placebo for morning and evening FEV1, and EXACT and BCSS
cough and sputum scores. AZD9668 60 mg BID was well tolerated and no new safety
concerns were identified.
CONCLUSIONS: This study confirmed the feasibility of using CT to assess
structural airway changes in COPD. However, there was no evidence of
improvements in CT structural measures following 12 weeks' treatment with
AZD9668 60 mg BID.
FUNDING: AstraZeneca. |
Which class of genomic elements was assessed as part of the FANTOM6 project? | Long noncoding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes, and yet, their functions remain largely unknown. As part of the FANTOM6 project, the expression of 285 lncRNAs was systematically knocked down in human dermal fibroblasts. Cellular growth, morphological changes, and transcriptomic responses were quantified using Capped Analysis of Gene Expression (CAGE). | Author information:
(1)RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045,
Japan.
(2)RIKEN Center for Life Science Technologies, Yokohama, Kanagawa 230-0045,
Japan.
(3)Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (CIB),
Trieste 34127, Italy.
(4)Engelhardt Institute of Molecular Biology, Russian Academy of Sciences,
Moscow 119991, Russia.
(5)Institute of Protein Research, Russian Academy of Sciences, Pushchino 142290,
Russia.
(6)Department of Computer Science, University of Toronto, Toronto, Ontario M5S
1A1, Canada.
(7)Program in Cardiovascular and Metabolic Disorders, Duke-National University
of Singapore Medical School, Singapore 169857, Singapore.
(8)Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, United
Kingdom.
(9)Center for RNA Medicine, Department of Clinical Medicine, Aalborg University,
Copenhagen 9220, Denmark.
(10)Institute of Clinical Sciences, Faculty of Medicine, Imperial College
London, London W12 0NN, United Kingdom.
(11)Computational Regulatory Genomics, MRC London Institute of Medical Sciences,
London W12 0NN, United Kingdom.
(12)Berlin Institute for Medical Systems Biology, Max Delbrük Center for
Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany.
(13)Institute of Bioengineering, Research Center of Biotechnology, Russian
Academy of Sciences, Moscow 117312, Russia.
(14)Graduate School of Integrated Sciences for Life, Hiroshima University,
Higashi-Hiroshima City 739-0046, Japan.
(15)Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and
Technology, Barcelona, Catalonia 08003, Spain.
(16)International Centre for Genetic Engineering and Biotechnology (ICGEB),
University of Cape Town, Cape Town 7925, South Africa.
(17)Institute of Infectious Diseases and Molecular Medicine (IDM), Department of
Pathology, Division of Immunology and South African Medical Research Council
(SAMRC) Immunology of Infectious Diseases, Faculty of Health Sciences,
University of Cape Town, Cape Town 7925, South Africa.
(18)School of Computer Science, McGill University, Montréal, Québec H3G 1Y6,
Canada.
(19)Department of Biochemistry, Rosalind and Morris Goodman Cancer Research
Center, McGill University, Montréal, Québec H3G 1Y6, Canada.
(20)Department of Molecular Biophysics and Biochemistry, Yale University, New
Haven, Connecticut 06510, USA
(21)Biomedical Cybernetics Group, Biotechnology Center (BIOTEC), Center for
Molecular and Cellular Bioengineering (CMCB), Center for Systems Biology Dresden
(CSBD), Cluster of Excellence Physics of Life (PoL), Department of Physics,
Technische Universität Dresden, Dresden 01062, Germany.
(22)Center for Complex Network Intelligence (CCNI) at the Tsinghua Laboratory of
Brain and Intelligence (THBI), Department of Bioengineering, Tsinghua
University, Beijing 100084, China.
(23)Institute of Cancer and Genomic Sciences, College of Medical and Dental
Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom.
(24)Center for Personal Dynamic Regulome, Stanford University, Stanford,
California 94305, USA.
(25)Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology,
Zurich 8093, Switzerland.
(26)Department of Computational Systems Biology, Vavilov Institute of General
Genetics, Russian Academy of Sciences, Moscow 119991, Russia.
(27)Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21287,
USA.
(28)Department of Biological Regulation, Weizmann Institute of Science, Rehovot
76100, Israel.
(29)Epigenetics and Genome Reprogramming Laboratory, IRCCS Fondazione Santa
Lucia, Rome 00179, Italy.
(30)Genome Biology of Neurodegenerative Diseases, German Center for
Neurodegenerative Diseases (DZNE), Tübingen 72076, Germany.
(31)Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871,
Japan.
(32)RIKEN Preventive Medicine and Diagnosis Innovation Program (PMI), Saitama
351-0198, Japan.
(33)Institute of Infection, Immunity, and Inflammation, University of Glasgow,
Glasgow, Scotland G12 8QQ, United Kingdom.
(34)Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge
14157, Sweden.
(35)Moscow Institute of Physics and Technology, Dolgoprudny 141701, Russia.
(36)Biological and Environmental Sciences and Engineering Division, King
Abdullah University of Science and Technology, Thuwal 23955-6900, Kingdom of
Saudi Arabia.
(37)Department of Biology and BRIC, University of Copenhagen, Denmark,
Copenhagen N DK2200, Denmark.
(38)MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 2XU, United
Kingdom.
(39)National Centre for Cell Science, Pune, Maharashtra 411007, India.
(40)Centre for Global Health Research, Usher Institute, University of Edinburgh,
Edinburgh EH8 9AG, United Kingdom.
(41)Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre
for Medical Research, The University of Western Australia, Nedlands, Perth,
Western Australia 6009, Australia.
(42)Universitat Pompeu Fabra (UPF), Barcelona, Catalonia 08002, Spain.
(43)Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.
(44)Stem Cells and Metabolism Research Program, University of Helsinki and
Folkhälsan Research Center, 00290 Helsinki, Finland.
(45)Sars International Centre for Marine Molecular Biology, University of
Bergen, Bergen N-5008, Norway.
(46)Department of Medicine and Consorzio Interuniversitario Biotecnologie p.zle
Kolbe 1 University of Udine, Udine 33100, Italy.
(#)Contributed equally The Functional ANnoTation Of the Mammalian genome (FANTOM) Consortium has
continued to provide extensive resources in the pursuit of understanding the
transcriptome, and transcriptional regulation, of mammalian genomes for the last
20 years. To share these resources with the research community, the FANTOM
web-interfaces and databases are being regularly updated, enhanced and expanded
with new data types. In recent years, the FANTOM Consortium's efforts have been
mainly focused on creating new non-coding RNA datasets and resources. The
existing FANTOM5 human and mouse miRNA atlas was supplemented with rat, dog, and
chicken datasets. The sixth (latest) edition of the FANTOM project was launched
to assess the function of human long non-coding RNAs (lncRNAs). From its
creation until 2020, FANTOM6 has contributed to the research community a large
dataset generated from the knock-down of 285 lncRNAs in human dermal
fibroblasts; this is followed with extensive expression profiling and cellular
phenotyping. Other updates to the FANTOM resource includes the reprocessing of
the miRNA and promoter atlases of human, mouse and chicken with the latest
reference genome assemblies. To facilitate the use and accessibility of all
above resources we further enhanced FANTOM data viewers and web interfaces. The
updated FANTOM web resource is publicly available at
https://fantom.gsc.riken.jp/. |
Which molecule is targeted by Camrelizumab? | Camrelizumab is a humanised antibody that targets programmed death-1 (PD-1) ligand. | BACKGROUND: Platinum-based doublet chemotherapy regimens, preferentially
gemcitabine plus cisplatin, are generally considered the first-line standard of
care for patients with recurrent or metastatic nasopharyngeal carcinoma.
However, no consensus has been reached regarding treatment following progression
after first-line therapy. Camrelizumab (SHR-1210) is a humanised anti-programmed
death-1 (anti PD-1) antibody. We present safety and preliminary antitumour
activity of camrelizumab alone as second-line therapy in patients with recurrent
or metastatic nasopharyngeal carcinoma and combined with gemcitabine and
cisplatin as first-line therapy in this patient population.
METHODS: We report the results from two single-arm, phase 1 trials. Both trials
included patients aged 18-70 years with histologically or cytologically
confirmed nasopharyngeal carcinoma and confirmed metastatic disease or
locoreginal recurrence, and an Eastern Cooperative Oncology Group performance
status of 0 or 1. Patients who received at least one previous line of treatment
were enrolled at five academic hospitals in China into the dose-escalation and
expansion trial to receive camrelizumab monotherapy intravenously at escalating
doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg, and a bridging dose of 200 mg per dose
once every 2 weeks (monotherapy trial). Treatment-naive patients were enrolled
from a single centre in China to receive six cycles of camrelizumab 200 mg (day
1), gemcitabine 1 g/m2 (days 1 and 8), and cisplatin 80 mg/m2 (day 1) every 3
weeks followed by camrelizumab 200 mg maintece once every 3 weeks
(combination trial). The primary endpoint of both trials was the safety and
tolerability of the study treatment. Analyses were done per protocol. Both
trials are registered with ClinicalTrials.gov, number NCT02721589 (camrelizumab
monotherapy trial) and NCT03121716 (camrelizumab combination trial). Both trials
are ongoing, but are no longer enrolling patients.
FINDINGS: In the camrelizumab monotherapy trial, between March 31, 2016, and
Sept 20, 2017, 121 patients were assessed for eligibility, of whom 93 patients
were enrolled across the dose-escalation and expansion cohorts and received at
least one dose of camrelizumab (safety population). 15 (16%) of 93 patients had
treatment-related adverse events of grade 3 or 4, the most common of which were
elevated conjugated bilirubin concentration (three [3%] of 93 patients),
stomatitis, anaemia, and increased concentrations of aspartate aminotransferase,
alanine aminotransferase, and total bilirubin, each of which occurred in two
(2%) patients. Eight (9%) patients had a treatment-related serious adverse
event. No dose-limiting toxic effects were observed during the dose-escalation
phase. 31 (34%; 95% CI 24-44) of 91 evaluable patients on camrelizumab
monotherapy had an overall response with a median follow-up of 9·9 months (IQR
8·1-11·7). In the camrelizumab combination trial, between April 18, 2017, and
Aug 15, 2017, 24 patients were assessed for eligibility, of whom 23 patients
were enrolled and treated (safety population). 20 (87%) of 23 patients had grade
3 or 4 treatment-related adverse events: neutropenia (13 [57%] of 23 patients),
anaemia (11 [48%] patients), leucopenia (11 [48%] patients), thrombocytopenia
(seven [30%] patients), oedema (two [9%] patients), hyponatraemia (two [9%]
patients), hypochloraemia (one [4%] patients), and rash (one [4%] patient). Two
patients had treatment-related serious adverse events. No treatment-related
deaths occurred in these trials. 20 (91% [95% CI 72-97]) of 22 evaluable
patients had an overall response with a median follow-up time of 10·2 months
(IQR 9·7-10·8).
INTERPRETATION: Camrelizumab is a well tolerated, potential treatment option for
patients with recurrent or metastatic nasopharyngeal carcinoma. The combination
of camrelizumab plus gemcitabine and cisplatin has a manageable toxicity profile
and promising preliminary antitumour activity for this disease in
treatment-naive patients. Randomised controlled trials are needed to further
establish the role of immune checkpoint inhibition for nasopharyngeal
carcinomas.
FUNDING: Hengrui Medicine Co, Chinese National Natural Science Foundation
project, Science and Technology Program of Guangdong, Pearl River Nova Program
of Guangzhou. BACKGROUND: A small proportion of patients with advanced esophageal squamous
cell carcinoma (ESCC) could benefit from immune checkpoint inhibitors; however,
reliable peripheral blood biomarkers for outcomes of anti-PD-1 immunotherapy in
ESCC have not been identified.
METHODS: The data of 43 patients in the ESCC cohort of a phase I trial at our
center were retrospectively reviewed. All patients were administered intravenous
camrelizumab (SHR-1210), a novel anti-PD-1 antibody, at doses of 60 mg, 200 mg,
or 400 mg (4-week interval after first dose followed by a 2-week schedule) until
disease progression or intolerable toxicity. Associations between lactate
dehydrogenase (LDH) and other peripheral blood biomarkers at baseline and the
efficacy of camrelizumab were also investigated.
RESULTS: After median follow-up of 19.6 months, the overall response rate was
25.6% (11/43), including one complete response. Median progression-free and
overall survival rates were 2.0 and 8.0 months, respectively. Patients with an
elevated baseline LDH had lower tumor response rates (P = 0.02) and shorter
progression-free (P = 0.002) and overall (P < 0.0001) survival than patients
with normal LDH levels. An increase in LDH levels during treatment was
significantly associated with disease progression. Multivariate Cox analysis
identified LDH (hazard ratio [HR] 0.18), CRP (HR 0.27), the number of organs
involved (HR 0.31), absolute monocyte count (HR 0.33), and Eastern Cooperative
Oncology Group performance status (HR 0.36) as independent prognostic factors.
CONCLUSIONS: Serum LDH, which is readily available in routine clinical practice,
is a potential marker for response and a powerful independent factor for
survival in advanced ESCC patients treated with anti-PD-1 therapy. Recent phase 1-2 trials reported manageable safety profiles and promising
antitumor activities of anti-PD-1 drugs (pembrolizumab, nivolumab, camrelizumab
and JS001) with/without chemotherapy in recurrent/metastatic nasopharyngeal
carcinoma (RM-NPC), however head-to-head comparison among these regimens is
lacking. We aimed to comprehensively compare the efficacy and safety of
different anti-PD-1 drugs, standard chemotherapy, and their combination therapy
in RM-NPC. Adverse event (AE) and objective response rate (ORR) were assessed.
The pooled incidence rates of grade 1-5/3-5 AEs were 74.1%/29.6, 54.2%/17.4,
92.3%/24.5, 96.8%/16.1, 91.2%/42.8, and 100%/87.9% for pembrolizumab, nivolumab,
JS001, camrelizumab, chemotherapy and camrelizumab+chemotherapy, respectively,
which suggested that nivolumab and pembrolizumab exhibited the optimal safety
regarding grade 1-5 AEs whereas camrelizumab and nivolumab regarding grade 3-5
AEs. As second- or later-line therapy, ORR was higher with camrelizumab (34.1%),
followed by pembrolizumab (26.3%), JS001 (23.3%), and nivolumab (19.0%); whereas
ORR with first-line nivolumab reached 40%. Additionally, first-line
camrelizumab+chemotherapy achieved a dramatically higher ORR than that with
chemotherapy alone (90.9% vs. 64.1%). Pooled ORR was 28.4 and 17.4% for
PD-L1-positive and PD-L1-negative patients, respectively (P = 0.11). Here, we
represent preliminary evidence for the comparative safety and efficacy of
existing anti-PD-1 agents with/without chemotherapy in RM-NPC, which indicated
that camrelizumab has the least toxicity profile and merits future
investigation. Our findings might provide insights into the future design of
immunotherapy trials in RM-NPC. BACKGROUND: Camrelizumab is a promising anti-programmed cell death-1 agent for
non-small cell lung cancer (NSCLC) and induces reactive capillary hemangiomas
(RCHs). Routine clinical management of this unique and prevalent toxicity has
been summarized in previous studies. The objective of this study was to provide
evidence of apatinib as a salvage therapy for RCHs.
MATERIALS AND METHODS: In this single-center, observational study, patients with
NSCLC who were over 18 years of age and treated with camrelizumab were enrolled.
The incidence of RCHs, onset and duration time, severity, evolution, and
clinical practices, especially with apatinib, for their management and impact on
quality of life, were recorded during a 6-month follow-up.
RESULTS: A total of 28 patients were included. The incidence of RCHs was 28.6%
(8/28). The median onset and duration time were 6 weeks and 8 weeks,
respectively. Six (21.4%) patients had mild and moderate RCHs and four (9.3%)
patients achieved a rapid regression of RCHs with the application of apatinib.
The impact of the RCHs on quality of life was limited and assessed with
Dermatology Life Quality Index scores. No treatment-associated termination was
observed.
CONCLUSION: The combination of camrelizumab and apatinib in the treatment of
NSCLC reduced the incidence of RCHs. Apatinib appeared to be a salvage therapy
of RCHs, which leads to rapid regression of RCHs with no impairment on the
quality of life. AIM: The present study evaluated the safety and efficacy of camrelizumab (a
programmed death-1 antibody) in combination with microwave ablation (MWA) in
advanced non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: A total of 21 patients were prospectively enrolled. MWA
was performed in 25 pulmonary lesions during 21 sessions. Camrelizumab was
administered 5-7 days after MWA as a dose of 200 mg, which was repeated every 2
weeks until disease progression or intolerable toxicities. The primary endpoints
were safety and the objective response rate (ORR). Other endpoints included
progression-free survival (PFS) and overall survival (OS).
RESULTS: The technical success rate was 100%. No treatment-associated deaths
were identified. Major complications, minor complications, and side effects of
MWA were observed in 9, 8, and 14 patients, respectively. The main major
complications included pneumothorax, pneumonia, hemorrhage, and pleural
effusion. The adverse events of camrelizumab included reactive skin capillary
hyperplasia (n = 9), hypothyroidism (n = 5), pneumonia (n = 4), fatigue (n = 2),
leukopenia (n = 1), and neutropenia (n = 1). Grade 2 and 3 camrelizumab adverse
events were identified in eight and three patients, respectively. The ORR was
33.3%, with two patients achieving complete response and five patients achieving
partial response. The median PFS was 5.1 months and OS was not reached.
CONCLUSIONS: Camrelizumab administration combined with MWA was safe in the
treatment of advanced NSCLC, and the combination improved the ORR of
camrelizumab alone compared to previous reports. Immune checkpoint inhibitors can enhance the antitumor activity of the immune
system by mainly promoting CD8+ T lymphocyte immune function. However, they can
also induce immune-related adverse events, especially skin toxicity. Some
studies found that patients with autoimmune or inflammatory disease are
susceptible to immune checkpoint inhibitors and were associated with a
significantly increased risk of immune-related adverse events. In our present
report, we described a newly diagnosed non-small-cell lung cancer patient who
suffered from focal vitiligo for approximately ten years and was treated with
the anti-programmed cell death-1 receptor antibody camrelizumab (SHR-1210),
which accelerated the aggravation of depigmentation of the skin over the whole
body in just half a year. BACKGROUND: Blocking the interaction between PD-1 and its ligands is a promising
treatment strategy for advanced hepatocellular carcinoma. This study aimed to
assess the antitumour activity and safety of the anti-PD-1 inhibitor
camrelizumab in pretreated patients with advanced hepatocellular carcinoma.
METHODS: This is a multicentre, open-label, parallel-group, randomised, phase 2
trial done at 13 study sites in China. Eligible patients were aged 18 years and
older with a histological or cytological diagnosis of advanced hepatocellular
carcinoma, had progressed on or were intolerant to previous systemic treatment,
and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients
were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every
2 or 3 weeks, via a centralised interactive web-response system using block
randomisation (block size of four). The primary endpoints were objective
response (per blinded independent central review) and 6-month overall survival,
in all randomly assigned patients who had at least one dose of study treatment.
Safety was analysed in all treated patients. This study is registered with
ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment
is closed.
FINDINGS: Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for
eligibility, of whom 220 eligible patients were randomly assigned and among whom
217 received camrelizumab (109 patients were given treatment every 2 weeks and
108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7-15·5). Objective
response was reported in 32 (14·7%; 95% CI 10·3-20·2) of 217 patients. The
overall survival probability at 6 months was 74·4% (95% CI 68·0-79·7)]. Grade 3
or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the
most common were increased aspartate aminotransferase (ten [5%]) and decreased
neutrophil count (seven [3%]). Two deaths were judged by the investigators to be
potentially treatment-related (one due to liver dysfunction and one due to
multiple organ failure).
INTERPRETATION: Camrelizumab showed antitumour activity in pretreated Chinese
patients with advanced hepatocellular carcinoma, with manageable toxicities, and
might represent a new treatment option for these patients.
FUNDING: Jiangsu Hengrui Medicine. Conflict of interest statement: Jason Lickliter and Mark Voskoboynik are
employees of Nucleus Network (Australia). Jianjun Zou, Lianshan Zhang and Stacey
Luo are employees of Jiangsu Hengrui Medicine Co. Ltd (China). Michael Lahn,
Andrea Mannucci and Catello Somma were or are employees of Incyte Biosciences
International Sarl (Switzerland). Howard Kallender is employee of Incyte
Corporation (USA). Michael Millward and Tarek Meniawy are employees of Linear
Clinical Research (Australia). Hui K. Gan reports receiving honoraria from
speaker bureau of Bristol-Myers Squibb, Ignyta, Eisai and Merck Serono and is a
consultant/advisory board member of AbbVie and Bristol-Myers Squibb. Andrea
Mannucci has ownership interests (including stock, patents, etc.) at Incyte
Biosciences International Sarl (Switzerland). Michael Millward has been or
currently is a member of consultant/advisory board of Merck Sharp & Dohme,
Novartis, Bristol-Myers Squib, Roche, AstraZeneca, and Pfizer, and has received
travel support from Bristol-Myers Squibb and Roche. Ad Nagrial is a member of
consultant/advisory board of Bristol-Myers Squibb, Merck Sharpe Dohme, Astra
Zeneca and Roche, and reports receiving speaking fees from Bristol-Myers Squibb,
Merck Sharpe Dohme and Roche. Andreas Behren receives research support from
Incyte (Switzerland) for the RO assay. Michael Lahn has ownership interests
(including stock, patents, etc.) at Incyte Biosciences International Sarl
(Switzerland), AstraZeneca and Eli Lilly. Surein Arulada reports receiving
personal fees from Merck Sharpe Dohme, Astra Zeneca, Roche and
Boehringer-Ingelheim. Pablo Ferdez Penas is member of advisory committee (AC)
or lecture (L, only educational, non-promotional lectures) of Janssen (AC, L),
Lilly (AC, L), Abbvie (AC, L), Novartis (AC, L), UCB (L), MSD (AC), La Roche
Posay (L), Merck (AC, L), Roche (AC, L), Amgen (L), Sun Pharma (AC, L), Sanofi
(AC), Leo (AC, L), Avene (L), Celgene (AC), Galderma (L) and Schering Plough
(L), and reports receiving clinical trial supports from Boehringer Ingelheim,
Pfizer, CSL, OncoSec, Lilly, CBP, Abbvie, miRagen, Galderma, Regeneron, BMS,
Eisai, Jiangsu Hengrui, Sun Pharma, Novartis, UCB, Leo, Janssen, Arena, Akaal
Pharma, Roche, Xoma, Kyowa Hakko Kirin, GSK, Amgen and Merck Sharpe Dohme. No
potential conflicts of interest were disclosed by other authors. BACKGROUND: Results of our previous study showed high objective response but
short-term activity of apatinib in advanced osteosarcoma. We aimed to
investigate the activity of apatinib in combination with camrelizumab in
patients with inoperable high-grade osteosarcoma progressing after chemotherapy.
METHODS: This open-label, phase 2 trial was conducted at Peking University
People's Hospital. We enrolled patients with advanced osteosarcoma progressed
after chemotherapy. Patients received 500 mg apatinib orally once daily plus
200 mg camrelizumab by intravenous infusion every 2 weeks until disease
progression or unacceptable toxicity. The primary endpoint was progression-free
survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST
V.1.1.
RESULTS: 43 patients were enrolled between January 25 and September 4, 2018.
With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%,
95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the
6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the
objective response rate was 20.9% (9/43) and two patients with durable disease
control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1)
tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS
in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led
to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and
permanent discontinuation in 4 (9.3%) patients. There were no treatment-related
deaths.
CONCLUSIONS: Although the combination of apatinib and camrelizumab seemed to
prolong PFS in comparison to single agent apatinib in treating advanced
osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or
greater. Overexpression of PD-L1 and the presence of pulmonary metastases only
were associated with longer PFS.
TRIAL REGISTRATION NUMBER: NCT03359018. Background: Radiation recall pneumonitis (RRP) is an unpredictable but
relatively severe subclinical radiation damage which occurs in the previously
irradiated fields of pulmonary tissue after administration of a systemic agent.
Previous reports of RRP were mainly attributed to chemotherapy and
molecular-target agents. RRP induced by immunotherapy has been rarely reported.
Here we describe a case of a novel pattern of RRP induced by anti-PD-1 blockade
Camrelizumab 2 years after radiotherapy, with some focus on further
understanding of this phenomenon. Case Report: A 64-year-old man with non-small
cell lung cancer (NSCLC) received two cycles of chemotherapy with cisplatin and
pemetrexed first. Subsequently, he underwent concomitant chemoradiotherapy with
cisplatin and pemetrexed to simultaneous integrated boost (SIB) radiotherapy.
After 15 months, due to tumor progression and brain metastasis, he started with
administration of anti-PD-1 blockade Camrelizumab (200 mg q2w) and stereotactic
radiosurgery (SRS). The patient developed fever, dyspnea and cough after the
eighth administration of Camrelizumab. Meanwhile, his chest CT revealed patchy
consolidation and ground-glass opacities localized within the previously
irradiated area. Subsequent treatment regimen was adjusted to 80 mg q12h
prednisolone with discontinuation of Camrelizumab. Then the symptoms gradually
eased and reexamination of CT showed significant improvement in RRP after 2
weeks. Conclusion: Our case report presents a novel pattern of RRP induced by
anti-PD-1 blockade Camrelizumab 2 years after radiotherapy. This indicates that
previous radiotherapy combined with subsequent anti-PD-1 blockade has a
potential to cause overlapping damage to lung, suggesting that intensive
attention might be needed for patients who are treated with anti-PD-1 blockade
in conjunction with a prior history of thoracic radiation. BACKGROUND: Patients with advanced or metastatic oesophageal squamous cell
carcinoma have poor prognosis and few treatment options after first-line
therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody
camrelizumab versus investigator's choice of chemotherapy in previously treated
patients.
METHODS: ESCORT is a randomised, open-label, phase 3 study of patients aged 18
to 75 years with a histological or cytological diagnosis of advanced or
metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China.
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1, and had progressed on, or were intolerant to, first-line
standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg
every 2 weeks) or chemotherapy with docetaxel (75 mg/m2 every 3 weeks) or
irinotecan (180 mg/m2 every 2 weeks), all given intravenously. Central
randomisation was done using the Randomization and Trial Supply Management
system with block size randomly generated as four or six and stratified by
disease and ECOG performance status. The primary endpoint was overall survival,
assessed in randomised patients who had received at least one dose of treatment.
Safety was assessed in all treated patients. The trial is registered with
ClinicalTrials.gov, NCT03099382, and is closed to new participants.
FINDINGS: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened
patients were randomly assigned to treatment, of whom 228 received camrelizumab
treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with
a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group
and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was
8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9)
in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided
p=0·0010). The most common treatment-related adverse events of grade 3 or worse
were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal
hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine
[4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228
patients in the camrelizumab group, and in 32 (15%) of 220 patients in the
chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the
camrelizumab group (three deaths from unknown causes, one enterocolitis, one
hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%)
in the chemotherapy group (two deaths from unknown causes, and one
gastrointestinal haemorrhage).
INTERPRETATION: Second-line camrelizumab significantly improved overall survival
in patients with advanced or metastatic oesophageal squamous cell carcinoma
compared with chemotherapy, with a manageable safety profile. It might represent
a potential option of standard second-line treatment for patients with
oesophageal squamous cell carcinoma in China.
FUNDING: Jiangsu Hengrui Medicine. Immune checkpoint blockade with monoclonal antibodies (mAbs) that target
programmed cell death protein-1 (PD-1) has remarkably revolutionized cancer
therapy. Their binding kinetics measured by surface plasmon resoce does not
always correlate well with their immunotherapeutic efficacies, mainly due to the
lack of two-dimensional cell plasma membrane and the capability of force sensing
and manipulation. In this regard, based on a more suitable and ultra-sensitive
biomechanical otool, biomembrane force probe (BFP), we developed a
Double-edge Smart Feedback control system as an ultra-stable platform to
characterize ultra-long bond lifetimes of receptor-ligand binding on living
cells. We further benchmarked the dissociation kinetics for three clinically
approved PD-1 blockade mAbs (Nivolumab, Pembrolizumab, and Camrelizumab),
intriguingly correlating well with the objective response rates in the
hepatocellular carcinoma second-line treatment. This ultra-stable BFP
potentially provides a compelling kinetic platform to direct the screening,
optimization, and clinical selection of therapeutic antibodies in the future. WHAT IS KNOWN AND OBJECTIVE: Pulmonary sarcomatoid carcinoma (PSC) is
characterized by dismal prognosis and resistance to platinum-based chemotherapy.
The immune checkpoint inhibitors showed promising efficacy in the treatment of
PSC. Camrelizumab is a programmed cell death protein 1 inhibitor; however,
current evidence of its efficacy in PSC is lacking.
CASE SUMMARY: A 47-year-old female non-smoker presented with central-type masses
in the right upper and lower lobes. PSC (cT4N2M0, stage IIIB) with positive
expression of programmed death ligand-1 was diagnosed. First-line camrelizumab
plus doxorubicin and cisplatin was introduced, followed by camrelizumab
monotherapy due to grade 4 leukopenia and thrombocytopenia during the
combination therapy. The lesions indicated a partial remission which endured for
more than 20 months.
WHAT IS NEW AND CONCLUSION: Camrelizumab plus doxorubicin and cisplatin regimen
is a promising option for PSC patients. Further high-quality trials are
warranted. PURPOSE: Camrelizumab is an antibody against programmed death protein 1. We
assessed the activity and safety of camrelizumab plus apatinib, a tyrosine
kinase inhibitor of vascular endothelial growth factor receptor-2, in patients
with advanced cervical cancer.
METHODS: This multicenter, open-label, single-arm, phase II study enrolled
patients with advanced cervical cancer who progressed after at least one line of
systemic therapy. Patients received camrelizumab 200 mg every 2 weeks and
apatinib 250 mg once per day. The primary end point was objective response rate
(ORR) assessed by investigators per RECIST version 1.1. Key secondary end points
were progression-free survival (PFS), overall survival (OS), duration of
response, and safety.
RESULTS: Forty-five patients were enrolled and received treatment. Median age
was 51.0 years (range, 33-67 years), and 57.8% of patients had previously
received two or more lines of chemotherapy for recurrent or metastatic disease.
Ten patients (22.2%) had received bevacizumab. Median follow-up was 11.3 months
(range, 1.0-15.5 months). ORR was 55.6% (95% CI, 40.0% to 70.4%), with two
complete and 23 partial responses. Median PFS was 8.8 months (95% CI, 5.6 months
to not estimable). Median duration of response and median OS were not reached.
Treatment-related grade 3 or 4 adverse events (AEs) occurred in 71.1% of
patients, and the most common AEs were hypertension (24.4%), anemia (20.0%), and
fatigue (15.6%). The most common potential immune-related AEs included grade 1-2
hypothyroidism (22.2%) and reactive cutaneous capillary endothelial
proliferation (8.9%).
CONCLUSION: Camrelizumab plus apatinib had promising antitumor activity and
manageable toxicities in patients with advanced cervical cancer. Larger
randomized controlled trials are warranted to validate our findings. PD-1 is a highly glycosylated inhibitory receptor expressed mainly on T cells.
Targeting of PD-1 with monoclonal antibodies (MAbs) to block the interaction
with its ligand PD-L1 has been successful for the treatment of multiple tumors.
However, polymorphisms at N-glycosylation sites of PD-1 exist in the human
population that might affect antibody binding, and dysregulated glycosylation
has been observed in the tumor microenvironment. Here, we demonstrate varied
N-glycan composition in PD-1, and show that the binding affinity of
camrelizumab, a recently approved PD-1-specific MAb, to non-glycosylated PD-1
proteins from E. coli is substantially decreased compared with glycosylated
PD-1. The structure of the camrelizumab/PD-1 complex reveals that camrelizumab
mainly utilizes its heavy chain to bind to PD-1, while the light chain
sterically inhibits the binding of PD-L1 to PD-1. Glycosylation of asparagine 58
(N58) promotes the interaction with camrelizumab, while the efficiency of
camrelizumab to inhibit the binding of PD-L1 is substantially reduced for
glycosylation-deficient PD-1. These results increase our understanding of how
glycosylation affects the activity of PD-1-specific MAbs during immune
checkpoint therapy. Author information:
(1)Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese
PLA General Hospital, Beijing, China. [email protected].
(2)Department of Oncology, The Affiliated Drum Tower Hospital of Nanjing
University Medical School, Nanjing, China.
(3)Radioactive Interventional Department, Hu Cancer Hospital, Changsha,
China.
(4)Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese
PLA General Hospital, Beijing, China.
(5)Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College
of Medicine, Zhejiang University, Hangzhou, China.
(6)Intervention Therapy Department, Zhejiang Cancer Hospital, Hangzhou, China.
(7)Department of Gastrointestinal Medical Oncology, Harbin Medical University
Cancer Hospital, Harbin, China.
(8)Hepatobiliary and Pancreatic Surgery, Sun Yat-Sen University Cancer Center,
Guangzhou, China.
(9)Department of Hepatic & Biliary & Pancreatic Surgery, Hubei Cancer Hospital,
Affiliated Hubei Cancer Hospital of Huazhong University of Science and
Technology, Wuhan, China.
(10)Liver Department, Mengchao Hepatobiliary Hospital of Fujian Medical
University, Fuzhou, China.
(11)Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai,
China.
(12)Oncology, The First Affiliated Hospital of Nanchang University, Nanchang,
China.
(13)Liver Surgery, Hu People's Hospital, Changsha, China.
(14)Hepatobiliary Surgery, He Cancer Hospital, Zhengzhou, China.
(15)Liver Transplantation Center, Department of Liver Surgery, West China
Hospital of Sichuan University, Chengdu, China.
(16)Department of Hepatobiliary Surgery, Guangxi Medical University Affiliated
Tumor Hospital, Nanning, China.
(17)Department of Interventional Radiology, Cancer Center, Guangdong Provincial
People's Hospital, Guangzhou, China.
(18)General Surgery, Liver & Thyroid Surgery, Xiangya Hospital Central South
University, Changsha, China.
(19)Department of Oncology, The First Affiliated Hospital of Anhui Medical
University, Hefei, China.
(20)Medical Oncology, 900 Hospital of the Joint Logistics Support Force, Fuzhou,
China.
(21)Department of Integrated Chinese and Western Medicine, Tianjin Medical
University Cancer Institute and Hospital, Tianjin, China.
(22)Hepatobiliary Surgery, The First Hospital Affiliated to AMU, Chongqing,
China.
(23)Digestive Department, The First Affiliated Hospital of The Fourth Military
Medical University, Xi'an, China.
(24)Infectious Disease, The First Affiliated Hospital of Zhengzhou University,
Zhengzhou, China.
(25)Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an,
China.
(26)Interventional Department, Jiangsu Cancer Hospital, Nanjing, China.
(27)Clinical Research & Development, Jiangsu Hengrui Medicine Co., Ltd,
Shanghai, China.
(#)Contributed equally The current evidence regarding immunotherapy plus targeted therapy in esophageal
neuroendocrine carcinoma (NEC) is lacking. Camrelizumab is a programmed cell
death protein 1 inhibitor. Apatinib is a selective tyrosine kinase inhibitor of
vascular endothelial growth factor receptor-2. A 50-year-old female was
initially diagnosed as primary esophageal NEC. Neoadjuvant chemotherapy and Ivor
Lewis esophagectomy were performed (ypT3N0M0, stage Ⅱ). Twenty months after the
surgery, an isolated mediastinal lymph node recurrence of NEC was recorded. The
specimen revealed a positive expression of vascular endothelial growth factor
and programmed cell death ligand 1. The diseased lymph node was slightly
enlarged after two cycles of first-line paclitaxel liposome and S-1. Second-line
apatinib and S-1 for 2 months also resulted in progressive disease.
Subsequently, third-line camrelizumab plus apatinib was continued for 5 months.
The patient demonstrated a progression-free status for more than 10 months
following the combination therapy. Meanwhile, relevant studies of camrelizumab
in gastric or esophageal cancer were briefly reviewed. Based on the current
evidence, camrelizumab is a promising agent for esophageal cancer. More
prospective trials are warranted before a definite recommendation could be
drawn. 1. Background: Although the programmed death 1 (PD-1)/programmed death-ligand 1
(PD-L1) inhibitors have markedly changed the strategies of cancer treatment,
most patients with advanced non-small cell lung cancer (NSCLC) do not respond to
PD-1/PD-L1 monotherapy. Epigenetic drugs have been hypothesized to possess the
potential to sensitize PD-1/PD-L1 inhibitors. Case Presentation: Three patients
with advanced metastatic NSCLC failed to respond to first-line systemic therapy
and had a low tumor mutation burden, low tumor neoantigen burden, low
microsatellite instability, and HLA loss of heterozygosity according to their
target lesion biopsies, all of which were considered unfavorable factors for
PD-1/PD-L1 blockage. However, all three patients responded to low-dose
decitabine, an epigenetic drug, in combination with camrelizumab (anti-PD-1
antibody), with only controllable adverse events, indicating that low-dose
decitabine can sensitize PD-1/PD-L1 inhibitors. Summary: We report a novel
therapy with low-dose decitabine plus camrelizumab for advanced NSCLC on the
basis of successful treatment of three patients, emphasizing the potential of
epigenetic drugs to regulate PD-1/PD-L1 inhibitors in advanced NSCLC. BACKGROUND: The clinical significance of programmed cell death protein-1
(PD-1)-targeted immunotherapy in Chinese patients is understudied. We thus aimed
to evaluate the safety and efficacy of PD-1 inhibitors with toripalimab,
camrelizumab or sintilimab for Chinese hepatocellular carcinoma (HCC) patients
in a real-life cohort.
METHODS: We analysed hepatitis B virus (HBV)-associated HCC patients treated
with toripalimab, camrelizumab, or sintilimab in a retrospective single-center
cohort from November 2018 to June 2020. Efficacy was evaluated with objective
response rate (ORR), disease control rate (DCR), progression-free survival
(PFS), time to tumor progression (TTP), and overall survival (OS). Safety data
were also recorded.
RESULTS: Seventy patients were finally included in the analysis: 23 were treated
with toripalimab, 33 with camrelizumab, and 14 with sintilimab. The mean
duration of follow-up was 44.7 (95% CI: 39.9-49.6) weeks and the mean cycles of
PD-1 at cutoff were 8.3±8.0 for all patients. The ORR and DCR for the whole
cohort were 30% and 72.9%, respectively. Overall, 25 (35.7%) patients had
radiological disease progression and 10 (14.3%) patients died during follow-up.
Median PFS, median TTP, and median OS had not yet been reached. Most frequent
drug-related adverse events (AEs) were rash (27.1%), hypertension (18.6%),
fatigue (17.1%), diarrhea (17.1%), paresthesia (15.7%), and nausea (15.7%).
CONCLUSIONS: Our findings suggest that (I) PD-1 targeted immunotherapy with
toripalimab, camrelizumab, or sintilimab yielded a promising outcome in Chinese
HBV patients with HCC and that (II) immunotherapy was well tolerated generally
and had manageable side effects. This approach thus warrants further
popularization and application in clinical practice. We report a case of a 68-year-old man diagnosed with pulmonary pleomorphic
carcinoma who showed partial response after a single treatment with camrelizumab
(PD1 monoclonal antibody). The patient's tumor was positive for programmed cell
death ligand 1 (PD-L1) and progressed rapidly after a course of chemotherapy.
Fortunately, the tumors dramatically shrank after one cycle of camrelizumab, an
anti-programmed cell death-1 (PD-1) antibody developed by Chinese Hengrui
Medicine. In conclusion, camrelizumab may be a good treatment option, especially
in tumors that express PD-L1. |
What is a foam cell? | Foam cell, a hallmark of atherosclerosis, is prominently derived from monocyte-differentiated macrophage, and vascular smooth muscle cells (VSMCs) through unlimitedly phagocytizing oxidized low-density lipoprotein (oxLDL). Therefore, the inhibition of monocyte adhesion to endothelium and uptake of oxLDL might be a breakthrough point for retarding atherosclerosis. | BACKGROUND: Atherosclerosis (AS) is a chronic inflammatory disease that
contributes to multiple cardiovascular diseases (CVDs), and foam cell formation
plays important roles in the progression of AS. There is an urgent need to
identify new molecular targets for treating AS, and thereby improve the quality
of life and reduce the ficial burden of individuals with CVD.
METHODS: An in vitro model of AS was generated by treating THP-1 cells and human
aortic vascular smooth muscle cells (HA-VSMCs) with oxidized low-density
lipoproteins (ox-LDLs). HA-VSMC proliferation and foam cell formation were
detected by the MTT assay and Oil Red O staining. C-X-C motif chemokine 12
(CXCL12) expression was suppressed by siRNA. An AS rat model was established by
feeding rats a high-fat diet and vitamin D2 for 3 weeks. Histopathology
examinations were conducted by Hematoxylin and Eosin (H&E) staining and the
levels ionized calcium-binding adapter molecule 1 (IBA1) and α smooth muscle
actin (α-SMA) expression were determined by ELISA assays and
immunohistochemistry.
RESULTS: An in vitro model of AS was established with THP-1 cells. CXCL12
expression in the model THP-1 cells was significantly increased when compared
with its expression in control cells. Suppression of CXCL12 expression reduced
the progression of AS in the cell model. Moreover, CXCL12 promoted AS in the in
vivo rat model.
CONCLUSION: Our results suggest that CXCL12 plays an important role in promoting
the progression of AS. Furthermore, inhibition of CXCL12 might suppress the
development of AS by inhibiting HA-VSMC proliferation and their transformation
to foam cells. Lipid droplet (LD) accumulation, a key feature of foam cells, constitutes an
attractive target for therapeutic intervention in atherosclerosis. However,
despite advances in cellular imaging techniques, current noninvasive and
quantitative methods have limited application in living foam cells. Here, using
optical diffraction tomography (ODT), we performed quantitative morphological
and biophysical analysis of living foam cells in a label-free manner. We
identified LDs in foam cells by verifying the specific refractive index using
correlative imaging comprising ODT integrated with three-dimensional
fluorescence imaging. Through time-lapse monitoring of three-dimensional
dynamics of label-free living foam cells, we precisely and quantitatively
evaluated the therapeutic effects of a odrug (mannose-polyethylene
glycol-glycol chitosan-fluorescein isothiocyanate-lobeglitazone; MMR-Lobe)
designed to affect the targeted delivery of lobeglitazone to foam cells based on
high mannose receptor specificity. Furthermore, by exploiting
machine-learning-based image analysis, we further demonstrated therapeutic
evaluation at the single-cell level. These findings suggest that refractive
index measurement is a promising tool to explore new drugs against LD-related
metabolic diseases. Background and Purpose: Atherosclerosis is an underlying cause of coronary heart
disease. Foam cell, a hallmark of atherosclerosis, is prominently derived from
monocyte-differentiated macrophage, and vascular smooth muscle cells (VSMCs)
through unlimitedly phagocytizing oxidized low-density lipoprotein (oxLDL).
Therefore, the inhibition of monocyte adhesion to endothelium and uptake of
oxLDL might be a breakthrough point for retarding atherosclerosis. Formononetin,
an isoflavone extracted from Astragalus membranaceus, has exhibited multiple
inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and
inflammation in different animal models. However, its effect on atherosclerosis
remains unknown. In this study, we determined if formononetin can inhibit
atherosclerosis and elucidated the underlying molecular mechanisms. Methods:
ApoE deficient mice were treated with formononetin contained in high-fat diet
for 16 weeks. After treatment, mouse aorta, macrophage and serum samples were
collected to determine lesions, immune cell profile, lipid profile and
expression of related molecules. Concurrently, we investigated the effect of
formononetin on monocyte adhesion, foam cell formation, endothelial activation,
and macrophage polarization in vitro and in vivo. Results: Formononetin reduced
en face and aortic root sinus lesions size. Formononetin enhanced lesion
stability by changing the composition of plaque. VSMC- and macrophage-derived
foam cell formation and its accumulation in arterial wall were attenuated by
formononetin, which might be attributed to decreased SRA expression and reduced
monocyte adhesion. Formononetin inhibited atherogenic monocyte adhesion and
inflammation. KLF4 negatively regulated the expression of SRA at transcriptional
and translational level. Conclusions: Our study demonstrate that formononetin
can substantially attenuate the development of atherosclerosis via regulation of
interplay between KLF4 and SRA, which suggests the formononetin might be a novel
therapeutic approach for inhibition of atherosclerosis. Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell
formation) caused by modified low-density lipoprotein (LDL) is the earliest and
most noticeable manifestation of atherosclerosis. The mechanisms of foam cell
formation are not fully understood and can involve altered lipid uptake,
impaired lipid metabolism, or both. Recently, we have identified the top 10
master regulators that were involved in the accumulation of cholesterol in
cultured macrophages induced by the incubation with modified LDL. It was found
that most of the identified master regulators were related to the regulation of
the inflammatory immune response, but not to lipid metabolism. A possible
explanation for this unexpected result is a stimulation of the phagocytic
activity of macrophages by modified LDL particle associates that have a
relatively large size. In the current study, we investigated gene regulation in
macrophages using transcriptome analysis to test the hypothesis that the primary
event occurring upon the interaction of modified LDL and macrophages is the
stimulation of phagocytosis, which subsequently triggers the pro-inflammatory
immune response. We identified genes that were up- or downregulated following
the exposure of cultured cells to modified LDL or latex beads (inert
phagocytosis stimulators). Most of the identified master regulators were
involved in the innate immune response, and some of them were encoding major
pro-inflammatory proteins. The obtained results indicated that pro-inflammatory
response to phagocytosis stimulation precedes the accumulation of intracellular
lipids and possibly contributes to the formation of foam cells. In this way, the
currently recognized hypothesis that the accumulation of lipids triggers the
pro-inflammatory response was not confirmed. Comparative analysis of master
regulators revealed similarities in the genetic regulation of the interaction of
macrophages with naturally occurring LDL and desialylated LDL. Oxidized and
desialylated LDL affected a different spectrum of genes than naturally occurring
LDL. These observations suggest that desialylation is the most important
modification of LDL occurring in vivo. Thus, modified LDL caused the gene
regulation characteristic of the stimulation of phagocytosis. Additionally, the
knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1,
TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked
down these genes in primary macrophages derived from human monocytes. The
addition of atherogenic naturally occurring LDL caused a significant
accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3
and IL15 genes completely prevented cholesterol accumulation in cultured
macrophages. The knock-down of the ANXA1 gene caused a further decrease in
cholesterol content in cultured macrophages. At the same time, knock-down of
F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to
explain in which way the inflammatory response and the accumulation of
cholesterol are related confirming our hypothesis of atherogenesis development
based on the following viewpoints: LDL particles undergo atherogenic
modifications that, in turn, accompanied by the formation of self-associates;
large LDL associates stimulate phagocytosis; as a result of phagocytosis
stimulation, pro-inflammatory molecules are secreted; these molecules cause or
at least contribute to the accumulation of intracellular cholesterol. Therefore,
it became obvious that the primary event in this sequence is not the
accumulation of cholesterol but an inflammatory response. |
What class of drugs frequently has muscle pain and other muscle toxicities such as mysositis and rhabdomyolysis as a side effect? | Muscular complaints are known side-effects of statin therapy, ranging from myalgia to clinically important myositis and rhabdomyolysis. | Drug-induced myopathy and rhabdomyolysis are rare adverse drug reactions (ADR).
They have been seen after the introduction of modern lipid-lowering drugs more
regularly. The first description after medication with clofibrate dates back to
1968. Apparently, all fibrates can induce myopathy. It usually starts after a
few days of medication, or after prolonged use, showing muscle weakness and/or
pain. Concomitantly, the enzyme creatininephosphokinase (CPK) is raised
dramatically. Muscular necrosis can follow leading secondarily to kidney
failure, and eventually to death. For the class of statins, myopathy was more
often seen after their introduction, and it became their most feared adverse
effect, especially in combination of statins with other drugs (mibefradil,
gemfibrozil, cyclosporin). In animal models the evolution of the disease and the
mechanism of action may be elucidated. Though strong epidemiological data are
lacking, the incidence of myopathy is probably similar for all lipid-lowering
drugs and is in the range of 0.1-0.5% with monotherapy, increasing to 0.5-2.5%
with combination therapy. Severe cases of rhabdomyolysis are rarer, but may have
a significant mortality. The market success of cerivastatin within a short
period has led to 100s of myopathies and some dozens of deaths. Though
interactions on metabolism and ensuing high plasma levels can partially explain
myopathy as intoxication, there are strong indications that other (endocrine,
metabolic, genetic) factors might play a role in the pathophysiology. The
patient population at risk should better be defined and withheld from
myopathy-inducing drugs. CONTEXT: Elevated total cholesterol (total-C) and low-density lipoprotein
cholesterol (LDL-C) levels are established risk factors for cardiovascular
disease (CVD). HMG-CoA reductase inhibitors (statins) are effective
cholesterol-lowering drugs that are commonly prescribed to treat this condition.
These drugs are often combined with another class of drugs, fibric acid
derivatives, to lower both cholesterol and triglyceride levels. Rhabdomyolysis
is a known, rare serious side effect of statin monotherapy and of statin-fibrate
combination therapy.
OBJECTIVE: To examine Food and Drug Administration's (FDA's) postmarketing
database for cases of rhabdomyolysis in relation to monotherapy and combination
use and calculate reporting rates for this event.
DESIGN: Domestic cases of statin- and statin/gemfibrozil-associated
rhabdomyolysis were culled from FDA's database and reviewed. Rhabdomyolysis was
defined by CPK > or = 10,000 IU/L, myopathic signs and symptoms and clinical
diagnosis of rhabdomyolysis. Reporting rates, consisting of number of reported
cases/number of prescriptions for each drug, were then calculated to determine
whether the reporting of rhabdomyolysis cases was commensurate with extent of
use of each statin in the population.
SETTING: Cases were obtained from the FDA adverse event reporting system (AERS)
database.
PATIENTS: NA.
MAIN OUTCOME MEASURES: Number of rhabdomyolysis cases were evaluated, along with
outcomes, such as renal failure, dialysis and death.
RESULTS: Of 866 total reported cases, 482 (56%) were associated with monotherapy
and 384 (44%) related to combination therapy. More than 80% of reported cases
for each drug resulted in hospitalization for renal failure and dialysis. 80
patients expired from events related directly to rhabdomyolysis. Reporting rates
for all statins, except for cerivastatin, were similar and much lower than 1 per
100,000 prescriptions. The cerivastatin-reporting rate was much higher at
4.24/100,000 prescriptions.
CONCLUSIONS: Rhabdomyolysis is a rare, serious side effect of statin monotherapy
and of statin-fibrate combination therapy. Clinicians need to remain cognizant
of this potential adverse event and discuss signs and symptoms of muscle
toxicity with patients in order improve the benefits-to-risks of treating
dyslipidemia with statins. Muscular side effects of various anesthetics, analgetics, antibiotics,
antihistaminic drugs, antiretrovirals, cardiotropics, immunosuppressants,
lipid-lowering drugs, psychotropic drugs, anticancer drugs, and other substances
are more frequent than assumed and are easily overlooked. Clinically, muscular
side effects manifest as fatigue, myalgias, persistent or transient weakness,
stiffness, intolerance to exercise, psychomotor slowing, muscle cramps, wasting,
dyspnea, dysphagia, fasciculations, reduced tendon reflexes, impaired
consciousness, myoglobinuria, renal failure, or hyperthermia. Diagnosis of these
drug-induced myopathies is based on history, clinical neurologic examination,
blood work, urine analysis, repetitive stimulation, electromyography, and muscle
biopsy. A drug which induces muscular side effects should never be given again.
Particularly in patients suffering from primary myopathy, myotoxic drugs should
be applied with caution. The drugs which most frequently induce muscular side
effects are steroids, statins, fibrates, antiretrovirals, immunosuppressants,
colchicine, amiodarone, and anticancer drugs. Many drugs exhibit their myotoxic
potential only in combination with other drugs or premorbid pathologic myogenic
conditions. Statin use is associated with a variety of overtly related muscle symptoms
including muscle pain, myalgia, creatine kinase elevations without pain with
myolysis and myositis (rhabdomyolysis), a potentially fatal side effect that led
to the withdrawal of cerivastatin in 2001. Unintended drug response phenotypes
have an impact on patient compliance and sometimes patient health and the
assessment of risk on an individual basis could enhance therapeutic benefit. We
therefore investigated whether common single nucleotide polymorphisms were
associated with the expression of broadly grouped atorvastatin-induced muscle
events in a case-control study (n=263 samples, n=388 SNPs). Of a number of
associations identified in a discovery sample (51 atorvastatin-induced muscle
and 55 normal) only those corresponding to the CYP2D6*4 allele were
significantly associated in the sample (24 atorvastatin-induced muscle and 133
normal) (Discovery P=0.004, odds ratio=3.6; Validation P=0.036, odds ratio=2.7;
total P=0.001, odds ratio=2.5). The frequency of the CYP2D6*4 allele was about
50% in atorvastatin-induced muscle patients but only 28% in controls, similar to
that of other patient types (28.5%). The association was independent of various
demographic variables and not explained by gross demographic, clinical or
population-structure differences among cases and controls. Surprisingly, the
CYP2D6*4 allele appeared similarly distributed among controls and patients
expressing simvastatin-induced muscle events (n=169, frequency in case
participants=49.2%, P=0.067, odds ratio=1.7). Our results suggest that the
CYP2D6*4 allele is associated with broadly related muscle events caused by at
least two structurally dissimilar HMG-CoA reductase inhibitors, and as such, may
have implications for a better understanding of this statin-wide phenomena. RATIONALE: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or
statins, are important drugs used in the treatment and prevention of
cardiovascular disease. Although statins are well tolerated, many patients
develop myopathy manifesting as muscle aches and pain. Rhabdomyolysis is a rare
but severe toxicity of statins. Interindividual differences in the activities of
hepatic membrane drug transporters and metabolic enzymes are known to influence
statin plasma pharmacokinetics and risk for myopathy. Interestingly, little is
known regarding the molecular determits of statin distribution into skeletal
muscle and its relevance to toxicity.
OBJECTIVE: We sought to identify statin transporters in human skeletal muscle
and determine their impact on statin toxicity in vitro.
METHODS AND RESULTS: We demonstrate that the uptake transporter OATP2B1 (human
organic anion transporting polypeptide 2B1) and the efflux transporters,
multidrug resistance-associated protein (MRP)1, MRP4, and MRP5 are expressed on
the sarcolemmal membrane of human skeletal muscle fibers and that atorvastatin
and rosuvastatin are substrates of these transporters when assessed using a
heterologous expression system. In an in vitro model of differentiated, primary
human skeletal muscle myoblast cells, we demonstrate basal membrane expression
and drug efflux activity of MRP1, which contributes to reducing intracellular
statin accumulation. Furthermore, we show that expression of human OATP2B1 in
human skeletal muscle myoblast cells by adenoviral vectors increases
intracellular accumulation and toxicity of statins and such effects were
abrogated when cells overexpressed MRP1.
CONCLUSIONS: These results identify key membrane transporters as modulators of
skeletal muscle statin exposure and toxicity. Les hypolipidémiants, tels que les statines, sont utilisés couramment pour
traiter environ 10 millions de Canadiens touchés par l’hypercholestérolémie.
L’effet secondaire des statines ressenti le plus souvent est la douleur
musculaire. La myopathie provoquée par les statines consiste en un spectre de
désordres myopathiques allant de la myalgie légère à la rhabdomyolyse mortelle.
Voici une présentation de 2 cas de myopathie provoquée par les statines chez des
patients d’un contexte chiropratique. En outre, la discussion portera sur le
mécanisme, les facteurs de risque prédisposants, et la fréquence de la myopathie
provoquée par les statines, tout en souligt le rôle que peuvent jouer les
chiropraticiens et autres thérapeutes manuels dans la reconnaissance et la
gestion de celle-ci. BACKGROUND: Muscular complaints are known side-effects of statin therapy,
ranging from myalgia to clinically important myositis and rhabdomyolysis. We
investigated the statin use and association with the presence and
characteristics of muscular complaints.
METHODS: We conducted a prospective observational study in internal medicine
departments. Patients with statin therapy before hospitalization were
interviewed for muscular complaints. When muscular complaints were reported,
information on type and severity of muscular symptoms, location and time to
onset was collected.
RESULTS: We identified 85 patients with statin treatment at hospital admission
out of 521 included. Nine (10.59%) patients reported muscular complaints
associated with statin therapy. A cluster of symptoms (cramps, stiffness,
decreased muscle power) was reported, affecting both upper and lower limbs. The
severity of pain was in most of the cases moderate or severe. All patients
reported that pain was intermittent. Five reported that pain was generalized.
Symptoms appeared in the first month of treatment or three months after the drug
initiation. Creatine kinase was raised in one patient. In two cases drug
interactions were probably responsible for muscular complaints.
CONCLUSION: In the studied set of patients muscular symptoms were a rather
frequent effect of statin therapy. As this side-effect could be troublesome for
patients and could lead to more severe outcomes, their timely detection and
management is important. BACKGROUND: 3-hydroxy-3-methylglutaryl coenzyme A reductase reductase inhibitors
(statins) are generally well tolerated, with statin-associated muscle symptoms
(SAMS) the most common side effect (~10%) seen in statin users. However, studies
and clinical observations indicate that many of the self-reported SAMS appear to
be nonspecific (ie, potentially not attributable to statins).
OBJECTIVE: Mental health and well-being influence self-perception of pain, so we
sought to assess the effect of baseline well-being and depression on the
development of muscle pain with 6 months of atorvastatin 80 mg/d (ATORVA) or
placebo in healthy, statin-naive adults.
METHODS: The Psychological General Well-being Index (n = 83) and Beck Depression
Inventory (n = 55) questionnaires were administered at baseline in participants
(aged 59.5 ± 1.2 years) from the effect of Statins on Skeletal Muscle Function
and Performance (STOMP) trial (NCT00609063). Muscle pain (Short-Form McGill Pain
Questionnaire [SF-MPQ]), pain that interferes with daily life (Brief Pain
Inventory [BPI]), and pain severity (BPI) were then measured before, throughout,
and after treatment.
RESULTS: At baseline, there were no differences in well-being (Psychological
General Well-being Index), depression (Beck Depression Inventory), or pain
measures (SF-MPQ and BPI) (P values ≥ .05) between the placebo and ATORVA
groups. Baseline well-being correlated negatively with baseline BPI pain
severity (r = -0.290, P = .008). Baseline depression correlated with baseline
pain (SF-MPQ; r = 0.314, P = .020). Baseline well-being and depression did not
predict the change in pain severity or interference after 6 months among the
total sample or between groups (P values ≥ .05).
CONCLUSION: Baseline well-being and depression were not significant predictors
of pain after 6 months of ATORVA (P values ≥ .05). Thus, they do not appear to
increase the risk of SAMS in otherwise healthy adults. Statins are the primary class of medication used to lower serum cholesterol
concentration for both primary and secondary prevention of cardiovascular
disease. Muscle pain is a frequent adverse effect of statins. Severe myonecrosis
leading to clinical rhabdomyolysis is rare. We encountered a 63-year-old
male with a medical history of hypertension, type 2 diabetes mellitus,
and coronary artery disease with angioplasty in 2008 and 2020. He was started on
rosuvastatin 40 mg (0-0-1) along with dual anti-platelets post angioplasty and
was discharged home. He traveled back to his hometown and noticed progressive
symmetric muscle weakness with decreased urine output. After visiting another
hospital he presented to us with severe proximal muscle weakness and acute renal
failure. Laboratory investigations were initiated which demonstrated
clinically significant derangement in serum creatinine phosphokinase,
serum creatinine, urine myoglobin along with deranged liver enzymes. He was
subjected to nerve conduction studies for his muscle weakness which was normal
and electromyography showed abnormal spontaneous muscle activity in all examined
muscles (fibrillations, positive sharp waves, and pseudomyotonic
discharges) suggestive of an irritable myopathy. The medication was stopped and
he was treated with eight cycles of hemodialysis until his muscle weakness and
laboratory parameters improved. He was then discharged with some improvement in
muscle weakness. On two week follow-up, the patient showed partial improvement
after discontinuation of all lipid-lowering medication. |
Which cytokine molecule activates SMADs? | SMADs are activated by Transforming growth factor beta (TGF beta) | Interleukin-6 (IL-6) is a pro-inflammatory cytokine that plays an important role
in the pathogenesis of inflammatory bowel disease. TGF-beta, a multifunctional
cytokine, is a potent negative regulator of mucosal inflammation in the
intestine. The aim of the present study is to determine possible cross-talk
between IL-6 and TGF-beta signaling pathways. Model intestinal epithelial cell
lines, Caco2-BBE were used. We show that TGF-beta receptor Type II is
predomitly present in the basolateral membrane of intestinal epithelial
cells. TGF-beta1 induces a time-dependent phosphorylation of Smad2 and
co-immunoprecipitation of SMAD-2 with Smad-4 and its subsequently translocation
to the nucleus. We show that pretreatment of cells with TGF-beta1 is associated
with a down-regulation of IL-6 induced tyrosine phosphorylation of STAT1 and
STAT3 and suppression of ICAM-1 expression. Furthermore, TGF-beta1 pretreatment
resulted in a significant inhibition of IL-6 induced ICAM-1 promoter activity.
TGF-beta mediated inhibition of IL-6 induced ICAM-1 expression was reversed by
transfection with domit negative Smad2 constructs. In conclusion, we show
that: 1) TGF-beta receptor Type II is predomitly located on basolateral
membrane and receptor stimulation activates Smad pathway; 2) TGF-beta1
down-regulates IL-6-induced tyrosine phoshorylation of STAT1 and STAT3 and
ICAM-1 expression; and 3) Smad2 is required for the down-regulation of IL-6
signaling by TGF-beta. Collectively, our data demonstrate a cross-talk between
TGF-beta and IL-6, and TGF-beta may play a role in the negative regulation of
IL-6 signaling in intestinal epithelial cells. Since pronounced differences exist between the fetal and adult repair processes,
we studied the proliferative response of skin fibroblasts from these two stages
to transforming growth factor-beta (TGF-beta), a cytokine with a broad range of
activities in tissue repair. Here, we present evidence that TGF-beta inhibits
fetal human skin fibroblasts, while it is stimulatory for adult ones. This
proliferative effect of TGF-beta was found to be concentration- dependent, but
isoform-independent. Furthermore, even a transient exposure of the cells to this
growth factor was sufficient to exert its stimulatory or inhibitory action.
Accordingly, we have studied the immediate responses provoked by TGF-beta in
major signaling pathways, and we have found that it induces a rapid activation
of the SMAD pathway, i.e., phosphorylation and nuclear translocation of SMAD2,
followed by dephosphorylation, most probably due to degradation by the
proteasome. However, similar intensity and kinetics of this activation have been
observed in both fetal and adult fibroblasts. On the other hand, curcumin, a
natural product with wound healing properties that inhibits several
intracellular signaling pathways, was found to completely abrogate the
inhibitory effect of TGF-beta1 on human fetal skin fibroblasts, without
affecting the stimulatory action on fibroblasts from adult donors. In
conclusion, there is a major radical in the proliferative response of fetal and
adult human skin fibroblasts to TGF-beta, possibly reflecting the different
repair strategies followed in these two stages of development. The hepatic stellate cell (HSC) is the predomit cell type responsible for
excess collagen deposition during liver fibrosis. Both transforming growth
factor-beta (TGF-beta), the most potent fibrogenic cytokine for HSCs, which
classically activates Smad signaling, and p38 MAPK signaling have been shown to
influence collagen gene expression; however, the relative contribution and
mechanisms that these two signaling pathways have in regulating collagen gene
expression have not been investigated. The aim of this study was to investigate
the relative roles and mechanisms of both Smad and p38 MAPK signaling in
alpha1(I) collagen gene expression in HSCs. Inhibiting either p38 MAPK or Smad
signaling reduced alpha1(I) collagen mRNA expression in untreated or
TGF-beta-treated HSCs, and when both signaling pathways were simultaneously
inhibited, alpha1(I) collagen gene expression was essentially blocked. Both
signaling pathways were found to independently and additively increase alpha1(I)
collagen gene expression by transcriptional mechanisms. TGF-beta treatment
increased alpha1(I) collagen mRNA half-life, mediated by increased stability of
alpha1(I) collagen mRNA through p38 MAPK signaling but not through Smad
signaling. In conclusion, both p38 MAPK and Smad signaling independently and
additively regulate alpha1(I) collagen gene expression by transcriptional
activation, whereas p38 MAPK and not Smad signaling increased alpha1(I) collagen
mRNA stability. Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, has been
widely suggested to play a role in the pathogenesis of Alzheimer's disease.
Supporting this, levels of TGF-beta are elevated in the cerebrospinal fluid,
sera, and brain of patients with Alzheimer's disease. Since TGF-beta is
neuroprotective, whereas Alzheimer's disease is typified by neurodegeneration,
we speculated that defects in TGF-beta signaling might abrogate its
neuroprotective properties. Consistently with an increase in TGF-beta in
Alzheimer's disease, we found significant increases in phospho-Smad2, a major
downstream signaling molecule of TGF-beta, in hippocampal neurons of Alzheimer's
disease compared with age-matched control patients. However, in contrast to an
expected nuclear localization, phosphorylated Smad2 in Alzheimer's disease was
predomitly, and ectopically, found in the neuronal cytoplasm, specifically
colocalized with neurofibrillary tangles and granulovacuolar degeneration. Given
that a nuclear localization is required to regulate the transcription of
TGF-beta target genes to afford neuroprotection, the ectopic localization of
phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of
TGF-beta in Alzheimer's disease and consequent loss of neuroprotective function. TGF-beta (Transforming Growth Factor-beta) cytokines employ Smad proteins as the
intracellular mediator of signaling. Upon TGF-beta stimulation, the cytoplasmic
Smads become phosphorylated and consequently accumulate in the nucleus to
regulate target gene expression. The cytoplasm-to-nucleus redistribution of
Smads, as well as the ability of Smads to activate or repress gene
transcription, is under multiple layers of regulation by factors not limited to
TGF-beta. With recent advance in the knowledge of regulatory factors impinged on
Smads, we are beginning to understand the complexity in cellular responses to
TGF-beta. Liver fibrosis is a progressive pathologic process that involves deposition of
excess extracellular matrix leading to distorted architecture and culminating in
cirrhosis. The role of transforming growth factor-beta (TGF-beta) as a key
molecule in the development and progression of hepatic fibrosis via the
activation of hepatic stellate cells, among other fibroblast populations, is
without controversy. We hereby show that TGF-beta1 induces an
epithelial-to-mesenchymal transition (EMT) state in mature hepatocytes in vitro.
EMT state was marked by significant upregulation of alpha(1)(I) collagen mRNA
expression and type I collagen deposition. Similar changes were found in a
"normal" mouse hepatocyte cell line (AML12), thus confirming that hepatocytes
are capable of EMT changes and type I collagen synthesis. We also show that in
hepatocytes in the EMT state, TGF-beta1 induces the snail-1 transcription factor
and activates the Smad2/3 pathway. Evidence for a central role of the
TGF-beta1/Smad pathway is further supported by the inhibition of EMT by Smad4
silencing using small interference RNA technology. In conclusion, TGF-beta1, a
known pro-apoptotic cytokine in mature hepatocytes, is capable of mediating
phenotypic changes and plasticity in the form of EMT, resulting in collagen
deposition. Our findings support a potentially crucial role for EMT in the
development and progression of hepatic fibrogenesis. Transforming growth factor beta (TGFbeta) controls cellular behavior in
embryonic and adult tissues. TGFbeta binding to serine/threonine kinase
receptors on the plasma membrane activates Smad molecules and additional
signaling proteins that together regulate gene expression. In this review,
mechanisms and models that aim at explaining the coordination between several
components of the signaling network downstream of TGFbeta are presented. We
discuss how the activity and duration of TGFbeta receptor/Smad signaling can be
regulated by post-translational modifications that affect the stability of key
proteins in the pathway. We highlight links between these mechanisms and human
diseases, such as tissue fibrosis and cancer. Transforming growth factor (TGF)-beta is a pleiotropic cytokine regulating a
variety of cellular processes such as cell growth, differentiation, apoptosis,
migration, cell adhesion, and immune response. In the well-understood classical
TGF-beta signaling pathway, TGF-beta activates Smad signalling via its two cell
surface receptors such as TbetaRII and ALK5/TbetaRI, leading to Smad-mediated
transcriptional regulation. In addition, TGF-beta may also activate other
signaling pathways like mitogen-activated protein kinase, PI3K, etc. The
signaling of TGF-beta is finely regulated at different levels. Inhibitory Smads,
including Smad6 and Smad7, are key regulators of TGF-beta/bone morphogenetic
protein (BMP) signaling by negative feedback loops. They can form stable
complexes with activated type I receptors and thereby blocking the
phosphorylation of R-Smads, or recruit ubiquitin E3 ligases, such as Smurf1/2,
resulting in the ubiquitination and degradation of the activated type I
receptors. Besides, these inhibitory Smad proteins also inhibit TGF-beta/BMP
signaling in the nucleus by interacting with transcriptional repressors, such as
histone deacetylases, Hoxc-8, and CtBP, or disrupting the formation of the
TGF-beta-induced functional Smad-DNA complexes. Smad7 is in turn regulated by
different stimuli, including TGF-beta, IFN-gamma, TNF-alpha as well as
ultraviolet and TPA, and mediates the crosstalk between TGF-beta and other
signaling pathways. Deregulation of Smad7 expression has been associated with
various human diseases, such as tissue fibrosis, inflammatory disease as well as
carcinogenesis. Overexpression of Smad7 has been shown to antagonize
TGF-beta-mediated fibrosis, carcinogenesis, and inflammation, suggesting a
therapeutic potential of Smad7 to treat these diseases. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that
induces growth arrest, tissue fibrosis, and epithelial-mesenchymal transition
(EMT) through activation of Smad and non-Smad signaling pathways. EMT is the
differentiation switch by which polarized epithelial cells differentiate into
contractile and motile mesenchymal cells. Cell motility and invasive capacity
are activated upon EMT. Multiple transcription factors, including deltaEF1/ZEB1,
SIP1/ZEB2, and Snail/SNAI1, are induced by TGF-beta-Smad signaling and play
critical roles in TGF-beta-induced EMT. In addition, both non-Smad signaling
activated by TGF-beta and cross-talk with other signaling pathways play
important roles in induction of EMT. Of these, Ras signaling synergizes with
TGF-beta-Smad signaling, and plays an important role in the induction of EMT.
TGF-beta inhibitors prevent invasion and metastasis of advanced cancer through
multiple mechanisms, including inhibition of EMT. The discovery of molecules
that inhibit TGF-beta-induced EMT but not TGF-beta-induced growth arrest may be
an ideal strategy for treatment of invasion and metastasis of cancer. Chronic inflammation plays an important role in the initiation and progression
of various human diseases including benign prostatic hyperplasia or prostate
cancer. Here we show that the proinflammatory cytokine interleukin-6 (IL-6) has
prosurvival effects and chronically activates the Jak2/STAT3 signalling pathway
in a model of benign prostatic hyperplasia (BPH-1). We demonstrate that the
antiinflammatory cytokine transforming growth factor-beta1 (TGF-beta1), which
also permanently activates its canonical signalling pathway through SMAD
proteins in BPH-1 cells, modifies the effects of IL-6 on cell proliferation.
Importantly, TGF-beta1 inhibits IL-6 signal transduction by decreasing the
phosphorylation levels of STAT3. This effect is associated with decreased
expression of Jak2 at both mRNA and protein levels. Moreover, we showed that
TGF-beta1 inhibits IL-6-induced expression of the cancer-associated gene MUC1.
These observations demonstrated a novel interaction between TGF-beta1 and IL-6
signalling and suggested another mechanism of how defects in TGF-beta
signalling, frequently associated with prostate pathologies, can contribute to
the disruption of tissue homeostasis. TGFβ is the quintessential cytokine of T cell homeostasis. TGFβ signaling is
required for the efficient differentiation and maintece of CD4(+)FOXP3(+) T
cells that inhibit immune responses. Conversely, in conjunction with the
inflammatory cytokine IL-6, TGFβ promotes Th17 cell differentiation. The
mechanism by which TGFβ signals synergize with IL-6 to generate inflammatory
versus immunosuppressive T cell subsets is unclear. TGFβ signaling activates
receptor SMADs, SMAD2 and SMAD3, which associate with a variety of nuclear
factors to regulate gene transcription. Defining relative contributions of
distinct SMAD molecules for CD4 T cell differentiation is critical for mapping
the versatile intracellular TGFβ-signaling pathways that tailor TGFβ activities
to the state of host interaction with pathogens. We show here that SMAD2 is
essential for Th17 cell differentiation and that it acts in part by modulating
the expression of IL-6R on T cells. Although mice lacking SMAD2 specifically in
T cells do not develop spontaneous lymphoproliferative autoimmunity,
Smad2-deficient T cells are impaired in their response to TGFβ in vitro and in
vivo, and they are more pathogenic than controls when transferred into
lymphopenic mice. These results demonstrate that SMAD2 is uniquely essential for
TGFβ signaling in CD4(+) T effector cell differentiation. Aberrant activation of receptor tyrosine kinases (RTK) is causally linked to the
pathobiological traits of glioblastoma and genesis of glioma stem-like cells
(GSC), but the underlying mechanism is still unknown. Here, we show that
epidermal growth factor receptor (EGFR) signaling regulates the proliferation,
angiogenesis, and acquisition of GSC characteristics by inducing inhibitor of
differentiation 3 (ID3) and ID3-regulated cytokines [GRO1 and interleukins
(IL)-6 and 8] induction. We found that EGFR-mediated ID3 expression was
regulated by Smad5, which was directly phosphorylated by AKT. Furthermore, ID3
alone imparted GSC features to primary astrocytes derived from
Ink4a/Arf-deficient mouse, and EGFR-ID3-IL-6 signaling axis gave rise to tumor
cell heterogeneity. Conversely, EGFR inhibitors suppressed EGFR-AKT-Smad5-driven
induction of ID3, which led to a decrease in the tumorsphere forming ability of
GSCs and U87MG cells that possess an active mutant EGFR, EGFRvIII, without
obvious cytotoxic effects. However, these cells seemed to regain colonogenic
ability after removal of the EGFR inhibitors. Together, the results delineate a
novel integrative molecular mechanism in which the RTK-ID signaling pathway
governs genesis and maintece of GBM histopathologic features, such as
GSCs-based tumor initiation, progression, and angiogenesis. A balanced immune response requires combating infectious assaults while striving
to maintain quiescence towards the self. One of the central players in this
process is the pleiotropic cytokine transforming growth factor-β (TGF-β), whose
deficiency results in spontaneous systemic autoimmunity in mice. The domit
function of TGF-β is to regulate the peripheral immune homeostasis, particularly
in the microbe-rich and antigen-rich environment of the gut. To maintain
intestinal integrity, the epithelial cells, myeloid cells and lymphocytes that
inhabit the gut secrete TGF-β, which acts in both paracrine and autocrine
fashions to activate its signal transducers, the SMAD transcription factors. The
SMAD pathway regulates the production of IgA by B cells, maintains the
protective mucosal barrier and promotes the balanced differentiation of CD4(+) T
cells into inflammatory T helper type 17 cells and suppressive FOXP3(+) T
regulatory cells. While encounters with pathogenic microbes activate SMAD
proteins to evoke a protective inflammatory immune response, SMAD activation and
synergism with immunoregulatory factors such as the vitamin A metabolite
retinoic acid enforce immunosuppression toward commensal microbes and innocuous
food antigens. Such complementary context-dependent functions of TGF-β are
achieved by the co-operation of SMAD proteins with distinct domit
transcription activators and accessory chromatin modifiers. This review
highlights recent advances in unravelling the molecular basis for the
multi-faceted functions of TGF-β in the gut that are dictacted by fluid
orchestrations of SMADs and their myriad partners. Transforming growth factor-β (TGF-β) is an anti-inflammatory cytokine and is
expressed in the injured spinal cord. TGF-β signals through receptors to
activate Smad proteins, which translocate into the nucleus. In the present
study, we investigated the chronological alterations and cellular locations of
the TGF-β/Smad signaling pathway following spinal cord injury (SCI) in mice.
ELISA analysis showed that the concentration of interleukin-6 (IL-6) in injured
spinal cords significantly increases immediately after SCI, while the
concentration of TGF-β gradually increased after SCI, peaked at 2 days, and then
gradually decreased. Immunohistochemical studies revealed that Smad3 was mainly
expressed in neurons of the spinal cord. Phosphorylated Smad3 at the C-terminus
(p-Smad3C) was stained within the motor neurons in the anterior horn, while
phosphorylated Smad3 at the linker regions (p-Smad3L) was expressed in
astrocytes within gray matter. These findings suggest that SCI induces gradual
increases in TGF-β and induces different activation of p-Smad3C and p-Smad3L.
Phosphorylated Smad3C might be involved in neuronal degeneration after SCI, and
p-Smad3L may play a role in glial scar formation by astrocytes. Nectin-like molecule-2 (Necl-2), a junction molecule, is exclusively expressed
by spermatogenic cells. It mediates homophilic interaction between germ cells
and heterophilic interaction between Sertoli and germ cells. Knockout studies
have shown that loss of Necl-2 causes male infertility, suggesting Necl-2-based
cell adhesion is crucial for spermatogenesis. Transforming growth factor-βs
(TGF-βs) are crucial for regulating cell junction restructuring that are
required for spermatogenesis. In the present study, we aim to investigate the
mechanism on how TGF-β1 regulates Necl-2 expression to achieve timely junction
restructuring in the seminiferous epithelium during spermatogenesis. We have
demonstrated that TGF-β1 reduces Necl-2 mRNA and protein levels at both
transcriptional and post-translational levels. Using inhibitor and clathrin
shRNA, we have revealed that TGF-β1 induces Necl-2 protein degradation via
clathrin-dependent endocytosis. Endocytosis assays further confirmed that TGF-β1
accelerates the internalization of Necl-2 protein to cytosol. Immunofluorescence
staining also revealed that TGF-β1 effectively removes Necl-2 from cell-cell
interface. In addition, TGF-β1 reduces Necl-2 mRNA via down-regulating Necl-2
promoter activity. Mutational studies coupled with knockdown experiments have
shown that TGF-β1-induced Necl-2 repression requires activation of Smad
proteins. EMSA and ChIP assays further confirmed that TGF-β1 promotes the
binding of Smad proteins onto MyoD and CCAATa motifs in vitro and in vivo. Taken
together, TGF-β1 is a potent cytokine that provides an effective mechanism in
controlling Necl-2 expression in the testis via Smad-dependent gene repression
and clathrin-mediated endocytosis. Inflammatory immune responses play an important role in mucosal homeostasis and
gut diseases. Nuclear factor κB (NF-κB), central to the proinflammatory cascade,
is activated in necrotizing enterocolitis (NEC), a devastating condition of
intestinal injury with extensive inflammation in premature infants. TGF-β is a
strong immune suppressor and a factor in breast milk, which has been shown to be
protective against NEC. In an NEC animal model, oral administration of the
isoform TGF-β1 activated the downstream effector Smad2 in intestine and
significantly reduced NEC incidence. In addition, TGF-β1 suppressed NF-κB
activation, maintained levels of the NF-κB inhibitor IκBα in the intestinal
epithelium, and systemically decreased serum levels of IL-6 and IFN-γ. The
immature human fetal intestinal epithelial cell line H4 was used as a
reductionistic model of the immature enterocyte to investigate mechanism. TGF-β1
pretreatment inhibited the TNF-α-induced IκBα phosphorylation that targets the
IκBα protein for degradation and inhibited NF-κB activation. Chromatin
immunoprecipitation (ChIP) assays demonstrated decreased NF-κB binding to the
promoters of IL-6, IL-8, and IκBα in response to TNF-α with TGF-β1 pretreatment.
These TGF-β1 effects appear to be mediated through the canonical Smad pathway as
silencing of the TGF-β central mediator Smad4 resulted in loss of the TGF-β1
effects. Thus, TGF-β1 is capable of eliciting anti-inflammatory effects by
inhibiting NF-κB specifically in the intestinal epithelium as well as by
decreasing systemic IL-6 and IFN-γ levels. Oral administration of TGF-β1
therefore can potentially be used to protect against gastrointestinal diseases. Transforming growth factor-β (TGF-β) is an immunosuppressive cytokine that
inhibits the proinflammatory functions of T cells, and it is a major factor in
abrogating T cell activity against tumors. Canonical TGF-β signaling results in
the activation of Smad proteins, which are transcription factors that regulate
target gene expression. We found that the cell surface molecule platelet
endothelial cell adhesion molecule-1 (PECAM-1) facilitated noncanonical
(Smad-independent) TGF-β signaling in T cells. Subcutaneously injected tumor
cells that are dependent on TGF-β-mediated suppression of immunity for growth
grew more slowly in PECAM-1(-/-) mice than in their wild-type counterparts. T
cells isolated from PECAM-1(-/-) mice demonstrated relative insensitivity to the
TGF-β-dependent inhibition of interferon-γ (IFN-γ) production, granzyme B
synthesis, and cellular proliferation. Similarly, human T cells lacking PECAM-1
demonstrated decreased sensitivity to TGF-β in a manner that was partially
restored by reexpression of PECAM-1. Co-incubation of T cells with TGF-β and a T
cell-activating antibody resulted in PECAM-1 phosphorylation on an
immunoreceptor tyrosine-based inhibitory motif (ITIM) and the recruitment of the
inhibitory Src homology 2 (SH2) domain-containing tyrosine phosphatase-2
(SHP-2). Such conditions also induced the colocalization of PECAM-1 with the
TGF-β receptor complex as identified by coimmunoprecipitation, confocal
microscopy, and proximity ligation assays. These studies indicate a role for
PECAM-1 in enhancing the inhibitory functions of TGF-β in T cells and suggest
that therapeutic targeting of the PECAM-1-TGF-β inhibitory axis represents a
means to overcome TGF-β-dependent immunosuppression within the tumor
microenvironment. The stimuli inducing expression of single immunoglobulin IL-1-related receptor
(SIGIRR) and the relevant regulatory mechanisms are not well defined.
Transforming growth factor β1 (TGFβ1) delays internalization of neurokinin-1
receptor (NK1R) and subsequently enhances cellular signaling. This study
investigated the effect of TGFβ1 on SIGIRR protein production by human M1
macrophages in response to stimulation with substance P (SP). SP caused
upregulation of SIGIRR expression in a concentration-dependent manner, whereas
aprepitant (an NK1R inhibitor) blunted this response. Silencing p38γMAPK or
TAK-1 partially attenuated the response to SP stimulation, while TGFβ1/2/3 siRNA
dramatically diminished it. SP induced much greater SIGIRR protein production
than either lipopolysaccharide (a TLR4 agonist) or resiquimod (a TLR7/8
agonist). Unexpectedly, silencing of transcription factor specificity protein 1
(Sp1) led to significant upregulation of SIGIRR expression after SP stimulation,
while KLF2 siRNA only partially enhanced it and Fli-1 siRNA reduced it. SP also
upregulated TGFβ1 expression, along with a corresponding increase of SIGIRR
protein, whereas silencing TGFβ1/2/3 blunted these responses. Sp1 siRNA or
mithramycin (a gene-selective Sp1 inhibitor) significantly enhanced the
expression of TGFβ1 and SIGIRR by macrophages after SP stimulation. Importantly,
this effect of Sp1 siRNA on TGFβ1 and SIGIRR was blunted by siRNA for Smad2,
Smad3, or Smad4, but not by TAK-1 siRNA. Next, we investigated the influence of
transcription factor cross-talk on SIGIRR expression in response to SP.
Co-transfection of macrophages with Sp1 siRNA and C/EBPβ or TIF1β siRNA
attenuated the upregulation of SIGIRR by SP, while a combination of Sp1 siRNA
and Fli-1 siRNA dramatically diminished it. In conclusion, TGFβ1 may be an
intermediary between SP/NK1R activation and SIGIRR expression in Sp1
siRNA-transfected macrophages. In addition, Sp1 modulates TGFβ1/Smad signaling
and negatively regulates SIGIRR protein production by macrophages after SP
stimulation. Author information:
(1)Jiangsu Cancer Hospital & Jiangsu Institue of Cancer Research & Nanjing
Medical University Affiliated Cancer Hospital, 42 Bai Zi Ting Road, Nanjing,
Jiangsu 210000, China; Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou,
Jiangsu, China.
(2)Jiangsu Cancer Hospital & Jiangsu Institue of Cancer Research & Nanjing
Medical University Affiliated Cancer Hospital, 42 Bai Zi Ting Road, Nanjing,
Jiangsu 210000, China.
(3)Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou, Jiangsu, China.
(4)The Fourth Clinical Medical College of Nanjing Medical University, Nanjing,
Jiangsu, China.
(5)Jiangsu Cancer Hospital & Jiangsu Institue of Cancer Research & Nanjing
Medical University Affiliated Cancer Hospital, 42 Bai Zi Ting Road, Nanjing,
Jiangsu 210000, China; Xuzhou Medical University, 209 Tong-Shan Road, Xuzhou,
Jiangsu, China. Electronic address: [email protected].
(6)Jiangsu Cancer Hospital & Jiangsu Institue of Cancer Research & Nanjing
Medical University Affiliated Cancer Hospital, 42 Bai Zi Ting Road, Nanjing,
Jiangsu 210000, China. Electronic address: [email protected]. The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by
regulating many physiological processes in development and tissue homeostasis.
The TGF-β signaling pathway outcome relies on the control of the spatial and
temporal expression of >500 genes, which depend on the functions of the Smad
protein along with those of diverse modulators of this signaling pathway, such
as transcriptional factors and cofactors. Ski (Sloan-Kettering Institute) and
SnoN (Ski novel) are Smad-interacting proteins that negatively regulate the
TGF-β signaling pathway by disrupting the formation of R-Smad/Smad4 complexes,
as well as by inhibiting Smad association with the p300/CBP coactivators. The
Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone
deacetylases to repress gene transcription. The TGF-β/Smad pathway and
coregulators Ski and SnoN clearly regulate each other through several positive
and negative feedback mechanisms. Thus, these cross-regulatory processes finely
modify the TGF-β signaling outcome as they control the magnitude and duration of
the TGF-β signals. As a result, any alteration in these regulatory mechanisms
may lead to disease development. Therefore, the design of targeted therapies to
exert tight control of the levels of negative modulators of the TGF-β pathway,
such as Ski and SnoN, is critical to restore cell homeostasis under the specific
pathological conditions in which these cofactors are deregulated, such as
fibrosis and cancer. In physiological conditions, the activity of the intestinal immune system is
tightly regulated to prevent tissue-damaging reactions directed against
components of the luminal flora. Various factors contribute to maintain immune
homeostasis and diminished production and/or function of such molecules trigger
and/or propagate detrimental signals, which can eventually lead to chronic
colitis and colon cancer. One such a molecule is transforming growth factor-β1
(TGF-β1), a cytokine produced by many inflammatory and non-inflammatory cells
and targeting virtually all the intestinal mucosal cell types, with the
down-stream effect of activating intracellular Smad2/3 proteins and suppressing
immune reactions. In patients with inflammatory bowel diseases (IBD), there is
defective TGF-β1/Smad signaling due to high Smad7, an inhibitor of TGF-β1
activity. Indeed, knockdown of Smad7 with a specific antisense oligonucleotide
restores endogenous TGF-β1 activity, thereby inhibiting inflammatory pathways in
patients with IBD and colitic mice. Consistently, mice over-expressing Smad7 in
T cells develop severe intestinal inflammation in various experimental models.
Smad7 expression is also upregulated in colon cancer cells, in which such a
protein controls positively intracellular pathways that sustain neoplastic cell
growth and survival. We here review the role of TGF-β1 and Smad7 in intestinal
immunity, inflammation, and cancer. Intestinal fibroblasts, the main effector cells of intestinal fibrosis, are
considered to be a good target for anti‑fibrotic therapy. The aim of the present
study was to examine the effects of pirfenidone (PFD) on human intestinal
fibroblasts (HIFs) stimulated by transforming growth factor (TGF)‑β1 and to
explore the potential mechanism. Prior to stimulation with TGF‑β1 (10 ng/ml),
HIFs were treated with or without PFD (1 mg/ml). Cell proliferation was
determined by Cell Counting Kit (CCK)‑8 and colony formation assays, and cell
apoptosis was assessed using flow cytometry and a TUNEL assay. Reverse
transcription‑quantitative polymerase chain reaction and western blotting were
performed to evaluate the mRNA and protein expressions of α‑smooth muscle actin
(α‑SMA), collagen I and fibronectin. The protein expression of TGF‑β1/mothers
against decapentaplegic homolog (Smad) and phosphoinositide 3‑kinase
(PI3K)/protein kinase B (AKT) signaling pathways was evaluated by western
blotting. CCK‑8 and colony formation assays demonstrated that PFD significantly
inhibited cell proliferation in HIFs stimulated with TGF‑β1. Flow cytometry and
TUNEL assays revealed that PFD treatment significantly enhanced apoptosis in
TGF‑β1‑stimulated HIFs. In addition, PFD markedly reduced TGF‑β1‑induced HIF
activities, such as myofibroblast differentiation (α‑SMA), and collagen
production (collagen I and fibronectin). These effects of PFD were mediated by
the inhibition of the TGF‑β1/Smad and PI3K/AKT signaling pathways. Therefore,
the present study demonstrated that PFD reduced TGF‑β1‑induced fibrogenic
activities of HIFs, suggesting that PFD may be a potential therapeutic agent for
intestinal fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening and
interstitial lung disease with the median survival of only 3-5 years. However,
due to the unclear etiology and problems in accurate diagnosis, up to now only
two drugs were approved by FDA for the treatment of IPF and their outcome
responses are limited. Numerous studies have shown that TGF-β is the most
important cytokine in the development of pulmonary fibrosis and plays a role
through its downstream signaling molecule TGF-binding receptor Smads protein. In
this paper, compounds bearing 2(1H)-quinolone scaffold were designed and their
anti-fibrosis effects were evaluated. Of these compounds, 20f was identified as
the most active one and could inhibit TGF-β-induced collagen deposition of
NRK-49F cells and mouse fibroblasts migration with comparable activity and lower
cytotoxicity than nintedanib in vitro. Further mechanism studies indicated that
20f reduced the expression of fibrogenic phenotypic protein α-SMA and collagen Ⅰ
by inhibiting the TGF-β/Smad dependent pathways and ERK1/2 and p38 pathways.
Moreover, compared with the nintedanib, 20f (100 mg/kg/day, p.o) more
effectively alleviated collagen deposition in lung tissue and delayed the
destruction of lung tissue structure both in bleomycin-induced prevention and
treatment mice pulmonary fibrosis models. The immunohistochemical experiments
further showed that 20f could block the expression level of phosphorylated Smad3
in the lung tissue cells, which resulted in its anti-fibrosis effects in vivo.
In addition, 20f demonstrated good bioavailability (F = 41.55% vs 12%, compare
with nintedanib) and an appropriate elimination half-life (T1/2 = 3.5 h),
suggesting that 20f may be a potential drug candidate for the treatment of
pulmonary fibrosis. |
What is the Oncomine Dx Target test? | The Oncomine Dx Target Test (ODxTT) is a next-generation sequencing-based companion diagnostic test, that could facilitate access to multiple biomarker testing using small tissue samples to support therapy decisions for patients with advanced NSCLC. | BACKGROUND: The Oncomine Dx Target Test (ODxTT) is a next-generation
sequencing-based companion diagnostic test which has been recently developed;
however, its analysis success rate could be improved, especially for small
samples. The aim of this study was to identify the pathological factors
associated with biopsy specimens that affect the analysis success rate of ODxTT.
METHODS: We retrospectively investigated 119 cases subjected to ODxTT at
Kanagawa Cancer Center. Data pertaining to the results of BRAF V600E mutation
analysis in ODxTT and pathological factors based on microscope slides were
collected. Pathological factors including tissue surface area, tumor cell count,
and tumor content rate were assessed. We constructed receiver operating
characteristic curves and determined the optimal cutoff values of each
pathological factor. Multivariate logistic analysis was used to identify
significant factors.
RESULTS: A total of 98 of 119 samples were successfully analyzed (75.6%). The
tissue surface area and tumor cell count were significantly higher in the group
associated with analysis success (P < 0.001 and P = 0.011, respectively), and
their optimal cutoff values were 1.04 mm2 and 375 cells, respectively. A tissue
surface area > 1.04 mm2 and tumor cell count >375 cells had a positive effect on
the analysis success rate of ODxTT (odds ratio [OR] 0.10; 95% confidence
interval [CI]: 0.03-0.35; P < 0.001 and OR 0.25; 95% CI: 0.07-0.90; P = 0.033,
respectively).
CONCLUSIONS: Selecting samples with a tissue surface area > 1.04 mm2 and a tumor
cell count >375 cells might improve the analysis success rate of ODxTT.
KEY POINTS: Significant findings of the study: We found that a tissue surface
area > 1.04 mm2 and tumor cell count >375 cells had a positive effect on the
analysis success rate of ODxTT in the analysis of biopsy tissue samples.
WHAT THIS STUDY ADDS: It is sometimes necessary to assess genetic alterations
with a small biopsy sample in daily practice. The criteria mentioned above will
help to determine which tests should be performed, ODxTT or multiple single-gene
testing. |
What are common variants at 12q14 and 12q24 associated with? | Common variants at 12q14 and 12q24 are associated with hippocampal volume. Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. | Collaborators: Stein JL, Medland SE, Arias Vasquez A, Hibar DP, Senstad RE,
Winkler AM, Toro R, Appel K, Bartecek R, Bergmann Ø, Bernard M, Brown AA, Cannon
DM, Chakravarty M, Christoforou A, Domin M, Grimm O, Hollinshead M, Holmes AJ,
Homuth G, Hottenga JJ, Langan C, Lopez LM, Hansell NK, Hwang KS, Kim S, Laje G,
Lee PH, Liu X, Loth E, Lourdusamy A, Maniega SM, Mattingsdal M, Mohnke S, Nho K,
Nugent AC, O'Brien C, Papmeyer M, Pütz B, Ramasamy A, Rasmussen J, Rijpkema M,
Risacher SL, Roddey JC, Rose EJ, Ryten M, Shen L, Sprooten E, Strengman E,
Teumer A, Trabzuni D, Turner J, van Eijk K, van Erp TG, van Tol MJ, Wittfeld K,
Wolf C, Woudstra S, Aleman A, Alhusaini S, Almasy L, Binder EB, Brohawn DG,
Cantor RM, Carless MA, Corvin A, Czisch M, Curran JE, Davies G, de Almeida MA,
Delanty N, Depondt C, Duggirala R, Dyer TD, Erk S, Fagerness J, Fox PT, Freimer
NB, Gill M, Göring HH, Hagler DJ, Hoehn D, Holsboer F, Hoogman M, Hosten N,
Jahanshad N, Johnson MP, Kasperaviciute D, Kent JW Jr, Kochunov P, Lancaster JL,
Lawrie SM, Liewald DC, Mandl R, Matarin M, Mattheisen M, Meisenzahl E, Melle I,
Moses EK, Mühleisen TW, Nauck M, Nöthen MM, Olvera RL, Pandolfo M, Pike GB, Puls
R, Reinvang I, Rentería ME, Rietschel M, Roffman JL, Royle NA, Rujescu D, Savitz
J, Schnack HG, Schnell K, Seiferth N, Smith C, Steen VM, Valdés Hernández MC,
Van den Heuvel M, van der Wee NJ, Van Haren NE, Veltman JA, Völzke H, Walker R,
Westlye LT, Whelan CD, Agartz I, Boomsma DI, Cavalleri GL, Dale AM, Djurovic S,
Drevets WC, Hagoort P, Hall J, Heinz A, Jack CR Jr, Foroud TM, Le Hellard S,
Macciardi F, Montgomery GW, Poline JB, Porteous DJ, Sisodiya SM, Starr JM,
Sussmann J, Toga AW, Veltman DJ, Walter H, Weiner MW, Andreassen OA, Apostolova
LG, Bastin ME, Blangero J, Brunner HG, Buckner RL, Cichon S, Coppola G, de
Zubicaray GI, Deary IJ, Donohoe G, de Geus EJ, Espeseth T, Fernández G, Glahn
DC, Grabe HJ, Hardy J, Hulshoff Pol HE, Jenkinson M, Kahn RS, McDonald C,
McIntosh AM, McMahon FJ, McMahon KL, Meyer-Lindenberg A, Morris DW,
Müller-Myhsok B, Nichols TE, Ophoff RA, Paus T, Pausova Z, Penninx BW, Potkin
SG, Sämann PG, Saykin AJ, Schumann G, Smoller JW, Wardlaw JM, Weale ME, Martin
NG, Franke B, Wright MJ, Thompson PM. |
Which mutation is targeted by Sotorasib? | Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. | Author information:
(1)From the Department of Investigational Cancer Therapeutics, Phase I Clinical
Trials Program, University of Texas M.D. Anderson Cancer Center, Houston
(D.S.H., F.M.-B.); the Department of Medical Oncology and Experimental
Therapeutics, City of Hope Comprehensive Cancer Center, Duarte (M.G.F.), the
University of California, San Francisco, San Francisco (P.N.M.), and Amgen,
Thousand Oaks (H.H., J.N., G.N., J.K., B.E.H., J.C., J.R.L., G.F.) - all in
California; Duke University Medical Center, Durham, NC (J.H.S.); Royal Melbourne
Hospital/Peter MacCallum Cancer Centre, Melbourne, VIC (J.D.), Queen Elizabeth
Hospital and University of Adelaide, Woodville South, SA (T.J.P.), and Scientia
Clinical Research, Randwick, NSW (J.C. Kuo) - all in Australia; the Department
of Medicine, Division of Hematology/Oncology, Indiana University School of
Medicine, Indianapolis (G.A.D.); Dana-Farber Cancer Institute, Harvard Medical
School, Boston (G.I.S.); the Sarah Cannon Research Institute at HealthONE,
Denver (G.S.F.); Princess Margaret Cancer Centre, University Health Network,
Toronto (A.S.); Fox Chase Cancer Center, Philadelphia (C.S.D.); the University
of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh,
Pittsburgh (T.F.B.); Seoul National University College of Medicine (Y.-J.B.),
Samsung Medical Center, Sungkyunkwan University School of Medicine (K.P.), and
the Department of Oncology, Asan Medical Center, University of Ulsan College of
Medicine (T.W.K.) - all in Seoul, South Korea; Roswell Park Cancer Institute,
Buffalo (G.K.D.), and Memorial Sloan Kettering Cancer Center and Weill Cornell
Medicine, New York (P.L., B.T.L.) - all in New York; the University of Michigan,
Ann Arbor (J.C. Krauss); the Department of Experimental Therapeutics, National
Cancer Center Hospital East, Kashiwa, Japan (Y.K.); the Department of Medicine,
Division of Oncology, University of Washington, Seattle (A.L.C.); Aix Marseille
University, Centre National de la Recherche Scientifique, INSERM, Centre de
Recherche en Cancérologie de Marseille, Assistance Publique-Hôpitaux de
Marseille, Marseille, France (F.B.); Winship Cancer Institute of Emory
University, Atlanta (S.S.R.); and the Alvin J. Siteman Cancer Center at
Washington University School of Medicine, St. Louis (R.G.). Evidence continues to grow that KRAS, once considered an "undruggable" target,
can be targeted successfully in non-small cell lung cancer. In a phase I trial,
the KRASG12C inhibitor sotorasib elicited responses in about a third of patients
with the disease and was generally well tolerated. |
When is DELE1 exiting the mitochondrion? | Mitochondrial stress stimulates OMA1-dependent cleavage of DELE1 and leads to the accumulation of DELE1 in the cytosol. | Mitochondrial fidelity is tightly linked to overall cellular homeostasis and is
compromised in ageing and various pathologies1-3. Mitochondrial malfunction
needs to be relayed to the cytosol, where an integrated stress response is
triggered by the phosphorylation of eukaryotic translation initiation factor 2α
(eIF2α) in mammalian cells4,5. eIF2α phosphorylation is mediated by the four
eIF2α kinases GCN2, HRI, PERK and PKR, which are activated by diverse types of
cellular stress6. However, the machinery that communicates mitochondrial
perturbation to the cytosol to trigger the integrated stress response
remains unknown1,2,7. Here we combine genome engineering and haploid genetics to
unbiasedly identify genes that affect the induction of C/EBP homologous protein
(CHOP), a key factor in the integrated stress response. We show that the
mitochondrial protease OMA1 and the poorly characterized protein DELE1, together
with HRI, constitute the missing pathway that is triggered by mitochondrial
stress. Mechanistically, stress-induced activation of OMA1 causes DELE1 to be
cleaved into a short form that accumulates in the cytosol, where it binds to and
activates HRI via its C-terminal portion. Obstruction of this pathway can be
beneficial or adverse depending on the type of mitochondrial perturbation. In
addition to the core pathway components, our comparative genetic screening
strategy identifies a suite of additional regulators. Together, these findings
could be used to inform future strategies to modulate the cellular response to
mitochondrial dysfunction in the context of human disease. In mammalian cells, mitochondrial dysfunction triggers the integrated stress
response, in which the phosphorylation of eukaryotic translation initiation
factor 2α (eIF2α) results in the induction of the transcription factor ATF41-3.
However, how mitochondrial stress is relayed to ATF4 is unknown. Here we show
that HRI is the eIF2α kinase that is necessary and sufficient for this relay. In
a genome-wide CRISPR interference screen, we identified factors upstream of HRI:
OMA1, a mitochondrial stress-activated protease; and DELE1, a
little-characterized protein that we found was associated with the inner
mitochondrial membrane. Mitochondrial stress stimulates OMA1-dependent cleavage
of DELE1 and leads to the accumulation of DELE1 in the cytosol, where it
interacts with HRI and activates the eIF2α kinase activity of HRI. In addition,
DELE1 is required for ATF4 translation downstream of eIF2α phosphorylation.
Blockade of the OMA1-DELE1-HRI pathway triggers an alternative response in which
specific molecular chaperones are induced. The OMA1-DELE1-HRI pathway therefore
represents a potential therapeutic target that could enable fine-tuning of the
integrated stress response for beneficial outcomes in diseases that involve
mitochondrial dysfunction. |
What is a ciliopathy? | A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function | The "ciliopathies" are a newly defined group of disorders characterized by
defects in the structure or function of the cellular primary cilium. Patients
with these disorders display variably expressive fibrocystic renal disease,
retinal blindness, polydactyly, obesity, and brain dysgenesis as well as
neurocognitive impairments. Joubert syndrome is a ciliopathy defined by
cerebellar vermis hypoplasia, oculomotor apraxia, intermittent hyperventilation,
and mental retardation. Recent evidence suggests important roles for the primary
cilium in mediating a host of extracellular signaling events such as morphogen,
mitogen, homeostatic and polarity signals. Based upon the clinical features of
ciliopathies and cilia mediated signaling pathways, the data support a role for
the primary cilium in modulating neurogenesis, cell polarity, axonal guidance
and possibly adult neuronal function. A group of disorders with disparate symptomatology, including congenital
cerebellar ataxia, retinal blindness, liver fibrosis, polycystic kidney disease,
and polydactyly, have recently been united under a single disease mechanism
called 'ciliopathies'. The ciliopathies are due to defects of the cellular
antenna known as the primary cilium, a microtubule-based extension of cellular
membranes found in nearly all cell types. Key among these ciliopathies is
Joubert syndrome, displaying ataxia, oculomotor apraxia, and mental retardation*
with a pathognomonic 'molar tooth sign' on brain magnetic resoce imaging. The
importance of ciliary function in neuronal development has been appreciated only
in the last decade with the classification of Joubert syndrome as a ciliopathy.
This, together with the identification of many of the clinical features of
ciliopathies in individuals with Joubert syndrome and the localization of
Joubert syndrome's causative gene products at or near the primary cilium, have
defined a new class of neurological disease. Cilia are involved in diverse
cellular processes including protein trafficking, photoreception, embryonic axis
patterning, and cell cycle regulation. Ciliary dysfunction can affect a single
tissue or manifest as multi-organ involvement. Ciliary defects have been
described in retinopathies such as retinitis pigmentosa and Leber congenital
amaurosis (defects in photoreceptor ciliary protein complexes), renal syndromes
with nephronophthisis and cystic dysplastic kidneys, and liver conditions such
as fibrosis and biliary cirrhosis. Recognizing the diverse presentations of the
ciliopathies and screening strategies following diagnosis is an important part
of the treatment plan of children with cilia-related disorders. Ciliopathies are a genetically and phenotypically heterogeneous group of human
developmental disorders whose root cause is the absence or dysfunction of
primary cilia. Joubert syndrome is characterized by a distinctive hindbrain
malformation variably associated with retinal dystrophy and cystic kidney
disease. Mutations in CC2D2A are found in ∼10% of patients with Joubert
syndrome. Here we describe the retinal phenotype of cc2d2a mutant zebrafish
consisting of disorganized rod and cone photoreceptor outer segments resulting
in abnormal visual function as measured by electroretinogram. Our analysis
reveals trafficking defects in mutant photoreceptors affecting transmembrane
outer segment proteins (opsins) and striking accumulation of vesicles,
suggesting a role for Cc2d2a in vesicle trafficking and fusion. This is further
supported by mislocalization of Rab8, a key regulator of opsin carrier vesicle
trafficking, in cc2d2a mutant photoreceptors and by enhancement of the cc2d2a
retinal and kidney phenotypes with partial knockdown of rab8. We demonstrate
that Cc2d2a localizes to the connecting cilium in photoreceptors and to the
transition zone in other ciliated cell types and that cilia are present in these
cells in cc2d2a mutants, arguing against a primary function for Cc2d2a in
ciliogenesis. Our data support a model where Cc2d2a, localized at the
photoreceptor connecting cilium/transition zone, facilitates protein transport
through a role in Rab8-dependent vesicle trafficking and fusion. 'Ciliopathies' are an emerging class of genetic multisystemic human disorders
that are caused by a multitude of largely unrelated genes that affect ciliary
structure/function. They are unified by shared clinical features, such as mental
retardation, cystic kidney, retinal defects and polydactyly, and by the common
localization of the protein products of these genes at or near the primary
cilium of cells. With the realization that many previously disparate conditions
are a part of this spectrum of disorders, there has been tremendous interest in
the function of cilia in developmental signaling and homeostasis. Ciliopathies
are mostly inherited as simple recessive traits, but phenotypic expressivity is
under the control of numerous genetic modifiers, putting these conditions at the
interface of simple and complex genetics. In this review, we discuss the
ever-expanding ciliopathy field, which has three interrelated goals: developing
a comprehensive understanding of genes mutated in the ciliopathies and required
for ciliogenesis; understanding how the encoded proteins work together in
complexes and networks to modulate activity and structure-function
relationships; and uncovering signaling pathways and modifier relationships. Loss of cilia and ciliary protein causes various abnormalities (called
ciliopathy), including situs inversus, renal cystic diseases, polydactyly and
dysgenesis of the nervous system. Renal cystic diseases are the most frequently
observed symptoms in ciliopathies. Cilia are microtubule-based organelles with
the following regions: a ciliary tip, shaft, transitional zone and basal
body/mother centriole. Joubert syndrome (JBTS), Meckel Gruber syndrome (MKS) and
Nephronophthisis (NPHP) are overlapping syndromes. Recent studies show that JBST
and MKS responsible gene products are localized in the transitional zone of the
cilia, where they function as a diffusion barrier, and control protein sorting
and ciliary membrane composition. Nephrocystins are gene products of NPHP
responsible genes, and at least 11 genes have been identified. Although some
nephrocystins interact with JBST and MKS proteins, proteomic analysis suggests
that they do not form a single complex. Localization analysis reveals that
nephrocystins can be divided into two groups. Group I nephrocystins are
localized in the transitional zone, whereas group II nephrocystins are localized
in the Inv compartment. Homologs of group I nephrocystins, but not group II
nephrocystins, have been reported in C. reinhardtii and C. elegans. In this
review, we summarize the structure of the ciliary base of C. reinhardtii, C.
elegans and mammalian primary cilia, and discuss function of nephrocystins. We
also propose a new classification of nephrocystins. Autosomal domit polycystic kidney disease (ADPKD) is an inherited genetic
disorder that results in progressive renal cyst formation with ultimate loss of
renal function and other systemic disorders. These systemic disorders include
abnormalities in cardiovascular, portal, pancreatic and gastrointestinal
systems. ADPKD is considered to be among the ciliopathy diseases due to the
association with abnormal primary cilia function. In order to understand the
full course of primary cilia and its association with ADPKD, the structure,
functions and role of primary cilia have been meticulously investigated. As a
result, the focus on primary cilia has emerged to support the vital roles of
primary cilia in ADPKD. The primary cilia have been shown to have not only a
mechanosensory function but also a chemosensory function. Both structural and
functional defects in primary cilia result in cystic kidney disease and vascular
hypertension. Thus, the mechanosenory and chemosensory functions will be
analyzed in regards to ADPKD. Mutations in genes encoding cilia proteins cause human ciliopathies, diverse
disorders affecting many tissues. Individual genes can be linked to ciliopathies
with dramatically different phenotypes, suggesting that genetic modifiers may
participate in their pathogenesis. The ciliary transition zone contains two
protein complexes affected in the ciliopathies Meckel syndrome (MKS) and
nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the
ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP
and BBS complex genes modify the phenotypic consequences of one another in both
C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog
of vertebrate MKS complex components called Tectonics, as an evolutionarily
conserved transition zone protein. Neither disruption of TCTN-1 alone or
together with MKS complex components abrogated ciliary structure in C. elegans.
In contrast, disruption of TCTN-1 together with either of two NPHP complex
components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly,
disruption of an NPHP complex component and the BBS complex component BBS-5
individually did not compromise ciliary structure, but together did. As in
nematodes, disrupting two components of the mouse MKS complex did not cause
additive phenotypes compared to single mutants. However, disrupting both Tctn1
and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and
cilia-associated developmental signaling, as did disrupting both Tctn1 and the
BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in
parallel to support ciliary function and suggest that human ciliopathy
phenotypes are altered by genetic interactions between different ciliary
biochemical complexes. BACKGROUND: Meckel-Gruber syndrome is a ciliopathy, a lethal autosomal recessive
disorder that occurs in all races and ethnicities; it is characterized by
central nervous system abnormalities, resulting in mental retardation, bilateral
renal cystic dysplasia and malformations of hands and feet. To date there have
been only about 200 cases reported worldwide. It is a disease with a recurrence
rate of 25% whose most reliable method for diagnosis is prenatal ultrasound. The
mortality rate is 100% and in view of the high index of recurrence, subsequent
pregcies should be investigated appropriately with genetic counseling.
CLINIC CASE: We present the case of a 15 years-old mother with 30.2 weeks
pregcy resulting from rape by consanguinity (grandfather), without prenatal
care. On admission HD ultrasound study is performed finding fetus fetometria
average 26.2 weeks (for discordant fetometria head circumference 187.5 mm to
21.0 weeks gestation -3DE-) lost in the skull shape of the shell line is
observed winding mean; not cut down, cavum septum pellucidum or herniated sac
cerebellum and occipital level (encephalocele) are evident. It starts cervical
ripening with prostaglandins for 24 hours to conduct further labor with oxytocic
and delivery care where a fetus death, female, 1516 g is obtained. Fetal autopsy
family is authorized; however, it not has done because it is legal and only
medical geneticist obtains medical case assessment.
CONCLUSIONS: The Meckel-Gruber syndrome is a very rare condition that occurs in
cases of consanguinity occasions. Mortality occurs in 100% of cases, so you
should talk to parents and explain the best maternal prognosis, with abortion in
the early stages and subsequent genetic counseling. Author information:
(1)Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
(2)Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich,
Switzerland.
(3)Department of Human Genetics, Radboud University Medical Center, 6500 HB
Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences,
Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
(4)Department of Pediatrics, University of Washington, Seattle, WA 98195, USA;
Center for Integrative Brain Research, Seattle Children's Research Institute,
Seattle, WA 98101, USA.
(5)Department of Genetics, King Faisal Specialist Hospital and Research Center,
Riyadh 12713, Saudi Arabia.
(6)Hunter Genetics, Waratah, NSW 2298, Australia; University of Newcastle,
Callaghan, NSW 2308, Australia.
(7)Genetics Institute, Soroka Medical Center and National Institute for
Biotechnology in the Negev (NIBN), Ben Gurion University, Beer Sheva 8499000,
Israel.
(8)Department of Genetics, King Faisal Specialist Hospital and Research Center,
Riyadh 12713, Saudi Arabia; Eye Institute, Cleveland Clinic Abu Dhabi, Abu
Dhabi, United Arab Emirates.
(9)Department of Pediatrics, University of Washington, Seattle, WA 98195, USA;
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
(10)Department of Genome Sciences, University of Washington, Seattle, WA 98195,
USA.
(11)Department of Pediatrics, University of Washington, Seattle, WA 98195, USA;
Center for Integrative Brain Research, Seattle Children's Research Institute,
Seattle, WA 98101, USA; Department of Neurology, University of Washington,
Seattle, WA 98195, USA.
(12)Department of Genetics, King Faisal Specialist Hospital and Research Center,
Riyadh 12713, Saudi Arabia; Department of Anatomy and Cell Biology, College of
Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome
Program, King Abdulaziz City for Science and Technology, Riyadh 12371, Saudi
Arabia.
(13)Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich,
Switzerland; Institute of Medical Genetics, University of Zurich, 8952
Schlieren, Switzerland. Electronic address: [email protected].
(14)Department of Pediatrics, University of Washington, Seattle, WA 98195, USA;
Center for Integrative Brain Research, Seattle Children's Research Institute,
Seattle, WA 98101, USA. Electronic address: [email protected]. Ciliopathies are human disorders caused by dysfunction of primary cilia,
ubiquitous organelles involved in transduction of environmental signals such as
light sensation in photoreceptors. Concentration of signal detection proteins
such as opsins in the ciliary membrane is achieved by RabGTPase-regulated
polarized vesicle trafficking and by a selective barrier at the ciliary base,
the transition zone (TZ). Dysfunction of the TZ protein CC2D2A causes
Joubert/Meckel syndromes in humans and loss of ciliary protein localization in
animal models, including opsins in retinal photoreceptors. The link between the
TZ and upstream vesicle trafficking has been little explored to date. Moreover,
the role of the small GTPase Rab8 in opsin-carrier vesicle (OCV) trafficking has
been recently questioned in a mouse model. Using correlative light and electron
microscopy and live imaging in zebrafish photoreceptors, we provide the first
live characterization of Rab8-mediated trafficking in photoreceptors in vivo.
Our results support a possibly redundant role for both Rab8a/b paralogs in OCV
trafficking, based on co-localization of Rab8 and opsins in vesicular
structures, and joint movement of Rab8-tagged particles with opsin. We further
investigate the role of the TZ protein Cc2d2a in Rab8-mediated trafficking using
cc2d2a zebrafish mutants and identify a requirement for Cc2d2a in the latest
step of OCV trafficking, namely vesicle fusion. Progressive accumulation of
opsin-containing vesicles in the apical portion of photoreceptors lacking Cc2d2a
is caused by disorganization of the vesicle fusion machinery at the periciliary
membrane with mislocalization and loss of the t-SNAREs SNAP25 and Syntaxin3 and
of the exocyst component Exoc4. We further observe secondary defects on upstream
Rab8-trafficking with cytoplasmic accumulation of Rab8. Taken together, our
results support participation of Rab8 in OCV trafficking and identify a novel
role for the TZ protein Cc2d2a in fusion of incoming ciliary-directed vesicles,
through organization of the vesicle fusion machinery at the periciliary
membrane. BACKGROUND: Ciliopathies are a class of inherited pleiotropic genetic disorders
in which alterations in cilia assembly, maintece, and/or function exhibit
penetrance in the multiple organ systems. Olfactory dysfunction is one such
clinical manifestation that has been shown in both patients and model organisms.
Existing therapies for ciliopathies are limited to the treatment or management
of symptoms. The last decade has seen an increase in potential curative
therapeutic options including small molecules and biologics. Recent work in
multiciliated olfactory sensory neurons has demonstrated the capacity of
targeted gene therapy to restore ciliation in terminally differentiated cells
and rescue olfactory function. This review will discuss the current
understanding of the penetrance of ciliopathies in the olfactory system.
Importantly, it will highlight both pharmacological and biological approaches,
and their potential therapeutic value in the olfactory system and other ciliated
tissues.
METHODS: We undertook a structured and comprehensive search of peer-reviewed
research literature encompassing in vitro, in vivo, model organism, and clinical
studies. From these publications, we describe the olfactory system, and discuss
the penetrance of ciliopathies and impact of cilia loss on olfactory function.
In addition, we outlined the developing therapies for ciliopathies across
different organ and cell culture systems, and discussed their potential
therapeutic application to the mammalian olfactory system.
RESULTS: One-hundred sixty-one manuscripts were included in the review,
centering on the understanding of olfactory penetrance of ciliopathies, and
discussing the potential therapeutic options for ciliopathies in the context of
the mammalian olfactory system. Forty-four manuscripts were used to generate a
table listing the known congenital causes of olfactory dysfunction, with the
first ten listed are linked to ciliopathies. Twenty-three manuscripts were used
to outline the potential of small molecules for the olfactory system. Emphasis
was placed on HDAC6 inhibitors and lithium, both of which were shown to
stabilize microtubule structures, contributing to ciliogenesis and cilia
lengthening. Seventy-five manuscripts were used to describe gene therapy and
gene therapeutic strategies. Included were the implementation of adenoviral,
adeno-associated virus (AAV), and lentiviral vectors to treat ciliopathies
across different organ systems and application toward the olfactory system. Thus
far, adenoviral and AAVmeditated ciliary restoration demonstrated successful
proof-of-principle preclinical studies. In addition, gene editing, ex vivo gene
therapy, and transplantation could serve as alternative therapeutic and
long-term approaches. But for all approaches, additional assessment of vector
immunogenicity, specificity, and efficacy need further investigation. Currently,
ciliopathy treatments are limited to symptomatic management with no curative
options. However, the accessibility and amenability of the olfactory system to
treatment would facilitate development and advancement of a viable therapy.
CONCLUSION: The findings of this review highlight the contribution of
ciliopathies to a growing list of congenial olfactory dysfunctions. Promising
results from other organ systems imply the feasibility of biologics, with
results from gene therapies proving to be a viable therapeutic option for
ciliopathies and olfactory dysfunction. Publisher: Ziliopathien umfassen Erkrankungen und Fehlbildungen einzelner oder
mehrerer Organe. Isolierte oder syndromale progressive Netzhautdystrophien
stellen die häufigste okuläre Manifestation der Ziliopathien dar. Hierbei ist
insbesondere die Struktur der Photorezeptoren mit dem Verbindungscilium
(connecting cilium) bedeutend. Durch die dysfunktionalen Zilien besteht eine
meist schwere Form der Netzhautdystrophie, der Leberʼschen kongenitalen Amaurose
(LCA). Die häufigsten syndromalen Ziliopathien mit okulärer Manifestation sind
das Bardet-Biedl-Syndrom (BBS) und das Usher-Syndrom. Die molekulargenetischen
Analysen wiesen bisher eine Vielzahl von Genen für ziliäre Proteine nach.
Mutationen in diesen Genen sind mit einer klinischen Heterogenität verbunden.
Die Diagnose einer LCA oder einer Netzhautdystrophie im Kindesalter sollte immer
eine multidisziplinäre Untersuchung und Betreuung einschließen. Eine kausale
Therapie der Ziliopathien befindet sich in einem erfolgversprechenden
Anfangsstadium, sodass zum jetzigen Zeitpunkt nur unterstützende und
rehabilitierende Maßnahmen zur Verfügung stehen. Ciliopathies are life-threatening human diseases caused by defective cilia. They
can often be traced back to mutations of genes encoding transition zone (TZ)
proteins demonstrating that the understanding of TZ organisation is of paramount
importance. The TZ consists of multimeric protein modules that are subject to a
stringent assembly hierarchy. Previous reports place Rpgrip1l at the top of the
TZ assembly hierarchy in Caenorhabditis elegans By performing quantitative
immunofluorescence studies in RPGRIP1L-/- mouse embryos and human embryonic
cells, we recognise a different situation in vertebrates in which Rpgrip1l
deficiency affects TZ assembly in a cell type-specific manner. In cell types in
which the loss of Rpgrip1l alone does not affect all modules, additional
truncation or removal of vertebrate-specific Rpgrip1 results in an impairment of
all modules. Consequently, Rpgrip1l and Rpgrip1 synergistically ensure the TZ
composition in several vertebrate cell types, revealing a higher complexity of
TZ assembly in vertebrates than in invertebrates. Ciliopathies are a group of disorders caused by a defect in ciliogenesis,
ciliary protein trafficking. Because nearly every cell in the body (including
the photoreceptors) contains cilia, defects in ciliary proteins typically affect
multiple organ systems. Usher syndrome is the most common syndromic cause of
retinitis pigmentosa (RP) and accounts for 10-20% of cases of RP Inheritance is
autosomal recessive, and the retinal dystrophy is usually rod-cone dystrophy
(Figs. 32.1 and 32.2). These patients have RP with sensorineural hearing loss
(partial or complete) since birth; some may have vestibular dysfunction. Most
patients retain central vision of about 20/40 until about age 40. Usher Syndrome
1 (USH1): Profound congenital sensorineural hearing loss on audiometry, absent
vestibular function, and typical RP (onset by 10 years of age); accounts for
about 70% of all Usher cases. Patient may benefit from a cochlear implant. The
retinitis pigmentosa occurs at an early age (childhood onset) and progress
slowly. Usher Syndrome 2 (USH2): Moderate to severe congenital sensorineural
hearing loss on audiometry (predomitly for higher frequencies), normal
vestibular function, and typical RP (onset by 20 years of age); accounts for
about 26% of all Usher cases. Usher Syndrome 3 (USH3): Progressive sensorineural
hearing loss and typical RP (onset in second decade); accounts for about 4% of
all Usher cases. Vestibular function is normal in about half of patients, but
abnormal in the other half. Primary cilium is a membrane-protruding immotile sensory organelle. It had been
supposed that the cilium was a static organelle for long periods. However,
recent studies have uncovered that the cilium is dynamically organized organelle
in a cell cycle-dependent manner; it is formed during G0/G1 phase and resorbed
when the cells enter cell division cycle. Despite the primary cilium is very
short and its surface area is extremely small, the cilium possesses a few kinds
of G protein-coupled receptors, growth factor receptors and ion channels.
Therefore, it can function as a signaling receptor for selective bioactive
ligands and mechanical stresses. Dysregulation of the ciliary dynamics is linked
with hereditary disorders, so called "ciliopathy", with clinical manifestations
of microcephaly, polycystic kidney, situs inversus, polydactyly, and so on. No
effective medical treatment for the ciliopathies has been available. Increasing
evidences about the molecular mechanisms of ciliary dynamics and ciliary
functions have revealed that enormous number of molecules regulate a cycle of
ciliogenesis, cilium-derived signaling, ciliary resorption and elimination.
However, it is a fact that research progress is far inferior to the full
disclosure of the molecular mechanisms. Further studies are required to clarify
the pathogenesis of the cilipathies. Moreover, efficient medical treatments are
expected to be developed by pharmacological approaches. Ciliopathies are a group of hereditary disorders that result from structural or
functional abnormalities of cilia. Recent intense research efforts have
uncovered the genetic bases of ciliopathies, and our understanding of the
assembly and functions of cilia has been improved significantly. Although
mechanism-specific therapies for ciliopathies have not yet received regulatory
approval, the use of innovative therapeutic modalities such as oligonucleotide
therapy, gene replacement therapy, and gene editing in addition to symptomatic
treatments are expected to provide valid treatment options in the near future.
Moreover, candidate chemical compounds for developing small molecule drugs to
treat ciliopathies have been identified. This review introduces the key features
of cilia and ciliopathies, and summarizes the advances as well as the challenges
that remain with the development of therapies for treating ciliopathies. |
Which histone mark is recognized by HP1? | h3k9me3 is the major histone mark that is recognized by hp1. | The chromodomain of the HP1 family of proteins recognizes histone tails with
specifically methylated lysines. Here, we present structural, energetic, and
mutational analyses of the complex between the Drosophila HP1 chromodomain and
the histone H3 tail with a methyllysine at residue 9, a modification associated
with epigenetic silencing. The histone tail inserts as a beta strand, completing
the beta-sandwich architecture of the chromodomain. The methylammonium group is
caged by three aromatic side chains, whereas adjacent residues form discerning
contacts with one face of the chromodomain. Comparison of dimethyl- and
trimethyllysine-containing complexes suggests a role for cation-pi and van der
Waals interactions, with trimethylation slightly improving the binding affinity. Specific modifications to histones are essential epigenetic markers---heritable
changes in gene expression that do not affect the DNA sequence. Methylation of
lysine 9 in histone H3 is recognized by heterochromatin protein 1 (HP1), which
directs the binding of other proteins to control chromatin structure and gene
expression. Here we show that HP1 uses an induced-fit mechanism for recognition
of this modification, as revealed by the structure of its chromodomain bound to
a histone H3 peptide dimethylated at Nzeta of lysine 9. The binding pocket for
the N-methyl groups is provided by three aromatic side chains, Tyr21, Trp42 and
Phe45, which reside in two regions that become ordered on binding of the
peptide. The side chain of Lys9 is almost fully extended and surrounded by
residues that are conserved in many other chromodomains. The QTAR peptide
sequence preceding Lys9 makes most of the additional interactions with the
chromodomain, with HP1 residues Val23, Leu40, Trp42, Leu58 and Cys60 appearing
to be a major determit of specificity by binding the key buried Ala7. These
findings predict which other chromodomains will bind methylated proteins and
suggest a motif that they recognize. We show that methylated lysine 9 of histone H3 (Me9H3) is a marker of
heterochromatin in divergent animal species. It localises to both constitutive
and facultative heterochromatin and replicates late in S-phase of the cell
cycle. Significantly, Me9H3 is enriched in the inactive mammalian X chromosome
(Xi) in female cells, as well as in the XY body during meiosis in the male, and
forms a G-band pattern along the arms of the autosomes. Me9H3 is a constituent
of imprinted chromosomes that are repressed. The paternal and maternal pronuclei
in one-cell mouse embryos show a striking non-equivalence in Me9H3: the paternal
pronucleus contains no immunocytologically detectable Me9H3. The levels of Me9H3
on the parental chromosomes only become equivalent after the two-cell stage.
Finally, we provide evidence that Me9H3 is neither necessary nor sufficient for
localisation of heterochromatin protein 1 (HP1) to chromosomal DNA. On the histone H3 tail, Lys 9 and Lys 27 are both methylation sites associated
with epigenetic repression, and reside within a highly related sequence motif
ARKS. Here we show that the chromodomain proteins Polycomb (Pc) and HP1
(heterochromatin protein 1) are highly discriminatory for binding to these sites
in vivo and in vitro. In Drosophila S2 cells, and on polytene chromosomes,
methyl-Lys 27 and Pc are both excluded from areas that are enriched in
methyl-Lys 9 and HP1. Swapping of the chromodomain regions of Pc and HP1 is
sufficient for switching the nuclear localization patterns of these factors,
indicating a role for their chromodomains in both target site binding and
discrimination. To better understand the molecular basis for the selection of
methyl-lysine binding sites, we solved the 1.8 A structure of the Pc
chromodomain in complex with a H3 peptide bearing trimethyl-Lys 27, and compared
it with our previously determined structure of the HP1 chromodomain in complex
with a H3 peptide bearing trimethyl-Lys 9. The Pc chromodomain distinguishes its
methylation target on the H3 tail via an extended recognition groove that binds
five additional residues preceding the ARKS motif. Post-translational modifications of histone proteins, the basic building blocks
around which eukaryotic DNA is organized, are crucially involved in the
regulation of genome activity as they control chromatin structure and dynamics.
The recruitment of specific binding proteins that recognize and interact with
particular histone modifications is thought to constitute a fundamental
mechanism by which histone marks mediate biological function. For instance,
tri-methylation of histone H3 lysine 9 (H3K9me3) is important for recruiting
heterochromatin protein 1 (HP1) to discrete regions of the genome, thereby
regulating gene expression, chromatin packaging, and heterochromatin formation.
Until now, little was known about the regulation of effector-histone mark
interactions, and in particular, of the binding of HP1 to H3K9me3. Recently, we
and others presented evidence that a "binary methylation-phosphorylation switch"
mechanism controls the dynamic release of HP1 from H3K9me3 during the cell
cycle: phosphorylation of histone H3 serine 10 (H3S10ph) occurs at the onset of
mitosis, interferes with HP1-H3K9me3 interaction, and therefore, ejects HP1 from
its binding site. Here, we discuss the biological function of HP1 release from
chromatin during mitosis, consider implications why the cell controls HP1
binding by such a methylation-phosphorylation switching mechanism, and reflect
on other cellular pathways where binary switching of HP1 might occur. All cells of a given organism contain nearly identical genetic information, yet
tissues display unique gene expression profiles. This specificity is in part due
to transcriptional control by epigenetic mechanisms that involve
post-translational modifications of histones. These modifications affect the
folding of the chromatin fiber and serve as binding sites for non-histone
chromosomal proteins. Here we discuss functions of the Heterochromatin Protein 1
(HP1) family of proteins that recognize H3K9me, an epigenetic mark generated by
the histone methyltransferases SU(VAR)3-9 and orthologues. Loss of HP1 proteins
causes chromosome segregation defects and lethality in some organisms; a
reduction in levels of HP1 family members is associated with cancer progression
in humans. These consequences are likely due to the role of HP1 in centromere
stability, telomere capping and the regulation of euchromatic and
heterochromatic gene expression. We previously suggested that ASXL1 (additional sex comb-like 1) functions as
either a coactivator or corepressor for the retinoid receptors retinoic acid
receptor (RAR) and retinoid X receptor in a cell type-specific manner. Here, we
provide clues toward the mechanism underlying ASXL1-mediated repression.
Transfection assays in HEK293 or H1299 cells indicated that ASXL1 alone
possessing autonomous transcriptional repression activity significantly
represses RAR- or retinoid X receptor-dependent transcriptional activation, and
the N-terminal portion of ASXL1 is responsible for the repression. Amino acid
sequence analysis identified a consensus HP1 (heterochromatin protein 1)-binding
site (HP1 box, PXVXL) in that region. Systematic in vitro and in vivo assays
revealed that the HP1 box in ASXL1 is critical for the interaction with the
chromoshadow domain of HP1. Transcription assays with HP1 box deletion or
HP1alpha knockdown indicated that HP1alpha is required for ASXL1-mediated
repression. Furthermore, we found a direct interaction of ASXL1 with histone H3
demethylase LSD1 through the N-terminal region nearby the HP1-binding site.
ASXL1 binding to LSD1 was greatly increased by HP1alpha, resulting in the
formation of a ternary complex. LSD1 cooperates with ASXL1 in transcriptional
repression, presumably by removing H3K4 methylation, an active histone mark, but
not H3K9 methylation, a repressive histone mark recognized by HP1. This
possibility was supported by chromatin immunoprecipitation assays followed by
ASXL1 overexpression or knockdown. Overall, this study provides the first
evidence that ASXL1 cooperates with HP1 to modulate LSD1 activity, leading to a
change in histone H3 methylation and thereby RAR repression. Binding of heterochromatin protein 1 (HP1) to the histone H3 lysine 9
trimethylation (H3K9me3) mark is a hallmark of establishment and maintece of
heterochromatin. Although genetic and cell biological aspects have been
elucidated, the molecular details of HP1 binding to H3K9me3 nucleosomes are
unknown. Using a combination of NMR spectroscopy and biophysical measurements on
fully defined recombit experimental systems, we demonstrate that H3K9me3
works as an on/off switch regulating distinct binding modes of hHP1β to the
nucleosome. The methyl-mark determines a highly flexible and very dynamic
interaction of the chromodomain of hHP1β with the H3-tail. There are no other
constraints of interaction or additional multimerization interfaces. In
contrast, in the absence of methylation, the hinge region and the N-terminal
tail form weak nucleosome contacts mainly with DNA. In agreement with the high
flexibility within the hHP1β-H3K9me3 nucleosome complex, the chromoshadow domain
does not provide a direct binding interface. Our results report the first
detailed structural analysis of a dynamic protein-nucleosome complex directed by
a histone modification and provide a conceptual framework for understanding
similar interactions in the context of chromatin. Pericentric regions form epigenetically organized, silent heterochromatin
structures that accumulate histone H3 lysine 9 tri-methylation (H3K9me3) and
heterochromatin protein 1 (HP1), a methylated H3K9-binding protein. At
pericentric regions, Suv39h is the major enzyme that generates H3K9me3. Suv39h
also interacts directly with HP1. However, the importance of HP1 interaction for
Suv39h-mediated H3K9me3 formation at the pericentromere is not well
characterized. To address this question, we introduced HP1 binding-defective,
N-terminally truncated mouse Suv39h1 (ΔN) into Suv39h-deficient cells.
Pericentric H3K9me3-positive cells were not detected by endogenous-level
expression of ΔN. Notably, ΔN could induce pericentric accumulation of H3K9me3
as wild type Suv39h1 did if it was overexpressed. These findings demonstrate
that the N-terminal region of Suv39h1, presumably via HP1-Suv39h1 interaction,
is required for Suv39h1-mediated pericentric H3K9me3 formation, but can be
overridden if Suv39h1 is overproduced, indicating that Suv39h1-mediated
heterochromatin formation is controlled by multiple modules, including HP1. |
What is AZD8601? | AZD8601 is a modified mRNA encoding vascular endothelial growth factor A (VEGF-A). Sequential dosing of AZD8601 improves vascularization and tissue oxygenation of the wound bed, leading to accelerated re-epithelialization during the early phase of diabetic wound healing. | |
List critical regions for 7p22.1 microduplication syndrome | 7p22.1 microduplication syndrome is mainly characterized by developmental and speech delay, craniofacial dysmorphism and skeletal abnormalities. The minimal critical region includes two OMIM genes: ACTB and RNF216. | 7p22.1 microduplication syndrome is mainly characterized by developmental and
speech delay, craniofacial dysmorphisms and skeletal abnormalities. The minimal
critical region includes two OMIM genes: ACTB and RNF216. Here, we report on a
girl carrying the smallest 7p22.1 microduplication detected to date,
contributing to the delineation of the clinical phenotype of the 7p22.1
duplication syndrome and to the refinement of the minimal critical region. Our
patient shares several major features of the 7p22.1 duplication syndrome,
including craniofacial dysmorphisms and speech and motor delay, but she also
presents with renal anomalies. Based on present and published dup7p22.1 patients
we suggest that renal abnormalities might be an additional feature of the 7p22.1
microduplication syndrome. We also pinpoint the ACTB gene as the key gene
affecting the 7p22.1 duplication syndrome phenotype. |
Which molecules are targeted by Trastuzumab Deruxtecan? | Trastuzumab deruxtecan is a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate being developed for the treatment of HER2-expressing solid tumours, including breast cancer, gastric cancer, colorectal cancer and non-small cell lung cancer | BACKGROUND: Antibody-drug conjugates have emerged as a powerful strategy in
cancer therapy and combine the ability of monoclonal antibodies to specifically
target tumour cells with the highly potent killing activity of drugs with
payloads too toxic for systemic administration. Trastuzumab deruxtecan (also
known as DS-8201) is an antibody-drug conjugate comprised of a humanised
antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I
inhibitor payload. We assessed its safety and tolerability in patients with
advanced breast and gastric or gastro-oesophageal tumours.
METHODS: This was an open-label, dose-escalation phase 1 trial done at two study
sites in Japan. Eligible patients were at least 20 years old with breast or
gastric or gastro-oesophageal carcinomas refractory to standard therapy
regardless of HER2 status. Participants received initial intravenous doses of
trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were
assessed over a 21-day cycle; thereafter, dose reductions were implemented as
needed and patients were treated once every 3 weeks until they had unacceptable
toxic effects or their disease progressed. Primary endpoints included
identification of safety and the maximum tolerated dose or recommended phase 2
dosing and were analysed in all participants who received at least one dose of
study drug. The dose-escalation study is the first part of a two-part study with
the second dose-expansion part ongoing and enrolling patients as of July 8,
2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov,
number NCT02564900.
FINDINGS: Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and
received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg
doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1,
2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects,
or deaths occurred. One patient was removed from the activity analysis because
they had insufficient target lesions for analysis. The most common grade 3
adverse events were decreased lymphocyte (n=3) and decreased neutrophil count
(n=2); and grade 4 anaemia was reported by one patient. Three serious adverse
events-febrile neutropenia, intestinal perforation, and cholangitis-were
reported by one patient each. Overall, in 23 evaluable patients, including six
patients with low HER2-expressing tumours, ten patients achieved an objective
response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95%
CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR
4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or
greater.
INTERPRETATION: The maximum tolerated dose of trastuzumab deruxtecan was not
reached. In this small, heavily pretreated study population, trastuzumab
deruxtecan showed antitumour activity, even in low HER2-expressing tumours.
Based on safety and activity, the most likely recommended phase 2 dosing is 5·4
or 6·4 mg/kg.
FUNDING: Daiichi Sankyo Co, Ltd. Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with
a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has
been reported to exert potent antitumor effects in xenograft mouse models and
clinical trials. In this study, the immune system-activating ability of DS-8201a
was assessed. DS-8201a significantly suppressed tumor growth in an
immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2)
cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2
cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to
both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd
upregulated CD86 expression on bone marrow-derived dendritic cells (DC) in vitro
and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86
expression in vivo DS-8201a also increased tumor-infiltrating CD8+ T cells and
enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore,
combination therapy with DS-8201a and anti-PD-1 antibody was more effective than
either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as
evidenced by the increased expression of DC markers, augmented expression of MHC
class I in tumor cells, and rejection of rechallenged tumor cells by adaptive
immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells.
Furthermore, DS-8201a treatment benefited from combination with anti-PD-1
antibody, possibly due to increased T-cell activity and upregulated PD-L1
expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494-503. ©2018 AACR. Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC) composed
of a monoclonal antibody targeting human epidermal growth factor receptor 2
(HER2) conjugated to a topoisomerase I inhibitor (DXd) at a drug-to-antibody
ratio (DAR) of 7-8. Here, we examined the pharmacokinetic (PK) profiles of
DS-8201a and DXd in cynomolgus monkeys, a cross-reactive species. Following
intravenous (iv) administration of DS-8201a, the linker was stable in plasma,
and systemic DXd exposure was low. DXd was rapidly cleared following iv dosing.
Biodistribution studies revealed that intact DS-8201a was present mostly in the
blood without tissue-specific retention. The major pathway of excretion for DXd
was the faecal route following iv administration of radiolabelled DS-8201a. The
only detectable metabolite in the urine and faeces was unmetabolized DXd. DXd is
a substrate of organic anion transporting polypeptides, P-gp, and breast cancer
resistance protein. In conclusion, the stable linker in circulation and the high
clearance of DXd upon release resulted in the low systemic exposure to DXd.
Furthermore, the minimal tissue-specific retention and rapid excretion of DXd
into faeces as its unmetabolized form with potentially limited impact on
drug - drug interaction as a victim were also critical elements of the PK
profile of DS-8201a. Therapies targeted to human epidermal growth factor receptor 2 (HER2) have
proven effective against tumors positive for HER2 amplification, but there is an
unmet clinical need for the treatment of tumors that express HER2 protein in the
absence of HER2 amplification. [fam-] trastuzumab deruxtecan (DS-8201a) is a
novel antibody-drug conjugate composed of the anti-HER2 antibody and the
topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against
tumors that express HER2 and is currently under evaluation in clinical trials.
We here show that the antitumor activity of [fam-] trastuzumab deruxtecan is
dependent on the expression level of HER2 protein in colorectal cancer (CRC)
cell lines negative for HER2 amplification. We established isogenic CRC cell
lines that express various levels of HER2 protein in the absence of HER2
amplification, and we found that cells that express HER2 at a high level were
sensitive to [fam-] trastuzumab deruxtecan but not to conventional HER2-targeted
therapies. Furthermore, [fam-] trastuzumab deruxtecan manifested a bystander
killing effect both in vitro and in vivo, with cells essentially negative for
HER2 expression also being killed in the presence of HER2-expressing cells, an
effect that has the potential to overcome heterogeneity of HER2 expression in
CRC tumors. Our results thus suggest that [fam-] trastuzumab deruxtecan warrants
further study as a potential treatment for CRC tumors that express HER2 protein
in the absence of HER2 amplification. BACKGROUND: There has been substantial interest in HER2 intratumoral
heterogeneity as an explanation for the development of resistance to anti-HER2
therapies in breast cancer, particularly to trastuzumab emtansine (T-DM1).
METHODS: Through a literature-based approach, we discuss mechanisms of
resistance to HER2-targeting antibody-drug conjugates (ADCs) in breast cancer.
RESULTS: We describe results from clinical studies reporting the effect of
anti-HER2 strategies particularly ADCs and their mechanistic effect. We review
biological findings underlying HER2 heterogeneity and its implication in the
development of novel anti-HER2 drugs including new ADCs in clinical development
like trastuzumab deruxtecan (DS-8201).
CONCLUSIONS: We suggest potential mechanisms to optimize these compounds and
their future clinical implementation. PURPOSE: Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human
epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC)
with a topoisomerase I inhibitor payload. A dose escalation and expansion phase
I study evaluated the safety and activity of T-DXd in patients with advanced
HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended
doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC]
1+ or IHC 2+/in situ hybridization-) breast cancer (ClinicalTrials.gov
identifier: NCT02564900) are reported.
PATIENTS AND METHODS: Eligible patients had advanced/metastatic
HER2-low-expressing breast cancer refractory to standard therapies. The RDE of
5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until
withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor
activity and safety were assessed.
RESULTS: Between August 2016 and August 2018, 54 patients were enrolled and
received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated
(median, 7.5 prior therapies). The confirmed objective response rate by
independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median
duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most
patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE;
grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in
neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase;
decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered
fatal events associated with T-DXd-induced interstitial lung disease
(ILD)/pneumonitis as determined by an independent adjudication committee.
CONCLUSION: The novel HER2-targeted ADC, T-DXd, demonstrated promising
preliminary antitumor activity in patients with HER2-low breast cancer. Most
toxicities were GI or hematologic in nature. ILD is an important identified risk
and should be monitored closely and proactively managed. Trastuzumab deruxtecan (ENHERTU®), a HER2-directed antibody and DNA
topoisomerase I inhibitor conjugate, is being developed for the treatment of
HER2-expressing solid tumours, including breast cancer, gastric cancer,
colorectal cancer and non-small cell lung cancer by Daiichi Sankyo Company Ltd
in collaboration with AstraZeneca. Based primarily on the results of the phase 2
DESTINY-Breast01 trial, trastuzumab deruxtecan was recently approved in the USA
under accelerated approval for the treatment of adult patients with unresectable
or metastatic HER2-positive breast cancer who have received two or more prior
anti-HER2-based regimens in the metastatic setting. This article summarizes the
milestones in the development of trastuzumab deruxtecan leading to this first
approval. The development of antibody-drug conjugates composed of a cytotoxic agent and a
monoclonal antibody carrier offers an important alternative to classic
chemotherapy strategies. Trastuzumab deruxtecan (DS-8201a) is a next-generation
antibody-drug conjugate composed of a monoclonal anti-HER2 antibody and a
topoisomerase I inhibitor, an exatecan derivative (DX-8951f). DS-8201a resulted
in favorable outcomes in HER2-positive heavily pretreated breast cancer patients
and also had a promising efficacy in patients with HER2-negative/low-expressing
disease, whose options are limited. Interestingly, a recently published phase 2
trial (NCT03248492) reported 60% overall response and 97% disease control in
patients with HER2-positive disease previously treated with multiple regimens,
including trastuzumab emtansine. On the basis of recent clinical trials, the US
Food and Drug Administration granted accelerated approval to DS-8201a in
advanced or unresectable HER2-positive breast cancer pretreated with at least
two HER2-targeting treatment lines. We review all preclinical and clinical data
of DS-8201a regarding breast cancer. Trastuzumab deruxtecan (DS-8201) is a human epidermal growth factor receptor 2
(HER2)-targeting antibody-drug conjugate with a novel enzyme-cleavable linker, a
topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have
characterized the population pharmacokinetics (PK) of trastuzumab deruxtecan and
released drug (topoisomerase I inhibitor) in patients with HER2-positive breast
cancer or other solid tumor maligcies. This analysis includes pooled data
from five clinical studies with 639 patients. Trastuzumab deruxtecan doses
ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of trastuzumab
deruxtecan and released drug were analyzed using a sequential two-step approach,
with the nonlinear mixed-effects modeling methods. Covariate assessment was
based upon stepwise forward-addition and backward-elimination process, followed
by both univariate and multivariate analysis quantifying their impact on
steady-state exposure of trastuzumab deruxtecan and released drug. A
two-compartment model with linear elimination best described PK profiles of
intact trastuzumab deruxtecan, while a one-compartment model with time-varying
release-rate constant and linear elimination described released-drug PK
profiles. Statistically significant covariates (country, tumor size, sex,
formulation, age, body weight, albumin, total bilirubin, and aspartate
aminotransferase) resulted in < 20% change in steady-state area under the
concentration-time curve of trastuzumab deruxtecan and released drug, except for
increased body weight (95th percentile, 86 kg) and decreased albumin (5th
percentile, 31 g/L). Analysis of patients stratified by country, race, renal
function, and hepatic function found no clinically meaningful differences in
steady-state exposure of intact trastuzumab deruxtecan or released drug.
Overall, results suggest that no dose adjustment based on tested covariates or
in specific patient populations is warranted. |
What is the function of the HSJ1 proteins? | HSJ1 is a neuronal enriched member of the HSP40/DNAJ co-chaperone family. | |
What is the indication for zolmitriptan? | Development of a novel zolmitriptan intracutaneous microneedle system (Qtrypta™) for the acute treatment of migraine | 311C90 (Zomig; zolmitriptan) is a novel, selective serotonin (5HT)1B/1D receptor
agonist with both central and peripheral activity, now in late-stage clinical
development for acute oral treatment of migraine. Several studies have
demonstrated the tolerability and efficacy of 311C90 in the treatment of a
single migraine headache. The objectives of this open-label study were to assess
the tolerability and efficacy of repeated doses of 5 mg of 311C90 for acute
treatment of multiple attacks for up to 1 year. Patients were allowed to treat
as many migraine headaches (mild, moderate, or severe) as desired with an
initial dose. A second 5-mg dose could be used to treat recurrence should it
develop. Safety assessments included ECG, the frequency, intensity, and duration
of adverse experiences, and routine hematology, urinalysis, and clinical
chemistry parameters. Efficacy assessments included headache severity at 2 hours
(i.e., severe, moderate, mild, or none), the proportion of patients pain-free at
2 hours, the use of a second tablet to treat headache recurrence if it
developed, and the consistency of these findings over time. The efficacy profile
and the nature/incidence of adverse events reported appear to be consistent with
previous 311C90 studies. The dosing regimen was well tolerated during multiple
exposures. Notably, headache response rates were consistently good after both
initial and repeated exposure (> 80% across 1 to 30 attacks). For 67% of
patients who treated at least five attacks, 311C90 was effective 80 to 100% of
the time. Zolmitriptan is a potent selective 5HT1B/1D receptor agonist for acute migraine
therapy. Zolmitriptan has vasoconstrictor activity in cerebral vessels and may
cause slight elevations of blood pressure in subjects without hypertension.
Therefore, the pharmacokinetics and pharmacodynamics of zolmitriptan (5, 10, and
20 mg) were evaluated in 16 patients with mild to moderate hypertension
(controlled by hydrochlorothiazide 50 mg once daily) and 17 healthy age- and
sex-matched control subjects in a randomized, placebo-controlled, double-blind,
four-period crossover study. The pharmacokinetics of zolmitriptan and its
metabolites were dose proportional. Although area under the concentration-time
curve (AUC0-infinity) and maximum concentration (Cmax) were slightly higher in
patients with hypertension at all doses, this was only statistically significant
for AUC at the 20-mg dose. Differences between subjects with and without
hypertension were not clinically significant. Zolmitriptan produced a small
increase in blood pressure, but this was similar in subjects with and without
hypertension and was of no clinical significance. Zolmitriptan was well
tolerated in both groups. Zolmitriptan plasma concentrations were higher in
women than in men, with higher values of AUC and Cmax and lower total clearance
in women. These results indicate that zolmitriptan can be administered for
treatment of migraine in patients with controlled hypertension without dose
adjustment. Zolmitriptan is a 5-HT1B/1D receptor agonist for the acute treatment of
migraine. This study examined the efficacy of a second dose of zolmitriptan for
the treatment of persistent or recurrent headache. Part 1 was a randomised,
placebo-controlled, double-blind evaluation of 2.5 mg and 5 mg zolmitriptan for
the treatment of persistent migraine headache, two hours after an initial dose
of 2.5 mg zolmitriptan. In part 2 (open-label), patients treated the first two
attacks with 2.5 mg zolmitriptan, thereafter patients could treat any initial,
persistent or recurrent migraine headache with 2.5 mg or 5 mg zolmitriptan. The
unique design of this trial allowed patients to adjust their treatment to attain
maximum headache relief and control of their disease. Of 2800 patients treating
an initial migraine headache in Part 1, 989 patients took a second dose to treat
persistent headache of moderate or severe intensity. Headache response rates
were similar across the three treatment groups, but the pain-free response rate
was significantly higher with 5 mg zolmitriptan than with placebo (p < 0.001).
In Part 2, 2499 patients treated 49,784 migraine attacks (excluding the first
two attacks, which had to be treated with 2.5 mg zolmitriptan), of which 66%
required only a single dose of zolmitriptan. Patients treated 22% of attacks
with a second dose of zolmitriptan for persistent headache. A headache response
was achieved in 80% and 73% of persistent headaches treated with 2.5 mg or 5 mg
zolmitriptan, respectively. Corresponding pain-free responses following
treatment of persistent headaches of any intensity were 64% and 52%. Eight per
cent of attacks were treated with a second dose of zolmitriptan for moderate or
severe recurrent headache. A headache response was achieved in 90% and 86% of
moderate/severe attacks, with a pain-free response in 78% and 70% of attacks of
any intensity treated with 2.5 mg and 5 mg, respectively. Zolmitriptan was well
tolerated. In conclusion, 2.5 mg and 5 mg zolmitriptan are highly effective in
treating both persistent and recurrent migraine headache. In the last two years, a number of 5-HT1B/1D agonist triptans with enhanced
lipophilicity (TELs) relative to the first drug of this class, sumatriptan, have
been approved for marketing in most countries of the world (naratriptan,
rizatriptan and zolmitriptan). In addition, at least three others are in
advanced stage of clinical development (almotriptan, eletriptan, and
frovatriptan). This paper sets out to review the recent data with the aim of
identifying: 1) What are the critical differences between the TELs and
sumatriptan? 2) How do the currently licensed TELs compare? 3) Is it possible to
provide a rational approach to migraine therapy based on objective differences
in the clinical profile of these new drugs? Recent randomised controlled and
comparator data were reviewed, including the independent FDA assessment of
rizatriptan. Critical differences for the new TELs (naratriptan, rizatriptan and
zolmitriptan) which may lead to more rational migraine management: Both
rizatriptan (10 mg) and zolmitriptan (2.5 mg and 5.0 mg) have demonstrated
superior efficacy to sumatriptan 100 mg, and 25 and 50 mg respectively.
Therefore, for first line use either rizatriptan or zolmitriptan would be
appropriate for moderate and severe headache. Rizatriptan has a more rapid onset
of action than sumatriptan 100 mg. Both rizatriptan and zolmitriptan have a more
rapid onset of action than naratriptan. Therefore, for a rapid onset of action
either rizatriptan or zolmitriptan would be appropriate. Naratriptan would
appear to have a lower recurrent headache rate than sumatriptan, rizatriptan or
zolmitriptan. However, 24-hour efficacy rates for zolmitriptan 2.5 mg were
significantly greater than for sumatriptan 25 mg and 50 mg and were not
significantly different from naratriptan. Therefore, for headaches of long
duration and with a tendency to recur (e.g. menstrual headaches) either
naratriptan or zolmitriptan would be appropriate. Naratriptan has lower reported
adverse event rates comparable with placebo. This would support the use of
naratriptan 2.5 mg in patients who have demonstrated poor tolerance to the
"triptan type" adverse events. RATIONALE: Zolmitriptan is an anti-migraine agent with action at 5-HT1B/D
receptors. It penetrates into the central nervous system and, like other
5-HT1B/D agonists, its pharmacotherapeutic profile may include significant
anti-aggressive effects.
OBJECTIVES: To examine whether zolmitriptan has potential anti-aggressive
effects by studying two kinds of aggressive behavior in mice--species-typical
and aggression under the influence of alcohol. A second objective was to study
whether pre- or post-synaptic receptors mediate these anti-aggressive effects.
METHODS: Initially, the anti-aggressive effects of zolmitriptan were studied in
male CFW mice during 5-min resident-intruder confrontations. To confirm the
5-HT1B receptor as a critical site of action for the anti-aggressive effects,
the zolmitriptan dose-effect determinations were repeated after pretreatment
with GR 127935 (10 mg/kg, i.p.). In further experiments, mice were treated
concurrently with alcohol (1.0 g/kg, p.o.) and zolmitriptan (1-30 mg/kg, i.p.)
in order to compare the effects of this agonist on species-typical and
alcohol-heightened aggression. Finally, mice were infused with the neurotoxin
5,7-DHT (10 microg) into the raphé area to eliminate somatodendritic and
presynaptic autoreceptors. The anti-aggressive effects of zolmitriptan (17
mg/kg, i.p.) or CP-94,253 (10 mg/kg, i.p.) were assessed 10 days after the
lesion, and levels of 5-HT and 5-HIAA were measured in the hippocampus and
prefrontal cortex.
RESULTS: Zolmitriptan exerted behaviorally specific anti-aggressive effects. The
reduction in aggression was antagonized by GR 127935, indicated by a rightward
shift in the dose-effect curves of zolmitriptan, showing the specificity for the
5-HT1B receptors. Zolmitriptan also decreased alcohol-heightened aggression with
equal efficacy. The anti-aggressive effects of CP-94,253 and zolmitriptan
remained unaltered by 5,7-DHT lesions that depleted cortical and hippocampal
5-HT by 60-80%.
CONCLUSIONS: Zolmitriptan proved to be an effective and behaviorally specific
anti-aggressive agent in situations that engender moderate and
alcohol-heightened levels of aggression. These effects are potentially due to
activation of post-synaptic 5-HT1BD receptors. Preclinical studies have shown that zolmitriptan is a selective serotonin
5-HT(1B/1D) receptor agonist (triptan). Randomised, placebo-controlled,
double-blind trials in patients with migraine have shown that zolmitriptan has
good efficacy measured using 2 h response and pain-free rates.
Migraine-associated symptoms, including nausea, photophobia and phonophobia, are
also improved with zolmitriptan. Oral zolmitriptan (2.5 and 5 mg) has an onset
of action within 45 min and efficacy is sustained in most patients who respond
at 2 h. The orally-disintegrating zolmitriptan tablet has the advantage that it
may be taken immediately, without the need for additional fluids, any time a
migraine headache occurs. Patients may benefit in terms of improved efficacy
from the convenience of the disintegrating tablet, since there is evidence that
taking triptan therapy as early as possible in an attack is advantageous. For
similar reasons, as well as improved efficacy, a nasal spray formulation is in
development. Zolmitriptan is effective in the treatment of migraine associated
with menses and migraine with aura. There is no tachyphylaxis following repeated
doses for multiple attacks of migraine over a prolonged period of time. Compared
to placebo, the incidence of persistent migraine headache is reduced by
zolmitriptan and recurrent migraine headache occurs less frequently.
Zolmitriptan has also shown efficacy in the treatment of persistent and/or
recurrent migraine headache. Comparative clinical studies have shown overall
that zolmitriptan has similar or superior efficacy to sumatriptan in the
treatment of migraine. Specifically, zolmitriptan 2.5 mg was significantly more
effective than sumatriptan 25 or 50 mg according to a number of end points,
including headache response at 2 h. Oral zolmitriptan is also effective in the
acute treatment of cluster headache. Zolmitriptan is generally well tolerated,
with most adverse events being mild-to-moderate, transient and resolving without
intervention or the need for treatment withdrawal. The consistent efficacy in
treating all types of migraine and the choice of available formulations make
zolmitriptan acceptable to patients and a suitable first-line therapy for the
treatment of migraine. Zolmitriptan, a selective 5-HT(1B/D) agonist was developed for the acute
treatment of migraine. Dose-finding studies show a clearly defined dose response
curve for the oral formulation with onset of efficacy demonstrated within 45 min
of dosing. Clinical trials support its efficacy in all types of migraine, with
excellent safety and tolerability in those patients for whom zolmitriptan is not
contraindicated. Future developments, including new formulations, will provide
patients with a greater choice of treatment. Zolmitriptan is a new oral acute treatment for migraine. It is a selective and
potent agonist at the serotonin (5-HT)(1B/1D) receptor and was developed to
improve on the oral bioavailability, tissue selectivity and CNS penetration of
earlier compounds. Animal studies confirmed that these objectives had been
attained. In man, zolmitriptan is rapidly absorbed after oral administration,
with at least 75% of the eventual C(max) reached within 1 h. Oral
bioavailability is approximately 40%. The elimination half-life of zolmitriptan
is approximately 2.5 h and the primary route of elimination is metabolism, with
one of the metabolites being pharmacologically active. A consistent 2-h headache
response rate of 60-70% was observed at doses of 2.5 mg and above. Long-term
treatment response is high (> 80%) and consistent. In addition, there is
evidence from electrophysiology in migraineurs that zolmitriptan has a central
action not shared by sumatriptan. Zolmitriptan is well-tolerated. The nature and
incidence of the most frequently reported adverse events are similar to those of
other 5-HT(1B/1D) agonists. Long-term zolmitriptan usage was associated with an
improvement in quality of life. Zolmitriptan is a suitable first-line drug for
acute treatment for migraine. INTRODUCTION: The objective is to analyse our experience with the new intranasal
formulation of zolmitriptan 5 mg in the symptomatic treatment of cluster
headache in daily clinical practice.
PATIENTS AND METHODS: We collected a total of 18 patients with cluster headache
and experience with intranasal zolmitriptan; 17 had used subcutaneous
sumatriptan and 8 oral triptans. The main reasons for trying intranasal
zolmitriptan were: poor tolerability in 12 patients and insufficient efficacy in
6.
RESULTS: Among the 17 patients experienced in subcutaneous sumatriptan, 12 (71
%) preferred nasal zolmitriptan, 2 (18 %) subcutaneous sumatriptan and 2 (12 %)
did not express any preference. The reasons for preferring intranasal
zolmitriptan were: higher convenience (n = 6), better tolerability (n = 5),
lower price (n = 2) and higher efficacy (n = 1). Seven out of the 8 patients who
had taken oral triptans preferred nasal zolmitriptan, in all cases due to higher
subjective efficacy. A total of 11 patients showed efficacy within 30 minutes.
Only 3 patients referred to adverse events, always mild.
CONCLUSIONS: The 5 mg nasal formulation of zolmitriptan is a potential new
option for the symptomatic treatment of cluster headache. This formulation
should be considered in patients with poor tolerability to subcutaneous
sumatriptan and in those attacks where quick access to inhaled oxygen is not
possible. These results suggest that a controlled trial with nasal zolmitriptan
in this indication would be worthwhile. Migraine is a common, often disabling, neurovascular disease that has been shown
to be associated with abnormal serotonergic activity. Drugs that modulate
serotonin receptors are commonly used in the acute treatment of a migraine
attack. Zolmitriptan, a 5-hydroxytryptophan(1B/1D) receptor agonist, is once
such drug that is used in acute migraine therapy. Zolmitriptan is FDA approved
for the treatment of acute migraine attacks and there is recent literature
demonstrating its efficacy in the acute treatment of cluster attacks. It is
rapidly absorbed and is detectable in the plasma within 2 - 5 min for the nasal
spray formulation and within 15 min for the oral formulations. Zolmitriptan
reaches peak plasma levels in 2 - 4 h and significant plasma levels are
maintained for up to 6 h and lower levels for over 15 h. As zolmitriptan's
metabolism is predomitly hepatic, patients with severe hepatic impairment
should not receive zolmitriptan. However, only 25% of zolmitriptan is bound to
plasma proteins and thus it is unlikely for drug interactions involving the
displacement of highly protein-bound drugs. Zolmitriptan is generally very well
tolerated and less than half of patients in clinical trials have reported
adverse events, most of which are mild and transient, although rare serious
cardiovascular events have been reported with all triptans. When patients are
appropriately selected, zolmitriptan is both a safe and effective acute care
migraine treatment. In this review the biological role of serotonin and its
receptors is covered, followed by an in-depth review of the pharmacodynamics,
pharmacokinetics and efficacy of zolmitriptan. Finally, the clinical application
of zolmitriptan's use in patients is dicussed. INTRODUCTION: Migraine has recently become a major interest to the
neuroscientists. Zolmitriptan is an effective medicine used in the treatment of
migraine. The nasal spray was prepared from Zolmitriptan loaded chitosan
oparticles and evaluated for pharmacokinetic properties.
METHODS: In this study male Wistar albino rats weighing between 200 and 250 g
were taken and divided into 4 groups with 6 rats in each group. Nasal spray
containing Zolmitriptan loaded Chitosan oparticles were administered nasally
(using specific inhalation mask) at a dose of 0.5 mg/kg as a test formulation
and compared with the control groups which received either water for injection
or marketed standard drug (Zolmist) or standard drug solution at a same dose.
The pharmacokinetic parameters such as Cmax, Tmax, and brain tissue analyses for
accumulation of drug were performed for Zolmitriptan by LC-MS method.
RESULTS: Amount of drug in the plasma from the test formulation, standard
marketed drug (Zolmist) and standard drug solution was found to be 41.37 ± 2.31,
34.76 ± 4.22 and 23.74 ± 2.42 ng/ml at 10 min respectively, which indicated
significantly (p < 0.05) greater amount of drug being delivered from the test
formulation compared to the both standard groups. The amount of the drug
(Zolmitriptan) present in brain tissue (Olfactory lobe) was found to be
15 ± 0.08, 13 ± 0.14 and 8 ± 0.13 ng/g at 60 min for test formulation, marketed
standard and standard drug solution respectively which indicates significantly
(p < 0.05) higher amount of drug absorption in brain tissue from the test
formulation compared to both the standard groups.
CONCLUSION: Pharmacokinetics studies of nasal spray containing Zolmitriptan
loaded chitosan oparticles proved rapid onset of action in animals and is
promising in treatment of migraine. There are many new treatment options available for migraine and more are coming.
Three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies
have been approved and a 4th is due in early 2020. Small molecule CGRP
receptor-blocking oral compounds, both for acute care and prevention, are also
coming. Four neurostimulators are available, with others on the way. New acute
treatments coming soon include the 5HT1F agonist lasmiditan, a zolmitriptan
intradermal micro-needle patch, and a nasal mist sumatriptan with a permeability
enhancer. Farther out, three novel dihydroergotamine delivery systems, and a
liquid-filled capsule of celecoxib show early promise. A new, safer form of
methysergide is in the works, as is a longer-duration onabotulinumtoxinA. As
always with new products, questions regarding safety, tolerability, cost, and
insurance coverage will need to be addressed. Despite these concerns and
uncertainties, a robust headache treatment pipeline is good for patients who are
not satisfied with the results of their treatment and/or cannot tolerate
existing treatments. |
What percentage of C. elegans genes reside in operons? | Nearly 15% of the ~20,000 C. elegans genes are contained in operons, multigene clusters controlled by a single promoter. Our evidence indicates that the genome contains at least 1,000 operons, 2 8 genes long, that contain about 15% of all C. elegans genes. | The nematode worm Caenorhabditis elegans and its relatives are unique among
animals in having operons. Operons are regulated multigene transcription units,
in which polycistronic pre-messenger RNA (pre-mRNA coding for multiple peptides)
is processed to monocistronic mRNAs. This occurs by 3' end formation and
trans-splicing using the specialized SL2 small nuclear ribonucleoprotein
particle for downstream mRNAs. Previously, the correlation between downstream
location in an operon and SL2 trans-splicing has been strong, but anecdotal.
Although only 28 operons have been reported, the complete sequence of the C.
elegans genome reveals numerous gene clusters. To determine how many of these
clusters represent operons, we probed full-genome microarrays for SL2-containing
mRNAs. We found significant enrichment for about 1,200 genes, including most of
a group of several hundred genes represented by complementary DNAs that contain
SL2 sequence. Analysis of their genomic arrangements indicates that >90% are
downstream genes, falling in 790 distinct operons. Our evidence indicates that
the genome contains at least 1,000 operons, 2 8 genes long, that contain about
15% of all C. elegans genes. Numerous examples of co-transcription of genes
encoding functionally related proteins are evident. Inspection of the operon
list should reveal previously unknown functional relationships. A recent report by Blumenthal et al. provides convincing evidence that at least
15% of Caenorhabditis elegans genes are co-transcribed within over a thousand
operons. Polycistronic transcription of gene clusters is very rare in
eukaryotes. The widespread occurrence of operons in C. elegans thus raises some
interesting questions about the origin and function of these multigenic
transcriptional units. Operons are found across multiple kingdoms and phyla, from prokaryotes to
chordates. In the nematode Caenorhabditis elegans, the genome contains >1000
operons that compose approximately 15% of the protein-coding genes. However,
determination of the force(s) promoting the origin and maintece of operons in
C. elegans has proved elusive. Compared to bacterial operons, genes within a C.
elegans operon often show poor coexpression and only sometimes encode proteins
with related functions. Using analysis of microarray and large-scale in situ
hybridization data, we demonstrate that almost all operon-encoded genes are
expressed in germline tissue. However, genes expressed during spermatogenesis
are excluded from operons. Operons group together along chromosomes in local
clusters that also contain monocistronic germline-expressed genes. Additionally,
germline expression of genes in operons is largely independent of the molecular
function of the encoded proteins. These analyses demonstrate that mechanisms
governing germline gene expression influence operon origination and/or
maintece. Thus, gene expression in a specific tissue can have profound
effects on the evolution of genome organization. Genes in nematode and ascidian genomes frequently occur in operons--multiple
genes sharing a common promoter to generate a polycistronic primary
transcript--and such genes comprise 15-20% of the coding genome for
Caenorhabditis elegans and Ciona intestinalis. Recent work in nematodes has
demonstrated that the identity of genes within operons is highly conserved among
species and that the unifying feature of genes within operons is that they are
expressed in germline tissue. However, it is generally unknown what processes
are responsible for generating the distribution of operon sizes across the
genome, which are composed of up to eight genes per operon. Here we investigate
several models for operon evolution to better understand their abundance,
distribution of sizes, and evolutionary dynamics over time. We find that
birth-death models of operon evolution reasonably describe the relative
abundance of operons of different sizes in the C. elegans and Ciona genomes and
generate predictions about the number of monocistronic, nonoperon genes that
likely participate in the birth-death process. This theory, and applications to
C. elegans and Ciona, motivates several new and testable hypotheses about
eukaryote operon evolution. Trans-splicing of one of two short leader RNAs, SL1 or SL2, occurs at the 5'
ends of pre-mRNAs of many C. elegans genes. We have exploited RNA-sequencing
data from the modENCODE project to analyze the transcriptome of C. elegans for
patterns of trans-splicing. Transcripts of ∼70% of genes are trans-spliced,
similar to earlier estimates based on analysis of far fewer genes. The mRNAs of
most trans-spliced genes are spliced to either SL1 or SL2, but most genes are
not trans-spliced to both, indicating that SL1 and SL2 trans-splicing use
different underlying mechanisms. SL2 trans-splicing occurs in order to separate
the products of genes in operons genome wide. Shorter intercistronic distance is
associated with greater use of SL2. Finally, increased use of SL1 trans-splicing
to downstream operon genes can indicate the presence of an extra promoter in the
intercistronic region, creating what has been termed a "hybrid" operon. Within
hybrid operons the presence of the two promoters results in the use of the two
SL classes: Transcription that originates at the promoter upstream of another
gene creates a polycistronic pre-mRNA that receives SL2, whereas transcription
that originates at the internal promoter creates transcripts that receive SL1.
Overall, our data demonstrate that >17% of all C. elegans genes are in operons. |
What is the most advanced phase of clinical trial that fingolimod has entered? | Fingolimod has been assessed in phase IV clinical trials. | INTRODUCTION: The mechanism of action of fingolimod within the central nervous
system and its efficacy in reducing/preventing both focal and diffuse grey
matter (GM) damage in active multiple sclerosis (MS) are not completely
understood.
METHODS: In this longitudinal, 2-year prospective, phase IV, single-blind study,
40 MS patients treated with fingolimod and 39 untreated age, gender, and
disability-matched MS patients were enrolled. Each patient underwent a
neurological examination every 6 months and a 3T MRI at the beginning of the
treatment and after 24 months. The accumulation of new cortical lesions (CLs)
and the progression of regional GM atrophy were compared between the two groups.
RESULTS: At the end of the study (T24), the percentage of patients with new CLs
(13.5 vs. 89%, p < 0.001) and the percentage of GM volume change was lower in
the treated group (p < 0.001). The regional analysis revealed that the treated
group had also less volume loss in thalamus, caudatus, globus pallidus,
cingulate cortex, and hippocampus (p < 0.001), as well as in, cerebellum,
superior frontal gyrus, and insular-long gyrus (p < 0.05). Patients with no
evidence of disease activity were 60% in the treated group and 10% in the
untreated group (p < 0.001).
CONCLUSIONS: These results suggest a possible protective effect of fingolimod on
focal and diffuse GM damage. |
What is caused by a gain-of-function mutation in CLCN2? | A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism, which is the most common and curable form of arterial hypertension. | Author information:
(1)Department of Nephrology, Medical School, Heinrich Heine University
Düsseldorf, Düsseldorf, Germany. [email protected].
(2)Department of Nephrology and Medical Intensive Care,
Charité-Universitätsmedizin Berlin, Berlin Institute of Health, Berlin, Germany.
[email protected].
(3)Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum
Jülich, Jülich, Germany.
(4)Department of Nephrology, Medical School, Heinrich Heine University
Düsseldorf, Düsseldorf, Germany.
(5)Department of Genetics, Yale University School of Medicine, New Haven, CT,
USA.
(6)Howard Hughes Medical Institute, Yale University School of Medicine, New
Haven, CT, USA.
(7)Yale Center for Mendelian Genomics, New Haven, CT, USA.
(8)Department of Biomedical Sciences, Seoul National University College of
Medicine, Seoul, Republic of Korea.
(9)Endocrine Hypertension Research Center, University of Queensland Diamantina
Institute, Greenslopes and Princess Alexandra Hospitals, Brisbane, Queensland,
Australia.
(10)Proteomics Platform, Max Delbrück Center for Molecular Medicine in the
Helmholtz Society and Core Unit of Proteomics, Berlin Institute of Health,
Berlin, Germany.
(11)Nephrology, Le Bonheur Children's Hospital, Memphis, TN, USA.
(12)Cooper Clinic, PA, Fort Smith, AR, USA.
(13)Peyton Manning Children's Hospital at St. Vincent, Indianapolis, IN, USA.
(14)Division of Metabolism, Endocrinology and Diabetes, University of Michigan
Medical School, Ann Arbor, MI, USA.
(15)Division of Nephrology and Hypertension, Department of Pediatrics,
Vanderbilt University School of Medicine, Nashville, TN, USA.
(16)Olin Teague Veterans Administration Hospital, Temple, TX, USA.
(17)Division of Endocrinology, Nemours Children's Specialty Care, Jacksonville,
FL, USA.
(18)Laboratory of Human Genetics and Genomics, The Rockefeller University, New
York, NY, USA.
(#)Contributed equally Author information:
(1)INSERM, UMRS 970, Paris Cardiovascular Research Center, Paris, France.
[email protected].
(2)Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
[email protected].
(3)Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou,
Service de Génétique, Paris, France. [email protected].
(4)INSERM, UMRS 970, Paris Cardiovascular Research Center, Paris, France.
(5)Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
(6)Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin,
Germany.
(7)Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany.
(8)Division of Pediatric Endocrinology, Department of Pediatrics, All India
Institute of Medical Sciences, New Delhi, India.
(9)Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou,
Service de Génétique, Paris, France.
(10)Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou,
Unité Hypertension Artérielle, Paris, France.
(11)Normandie Université, UNIROUEN, Rouen, France.
(12)INSERM, DC2N, Rouen, France.
(13)Department of Endocrinology, Diabetes and Metabolic Diseases, University
Hospital of Rouen, Rouen, France.
(14)Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
(15)Institute of Human Genetics, Technische Universität München, Munich,
Germany.
(16)Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin,
Germany. [email protected].
(17)Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany.
[email protected].
(18)INSERM, UMRS 970, Paris Cardiovascular Research Center, Paris, France.
[email protected].
(19)Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
[email protected].
(20)Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou,
Service de Génétique, Paris, France. [email protected].
(#)Contributed equally |
Which treatments were compared in the UNBLOCS trial? | The UNBLOCS trial compared thulium laser transurethral vaporesection of the prostate versus transurethral resection of the prostate for men with lower urinary tract symptoms or urinary retention. | OBJECTIVE: To determine the cost-effectiveness of the current 'gold standard'
operation of transurethral resection of the prostate (TURP) compared to the new
laser technique of thulium laser transurethral vaporesection of the prostate
(ThuVARP) in men with benign prostatic obstruction (BPO) within the UK National
Health Service (NHS).
PATIENTS AND METHODS: The trial was conducted across seven UK centres (four
university teaching hospitals and three district general hospitals). A total of
410 men aged ≥18 years presenting with either bothersome lower urinary tract
symptoms (LUTS) or urinary retention secondary to BPO, and suitable for surgery,
were randomised (whilst under anaesthetic) 1:1 to receive the TURP or ThuVARP
procedure. Resource use in relation to the operation, initial inpatient stay,
and subsequent use of NHS services was collected for 12 months from
randomisation (equivalent to primary effectiveness outcome) using hospital
records and patient questionnaires. Resources were valued using UK reference
costs. Quality adjusted life years (QALYs) were calculated from the EuroQoL five
Dimensions five Levels (EQ-5D-5L) questionnaire completed at baseline, 3- and
12-months. Total adjusted mean costs, QALYs and incremental Net Monetary Benefit
statistics were calculated: cost-effectiveness acceptability curves and
sensitivity analyses addressed uncertainty.
RESULTS: The total adjusted mean secondary care cost over the 12 months in the
TURP arm (£4244) was £9 (95% CI -£376, £359) lower than the ThuVARP arm (£4253).
The ThuVARP operation took on average 21 min longer than TURP. The adjusted mean
difference of QALYs (0.01 favouring TURP, 95% CI -0.01, 0.04) was similar
between the arms. There is a 76% probability that TURP is the cost-effective
option compared with ThuVARP at the £20 000 per QALY willingness to pay
threshold used by National Institute for Health and Care Excellence (NICE).
CONCLUSION: One of the anticipated benefits of the laser surgery, reduced length
of hospital stay with an associated reduction in cost, did not materialise
within the study. The longer duration of the ThuVARP procedure is important to
consider, both from a patient perspective in terms of increased time under
anaesthetic, and from a service delivery perspective. TURP remains a highly
cost-effective treatment for men with BPO. BACKGROUND: Transurethral resection of the prostate (TURP) is the standard
operation for benign prostatic obstruction (BPO). Thulium laser transurethral
vaporesection of the prostate (ThuVARP) vaporises and resects the prostate using
a technique similar to TURP. The small amount of existing literature suggests
that there may be potential advantages of ThuVARP over TURP.
OBJECTIVE: To determine whether or not the outcomes from ThuVARP are equivalent
to the outcomes from TURP in men with BPO treated in the NHS.
DESIGN: A multicentre, pragmatic, randomised controlled parallel-group trial,
with an embedded qualitative study and economic evaluation.
SETTING: Seven UK centres - four university teaching hospitals and three
district general hospitals.
PARTICIPANTS: Men aged ≥ 18 years who were suitable to undergo TURP, presenting
with bothersome lower urinary tract symptoms (LUTS) or urinary retention
secondary to BPO.
INTERVENTIONS: Patients were randomised 1 : 1 to receive TURP or ThuVARP and
remained blinded.
MAIN OUTCOME MEASURES: Two co-primary outcomes - patient-reported International
Prostate Symptom Score (IPSS) and clinical measure of maximum urine flow rate
(Qmax) at 12 months post surgery.
RESULTS: In total, 410 men were randomised, 205 to each arm. The two procedures
were equivalent in terms of IPSS [adjusted mean difference 0.28 points higher
for ThuVARP (favouring TURP), 95% confidence interval (CI) -0.92 to 1.49
points]. The two procedures were not equivalent in terms of Qmax (adjusted mean
difference 3.12 ml/second in favour of TURP, 95% CI 0.45 to 5.79 ml/second),
with TURP deemed superior. Surgical outcomes, such as complications and blood
transfusion rates, and hospital stay were similar for both procedures.
Patient-reported urinary and sexual symptoms were also similar between the arms.
Qualitative interviews indicated similar patient experiences with both
procedures. However, 25% of participants in the ThuVARP arm did not undergo
their randomised allocation, compared with 2% of participants in the TURP arm.
Prostate cancer was also detected less frequently from routine histology after
ThuVARP (65% lower odds of detection) in an exploratory analysis. The adjusted
mean differences between the arms were similar for secondary care NHS costs (£9
higher for ThuVARP, 95% CI -£359 to £376) and quality-adjusted life-years (0.01
favouring TURP, 95% CI -0.04 to 0.01).
LIMITATIONS: Complications were recorded in prespecified categories; those not
prespecified were excluded owing to variable reporting. Preoperative Qmax and
IPSS data could not be collected for participants with indwelling catheters,
making adjustment for baseline status difficult.
CONCLUSIONS: TURP was superior to ThuVARP in terms of Qmax, although both
operations resulted in a Qmax considered clinically successful. ThuVARP also
potentially resulted in lower detection rates of prostate cancer as a result of
the smaller volume of tissue available for histology. Length of hospital stay
after ThuVARP, anticipated to be a key benefit, was equal to that after TURP in
this trial. Overall, both ThuVARP and TURP were effective procedures for BPO,
with minor benefits in favour of TURP. Therefore, the results suggest that it
may be appropriate that new treatment alternatives continue to be compared with
TURP.
FUTURE WORK: Longer-term follow-up to assess reoperation rates over time, and
research into the comparative effectiveness of ThuVARP and TURP in large
prostates.
TRIAL REGISTRATION: Current Controlled Trials ISRCTN00788389.
FUNDING: This project was funded by the National Institute for Health Research
(NIHR) Health Technology Assessment programme and will be published in full in
Health Technology Assessment; Vol. 24, No. 41. See the NIHR Journals Library
website for further project information. |
Which are the ligands of the Roundabout (Robo) receptors? | Roundabouts comprise a family of single-pass transmembrane receptors facilitating this process upon interaction with the soluble extracellular ligand Slit protein family emanating from the midline. | The signaling pathways that are mediated by Slit ligands and their Roundabout
(Robo) family of receptors play multifunctional roles in the development of the
nervous system and other organs. A recent study identified neural epidermal
growth factor-like (NEL)-like 2 (NELL2) as a novel ligand for Robo3. In this
study, we carried out a comprehensive analysis of the interaction between NELL1
and the Robo family of receptors and demonstrated that Robo2 contains a cryptic
binding site for both NELL1 and NELL2. NELL1/2 binds to the first fibronectin
type III (FNIII) domain of Robo2 but not to intact Robo2. Mutation analysis
revealed that several amino acids within the first FNIII domain are critical for
NELL1 binding to Robo2 but not to Robo1. The Robo2 deletion mutants without the
fourth immunoglobulin domain and single amino acid substitution mutants that can
influence the architecture of the ectodomain facilitated binding to NELL1/2.
Acidic conditions increased the binding affinity of Robo2 for NELL1. These
results suggest that Robo2 functions as a receptor for NELL1/2, particularly
under circumstances where Robo2 undergoes proteolytic digestion. If this is not
the case, conformational changes of the ectodomain of Robo2 may unmask the
binding site for NELL1/2. INTRODUCTION: SLIT-ROBO is a ligand-receptor family of neuronal guidance cues
that has been involved in pathological and physiological angiogenesis. SLIT-ROBO
expression is altered in many tumours. However, no data exist about the role of
the whole family in acute myelogenous myeloid leukemia (AML).
PURPOSE: Herein, we assessed the expression of all SLIT-ROBO family in bone
marrow (BM) biopsy of AML patients and control group on both protein and RNA
levels.
METHODS: The paraffin-embedded tissue blocks were subjected to
immunohistochemistry for SLIT1, SLIT2, SLIT3, ROBO1, ROBO2, ROBO3, and ROBO4.
Microvessel density (MVD) was evaluated by CD34 immunohistochemistry. An in
silico analysis using The Cancer Genome Atlas data repository was conducted for
assessment of RNA level.
RESULTS: Acute myeloid leukemia patients were generally high expressers of ROBO1
and ROBO2 compared to the controls (p < 0.0001, p < 0.001, respectively). In
contrast, low expression of SLIT1, SLIT2, and SLIT3 ligands has been noted more
commonly in AML than in control BM samples (p < 0.0001, p = 0.003, and
p = 0.001, respectively). ROBO4 expression correlated with MVD. The in silico
analysis showed a poor prognostic value of high ROBO3 and low SLIT2 RNA levels
(p = 0.0003 and p = 0.0008, respectively), as well as high ROBO3 and ROBO4 RNA
levels in cytogenetic poor risk groups of patients (p = 0.0029 and p = 0.0003,
respectively).
CONCLUSIONS: These data indicate that SLIT-ROBO family members play a role in
the biology of AML. Low expression of SLIT in BM of AML patients may suggest its
expression alterations in AML. Increased expression of ROBO1 and ROBO2 in AML
patients suggests their participation in AML pathogenesis. The creation of complex neuronal networks relies on ligand-receptor interactions
that mediate attraction or repulsion towards specific targets. Roundabouts
comprise a family of single-pass transmembrane receptors facilitating this
process upon interaction with the soluble extracellular ligand Slit protein
family emanating from the midline. Due to the complexity and flexible nature of
Robo receptors , their overall structure has remained elusive until now. Recent
structural studies of the Robo 1 and Robo 2 ectodomains have provided the basis
for a better understanding of their signalling mechanism. These structures
reveal how Robo receptors adopt an auto-inhibited conformation on the cell
surface that can be further stabilised by cis and/or trans oligmerisation
arrays. Upon Slit -N binding Robo receptors must undergo a conformational change
for Ig4 mediated dimerisation and signaling, probably via endocytosis.
Furthermore, it's become clear that Robo receptors do not only act alone, but as
large and more complex cell surface receptor assemblies to manifest directional
and growth effects in a concerted fashion. These context dependent assemblies
provide a mechanism to fine tune attractive and repulsive signals in a
combinatorial manner required during neuronal development. While a mechanistic
understanding of Slit mediated Robo signaling has advanced significantly further
structural studies on larger assemblies are required for the design of new
experiments to elucidate their role in cell surface receptor complexes. These
will be necessary to understand the role of Slit -Robo signaling in
neurogenesis, angiogenesis, organ development and cancer progression. In this
chapter, we provide a review of the current knowledge in the field with a
particular focus on the Roundabout receptor family. |
What is the function of kisspeptin in the brain? | Kisspeptin is a neuropeptide that plays an integral role in the regulation of energy intake and reproduction by acting centrally on the hypothalamus-pituitary-gonadal axis. It is the most potent factor known to induce GnRH release. Kisspeptin preserves mitochondrial function by inducing mitophagy and autophagy in aging rat brain hippocampus | Kisspeptin (also known as metastin), a hypothalamic peptide, has attracted
attention as a key molecule in the release of gonadotrophin-releasing hormone
(GnRH) in various mammalian species, such as rodents, sheep and primates. Two
populations of kisspeptin neurones in the brain may control two modes of GnRH
release to time the onset of puberty and regulate oestrous cyclicity in rats and
mice. One population of kisspeptin neurones, located in the anteroventral
periventricular nucleus, appears to be responsible for the induction of the GnRH
surge that leads to the luteinising hormone surge and ovulation. The other,
located in the hypothalamic arcuate nucleus, appears to be involved in
generating GnRH pulses, resulting in luteinising hormone pulses followed by
follicular development and steroidogenesis in the ovary. The present review
focuses on the physiological role of the two populations of kisspeptin neurones
in controlling gonadal functions by generating the two modes of GnRH release in
a female rat model. Kisspeptin is a potent regulator of the hypothalamo-pituitary-gonadal axis. The
activation of several vernal and pubertal behaviors involves the action of
locally synthesized estradiol by hypothalamic aromatase-expressing neurons.
Little is known about kisspeptin in non-mammalian systems, and its interaction
with aromatase remains unexamined. The Mallard drake is a seasonal breeder and
an excellent model for studying the neural mechanisms that regulate the HPG. The
goals of these studies were to determine (a) if and how kisspeptin regulates the
drake HPG, (b) if kisspeptin and aromatase are expressed in the Mallard brain,
and (c) if kisspeptin is co-localized or in apposition with, aromatase- and
gonadotropin hormone releasing hormone (GnRH) positive neurons. Central
kisspeptin administration increased plasma luteinizing hormone, an effect
blocked by pretreatment with the GnRH antagonist, acyline, suggesting a
conservation of kisspeptin function and mechanism of action in birds and
mammals. The distribution of kisspeptin in the mallard brain was examined with
immunocytochemistry (ICC). Neurons that express kisspeptin-like immunoreactive
(ir) protein were observed in the medial preoptic nucleus (POM) and in ir fibers
throughout the drake brain. Virtually all POM kisspeptin-ir soma also expressed
aromatase-ir, suggesting that autocrine mechanisms may predominate in the
interaction between steroid provision and kisspeptin expression. No
co-localization was observed between KP-ir and GnRH-ir, although both were
easily detected in close-proximity in the tuberoinfundibular area. Taken
together, these data suggest that in the drake, estradiol synthesized by
aromatase and kisspeptin co-expressing POM neurons may regulate the HPG via an
effect on GnRH secretion. The kiss1 gene product kisspeptin is now considered to be an essential regulator
of the hypothalamic-pituitary-gonadal (HPG) axis in most vertebrate species.
Recent findings in fishes are beginning to set a new stage for the kisspeptin
study; the existence of paralogous kisspeptin genes as well as kisspeptin
receptor (formerly called GPR54) genes has quite recently been reported in
several fish and amphibian species. The fishes may provide excellent animal
models for the study of general principles underlying the kisspeptin and
kisspeptin receptor systems of vertebrates from the evolutionary viewpoint.
Unlike placental and marsupial mammalian species mainly studied so far, many
teleost species have two paralogous genes of kisspeptin, kiss1 and kiss2.
Medaka, Oryzias latipes, in which kiss1 and kiss2 are expressed in distinctive
hypothalamic neuron populations, is a good model system for the study of central
regulation of reproduction. Here, the kiss1 system but not the kiss2 system
shows expression dynamics strongly indicative of its direct involvement in the
HPG axis regulation via its actions on GnRH1 neurons. On the other hand, the
kiss1 gene is missing, and only kiss2 is expressed in some fish species. Also,
there are some recent reports that Kiss2 peptide may be a potent regulator of
reproduction in some fish species. The ancestral vertebrate probably already had
two paralogous kiss genes, and their main function was the HPG axis regulation.
In the species that retained both paralogues during evolution, either Kiss1 or
Kiss2 predomitly retains its ability for the HPG axis regulation, while the
other may assume new non-reproductive functions (neofunctionalization).
Alternatively, both the paralogues may assume complementary functions in the HPG
axis regulation (subfunctionalization). After the divergence of teleost and
tetrapod lineages, either one of the two paralogues, or even both in birds, have
been lost (degradation) or became a pseudogene (non-functionalization), but the
remaining paralogue retained its original function of HPG axis regulation. The
identification of multiple forms of kisspeptin receptors and the rather
promiscuous ligand-receptor relationships has led to the further proposal that
such promiscuousness may be the basis for the functional robustness of
kisspeptin and kisspeptin receptor systems in the HPG axis regulation, when one
or both paralogous genes are lost or functionally partitioned during evolution. Kisspeptins are G protein-coupled receptor ligands originally identified as
human metastasis suppressor gene products that have the ability to suppress
melanoma and breast cancer metastasis and recently found to play an important
role in initiating the secretion of gonadotropin-releasing hormone at puberty.
Kisspeptin-13 is an endogenous isoform that consists of 13 amino acids. The
action of kisspeptin in the regulation of gonadal function has been widely
studied, but little is known as concerns its function in limbic brain
structures. In the brain, the gene is transcribed within the hippocampal dentate
gyrus. This paper reports on a study the effects of kisspeptin-13 on passive
avoidance learning and the involvement of the adrenergic, serotonergic,
cholinergic, dopaminergic and GABA-A-ergic, opiate receptors and nitric oxide in
its action in mice. Mice were pretreated with a nonselective α-adrenergic
receptor antagonist, phenoxybenzamine, an α2-adrenergic receptor antagonist,
yohimbine, a β-adrenergic receptor antagonist, propranolol, a mixed 5-HT1/5-HT2
serotonergic receptor antagonist, methysergide, a nonselective 5-HT2
serotonergic receptor antagonist, cyproheptadine, a nonselective muscarinic
acetylcholine receptor antagonist, atropine, D2, D3, D4 dopamine receptor
antagonist, haloperidol, a γ-aminobutyric acid subunit A (GABAA) receptor
antagonist, bicuculline, naloxone, a nonselective opioid receptor antagonist and
nitro-l-arginine, a nitric oxide synthase inhibitor. Kisspeptin-13 facilitated
learning and memory consolidation in a passive avoidance paradigm.
Phenoxybenzamine, yohimbine, propranolol, methysergide, cyproheptadine,
atropine, bicuculline and nitro-l-arginine prevented the action of kisspeptin-13
on passive avoidance learning, but haloperidol and naloxone did not block the
effects of kisspeptin-13. The results demonstrated that the action of
kisspeptin-13 on the facilitation of passive avoidance learning and memory
consolidation is mediated, at least in part, through interactions of the
α2-adrenergic, beta-adrenergic, 5-HT2 serotonergic, muscarinic cholinergic and
GABA-A-ergic receptor systems and nitric oxide. Research in the nineteenth and early twentieth century established that the
brain awakens reproduction, governs reproductive activity in the adult of
virtually all vertebrates. By 1950, nearly 100 years later, scientists realized
that the hypothalamus and its neurosecretory products play a key role in
regulating gonadal function in both males and females. Another 20 years would be
required to reveal the chemical identity of GnRH and establish that neurons
producing GnRH represent the final common pathway through which the brain
regulates gonadotropin secretion. It had also become clear that GnRH neurons
behave more like motor neurons-better perhaps at going than stopping-and are
themselves regulated by a complex network of afferent inputs, which guide the
tempo of sexual maturation, regulate estrous and menstrual cycles, control
seasonal breeding, and stop reproduction under adversity. In 2003, the
revelation that kisspeptin and its receptor are critical for reproduction opened
a floodgate of research documenting the role of kisspeptin neurons as central
processors of reproduction. Today, there is wide consensus that kisspeptin
signaling in the brain is essential, providing the impetus to GnRH neurons to
awaken at puberty and reigning the activity of these neurons when discretion is
advised. We celebrate this watershed moment-with full knowledge that time and
discovery will provide context and perspective to even these heady days. Neuropeptide kisspeptin has been suggested to be an essential central regulator
of reproduction in response to changes in serum gonadal steroid concentrations.
However, in spite of wide kisspeptin receptor distribution in the brain,
especially in the preoptic area and hypothalamus, the research focus has mostly
been confined to the kisspeptin regulation on GnRH neurons. Here, by using
medaka whose kisspeptin (kiss1) neurons have been clearly demonstrated to be
regulated by sex steroids, we analyzed the anatomical distribution of kisspeptin
receptors Gpr54-1 and Gpr54-2. Because the both receptors were shown to be
activated by kisspeptins (Kiss1 and Kiss2), we analyzed the anatomical
distribution of the both receptors by in situ hybridization. They were mainly
expressed in the ventral telencephalon, preoptic area, and hypothalamus, which
have been suggested to be involved in homeostatic functions including
reproduction. First, we found gpr54-2 mRNA expression in nucleus preopticus pars
magnocellularis and demonstrated that vasotocin and isotocin (Vasopressin and
Oxytocin ortholog, respectively) neurons express gpr54-2 by dual in situ
hybridization. Given that kisspeptin administration increases serum oxytocin and
vasopressin concentration in mammals, the present finding are likely to be
vertebrate-wide phenomenon, although direct regulation has not yet been
demonstrated in mammals. We then analyzed co-expression of kisspeptin receptors
in three types of GnRH neurons. It was clearly demonstrated that
gpr54-expressing cells were located adjacent to GnRH1 neurons, although they
were not GnRH1 neurons themselves. In contrast, there was no gpr54-expressing
cell in the vicinities of neuromodulatory GnRH2 or GnRH3 neurons. From these
results, we suggest that medaka kisspeptin neurons directly regulate some
behavioral and neuroendocrine functions via vasotocin/isotocin neurons, whereas
they do not regulate hypophysiotropic GnRH1 neurons at least in a direct manner.
Thus, direct kisspeptin regulation of GnRH1 neurons proposed in mammals may not
be the universal feature of vertebrate kisspeptin system in general. Elucidating the physiological mechanisms that control reproduction is an obvious
strategy for improving the fertility of cattle and developing new agents to
control reproductive functions. The present study aimed to identify kisspeptin
neurons in the bovine hypothalamus, clarifying that a central mechanism is also
present in the cattle brain, as kisspeptin is known to play an important role in
the stimulation of gonadotropin-releasing hormone (GnRH)/gonadotropin secretion
in other mammals. To characterize kisspeptin neurons in the bovine hypothalamus,
the co-localizations of kisspeptin and neurokinin B (NKB) or kisspeptin and
dynorphin A (Dyn) were examined. Hypothalamic tissue was collected from Japanese
Black or Japanese Black × Holstein crossbred cows during the follicular and
luteal phases. Brain sections, including the arcuate nucleus (ARC) and the
preoptic area (POA), were dual immunostained with kisspeptin and either NKB or
Dyn. In the ARC, both NKB and Dyn were co-localized in kisspeptin neurons during
both the follicular and luteal phases, demonstrating the presence of
kisspeptin/NKB/Dyn-containing neurons, referred to as KNDy neurons, in cows. In
the POA, no co-localization of kisspeptin with either NKB or Dyn was detected.
Kisspeptin expression in the follicular phase was higher than that in the luteal
phase, suggesting that kisspeptin expression in the POA is positively controlled
by estrogen in cows. The kisspeptin neuronal populations in the ARC and POA
likely play important roles in regulating the GnRH pulse and surge,
respectively, in cows. BACKGROUND: Resting brain connectivity is a crucial component of human behavior
demonstrated by disruptions in psychosexual and emotional disorders. Kisspeptin,
a recently identified critical reproductive hormone, can alter activity in
certain brain structures but its effects on resting brain connectivity and
networks in humans remain elusive.
METHODS: We determined the effects of kisspeptin on resting brain connectivity
(using functional neuroimaging) and behavior (using psychometric analyses) in
healthy men, in a randomized double-blinded 2-way placebo-controlled study.
RESULTS: Kisspeptin's modulation of the default mode network (DMN) correlated
with increased limbic activity in response to sexual stimuli (globus pallidus r
= 0.500, P = 0.005; cingulate r = 0.475, P = 0.009). Furthermore, kisspeptin's
DMN modulation was greater in men with less reward drive (r = -0.489, P = 0.008)
and predicted reduced sexual aversion (r = -0.499, P = 0.006), providing key
functional significance. Kisspeptin also enhanced key mood connections including
between the amygdala-cingulate, hippocampus-cingulate, and hippocampus-globus
pallidus (all P < 0.05). Consistent with this, kisspeptin's enhancement of
hippocampus-globus pallidus connectivity predicted increased responses to
negative stimuli in limbic structures (including the thalamus and cingulate [all
P < 0.01]).
CONCLUSION: Taken together, our data demonstrate a previously unknown role for
kisspeptin in the modulation of functional brain connectivity and networks,
integrating these with reproductive hormones and behaviors. Our findings that
kisspeptin modulates resting brain connectivity to enhance sexual and emotional
processing and decrease sexual aversion, provide foundation for kisspeptin-based
therapies for associated disorders of body and mind.
FUNDING: NIHR, MRC, and Wellcome Trust. BACKGROUND: Kisspeptin is a neuropeptide that plays an integral role in the
regulation of energy intake and reproduction by acting centrally on the
hypothalamus-pituitary-gonadal axis. Our current study explores for the first
time the effects of a pharmacological treatment of intraperitoneal kisspeptin-10
on murine feeding behavior, respirometry parameters, energy balance, and
metabolic hormones.
METHODS: Two groups (n = 16) of age- and sex-matched C57BL/6 wild-type adult
mice were individually housed in metabolic cages and intraperitoneally injected
with either kisspeptin-10 (2 nmol in 200 µl of saline) (10 µM) or vehicle before
the beginning of a dark-phase cycle. Microstructure of feeding and drinking
behavior, respirometry gases, respiratory quotient (RQ), total energy
expenditure (TEE), metabolic hormones, oral glucose tolerance, and lipid
profiles were measured.
RESULTS: Intraperitoneal treatment with kisspeptin-10 caused a significant
reduction in food intake, meal frequency, meal size, and eating rate.
Kisspeptin-10 significantly decreased TEE during both the dark and light phase
cycles, while also increasing the RQ during the dark-phase cycle. In addition,
mice injected with kisspeptin-10 had significantly higher plasma levels of
insulin (343.8 pg/ml vs. 106.4 pg/ml; p = 0.005), leptin (855.5 pg/ml vs.
173.1 pg/ml; p = 0.02), resistin (9411.1 pg/ml vs. 4116.5 pg/ml; p = 0.001), and
HDL (147.6 mg/dl vs 97.1 mg/dl; p = 0.04).
CONCLUSION: A pharmacological dose of kisspeptin-10 significantly altered
metabolism by suppressing food intake, meal size, eating rate, and TEE while
increasing the RQ. These changes were linked to increased levels of insulin,
leptin, resistin, and HDL. The current results suggest that a peripheral
kisspeptin treatment could alter metabolism and energy homeostasis by
suppressing appetite, food intake, and fat accumulation. Gonadotrophin-releasing hormone (GnRH) is the main controller of the
reproductive axis and stimulates the synthesis and secretion of gonadotrophins.
Estrogen is the main peripheral factor controlling GnRH secretion, and this
action is mainly mediated by the transsynaptic pathway through nitric oxide,
kisspeptin, leptin, among other factors. Kisspeptin is the most potent factor
known to induce GnRH release. Nitric oxide and leptin also promote GnRH release;
however, neurons expressing GnRH do not express the leptin receptor (OB-R).
Leptin seems to modulate the expression of genes and proteins involved in the
kisspeptin system. However, few kisspeptin-synthesizing cells in the arcuate
nucleus (ARC) and few cells, if any, in the preoptic area (POA) express OB-R;
this indicates an indirect mechanism of leptin action on kisspeptin. Nitric
oxide is an important intermediate in the actions of leptin in the central
nervous system. Thus, this work aimed to verify the numbers of nNOS cells were
activated by leptin in different hypothalamic areas; the modulatory effects of
the nitrergic system on the kisspeptin system; and the indirect regulatory
effect of leptin on the kisspeptin system via nitric oxide. Ovariectomized rats
were treated with estrogen or a vehicle and received an intracerebroventricular
(i.c.v.) injection of a nitric oxide donor, leptin or neuronal nitric oxide
synthase (nNOS) enzyme inhibitor. Thirty minutes after the injection, the
animals were decapitated. Leptin acts directly on nitrergic neurons in different
hypothalamic regions, and the effects on the ventral premammillary nucleus (PMV)
and ventral dorsomedial hypothalamus (vDMH) are enhanced. The use of a nitric
oxide donor or the administration of leptin stimulates the expression of the
kisspeptin mRNA in the ARC of animals with or without estrogenic action;
however, these changes are not observed in the POA. In addition, the action of
leptin on the expression of the kisspeptin mRNA in the ARC is blocked by a
nitric oxide synthesis inhibitor. We concluded that the effects of leptin on the
central nervous system are at least partially mediated by the nitrergic system.
Also, nitric oxide acts on the kisspeptin system by modulating the expression of
the kisspeptin mRNA, and leptin at least partially modulates the kisspeptin
system through the nitrergic system, particularly in the ARC. It has become amply clear that mitochondrial function defined by quality,
quantity, dynamics, homeostasis, and regulated by mitophagy and mitochondrial
biogenesis is a critical metric of human aging and disease. As a consequence,
therapeutic interventions that can improve mitochondrial function can have a
profound impact on human health and longevity. Kisspeptins are neuropeptides
belonging to the family of metastasis suppressors that are known to regulate
functions like fertility, reproduction, and metabolism. Using SKNSH cell line,
hippocampus explant cultures and hippocampus of aging Wistar rat models, we show
that Kisspeptin-10 (Kp) induces autophagy and mitophagy via calcium,
Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), AMP-activated protein
kinase (AMPK), and Unc-51 like autophagy activating kinase (ULK1) signaling
pathway that is independent of mammalian target of rapamycin (mTOR).
Intriguingly, Kp administration in vivo also results in the enhancement of
mitochondrial number, complex I activity, and Adenosine Triphosphate (ATP)
levels. This study uncovers potential effects of Kp in protecting mitochondrial
health and as a possible therapeutic intervention to hippocampus associated
impairments such as memory, cognitive aging, and other diseases linked to
mitochondrial dysfunction. |
Is Nanog repressed in pluripotent stem cells? | The homeobox gene Nanog is a key intrinsic determinant of self renewal in embryonic stem (ES) cells, and its repression leads ES cells to selectively differentiate into primitive endoderm. | When embryonic stem cells are allowed to aggregate, the outer layer of the
aggregated spheres (referred to as embryoid bodies) differentiates into
primitive endoderm. This initial specification of cell lineage facilitates
further differentiation of the inner mass of the embryoid bodies. These
processes are considered to recapitulate early embryonic development from the
blastocyst stage to the egg-cylinder stage. Formation of the primitive endoderm
layer in the embryoid bodies was induced solely by aggregation of embryonic stem
cells, in the presence of leukemia inhibitory factor/STAT3 and serum/BMP4, which
were considered to be sufficient for embryonic stem cell self-renewal.
Interestingly, cell aggregation by itself induced Nanog repression at the outer
layer, which was essential for aggregation-induced primitive endoderm formation.
These data illustrate aggregation-based cell-fate specification during early
embryonic development, when downregulation of Nanog plays a crucial role. Nanog is a newly identified transcriptional factor bearing a homeodomain and
expressed in pluripotential cells of preimplantation and early postimplantation
embryos, and embryonic stem (ES) and embryonic germ (EG) cells. Knockout
experiments indicate that Nanog functions as a key player in maintaining the
pluripotency of stem cells. Importantly, Nanog expression is highly expressed in
primordial germ cells (PGCs) of E11.5 and E12.5 mouse embryos. However, its
temporal and spatial expression pattern and function in germ cells are largely
unknown. To address these issues, whole embryos and cryosections of embryos were
immunostained with anti-NANOG and anti-STELLA/PGC7 antibodies. NANOG expression,
repressed in colonized PGCs of E7.25-E7.5 embryos, became detectable in
migrating PGCs of E7.75-E8.0 embryos. Both male and female PGCs migrating in
E9.5 and E10.5 embryos and colonizing the genital ridges of E11.5 and E12.5
embryos were positive for NANOG immunostaining, while the NANOG expression
pattern differed between the sexes in the later developmental stage. In female
gonadal PGCs of E13.5 and E14.5 embryos, NANOG became undetectable in germ cells
positive for the synaptonemal complex-specific protein SCP3, while in male PGCs
of E14.5-E16.5 embryos, the number of NANOG-positive germ cells drastically
decreased during the mitotic arrest. No germ cells positive for NANOG were
detectable in testes and ovaries of adult mice. Thus, in germ cell development,
NANOG is expressed in proliferating germ cells, in which nuclear reprogramming
is progressing. Embryonic stem (ES) cells possess the ability to renew themselves while
maintaining the capacity to differentiate into virtually all cell types of the
body. Current evidence suggests that ES cells maintain their pluripotent state
by expressing a battery of transcription factors including Oct4 and Nanog.
However, little is known about how ES cells maintain the expression of these
pluripotent factors in ES cells. Here we present evidence that Oct4, Nanog, and
FoxD3 form a negative feedback loop to maintain their expression in pluripotent
ES cells. First, Oct4 maintains Nanog activity by directly activating its
promoter at sub-steady-state concentration but repressing it at or above
steady-state levels. On the other hand, FoxD3 behaves as a positive activator of
Nanog to counter the repressive effect of Oct4. The expression of Oct4 is
activated by FoxD3 and Nanog but repressed by Oct4 itself, thus, exerting an
important negative feedback loop to limit its own activity. Indeed,
overexpression of either FoxD3 or Nanog in ES cells failed to increase the
concentration of Oct4 beyond the steady-state concentration, whereas knocking
down either FoxD3 or Nanog reduces the expression of Oct4 in ES cells. Finally,
overexpression of Oct4 or Nanog failed to compensate the loss of Nanog or Oct4,
respectively, suggesting that both are required for ES self-renewal and
pluripotency. Our results suggest the FoxD3-Nanog-Oct4 loop anchors an
interdependent network of transcription factors that regulate stem cell
pluripotency. The homeobox gene Nanog is a key intrinsic determit of self renewal in
embryonic stem (ES) cells, and its repression leads ES cells to selectively
differentiate into primitive endoderm. Although Nanog repression occurs at the
outermost layer of ES cell aggregates independent of the leukemia inhibitory
factor (LIF)/STAT3 pathway, it is largely undetermined what external cues and
intracellular signals cause the event. Of interest, addition of the tyrosine
phosphatase inhibitor, sodium vanadate, selectively repressed Nanog
transcription without any detectable changes in upstream transcriptional
regulators Oct3/4 and Sox2. Furthermore, sodium vanadate induced primitive
endoderm differentiation, even in the inner cells of ES cell aggregates.
Expression of Gata6 and Zfp42, two putative downstream Nanog effectors, was also
increased and decreased by the addition of sodium vanadate, respectively, but
these changes were eliminated by exogenous Nanog expression. The effects of
sodium vanadate were abrogated by Grb2 deficiency or by the addition of the Mek
inhibitor, PD98059. Indeed, PD98059 prevented Nanog repression induced by ES
cell aggregation as well. Furthermore, transfection of a constitutive active Mek
mutant into ES cells induced Nanog repression and primitive endoderm
differentiation. These data indicate that the Grb2/Mek pathway primarily
mediates Nanog gene repression upon ES cell differentiation into primitive
endoderm. Embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass
of blastocysts. Self-renewal of mouse ES cells depends on activation of Stat3 by
leukaemia inhibitory factor (LIF) in collaboration with bone morphogenetic
protein signalling. The transcription factor Nanog is essential in maintaining
pluripotency but the mechanisms involved are poorly understood. Here we examine
the functional interactions of Nanog with the Stat3 and NFkappaB pathways. Nanog
and Stat3 were found to bind to and synergistically activate Stat3-dependent
promoters. We also found that Nanog binds to NFkappaB proteins; however, Nanog
binding inhibited transcriptional activity of NFkappaB proteins. Endogenous
NFkappaB activity and target-gene expression increased during differentiation of
ES cells. Overexpression of NFkappaB proteins promoted differentiation, whereas
inhibition of NFkappaB signalling, either by genetic ablation of the Ikbkg gene
or overexpression of the IkappaBalpha super-repressor, increased expression of
pluripotency markers. We conclude that Nanog represses the pro-differentiation
activities of NFkappaB and cooperates with Stat3 to maintain pluripotency. Nanog, Oct4, and Sox2 form the core of a transcription factor network that
maintains embryonic stem cells in the pluripotent state in both humans and mice.
These critical factors have been implicated as both positive and negative
regulators of transcription, varying by promoter and differentiation state of
the cell. The Mediator complex, a ubiquitous conserved complex of approximately
30 subunits, facilitates transcription by coordinating RNA polymerase II binding
to target promoters via gene-specific activators and can be divided into several
functional subcomplexes. Med12 is part of a subcomplex of four proteins
associated with the core Mediator complex and has been found to function both in
repressing and activating transcription when recruited to target promoters. We
identified an interaction between Med12 and Nanog and present evidence of
involvement of Med12 in regulation of Nanog function. Gene expression analysis
of embryonic stem cells knocked down for Med12 showed a similarity to Nanog
knockdown, with increased expression of Nanog-repressed targets and decreased
expression of Nanog-activated targets. Using chromatin immunoprecipitation, we
found that Med12 and Nanog co-occupied Nanog target promoters in embryonic stem
cells and that Med12 dissociated from target promoters upon differentiation with
kinetics similar to Nanog. Our results indicate that Nanog and Med12 function in
concert to regulate Nanog target genes and identify a novel role for Med12 in
embryonic stem cell regulation. Mammalian spermatogonial stem cells are a special type of adult stem cells
because they can contribute to the next generation. Knockout studies have
indicated a role for TRP53 and PTEN in insulating male germ cells from
pluripotency, but the mechanism by which this is achieved is largely unknown. To
get more insight in these processes, an RNAi experiment was performed on the
mouse spermatogonial stem cell line GSDG1. Lipofectaminemediated transfection of
siRNAs directed against Trp53 and Pten resulted in decreased expression levels
as determined by quantitative RT-PCR and immunoblotting. The effects of
knockdown were examined by determining the expression levels of genes that are
involved in reprogramming and pluripotency of cells, specifically Nanog, Eras,
c-Myc, Klf4, Oct4, and Sox2. Additionally, the effects of TRP53 or PTEN
knockdown on Plzf and Ddx4 expression were measured, which are highly expressed
in spermatogonial stem cells and differentiating male germ cells, respectively.
The main finding of this study is that knockdown of Trp53 and Pten independently
resulted in significantly higher expression levels of the
pluripotency-associated gene Nanog, and we hypothesize that TRP53 and PTEN
mediated repression is important for the insulation of male germ cells from
pluripotency. Pluripotent stem cells (PSCs) hold significant promise in regenerative medicine
due to their unlimited capacity for self-renewal and potential to differentiate
into every cell type in the body. One major barrier to the use of PSCs is their
potential risk for tumor initiation following differentiation and
transplantation in vivo. In the current study we sought to evaluate the role of
the tumor suppressor Pten in murine PSC neoplastic progression. Using eight
functional assays that have previously been used to indicate PSC adaptation or
transformation, Pten null embryonic stem cells (ESCs) failed to rate as
significant in five of them. Instead, our data demonstrate that the loss of Pten
causes the emergence of a small number of aggressive, teratoma-initiating
embryonic carcinoma cells (ECCs) during differentiation in vitro, while the
remaining 90-95% of differentiated cells are non-tumorigenic. Furthermore, our
data show that the mechanism by which Pten null ECCs emerge in vitro and cause
tumors in vivo is through increased survival and self-renewal, due to failed
repression of the transcription factor Nanog. The transcription factors Nanog and Gata6 are critical to specify the epiblast
versus primitive endoderm (PrE) lineages. However, little is known about the
mechanisms that regulate the protein stability and activity of these factors in
the developing embryo. Here we uncover an early developmental function for the
Polycomb group member Bmi1 in supporting PrE lineage formation through Gata6
protein stabilization. We show that Bmi1 is enriched in the extraembryonic
(endoderm [XEN] and trophectodermal stem [TS]) compartment and repressed by
Nanog in pluripotent embryonic stem (ES) cells. In vivo, Bmi1 overlaps with the
nascent Gata6 and Nanog protein from the eight-cell stage onward before it
preferentially cosegregates with Gata6 in PrE progenitors. Mechanistically, we
demonstrate that Bmi1 interacts with Gata6 in a Ring finger-dependent manner to
confer protection against Gata6 ubiquitination and proteasomal degradation. A
direct role for Bmi1 in cell fate allocation is established by loss-of-function
experiments in chimeric embryoid bodies. We thus propose a novel regulatory
pathway by which Bmi1 action on Gata6 stability could alter the balance between
Gata6 and Nanog protein levels to introduce a bias toward a PrE identity in a
cell-autonomous manner. Author information:
(1)College of Life Sciences, Northwest A&F University, Yangling 712100, PR
China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture,
Northwest A&F University, Yangling 712100, PR China.
(2)School of Life Sciences and Medical Center, University of Science and
Technology of China, Hefei, Anhui 230027, PR China.
(3)College of Veterinary Medicine, Northwest A&F University, Yangling 712100, PR
China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture,
Northwest A&F University, Yangling 712100, PR China. Electronic address:
[email protected].
(4)College of Veterinary Medicine, Northwest A&F University, Yangling 712100, PR
China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture,
Northwest A&F University, Yangling 712100, PR China. Electronic address:
[email protected]. |
What is the mode of administration of Ubrogepant? | Ubrogepant (MK-1602) is administered orally. | Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated
strategy for implementation of dried blood spots (DBS) in late-stage trials for
population pharmacokinetic (PK) modeling. We applied this strategy for another
late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin
gene-related peptide receptor antagonist for acute treatment of migraine. At the
time of implementation, ubrogepant was entering phase 2 development. DBS was
implemented to acquire PK information proximal to an acute migraine event to
enable exposure-response modeling. The clinical endpoint was a spontaneous
event, which generally occurs outside a clinic visit. Thus, an innovative
feature of this trial was facilitating DBS in an outpatient setting. In vitro
and bioanalytical tests established initial method feasibility and suitability
for further evaluations in the clinic. A quantitative relationship was developed
between blood and plasma concentrations from concurrently collected samples in a
phase 1 (healthy subjects) and phase 2 (target patient population) study using
graphical and population PK approaches. This integrated information was
presented to the Food and Drug Administration for regulatory input. Following
regulatory concurrence, DBS was poised for use in further clinical studies.
Population PK modeling was used to dissect sources of variability contributing
to DBS collection in the outpatient setting. What has been learned from this
program has informed the broader integrated strategy of Merck & Co., Inc.
(Kenilworth, NJ) for DBS implementation in clinical trials and research to
improve the precision of PK data collected in an outpatient setting. BACKGROUND: Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP)
receptor antagonist in development for the acute treatment of migraine. This
trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic
safety, when administered intermittently with high-frequency dosing to healthy
participants.
METHODS: In this phase 1, multicenter, double-blind, parallel-group trial,
healthy adults (age 18-50 years) were randomized 1:1 to placebo or ubrogepant.
Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days
followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary
outcome measures were safety and tolerability.
RESULTS: Of participants randomized (n = 518), 516 were included in the safety
population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse
events were reported in 45% of placebo and 44% of ubrogepant participants. The
most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of
alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the
upper limit of normal (five placebo, two ubrogepant) were reported and
adjudicated by a panel of independent liver experts blinded to treatment. Four
cases were judged unlikely related to treatment. Two cases (one placebo, one
ubrogepant) were judged possibly related, and one (ubrogepant) probably related.
Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two
ubrogepant cases (possibly or probably related) were transient and resolved with
continued dosing; both cases were asymptomatic, with no concurrent bilirubin
elevation.
CONCLUSION: Ubrogepant was well tolerated following intermittent, high-frequency
dosing in healthy participants, with no clinically relevant signal of
hepatotoxicity.
TRIAL REGISTRATION: NA. Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor
antagonist in clinical development with positive phase III outcomes for acute
treatment of migraine. This paper describes the population exposure-response
(E-R) modeling and simulations, which were used to inform the phase III
dose-selection rationale, based on ~ 800 participants pooled across two phase
IIb randomized dose-finding clinical trials. The E-R model describes the placebo
and ubrogepant treatment effects based on migraine pain end points (2-hour pain
relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses
were conducted to evaluate various assumptions of placebo response in light of
the high placebo response observed in one phase II trial. A population
pharmacokinetic model describing the effect of formulations was included in the
E-R simulation framework to assess potential dose implications of a formulation
switch from phase II to phase III. Model-based simulations predict that a dose
of 25 mg or higher is likely to achieve significantly better efficacy than
placebo with desirable efficacy levels. The understanding of E-R helped support
the dose selection for the phase III clinical trials. Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor
antagonist intended for the acute treatment of migraine attacks. Ubrogepant has
a chemical structure distinct from previous small-molecule CGRP receptor
antagonists that were associated with elevated serum alanine aminotransferase
(ALT) in clinical trials. Here, we report overall and hepatic safety data from
two placebo-controlled phase I trials of ubrogepant, spray-dried oral compressed
tablet (SD-OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK)
trial of single (100-400 mg) and multiple (40-400 mg) ascending doses. Trial B
was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg
for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported.
Ubrogepant was well-tolerated in both trials, with a low incidence of adverse
events that did not differ greatly from placebo. Changes in mean ALT levels were
minimal and similar to placebo. Over 28 days of treatment, the mean percentage
change in ALT from baseline was < 5% at all time points. No participant in
either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant
SD-OCT demonstrated linear PK appropriate for acute treatment of migraine, with
rapid uptake (time of maximum plasma concentration (tmax ): 2-3 hours) and no
accumulation with daily use. Overall, there was no evidence of
ubrogepant-associated hepatotoxicity with daily doses up to 400 mg for 10 days
or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful
strategy for characterizing hepatic safety in early drug development. Ubrogepant (Ubrelvy™) is an orally administered, small molecule,
highly-selective, calcitonin gene-related peptide (CGRP) antagonist that was
developed by Allergan under license to Merck & Co. as an acute treatment for
migraine. In December 2019, ubrogepant received its first global approval in the
USA for the acute treatment of migraine (± aura) in adults. This article
summarizes the milestones in the development of ubrogepant leading to its first
global approval for the acute treatment of migraine (± aura) in adults. |
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