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http://www.ncbi.nlm.nih.gov/pubmed/35899182
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1. Health Sci Rep. 2022 Jul 22;5(4):e554. doi: 10.1002/hsr2.554. eCollection 2022
Jul.
SARS-CoV-2 reinfection across a spectrum of immunological states.
McKittrick JM(1), Burke TW(2), Petzold E(2), Sempowski GD(3), Denny TN(3),
Polage CR(1), Tsalik EL(2)(4)(5), McClain MT(2)(4)(5).
Author information:
(1)Duke University School of Medicine Durham North Carolina USA.
(2)Center for Applied Genomics and Precision Medicine Duke University Durham
North Carolina USA.
(3)Duke Human Vaccine Institute Durham North Carolina USA.
(4)Durham Veterans Affairs Medical Center Durham North Carolina USA.
(5)Division of Infectious Diseases Duke University Medical Center Durham North
Carolina USA.
PURPOSE: Several cases of symptomatic reinfection with severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) after full recovery from a prior episode
have been reported. As reinfection has become an increasingly common phenomenon,
an improved understanding of the risk factors for reinfection and the character
and duration of the serological responses to infection and vaccination is
critical for managing the coronavirus disease 2019 (COVID-19) pandemic.
METHODS: We described four cases of SARS-CoV-2 reinfection in individuals
representing a spectrum of healthy and immunocompromised states, including (1) a
healthy 41-year-old pediatrician, (2) an immunocompromised 31-year-old with
granulomatosis with polyangiitis, (3) a healthy 26-year-old pregnant woman, and
(4) a 50-year-old with hypertension and hyperlipidemia. We performed
confirmatory quantitative reverse transcription-polymerase chain reaction and
qualitative immunoglobulin M and quantitative IgG testing on all available
patient samples to confirm the presence of infection and serological response to
infection.
RESULTS: Our analysis showed that patients 1 and 2, a healthy and an
immunocompromised patient, both failed to mount a robust serologic response to
the initial infection. In contrast, patients 3 and 4, with minimal comorbid
disease, both mounted a strong serological response to their initial infection,
but were still susceptible to reinfection.
CONCLUSION: Repeat episodes of COVID-19 are capable of occurring in patients
regardless of the presence of known risk factors for infection or level of
serological response to infection, although this did not trigger critical
illness in any instance.
© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.
DOI: 10.1002/hsr2.554
PMCID: PMC9308002
PMID: 35899182
Conflict of interest statement: The authors declare no conflicts of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/30065630
|
1. Front Cell Neurosci. 2018 Jul 17;12:188. doi: 10.3389/fncel.2018.00188.
eCollection 2018.
Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in
Friedreich's Ataxia Models.
Abeti R(1), Baccaro A(1), Esteras N(2), Giunti P(1).
Author information:
(1)Ataxia Centre, Department of Molecular Neuroscience, UCL Institute of
Neurology, London, United Kingdom.
(2)Department of Molecular Neuroscience, UCL Institute of Neurology, London,
United Kingdom.
Friedreich's Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder,
affecting dorsal root ganglia (DRG), cerebellar dentate nuclei and heart. It is
caused by a GAA repeat expansion mutation within the frataxin gene (FXN). This
impedes FXN transcription resulting in a progressive decrease of the
mitochondrial protein, frataxin. Increased oxidative stress leading to a chronic
depletion of endogenous antioxidants affects the survival of the cells and
causes neurodegeneration. In particular, cerebellar granule neurons (CGNs) show
a significant increase of reactive oxygen species (ROS), lipid peroxidation and
lower level of reduced glutathione (GSH). In FRDA, one of the major pathways of
oxidant scavengers, the Nrf2 antioxidant pathway, is defective. Previous studies
on FRDA-like CGNs showed that the reduced level of frataxin and the oxidative
stress induce mitochondrial impairments. By triggering the Nrf2 endogenous
pathway pharmacologically we determined whether this could promote mitochondrial
fitness and counteract oxidative stress. In this work, we sought to investigate
the beneficial effect of a promising Nrf2-inducer, omaveloxolone (omav), in CGNs
from two FRDA mouse models, KIKO and YG8R, and human fibroblasts from patients.
We found that CGNs from both KIKO and YG8R presented Complex I deficiency and
that omav was able to restore substrate availability and Complex I activity.
This was also confirmed in human primary fibroblasts from FRDA patients.
Although fibroblasts are not the major tissue affected, we found that they show
significant differences recapitulating the disease; this is therefore an
important tool to investigate patients' pathophysiology. Interestingly, we found
that patient fibroblasts had an increased level of endogenous lipid peroxidation
and mitochondrial ROS (mROS), and lower GSH at rest. Omav was able to reverse
this phenotype, protecting the cells against oxidative stress. By stimulating
the cells with hydrogen peroxide (H2O2) and looking for potential mitochondrial
pathophysiology, we found that fibroblasts could not maintain their
mitochondrial membrane potential (ΔΨm). Remarkably, omav was protective to
mitochondrial depolarization, promoting mitochondrial respiration and preventing
cell death. Our results show that omav promotes Complex I activity and protect
cells from oxidative stress. Omav could, therefore, be used as a novel
therapeutic drug to ameliorate the pathophysiology of FRDA.
DOI: 10.3389/fncel.2018.00188
PMCID: PMC6056642
PMID: 30065630
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http://www.ncbi.nlm.nih.gov/pubmed/35264078
|
1. Emerg Microbes Infect. 2022 Dec;11(1):894-901. doi:
10.1080/22221751.2022.2052358.
SARS-CoV-2 reinfection and COVID-19 severity.
Nguyen NN(#)(1)(2), Houhamdi L(#)(1)(2), Hoang VT(3), Delerce J(2)(4), Delorme
L(1)(2), Colson P(2)(4), Brouqui P(2)(4), Fournier PE(1)(2), Raoult D(2)(4),
Gautret P(1)(2).
Author information:
(1)IRD, AP-HM, SSA, VITROME, Aix Marseille University, Marseille, France.
(2)IHU-Méditerranée Infection, Marseille, France.
(3)Thai Binh University of Medicine and Pharmacy, Thai Binh, Vietnam.
(4)IRD, AP-HM, MEPHI, Aix-Marseille University, Marseille, France.
(#)Contributed equally
SARS-CoV-2 reinfection rate is low. The relative severity of the first and
second episodes of infection remains poorly studied. In this study, we aimed at
assessing the frequency of SARS-CoV-2 reinfections and comparing the severity of
the first and second episodes of infection. We retrospectively included patients
with SARS-CoV-2 positive RT-PCR at least 90 days after clinical recovery from a
COVID-19 episode and with at least one negative RT-PCR after the first
infection. Whole genome sequencing and variant-specific RT-PCR were performed
and clinical symptoms and severity of infection were retrospectively documented
from medical files. A total of 209 COVID-19 reinfected patients were identified,
accounting for 0.4% of positive cases diagnosed from 19 March 2020 to 24 August
2021. Serology was performed in 64 patients, of whom 39 (60.1%) had antibodies
against SARS-CoV-2 when sampled at the early stage of their second infection.
Only seven patients (3.4%) were infected twice with the same variant. We
observed no differences in clinical presentation, hospitalization rate, and
transfer to ICU when comparing the two episodes of infections. Our results
suggest that the severity of the second episode of COVID-19 is in the same range
as that of the first infection, including patients with antibodies.
DOI: 10.1080/22221751.2022.2052358
PMCID: PMC8942490
PMID: 35264078 [Indexed for MEDLINE]
Conflict of interest statement: No potential conflict of interest was reported
by the author(s).
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http://www.ncbi.nlm.nih.gov/pubmed/19461958
|
1. J Biomed Biotechnol. 2009;2009:325210. doi: 10.1155/2009/325210. Epub 2009 May
19.
Duchenne and Becker muscular dystrophy: contribution of a molecular and
immunohistochemical analysis in diagnosis in Morocco.
Bellayou H(1), Hamzi K, Rafai MA, Karkouri M, Slassi I, Azeddoug H, Nadifi S.
Author information:
(1)Genetic and Molecular Pathology Laboratory, Medical School, Hassan II
University, 19, rue Tarik-Ibn-Ziad, BP 9154, 10000 Casablanca, Morocco.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are
X-linked recessive disorders caused by mutations of the DMD gene located at
Xp21. In DMD patients, dystrophin is virtually absent; whereas BMD patients have
10% to 40% of the normal amount. Deletions in the dystrophin gene represent 65%
of mutations in DMD/BMD patients. To explain the contribution of
immunohistochemical and genetic analysis in the diagnosis of these dystrophies,
we present 10 cases of DMD/BMD with particular features. We have analyzed the
patients with immunohistochemical staining and PCR multiplex to screen for exons
deletions. Determination of the quantity and distribution of dystrophin by
immunohistochemical staining can confirm the presence of dystrophinopathy and
allows differentiation between DMD and BMD, but dystrophin staining is not
always conclusive in BMD. Therefore, only identification involved mutation by
genetic analysis can establish a correct diagnosis.
DOI: 10.1155/2009/325210
PMCID: PMC2683945
PMID: 19461958 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35488305
|
1. Glob Health Res Policy. 2022 Apr 29;7(1):12. doi: 10.1186/s41256-022-00245-3.
Reinfection in patients with COVID-19: a systematic review.
Ren X(1)(2), Zhou J(3), Guo J(4), Hao C(5), Zheng M(5), Zhang R(6), Huang Q(1),
Yao X(7)(8), Li R(9), Jin Y(10).
Author information:
(1)Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of
Wuhan University, Wuhan, China.
(2)College of Nursing and Health, Henan University, Kaifeng, Henan, China.
(3)School of Nursing, Wuhan University, Wuhan, China.
(4)Department of Acupuncture Rehabilitation, The Affiliated Hospital of Nanjing
University of Chinese Medicine, Nanjing, China.
(5)The First Clinical College of Wuhan University, Wuhan, Hubei, China.
(6)Department of Neurotumor Disease Diagnosis and Treatment Center, Taihe
Hospital, Hubei University of Medicine, Shiyan, China.
(7)Department of Health Research Methods, Evidence, and Impact, McMaster
University, Hamilton, ON, Canada. [email protected].
(8)Center for Clinical Practice Guideline Conduction and Evaluation, Children's
Hospital of Fudan University, Shanghai, China. [email protected].
(9)College of Nursing and Health, Henan University, Kaifeng, Henan, China.
[email protected].
(10)Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of
Wuhan University, Wuhan, China. [email protected].
BACKGROUND: With the continuation of the COVID-19 pandemic, some COVID-19
patients have become reinfected with the virus. Viral gene sequencing has found
that some of these patients were reinfected by the different and others by same
strains. This has raised concerns about the effectiveness of immunity after
infection and the reliability of vaccines. To this end, we conducted a
systematic review to assess the characteristics of patients with reinfection and
possible causes.
METHODS: A systematic search was conducted across eight databases: PubMed,
Embase, Web of Science, The Cochrane Library, CNKI, WanFang, VIP and SinoMed
from December 1, 2019 to September 1, 2021. The quality of included studies were
assessed using JBI critical appraisal tools and Newcastle-Ottawa Scale.
RESULTS: This study included 50 studies from 20 countries. There were 118 cases
of reinfection. Twenty-five patients were reported to have at least one
complication. The shortest duration between the first infection and reinfection
was 19 days and the longest was 293 days. During the first infection and
reinfection, cough (51.6% and 43.9%) and fever (50% and 30.3%) were the most
common symptoms respectively. Nine patients recovered, seven patients died, and
five patients were hospitalized, but 97 patients' prognosis were unknown. B.1 is
the most common variant strain at the first infection. B.1.1.7, B.1.128 and
B.1.351 were the most common variant strains at reinfection. Thirty-three
patients were infected by different strains and 9 patients were reported as
being infected with the same strain.
CONCLUSIONS: Our research shows that it is possible for rehabilitated patients
to be reinfected by SARS-COV-2. To date, the causes and risk factors of COVID-19
reinfection are not fully understood. For patients with reinfection, the
diagnosis and management should be consistent with the treatment of the first
infection. The public, including rehabilitated patients, should be fully
vaccinated, wear masks in public places, and pay attention to maintaining social
distance to avoid reinfection with the virus.
© 2022. The Author(s).
DOI: 10.1186/s41256-022-00245-3
PMCID: PMC9051013
PMID: 35488305 [Indexed for MEDLINE]
Conflict of interest statement: YH Jin, XM Yao, XY Ren, and Q Huang conducted
clinical practice guidelines on COVID-19. YH Jin reported research projects
involving infection of healthcare workers during this epidemic, which was
supported by Special Project for Emergency of Hubei Province (2020FCA008). All
other authors declare they have nothing to disclose and have no conflicts of
interest.
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http://www.ncbi.nlm.nih.gov/pubmed/10422002
|
1. Electromyogr Clin Neurophysiol. 1999 Jul-Aug;39(5):315-8.
Comparative analysis between Duchenne and Becker types muscular dystrophy.
Ishpekova B(1), Milanov I, Christova LG, Alexandrov AS.
Author information:
(1)Department of Neurology, University Hospital Tzarita Ioanna, Sofia, Bulgaria.
Duchenne and Becker types of muscular dystrophy are usually differentiated
according to age of onset and rate of progression criteria which are not
sufficient. The aim of this paper was to re-establish the clues for
distinguishing Duchenne from Becker types of muscular dystrophy. According to
the onset and progression of the disease, one hundred and eleven patients were
subdivided into two groups. First group--Becker muscular dystrophy--consisted of
40 patients and second one of 71 patients with Duchenne type of muscular
dystrophy. Clinical data confirm some well known differences between Duchenne
and Becker muscular dystrophy concerning the age of onset, severity of disease
and rate of progression. Electromyographic signs of myopathic changes and
spontaneous activity were found in both diseases. Spontaneous activity--bizarre
and fibrillation potentials, as well as sharp waves are more common for Duchenne
type. The differences between the Becker from Duchenne type of muscular
dystrophy can be described on the basis of complex investigations (clinical,
electromyographical, histological and biochemical).
PMID: 10422002 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18056690
|
1. J Child Neurol. 2008 Feb;23(2):155-62. doi: 10.1177/0883073807307975. Epub
2007 Dec 3.
Cognitive and psychological profile of males with Becker muscular dystrophy.
Young HK(1), Barton BA, Waisbren S, Portales Dale L, Ryan MM, Webster RI, North
KN.
Author information:
(1)Institute for Neuromuscular Research, The Children's Hospital at Westmead,
Sydney, Australia. [email protected]
Duchenne and Becker muscular dystrophy are allelic X-linked disorders causing
progressive muscle weakness in males. Duchenne muscular dystrophy is caused by
absence of dystrophin in muscle and brain; boys with Duchenne muscular dystrophy
have a static cognitive impairment with mean Full Scale IQ approximately 1
standard deviation below the mean. Less is known of the cognitive profile of
males with Becker muscular dystrophy, which is associated with variable
alterations in the amount or size of the dystrophin protein. The aim of this
study was to describe the cognitive and psychological profile of males with
Becker muscular dystrophy. This was a prospective cohort study. Clinical data
collected included age at diagnosis and assessment, socioeconomic status, serum
creatine kinase level, and site of gene deletion/mutation (by exon number). The
following psychological tests were used to assess general intellectual
functioning, academic achievement, incidence and nature of behavioral problems:
The Wechsler Intelligence Scales, The Wide Range Achievement Test-Revised, The
Developmental Test of Visual-Motor Integration, The Child Behavior Checklist,
and The Conner's Parent Rating Scale. Twenty-four males were enrolled. The
Wechsler Full Scale IQ was normally distributed with a mean of 95.6 (SD 23.3),
which did not differ significantly from the population mean. The frequency of
learning difficulties for reading was 21%, for spelling was 32%, and for
arithmetic was 26%, significantly higher than the frequency in the general
population. The frequency of total behavioral problems in the clinical range was
67%, and the frequency of autism was 8.3%. Patients with Becker muscular
dystrophy demonstrate a less homogeneous cognitive phenotype than that seen in
Duchenne muscular dystrophy. Males with Becker muscular dystrophy have a high
incidence of learning difficulties. Autism and behavioral and attention problems
are also more common in Becker muscular dystrophy than in the general
population.
DOI: 10.1177/0883073807307975
PMID: 18056690 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/164552
|
1. J Med Genet. 1975 Mar;12(1):49-54. doi: 10.1136/jmg.12.1.49.
Distinction between Duchenne and other muscular dystrophies by ribosomal protein
synthesis.
Ionasescu V.
Ribosome concentration, ribosome distribution on sucrose density gradients, and
in-vitro ribosomal amino-acid incorporation (noncollagen and collagen synthesis)
were studied in muscle biopsy samples obtained from 30 patients with Duchenne
muscular dystrophy, seven patients with Becker muscular dystrophy, and 10 with
facioscapulohumeral muscular dystrophy. Ribosome concentration was normal in
Duchenne and facioscapulohumeral and decreased in Becker muscular dystrophy.
Distribution of ribosomes in sucrose density gradients showed abnormalities
(sharp monosomal peak and fewer polyribosomes) only in Duchenne muscular
dystrophy and was normal in the other two types. In-vitro amino-acid
incorporation of ribosomes in Duchenne muscular dystrophy revealed high collagen
and low noncollagen synthesis of the heavy polyribosomes. This abnormality is
controlled by an undetermined enzymatic factor belonging to the soluble enzyme
fraction. Supplementation of the dystrophic heavy polyribosomes with normal
soluble enzymes restored the synthesis of collagen to that of the controls.
Heavy polyribosomes extracted from normals or from carriers produce
proportionately more collagen in the presence of soluble enzyme fraction from
Duchenne muscular dystrophy than in the presence of their homologous enzymes. In
Becker muscular dystrophy, both noncollagen and collagen synthesis of the heavy
polyribosomes were increased, under the influence of ribosomal factors. The
different protein synthesis in Duchenne and Becker muscular dystrophies suggests
that these conditions are non-allelic. In facioscapulohumeral muscular dystrophy
the changes in protein synthesis occurred only in the early stage of the disease
and consisted of increased noncollagen synthesis of the light polyribosomes,
while the heavy polyribosomes had normal activity including collagen synthesis.
This reaction was controlled by ribosomal factors.
DOI: 10.1136/jmg.12.1.49
PMCID: PMC1013230
PMID: 164552 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8894415
|
1. Curr Opin Neurol. 1996 Oct;9(5):380-8. doi: 10.1097/00019052-199610000-00012.
The differential diagnosis of the human dystrophinopathies and related
disorders.
Kakulas BA(1).
Author information:
(1)Australian Neuromuscular Research Institute, University of Western Australia,
Perth, Australia.
Comment in
Curr Opin Neurol. 1996 Oct;9(5):367-8. doi:
10.1097/00019052-199610000-00009.
In addition to the now well recognized dystrophinopathies, recent investigation
of the dystrophin-associated proteins has revealed a new group of disorders
referred to as the 'sarcoglycanopathies'. These autosomal recessive muscle
diseases are results of mutations of alpha-, beta-, or gamma-sarcoglycans and
may be severe (Duchenne muscular dystrophy-like) or mild (limb girdle muscular
dystrophy) depending upon whether there is a 'null' mutation with no gene
product formed or a 'missense' mutation in which reduced amounts of the protein
product are made. The relationship between the severe Duchenne muscular
dystrophy-like phenotype and the milder limb girdle muscular dystrophy phenotype
is therefore similar to that of Duchenne muscular dystrophy to Becker muscular
dystrophy, where there is absence of dystrophin in Duchenne muscular dystrophy
and reduced amounts in Becker muscular dystrophy. Not all of the limb girdle
muscular dystrophies have been identified in molecular terms and, as yet, no
disorder has been associated with mutations of the syntrophin or the
dystroglycan genes. Nevertheless, progress in this field has been so rapid and
of such practical importance that the clinical neurologist should become aware
of these developments.
DOI: 10.1097/00019052-199610000-00012
PMID: 8894415 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35952340
|
1. A A Pract. 2022 Aug 10;16(8):e01605. doi: 10.1213/XAA.0000000000001605.
eCollection 2022 Aug 1.
Lance Adams Syndrome After Hypoxic Cardiac Arrest: A Case Report.
Lim ML(1), Lim RRZ(2), Tien JC(1), Lim SZZ(3), Lee YL(1).
Author information:
(1)From the Department of Surgical Intensive Care, Division of Anaesthesiology,
Singapore General Hospital, Singapore.
(2)Department of Anesthesia, Division of Anaesthesiology and Perioperative
Medicine, Singapore General Hospital, Singapore.
(3)Department of Neurology, National Neuroscience Institute, Singapore General
Hospital Campus, Singapore.
Lance-Adams syndrome (chronic post-hypoxic myoclonus) is a rare syndrome
occurring in patients after cardiopulmonary resuscitation. Awareness of this
condition is important to distinguish it from myoclonic status epilepticus,
which is a poor prognostic sign. We present the case of a 32-year-old woman who
developed Lance-Adams syndrome after an episode of hypoxic cardiac arrest from
severe pneumonia. Brain computed tomography, magnetic resonance imaging, and an
electroencephalogram were used to rule out other causes of myoclonus. In this
report, we discuss the diagnosis, treatment, and prognosis of patients with
Lance-Adams syndrome.
Copyright © 2022 International Anesthesia Research Society.
DOI: 10.1213/XAA.0000000000001605
PMID: 35952340 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflicts of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/35530854
|
1. Cureus. 2022 Apr 7;14(4):e23914. doi: 10.7759/cureus.23914. eCollection 2022
Apr.
Cervical Osteomyelitis, Cardiac Arrest, and Lance-Adams Syndrome: A Case Report.
Wasey W(1), Carter C(2), Badesha NS(3), Rossi M(3), Baig M(3).
Author information:
(1)Family and Community Medicine, Southern Illinois University School of
Medicine, Springfield, USA.
(2)Psychiatry, Southern Illinois University School of Medicine, Springfield,
USA.
(3)Family Medicine, Southern Illinois University School of Medicine,
Springfield, USA.
Lance-Adams syndrome (LAS) is a rare complication of successful cardiopulmonary
resuscitation, often accompanied by action myoclonus. Myoclonus may occur as
generalized, focal, or multifocal movements and can include the face, trunk,
and/or extremities. Only 100 cases of LAS have been reported worldwide. Here, we
present the case of a 53-year-old female who had a cardiac arrest event after
being admitted for posterior cervical wound dehiscence management following a
posterior cervical fusion from C3-T1. The patient was successfully resuscitated
but developed action myoclonus in all extremities shortly after. Anoxic brain
injury and myoclonus led to debilitation and prolonged hospital stay. During her
inpatient stay, she was treated with clonazepam, levetiracetam, and sodium
valproate with mild improvement.
Copyright © 2022, Wasey et al.
DOI: 10.7759/cureus.23914
PMCID: PMC9078145
PMID: 35530854
Conflict of interest statement: The authors have declared that no competing
interests exist.
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http://www.ncbi.nlm.nih.gov/pubmed/34987744
|
1. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. doi:
10.1177/20406207211066070. eCollection 2021.
Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary
hemolytic anemias.
Al-Samkari H(1), van Beers EJ(2).
Author information:
(1)Division of Hematology, Massachusetts General Hospital, Harvard Medical
School, Zero Emerson Place, Suite 118, Office 112, Boston, MA 02114, USA.
(2)Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands.
Mitapivat (AG-348) is a novel, first-in-class oral small molecule allosteric
activator of the pyruvate kinase enzyme. Mitapivat has been shown to
significantly upregulate both wild-type and numerous mutant forms of erythrocyte
pyruvate kinase (PKR), increasing adenosine triphosphate (ATP) production and
reducing levels of 2,3-diphosphoglycerate. Given this mechanism, mitapivat has
been evaluated in clinical trials in a wide range of hereditary hemolytic
anemias, including pyruvate kinase deficiency (PKD), sickle cell disease, and
the thalassemias. The clinical development of mitapivat in adults with PKD is
nearly complete, with the completion of two successful phase III clinical trials
demonstrating its safety and efficacy. Given these findings, mitapivat has the
potential to be the first approved therapeutic for PKD. Mitapivat has
additionally been evaluated in a phase II trial of patients with alpha- and
beta-thalassemia and a phase I trial of patients with sickle cell disease, with
findings suggesting safety and efficacy in these more common hereditary anemias.
Following these successful early-phase trials, two phase III trials of mitapivat
in thalassemia and a phase II/III trial of mitapivat in sickle cell disease are
beginning worldwide. Promising preclinical studies have additionally been done
evaluating mitapivat in hereditary spherocytosis, suggesting potential efficacy
in erythrocyte membranopathies as well. With convenient oral dosing and a safety
profile comparable with placebo in adults with PKD, mitapivat is a promising new
therapeutic for several hereditary hemolytic anemias, including those without
any currently US Food and Drug Administration (FDA) or European Medicines Agency
(EMA)-approved drug therapies. This review discusses the preclinical studies,
pharmacology, and clinical trials of mitapivat.
© The Author(s), 2021.
DOI: 10.1177/20406207211066070
PMCID: PMC8721383
PMID: 34987744
Conflict of interest statement: Conflict of interest statement: The authors
declared the following potential conflicts of interest with respect to the
research, authorship, and/or publication of this article: Hanny Al-Samkari:
Consultancy (Agios, Dova/Sobi, Argenx, Rigel, Novartis, Moderna, Forma),
Research funding (Agios, Dova, Amgen). Eduard J. van Beers: Consultancy and
Research Funding (Agios).
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http://www.ncbi.nlm.nih.gov/pubmed/35220777
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1. J Int Med Res. 2022 Feb;50(2):3000605211059933. doi:
10.1177/03000605211059933.
Lance Adams syndrome: two cases report and literature review.
Guo Y(1), Xiao Y(1), Chen LF(1), Yin DH(1), Wang RD(1).
Author information:
(1)Department of Neurology, Second Affiliated Hospital of Army Medical
University, Chongqing, China.
Hypoxic myoclonus, also known as Lance Adams syndrome, is a rare syndrome that
results from the serious brain damage caused by cerebral hypoxia that often
follows cardiopulmonary resuscitation. This current case report describes two
patients with post-hypoxic myoclonus, both of whom received cardiopulmonary
resuscitation. The neurological symptoms of these two patients were
significantly improved by the administration of clonazepam and sodium valproate
sustained-release tablets. The report presents a literature review detailing the
pathogenesis, diagnosis and treatment of Lance Adams syndrome. The timely
diagnosis and treatment of Lance Adams syndrome can significantly improve the
quality of life of patients. Valproic acid, clonazepam and other antiepileptic
drugs can be used. Whether levetiracetam is effective for cortical myoclonus
requires further clinical study.
DOI: 10.1177/03000605211059933
PMCID: PMC8894979
PMID: 35220777 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of conflicting interest: The authors
declare that there are no conflicts of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/31483964
|
1. N Engl J Med. 2019 Sep 5;381(10):933-944. doi: 10.1056/NEJMoa1902678.
Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.
Grace RF(1), Rose C(1), Layton DM(1), Galactéros F(1), Barcellini W(1), Morton
DH(1), van Beers EJ(1), Yaish H(1), Ravindranath Y(1), Kuo KHM(1), Sheth S(1),
Kwiatkowski JL(1), Barbier AJ(1), Bodie S(1), Silver B(1), Hua L(1), Kung C(1),
Hawkins P(1), Jouvin MH(1), Bowden C(1), Glader B(1).
Author information:
(1)From the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and
Harvard Medical School, Boston (R.F.G.), and Agios Pharmaceuticals, Cambridge
(A.J.B., S.B., L.H., C.K., P.H., M.-H.J., C.B.) - all in Massachusetts; Hôpital
Saint Vincent de Paul, Lille (C.R.), and Unité des Maladies Génétiques du
Globule Rouge, Centre Hospitalier Universitaire Henri Mondor, Créteil (F.G.) -
both in France; Hammersmith Hospital, Imperial College Healthcare NHS Trust,
London (D.M.L.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,
Milan (W.B.); Central Pennsylvania Clinic, Belleville (D.H.M.), and Children's
Hospital of Philadelphia and Perelman School of Medicine of the University of
Pennsylvania, Philadelphia (J.L.K.); Van Creveldkliniek, University Medical
Center Utrecht, Utrecht University, Utrecht, the Netherlands (E.J.B.);
University of Utah, Salt Lake City (H.Y.); Wayne State University School of
Medicine, Children's Hospital of Michigan, Detroit (Y.R.); University of
Toronto, Toronto (K.H.M.K.); Weill Cornell Medical College, New York (S.S.);
Bruce A. Silver Clinical Science and Development, Dunkirk, MD (B.S.); and
Stanford University School of Medicine, Palo Alto, CA (B.G.).
BACKGROUND: Pyruvate kinase deficiency is caused by mutations in PKLR and leads
to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric
activator of pyruvate kinase in red cells.
METHODS: In this uncontrolled, phase 2 study, we evaluated the safety and
efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not
receiving red-cell transfusions. The patients were randomly assigned to receive
either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period;
eligible patients could continue treatment in an ongoing extension phase.
RESULTS: Common adverse events, including headache and insomnia, occurred at the
time of drug initiation and were transient; 92% of the episodes of headache and
47% of the episodes of insomnia resolved within 7 days. The most common serious
adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients
(4%). A total of 26 patients (50%) had an increase of more than 1.0 g per
deciliter in the hemoglobin level. Among these patients, the mean maximum
increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until
the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to
187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the
hemoglobin level at more than 50% of visits during the core study period, with
improvement in markers of hemolysis. The response was sustained in all 19
patients remaining in the extension phase, with a median follow-up of 29 months
(range, 22 to 35). Hemoglobin responses were observed only in patients who had
at least one missense PKLR mutation and were associated with the red-cell
pyruvate kinase protein level at baseline.
CONCLUSIONS: The administration of mitapivat was associated with a rapid
increase in the hemoglobin level in 50% of adults with pyruvate kinase
deficiency, with a sustained response during a median follow-up of 29 months
during the extension phase. Adverse effects were mainly low-grade and transient.
(Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).
Copyright © 2019 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa1902678
PMID: 31483964 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35417638
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1. N Engl J Med. 2022 Apr 14;386(15):1432-1442. doi: 10.1056/NEJMoa2116634.
Mitapivat versus Placebo for Pyruvate Kinase Deficiency.
Al-Samkari H(1), Galactéros F(1), Glenthøj A(1), Rothman JA(1), Andres O(1),
Grace RF(1), Morado-Arias M(1), Layton DM(1), Onodera K(1), Verhovsek M(1),
Barcellini W(1), Chonat S(1), Judge MP(1), Zagadailov E(1), Xu R(1), Hawkins
P(1), Beynon V(1), Gheuens S(1), van Beers EJ(1); ACTIVATE Investigators.
Collaborators: Henrique G, Fonseca H, Kuo KHM, Verhovsek M, Cermak J, Glenthøj
AB, Galactéros F, Garcon L, Bernit E, Jean-Mignard E, Duffau P, Cougoul P,
Andres O, Holzhauer S, Forni GL, Perrotta S, Barcellini W, Nakao T, Kawasaki H,
Satake A, Omachi T, O'Hara A, Haga Y, Amano K, Onodera K, Moriguchi T, Lee JM,
van Beers EJ, Morado-Arias M, Beneitez Pastor D, Salido Fierrez EJ, Renella R,
Viprakasit V, Unal Cangul S, Layton DM, Porter J, Besser M, Sadasivam N, Simcox
D, Kuter D, Al-Samkari H, Knupp CL, Rothman J, Chonat S, Yaish H, Prchal J,
Ravindranath Y, Shapiro A, Grace RF, Sasapu A, Rice L, Fertrin KY, Kalfa T.
Author information:
(1)From the Division of Hematology Oncology, Massachusetts General Hospital
(H.A.-S.) and the Dana-Farber/Boston Children's Cancer and Blood Disorders
Center (R.F.G.), Harvard Medical School, Boston, and Agios Pharmaceuticals,
Cambridge (M.P.J., E.Z., R.X., P.H., V.B., S.G.) - all in Massachusetts; Unité
des Maladies Génétiques du Globule Rouge, Centre Hospitalier Universitaire Henri
Mondor, Créteil, France (F.G.); the Department of Hematology, Copenhagen
University Hospital, Rigshospitalet, Copenhagen (A.G.); Duke University Medical
Center, Durham, NC (J.A.R.); the Department of Pediatrics, University of
Würzburg, Würzburg, Germany (O.A.); the Hematology Department, Hospital
Universitario La Paz, Madrid (M.M.-A.); Hammersmith Hospital, Imperial College
Healthcare NHS Trust, London (D.M.L.); Tohoku University Hospital, Sendai, Japan
(K.O.); McMaster University, Hamilton, ONT, Canada (M.V.); Fondazione IRCCS Ca'
Granda Ospedale Maggiore Policlinico, Milan (W.B.); Aflac Cancer and Blood
Disorders Center, Children's Healthcare of Atlanta, and the Department of
Pediatrics, Emory University, Atlanta (S.C.); and the Benign Hematology Center,
Van Creveldkliniek, University Medical Center Utrecht, University Utrecht,
Utrecht, the Netherlands (E.J.B.).
Comment in
N Engl J Med. 2022 Jun 30;386(26):2538-2539. doi: 10.1056/NEJMc2206275.
BACKGROUND: Pyruvate kinase deficiency is a rare, hereditary, chronic condition
that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an
oral, first-in-class activator of erythrocyte pyruvate kinase, increased the
hemoglobin level in patients with pyruvate kinase deficiency.
METHODS: In this global, phase 3, randomized, placebo-controlled trial, we
evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase
deficiency who were not receiving regular red-cell transfusions. The patients
were assigned to receive either mitapivat (5 mg twice daily, with potential
escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end
point was a hemoglobin response (an increase from baseline of ≥1.5 g per
deciliter in the hemoglobin level) that was sustained at two or more scheduled
assessments at weeks 16, 20, and 24. Secondary efficacy end points were the
average change from baseline in the hemoglobin level, markers of hemolysis and
hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase
deficiency-specific patient-reported outcome measures.
RESULTS: Sixteen of the 40 patients (40%) in the mitapivat group had a
hemoglobin response, as compared with none of the 40 patients in the placebo
group (adjusted difference, 39.3 percentage points; 95% confidence interval,
24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater
response than those who received placebo with respect to each secondary end
point, including the average change from baseline in the hemoglobin level. The
most common adverse events were nausea (in 7 patients [18%] in the mitapivat
group and 9 patients [23%] in the placebo group) and headache (in 6 patients
[15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher
occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who
received placebo.
CONCLUSIONS: In patients with pyruvate kinase deficiency, mitapivat
significantly increased the hemoglobin level, decreased hemolysis, and improved
patient-reported outcomes. No new safety signals were identified in the patients
who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE
ClinicalTrials.gov number, NCT03548220.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2116634
PMID: 35417638 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/36213707
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1. Indian J Crit Care Med. 2022 Sep;26(9):1052-1053. doi:
10.5005/jp-journals-10071-24299.
A Case of Lance Adams Syndrome in a Patient with Attempted Hanging.
Subramanian M(1), Velayudham S(1), Jeyaraj M(1), Arunan S(1), Perumal S(1),
Mohan K(1).
Author information:
(1)Department of Neurology, Stanley Medical College and Hospital, Chennai, Tamil
Nadu, India.
Lance Adams syndrome is the term used to describe late post-hypoxic myoclonus.
Here we describe a patient who developed action and intention myoclonus after 7
days of attempted partial hanging. The similarity of Lance Adams syndrome, which
is a treatable condition to a cerebellar syndrome, and the diagnostic
difficulties have been highlighted.
HOW TO CITE THIS ARTICLE: Subramanian M, Velayudham S, Jeyaraj M, Arunan S,
Perumal S, Mohan K. A Case of Lance Adams Syndrome in a Patient with Attempted
Hanging. Indian J Crit Care Med 2022;26(9):1052-1053.
Copyright © 2022; The Author(s).
DOI: 10.5005/jp-journals-10071-24299
PMCID: PMC9492758
PMID: 36213707
Conflict of interest statement: Source of support: Nil Conflict of interest:
None
|
http://www.ncbi.nlm.nih.gov/pubmed/35964609
|
1. Lancet. 2022 Aug 13;400(10351):493-501. doi: 10.1016/S0140-6736(22)01337-X.
Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults
with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open-label,
multicentre, phase 2 study.
Kuo KHM(1), Layton DM(2), Lal A(3), Al-Samkari H(4), Bhatia J(5), Kosinski
PA(5), Tong B(5), Lynch M(5), Uhlig K(5), Vichinsky EP(3).
Author information:
(1)Division of Haematology, University of Toronto, Toronto, ON, Canada.
Electronic address: [email protected].
(2)Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK.
(3)Division of Hematology, University of California San Francisco Benioff
Children's Hospital, Oakland, CA, USA.
(4)Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
(5)Agios Pharmaceuticals, Cambridge, MA, USA.
Comment in
Lancet. 2022 Aug 13;400(10351):470-471. doi: 10.1016/S0140-6736(22)01431-3.
Cell Rep Med. 2022 Oct 18;3(10):100790. doi: 10.1016/j.xcrm.2022.100790.
BACKGROUND: Patients with non-transfusion-dependent thalassaemia (NTDT),
although they do not require regular blood transfusions for survival, can still
accrue a heavy burden of comorbidities. No approved disease-modifying therapies
exist for these patients. We aimed to investigate the safety and efficacy of
mitapivat (Agios Pharmaceuticals, Cambridge, MA, USA), a pyruvate kinase
activator, in adults with non-transfusion-dependent (NTD) α-thalassaemia or NTD
β-thalassaemia.
METHODS: In this open-label, multicentre, phase 2 study, patients were recruited
from four academic clinical study sites in Oakland, CA, and Boston, MA, USA;
Toronto, ON, Canada; and London, UK. Patients were eligible if they were aged 18
years or older, with NTDT (including β-thalassaemia with or without α-globin
gene mutations, haemoglobin E β-thalassaemia, or α-thalassaemia), and a baseline
haemoglobin concentration of 10·0 g/dL or lower. During a 24-week core period,
mitapivat was administered orally at 50 mg twice daily for the first 6 weeks
followed by an escalation to 100 mg twice daily for 18 weeks thereafter. The
primary endpoint was haemoglobin response (a ≥1·0 g/dL increase in haemoglobin
concentration from baseline at one or more assessments between weeks 4 and 12).
Efficacy and safety were assessed in the full analysis set (ie, all patients who
received at least one dose of study drug). This study is registered with
ClinicalTrials.gov, NCT03692052, and is closed to accrual.
FINDINGS: Between Dec 28, 2018, and Feb 6, 2020, 27 patients were screened, of
whom 20 were enrolled (15 [75%] with β-thalassaemia and five [25%] with
α-thalassaemia) and received mitapivat. The median age of patients was 44 years
(IQR 35-56), 15 (75%) of 20 patients were female, five (25%) were male, and ten
(50%) identified as Asian. 16 (80% [90% CI 60-93]) of 20 patients had a
haemoglobin response (p<0·0001), five (100%) of five with α-thalassaemia and 11
(73%) of 15 with β-thalassaemia. 17 (85%) patients had a treatment-emergent
adverse event, and 13 had a treatment-emergent event that was considered to be
treatment related. One serious treatment-emergent adverse event occurred (grade
3 renal impairment), which was considered unrelated to study drug, resulting in
discontinuation of treatment. The most commonly reported treatment-emergent
adverse events were initial insomnia (ten [50%] patients), dizziness (six
[30%]), and headache (five [25%]). No patients died during the 24-week core
period.
INTERPRETATION: These efficacy and safety results support the continued
investigation of mitapivat for the treatment of both α-thalassaemia and
β-thalassaemia.
FUNDING: Agios Pharmaceuticals.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S0140-6736(22)01337-X
PMID: 35964609 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests KHMK reports
consultancy fees from Agios Pharmaceuticals, Alexion, Apellis, bluebird bio,
Celgene, Forma, Pfizer, and Novartis; honoraria from Alexion and Novartis;
membership on an advisory committee for Agios Pharmaceuticals and
Bioverativ/Sanofi/Sangamo; and research funding from Pfizer. DML reports
consultancy fees from Agios Pharmaceuticals and membership on the Board of
Directors or advisory committee for Agios Pharmaceuticals and Cerus. AL reports
research funding from bluebird bio, Celgene, Insight Magnetics, La Jolla
Pharmaceutical Company, Novartis, Protagonist Therapeutics, Terumo Corporations,
and Forma; consultancy fees from Agios Pharmaceuticals and Chiesi USA; and
membership on the Board of Directors or advisory committee for Celgene and
Protagonist Therapeutics. HA-S reports consultancy fees from Agios
Pharmaceuticals, argenx, Dova/Sobi, Moderna, Novartis, Rigel, and Forma and
research funding from Agios Pharmaceuticals, Amgen, and Dova. JB, PAK, BT, ML,
and KU are employees and shareholders of Agios Pharmaceuticals. EPV reports
consultancy fees and research funding from Agios Pharmaceuticals, bluebird bio,
Global Blood Therapeutics, Novartis, and Pfizer.
|
http://www.ncbi.nlm.nih.gov/pubmed/35988546
|
1. Lancet Haematol. 2022 Oct;9(10):e724-e732. doi: 10.1016/S2352-3026(22)00214-9.
Epub 2022 Aug 18.
Mitapivat in adult patients with pyruvate kinase deficiency receiving regular
transfusions (ACTIVATE-T): a multicentre, open-label, single-arm, phase 3 trial.
Glenthøj A(1), van Beers EJ(2), Al-Samkari H(3), Viprakasit V(4), Kuo KHM(5),
Galactéros F(6), Chonat S(7), Porter J(8), Zagadailov E(9), Xu R(9), Oluyadi
A(9), Hawkins P(9), Gheuens S(9), Beynon V(9), Barcellini W(10); ACTIVATE-T
investigators.
Author information:
(1)Department of Haematology, Copenhagen University Hospital - Rigshospitalet,
Copenhagen, Denmark. Electronic address: [email protected].
(2)Benign Hematology Center, Van Creveldkliniek, University Medical Center
Utrecht, University Utrecht, Utrecht, the Netherlands.
(3)Division of Hematology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA.
(4)Siriraj Hospital, Mahidol University, Bangkok, Thailand.
(5)Division of Hematology, University of Toronto, Toronto, ON, Canada.
(6)Unité des Maladies Génétiques du Globule Rouge, CHU Henri Mondor, Créteil,
France.
(7)Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and
Department of Pediatrics, Emory University, Atlanta, GA, USA.
(8)Department of Haematology, University College London Cancer Institute,
London, UK.
(9)Agios Pharmaceuticals, Cambridge, MA, USA.
(10)Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Comment in
Lancet Haematol. 2022 Oct;9(10):e708-e709. doi:
10.1016/S2352-3026(22)00249-6.
BACKGROUND: Mitapivat, an oral activator of pyruvate kinase (PK) in red blood
cells (RBCs), has shown significant improvements in haemoglobin and haemolysis
among patients with pyruvate kinase deficiency who were not receiving regular
transfusions. We aimed to evaluate the efficacy and safety of mitapivat in
adults with pyruvate kinase deficiency receiving regular transfusions.
METHODS: ACTIVATE-T was an open-label, single-arm, phase 3 trial conducted in 20
centres across Europe, North America, and Asia. Eligible participants were
adults (aged ≥18 years) with a clinical laboratory confirmation of pyruvate
kinase deficiency receiving regular transfusions (at least six episodes in the
previous year). Participants received oral mitapivat during a 16-week
dose-optimisation period (5 mg, 20 mg, 50 mg twice daily) and 24-week fixed-dose
period. The primary endpoint was a reduction in transfusion burden (≥33%
reduction in number of RBC units transfused during the fixed-dose period,
compared with the participant's individual historical transfusion burden,
standardised to 24 weeks). Efficacy and safety were assessed in all participants
who received at least one dose of mitapivat. This trial is registered with
ClinicalTrials.gov, NCT03559699, and is complete.
FINDINGS: Between June 26, 2018, and Feb 4, 2020, 27 participants (20 [74%]
female and seven [26%] male; 20 [74%] White, three [11%] Asian, and four [15%]
not reported) were enrolled and received at least one dose of mitapivat. Median
duration of exposure to mitapivat was 40·3 weeks (IQR 40·0-41·3). A reduction in
transfusion burden by at least 33% was found in ten (37%) participants (95% CI
19-58; p=0·0002). The most common treatment-emergent adverse events were
increase in alanine aminotransferase (ten [37%] participants), headache (ten
[37%]), increase in aspartate aminotransferase (five [19%]), fatigue (five
[19%]), and nausea (five [19%]). Two grade 3 treatment-emergent adverse events
were related to study treatment: joint swelling (one participant [4%]) and an
increase in aspartate aminotransferase (one participant [4%]). Three
participants had serious treatment-emergent adverse events, none related to the
study treatment: increased blood triglycerides, ovarian cyst, and renal colic
(each in one participant [4%]). No treatment-related deaths were observed.
INTERPRETATION: Mitapivat represents a novel therapy that can reduce transfusion
burden in some adults with pyruvate kinase deficiency receiving regular
transfusions, and is the first disease-modifying agent approved in this disease.
FUNDING: Agios Pharmaceuticals.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S2352-3026(22)00214-9
PMID: 35988546 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests EZ, RX, AO, PH, SG, and
VB are employees and shareholders of Agios Pharmaceuticals. AG has received fees
for consultancy work and as a member of advisory boards from Agios
Pharmaceuticals, bluebird bio, Celgene, Novartis, and Novo Nordisk; and research
grants from Alexion, Saniona, and Sanofi. EJvB has received fees as a member of
advisory board from Agios Pharmaceuticals; and research funding from Agios
Pharmaceuticals, Novartis, Pfizer, and RR Mechatronics. HA-S has received fees
for consultancy work from Agios Pharmaceuticals, argenx, Dova–Sobi, Novartis,
Rigel, Forma Therapeutics, and Moderna; and research funding from Agios
Pharmaceuticals, Dova, and Amgen. VV has received fees for consultancy work,
honoraria, research funding, and speakers bureau from Bristol-Myers Squibb; and
fees for consultancy work and research funding from Agios Pharmaceuticals,
Ionis, La Jolla Pharmaceuticals, Protagonist Therapeutics, and Vifor Pharma.
KHMK has received fees for consultancy work from Agios Pharmaceuticals, Alexion,
Apellis, bluebird bio, Celgene, Pfizer, and Novartis; honoraria from Alexion and
Novartis; research funding from Pfizer; and membership on an entity's Board of
Directors or advisory committees from Bioverativ. FG has been on board
membership or advisory committee for Addmedica. SC has received fees for
consultancy work from Agios Pharmaceuticals, Alexion, Daiichi Sankyo, Novartis,
and Takeda; and research funding from Agios Pharmaceuticals, Alexion, Apellis,
Global Blood Therapeutics, Novartis, and Takeda. WB has received honoraria from
Agios Pharmaceuticals, Alexion, and Novartis; and been on board membership or
advisory committee for Bioverativ and Incyte. JP declares no competing
interests.
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http://www.ncbi.nlm.nih.gov/pubmed/35576529
|
1. Blood. 2022 Nov 10;140(19):2053-2062. doi: 10.1182/blood.2022015403.
A phase 1 dose escalation study of the pyruvate kinase activator mitapivat
(AG-348) in sickle cell disease.
Xu JZ(1), Conrey A(1), Frey I(1), Gwaabe E(1), Menapace LA(1), Tumburu L(1),
Lundt M(1), Lequang T(1), Li Q(2), Glass K(2), Dunkelberger EB(2), Iyer V(3),
Mangus H(3), Kung C(3), Dang L(3), Kosinski PA(3), Hawkins P(3), Jeffries N(4),
Eaton WA(2), Lay Thein S(1).
Author information:
(1)Sickle Cell Branch, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD.
(2)Laboratory of Chemical Physics, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Bethesda, MD.
(3)Agios Pharmaceuticals, Inc., Cambridge, MA.
(4)Office of Biostatistics Research, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, MD.
Comment in
Blood. 2022 Nov 10;140(19):2005-2006. doi: 10.1182/blood.2022016930.
Polymerization of deoxygenated hemoglobin S underlies the pathophysiology of
sickle cell disease (SCD). In activating red blood cell pyruvate kinase and
glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and
decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream
precursor in glycolysis. Both changes have therapeutic potential for patients
with SCD. Here, we evaluated the safety and tolerability of multiple ascending
doses of mitapivat in adults with SCD with no recent blood transfusions or
changes in hydroxyurea or l-glutamine therapy. Seventeen subjects were enrolled;
1 subject was withdrawn shortly after starting the study. Sixteen subjects
completed 3 ascending dose levels of mitapivat (5, 20, and 50 mg, twice daily
[BID]) for 2 weeks each; following a protocol amendment, the dose was escalated
to 100 mg BID in 9 subjects. Mitapivat was well tolerated at all dose levels,
with the most common treatment-emergent adverse events (AEs) being insomnia,
headache, and hypertension. Six serious AEs (SAEs) included 4 vaso-occlusive
crises (VOCs), non-VOC-related shoulder pain, and a preexisting pulmonary
embolism. Two VOCs occurred during drug taper and were possibly drug related; no
other SAEs were drug related. Mean hemoglobin increase at the 50 mg BID dose
level was 1.2 g/dL, with 9 of 16 (56.3%) patients achieving a hemoglobin
response of a ≥1 g/dL increase compared with baseline. Mean reductions in
hemolytic markers and dose-dependent decreases in 2,3-DPG and increases in ATP
were also observed. This study provides proof of concept that mitapivat has
disease-modifying potential in patients with SCD. This trial was registered at
www.clinicaltrials.gov as #NCT04000165.
DOI: 10.1182/blood.2022015403
PMCID: PMC9837441
PMID: 35576529 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest disclosure: V.I., H.M.,
C.K., L.D., P.A.K., and P.H. are employed by and are stockholders in Agios. H.M.
and P.H. are stockholders in Bristol-Myers Squibb. V.I. is a stockholder in
Novartis. The remaining authors declare no competing financial interests.
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http://www.ncbi.nlm.nih.gov/pubmed/36124781
|
1. Expert Rev Hematol. 2022 Oct;15(10):875-885. doi:
10.1080/17474086.2022.2125865. Epub 2022 Sep 22.
An evaluation of mitapivat for the treatment of hemolytic anemia in adults with
pyruvate kinase deficiency.
Song AB(1)(2), Al-Samkari H(2)(3).
Author information:
(1)Department of Medicine, Massachusetts General Hospital, Boston,
Massachusetts, USA.
(2)Harvard Medical School, Boston, Massachusetts, USA.
(3)Division of Hematology, Massachusetts General Hospital, Boston,
Massachusetts, USA.
INTRODUCTION: Pyruvate kinase deficiency (PKD) is the most common cause of
congenital nonspherocytic hemolytic anemia. Until recently, treatment had been
limited to supportive management including red blood cell transfusions,
splenectomy, and management of chronic disease complications such as iron
overload and decreased bone mineral density.
AREAS COVERED: We discuss preclinical data and phase 1, 2, and 3 clinical
studies evaluating mitapivat for adult patients with hemolytic anemia secondary
to PKD. Mitapivat has been shown to offer early and durable improvement in
hemoglobin with reduction in transfusion burden, and preliminary data suggest it
can induce a negative iron balance in many patients without the use of dedicated
iron chelators.
EXPERT OPINION: Mitapivat is a first-in-class allosteric activator of pyruvate
kinase and the first FDA-approved disease directed therapy for PKD. It has a
favorable safety profile and clear clinical efficacy. Given the considerable
genetic heterogeneity of PKD and the rapid effect on improving hemoglobin and
reducing hemolysis, a therapeutic trial of mitapivat should be considered in all
patients with PKD who are not homozygous for the PKLR R479H mutation. Further
investigations are needed regarding long-term safety and efficacy profiles and
whether long-term PKD-associated complications can be reduced or even reversed.
DOI: 10.1080/17474086.2022.2125865
PMID: 36124781 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/36260990
|
1. Cell Rep Med. 2022 Oct 18;3(10):100790. doi: 10.1016/j.xcrm.2022.100790.
Right in time: Mitapivat for the treatment of anemia in α- and β-thalassemia.
Musallam KM(1), Taher AT(2), Cappellini MD(3).
Author information:
(1)Thalassemia Center, Burjeel Medical City, Abu Dhabi, United Arab Emirates.
(2)Department of Internal Medicine, American University of Beirut Medical
Center, Beirut, Lebanon.
(3)Department of Clinical Sciences and Community, University of Milan, Ca'
Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, Italy. Electronic
address: [email protected].
Comment on
Lancet. 2022 Aug 13;400(10351):493-501. doi: 10.1016/S0140-6736(22)01337-X.
Kuo and colleagues1 evaluated the safety and efficacy of mitapivat, an oral
pyruvate kinase activator, in adults with non-transfusion-dependent
α-thalassemia or β-thalassemia. The high rate of hemoglobin response and good
tolerability encourages further development in thalassemia.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.xcrm.2022.100790
PMCID: PMC9589095
PMID: 36260990 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests K.M.M. reports
consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb), Agios
Pharmaceuticals, CRISPR Therapeutics, Vifor Pharma, and Pharmacosmos. M.D.C.
reports consultancy fees from Novartis, Celgene Corp (Bristol Myers Squibb),
Vifor Pharma, and Ionis Pharmaceuticals and research funding from Novartis,
Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche,
Protagonist Therapeutics, and CRISPR Therapeutics. A.T.T. reports consultancy
fees from Novartis, Celgene Corp (Bristol Myers Squibb), Vifor Pharma, Silence
Therapeutics, and Ionis Pharmaceuticals and research funding from Novartis,
Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche,
Protagonist Therapeutics, and Agios Pharmaceuticals.
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http://www.ncbi.nlm.nih.gov/pubmed/31974203
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1. Haematologica. 2021 Jan 1;106(1):238-249. doi: 10.3324/haematol.2019.238865.
AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase,
increases enzymatic activity, protein stability, and ATP levels over a broad
range of PKLR genotypes.
Rab MAE(1), Van Oirschot BA(2), Kosinski PA(3), Hixon J(4), Johnson K(3),
Chubukov V(3), Dang L(3), Pasterkamp G(2), Van Straaten S(1), Van Solinge WW(1),
Van Beers EJ(5), Kung C(3), Van Wijk R(1).
Author information:
(1)Laboratory of Clinical Chemistry and Haematology, University Medical Center
Utrecht.
(2)Laboratory of Clinical Chemistry and Haematology, University Medical Center
Utrecht, The Netherlands.
(3)Agios Pharmaceuticals, Inc., Cambridge, MA.
(4)KSQ Therapeutics, Cambridge, MA.
(5)Van Creveldkliniek, University Medical Center Utrecht, Utrecht University,
Utrecht, The Netherlands.
Comment in
Haematologica. 2021 Jan 01;106(1):9-11. doi: 10.3324/haematol.2020.266585.
Pyruvate kinase (PK) deficiency is a rare hereditary disorder affecting red cell
(RBC) glycolysis, causing changes in metabolism including a deficiency in ATP.
This affects red cell homeostasis, promoting premature removal of RBCs from the
circulation. In this study we characterized and evaluated the effect of AG-348,
an allosteric activator of PK that is currently in clinical trials for treatment
of PK deficiency, on RBCs and erythroid precursors from PK-deficient patients.
In 15 patients ex vivo treatment with AG-348 resulted in increased enzymatic
activity in all patient cells after 24 hours (mean increase 1.8-fold, range
1.2-3.4). ATP levels increased (mean increase 1.5-fold, range 1.0-2.2) similar
to control cells (mean increase 1.6-fold, range, 1.4-1.8). Generally, PK
thermostability was strongly reduced in PK-deficient RBCs. Ex vivo treatment
with AG-348 increased residual activity 1.4 to >10-fold than residual activity
of vehicle-treated samples. Protein analyses suggests that a sufficient level of
PK protein is required for cells to respond to AG-348 treatment ex-vivo, as
treatment effects were minimal in patient cells with very low or undetectable
levels of PK-R. In half of the patients, ex vivo treatment with AG-348 was
associated with an increase in RBC deformability. These data support the
hypothesis that drug intervention with AG-348 effectively upregulates PK
enzymatic activity and increases stability in PK-deficient RBCs over a broad
range of PKLR genotypes. The concomitant increase in ATP levels suggests that
glycolytic pathway activity may be restored. AG-348 treatment may represent an
attractive way to correct the underlying pathologies of PK deficiency. (AG-348
is currently in clinical trials for the treatment of PK deficiency.
ClinicalTrials.gov: NCT02476916, NCT03853798, NCT03548220, NCT03559699).
DOI: 10.3324/haematol.2019.238865
PMCID: PMC7776327
PMID: 31974203 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35934590
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1. Trends Genet. 2022 Dec;38(12):1217-1227. doi: 10.1016/j.tig.2022.07.005. Epub
2022 Aug 4.
Transperons: RNA operons as effectors of coordinated gene expression in
eukaryotes.
Nair RR(1), Pataki E(1), Gerst JE(2).
Author information:
(1)Department of Molecular Genetics, Weizmann Institute of Science, Rehovot
7610001, Israel.
(2)Department of Molecular Genetics, Weizmann Institute of Science, Rehovot
7610001, Israel. Electronic address: [email protected].
Coordinated gene expression allows spatiotemporal control of cellular processes
and is achieved by the cotranscription/translation of functionally related
genes/proteins. Prokaryotes evolved polycistronic messages (operons) to confer
expression from a single promoter to efficiently cotranslate proteins
functioning on the same pathway. Yet, despite having far greater diversity
(e.g., gene number, distribution, modes of expression), eukaryotic cells employ
individual promoters and monocistronic messages. Although gene expression is
modular, it does not account for how eukaryotes achieve coordinated localized
translation. The RNA operon theory states that mRNAs derived from different
chromosomes assemble into ribonucleoprotein particles (RNPs) that act as
functional operons to generate protein cohorts upon cotranslation. Work in yeast
has now validated this theory and shown that intergenic associations and
noncanonical histone functions create pathway-specific RNA operons (transperons)
that regulate cell physiology. Herein the involvement of chromatin organization
in transperon formation and programmed gene coexpression is discussed.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tig.2022.07.005
PMID: 35934590 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors have no
interests to declare.
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http://www.ncbi.nlm.nih.gov/pubmed/32209657
|
1. J Biol Chem. 2020 May 8;295(19):6372-6386. doi: 10.1074/jbc.RA120.013148. Epub
2020 Mar 24.
RNA helicase-regulated processing of the Synechocystis rimO-crhR operon results
in differential cistron expression and accumulation of two sRNAs.
Rosana ARR(1), Whitford DS(1), Migur A(2), Steglich C(2), Kujat-Choy SL(1), Hess
WR(2)(3), Owttrim GW(4).
Author information:
(1)Department of Biological Sciences, University of Alberta, Edmonton, Alberta
T6G 2E9, Canada.
(2)Faculty of Biology, University of Freiburg, Schänzlestrasse 1, D-79104
Freiburg, Germany.
(3)Freiburg Institute for Advanced Studies, University of Freiburg,
Albertstrasse 19, D-79104 Freiburg, Germany.
(4)Department of Biological Sciences, University of Alberta, Edmonton, Alberta
T6G 2E9, Canada [email protected].
The arrangement of functionally-related genes in operons is a fundamental
element of how genetic information is organized in prokaryotes. This
organization ensures coordinated gene expression by co-transcription. Often,
however, alternative genetic responses to specific stress conditions demand the
discoordination of operon expression. During cold temperature stress,
accumulation of the gene encoding the sole Asp-Glu-Ala-Asp (DEAD)-box RNA
helicase in Synechocystis sp. PCC 6803, crhR (slr0083), increases 15-fold. Here,
we show that crhR is expressed from a dicistronic operon with the
methylthiotransferase rimO/miaB (slr0082) gene, followed by rapid processing of
the operon transcript into two monocistronic mRNAs. This cleavage event is
required for and results in destabilization of the rimO transcript. Results from
secondary structure modeling and analysis of RNase E cleavage of the rimO-crhR
transcript in vitro suggested that CrhR plays a role in enhancing the rate of
the processing in an auto-regulatory manner. Moreover, two putative small RNAs
are generated from additional processing, degradation, or both of the rimO
transcript. These results suggest a role for the bacterial RNA helicase CrhR in
RNase E-dependent mRNA processing in Synechocystis and expand the known range of
organisms possessing small RNAs derived from processing of mRNA transcripts.
© 2020 Rosana et al.
DOI: 10.1074/jbc.RA120.013148
PMCID: PMC7212639
PMID: 32209657 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflicts
of interest with the contents of this article
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http://www.ncbi.nlm.nih.gov/pubmed/24012761
|
1. Cell Rep. 2013 Sep 12;4(5):938-44. doi: 10.1016/j.celrep.2013.07.049. Epub
2013 Sep 5.
Differential translation tunes uneven production of operon-encoded proteins.
Quax TE(1), Wolf YI, Koehorst JJ, Wurtzel O, van der Oost R, Ran W, Blombach F,
Makarova KS, Brouns SJ, Forster AC, Wagner EG, Sorek R, Koonin EV, van der Oost
J.
Author information:
(1)Laboratory of Microbiology, Wageningen University, Dreijenplein 10, 6703 HB
Wageningen, The Netherlands. Electronic address: [email protected].
Clustering of functionally related genes in operons allows for coregulated gene
expression in prokaryotes. This is advantageous when equal amounts of gene
products are required. Production of protein complexes with an uneven
stoichiometry, however, requires tuning mechanisms to generate subunits in
appropriate relative quantities. Using comparative genomic analysis, we show
that differential translation is a key determinant of modulated expression of
genes clustered in operons and that codon bias generally is the best in silico
indicator of unequal protein production. Variable ribosome density profiles of
polycistronic transcripts correlate strongly with differential translation
patterns. In addition, we provide experimental evidence that de novo initiation
of translation can occur at intercistronic sites, allowing for differential
translation of any gene irrespective of its position on a polycistronic
messenger. Thus, modulation of translation efficiency appears to be a universal
mode of control in bacteria and archaea that allows for differential production
of operon-encoded proteins.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2013.07.049
PMID: 24012761 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/16755590
|
1. Proteins. 2006 Aug 15;64(3):615-28. doi: 10.1002/prot.21021.
Detection of operons.
Yan Y(1), Moult J.
Author information:
(1)Center for Advanced Research in Biotechnology, University of Maryland
Biotechnology Institute, Rockville, Maryland 20850, USA.
Operons are clusters of genes that are transcribed as a single message, and
regulated by the same gene expression machinery. They are found primarily in
prokaryotic genomes. Because genes in the same operon are likely to have related
functions, identification of the operon structure is potentially useful for
assigning gene function. We report the development and benchmarking of two
different methods for detecting operons, based on an analysis of 42 fully
sequenced prokaryotic organisms. The Gene Neighbor method (GNM) utilizes the
relatively high conservation of gene order in operons, compared with genes in
general. The Gene Gap Method (GGM) makes use of the relatively short gap between
genes in operons compared with that otherwise found between adjacent genes. The
methods have been benchmarked using KEGG pathway data and RegulonDB Escherichia
coli operon data. With optimum parameters, the specificity of the GNM is 93% and
the sensitivity is 70%. For the GGM, the specificity is 95% and the sensitivity
is 68%. Together, the two methods have a sensitivity of 87.2%, while joint
predictions have a sensitivity of 50% and a specificity of 98%. The methods are
used to infer possible functions for some hypothetical genes in prokaryotic
genomes. The methods have proven a useful addition to structure information in
deriving protein function in a structural genomics project.
DOI: 10.1002/prot.21021
PMID: 16755590 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15487932
|
1. Annu Rev Microbiol. 2004;58:119-42. doi:
10.1146/annurev.micro.58.030603.123806.
Selection for gene clustering by tandem duplication.
Reams AB(1), Neidle EL.
Author information:
(1)Section of Microbiology, University of California, Davis, California 95616,
USA. [email protected]
In prokaryotic genomes, related genes are frequently clustered in operons and
higher-order arrangements that reflect functional context. Organization emerges
despite rearrangements that constantly shuffle gene and operon order. Evidence
is presented that the tandem duplication of related genes acts as a driving
evolutionary force in the origin and maintenance of clusters. Gene amplification
can be viewed as a dynamic and reversible regulatory mechanism that facilitates
adaptation to variable environments. Clustered genes confer selective benefits
via their ability to be coamplified. During evolution, rearrangements that bring
together related genes can be selected if they increase the fitness of the
organism in which they reside. Similarly, the benefits of gene amplification can
prevent the dispersal of existing clusters. Examples of frequent and spontaneous
amplification of large genomic fragments are provided. The possibility is raised
that tandem gene duplication works in concert with horizontal gene transfer as
interrelated evolutionary forces for gene clustering.
DOI: 10.1146/annurev.micro.58.030603.123806
PMID: 15487932 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17671982
|
1. Proteins. 2008 Feb 1;70(2):344-52. doi: 10.1002/prot.21564.
Operons and the effect of genome redundancy in deciphering functional
relationships using phylogenetic profiles.
Moreno-Hagelsieb G(1), Janga SC.
Author information:
(1)Department of Biology, Wilfrid Laurier University, 75 University Avenue West,
Waterloo, ON N2L 3C5, Canada. [email protected]
Phylogenetic profiles (PPs) are one of the most promising methods for predicting
functional relationships by genomic context. The idea behind PPs is that if the
products of two genes have a functional interdependence, the genes should both
be either present or absent across genomes. One of the main problems with PPs is
that evolutionarily close organisms tend to share a higher number of genes
resulting in the overscoring of PP-relatedness. The proper measure of the
overscoring effect of evolutionary redundancy requires examples of both
functionally related genes (positive gold standards) and functionally unrelated
genes (negative gold standards). Since experimentally verified functional
interactions are only available for a few model organisms, there is a need for
an alternative to gold standards. The presence of operons (polycistronic
transcription units formed of functionally related genes) in prokaryotic genomes
offers such an alternative. Genes in operons are located next to each other in
the same DNA strand, and thus their presence should result in a higher
proportion of predicted functional interactions among adjacent genes in the same
strand than among adjacent genes in opposite strands. Under the preceding
principle, we present a confidence value (CV) designed for evaluating
predictions of functional interactions obtained using PPs. We first show that
the CV corresponds to a positive predictive value calculated using
experimentally known operons and further validate operon predictions based on
this CV in other organisms using available microarray data. Then, we use a fixed
CV of 0.90 as a reference to compare PP predictions obtained using different
nonredundant genome datasets filtered at varying thresholds of genomic
similarity. Our results demonstrate that nonredundant genome datasets increase
the number of high-quality predictions by an average of 20%. Confidence values
as those presented here should help compare other strategies and scoring systems
to use phylogenetic profiles and other genomic context methods for predicting
functional interactions.
(c) 2007 Wiley-Liss, Inc.
DOI: 10.1002/prot.21564
PMID: 17671982 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18269733
|
1. BMC Genomics. 2008 Feb 12;9:79. doi: 10.1186/1471-2164-9-79.
Predicted transcription factor binding sites as predictors of operons in
Escherichia coli and Streptomyces coelicolor.
Laing E(1), Sidhu K, Hubbard SJ.
Author information:
(1)Faculty of Life Sciences, The University of Manchester, Michael Smith
Building, Oxford Road, Manchester, M13 9PT, UK. [email protected]
BACKGROUND: As a polycistronic transcriptional unit of one or more adjacent
genes, operons play a key role in regulation and function in prokaryotic
biology, and a better understanding of how they are constituted and controlled
is needed. Recent efforts have attempted to predict operonic status in sequenced
genomes using a variety of techniques and data sources. To date, non-homology
based operon prediction strategies have mainly used predicted promoters and
terminators present at the extremities of transcriptional unit as predictors,
with reasonable success. However, transcription factor binding sites (TFBSs),
typically found upstream of the first gene in an operon, have not yet been
evaluated.
RESULTS: Here we apply a method originally developed for the prediction of TFBSs
in Escherichia coli that minimises the need for prior knowledge and tests its
ability to predict operons in E. coli and the 'more complex', pharmaceutically
important, Streptomyces coelicolor. We demonstrate that through building genome
specific TFBS position-specific-weight-matrices (PSWMs) it is possible to
predict operons in E. coli and S. coelicolor with 83% and 93% accuracy
respectively, using only TFBS as delimiters of operons. Additionally, the
'palindromicity' of TFBS footprint data of E. coli is characterised.
CONCLUSION: TFBS are proposed as novel independent features for use in
prokaryotic operon prediction (whether alone or as part of a set of features)
given their efficacy as operon predictors in E. coli and S. coelicolor. We also
show that TFBS footprint data in E. coli generally contains inverted repeats
with significantly (p < 0.05) greater palindromicity than random sequences.
Consequently, the palindromicity of putative TFBSs predicted can also enhance
operon predictions.
DOI: 10.1186/1471-2164-9-79
PMCID: PMC2276206
PMID: 18269733 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26543854
|
1. Biomed Res Int. 2015;2015:318217. doi: 10.1155/2015/318217. Epub 2015 Oct 12.
OperomeDB: A Database of Condition-Specific Transcription Units in Prokaryotic
Genomes.
Chetal K(1), Janga SC(2).
Author information:
(1)Department of Biohealth Informatics, School of Informatics and Computing,
Indiana University-Purdue University Indianapolis (IUPUI), 719 Indiana Avenue,
Suite 319, Walker Plaza Building, Indianapolis, IN 46202, USA.
(2)Department of Biohealth Informatics, School of Informatics and Computing,
Indiana University-Purdue University Indianapolis (IUPUI), 719 Indiana Avenue,
Suite 319, Walker Plaza Building, Indianapolis, IN 46202, USA ; Center for
Computational Biology and Bioinformatics, Indiana University School of Medicine,
5021 Health Information and Translational Sciences (HITS), 410 West 10th Street,
Indianapolis, IN 46202, USA ; Department of Medical and Molecular Genetics,
Indiana University School of Medicine, Medical Research and Library Building,
975 West Walnut Street, Indianapolis, IN 46202, USA.
Background. In prokaryotic organisms, a substantial fraction of adjacent genes
are organized into operons-codirectionally organized genes in prokaryotic
genomes with the presence of a common promoter and terminator. Although several
available operon databases provide information with varying levels of
reliability, very few resources provide experimentally supported results.
Therefore, we believe that the biological community could benefit from having a
new operon prediction database with operons predicted using next-generation
RNA-seq datasets. Description. We present operomeDB, a database which provides
an ensemble of all the predicted operons for bacterial genomes using available
RNA-sequencing datasets across a wide range of experimental conditions. Although
several studies have recently confirmed that prokaryotic operon structure is
dynamic with significant alterations across environmental and experimental
conditions, there are no comprehensive databases for studying such variations
across prokaryotic transcriptomes. Currently our database contains nine
bacterial organisms and 168 transcriptomes for which we predicted operons. User
interface is simple and easy to use, in terms of visualization, downloading, and
querying of data. In addition, because of its ability to load custom datasets,
users can also compare their datasets with publicly available transcriptomic
data of an organism. Conclusion. OperomeDB as a database should not only aid
experimental groups working on transcriptome analysis of specific organisms but
also enable studies related to computational and comparative operomics.
DOI: 10.1155/2015/318217
PMCID: PMC4620388
PMID: 26543854 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34889443
|
1. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):600-606. doi:
10.1182/hematology.2021000313.
β-Thalassemia: evolving treatment options beyond transfusion and iron chelation.
Langer AL(1), Esrick EB(2).
Author information:
(1)Division of Hematology, Brigham and Women's Hospital, Harvard Medical School,
Boston, MA.
(2)Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical
School, Boston, MA.
After years of reliance on transfusion alone to address anemia and suppress
ineffective erythropoiesis in β-thalassemia, many new therapies are now in
development. Luspatercept, a transforming growth factor-β inhibitor, has
demonstrated efficacy in reducing ineffective erythropoiesis, improving anemia,
and possibly reducing iron loading. However, many patients do not respond to
luspatercept, so additional therapeutics are needed. Several medications in
development aim to induce hemoglobin F (HbF): sirolimus, benserazide, and
IMR-687 (a phosphodiesterase 9 inhibitor). Another group of agents seeks to
ameliorate ineffective erythropoiesis and improve anemia by targeting abnormal
iron metabolism in thalassemia: apotransferrin, VIT-2763 (a ferroportin
inhibitor), PTG-300 (a hepcidin mimetic), and an erythroferrone antibody in
early development. Mitapivat, a pyruvate kinase activator, represents a unique
mechanism to mitigate ineffective erythropoiesis. Genetically modified
autologous hematopoietic stem cell transplantation offers the potential for
lifelong transfusion independence. Through a gene addition approach, lentiviral
vectors have been used to introduce a β-globin gene into autologous
hematopoietic stem cells. One such product, betibeglogene autotemcel (beti-cel),
has reached phase 3 trials with promising results. In addition, 2 gene editing
techniques (CRISPR-Cas9 and zinc-finger nucleases) are under investigation as a
means to silence BCL11A to induce HbF with agents designated CTX001 and ST-400,
respectively. Results from the many clinical trials for these agents will yield
results in the next few years, which may end the era of relying on transfusion
alone as the mainstay of thalassemia therapy.
Copyright © 2021 by The American Society of Hematology.
DOI: 10.1182/hematology.2021000313
PMCID: PMC8791140
PMID: 34889443 [Indexed for MEDLINE]
Conflict of interest statement: Arielle L. Langer: no competing financial
interests to declare. Erica B. Esrick: steering committee (consulting) for
bluebird bio and research funding to institution from Celgene (site for
luspatercept trial).
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http://www.ncbi.nlm.nih.gov/pubmed/21690561
|
1. Mol Biol Evol. 2011 Dec;28(12):3309-18. doi: 10.1093/molbev/msr163. Epub 2011
Jun 20.
The operonic location of auto-transcriptional repressors is highly conserved in
bacteria.
Rubinstein ND(1), Zeevi D, Oren Y, Segal G, Pupko T.
Author information:
(1)Department of Cell Research and Immunology, George S. Wise Faculty of Life
Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
Bacterial genes are commonly encoded in clusters, known as operons, which share
transcriptional regulatory control and often encode functionally related
proteins that take part in certain biological pathways. Operons that are
coregulated are known to colocalize in the genome, suggesting that their spatial
organization is under selection for efficient expression regulation. However,
the internal order of genes within operons is believed to be poorly conserved,
and hence expression requirements are claimed to be too weak to oppose gene
rearrangements. In light of these opposing views, we set out to investigate
whether the internal location of the regulatory genes within operons is under
selection. Our analysis shows that transcription factors (TFs) are
preferentially encoded as either first or last in their operons, in the two
diverged model bacteria Escherichia coli and Bacillus subtilis. In a higher
resolution, we find that TFs that repress transcription of the operon in which
they are encoded (autorepressors), contribute most of this signal by specific
preference of the first operon position. We show that this trend is strikingly
conserved throughout highly diverged bacterial phyla. Moreover, these
autorepressors regulate operons that carry out highly diverse biological
functions. We propose a model according to which autorepressors are selected to
be located first in their operons in order to optimize transcription regulation.
Specifically, the first operon position helps autorepressors to minimize leaky
transcription of the operon structural genes, thus minimizing energy waste. Our
analysis provides statistically robust evidence for a paradigm of bacterial
autorepressor preferential operonic location. Corroborated with our suggested
model, an additional layer of operon expression control that is common
throughout the bacterial domain is revealed.
DOI: 10.1093/molbev/msr163
PMID: 21690561 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33483546
|
1. Sci Rep. 2021 Jan 22;11(1):2124. doi: 10.1038/s41598-021-81169-9.
Detecting operons in bacterial genomes via visual representation learning.
Assaf R(1), Xia F(2)(3), Stevens R(4)(2).
Author information:
(1)Department of Computer Science, University of Chicago, Chicago, 60637, USA.
[email protected].
(2)Computing Environment and Life Sciences Division, Argonne National
Laboratory, Lemont, 60439, USA.
(3)Data Science and Learning Division, Argonne National Laboratory, Lemont,
60439, USA.
(4)The University of Chicago Consortium for Advanced Science and Engineering,
University of Chicago, Chicago, 60637, USA.
Contiguous genes in prokaryotes are often arranged into operons. Detecting
operons plays a critical role in inferring gene functionality and regulatory
networks. Human experts annotate operons by visually inspecting gene
neighborhoods across pileups of related genomes. These visual representations
capture the inter-genic distance, strand direction, gene size, functional
relatedness, and gene neighborhood conservation, which are the most prominent
operon features mentioned in the literature. By studying these features, an
expert can then decide whether a genomic region is part of an operon. We propose
a deep learning based method named Operon Hunter that uses visual
representations of genomic fragments to make operon predictions. Using transfer
learning and data augmentation techniques facilitates leveraging the powerful
neural networks trained on image datasets by re-training them on a more limited
dataset of extensively validated operons. Our method outperforms the previously
reported state-of-the-art tools, especially when it comes to predicting full
operons and their boundaries accurately. Furthermore, our approach makes it
possible to visually identify the features influencing the network's decisions
to be subsequently cross-checked by human experts.
DOI: 10.1038/s41598-021-81169-9
PMCID: PMC7822928
PMID: 33483546 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/12220896
|
1. Trends Biotechnol. 2002 Oct;20(10):407-10; discussion 410. doi:
10.1016/s0167-7799(02)02032-2.
Conservation of gene co-regulation in prokaryotes and eukaryotes.
Teichmann SA(1), Babu MM.
Author information:
(1)MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
[email protected]
Genes that are part of the same operon in prokaryotes, or have the same
expression pattern in eukaryotes, are transcriptionally co-regulated. If genes
are consistently co-regulated across distantly related organisms, the genes have
closely associated functions. It has been shown previously that such genes have
a strong tendency to belong to the same protein complex in prokaryotes, and we
show by an analysis of the sequences and their expression in the yeast
Saccharomyces cerevisiae and the worm Caenorhabditis elegans that this is also
true for eukaryotes. Our analysis reveals that the number of conserved
co-regulated genes is small in eukaryotes, as has been shown previously in
prokaryotes, indicating that there are extensive variations in the gene
regulatory network across organisms.
DOI: 10.1016/s0167-7799(02)02032-2
PMID: 12220896 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35868358
|
1. J Control Release. 2022 Sep;349:1045-1051. doi: 10.1016/j.jconrel.2022.05.061.
Epub 2022 Sep 8.
Suprachoroidal delivery enables targeting, localization and durability of small
molecule suspensions.
Kansara VS(1), Hancock SE(1), Muya LW(1), Ciulla TA(2).
Author information:
(1)Clearside Biomedical Inc., 900 North Point Parkway, Suite 200, Alpharetta, GA
30005, United States of America.
(2)Clearside Biomedical Inc., 900 North Point Parkway, Suite 200, Alpharetta, GA
30005, United States of America. Electronic address:
[email protected].
Drug delivery to the suprachoroidal space (SCS®) has become a clinical reality
after the 2021 FDA approval of CLS-TA, a triamcinolone acetonide injectable
suspension for suprachoroidal use (XIPERE®), administered via a
microneedle-based device, the SCS Microinjector®. Suprachoroidal (SC) delivery
facilitates targeting, compartmentalization, and durability of small molecule
suspensions, thereby potentially addressing some of the efficacy, safety, and
treatment burden limitations of current retinal therapies. Herein, the design
features of the SCS Microinjector are reviewed, along with the biomechanics of
SC drug delivery. Also presented are preclinical evaluations of SC small
molecule suspensions from 4 different therapeutic classes (plasma kallikrein
inhibitor, receptor tyrosine kinase inhibitor, corticosteroid, complement factor
D inhibitor), highlighting their potential for durability, targeted
compartmentalization, and acceptable safety profiles following
microinjector-based SC delivery. The clinical evaluations of the safety,
tolerability and efficacy of SC delivered triamcinolone further supports
potential of SC small molecule suspensions as a clinically viable strategy for
the treatment of chorioretinal diseases. Also highlighted are current
limitations, key pharmacological considerations, and future opportunities to
optimize the SC microinjector platform for safe, effective, and potentially
long-acting drug delivery for the treatment of chorioretinal disorders.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.jconrel.2022.05.061
PMID: 35868358 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30635413
|
1. Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1733-1738. doi:
10.1073/pnas.1812746116. Epub 2019 Jan 11.
Noncontiguous operon is a genetic organization for coordinating bacterial gene
expression.
Sáenz-Lahoya S(1), Bitarte N(1), García B(1), Burgui S(1), Vergara-Irigaray
M(1), Valle J(1), Solano C(1), Toledo-Arana A(2), Lasa I(3).
Author information:
(1)Laboratory of Microbial Pathogenesis, Navarrabiomed, Complejo Hospitalario de
Navarra-Universidad Pública de Navarra (UPNA), Instituto de Investigación
Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain.
(2)Instituto de Agrobiotecnología (IDAB), Consejo Superior de Investigaciones
Cientificas (CSIC)-UPNA-Gobierno de Navarra, 31192 Mutilva, Navarra, Spain.
(3)Laboratory of Microbial Pathogenesis, Navarrabiomed, Complejo Hospitalario de
Navarra-Universidad Pública de Navarra (UPNA), Instituto de Investigación
Sanitaria de Navarra (IDISNA), 31008 Pamplona, Spain; [email protected].
Bacterial genes are typically grouped into operons defined as clusters of
adjacent genes encoding for proteins that fill related roles and are transcribed
into a single polycistronic mRNA molecule. This simple organization provides an
efficient mechanism to coordinate the expression of neighboring genes and is at
the basis of gene regulation in bacteria. Here, we report the existence of a
higher level of organization in operon structure that we named noncontiguous
operon and consists in an operon containing a gene(s) that is transcribed in the
opposite direction to the rest of the operon. This transcriptional architecture
is exemplified by the genes menE-menC-MW1733-ytkD-MW1731 involved in menaquinone
synthesis in the major human pathogen Staphylococcus aureus We show that
menE-menC-ytkD-MW1731 genes are transcribed as a single transcription unit,
whereas the MW1733 gene, located between menC and ytkD, is transcribed in the
opposite direction. This genomic organization generates overlapping transcripts
whose expression is mutually regulated by transcriptional interference and RNase
III processing at the overlapping region. In light of our results, the canonical
view of operon structure should be revisited by including this operon
arrangement in which cotranscription and overlapping transcription are combined
to coordinate functionally related gene expression.
DOI: 10.1073/pnas.1812746116
PMCID: PMC6358700
PMID: 30635413 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/35359537
|
1. Ann Indian Acad Neurol. 2021 Nov-Dec;24(6):873-878. doi:
10.4103/aian.AIAN_126_21. Epub 2021 Aug 20.
Duchenne Muscular Dystrophy: Genetic and Clinical Profile in the Population of
Rajasthan, India.
Goyal M(1), Gupta A(1), Agarwal K(1), Kapoor S(2), Kumar S(2).
Author information:
(1)Department of Pediatrics, SMS Medical College, Jaipur, Rajasthan, India.
(2)Division of Genetics, Department of Pediatrics, Maulana Azad Medical College,
New Delhi, India.
BACKGROUND: Duchenne Muscular Dystrophy (DMD) is an X-linked recessive muscular
dystrophy that affects young boys and is caused by mutation of the dystrophin
gene located over X chromosome.
MATERIALS AND METHODS: In this prospective study, 120 clinically diagnosed DMD
patients were tested for exon deletions, duplication or point mutation.
RESULTS: Of the 120 clinically suspected DMD patients, the diagnosis of DMD was
confirmed by the genetic study or muscle biopsy in 116 patients. The mean age of
onset was 3.2 years and the mean age at presentation was 7.2 years. 110/120
cases were confirmed by genetic testing and six were by absence of staining for
dystrophin on muscle biopsy. DMD gene deletion was present in 78.5%, duplication
in 5.3% and point mutation in 11.2% cases. 70.3% of patients had deletion
located at a distal hot spot region. Single exon deletion was found in 16.5%.
Distal hotspot exons 47, 48 and 50 were the commonly deleted exons.
CONCLUSIONS: In our study, 94.8% cases showed genetic change in the DMD gene.
Muscle biopsy was the choice of investigation in earlier days. Detection of DMD
by DNA based method eliminates the need to do an invasive procedure for
diagnosis. Hence the genetic testing should be the investigation of choice in
suspected cases of DMD. The pattern of deletion, obtained in the population of
Rajasthan was similar when compared with other ethnic groups of the Indian
population. It would be helpful for researchers to develop drugs specific to
exons or for ongoing mutation-specific therapies.
Copyright: © 2006 - 2021 Annals of Indian Academy of Neurology.
DOI: 10.4103/aian.AIAN_126_21
PMCID: PMC8965960
PMID: 35359537
Conflict of interest statement: There are no conflicts of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/33101180
|
1. Front Neurol. 2020 Sep 30;11:572006. doi: 10.3389/fneur.2020.572006.
eCollection 2020.
A Comprehensive Analysis of 2013 Dystrophinopathies in China: A Report From
National Rare Disease Center.
Tong YR(1), Geng C(1), Guan YZ(2), Zhao YH(2), Ren HT(2), Yao FX(3), Ling C(3),
Wang DC(4), Chen L(2), Cui LY(2), Zhang SY(5), Dai Y(2).
Author information:
(1)Peking Union Medical College Hospital, Chinese Academy of Medical Sciences &
Peking Union Medical College, Beijing, China.
(2)Department of Neurology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
(3)Laboratory of Clinical Genetics, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing,
China.
(4)Department of Clinical Laboratory, Peking Union Medical College Hospital,
Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing,
China.
(5)Department of Cardiology, Peking Union Medical College Hospital, Chinese
Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are
X-linked recessive neuromuscular disorders caused by mutations in DMD. A
high-quality database of DMD/BMD is essential not only for clinical practice but
also for fundamental research. Here, we aimed to build the largest Chinese
national dystrophinopathy database using the National Rare Diseases Registry
System of China. Peking Union Medical College Hospital (PUMCH) was the National
Rare Diseases Center of China. This research involved 2013 patients with
dystrophinopathies, whose diagnoses were confirmed; they were registered and
followed up at PUMCH from March 2011 to December 2018. Family history, clinical
signs, and treatment data were reported for patients with DMD and BMD at
different rates. All six serum biochemical indexes could accurately distinguish
between DMD and BMD patients. Copy number variations were the most frequent
mutation type (79.2% in DMD and 84.3% in BMD), of which large deletions
accounted for 88.4 and 88.6%, large duplications accounted for 11.6 and 11.4% in
DMD and BMD, respectively. An exon deletion hotspot, located in exons 45-54, was
observed in DMD, and intron 44 was the most frequent deletion starting point
(26.5%). Duplication and single nucleotide variations appeared to be uniformly
distributed among all exons. Eleven patients were identified to have ultrarare
mutation types. Eleven other patients suffered from two separate mutations
simultaneously, some of which may have taken place via dependent mechanisms.
Thus, we have established the largest hospital-based Chinese dystrophinopathy
database via the National Rare Diseases Registry System. This study provides
valuable information for further diagnostic and therapeutic studies of
dystrophinopathy.
Copyright © 2020 Tong, Geng, Guan, Zhao, Ren, Yao, Ling, Wang, Chen, Cui, Zhang
and Dai.
DOI: 10.3389/fneur.2020.572006
PMCID: PMC7554367
PMID: 33101180
|
http://www.ncbi.nlm.nih.gov/pubmed/35897138
|
1. Ann Neurol. 2022 Nov;92(5):793-806. doi: 10.1002/ana.26461. Epub 2022 Sep 7.
Dystrophinopathy Phenotypes and Modifying Factors in DMD Exon 45-55 Deletion.
Poyatos-García J(1)(2), Martí P(1)(2), Liquori A(3)(4), Muelas N(1)(2)(5),
Pitarch I(5)(6), Martinez-Dolz L(7)(8), Rodríguez B(9)(10), Gonzalez-Quereda
L(9)(10), Damiá M(5)(6), Aller E(11), Selva-Gimenez M(1)(2), Vilchez R(1)(2),
Diaz-Manera J(12)(13)(14), Alonso-Pérez J(12)(13)(14), Barcena JE(15), Jauregui
A(15), Gámez J(13)(16), Aladrén JA(17), Fernández A(17), Montolio M(18)(19),
Azorin I(1)(2), Hervas D(20), Casasús A(1)(2), Nieto M(1)(2), Gallano P(9)(10),
Sevilla T(1)(2)(5)(21), Vilchez JJ(1)(2)(5)(21).
Author information:
(1)Neuromuscular and Ataxias Research Group, Health Research Institute Hospital
La Fe (IIS La Fe), Valencia, Spain.
(2)Centre for Biomedical Network Research on Rare Diseases (CIBERER); U763,
CB06/05/0091, Valencia, Spain.
(3)Hematology Research Group, Health Research Institute Hospital La Fe (IIS La
Fe), Valencia, Spain.
(4)Centre for Biomedical Network Research on Cancer (CIBERONC); CB16/12/00284,
Madrid, Spain.
(5)Neuromuscular Referral Center, European Reference Network on Rare
Neuromuscular Diseases (ERN EURO-NMD), Universitary and Polytechnic La Fe
Hospital, Valencia, Spain.
(6)Neuropediatric Department, Universitary and Polytechnic La Fe Hospital,
Valencia, Spain.
(7)Cardiology Department, University and Polytechnic La Fe Hospital, IIS La Fe,
Valencia, Spain.
(8)Centre for Biomedical Network Research on Cardiovascular Diseases (CIBERCV),
Valencia, Spain.
(9)Genetics Department, IIB Sant Pau, Hospital of Sant Pau, Barcelona, Spain.
(10)Centre for Biomedical Network Research on Rare Diseases (CIBERER), U705,
U745, CB06/07/0011, Barcelona, Spain.
(11)Genetics Unit, Universitary and Polytechnic La Fe Hospital, Valencia, Spain.
(12)Neuromuscular Disorders Unit, Neurology Department, European Reference
Network on Rare Neuromuscular Diseases (ERN EURO-NMD), Hospital of Sant Pau,
Barcelona, Spain.
(13)Autonomous University of Barcelona, Barcelona, Spain.
(14)Centre for Biomedical Network Research on Rare Diseases (CIBERER), U762,
CB06/05/0030, Barcelona, Spain.
(15)Neuromuscular Section, Neurology Service, Cruces University Hospital,
Barakaldo, Spain.
(16)Neurology Department, European Reference Network on Rare Neuromuscular
Diseases (ERN EURO-NMD), GMA Clinic, Barcelona, Spain.
(17)Calahorra Hospital Foundation, Calahorra, Spain.
(18)Duchenne Parent Project Spain, Madrid, Spain.
(19)Department of Cell Biology, Physiology, and Immunology, Faculty of Biology,
Barcelona, Spain.
(20)Department of Applied Statistics and Operations Research, and Quality,
Polytechnic University of Valencia, Valencia, Spain.
(21)Department of Medicine, University of Valencia, Valencia, Spain.
OBJECTIVE: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has
been postulated as a model that could treat up to 60% of DMD patients, but the
associated clinical variability and complications require clarification. We
aimed to understand the phenotypes and potential modifying factors of this
dystrophinopathy subset.
METHODS: This cross-sectional, multicenter cohort study applied clinical and
functional evaluation. Next generation sequencing was employed to identify
intronic breakpoints and their impact on the Dp140 promotor, intronic long
noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4,
ACTN3) and concomitant mutations were also assessed. Haplotypes were built using
DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via
immunostaining, Western blotting, reverse transcription polymerase chain
reaction (PCR), and droplet digital PCR in 9 muscle biopsies.
RESULTS: The series comprised 57 subjects (23 index) expressing Becker phenotype
(28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive
impairment occurred in 90% of children. Patients were classified according to 10
distinct index-case breakpoints; 4 of them were recurrent due to founder events.
A specific breakpoint (D5) was associated with severity, but no significant
effect was appreciated due to the changes in intronic sequences. All biopsies
showed dystrophin expression of >67% and traces of alternative del45-57
transcript that were not deemed pathogenically relevant. Only the LTBP4
haplotype appeared associated the presence of cardiopathy among the explored
extragenic factors.
INTERPRETATION: We confirmed that del45-55 segregates a high proportion of
benign phenotypes, severe cases, and isolated cardiac and cognitive
presentations. Although some influence of the intronic breakpoint position and
the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic
variability remain largely unresolved. ANN NEUROL 2022;92:793-806.
© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on
behalf of American Neurological Association.
DOI: 10.1002/ana.26461
PMCID: PMC9825930
PMID: 35897138 [Indexed for MEDLINE]
Conflict of interest statement: J.P.‐G. has received a PhD grant from Fundación
Isabel Gemio. J.J.V. has received grants from Fundación Isabel Gemio and ISCIII
and has been a consultant to BioMarin, Genzyme Therapeutics, and PTC
Therapeutics. I.P. has received grants from Duchenne Parent Project España
(DPPE) and has received speaker honoraria from Genzyme Therapeutics and PTC
Therapeutics. J.D‐M. is an external advisor for Sanofi‐Genzyme Spain and has
participated in advisory meetings for Sanofi‐Genzyme, Amicus, Audentes, Sarepta,
and Lupin. He has received funding for research from Sanofi‐Genzyme, Amicus,
Spark Therapeutics, and Boehringer‐Ingelheim. He has also received grants from
DPPE, Fundación Isabel Gemio, ISCIII, CIBERER, and AFM. The other authors
declare no conflicts of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/29771942
|
1. PLoS One. 2018 May 17;13(5):e0197084. doi: 10.1371/journal.pone.0197084.
eCollection 2018.
Antisense PMO cocktails effectively skip dystrophin exons 45-55 in myotubes
transdifferentiated from DMD patient fibroblasts.
Lee J(1), Echigoya Y(2), Duddy W(3), Saito T(4), Aoki Y(4), Takeda S(4), Yokota
T(1)(5).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB, Canada.
(2)Department of Veterinary Medicine, Nihon University, Fujisawa, Kanagawa,
Japan.
(3)Northern Ireland Centre for Stratified Medicine, Altnagelvin Hospital Campus,
Ulster University, Londonderry, United Kingdom.
(4)Department of Molecular Therapy, National Institute of Neuroscience, National
Center of Neurology and Psychiatry, Kodaira, Japan.
(5)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin
Neurological Science Research Chair, Edmonton, AB, Canada.
Antisense-mediated exon skipping has made significant progress as a therapeutic
platform in recent years, especially in the case of Duchenne muscular dystrophy
(DMD). Despite FDA approval of eteplirsen-the first-ever antisense drug
clinically marketed for DMD-exon skipping therapy still faces the significant
hurdles of limited applicability and unknown truncated protein function.
In-frame exon skipping of dystrophin exons 45-55 represents a significant
approach to treating DMD, as a large proportion of patients harbor mutations
within this "hotspot" region. Additionally, patients harboring dystrophin exons
45-55 deletion mutations are reported to have exceptionally mild to asymptomatic
phenotypes. Here, we demonstrate that a cocktail of phosphorodiamidate
morpholino oligomers can effectively skip dystrophin exons 45-55 in vitro in
myotubes transdifferentiated from DMD patient fibroblast cells. This is the
first report of substantive exons 45-55 skipping in DMD patient cells. These
findings help validate the use of transdifferentiated patient fibroblast cells
as a suitable cell model for dystrophin exon skipping assays and further
emphasize the feasibility of dystrophin exons 45-55 skipping in patients.
DOI: 10.1371/journal.pone.0197084
PMCID: PMC5957359
PMID: 29771942 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/33531685
|
1. Gene Ther. 2021 Sep;28(9):542-548. doi: 10.1038/s41434-021-00222-4. Epub 2021
Feb 2.
Genome editing for Duchenne muscular dystrophy: a glimpse of the future?
Kupatt C(1)(2), Windisch A(3)(4), Moretti A(3)(4), Wolf E(5), Wurst W(6)(7),
Walter MC(8).
Author information:
(1)Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar,
Technical University Munich, Munich, Germany. [email protected].
(2)DZHK (German Center for Cardiovascular Research), Munich Heart Alliance,
Munich, Germany. [email protected].
(3)Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar,
Technical University Munich, Munich, Germany.
(4)DZHK (German Center for Cardiovascular Research), Munich Heart Alliance,
Munich, Germany.
(5)Chair for Molecular Animal Breeding and Biotechnology, Gene Center and
Department of Veterinary Sciences, and Center for Innovative Medical Models
(CiMM), LMU Munich, Munich, Germany.
(6)Institute of Development Genetics, Helmholtz-Centre Munich, Munich, Germany.
(7)German Center for Neurodegenerative Diseases, Munich, Munich Cluster for
Systems Neurology (SyNergy), Munich, Germany.
(8)Friedrich Baur Institute, Department of Neurology, LMU Munich, Munich,
Germany.
Mutations in Dystrophin, one of the largest proteins in the mammalian body, are
causative for a severe form of muscle disease, Duchenne Muscular Dystrophy
(DMD), affecting not only skeletal muscle, but also the heart. In particular,
exons 45-52 constitute a hotspot for DMD mutations. A variety of molecular
therapies have been developed, comprising vectors encoding micro- and
minidystrophins as well as utrophin, a protein with partially overlapping
functions. With the advent of the CRISPR-Cas9-nuclease, genome editing offers a
novel option of correction of the disease-cuasing mutations. Full restoration of
the healthy gene by homology directed repair is a rare event. However,
non-homologous end-joining (NHEJ) may restore the reading frame by causing exon
excision. This approach has first been demonstrated in mice and then translated
to large animals (dogs, pigs). This review discusses the potential opportunities
and limitations of genome editing in DMD, including the generation of
appropriate animal models as well as new developments in genome editing tools.
© 2021. The Author(s).
DOI: 10.1038/s41434-021-00222-4
PMCID: PMC8455335
PMID: 33531685 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/27009627
|
1. J Hum Genet. 2016 Jul;61(7):663-7. doi: 10.1038/jhg.2016.28. Epub 2016 Mar 24.
Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene
presents an asymptomatic phenotype, indicating a target region for multiexon
skipping therapy.
Nakamura A(1)(2), Fueki N(3), Shiba N(4), Motoki H(5), Miyazaki D(1)(2),
Nishizawa H(6), Echigoya Y(7), Yokota T(7), Aoki Y(8), Takeda S(8).
Author information:
(1)Intractable Disease Care Center, Shinshu University Hospital, Matsumoto,
Japan.
(2)Department of Neurology and Rheumatology, Shinshu University Hospital,
Matsumoto, Japan.
(3)Division of Rehabilitation, Nagano Children's Hospital, Azumino, Japan.
(4)Department of Pediatrics, Shinshu University School of Medicine, Matsumoto,
Japan.
(5)Department of Cardiovascular Medicine, Shinshu University School of Medicine,
Matsumoto, Japan.
(6)School of Health Science, Shinshu University, Matsumoto, Japan.
(7)Department of Medical Genetics, School of Human Development, Faculty of
Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
(8)Department of Molecular Therapy, National Institute of Neuroscience, National
Center of Neurology and Psychiatry, Tokyo, Japan.
Few cases of dystrophinopathy show an asymptomatic phenotype with mutations in
the 5' (exons 3-7) hot spot in the Duchenne muscular dystrophy (DMD) gene. Our
patient showed increased serum creatine kinase levels at 12 years of age. A
muscle biopsy at 15 years of age led to a diagnosis of Becker muscular
dystrophy. The patient showed a slight decrease in cardiac function at the age
of 21 years and was administered a β-blocker, but there was no muscle
involvement even at the age of 27 years. A deletion of exons 3-9 encompassing a
mutational hot spot in the DMD gene was detected, and dystrophin protein
expression was ∼15% that of control level. We propose that in-frame deletion of
exons 3-9 may produce a functional protein, and that multiexon skipping therapy
targeting these exons may be feasible for severe dystrophic patients with a
mutation in the 5' hot spot of the DMD gene.
DOI: 10.1038/jhg.2016.28
PMID: 27009627 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30544634
|
1. J Pers Med. 2018 Dec 7;8(4):41. doi: 10.3390/jpm8040041.
Multiple Exon Skipping in the Duchenne Muscular Dystrophy Hot Spots: Prospects
and Challenges.
Echigoya Y(1), Lim KRQ(2), Nakamura A(3)(4), Yokota T(5)(6).
Author information:
(1)Laboratory of Biomedical Science, Department of Veterinary Medicine, Nihon
University College of Bioresource Sciences, Fujisawa 252-0880, Japan.
[email protected].
(2)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB T6G2H7, Canada. [email protected].
(3)Third Department of Medicine, Shinshu University School of Medicine,
Matsumoto 390-8621, Japan. [email protected].
(4)Department of Neurology, National Hospital Organization, Matsumoto Medical
Center, Matsumoto 399-8701, Japan. [email protected].
(5)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB T6G2H7, Canada. [email protected].
(6)The Friends of Garrett Cumming Research and Muscular Dystrophy Canada HM
Toupin Neurological Science Endowed Research Chair, Edmonton, AB, T6G2H7,
Canada. [email protected].
Duchenne muscular dystrophy (DMD), a fatal X-linked recessive disorder, is
caused mostly by frame-disrupting, out-of-frame deletions in the dystrophin
(DMD) gene. Antisense oligonucleotide-mediated exon skipping is a promising
therapy for DMD. Exon skipping aims to convert out-of-frame mRNA to in-frame
mRNA and induce the production of internally-deleted dystrophin as seen in the
less severe Becker muscular dystrophy. Currently, multiple exon skipping has
gained special interest as a new therapeutic modality for this approach.
Previous retrospective database studies represented a potential therapeutic
application of multiple exon skipping. Since then, public DMD databases have
become more useful with an increase in patient registration and advances in
molecular diagnosis. Here, we provide an update on DMD genotype-phenotype
associations using a global DMD database and further provide the rationale for
multiple exon skipping development, particularly for exons 45⁻55 skipping and an
emerging therapeutic concept, exons 3⁻9 skipping. Importantly, this review
highlights the potential of multiple exon skipping for enabling the production
of functionally-corrected dystrophin and for treating symptomatic patients not
only with out-of-frame deletions but also those with in-frame deletions. We will
also discuss prospects and challenges in multiple exon skipping therapy,
referring to recent progress in antisense chemistry and design, as well as
disease models.
DOI: 10.3390/jpm8040041
PMCID: PMC6313462
PMID: 30544634
Conflict of interest statement: The authors declare no conflict of interest in
this work.
|
http://www.ncbi.nlm.nih.gov/pubmed/35729475
|
1. J Clin Immunol. 2022 Aug;42(6):1321-1329. doi: 10.1007/s10875-022-01307-4.
Epub 2022 Jun 22.
Severe Combined Immunodeficiency (SCID) Screening in Arizona: Lessons Learned
from the First 2 Years.
Booth NA(1)(2), Freeman CM(3)(4), Wright BL(3)(4), Rukasin C(5)(3)(4), Badia
P(6)(7), Daines M(8), Bauer CS(5)(3)(4), Miller H(6)(7).
Author information:
(1)Center for Cancer and Blood Disorders, Phoenix Children's Hospital, 1919 E.
Thomas Road, Phoenix, AZ, 85016, USA. [email protected].
(2)Department of Child Health, University of Arizona College of Medicine -
Phoenix, Phoenix, AZ, USA. [email protected].
(3)Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic,
Scottsdale, AZ, USA.
(4)Division of Allergy and Immunology, Phoenix Children's Hospital, Phoenix, AZ,
USA.
(5)Department of Child Health, University of Arizona College of Medicine -
Phoenix, Phoenix, AZ, USA.
(6)Center for Cancer and Blood Disorders, Phoenix Children's Hospital, 1919 E.
Thomas Road, Phoenix, AZ, 85016, USA.
(7)Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
(8)Department of Pediatrics, University of Arizona College of Medicine - Tucson,
Tucson, AZ, USA.
PURPOSE: The incidence of severe combined immunodeficiency (SCID) in the USA was
reported as 1 in 58,000 live births. In Arizona, it was anticipated that newborn
screening would identify two to four cases of SCID per year. This estimate did
not consider ethnic nuances in Arizona, with higher percentages of Native
American and Hispanic populations compared to national percentages. The true
incidence of SCID and non-SCID T cell lymphopenia has not previously been
reported in Arizona.
METHODS: A retrospective chart review was performed on all abnormal SCID newborn
screening (NBS) tests in Arizona from January 1, 2018, to December 31, 2019,
using data from the Arizona Department of Health Services and the Phoenix
Children's Hospital's electronic medical record [IRB# 20-025].
RESULTS: Seven infants were diagnosed with SCID, yielding an incidence of 1 in
22,819 live births. Four of these infants had Artemis-type SCID. Thirteen
infants were identified with an abnormal initial NBS which ultimately did not
lead to a diagnosis of SCID. Four of these infants were diagnosed with
congenital syndromes associated with T cell lymphopenia. Infants of Hispanic
ethnicity were over-represented in this cohort.
CONCLUSION: Over 2 years, NBS in Arizona confirmed an incidence more than 2.5
times that reported nationally. This increased incidence is likely reflective of
Arizona's unique population profile, with a higher percentage of Native American
population. The findings in our non-SCID cohort are in alignment with previously
published data, except for an increased percentage of infants of Hispanic/Latino
ethnicity, possibly reflecting Arizona's increased percentage of Hispanic/Latino
population compared to the general US population.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s10875-022-01307-4
PMID: 35729475 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35801871
|
1. Nucleic Acids Res. 2022 Jul 22;50(13):7697-7720. doi: 10.1093/nar/gkac564.
Structural analysis of the basal state of the Artemis:DNA-PKcs complex.
Watanabe G(1), Lieber MR(1), Williams DR(2).
Author information:
(1)Department of Pathology, Department of Biochemistry & Molecular Biology,
Department of Molecular Microbiology & Immunology, and Section of Computational
& Molecular Biology, USC Norris Comprehensive Cancer Center, University of
Southern California Keck School of Medicine, 1441 Eastlake Ave, Rm. 5428, Los
Angeles, CA 90089, USA.
(2)Eyring Materials Center, John Cowley Center for High Resolution Electron
Microscopy, Arizona State University, Tempe, AZ 85281, USA.
Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKcs)
are key components in nonhomologous DNA end joining (NHEJ), the major repair
mechanism for double-strand DNA breaks. Artemis activation by DNA-PKcs resolves
hairpin DNA ends formed during V(D)J recombination. Artemis deficiency disrupts
development of adaptive immunity and leads to radiosensitive T- B- severe
combined immunodeficiency (RS-SCID). An activated state of Artemis in complex
with DNA-PK was solved by cryo-EM recently, which showed Artemis bound to the
DNA. Here, we report that the pre-activated form (basal state) of the
Artemis:DNA-PKcs complex is stable on an agarose-acrylamide gel system, and
suitable for cryo-EM structural analysis. Structures show that the Artemis
catalytic domain is dynamically positioned externally to DNA-PKcs prior to ABCDE
autophosphorylation and show how both the catalytic and regulatory domains of
Artemis interact with the N-HEAT and FAT domains of DNA-PKcs. We define a
mutually exclusive binding site for Artemis and XRCC4 on DNA-PKcs and show that
an XRCC4 peptide disrupts the Artemis:DNA-PKcs complex. All of the findings are
useful in explaining how a hypomorphic L3062R missense mutation of DNA-PKcs
could lead to insufficient Artemis activation, hence RS-SCID. Our results
provide various target site candidates to design disruptors for Artemis:DNA-PKcs
complex formation.
© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkac564
PMCID: PMC9303282
PMID: 35801871 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35773051
|
1. Hematol Oncol Clin North Am. 2022 Aug;36(4):813-827. doi:
10.1016/j.hoc.2022.03.010. Epub 2022 Jun 27.
Gene Therapy for Inborn Errors of Immunity: Severe Combined Immunodeficiencies.
Chetty K(1), Houghton BC(2), Booth C(3).
Author information:
(1)Department of Paediatric Immunology and Gene Therapy, Level 3, Zayed Centre
for Research Great Ormond Street Hospital, Great Ormond Street, London, WC1N
3JH, United Kingdom.
(2)UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
(3)Department of Paediatric Immunology and Gene Therapy, Level 3, Zayed Centre
for Research Great Ormond Street Hospital, Great Ormond Street, London, WC1N
3JH, United Kingdom; UCL Great Ormond Street Institute of Child Health, London,
United Kingdom. Electronic address: [email protected].
Severe combined immune deficiency (SCID) causes profound deficiency in T cells
and variable deficiencies in B and NK cells. Untreated, the condition is fatal
within the first 2 years of life. HSCT has traditionally been the only curative
approach; however, success rates are suboptimal in those lacking an HLA-matched
donor and conditioning regimens can cause significant toxicity. Gene therapy was
pioneered for adenosine deaminase (ADA-SCID) over 3 decades ago and has produced
highly successful results. Encouraging data for X-SCID and preclinical work for
Artemis-SCID and RAG1-SCID are paving the way for the therapy to become a viable
curative treatment option.
Copyright © 2022 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.hoc.2022.03.010
PMID: 35773051 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36385359
|
1. J Clin Immunol. 2023 Apr;43(3):585-594. doi: 10.1007/s10875-022-01405-3. Epub
2022 Nov 16.
Clinical and Genetic Characterization of Patients with Artemis Deficiency in
Japan.
Inoue K(1), Miyamoto S(1)(2), Tomomasa D(1), Adachi E(1), Azumi S(3), Horikoshi
Y(3), Ishihara T(4), Osone S(5), Kawahara Y(6), Kudo K(7), Kato Z(8)(9), Ohnishi
H(8), Kashimada K(1), Imai K(10)(11), Ohara O(12), van Zelm MC(13), Cowan
MJ(14), Morio T(1), Kanegane H(15).
Author information:
(1)Department of Pediatrics and Developmental Biology, Graduate School of
Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo,
Japan.
(2)Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
(3)Department of Hematology and Oncology, Shizuoka Children's Hospital,
Shizuoka, Japan.
(4)Department of Pediatrics, Nara Medical University, Kashihara, Japan.
(5)Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto,
Japan.
(6)Department of Pediatric, Jichi Medical University School of Medicine,
Tochigi, Japan.
(7)Department of Pediatrics, Hirosaki University Graduate School of Medicine,
Hirosaki, Japan.
(8)Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu,
Japan.
(9)Structural Medicine, United Graduate School of Drug Discovery and Medical
Information Sciences, Gifu University, Gifu, Japan.
(10)Department of Community Pediatrics, Perinatal and Maternal Medicine,
Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental
University (TMDU), Tokyo, Japan.
(11)Department of Pediatrics, National Defense Medical College, Saitama, Japan.
(12)Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu,
Japan.
(13)Department of Immunology and Pathology, Central Clinical School, Monash
University and Alfred Hospital, Melbourne, VIC, Australia.
(14)Division of Allergy, Immunology and Blood and Marrow Transplantation,
Department of Pediatrics, University of California San Francisco School of
Medicine, San Francisco, CA, USA.
(15)Department of Child Health and Development, Graduate School of Medical and
Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima,
Bunkyo-Ku, Tokyo, 113-8519, Japan. [email protected].
PURPOSE: Artemis is an exonuclease essential for V(D)J recombination and repair
of DNA double-stranded breaks. Pathogenic variants in DCLRE1C encoding Artemis
cause T-B-NK+ severe combined immunodeficiency (SCID), and patients with
Artemis-deficient SCID (ART-SCID) require definitive therapy with allogeneic
hematopoietic cell transplantation (HCT). Here we describe the clinical and
genetic characteristics of patients with ART-SCID who were diagnosed in Japan
from 2003 to 2022.
METHODS: Clinical data of ART-SCID patients who were diagnosed between 2003 and
2022 in Japan were collected from their physicians using a questionnaire.
RESULTS: ART-SCID diagnosis was made in eight patients from seven families with
severe infections within 6 months of life. Two patients had missense variants,
five patients had large genomic deletions, and one patient was compound
heterozygous for a missense variant and large genomic deletion. All eight
underwent allogeneic HCT within 4 months after the diagnosis, 7 receiving a
conditioning regimen containing alkylating agents, and one patient without
conditioning due to uncontrolled infection. Two patients with poor performance
status (PS) died of complications 410 days and 32 days post-HCT, respectively.
Of the six surviving patients with a median follow-up time of 8.3 (0.5-17.9)
years, three patients had growth retardation. The patients with PS of 0-2 showed
a tendency for better overall survival than those with PS 3-4.
CONCLUSION: Large deletions were the most common genetic cause of ART-SCID in
Japan. To improve HCT outcome, early diagnosis with newborn screening for SCID
is urgently needed.
© 2022. The Author(s), under exclusive licence to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/s10875-022-01405-3
PMID: 36385359 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35322347
|
1. Acta Neurol Belg. 2022 Jun;122(3):745-751. doi: 10.1007/s13760-022-01915-2.
Epub 2022 Mar 23.
Sleep disturbances in newly diagnosed treatment-naïve patients with Wilson's
disease.
Jernajczyk W(1), Litwin T(2), Członkowska A(2), Bembenek JP(3).
Author information:
(1)Department of Clinical Neurophysiology, Institute of Psychiatry and
Neurology, Sobieskiego 9, 02-957, Warsaw, Poland.
(2)Second Department of Neurology, Institute of Psychiatry and Neurology,
Warsaw, Poland.
(3)Department of Clinical Neurophysiology, Institute of Psychiatry and
Neurology, Sobieskiego 9, 02-957, Warsaw, Poland. [email protected].
INTRODUCTION: Most neurodegenerative and chronic liver disorders are associated
with sleep disturbances (SD). SD may be expected to occur in patients with
Wilson's disease (WD), an inherited disorder of copper metabolism that mostly
affects the liver and brain; however, there is a lack of observations,
particularly in treatment-naïve WD patients.
METHODS: We evaluated SD in 19 newly diagnosed treatment-naïve WD patients. All
patients completed the Beck Depression Inventory (BDI), the Athens Insomnia
Scale (AIS) and the Epworth Sleepiness Scale (ESS), and underwent nightlong
video polysomnography (vPSG). Results of vPSG in WD patients were compared with
results from 19 sex- and age-matched healthy controls.
RESULTS: Depressive symptoms were not reported by patients on routine
examination although three patients were diagnosed with mild depression. No
patients reported SD during routine examination; three patients had insomnia
according to the AIS and all patients scored 0 on the ESS. Despite the lack of
reporting of SD by patients, significant differences were observed between WD
patients and controls following vPSG analysis: WD patients had shorter mean
total sleeping time (366.2 vs. 451.7 min), a lower percentage of rapid-eye
movement (15.4 vs. 20.6%), longer sleep latency (36.7 vs. 10.4 min) and lower
sleep efficiency (76.2 vs. 93.8%) (all P ≤ 0.01). SD tended to be worse in
patients with neurological WD compared with hepatic WD.
CONCLUSIONS: As SD may precede depression and severely affect quality of life,
our findings suggest that patients with WD should be screened for SD with
suitable methods.
© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.
DOI: 10.1007/s13760-022-01915-2
PMCID: PMC8942388
PMID: 35322347 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no Conflict
of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/8757902
|
1. Ugeskr Laeger. 1996 Jul 22;158(30):4305-6.
[Recurrent arthritis in a child. A rare manifestation of Wilson's disease].
[Article in Danish]
Olsen BS(1), Helin P, Mortensen HB.
Author information:
(1)Børneafdelingen og reumatologisk afdeling, Amtssygehuset i Glostrup.
Wilsons disease is a rare autosomal recessive disorder of copper transportation,
which is fatal if not treated. The disease often starts in adolescence, and most
common symptoms are due to liver-and/or brain involvement. This paper deals with
an adolescent with Wilsons disease. His clinical presentation was joint
complaints for almost two years. The final diagnosis was made by mutation
analysis. It is stressed that the clinician should consider Wilson's disease in
cases of unexplained liver- and neurological involvement as well as cases of
repetitive unexplained joint symptoms in the pubertal period.
PMID: 8757902 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23583003
|
1. Vet J. 2013 Aug;197(2):468-73. doi: 10.1016/j.tvjl.2013.03.003. Epub 2013 Apr
9.
Urinary excretion of copper, zinc and iron with and without D-penicillamine
administration in relation to hepatic copper concentration in dogs.
Fieten H(1), Hugen S, van den Ingh TS, Hendriks WH, Vernooij JC, Bode P, Watson
AL, Leegwater PA, Rothuizen J.
Author information:
(1)Department of Clinical Sciences of Companion Animals, Faculty of Veterinary
Medicine, Utrecht University, Utrecht, The Netherlands. [email protected]
Hereditary copper-associated hepatitis in dogs resembles Wilson's disease, a
copper storage disease in humans. Values for urinary copper excretion are well
established in the diagnostic protocol of Wilson's disease, whereas in dogs
these have not been evaluated. The objectives of this study were to characterize
both basal and D-penicillamine induced urinary copper, zinc and iron excretion
in dogs in relation to hepatic copper concentration. Beagles, Beagle-Bedlington
terrier cross-breeds homozygous for the COMMD1 gene mutation that causes copper
toxicosis, and Labrador retrievers with normal or increased hepatic copper
concentrations were investigated. The hepatic copper phenotype was determined by
histological evaluation of liver biopsies and measurement of the hepatic copper
concentration by instrumental neutron activation analysis. Urinary excretion of
copper, iron and zinc was measured via inductively coupled plasma optical
emission spectrometry under basal conditions and after oral administration of a
single dose (20mg/kg bodyweight) of the chelator D-penicillamine. There was a
rapid increase in urinary excretion of copper and zinc, but not iron after
D-penicillamine administration. This increase was not different between dogs
with high or normal hepatic copper concentrations. D-penicillamine-induced
urinary copper excretion and the copper/creatinine ratio did not correlate with
hepatic copper concentrations in the dogs studied, although basal urinary
copper/zinc ratios did correlate with hepatic copper concentrations in Labrador
retrievers. The latter parameter may be useful in diagnostic and follow-up
protocols for copper-associated hepatitis in Labrador retrievers.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.tvjl.2013.03.003
PMID: 23583003 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/30646728
|
1. Ceska Slov Farm. 2018 Winter;67(4):143-153.
Biological role of copper as an essential trace element in the human organism.
[Article in English]
Vetchý MPJVKKD.
This paper presents an overview of the physiological properties of copper (Cu),
an essential trace element playing an important role in the human metabolism,
primarily as a cofactor of many metalloenzymes. The maintenance of Cu
homeostasis is required for proper functioning of the human body. However, when
the disturbance of Cu homeostasis occurs, strong pathological manifestations may
develop. Wilsons disease and idiopathic toxicosis are examples of severe chronic
liver diseases that are the results of genetic predisposition to the hepatic
accumulation of copper. Conversely, congenital Menkes disease is manifested as
serious Cus nutritional deficiency. Although Cu is necessary for many life
processes, it is also a powerful weapon used since the ancient times against
many microorganisms. Finally, the theories of Cu antimicrobial and antiviral
mechanisms of action are summarized, including contemporary and potential future
utilizations in medical and non-medical fields of human life. Key words: copper
metalloenzymes copper toxicity copper deficiency copper-related diseases copper
applications.
PMID: 30646728 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23542331
|
1. Clin Gastroenterol Hepatol. 2013 Aug;11(8):1028-35.e1-2. doi:
10.1016/j.cgh.2013.03.012. Epub 2013 Mar 28.
Efficacy and safety of oral chelators in treatment of patients with Wilson
disease.
Weiss KH(1), Thurik F, Gotthardt DN, Schäfer M, Teufel U, Wiegand F, Merle U,
Ferenci-Foerster D, Maieron A, Stauber R, Zoller H, Schmidt HH, Reuner U, Hefter
H, Trocello JM, Houwen RH, Ferenci P, Stremmel W; EUROWILSON Consortium.
Author information:
(1)Department of Gastroenterology, University Hospital Heidelberg, Heidelberg,
Germany. [email protected]
BACKGROUND & AIMS: Wilson disease is a genetic copper storage disorder that
causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine,
trientine) are used as first-line therapies for symptomatic patients, but there
are few data from large cohorts. We assessed the safety of D-penicillamine and
trientine therapy and outcomes of patients with Wilson disease.
METHODS: We performed a retrospective analysis of data on 380 patients with
Wilson disease from tertiary care centers in Germany and Austria, and 25
additional patients from the EUROWILSON registry. Chelator-based treatment
regimens were analyzed for their effect on neurologic and hepatic symptoms and
for adverse events that led to discontinuation of therapy (Kaplan-Meier
estimation; data were collected for a mean of 13.3 y after therapy began).
RESULTS: Changes in medication were common, resulting in analysis of 471
chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving
trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141
patients given trientine underwent liver transplantation. Adverse events leading
to discontinuation of treatment were more frequent among those receiving
D-penicillamine than trientine (P = .039). Forty-eight months after therapy,
hepatic deterioration was reported in only 4 of 333 patients treated initially
with a chelating agent. Hepatic improvements were observed in more than 90%, and
neurologic improvements were observed in more than 55%, of therapy-naive
patients, and values did not differ significantly between treatments. However,
neurologic deterioration was observed less frequently in patients given
D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P =
.018).
CONCLUSIONS: Chelating agents are effective therapies for most patients with
Wilson disease; D-penicillamine and trientine produce comparable outcomes,
although D-penicillamine had a higher rate of adverse events. Few patients
receiving chelation therapy had neurologic deterioration, which occurred more
frequently in patients who received trientine.
Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cgh.2013.03.012
PMID: 23542331 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12508671
|
1. Praxis (Bern 1994). 2002 Nov 27;91(48):2077-85. doi:
10.1024/0369-8394.91.48.2077.
[Rare, but important chronic liver diseases].
[Article in German]
Maier KP(1).
Author information:
(1)Medizinische Klinik, Fachbereich Gastroenterologie, Städtische Kliniken
Esslingen, Akademisches Lehrkrankenhaus der Universität Tübingen.
The presence of steatosis and inflammatory infiltrate in liver biopsies is
essential for the diagnosis of non-alcoholic steatohepatitis (NASH). These
findings are similar to those with alcoholic liver disease. However, in the
NASH-situation alcohol doesn't play an important role. Risk factors for the
development of NASH are obesity and diabetes. Most of the patients are
clinically asymptomatic. This means, that a diagnosis of NASH is a diagnosis of
exclusion: Viral induced, autoimmune, metabolic and toxic liver disease have to
be excluded. The disease has a benign clinical course. The risk of cirrhosis is
low. So far, there is no established treatment. Preliminary reports suggest a
positive effect of weight-loss and ursodeoxycholic acid. Wilson's disease, a
copper storage disorder, in which biliary copper excretion is reduced, is
inherited as an autosomal recessive trait. Most patients with Wilson disease
become symptomatic between the ages of 6 and 15. In about 90% of patients serum
ceruloplasmin levels and serum copper concentrations are reduced. Copper
excreation is increased. Histologic examination of liver biopsy specimens
reveals fatty infiltration, Mallory bodies and ballooned glycogen nuclei,
abnormalities which are also found in alcoholic liver disease. The definitive
diagnostic parameter is the quantitative determination of liver copper content
(> 250 micrograms/g dryweight). Untreated Wilson disease is always fatal.
Lifelong treatment with anti-copper drugs are essential, D-penicillamine being
the firstline therapy. Hereditary hemochromatosis (HH) is an iron overload
disease inherited as an autosomal recessive trait. The frequency of the disease
is high. The first symptoms usually can be found at the age of 20-50 years.
Arthralgia develops in up to 50% of the patients. Many organs are involved, most
often the liver. The organ is usually enlarged, transaminases are always
moderately elevated. Laboratory findings disclose a marked elevation in serum
ferritin and transferrin saturation. More than 80% of HH-patients are homozygous
for the C282Y-mutation in the HFE-gene. The firstline treatment of HH is
phlebotomy. Treatment is lifelong. When serum ferritin drops below 50
micrograms/l, the frequency of phlebotomy should be reduced (4-12 per year). If
the patient already has cirrhosis, the risk of HCC is very high.
DOI: 10.1024/0369-8394.91.48.2077
PMID: 12508671 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/31345362
|
1. J Trace Elem Med Biol. 2019 Sep;55:33-38. doi: 10.1016/j.jtemb.2019.05.010.
Epub 2019 May 24.
The effects of iron and zinc status on prognosis in pediatric Wilson's disease.
Güngör Ş(1), Selimoğlu MA(2), Varol Fİ(3), Güngör S(4), Üremiş MM(5).
Author information:
(1)Department of Pediatric Gastroenterology, Hepatology and Nutrition, İnönü
University, Faculty of Medicine, Malatya,Turkey. Electronic address:
[email protected].
(2)Department of Pediatric Gastroenterology, Hepatology and Nutrition, İnönü
University, Faculty of Medicine, Malatya,Turkey. Electronic address:
[email protected].
(3)Department of Pediatric Gastroenterology, Hepatology and Nutrition, İnönü
University, Faculty of Medicine, Malatya,Turkey. Electronic address:
[email protected].
(4)Department of Pediatric Neurology, İnönü University, Faculty of Medicine,
Malatya,Turkey. Electronic address: [email protected].
(5)Department of Medicinal Biochemistry, İnönü University, Faculty of Medicine,
Malatya, Turkey. Electronic address: [email protected].
OBJECTIVES: Wilson's disease (WD) is a metabolic disorder leading to hepatic and
extrahepatic copper deposition. Several studies have reported that besides
copper (Cu), iron (Fe) and zinc (Zn) are also accumulated at varying levels in
various tissues in WD. However, there is not an adequate number of studies
investigating the effects of Fe and Zn status on WD presentation and prognosis.
We aimed to evaluate serum levels of ferritin (SFr), copper (SCu), and zinc
(SZn) in WD and determine their role in disease presentation and prognosis.
MATERIALS-METHOD: We retrospectively reviewed the medical records of 97
pediatric patients with WD who were diagnosed and followed at İnönü University
Pediatric Gastroenterology, Hepatology and Nutrition Department between January
2006 and May 2017. Serum Cu and Zn levels were analyzed by using flame atomic
absorption spectrophotometer. Ferritin was analyzed by chemiluminescence
immunoassay method.
RESULTS: Analysis of serum levels of the elements according to the type of
presentation, there was no significant difference between the groups for
ceruloplasmin. However, SCU, FSCu, SFr and 24 h urinary copper levels were
significantly higher (p = 0.002, p = 0.003, p = 0.023 and p < 0.001,
respectively) and SZn and CSZn levels were significantly lower (fulminant WD).
p < 0.001, p < 0.001). There was a positive correlation between SFr, SCu serum
levels and mortality scores (respectively, r: 0.501, 0.564 for PELD, r:0.490,
0.504 for MELD, r: 0.345, 0.374 for Dhwan), and a negative correlation between
SZn level and mortality scores. (r:-0.650 for PELD, r:-0.703 for MELD, r:-0.642
for Dhwan) We used the ROC curves to determine the worst prognosis for fulminant
Wilson disease. According to these limit values, we found that the sensitivity
and specificity of FWD development was significantly higher. (for SZn
sensitivity of 91.5%, a specificity of 100%, p=<0,001, for SCu predicted FWD
development with a sensitivity of 100%, a specificity of 73.7%, p=<0,001, for
SFr predicted FWD development with a sensitivity of 92.9%, a specificity of
66.2%, p < 0,001) CONCLUSION: Our study suggests that SFr, SCu, SZn levels might
have prognostic importance for WD.
Copyright © 2019 Elsevier GmbH. All rights reserved.
DOI: 10.1016/j.jtemb.2019.05.010
PMID: 31345362 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22774841
|
1. Scand J Gastroenterol. 2012 Sep;47(8-9):1014-20. doi:
10.3109/00365521.2012.703240. Epub 2012 Jul 7.
Common local founder effects for Wilson's disease and hereditary
hemochromatosis; mutation studies of a large family.
Olsson KS(1), Wålinder O, Kindmark A, Williams R.
Author information:
(1)Department of Medicine, Section of Hematology and Coagulation, Sahlgrenska
University Hospital, Göteborg, Sweden. [email protected]
Wilson's disease (WND) and hereditary hemochromatosis (HH) are two metal loading
diseases of copper and iron, respectively, and are both recessively inherited.
In central Sweden, where HH is common, 9 Wilson kindred (14 members) were
identified. Aims of the study were to test whether nine WND families shared a
common origin, a common mutation and if carrying HFE mutations affected their
phenotype.
RESULTS: The nine families were traced through 13 generations to a common
founder origin in the mid-seventeenth century. Despite identity of descent, four
different ATP7B mutations appeared with homozygosity in four, with two different
mutations, W779X and T977M. There were three compound heterozygotes,
W779X/T977M, R1319X/H1069Q and one T977M combined with a new, previously not
described mutation, probably of Finnish origin. The founder family also included
26 descendant kindred (55 members) with HH as shown by HFE mutations. This
admixture coincided with a migration out of the original parish into
hemochromatosis-rich localities. One WND patient had iron overload (serum
ferritin 672 µg/l and raised liver enzymes), but lacked HFE mutations. In
another family with serious hemochromatosis (two sons dying from bronze
diabetes), the coinheritance of congenital spherocytosis was probably the cause
rather than an additional effect of WND.
CONCLUSIONS: WND though a rare disease may become aggregated like HH in certain
areas due to local founder effects. Despite extensive pedigree studies leading
back to the local founder family, the authors were unable to find a single
defining mutation of the ATP7B gene.
DOI: 10.3109/00365521.2012.703240
PMID: 22774841 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24266916
|
1. Med Clin North Am. 2014 Jan;98(1):87-102. doi: 10.1016/j.mcna.2013.09.008.
Epub 2013 Oct 28.
Metal storage disorders: Wilson disease and hemochromatosis.
Kanwar P(1), Kowdley KV.
Author information:
(1)Liver Center of Excellence, Department of Gastroenterology, Digestive Disease
Institute, Virginia Mason Medical Center, 1100 9th Avenue, Mailstop C3-GAS,
Seattle, WA 98101, USA.
Hereditary hemochromatosis and Wilson disease are autosomal recessive storage
disorders of iron and copper overload, respectively. These metals are involved
in multiple redox reactions, and their abnormal accumulation can cause
significant injury in the liver and other organs. Over the last few decades
clinicians have developed a much better understanding of these metals and their
mechanism of action. Moreover, sophisticated molecular genetic testing
techniques that make diagnostic testing less invasive are now available. This
article updates and discusses the pathogenesis, diagnosis, and management of
these metal storage disorders.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.mcna.2013.09.008
PMID: 24266916 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8984578
|
1. Praxis (Bern 1994). 1996 Nov 19;85(47):1513-7.
[Current diagnosis: hereditary metabolic diseases of the liver (primary
hemochromatosis, Wilson disease)].
[Article in German]
Stremmel W(1).
Author information:
(1)Medizinische Klinik, Universität Heidelberg.
Primary hemochromatosis is characterized by a specific pattern of clinical
manifestations. It includes liver disease with hepatomegaly, glucose
intolerance, e.g. diabetes, hyperpigmentation oft the skin, impotence/
amenorrhea, arthropathy, cardiomyopathy and fatigue. Laboratory investigation
reveals significantly elevated serum ferritin and transferrin saturation with
iron. The diagnosis is confirmed by liver biopsy and quantitative determination
of elevated liver iron content. Wilson's disease represents a copper storage
disease. Prominent clinical features are hepatomegaly and splenomegaly.
Neurological alterations and detection of Kayser-Fleischer corneal rings are
typical. In the acute initial phase the often young patients present with
Coombs-negative hemolysis. Psychiatric alterations, cardiomyopathy, arthropathy,
nephropathy, as well as thrombocytopenia and leucopenia are other clinical
features. Laboratory parameters of Wilson's disease include low serum
ceruloplasmin and serum copper. There is an elevated urinary copper excretion
and elevated serum free copper concentration. The diagnosis is confirmed by
liver biopsy with quantitative determination of an elevated liver copper
content.
PMID: 8984578 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/34341141
|
1. J Neurol Neurosurg Psychiatry. 2021 Oct;92(10):1053-1061. doi:
10.1136/jnnp-2021-326123. Epub 2021 Aug 2.
Wilson's disease: update on pathogenesis, biomarkers and treatments.
Shribman S(1), Poujois A(2), Bandmann O(3), Czlonkowska A(4), Warner TT(5).
Author information:
(1)Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London,
UK [email protected].
(2)Department of Neurology, National Reference Centre for Wilson's Disease,
Rothschild Foundation Hospital, Paris, France.
(3)Department of Neuroscience, Sheffield Institute for Translational
Neuroscience, Sheffield, UK.
(4)Second Department of Neurology, Institute of Psychiatry and Neurology,
Warsaw, Poland.
(5)Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London,
UK.
Wilson's disease is an autosomal-recessive disorder of copper metabolism caused
by mutations in ATP7B and associated with neurological, psychiatric,
ophthalmological and hepatic manifestations. Decoppering treatments are used to
prevent disease progression and reduce symptoms, but neurological outcomes
remain mixed. In this article, we review the current understanding of
pathogenesis, biomarkers and treatments for Wilson's disease from the
neurological perspective, with a focus on recent advances. The genetic and
molecular mechanisms associated with ATP7B dysfunction have been well
characterised, but despite extensive efforts to identify genotype-phenotype
correlations, the reason why only some patients develop neurological or
psychiatric features remains unclear. We discuss pathological processes through
which copper accumulation leads to neurodegeneration, such as mitochondrial
dysfunction, the role of brain iron metabolism and the broader concept of
selective neuronal vulnerability in Wilson's disease. Delayed diagnoses continue
to be a major problem for patients with neurological presentations. We highlight
limitations in our current approach to making a diagnosis and novel diagnostic
biomarkers, including the potential for newborn screening programmes. We
describe recent progress in developing imaging and wet (fluid) biomarkers for
neurological involvement, including findings from quantitative MRI and other
neuroimaging studies, and the development of a semiquantitative scoring system
for assessing radiological severity. Finally, we cover the use of established
and novel chelating agents, paradoxical neurological worsening, and progress
developing targeted molecular and gene therapy for Wilson's disease, before
discussing future directions for translational research.
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and
permissions. Published by BMJ.
DOI: 10.1136/jnnp-2021-326123
PMID: 34341141 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared.
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http://www.ncbi.nlm.nih.gov/pubmed/34289020
|
1. Brain. 2022 Mar 29;145(1):263-275. doi: 10.1093/brain/awab274.
Neuroimaging correlates of brain injury in Wilson's disease: a multimodal,
whole-brain MRI study.
Shribman S(1), Bocchetta M(2), Sudre CH(3)(4)(5), Acosta-Cabronero J(6), Burrows
M(1), Cook P(7), Thomas DL(2)(8)(9), Gillett GT(10), Tsochatzis EA(11), Bandmann
O(12), Rohrer JD(2), Warner TT(1).
Author information:
(1)Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London
WC1N 1PJ, UK.
(2)Dementia Research Centre, UCL Queen Square Institute of Neurology, London
WC1N 3AR, UK.
(3)MRC Unit for Lifelong Health and Ageing, University College London, London
WC1E 7HB, UK.
(4)Centre for Medical Image Computing, University College London, London WC1V
6LJ, UK.
(5)Biomedical Engineering and Imaging Sciences, King's College London, London
WC2R 2LS, UK.
(6)Tenoke Ltd, Cambridge CB2 0AH, UK.
(7)Department of Clinical Biochemistry, Southampton General Hospital,
Southampton SO16 6YD, UK.
(8)Neuroradiological Academic Unit, UCL Queen Square Institute of Neurology,
London WC1N 3BG, UK.
(9)Wellcome Centre for Human Neuroimaging, UCL Queen Square Institute of
Neurology, London WC1N 3AR, UK.
(10)Department of Clinical Chemistry, Northern General Hospital, Sheffield S5
7AU, UK.
(11)UCL Institute of Liver and Digestive Health and Royal Free Hospital, London
NW3 2PF, UK.
(12)Sheffield Institute of Translational Neuroscience, Sheffield S10 2HQ, UK.
Wilson's disease is an autosomal-recessive disorder of copper metabolism with
neurological and hepatic presentations. Chelation therapy is used to 'de-copper'
patients but neurological outcomes remain unpredictable. A range of neuroimaging
abnormalities have been described and may provide insights into disease
mechanisms, in addition to prognostic and monitoring biomarkers. Previous
quantitative MRI analyses have focused on specific sequences or regions of
interest, often stratifying chronically treated patients according to persisting
symptoms as opposed to initial presentation. In this cross-sectional study, we
performed a combination of unbiased, whole-brain analyses on T1-weighted,
fluid-attenuated inversion recovery, diffusion-weighted and
susceptibility-weighted imaging data from 40 prospectively recruited patients
with Wilson's disease (age range 16-68). We compared patients with neurological
(n = 23) and hepatic (n = 17) presentations to determine the neuroradiological
sequelae of the initial brain injury. We also subcategorized patients according
to recent neurological status, classifying those with neurological presentations
or deterioration in the preceding 6 months as having 'active' disease. This
allowed us to compare patients with active (n = 5) and stable (n = 35) disease
and identify imaging correlates for persistent neurological deficits and copper
indices in chronically treated, stable patients. Using a combination of
voxel-based morphometry and region-of-interest volumetric analyses, we
demonstrate that grey matter volumes are lower in the basal ganglia, thalamus,
brainstem, cerebellum, anterior insula and orbitofrontal cortex when comparing
patients with neurological and hepatic presentations. In chronically treated,
stable patients, the severity of neurological deficits correlated with grey
matter volumes in similar, predominantly subcortical regions. In contrast, the
severity of neurological deficits did not correlate with the volume of white
matter hyperintensities, calculated using an automated lesion segmentation
algorithm. Using tract-based spatial statistics, increasing neurological
severity in chronically treated patients was associated with decreasing axial
diffusivity in white matter tracts whereas increasing serum
non-caeruloplasmin-bound ('free') copper and active disease were associated with
distinct patterns of increasing mean, axial and radial diffusivity. Whole-brain
quantitative susceptibility mapping identified increased iron deposition in the
putamen, cingulate and medial frontal cortices of patients with neurological
presentations relative to those with hepatic presentations and neurological
severity was associated with iron deposition in widespread cortical regions in
chronically treated patients. Our data indicate that composite measures of
subcortical atrophy provide useful prognostic biomarkers, whereas abnormal mean,
axial and radial diffusivity are promising monitoring biomarkers. Finally,
deposition of brain iron in response to copper accumulation may directly
contribute to neurodegeneration in Wilson's disease.
© The Author(s) (2021). Published by Oxford University Press on behalf of the
Guarantors of Brain.
DOI: 10.1093/brain/awab274
PMCID: PMC8967100
PMID: 34289020 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9093597
|
1. QJM. 1997 Mar;90(3):197-202. doi: 10.1093/qjmed/90.3.197.
Western blot analysis in patients with hypocaeruloplasminaemia.
Chowrimootoo GF(1), Andoh J, Seymour CA.
Author information:
(1)Department of Cardiological Sciences & Metabolic Medicine, St George's
Hospital Medical School, London, UK.
Inherited copper toxic disease, Wilson's disease, is an autosomal recessive
disorder arising from a defect in biliary copper excretion. Although there are
several pathognomonic clinical features, such a multisystem disease can be
difficult to diagnose, particularly in the early stages of copper toxicity. Even
measurements of serum copper and caeruloplasmin, the major copper-transporting
protein typically reduced in Wilson's disease, may mimic other metabolic
conditions such as Menke's disease and chronic active hepatitis. We have
previously shown that the major biliary isoform of copper-transporting protein
is 125 kDa caeruloplasmin, and this is always absent in the bile of Wilson's
disease patients. In this paper we describe Western blot analysis of molecular
species of caeruloplasmin in hypocaeruloplasminaemia, which can distinguish
between the overlap which occurs in Wilson's disease homozygotes, heterozygotes
and other conditions mimicking Wilson's disease. This may be useful for
identifying patients with low plasma caeruloplasmin concentrations, and hepatic
or neurological clinical features which may also be found in Wilson's disease.
DOI: 10.1093/qjmed/90.3.197
PMID: 9093597 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17505988
|
1. Scand J Gastroenterol. 2007 Jun;42(6):673-81. doi: 10.1080/00365520601075662.
Hereditary iron and copper deposition: diagnostics, pathogenesis and
therapeutics.
Aaseth J(1), Flaten TP, Andersen O.
Author information:
(1)Department of Medicine, Sykehuset Innlandet, Kongsvinger Hospital Division,
Kongsvinger, Norway.
Hereditary deposition of iron (primary haemochromatosis) or copper (Wilson's
disease) are autosomal recessive metabolic disease characterized by progressive
liver pathology and subsequent involvement of various other organs. The
prevalence of primary haemochromatosis is approximately 0.5%, about 200 times
higher than the prevalence of Wilson's disease. The two diseases are
characterized by homozygous occurrences of mutations in the HFE gene on
chromosome 6 (primary haemochromatosis) and the ATP7B gene on chromosome 13
(Wilson's disease). Unlike most other inherited conditions, these diseases can
be successfully treated, emphasizing the importance of early diagnosis. Serum
ferritin values, transferrin saturation and genetic analysis are used when
diagnosing haemochromatosis. The diagnostics of Wilson's disease depends on the
use of urinary copper values, serum ceruloplasmin and liver biopsy. If
untreated, both of these genetic diseases result in rapidly progressing
multiorgan damage and early death. The key treatment for haemochromatosis is
phlebotomy, for Wilson's disease chelation or Zn treatment. Although the present
treatments considerably improve the prognosis of patients, they may be
inadequate in patients diagnosed so late that extensive body deposits of metal
have been developed. The main research needs in this field are to further
clarify molecular mechanisms of disease progression and to develop new chelators
that are more effective and less toxic than those presently available.
DOI: 10.1080/00365520601075662
PMID: 17505988 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33573009
|
1. Medicina (Kaunas). 2021 Jan 29;57(2):123. doi: 10.3390/medicina57020123.
A Novel Mutation of ATP7B Gene in a Case of Wilson Disease.
Kahraman CY(1), Islek A(2), Tatar A(1), Özdemir Ö(3), Mardinglu A(4)(5), Turkez
H(6).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine, Ataturk University,
25240 Erzurum, Turkey.
(2)Department of Pediatric Gastroenterology, Faculty of Medicine, Ataturk
University, 25240 Erzurum, Turkey.
(3)Department of Molecular Biology and Genetics, Faculty of Science, Erzurum
Technical University University, 25250 Erzurum, Turkey.
(4)Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral &
Craniofacial Sciences, King's College London, London SE1 9RT, UK.
(5)Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121
Stockholm, Sweden.
(6)Department of Medical Biology, Faculty of Medicine, Ataturk University, 25240
Erzurum, Turkey.
Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder
characterized by excess copper (Cu) storage in different human tissues, such as
the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs
in approximately 1 in 30,000 individuals. The clinical presentations of WD are
highly varied, primarily consisting of hepatic and neurological conditions. WD
is caused by homozygous or compound heterozygous mutations in the ATP7B gene.
The diagnosis of the disease is complicated because of its heterogeneous
phenotypes. The molecular genetic analysis encourages early diagnosis,
treatment, and the opportunity to screen individuals at risk in the family. In
this paper, we reported a case with a novel, hotspot-located mutation in WD. We
have suggested that this mutation in the ATP7B gene might contribute to liver
findings, progressing to liver failure with a loss of function effect. Besides
this, if patients have liver symptoms in childhood and/or are children of
consanguineous parents, WD should be considered during the evaluation of the
patients.
DOI: 10.3390/medicina57020123
PMCID: PMC7912016
PMID: 33573009 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest,
financial or otherwise.
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http://www.ncbi.nlm.nih.gov/pubmed/22098612
|
1. Liver Int. 2012 Jan;32(1):165-70. doi: 10.1111/j.1478-3231.2011.02661.x. Epub
2011 Oct 17.
Iron metabolism and the role of HFE gene polymorphisms in Wilson disease.
Pfeiffenberger J(1), Gotthardt DN, Herrmann T, Seessle J, Merle U, Schirmacher
P, Stremmel W, Weiss KH.
Author information:
(1)Department of Gastroenterology, University Hospital Heidelberg, Heidelberg,
Germany.
Comment in
Liver Int. 2012 May;32(5):869-70; author reply 870. doi:
10.1111/j.1478-3231.2012.02756.x.
Wilson disease (WD) is a rare inherited disorder of copper metabolism, which can
lead to severe liver failure and to a variety of neuropsychiatric symptoms.
Previous animal studies and case reports suggest that hepatic iron overload and
alterations in iron processing are associated with WD. The aim of this study was
the assessment of iron metabolism and of the frequency of the most common HFE
gene polymorphisms in WD patients.
PATIENTS AND METHODS: Data from 143 patients with WD were analysed. Clinical
presentation, liver function and iron metabolism parameters were recorded. Blood
samples of the patients were analysed for HFE gene alterations (H63D; C282Y).
Twenty-seven liver biopsies of these patients were studied with regard to iron
content and fibrosis score.
RESULTS: Contrary to previous reports of HFE gene polymorphisms in WD patients,
in our cohort the allele frequencies (C282Y: 2.1%; H63D: 7.3%) were in line with
frequencies obtained for general population. Male WD patients with decreased
serum ceruloplasmin (Cp), showed increased serum ferritin levels. Hepatic iron
content was normal in most cases.
DISCUSSION: Male patients with very low Cp serum concentrations showed slightly
elevated median serum ferritin concentrations, probably related to lack of
ferroxidase acitivity. However, in consideration of absolute numbers of ferritin
concentrations, these changes seem to be of minor clinical relevance.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1478-3231.2011.02661.x
PMID: 22098612 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36381061
|
1. Clin Case Rep. 2022 Nov 6;10(11):e6513. doi: 10.1002/ccr3.6513. eCollection
2022 Nov.
Black liver in a patient with Wilson's disease.
Jiang W(1), Zeng Q(1), Liu CH(1), Wu D(1), Tang H(1).
Author information:
(1)Center of Infectious Diseases West China Hospital of Sichuan University
Chengdu China.
Wilson's disease is an autosomal recessive inherited disease with congenital
copper metabolism disorder, characterized by decreased ceruloplasmin and
increased urine copper, which can involve multiple organs. This case was
complicated by iron overload, which is of great value in differentiating
hereditary hemochromatism.
© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
DOI: 10.1002/ccr3.6513
PMCID: PMC9637920
PMID: 36381061
Conflict of interest statement: None declared conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/11787982
|
1. J Trace Elem Med Biol. 2001;15(2-3):155-60. doi:
10.1016/S0946-672X(01)80060-2.
Brain copper, iron, magnesium, zinc, calcium, sulfur and phosphorus storage in
Wilson's disease.
Faa G(1), Lisci M, Caria MP, Ambu R, Sciot R, Nurchi VM, Silvagni R, Diaz A,
Crisponi G.
Author information:
(1)Dipartimento di Citomorfologia, Università di Cagliari, Italy.
PROJECT: Wilson's disease (WD) is an inherited disorder of copper metabolism
characterised by juvenile liver cirrhosis and by neurological symptoms. Copper
levels in brain in WD have been reported to be 10 to 15 fold normal values,
depending on the different brain regions. Being very few data on copper
distribution in central nervous system in WD available, it seemed of interest to
study the concentration of copper and of other trace elements (Zn, P, Mg, Ca, Fe
and S) in the brain of a patient died for WD.
PROCEDURE: a 56 year old woman affected by WD was admitted to our hospital with
signs of hepatic failure and died few days later. At autopsy, a brain slice
extending from the left to the right hemisphere was divided in 28 samples. On
each sample Copper, Iron, Magnesium, Phosphorus, Sulphur, Zinc and Calcium were
determined by Induced Coupled Plasma Atomic Emission Spectroscopy.
RESULTS: the mean concentration of copper, ranging from 88 to 158 microg/g of
dry tissue in all the brain specimens was higher than literature reference
values, while that of the other tested elements was considerably lower.
CONCLUSIONS: 1) In the brain of WD patient examined the status of trace elements
was extensively altered. Further studies are necessary to correlate the
concentration of trace elements with pathological lesions and with clinical
pictures. 2) The elements considered in our study showed an uneven distribution
in different brain areas.
DOI: 10.1016/S0946-672X(01)80060-2
PMID: 11787982 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21886393
|
1. Indian J Hematol Blood Transfus. 2010 Sep;26(3):101-2. doi:
10.1007/s12288-010-0034-2. Epub 2010 Oct 17.
Hemolytic Anemia as a Presenting Feature of Wilson's Disease: A Case Report.
Sharma S, Toppo A, Rath B, Harbhajanka A, Lalita Jyotsna P.
Wilson's disease is a rare inherited disorder of copper metabolism causing
severe damage to vital organs. Liver and brain disorders are the main
manifestations. Severe hemolytic anemia is an unusual complication of Wilson's
disease. We present a case who developed spherocytic acute hemolytic anemia
(Coomb's negative) as the initial manifestation of Wilson's disease. On
examination Kayser- Fleischer ring was found. Laboratory data supported a
diagnosis of Wilson's disease.
DOI: 10.1007/s12288-010-0034-2
PMCID: PMC3002091
PMID: 21886393
|
http://www.ncbi.nlm.nih.gov/pubmed/8114295
|
1. Nihon Rinsho. 1994 Jan;52(1):209-14.
[Liver cirrhosis in primary hemochromatosis and Wilson's disease].
[Article in Japanese]
Kobune M(1), Kato J, Kohgo Y, Niitsu Y.
Author information:
(1)Department of Internal Medicine, Sapporo Medical University School of
Medicine.
Iron is an essential element in all living cells because it serves machineries
for biological oxidation including hemoglobin, cytochrome c oxidase, etc. Copper
is also essential for mammalian life since copper is the prosthetic element of
several life-essential enzymes. Although intracellular excessive iron and copper
were usually sequestrated in ferritin and metallothionein molecules,
accumulation of excess iron and copper may also cause severe tissue injury by
including oxyradicals and lipid peroxidation and eventually bring about tissue
fibrosis such as liver cirrhosis. Hemochromatosis and Wilson's disease are known
as iron and copper accumulation disorders, respectively. In this chapter, we
review the cirrhosis in hemochromatosis and Wilson's disease.
PMID: 8114295 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33175593
|
1. Int J Neurosci. 2022 Sep;132(9):894-900. doi: 10.1080/00207454.2020.1849190.
Epub 2020 Nov 18.
Effect of homeostatic iron regulator protein gene mutation on Wilson's disease
clinical manifestation: original data and literature review.
Gromadzka G(1), Wierzbicka DW(2), Przybyłkowski A(3), Litwin T(2).
Author information:
(1)Faculty of Medicine (Collegium Medicum), Cardinal Stefan Wyszyński University
in Warsaw, Warsaw, Poland.
(2)Second Department of Neurology, Institute of Psychiatry and Neurology,
Warsaw, Poland.
(3)Department of Gastroenterology and Internal Medicine, Medical University in
Warsaw, Warsaw, Poland.
OBJECTIVE: Wilson's disease (WD) is a hereditary disorder of copper metabolism.
The metabolic pathways of copper and iron are interrelated. Our goal was to
determine the frequency of the two most common mutations in the coding region of
the human iron homeostatic protein gene (HFE) in Europe: C282Y (rs1800562) and
H63D (rs1799945) in WD patients, as well as to analyze their relation with WD
phenotypic traits.
MATERIAL AND METHODS: HFE mutations were studied by PCR RFLP method in 445 WD
patients and 102 controls. All patients met the diagnostic criteria of WD 8th
International Conference on Wilson Disease and Menkes Disease.
RESULTS: HFE C282Y heterozygotes, both women and men, showed WD symptoms earlier
than patients with wild-type HFE genotype. HFE 63HD heterozygous men presented
symptoms later than HFE 63HH homozygotes, but HFE 63HD women manifested symptoms
later than those with HFE 63HH genotype.
CONCLUSIONS: HFE genotype seems to be one of the factors modifying Wilson's
disease phenotype.
DOI: 10.1080/00207454.2020.1849190
PMID: 33175593 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25704483
|
1. J Cell Mol Med. 2015 Apr;19(4):806-14. doi: 10.1111/jcmm.12497. Epub 2015 Feb
20.
Laser ablation inductively coupled plasma mass spectrometry imaging of metals in
experimental and clinical Wilson's disease.
Boaru SG(1), Merle U, Uerlings R, Zimmermann A, Flechtenmacher C, Willheim C,
Eder E, Ferenci P, Stremmel W, Weiskirchen R.
Author information:
(1)Institute of Molecular Pathobiochemistry, Experimental Gene Therapie and
Clinical Chemistry, RWTH Aachen University Hospital Aachen, Aachen, Germany.
Wilson's disease is an autosomal recessive disorder in which the liver does not
properly release copper into bile, resulting in prominent copper accumulation in
various tissues. Affected patients suffer from hepatic disorders and severe
neurological defects. Experimental studies in mutant mice in which the
copper-transporting ATPase gene (Atp7b) is disrupted revealed a drastic,
time-dependent accumulation of hepatic copper that is accompanied by formation
of regenerative nodes resembling cirrhosis. Therefore, these mice represent an
excellent exploratory model for Wilson's disease. However, the precise time
course in hepatic copper accumulation and its impact on other trace metals
within the liver is yet poorly understood. We have recently established novel
laser ablation inductively coupled plasma mass spectrometry protocols allowing
quantitative metal imaging in human and murine liver tissue with high
sensitivity, spatial resolution, specificity and quantification ability. By use
of these techniques, we here aimed to comparatively analyse hepatic metal
content in wild-type and Atp7b deficient mice during ageing. We demonstrate that
the age-dependent accumulation of hepatic copper is strictly associated with a
simultaneous increase in iron and zinc, while the intrahepatic concentration and
distribution of other metals or metalloids is not affected. The same findings
were obtained in well-defined human liver samples that were obtained from
patients suffering from Wilson's disease. We conclude that in Wilson's disease
the imbalances of hepatic copper during ageing are closely correlated with
alterations in intrahepatic iron and zinc content.
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John
Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
DOI: 10.1111/jcmm.12497
PMCID: PMC4395195
PMID: 25704483 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18436437
|
1. Curr Opin Cell Biol. 2008 Jun;20(3):253-9. doi: 10.1016/j.ceb.2008.03.003.
Epub 2008 Apr 22.
The RNA polymerase II core promoter - the gateway to transcription.
Juven-Gershon T(1), Hsu JY, Theisen JW, Kadonaga JT.
Author information:
(1)Section of Molecular Biology, University of California, San Diego, 9500
Gilman Drive, La Jolla, CA 92093-0347, USA.
The RNA polymerase II core promoter is generally defined to be the sequence that
directs the initiation of transcription. This simple definition belies a diverse
and complex transcriptional module. There are two major types of core promoters
- focused and dispersed. Focused promoters contain either a single transcription
start site or a distinct cluster of start sites over several nucleotides,
whereas dispersed promoters contain several start sites over 50-100 nucleotides
and are typically found in CpG islands in vertebrates. Focused promoters are
more ancient and widespread throughout nature than dispersed promoters; however,
in vertebrates, dispersed promoters are more common than focused promoters. In
addition, core promoters may contain many different sequence motifs, such as the
TATA box, BRE, Inr, MTE, DPE, DCE, and XCPE1, that specify different mechanisms
of transcription and responses to enhancers. Thus, the core promoter is a
sophisticated gateway to transcription that determines which signals will lead
to transcription initiation.
DOI: 10.1016/j.ceb.2008.03.003
PMCID: PMC2586601
PMID: 18436437 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35379293
|
1. Genome Biol. 2022 Apr 4;23(1):89. doi: 10.1186/s13059-022-02634-w.
The contribution of evolutionarily volatile promoters to molecular phenotypes
and human trait variation.
Young RS(1)(2)(3), Talmane L(4), Marion de Procé S(5)(4), Taylor MS(6).
Author information:
(1)Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG,
UK. [email protected].
(2)Zhejiang University - University of Edinburgh Institute, Zhejiang University,
718 East Haizhou Road, 314400, Haining, China. [email protected].
(3)MRC Human Genetics Unit, Institute for Genetics and Cancer, University of
Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK. [email protected].
(4)MRC Human Genetics Unit, Institute for Genetics and Cancer, University of
Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.
(5)Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG,
UK.
(6)MRC Human Genetics Unit, Institute for Genetics and Cancer, University of
Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK. [email protected].
BACKGROUND: Promoters are sites of transcription initiation that harbour a high
concentration of phenotype-associated genetic variation. The evolutionary gain
and loss of promoters between species (collectively, termed turnover) is
pervasive across mammalian genomes and may play a prominent role in driving
human phenotypic diversity.
RESULTS: We classified human promoters by their evolutionary history during the
divergence of mouse and human lineages from a common ancestor. This defined
conserved, human-inserted and mouse-deleted promoters, and a class of
functional-turnover promoters that align between species but are only active in
humans. We show that promoters of all evolutionary categories are hotspots for
substitution and often, insertion mutations. Loci with a history of insertion
and deletion continue that mode of evolution within contemporary humans. The
presence of an evolutionary volatile promoter within a gene is associated with
increased expression variance between individuals, but only in the case of
human-inserted and mouse-deleted promoters does that correspond to an enrichment
of promoter-proximal genetic effects. Despite the enrichment of these molecular
quantitative trait loci (QTL) at evolutionarily volatile promoters, this does
not translate into a corresponding enrichment of phenotypic traits mapping to
these loci.
CONCLUSIONS: Promoter turnover is pervasive in the human genome, and these
promoters are rich in molecularly quantifiable but phenotypically
inconsequential variation in gene expression. However, since evolutionarily
volatile promoters show evidence of selection, coupled with high mutation rates
and enrichment of QTLs, this implicates them as a source of evolutionary
innovation and phenotypic variation, albeit with a high background of
selectively neutral expression variation.
© 2022. The Author(s).
DOI: 10.1186/s13059-022-02634-w
PMCID: PMC8978360
PMID: 35379293 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/36192696
|
1. BMC Genomics. 2022 Oct 3;23(Suppl 5):681. doi: 10.1186/s12864-022-08829-6.
iPromoter-Seqvec: identifying promoters using bidirectional long short-term
memory and sequence-embedded features.
Nguyen-Vo TH(1), Trinh QH(2), Nguyen L(1), Nguyen-Hoang PU(3), Rahardja S(4)(5),
Nguyen BP(6).
Author information:
(1)School of Mathematics and Statistics, Victoria University of Wellington, Gate
7, Kelburn Parade, 6140, Wellington, New Zealand.
(2)School of Information and Communication Technology, Hanoi University of
Science and Technology, 1 Dai Co Viet, 100000, Hanoi, Vietnam.
(3)Computational Biology Center, International University - VNU HCMC, Quarter 6,
Linh Trung Ward, Thu Duc District, 700000, Ho Chi Minh City, Vietnam.
(4)School of Marine Science and Technology, Northwestern Polytechnical
University, 127 West Youyi Road, 710072, Xi'an, China. [email protected].
(5)Infocomm Technology Cluster, Singapore Institute of Technology, 10 Dover
Drive, 138683, Singapore, Singapore. [email protected].
(6)School of Mathematics and Statistics, Victoria University of Wellington, Gate
7, Kelburn Parade, 6140, Wellington, New Zealand. [email protected].
BACKGROUND: Promoters, non-coding DNA sequences located at upstream regions of
the transcription start site of genes/gene clusters, are essential regulatory
elements for the initiation and regulation of transcriptional processes.
Furthermore, identifying promoters in DNA sequences and genomes significantly
contributes to discovering entire structures of genes of interest. Therefore,
exploration of promoter regions is one of the most imperative topics in
molecular genetics and biology. Besides experimental techniques, computational
methods have been developed to predict promoters. In this study, we propose
iPromoter-Seqvec - an efficient computational model to predict TATA and non-TATA
promoters in human and mouse genomes using bidirectional long short-term memory
neural networks in combination with sequence-embedded features extracted from
input sequences. The promoter and non-promoter sequences were retrieved from the
Eukaryotic Promoter database and then were refined to create four benchmark
datasets.
RESULTS: The area under the receiver operating characteristic curve (AUCROC) and
the area under the precision-recall curve (AUCPR) were used as two key metrics
to evaluate model performance. Results on independent test sets showed that
iPromoter-Seqvec outperformed other state-of-the-art methods with AUCROC values
ranging from 0.85 to 0.99 and AUCPR values ranging from 0.86 to 0.99. Models
predicting TATA promoters in both species had slightly higher predictive power
compared to those predicting non-TATA promoters. With a novel idea of
constructing artificial non-promoter sequences based on promoter sequences, our
models were able to learn highly specific characteristics discriminating
promoters from non-promoters to improve predictive efficiency.
CONCLUSIONS: iPromoter-Seqvec is a stable and robust model for predicting both
TATA and non-TATA promoters in human and mouse genomes. Our proposed method was
also deployed as an online web server with a user-friendly interface to support
research communities. Links to our source codes and web server are available at
https://github.com/mldlproject/2022-iPromoter-Seqvec .
© 2022. The Author(s).
DOI: 10.1186/s12864-022-08829-6
PMCID: PMC9531353
PMID: 36192696 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/31750297
|
1. Front Bioeng Biotechnol. 2019 Nov 5;7:305. doi: 10.3389/fbioe.2019.00305.
eCollection 2019.
Classifying Promoters by Interpreting the Hidden Information of DNA Sequences
via Deep Learning and Combination of Continuous FastText N-Grams.
Le NQK(1), Yapp EKY(2), Nagasundaram N(3), Yeh HY(3).
Author information:
(1)Professional Master Program in Artificial Intelligence in Medicine, Taipei
Medical University, Taipei, Taiwan.
(2)Singapore Institute of Manufacturing Technology, Innovis, Singapore,
Singapore.
(3)Medical Humanities Research Cluster, School of Humanities, Nanyang
Technological University, Singapore, Singapore.
A promoter is a short region of DNA (100-1,000 bp) where transcription of a gene
by RNA polymerase begins. It is typically located directly upstream or at the 5'
end of the transcription initiation site. DNA promoter has been proven to be the
primary cause of many human diseases, especially diabetes, cancer, or
Huntington's disease. Therefore, classifying promoters has become an interesting
problem and it has attracted the attention of a lot of researchers in the
bioinformatics field. There were a variety of studies conducted to resolve this
problem, however, their performance results still require further improvement.
In this study, we will present an innovative approach by interpreting DNA
sequences as a combination of continuous FastText N-grams, which are then fed
into a deep neural network in order to classify them. Our approach is able to
attain a cross-validation accuracy of 85.41 and 73.1% in the two layers,
respectively. Our results outperformed the state-of-the-art methods on the same
dataset, especially in the second layer (strength classification). Throughout
this study, promoter regions could be identified with high accuracy and it
provides analysis for further biological research as well as precision medicine.
In addition, this study opens new paths for the natural language processing
application in omics data in general and DNA sequences in particular.
Copyright © 2019 Le, Yapp, Nagasundaram and Yeh.
DOI: 10.3389/fbioe.2019.00305
PMCID: PMC6848157
PMID: 31750297
|
http://www.ncbi.nlm.nih.gov/pubmed/27557757
|
1. Methods Mol Biol. 2016;1482:1-13. doi: 10.1007/978-1-4939-6396-6_1.
What Have We Learned About Synthetic Promoter Construction?
Rushton PJ(1).
Author information:
(1)22nd Century Group Inc., 9530 Main Street, Clarence, NY, 14031, USA.
[email protected].
The molecular components of transcriptional regulation are modular.
Transcription factors have domains for specific functions such as DNA binding,
dimerization, and protein-protein interactions associated with transcriptional
activation and repression. Similarly, promoters are modular. They consist of
combinations of cis-acting elements that are the binding sites for transcription
factors. It is this promoter architecture that largely determines the expression
pattern of a gene. The modular nature of promoters is supported by the
observation that many cis-acting elements retain their activities when they are
taken out of their native promoter context and used as building blocks in
synthetic promoters. We therefore have a large collection of cis-acting elements
to use in building synthetic promoters and many minimal promoters upon which to
build them. This review discusses what we have learned concerning how to use
these building blocks to make synthetic promoters. It has become clear that we
can increase the strength of a promoter by adding increasing numbers of
cis-acting elements. However, it appears that there may be a sweet spot with
regard to inducibility as promoters with increasing numbers of copies of an
element often show increased background expression. Spacing between elements
appears important because if elements are placed too close together activity is
lost, presumably due to reduced transcription factor binding due to steric
hindrance. In many cases, promoters that contain combinations of cis-acting
elements show better expression characteristics than promoters that contain a
single type of element. This may be because multiple transcription factor
binding sites in the promoter places it at the end of multiple signal
transduction pathways. Finally, some cis-acting elements form functional units
with other elements and are inactive on their own. In such cases, the complete
unit is required for function in a synthetic promoter. Taken together, we have
learned much about how to construct synthetic promoters and this knowledge will
be crucial in both designing promoters to drive transgenes and also as
components of defined regulatory networks in synthetic biology.
DOI: 10.1007/978-1-4939-6396-6_1
PMID: 27557757 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35533969
|
1. Genomics. 2022 May;114(3):110384. doi: 10.1016/j.ygeno.2022.110384. Epub 2022
May 6.
iProm-Zea: A two-layer model to identify plant promoters and their types using
convolutional neural network.
Kim J(1), Shujaat M(2), Tayara H(3).
Author information:
(1)Department of New & Renewable Energy, VISION College of Jeonju, Jeonju 55069,
Republic of Korea. Electronic address: [email protected].
(2)Department of Electronics and Information Engineering, Jeonbuk National
University, Jeonju 54896, Republic of Korea. Electronic address:
[email protected].
(3)School of International Engineering and Science, Jeonbuk National University,
Jeonju 54896, Republic of Korea. Electronic address: [email protected].
A promoter is a short DNA sequence near the start codon, responsible for
initiating the transcription of a specific gene in the genome. The accurate
recognition of promoters is important for achieving a better understanding of
transcriptional regulation. Because of their importance in the process of
biological transcriptional regulation, there is an urgent need to develop in
silico tools to identify promoters and their types in a timely and accurate
manner. A number of prediction methods have been developed in this regard;
however, almost all of them are merely used for identifying promoters and their
strength or sigma types. The TATA box region in TATA promoter influences the
post-transcriptional processes; therefore, in the current study, we developed a
two-layer predictor called "iProm-Zea" using the convolutional neural network
(CNN) for identify TATA and TATA less promoters. The first layer can be used to
identify a given DNA sequence as a promoter or non-promoter. The second layer
can be used to identify whether the recognized promoter is the TATA promoter. To
find an optimal feature encoding scheme and model, we employed four feature
encoding schemes on different machine learning and CNN algorithms, and based on
the evaluation results, we selected a one-hot encoding scheme and a CNN model
for iProm-Zea. The 5-fold cross validation testing results demonstrated that the
constructed predictor showed great potential for identifying promoters and
classifying them as TATA and TATA less promoters. Furthermore, we performed
cross-species analysis of iProm-Zea to evaluate its performance in other
species. Moreover, to make it easier for other experimental scientists to obtain
the results they need, we established a freely accessible and user-friendly web
server at http://nsclbio.jbnu.ac.kr/tools/iProm-Zea/.
Copyright © 2022. Published by Elsevier Inc.
DOI: 10.1016/j.ygeno.2022.110384
PMID: 35533969 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest No conflict of
interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/33488763
|
1. Comput Math Methods Med. 2021 Jan 5;2021:6636350. doi: 10.1155/2021/6636350.
eCollection 2021.
iPTT(2 L)-CNN: A Two-Layer Predictor for Identifying Promoters and Their Types
in Plant Genomes by Convolutional Neural Network.
Sun A(1), Xiao X(1), Xu Z(1).
Author information:
(1)Jing-De-Zhen Ceramic Institute, Jingdezhen, China.
A promoter is a short DNA sequence near to the start codon, responsible for
initiating transcription of a specific gene in genome. The accurate recognition
of promoters has great significance for a better understanding of the
transcriptional regulation. Because of their importance in the process of
biological transcriptional regulation, there is an urgent need to develop in
silico tools to identify promoters and their types timely and accurately. A
number of prediction methods had been developed in this regard; however, almost
all of them were merely used for identifying promoters and their strength or
sigma types. Owing to that TATA box region in TATA promoter that influences
posttranscriptional processes, in the current study, we developed a two-layer
predictor called iPTT(2L)-CNN by using the convolutional neural network (CNN)
for identifying TATA and TATA-less promoters. The first layer can be used to
identify a given DNA sequence as a promoter or nonpromoter. The second layer is
used to identify whether the recognized promoter is TATA promoter or not. The
5-fold crossvalidation and independent testing results demonstrate that the
constructed predictor is promising for identifying promoter and classifying TATA
and TATA-less promoter. Furthermore, to make it easier for most experimental
scientists get the results they need, a user-friendly web server has been
established at http://www.jci-bioinfo.cn/iPPT(2L)-CNN.
Copyright © 2021 Ang Sun et al.
DOI: 10.1155/2021/6636350
PMCID: PMC7803414
PMID: 33488763 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that there is no conflict of
interest regarding the publication of this paper.
|
http://www.ncbi.nlm.nih.gov/pubmed/22392219
|
1. Nat Rev Genet. 2012 Mar 6;13(4):233-45. doi: 10.1038/nrg3163.
Metazoan promoters: emerging characteristics and insights into transcriptional
regulation.
Lenhard B(1), Sandelin A, Carninci P.
Author information:
(1)Institute of Clinical Sciences, Faculty of Medicine, Imperial College London,
London, UK. [email protected]
Promoters are crucial for gene regulation. They vary greatly in terms of
associated regulatory elements, sequence motifs, the choice of transcription
start sites and other features. Several technologies that harness
next-generation sequencing have enabled recent advances in identifying promoters
and their features, helping researchers who are investigating functional
categories of promoters and their modes of regulation. Additional features of
promoters that are being characterized include types of histone modifications,
nucleosome positioning, RNA polymerase pausing and novel small RNAs. In this
Review, we discuss recent findings relating to metazoan promoters and how these
findings are leading to a revised picture of what a gene promoter is and how it
works.
DOI: 10.1038/nrg3163
PMID: 22392219 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33227813
|
1. Brief Bioinform. 2021 Jul 20;22(4):bbaa299. doi: 10.1093/bib/bbaa299.
Computational identification of eukaryotic promoters based on cascaded deep
capsule neural networks.
Zhu Y(1), Li F(2), Xiang D(3), Akutsu T(4), Song J(5), Jia C(6).
Author information:
(1)School of Science, Dalian Maritime University, China.
(2)Peter Doherty Institute for Infection and Immunity, The University of
Melbourne, Australia.
(3)Northwest A&F University, China.
(4)Bioinformatics Center, Institute for Chemical Research, Kyoto University.
(5)Biomedicine Discovery Institute and Department of Biochemistry and Molecular
Biology, Monash University, Melbourne, Australia.
(6)College of Science, Dalian Maritime University.
A promoter is a region in the DNA sequence that defines where the transcription
of a gene by RNA polymerase initiates, which is typically located proximal to
the transcription start site (TSS). How to correctly identify the gene TSS and
the core promoter is essential for our understanding of the transcriptional
regulation of genes. As a complement to conventional experimental methods,
computational techniques with easy-to-use platforms as essential bioinformatics
tools can be effectively applied to annotate the functions and physiological
roles of promoters. In this work, we propose a deep learning-based method termed
Depicter (Deep learning for predicting promoter), for identifying three specific
types of promoters, i.e. promoter sequences with the TATA-box (TATA model),
promoter sequences without the TATA-box (non-TATA model), and indistinguishable
promoters (TATA and non-TATA model). Depicter is developed based on an
up-to-date, species-specific dataset which includes Homo sapiens, Mus musculus,
Drosophila melanogaster and Arabidopsis thaliana promoters. A convolutional
neural network coupled with capsule layers is proposed to train and optimize the
prediction model of Depicter. Extensive benchmarking and independent tests
demonstrate that Depicter achieves an improved predictive performance compared
with several state-of-the-art methods. The webserver of Depicter is implemented
and freely accessible at https://depicter.erc.monash.edu/.
© The Author(s) 2020. Published by Oxford University Press. All rights reserved.
For Permissions, please email: [email protected].
DOI: 10.1093/bib/bbaa299
PMCID: PMC8522485
PMID: 33227813 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/33958766
|
1. Nat Microbiol. 2021 Jun;6(6):746-756. doi: 10.1038/s41564-021-00898-9. Epub
2021 May 6.
Widespread divergent transcription from bacterial and archaeal promoters is a
consequence of DNA-sequence symmetry.
Warman EA(1), Forrest D(1), Guest T(1), Haycocks JJRJ(1), Wade JT(2)(3),
Grainger DC(4).
Author information:
(1)Institute of Microbiology and Infection, School of Biosciences, University of
Birmingham, Birmingham, UK.
(2)Wadsworth Centre, New York State Department of Health, Albany, NY, USA.
(3)Department of Biomedical Sciences, University at Albany, Albany, NY, USA.
(4)Institute of Microbiology and Infection, School of Biosciences, University of
Birmingham, Birmingham, UK. [email protected].
Transcription initiates at promoters, DNA regions recognized by a DNA-dependent
RNA polymerase. We previously identified horizontally acquired Escherichia coli
promoters from which the direction of transcription was unclear. In the present
study, we show that more than half of these promoters are bidirectional and
drive divergent transcription. Using genome-scale approaches, we demonstrate
that 19% of all transcription start sites detected in E. coli are associated
with a bidirectional promoter. Bidirectional promoters are similarly common in
diverse bacteria and archaea, and have inherent symmetry: specific bases
required for transcription initiation are reciprocally co-located on opposite
DNA strands. Bidirectional promoters enable co-regulation of divergent genes and
are enriched in both intergenic and horizontally acquired regions. Divergent
transcription is conserved among bacteria, archaea and eukaryotes, but the
underlying mechanisms for bidirectionality are different.
DOI: 10.1038/s41564-021-00898-9
PMCID: PMC7612053
PMID: 33958766 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests Ststement The authors
declare that there are no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/24503515
|
1. Curr Opin Struct Biol. 2014 Apr;25:77-85. doi: 10.1016/j.sbi.2014.01.007. Epub
2014 Feb 4.
Role of DNA sequence based structural features of promoters in transcription
initiation and gene expression.
Bansal M(1), Kumar A(2), Yella VR(2).
Author information:
(1)Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012,
India. Electronic address: [email protected].
(2)Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012,
India.
Regulatory information for transcription initiation is present in a stretch of
genomic DNA, called the promoter region that is located upstream of the
transcription start site (TSS) of the gene. The promoter region interacts with
different transcription factors and RNA polymerase to initiate transcription and
contains short stretches of transcription factor binding sites (TFBSs), as well
as structurally unique elements. Recent experimental and computational analyses
of promoter sequences show that they often have non-B-DNA structural motifs, as
well as some conserved structural properties, such as stability, bendability,
nucleosome positioning preference and curvature, across a class of organisms.
Here, we briefly describe these structural features, the differences observed in
various organisms and their possible role in regulation of gene expression.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.sbi.2014.01.007
PMID: 24503515 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23020586
|
1. BMC Genomics. 2012 Sep 28;13:512. doi: 10.1186/1471-2164-13-512.
Eukaryotic genomes may exhibit up to 10 generic classes of gene promoters.
Gagniuc P(1), Ionescu-Tirgoviste C.
Author information:
(1)Institute of Genetics, University of Bucharest, Bucharest 060101, Romania.
[email protected]
BACKGROUND: The main function of gene promoters appears to be the integration of
different gene products in their biological pathways in order to maintain
homeostasis. Generally, promoters have been classified in two major classes,
namely TATA and CpG. Nevertheless, many genes using the same combinatorial
formation of transcription factors have different gene expression patterns.
Accordingly, we tried to ask ourselves some fundamental questions: Why certain
genes have an overall predisposition for higher gene expression levels than
others? What causes such a predisposition? Is there a structural relationship of
these sequences in different tissues? Is there a strong phylogenetic
relationship between promoters of closely related species?
RESULTS: In order to gain valuable insights into different promoter regions, we
obtained a series of image-based patterns which allowed us to identify 10
generic classes of promoters. A comprehensive analysis was undertaken for
promoter sequences from Arabidopsis thaliana, Drosophila melanogaster, Homo
sapiens and Oryza sativa, and a more extensive analysis of tissue-specific
promoters in humans. We observed a clear preference for these species to use
certain classes of promoters for specific biological processes. Moreover, in
humans, we found that different tissues use distinct classes of promoters,
reflecting an emerging promoter network. Depending on the tissue type,
comparisons made between these classes of promoters reveal a complementarity
between their patterns whereas some other classes of promoters have been
observed to occur in competition. Furthermore, we also noticed the existence of
some transitional states between these classes of promoters that may explain
certain evolutionary mechanisms, which suggest a possible predisposition for
specific levels of gene expression and perhaps for a different number of factors
responsible for triggering gene expression. Our conclusions are based on
comprehensive data from three different databases and a new computer model whose
core is using Kappa index of coincidence.
CONCLUSIONS: To fully understand the connections between gene promoters and gene
expression, we analyzed thousands of promoter sequences using our Kappa Index of
Coincidence method and a specialized Optical Character Recognition (OCR) neural
network. Under our criteria, 10 classes of promoters were detected. In addition,
the existence of "transitional" promoters suggests that there is an evolutionary
weighted continuum between classes, depending perhaps upon changes in their gene
products.
DOI: 10.1186/1471-2164-13-512
PMCID: PMC3549790
PMID: 23020586 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23080252
|
1. Subcell Biochem. 2012;64:203-21. doi: 10.1007/978-94-007-5055-5_10.
Analysis of Corynebacterium glutamicum promoters and their applications.
Nešvera J(1), Holátko J, Pátek M.
Author information:
(1)Institute of Microbiology, Academy of Sciences of the Czech Republic,
Vídeňská 1083, CZ-14220, Prague 4, Czech Republic.
Promoters are DNA sequences which function as regulatory signals of
transcription initiation catalyzed by RNA polymerase. Since promoters
substantially influence levels of gene expression, they have become powerful
tools in metabolic engineering. Methods for their localization used in
Corynebacterium glutamicum and techniques for the analysis of their function are
described in this review. C. glutamicum promoters can be classified according to
the respective σ factors which direct RNA polymerase to these structures. C.
glutamicum promoters are recognized by holo-RNA polymerase formed by subunits
α(2)ββ'ω + σ. C. glutamicum codes for seven different sigma factors: the
principal sigma factor σ(A) and alternative sigma factors σ(B), σ(C), σ(D),
σ(E), σ(H) and σ(M), which recognize various classes of promoters. The promoters
of housekeeping genes recognized by σ(A), which are active during the
exponential growth, form the largest described group. These promoters and their
mutant derivatives are the most frequently used elements in modulation of gene
expression in C. glutamicum. Promoters recognized by alternative sigma factors
and their consensus sequences are gradually emerging.
DOI: 10.1007/978-94-007-5055-5_10
PMID: 23080252 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12948648
|
1. J Biotechnol. 2003 Sep 4;104(1-3):311-23. doi: 10.1016/s0168-1656(03)00155-x.
Promoters of Corynebacterium glutamicum.
Pátek M(1), Nesvera J, Guyonvarch A, Reyes O, Leblon G.
Author information:
(1)Institute of Microbiology, Academy of Sciences of the Czech Republic,
Vídenská 1083, CZ-14220 Prague 4, Czech Republic. [email protected]
Regulation of gene expression in Corynebacterium glutamicum represents an
important issue since this Gram-positive bacterium is a notable industrial amino
acid producer. Transcription initiation, beginning by binding of RNA polymerase
to the promoter DNA sequence, is one of the main points at which bacterial gene
expression is regulated. More than 50 transcriptional promoters have so far been
experimentally localized in C. glutamicum. Most of them are assumed to be
promoters of vegetative genes recognized by the main sigma factor. Although
transcription initiation rate defined by many of these promoters may be affected
by transcription factors, which activate or repress their function, the promoter
regions share common sequence features, which may be generalized in a consensus
sequence. In the consensus C. glutamicum promoter, the prominent feature is a
conserved extended -10 region tgngnTA(c/t)aaTgg, while the -35 region is much
less conserved. Some commonly utilized heterologous promoters were shown to
drive strong gene expression in C. glutamicum. Conversely, some C. glutamicum
promoters were found to function in Escherichia coli and in other bacteria.
These observations suggest that C. glutamicum promoters functionally conform
with the common bacterial promoter scheme, although they differ in some sequence
structures.
DOI: 10.1016/s0168-1656(03)00155-x
PMID: 12948648 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24467902
|
1. Plant Sci. 2014 Mar;217-218:109-19. doi: 10.1016/j.plantsci.2013.12.007. Epub
2013 Dec 14.
Identification and validation of promoters and cis-acting regulatory elements.
Hernandez-Garcia CM(1), Finer JJ(2).
Author information:
(1)Department of Horticulture and Crop Science, OARDC/The Ohio State University,
1680 Madison Avenue, Wooster, OH 44691, USA.
(2)Department of Horticulture and Crop Science, OARDC/The Ohio State University,
1680 Madison Avenue, Wooster, OH 44691, USA. Electronic address:
[email protected].
Studies of promoters that largely regulate gene expression at the
transcriptional level are crucial for improving our basic understanding of gene
regulation and will expand the toolbox of available promoters for use in plant
biotechnology. In this review, we present a comprehensive analysis of promoters
and their underlying mechanisms in transcriptional regulation, including
epigenetic marks and chromatin-based regulation. Large-scale prediction of
promoter sequences and their contributing cis-acting elements has become routine
due to recent advances in transcriptomic technologies and genome sequencing of
several plants. However, predicted regulatory sequences may or may not be
functional and demonstration of the contribution of the element to promoter
activity is essential for confirmation of regulatory sequences. Synthetic
promoters and introns provide useful approaches for functional validation of
promoter sequences. The development and improvement of gene expression tools for
rapid, efficient, predictable, and high-throughput analysis of promoter
components will be critical for confirmation of the functional regulatory
element sequences identified through transcriptomic and genomic analyses.
Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights
reserved.
DOI: 10.1016/j.plantsci.2013.12.007
PMID: 24467902 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36377861
|
1. Elife. 2022 Nov 15;11:e80943. doi: 10.7554/eLife.80943.
Promoter sequence and architecture determine expression variability and confer
robustness to genetic variants.
Einarsson H(1), Salvatore M(1), Vaagensø C(1), Alcaraz N(1), Bornholdt J(1),
Rennie S(1), Andersson R(1).
Author information:
(1)Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Comment in
doi: 10.7554/eLife.85298.
Genetic and environmental exposures cause variability in gene expression.
Although most genes are affected in a population, their effect sizes vary
greatly, indicating the existence of regulatory mechanisms that could amplify or
attenuate expression variability. Here, we investigate the relationship between
the sequence and transcription start site architectures of promoters and their
expression variability across human individuals. We find that expression
variability can be largely explained by a promoter's DNA sequence and its
binding sites for specific transcription factors. We show that promoter
expression variability reflects the biological process of a gene, demonstrating
a selective trade-off between stability for metabolic genes and plasticity for
responsive genes and those involved in signaling. Promoters with a rigid
transcription start site architecture are more prone to have variable expression
and to be associated with genetic variants with large effect sizes, while a
flexible usage of transcription start sites within a promoter attenuates
expression variability and limits genotypic effects. Our work provides insights
into the variable nature of responsive genes and reveals a novel mechanism for
supplying transcriptional and mutational robustness to essential genes through
multiple transcription start site regions within a promoter.
© 2022, Einarsson et al.
DOI: 10.7554/eLife.80943
PMCID: PMC9844987
PMID: 36377861 [Indexed for MEDLINE]
Conflict of interest statement: HE, MS, CV, NA, JB, SR, RA No competing
interests declared
|
http://www.ncbi.nlm.nih.gov/pubmed/25934543
|
1. Biochim Biophys Acta. 2015 Aug;1849(8):1116-31. doi:
10.1016/j.bbagrm.2015.04.003. Epub 2015 Apr 28.
The core promoter: At the heart of gene expression.
Danino YM(1), Even D(1), Ideses D(1), Juven-Gershon T(2).
Author information:
(1)The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University,
Ramat Gan 5290002, Israel.
(2)The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University,
Ramat Gan 5290002, Israel. Electronic address: [email protected].
The identities of different cells and tissues in multicellular organisms are
determined by tightly controlled transcriptional programs that enable accurate
gene expression. The mechanisms that regulate gene expression comprise diverse
multiplayer molecular circuits of multiple dedicated components. The RNA
polymerase II (Pol II) core promoter establishes the center of this
spatiotemporally orchestrated molecular machine. Here, we discuss transcription
initiation, diversity in core promoter composition, interactions of the basal
transcription machinery with the core promoter, enhancer-promoter specificity,
core promoter-preferential activation, enhancer RNAs, Pol II pausing,
transcription termination, Pol II recycling and translation. We further discuss
recent findings indicating that promoters and enhancers share similar features
and may not substantially differ from each other, as previously assumed. Taken
together, we review a broad spectrum of studies that highlight the importance of
the core promoter and its pivotal role in the regulation of metazoan gene
expression and suggest future research directions and challenges.
Copyright © 2015 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbagrm.2015.04.003
PMID: 25934543 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17130462
|
1. Diabetes. 2006 Dec;55(12):3201-13. doi: 10.2337/db06-0788.
Comparative analysis of insulin gene promoters: implications for diabetes
research.
Hay CW(1), Docherty K.
Author information:
(1)School of Medical Sciences, University of Aberdeen, Institute of Medical
Sciences, Aberdeen, AB25 2ZD, UK.
DNA sequences that regulate expression of the insulin gene are located within a
region spanning approximately 400 bp that flank the transcription start site.
This region, the insulin promoter, contains a number of cis-acting elements that
bind transcription factors, some of which are expressed only in the beta-cell
and a few other endocrine or neural cell types, while others have a widespread
tissue distribution. The sequencing of the genome of a number of species has
allowed us to examine the manner in which the insulin promoter has evolved over
a 450 million-year period. The major findings are that the A-box sites that bind
PDX-1 are among the most highly conserved regulatory sequences, and that the
conservation of the C1, E1, and CRE sequences emphasize the importance of MafA,
E47/beta2, and cAMP-associated regulation. The review also reveals that of all
the insulin gene promoters studied, the rodent insulin promoters are
considerably dissimilar to the human, leading to the conclusion that extreme
care should be taken when extrapolating rodent-based data on the insulin gene to
humans.
DOI: 10.2337/db06-0788
PMID: 17130462 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/33904220
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1. Nurs Crit Care. 2022 Sep;27(5):658-666. doi: 10.1111/nicc.12636. Epub 2021 Apr
26.
Pain intensity of sedated paediatric intensive care unit patients during
treatment and care procedures.
Akgün D(1), İnal S(2).
Author information:
(1)Sadi Sun Intensive Care Department, Cerrahpaşa Sadisun Intensive Care Unit,
Istanbul University-Cerrahpaşa, Fatih, Istanbul, Turkey.
(2)Midwifery Department, Faculty of Health Sciences, Istanbul
University-Cerrahpaşa, Büyükçekmece, Istanbul, Turkey.
BACKGROUND: Although various pharmacological and non-pharmacological methods are
used in the management of pain in the Paediatric Intensive Care Unit, patients
experience more pain than those being treated in other units.
AIM AND OBJECTIVES: This study was conducted to determine the intensity of pain
during invasive patient care and dressing change procedures in sedated
paediatric intensive care unit (PICU) patients and to assess the impact of
analgesics and demographic factors. The study also sought to evaluate any
correlation between the face, legs, activity, cry, consolability (FLACC) and
COMFORT scales.
DESIGN: The research was conducted as a descriptive cross-sectional study.
METHODS: The total sample size consisted of 30 mild-to-moderately sedated
patients under the age of 18 in the PICU of a university hospital in Turkey
between September the 1st, 2016, and December the 31st, 2016. The procedures
were classified in to three groups: Invasive, Patient Care and Dressing Change.
The FLACC and COMFORT scales were utilized to assess pain.
RESULTS: The intensity of pain did not differ according to the demographic
characteristics (median [IQR]) by gender-COMFORT female: (16.05 [15.10-17.0]);
male: (15.15 [14.7-16.5]) (P = .284)-age: (COMFORT: P = .165); intensive care
admission indications: (COMFORT: P = .647); or administration of
analgesics-COMFORT Yes: (15.90 [14.80-16.65]), No: (15.50 [14.70-16.45])
(P = .634). The invasive procedures produced the most intense pain (median
[IQR]): FLACC: (5 [4-6])/COMFORT: (16 [15-20]). Patient care procedures were
second in intensity of pain FLACC: (4 [3-5])/COMFORT: (15 [14-17]), while
dressing changes produced significantly less pain FLACC: (3 [2-4])/COMFORT: (14
[12-17]) (P < .001). A positive correlation was noted between the pain scores
observed on the FLACC and COMFORT scales (rs: Invasive procedures:0.992/Care
procedure:0.991/Dressing procedures: 0.996) (P < .001).
CONCLUSIONS: Besides invasive procedures, patient care and dressing changes also
cause sedated PICU patients' pain. The pain management was insufficient to
prevent pain for most of the procedures in the PICU.
RELEVANCE TO CLINICAL PRACTICE: Besides making use of evidence-based
pharmacological and non-pharmacological methods in invasive procedures, care
must also be focused on preventing pain during patient care and dressing
procedures so that the most effective treatment can be achieved.
© 2021 British Association of Critical Care Nurses.
DOI: 10.1111/nicc.12636
PMID: 33904220 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35626783
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1. Children (Basel). 2022 Apr 24;9(5):606. doi: 10.3390/children9050606.
The Effects of Remifentanil and Fentanyl on Emergence Agitation in Pediatric
Strabismus Surgery.
Baek J(1), Park SJ(1), Kim JO(1), Kim M(1), Kim DY(1), Choi EK(1).
Author information:
(1)Department of Anesthesiology and Pain Medicine, Yeungnam University College
of Medicine, 170, Hyeonchung-ro, Nam-gu, Daegu 42415, Korea.
Emergence agitation (EA) is one of the main concerns in the field of pediatric
anesthesia using sevoflurane. We investigated the effects of remifentanil and
fentanyl on the incidence of EA in pediatric patients undergoing strabismus
surgery. Ninety children were randomly allocated into two groups and received
either remifentanil (group R: intraoperatively remifentanil 0.2 μg/kg/min) or
fentanyl (group F: fentanyl 2 μg/kg at anesthetic induction) intraoperatively.
After surgery, EA incidence was assessed using a four-point agitation scale and
Pediatric Anesthesia Emergence Delirium (PAED) scale in the post-anesthesia care
unit. Face, leg, activity, cry, and consolability (FLACC) scores for
postoperative pain were also assessed. The incidence of EA using the four-point
agitation scale (scores ≥ 3) was similar in both groups (remifentanil group,
28.89% vs. fentanyl group, 24.44%). Similar results were obtained using the PAED
scale (scores > 12), with an incidence of 33.33% in the remifentanil group and
26.67% in the fentanyl group. Differences in FLACC scores were not found to be
statistically significant. A single bolus administration of fentanyl during
anesthetic induction and continuous infusion of remifentanil during surgery had
similar effects on the EA incidence in these pediatric patients.
DOI: 10.3390/children9050606
PMCID: PMC9139967
PMID: 35626783
Conflict of interest statement: The authors declare no conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/35628840
|
1. J Clin Med. 2022 May 11;11(10):2713. doi: 10.3390/jcm11102713.
The Effect of Pre-Emptive Analgesia on the Postoperative Pain in Pediatric
Otolaryngology: A Randomized, Controlled Trial.
Zieliński J(1), Morawska-Kochman M(1), Dudek K(2), Czapla M(3)(4), Zatoński
T(1).
Author information:
(1)Department of Otolaryngology, Head and Neck Surgery, Wroclaw Medical
University, 50-556 Wroclaw, Poland.
(2)Faculty of Mechanical Engineering, Wroclaw University of Technology, 50-231
Wroclaw, Poland.
(3)Laboratory for Experimental Medicine and Innovative Technologies, Department
of Emergency Medical Service, Wroclaw Medical University, 51-616 Wroclaw,
Poland.
(4)Group of Research in Care (GRUPAC), Faculty of Nursing, University of La
Rioja, 26006 Logrono, Spain.
The aim of this randomized, controlled trial was to determine whether children
undergoing otolaryngological procedures (adenoidectomy, adenotonsillotomy, or
tonsillectomy) benefit from pre-emptive analgesia in the postoperative period.
Methods: Fifty-five children were assessed for eligibility for the research.
Four children refused to participate during the first stage of the study,
leaving fifty-one (n = 51) to be randomly assigned either to receive pre-emptive
analgesic acetaminophen (15 mg/kg; n = 26) or a placebo (n = 25) in addition to
midazolam (0.5 mg/kg) as premedication. All children were anesthetized with
sevoflurane, propofol (2−4 mg/kg), and fentanyl (2 mcg/kg). Postoperative pain
was assessed using the Visual Analogue Scale (VAS), the Wong−Baker Faces Pain
Rating Scale, and the Face, Legs, Activity, Cry, and Consolability (FLACC)
scale. The postoperative pain was measured 1, 2, 4, and 6 h after the surgery.
Results: The clinical trial reported a statistically significant correlation
between administering pre-emptive analgesia (acetaminophen) and reducing pain in
children after otolaryngological procedures compared to placebo. The ratio of
boys to girls and age were similar among the groups (p > 0.05), so the groups of
children were not divided by gender or age. Conclusions: Standard pre-emptive
analgesia reduced the severity of pain in the postoperative period after
otolaryngological procedures in children. Acetaminophen given before surgery
reduces postoperative pain in children undergoing otolaryngological procedures.
DOI: 10.3390/jcm11102713
PMCID: PMC9146866
PMID: 35628840
Conflict of interest statement: The authors declare no conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/34573098
|
1. Antioxidants (Basel). 2021 Sep 15;10(9):1466. doi: 10.3390/antiox10091466.
The Effects of Two Nrf2 Activators, Bardoxolone Methyl and Omaveloxolone, on
Retinal Ganglion Cell Survival during Ischemic Optic Neuropathy.
Chien JY(1), Chou YY(2), Ciou JW(2), Liu FY(2), Huang SP(1)(2)(3).
Author information:
(1)Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.
(2)Department of Molecular Biology and Human Genetics, Tzu Chi University,
Hualien 970, Taiwan.
(3)Department of Ophthalmology, Tzu Chi University, Hualien 970, Taiwan.
Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most
common acute optic neuropathies that affect the over 55-year-old population.
NAION causes the loss of visual function, and it has no safe and effective
therapy. Bardoxolone methyl (methyl
2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate; CDDO-Me; RTA 402) is a
semisynthetic triterpenoid with effects against antioxidative stress and
inflammation in neurodegeneration and kidney disease that activates the nuclear
factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Moreover, RTA 402
is an FDA-approved compound for the treatment of solid tumors, lymphoid
malignancies, melanoma, and chronic kidney disease. Omaveloxolone (RTA 408) is
an activator of Nrf2 and an inhibitor of NFκB, possessing antioxidative and
anti-inflammatory activities in mitochondrial bioenergetics. RTA 408 is also
under clinical investigation for Friedreich ataxia (FA). In this study, a rodent
anterior ischemic optic neuropathy (rAION) model induced by photothrombosis was
used to examine the therapeutic effects of RTA 402 and RTA 408. Treatment with
RTA402 results in antiapoptotic, antioxidative stress, anti-inflammatory, and
myelin-preserving effects on retinal ganglion cell (RGC) survival and visual
function via regulation of NQO1 and HO-1, reduced IL-6 and Iba1 expression in
macrophages, and promoted microglial expression of TGF-β and Ym1 + 2 in the
retina and optic nerve. However, these effects were not observed after RTA 408
treatment. Our results provide explicit evidence that RTA 402 modulates the Nrf2
and NFκB signaling pathways to protect RGCs from apoptosis and maintain the
visual function in an rAION model. These findings indicate that RTA 402 may a
potential therapeutic agent for ischemic optic neuropathy.
DOI: 10.3390/antiox10091466
PMCID: PMC8470542
PMID: 34573098
Conflict of interest statement: The authors declare no conflict of interest. The
funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript; or in the decision to
publish the results.
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http://www.ncbi.nlm.nih.gov/pubmed/35361254
|
1. Crit Care. 2022 Mar 31;26(1):88. doi: 10.1186/s13054-022-03957-7.
Pain and sedation management and monitoring in pediatric intensive care units
across Europe: an ESPNIC survey.
Daverio M(#)(1), von Borell F(#)(2)(3), Ramelet AS(4)(5), Sperotto F(1)(6),
Pokorna P(7)(8)(9)(10), Brenner S(3), Mondardini MC(11)(12), Tibboel D(13),
Amigoni A(#)(1), Ista E(#)(13); Analgosedation CONSORTIUM on behalf of the
Pharmacology Section and the Nurse Science Section of the European Society of
Paediatric and Neonatal Intensive Care.
Collaborators: Kola E, Vittinghoff M, Duval E, Polić B, Valla F, Neunhoeffer F,
Konstantinos T, Györgyi Z, Tan MH, Hasani A, Poluzioroviene E, Balmaks R,
Afanetti M, Bentsen G, Bartkowska-Sniatkowska A, Camilo C, Simic D,
López-Fernández YM, Mattsson J, Özen H, Dmytriiev D, Manning JC, Tekgüç H.
Author information:
(1)Pediatric Intensive Care Unit, Department of Woman's and Child's Health,
University Hospital of Padua, Padua, Italy.
(2)Department of Pediatric Cardiology and Intensive Care Medicine, Hannover
Medical School, Hannover, Germany.
(3)Department of Pediatric and Adolescent Medicine, University Clinic Carl
Gustav Carus, Dresden, Germany.
(4)Institute of Higher Education and Research in Healthcare, Faculty of Biology
and Medicine, University of Lausanne, Lausanne, Switzerland.
[email protected].
(5)Department Woman-Mother-Child, Lausanne University Hospital, Lausanne,
Switzerland. [email protected].
(6)Department of Cardiology, Boston Children's Hospital, Harvard Medical School,
Boston, MA, USA.
(7)Institute of Pharmacology, First Faculty of Medicine, Charles University and
General University Hospital, Prague, Czech Republic.
(8)Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of
Medicine, Charles University and General University Hospital, Prague, Czech
Republic.
(9)Intensive Care and Department of Paediatric Surgery, Erasmus Medical Center
Sophia Children's Hospital, Rotterdam, The Netherlands.
(10)Department of Physiology and Pharmacology, Karolinska Institutet and
Karolinska University Hospital, Stockholm, Sweden.
(11)Pediatric Anesthesia and Intensive Care Unit, Department of Woman's and
Child's Health, IRCCS University Hospital of Bologna Policlinico S.Orsola,
Bologna, Italy.
(12)Department of Woman's and Child's Health, IRCCS University Hospital of
Bologna Policlinico S.Orsola, Bologna, Italy.
(13)Pediatric Intensive Care Unit, Department of Pediatric Surgery, • Erasmus MC
- Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam,
The Netherlands.
(#)Contributed equally
Erratum in
Crit Care. 2022 May 16;26(1):139. doi: 10.1186/s13054-022-03992-4.
BACKGROUND: Management and monitoring of pain and sedation to reduce discomfort
as well as side effects, such as over- and under-sedation, withdrawal syndrome
and delirium, is an integral part of pediatric intensive care practice. However,
the current state of management and monitoring of analgosedation across European
pediatric intensive care units (PICUs) remains unknown. The aim of this survey
was to describe current practices across European PICUs regarding the management
and monitoring of pain and sedation.
METHODS: An online survey was distributed among 357 European PICUs assessing
demographic features, drug choices and dosing, as well as usage of instruments
for monitoring pain and sedation. We also compared low- and high-volume PICUs
practices. Responses were collected from January to April 2021.
RESULTS: A total of 215 (60% response rate) PICUs from 27 European countries
responded. Seventy-one percent of PICUs stated to use protocols for
analgosedation management, more frequently in high-volume PICUs (77% vs 63%,
p = 0.028). First-choice drug combination was an opioid with a benzodiazepine,
namely fentanyl (51%) and midazolam (71%) being the preferred drugs. The
starting doses differed between PICUs from 0.1 to 5 mcg/kg/h for fentanyl, and
0.01 to 0.5 mg/kg/h for midazolam. Daily assessment and documentation for pain
(81%) and sedation (87%) was reported by most of the PICUs, using the preferred
validated FLACC scale (54%) and the COMFORT Behavioural scale (48%),
respectively. Both analgesia and sedation were mainly monitored by nurses (92%
and 84%, respectively). Eighty-six percent of the responding PICUs stated to use
neuromuscular blocking agents in some scenarios. Monitoring of paralysed
patients was preferably done by observation of vital signs with electronic
devices support.
CONCLUSIONS: This survey provides an overview of current analgosedation
practices among European PICUs. Drugs of choice, dosing and assessment
strategies were shown to differ widely. Further research and development of
evidence-based guidelines for optimal drug dosing and analgosedation assessment
are needed.
© 2022. The Author(s).
DOI: 10.1186/s13054-022-03957-7
PMCID: PMC8969245
PMID: 35361254 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/34599744
|
1. Eur Arch Paediatr Dent. 2022 Oct;23(5):777-785. doi:
10.1007/s40368-021-00669-4. Epub 2021 Oct 2.
Treatment time, pain experience and acceptability of the technique for caries
removal in primary teeth using the ART approach with or without Brix3000™ papain
gel: a preliminary randomised controlled clinical trial.
de Souza TF(1), Martins ML(1), Tavares-Silva CM(1), Fonseca-Gonçalves A(2), Maia
LC(3).
Author information:
(1)Faculty of Dentistry, Universidade Federal do Rio de Janeiro, Rio de Janeiro,
RJ, Brazil.
(2)Department of Pediatric Dentistry and Orthodontics, Faculty of Dentistry,
Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco, 325
Cidade Universitária, Rio de Janeiro, RJ, CEP 21941-617, Brazil.
(3)Department of Pediatric Dentistry and Orthodontics, Faculty of Dentistry,
Universidade Federal Do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco, 325
Cidade Universitária, Rio de Janeiro, RJ, CEP 21941-617, Brazil.
[email protected].
PURPOSE: To compare the Atraumatic Restorative Treatment (ART) associated with
Brix3000™ to ART considering treatment time, pain experienced, and acceptability
to children.
METHODS: This study was accepted in Research Ethics Committee in July 2019
(number 3469402). Healthy patients (n = 20) aged 3-9 years, with at least one
primary molar with occlusal dentine caries without cusp involvement were
randomly allocated to either the ART + Brix3000™ group or the ART-only group.
The sample was characterised by sex, age, tooth location and caries experience.
Time spent and pain experience scores were recorded at prophylaxis, caries
removal and restoration. The pain experience (intense, moderate, or mild) was
evaluated by the Face, Legs, Activity, Cry, Consolability-revised scale
(FLACC-r). Acceptability was assessed by a five-point hedonic facial scale
(dichotomised into 'like' and 'indifferent/dislike' bins) and by an
open-question interview. Mann-Whitney, Chi-square, and Fisher's exact tests were
applied to discern differences in time, pain/sample characterisation and
acceptability, respectively.
RESULTS: The ART + Brix3000™ group required 8.6 ± 3.1 min to remove caries
tissue, whereas the ART group required only 4.8 ± 2.0 min (p = 0.03). The total
time spent with treatments was 13.1 ± 4.0 min for ART + Brix3000™, and
9.8 ± 2.7 min for ART (p = 0.03). There was no difference in pain experience and
acceptability found among the groups (p > 0.05).
CONCLUSION: Although the ART + Brix3000™ technique demanded more treatment time
than the ART alone, there were no differences in either pain experience or
acceptability.
© 2021. European Academy of Paediatric Dentistry.
DOI: 10.1007/s40368-021-00669-4
PMCID: PMC8486961
PMID: 34599744 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that Brix3000™ was donated
for the study but any researcher have direct connection with the company
involved in the donation. Besides, the company did not interfere in the analysis
and results of this research.
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http://www.ncbi.nlm.nih.gov/pubmed/35426136
|
1. Clin Pharmacol Ther. 2022 Jun;111(6):1334-1342. doi: 10.1002/cpt.2592. Epub
2022 Apr 20.
Driving Performance after Bedtime Administration of Daridorexant, Assessed in a
Sensitive Simulator.
Muehlan C(1), Brooks S(2)(3), Vaillant C(4), Meinel M(5), Jacobs GE(2)(6),
Zuiker RG(2), Dingemanse J(1).
Author information:
(1)Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd., Allschwil,
Switzerland.
(2)Centre for Human Drug Research, Leiden, The Netherlands.
(3)Department of Anesthesiology, Erasmus University Medical Center, Rotterdam,
The Netherlands.
(4)Global Life Cycle Management, Idorsia Pharmaceuticals Ltd., Allschwil,
Switzerland.
(5)Department of Biometry, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.
(6)Department of Psychiatry, Leiden University Medical Center, Leiden, The
Netherlands.
Use of hypnotics is often associated with next-morning residual effects and a
higher risk of motor vehicle accidents. Measuring next-morning effects on
driving performance is therefore advised by regulatory agencies. Here, we
examined driving performance following administration of daridorexant, a new
dual orexin receptor antagonist developed to treat insomnia. Sixty healthy male
and female subjects (50-79 years of age) were randomized in a placebo- and
active-controlled, four-way cross-over study. Each subject received evening
administration of daridorexant 50 and 100 mg, zopiclone 7.5 mg, and placebo, in
separate treatment phases of 4 days. Simulated driving performance was assessed
after initial (day 2) and repeated dosing (day 5), 9 hours postdose. Standard
deviation of the lateral position (SDLP) was the main outcome. On both days,
with zopiclone, SDLP increased significantly compared with placebo, which
confirmed sensitivity of the simulator. With daridorexant, on day 2, the
placebo-corrected mean (97.5% confidence interval) SDLP increased by 2.19 cm
(0.46-3.93) and 4.43 cm (2.72-6.15) for 50 and 100 mg, respectively. On day 5,
SDLP values for both daridorexant doses were significantly below the
prespecified threshold of impairment (2.6 cm) and statistically not different
from placebo. Daridorexant showed a lower self-rated driving quality and higher
effort compared to placebo on day 2 but not on day 5. In non-insomnia subjects,
daridorexant impaired simulated driving after initial but not after repeated
dosing. Subjects should be cautioned about driving until they know how
daridorexant affects them.
© 2022 Idorsia Pharmaceuticals Ltd. Clinical Pharmacology & Therapeutics
published by Wiley Periodicals LLC on behalf of American Society for Clinical
Pharmacology and Therapeutics.
DOI: 10.1002/cpt.2592
PMCID: PMC9320895
PMID: 35426136 [Indexed for MEDLINE]
Conflict of interest statement: C.M., C.V., M.M., and J.D. are employees and
stockholders of Idorsia Pharmaceuticals Ltd. S.B., G.E.J., and R.G.Z. are
employees of CHDR that received financial compensation for the conduct of the
study.
|
http://www.ncbi.nlm.nih.gov/pubmed/36473030
|
1. Int Clin Psychopharmacol. 2023 Jan 1;38(1):57-65. doi:
10.1097/YIC.0000000000000425. Epub 2022 Nov 30.
Safety and efficacy of daridorexant in the treatment of insomnia: a systematic
review and meta-analysis of randomized controlled trials.
Albadrani MS(1), Albadrani MS(1), Fadlalmola HA(2), Elhusein AM(3), Abobaker
RM(4), Merghani MM(5), Gomaa SM(5), Abdalla AM(6), Alhujaily M(7), Omair AA(8),
Ali Abdalla AM(9), Masada HK(10), Veerabhadra Swamy DS(11), Al-Sayaghi KM(12).
Author information:
(1)Department of Family and Community Medicine, College of Medicine, Taibah
University, Madinah.
(2)Department of Community Health Nursing, Nursing college, Taibah University.
(3)College of Aapplied Medical Science, Nursing Department, University of Bisha,
Bisha.
(4)Gulf Collages, Hospitals and Health Services Administration Department, Hafer
Al-Batin Governorate.
(5)Nursing Department, College of Applied Medical Sciences, Hafr Al-Batin
University.
(6)Department of Community and Mental Health, College of Nursing, Najran
University, Najran.
(7)Department of Clinical Laboratory Sciences, College of Applied Medical
Sciences, University of Bisha.
(8)Director of Nursing - Senior Specialist, Psychiatric and Long Term Care
Hospital (PLTCH), Bisha.
(9)Assistant Professor Applied Medical College, Nursing Department Shaqra
University.
(10)Maternal and Child Health Nursing Department, Northern College of Nursing,
Riyadh, Saudi Arabia.
(11)College of Applied Medical Science, Nursing Department, University of Bisha,
Bisha.
(12)Department of Medical Surgical Nursing, College of Nursing, Taibah
University, Al-Madinah Al-Munawarah, Saudi Arabia.
Daridorexant is a novel dual orexin receptor antagonist used in treating
insomnia disorder. Daridorexant improves sleep quality without impairing daytime
functioning. We assess the safety and efficacy of this novel drug in the
treatment of insomnia. We performed a systematic search for electronic databases
in SCOPUS, PubMed, Web of Science and the Cochrane library. Seven randomized
controlled trials were included in this review, with 2425 participants enrolled.
Daridorexant was superior to placebo in reducing wake time after sleep onset
(MD = -13.26; 95% CI, -15.48 to -11.03; P < 0.00001), latency to persistent
sleep (MD = -7.23; 95% CI, -9.60 to -4.85; P < 0.00001), with increasing the
total sleep time (MD = 14.80; 95% CI, 11.18-18.42; P < 0.00001) and subjective
total sleep time (MD = 14.80; 95% CI, 11.18-18.42], P < 0.00001). The 25 mg and
50 mg were the most officious doses. Treatment with daridorexant has resulted in
a slightly higher incidence of adverse events [risk ratio (RR) = 1.19; 95% CI,
1.05-1.35;, P = 0.005], specifically somnolence (RR = 1.19; 95% CI, 1.13-3.23;
P = 0.005) and fatigue (RR = 2.01; 95% CI, 1.21-3.36; P = 0.007). Daridorexant
is superior to placebo in improving sleep quality. However, the drug resulted in
a slightly higher incidence of adverse events, including somnolence and fatigue.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/YIC.0000000000000425
PMID: 36473030 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/35306405
|
1. Sleep Med. 2022 Apr;92:4-11. doi: 10.1016/j.sleep.2021.11.015. Epub 2022 Feb
12.
Assessment of the effect of the dual orexin receptor antagonist daridorexant on
various indices of disease severity in patients with mild to moderate
obstructive sleep apnea.
Boof ML(1), Ufer M(2), Fietze I(3), Pépin JL(4), Guern AS(2), Lemoine V(2),
Dingemanse J(2).
Author information:
(1)Idorsia Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil,
Switzerland. Electronic address: [email protected].
(2)Idorsia Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil,
Switzerland.
(3)Advanced Sleep Research, Berlin, Germany.
(4)HP2 Laboratory, INSERM U1042, Grenoble Alpes University Hospital and EFCR
Laboratory, Thorax and Vessels Division, Grenoble, France.
BACKGROUND: The dual orexin receptor antagonist daridorexant did not impact
nighttime respiratory function as assessed by the apnea/hypopnea index (AHI) and
nocturnal oxygen saturation (SpO2) and improved sleep in patients with mild to
moderate obstructive sleep apnea (OSA). These analyses were supplemented with
further evaluations of various indices of OSA severity and sleep variables.
METHODS: In this randomized, double-blind, placebo-controlled, two-period,
crossover study, 50 mg daridorexant or placebo was administered every evening
for 5 days to 28 patients with mild to moderate OSA. Treatment differences
(daridorexant - placebo) were explored for indices of OSA severity including the
number and duration of apneas and hypopneas, mean and lowest nocturnal SpO2,
sleep duration during each hour of polysomnography recording, and the number and
mean and longest duration of awakenings.
RESULTS: After repeated-dose daridorexant, more respiratory events were observed
compared to placebo, ie., treatment difference of 16.4 events (90% confidence
interval: -0.4, 33.2) which is explained by a longer total sleep time. However,
no treatment difference was detected for the longest duration of apneas and
hypopneas (1.5 s [-8.3, 11.2] and 8.2 s [-6.6, 23.0], respectively), and lowest
SpO2 (0.9% [-0.3, 2.1]). The number of awakenings was similar between
daridorexant and placebo while daridorexant shortened the longest duration by
16.2 min (8.5, 23.8). Overall, results were similar after single and repeated
dosing for both respiratory and sleep aspects.
CONCLUSION: These results suggest safe use of daridorexant in patients with mild
to moderate OSA.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03765294. A study to
investigate the effects of ACT-541468 on nighttime respiratory function in
patients with mild to moderate obstructive sleep apnea.
https://clinicaltrials.gov/ct2/show/NCT03765294.
Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
DOI: 10.1016/j.sleep.2021.11.015
PMID: 35306405 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/35298826
|
1. Drugs. 2022 Apr;82(5):601-607. doi: 10.1007/s40265-022-01699-y.
Daridorexant: First Approval.
Markham A(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. [email protected].
Erratum in
Drugs. 2022 May;82(7):841. doi: 10.1007/s40265-022-01719-x.
Daridorexant (Quviviq™; Idorsia Pharmaceuticals Ltd.) is an orally administered
dual orexin type 1 and type 2 (OX1 and OX2) receptor antagonist (DORA) being
developed for the treatment of insomnia. It was selected from a pool of drug
candidates on the basis of an expected effect duration of ≈ 8 h at a dose of
25 mg, with a half-life intended to minimize residual effects that might impair
daytime functioning. Based on the results of two pivotal phase III trials,
daridorexant was recently approved in the USA for the treatment of adult
patients with insomnia characterized by difficulties with sleep onset and/or
sleep maintenance. This article summarizes the milestones in the development of
daridorexant leading to this first approval.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01699-y
PMCID: PMC9042981
PMID: 35298826 [Indexed for MEDLINE]
Conflict of interest statement: During the peer review process the manufacturer
of the agent under review was offered an opportunity to comment on the article.
Changes resulting from any comments received were made by the authors on the
basis of scientific completeness and accuracy. A. Markham is a salaried employee
of Adis International Ltd/Springer Nature, and declares no relevant conflicts of
interest. All authors contributed to the review and are responsible for the
article content.
|
http://www.ncbi.nlm.nih.gov/pubmed/35266155
|
1. Aliment Pharmacol Ther. 2022 Apr;55(8):1028-1037. doi: 10.1111/apt.16836. Epub
2022 Mar 9.
A novel phenotype-based drug-induced liver injury causality assessment tool
(DILI-CAT) allows for signal confirmation in early drug development.
Hermann RP(1), Rockey DC(2), Suzuki A(3)(4), Merz M(5), Tillmann HL(6)(7).
Author information:
(1)AstraZeneca, Gaithersburg, Maryland, USA.
(2)Digestive Disease Research Center, Medical University South Carolina,
Charleston, South Carolina, USA.
(3)Duke University Medical Center, Durham, North Carolina, USA.
(4)Durham VA Medical Center, Durham, North Carolina, USA.
(5)AstraZeneca, Freiburg, Germany.
(6)Division of Gastroenterology, Hepatology & Nutrition, East Carolina
University, Greenville, North Carolina, USA.
(7)Greenville VA Health Care Center, Greenville, North Carolina, USA.
BACKGROUND: Drug-induced liver injury (DILI) requires accurate case
adjudication, with expert opinion being the current best practice.
AIM: We utilised a novel DILI causality assessment tool (DILI-CAT), which uses
drug-specific liver injury phenotypes, to examine potential DILI in early phase
ximelagatran clinical development.
METHODS: We conducted a retrospective analysis of liver injury events from four
Stroke Prevention using an ORal Thrombin Inhibitor in Atrial Fibrillation
(SPORTIF) trials, in which patients were randomised to receive oral ximelagatran
or adjusted-dose warfarin. A stepwise process was used with iterative
adjustments. The DILI phenotype was characterised by latency, R-value, and
AST/ALT ratio. A scoring algorithm was applied to liver events to assess how
closely the liver events matched the Interquatile-Range for the working
phenotype for each of the three parameters.
FINDINGS: Data from 3115 patients included in the SPORTIF trials as above were
available. The initial ximelagatran phenotype was developed based on five liver
injury cases from the ximelagatran arm and was then validated against an
additional eight cases (5 ximelagatran, 3 warfarin); in these eight cases, there
was a statistically significant difference in the total DILI-CAT scores of the
two drugs (p = 0.016) between ximelagatran and warfarin. Together, these ten
ximelagatran cases generated a second, refined ximelagatran phenotype, which was
validated against an additional 75 cases (53 ximelagatran/22 warfarin)-again
with statistically significant different DILI-CAT ximelagatran vs. warfarin
scores (p < 0.001).
CONCLUSION: DILI-CAT, a clinically intuitive, data-driven, computer-assisted
scoring algorithm, is a useful tool for early detection of drug's hepatotoxicity
in clinical drug development.
© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John
Wiley & Sons Ltd.
DOI: 10.1111/apt.16836
PMCID: PMC9164935
PMID: 35266155 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/36174069
|
1. PLoS One. 2022 Sep 29;17(9):e0271304. doi: 10.1371/journal.pone.0271304.
eCollection 2022.
A novel quantitative computer-assisted drug-induced liver injury causality
assessment tool (DILI-CAT).
Tillmann HL(1)(2), Suzuki A(3)(4), Merz M(5), Hermann R(6), Rockey DC(7).
Author information:
(1)Division of Gastroenterology, Hepatology & Nutrition, East Carolina
University, Greenville, NC, United States of America.
(2)Greenville VA Health Care Center, Greenville, NC, United States of America.
(3)Duke University Medical Center, Durham, NC, United States of America.
(4)Durham VA Medical Center, Durham, NC, United States of America.
(5)AstraZeneca, independent consultant, Freiburg, Germany.
(6)AstraZeneca, Gaithersburg, MD, United States of America.
(7)Digestive Disease Research Center, Medical University South Carolina,
Charleston, SC, United States of America.
BACKGROUND AND AIMS: We hypothesized that a drug's clinical signature (or
phenotype) of liver injury can be assessed and used to quantitatively develop a
computer-assisted DILI causality assessment-tool (DILI-CAT). Therefore, we
evaluated drug-specific DILI-phenotypes for amoxicillin-clavulanate (AMX/CLA),
cefazolin, cyproterone, and Polygonum multiflorum using data from published case
series, to develop DILI-CAT scores for each drug.
METHODS: Drug specific phenotypes were made up of the following three clinical
features: (1) latency, (2) R-value, and (3) AST/ALT ratio. A point allocation
system was developed with points allocated depending on the variance from the
norm (or "core") for the 3 variables in published datasets.
RESULTS: The four drugs had significantly different phenotypes based on latency,
R-value, and AST/ALT ratio. The median cyproterone latency was 150 days versus <
43 days for the other three drugs (median: 26 for AMX/CLA, 20 for cefazolin, and
20 for Polygonum multiflorum; p<0.001). The R-value for the four drugs was also
significantly different among drugs (cyproterone [median 12.4] and Polygonum
multiflorum [median 10.9]) from AMX/CLA [median 1.44] and cefazolin [median
1.57; p<0.001]). DILI-CAT scores effectively separated cyproterone and Polygonum
multiflorum from AMX/CLA and cefazolin, respectively (p<0.001). As expected,
because of phenotypic overlap, AMX/CLA and cefazolin could not be well
differentiated.
CONCLUSIONS: DILI-CAT is a data-driven, diagnostic tool built to define
drug-specific phenotypes for DILI adjudication. The data provide proof of
principle that a drug-specific, data-driven causality assessment tool can be
developed for different drugs and raise the possibility that such a process
could enhance causality assessment methods.
DOI: 10.1371/journal.pone.0271304
PMCID: PMC9521919
PMID: 36174069 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/35186791
|
1. Front Cell Infect Microbiol. 2022 Feb 2;12:804175. doi:
10.3389/fcimb.2022.804175. eCollection 2022.
Isolation of SARS-CoV-2 in Viral Cell Culture in Immunocompromised Patients With
Persistently Positive RT-PCR Results.
Sung A(1), Bailey AL(1), Stewart HB(1), McDonald D(1), Wallace MA(2), Peacock
K(1), Miller C(1), Reske KA(1), O'Neil CA(1), Fraser VJ(1), Diamond MS(1)(2)(3),
Burnham CD(2)(3)(4), Babcock HM(1), Kwon JH(1).
Author information:
(1)Department of Medicine, Division of Infectious Diseases, Washington
University School of Medicine in St. Louis, St. Louis, MO, United States.
(2)Department of Pathology and Immunology, Washington University School of
Medicine in St. Louis, St. Louis, MO, United States.
(3)Department of Molecular Microbiology, Washington University School of
Medicine in St. Louis, St. Louis, MO, United States.
(4)Departments of Medicine and Pediatrics, Washington University School of
Medicine in St. Louis, St. Louis, MO, United States.
Immunocompromised adults can have prolonged acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) positive RT-PCR results, long after the initial
diagnosis of coronavirus disease 2019 (COVID-19). This study aimed to determine
if SARS-CoV-2 virus can be recovered in viral cell culture from
immunocompromised adults with persistently positive SARS-CoV-2 RT-PCR tests. We
obtained 20 remnant SARS-CoV-2 PCR positive nasopharyngeal swabs from 20
immunocompromised adults with a positive RT-PCR test ≥14 days after the initial
positive test. The patients' 2nd test samples underwent SARS-CoV-2 antigen
testing, and culture with Vero-hACE2-TMPRSS2 cells. Viral RNA and cultivable
virus were recovered from the cultured cells after qRT-PCR and plaque assays. Of
20 patients, 10 (50%) had a solid organ transplant and 5 (25%) had a hematologic
malignancy. For most patients, RT-PCR Ct values increased over time. There were
2 patients with positive viral cell cultures; one patient had chronic
lymphocytic leukemia treated with venetoclax and obinutuzumab who had a low
viral titer of 27 PFU/mL. The second patient had marginal zone lymphoma treated
with bendamustine and rituximab who had a high viral titer of 2 x 106 PFU/mL.
Most samples collected ≥7 days after an initial positive SARS-CoV-2 RT-PCR had
negative viral cell cultures. The 2 patients with positive viral cell cultures
had hematologic malignancies treated with chemotherapy and B cell depleting
therapy. One patient had a high concentration titer of cultivable virus. Further
data are needed to determine risk factors for persistent viral shedding and
methods to prevent SARS-CoV-2 transmission from immunocompromised hosts.
Copyright © 2022 Sung, Bailey, Stewart, McDonald, Wallace, Peacock, Miller,
Reske, O’Neil, Fraser, Diamond, Burnham, Babcock and Kwon.
DOI: 10.3389/fcimb.2022.804175
PMCID: PMC8847756
PMID: 35186791 [Indexed for MEDLINE]
Conflict of interest statement: MD is a consultant for Inbios, Vir
Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards
of Moderna and Immunome. The Diamond laboratory has received funding support in
sponsored research agreements from Moderna, Vir Biotechnology, and Emergent
BioSolutions. The remaining authors declare that the research was conducted in
the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
|
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