question
stringlengths 13
215
| ground_truth
stringlengths 2
3.15k
| context
stringlengths 0
157k
|
|---|---|---|
Is NfL (neurofilament light chain) a biomarker of neurodegeneration? | Yes,
Neurofilament light chain (NfL) has recently been proposed as a promising biomarker in frontotemporal dementia (FTD). | Frontotemporal dementia (FTD) is the second most frequent dementia, after
Alzheimer's, in patients under the age of 65. It encompasses clinical entities
characterized by behavioral, language, and executive control dysfunction.
Neurofilament light chain (NfL) is a new, non-disease specific, widely studied
biomarker indicative of axonal injury and degeneration. Various studies have
previously explored the role of NfL in the diagnostic process, monitoring, and
prognosis of dementia. The current systematic review and meta-analysis include
all the available data concerning the role of NfL in frontotemporal dementia and
its use as a potential biomarker in differentiating patients with FTD from (a)
healthy individuals, (b) Alzheimer's dementia, (c) Dementia with Lewy bodies,
(d) Motor Neuron disease, (e) Parkinsonian syndromes, and (f) psychiatric
disorders. We also analyze the utility of NfL in distinguishing specific FTD
subgroups. Neurofilament light chain has a potential role in differentiating
patients with frontotemporal dementia from healthy controls, patients with
Alzheimer's dementia, and psychiatric disorders. Higher NfL levels were also
noted in patients with semantic primary progressive aphasia (PPA) when compared
with behavioral FTD and non-fluent PPA patients. Further studies exploring the
use of NfL in frontotemporal dementia are needed. BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) has recently been
proposed as a promising biomarker in frontotemporal dementia (FTD). We
investigated the correlation of both cerebrospinal fluid (CSF) and serum NfL
with detailed neuropsychological data and cognitive decline in a cohort of
sporadic and familial FTD.
METHODS: CSF and serum NfL, as well as conventional CSF Alzheimer's disease (AD)
biomarkers (Aβ42, t-Tau, p-Tau181), were determined in 63 FTD patients (30
sporadic-FTD, 20 with progranulin (GRN) mutations [FTD-GRN], 13 with chromosome
9 open reading frame 72 [C9orf72] expansions [C9orf72-FTD]), 37 AD patients, and
31 neurologic controls. Serum NfL was also quantified in 37 healthy individuals.
Correlations between baseline CSF and serum NfL levels, standardized
neuropsychological tests, and the rate of cognitive decline in FTD patients were
assessed.
RESULTS: CSF and serum NfL presented with significantly higher levels in FTD
than in AD patients and both control groups. Within FTD subtypes, genetic cases,
and particularly FTD-GRN, had higher CSF and serum NfL levels. Significant
correlations between NfL levels and overall cognitive function, abstract
reasoning (CSF and serum), executive functions, memory, and language (serum)
were found. A relationship between increased baseline CSF and serum NfL and a
decay in cognitive performance over time was also observed.
CONCLUSIONS: Our findings highlight the potential of serum NfL as a useful
surrogate end point of disease severity in upcoming targeted treatments. BACKGROUND: Neurofilament light chain protein (NfL) is a promising biomarker of
neurodegeneration.
OBJECTIVES: To determine whether plasma and CSF NfL (1) associate with motor or
cognitive status in Parkinson's disease (PD) and (2) predict future motor or
cognitive decline in PD.
METHODS: Six hundred and fifteen participants with neurodegenerative diseases,
including 152 PD and 200 healthy control participants, provided a plasma and/or
cerebrospinal fluid (CSF) NfL sample. Diagnostic groups were compared using the
Kruskal-Wallis rank test. Within PD, cross-sectional associations between NfL
and Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and Mattis
Dementia Rating Scale (DRS-2) scores were assessed by linear regression;
longitudinal analyses were performed using linear mixed-effects models and Cox
regression.
RESULTS: Plasma and CSF NfL levels correlated substantially (Spearman r = 0.64,
P < 0.001); NfL was highest in neurocognitive disorders. PD participants with
high plasma NfL were more likely to develop incident cognitive impairment (HR
5.34, P = 0.005).
CONCLUSIONS: Plasma NfL is a useful prognostic biomarker for PD, predicting
clinical conversion to mild cognitive impairment or dementia. © 2021
International Parkinson and Movement Disorder Society. BACKGROUND: No comprehensive meta-analysis has ever been performed to assess the
value of neurofilament light chain (NfL) as a biomarker in genetic ataxia.
OBJECTIVE: We conducted a meta-analysis to summarize NfL concentration and
evaluate its utility as a biomarker in genetic ataxia.
METHODS: Studies were included if they reported NfL concentration of genetic
ataxia. We used log (mean ± SD) NfL to describe mean raw value of NfL. The
effect size of NfL between genetic ataxia and healthy controls (HC) was
expressed by mean difference. Correlation between NfL and disease severity was
calculated.
RESULTS: We identified 11 studies of 624 HC and 1006 patients, here referred to
as spinocerebellar ataxia (SCA1, 2, 3, 6, and 7), Friedreich ataxia (FRDA), and
ataxia telangiectasia (A-T). The concentration of blood NfL (bNfL) elevated with
proximity to expected onset, and progressively increased from asymptomatic to
preclinical to clinical stage in SCA3. Compared with HC, bNfL levels were
significantly higher in SCA1, 2, 3, and 7, FRDA, as well as A-T, and the
difference increased with the advancing disease in SCA3. bNfL levels correlated
with disease severity in SCA3. There was a significant correlation between bNfL
and longitudinal progression in SCA3. Additionally, bNfL increased with age in
HC, yet this is probably masked by higher disease-related effects on bNfL in
genetic ataxia.
CONCLUSIONS: bNfL can be used as a potential biomarker to predict disease onset,
severity, and progression of genetic ataxia. Reference-value setting of bNfL
should be divided according to age. © 2021 International Parkinson and Movement
Disorder Society. Author information:
(1)From the Barcelonaβeta Brain Research Center (BBRC) (M.M.-A., M.S., G.O.,
G.S., C.F., J.D.G., N.V.-T., E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E.,
C.M., K.F., J.L.M., M.S.-C.), Pasqual Maragall Foundation; IMIM (Hospital del
Mar Medical Research Institute) (M.M.-A., M.S., G.O., G.S., C.F., J.D.G.,
E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E., C.M., M.S.-C.), Barcelona;
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento
Saludable (CIBERFES) (M.M.-A., G.O., E.M.A.-U., O.G.-R., G.S.-B., C.M., K.F.,
M.S.-C.), Madrid; Universitat Pompeu Fabra (M.M.-A., M.S.), Barcelona, Spain;
Department of Psychiatry and Neurochemistry (A.B., N.J.A., H.K., H.Z., K.B.),
Institute of Neuroscience and Physiology, University of Gothenburg; Clinical
Neurochemistry Laboratory (A.B., H.K., H.Z., K.B.), Sahlgrenska University
Hospital, Mölndal; Wallenberg Centre for Molecular and Translational Medicine
(A.B., N.J.A., H.K.), Department of Psychiatry and Neurochemistry, Institute of
Neuroscience and Physiology, the Sahlgrenska Academy at the University of
Gothenburg, Sweden; King's College London (N.J.A.), Institute of Psychiatry,
Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute; NIHR
Biomedical Research Centre for Mental Health & Biomedical Research Unit for
Dementia at South London & Maudsley NHS Foundation (N.J.A.), London, UK; Centro
de Investigación Biomédica en Red de Bioingeniería (C.F., J.D.G., A.N.-B.,
A.P.), Biomateriales y Nanomedicina (CIBER-BBN), Madrid; Centre for Genomic
Regulation (CRG) (N.V.-T.), Barcelona Institute for Science and Technology;
Department of Clinical Genetics (N.V.-T.), Erasmus MC, University Medical Center
Rotterdam, the Netherlands; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital
del Mar; Servei de Medicina Nuclear (A.N.-B., A.P.), Hospital Clínic, Barcelona,
Spain; Roche Diagnostics GmbH (G.K.), Penzberg, Germany; Roche Diagnostics
International Ltd (I.S.), Rotkreuz, Switzerland; UK Dementia Research Institute
at UCL (H.Z.), London; Department of Neurodegenerative Disease (H.Z.), UCL Queen
Square Institute of Neurology, London, UK; and H. Lundbeck A/S (J.L.M.),
Copenhagen, Denmark.
(2)From the Barcelonaβeta Brain Research Center (BBRC) (M.M.-A., M.S., G.O.,
G.S., C.F., J.D.G., N.V.-T., E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E.,
C.M., K.F., J.L.M., M.S.-C.), Pasqual Maragall Foundation; IMIM (Hospital del
Mar Medical Research Institute) (M.M.-A., M.S., G.O., G.S., C.F., J.D.G.,
E.M.A.-U., O.G.-R., A.S.-V., G.S.-B., J.M.G.-d-E., C.M., M.S.-C.), Barcelona;
Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento
Saludable (CIBERFES) (M.M.-A., G.O., E.M.A.-U., O.G.-R., G.S.-B., C.M., K.F.,
M.S.-C.), Madrid; Universitat Pompeu Fabra (M.M.-A., M.S.), Barcelona, Spain;
Department of Psychiatry and Neurochemistry (A.B., N.J.A., H.K., H.Z., K.B.),
Institute of Neuroscience and Physiology, University of Gothenburg; Clinical
Neurochemistry Laboratory (A.B., H.K., H.Z., K.B.), Sahlgrenska University
Hospital, Mölndal; Wallenberg Centre for Molecular and Translational Medicine
(A.B., N.J.A., H.K.), Department of Psychiatry and Neurochemistry, Institute of
Neuroscience and Physiology, the Sahlgrenska Academy at the University of
Gothenburg, Sweden; King's College London (N.J.A.), Institute of Psychiatry,
Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute; NIHR
Biomedical Research Centre for Mental Health & Biomedical Research Unit for
Dementia at South London & Maudsley NHS Foundation (N.J.A.), London, UK; Centro
de Investigación Biomédica en Red de Bioingeniería (C.F., J.D.G., A.N.-B.,
A.P.), Biomateriales y Nanomedicina (CIBER-BBN), Madrid; Centre for Genomic
Regulation (CRG) (N.V.-T.), Barcelona Institute for Science and Technology;
Department of Clinical Genetics (N.V.-T.), Erasmus MC, University Medical Center
Rotterdam, the Netherlands; Servei de Neurologia (O.G.-R., M.S.-C.), Hospital
del Mar; Servei de Medicina Nuclear (A.N.-B., A.P.), Hospital Clínic, Barcelona,
Spain; Roche Diagnostics GmbH (G.K.), Penzberg, Germany; Roche Diagnostics
International Ltd (I.S.), Rotkreuz, Switzerland; UK Dementia Research Institute
at UCL (H.Z.), London; Department of Neurodegenerative Disease (H.Z.), UCL Queen
Square Institute of Neurology, London, UK; and H. Lundbeck A/S (J.L.M.),
Copenhagen, Denmark. [email protected]. |
Is Epistaxis associated with dental implant placement? | Epistaxis is a frequent complication associated with dental implant placement. | BACKGROUND: To assess the survival rate of implants placed in the posterior
maxilla by intentionally perforating the Schneiderian membrane and protruding
the implant up to 3mm beyond the sinus floor in cases of reduced crestal bone
height (CBH).
MATERIALS & METHODS: 56 patients with reduced CBH received 63 implants in the
posterior maxilla. All implants intentionally penetrated the Schneiderian
membrane and engaged the sinus floor cortical bone. All patients were followed
up and implant survival was assessed at the end of one year post implant
restoration.
RESULTS: Out of 63 implants, there was only one failure (98.4% Survival rate)
after a follow up period of one year. 7 patients experienced mild epistaxis
during the immediate post-operative period with no associated implant loss. One
patient developed sinusitis secondary to the surgical procedure, which was
treated by antibiotic therapy and the patient improved clinically with no
associated implant loss.
CONCLUSION: An intentional perforation of the Schneiderian membrane using a 2mm
twist drill at the time of implant placement and protrusion of the implant up to
3mm beyond the sinus floor does not alter the stability and outcome of dental
implants, one year post-restoration. This could be associated with minor
complications ranging from epistaxis to sinusitis, which are manageable. How to
cite this article: Nooh N. Effect of Schneiderian Membrane Perforation on
Posterior Maxillary Implant Survival. J Int Oral Health 2013; 5(3):28-34. BACKGROUND: After tooth loss, the posterior maxilla is usually characterized by
limited bone height secondary to pneumatization of the maxillary sinus and/or
collapse of the alveolar ridge that preclude in many instances the installation
of dental implants. In order to compensate for the lack of bone height, several
treatment options have been proposed. These treatment alternatives aimed at the
installation of dental implants with or without the utilization of bone grafting
materials avoiding the perforation of the Schneiderian membrane. Nevertheless,
membrane perforations represent the most common complication among these
procedures. Consequently, the present review aimed at the elucidation of the
relevance of this phenomenon on implant survival and complications.
MATERIAL AND METHODS: Electronic and manual literature searches were performed
by two independent reviewers in several databases, including MEDLINE, EMBASE,
and Cochrane Oral Health Group Trials Register, for articles up to January 2018
reporting outcome of implant placement perforating the sinus floor without
regenerative procedure (lateral sinus lift or transalveolar technique) and graft
material. The intrusion of the implants can occur during drilling or implant
placement, with and without punch out Schneiderian. Only studies with at least
6 months of follow-up were included in the qualitative assessment.
RESULTS: Eight studies provided information on the survival rate, with a global
sample of 493 implants, being the weighted mean survival rate 95.6% (IC 95%),
after 52.7 months of follow-up. The level of implant penetration (≤ 4 mm or
> 4 mm) did not report statistically significant differences in survival rate
(p = 0.403). Seven studies provided information on the rate of clinical
complications, being the mean complication rate 3.4% (IC 95%). The most frequent
clinical complication was epistaxis, without finding significant differences
according to the level of penetration. Five studies provide information on the
radiographic complication; the most common complication was thickening of the
Schneiderian membrane. The weighted complication rate was 14.8% (IC 95%), and
penetration level affects the rate of radiological complications, being these of
5.29% in implant penetrating ≤4 mm and 29.3% in implant penetrating > 4 mm,
without reaching statistical significant difference (p = 0.301).
CONCLUSION: The overall survival rate of the implants into the sinus cavity was
95.6%, without statistical differences according to the level of penetration.
The clinical and radiological complications were 3.4% and 14.8% respectively.
The most frequent clinical complication was the epistaxis, and the radiological
complication was thickening of the Schneiderian membrane, without reaching
statistical significant difference according to the level of implant penetration
inside the sinus. |
What is the effect of grapefruit juice on CYP3A4? | Grapefruit juice inhibits CYP3A4 activity. | |
Which is the major clinical feature observed in FDXR-associated disease? | FDXR-associated disease is a phenotypically heterogeneous disorder with retinal dystrophy being a major clinical feature observed in this cohort. | |
Is Daprodustat effective for anemia? | Yes. Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor for the treatment of anemia of chronic kidney disease. | BACKGROUND: Daprodustat (GSK1278863) is an oral hypoxia-inducible factor prolyl
hydroxylase inhibitor being developed for treatment of anemia associated with
chronic kidney disease (CKD). The effect of daprodustat in Japanese CKD patients
with anemia has not been previously investigated.
METHODS: We evaluated the relationship between daprodustat dose and hemoglobin
response in Japanese patients on hemodialysis (HD) with anemia in a 4-week,
phase II, double-blind, placebo-controlled study. After interrupting their
erythropoiesis-stimulating agent for between 2 and 8 weeks, subjects with
hemoglobin 8.5-10.5 g/dL were randomized to placebo or daprodustat 4, 6, 8, or
10 mg orally once daily. Hemoglobin, erythropoietin (EPO), and vascular
endothelial growth factor (VEGF) levels during therapy were evaluated.
RESULTS: Eighty-six of 97 randomized subjects completed the study. Mean baseline
hemoglobin ranged from 9.68 to 9.92 g/dL across groups. After 4-week
administration, mean hemoglobin changes were -0.28, -0.01, 0.54, and 0.97 g/dL
in the 4, 6, 8, and 10 mg groups, respectively, as compared to -1.41 g/dL for
placebo. Dose-dependent increase in plasma EPO concentration were observed up to
8 mg, with the 10 mg dose responses being similar to 8 mg. Plasma VEGF
concentrations were minimally changed, even though 5 subjects treated with 6-10
mg reached EPO >500 mIU/mL.
CONCLUSION: Daprodustat 4-10 mg once-daily produced dose-dependent increase in
hemoglobin relative to placebo in Japanese HD subjects. The doses evaluated in
the study have moderately increased endogenous EPO without changes in
circulating VEGF levels. Daprodustat (GSK1278863) is a hypoxia-inducible factor (HIF)-prolyl hydroxylase
(PHD) inhibitor in development for treatment of anemia of chronic kidney
disease. Daprodustat's biological activity simulates components of the natural
response to hypoxia; inhibition of PHDs results in HIF stabilization and
modulation of HIF-controlled gene products, including erythropoietin. The
carcinogenic potential of daprodustat was evaluated in 2-year carcinogenicity
studies in Sprague-Dawley rats and CD-1 mice, where once-daily doses were
administered. The mouse study also included evaluation of daprodustat's 3 major
circulating human metabolites. There were no neoplastic findings that were
considered treatment related in either study. Exaggerated pharmacology resulted
in significantly increased red cell mass and subsequent multiorgan congestion
and secondary non-neoplastic effects in both species, similar to those observed
in chronic toxicity studies. In rats, these included aortic thrombosis and an
exacerbation of spontaneous rodent cardiomyopathy, which contributed to a
statistically significant decrease in survival in high-dose males (group
terminated in week 94). Survival was not impacted in mice at any dose. Systemic
exposures (area under the plasma concentration-time curve) to daprodustat at the
high doses in rats and mice exceed predicted maximal human clinical exposure by
≥143-fold. These results suggest that daprodustat and metabolites do not pose a
carcinogenic risk at clinical doses. Daprodustat is a prolyl hydroxylase inhibitor that stimulates erythropoiesis in
a manner similar to the natural response to hypoxia, whereby inhibition of
hypoxia inducible factor (HIF) prolyl-4-hydroxylases by daprodustat ultimately
results in increased levels of HIF-responsive genes. Daprodustat is under
development as an emerging new class of agents for the treatment of anemia
associated with chronic kidney disease (CKD). This was a single-center,
single-dose, open-label, randomized, 2-way crossover study in healthy Japanese
male participants consisting of 2 parts. The primary objective was to evaluate
the bioequivalence (BE) between daprodustat tablet strengths (part 1) and to
evaluate the food effect on the pharmacokinetics (PK) of daprodustat (part 2). A
total of 64 healthy Japanese male participants were enrolled; 52 participants
were included in part 1 and 12 in part 2. BE was demonstrated between the
daprodustat 2-mg tablet and the daprodustat 4-mg tablet. A standard CKD meal did
not have a large effect on the PK parameters of daprodustat after a single oral
dose of daprodustat 4 mg. Administration of single oral doses of daprodustat 4
mg was generally well tolerated in the healthy Japanese participants, and no new
safety signals were identified without regard to food. BACKGROUND: Daprodustat is an oral agent that stimulates erythropoiesis by
inhibiting the prolyl hydroxylases which mark hypoxia-inducible factor for
degradation through hydroxylation. Its safety and efficacy (noninferiority) were
assessed in this 52-week, open-label study.
METHODS: Japanese patients not on dialysis (ND) (N = 299) with anemia of CKD
(stages G3, G4, and G5) with iron parameters of ferritin >100 ng/mL or
transferrin saturation >20% at screening were randomized to daprodustat or
epoetin beta pegol (continuous erythropoietin receptor activator [CERA], also
known as methoxy polyethylene glycol-epoetin beta). After initiation of the
study, the daprodustat starting dose for erythropoiesis-stimulating agent
(ESA)-naïve participants was revised, and daprodustat was started at 2 or 4 mg
once daily depending on baseline hemoglobin. ESA users switched to daprodustat 4
mg once daily. CERA was started at 25 μg every 2 weeks for ESA-naïve patients
and 25-250 μg every 4 weeks for ESA users based on previous ESA dose. In both
treatment groups, dose was adjusted every 4 weeks based on hemoglobin level and
changed according to a prespecified algorithm. The primary endpoint was mean
hemoglobin level during weeks 40-52 in the intention-to-treat (ITT) population.
ESA-naïve patients who entered before the protocol amendment revising the
daprodustat starting dose were excluded from the ITT population.
RESULTS: Mean hemoglobin levels during weeks 40-52 were 12.0 g/dL in the
daprodustat group (n = 108; 95% confidence interval [CI], 11.8-12.1) and 11.9
g/dL for CERA (n = 109; 95% CI 11.7-12.0); the difference between the groups was
0.1 g/dL (95% CI -0.1 to 0.3 g/dL). The lower limit of the 95% CI of the
difference was greater than the prespecified margin of -1.0 g/dL. The mean
hemoglobin level was within the target range (11.0-13.0 g/dL) during weeks 40-52
for 92% of participants in both groups. There was no meaningful difference in
the frequencies of adverse events.
CONCLUSIONS: Oral daprodustat was noninferior to CERA in achieving and
maintaining target hemoglobin levels in Japanese ND patients. Daprodustat was
well tolerated, with no new safety concerns identified. Objective: Daprodustat is a novel oral agent in treating anemia of chronic
kidney disease (CKD), and several clinical trials have been conducted to compare
daprodustat with recombit human erythropoietin (rhEPO) or placebo. Our
systematic review aimed to investigate the efficacy and safety of daprodustat
for anemia treatment in both dialysis-dependent (DD) and non-dialysis-dependent
(NDD) patients. Methods: Six databases were searched for randomized controlled
trials (RCTs) reporting daprodustat vs. rhEPO or placebo for anemia patients in
CKD. The outcome indicators were focused on hemoglobin (Hb), ferritin,
transferrin saturation (TSAT), total iron-binding capacity (TIBC), vascular
endothelial growth factor (VEGF), and serious adverse events (SAEs). Results:
Eight eligible studies with 1,516 participants were included. For both NDD and
DD patients, changes in Hb levels from baseline were significantly higher in
daprodustat group than that in the placebo (mean difference (MD) = 1.73, [95%
confidence interval (CI), 0.34 to 3.12], p = 0.01; MD = 1.88, [95% CI, 0.68 to
3.09], p = 0.002; respectively), and there was no significant difference between
daprodustat and rhEPO group (MD = 0.05, [95% CI, -0.49 to 0.59], p = 0.86; MD =
0.12, [95% CI, -0.28 to 0.52], p = 0.55; respectively). The indexes of iron
metabolism were improved significantly in the daprodustat group compared to
placebo- or rhEPO-treated patients, while there was no similar change in terms
of TSAT for DD patients. Furthermore, no trend of increasing plasma VEGF was
observed in daprodustat-treated subjects. As for safety, there was no
significant difference in the incidence of SAEs between daprodustat and placebo
treatment, while the incidence of SAEs in the daprodustat group was
significantly lower than that in the rhEPO group. Conclusion: Daprodustat was
efficacious and well tolerated for anemia in both NDD and DD patients in the
short term based on current RCTs. And daprodustat may become an effective
alternative for treatment of anemia with CKD. Since the application of
daprodustat is still under exploration, future researches should consider the
limitations of our study to evaluate the value of daprodustat. Anemia is a major complication of chronic kidney disease (CKD), which mainly
results from appropriate erythropoietin production impairment. Prolyl
hydroxylase domain (PHD) inhibitors are currently being developed and approved
in some countries as a new treatment for CKD patients with anemia due to the
stabilization of intracellular hypoxia-inducible factor (HIF) 1α and HIF2α by
PHD inhibition. Daprodustat is one of the orally administrated small-molecule
HIF-PH inhibitors, leading to an increase in erythropoietin production, which is
regulated by HIF. Also, daprodustat is expected to improve iron metabolism.
Recently, several clinical trials showed its efficacy and safety in both
hemodialysis- and non-hemodialysis- dependent CKD patients. In addition, some
international Phase 3 studies are underway to confirm these effects and reveal
the safety profile. This article summarizes the development process and results
of each clinical trial. BACKGROUND: The Anemia Studies in chronic kidney disease (CKD): Erythropoiesis
via a Novel prolyl hydroxylase inhibitor Daprodustat-Dialysis (ASCEND-D) trial
will test the hypothesis that daprodustat is noninferior to comparator epoetin
alfa or darbepoetin alfa for two co-primary endpoints: hemoglobin (Hb) efficacy
and cardiovascular (CV) safety.
METHODS: We report the trial design, key demographic, clinical and laboratory
findings, and baseline therapies of 2964 patients randomized in the open-label
(sponsor-blinded) active-controlled, parallel-group, randomized ASCEND-D
clinical trial. We also compare baseline characteristics of ASCEND-D patients
with patients who are on dialysis (CKD G5D) enrolled in other large CV outcome
trials (CVOTs) and in the most relevant registries.
RESULTS: The median age of patients was 58 years, 43% were female; 67% were
White and 16% were Black. The median Hb at baseline was 10.4 g/dL. Among
randomized patients, 89% were receiving hemodialysis and 11% peritoneal
dialysis. Among key comorbidities, 42% reported a history of diabetes mellitus
and 45% a history of CV disease. Median blood pressure was 134/74 mmHg. The
median weekly dose of epoetin was 5751 units. Intravenous and oral iron uses
were noted in 64 and 11% of patients, respectively. Baseline demographics were
similar to patients with CKD G5D enrolled in other CVOTs and renal patient
registries.
CONCLUSIONS: ASCEND-D will evaluate the efficacy and safety of daprodustat
compared with epoetin alfa or darbepoetin alfa in the treatment of patients with
anemia with CKD G5D.This trial is registered with ClinicalTrials.gov:
NCT02879305. EudraCT Number: 2016-000541-31; Sponsor Protocol Number: 200807. Daprodustat is a hypoxia-inducible factor-prolyl hydroxylase inhibitor for the
treatment of anemia of chronic kidney disease. This phase 3 study evaluated the
efficacy and safety of daprodustat in an uncontrolled cohort of 56 Japanese
peritoneal dialysis patients with anemia over 52 weeks. Subjects received
daprodustat 4 mg orally once daily for 4 weeks and the dose was subsequently
adjusted every 4 weeks. Mean baseline hemoglobin was 10.9 g/dL (95% CI 10.59,
11.12). Mean hemoglobin reached the target range (11.0-13.0 g/dL) at week 12 and
was maintained until week 52. Mean hemoglobin during weeks 40-52 was 12.1 g/dL
(95% CI 12.0, 12.2). The most frequent adverse events included nasopharyngitis
(29%), catheter-site infection (18%), peritonitis (16%), diarrhea (14%), and
nausea (11%). No deaths were reported. Once-daily oral daprodustat treatment was
generally well tolerated and mean hemoglobin was achieved and maintained within
the target range in Japanese peritoneal dialysis participants. Collaborators: Guinsburg M, Cusumano C, Santos J, Guinsburg A, Najun Zarazaga C,
Marín I, Bevione P, Ramirez N, Laham G, Valtuille R, Douthat W, Rosa Diez G,
Hawley C, Lee V, Kerr PG, Gray N, Mather A, Badve SV, Jesudason S, Pedagogos E,
Komala M, Foote C, Ratanjee S, Irish A, Suranyi M, Prager R, Wiesholzer M,
Rosenkranz A, Bovy C, Warling X, De Keyzer K, Maes B, Claes K, Cornelis T,
Vandewiele B, Debelle F, Morelle J, Herdes F, Bruno R, Deboni LM, Noronha I,
Carvalho N, Canziani ME, Piovesan F, Sato V, Riella M, Paschoalin R, Ramalho R,
Pecoits-Filho R, Lorenzoni dAvila D, Lotaif LD, Prompt C, Capanema Silva G,
Yanakieva T, Rangelov R, Kirov B, Vasileva A, Bakardzhiev T, Boyadzhieva S,
Georgiev I, Paunova P, Karagyozova R, Kambova L, Iliev V, Nikolov D, Shikov P,
Atanasova-Ashikova K, Angelova A, Hercz G, McMahon A, Muirhead N, Jirovec M,
Vlasak J, Stilec R, Bucek P, Oplustilova A, Parikova A, Tesar V, Mokrejsova M,
Sevcik J, Hagstrup Christensen J, Juul-Sandberg R, Aarup M, Mose FH, Rosenberg
M, Lilienthal K, Kõlvald K, Rieu P, Belmouaz M, Francois M, Vilaine E, Henri P,
Legrand E, Chantrel F, Kraemer-Guth A, Schulte K, Feldkamp T, Strutz F, Kraemer
B, Benck U, Krüger T, Rath T, Radermacher J, Lüders S, Kupka J, Goumenos D,
Ntounousi E, Passadakis P, Stefanidis I, Stylianou K, Liakopoulos V, Papagianni
A, Gouva C, Georgoulidou A, Mavromatidis K, Papadopoulou D, Petras D, Patsialas
S, Andrikos E, Major L, Csiky B, Molnar M, Rikker C, Ladanyi E, Keresztesi S,
Bhalla AK, Gang S, Mali M, Jeloka T, Almeida A, Kumar C D, Khandekar A, Aggarwal
M, Eswarappa M, Saha TK, Sreelatha M, Agrawal D, George J, Chakravarthi R,
Parthasarathy R, Abraham G, Narula A, Jasuja S, Gesualdo L, Roccatello D,
Cozzolino M, Moriero E, Boligo D, Scarpioni R, Russo D, Esposito C, Pani A,
Cavalli A, Mallamaci F, Romano P, Pieruzzi F, Pedrini L, Kim S, Han SY, Shin SK,
Kim KM, Chung W, Park HC, Han S, Lee JP, Han BG, Lee YK, Song HC, Oh DJ, Koh ES,
Lee S, Kim SJ, Kim HW, Lee SH, Shin DH, Jo YI, Loh CL, Liu WJ, Abdullah R, Ong
LM, Wong HS, Ng KP, Monteon Ramos F, Rodríguez OO, Chew Wong A, Rodriguez Ruiz
E, Herrera L, Orozco Castellanos R, Mayorga Madrigal H, García de León Guerrero
M, Herdez Diaz JC, Correa-Rotter R, Perez Grovas Garza H, Leyva Campillo SA,
Melo Sanchez MG, van den Dorpel M, Vervloet M, de Boer JD, Hood C, Rabindranath
K, Hutchison C, Wolff M, Bækken M, Nowicki M, Wroblewski K, Kaniewski M,
Kozminski P, Lewanski R, Rajca D, Kopecka-Mechlinska L, Chmielarska I, Brzósko
S, Wyszynska A, Górecki P, Komorowski G, Piorecki M, Jaroszynski A, Azevedo P,
Bernardo I, Ferreira A, Cruz J, Branco P, Santos C, Sousa H, Gil C, Oliveira C,
Ponce P, Castro R, Berca S, Ismail G, Stirbu O, Olariu N, Khrustaleva E,
Novoseltsev I, Vasilyeva G, Eremeeva L, Antropenko N, Fedotova L, Timokhovskaya
G, Zemchenkov A, Selutin A, Apartsin K, Vasilevskaya O, Staroselskiy K, Perlin
D, Wong J, Weng W, Lau TWL, Swanepoel C, Prozesky H, Loreto M, Santos Herrera M,
Díaz Rodríguez C, García Maset R, de Arriba de la Fuente G, González Parra E,
Martínez Ocaña JC, Gascó Company JM, Santos JP, Bastons JB, Del Carmen
Vozmediano Poyatos M, Calabia Martinez J, Salgueira M, Portoles Pérez J,
Martinez Campos E, Abad S, Herrero Calvo JA, Calls Ginesta J, Linde T,
Supranaviciene L, Lee CT, Huang JW, Sue YM, Wu IW, Peng YS, Huang WH, Wang MC,
Hsu YH, Lin CY, Chen HC, Ates K, Karayaylali I, Ustundag S, Tokgoz B,
Suleymanlar G, Ozkurt S, Martynyuk L, Kolesnyk M, Ovska O, Dudar I, Korneyeva S,
Prylypko M, Legun O, Fomenko G, Bilyk S, Stepanenko O, Kostynenko T, Kolomiichuk
N, Kalra P, Bhandari S, Ahmed A, Ramakrishna B, Dasgupta I, McCafferty K, Shah
S, Mason P, El Kossi M, Patel R, Sridharan S, Provenzano C, Raissi S, Suri A,
El-Shahawy M, Gandhi K, Fadda G, Hendon K, Rastogi A, Khawar O, Horeish A,
Darwish R, Aiello J, Galperin E, Velar A, Zeig S, Steer D, Kopyt N, Lehrner L,
Suchinda P, Hon G, Polack D, Wooldridge T, Martin E, Linfert D, Casey M, Reddy
P, Daswani A, Tietjen D, Sekkarie M, Masani N, Sun C, Awad A, Ayodeji O,
Baranski J, Minasian R, Levine M, Kleinman K, Joshi S, Kambhampati G, Lee J,
Alappan R, Adaimy M, Mulloy L, Desai A, Silva A, Bernardo M, Lynn R, Yan J,
Greenwood G, Shemin D, Carvalho C, Nazeer I, Aqeel A, Joshi S, Lanier D Jr,
Abramowitz M, Berenji R, Kumar N, Rubin O, Gonzalez J, Bhat P, Wright S, Kant K,
Shakeel M, Rodriguez A, Assefi A, Calhoun W, Sun A, Maasarani E, Gandhi N,
Arfeen S, Al-Saghir F, Brar H, Myrie K, Broumand V, Campbell R, Dev D, Porter I,
Ranjan R, Kamyar A, Reichel R, Schlessinger F, O'Shaughnessy A, Niu PC, Rivers
D, Erinle A, Szewc R, Kaveh K, Lu CM, Rajan J, Jacobs A, Weisinger-Hirsh J,
Sloan L, Dixon B, Brezina B, Coyne D, Saggi S, Sawhney A, Charytan C, Buridi A,
Cuellar J, Bleyer A, Said-Herdez N, Obhrai J, Chowdhury P, Arora A, Durham W,
Ansari N, Kupor L, Bhadra S, Guadiz R, Arias C, Ukponmwan O, Cheung A, Ali N,
Anaheim D, Lapsia V, Ferdez J, Luscy C, Vaghela M, Nieto J, Lee SM, Gandhi D,
Posada J. Collaborators: Cuadrado J, Ulla M, Alvarisqueta A, Cusumano C, Najun Zarazaga C,
Vallejos A, Santos J, Vasquez N, Ramirez N, Guinsburg M, Resk J, Marín I,
Guinsburg A, Laham G, Alberdi C, Maurich M, Douthat W, Talaulikar G, Packham D,
Gray N, Roger S, Mather A, Australia A, Murali K, Pedagogos E, Komala M, Badve
SV, Boudville N, Ritchie A, Wilson S, Suranyi M, Van Viem B, Warling X, De
Meester J, De Keyzer K, Claes K, Maes B, Vandewiele B, Debelle F, Demoulin N,
Vanuytsel J, Herdes F, Deboni LM, Bruno R, Canziani ME, Riella M, Bastos M,
Noronha I, Piovesan F, Carvalho N, Contieri F, Sato V, Paschoalin R, Herdes
M, Ramalho R, Pecoits-Filho R, Lorenzoni dAvila D, Prompt C, Capanema Silva G,
Rangelov R, Yanakieva T, Boyadzhieva S, Shikov P, Bakardzhiev T, Iliev V,
Nikolov D, Vasileva A, Nikolova M, Staykova S, Hristozov V, Aggarwal N, McMahon
A, Chow S, Cournoyer S, Wong G, Zidel B, Tenkore K, Muirhead N, Mac-Way F,
Mesa L, Garcia Padilla P, Gelvez J, Carvajal JN, Cadena Bonfanti A, Vlasak J,
Jirovec M, Saudek F, Kovar R, Oplustilova A, Honova V, Sevcik J, Hagstrup
Christensen J, Juul-Sandberg R, Aarup M, Mose FH, Rosenberg M, Massy Z, Belmouaz
M, Henri P, Legrand E, Chantrel F, Le Quintrec M, Urena-Torres PA, Heng AE,
Juillard L, Strutz F, Marsen T, Krüger T, Gabriels G, Lüders S, Goumenos D,
Ntounousi E, Liakopoulos V, Gouva C, Stylianou K, Dafnis E, Stefanidis I,
Papadopoulou D, Papagianni A, Kaperonis N, Vlahakos D, Georgoulidou A,
Mavromatidi K, Patsialas S, Passadakis P, Andrikos E, Bamichas G, Moutafis S,
Chatzigiannakos D, Spaia S, Cheung SF, Chan TMD, Fung S, Tong M, Zsom M, Major
L, Ladanyi E, Molnar M, Gurzo M, Csiky B, Bhalla AK, Ahlawat R, Gang S, Mali M,
Jeloka T, Khandekar A, Kumar C D, Parthasarathy R, Abraham G, Sajgure A, Prabhu
A R, Aggarwal M, Agrawal D, Eswarappa M, Sreelatha M, Kumar Saha T, George J,
Chakravarthi R, Narula A, Chhabra GD, Bhalla D, Goplani K, Jain A, Kher V, Sahay
M, Prasad N, Ramachandran R, Berar Yanay N, Beberashvili I, Hassan K, Armaly Z,
Farber E, Yagil Y, Benchetrit S, Manunta P, Scarpioni R, Pani A, Esposito C,
Romano P, Kim S, Joo KW, Kim HW, Shin DH, Han SY, Yoon SA, Han BG, Lim CS, Yang
CW, Shin SK, Lee SH, Park MY, Kwon YJ, Shin SJ, Kim YG, Han S, Park I, Jeong KH,
Lee S, Chang JH, Kim SJ, Kim YW, Kim SH, Lee KY, Loh CL, Ching CH, Abdullah R,
Ong LM, Fatnoon Nik Ahmad NN, Ng KP, Lee LY, Morales LS, Nevarez Ruiz LA,
Monteon Ramos F, Burgos Soto MA, Rodriguez Ruiz E, Orozco Castellanos R, Herrera
L, Elizondo Moreno E, Chew Wong A, Orea Rodríguez O, Mayorga Madrigal H, García
de León Guerrero M, Venegas Carrillo LA, Herdez Diaz JC, Bazzoni Ruiz AE,
Tamayo J, Bochicchio Riccardelli T, Ramos Ibarra DR, Leyva Campillo SA, Dehesa
López E, Irizar Santana SS, Vervloet M, van den Dorpel M, de Boer JD,
Rabindranath K, Schollum J, Hood C, Hutchison C, Maher E, Ang E, Isidto R,
Solimen D, Mondano-Yap Y, AngelineGumba M, Afaga A, Nazareth MG, Vergara Lim-Dy
MF, Perez R, Nowicki M, Sokalski A, Naumnik B, Wroblewski K, Chmielarska I,
Górecki P, Jaroszynski A, Wiecek A, Lizakowski S, Nolasco F, Rodrigues B,
Figueiredo N, Birne R, Santos P, Santos C, Bob FR, Bako G, Bobeica R, Ismail G,
Tuta LA, Petrica L, Peride I, Eremeeva L, Novoseltsev I, Gerasimchuk R,
Zemchenkov A, Smolyarchuk E, Shutov A, Staroselskiy K, Antropenko N, Yakushin S,
Smakotina S, Federation F, Vasilevskaya O, Borsukov A, Apartsin K, Perlin D,
Wong J, Weng W, Lau WLT, Liu AYL, Rayner B, Urbach D, Malan D, Prozesky H, Díaz
Rodríguez C, de Arriba de la Fuente G, Agraz Pamplona I, Ambrós JT, Cases A,
Santos JP, Diaz Gomez JM, Bover Sanjuan J, Cigarran Guldris S, Labrador Gomez
PJ, Graterol Torres F, Bonal Bastons J, Portoles Pérez J, Calabia Martinez J,
Nieto Iglesias J, Salgueira M, Calls Ginesta J, Barany P, Supranaviciene L, Lee
CT, Wu CJ, Sue YM, Wu V, Wu IW, Peng YS, Huang WH, Wang MC, Chen HC,
Prasithsirikul W, Noppakun K, Vareesangthip K, Traitanon O, Supasyndh O,
Praditpornsilpa K, Anutrakulchai S, Ates K, Tokgoz B, Ustundag S, Karayaylali I,
Karadag S, Ozturk S, Suleymanlar G, Ecder ST, Koc M, Zub L, Martynyuk L,
Kolesnyk M, Dudar I, Korneyeva S, Prylypko M, Legun O, Ovska O, Bilyk S, Topchiy
I, Stepanenko O, Katerenchuk I, Kostynenko T, Doretskii V, Tereshchenko N,
Kolomiichuk N, Kalra P, Bhandari S, Mitra S, Ahmed A, Shah S, Ramakrishna B,
Dasgupta I, Yaqoob M, Mooney A, Jones C, Mason P, Pritchard N, El Kossi M, Wroe
C, Tez D, Leung J, Fraser D, Power A, Sharma A, Wheeler D, Sridharan S, Chuang
P, El-Shahawy M, Rastogi A, Velar A, Wooldridge T, Zeig S, Donner B, Galperin E,
Ross D, Steer D, Horeish A, Suchinda P, Linfert D, Kopyt N, Hendon K, Ayodeji O,
Perez J, Reddy P, Alappan R, Shakeel M, Casey M, Gonzalez C, Mulloy L, Tietjen
D, Mehta A, Betts J, Galvez O, Martin E, Baranski J, Khawar O, Fischbach B,
Gandhi N, Kotzker W, Bernardo M, Naraya M, Sun C, Silva A, Yan J, Kanade P,
Carvalho C, Zaw Y, Cortez A, Berenji R, Lee S, Joshi S, Nazeer I, Belz M,
Ghanekar H, Abramowitz M, Bala Subramanian V, Atta M, Oo T, Flack J, Greenwood
G, Steed L, Kantor S, Fadia A, Ruiz J, Saggi S, Assefi A, Comunale R, Shafik S,
Kronfli S, Al-Saghir F, Crawford P, Ortiz-Butcher C, Porter I, Dev D, Rajan J,
O'Shaughnessy A, Calhoun W, Arfeen S, Schlessinger F, Kamyar A, Reichel R,
Kalirao P, Jones A, Nica R, Scott D, Campbell R, Kaveh K, Ghossein C, Pedraza F,
Tran TH, Belledonne M, Jacobs A, Gutierrez O, Behara V, Sloan L, Dixon B, Coyne
D, Brezina B, Buridi A, Garver R, Said-Herdez N, Obhrai J, Posada J,
Patrikyan A, Arora A, Vaz A, Guadiz R, Troyan B, Ukponmwan O, Vernace M,
Arencibia F, Yablon Z, Cheung A, Ali N, Shafi T, Othersen J, Luscy C, Ferdez
J, Kalim S, Islam S, Vaghela M, Dukes C, Nieto J, Reyes K, Fluck P, Friedenberg
K, Drawz P, Weissman P, Herdez L, Somerman D, Ayesu K, Kovesdy C, Demko T,
Jere C, Ramon P, Agha I, Pergola P, Okechukwu C, Kapoor A, Lohiya P, Amberker D,
Danda R, Sikora M, Raissi S, Nguyen B, Ta D, Do T, Ha A, Nguyen T, Huynh T, Minh
D. |
Where is the the protein perforin localized? | Perforin are stored inside the leukocytes in secretory granules. | Severe malaria caused by Plasmodium falciparum poses a major global health
problem with high morbidity and mortality. P. falciparum harbors a family of
pore-forming proteins (PFPs), known as perforin like proteins (PLPs), which are
structurally equivalent to prokaryotic PFPs. These PLPs are secreted from the
parasites and, they contribute to disease pathogenesis by interacting with host
cells. The severe malaria pathogenesis is associated with the dysfunction of
various barrier cells, including endothelial cells (EC). Several factors,
including PLPs secreted by parasites, contribute to the host cell dysfunction.
Herein, we have tested the hypothesis that PLPs mediate dysfunction of barrier
cells and might have a role in disease pathogenesis. We analyzed various
dysfunctions in barrier cells following rPLP2 exposure and demonstrate that it
causes an increase in intracellular Ca2+ levels. Additionally, rPLP2 exposed
barrier cells displayed features of cell death, including Annexin/PI positivity,
depolarized the mitochondrial membrane potential, and ROS generation. We have
further performed the time-lapse video microscopy of barrier cells and found
that the treatment of rPLP2 triggers their membrane blebbing. The cytoplasmic
localization of HMGB1, a marker of necrosis, further confirmed the necrotic type
of cell death. This study highlights the role of parasite factor PLP in
endothelial dysfunction and provides a rationale for the design of adjunct
therapies against severe malaria. BACKGROUND: Uranium mining and processing are an ancient occupation, recognized
as being grueling and accountable for injury and disease. Uranium (U) is a
radioactive heavy metal used in many industrial applications. It increases the
micronuclei frequencies as well as chromosomal aberration and sister chromatid
exchange in peripheral blood lymphocytes. Granzyme B and perforin are stored
inside the leukocytes in secretory granules. These proteins are released outside
the cells by a cell-to-cell contact under specific conditions for inducing
apoptosis. So, this study investigated the potential health hazards with
prominence on the biological effects of radiation exposure.
METHODS: A cross-sectional analytic research was conducted on Egyptian male
mining field workers. Leucocytes' genotoxicity was evaluated using DNA
fragmentation assay and comet assay. Furthermore, flow cytometric analysis of
Granzyme B protein was done.
RESULTS: A significant increase in dead cells after dual acridine
orange/ethidium bromide (AO/EB) fluorescent staining in radiation-exposed groups
was noticed compared to control groups. Moreover, a significant increase in the
fragmented DNA was evident in exposed groups relative to the control one.
Granzyme B protein levels showed a significant increase concerning control.
CONCLUSION: A wide variety of adverse human health risks are considered a
potential risk to Egyptian uranium miners. For employers working in both mining
and processing fields, the most common molecular shift highlighted was the
leucocyte damage in blood samples. To preserve the health of all employees,
health education and administration of effective hazard management procedures
are necessary. As part of the adaptive immune system, T cells are vital for the eradication of
infected and maligtly transformed cells. To perform their protective
function, T cells produce effector molecules that are either directly cytotoxic,
such as granzymes, perforin, interferon-γ and tumour necrosis factor α, or
attract and stimulate (immune) cells, such as interleukin-2. As these molecules
can also induce immunopathology, tight control of their production is required.
Indeed, inflammatory cytokine production is regulated on multiple levels.
Firstly, locus accessibility and transcription factor availability and activity
determine the amount of mRNA produced. Secondly, post-transcriptional
mechanisms, influencing mRNA splicing/codon usage, stability, decay,
localization and translation rate subsequently determine the amount of protein
that is produced. In the immune suppressive environments of tumours, T cells
gradually lose the capacity to produce effector molecules, resulting in tumour
immune escape. Recently, the role of post-transcriptional regulation in
fine-tuning T-cell effector function has become more appreciated. Furthermore,
several groups have shown that exhausted or dysfunctional T cells from cancer
patients or murine models possess mRNA for inflammatory mediators, but fail to
produce effector molecules, hinting that post-transcriptional events also play a
role in hampering tumour-infiltrating lymphocyte effector function. Here, the
post-transcriptional regulatory events governing T-cell cytokine production are
reviewed, with a specific focus on the importance of post-transcriptional
regulation in anti-tumour responses. Furthermore, potential approaches to
circumvent tumour-mediated dampening of T-cell effector function through the
(dis)engagement of post-transcriptional events are explored, such as
CRISPR/Cas9-mediated genome editing or chimeric antigen receptors. |
Is REGN5458 a single-targeted antibody? | No, REGN5458 is a bispecific antibody. | |
Which disease is associated with X-linked recessive TLR7 deficiency? | X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. | Collaborators: Abel L, Aiuti A, Al-Muhsen S, Al-Mulla F, Anderson MS, Andreakos
E, Arias AA, Feldman HB, Belot A, Biggs CM, Bogunovic D, Bolze A, Bondarenko A,
Bousfiha AA, Brodin P, Bryceson Y, Bustamante CD, Butte MJ, Casari G,
Chakravorty S, Christodoulou J, Condino-Neto A, Constantinescu SN, Cooper MA,
Dalgard CL, Desai M, Drolet BA, El Baghdadi J, Espinosa-Padilla S, Fellay J,
Flores C, Franco JL, Froidure A, Gregersen PK, Haerynck F, Hagin D, Halwani R,
Hammarström L, Heath JR, Henrickson SE, Hsieh EWY, Husebye E, Imai K, Itan Y,
Jarvis ED, Karamitros T, Kisand K, Ku CL, Lau YL, Ling Y, Lucas CL, Maniatis T,
Mansouri D, Maródi L, Meyts I, Milner JD, Mironska K, Mogensen TH, Morio T, Ng
LFP, Notarangelo LD, Novelli A, Novelli G, O'Farrelly C, Okada S, Ozcelik T,
Pan-Hammarström Q, de Diego RP, Planas AM, Prando C, Pujol A, Quintana-Murci L,
Renia L, Resnick I, Rodríguez-Gallego C, Sancho-Shimizu V, Sediva A, Seppänen
MRJ, Shahrooei M, Shcherbina A, Slaby O, Snow AL, Soler-Palacín P, Spaan AN,
Tancevski I, Tangye SG, Abou Tayoun A, Ramaswamy S, Turvey SE, Uddin KMF, Uddin
MJ, van de Beek D, Vinh DC, von Bernuth H, Zatz M, Zawadzki P, Su HC, Casanova
JL, Foti G, Bellani G, Citerio G, Contro E, Pesci A, Valsecchi MG, Cazzaniga M,
Abad J, Accordino G, Achille C, Aguilera-Albesa S, Aguiló-Cucurull A, Aiuti A,
Özkan EA, Darazam IA, Roblero Albisures JA, Aldave JC, Ramos MA, Khan TA,
Aliberti A, Nadji SA, Alkan G, AlKhater SA, Allardet-Servent J, Allende LM,
Alonso-Arias R, Alshahrani MS, Alsina L, Alyanakian MA, Borrero BA, Amoura Z,
Antolí A, Arrestier R, Aubart M, Auguet T, Avramenko I, Aytekin G, Azot A,
Bahram S, Bajolle F, Baldanti F, Baldolli A, Ballester M, Feldman HB, Barrou B,
Barzagh F, Basso S, Bayhan GI, Belot A, Bezrodnik L, Bilbao A, Blanchard-Rohner
G, Blanco I, Blandinières A, Blázquez-Gamero D, Bleibtreu A, Bloomfield M,
Bolivar-Prados M, Bondarenko A, Borghesi A, Borie R, Botdhlo-Nevers E, Bousfiha
AA, Bousquet A, Boutolleau D, Bouvattier C, Boyarchuk O, Bravais J, Briones ML,
Brunner ME, Bruno R, Bueno MRP, Bukhari H, Bustamante J, Cáceres Agra JJ, Capra
R, Carapito R, Carrabba M, Casari G, Casasnovas C, Caseris M, Cassaniti I,
Castelle M, Castelli F, de Vera MC, Castro MV, Catherinot E, Celik JB, Ceschi A,
Chalumeau M, Charbit B, Cheng MP, Clavé P, Clotet B, Codina A, Cohen Y, Colobran
R, Comarmond C, Combes A, Comoli P, Corsico AG, Coşkuner T, Cvetkovski A, Cyrus
C, Dalmau D, Danion F, Darley DR, Das V, Dauby N, Dauger S, De Munter P, de
Pontual L, Dehban A, Delplancq G, Demoule A, Desguerre I, Di Sabatino A, Diehl
JL, Dobbelaere S, Domínguez-Garrido E, Dubost C, Ekwall O, Bozdemir ŞE, Elnagdy
MH, Emiroglu M, Endo A, Erdeniz EH, Aytekin SE, Lasa MPE, Euvrard R, Fabio G,
Faivre L, Falck A, Fartoukh M, Faure M, Arquero MF, Ferrer R, Ferreres J, Flores
C, Francois B, Fumadó V, Fung KSC, Fusco F, Gagro A, Solis BG, Gaussem P,
Gayretli Z, Gil-Herrera J, Gilardin L, Gatineau AG, Girona-Alarcón M, Cifuentes
Godínez KA, Goffard JC, Gonzales N, Gonzalez-Granado LI, González-Montelongo R,
Guerder A, Gülhan B, Gumucio VD, Hanitsch LG, Gunst J, Gut M, Hadjadj J,
Haerynck F, Halwani R, Hammarström L, Hancerli S, Hariyan T, Hatipoglu N,
Heppekcan D, Herdez-Brito E, Ho PK, Holanda-Peña MS, Horcajada JP, Hraiech S,
Humbert L, Hung IFN, Iglesias AD, Íñigo-Campos A, Jamme M, Arranz MJ, Jimeno MT,
Jordan I, Kanık-Yüksek S, Kara Y, Karahan A, Karbuz A, Yasar KK, Kasapcopur O,
Kashimada K, Keles S, Demirkol YK, Kido Y, Kizil C, Kılıç AO, Klocperk A,
Koutsoukou A, Król ZJ, Ksouri H, Kuentz P, Kwan AMC, Kwan YWM, Kwok JSY, Lagier
JC, Lam DSY, Lampropoulou V, Lanternier F, Lau YL, Le Bourgeois F, Leo YS, Lopez
RL, Leung D, Levin M, Levy M, Lévy R, Li Z, Lilleri D, Bolanos Lima EJA,
Linglart A, López-Collazo E, Lorenzo-Salazar JM, Louapre C, Lubetzki C, Lung KC,
Luyt CE, Lye DC, Magnone C, Mansouri D, Marchioni E, Marioli C, Marjani M,
Marques L, Pereira JM, Martín-Nalda A, Pueyo DM, Martinez-Picado J, Marzana I,
Mata-Martínez C, Mathian A, Matos LR, Matthews GV, Mayaux J, McLaughlin-Garcia
R, Meersseman P, Mège JL, Mekontso-Dessap A, Melki I, Meloni F, Meritet JF,
Merlani P, Akcan ÖM, Meyts I, Mezidi M, Migeotte I, Millereux M, Million M,
Mirault T, Mircher C, Mirsaeidi M, Mizoguchi Y, Modi BP, Mojoli F, Moncomble E,
Melián AM, Martinez AM, Morandeira F, Morange PE, Mordacq C, Morelle G, Mouly
SJ, Muñoz-Barrera A, Nafati C, Nagashima S, Nakagama Y, Neven B, Neves JF, Ng
LF, Ng YY, Nielly H, Medina YN, Cuadros EN, Ocejo-Vinyals JG, Okamoto K, Oualha
M, Ouedrani A, Özçelik T, Ozkaya-Parlakay A, Pagani M, Pan-Hammarström Q,
Papadaki M, Parizot C, Parola P, Pascreau T, Paul S, Paz-Artal E, Pedraza S,
González Pellecer NC, Pellegrini S, de Diego RP, Pérez-Fernández XL, Philippe A,
Philippot Q, Picod A, de Chambrun MP, Piralla A, Planas-Serra L, Ploin D, Poissy
J, Poncelet G, Poulakou G, Pouletty MS, Pourshahnazari P, Qiu-Chen JL, Quentric
P, Rambaud T, Raoult D, Raoult V, Rebillat AS, Redin C, Resmini L, Ricart P,
Richard JC, Rigo-Bonnin R, Rivet N, Rivière JG, Rocamora-Blanch G, Rodero MP,
Rodrigo C, Rodriguez LA, Rodriguez-Gallego C, Rodriguez-Palmero A, Romero CS,
Rothenbuhler A, Roux D, Rovina N, Rozenberg F, Ruch Y, Ruiz M, Ruiz Del Prado
MY, Ruiz-Rodriguez JC, Sabater-Riera J, Saks K, Salagianni M, Sanchez O,
Sánchez-Montalvá A, Sánchez-Ramón S, Schidlowski L, Schluter A, Schmidt J,
Schmidt M, Schuetz C, Schweitzer CE, Scolari F, Sediva A, Seijo L, Seminario AG,
Sene D, Seng P, Senoglu S, Seppänen M, Llovich AS, Shahrooei M, Shcherbina A,
Siguret V, Siouti E, Smadja DM, Smith N, Sobh A, Solanich X, Solé-Violán J,
Soler C, Soler-Palacín P, Sözeri B, Stella GM, Stepanovskiy Y, Stoclin A,
Taccone F, Tandjaoui-Lambiotte Y, Taupin JL, Tavernier SJ, Tello LV, Terrier B,
Thiery G, Thorball C, Thorn K, Thumerelle C, Tipu I, Tolstrup M, Tomasoni G,
Toubiana J, Alvarez JT, Triantafyllia V, Trouillet-Assant S, Troya J, Tsang OTY,
Tserel L, Tso EYK, Tucci A, Tüter Öz ŞK, Ursini MV, Utsumi T, Uzunhan Y, Vabres
P, Valencia-Ramos J, Van Den Rym AM, Vandernoot I, Velez-Santamaria V, Zuniga
Veliz SP, Vidigal MC, Viel S, Vilain C, Vilaire-Meunier ME, Villar-García J,
Vincent A, Vogt G, Voiriot G, Volokha A, Vuotto F, Wauters E, Wauters J, Wu AKL,
Wu TC, Yahşi A, Yesilbas O, Yildiz M, Young BE, Yükselmiş U, Zatz M, Zecca M,
Zuccaro V, Jens VP, Lambrecht BN, Eva VB, Cédric B, Levi H, Eric H, Bauters F,
De Clercq J, Cathérine H, Slabbynck H, Leslie N, Florkin B, Boulanger C,
Vanderlinden D, Annereau JP, Briseño-Roa L, Gribouval O, Pelet A, Abel L,
Andrejak C, Angoulvant F, Bachelet D, Bartoli M, Basmaci R, Behilill S, Beluze
M, Benkerrou D, Bhavsar K, Bouadma L, Bouchez S, Bouscambert M,
Cervantes-Gonzalez M, Chair A, Chirouze C, Coelho A, Couffignal C,
Couffin-Cadiergues S, d'Ortenzio E, Debray MP, Deconinck L, Deplanque D,
Descamps D, Desvallée M, Diallo A, Diouf A, Dorival C, Dubos F, Duval X,
Elharrar B, Eloy P, Enouf V, Esperou H, Esposito-Farese M, Etienne M, Devouge
EF, Gault N, Gaymard A, Ghosn J, Gigante T, Gilg M, Guedj J, Hoctin A, Hoffmann
I, Houas I, Hulot JS, Jaafoura S, Kafif O, Kaguelidou F, Kali S, Khalil A, Khan
C, Laoué C, Laribi S, Le M, Le Hingrat Q, Le Mestre S, Le Nagard H, Lescure
FX, Letrou S, Levy Y, Lina B, Lingas G, Lucet JC, Malvy D, Mambert M, Mentré F,
Meziane A, Mouquet H, Mullaert J, Neant N, Nguyen D, Noret M, Nseir S,
Papadopoulos A, Paul C, Peiffer-Smadja N, Perpoint T, Petrov-Sanchez V, Peytavin
G, Pham H, Picone O, Piquard V, Puéchal O, Rabaud C, Rosa-Calatrava M, Rossignol
B, Rossignol P, Roy C, Schneider M, Su R, Tardivon C, Tellier MC, Téoulé F,
Terrier O, Timsit JF, Tual C, Tubiana S, Van Der Werf S, Vanel N, Veislinger A,
Visseaux B, Wiedemann A, Yazdanpanah Y, Alavoine L, Behillil S, Burdet C,
Charpentier C, Dechanet A, Descamps D, Duval X, Ecobichon JL, Enouf V, Frezouls
W, Houhou N, Kafif O, Lehacaut J, Letrou S, Lina B, Lucet JC, Manchon P,
Nouroudine M, Piquard V, Quintin C, Thy M, Tubiana S, van der Werf S, Vignali V,
Visseaux B, Yazdanpanah Y, Chahine A, Waucquier N, Migaud MC, Deplanque D,
Djossou F, Mergeay-Fabre M, Lucarelli A, Demar M, Bruneau L, Gérardin P, Maillot
A, Payet C, Laviolle B, Laine F, Paris C, Desille-Dugast M, Fouchard J, Malvy D,
Nguyen D, Pistone T, Perreau P, Gissot V, Le Goas C, Montagne S, Richard L,
Chirouze C, Bouiller K, Desmarets M, Meunier A, Lefévre B, Jeulin H, Legrand K,
Lomazzi S, Tardy B, Gagneux-Brunon A, Bertholon F, Botelho-Nevers E, Kouakam C,
Leturque N, Roufai L, Amat K, Couffin-Cadiergues S, Espérou H, Hendou S, van
Agtmael M, Algera AG, Appelman B, van Baarle F, Bax D, Beudel M, Bogaard HJ,
Bomers M, Bonta P, Bos L, Botta M, de Brabander J, de Bree G, de Bruin S, Buis
DTP, Bugiani M, Bulle E, Chouchane O, Cloherty A, Dijkstra M, Dongelmans DA,
Dujardin RWG, Elbers P, Fleuren L, Geerlings S, Geijtenbeek T, Girbes A,
Goorhuis B, Grobusch MP, Hafkamp F, Hagens L, Hamann J, Harris V, Hemke R,
Hermans SM, Heunks L, Hollmann M, Horn J, Hovius JW, de Jong MD, Koning R, Lim
EHT, van Mourik N, Nellen J, Nossent EJ, Paulus F, Peters E, Pina-Fuentes DAI,
van der Poll T, Preckel B, Prins JM, Raasveld J, Reijnders T, de Rotte MCFJ,
Schinkel M, Schultz MJ, Schrauwen FAP, Schuurmans A, Schuurmans J, Sigaloff K,
Slim MA, Smeele P, Smit M, Stijnis CS, Stilma W, Teunissen C, Thoral P, Tsonas
AM, Tuinman PR, van der Valk M, Veelo D, Volleman C, de Vries H, Vught LA, van
Vugt M, Wouters D, Zwinderman AHK, Brouwer MC, Wiersinga WJ, Vlaar APJ, van de
Beek D, Tompkins MF, Alba C, Snow AL, Hupalo DN, Rosenberger J, Sukumar G,
Wilkerson MD, Zhang X, Lack J, Oler AJ, Dobbs K, Delmonte OM, Danielson JJ,
Biondi A, Bettini LR, D'Angio M, Beretta I, Imberti L, Sottini A, Quaresima V,
Quiros-Roldan E, Rossi C. |
Is Benralizumab effective for Chronic Spontaneous Urticaria? | Yes, the anti-IL-5 antibody benralizumab has been reported to reduce Chronic Spontaneous Urticaria symptoms. | PURPOSE OF REVIEW: Symptomatic management of chronic spontaneous urticaria (CSU)
basically depends on second-generation H1 antihistamines and omalizumab.
Omalizumab is a game changer in the management, but still there is a need for
new targets and new biologics targeting new pathways in the treatment which will
provide long-lasting remission, which will be given orally and which will be
cheaper. This review will focus on new biologics that are underway of production
or are already under use for different disorders but could be beneficial for the
treatment of Chronic urticaria.
RECENT FINDINGS: In this review, the treatment targets are classified according
to the cells which are involved in the pathogenesis of CSU. Those are mast
cells/basophils, B cells, T cells and eosinophils. The treatments that are under
clinical trials for CSU are anti-IgE treatments such as ligelizumab, molecules
targeting intracellular signaling pathways such as spleen tyrosine kinase
inhibitors, surface inhibitory molecules such as siglec-8, anti-IL-1s such as
canakinumab, Bruton kinase (BTK) inhibitors such as GDC-0853 and anti-IL-5s such
as benralizumab and mepolizumab.
SUMMARY: The ongoing clinical trials on new targets of treatment hold new hopes
not only for a better care of the disease but also a better understanding of the
pathomechanisms lying underneath. Guidelines for the treatment of chronic spontaneous urticaria (CSU) recommend
the use of the IgE-targeted biologic omalizumab in patients with
antihistamine-refractory disease. The rationale for this is supported by the key
role of IgE and its high-affinity receptor, FcεRI, in the degranulation of skin
mast cells that drives the development of the signs and symptoms of CSU, itchy
wheals, and angioedema. Here, we review the current understanding of the
pathogenesis of CSU and its autoimmune endotypes. We describe the mechanisms of
action of omalizumab, the only biologic currently approved for CSU, its efficacy
and ways to improve it, biomarkers for treatment response, and strategies for
its discontinuation. We provide information on the effects of the off-label use,
in CSU, of biologics licensed for the treatment of other diseases, including
dupilumab, benralizumab, mepolizumab, reslizumab, and secukinumab. Finally, we
discuss targets for novel biologics and where we stand with their clinical
development. These include IgE/ligelizumab, IgE/GI-310, thymic stromal
lymphopoietin/tezepelumab, C5a receptor/avdoralimab, sialic acid-binding Ig-like
lectin 8/lirentelimab, CD200R/LY3454738, and KIT/CDX-0159. Our aim is to provide
updated information and guidance on the use of biologics in the treatment of
patients with CSU, now and in the near future. |
Do the proteins Talin and Amot interact? | Yes,
Amot binds Talin | |
Do RNA binding Proteins that bind to adenine uridine (AU)-rich elements (AREs) in the 5' untranslated region (UTR) of mRNAs (AU-RBPs) regulate the DNA Damage Response? | RNA Binding Proteins (RBPs) that bind to adenine uridine (AU)-rich elements (AREs) in the 3' untranslated region (UTR) of mRNAs (AU-RBPs) have emerged as key players in regulating the DNA Damage Response (DDR) and preserving genome integrity. | Tumors of the central nervous system (CNS) often have sustained expression of
labile genes, including angiogenic growth factors and immunosuppressive
cytokines, which promote tumor progression. Stabilization of the RNA transcripts
for these genes, such as vascular endothelial growth factor (VEGF), is an
important molecular pathway for this up-regulation. HuR, a member of the Elav
family of RNA-binding proteins, has been implicated in this pathway through its
binding to adenine and uridine (AU)-rich stability elements (ARE) located in the
3' untranslated regions (3'-UTRs) of the mRNA. Whereas three of the Elav family
members (Hel-N1, HuC, and HuD) are restricted to young and mature neurons, HuR
is more broadly expressed, including proliferating cells of the developing CNS.
Because RNA stabilization of labile genes may promote tumor growth, we analyzed
and compared the expression pattern of HuR in 35 freshly resected and cultured
CNS tumors to determine whether there was any correlation with tumor grade or
histological type. We found that HuR mRNA was consistently expressed in all of
the tumors, regardless of cell origin or degree of maligcy. Using a novel
HuR-specific polyclonal antibody, we found that strong HuR protein expression
was limited to high-grade maligcies (glioblastoma multiforme and
medulloblastoma). Within the glioblastoma multiforme, prominent HuR expression
was also detected in perinecrotic areas in which angiogenic growth factors are
up-regulated. To further define its role as a potential RNA stabilizer, we
analyzed whether HuR could bind to the stability motifs within the 3'-UTRs of
cytokines and growth factors linked to brain tumor progression. We used a novel
ELISA-based RNA binding assay and focused on the 3'-UTRs of angiogenic factors
VEGF, COX-2, and (interleukin) IL-8 as well as the immunomodulating factors
IL-6, transforming growth factor (TGF)-beta and tumor necrosis factor
(TNF)-alpha as potential RNA ligands. Our results indicated overall a very high
binding affinity to these RNA targets. A comparison of these ligands revealed a
hierarchy of binding affinities with the angiogenic factors, and TGF-beta
showing the highest (Kd of 1.8-3.4 nM), and TNF-alpha the lowest (Kd of 18.3
nM). The expression pattern of HuR, coupled with the RNA binding data, strongly
suggests a role for this protein in the posttranscriptional regulation of these
genes in CNS tumors. Two different mechanisms have been well known to regulate the amounts of various
transcripts in response to internal and external environmental stimuli. First,
by binding of activated transcription factors to DNA regulatory regions
including the cAMP response element, hormone response element, and activator
protein-1 region upstream in various genes, the rate of transcription from DNA
to mRNA is regulated. Secondly, the degradation of some mRNAs related to immune
responses has been reported to be regulated by binding of RNA-binding proteins
to adenylate uridylate-rich elements (AU-rich elements, AREs) located in the
3'-untranslated region (3'-UTR). The original study identifying the existence of
a common regulatory nucleotide sequence in the 3'-UTR of inflammatory mediator
transcripts pointed out that the AREs are characteristic of immune-related
functional proteins. The number of transcripts containing AREs in the 3'-UTR has
increased and several neuronal proteins including beta 2-adrenergic receptor,
nerve growth factor, tyrosine hydroxylase, and nitric-oxide synthase II, have
been reported to have AREs. We here reviewed the recent advances in the
neuropsychopharmacological understanding of post-transcriptional regulation by
RNA-binding protein and also pointed out the importance of this regulation in
future studies using various stress paradigms. Hu proteins have been shown to bind to AU-rich elements (AREs) in the
3'-untranslated region of unstable mRNAs. They can thereby inhibit the decay of
labile transcripts by antagonizing destabilizing proteins that target these
AU-rich sequences. Here we examine the sequence preferences of HuD to elucidate
its possible role in counteracting mRNA decay. Using repeats of the prototype
destabilizing sequence UU(AUUU)nAUU, we show that all three HuD RNA-binding
domains participate in binding to AU-tracts that can be as short as 13 residues,
depending on the position of the remaining As. Removal of the A residues,
resulting in a poly(U)-tract, increased the affinity of HuD for RNA, suggesting
that the presence of As in destabilizing elements might favor the recruitment of
other proteins and/or prevent HuD from binding too tightly to AREs. In vitro
selection experiments with randomized RNAs confirmed the preference of HuD for
poly(U). RNA binding analysis of the related protein HuB showed a similar
preference for poly(U). In contrast, tristetraprolin, an mRNA destabilizing
protein, strongly prefers AU-rich RNA. Many labile mRNAs contain U-tracts in or
near their AREs. Individual AREs may thus differentially affect mRNA half-life
by recruiting a unique complement of stabilizing and destabilizing factors. Hu proteins are RNA-binding proteins that are implicated in the control of
stabilization, nuclear export, and/or translation of specific mRNAs with AU-rich
elements (AREs) in the 3'-untranslated region. Three neuron-specific Hu proteins
(HuD, HuB, and HuC), but not a ubiquitously expressed Hu protein HuR, have an
activity to induce neurite outgrowth when they are overexpressed in a rat
neuronal cell line PC12. Here we show that TAP/NXF1, the primary export receptor
for the bulk mRNA, is a specific binding partner for HuD. In vitro binding
experiments using recombit proteins revealed that the interaction between TAP
and HuD is direct and that HuD can form a ternary complex together with both TAP
and RNA. Interestingly, HuR does not interact with TAP. These results suggest
that HuD acts as a novel adaptor protein to recruit TAP for efficient export of
ARE-containing mRNAs in neuronal cells. BACKGROUND: There is often a poor correlation observed between protein and RNA
in eukaryotic systems, supporting the emerging pardigm that many of the
abnormalities in a cancer cell's proteome may be achieved by differential
recruitment of mRNAs to polysomes referred to as the translational profile. The
MCT-1 oncogene product has recently been shown to interact with the cap complex
and to modulate the translational profile of cell lines when MCT-1 was highly
expressed. The MCT-1 protein modifies mRNA translational profiles through its
interaction with DENR/DRP, a protein containing an SUI1 domain involved in
recognition of the translation initiation codon. It has been shown previously
that the protein levels of DENR/DRP go up in parallel with increasing cell
density, however the mechanism(s) underlying this increase is poorly understood
at present. The 3'-untranslated region (3'UTR) of DENR/DRP was found to have a
high number of uracyl (U)- and adenine (A)-rich sequences (AREs). Many
RNA-binding proteins (RBPs) have been shown to recognize and bind to mRNAs that
contains AREs generally present in the 3'UTR of mRNAs. RBPs binding to AREs such
as AUF1, BRF1, KSRP, and TTP are known to regulate mRNA turnover, while TIAR and
TIA-1 influence mRNA translation.
MATERIALS AND METHODS: We assessed the association of several ARE binding
proteins with DENR/DRP mRNA by reverse transcription of the RNA obtained after
immunoprecipitation of cell lysates from HEK 293 cells growing at varying levels
of cell density. HEK 293 cells were transfected with an AUF1 silencing vector
(shRNA), and protein levels of DENR/DRP were analyzed by Western blotting.
RESULTS: We demonstrated that both HuR and AUF1 bind to discrete regions of
DENR/DRP mRNA and that AUF1 silencing increases DENR/DRP protein levels.
CONCLUSION: Our data established a cell density-dependent interaction of AUF1
protein with DENR/DRP mRNA that modulates DENR/DRP protein levels. Regulator of G protein signaling 4 (RGS4) regulates the strength and duration of
G protein signaling and plays an important role in smooth muscle contraction,
cardiac development, and psychiatric disorders. Little is known about the
posttranscriptional regulation of RGS4 expression. We cloned the full-length
cDNA of rabbit RGS4, which contains a long 3'-untranslated region (UTR) with
several AU-rich elements (AREs). We determined whether RGS4 mRNA stability is
mediated by the RNA-binding protein human antigen R (HuR) and contributes to
IL-1β-induced upregulation of RGS4 expression. We show that IL-1β treatment in
colonic smooth muscle cells doubled the half-life of RGS4 mRNA. Addition of RGS4
3'-UTR to the downstream of Renilla luciferase reporter induced dramatic
reduction in the enzyme activity and mRNA expression of luciferase, which was
attenuated by the site-directed mutation of the two 3'-most ARE sites. IL-1β
increased luciferase mRNA stability in a UTR-dependent manner. Knockdown of HuR
significantly aggravated UTR-mediated instability of luciferase and inhibited
IL-1β-induced upregulation of RGS4 mRNA. In addition, IL-1β increased cytosolic
translocation and RGS4 mRNA binding of HuR. These findings suggest that 3'-most
ARE sites within RGS4 3'-UTR are essential for the instability of RGS4 mRNA and
IL-1β promotes the stability of RGS4 mRNA through HuR. Thrombospondin-1 (TSP-1) is a matricellular protein that participates in
numerous normal and pathological tissue processes and is rapidly modulated by
different stimuli. The presence of 8 highly-conserved AU rich elements (AREs)
within the 3'-untranslated region (3'UTR) of the TSP-1 mRNA suggests that
post-transcriptional regulation is likely to represent one mechanism by which
TSP-1 gene expression is regulated. We investigated the roles of these AREs, and
proteins which bind to them, in the control of TSP-1 mRNA stability. The
endogenous TSP-1 mRNA half-life is approximately 2.0 hours in HEK293 cells.
Luciferase reporter mRNAs containing the TSP-1 3'UTR show a similar rate of
decay, suggesting that the 3'UTR influences the decay rate. Site-directed
mutagenesis of individual and adjacent AREs prolonged reporter mRNA halflife to
between 2.2 and 4.4 hours. Mutation of all AREs increased mRNA half life to 8.8
hours, suggesting that all AREs have some effect, but that specific AREs may
have key roles in stability regulation. A labeled RNA oligonucleotide derived
from the most influential ARE was utilized to purify TSP-1 ARE-binding proteins.
The AU-binding protein AUF1 was shown to associate with this motif. These
studies reveal that AREs in the 3'UTR control TSP-1 mRNA stability and that the
RNA binding protein AUF1 participates in this control. These studies suggest
that ARE-dependent control of TSP-1 mRNA stability may represent an important
component in the control of TSP-1 gene expression. BACKGROUND: Bile salts increase intestinal mucosal proliferation through an
increase in c-Myc, a transcription factor that controls the expression of
numerous translation regulatory proteins. HuR is an RNA-binding protein that
regulates translation of target mRNAs. RNA-binding proteins can control mRNA
stability by binding to AU- and U-rich elements located in the 3'-untranslated
regions (3'-UTRs) of target mRNAs.
AIM: To determine how bile salt-induced c-Myc stimulates enterocyte
proliferation.
METHODS: Enterocyte proliferation was measured both in vivo using C57Bl6 mice
and in vitro using IEC-6 cells after taurodeoxycholate (TDCA) supplementation.
HuR and c-Myc protein expression was determined by immunoblot. c-Myc mRNA
expression was determined by PCR. HuR expression was inhibited using specific
small interfering RNA. HuR binding to c-Myc mRNA was determined by
immunoprecipitation.
RESULTS: TDCA increased enterocyte proliferation in vivo and in vitro. TDCA
stimulates translocation of HuR from the nucleus to the cytoplasm. Cytoplasmic
HuR regulates c-Myc translation by HuR binding to the 3'-UTR of c-Myc mRNA.
Increased TDCA-induced c-Myc increases enterocyte proliferation.
CONCLUSIONS: Bile salts have beneficial effects on the intestinal epithelial
mucosa, which are important in maintaining intestinal mucosal integrity and
function. These data further support an important beneficial role of bile salts
in regulation of mucosal growth and repair. Decreased enterocyte exposure to
luminal bile salts, as occurs during critical illness, liver failure,
starvation, and intestinal injury, may have a detrimental effect on mucosal
integrity. Complex regulation of brain-derived neurotrophic factor (BDNF) governs its
intricate functions in brain development and neuronal plasticity. Besides tight
transcriptional control from multiple distinct promoters, alternative 3'end
processing of the BDNF transcripts generates either a long or a short
3'untranslated region (3'UTR). Previous reports indicate that distinct RNA
sequence in the BDNF 3'UTRs differentially regulates BDNF production in the
brain to accommodate neuronal activity changes, conceivably through differential
interactions with undefined trans-acting factors that regulate stability and
translation of these BDNF mRNA isoforms. In this study, we report that the
neuronal RNA-binding protein (RBP) HuD interacts with a highly conserved AU-rich
element (ARE) specifically located in the BDNF long 3'UTR. Such interaction is
necessary and sufficient for selective stabilization of mRNAs that contain the
BDNF long 3'UTR in vitro and in vivo. Moreover, in a HuD transgenic mouse model,
the BDNF long 3'UTR mRNA is increased in the hippocampal dentate granule cells
(DGCs), leading to elevated expression of BDNF protein that is transported and
stored in the mossy fiber (MF) terminals. Our results identify HuD as the first
trans-acting factor that enhances BDNF expression specifically through the long
3'UTR and a novel mechanism that regulates BDNF protein production in selected
neuronal populations by HuD abundance. In the present study, we investigated the 3' untranslated region (UTR) of the
mouse core clock gene cryptochrome 1 (Cry1) at the post-transcriptional level,
particularly its translational regulation. Interestingly, the 3'UTR of Cry1 mRNA
decreased its mRNA levels but increased protein amounts. The 3'UTR is widely
known to function as a cis-acting element of mRNA degradation. The 3'UTR also
provides a binding site for microRNA and mainly suppresses translation of target
mRNAs. We found that AU-rich element RNA binding protein 1 (AUF1) directly binds
to the Cry1 3'UTR and regulates translation of Cry1 mRNA. AUF1 interacted with
eukaryotic translation initiation factor 3 subunit B and also directly
associated with ribosomal protein S3 or ribosomal protein S14, resulting in
translation of Cry1 mRNA in a 3'UTR-dependent manner. Expression of cytoplasmic
AUF1 and binding of AUF1 to the Cry1 3'UTR were parallel to the circadian CRY1
protein profile. Our results suggest that the 3'UTR of Cry1 is important for its
rhythmic translation, and AUF1 bound to the 3'UTR facilitates interaction with
the 5' end of mRNA by interacting with translation initiation factors and
recruiting the 40S ribosomal subunit to initiate translation of Cry1 mRNA. CXCR4 is a chemokine receptor that is overexpressed in certain cancer types and
involved in migration toward distant organs. The molecular mechanisms underlying
CXCR4 expression in invasive cancer, particularly posttranscriptional
regulation, are poorly understood. Here, we find that CXCR4 harbors AU-rich
elements (AREs) in the 3'-untranslated region (3'-UTR) that bind and respond to
the RNA-binding proteins, tristetraprolin (TTP/ZFP36) and HuR (ELAVL1).
Different experimental approaches, including RNA immunoprecipitation, 3'-UTR
reporter, RNA shift and messenger RNA (mRNA) half-life studies confirmed
functionality of the CXCR4 ARE. Wild-type TTP, but not the zinc finger mutant,
C124R, was able to bind CXCR4 mRNA and ARE. In the invasive breast cancer
phenotype, aberrant expression of CXCR4 is linked to both TTP deficiency and HuR
overexpression. HuR silencing led to decreased CXCR4 mRNA stability and
expression, and significant reduction in migration of the cells toward the CXCR4
ligand, CXCL12. Derepression of TTP using miR-29a inhibitor led to significant
reduction in CXCR4 mRNA stability, expression and migration capability of the
cells. The study shows that CXCR4 is regulated by ARE-dependent
posttranscriptional mechanisms that involve TTP and HuR, and that aberration in
this pathway helps cancer cells migrate toward the CXCR4 ligand. Targeting
posttranscriptional control of CXCR4 expression may constitute an alternative
approach in cancer therapy. BRCA1 tumor suppressor regulates crucial cellular processes involved in DNA
damage repair and cell cycle control. We showed that expression of BCR-ABL1
correlates with decreased level of BRCA1 protein, which promoted aberrant
mitoses and aneuploidy as well as altered DNA damage response. Using polysome
profiling and luciferase-BRCA1 3'UTR reporter system here we demonstrate that
downregulation of BRCA1 protein in CML is caused by inhibition of BRCA1 mRNA
translation, but not by increased protein degradation or reduction of mRNA level
and half-life. We investigated 2 mRNA-binding proteins - HuR and TIAR showing
specificity to AU-Rich Element (ARE) sites in 3'UTR of mRNA. BCR-ABL1 promoted
cytosolic localization of TIAR and HuR, their binding to BRCA1 mRNA and
formation of the TIAR-HuR complex. HuR protein positively regulated BRCA1 mRNA
stability and translation, conversely TIAR negatively regulated BRCA1
translation and was found localized predomitly in the cytosolic stress
granules in CML cells. TIAR-dependent downregulation of BRCA1 protein level was
a result of ER stress, which is activated in BCR-ABL1 expressing cells, as we
previously shown. Silencing of TIAR in CML cells strongly elevated BRCA1 level.
Altogether, we determined that TIAR-mediated repression of BRCA1 mRNA
translation is responsible for downregulation of BRCA1 protein level in BCR-ABL1
-positive leukemia cells. This mechanism may contribute to genomic instability
and provide justification for targeting PARP1 and/or RAD52 to induce synthetic
lethality in "BRCAness" CML and BCR-ABL1 -positive ALL cells. Tumor suppressor protein p53 plays a crucial role in maintaining genomic
integrity in response to DNA damage. Regulation of translation of p53 mRNA is a
major mode of regulation of p53 expression under genotoxic stress. The AU/U-rich
element-binding protein HuR has been shown to bind to p53 mRNA 3'UTR and enhance
translation in response to DNA-damaging UVC radiation. On the other hand, the
microRNA miR-125b is reported to repress p53 expression and stress-induced
apoptosis. Here, we show that UVC radiation causes an increase in miR-125b level
in a biphasic manner, as well as nuclear cytoplasmic translocation of HuR.
Binding of HuR to the p53 mRNA 3'UTR, especially at a site adjacent to the
miR-125b target site, causes dissociation of the p53 mRNA from the RNA-induced
silencing complex (RISC) and inhibits the miR-125b-mediated translation
repression of p53. HuR prevents the oncogenic effect of miR-125b by reversing
the decrease in apoptosis and increase in cell proliferation caused by the
overexpression of miR-125b. The antagonistic interplay between miR-125b and HuR
might play an important role in fine-tuning p53 gene expression at the
post-transcriptional level, and thereby regulate the cellular response to
genotoxic stress. mRNA metabolism is tightly orchestrated by highly-regulated RNA Binding Proteins
(RBPs) that determine mRNA fate, thereby influencing multiple cellular functions
across biological contexts. Here, we review the interplay between six well-known
RBPs (TTP, AUF-1, KSRP, HuR, TIA-1, and TIAR) that recognize AU-rich elements
(AREs) at the 3' untranslated regions of mRNAs, namely ARE-RBPs. Examples of the
links between their cross-regulations and modulation of their targets are
analyzed during mRNA processing, turnover, localization, and translational
control. Furthermore, ARE recognition can be self-regulated by several factors
that lead to the prevalence of one RBP over another. Consequently, we examine
the factors that modulate the dynamics of those protein-RNA transient
interactions to better understand the final consequences of the regulation
mediated by ARE-RBPs. For instance, factors controlling the RBP isoforms, their
conformational state or their post-translational modifications (PTMs) can
strongly determine the fate of the protein-RNA complexes. Moreover, mRNA
specific sequence and secondary structure or subtle environmental changes are
also key determits to take into account. To sum up, the whole understanding
of such a fine tuned regulation is a challenge for future research and requires
the integration of all the available structural and functional data by in vivo,
in vitro and in silico approaches. Nucleolin (NCL) is an abundant stress-responsive, RNA-binding phosphoprotein
that controls gene expression by regulating either mRNA stability and/or
translation. NCL binds to the AU-rich element (ARE) in the 3'UTR of target
mRNAs, mediates miRNA functions in the nearby target sequences, and regulates
mRNA deadenylation. However, the mechanism by which NCL phosphorylation affects
these functions and the identity of the deadenylase involved, remain largely
unexplored. Earlier we demonstrated that NCL phosphorylation is vital for cell
cycle progression and proliferation, whereas phosphorylation-deficient NCL at
six consensus CK2 sites confers domit-negative effect on proliferation by
increasing p53 expression, possibly mimicking cellular DNA damage conditions. In
this study, we show that NCL phosphorylation at those CK2 consensus sites in the
N-terminus is necessary to induce deadenylation upon oncogenic stimuli and UV
stress. NCL-WT, but not hypophosphorylated NCL-6/S*A, activates poly
(A)-specific ribonuclease (PARN) deadenylase activity. We further demonstrate
that NCL interacts directly with PARN, and under non-stress conditions also
forms (a) complex (es) with factors that regulate deadenylation, such as p53 and
the ARE-binding protein HuR. Upon UV stress, the interaction of
hypophosphorylated NCL-6/S*A with these proteins is favored. As an RNA-binding
protein, NCL interacts with PARN deadenylase substrates such as TP53 and BCL2
mRNAs, playing a role in their downregulation under non-stress conditions. For
the first time, we show that NCL phosphorylation offers specificity to its
protein-protein, protein-RNA interactions, resulting in the PARN deadenylase
regulation, and hence gene expression, during cellular stress responses. The zinc finger protein 36-like 2, ZFP36L2, is a member of a small family of
RNA-binding proteins composed by ZFP36 (also known as tristetraprolin, TTP),
ZFP36L1 and ZFP36L2 in humans, with corresponding murine orthologs. These
proteins bind to adenine uridine-rich element (ARE) in the 3'untranslated region
of target messenger RNA and stimulate target degradation. ZFP36 functions as an
anti-inflammatory modulator in murine models of inflammatory diseases by
down-regulating the production of inflammatory cytokines such as tumor necrosis
factor-α. However, how ZFP36L1 and ZFP36L2 alter the function of CD4+ T cells is
not completely understood. We addressed this issue by searching for the target
genes of ZFP36L2 by comprehensive transcriptome analysis. We observed that
ZFP36L2 is highly expressed in naïve CD4+ T cells; however, when CD4+ T cells
are stimulated through their T cell receptors, ZFP36L2 expression is rapidly
reduced in both humans and mice. Among CD4+ T cell populations, the expression
levels of ZFP36L2 in regulatory T cells (Tregs) were significantly lower than
those in naïve or effector CD4+ T cells. RNA-sequence analysis revealed that the
forced expression of ZFP36L2 decreased Ikzf2 (encoding Helios) expression in
Foxp3+ Tregs and inhibited the ability of induced Tregs (iTregs). ZFP36L2
directly bound to and destabilized the 3'untranslated region of Ikzf2 mRNA,
which contains AU-rich elements. These results indicate that ZFP36L2 reduces the
expression of Ikzf2 and suppresses iTreg function, raising the interesting
possibility that the inhibition of ZFP36L2 in iTregs could be a therapeutic
strategy for autoimmune diseases. |
Has CPX-351 been approved by the FDA and the EMA? | Yes, CPX-351 has been approved by the US FDA and the EMA. | BACKGROUND: CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a
dual-drug liposomal encapsulation of daunorubicin and cytarabine in a
synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the
treatment of adults with newly diagnosed therapy-related acute myeloid leukemia
or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal
phase 3 study that evaluated 309 patients aged 60 to 75 years with newly
diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly
improved median overall survival versus conventional 7 + 3 chemotherapy
(cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a
comparable safety profile. A Quality-adjusted Time Without Symptoms of disease
or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare
survival quality between patients receiving CPX-351 versus conventional 7 + 3
after 5 years of follow-up.
METHODS: Patients were randomized 1:1 between December 20, 2012 and November 11,
2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient
was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity
or prior to remission), TWiST (time in remission without relapse or grade 3 or 4
toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was
calculated by adding the mean time spent in each health state weighted by its
respective quality-of-life, represented by health utility. The relative Q-TWiST
gain, calculated as the difference in Q-TWiST between treatment arms divided by
the mean survival of the 7 + 3 control arm, was determined in order to evaluate
results in the context of other Q-TWiST analyses.
RESULTS: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the
base case scenario and 39.8% among responding patients. Across various
sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to
57.6%, remaining well above the standard clinically important difference
threshold of 15% for oncology.
CONCLUSIONS: This post hoc analysis demonstrates that CPX-351 improved
quality-adjusted survival, further supporting the clinical benefit in patients
with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial
registration This trial was registered on September 28, 2012 at
www.clinicaltrials.gov as NCT01696084 (
https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete. |
What is the role of KAT7 in AML? | KAT7 is a genetic vulnerability of acute myeloid leukemias driven by MLL rearrangements and more specifically driven by the MLL-X gene fusions. | |
Which drugs are included in the CAPIRI regimen? | CAPIRI regimen includes capecitabine plus irinotecan. | PURPOSE: To establish the feasibility and efficacy of capecitabine in
combination with weekly irinotecan (CAPIRI) with concurrent pelvic radiotherapy
(RT) in patients with locally advanced rectal cancer.
PATIENTS AND METHODS: Nineteen patients with rectal cancer clinical stage T3-4,
Nx received weekly irinotecan 50 mg/m(2) (days 1, 8, 15, 22, 29) and two doses
of capecitabine (days 1 through 38; dose level [DL] I, 500 mg/m(2) bid; DL II,
625 mg/m(2) bid) according to phase I methodology. Three-dimensional conformal
RT was given to a dose of 50.4 Gy (45 Gy + 5.4 Gy).
RESULTS: On DL I, no dose-limiting toxicities occurred, whereas diarrhea grade 3
affected three of seven patients on DL II. Twelve patients were treated on DL I
and received a median relative dose-intensity of 100% for both drugs. Grade 3 or
4 adverse events were observed in only one of these patients (asthenia grade 3).
All patients underwent surgery and R0 resection was achieved in all patients.
Pathologic complete remission was observed in four patients and another five
patients had only microfoci of residual tumor.
CONCLUSION: Preoperative chemoradiotherapy with CAPIRI is feasible and well
tolerated. The preliminary efficacy is good, and the tolerability is at least
comparable with data for fluorouracil plus irinotecan chemoradiotherapy. Larger
phase II trials of the CAPIRI-RT schedule clearly are warranted. We sought to evaluate the efficacy and safety data of a combination regimen
using weekly irinotecan in combination with capecitabine and concurrent
radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II
trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited
to receive irinotecan (50 mg m(-2) weekly) and capecitabine (500 mg m(-2) bid
days 1-38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4-6 weeks
after the completion of chemoradiation. A total of 36 patients (median age 62
years; m/f: 27:9) including three patients with local recurrence were enclosed
onto the trial. The median distance of the tumour from the anal verge was 5 cm.
The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/-/-;
leucocytopenia 12/7/7/2, diarrhoea 13/15/4/-, nausea/vomiting 9/10/2/-, and
increased activity of transaminases 3/3/1/-. One patient had a reversible
episode of ventricular fibrillation during chemoradiation, most probably caused
by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan
95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior
resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3).
R0-resection was accomplished in all patients. Two patients died in the
postoperative course from septic complications. Pathological complete remission
was observed in five out of 34 resected patients (15%), and nine patients showed
microfoci of residual tumour (26%). After a median follow-up of 28 months one
patient had developed a local recurrence, and five patients distant metastases.
Three-year overall survival for all patients with surgery (excluding three
patients treated for local relapse or with primary metastatic disease) was 80%.
In summary, preoperative chemoradiation with CapIri-RT exhibits promising
efficacy whereas showing managable toxicity. The local recurrence and distant
failure rates observed after a median 28 months are low compared with standard
5-fluorouracil based therapy. Colorectal cancer (CRC) is a worldwide public health problem, with nearly
800,000 new cases diagnosed each year, resulting in approximately 500,000
deaths. When advanced metastatic disease is diagnosed, CRC is associated with a
poor prognosis, and 5-year survival rates are in the range of 5%-8%.
Chemotherapy has been the mainstay approach for patients with advanced CRC. For
nearly 40 years, the main drug used for this disease was the fluoropyrimidine
5-fluorouracil (5-FU). Significant advances have been made in chemotherapy
treatment options for patients with metastatic disease, such that improvements
in 2-year survival are now being reported with median survival rates of 21
months to 24 months. Over the past 10 years, 3 new cytotoxic chemotherapy agents
have been approved by the FDA for metastatic CRC. These compounds include the
topoisomerase I inhibitor irinotecan, the third-generation platinum analogue
oxaliplatin, and the oral fluoropyrimidine capecitabine. Since 2004, 3 novel
biologic agents have been approved by the FDA, and they include the
anti-epidermal growth factor receptor antibodies cetuximab and panitumumab and
the anti-vascular endothelial growth factor bevacizumab. The oral
fluoropyrimidine capecitabine has been effectively and safely combined with
irinotecan (CAPIRI) and/or oxaliplatin (CAPOX). Three randomized phase III
studies have now shown that CAPOX is equivalent to FOLFOX
(5-FU/leucovorin/oxaliplatin)-based regimens. Significant interest has centered
around combining capecitabine-based cytotoxic regimens with the biologic agents,
and specifically, bevacizumab and cetuximab. This review will update the current
status of these capecitabine-based combination regimens. AIM: To investigate the efficacy and safety of cape-citabine plus irinotecan +/-
bevacizumab in advanced or metastatic colorectal cancer patients.
METHODS: Forty six patients with previously untreated, locally-advanced or
metastatic colorectal cancer (mCRC) were recruited between 2001-2006 in a
prospective open-label phase II trial, in German community-based outpatient
clinics. Patients received a standard capecitabine plus irinotecan (CAPIRI) or
CAPIRI plus bevacizumab (CAPIRI-BEV) regimen every 3 wk. Dose reductions were
mandatory from the first cycle in cases of > grade 2 toxicity. The treatment
choice of bevacizumab was at the discretion of the physician. The primary
endpoints were response and toxicity and secondary endpoints included
progression-free survival and overall survival.
RESULTS: In the CAPIRI group vs the CAPRI-Bev group there were more female than
male patients (47% vs 24%), and more patients had colon as the primary tumor
site (58.8% vs 48.2%) with fewer patients having sigmoid colon as primary tumor
site (5.9% vs 20.7%). Grade 3/4 toxicity was higher with CAPIRI than CAPIRI-Bev:
82% vs 58.6%. Partial response rates were 29.4% and 34.5%, and tumor control
rates were 70.6% and 75.9%, respectively. No complete responses were observed.
The median progression-free survival was 11.4 mo and 12.8 mo for CAPIRI and
CAPIRI-Bev, respectively. The median overall survival for CAPIRI was 15 mo (458
d) and for CAPIRI-Bev 24 mo (733 d). These differences were not statistically
different. In the CAPIRI-Bev, group, two patients underwent a full secondary
tumor resection after treatment, whereas in the CAPIRI group no cases underwent
this procedure.
CONCLUSION: Both regimens were well tolerated and offered effective tumor growth
control in this outpatient setting. Severe gastrointestinal toxicities and
thromboembolic events were rare and if observed were never fatal. BACKGROUND: To determine the efficacy and tolerability of capecitabine combined
with oxaliplatin (CAPOX) or irinotecan (CAPIRI) as first-line treatment in
patients with advanced/metastatic colorectal cancer aged > or =70 years.
PATIENTS AND METHODS: Patients aged > or =70 years were randomly assigned to
receive CAPOX [oxaliplatin 65 mg/m(2) intravenously (i.v.) days 1 and 8 and
capecitabine 1000 mg/m(2) orally b.i.d. days 1-14; q21d] or CAPIRI (irinotecan
80 mg/m(2) i.v. days 1 and 8 and capecitabine 1000 mg/m(2) orally b.i.d. days
1-14; q21d). The primary study end point was overall response rate (ORR).
RESULTS: Ninety-four patients were enrolled. In an intent-to-treat analysis, 2
complete responses (CRs) and 16 partial responses (PRs) were reported with CAPOX
(ORR 38%), and 2 CRs and 15 PRs with CAPIRI (ORR 36%; P = 0.831). Median time to
progression was 8 months for CAPOX and 7 months for CAPIRI (P = 0.195), with
median survival times of 19.3 months and 14.0 months (P = 0.165), respectively.
Global health status was improved in 45% and in 21% of patients in the CAPOX and
CAPIRI arms, respectively. The most common treatment-related grade 3-4 adverse
events in CAPIRI versus CAPOX patients were diarrhea (32% versus 15%; P = 0.052)
and neutropenia (23% versus 6%; P = 0.021).
CONCLUSION: CAPOX and CAPIRI had similar efficacy in elderly patients, although
CAPOX seemed to be better tolerated. PURPOSE: The AIO KRK-0104 randomized phase II trial investigated the efficacy
and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or
capecitabine and oxaliplatin (CAPOX) in the first-line treatment of metastatic
colorectal cancer (mCRC).
PATIENTS AND METHODS: A total of 185 patients with mCRC were randomly assigned
to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI
(irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice daily days 1
through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day
1; capecitabine 1,000 mg/m(2) twice daily day 1 through 14, every 3 weeks). The
primary study end point was objective response rate (ORR).
RESULTS: In the intention-to-treat patient population (n = 177), ORR was 46%
(95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for
CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in
81.4% of the intention to treat population. Patients with KRAS wild-type in the
CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS
of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1
months and an OS of 23.5 months were observed. While ORR and PFS were comparable
in KRAS wild-type and mutant subgroups, a trend toward longer survival was
associated with KRAS wild-type. Both regimens had manageable toxicity profiles
and were safe.
CONCLUSION: This randomized trial demonstrates that the addition of cetuximab to
CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the
analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation
status. BACKGROUND: To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in
comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic
colorectal cancer (mCRC).
METHODS: Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg(-1)
every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg(-1) every 3 weeks (Arm-B).
RESULTS: Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were
enrolled into the study. No difference was observed in median progression-free
survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5
months; P=0.55) or response rates (45.5 and 39.8.7%; P=0.32) for FOLFIRI-Bev and
CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented
significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia
(P=0.003) and hand-foot skin reactions (P=0.02) compared with patients treated
with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and
treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in
the CAPIRI-Bev arm.
CONCLUSION: The PFS of FOLFIRI-BEV is not superior to that observed with the
CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring
dose reductions, in order to be considered as an option in first-line treatment
of patients with mCRC. BACKGROUND: This study investigated the local effect and acute toxicity of
irinotecan and capecitabine with concurrent intensity-modulated radiation
therapy (IMRT) for the treatment of recurrent rectal cancer without prior pelvic
irradiation.
METHODS: Seventy-one patients diagnosed with recurrent rectal cancer who did not
previously receive pelvic irradiation were treated in our hospital from October
2009 to July 2012. Radiotherapy was delivered to the pelvis, and IMRT of 45 Gy
(1.8 Gy per fraction), followed by a boost of 10 Gy to 16 Gy (2 Gy per
fraction), was delivered to the recurrent sites. The concurrent chemotherapy
regimen was 50 mg/m(2) irinotecan weekly and 625 mg/m(2) capecitabine twice
daily (Mon-Fri). Radical surgery was recommended for medically fit patients
without extra-pelvic metastases. The patients were followed up every 3 months.
Tumor response was evaluated using CT/MRIs according to the RECIST criteria or
postoperative pathological findings. NCI-CTC 3.0 was used to score the
toxicities.
RESULTS: Forty-eight patients (67.6%) had confirmed recurrent rectal cancer
without extra pelvic metastases, and 23 patients (32.4%) had extra pelvic
metastases. Fourteen patients (19.7%) underwent radical resections (R0)
post-chemoradiation. A pathologic complete response was observed in 7 of 14
patients. A clinical complete response was observed in 4 patients (5.6%), and a
partial response was observed in 22 patients (31.0%). Only 5 patients (7.0%)
showed progressive disease during or shortly after treatment. Of 53 symptomatic
patients, clinical complete and partial symptom relief with chemoradiation was
achieved in 56.6% and 32.1% of patients, respectively. Only 2 patients (2.8%)
experienced grade 4 leukopenia. The most common grade 3 toxicity was diarrhea
(16 [22.5%] patients). The median follow-up was 31 months. The cumulative local
progression-free survival rate was 74.2% and 33.9% at 1 and 3 years after
chemoradiation, respectively. The cumulative total survival rate was 80.1% and
36.5% at 1 and 3 years after chemoradiation, respectively.
CONCLUSIONS: This study revealed that concurrent irinotecan and capecitabine
with IMRT significantly relieves local symptoms and exhibits promising efficacy
with manageable toxicities in recurrent rectal cancer without prior pelvic
irradiation. Improving the rate of R0 resections will be investigated in a
future study. ABT-751 is an orally bioavailable sulfonamide with antimitotic properties. A
nonrandomized phase 1 dose-escalation study of ABT-751 in combination with
CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the
maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics in
patients with advanced colorectal cancer. Patients were treated with ABT-751
daily for 7 days (alone) and then began 21-day cycles of treatment with ABT-751
daily and capecitabine twice daily for 14 days plus irinotecan on day 1
intravenously. Bevacizumab was added as standard of care at 7.5 mg/kg on day 1
after the first 2 dose levels. Because of intolerance to the regimen, a reduced
dose of ABT-751 was also explored with reduced-dose and full-dose CAPIRI with
bevacizumab. ABT-751 and irinotecan pharmacokinetics, ABT-751 glucuronidation,
and protein binding were explored. Twenty-four patients were treated over 5 dose
levels. The maximum tolerated dose was ABT-751 125 mg combined with full-dose
CAPIRI and bevacizumab 7.5 mg/kg on day 1. DLTs were hypokalemia, elevated liver
tests, and febrile neutropenia. ABT-751 is metabolized by UGT1A8 and to a lesser
extent UGT1A4 and UGT1A1. Irinotecan and APC exposure were increased, SN-38
exposure was similar, and SN-38 glucuronide exposure was decreased. Clinically
relevant alterations in ABT-751 and irinotecan pharmacokinetics were not
observed. Despite modest efficacy, the combination of ABT-751, CAPIRI, and
bevacizumab will not be studied further in colorectal cancer. Diversity in colorectal cancer biology is associated with variable responses to
standard chemotherapy. We aimed to identify and validate DNA hypermethylated
genes as predictive biomarkers for irinotecan treatment of metastatic CRC
patients. Candidate genes were selected from 389 genes involved in DNA Damage
Repair by correlation analyses between gene methylation status and drug response
in 32 cell lines. A large series of samples (n=818) from two phase III clinical
trials was used to evaluate these candidate genes by correlating methylation
status to progression-free survival after treatment with first-line single-agent
fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy
(Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the
discovery (n=185) and initial validation set (n=166), patients with methylated
Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine treatment
(discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI
0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 did (discovery set:
HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7,
p=0.0008)). These results could not be replicated in the external data set
(n=467), where a similar effect size was found in patients with methylated and
unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1: HR=0.7 (95%CI
0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). In
conclusion, DCR1 promoter hypermethylation status is a potential predictive
biomarker for response to treatment with irinotecan, when combined with
capecitabine. This finding could not be replicated in an external validation
set, in which irinotecan was combined with 5FU. These results underline the
challenge and importance of extensive clinical evaluation of candidate
biomarkers in multiple trials. PURPOSE: The aim of this randomized, multicenter, noncomparative, phase II trial
was to investigate the efficacy and safety of two potential first-line
treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and
capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with
metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS: Patients with untreated mCRC were randomly assigned to
receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and
oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2 on days 1-14,
every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg
and irinotecan 200 mg/m2 on day 1 and capecitabine 1,600 mg/m2 on days 1-14,
every 3 weeks). The primary endpoint was overall response rate (ORR), and the
secondary endpoints included progression-free survival (PFS), overall survival
(OS), and safety.
RESULTS: A total of 107 patients were enrolled. The intent-to-treat population
comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV
arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV
arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months
in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm,
respectively. The frequencies of hematological and nonhematological adverse
events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in
the CapIRI/BEV arm, respectively.
CONCLUSION: CapOX plus bevacizumab and CapIRI plus bevacizumab are equally
effective and feasible as the first-line treatments in Japanese patients with
mCRC.
IMPLICATIONS FOR PRACTICE: The CCOG-1201 study was designed to evaluate the
efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and
capecitabine and irinotecan plus bevacizumab as a first-line treatment in
Japanese patients with metastatic colorectal cancer. This article reports on the
trial and efforts to define the role of these regimens, including the effect of
KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer. BACKGROUND: Triweekly capecitabine plus irinotecan (CAPIRI) was not a
replacement for fluorouracil, leucovorin, and irinotecan (FOLFIRI) in the
treatment of metastatic colorectal cancer (mCRC) because of the potential for
greater toxicity. Recently, it has reported that mCAPIRI is well tolerated and
non-inferior to FOLFIRI. In this study, we conducted a multicenter phase II
trial to assess the efficacy and safety of biweekly CAPIRI plus bevacizumab as
second-line chemotherapy for mCRC with reduced toxicity and preserved efficacy.
METHODS: Patients with mCRC who had received prior chemotherapy, including
oxaliplatin-based regimens, were eligible for this study. The treatment protocol
administered capecitabine at 1000 mg/m2 twice daily from the evening of day 1 to
the morning of day 8, intravenous irinotecan at 150 mg/m2 on day 1, and
bevacizumab at 10 mg/kg on day 1 every 2 weeks. Primary endpoints for this study
were progression-free survival (PFS) and safety. Secondary endpoints were
overall survival (OS), time to treatment failure, response rate (RR), and
disease control rate (DCR).
RESULTS: Fifty-one patients were enrolled in this study. Median PFS was
5.5 months [95% confidence interval (CI) 4.23-7.40 months], and median OS was
13.5 months (95% CI 11.57-20.23 months). The RR was 14.6% (95% CI 6.5-28.4%),
and the DCR was 66.7% (95% CI 51.5-79.2%). Hypertension was the most common
Grade 3 adverse event (27.5%), followed by neutropenia (17.6%). Only two
patients suffered from grade 3 hand-foot syndrome.
CONCLUSIONS: In mCRC patients, biweekly CAPIRI + bevacizumab appears effective
and feasible as a second-line chemotherapy with relatively low toxicities, and
has potential as a useful substitute for FOLFIRI + bevacizumab. BACKGROUND: First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly
effective and regarded as one of the standards-of-care for patients with
metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia
and diarrhea as side effects. AXEPT, an Asian phase III study, showed that
modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m2), irinotecan (IRI:
200 mg/m2), and BEV (7.5 mg/m2)] was non-inferior to FOLFIRI+BEV as a
second-line therapy for mCRC patients and was associated with a lower incidence
of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in
combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible
than FOLFOXIRI+BEV, without compromising efficacy.
METHODS: QUATTRO-II is an open-label, multicenter, randomized phase II study. In
Step 1, the recommended doses of OX and IRI will be investigated as a safety
lead-in. In Step 2, patients will be randomized to the recommended dose of
either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV
treatments will be administered for up to 4 months followed by fluoropyrimidine
plus BEV maintece. The primary endpoint is progression-free survival (PFS).
The similarity in PFS between the two arms will be evaluated by observing
whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and
1.25. Ensuring a 70% probability that the observed HR will be "0.8 < HR < 1.25"
under the assumption of the true HR of 1.0, and 100 patients will be evaluated
during the 3-year study period. Secondary endpoints include overall survival,
overall response rate, safety, and patient reported outcome (PRO)
(FACT/GOG-Ntx4).
DISCUSSION: Considering the lower incidence of hematologic toxicities with
modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising
treatment option if sufficient efficacy and lower hematologic toxicities are
indicated in this study. Additionally, a lower incidence of peripheral sensory
neuropathy (PSN) reported following CAPEOX treatment compared to that after
FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can
mitigate OX-induced PSN.
TRIAL REGISTRATION: Clinicaltrials.gov NCT04097444 . Registered September 20,
2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of
Clinical Trials jRCTs041190072. Registered October 9, 2019. |
What is the p-crAssphage? | CrAssphage is the most abundant human-associated virus and the founding member of a large group of bacteriophages, discovered in animal-associated and environmental metagenomes, that infect bacteria of the phylum Bacteroidetes. | CrAssphage is the most abundant human-associated virus and the founding member
of a large group of bacteriophages, discovered in animal-associated and
environmental metagenomes, that infect bacteria of the phylum Bacteroidetes. We
analyze 4907 Circular Metagenome Assembled Genomes (cMAGs) of putative viruses
from human gut microbiomes and identify nearly 600 genomes of crAss-like phages
that account for nearly 87% of the DNA reads mapped to these cMAGs. Phylogenetic
analysis of conserved genes demonstrates the monophyly of crAss-like phages, a
putative virus order, and of 5 branches, potential families within that order,
two of which have not been identified previously. The phage genomes in one of
these families are almost twofold larger than the crAssphage genome (145-192
kilobases), with high density of self-splicing introns and inteins. Many
crAss-like phages encode suppressor tRNAs that enable read-through of UGA or UAG
stop-codons, mostly, in late phage genes. A distinct feature of the crAss-like
phages is the recurrent switch of the phage DNA polymerase type between A and B
families. Thus, comparative genomic analysis of the expanded assemblage of
crAss-like phages reveals aspects of genome architecture and expression as well
as phage biology that were not apparent from the previous work on phage
genomics. Recently, crAssphage has been proposed as a human-specific marker for tracking
fecal contamination. However, its performance has always been validated in a
limited number of host samples, which may obscure our understanding of its
utility. Furthermore, few studies have quantified confidence of fecal
contamination when using crAssphage. Here, we evaluate the performance and
confidence of crAssphage by analyzing a large panel of metagenomic data sets
combined with Bayesian analyses. Results demonstrate that crAssphage exhibits
superior performance with high host sensitivity and specificity, indicating its
suitability for tracking human fecal sources. With the marker, a high confidence
(>90%) can be obtained and particularly, multiple samples with positive results
provide a near certainty of confidence. The application of crAssphage in the
sediments of three Chinese urban rivers shows a high confidence of >97% of human
fecal contamination, suggesting the serious challenge of sewage pollution in
these environments. Additionally, significant correlation is observed between
crAssphage and antibiotic resistance genes (ARGs), expanding the utilization of
crAssphage for pollution management of ARGs. This study highlights the benefit
of using metagenomic-based analysis for evaluating the performance and
confidence of microbial source tracking markers in the coming era of big data
with increasing resources in available metagenomic data. |
What is the function of Circular RNA (circRNA)? | Circular RNAs (circRNAs) are a class of conserved, endogenous non-coding RNAs that are involved in transcriptional and post-transcriptional gene regulation as well as the pathogenesis of diseases. including cancer | AIMS: Circular RNA (circRNA) is a newly validated class of single-stranded RNA,
ubiquitously expressed in mammalian tissues and possessing key functions
including acting as microRNA sponges and as transcriptional regulators by
binding to RNA-binding proteins. While independent studies confirm the
expression of circRNA in various tissue types, genome-wide circRNA expression in
the heart has yet to be described in detail.
METHODS AND RESULTS: We performed deep RNA-sequencing on ribosomal-depleted RNA
isolated from 12 human hearts, 25 mouse hearts and across a 28-day
differentiation time-course of human embryonic stem cell-derived cardiomyocytes.
Using purpose-designed bioinformatics tools, we uncovered a total of 15 318 and
3017 cardiac circRNA within human and mouse, respectively. Their abundance
generally correlates with the abundance of their cognate linear RNA, but
selected circRNAs exist at disproportionately higher abundance. Top highly
expressed circRNA corresponded to key cardiac genes including Titin (TTN), RYR2,
and DMD. The most abundant cardiac-expressed circRNA is a cytoplasmic localized
single-exon circSLC8A1-1. The longest human transcript TTN alone generates up to
415 different exonic circRNA isoforms, the majority (83%) of which originates
from the I-band domain. Finally, we confirmed the expression of selected cardiac
circRNA by RT-PCR, Sanger sequencing and single molecule RNA-fluorescence in
situ hybridization.
CONCLUSIONS: Our data provide a detailed circRNA expression landscape in hearts.
There is a high-abundance of specific cardiac-expressed circRNA. These findings
open up a new avenue for future investigation into this emerging class of RNA. Circular RNAs (circRNAs) are currently classed as non-coding RNA (ncRNA) that,
unlike linear RNAs, form covalently closed continuous loops and act as gene
regulators in mammals. They were originally thought to represent errors in
splicing and considered to be of low abundance, however, there is now an
increased appreciation of their important function in gene regulation. circRNAs
are differentially generated by backsplicing of exons or from lariat introns.
Unlike linear RNA, the 3' and 5' ends normally present in an RNA molecule have
been joined together by covalent bonds leading to circularization.
Interestingly, they have been found to be abundant, evolutionally conserved and
relatively stable in the cytoplasm. These features confer numerous potential
functions to circRNAs, such as acting as miRNA sponges, or binding to
RNA-associated proteins to form RNA-protein complexes that regulate gene
transcription. It has been proposed that circRNA regulate gene expression at the
transcriptional or post-transcriptional level by interacting with miRNAs and
that circRNAs may have a role in regulating miRNA function in cancer initiation
and progression. circRNAs appear to be more often downregulated in tumor tissue
compared to normal tissue and this may be due to (i) errors in the back-splice
machinery in maligt tissues, (ii) degradation of circRNAs by deregulated
miRNAs in tumor tissue, or (iii) increasing cell proliferation leading to a
reduction of circRNAs. circRNAs have been identified in exosomes and more
recently, chromosomal translocations in cancer have been shown to generate
aberrant fusion-circRNAs associated with resistance to drug treatments. In
addition, though originally thought to be non-coding, there is now increasing
evidence to suggest that select circRNAs can be translated into functional
proteins. Although much remains to be elucidated about circRNA biology and
mechanisms of gene regulation, these ncRNAs are quickly emerging as potential
disease biomarkers and therapeutic targets in cancer. Circular RNAs (circRNAs) are a novel type of universal and diverse endogenous
noncoding RNAs (ncRNAs) and they form a covalently closed continuous loop
without 5' or 3' tails unlike linear RNAs. Most circRNAs are presented with
characteristics of abundance, stability, conservatism, and often exhibiting
tissue/developmental-stage-specific expression. CircRNAs are generated either
from exons or introns by back splicing or lariat introns. CircRNAs play
important roles as miRNA sponges, gene transcription and expression regulators,
RNA-binding protein (RBP) sponges and protein/peptide translators. Emerging
evidence revealed the function of circRNAs in cancer and may potentially serve
as a required novel biomarker and therapeutic target for cancer treatment. In
this review, we discuss about the origins, characteristics and functions of
circRNA and how they work as miRNA sponges, gene transcription and expression
regulators, RBP sponges in cancer as well as current research methods of
circRNAs, providing evidence for the significance of circRNAs in cancer
diagnosis and clinical treatment. Circular (circ)RNAs, naturally formed endogenous non-coding RNAs, have received
extensive attention in recent years due to their special loop structures and
specific function. circRNAs are formed with covalently closed continuous loops
and are mainly generated by back-splicing processes or lariat introns from exons
and/or introns. Usually, circRNAs are stable, abundant, and evolutionarily
conserved in the cytoplasm. circRNAs often exhibit abnormal expression in
different diseases, notably in human cancers, and the presence of abundant
circRNAs in serum, saliva and exosomes renders them potential diagnostic or
predictive biomarkers for diseases, including multiple types of cancer.
Presently, certain circRNAs have been reported to function as microRNA sponges
and RNA-binding protein sponges to regulate downstream gene transcription, which
suggests a potential for circRNAs in cancer diagnosis, prognosis and clinical
therapy. The present study assessed the latest advances in the study of circRNAs
in cancer, summarized the functions of circRNAs in different types of cancer,
highlighted the competing endogenous RNA function of circRNAs in the occurrence
and development of human maligcies, and provided evidence for the future
application of circRNAs in the diagnosis, prognosis and treatment of multiple
types of cancer. Circular RNAs (circRNAs) are a novel class of regulatory RNAs that despite being
relatively abundant have only recently begun to be explored. There are many
thousands of genes that appear capable of producing circRNAs, however the
function of all but a handful remain to be determined. What is emerging about
these highly conserved molecules is that they play important roles in biology
and cancer biology in particular. The most explored function of circRNAs is as
master regulators of gene expression that act to sequester or ´sponge´ other
gene expression regulators, in particular miRNAs. They have also been
demonstrated to function via direct modulation of transcription, and by
interfering with splicing mechanisms. Although generally expressed in low
abundance when compared to their linear counterparts, they are often expressed
in a tissue- and developmental stage- specific manner. Coupled with their
remarkable resistance to RNAse activity due to a covalent closed cyclic
structure, circRNAs show great promise as novel biomarkers of cancer and other
diseases. In this review we consider the current state of knowledge regarding
these molecules, their synthesis, function, and association with cancer. We will
also review some of the challenges that remain to be resolved if this emerging
class of RNAs are really to become useful in the clinic. Circular RNAs (circRNAs) are a type of single-stranded RNA molecules that
normally do not encode proteins. circRNAs are involved in many physiological
processes as well as the pathogenesis of diseases. Cardiac fibrosis is
increasingly recognized as a pathological force in advanced heart diseases. A
growing number of studies have reported that the occurrence and development of
cardiac fibrosis is closely associated with the regulation of circRNAs. This
review summarizes the current understanding of circRNA biogenesis and function
and will highlight the recent updates regarding the involvement of circRNAs in
cardiac fibrosis, and their potential as emerging biomarkers and therapeutic
targets. Circular RNAs (circRNAs) are covalently closed RNA molecules that have been
linked to various diseases, including cancer. However, a precise function and
working mechanism are lacking for the larger majority. Following many different
experimental and computational approaches to identify circRNAs, multiple circRNA
databases were developed as well. Unfortunately, there are several major issues
with the current circRNA databases, which substantially hamper progression in
the field. First, as the overlap in content is limited, a true reference set of
circRNAs is lacking. This results from the low abundance and highly specific
expression of circRNAs, and varying sequencing methods, data-analysis pipelines,
and circRNA detection tools. A second major issue is the use of ambiguous
nomenclature. Thus, redundant or even conflicting names for circRNAs across
different databases contribute to the reproducibility crisis. Third, circRNA
databases, in essence, rely on the position of the circRNA back-splice junction,
whereas alternative splicing could result in circRNAs with different length and
sequence. To uniquely identify a circRNA molecule, the full circular sequence is
required. Fourth, circRNA databases annotate circRNAs' microRNA binding and
protein-coding potential, but these annotations are generally based on presumed
circRNA sequences. Finally, several databases are not regularly updated, contain
incomplete data or suffer from connectivity issues. In this review, we present a
comprehensive overview of the current circRNA databases and their content,
features, and usability. In addition to discussing the current issues regarding
circRNA databases, we come with important suggestions to streamline further
research in this growing field. Author information:
(1)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang
Street 218, Changchun, Jilin 130041, China; Research Centre of the Second
Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041,
China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment
for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun,
Jilin 130041, China. Electronic address: [email protected].
(2)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang
Street 218, Changchun, Jilin 130041, China; Research Centre of the Second
Hospital of Jilin University, Ziqiang Street 218, Changchun, Jilin 130041,
China; The Engineering Research Centre of Molecular Diagnosis and Cell Treatment
for Metabolic Bone Diseases of Jilin Province, Ziqiang Street 218, Changchun,
Jilin 130041, China.
(3)Research Centre of the Second Hospital of Jilin University, Ziqiang Street
218, Changchun, Jilin 130041, China; The Engineering Research Centre of
Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin
Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic
address: [email protected].
(4)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang
Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of
Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin
Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic
address: [email protected].
(5)Department of Orthopedics, The Second Hospital of Jilin University, Ziqiang
Street 218, Changchun, Jilin 130041, China; The Engineering Research Centre of
Molecular Diagnosis and Cell Treatment for Metabolic Bone Diseases of Jilin
Province, Ziqiang Street 218, Changchun, Jilin 130041, China. Electronic
address: [email protected]. Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently
closed loops through backsplicing. Recent methodologies have enabled in-depth
characterization of circRNAs for identification and potential functions.
CircRNAs play important roles in various biological functions as microRNA
sponges, transcriptional regulators and combining with RNA binding proteins.
Recent studies indicated that some cytoplasmic circRNAs can be effectively
translated into detectable peptides, which enlightened us on the importance of
circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)-
and N6-methyladenosines (m6A)-mediated cap-independent translation initiation
have been suggested to be potential mechanism for circRNA translation. To date,
several translated circRNAs have been uncovered to play pivotal roles in human
cancers. In this review, we introduced the properties and functions of circRNAs,
and characterized the possible mechanism of translation initiation and
complexity of the translation ability of circRNAs. We summarized the emerging
functions of circRNA-encoded proteins in human cancer. The works on circRNA
translation will open a hidden human proteome, and enhance us to understand the
importance of circRNAs in human cancer, which has been poorly explored so far. Circular RNAs (circRNA) have been reported as regulators involved in
hepatocellular carcinoma (HCC), but their mechanism of activity remains unknown.
This study performed quantitative reverse-transcription polymerase chain
reaction to determine if circNFATC3 was downregulated in 46 paired HCC tissues
and cell lines. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,
apoptotic, and transwell assay proved that circNFATC3 can inhibit hepatoma cell
proliferation, apoptosis, and migration/invasion in vitro. Mouse xenograft assay
demonstrated that circNFATC3 suppressed tumor size and weight and reduced lung
metastasis in vivo, and vice versa. The RNA-seq results showed that NFATC3
itself was the most significantly differentially expressed gene when circNFATC3
was manipulated, and bioinformatics and luciferase reporter assays verified
circNFATC3 regulated the expression of NFATC3 by interacting with the
hsa-miR-548I. Additionally, it was also indicated that the level of NFATC3 was
downregulated in HCC patients also and was significantly correlated with the
staging and prognosis of HCC. Moreover, both circNFATC3 and NFATC3 were shown to
inhibit the phosphorylation of JNK, c-Jun, AKT, and mTOR signaling pathways.
Overall, the circNFATC3 can sponge miR-548I to protect NFATC3 itself, then it
regulates hepatoma cell function via the JNK, c-Jun, AKT, and mTOR signaling
pathways, and the circNFATC3 can be a tumor-repressor on HCC. Circular RNA (circRNA) participates in regulation of gene transcription, while
estrogen receptor alpha (ERα) and quercetin (QUE) positively regulate bone
formation, but little is known about the correlation among circRNA, ERα and QUE.
In this experiment, we created an ERα-deficient rBMSC model treated with QUE and
evaluated the effects of ERα or QUE on rBMSCs, then analyzed
differentially-expressed circRNAs by RNA-Seq and bioinformatics. The results
showed that ERα deficiency constrained osteogenic differentiation and stimulated
adipocytic differentiation of rBMSCs, while QUE abrogated those effects. We
identified 136 differentially-expressed circRNAs in the Lv-shERα group and 120
differentially-expressed circRNAs in the Lv-shERα + QUE group. Thirty-two
circRNAs retroregulated by ERα and QUE were involved in Rap1 and Wnt signaling,
and four of them together sponged miR-326-5p, the target genes of which are
osteogenic and adipogenic differentiation factors. Further study showed that
over-expressed miR-326-5p could stimulate osteogenic differentiation, while
attenuating adipogenic differentiation of rBMSCs. Therefore, we concluded that
ERα and QUE might regulate the differentiation of rBMSCs through the
circRNA-miR-326-5p-mRNA axis. BACKGROUND: Circular RNA (circRNA) plays an important role in regulating cell
biological function and has been shown to be involved in cancer progression,
including oral squamous cell carcinoma (OSCC). Circ-KIAA0907 has been found to
play an anti-cancer role in OSCC, so it is worth exploring more functions and
new mechanisms of circ-KIAA0907 in OSCC progression.
METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect the expression
of circ-KIAA0907, microRNA (miR)-96-5p, and unc-13 homolog C (UNC13C). Transwell
assay, flow cytometry, and colony formation assay were employed to measure the
migration, invasion, apoptosis, and radiosensitivity of cells. Besides, glucose
uptake, lactate production, and extracellular acidification rate (ECAR) were
determined to evaluate the glycolysis ability of cells. Dual-luciferase reporter
assay and RIP assay were performed to confirm the interactions among
circ-KIAA0907, miR-96-5p, and UNC13C. And RNA pull-down assay was used to verify
the binding degree of miR-96-5p to its targets. Moreover, UNC13C protein level
was examined using western blot (WB) analysis. OSCC xenograft models were
constructed to perform in vivo experiments.
RESULTS: Circ-KIAA0907 was a stability circRNA with lowly expression in OSCC.
Overexpressed circ-KIAA0907 could inhibit migration, invasion, and glycolysis,
while promoting apoptosis and radiosensitivity in OSCC cells. In the terms of
mechanism, circ-KIAA0907 could sponge miR-96-5p to regulate UNC13C expression.
MiR-96-5p overexpression could reverse the inhibitory effect of circ-KIAA0907 on
OSCC progression, and UNC13C knockdown also could overturn the suppressive
effect of miR-96-5p inhibitor on OSCC progression. Animal experiments revealed
that circ-KIAA0907 could reduce the tumor growth of OSCC by regulating the
miR-96-5p/UNC13C axis.
CONCLUSION: Our study suggests that circ-KIAA0907 restrains OSCC progression via
the miR-96-5p/UNC13C axis, indicating that it may be a potential target for OSCC
treatment. Circular RNA (or circRNA) is a type of single-stranded covalently closed
circular RNA molecule and play important roles in diverse biological pathways. A
comprehensive functionally annotated circRNA database will help to understand
the circRNAs and their functions. CircFunBase is such a web-accessible database
that aims to provide a high-quality functional circRNA resource including
experimentally validated and computationally predicted functions. CircFunBase
provides visualized circRNA-miRNA interaction networks. In addition, a genome
browser is provided to visualize the genome context of circRNA. In this chapter,
we illustrate examples of searching for circRNA and getting detailed information
of circRNA. Moreover, other circRNA related databases are outlined. Circular RNAs (circRNAs) are a class of conserved, endogenous non-coding RNAs
that are involved in transcriptional and post-transcriptional gene regulation
and are highly enriched in the nervous system. They participate in the survival
and differentiation of multiple nerve cells, and may even promote the recovery
of neurological function after stroke. However, their role in the inflammatory
response after spinal cord injury remains unclear. In the present study, we
established a mouse model of T9 spinal cord injury using the modified Allen's
impact method, and identified 16,013 circRNAs and 960 miRNAs that were
differentially expressed after spinal cord injury. Of these, the expression
levels of circPrkcsh were significantly different between injured and
sham-treated mice. We then treated astrocytes with tumor necrosis factor-α in
vitro to simulate the inflammatory response after spinal cord injury. Our
results revealed an elevated expression of circPrkcsh with a concurrent decrease
in miR-488 expression in injured cells. We also found that circPrkcsh regulated
the expression of the inflammation-related gene Ccl2. Furthermore, in tumor
necrosis factor-α-treated astrocytes, circPrkcsh knockdown decreased the
expression of Ccl2 by upregulating miR-488 expression, and reduced the secretion
of inflammatory cytokines in vitro. These findings suggest that differentially
expressed circRNAs participate in the inflammatory response after spinal cord
injury and act as the regulators of certain microRNAs. Furthermore, circPrkcsh
may be used as an miR-488 sponge to regulate Ccl2 expression, which might
provide a new potential therapy for SCI. The study was approved by the Animal
Ethics Committee of Shandong University of China (approval No. KYLL-20170303) on
March 3, 2017. Circular RNAs (circRNAs) are noncoding RNAs that form covalently closed loop
structures. CircRNAs are dysregulated in cancer and play key roles in
tumorigenesis, diagnosis, and tumor therapy. CircRNAs function as competing
endogenous RNAs or microRNA sponges that regulate transcription and splicing,
binding to proteins, and translation. CircRNAs may serve as novel biomarkers for
cancer diagnosis, and they show potential as therapeutic targets in cancers
including breast cancer (BC). In women, BC is the most common maligt tumor
worldwide and the second leading cause of cancer death. Although evidence
indicates that circRNAs play a critical role in BC, the mechanisms regulating
the function of circRNAs in BC remain poorly understood. Here, we provide
literature review aiming to clarify the role of circRNAs in BC and summarize the
latest research. We provide a systematic overview of the biogenesis and
biological functions of circRNAs, elaborate on the functional roles of circRNAs
in BC, and highlight the value of circRNAs as diagnostic and therapeutic targets
in BC. Circular RNA (circRNA) is a type of noncoding RNA that can interact with miRNAs
to regulate gene expression. However, little is known concerning circRNA, which
is crucial in the pathogenesis of lung cancer. To date, limited studies have
explored the role of circ_0044516 in lung cancer progression. Recently, we
observed that circ_0044516 expression levels were obviously elevated in lung
cancer tissues and cells. A549 and SPCA1 cells were transfected with
circ_0044516 siRNA. We observed that knockdown of circ_0044516 dramatically
repressed cell proliferation, increased cell apoptosis, and repressed the cell
cycle. Moreover, A549 and SPCA1 cell migration and invasion abilities were
greatly repressed by circ_0044516 siRNA. Due to accumulating evidence
demonstrating the vital role of cancer stem cells, their mechanism of
involvement has drawn increasing attention in tumor progression and metastasis
research. We also found that cancer stem cell properties were restrained by
silencing circ_0044516 in A549 and SPC-A1 cells. Moreover, in vivo xenograft
experiments showed that circ_0044516 downregulation reduced tumor growth.
Mechanistically, in lung cancer and using bioinformatics, we demonstrated that
circ_0044516 sponges miR-136 targeting MAT2A. Furthermore, rescue assays were
carried out to identify that circ_0044516 modulates cell proliferation,
invasion, and stemness by regulating miR-136 and MAT2A in lung cancer. In
summary, our study revealed that the circ_0044516/miR-136/MAT2A axis is involved
in lung cancer progression. Our findings may provide novel targets for diagnosis
and therapeutic intervention in lung cancer patients. Circular RNA (circRNA) is a highly stable, single-stranded, closed-loop RNA that
works as RNA or as a protein decoy to regulate gene expression. In humans,
thousands of circRNA transcriptional products precisely express in specific
developmental stages, tissues and cell types. Due to their stability and
specificity, circRNAs are ideal biomarkers for cancer diagnosis and prognosis.
To provide an integrated and standardized circRNA expression profile for human
cancers, we performed extensive data curation across 11 technical platforms,
collecting 48 expression profile data sets for 18 cancer types and amassing
860 751 expression records. We also identified 189 193 differential expression
signatures that are significantly different between normal and cancer samples.
All the pre-calculated expression analysis results are organized into 132 plain
text files for bulk download. Our online interface, circExp, provides data
browsing and search functions. For each data set, a dynamic expression heatmap
provides a profile overview. Based on the processed data, we found that 52
circRNAs were consistently and differentially expressed in 20 or more processed
analyses. By mapping those circRNAs to their parent protein-coding genes, we
found that they may have profoundly affected the survival of 10 797 patients in
the The Cancer Genome Atlas pan-cancer data set. In sum, we developed circExp
and demonstrated that it is useful to identify circRNAs that have potential
diagnostic and prognostic significance for a variety of cancer types. In this
online and reusable database, found at http://soft.bioinfo-minzhao.org/circexp,
we have provided pre-calculated expression data about circRNAs and their
parental genes, as well as data browsing and searching functions. Database URL:
http://soft.bioinfominzhao.org/circexp/. Colorectal cancer (CRC) is the 3rd most common type of cancer worldwide. Late
detection plays role in one-third of annual mortality due to CRC. Therefore, it
is essential to find a precise and optimal diagnostic and prognostic biomarker
for the identification and treatment of colorectal tumorigenesis. Covalently
closed, circular RNAs (circRNAs) are a class of non-coding RNAs, which can have
the same function as microRNA (miRNA) sponges, as regulators of splicing and
transcription, and as interactors with RNA-binding proteins (RBPs). Therefore,
circRNAs have been investigated as specific targets for diagnostic and
prognostic detection of CRC. These non-coding RNAs are also linked to
metastasis, proliferation, differentiation, migration, angiogenesis, apoptosis,
and drug resistance, illustrating the importance of understanding their
involvement in the molecular mechanisms of development and progression of CRC.
In this review, we present a detailed summary of recent findings relating to the
dysregulation of circRNAs and their potential role in CRC. Circular RNAs (circRNAs) are found across eukaryotes and can function in
post-transcriptional gene regulation. Their biogenesis through a circle-forming
backsplicing reaction is facilitated by reverse-complementary repetitive
sequences promoting pre-mRNA folding. Orthologous genes from which circRNAs
arise, overall contain more strongly conserved splice sites and exons than other
genes, yet it remains unclear to what extent this conservation reflects
purifying selection acting on the circRNAs themselves. Our analyses of circRNA
repertoires from five species representing three mammalian lineages (marsupials,
eutherians: rodents, primates) reveal that surprisingly few circRNAs arise from
orthologous exonic loci across all species. Even the circRNAs from orthologous
loci are associated with young, recently active and species-specific
transposable elements, rather than with common, ancient transposon integration
events. These observations suggest that many circRNAs emerged convergently
during evolution - as a byproduct of splicing in orthologs prone to transposon
insertion. Overall, our findings argue against widespread functional circRNA
conservation. |
Which one was the first chromone in clinical use? | The first chromone in clinical use, khellin. | The chromones are a class of chemical compounds characterised by the presence of
the structure 5:6 benz-1:4-pyrone in their chemical make-up. The first chromone
in clinical use, khellin, was extracted from the seeds of the plant Ammi
visnaga, and had been used for centuries as a diuretic and as a smooth muscle
relaxant. Its use in bronchial asthma was reported in 1947. In the 1950s,
Benger's Laboratories embarked on a research programme to synthesise and develop
modifications of khellin for the treatment of asthma. New compounds were
screened using animal models to test the ability of the compound to prevent the
anaphylactic release of histamine and SRS-A (leukotrienes) from sensitised
guinea pig lung, and a human model to check the ability to reduce the
bronchoconstriction induced by inhaled antigen bronchial challenge. For initial
screening the human work was undertaken by Dr. R.E.C. Altounyan, who suffered
from allergic bronchial asthma and was employed by Benger's Laboratories. After
8 years and more than 600 challenges using over 200 compounds, in 1965 Altounyan
arrived at disodium cromoglycate (DSCG), the chromone that met the criteria of
providing more than 6 h of protection. DSCG is still used today as a mast cell
stabiliser. |
Which resource is used for visualisation of non-covalent contacts? | The Protein Contacts Atlas is an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. The Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein-ligand contacts and by mapping external information. The Protein Contacts Atlas is available at http://www.mrc-lmb.cam.ac.uk/pca/ and also through PDBe. | |
Which disease is treated with Emapalumab? | Emapalumab is a human monoclonal antibody directed against interferon-γ (IFN-γ) that was approved by the Food and Drug Administration for primary hemophagocytic lymphohistiocytosis (HLH). | Emapalumab-Izsg (hereafter referred to as emapalumab) [Gamifant®] is a
monoclonal antibody directed against interferon gamma that is available as an
intravenous infusion. Emapalumab is being developed by Novimmune and Swedish
Orphan Biovitrum for the treatment of haemophagocytic lymphohistiocytosis (HLH).
In November 2018, emapalumab received its first global approval in the USA, for
the treatment of paediatric (newborn and older) and adult patients with primary
HLH, who have refractory, recurrent or progressive disease or intolerance to
conventional HLH therapy. Emapalumab is under regulatory review in the EU for
the treatment of primary HLH. This article summarizes the milestones in the
development of emapalumab leading to this first global approval for HLH in the
USA. Emapalumab is a fully human immunoglobulin G1 monoclonal antibody directed
against interferon-γ (IFN-γ), which in November 2018 received the first global
approval for the treatment of pediatric and adult patients with primary
hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or
progressive disease or intolerance to HLH therapy. This review will highlight
the pathophysiology of primary HLH, the therapeutic rationale for use of
IFN-γ-targeting therapy, and potential limitations to its broader use in the
treatment of HLH. BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome
characterized by immune dysregulation and hyperinflammation. It typically
manifests in infancy and is associated with high mortality.
METHODS: We investigated the efficacy and safety of emapalumab (a human
anti-interferon-γ antibody), administered with dexamethasone, in an open-label,
single-group, phase 2-3 study involving patients who had received conventional
therapy before enrollment (previously treated patients) and previously untreated
patients who were 18 years of age or younger and had primary hemophagocytic
lymphohistiocytosis. The patients could enter a long-term follow-up study until
1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year
after the last dose of emapalumab, if transplantation was not performed. The
planned 8-week treatment period could be shortened or extended if needed
according to the timing of transplantation. The primary efficacy end point was
the overall response, which was assessed in the previously treated patients
according to objective clinical and laboratory criteria.
RESULTS: At the cutoff date of July 20, 2017, a total of 34 patients (27
previously treated patients and 7 previously untreated patients) had received
emapalumab; 26 patients completed the study. A total of 63% of the previously
treated patients and 65% of the patients who received an emapalumab infusion had
a response; these percentages were significantly higher than the prespecified
null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously
treated group, 70% of the patients were able to proceed to transplantation, as
were 65% of the patients who received emapalumab. At the last observation, 74%
of the previously treated patients and 71% of the patients who received
emapalumab were alive. Emapalumab was not associated with any organ toxicity.
Severe infections developed in 10 patients during emapalumab treatment.
Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.
CONCLUSIONS: Emapalumab was an efficacious targeted therapy for patients with
primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the
European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers,
NCT01818492 and NCT02069899.). Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune
system activation driven mainly by high levels of interferon gamma. The clinical
presentation of HLH can have considerable overlap with other inflammatory
conditions. We present a cohort of patients with therapy refractory HLH referred
to our center who were found to have a simultaneous presentation of
complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had
therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger).
Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal
replacement therapy, severe hypertension, serositis, and gastrointestinal
bleeding were documented only in patients with HLH who had concomitant
complement-mediated TMA. Patients with HLH and without TMA required ventilator
support mainly due to CNS symptoms, while those with HLH and TMA had respiratory
failure predomitly associated with pulmonary hypertension, a known
presentation of pulmonary TMA. Ten patients received eculizumab for
complement-mediated TMA management while being treated for HLH. All patients who
received the complement blocker eculizumab in addition to the interferon gamma
blocker emapalumab had complete resolution of their TMA and survived. Our
observations suggest co-activation of both interferon and complement pathways as
a potential culprit in the evolution of thrombotic microangiopathy in patients
with inflammatory disorders like refractory HLH and may offer novel therapeutic
approaches for these critically ill patients. TMA should be considered in
children with HLH and multi-organ failure, as an early institution of a brief
course of complement blocking therapy in addition to HLH-targeted therapy may
improve clinical outcomes in these patients. Emapalumab-Igsz (Gamifant) is a human monoclonal antibody directed against
interferon-γ (IFN-γ), and the first Food and Drug Administration (FDA)-approved
therapy for primary hemophagocytic lymphohistiocytosis (HLH). HLH is a disorder
characterized by hypercytokinemia in the setting of unbridled immune activation,
and emapalumab represents the first therapeutic developed to address the
underlying pathophysiology of HLH. Emapalumab is approved for treatment of
primary HLH that is refractory, recurrent, progressing or intolerant to current
HLH treatments in both adult and pediatric patients. FDA approval was based on
the results of a phase II/III clinical trial evaluating the safety and efficacy
of emapalumab in 34 pediatric patients with primary HLH, 27 of whom were
refractory to current therapies. Additional studies of emapalumab are currently
ongoing in adults and other pediatric populations. Here, we will review the
pharmacology, safety and efficacy of emapalumab for the treatment of HLH. Emapalumab, a fully human anti-IFNγ monoclonal antibody, has been approved in
the US as second-line treatment of primary hemophagocytic lymphohistiocytosis
(HLH) patients and has shown promise in patients with graft failure (GF)
requiring a second allogeneic hematopoietic stem cell transplantation (HSCT).
The blockade of IFNγ activity may increase the risk of severe infections,
including fatal mycobacteriosis. We report a case of secondary HLH-related GF in
the context of HLA-haploidentical HSCT successfully treated with emapalumab in
the presence of concomitant life-threatening infections, including disseminated
tuberculosis (TB). A 4 years old girl with Adenosine Deaminase-Severe Combined
Immunodeficiency complicated by disseminated TB came to our attention for
ex-vivo hematopoietic stem cell-gene therapy. After engraftment failure of gene
corrected cells, she received two HLA-haploidentical T-cell depleted HSCT from
the father, both failed due to GF related to concomitant multiple infections and
secondary HLH. Emapalumab administration allowed to control HLH, as well as to
prevent GF after a third haplo-HSCT from the mother. Remarkably, all infections
improved with antimicrobial medications and disseminated TB did not show any
reactivation. This seminal case supports emapalumab use for treatment of
secondary HLH and prevention of GF in patients undergoing haplo-HSCT even in the
presence of multiple infections, including TB. Primary Hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening,
hyperinflammatory disorder, characterized by uncontrolled activation of the
immune system. Mutations affecting several genes coding for proteins involved in
the cytotoxicity machinery of both natural killer (NK) and T cells have been
found to be responsible for the development of pHLH. So far, front-line
treatment, established on the results of large international trials, is based on
the use of glucocorticoids, etoposide ± cyclosporine, followed by allogeneic
hematopoietic stem cell transplantation (HSCT), the sole curative treatment for
the genetic forms of the disease. However, despite major efforts to improve the
outcome of pHLH, many patients still experience unfavorable outcomes, as well as
severe toxicities; moreover, treatment-refractory or relapsing disease is a
major challenge for pediatricians/hematologists. In this article, we review the
epidemiology, etiology and pathophysiology of pHLH, with a particular focus on
different cytokines at the origin of the disease. The central role of
interferon-γ (IFNγ) in the development and maintece of hyperinflammation is
analyzed. The value of emapalumab, a novel IFNγ-neutralizing monoclonal antibody
is discussed. Available data support the use of emapalumab for treatment of pHLH
patients with refractory, recurrent or progressive disease, or intolerance to
conventional therapy, recently, leading to FDA approval of the drug for these
indications. Additional data are needed to define the role of emapalumab in
front-line treatment or in combination with other drugs. Interferon-gamma (IFN-γ) plays a key role in the pathophysiology of
hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to
a role in other conditions, including aplastic anemia (AA) and graft failure
following allogeneic hematopoietic stem cell transplantation. Recently, the
therapeutic potential of IFN-γ inhibition has been documented; emapalumab, an
anti-IFN-γ monoclonal antibody, has been approved in the United States for
treatment of primary HLH that is refractory, recurrent or progressive, or in
patients with intolerance to conventional therapy. Moreover, ruxolitinib, an
inhibitor of JAK/STAT intracellular signaling, is currently being investigated
for treating HLH. In AA, IFN-γ inhibits hematopoiesis by disrupting the
interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a
small-molecule agonist of c-MPL, acts at a different binding site to IFN-γ and
is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate
the role of IFN-γ neutralization in secondary HLH and future studies could
explore this strategy in controlling hyperinflammation due to CAR T cells. INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare
life-threatening hyperinflammatory syndrome. Standard treatment is based on
immunosuppressive, cytotoxic drugs and hematopoietic stem cell transplantation
(HSCT) in primary HLH. Interferon-gamma (IFN-γ) plays a key pathogenic role.
Emapalumab, a monoclonal antibody directed against IFN-γ, is the first target
therapy approved for primary HLH with refractory, recurrent or progressive
disease or intolerance to conventional therapy.
AREAS COVERED: We reviewed the pharmacological characteristics, safety, efficacy
and clinical uses of emapalumab. We summarized the results of current standard
treatment based on chemo-immunosuppressive protocols and outlined the
alternative options available.
EXPERT OPINION: Emapalumab is an effective treatment for HLH with a good safety
profile. Its efficacy was demonstrated in a phase II/III study on primary HLH
pediatric patients with refractory, relapsing HLH or intolerance to first-line
treatment. The use of emapalumab allowed most patients to proceed to HSCT, with
a high estimated probability of survival 12 months after transplantation. The
outcomes in patients who underwent transplantation compare favorably with those
reported previously with either myeloablative or reduced-intensity conditioning
regimens. The potential role of emapalumab in the treatment of secondary HLH and
as a prevention of graft failure after HSCT deserves to be further assessed. Primary (familial/hereditary) and secondary (non-familial/hereditary)
hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and
hypercytokinemic syndromes. Secondary HLH includes infection- (eg
viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or
maligcy) related diseases. Viral HLH is the major type among all age groups.
Secondary viral HLH and primary HLH must be differentiated carefully because
primary HLH can be associated with viral infection(s), and the outcome is dismal
without a timely diagnosis and hematopoietic stem cell transplantation (HSCT).
Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral
HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection,
followed by immunomodulatory agent(s) such as corticosteroids, intravenous
immunoglobulin or cyclosporine A, is usually successful; however, recent
SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur
heterogeneously associated with the primary infection, with chronic active EBV
infection or with underlying primary HLH. Although immunomodulatory agent(s) are
effective in the majority of EBV-HLH cases, management differs from that of
non-EBV-HLH because severe and refractory cases may require etoposide-containing
HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab
(an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid
the risk of secondary maligcy due to etoposide. Finally, HSCT is required for
refractory EBV-HLH cases and can also be curative in some other cases. |
Do we find bacteriophages in the gut? | yes,
Bacterial viruses (bacteriophages, phages) of the gut have increasingly become a focus in microbiome studies, with an understanding that they are likely key players in health and disease. | We are surrounded by microbes, mostly bacteria and their viruses or phages, on
the inside and outside of our bodies. These bacteria in constant interactions
with phages are regulating multiple functions critical to our health. Luckily,
they are amenable, but we need precise tools for their safe manipulation and
improving human health. Here, we argue that recent advances in single-cell
technologies, culturomics and synthetic biology offer exciting opportunities to
create these tools as well as revealing specific phages-bacteria interactions in
the body. The concept of (bacterio)phage therapy is simple; target the phage to the
bacterial pathogen causing disease. As phages are natural killers of bacteria,
one could expect this to be an easy task. However, when it comes to phage
therapy within the gut, it might not be quite that simple. Already without
exogenous intervention, a multitude of phage-bacterial interactions occur within
the human gut, some of which might play a direct role in disease progression. In
this perspective, we aim to summarise the current understanding of phages within
our gut, moving from infancy, adulthood, and then into disease progression. We
then highlight recent advances in phage-based interventions, both conventional
phage therapy and the progressing field of whole virome transplant. Bacterial viruses (bacteriophages, phages) of the gut have increasingly become a
focus in microbiome studies, with an understanding that they are likely key
players in health and disease. However, characterization of the virome remains
largely based on bioinformatic approaches, with the impact of these viromes
inferred based on a century of knowledge from aerobic phage work. Studying the
phages infecting anaerobes is difficult, as they are often technically demanding
to isolate and propagate. In this review, we primarily discuss the phages
infecting three well-studied anaerobes in the gut: Bifidobacterium, Clostridia
and Bacteroides, with a particular focus on the challenges in isolating and
characterizing these phages. We contrast the lessons learned from these to other
anaerobic work on phages infecting facultative anaerobes of the gut:
Enterococcus and Lactobacillus. Phages from the gut do appear to adhere to the
lessons learned from aerobic work, but the additional challenges of working on
them has required ingenious new approaches to enable their study. This, in turn,
has uncovered remarkable biology likely underpinning phage-host relationships in
many stable environments. Since the outset of the coronavirus disease 2019 (COVID-19) pandemic, the gut
microbiome in COVID-19 has garnered substantial interest, given its significant
roles in human health and pathophysiology. Accumulating evidence is unveiling
that the gut microbiome is broadly altered in COVID-19, including the bacterial
microbiome, mycobiome, and virome. Overall, the gut microbial ecological network
is significantly weakened and becomes sparse in patients with COVID-19, together
with a decrease in gut microbiome diversity. Beyond the existence of severe
acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the gut microbiome
of patients with COVID-19 is also characterized by enrichment of opportunistic
bacteria, fungi, and eukaryotic viruses, which are also associated with disease
severity and presentation. Meanwhile, a multitude of symbiotic bacteria and
bacteriophages are decreased in abundance in patients with COVID-19. Such gut
microbiome features persist in a significant subset of patients with COVID-19
even after disease resolution, coinciding with 'long COVID' (also known as
post-acute sequelae of COVID-19). The broadly-altered gut microbiome is largely
a consequence of SARS-CoV-2infection and its downstream detrimental effects on
the systemic host immunity and the gut milieu. The impaired host immunity and
distorted gut microbial ecology, particularly loss of low-abundance beneficial
bacteria and blooms of opportunistic fungi including Candida, may hinder the
reassembly of the gut microbiome post COVID-19. Future investigation is
necessary to fully understand the role of the gut microbiome in host immunity
against SARS-CoV-2 infection, as well as the long-term effect of COVID-19 on the
gut microbiome in relation to the host health after the pandemic. |
What is the function of the protein encoded by PUMILIO1? | Pumilio1 (Pum1) has been shown to play key roles in translational regulation of target mRNAs in many systems of diverse organisms. | Puf proteins bind RNA sequence specifically and regulate translation and
stability of target mRNAs. A "code" for RNA recognition has been deduced from
crystal structures of the Puf protein, human Pumilio1, where each of eight
repeats binds an RNA base via a combination of three side chains at conserved
positions. Here, we report the creation of seven soluble mutant proteins with
predictably altered sequence specificity, including one that binds tightly to
adenosine-uracil-rich element RNA. These data show that Pumilio1 can be used as
a scaffold to engineer RNA-binding proteins with designed sequence specificity. Human PUMILIO1 (PUM1) and PUMILIO2 (PUM2) are members of the PUMILIO/FBF (PUF)
family that regulate specific target mRNAs posttranscriptionally. Recent studies
have identified mRNA targets associated with human PUM1 and PUM2. Here, we
explore the structural basis of natural target RNA recognition by human PUF
proteins through crystal structures of the RNA-binding domains of PUM1 and PUM2
in complex with four cognate RNA sequences, including sequences from p38α and
erk2 MAP kinase mRNAs. We observe three distinct modes of RNA binding around the
fifth RNA base, two of which are different from the prototypical 1 repeat:1 RNA
base binding mode previously identified with model RNA sequences. RNA-binding
affinities of PUM1 and PUM2 are not affected dramatically by the different
binding modes in vitro. However, these modes of binding create structurally
variable recognition surfaces that suggest a mechanism in vivo for recruitment
of downstream effector proteins defined by the PUF:RNA complex. Author information:
(1)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at
Texas Children's Hospital, Houston, TX 77030, USA.
(2)Department of Pathology and Immunology, Baylor College of Medicine, Houston,
TX 77030, USA.
(3)Department of Pathology and Immunology, Baylor College of Medicine, Houston,
TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston,
TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas
Children's Hospital, Houston, TX 77030, USA.
(4)Program in Developmental Biology, Baylor College of Medicine, Houston, TX
77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas
Children's Hospital, Houston, TX 77030, USA.
(5)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of
Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research
Institute at Texas Children's Hospital, Houston, TX 77030, USA.
(6)Department of Pathology and Immunology, Baylor College of Medicine, Houston,
TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine,
Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor
College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor
College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology
and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
(7)Institute for Translational Neuroscience, Department of Laboratory Medicine
and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
(8)Department of Pathology and Immunology, Baylor College of Medicine, Houston,
TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston,
TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine,
Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at
Texas Children's Hospital, Houston, TX 77030, USA.
(9)Department of Molecular and Human Genetics, Baylor College of Medicine,
Houston, TX 77030, USA; Department of Pathology and Immunology, Baylor College
of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor
College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute,
Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics,
Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan
Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030,
USA. Electronic address: [email protected]. Pumilio is a member of the highly conserved PUF family of RNA-binding proteins
that function as a developmental regulator in diverse animal species. Two
Pumilio genes, Pum1 and Pum2, have been identified in mammals and are found to
be involved in sperm development, neuron development as well as human diseases
such as neurodegeneration. Generation of animal models disrupting different
parts of Pum protein could help to further dissect their physiological function.
Here we described characterization and analysis of a mouse line possessing a
gene trap mutation of the Pumilio1 (Pum1) gene. Mice homozygous for the mutation
(Pum1(XE002)) cannot be recovered in the adult offspring, at birth or at
different time points of embryonic development (E18, E14, E12). Careful analysis
of preimplantation embryos showed that no homozygous blastocysts could be
detected on day 3.5 of gestation. 96-hr in vitro culture of 1-cell embryos
either by natural mating or in vitro fertilization between heterozygotes failed
to uncover any homozygous blastocysts, suggesting an early loss of homozygous
preimplantation embryos. The lack of Pum1 gene trap homozygotes suggests a role
of Pum1 in very early embryonic development or fertilization. This novel animal
model affecting the beginning of embryonic development could help to understand
not only the genetic mechanism underlying preimplantation embryonic development
but also the translational regulation in development and diseases. SummaryTranslational regulation of mRNAs is crucial for promoting various
cellular and developmental processes. Pumilio1 (Pum1) has been shown to play key
roles in translational regulation of target mRNAs in many systems of diverse
organisms. In zebrafish immature oocytes, Pum1 was shown to bind to cyclin B1
mRNA and promote the formation of cyclin B1 RNA granules. This Pum1-mediated RNA
granule formation seemed critical to determine the timing of translational
activation of cyclin B1 mRNA during oocyte maturation, leading to activation of
maturation/M-phase-promoting factor (MPF) at the appropriate timing. Despite its
fundamental importance, the mechanisms of translational regulation by Pum1
remain elusive. In this study, we examined the phosphorylation of Pum1 as a
first step to understand the mechanisms of Pum1-mediated translation. SDS-PAGE
analyses and phosphatase treatments showed that Pum1 was phosphorylated at
multiple sites during oocyte maturation. This phosphorylation began in an early
period after induction of oocyte maturation, which preceded the polyadenylation
of cyclin B1 mRNA. Interestingly, depolymerization of actin filaments in
immature oocytes caused phosphorylation of Pum1, disassembly of cyclin B1 RNA
granules, and polyadenylation of cyclin B1 mRNA but not translational activation
of the mRNA. Overexpression of the Pum1 N-terminus prevented the phosphorylation
of Pum1, disassembly of cyclin B1 RNA granules, and translational activation of
the mRNA even after induction of oocyte maturation. These results suggest that
Pum1 phosphorylation in the early period of oocyte maturation is one of the key
processes for promoting the disassembly of cyclin B1 RNA granules and
translational activation of target mRNA. The elimination of schistosomiasis, a parasitic disease caused by Schistosoma
and a major source of morbidity and mortality in developing countries, faces
serious challenges. Although the pumilio protein regulates the reproductive
organ development in many species, its role in Schistosoma japonicum is unknown.
Thus, this study investigated the function of pumilio in S. japonicum
reproduction. The complete coding sequences of S. japonicum Pumilio1 (SjPum1)
and SjPum2 genes were cloned and characterized. The full-length open-reading
frame SjPum1 (2613 nucleotides) and SjPum2 (4479 nucleotides) genes were
obtained. Bioinformatics analysis showed that those genes belonged to the PUF
(pumilio and FBF) family. Quantitative polymerase chain reaction analyses
revealed that SjPum1 and SjPum2 were differentially expressed throughout the S.
japonicum life cycle and were highly expressed in reproductive organs. In situ
hybridization results showed that mRNA expression of SjPum2 was higher than that
of SjPum1 in the ovary and testis. Knocking down SjPum2 using RNA interference
techniques to explore potential reproductive functions showed that compared with
the control (untransfected or scrambled mRNA-transfected) worms, the morphology
of both male and female reproductive organs was altered, the number of eggs
produced by paired females was significantly decreased, and the transcription
levels of caspase 3 and caspase 7 genes related to apoptosis were significantly
increased. The transcription level of Nanos1 gene which related to reproduction
was also significantly increased. Therefore, SjPum2 may play a role in the
reproductive development of S. japonicum. Posttranscriptional regulation plays a fundamental role in the biology of
embryonic stem cells (ESCs). Many studies have demonstrated that multiple mRNAs
are coregulated by one or more RNA-binding proteins (RBPs) that orchestrate mRNA
expression. A family of RBPs, which is known as the Pumilio-FBF (PUF) family, is
highly conserved among different species and has been associated with the
undifferentiated and differentiated states of different cell lines. In humans,
two homologs of the PUF family have been found: Pumilio 1 (PUM1) and Pumilio 2
(PUM2). To understand the role of these proteins in human ESCs (hESCs), we first
assessed the influence of the silencing of PUM1 and PUM2 on pluripotency genes
and found that the knockdown of Pumilio genes significantly decreased the OCT4
and NANOG mRNA levels and reduced the amount of nuclear OCT4, which suggests
that Pumilio proteins play a role in the maintece of pluripotency in hESCs.
Furthermore, we observed that PUM1-and-PUM2-silenced hESCs exhibited improved
efficiency of in vitro cardiomyogenic differentiation. Through an in silico
analysis, we identified mRNA targets of PUM1 and PUM2 that are expressed at the
early stages of cardiomyogenesis, and further investigation will determine
whether these target mRNAs are active and involved in the progression of
cardiomyogenesis. Our findings contribute to the understanding of the role of
Pumilio proteins in hESC maintece and differentiation. Colon cancer is the third leading cause of death worldwide and sixth in India,
where it is the cause of 5.8% of the total deaths. Pumilio-1 (PUM1) is an RNA
binding protein whose regulatory role is by binding to the consensus
5'UGUANAUA3' sequence on the 3'UTR of the mRNA targets and
post-transcriptionally repressing their expression. This study is the first of
its kind to report the expression or function of PUM1 in colon cancer. We found
that PUM1 mRNA expression is high in primary and metastatic colon cancer cell
lines when compared to the normal colon cell line. Immunohistochemistry analysis
showed similar trend wherein compared to the normal colon tissue, PUM1 was found
to be overexpressed in both adenocarcinoma and in metastatic carcinoma. This
confirms the role of PUM1 in colon cancer progression. PUM1 overexpression study
in HCT116 revealed that cells transfected with PUM1 plasmid show an increased
rate of proliferation, migration and colony formation. Overexpressing PUM1
increases the number and size of spheroids indicating the role of PUM1 in
maintaining cancer stem cells. Overall, this is the first study that has shown
the role of PUM1 in colon cancer development. Posttranscriptional regulation of cancer gene expression programs plays a vital
role in carcinogenesis; identifying the critical regulators of tumorigenesis and
their molecular targets may provide novel strategies for cancer diagnosis and
therapeutics. Highly conserved RNA-binding protein Pumilio-1 (PUM1) regulates
mouse growth and cell proliferation, propelling us to examine its role in
cancer. We found human PUM1 is highly expressed in a diverse group of cancer,
including prostate cancer; enhanced PUM1 expression is also correlated with
reduced survival among prostate cancer patients. Detailed expression analysis in
twenty prostate cancer tissues showed enhanced expression of PUM1 at mRNA and
protein levels. Knockdown of PUM1 reduced prostate cancer cell proliferation and
colony formation, and subcutaneous injection of PUM1 knockdown cells led to
reduced tumor size. Downregulation of PUM1 in prostate cancer cells consistently
elevated cyclin-dependent kinase inhibitor 1B (CDKN1B) protein expression
through increased translation but did not impact its mRNA level, while
overexpression of PUM1 reduced CDKN1B protein level. Our finding established a
critical role of PUM1 mediated translational control, particularly the
PUM1-CDKN1B axis, in prostate cancer cell growth and tumorigenesis. We proposed
that PUM1-CDKN1B regulatory axis may represent a novel mechanism for the loss of
CDKN1B protein expression in diverse cancers and potential targets for
therapeutics development. Human Pumilio (hPUM) is a structurally well-analyzed RNA-binding protein that
has been used recently for artificial RNA binding. Structural analysis revealed
that amino acids at positions 12, 13, and 16 in the repeats from R1 to R8 each
contact one specific RNA base in the eight-nucleotide RNA target. The functions
of the N- and C-terminal flanking repeats R1' and R8', however, remain unclear.
Here, we report how the repeats contribute to overall RNA binding. We first
prepared three mutants in which R1' and/or R8' were deleted and then analyzed
RNA binding using gel shift assays. The assays showed that all deletion mutants
bound to their target less than the original hPUM, but that R1' contributed more
than R8', unlike Drosophila PUM. We next investigated which amino acid residues
of R1' or R8' were responsible for RNA binding. With detailed analysis of the
protein tertiary structure, we found a hydrophobic core in each of the repeats.
We therefore mutated all hydrophobic amino residues in each core to alanine. The
gel shift assays with the resulting mutants revealed that both hydrophobic cores
contributed to the RNA binding: especially the hydrophobic core of R1' had a
significant influence. In the present study, we demonstrated that the flanking
R1' and R8' repeats are indispensable for RNA binding of hPUM and suggest that
hydrophobic R1'-R1 interactions may stabilize the whole hPUM structure. |
What is CPX-351 | CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. | BACKGROUND: CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a
dual-drug liposomal encapsulation of daunorubicin and cytarabine in a
synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the
treatment of adults with newly diagnosed therapy-related acute myeloid leukemia
or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal
phase 3 study that evaluated 309 patients aged 60 to 75 years with newly
diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly
improved median overall survival versus conventional 7 + 3 chemotherapy
(cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a
comparable safety profile. A Quality-adjusted Time Without Symptoms of disease
or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare
survival quality between patients receiving CPX-351 versus conventional 7 + 3
after 5 years of follow-up.
METHODS: Patients were randomized 1:1 between December 20, 2012 and November 11,
2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient
was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity
or prior to remission), TWiST (time in remission without relapse or grade 3 or 4
toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was
calculated by adding the mean time spent in each health state weighted by its
respective quality-of-life, represented by health utility. The relative Q-TWiST
gain, calculated as the difference in Q-TWiST between treatment arms divided by
the mean survival of the 7 + 3 control arm, was determined in order to evaluate
results in the context of other Q-TWiST analyses.
RESULTS: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the
base case scenario and 39.8% among responding patients. Across various
sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to
57.6%, remaining well above the standard clinically important difference
threshold of 15% for oncology.
CONCLUSIONS: This post hoc analysis demonstrates that CPX-351 improved
quality-adjusted survival, further supporting the clinical benefit in patients
with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial
registration This trial was registered on September 28, 2012 at
www.clinicaltrials.gov as NCT01696084 (
https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete. |
What is the prevalence of the inactivating AKT variant p.Pro50Thr in the Finnish population? | 1.1% frequency | Author information:
(1)Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
(2)Center for Human Genetic Research, Department of Medicine, Massachusetts
General Hospital, Boston, MA.
(3)Department of Medicine, Harvard Medical School, Boston, MA.
(4)Human Genetics Center, The University of Texas MD Anderson Cancer Center and
The University of Texas Health Science Center at Houston Graduate School of
Biomedical Sciences, Houston, TX.
(5)Department of Epidemiology, The University of North Carolina at Chapel Hill,
Chapel Hill, NC.
(6)Department of Biostatistics and Center for Statistical Genetics, School of
Public Health, University of Michigan, Ann Arbor, MI.
(7)Saw Swee Hock School of Public Health, National University of Singapore,
Singapore.
(8)Analytic and Translational Genetics Unit, Department of Medicine,
Massachusetts General Hospital, Boston, MA.
(9)Department of Genetics, Harvard Medical School, Boston, MA.
(10)23andMe, Mountain View, CA.
(11)The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of
Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
(12)Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine,
University of Oxford, Oxford, U.K.
(13)School of Computer Science, McGill University, Montreal, Canada.
(14)McGill University and Génome Québec Innovation Centre, Montreal, Canada.
(15)Divisions of Endocrinology and Genetics and Genomics and Center for Basic
and Translational Obesity Research, Boston Children's Hospital, Boston, MA.
(16)Department of Epidemiology Research, Statens Serum Institut, Copenhagen,
Denmark.
(17)Department of Twin Research & Genetic Epidemiology, King's College London,
London, U.K.
(18)Department of Genetic Medicine and Development, University of Geneva Medical
School, Geneva, Switzerland.
(19)Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva,
Switzerland.
(20)Wellcome Trust Sanger Institute, Hinxton, U.K.
(21)Norwegian Centre for Mental Disorders Research and KG Jebsen Center for
Psychosis Research, Division of Mental Health and Addiction, Oslo University
Hospital, Oslo, Norway.
(22)Department of Genetics, The University of North Carolina at Chapel Hill,
Chapel Hill, NC.
(23)Department of Molecular Biology, Massachusetts General Hospital, Boston, MA.
(24)Section of Genetic Medicine, Department of Medicine, The University of
Chicago, Chicago, IL.
(25)Academic Medical Center, University of Amsterdam, Amsterdam, the
Netherlands.
(26)Department of Pediatrics, University of California, San Diego, La Jolla, CA.
(27)Chronic Disease Epidemiology Unit, Swiss Tropical and Public Health
Institute, University of Basel, Basel, Switzerland.
(28)Diabetes and Endocrinology Unit, Department of Clinical Sciences Malmö, Lund
University Diabetes Centre, Malmö, Sweden.
(29)Genetics of Complex Traits, University of Exeter Medical School, Exeter,
U.K.
(30)MRC Epidemiology Unit, Institute of Metabolic Science, University of
Cambridge, Cambridge, U.K.
(31)Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department
of Medicine, University of Oxford, Oxford, U.K.
(32)Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, U.K.
(33)Department of General Practice and Primary Health Care, University of
Helsinki, Helsinki, Finland.
(34)Unit of General Practice, Helsinki University Central Hospital, Helsinki,
Finland.
(35)Folkhälsan Research Center, Helsinki, Finland.
(36)Vaasa Central Hospital, Vaasa, Finland.
(37)Department of Health, National Institute for Health and Welfare, Helsinki,
Finland.
(38)Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere
School of Medicine, Tampere, Finland.
(39)Institute for Molecular Medicine Finland, University of Helsinki, Helsinki,
Finland.
(40)Department of Clinical Physiology and Nuclear Medicine, Turku University
Hospital, Turku, Finland.
(41)Research Centre of Applied and Preventive Cardiovascular Medicine,
University of Turku, Turku, Finland.
(42)Department of Epidemiology, Fairbanks School of Public Health, Indianapolis,
IN.
(43)Department of Medicine, Indiana University School of Medicine, Indianapolis,
IN.
(44)Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA.
(45)Division of Endocrinology, Diabetes & Metabolism, Department of Medicine,
Cedars-Sinai Medical Center, Los Angeles, CA.
(46)Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles,
CA.
(47)High-Throughput Genomics, Oxford Genomics Centre, Wellcome Trust Centre for
Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford,
U.K.
(48)National Human Genome Research Institute, National Institutes of Health,
Bethesda, MD.
(49)Institute of Experimental Genetics, Helmholtz Zentrum München, German
Research Center for Environmental Health, Neuherberg, Germany.
(50)German Center for Diabetes Research (DZD), Neuherberg, Germany.
(51)Institute of Experimental Genetics, School of Life Science Weihenstephan,
Technische Universität München, Freising, Germany.
(52)Department of Psychiatry, Icahn Institute for Genomics & Multiscale Biology,
Icahn School of Medicine at Mount Sinai, New York, NY.
(53)Institute of Human Genetics, Helmholtz Zentrum München, German Research
Center for Environmental Health, Neuherberg, Germany.
(54)Department of Genome Sciences, University of Washington School of Medicine,
Seattle, WA.
(55)Institute of Human Genetics, Technische Universität München, Neuherberg,
Germany.
(56)Diabetes Prevention Unit, National Institute for Health and Welfare,
Helsinki, Finland.
(57)Department of Regional Health Research, University of Southern Denmark,
Odense, Denmark.
(58)Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark.
(59)Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle,
Denmark.
(60)Department of Physiology, Institute of Biomedicine, University of Eastern
Finland, Kuopio, Finland.
(61)Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
(62)Department of Clinical Physiology and Nuclear Medicine, Kuopio University
Hospital, Kuopio, Finland.
(63)Division of Cardiovascular & Diabetes Medicine, Medical Research Institute,
Ninewells Hospital and Medical School, Dundee, U.K.
(64)Department of Clinical Sciences, Faculty of Medicine, Lund University,
Malmö, Sweden.
(65)Department of Clinical Sciences, Lund University Diabetes Centre, and
Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
(66)Department of Nutrition, Harvard School of Public Health, Boston, MA.
(67)Department of Public Health and Clinical Medicine, Umeå University, Umeå,
Sweden.
(68)Department of Genetics, Texas Biomedical Research Institute, San Antonio,
TX.
(69)Department of Medicine, The University of Texas Health Science Center, San
Antonio, TX.
(70)Research and Development Service, South Texas Veterans Health Care System,
San Antonio, TX.
(71)Department of Pediatrics, The University of Texas Health Science Center, San
Antonio, TX.
(72)Molecular Medicine and Science for Life Laboratory, Department of Medical
Sciences, Uppsala University, Uppsala, Sweden.
(73)Center for Genomics and Personalized Medicine Research, Wake Forest School
of Medicine, Winston-Salem, NC.
(74)Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem,
NC.
(75)Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem,
NC.
(76)Section on Nephrology, Department of Internal Medicine, Wake Forest School
of Medicine, Winston-Salem, NC.
(77)Division of Endocrinology, Boston Children's Hospital, Boston, MA.
(78)Estonian Genome Center, University of Tartu, Tartu, Estonia.
(79)Program in Personalized and Genomic Medicine, Department of Medicine,
University of Maryland, Baltimore, MD.
(80)Departments of Medicine and Genetics, Albert Einstein College of Medicine,
New York, NY.
(81)Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
(82)Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical
Center, Jerusalem, Israel.
(83)Institute of Epidemiology II, Helmholtz Zentrum München, German Research
Center for Environmental Health, Neuherberg, Germany.
(84)Institute of Genetic Epidemiology, Helmholtz Zentrum München, German
Research Center for Environmental Health, Neuherberg, Germany.
(85)Department of Genetic Epidemiology, Institute of Medical Informatics,
Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
(86)Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Partner Site Munich
Heart Alliance, Munich, Germany.
(87)Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center
for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
(88)German Center for Diabetes Research, Partner Düsseldorf, Germany.
(89)Department of Medicine I, University Hospital Grosshadern,
Ludwig-Maximilians-Universität, Munich, Germany.
(90)Department of Epidemiology, Harvard School of Public Health, Boston, MA.
(91)Department of Biostatistics, Harvard School of Public Health, Boston, MA.
(92)Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German
Research Center for Environmental Health, Neuherberg, Germany.
(93)Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
(94)Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
(95)Geriatrics, Department of Public Health and Caring Sciences, Uppsala
University, Uppsala, Sweden.
(96)Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS.
(97)Center of Biostatistics and Bioinformatics, University of Mississippi
Medical Center, Jackson, MS.
(98)Department of Medicine, University of Mississippi Medical Center, Jackson,
MS.
(99)College of Public Services, Jackson State University, Jackson, MS.
(100)Pirkanmaa Hospital District, Tampere, Finland.
(101)Department of Epidemiology and Biostatistics, Imperial College London,
London, U.K.
(102)Cardiovascular Sciences, National Heart and Lung Institute, Imperial
College London, London, U.K.
(103)Department of Cardiology, Ealing Hospital NHS Trust, Southall, U.K.
(104)Institute of Health Sciences, University of Oulu, Oulu, Finland.
(105)Translational Laboratory in Genetic Medicine, Agency for Science,
Technology and Research (A*STAR), Singapore.
(106)Imperial College Healthcare NHS Trust, Imperial College London, London,
U.K.
(107)Department of Biomedical Science, Hallym University, Chuncheon, Republic of
Korea.
(108)Ministry of Health and Welfare, Seoul, Republic of Korea.
(109)Center for Genome Science, Korea National Research Institute of Health,
Chungcheongbuk-do, Republic of Korea.
(110)Vaasa Health Care Center, Vaasa, Finland.
(111)Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland.
(112)Department of Epidemiology and Population Health, Albert Einstein College
of Medicine, New York, NY.
(113)Channing Division of Network Medicine, Department of Medicine, Brigham and
Women's Hospital and Harvard Medical School, Boston, MA.
(114)Hypertension and Cardiovascular Disease, Department of Clinical Sciences,
Lund University, Malmö, Sweden.
(115)Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of
Clinical Sciences, Lund University, Malmö, Sweden.
(116)Human Genetics Center, School of Public Health, The University of Texas
Health Science Center at Houston, Houston, TX.
(117)Cardiovascular Division, Baylor College of Medicine, Houston, TX.
(118)Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.
(119)Department of Ophthalmology, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore.
(120)Division of Human Genetics, Genome Institute of Singapore, Agency for
Science, Technology and Research (A*STAR), Singapore.
(121)Department of Paediatrics, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore.
(122)Office of Clinical Sciences, Centre for Quantitative Medicine, Duke-NUS
Graduate Medical School Singapore, Singapore.
(123)Department of Medicine, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore.
(124)Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical
School Singapore, Singapore.
(125)Research Centre for Prevention and Health, Glostrup University Hospital,
Glostrup, Denmark.
(126)Department of Clinical Experimental Research, Rigshospitalet, Glostrup,
Denmark.
(127)Department of Clinical Medicine, Faculty of Health and Medical Sciences,
University of Copenhagen, Copenhagen, Denmark.
(128)Department of Social Services and Health Care, Jakobstad, Finland.
(129)Department of Endocrinology, Helsinki University Central Hospital,
Helsinki, Finland.
(130)Steno Diabetes Center, Gentofte, Denmark.
(131)Section of General Practice, Department of Public Health, Aarhus
University, Aarhus, Denmark.
(132)William Harvey Research Institute, Barts and The London School of Medicine
and Dentistry, Queen Mary University of London, London, U.K.
(133)Department of Haematology, University of Cambridge, Cambridge, U.K.
(134)Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust,
Oxford, U.K.
(135)Department of Primary Care Health Sciences, University of Oxford, Oxford,
U.K.
(136)Metabolic Research Laboratories, Institute of Metabolic Science, University
of Cambridge, Cambridge, U.K.
(137)Institute of Cellular Medicine, University of Newcastle, Newcastle, U.K.
(138)University of Exeter Medical School, Exeter, U.K.
(139)Internal Medicine, Institute of Clinical Medicine, Faculty of Health
Sciences, University of Eastern Finland, Kuopio, Finland.
(140)Functional Genomics Unit, CSIR-Institute of Genomics & Integrative Biology,
New Delhi, India.
(141)Department of Medicine and Therapeutics, The Chinese University of Hong
Kong, Hong Kong, China.
(142)Li Ka Shing Institute of Health Sciences, The Chinese University of Hong
Kong, Hong Kong, China.
(143)Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong
Kong, Hong Kong, China.
(144)CSIR-Centre for Cellular & Molecular Biology, Hyderabad, India.
(145)Department of Statistics, University of Oxford, Oxford, U.K.
(146)Centre for Chronic Disease Control, New Delhi, India.
(147)MRC-PHE Centre for Environment & Health, Imperial College London, London,
U.K.
(148)Department of Epidemiology, Colorado School of Public Health, University of
Colorado, Aurora, CO.
(149)Genomics and Molecular Physiology, CNRS Institut de Biologie de Lille,
Lille, France.
(150)Department of Endocrinology and Metabolism, Shanghai Diabetes Institute,
Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai,
China.
(151)Interdisciplinary Program in Bioinformatics, Seoul National University,
Seoul, Republic of Korea.
(152)Department of Statistics, Seoul National University, Seoul, Republic of
Korea.
(153)Institute of Public Health, Department of Public Health and Primary Care,
University of Cambridge, Cambridge, U.K.
(154)Department of Human Genetics, McGill University, Montreal, Canada.
(155)Division of Endocrinology and Metabolism, Department of Medicine, McGill
University, Montreal, Canada.
(156)Department of Endocrinology and Metabolism, All India Institute of Medical
Sciences, New Delhi, India.
(157)Life Sciences Institute, National University of Singapore, Singapore.
(158)Department of Statistics and Applied Probability, National University of
Singapore, Singapore.
(159)Department of Preventive Medicine, Keck School of Medicine, University of
Southern California, Los Angeles, CA.
(160)Department of Physiology and Biophysics, Keck School of Medicine,
University of Southern California, Los Angeles, CA.
(161)Diabetes & Obesity Research Institute, Keck School of Medicine, University
of Southern California, Los Angeles, CA.
(162)Department of Medicine and Abdominal Center, Endocrinology, University of
Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
(163)Minerva Foundation Institute for Medical Research, Helsinki, Finland.
(164)Institute of Clinical Medicine, Faculty of Medicine, University of Oulu,
Oulu, Finland.
(165)Institute of Public Health and Clinical Nutrition, University of Eastern
Finland, Kuopio, Finland.
(166)Foundation for Research in Health Exercise and Nutrition, Kuopio Research
Institute of Exercise Medicine, Kuopio, Finland.
(167)Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical
Research Institute, Ninewells Hospital and Medical School, Dundee, U.K.
(168)Department of Genomics of Common Disease, School of Public Health, Imperial
College London, London, U.K.
(169)Division for Molecular Medicine, Clinical Research Centre, Ninewells
Hospital and Medical School, Dundee, U.K.
(170)Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los
Angeles, CA.
(171)Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
(172)Division of Cardiovascular Medicine, Department of Medicine, Stanford
University School of Medicine, Stanford, CA.
(173)Center for Vascular Prevention, Danube University Krems, Krems, Austria.
(174)Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
(175)Dasman Diabetes Institute, Dasman, Kuwait.
(176)Faculty of Medicine, University of Aalborg, Aalborg, Denmark.
(177)Faculty of Health Sciences, University of Southern Denmark, Odense,
Denmark.
(178)Kuopio University Hospital, Kuopio, Finland.
(179)Departments of Medicine and Human Genetics, The University of Chicago,
Chicago, IL.
(180)Department of Laboratory Medicine, Institute for Human Genetics, University
of California, San Francisco, San Francisco, CA.
(181)Blood Systems Research Institute, San Francisco, CA.
(182)Department of Physiology and Biophysics, University of Mississippi Medical
Center, Jackson, MS.
(183)Department of Biostatistics, Boston University School of Public Health,
Boston, MA.
(184)Framingham Heart Study, National Heart, Lung, and Blood Institute,
Framingham, MA.
(185)Hjelt Institute, University of Helsinki, Helsinki, Finland.
(186)Diabetes Research Center (Diabetes Unit), Department of Medicine,
Massachusetts General Hospital, Boston, MA.
(187)Division of General Internal Medicine, Massachusetts General Hospital,
Boston, MA.
(188)Department of Biostatistics, University of Liverpool, Liverpool, U.K.
(189)Department of Biology, Massachusetts Institute of Technology, Cambridge,
MA.
(190)Big Data Institute, Li Ka Shing Centre for Health Information and
Discovery, University of Oxford, Oxford, U.K. |
Which mutations are inhibited by Ripretinib? | Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations. | Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT
and PDGFRA kinases found in cancers and myeloproliferative neoplasms,
particularly in gastrointestinal stromal tumors (GISTs), in which the
heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib
is a "switch-control" kinase inhibitor that forces the activation loop (or
activation "switch") into an inactive conformation. Ripretinib inhibits all
tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor
demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA,
previously thought only achievable with type I inhibitors. Ripretinib shows
efficacy in preclinical cancer models, and preliminary clinical data provide
proof-of-concept that ripretinib inhibits a wide range of KIT mutants in
patients with drug-resistant GISTs. Author information:
(1)The University of Toledo College of Medicine & Life Sciences, Toledo,
OH 43606, USA.
(2)ProMedica Health System, Toledo, OH 43606, USA.
(3)West German Cancer Center, Deparment of Medical Oncology, University Hospital
Essen, University of Duisburg-Essen, Essen, Germany.
(4)Centre Léon Bérard, Unicancer, LYRICAN and Université Claude Bernard Lyon 1,
Lyon, France.
(5)Leiden University Medical Center, Leiden, The Netherlands.
(6)Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
(7)University Hospitals Leuven, Department of General Medical Oncology, Leuven
Cancer Institute, Leuven, Belgium.
(8)Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
(9)Department of Epidemiology & Preventive Medicine, School of Public Health &
Preventive Medicine, Monash University & Department of Medical Oncology Alfred
Health, Melbourne, Australia.
(10)Deciphera Pharmaceuticals, LLC, Waltham, MA 02451, USA.
(11)Portland VA Health Care System & OHSU Knight Cancer Institute, Oregon Health
& Science University, Portland, OR 97239, USA. BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor
tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is
a clinical challenge for patients with advanced gastrointestinal stromal
tumours. We compared the efficacy and safety of ripretinib, a switch-control
tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA
mutations, with placebo in patients with previously treated, advanced
gastrointestinal stromal tumours.
METHODS: In this double-blind, randomised, placebo-controlled, phase 3 study, we
enrolled adult patients in 29 specialised hospitals in 12 countries. We included
patients aged 18 years or older who had advanced gastrointestinal stromal
tumours with progression on at least imatinib, sunitinib, and regorafenib or
documented intolerance to any of these treatments despite dose modifications,
and who had an Eastern Cooperative Oncology Group (ECOG) performance status of
0-2. Eligible patients were randomly assigned (2:1) to receive either oral
ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo
group). Randomisation was done via an interactive response system using randomly
permuted block sizes of six and stratified according to number of previous
therapies and ECOG performance status. Patients, investigators, research staff,
and the sponsor study team were masked to a patient's treatment allocation until
the blinded independent central review (BICR) showed progressive disease for the
patient. The primary endpoint was progression-free survival, assessed by BICR.
The primary analysis was done in the intention-to-treat population and safety
was assessed in patients who received at least one dose of study drug. Patients
randomly assigned to placebo were permitted to cross over to ripretinib 150 mg
at the time of disease progression. The INVICTUS study is registered with
ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical
Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing.
FINDINGS: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients
were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At
data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in
the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients
in the ripretinib group and 37 in the placebo group had had progression-free
survival events. In the double-blind period, median progression-free survival
was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months
(0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most
common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in
the ripretinib group (n=85) included lipase increase (four [5%]), hypertension
(three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the
placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related
treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]),
diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]),
hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema
(one [2%]). Treatment-related serious adverse events were reported in eight (9%)
of 85 patients who received ripretinib and three (7%) of 43 patients who
received placebo. Treatment-related deaths occurred in one patient in the
placebo group (septic shock and pulmonary oedema) and one patient in the
ripretinib group (cause of death unknown; the patient died during sleep).
INTERPRETATION: Ripretinib significantly improved median progression-free
survival compared with placebo and had an acceptable safety profile in patients
with advanced gastrointestinal stromal tumours who were resistant to approved
treatments.
FUNDING: Deciphera Pharmaceuticals. Ripretinib (QINLOCK™) is a novel type II tyrosine switch control inhibitor being
developed by Deciphera Pharmaceuticals for the treatment of KIT proto-oncogene
receptor tyrosine kinase (KIT)-driven and/or platelet derived growth factor
receptor A (PDGFRA)-driven cancers, including gastrointestinal stromal tumour
(GIST). Ripretinib inhibits KIT and PDGFRA kinase, including wild-type, primary
and secondary mutations, as well as other kinases, such as PDGFRB, TIE2, VEGFR2
and BRAF. In May 2020, oral ripretinib received its first approval in the USA
for the treatment of adult patients with advanced GIST who have received prior
treatment with ≥ 3 kinase inhibitors, including imatinib. The US FDA, Health
Canada and the Australian Therapeutic Goods Administration collaborated on the
review of the ripretinib new drug application in this indication as part of
Project Orbis; regulatory review in Australia and Canada is ongoing. Clinical
development for GIST, solid tumours and systemic mastocytosis is underway in
several countries worldwide. This article summarizes the milestones in the
development of ripretinib leading to this first approval for the treatment of
advanced GIST. PURPOSE: In advanced gastrointestinal stromal tumor (GIST), there is an unmet
need for therapies that target both primary and secondary mutations of
pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase
inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations.
PATIENTS AND METHODS: This first-in-human, to our knowledge, phase I study of
ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a
dose-escalation phase and subsequent expansion phase at the recommended phase II
dose (RP2D). Eligible patients included those with advanced GIST, intolerant to
or experienced progression on ≥ 1 line of systemic therapy, and other advanced
maligcies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose
(MTD), and preliminary antitumor activity were evaluated.
RESULTS: At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were
enrolled, with 68 patients in the dose-escalation phase. Three DLTs were
reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and
grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not
reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was
established as the RP2D. The most frequent (> 30%) treatment-emergent adverse
events in patients with GIST receiving ripretinib 150 mg once daily (n = 142)
were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69
[48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62
[43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]),
and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n =
16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31;
second line) and median progression-free survival ranging from 5.5 months
(fourth line or greater) to 10.7 months (second line), on the basis of
investigator assessment, were observed.
CONCLUSION: Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA
mutant kinases with promising activity in patients with refractory advanced
GIST. 1. Gastrointestinal stromal tumor (GIST) represents a paradigm for clinically
effective targeted inhibition of oncogenic driver mutations in cancer. Five
drugs are currently positioned as the standard of care for the treatment of
advanced or metastatic GIST patients. This is the result of continuous, deep
understanding of KIT and PDGFRA GIST oncogenic drivers as well as the resistance
mechanisms associated to tumor progression. However, the complexity of GIST
molecular heterogeneity is an evolving field, and critical questions remain
open. Specifically, the clinical benefit of approved and/or investigated
targeted agents is strikingly modest at advanced stages of the disease when
compared with the activity of first-line imatinib. Ripretinib is a novel
switch-pocket inhibitor with broad activity against KIT and PDGFRA oncoproteins
and has recently demonstrated antitumoral activity across phase I to phase III
clinical trials. Therefore, ripretinib has emerged as a new standard of care for
advanced, multi-resistant GIST patients. Based on this data, the Food and Drug
Administration has granted in 2020 the approval of ripretinib for GIST patients
after progression to imatinib, sunitinib and regorafenib. This, in turn,
constitutes a major breakthrough in sarcoma drug development, as there have not
been new treatment approvals in GIST for nearly a decade. Herein, we provide a
critical review on the preclinical and clinical development of ripretinib in
GIST. Furthermore, we seek to assess the biological and clinical impact of this
new standard of care on the course of the disease, aiming to provide an insight
on future treatments strategies for the next coming years. Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the
interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in
adult patients have c-Kit mutation and smaller fractions have platelet derived
growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative
treatment for localized disease. Imatinib improves survival when used adjuvantly
and in advanced disease. Several targeted therapies have also improved survival
in GIST patients after progression on imatinib including sunitinib and
regorafenib. Recently, United States Federal and Drug Administration (FDA)
approved two new tyrosine kinase inhibitors for the treatment of heavily
pretreated advanced/unresectable GIST including avapritinib (a selective
inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib
(a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we
will provide a comprehensive review of GIST including the current standard of
care treatment and exploring future paradigm shifts in therapy. The majority of gastrointestinal stromal tumors (GIST) harbor constitutively
activating mutations in KIT tyrosine kinase. Imatinib, sunitinib, and
regorafenib are available as first-, second-, and third-line targeted therapies,
respectively, for metastatic or unresectable KIT-driven GIST. Treatment of
patients with GIST with KIT kinase inhibitors generally leads to a partial
response or stable disease but most patients eventually progress by developing
secondary resistance mutations in KIT. Tumor heterogeneity for secondary
resistant KIT mutations within the same patient adds further complexity to GIST
treatment. Several other mechanisms converge and reactivate the MAPK pathway
upon KIT/PDGFRA-targeted inhibition, generating treatment adaptation and
impairing cytotoxicity. To address the multiple potential pathways of drug
resistance in GIST, the KIT/PDGFRA inhibitor ripretinib was combined with MEK
inhibitors in cell lines and mouse models. Ripretinib potently inhibits a broad
spectrum of primary and drug-resistant KIT/PDGFRA mutants and is approved by the
FDA for the treatment of adult patients with advanced GIST who have received
previous treatment with 3 or more kinase inhibitors, including imatinib. Here we
show that ripretinib treatment in combination with MEK inhibitors is effective
at inducing and enhancing the apoptotic response and preventing growth of
resistant colonies in both imatinib-sensitive and -resistant GIST cell lines,
even after long-term removal of drugs. The effect was also observed in systemic
mastocytosis (SM) cells, wherein the primary drug-resistant KIT D816V is the
driver mutation. Our results show that the combination of KIT and MEK inhibition
has the potential to induce cytocidal responses in GIST and SM cells. Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal
(GI) tract yet represent the most common GI sarcomas. Most GISTs are driven by
activating mutations of the KIT and/or PDGFRA genes. Prior to the development of
tyrosine kinase inhibitors (TKIs), GISTs were associated with a poor prognosis
because conventional cytotoxic chemotherapy was relatively ineffective. However,
TKIs that inhibit the most common driver mutations in KIT or PDGFRA have
revolutionized the treatment of GISTs over the past two decades.
Notwithstanding, ongoing management challenges relate to the development of
secondary mutations in these genes, resulting in tumor progression. Due to both
the intra- and inter-patient heterogeneity of these secondary mutations in
GISTs, optimal treatment requires an agent that blocks as many mutant genes as
possible. Ripretinib - a novel switch-control TKI - inhibits many of the most
common primary and secondary activating KIT and PDGFRA mutants involved in GIST
progression through a dual mechanism of action. In the pivotal INVICTUS
phase III trial, patients with advanced GIST that had progressed on at least
imatinib, sunitinib, and regorafenib and who received ripretinib experienced
significantly longer progression-free survival (primary endpoint) as well as
prolongation of overall survival, compared with those receiving placebo.
Treatment with ripretinib was associated with durable improvements in
quality-of-life indices and a manageable toxicity profile. The most frequent
side effects were common to the class of TKIs used in the management of GIST.
These results led to the approval of ripretinib for treatment of advanced GIST
in adults who have received three or more TKIs, including imatinib. Ripretinib
is also under investigation in the second-line treatment of advanced GIST in a
phase III trial (INTRIGUE) comparing ripretinib with sunitinib in patients with
advanced GIST after treatment with imatinib.
PLAIN LANGUAGE SUMMARY: Use of ripretinib for the treatment of gastrointestinal
stromal tumors (GISTs) Gastrointestinal stromal tumors (GISTs) are a rare type
of tumor most commonly located in the stomach and small intestine but can
develop anywhere throughout the gastrointestinal tract. The symptoms of GISTs
vary in extent depending on location of the primary tumor and include a feeling
of fullness, abdominal pain, intestinal bleeding, and fatigue. Since these
symptoms are nonspecific, making a diagnosis can be challenging. Most GISTs
carry initial mutations in genes that control specific enzymes called tyrosine
kinases. Historically, treatment of GISTs was limited because traditional
chemotherapy is ineffective against these tumors. However, with the introduction
of drugs that inhibit tyrosine kinases [i.e., tyrosine kinase inhibitors
(TKIs)], survival has been extended substantially. However, many GISTs go on to
develop secondary mutations that render them resistant to a given TKI. Prior to
the approval of ripretinib, four TKIs were available for the treatment of GIST:
imatinib; sunitinib; regorafenib; and, recently, avapritinib. Each drug is used
until resistance develops or patients are unable to tolerate the side effects of
treatment, after which the next drug is started. Ripretinib was recently
approved by the FDA as the fourth drug in the usual treatment sequence
recommended for patients with advanced GIST who have progressed (or are
treatment intolerant) after receiving three or more TKIs, including imatinib.
Approval of ripretinib was based on the results of the INVICTUS trial, which
demonstrated that the drug significantly improves the time patients have without
progression of the disease or death compared with placebo. The most common side
effects related to ripretinib were hair loss, muscle pain, nausea, fatigue,
hand-foot syndrome, and diarrhea, although most events were not very severe.
Ripretinib is being further studied as the second TKI used in patients with GIST
who have progressed on or could not tolerate first-line treatment with imatinib. Conflict of interest statement: Conflict of interest statement The authors
declare the following ficial interests/personal relationships, which may be
considered as potential competing interests: S.G. serves in an
advisory/consultancy role for AstraZeneca, Bayer, Blueprint Medicines, Daiichi
Sankyo, Deciphera Pharmaceuticals, Eli Lilly and Exelixis; has a leadership role
in Alliance Foundation; receives licensing royalties from Wolters Kluwer Health
and is a shareholder/stockholder of Abbott Laboratories and Allergan, and her
institution receives research support from Bayer, Blueprint Medicines, Deciphera
Pharmaceuticals, Novartis and Pfizer. P.C. serves in an advisory role for
Deciphera Pharmaceuticals, Exelixis and Zailab; has received grant funding from
Deciphera Pharmaceuticals, Exelixis, Novartis and Array and has licensing
royalties and owns stock in ORIC. M.C.H. serves in a consultancy role for
Blueprint Medicines, Deciphera Pharmaceuticals and Novartis; receives royalties
from Novartis; receives grant funding from Blueprint Medicines and Deciphera
Pharmaceuticals and has received travel, accommodations, and expenses from
Blueprint Medicines and Deciphera Pharmaceuticals. M.v.M. serves in an
advisory/consultancy role for Blueprint Medicines, Deciphera Pharmaceuticals and
Exelexis and has received travel/accommodation expenses from Deciphera
Pharmaceuticals and NCCN, and her institution has received funding from Arog,
ASCO, Blueprint Medicines, Deciphera Pharmaceuticals, Gradalis, Genmab, Novartis
and Solarius. R.L.J. has received honoraria and serves in an advisory role for
Adaptimmune Therapeutics, Athenex, Bayer, Boehringer Ingelheim, Blueprint
Medicines, Clinigen Group, Daiichi Sankyo, Deciphera Pharmaceuticals, Eisai,
Epizyme, Immune Design, Eli Lilly, Merck, PharmaMar, UpToDate; serves in an
advisory role for Boehringer Ingelheim and Tracon and has received funding from
MSD. K.G. serves in an advisory role for Daiichi Sankyo and Foundation Medicine,
and her institution has received grant funding from Deciphera Pharmaceuticals.
J.T. serves in an advisory/consultancy role for Blueprint Medicines, Deciphera
Pharmaceuticals, Daiichi Sankyo, Epizyme and Agios, and his institution has
received grant funding from Advenchen, Agios, Blueprint Medicines, Deciphera
Pharmaceuticals, and Plexxikon. H.G. institution has received grant funding from
Daiichi Sankyo, Five Prime, Novartis, Deciphera Pharmaceuticals, Eli Lilly,
Roche, Eisai, Debio, Boehringer Ingelheim, Pfizer, Amgen and TEVA. A.A.R.
institution has received grant funding from Deciphera Pharmaceuticals. M.S.G.
serves in an advisory/consultancy role for Agenus, Daiichi Sankyo, Deciphera
Pharmaceuticals, ImaginAB, Imaging Endpoints, RedHill Biopharma, Salarius and
Tracon, and has a leadership role in CareMission; his institution has received
grant funding from AbbVie, Aeglea, Agenus, Amgen, Arcus, Astex, BeiGene,
Blueprint Medicines, Bristol Meyers Squibb, Calithera, CellDex, Corcept, Clovis,
Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly, Endocyte, Five Prime,
Fujifilm Pharma, Genocea, ImaginAB, Medimmune, Merck, Neon, Plexxikon, RedHill
Biopharma, Revolution Medicine, Roche/Genentech, Salarius, Seattle Genetics,
Serono, Syndax, SynDevRx, Tesaro, Tolero, Tracon, and Veru, and he owns stock in
Medelis. N.S. serves in an advisory role for Bayer, Blueprint Medicines and
Deciphera Pharmaceuticals; has stocks in Pfizer and has received grant funding
from Ascentage, AstraZeneca, Daiichi Sankyo, Deciphera Pharmaceuticals, GSK and
Karyopharm. J.J. is employed by Deciphera Pharmaceuticals. J.M. is employed by
Deciphera Pharmaceuticals and owns stock in Deciphera Pharmaceuticals. K.S. is
employed by Deciphera Pharmaceuticals and owns stock in Alberio, Alnylam,
AstraZeneca, Immunogen, Karyopharm, Deciphera Pharmaceuticals, and Spectrum.
Y.S. is employed by Deciphera Pharmaceuticals. R.R-S. is employed by Deciphera
Pharmaceuticals and owns stock in Deciphera Pharmaceuticals and Immunogen. F.J.
serves in an advisory role for Asana, Baush Health, Cardiff Oncology, Deciphera,
Guardant Health, Ideaya, IFM Therapeutics, Immunomet, Illumina, Jazz
Pharmaceuticals, Novartis, PureTech Health, Sotio and Synlogic and has stocks in
Cardiff Oncology, and his institution receives funding from Agios, Asana,
Astellas, Astex, Bayer, Bicara, BioMed Valley Discoveries, Bioxcel, Bristol
Myers Squibb, Deciphera, Fujifilm Pharma, Genentech, Ideaya, JS InnoPharm, Eli
Lilly, Merck, Novartis, Novellus, Plexxikon, Proximagen, Sanofi, Sotio,
SpringBank Pharmaceuticals, SQZ Biotechnologies, Synlogic, Synthorx and
Symphogen. PURPOSE: Most patients with gastrointestinal stromal tumor (GIST) have
activating mutations in KIT/PDGFRA and are initially responsive to tyrosine
kinase inhibitors (TKI). The acquisition of secondary mutations leads to
refractory/relapsed disease. This study reports the results of an analysis from
the phase III INVICTUS study (NCT03353753) characterizing the genomic
heterogeneity of tumors from patients with advanced GIST and evaluating
ripretinib efficacy across KIT/PDGFRA mutation subgroups.
PATIENTS AND METHODS: Tumor tissue and liquid biopsy samples that captured
circulating tumor DNA were collected prior to study enrollment and sequenced
using next-generation sequencing. Subgroups were determined by KIT/PDGFRA
mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status
was assessed.
RESULTS: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85;
placebo, n = 44). The most common primary mutation subgroup detected by combined
tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo,
77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving
ripretinib demonstrated progression-free survival (PFS) benefit versus placebo
regardless of mutation status (HR 0.16) and in all assessed subgroups in
Kaplan-Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P <
0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor
tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months
for placebo.
CONCLUSIONS: Ripretinib provided clinically meaningful activity across mutation
subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits
a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were
previously treated with three or more TKIs. |
What is known about the PYHIN proteins? | The human PYHIN proteins, AIM2, IFI16, IFIX, and MNDA, are critical regulators of immune response, transcription, apoptosis, and cell cycle.
Absent in melanoma 2 (AIM2) is a member of the PYHIN (pyrin and HIN domain-containing protein) family with important roles in sensing double-stranded DNA (dsDNA) and assembling the AIM2 inflammasome, which has wide-ranging, pro-inflammatory and pro-pyroptotic properties. | Pattern recognition receptors such as nucleotide-binding oligomerization domain
(NOD)-containing protein receptors (NLRs) and the pyrin and hematopoitic
interferon-inducible nuclear protein (HIN) domain (PYHIN) receptors initiate the
inflammatory response following cell stress or pathogenic challenge. When
activated, some of these receptors oligomerize to form the structural backbone
of a signalling platform known as an inflammasome. Inflammasomes promote the
activation of caspase-1 and the maturation of the proinflammatory cytokines,
interleukin (IL)-1β and IL-18. The gut dysregulation of the inflammasome complex
is thought to be a contributing factor in the development of inflammatory bowel
diseases (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD). The
importance of inflammasomes to intestinal health has been emphasized by various
inflammasome-deficient mice in dextran sulphate sodium (DSS) models of
intestinal inflammation and by the identification of novel potential candidate
genes in population-based human studies. In this review, we summarise the most
recent findings with regard to the formation, sensing, and regulation of the
inflammasome complex and highlight their importance in maintaining intestinal
health. Absent in melanoma 2 (AIM2) is a member of the PYHIN (pyrin and HIN
domain-containing protein) family with important roles in sensing
double-stranded DNA (dsDNA) and assembling the AIM2 inflammasome, which has
wide-ranging, pro-inflammatory and pro-pyroptotic properties. The AIM2
inflammasome can become activated in atherosclerotic plaque, abdominal aortic
aneurysm wall and injured myocardium, and its activation is tightly regulated by
a variety of atherogenic factors. Activation of the AIM2 inflammasome has close
links to the progression of several cardiovascular diseases. This review will
summarize the current knowledge of AIM2 biology, providing the latest insights
into the mechanisms and contributions of atherogenic factors to AIM2
inflammasome activation. In addition, we will also explore crosstalk between
AIM2 and the pathologies of atherosclerosis, abdominal aortic aneurysm,
myocardial infarction and heart failure. A better understanding of the
pathological roles of AIM2 in these disorders will be helpful in developing
novel therapeutic approaches. |
What class of drugs is commonly associated with Drug-induced interstitial lung disease (DIILD)? | [' Numerous agents including cytotoxic and noncytotoxic drugs have the potential to cause pulmonary toxicity.'] | The problem of the drug induced pulmonary toxicity (cytotoxic and non-cytotoxic
drugs) is discussed. This domain of modern pathology is in continuous
development, although yet insufficiently delineated. The essential pathogenic
mechanisms are presented as well as the main histopathological lesions (i.e.,
interstitial pneumonia and pulmonary fibrosis). The usual lesional aspects
specific to certain drugs are also reviewed. For the principal chemical
substances in this category, the clinical and radiological aspects are given,
also the various treatment indicated, the evolution and the prognosis of the
drugs induced pulmonary disease. Cytotoxic agents may cause interstitial or eosinophilic pneumonitis, alveolar
proteinosis, pulmonary venous occlusive disease, pulmonary fibrosis,
pneumothorax, or pulmonary oedema. These agents may also potentiate lung injury
caused by radiotherapy or high oxygen fractions in inspired air. Clinical and
roentgenological features of lung damage induced by cytotoxic drugs are usually
non-specific, and differential diagnoses include progression of the maligt
disease and a plethora of opportunistic infections. Monitoring of blood gases
and carbon monoxide transfer factor may facilitate early detection of drug
induced lung injury. Fiberoptic bronchoscopy, bronchoalveolar lavage,
transbronchial biopsy, or open lung biopsy may be necessary for reliable
diagnosis. Early detection of lung damage and immediate withdrawal of the
responsible agent(s) are essential. Steroids may be of therapeutic value in some
patients. A number of anticancer drugs, especially molecularly-targeted drugs, have been
developed every year. Drug-induced interstitial lung disease(DILD)is a common
adverse event associated with molecularly-targeted drugs, and it is therefore
important to obtain information about the DILD risks of each drug. Recently,
all-case surveillance of new drugs have been carried out frequently as
post-marketing surveillance. This allows one to understand the accurate status
of DILD, such as its incidence rate and prognosis. The diagnosis of DILD is
often difficult because there is no specific diagnostic approach. It is
necessary to distinguish DILD from various other diseases including infectious
disease, cancer progression, congestive heart failure, etc. Among those,
respiratory infection is an important disease in the differential diagnosis of
DILD, because patients receiving anticancer drugs are likely to be susceptible
to infection. As for the treatment of DILD, the general rule is the
discontinuation of the offending drug, and if necessary, the administration of
corticosteroid is indicated. However, an exceptional treatment is required for
DILD caused by mTOR inhibitor, for which we must take account of the adequate
management. With an increasing number of therapeutic drugs, the list of drugs that is
responsible for severe pulmonary disease also grows. Many drugs have been
associated with pulmonary complications of various types, including interstitial
inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions.
Drug-induced interstitial lung disease (DILD) can be caused by chemotherapeutic
agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. There
are no distinct physiologic, radiographic or pathologic patterns of DILD, and
the diagnosis is usually made when a patient with interstitial lung disease
(ILD) is exposed to a medication known to result in lung disease. Other causes
of ILD must be excluded. Treatment is avoidance of further exposure and systemic
corticosteroids in patients with progressive or disabling disease. Although pneumothorax has been reported to be a major pulmonary adverse event in
patients treated with pazopanib, a multikinase inhibitor, drug-induced
interstitial lung disease (DILD) has not been reported. A 74-year-old Japanese
man who received pazopanib for the treatment of femoral leiomyosarcoma and lung
metastasis presented with dyspnea and fatigue. He had mild interstitial
pneumonia when pazopanib treatment was initiated. Chest computed tomography
revealed progressive bilateral ground-glass opacity (GGO) and traction
bronchiectasis. We diagnosed DILD due to pazopanib. The patient's pazopanib
treatment was interrupted and a steroid was administered. The symptoms and GGO
were improved with treatment. Physicians should be aware of DILD due to
pazopanib in patients with pre-existing interstitial lung disease. Treatment of patients often includes the administration of medications and
sometimes radiation. While the intent is to treat an underlying condition, in
some cases, adverse effects occur due to these agents. Most of these adverse
effects are mild, however, some can be severe and life-threatening. Furthermore,
while these effects are often reversible upon cessation of exposure, especially
if the inciting agent is recognized and withdrawn early, others might be
permanent or even progressing. Most common histopathologic findings in
drug-induced interstitial lung disease include nonspecific interstitial
pneumonia (cellular and/or fibrotic), organizing pneumonia with or without
bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage,
hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic
bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or
constrictive bronchiolitis can also occur. Drugs that are more commonly
associated with lung toxicity include nitrofurantoin, amiodarone, and
chemotherapeutic agents such as bleomycin and methotrexate. More recently
introduced immune modulating agents including rituximab and immune checkpoint
inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been
associated with adverse effects in the lung. Radiation therapy to the chest can
trigger acute or chronic lung toxicity. While newer radiation techniques are
aimed to decrease and minimize side effects other risk factors such as
additional chemotherapy, oxygen, and older age may be rising. Foreign substances
such as talc, hydrogel, and medical devices such as hydrophilic polymer coated
catheter may rarely also lead to pulmonary complications. It is important that
clinicians and pathologists are aware of these potential adverse effects of
drugs, radiation and medical devices and raise the possibility of drug-induced
lung toxicity after exclusion of other differential diagnoses. It is the role of
the clinician to provide the pathologist with an appropriate drug history. Early
intervention to a drug-induced lung toxicity might prevent progression of side
effects and permanent changes. Author information:
(1)Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal
and Dermatological Sciences, School of Biological Sciences, Faculty of Biology
Medicine & Health, University of Manchester, Manchester Academic Health Sciences
Centre, Manchester M13 9PL, UK. [email protected].
(2)Royal National Hospital for Rheumatic Diseases, Royal United Hospitals Bath
NHS Foundation Trust, Bath BA1 1RL, UK. [email protected].
(3)Department of Infection, Immunity & Cardiovascular Disease, University of
Sheffield, Sheffield S10 2TN, UK. [email protected].
(4)Department of Infection, Immunity & Cardiovascular Disease, University of
Sheffield, Sheffield S10 2TN, UK. [email protected].
(5)Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal
and Dermatological Sciences, School of Biological Sciences, Faculty of Biology
Medicine & Health, University of Manchester, Manchester Academic Health Sciences
Centre, Manchester M13 9PL, UK. [email protected].
(6)Department of Infection, Immunity & Cardiovascular Disease, University of
Sheffield, Sheffield S10 2TN, UK. [email protected].
(7)North West Lung Centre, Manchester University NHS Foundation Trust,
Manchester Academic Health Science Centre, Manchester M6 8HD, UK.
[email protected].
(8)Leeds Institute of Rheumatic and Musculoskeletal Medicine, NIHR Leeds
Biomedical Research Centre, University of Leeds, Leeds LS2 9JT, UK.
[email protected].
(9)Rheumatology Unit, Department of Medicine, University of Verona, 37134
Verona, Italy. [email protected].
(10)Department of Infection, Immunity & Cardiovascular Disease, University of
Sheffield, Sheffield S10 2TN, UK. [email protected].
(11)Bioxydyn Limited, Rutherford House, Manchester Science Park, Manchester M15
6SZ, UK. [email protected].
(12)Centre for Imaging Sciences, Division of Informatics Imaging & Data
Sciences, School of Health Sciences, Faculty of Biology Medicine & Health,
University of Manchester, Manchester Academic Health Sciences Centre, Manchester
M13 9PL, UK. [email protected].
(13)Leeds Institute of Rheumatic and Musculoskeletal Medicine, NIHR Leeds
Biomedical Research Centre, University of Leeds, Leeds LS2 9JT, UK.
[email protected].
(14)Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology
Medicine and Health, University of Manchester, Manchester Academic Health
Sciences Centre, Manchester M13 9PL, UK. [email protected].
(15)Arthritis Research UK Centre for Epidemiology, Division of Musculoskeletal
and Dermatological Sciences, School of Biological Sciences, Faculty of Biology
Medicine & Health, University of Manchester, Manchester Academic Health Sciences
Centre, Manchester M13 9PL, UK. [email protected].
(16)The Kellgren Centre for Rheumatology, NIHR Manchester Biomedical Research
Centre, Manchester University NHS Foundation Trust, Manchester Academic Health
Science Centre, Manchester M6 8HD, UK. [email protected].
(17)North West Lung Centre, Manchester University NHS Foundation Trust,
Manchester Academic Health Science Centre, Manchester M6 8HD, UK.
[email protected].
(18)Academic Directorate of Respiratory Medicine, Sheffield Teaching Hospitals
NHS Foundation Trust, Sheffield S10 2JF, UK. [email protected].
(19)North West Lung Centre, Manchester University NHS Foundation Trust,
Manchester Academic Health Science Centre, Manchester M6 8HD, UK.
[email protected]. |
What pathological phenotype could potentially concomitant pomegranate juice and rosuvastatin use cause? | Concomitant use of rosuvastatin and pomegranate juice has been hypothesized to be associated with the development of rhabdomyolysis in a case report. | This 48-year-old man with possible underlying myopathy was successfully treated
with ezetimibe 10 mg/day and rosuvastatin 5 mg every other day for 17 months.
Three weeks before presentation, he began drinking pomegranate juice (200 ml
twice weekly). He presented urgently with thigh pain and an elevated serum
creatine kinase level (138,030 U/L, normal < 200 U/L). In conclusion, because
both grapefruit and pomegranate juice are known to inhibit intestinal cytochrome
P450 3A4, this report suggests that pomegranate juice may increase the risk of
rhabdomyolysis during rosuvastatin treatment, despite the fact that rosuvastatin
is not known to be metabolized by hepatic P450 3A4. |
Which tool has been developed to discover VNTR-associated deletions? | Τrfermikit is a software tool designed to detect deletions larger than 50 bp occurring in Variable Number Tandem Repeats (VNTRs) using Illumina DNA sequencing reads. In such regions, it achieves a better trade-off between sensitivity and false discovery than a state-of-the-art structural variation (SV) caller, Manta, and complements it by recovering a significant number of deletions that Manta missed. trfermikit is based upon the fermikit pipeline, which performs read assembly, maps the assembly to the reference genome, and calls variants from the alignment. | |
Is tirabrutinib effective for lymphoma? | Yes, tirabrutinib appears to be effective for lymphoma. It was approved in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma. | Conflict of interest statement: W. Munakata has received grants from Ono
Pharmaceutical Co., Ltd. K. Ando has received grants from Ono Pharmaceutical
Co., Ltd. K. Hatake has received grants from Ono Pharmaceutical Co., Ltd. and
Chugai Pharmaceutical Co., Ltd. N. Fukuhara has received grants from Ono
Pharmaceutical Co., Ltd. T. Kinoshita has received grants and/or personal fees
from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Solasia
Pharma K.K., Ono Pharmaceutical Co., Ltd., Gilead Sciences, Inc., MSD, Zenyaku
Kogyo, Bristol‐Myers Squibb, Kyowa Hakko Kirin Co., Ltd., Eisai Co., Ltd., and
Janssen Pharmaceutica. S. Fukuhara has received grants from Ono Pharmaceutical
Co., Ltd. Y. Shirasugi has received personal fees from Novartis. M. Yokoyama has
received grants from Ono Pharmaceutical Co., Ltd. and personal fees from Chugai
Pharmaceutical Co., Ltd. S. Ichikawa has received grants from Ono Pharmaceutical
Co., Ltd. K. Ohmachi has received grants from Ono Pharmaceutical Co., Ltd. and
personal fees from Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd.,
Eisai Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Inc., Takeda
Pharmaceutical Co., Ltd., and Meiji Seika Pharma Co., Ltd. N. Gion is an
employee of Ono Pharmaceutical Co., Ltd., and has received personal fees. A. Aoi
is an employee of Ono Pharmaceutical Co., Ltd., and has received personal fees.
K. Tobinai has received grants and/or personal fees from Ono Pharmaceutical Co.,
Ltd., Celgene, Zenyaku Kogyo, HUYA Bioscience International LLC, Eisai Co.,
Ltd., Takeda Pharmaceutical Co., Ltd., Mundipharma, Janssen Pharmaceutical,
Kyowa Hakko Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., GlaxoSmithKline,
and AbbVie Inc. Tirabrutinib (Velexbru®) is an orally administered, small molecule, Bruton's
tyrosine kinase (BTK) inhibitor being developed by Ono Pharmaceutical and its
licensee Gilead Sciences for the treatment of autoimmune disorders and
haematological maligcies. Tirabrutinib irreversibly and covalently binds to
BTK in B cells and inhibits aberrant B cell receptor signalling in B
cell-related cancers and autoimmune diseases. In March 2020, oral tirabrutinib
was approved in Japan for the treatment of recurrent or refractory primary
central nervous system lymphoma. Tirabrutinib is also under regulatory review in
Japan for the treatment of Waldenström's macroglobulinemia and lymphoplasmacytic
lymphoma. Clinical development is underway in the USA, Europe and Japan for
autoimmune disorders, chronic lymphocytic leukaemia, B cell lymphoma, Sjogren's
syndrome, pemphigus and rheumatoid arthritis. This article summarizes the
milestones in the development of tirabrutinib leading to the first approval of
tirabrutinib for the treatment of recurrent or refractory primary central
nervous system lymphoma in Japan. BACKGROUND: The safety, tolerability, efficacy, and pharmacokinetics of
tirabrutinib, a second-generation, highly selective oral Bruton's tyrosine
kinase inhibitor, were evaluated for relapsed/refractory primary central nervous
system lymphoma (PCNSL).
METHODS: Patients with relapsed/refractory PCNSL, Karnofsky performance status
≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once
daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days
using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted
conditions in phase II.
RESULTS: Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib
at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were
observed, and the maximum tolerated dose was not reached at 480 mg. Common grade
≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and
erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs
(pneumocystis jirovecii pneumonia and interstitial lung disease). Independent
review committee assessed overall response rate (ORR) at 64%: 60% with 5
complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100%
with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted
conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8
months at 320, 480, and 480 mg under fasted conditions, respectively. Median
overall survival was not reached. ORR was similar among patients harboring
CARD11, MYD88, and CD79B mutations, and corresponding wild types.
CONCLUSION: These data indicate favorable efficacy of tirabrutinib in patients
with relapsed/refractory PCNSL.
TRIAL REGISTRATION: JapicCTI-173646. Bruton tyrosine kinase (BTK) plays an important role in the B-cell receptor
(BCR) signaling pathway by mediating proliferation, migration and adhesion in
B-cell maligcies. Therefore, the components of BCR signaling, especially BTK,
are considered to be attractive therapeutic targets. Ibrutinib, a first-in-class
BTK inhibitor, has been approved for the treatment of several types of B-cell
maligcies worldwide. However, ibrutinib has off-target activities on non-BTK
kinase that are related to adverse effects or might translate into clinical
limitations. To overcome these limitations, more specific BTK inhibitors are
needed. Tirabrutinib hydrochloride (tirabrutinib) is a potent, highly selective,
irreversible oral inhibitor of BTK. Tirabrutinib irreversibly and covalently
binds to BTK in B cells and has demonstrated effective in vitro cytotoxicity in
many types of B-cell maligcies and in vivo antitumor activity in mouse
models. Here, we provide a comprehensive review of the preclinical and clinical
activity of tirabrutinib, a drug approved in Japan for relapsed or refractory
primary central nervous system lymphoma and all lines of Waldenström
macroglobulinemia/lymphoplasmacytic lymphoma. Tirabrutinib (ONO/GS-4059; Ono Pharmaceutical) is a newly developed drug that
selectively and irreversibly inhibits Bruton's tyrosine kinase (BTK) and has
been approved in Japan for treating relapsed/refractory primary central nervous
system lymphoma (PCNSL). However, its therapeutic effect is yet to be verified
at the pathological level in human patients. A 64-year-old patient with
recurrent PCNSL enrolled in the phase I/II clinical trial of tirabrutinib, a
second-generation BTK inhibitor designed for treating relapsed/refractory PCNSL.
The left cerebellum lesions on magnetic resoce imaging disappeared one month
after tirabrutinib treatment. The patient died because of suspected pneumocystis
pneumonia and acute exacerbation of interstitial pneumonia 43 days after
starting tirabrutinib. An autopsy confirmed no viable tumor cells in the entire
brain, including the left cerebellum lesion, confirming complete obliteration of
tumor cells by tirabrutinib. This letter pathologically confirms the effect of
tirabrutinib on relapsed/refractory PCNSL for the first time in humans.Trial
registration: JapicCTI-173646. Registered 14 July 2017,
https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-173646. Management of primary central nervous system lymphoma (PCNSL) includes induction
and consolidation therapies in newly diagnosed patients, as well as second-line
therapy in relapsed or refractory patients. The current standard-of-care
induction therapy involves methotrexate (MTX)-based multi-agent
immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine.
Deferral or dose reduction of radiation therapy is considered in consolidation
therapy, especially in elderly patients who carry a high risk of
radiation-induced delayed neurotoxicity. Since elderly patients comprise the
main population of PCNSL, minimally toxic treatments that are effective and
feasible for them are strongly needed. For second-line therapy, rechallenge
using MTX-based chemotherapy (in patients with a prior durable response to
MTX-based chemotherapy) or radiation therapy is considered. Bruton's tyrosine
kinase inhibitor tirabrutinib (for relapsed and refractory PCNSL) and high-dose
chemotherapy with autologous stem cell transplantation support using thiotepa
and busulfan (BuTT) were approved by the Japanese Ministry of Health and Welfare
in March 2020 and has recently become available for clinical practice. While
these novel treatments seem promising, the optimal use of these treatments along
with the standard-of-care therapy of PCNSL should be defined and investigated in
clinical trials. |
Is covid-19 induced anosmia caused by disruption of nuclear architecture? | Yes. Disruption of nuclear architecture is a cause of COVID-19 induced anosmia. | Author information:
(1)Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia
University, New York, NY 10027, USA.
(2)Department of Genetics and Development, Columbia University Irving Medical
Center, Vagelos College of Physicians and Surgeons, Columbia University, New
York, NY, 10032, USA.
(3)Department of Microbiology, Icahn School of Medicine at Mt. Sinai, New York,
NY, 10029, USA.
(4)Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at
Mt. Sinai, New York, NY, 10029, USA.
(5)Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt.
Sinai, New York, NY, 10029, USA.
(6)Icahn Institute for Data Science and Genomic Technology, Icahn School of
Medicine at Mt. Sinai, New York, NY, 10029, USA.
(7)Baylor Genetics, 2450 Holcombe Blvd, Houston, TX, 77021, USA.
(8)Department of Biological Sciences, Columbia University New York, NY, 10027,
USA.
(9)Department of Cell Biology and Human Anatomy, School of Medicine, University
of California at Davis, Davis, CA 95616, USA.
(10)Department of Pathology and Cell Biology, Columbia University Irving Medical
Center, Vagelos College of Physicians and Surgeons, Columbia University, New
York, NY, 10032, USA.
(11)Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York,
NY, 10029, USA.
(12)Department of Otolaryngology- Head and Neck Surgery, Columbia University
Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia
University, New York, NY, 10032, USA. |
What is the mechanism of action of Toripalimab? | Toripalimab is IgG4 monoclonal antibody targeting PD-1, which has been approved for treatment of patients with metastatic melanoma after previous systemic therapy. | Toripalimab, a recombit, humanized programmed death receptor-1 (PD-1)
monoclonal antibody that binds to PD-1 and prevents binding of PD-1 with
programmed death ligands 1 (PD-L1) and 2 (PD-L2), is being developed by Shanghai
Junshi Bioscience Co., Ltd in China for the treatment of various cancers. In
December 2018, based on positive efficacy results of a phase 2 trial and safety
data from several clinical studies, toripalimab received conditional approval in
China for the treatment of unresectable or metastatic melanoma that has failed
previous systemic therapy. This article summarizes the milestones in the
development of toripalimab leading to this first global approval for the
treatment of unresectable or metastatic melanoma. Monoclonal antibody (mAb)-based blockade of programmed cell death 1 (PD-1) or
its ligand to enable antitumor T-cell immunity has been successful in treating
multiple tumors. However, the structural basis of the binding mechanisms of the
mAbs and PD-1 and the effects of glycosylation of PD-1 on mAb interaction are
not well understood. Here, we report the complex structure of PD-1 with
toripalimab, a mAb that is approved by China National Medical Products
Administration as a second-line treatment for melanoma and is under multiple
Phase 1-Phase 3 clinical trials in both China and the US. Our analysis reveals
that toripalimab mainly binds to the FG loop of PD-1 with an unconventionally
long complementarity-determining region 3 loop of the heavy chain, which is
distinct from the known binding epitopes of anti-PD-1 mAbs with structural
evidences. The glycan modifications of PD-1 could be observed in three potential
N-linked glycosylation sites, while no substantial influences were detected to
the binding of toripalimab. These findings benefit our understanding of the
binding mechanisms of toripalimab to PD-1 and shed light for future development
of biologics targeting PD-1. Atomic coordinates have been deposited in the
Protein Data Bank under accession code 6JBT. Author information:
(1)State Key Laboratory of Oncology in South China, Department of Medical
Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center
for Cancer Medicine, Guangzhou.
(2)Department of Medical Oncology, The First Affiliated Hospital, School of
Medicine, Zhejiang University, Hangzhou.
(3)Laboratory of Carcinogenesis & Translational Research for the Ministry of
National Education, Department of GI Oncology, Peking University School of
Oncology, Beijing Cancer Hospital & Institute, Beijing.
(4)Department of Medical Oncology, Chinese PLA General Hospital & Chinese PLA
Medical Academy, Beijing.
(5)Department of Oncology, Tongji Hospital, Huazhong University of Science and
Technology, Wuhan.
(6)The State Key Laboratory of Biotherapy, Department of Abdominal Cancer, West
China Medical School, Cancer Center, West China Hospital, Sichuan University,
Chengdu.
(7)Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou
University, He Cancer Hospital, Zhengzhou.
(8)Department of Medical Oncology, Linyi Cancer Hospital, Linyi.
(9)Department of Medical Oncology, Fudan University Shanghai Cancer Center,
Shanghai; Department of Oncology, Shanghai Medical College, Fudan University,
Shanghai.
(10)Department of Medical Oncology, Fujian Medical University Union Hospital,
Fuzhou.
(11)Department of Medical Oncology, Harbin Medical University Cancer Hospital,
Harbin.
(12)Department of Oncology, Nanjing Medical University Affiliated Cancer
Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research,
Nanjing.
(13)Department of Gastrointestinal Oncology, Tianjin Cancer Hospital, Tianjin.
(14)Department of Medical Oncology, The First Hospital of China Medical
University, Shenyang.
(15)Department of Medical Oncology, The First Hospital of Jilin University,
Changchun.
(16)Department of Oncology, Jiangsu Provincial Hospital, Nanjing.
(17)Digestive Medical Oncology, Cancer Hospital of Shantou University Medical
College, Shantou.
(18)Department of Medical Oncology, Shanghai General Hospital, Shanghai Jiao
Tong University School of Medicine, Shanghai.
(19)State Key Laboratory of Oncology in South China, Department of
Ultrasonography, Sun Yat-sen University Cancer Center, Collaborative Innovation
Center for Cancer Medicine, Guangzhou.
(20)Shanghai Junshi Biosciences Co., Ltd, Shanghai, China.
(21)State Key Laboratory of Oncology in South China, Department of Medical
Oncology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center
for Cancer Medicine, Guangzhou. Electronic address: [email protected]. PURPOSE: Metastatic mucosal melanoma responds poorly to anti-programmed cell
death-1 (PD-1) monotherapy. Vascular endothelial growth factor (VEGF) has been
shown to play an important immunosuppressive role in the tumor microenvironment.
The combination of VEGF inhibition and PD-1 blockade provides therapeutic
opportunities for patients refractory to either therapy alone.
PATIENTS AND METHODS: We conducted a single-center, phase IB trial evaluating
the safety and preliminary efficacy of toripalimab, a humanized immunoglobulin
G4 monoclonal antibody against PD-1 in combination with the VEGF receptor
inhibitor axitinib in patients with advanced melanoma, including patients with
chemotherapy-naïve mucosal melanomas (88%). Patients received toripalimab at 1
or 3 mg/kg via intravenous infusion every 2 weeks, in combination with axitinib
5 mg orally twice a day, in a dose-escalation and cohort-expansion study until
confirmed disease progression, unacceptable toxicity, or voluntary withdrawal.
The primary objective was safety. Secondary objectives included efficacy,
pharmacokinetics, pharmacodynamics, immunogenicity, and tumor tissue biomarkers.
RESULTS: Thirty-three patients were enrolled. No dose-limiting toxicities were
observed. Ninety-seven percent of patients experienced treatment-related adverse
events (TRAEs). The most common TRAEs were mild (grade 1 or 2) and included
diarrhea, proteinuria, hand and foot syndrome, fatigue, AST or ALT elevation,
hypertension, hypo- or hyperthyroidism, and rash. Grade 3 or greater TRAEs
occurred in 39.4% of patients. By the cutoff date, among 29 patients with
chemotherapy-naïve mucosal melanoma, 14 patients (48.3%; 95% CI, 29.4% to 67.5%)
achieved objective response, and the median progression-free survival time was
7.5 months (95% CI, 3.7 months to not reached) per Response Evaluation Criteria
in Solid Tumors (RECIST) version 1.1.
CONCLUSION: The combination of toripalimab plus axitinib was tolerable and
showed promising antitumor activity in patients with treatment-naïve metastatic
mucosal melanoma. Patients enrolled in this study were all Asian, and this
combination therapy must be validated in a randomized phase III trial that
includes a non-Asian population before it can become a standard of care. INTRODUCTION: Immune therapies have dramatically changed the treatment landscape
for melanoma in the past decade. Ipilimumab, nivolumab, and pembrolizumab have
been approved by U.S. Food and Drug Administration for the treatment of
metastatic melanoma sequentially. Toripalimab, a humanized IgG4 monoclonal
antibody against programmed cell death protein-1 (PD-1), was approved by
National Medical Product Administration in China in 2018 as second-line therapy
for metastatic melanoma.
AREAS COVERED: This is a comprehensive review of the literature and studies of
toripalimab in melanoma, including clinical trials and translational research.
EXPERT OPINION: Toripalimab is not inferior to pembrolizumab as a second-line
therapy for metastatic melanoma. Prospective validated predictive markers are
lacking. Programmed cell death ligand 1 expression and tumor mutational burden
are two common recognized biomarkers, but the predictability of these markers
requires additional improvement. A number of studies have confirmed that PD-1
inhibitors, including toripalimab, are not as effective in mucosal and acral
melanomas as in non-acral cutaneous subtype. Toripalimab in combination with
tyrosine kinase inhibitor axitinib has shown a promising result for metastatic
mucosal melanoma. It is crucial to explore the mechanisms underlying the varying
biological behavior of melanoma subtypes, which may also provide clues of innate
and acquired resistance to PD-1 blockade. Toripalimab is a monoclonal antibody targeting programmed cell death protein 1
(PD-1). It has recently been approved as an immune checkpoint inhibitor in
second-line therapies in patients with unresectable or metastatic melanoma;
however, it may be associated with various immune-related adverse events
(irAEs). Here we report a case of toripalimab-induced dermatomyositis in a
patient receiving treatment for metastatic melanoma. The symptoms were relieved
by discontinuing toripalimab and administering once-daily intravenous
methylprednisolone 1 mg/kg. We suggest that this case serves a warning to
clinicians of the need to be aware of the possiblilty of toripalimab-induced
dermatomyositis. Early recognition and treatment may prevent progression and
improve prognosis of this irAE. BACKGROUND: Several programmed cell death ligand 1 (PD-L1)/programmed cell death
protein 1 (PD-1) antibodies have been approved for cancer treatment worldwide.
Their pharmacokinetic and pharmacodynamic characteristics have been reported
mainly in western countries, but related data in Chinese patients are limited.
This study was conducted to investigate the safety, efficacy, pharmacokinetics,
and pharmacodynamics of an anti-PD-1 antibody, toripalimab, in Chinese patients.
METHODS: A single-center phase I study was conducted in Sun Yat-sen University
Cancer Center. Eligible patients were adults with histologically confirmed,
treatment-refractory, advanced, solitary maligt tumors. Toripalimab was
intravenously infused every 2 weeks in dose-escalating cohorts at 0.3 mg/kg,
1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3
design.
RESULTS: Between 15th March 2016 and 27th September 2016, 25 patients were
enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received
0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively.
After a median follow-up time of 5.0 months (range: 1.5-19.8 months), we
observed that the commonest treatment-related adverse events (TRAEs) were
fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No
dose-limiting toxicity, treatment-related serious adverse events (SAEs), or
treatment-related death occurred. Objective response rate was 12.5%. The
half-life of toripalimab was 150-222 h after a single dose infusion. Most
patients, including those from the 0.3 mg/kg group, maintained complete PD-1
receptor occupancy (> 80%) on activated T cells since receiving the first dose
of toripalimab.
CONCLUSIONS: Toripalimab is a promising anti-PD-1 antibody, which was well
tolerated and demonstrated anti-tumor activity in treatment-refractory advanced
solitary maligt tumors. Further exploration in various tumors and combination
therapies is warranted. INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of
non-small cell lung carcinoma (NSCLC), which characterized by insensitive to
conventional radiotherapy and chemotherapy and poor prognosis. Except MET exon
14 alterations and other oncogene mutations, PSC commonly harbor high tumor
mutational burden (TMB) and high level of PD-L1, which provide new therapeutic
opportunities. Toripalimab (JS001) is IgG4 monoclonal antibody targeting PD-1,
which has been approved for treatment of patients with metastatic melanoma after
previous systemic therapy. PD-1 combined with radiotherapy has been tried in
several cancer types.
CASE PRESENTATION: We reported a case of a PSC patient with PD-L1 overexpression
responding to toripalimab and after progression the patients also benefits from
toripalimab combined with local radiotherapy, which provides a promising option
for PSC patients.
CONCLUSION: This case provides the evidence of the effective role of toripalimab
and PD-1 combined with local radiotherapy in PSC patients, which was the first
application as far as we know. PURPOSE: As yet, no checkpoint inhibitor has been approved to treat
nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor
activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1)
inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard
chemotherapy.
PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients
with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous
infusion until confirmed disease progression or unacceptable toxicity. The
primary end point was objective response rate (ORR). The secondary end points
included safety, duration of response (DOR), progression-free survival (PFS),
and overall survival (OS).
RESULTS: Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months,
median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed
at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were
27.1% and 19.4% in PD-L1+ and PD-L1- patients, respectively (P = .31). Patients
with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28
had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7%
(P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base
in the cohort and had no predictive value for response. Whole-exome sequencing
results from 174 patients revealed that the patients with genomic amplification
in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab.
CONCLUSION: The POLARIS-02 study demonstrated a manageable safety profile and
durable clinical response of toripalimab in patients with chemorefractory
metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with
favorable response. Background: Anti-programmed cell death protein 1 (PD-1) has been successfully
used in carcinomas treatment. However, it causes significant adverse effects
(AEs), including cutaneous reactions, particularly the life-threatening severe
bullous skin reactions (SBSR) and toxic epidermal necrolysis (TEN). Case
summary: Herein, we described for the first time a case report of SBSR induced
by anti-PD-1 therapy in a cervical cancer patient. In addition, we revised
existing literature on anti-PD-1 induced cutaneous reactions. We reported a
cervical cancer patient who was treated with four successive cycles of
Sintilimab and Toripalimab injections and developed systemic rashes, bullae, and
epidermal desquamation, which worsened and led to infection, eventually causing
death after being unresponsive to aggressive treatments. Conclusion: Anti-PD-1
antibodies commonly cause skin toxicity effects, some of which may be deadly.
Therefore, healthcare providers should observe early symptoms and administer
proper treatment to prevent aggravation of symptoms. BACKGROUND: Lung cancer is the leading cause of cancer-related death, of which
non-small cell lung cancer (NSCLC) is the most common type. Immune checkpoint
inhibitors (ICIs) have now become one of the main treatments for advanced NSCLC.
This paper retrospectively investigated the effect of peripheral blood
inflammatory indexes on the efficacy of immunotherapy and survival of patients
with advanced non-small cell lung cancer, in order to find strategies to guide
immunotherapy in NSCLC.
METHODS: Patients with advanced non-small cell lung cancer who were hospitalized
in The Affiliated Cancer Hospital of Nanjing Medical University from October
2018 to August 2019 were selected to receive anti-PD-1 (pembrolizumab,
sintilimab or toripalimab) monotherapy or combination regimens. And were
followed up until 10 December 2020, and the efficacy was evaluated according to
RECIST1.1 criteria. Progression-free survival (PFS) and overall survival (OS)
were followed up for survival analysis. A clinical prediction model was
constructed to analyze the predictive value of neutrophil-to-lymphocyte ratio
(NLR) based on NLR data at three different time points: before treatment, 6
weeks after treatment and 12 weeks after treatment (0w, 6w and 12w), and the
accuracy of the model was verified.
RESULTS: 173 patients were finally included, all of whom received the above
treatment regimen, were followed up for a median of 19.7 months. The objective
response rate (ORR) was 27.7% (48/173), the disease control rate (DCR) was 89.6%
(155/173), the median PFS was 8.3 months (7.491-9.109) and the median OS was
15.5 months (14.087-16.913). The chi-square test and logistic multi-factor
analysis showed that NLR6w was associated with ORR and NLR12w was associated
with ORR and DCR. Further Cox regression analysis showed that NLR6w and NLR12w
affected PFS and NLR0w, NLR6w and NLR12w were associated with OS.
CONCLUSIONS: In patients with advanced non-small cell lung cancer, NLR values at
different time points are valid predictors of response to immunotherapy, and NLR
<3 is often associated with a good prognosis. Patients diagnosed with advanced adenoid cystic carcinoma (ACC) with metastasis
to the lung generally have poor prognosis when they exhibit resistance to
conventional therapies. Programmed cell-death protein 1 (PD-1) inhibitors, a
type of Immune checkpoint inhibitors (ICI), have shown good response in the
treatment of various types of maligt tumors; however, objective response
rates of monotherapy for advanced ACC are low. Anlotinib, a novel, orally
managed tyrosine kinase inhibitor, that targets vascular endothelial growth
factor receptor (VEGFR), fibroblast growth factor receptor (FGFR),
platelet-derived growth factor receptor (PDGFR), and c-kit, has appeared great
adequacy in treating numerous sorts of maligt tumors, particularly tumors
with lung metastases. Here, we have presented a case of refractory ACC with lung
metastases that was reduced after combinatorial treatment using the immune
checkpoint inhibitor (ICI) toripalimab and anti-angiogenesis agent anlotinib.
The patient achieved a reduction in lung metastases by chest computed tomography
(CT) examination, with an outcome of stable disease (SD) of 5 months, a
significant decrease in the levels of peripheral blood cytokines interleukin 6
(IL-6) and tumor necrosis factor-α (TNF-α), as well as good tolerance without
noteworthy unfavorable reactions, indicating that the combined therapy of
toripalimab and anlotinib may be utilized in the management of advanced ACC. BACKGROUND: The most effective treatment of immune checkpoint inhibitors (ICIs)
is restricted in microsatellite instability (MSI-H) subsets of advanced
colorectal cancer, but MSI-H only accounts for 4-5% among them. ICIs are
completely ineffective in advanced colorectal cancer patients with
microsatellite stable (MSS), according to literatures published. Regorafenib is
a novel tyrosine kinase inhibitor (TKIs) that could normalize tumor blood
vessels by inhibiting vascular endothelial growth factor receptor and its
downstream, thus improving cytotoxic T cell infiltration in tumor
microenvironment, which has a synergistic effect with ICIs. Toripalimab is a
type of anti-PD-1 monoclonal antibody produced by Junshi Biosciences in China.
Herein, we aimed to explore the efficacy and safety of regorafenib combined with
toripalimab in the third-line and beyond treatment of advanced colorectal
cancer.
METHODS: We evaluated the outcomes of MSS patients with advanced colorectal
cancer who received regorafenib combined with toripalimab in the Second
Affiliated Hospital of Nanchang University from June 2019 to January 2021. These
patients had previously received at least second-line treatment; the regimens
were oxaliplatin and irinotecan-based chemotherapy and/or accompanied with
bevacizumab or cetuximab. Thirty-three patients were treated orally with
regorafenib 80 mg or 120 mg once daily for 21 days, 28 days as a cycle, combined
with intravenous toripalimab until disease progression or intolerant to adverse
reactions. We used the Kaplan-Meier method to estimate the rate of
progression-free survival (PFS) and log-rank method to do a statistical test of
the survival curve. The Cox regression model was used to analyze the influence
of multiple factors on PFS. The primary endpoints were objective remission rate
(ORR) and disease control rate (DCR). The secondary endpoints were the incidence
of adverse reactions and median progression-free survival (mPFS).
RESULTS: The evaluation of treatment effects was assessed according to RECIST
1.1. Four patients (12.12%) got partial response, twelve patients (36.36%)
experienced stable disease, and seventeen patients (51.52%) suffered progressive
disease. ORR was 12.12% and DCR was 48.48%. mPFS was 113 days (95% CI: 0-272.1).
In univariate analysis, patients who had previously received second-line
treatment were significantly better than those who had received third-line or
more treatment (p=0.005). Lung metastasis was a negative factor in combined
therapy (p=0.032). Five patients without previous treatment of bevacizumab were
effective. Previous treatment without bevacizumab showed a trend of effective
when combination therapy (p=0.034). It was also a positive factor that the
Eastern Cooperative Oncology Group performance status (ECOG) score was 0
(p=0.034). Multivariable Cox regression analysis showed the number of previous
chemotherapy lines and excision of primary lesions were independent prognostic
factors. The most common treatment-related adverse reactions were hand-foot
syndrome (33.33%), liver dysfunction (27.27), hypothyroidism (24.24%), fever
(24.24%), fatigue (21.21%), leukopenia (15.15%), hypertension (12.12%), platelet
count decreased (6.06%), diarrhea (3.03%), and myocarditis (3.03%); one patient
stopped treatment as myocarditis. The incidence of grade 3/4 adverse reactions
was 9.09%.
CONCLUSIONS: Regorafenib combined with toripalimab has a promising effect in the
third-line and beyond treatment of advanced colorectal cancer. In the early use
of combination therapy, excision of primary lesions can have a positive impact
in regorafenib and toripalimab combination. This treatment-related adverse
reactions are tolerant in combined therapy. Anti-PD-1/PD-L1 monoclonal antibodies result in a unique spectrum of side
effects, widely known as immune-related adverse events. Toripalimab is
an anti-PD-1 monoclonal antibody used for the treatment of some cancers. Here we
report the first case, to our knowledge, of oral lichenoid drug reaction
triggered by toripalimab. A 78-year-old man who was diagnosed with systemic
metastatic prostate cancer presented with ulcers on the lower lip after the
fifth cycle of toripalimab. We diagnosed him with oral lichenoid drug reaction
based on clinical manifestation, histopathological findings and the history of
anti-PD-1 therapy. The patient responded well to oral corticosteroids combined
with helium-neon laser therapy. The anti-PD-1 therapy was not restarted because
of stable disease, and the eruptions did not recur. RATIONALE: The targeting of signal transduction through programmed cell death
receptor-1 (PD-1) and its ligand programmed cell death-ligand 1 (PD-L1) in
patients with non-small cell lung cancer (NSCLC) has been widely applied in
clinical research. However, the subtypes and treatment patterns that predict
responses to PD-1/PD-L1 inhibitors are not fully understood. Biomarkers, such as
PD-L1 expression, tumor mutation load, and DNA mismatch repair defects, have
been used to screen patients who respond to PD-1/PD-L1 inhibitors, but the
appropriate treatment mode requires further investigation. Immune checkpoint
inhibitors combined with radiotherapy provide benefits from remote effects,
especially in NSCLC patients with increased PD-L1 expression.
PATIENT CONCERNS: We report a 64-year-old man who presented with left back pain
for 40 days. A computed tomography scan showed a mass in the right upper lobe of
the lung, with metastases in the right hilar and mediastinal lymph nodes.
DIAGNOSIS: NSCLC-not otherwise specified was diagnosed by computed
tomography-guided lung biopsy.
INTERVENTIONS: After the failure of first-line chemotherapy, next-generation
sequencing was performed for comprehensive gene analysis, and PD-L1 expression
levels were evaluated by immunohistochemistry. The patient was treated with
toripalimab (a PD-1 inhibitor) concurrently with radiotherapy for bone
metastases.
OUTCOMES: The detection results showed a high tumor mutation burden and
increased PD-L1 expression. On the basis of these findings, the patient received
toripalimab (PD-1 inhibitor) combined with radiotherapy for bone metastases.
Partial response was achieved after 3 cycles, and the patient showed stable
disease at the end of the sixth and ninth cycles of toripalimab. The patient was
followed up for 26 months. At present, the patient is receiving toripalimab
maintece treatment, which has been well-tolerated without adverse events.
LESSON: Toripalimab combined with radiotherapy may exert a synergistic
anti-tumor effect through remote effects in advanced or metastatic NSCLC with
high PD-L1 expression. However, the specific treatment mode requires further
confirmation by the investigation of additional cases. Toripalimab, a humanized IgG4 monoclonal antibody (mAb) against programmed death
receptor-1, is being extensively studied to treat various maligcies. At
present, there is no complete methodology reported for quantifying toripalimab,
except for an electrochemiluminescence immunoassay (ECLIA) mentioned in several
clinical studies. Therefore, a sensitive and robust ultra-high performance
liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed to
accurately detect toripalimab levels, compared with the ECLIA. Plasma samples
were pretreated by a five-step process, encompassing denaturation, reduction,
alkylation, enzymatic hydrolysis and quenching. And a unique, sensitive and
stable enzymatic peptide (ASGYTFTDYEMHWVR) selected as surrogate of toripalimab
was eluted and monitored by UPLC-MS/MS system with the linear range of
5.0375-201.5 μg/mL. After fully validated, the UPLC-MS/MS method was applied to
determine 77 plasma samples from 29 patients in a phase I clinical trial, and
compared with ECLIA based on 56 samples. Wilcoxon paired samples test showed
toripalimab levels by UPLC-MS/MS were significantly higher than that by ECLIA
(p < 0.001), though a strong correlation was observed (r = 0.96). Moreover,
Passing-Bablok regression analysis exhibited constant and proportional biases:
UPLC-MS/MS = 2.25 + 1.21 * ECLIA. This discrepancy could be mainly attributed to
different forms determined: total mAb for UPLC-MS/MS and free mAb for ECLIA,
respectively. As a result, this UPLC-MS/MS method may be complementary to ECLIA
to monitor different forms of toripalimab. Beyond that, it can be easily
modified to simultaneously quantitate multiple-analyte with a small volume of
plasma. |
Is taxilin a cancer marker? | Yes,
α-Taxilin, a binding partner of the syntaxin family, is a candidate tumor marker. | The membrane traffic system has been recognized to be involved in carcinogenesis
and tumor progression in several types of tumors. α-taxilin is a newly
identified membrane traffic-related molecule, and its up-regulation has been
reported in embryonic and maligt tissues of neural origin. In the present
study, we analyzed the expression of α-taxilin in relation to
clinicopathological features of hepatocellular carcinomas (HCC) and
proliferative activity of the tumor determined by proliferating cell nuclear
antigen labeling index (PCNA-LI). Twenty-nine surgically resected nodules of HCC
(8 well-, 11 moderately-, and 10 poorly-differentiated) were studied. Fifteen
cases showed 'strong staining', while 14 cases showed 'weak staining' for
α-taxilin. A significantly higher expression of α-taxilin was observed in
less-differentiated (p=0.005), and more invasive (p=0.016) HCCs. The 'strong
staining' group showed significantly higher PCNA-LI than the 'weak staining'
group (the medians of PCNA-LI were 59.4% vs. 14.4%, p<0.0001). We also evaluated
the expression of α-taxilin in hepatoma cell lines (PLC/PRF/5, Hep G2 and HuH-6)
in association with cell proliferation. The expression levels of α-taxilin
protein were correlated with their growth rates. In conclusion, the expression
of the α-taxilin protein was related with an increased proliferative activity
and a less-differentiated histological grade of HCC. α-taxilin may be involved
in cell proliferation of HCC, and its expression can be a marker of maligt
potential of HCC. α-taxilin is a binding partner of syntaxins, which are the central coordinators
of membrane traffic. Expression of α-taxilin has been implicated in the
development of human glioblastoma, hepatocellular carcinoma and renal cell
carcinoma. In the present study, the clinical significance of α-taxilin
expression in colorectal cancer (CRC) was investigated. A total of 20 cases of
colorectal intramucosal adenocarcinoma (IMA) with adenoma were analyzed using
immunohistochemical analysis. The results demonstrated that α-taxilin expression
was significantly associated with Ki-67 indices in adenoma and IMA. The patients
expressed equally high levels of α-taxilin in the upper third of the
intramucosal glands. These results suggest that α-taxilin expression is
significantly associated with the proliferative activity of CRC, but that its
overexpression alone is not a biomarker of maligcy. Next, α-taxilin
expression was investigated in 57 advanced CRCs and its association with
prognosis was determined. Well-differentiated and/or moderately differentiated
adenocarcinomas in the left-sided colon with anatomic stage II and/or III were
analyzed. α-taxilin expression levels were high on the surface of nearly all
tumors, but variable at the deep advancing edge. α-taxilin levels at the
advancing edge were not significantly associated with local invasiveness or
prognosis. In conclusion, α-taxilin is a cell proliferation marker in colorectal
epithelial neoplasms but cannot be a marker of maligcy or prognosis of CRCs. Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease affecting
the joints and surrounding tissue. Identification of novel proteins associated
with the progression of a disease is a prerequisite for understanding the
pathogenesis of RA. The present study was undertaken to identify the potential
biomarkers from a less explored biological sample such as synovial fluid (SF)
cells which is specific for RA and to analyze their functional aspects using
proteomic approach. Two-dimensional gel electrophoresis (2-DE) was performed
using synovial fluid cells of RA and osteoarthritis (OA) patients, and 7
differentially expressed proteins were identified using matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS/MS).
Αlpha-Taxilin (α-Taxilin) has been found as one of the novel, significantly up
regulated protein in RA. It has been validated in the synovium, synovial fluid
(SF), SF cells, and plasma samples by Western blot, enzyme-linked immunosorbent
assay (ELISA), fluorescence-activated cell sorting (FACS), immunohistochemistry
(IHC), and real-time PCR. The identification of autoantibody against α-Taxilin
and in silico studies has further helped us to understand its involvement in
disease mechanism. The present study will therefore provide knowledge towards
the etiology of RA that pave the way for suitable prognostic marker
identification along with other clinical parameters. |
What are the symptoms of an incidental durotomy (ID). | Incidental durotomy can cause postural headaches, nausea, vomiting, dizziness, photophobia, tinnitus, and vertigo. Meningitis is a rare complication reported to occur with a frequency of 0.18% | STUDY DESIGN: A retrospective review of 20 patients with incidental durotomy
treated without mandatory bed rest.
OBJECTIVES: To determine whether patients with incidental durotomy can be
treated effectively without multiple days of bed rest.
SUMMARY OF BACKGROUND DATA: Incidental durotomy can cause postural headaches,
nausea, vomiting, dizziness, photophobia, tinnitus, and vertigo. These symptoms
are believed to result from a decrease in cerebrospinal fluid pressure, leading
to traction on the supporting structures of the brain. Traditional management
includes bed rest for up to 7 days to eliminate traction and reduce hydrostatic
pressure during the healing process.
METHODS: Twenty incidental durotomies were repaired intraoperatively with dural
stitches and fibrin glue. Patients were allowed to ambulate according to the
natural course after surgery without mandatory bed rest. Symptoms were monitored
closely for 1 week, and long-term follow-up assessments were obtained at a
minimum of 10 months.
RESULTS: Of the 20 patients in this study, 75% had no symptoms after repair of
the incidental durotomy. Each of the dural tears was 1-3 mm in length. Two
patients reported headache, two reported nausea, and one reported tinnitus; no
patients experienced vomiting. One patient (5%) had stitch loosening requiring
revision surgery. There were no additional serious complications.
CONCLUSIONS: This study has shown that the majority of patients with incidental
durotomy can be treated effectively with dural stitches and fibrin glue.
Patients can be permitted to ambulate immediately after surgery but should be
cautioned to lay flat if they develop symptoms. This will reduce the costs
related to the hospital stay and missed work. Despite the frequency of dural tears in spinal surgery, meningitis is a rare
complication reported to occur with a frequency of 0.18%. To the best of our
knowledge, no case of Acinetobacter baumanii meningitis has been reported in the
literature after a dural tear secondary to lumbar spine discectomy. This case
highlights the importance of repairing all dural tears and commencing
antibiotics that cover uncommon bacteria in those who develop symptoms of
meningitis in this setting. |
Is PCAT6 a microRNA? | No, PCAT6 is a long noncoding RNA. | Breast cancer is an aggressive maligcy with high morbidity in females
worldwide. Extensive studies reveal that long noncoding RNAs (lncRNAs) are
abnormally expressed and act as key regulators in various cancers, including
breast cancer. In this work, we investigated the role and regulatory mechanism
of lncRNA prostate cancer-associated transcript 6 (PCAT6) in breast cancer
progression. Our findings revealed that PCAT6 was overexpressed in breast cancer
tissues and cell lines. Furthermore, elevation of PCAT6 reflected an adverse
prognosis of patients. Functional experiments indicated that PCAT6 knockdown
hampered cell proliferation, facilitated apoptosis and cell cycle arrest in
vitro, and inhibited tumor growth in vivo. We also found that the transcription
factor SP1 could bind to the PCAT6 promoter and promoted its expression.
Subsequently, it was verified that PCAT6 was a molecular sponge for microRNA-326
(miR-326), and the leucine-rich repeat containing the eight family member E
(LRRC8E) was a direct target of miR-326. Rescue assays revealed that LRRC8E
overexpression attenuated the suppressive effect of PCAT6 knockdown on cellular
progression of breast cancer. In summary, this study demonstrated that
SP1-activated PCAT6 promoted the maligt behaviors of breast cancer cells by
regulating the miR-326/LRRC8E axis. |
Is HDAC1 required for GATA-1 transcriptional activity? | Yes. HDAC1 is required for GATA-1 transcription activity, global chromatin occupancy and hematopoiesis. | |
Which enzyme is inhibited by Aramchol? | Arachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression. | BACKGROUND AND AIMS: Suppression of stearoyl-coenzyme A desaturase (SCD)
activity leads to reduction of obesity, fatty liver as well as of insulin
resistance. It was, however, recently reported to enhance atherogenesis. The aim
of the present study was to investigate whether inhibition of SCD by Aramchol, a
fatty acid bile conjugate with known hypocholesterolemic effects, will affect
atherogenesis and how.
METHODS: Aramchol was tested in vitro in cultured cells and in vivo in rodents.
RESULTS: Aramchol, at very low concentrations, reduced SCD activity in liver
microsomes of mice. Aramchol enhanced cholesterol efflux from macrophages more
than twofold. In vivo it increased fecal sterol output and decreased markedly
plasma cholesterol levels in mice. In ApoE(-/-), LDRL(-/-) and C57Bl6 mice, the
effects of Aramchol on atherogenesis were non-atherogenic.
CONCLUSIONS: Aramchol reduces SCD activity and is non-atherogenic. It may offer
a means to obtain the desirable hepatic metabolic effects of SCD inhibition
without the deleterious atherogenic effect. Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty
liver disease (NAFLD) which sets the stage for further liver damage. The
mechanism for the progression of NASH involves multiple parallel hits including
oxidative stress, mitochondrial dysfunction, inflammation and others.
Manipulation of any of these pathways may be an approach to prevent NASH
development and progression. Aramchol (arachidyl-amido cholanoic acid) is
presently in a phase IIb NASH study. The aim of this study was to investigate
Aramchol's mechanism of action and its effect on fibrosis using the methionine-
and choline-deficient (MCD) diet model of NASH. We collected liver and serum
from mice fed a MCD diet containing 0.1% methionine (0.1MCD) for four weeks,
which developed steatohepatitis and fibrosis, as well as mice receiving a
control diet; the metabolomes and proteomes were determined. 0.1MCD fed mice
were given Aramchol (5mg/kg/day for the last 2 weeks); liver samples were
analyzed histologically. Aramchol administration reduced features of
steatohepatitis and fibrosis in 0.1MCD fed mice. Aramchol downregulated
stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in triglyceride
biosynthesis whose loss enhances fatty acid β-oxidation. Aramchol increased the
flux through the transsulfuration pathway, leading to a rise in glutathione
(GSH) and GSH/GSSG ratio, the main cellular antioxidant that maintains
intracellular redox status. Comparison of serum metabolomic pattern between
0.1MCD fed mice and NAFLD patients showed a substantial overlap.
CONCLUSIONS: Aramchol treatment improved steatohepatitis and fibrosis by 1)
decreasing SCD1, and 2) increasing the flux through the transsulfuration pathway
maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD
model resembles the metabolic phenotype observed in about 50% of NAFLD patients,
which supports the potential use of Aramchol in NASH treatment. Aramchol, an oral stearoyl-coenzyme-A-desaturase-1 inhibitor, has been shown to
reduce hepatic fat content in patients with primary nonalcoholic fatty liver
disease (NAFLD); however, its effect in patients with human immunodeficiency
virus (HIV)-associated NAFLD is unknown. The aramchol for HIV-associated NAFLD
and lipodystrophy (ARRIVE) trial was a double-blind, randomized,
investigator-initiated, placebo-controlled trial to test the efficacy of 12
weeks of treatment with aramchol versus placebo in HIV-associated NAFLD. Fifty
patients with HIV-associated NAFLD, defined by magnetic resoce imaging
(MRI)-proton density fat fraction (PDFF) ≥5%, were randomized to receive either
aramchol 600 mg daily (n = 25) or placebo (n = 25) for 12 weeks. The primary
endpoint was a change in hepatic fat as measured by MRI-PDFF in colocalized
regions of interest. Secondary endpoints included changes in liver stiffness
using magnetic resoce elastography (MRE) and vibration-controlled transient
elastography (VCTE), and exploratory endpoints included changes in total-body
fat and muscle depots on dual-energy X-ray absorptiometry (DXA), whole-body MRI,
and cardiac MRI. The mean (± standard deviation) of age and body mass index were
48.2 ± 10.3 years and 30.7 ± 4.6 kg/m2 , respectively. There was no difference
in the reduction in mean MRI-PDFF between the aramchol group at -1.3% (baseline
MRI-PDFF 15.6% versus end-of-treatment MRI-PDFF 14.4%, P = 0.24) and the placebo
group at -1.4% (baseline MRI-PDFF 13.3% versus end-of-treatment MRI-PDFF 11.9%,
P = 0.26). There was no difference in the relative decline in mean MRI-PDFF
between the aramchol and placebo groups (6.8% versus 1.1%, P = 0.68). There were
no differences in MRE-derived and VCTE-derived liver stiffness and whole-body
(fat and muscle) composition analysis by MRI or DXA. Compared to baseline,
end-of-treatment aminotransferases were lower in the aramchol group but not in
the placebo arm. There were no significant adverse events. Conclusion: Aramchol,
over a 12-week period, did not reduce hepatic fat or change body fat and muscle
composition by using MRI-based assessment in patients with HIV-associated NAFLD
(clinicaltrials.gov ID:NCT02684591). Publisher: Die nichtalkoholische Fettleber (NAFLD) ist die am stärksten
zunehmende Lebererkrankung weltweit. Vielen Patienten gelingt es nicht, durch
eine Änderung des Lebensstils einen positiven Einfluss auf die Erkrankung zu
erzielen, und der Bedarf an einer pharmakologischen Therapie in dieser Gruppe
ist hoch. In Analogie zu anderen metabolischen Erkrankungen wie z. B. dem
Diabetes mellitus Typ 2 oder Fettstoffwechselstörungen wird vermutlich ein
großer Teil von Patienten eine dauerhafte medikamentöse Therapie benötigten.
Derzeit sind mehrere Substanzen mit verschiedenen pathophysiologischen Ansätzen
in klinischer Testung. Dabei können metabolische, antiinflammatorische und
antifibrotische Wirkmechanismen unterschieden werden. Mehrere Substanzen
befinden sich bereits in Phase-3-Studien. Dazu zählen Elafibranor
(PPAR-α/δ-Agonist), Cenicriviroc (CCR2/CCR5-Inhibitor), Obeticholsäure
(FXR-Agonist), Aramchol (SCD1-Modulator) und Resmetrion
(Thyroid-Hormon-Rezeptor-beta-Agonist). Weitere Studien mit pathophysiologisch
vielversprechenden Wirkmechanismen, z. B. dem ASK-1-Inhibitor Selonsertib oder
dem Caspase-Inhibitor Emricasan, haben bislang negative Ergebnisse gezeigt,
werden jedoch z. T. in Kombinationstherapien weiter evaluiert. Die komplexe
Pathophysiologie der Erkrankung, die Entzündung, Stoffwechsel und Fibrose
verknüpft, hat dazu geführt, dass auch Kombinationen mehrerer Substanzen mit
verschiedenen Wirkansätzen untersucht werden. Die vorliegende Übersicht fasst
die Ende 2019 in klinischen Studien der Phase 3 befindlichen Substanzen für
Patienten mit NASH ohne Leberzirrhose zusammen. BACKGROUND: Arachidyl amido cholanoic acid (Aramchol) is a potent downregulator
of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression that reduces
liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase
IIb clinical trial in patients with nonalcoholic steatohepatitis (NASH), 52 wk
of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an
indicator of glycemic control.
AIM: To assess lipid and glucose metabolism in mouse hepatocytes and in a NASH
mouse model [induced with a 0.1% methionine and choline deficient diet (0.1MCD)]
after treatment with Aramchol.
METHODS: Isolated primary mouse hepatocytes were incubated with 20 μmol/L
Aramchol or vehicle for 48 h. Subsequently, analyses were performed including
Western blot, proteomics by mass spectrometry, and fluxomic analysis with
13C-uniformly labeled glucose. For the in vivo part of the study, male C57BL/6J
mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d
Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics
were assessed using ultra-high-performance liquid chromatography-time of
flight-MS for the determination of glucose metabolism-related metabolites.
RESULTS: Combination of proteomics and Western blot analyses showed increased
AMPK activity while the activity of nutrient sensor mTORC1 was decreased by
Aramchol in hepatocytes. This translated into changes in the content of their
downstream targets including proteins involved in fatty acid (FA) synthesis and
oxidation [P-ACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative
phosphorylation (NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2),
tricarboxylic acid (TCA) cycle (MDH2, SUCLA2, and SUCLG2), and ribosome
(P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with 13C-uniformely
labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in
hepatocytes, as indicated by the increase in the number of rounds that malate
remained in the TCA cycle. Finally, liver metabolomic analysis showed that
glucose homeostasis was improved by Aramchol in 0.1MCD fed mice in a
dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose,
and Rbl5P/Xyl5P.
CONCLUSION: Aramchol exerts its effect on glucose and lipid metabolism in NASH
through activation of AMPK and inhibition of mTORC1, which in turn activate FA
β-oxidation and oxidative phosphorylation. BACKGROUND & AIMS: Aramchol is a fatty acid-bile acid conjugate that reduces
liver fat content and is being evaluated in a phase III clinical trial for
non-alcoholic steatohepatitis (NASH). Aramchol attenuates NASH in mouse models
and decreases steatosis by downregulating the fatty acid synthetic enzyme
stearoyl CoA desaturase 1 (SCD1) in hepatocytes. Although hepatic stellate cells
(HSCs) also store lipids as retinyl esters, the impact of Aramchol in this cell
type is unknown.
METHODS: We investigated the effects of Aramchol on a human HSC line (LX-2),
primary human HSCs (phHSCs), and primary human hepatocytes (phHeps).
RESULTS: In LX-2 and phHSCs, 10 μM Aramchol significantly reduced SCD1 mRNA
while inducing PPARG (PPARγ) mRNA, with parallel changes in the 2 proteins;
ACTA2, COL1A1, β-PDGFR (bPDGFR) mRNAs were also significantly reduced in LX-2.
Secretion of collagen 1 (Col1α1) was inhibited by 10 μM Aramchol. SCD1 knockdown
in LX-2 cells phenocopied the effect of Aramchol by reducing fibrogenesis, and
addition of Aramchol to these cells did not rescue fibrogenic gene expression.
Conversely, in LX-2 overexpressing SCD1, Aramchol no longer suppressed
fibrogenic gene expression. The drug also induced genes in LX-2 that promote
cholesterol efflux and inhibited ACAT2, which catalyses cholesterol synthesis.
In phHeps, Aramchol also reduced SCD1 and increased PPARG mRNA expression.
CONCLUSIONS: Aramchol downregulates SCD1 and elevates PPARG in HSCs, reducing
COL1A1 and ACTA2 mRNAs and COL1A1 secretion. These data suggest a direct
inhibitory effect of Aramchol in HSCs through SCD1 inhibition, as part of a
broader impact on both fibrogenic genes as well as mediators of cholesterol
homeostasis. These findings illustrate novel mechanisms of Aramchol activity,
including potential antifibrotic activity in patients with NASH and fibrosis.
LAY SUMMARY: In this study, we have explored the potential activity of Aramchol,
a drug currently in clinical trials for fatty liver disease, in blocking
fibrosis, or scarring, by hepatic stellate cells, the principal
collagen-producing (i.e. fibrogenic) cell type in liver injury. In both isolated
human hepatic stellate cells and in a human hepatic stellate cell line, the drug
suppresses the key fat-producing enzyme, stearoyl CoA desaturase 1 (SCD1), which
leads to reduced expression of genes and proteins associated with hepatic
fibrosis, while inducing the protective gene, PPARγ. The drug loses activity
when SCD1 is already reduced by gene knockdown, reinforcing the idea that
inhibition of SCD1 is a main mode of activity for Aramchol. These findings
strengthen the rationale for testing Aramchol in patients with NASH. Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved
therapy, is associated with lipotoxicity and insulin resistance and is a major
cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor
of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis
in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week,
double-blind, placebo-controlled, phase 2b trial randomized 247 patients with
NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo
arms, respectively; NCT02279524 ). The primary end point was a decrease in
hepatic triglycerides by magnetic resoce spectroscopy at 52 weeks with a dose
of 600 mg of Aramchol. Key secondary end points included liver histology and
alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected
decrease in liver triglycerides without meeting the prespecified significance
(-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further
formal statistical analysis. NASH resolution without worsening fibrosis was
achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of
the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis
improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88,
95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for
600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to
adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well
tolerated and without imbalance in serious or severe AEs between arms. Although
the primary end point of a reduction in liver fat did not meet the prespecified
significance level with Aramchol 600 mg, the observed safety and changes in
liver histology and enzymes provide a rationale for SCD1 modulation as a
promising therapy for NASH and fibrosis and are being evaluated in an ongoing
phase 3 program. |
What is the cause of the Diamond Blackfan Anemia? | Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. | Diamond-Blackfan anemia is an autosomal domit syndrome, characterized by
anemia and a predisposition for maligcies. Ribosomal proteins are responsible
for this syndrome, and the incidence of colorectal cancer in patients with this
syndrome is higher than the general population. This patient's Diamond-Blackfan
anemia was caused by a novel ribosomal protein S19 gene mutation, and he
received chemotherapy for colorectal cancer caused by it. In his cancer,
ribosomal proteins S19 and TP53 were overexpressed. He received 5FU and
cetuximab; however, his anemia made chemotherapy difficult, and he did not
survive long. Patients with Diamond-Blackfan anemia should be screened earlier
and more often for colorectal cancer than usual. |
What are the functions of DNA and RNA G-quadruplexes? | G-Quadruplex, a unique secondary structure in nucleic acids found throughout human genome, elicited widespread interest in the field of therapeutic research. Being present in key regulatory regions of oncogenes, RNAs and telomere, G-Quadruplex structure regulates transcription, translation, splicing, etc | Guanine-rich sequences of DNA and RNA may fold in vitro and in vivo into
G-quadruplexes, four-stranded helical structures held together by a guanine
core. G-quadruplexes have various biological functions, including inhibition of
telomerase and the regulation of gene transcription and translation, and have
become an active target for drug development, particularly for novel anticancer
therapies. The physiological functions of G-quadruplexes are discussed in this
review and the current knowledge of G-quadruplex ligand and drug development is
outlined. G-quadruplex is a kind of special secondary structure of nuclei acids, which
exists in genome DNA and RNA and preferentially located in functional regions
such as telomeres, promoters, 5' untranslated region (5' UTR) of mRNA and so on.
G-quadruplex has been implicated by a lot of studies as an important structure
in many biological processes including gene stability, telomere synthesis,
transcriptional or translational regulation of gene expression and
recombination. We here review the recent studies of G-quadruplex in genome DNA,
RNA and G-quadruplex oligonucleotides, focusing on their biological function. G-quadruplexes are noncanonical structures formed by G-rich DNA and RNA
sequences that fold into a four-stranded conformation. Experimental studies and
computational predictions show that RNA G-quadruplexes are present in
transcripts associated with telomeres, in noncoding sequences of primary
transcripts and within mature transcripts. RNA G-quadruplexes at these specific
locations play important roles in key cellular functions, including telomere
homeostasis and gene expression. Indeed, RNA G-quadruplexes appear as important
regulators of pre-mRNA processing (splicing and polyadenylation), RNA turnover,
mRNA targeting and translation. The regulatory mechanisms controlled by RNA
G-quadruplexes involve the binding of protein factors that modulate G-quadruplex
conformation and/or serve as a bridge to recruit additional protein regulators.
In this review, we summarize the current knowledge on the role of G-quadruplexes
in RNA biology with particular emphasis on the molecular mechanisms underlying
their specific function in RNA metabolism occurring in physiological or
pathological conditions. Telomeric repeat-containing RNA, a non-coding RNA molecule, has recently been
found in mammalian cells. The detailed structural features and functions of the
telomeric RNA at human chromosome ends remain unclear, although this RNA
molecule may be a key component of the telomere machinery. In this study, using
model human telomeric DNA and RNA sequences, we demonstrated that human
telomeric RNA and DNA oligonucleotides form a DNA-RNA G-quadruplex. We next
employed chemistry-based oligonucleotide probes to mimic the naturally formed
telomeric DNA-RNA G-quadruplexes in living cells, suggesting that the process of
DNA-RNA G-quadruplex formation with oligonucleotide models of telomeric DNA and
RNA could occur in cells. Furthermore, we investigated the possible roles of
this DNA-RNA G-quadruplex. The formation of the DNA-RNA G-quadruplex causes a
significant increase in the clonogenic capacity of cells and has an effect on
inhibition of cellular senescence. Here, we have used a model system to provide
evidence about the formation of G-quadruplex structures involving telomeric DNA
and RNA sequences that have the potential to provide a protective capping
structure for telomere ends. The expansion of a (G(4)C(2))n repeat within the human C9orf72 gene has been
causally linked to a number of neurodegenerative diseases, most notably familial
amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent
studies have shown that the repeat expansion alters gene function in four ways,
disrupting the gene's normal cellular roles and introducing toxic gain of
function at the level of both DNA and RNA. (G(4)C(2))n DNA, as well as the RNA
transcribed from it, are found to fold into four-stranded G-quadruplex
structures. It has been shown that the toxicity of the RNA G-quadruplexes, often
localized in intracellular RNA foci, lies in their ability to sequester many
important RNA binding proteins. Herein we propose that a distinct toxic property
of such RNA and DNA G-quadruplexes from the C9orf72 gene may arise from their
ability to bind and oxidatively activate cellular heme. We show that
G-quadruplexes formed by both (G(4)C(2))(4) RNA and DNA not only complex tightly
with heme but also enhance its intrinsic peroxidase and oxidase propensities. By
contrast, the antisense (C(4)G(2))(4) RNA and DNA neither bind heme nor
influence its oxidative activity. Curiously, the ability of C9orf72 DNA and
transcripts to bind and activate heme mirror similar properties that have been
reported for the Aβ peptide and its oligomers in Alzheimer's disease neurons. It
is therefore conceivable that C9orf72 RNA G-quadruplex tangles play roles in
sequestering intracellular heme and promoting oxidative damage in ALS and FTD
analogous to those proposed for Aβ peptide and its tangles in Alzheimer's
Disease. Given that neurodegenerative diseases in general are characterized by
mitochondrial and respiratory malfunctions, the role of C9orf72 DNA and RNA in
heme sequestration as well as its inappropriate activation in ALS and FTD
neurons may warrant examination. 'If G-quadruplexes form so readily in vitro, Nature will have found a way of
using them in vivo' (Statement by Aaron Klug over 30 years ago).During the last
decade, four-stranded helical structures called G-quadruplex (or G4) have
emerged from being a structural curiosity observed in vitro, to being recognized
as a possible nucleic acid based mechanism for regulating multiple biological
processes in vivo. The sequencing of many genomes has revealed that they are
rich in sequence motifs that have the potential to form G-quadruplexes and that
their location is non-random, correlating with functionally important genomic
regions. In this short review, we summarize recent evidence for the in vivo
presence and function of DNA and RNA G-quadruplexes in various cellular pathways
including DNA replication, gene expression and telomere maintece. We also
highlight remaining open questions that will have to be addressed in the future. Growing evidence indicates that RNA G-quadruplexes have important roles in
various processes such as transcription, translation, regulation of telomere
length, and formation of telomeric heterochromatin. Investigation of RNA
G-quadruplex structures associated with biological events is therefore essential
to understanding the functions of these RNA molecules. We recently demonstrated
that the sensitivity and simplicity of 19F NMR can be used to directly observe
higher-order telomeric G-quadruplexes of labeled RNA molecules in vitro and in
living cells, as well as their interactions with ligands and proteins. This
protocol describes detailed procedures for preparing 19F-labeled RNA, the
evaluation of 19F-labeled RNA G-quadruplexes in vitro and in living Xenopus
laevis oocytes by 19F NMR spectroscopy, the quantitative characterization of
thermodynamic properties of the G-quadruplexes, and monitoring of RNA
G-quadruplex interactions with ligand molecules and proteins. This approach has
several advantages over existing techniques. First, it is relatively easy to
prepare 19F-labeled RNA molecules by introducing a 3,5-bis(trifluoromethyl)
benzene moiety into its 5' terminus. Second, the absence of any natural fluorine
background signal in RNA and cells results in a simple and clear 19F NMR
spectrum and does not suffer from high background signals as does 1H NMR.
Finally, the simplicity and sensitivity of 19F NMR can be used to easily
distinguish different RNA G-quadruplex conformations under various conditions,
even in living cells, and to obtain the precise thermodynamic parameters of
higher-order G-quadruplexes. This protocol can be completed in 2 weeks. G-quadruplexes form folded structures because of tandem repeats of guanine
sequences in DNA or RNA. They adopt a variety of conformations, depending on
many factors, including the type of loops and cations, the nucleotide strand
number, and the main strand polarity of the G-quadruplex. Meanwhile, the
different conformations of G-quadruplexes have certain influences on their
biological functions, such as the inhibition of transcription, translation, and
DNA replication. In addition, G-quadruplex binding proteins also affect the
structure and function of G-quadruplexes. Some chemically synthesized
G-quadruplex sequences have been shown to have biological activities. For
example, bimolecular G-quadruplexes of AS1411 act as targets of exogenous drugs
that inhibit the proliferation of maligt tumours. G-quadruplexes are also
used as vehicles to deliver oparticles. Thus, it is important to identify the
factors that influence G-quadruplex structures and maintain the stability of
G-quadruplexes. Herein, we mainly discuss the factors influencing G-quadruplexes
and the synthetic G-quadruplex, AS1411. SIGNIFICANCE OF THE STUDY: This review
summarizes the factors that influence G-quadruplexes and the functions of the
synthetic G-quadruplex, AS1411. It also discusses the use of G-quadruplexes for
drug delivery in tumour therapy. G-quadruplexes are four-stranded helical nucleic acid structures formed by
guanine-rich sequences. A considerable number of studies have revealed that
these noncanonical structural motifs are widespread throughout the genome and
transcriptome of numerous organisms, including humans. In particular,
G-quadruplexes occupy strategic locations in genomic DNA and both coding and
noncoding RNA molecules, being involved in many essential cellular and
organismal functions. In this review, we first outline the fundamental
structural features of G-quadruplexes and then focus on the concept that these
DNA and RNA structures convey a distinctive layer of epigenetic information that
is critical for the complex regulation, either positive or negative, of
biological activities in different contexts. In this framework, we summarize and
discuss the proposed mechanisms underlying the functions of G-quadruplexes and
their interacting factors. Furthermore, we give special emphasis to the
interplay between G-quadruplex formation/disruption and other epigenetic marks,
including biochemical modifications of DNA bases and histones, nucleosome
positioning, and three-dimensional organization of chromatin. Finally,
epigenetic roles of RNA G-quadruplexes in post-transcriptional regulation of
gene expression are also discussed. Undoubtedly, the issues addressed in this
review take on particular importance in the field of comparative epigenetics, as
well as in translational research. Guanine (G)-rich single-stranded nucleic acids can adopt G-quadruplex
structures. Accumulating evidence indicates that G-quadruplexes serve important
regulatory roles in fundamental biological processes such as DNA replication,
transcription, and translation, while aberrant G-quadruplex formation is linked
to genome instability and cancer. Understanding the biological functions played
by G-quadruplexes requires detailed knowledge of their protein interactome.
Here, we report that both RNA and DNA G-quadruplexes are bound by human Dicer in
vitro. Using in vitro binding assays, mutation studies, and computational
modeling we demonstrate that G-quadruplexes can interact with the
Platform-PAZ-Connector helix cassette of Dicer, the region responsible for
anchoring microRNA precursors (pre-miRNAs). Consequently, we show that
G-quadruplexes efficiently and stably inhibit the cleavage of pre-miRNA by
Dicer. Our data highlight the potential of human Dicer for binding of
G-quadruplexes and allow us to propose a G-quadruplex-driven sequestration
mechanism of Dicer regulation. G-Quadruplex, a unique secondary structure in nucleic acids found throughout
human genome, elicited widespread interest in the field of therapeutic research.
Being present in key regulatory regions of oncogenes, RNAs and telomere,
G-Quadruplex structure regulates transcription, translation, splicing, etc.
Changes in its structure and stability leads to differential expression of
oncogenes causing cancer. Thus, targeting G-Quadruplex structures with small
molecules/other biologics has shown elevated research interest. Covering
previous reports, in this review, we try to enlighten the facts on the
structural diversity in G-Quadruplex ligands aiming to provide newer insights to
design first-in-class drugs for the next-generation cancer treatment. Cell identity is maintained by activation of cell-specific gene programs,
regulated by epigenetic marks, transcription factors and chromatin organization.
DNA G-quadruplex (G4)-folded regions in cells were reported to be associated
with either increased or decreased transcriptional activity. By
G4-ChIP-seq/RNA-seq analysis on liposarcoma cells we confirmed that G4s in
promoters are invariably associated with high transcription levels in open
chromatin. Comparing G4 presence, location and transcript levels in liposarcoma
cells to available data on keratinocytes, we showed that the same promoter
sequences of the same genes in the two cell lines had different G4-folding
state: high transcript levels consistently associated with G4-folding.
Transcription factors AP-1 and SP1, whose binding sites were the most
significantly represented in G4-folded sequences, coimmunoprecipitated with
their G4-folded promoters. Thus, G4s and their associated transcription factors
cooperate to determine cell-specific transcriptional programs, making G4s to
strongly emerge as new epigenetic regulators of the transcription machinery. Author information:
(1)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of
Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit,
Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las
Nieves, Granada 18014, Spain; Department of Biochemistry, Molecular Biology III
and Immunology, University of Granada, Granada 18016, Spain.
(2)Department of Biochemistry and Molecular Genetics, University of Alabama at
Birmingham, Birmingham, AL 35294, USA.
(3)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of
Granada/Andalusian Regional Government, Granada 18016, Spain; Centre for
Intensive Mediterranean Agrosystems and Agri-food Biotechnology (CIAIMBITAL),
University of Almeria, Almeria 04001, Spain.
(4)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of
Granada/Andalusian Regional Government, Granada 18016, Spain; Department of
Physiology, University of Granada, Granada 18011, Spain.
(5)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of
Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit,
Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las
Nieves, Granada 18014, Spain.
(6)Microbiology Unit, Biosanitary Research Institute IBS.Granada, University
Hospital Virgen de las Nieves, Granada 18014, Spain; Department of Microbiology,
University of Granada, Granada 18011, Spain.
(7)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of
Granada/Andalusian Regional Government, Granada 18016, Spain; Department of
Biochemistry, Molecular Biology III and Immunology, University of Granada,
Granada 18016, Spain.
(8)Instituto de Química Física "Rocasolano", CSIC, Madrid 28006, Spain.
(9)GENYO. Centre for Genomics and Oncological Research: Pfizer/University of
Granada/Andalusian Regional Government, Granada 18016, Spain; Microbiology Unit,
Biosanitary Research Institute IBS.Granada, University Hospital Virgen de las
Nieves, Granada 18014, Spain. Electronic address: [email protected]. G-quadruplexes (G4s) are higher-order structures formed by guanine-rich
sequences of nucleic acids, such as the telomeric 5'-TTAGGG-3'/5'-UUAGGG-3'
repeats and those in gene regulatory regions. G4s regulate various biological
events, including replication, transcription, and translation. Imbalanced G4
dynamics is associated with diseases, such as cancer and neurodegenerative
diseases. Telomestatin is a natural macrocyclic compound derived from
Streptomyces anulatus 3533-SV4. It interacts with the guanine quartet via π-π
stacking and potently stabilizes G4. Because G4 stabilization at the telomeric
repeat inhibits the telomere-synthesizing enzyme telomerase, telomestatin was
originally identified as a telomerase inhibitor. Whereas non-toxic doses of
telomestatin induce gradual shortening of telomeres and eventual crisis in human
cancer cells, higher doses trigger prompt replication stress and DNA damage
responses, resulting in acute cell death. Suppression of the transcription and
translation of G4-containing genes is also implicated in the anticancer effects
of telomestatin. Because telomestatin is rare, labile, and insoluble, synthetic
oxazole telomestatin derivatives have been developed and verified for their
therapeutic efficacies in preclinical cancer models. Furthermore, a variety of
G4-stabilizing compounds have been reported as promising seeds for molecular
cancer therapeutics. To improve the design of future clinical studies, it will
be important to identify predictive biomarkers of drug efficacy. |
What is the effect of epiregulin expression in tumors? | Epiregulin has elevated expression in a variety of human cancers. Epiregulin expression promotes tumor progression and metastasis and reduces patient survival. | Author information:
(1)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University,
Zhangjiagang 215617, China.
(2)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University,
Zhangjiagang 215617, China; Jiangsu University Aoyang Institute of Oncology,
Zhangjiagang 215617, China.
(3)Department of Oncology, Huai'an Hospital Affiliated of Xuzhou Medical College
and Huai'an Second People's Hospital, Huai'an 223200, China.
(4)Clinical Biobank, Affiliated Hospital of Nantong University, Nantong 226001,
China.
(5)Department of Pathology, Nanjing Medical University, Nanjing 210029, China.
(6)Huadong Medical Institute of Biotechniques, Nanjing 210029, China.
(7)The Center for Pathology & Laboratory Medicine, The Affiliated Aoyang
Hospital of Jiangsu University, Zhangjiagang 215617, China; School of Medicine,
Jiangsu University, Zhenjiang 212013, China; The Second Affiliated Hospital of
Nanjing Medical University, Nanjing 210029, China.
(8)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University,
Zhangjiagang 215617, China; Key Laboratory of Antibody Technique of Ministry of
Health, Nanjing Medical University, Nanjing 210029, China; Collaborative
Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer
Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing
210029, China. Electronic address: [email protected].
(9)Department of Oncology, The Affiliated Aoyang Hospital of Jiangsu University,
Zhangjiagang 215617, China; Department of Oncology, Shanghai Ruijin Hospital
Luwan Branch, Shanghai Jiaotong University, Shanghai 200020, China. Electronic
address: [email protected]. |
Name scRNA-seq workflows which harness graph attention networks | SCDRHA and CellVGAE | Dimensionality reduction of high-dimensional data is crucial for single-cell RNA
sequencing (scRNA-seq) visualization and clustering. One prominent challenge in
scRNA-seq studies comes from the dropout events, which lead to zero-inflated
data. To address this issue, in this paper, we propose a scRNA-seq data
dimensionality reduction algorithm based on a hierarchical autoencoder, termed
SCDRHA. The proposed SCDRHA consists of two core modules, where the first module
is a deep count autoencoder (DCA) that is used to denoise data, and the second
module is a graph autoencoder that projects the data into a low-dimensional
space. Experimental results demonstrate that SCDRHA has better performance than
existing state-of-the-art algorithms on dimension reduction and noise reduction
in five real scRNA-seq datasets. Besides, SCDRHA can also dramatically improve
the performance of data visualization and cell clustering. |
Which molecule is targeted by Fenebrutinib? | Fenebrutinib is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). | Fenebrutinib (GDC-0853) is an orally administered small molecule inhibitor of
Bruton's tyrosine kinase being investigated for treatment of rheumatoid
arthritis in patients with inadequate responses to methotrexate (MTX). This
study interrogated the potential for pharmacokinetic drug interactions between
fenebrutinib and MTX. Eighteen healthy male subjects were enrolled in the study.
They received a single oral dose of MTX (7.5 mg) on day 1 followed by a 13-day
washout period. Subsequently, on days 15-20 the participants received 200 mg of
fenebrutinib twice daily. On day 21, they received a 7.5 mg dose of MTX and a
200 mg dose of fenebrutinib under fasting conditions. The geometric mean ratios
of MTX area under the plasma concentration-time curve (AUC) and C max on day 21
relative to day 1 (90% confidence interval [CI]) were 0.96 (0.88-1.04) and 1.05
(0.94-1.18), respectively. The geometric mean ratios of fenebrutinib AUC and C
max for day 21 relative to day 20 (90% CI) were 1.03 (0.95-1.11) and 1.02
(0.90-1.15), respectively. The combination treatment was well tolerated, with an
adverse event profile similar to that reported in other MTX trials. These
results indicate that there is no clinically significant pharmacokinetic
interaction between fenebrutinib and MTX. OBJECTIVE: To review the published literature on current and new treatments for
chronic spontaneous urticaria (CSU) and to provide guidance on the potential use
of these therapeutics.
DATA SOURCES: A PubMed search was performed to include English-language articles
with the keywords chronic spontaneous urticaria, pathophysiology, quality of
life, and treatments, with a preference to those articles written in the last 5
years. ClinicalTrials.gov was reviewed for recent relevant clinical trials
related to potential CSU therapeutics.
STUDY SELECTIONS: Literature was included if it provided information related to
the current understanding of the pathophysiology and management of CSU as well
as potential novel therapeutics currently in development.
RESULTS: CSU has a significant effect on patients' quality of life. Current
therapies include antihistamines, leukotriene receptor antagonists, omalizumab,
and immunosuppressants; however, additional treatments are needed. New
therapeutics under investigation include IgG1 anti-IgE monoclonal antibodies
(ligelizumab), chemoattractant rector-homologous molecule expressed on TH2 cells
antagonists (AZD1981), Bruton tyrosine kinase inhibitors (fenebrutinib),
anti-siglec-8 monoclonal antibody (AK002), and topical spleen tyrosine kinase
inhibitors (GSK2646264). We review the mechanisms of action as well as recently
published data from clinical trials regarding the efficacy and safety of these
treatments.
CONCLUSION: The development of new treatments for CSU will lead to improved
options for patients and may assist with improving our understanding of disease
pathophysiology. PURPOSE: Fenebrutinib (GDC-0853), a Bruton's tyrosine kinase (BTK) inhibitor was
investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis
(RA). Our aim was to apply a model-informed drug development (MIDD) approach to
examine the totality of available clinical efficacy data.
METHODS: Population pharmacokinetics (popPK) modeling, exposure-response (E-R)
analysis, and model-based meta-analysis (MBMA) of fenebrutinib were performed
based on the Phase 2 data.
RESULTS: PopPK of fenebrutinib after oral administration was described using a
3-compartment model with linear elimination and a flexible absorption transit
compartment model. Healthy subjects had a 52% higher apparent clearance than
patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28
(CRP) data modeled fenebrutinib effect with an Emax function, and an efficacy
plateau was achieved within the exposure range obtained in the Phase 2 clinical
trial. Based on literature data, a summary-level clinical efficacy database was
constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the
placebo and adalimumab arms of the Phase 2 clinical trial were found to be
consistent with historical data for these treatments.
CONCLUSIONS: Our multi-pronged approach applied MIDD to maximize knowledge
extraction of efficacy data and enabled robust interpretation from a Phase 2
clinical trial. OBJECTIVE: To evaluate fenebrutinib, an oral and highly selective non-covalent
inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid
arthritis (RA).
METHODS: Patients with RA and inadequate response to methotrexate (cohort 1,
n=480) were randomized to fenebrutinib (50 mg once daily, 150 mg once daily, 200
mg twice daily), 40 mg adalimumab every other week, or placebo. Patients with RA
and inadequate response to tumor necrosis factor inhibitors (cohort 2, n=98)
received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued
methotrexate therapy.
RESULTS: In cohort 1, American College of Rheumatology scores (ACR50) at week 12
were similar for fenebrutinib 50 mg once daily and placebo, and higher for
fenebrutinib 150 mg once daily (28%) and 200 mg twice daily (35%) than placebo
(15%) (p=0.017; p=0.0003). Fenebrutinib 200 mg twice daily and adalimumab (36%)
were comparable (p=0.81). In cohort 2, more patients achieved ACR50 with
fenebrutinib 200 mg twice daily (25%) than placebo (12%) (p=0.072). The most
common adverse events for fenebrutinib included nausea, headache, anemia, and
upper respiratory tract infections. Fenebrutinib had significant effects on
myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and
adalimumab caused overlapping as well as distinct changes in B cell and myeloid
biomarkers.
CONCLUSION: Fenebrutinib demonstrated efficacy comparable to adalimumab in
patients with an inadequate response to methotrexate, and safety consistent with
existing immunomodulatory therapies for RA. These data support targeting both B
and myeloid cells via this novel mechanism for potential efficacy in the
treatment of RA. Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic
immune diseases such as rheumatoid arthritis and lupus. While covalent,
irreversible Btk inhibitors are approved for treatment of hematologic
maligcies, they are not approved for autoimmune indications. In efforts to
develop additional series of reversible Btk inhibitors for chronic immune
diseases, we sought to differentiate from our clinical stage inhibitor
fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to
occupy the flat, lipophilic H2 pocket. While drug-like properties were
retained-and in some cases improved-a safety liability in the form of hERG
inhibition was observed. When a fluorocyclopropyl amide was incorporated, Btk
and off-target activity was found to be stereodependent and a lead compound was
identified in the form of the (R,R)- stereoisomer. Spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) play critical
roles in platelet physiology, facilitating intracellular immunoreceptor
tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet
glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase
inhibitors (TKIs) targeting Syk and BTK have been developed as antineoplastic
and anti-inflammatory therapeutics and have also gained interest as antiplatelet
agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors
on GPVI-mediated platelet signaling and function. These inhibitors include four
Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four
irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib),
AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177,
BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced
platelet adhesion to collagen, dense granule secretion, and alpha granule
secretion in response to the GPVI agonist cross-linked collagen-related peptide
(CRP-XL). Similarly, these TKIs reduced the percentage of activated integrin
αIIbβ3 on the platelet surface in response to CRP-XL, as determined by PAC-1
binding. Although all TKIs tested inhibited phospholipase C γ2 (PLCγ2)
phosphorylation following GPVI-mediated activation, other downstream signaling
events proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially
affected. In addition, reversible BTK inhibitors had less pronounced effects on
GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered
the organization of PI3K around microtubules during platelets spreading on
fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen
under physiological flow conditions. Together, our results suggest that TKIs
targeting Syk or BTK inhibit central platelet functional responses but may
differentially affect protein activities and organization in critical systems
downstream of Syk and BTK in platelets. Conflict of interest statement: M. Metz reports receiving honoraria as a speaker
and/or consultant for Amgen, Aralez, argenx, Moxie, Novartis, Roche, Sanofi,
Shire and Uriach. G.S. reports serving as a principal investigator for
Genentech, Novartis, CSL Behring, Shire, Sanofi, AstraZeneca, DBV Technologies,
Aimmune Therapeutics, Greencross, Kedrion, ALK-Abelló, Stallergenes, LEO Pharma,
Amgen, BioCryst, Regeneron and Cliantha; serving on advisory boards for
Novartis, CSL Behring, Shire, Sanofi, Aralez, Pediapharm and AstraZeneca;
serving as a speaker for Novartis, Sanofi, Aralez, Pediapharm, Genentech and
AstraZeneca; receiving personal fees from Novartis, CSL Behring, Shire, Sanofi,
Aralez, Pediapharm and AstraZeneca. T.T. reports receiving funding from
Genentech to his institution for the conduct of this study. W.H.Y. reports
receiving speakers’ fees from Novartis, Merck, CSL Behring, Takeda (Shire) and
AstraZeneca; serving on advisory boards for Novartis, Takeda (Shire), CSL
Behring, Sanofi, BioCryst and Merck; and receiving research grants from
Novartis, Takeda (Shire), CSL Behring, BioCryst, AstraZeneca, Regeneron, Sanofi,
Genentech, Glenmark, AnaptysBio, Dermira, Galderma, ALK, DBV Technologies,
Aimmune Therapeutics, Colgene and Pharming. J.J.L., H.J.C., J.G., L.W.C., T.C.,
T.B., D.J.H. and T.T.L. are current or former employees of Genentech, a member
of the Roche group, at the time this work was performed and own/owned Roche
stock and/or options. L.W.C. is currently an employee of Principia Biopharma and
owns Principia Biopharma stock and/or options. D.J.H. owns Principia Biopharma
stock. T.T.L. is currently an employee of DiCE Molecules. M. Maurer is or
recently was a speaker and/or advisor for and/or has received research funding
from Allakos, Amgen, Aralez, AstraZeneca, Celldex, Centogene, CSL Behring, FAES,
Genentech, GI Innovation, Innate Pharma, Kyowa Kirin, LEO Pharma, Lilly,
Menarini, Moxie, Merck Sharp & Dohme, Novartis, Roche, Sanofi/Regeneron, Third
Harmonic Bio, UCB and Uriach. R.G. and P.S. declare no competing interests. |
What is Cereblon? | Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin complex. The binding target of CRBN varies according to tissues and cells, and the protein regulates various biological functions by regulating tissue-specific targets. | Author information:
(1)Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery,
Miller School of Medicine, University of Miami, Miami, FL, USA.
(2)The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School
of Medicine, University of Miami, Miami, FL, USA.
(3)Department of Medicine, University of Maryland, Baltimore, MD, USA.
(4)Department of Molecular and Systems Biology and the Norris Cotton Cancer
Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
(5)Department of Cell and Developmental Biology, Vanderbilt University,
Nashville, TN, USA.
(6)Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown
University, Washington, DC, USA.
(7)Center for Therapeutic Innovation, Department of Neurological Surgery, Miami
Project to Cure Paralysis, Miller School of Medicine, University of Miami,
Miami, FL, USA.
(8)Sylvester Comprehensive Cancer Center, Miller School of Medicine, University
of Miami, Miami, FL, USA.
(9)Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery,
Miller School of Medicine, University of Miami, Miami, FL, USA.
[email protected].
(10)Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown
University, Washington, DC, USA. [email protected].
(11)Sylvester Comprehensive Cancer Center, Miller School of Medicine, University
of Miami, Miami, FL, USA. [email protected].
(#)Contributed equally Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin
complex. The binding target of CRBN varies according to tissues and cells, and
the protein regulates various biological functions by regulating tissue-specific
targets. As new endogenous targets of CRBN have been identified over the past
decade, the physiological and pathological functions of CRBN and its potential
as a therapeutic target in various diseases have greatly expanded. For this
purpose, in this review article, we introduce the basic principle of the
ubiquitin-proteasome system, the regulation of physiological/pathological
functions related to the endogenous substrate of CRBN, and the discovery of
immunomodulatory imide drug-mediated neo-substrates of CRBN. In addition, the
development of CRBN-based proteolysis-targeting chimeras, which has been
actively researched recently, and strategies for developing therapeutic agents
using them are introduced. These recent updates on CRBN will be useful in the
establishment of strategies for disease treatment and utilization of CRBNs in
biomedical engineering and clinical medicine. |
What is Abbreviated Injury Scale (AIS) used to determine? | The Abbreviated Injury Scale (AIS) is an objective anatomically-based injury severity scoring system that classifies each injury by body region on a 6 point scale. AIS is the system used to determine the Injury Severity Score (ISS) of the multiply injured trauma patient.
AIS CLASSIFICATIONS
The AIS classifies individual injuries by body region as follows:
AIS 1 – Minor
AIS 2 – Moderate
AIS 3 – Serious
AIS 4 – Severe
AIS 5 – Critical
AIS 6 – Maximal (currently untreatable) | Refinements in injury scaling of blunt trauma and expansion to include
penetrating injuries have resulted in the publication of the 1985 revision of
the Abbreviated Injury Scale (AIS). To simplify use of this scale for Injury
Severity Scoring in clinical practice, two 8 1/2" x 11" charts, which can be
included in the patient record, have been developed from the AIS dictionary.
Separate charts apply to blunt and penetrating trauma. Previous experience with
a condensed AIS chart (CAIS) using the 1980 revision of the dictionary suggests
that such edited revisions can result in accurate injury scaling in more than
95% of patients presenting to a Level I Trauma Center. The availability of such
charts assists in calculation of the ISS soon after admission, which may prove
to be a valuable teaching tool and useful in resource allocation, audit, and
assessment for prospective payment. Trauma, which accounts for a substantial part of the morbidity and mortality in
industrial nations, is a natural area of interest for orthopaedic surgeons.
Trauma, and trauma prevention, can be conveniently studied in emergency rooms
and casualty units which are often run by hospital orthopaedic departments. In
order to identify the most serious types of accidents and assign priorities as
regards preventive measures it is necessary to be able to determine in an
objective way the severity of different types of trauma. The Abbreviated Injury
Scale is a system developed in the United States for ranking the severity of
specific trauma lesions. This paper discusses general issues relating to injury
scaling and accident epidemiology research. Injuries from piercing or cutting instruments or objects are commonly seen in
the pediatric emergency department. In this study, we present the epidemiology
of piercing injuries resulting in hospitalization. Medical records for a
one-year period with E-codes 920.0-920.9 were reviewed for victim-related
demographic data, anatomic injury location, vehicle of injury, treatment, and
hospital charges. The Abbreviated Injury Scale (AIS) was used to ascertain
injury severity. The most common vehicles of injury were glass (n = 24, 34%),
nails (n = 11, 16%), and needles (n = 10, 14%). The median AIS score was
significantly higher for hand injuries compared to the sample median AIS.
Piercing injuries from consumer-related products were associated with the
highest AIS scores (median = 2.5). Although the mean AIS for all injuries was
only 1.5, these injuries resulted in significant costs, with a mean
hospitalization charge of $3884 +/- 3528. Surgical procedures under general
anesthesia were required in 81% of the patients. One of the more often used measures of multiple injuries is the injury severity
score (ISS). Determination of the ISS is based on the abbreviated injury scale
(AIS). This paper suggests a new algorithm to sort the AISs for each case and
calculate ISS. The program uses unsorted abbreviated injury scale (AIS) levels
for each case and rearranges them in descending order. The first three sorted
AISs representing the three most severe injuries of a person are then used to
calculate injury severity score (ISS). This algorithm should be useful for
analyses of clusters of injuries especially when more patients have multiple
injuries. INTRODUCTION: Various trauma scoring systems were developed in order to assess
injury severity and aid in decision making regarding further therapy and
probable outcome.
ANATOMIC INJURY SEVERITY SCALES: AIS--Abbreviated Injury Scale is a summary of
all the values (from 1-9) for each organ or body part that is injured.
ISS--Injury Severity Scale scores three domit injuries from AIS scale. The
maximum score for ISS is 75. MISS--Modified Injury Severity Score is a square of
the AIS value for the three body parts with most severe injuries.
PHYSIOLOGIC INJURY SEVERITY SCALES: GCS--Glasgow Coma Score is a numerical scale
that assesses the severity of CNS injuries, that is the most appropriate system
for numerical assessment of consciousness disturbance. Trauma score is a sum of
GCS decreased for 1/3, plus the assessment of cardiopulmonary function. COMBINED
ANATOMIC-PHYSIOLOGIC SCORING SYSTEMS: TRISS score (TS-ISS--trauma and injury
severity score) TRISS combines ISS, TS, age of the patient and mechanism of
injury, in order to determine survival probability. PTS--Pediatric Trauma Score
takes into consideration all of the peculiarities of pediatric patients in
response to trauma. Score values are from -6 to +12. APACHE--Acute Physiology
And Chronic Health Evaluation Although it is complicated for general use, it
still represents the most commonly used scoring system in Intensive Care Units.
NEW SCORING SYSTEMS: MPM--Mortality Probability Models. MODS--Multiple Organ
Dysfunction Syndrome. LODS--Logistic Organ Dysfunction Syndrome.
SAPS--Simplified Acute Physiologic Score. In the advanced nations trauma represents the third cause of death after
cardiovascular diseases and tumours. Recently, great importance has been given
to the need to treat traumas as quickly as possible in order to reduce mortality
and morbidity. Prompt management of is the gold standard in the emergency
setting and the phrase "golden hour" is now commonly used. The authors report on
their experience with the management of multiple trauma, through the study of
617 clinical cases. Patients were evaluated with the Revised Trauma Score (RTS),
Injury Severity Score (ISS) and Abbreviated Injury Scale (AIS). Of 420 (68%)
cases of major trauma only one patient had ISS > 60. Patients were admitted on
average after 47 +/- 18 min. Only two deaths occurred in the emergency unit. The
task of the emergency unit is to stabilise the patients, anticipate the
complications, including mainly shock and multiple organ failure, optimizing
time, interventions and resources to reduce morbidity and mortality. To determine and to quantify outcome from injury demands that multiple factors
be universally applied so that there is uniform understanding that the same
outcome is understood for the same injury. It is thus important to define the
variables used in any outcome assessment. Critical to defining outcomes is the
need for a universal language that defines individual injuries. The abbreviated
injury scale (AIS) is the only dictionary specifically designed as a system to
define the severity of injuries throughout the body. In addition to a universal
injury language, it provides measures of injury severity that can be used to
stratify and classify injury severity in all body regions. Its revision, AIS
2005 will be discussed here. INTRODUCTION: There is no specific injury among fatally injured frontal
car-occupants in frontal car collisions, used in forensic expertise. We tried to
point out the usefulness of the Abbreviated Injury Scale (AIS) and Injury
Severity Score (ISS) for the expertise in such cases.
OBJECTIVE: Analyzing the severity of body region injuries and total injury
severity of deceased car occupants, to point out their importance in forensic
expertise.
METHOD: Retrospective autopsy study was performed. Autopsy records of all
deceased car-occupants in frontal car collisions were analyzed in order to
establish the severity of injuries in body regions (AIS) and total severity of
injuries (ISS). Statistical analysis was performed using the chi-square test,
t-test, and logistic regression, with significance set at p < 0.05.
RESULTS: A total of 500 cases were analyzed: 282 car-drivers and 218 front
car-passengers, average age of 41.48 +/- 15.31 and 39.78 +/- 16.93. There were
401 males and 99 females. The most injured body region was head with neck: AIS =
3.50 +/- 2.48, for car-drivers, and AIS = 3.54 +/- 2.50, for front
car-passengers, as well as thorax: AIS = 3.63 +/- 2.16 car-drivers, and AIS =
3.37 +/- 2.14, for front car-passengers. More severe injuries of head (AIS > or
=4) suggested that deceased was a front car-passenger (Wald = 13.27; p = 0.04).
More severe injuries of thorax and abdomen (AIS > or =5) indicated that deceased
was a car-driver (Wald = 5.72; p = 0.02, and Wald = 8.23; p = 0.01,
respectively). The injury severity of the face and limbs were useless in such
expertise (Wald = 1.72; p = 0.19, and Wald =0.89; p = 0.34, respectively). An
average ISS was 57.31 +/- 20.16 for car-drivers, and 54.54 +/- 21.01 for front
car-passengers. The ISS value was useless in expertise (t=1.50; p = 0.13, and
Wald = 2.24; p = 0.13).
CONCLUSION: As the injury of the head is more severe, the deceased is more
likely to be the front car-passenger. Severe thoracic and abdominal injuries are
more characteristic for car-drivers. A total injury severity is useless for
forensic expertise in cases of fatally injured in car collisions. BACKGROUND: Injury severity measures are based either on the Abbreviated Injury
Scale (AIS) or the International Classification of diseases (ICD). The latter is
more convenient because routinely collected by clinicians for administrative
reasons. To exploit this advantage, a proprietary program that maps ICD-9-CM
into AIS codes has been used for many years. Recently, a program called ICDPIC
trauma and developed in the USA has become available free of charge for
registered STATA users. We compared the ICDPIC calculated Injury Severity Score
(ISS) with the one from direct, prospective AIS coding by expert trauma
registrars (dAIS).
METHODS: The administrative records of the 289 major trauma cases admitted to
the hospital of Udine-Italy from 1 July 2004 to 30 June 2005 and enrolled in the
Italian Trauma Registry were retrieved and ICDPIC-ISS was calculated. The
agreement between ICDPIC-ISS and dAIS-ISS was assessed by Cohen's Kappa and
Bland-Altman charts. We then plotted the differences between the 2 scores
against the ratio between the number of traumatic ICD-9-CM codes and the number
of dAIS codes for each patient (DIARATIO). We also compared the absolute
differences in ISS among 3 groups identified by DIARATIO. The discriminative
power for survival of both scores was finally calculated by ROC curves.
RESULTS: The scores matched in 33/272 patients (12.1%, k 0.07) and, when
categorized, in 80/272 (22.4%, k 0.09). The Bland-Altman average difference was
6.36 (limits: minus 22.0 to plus 34.7). ICDPIC-ISS of 75 was particularly
unreliable. The differences increased (p < 0.01) as DIARATIO increased
indicating incomplete administrative coding as a cause of the differences. The
area under the curve of ICDPIC-ISS was lower (0.63 vs. 0.76, p = 0.02).
CONCLUSIONS: Despite its great potential convenience, ICPIC-ISS agreed poorly
with its conventionally calculated counterpart. Its discriminative power for
survival was also significantly lower. Incomplete ICD-9-CM coding was a main
cause of these findings. Because this quality of coding is standard in Italy and
probably in other European countries, its effects on the performances of other
trauma scores based on ICD administrative data deserve further research. Mapping
ICD-9-CM code 862.8 to AIS of 6 is an overestimation. The new AIS (Abbreviated Injury Scale) was released with an update by the AAAM
(Association for the Advancement of Automotive Medicine) in 2008. It is a
universal scoring system in the field of trauma applicable in clinic and
research. In engineering it is used as a classification system for vehicle
safety. The AIS can therefore be considered as an international,
interdisciplinary and universal code of injury severity. This review focuses on
a historical overview, potential applications and new coding options in the
current version and also outlines the associated problems. BACKGROUND: The Abbreviated Injury Scale (AIS) is an anatomical-based coding
system created by the Association for the Advancement of Automotive Medicine,
utilized to classify and code injuries resulting from trauma, in order of
severity. According to the latest version, all Thoraco-Lumbar Compression
Fractures (TLCF), even without injury to other spine components and with >20%
loss of height, were branded AIS 3 injuries, reflecting a serious threat to life
or permanent disability. Advances in spine imaging, recent biomechanical
studies, and long-term outcomes research offer the opportunity to consider these
injuries differently.
OBJECTIVE: To re-evaluate the percent compression threshold of TLCF of the spine
from motor vehicle crashes (MVC) for serious risk to life identified as surgical
treatment, delineating a reliable cut-off for fracture severity and morbidity.
Little national data considers degree of compression and provides adequate
followup imaging to determine degree of compression, justifying this effort.
METHODS: Charts and radiographs of patients admitted to our institution due to
vehicle crashes with isolated (vertebral body only) TLCF between 2008 and 2015
were reviewed. Data were collected on degree of compression, treatment, and
long-term outcomes to determine the threshold of permanent injury. Vertebral
bodies at the level of fracture were measured both anteriorly and posteriorly,
and compared to adjacent segments; percentage compression was calculated.
RESULTS: 1470 patient records with diagnoses of spine trauma were reviewed; 695
isolated compression fractures were identified, of which 194 were in vehicle
crashes and had adequate imaging and follow-up. Ages ranged from 19 to 82, with
a male: female ratio of 60:40. No patient with vertebral body compression of
less than 30% underwent surgery unless presenting with a neurological deficit.
All 22 surgical patients demonstrated significant retropulsion of bone into the
spinal canal. Five surgical patients suffered eight complications; there were no
adverse outcomes in the nonsurgical group.
CONCLUSIONS: These results are consistent with evolving clinical thinking,
resulting in decreasing surgical incidence and orthosis use. Our data strongly
suggests that isolated compression fractures in the absence of neurologic
deficit or severe cord compression due to retropulsed bone are self-limiting.
Therefore, the AIS scores for these common injuries could be reconsidered and
reflect their relatively benign outlook. Background: The most widely used methods of describing traumatic brain injury
(TBI) are the Glasgow Coma Scale (GCS) and the Abbreviated Injury Scale (AIS).
Recent evidence suggests that presenting GCS in older patients may be higher
than that in younger patients for an equivalent anatomical severity of TBI. This
study aimed to assess these observations with a propensity-score matching
approach using the data from Trauma Registry System in a Level I trauma center.
Methods: We included all adult patients (aged ≥20 years old) with moderate to
severe TBI from 1 January 2009 to 31 December 2016. Patients were categorized
into elderly (aged ≥65 years) and young adults (aged 20-64 years). The severity
of TBI was defined by an AIS score in the head (AIS 3‒4 and 5 indicate moderate
and severe TBI, respectively). We examined the differences in the GCS scores by
age at each head AIS score. Unpaired Student's t- and Mann-Whitney U-tests were
used to analyze normally and non-normally distributed continuous data,
respectively. Categorical data were compared using either the Pearson chi-square
or two-sided Fisher's exact tests. Matched patient populations were allocated in
a 1:1 ratio according to the propensity scores calculated using NCSS software
with the following covariates: sex, pre-existing chronic obstructive pulmonary
disease, systolic blood pressure, hemoglobin, sodium, glucose, and alcohol
level. Logistic regression was used to evaluate the effects of age on the GCS
score in each head AIS stratum. Results: The study population included 2081
adult patients with moderate to severe TBI. These patients were categorized into
elderly (n = 847) and young adults (n = 1234): each was exclusively further
divided into three groups of patients with head AIS of 3, 4, or 5. In the 162
well-balanced pairs of TBI patients with head AIS of 3, the elderly demonstrated
a significantly higher GCS score than the young adults (14.1 ± 2.2 vs. 13.1 ±
3.3, respectively; p = 0.002). In the 362 well-balanced pairs of TBI patients
with head AIS of 4, the elderly showed a significantly higher GCS score than the
young adults (13.1 ± 3.3 vs. 12.2 ± 3.8, respectively; p = 0.002). In the 89
well-balance pairs of TBI patients with head AIS of 5, no significant
differences were observed for the GCS scores. Conclusions: This study
demonstrated that elderly patients with moderate TBI present higher GCS score
than younger patients. This study underscores the importance of determining of
TBI severity in this group of elderly patients based on the GCS score alone. A
lower threshold of GCS cutoff should be adopted in the management of the elderly
patients with TBI. Chest injuries in children are part of polytrauma resulting from high-energy
violence, most often caused by traffic accidents. Blunt chest injuries (95%) are
significantly more frequent than penetrating injuries (5%). Lung contusion, rib
fracture, pneumothorax or haemothorax, are the more common injuries, but
tracheobronchial rupture, cardiac or diaphragmatic injuries may also occur. The
anterior X-ray image remains the basic examination method for isolated chest
injuries. CT trauma scan with a contrast medium is done in polytraumatized
children. Blunt injuries of intra-thoracic organs in haemodynamically stable
children are treated mostly conservatively (85%) under full monitoring at the
ICU. Surgical treatment is necessary in a minority of patients. Mortality and
morbidity of patients with chest injury depend on the actual combination of
multiple body systems injury. The severity of total injury can be predicted
using objective scoring systems (Abbreviated Injury Scale=AIS; Injury Severity
Score=ISS). Overall mortality ranges from 6 to 20%. Mortality is high but this
is mainly due to associated head injuries.Key words: multiple trauma thoracic
trauma - paediatric lung contusion Injury Severity Score=ISS. BACKGROUND: The International Statistical Classification of Diseases and Related
Health Problems (ICD) is currently undergoing a revision process to develop the
Eleventh Revision (ICD-11), but substantial modification of chapter 19 has not
been proposed despite its known problems in describing injury severity and
multiple injuries. Many facilities treating trauma patients perform duplicate
coding for trauma diagnoses using two different classification systems, the ICD
for administrative purposes and the Abbreviated Injury Scale (AIS) for trauma
registry, because unambiguous conversion of codes between the ICD and AIS is not
always possible due to structural differences.
AIM: We developed a new bridging classification system which can be
unambiguously converted to both ICD and AIS.
METHODS AND RESULTS: The bridging classification adopted multidimensional coding
and addressed differences in granularity and classification boundaries by
adopting the more detailed categorizations whenever the granularity and
classification boundaries differed between the ICD and AIS. Then we showed that
the bridging classification codes could unambiguously converted to both ICD and
AIS.
CONCLUSION: Once injuries are coded using the bridging classification, the ICD
and AIS codes are readily available. Integrating the new bridging classification
into the ICD-11, possibly as a clinical modification, would eliminate the
necessity of complicated procedures for code conversion and duplicate coding,
and benefit users by building on the strengths of both the ICD and AIS. In-hospital complications in trauma patients are frequent and associated with
increased morbidity and mortality. The aim of this study was to analyze the
association between posttraumatic complications and the injured body region,
injury and trauma severity, length of stay, and mortality in hospitalized trauma
patients. This observational and retrospective study included 147 trauma
patients with posttraumatic complications hospitalized in a university hospital
located in São Paulo, Brazil. The injury and trauma severity was measured using
the Abbreviated Injury Scale (AIS) and the Injury Severity Score (ISS),
respectively. The association between variables was verified applying χ test,
Fisher exact text, likelihood ratio, and Mann-Whitney U test, considering
significance level of 5%. The most frequent in-hospital complications were
infectious, cardiovascular, metabolic, and renal. Patients with head injury AIS
score of 3 or more had higher percentage of neurological complications and those
with lower extremity injury AIS score of less than 3 had higher percentage of
metabolic and renal complications. There was no association between thoracic
injury and cardiovascular complications, nor between types of complications and
trauma severity (ISS). Patients without cardiovascular complication and those
with infections had longer hospital length of stay, and mortality was higher in
those with cardiovascular complications. Complication's studies in trauma
patients may contribute to identify events related with poor outcome and to
implement specific measures for improving quality of trauma care and patient
security. OBJECTIVE: The purpose of this study is to investigate the injury patterns of
noncatastrophic accidents by individual age groups.
METHODS: Data were collected from the Korean In-Depth Accident Study database
based on actual accident investigation. The noncatastrophic criteria were
classified according to U.S. experts from the Centers for Disease Control and
Prevention's recommendations for field triage guidelines of high-risk automobile
crash criteria by vehicle intrusions more than 12 in. on occupant sites
(including the roof) and more than 18 in. on any site. The Abbreviated Injury
Scale (AIS) was used to determine injury patterns for each body region. Severely
injured patients were classified as Maximum Abbreviated Injury Scale (MAIS) 3 or
higher.
RESULTS: In this study, the most significant injury regions were the head and
neck, extremities, and thorax. In addition, the incidence of severe injury among
elderly patients was nearly 1.6 times higher than that of non-elderly patients.
According to age group, injured body regions among the elderly were the thorax,
head and neck, and extremities, in that order. For the non-elderly groups, these
were head and neck, extremities, and thorax. Severe injury rates were slightly
different for the elderly group (head and neck, abdomen) and non-elderly group
(thorax, head and neck).
CONCLUSIONS: In both age groups, the rate of severe injury is proportional to an
increase in crush extent zone. Front airbag deployment may have a relatively
significant relationship to severe injuries. |
Which protein family is epiregulin a member of? | EREG (epiregulin), a member of the epidermal growth factor (EGF) family. | OBJECTIVES: EREG (epiregulin), a member of the epidermal growth factor (EGF)
family, plays a role in inflammation, wound healing, normal physiology and
maligcies. However, little is known about its function on hair growth.
MATERIALS AND METHODS: Cell growth assay, QPCR and immunostaining were carried
out. Telogen-to-anagen transition and organ culture were conducted. ROS level
was monitored by staining DCFDA.
RESULTS: We investigated the hair inductive effect of EREG and the mechanism of
stimulation on DPCs and ORS cells during hair cycling. Whereas EREG promoted
hair growth, EREG knockdown inhibited hair growth as evidenced by
telogen-to-anagen transition and organ culture models. EREG was expressed in
epidermal cells including ORS cells in vivo. EREG activated phospho-ErbB4 in
DPCs during hair cycling and stimulated DPCs via ErbB4 activation in vitro. In
terms of the underlying mechanism, reactive oxygen species (ROS) played a key
role in DPC stimulation. EREG also activated phospho-EGF receptor (EGFR) in
epidermal cells including matrix and ORS cells in vivo and stimulated ORS cells
via EGFR activation in vitro.
CONCLUSIONS: EREG, which is released from ORS cells, activated EGFR and ErbB4 on
epidermal cells and DPCs during hair cycling, respectively. As a result, EREG
stimulated epidermal cells a positive feedback and DPCs via regulating ROS
generation for hair growth. Therefore, EREG therapy may be a novel solution for
hair loss treatment. |
Describe Cap Trap RNA-seq | Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Cap Trap RNA-seq is a technology which combines cap trapping and long read MinION sequencing. | Collaborators: Abugessaisa I, Aitken S, Aken BL, Alam I, Alam T, Alasiri R,
Alhendi AMN, Alinejad-Rokny H, Alvarez MJ, Andersson R, Arakawa T, Araki M,
Arbel T, Archer J, Archibald AL, Arner E, Arner P, Asai K, Ashoor H, Astrom G,
Babina M, Baillie JK, Bajic VB, Bajpai A, Baker S, Baldarelli RM, Balic A,
Bansal M, Batagov AO, Batzoglou S, Beckhouse AG, Beltrami AP, Beltrami CA,
Bertin N, Bhattacharya S, Bickel PJ, Blake JA, Blanchette M, Bodega B, Bonetti
A, Bono H, Bornholdt J, Bttcher M, Bougouffa S, Boyd M, Breda J, Brombacher F,
Brown JB, Bult CJ, Burroughs AM, Burt DW, Busch A, Caglio G, Califano A, Cameron
CJ, Cannistraci CV, Carbone A, Carlisle AJ, Carninci P, Carter KW, Cesselli D,
Chang JC, Chen JC, Chen Y, Chierici M, Christodoulou J, Ciani Y, Clark EL,
Coskun M, Dalby M, Dalla E, Daub CO, Davis CA, de Hoon MJL, de Rie D, Denisenko
E, Deplancke B, Detmar M, Deviatiiarov R, Di Bernardo D, Diehl AD, Dieterich LC,
Dimont E, Djebali S, Dohi T, Dostie J, Drablos F, Edge ASB, Edinger M, Ehrlund
A, Ekwall K, Elofsson A, Endoh M, Enomoto H, Enomoto S, Faghihi M, Fagiolini M,
Farach-Carson MC, Faulkner GJ, Favorov A, Ferdes AM, Ferrai C, Forrest ARR,
Forrester LM, Forsberg M, Fort A, Francescatto M, Freeman TC, Frith M, Fukuda S,
Funayama M, Furlanello C, Furuno M, Furusawa C, Gao H, Gazova I, Gebhard C,
Geier F, Geijtenbeek TBH, Ghosh S, Ghosheh Y, Gingeras TR, Gojobori T, Goldberg
T, Goldowitz D, Gough J, Greco D, Gruber AJ, Guhl S, Guigo R, Guler R, Gusev O,
Gustincich S, Ha TJ, Haberle V, Hale P, Hallstrom BM, Hamada M, Handoko L, Hara
M, Harbers M, Harrow J, Harshbarger J, Hase T, Hasegawa A, Hashimoto K, Hatano
T, Hattori N, Hayashi R, Hayashizaki Y, Herlyn M, Heutink P, Hide W, Hitchens
KJ, Sui SH, 't Hoen PAC, Hon CC, Hori F, Horie M, Horimoto K, Horton P, Hou R,
Huang E, Huang Y, Hugues R, Hume D, Ienasescu H, Iida K, Ikawa T, Ikemura T,
Ikeo K, Inoue N, Ishizu Y, Ito Y, Itoh M, Ivshina AV, Jankovic BR, Jenjaroenpun
P, Johnson R, Jorgensen M, Jorjani H, Joshi A, Jurman G, Kaczkowski B, Kai C,
Kaida K, Kajiyama K, Kaliyaperumal R, Kaminuma E, Kanaya T, Kaneda H, Kapranov
P, Kasianov AS, Kasukawa T, Katayama T, Kato S, Kawaguchi S, Kawai J, Kawaji H,
Kawamoto H, Kawamura YI, Kawasaki S, Kawashima T, Kempfle JS, Kenna TJ, Kere J,
Khachigian L, Kiryu H, Kishima M, Kitajima H, Kitamura T, Kitano H, Klaric E,
Klepper K, Klinken SP, Kloppmann E, Knox AJ, Kodama Y, Kogo Y, Kojima M, Kojima
S, Komatsu N, Komiyama H, Kono T, Koseki H, Koyasu S, Kratz A, Kukalev A,
Kulakovskiy I, Kundaje A, Kunikata H, Kuo R, Kuo T, Kuraku S, Kuznetsov VA, Kwon
TJ, Larouche M, Lassmann T, Law A, Le-Cao KA, Lecellier CH, Lee W, Lenhard B,
Lennartsson A, Li K, Li R, Lilje B, Lipovich L, Lizio M, Lopez G, Magi S, Mak
GK, Makeev V, Manabe R, Mandai M, Mar J, Maruyama K, Maruyama T, Mason E,
Mathelier A, Matsuda H, Medvedeva YA, Meehan TF, Mejhert N, Meynert A, Mikami N,
Minoda A, Miura H, Miyagi Y, Miyawaki A, Mizuno Y, Morikawa H, Morimoto M,
Morioka M, Morishita S, Moro K, Motakis E, Motohashi H, Mukarram AK, Mummery CL,
Mungall CJ, Murakawa Y, Muramatsu M, Murata M, Nagasaka K, Nagase T, Nakachi Y,
Nakahara F, Nakai K, Nakamura K, Nakamura Y, Nakamura Y, Nakazawa T, Nason GP,
Nepal C, Nguyen QH, Nielsen LK, Nishida K, Nishiguchi KM, Nishiyori H, Nitta K,
Noguchi S, Noma S, Notredame C, Ogishima S, Ohkura N, Ohno H, Ohshima M, Ohtsu
T, Okada Y, Okada-Hatakeyama M, Okazaki Y, Oksvold P, Orlando V, Ow GS, Ozturk
M, Pachkov M, Paparountas T, Parihar SP, Park SJ, Pascarella G, Passier R,
Persson H, Philippens IH, Piazza S, Plessy C, Pombo A, Ponten F, Poulain S,
Poulsen TM, Pradhan S, Prezioso C, Pridans C, Qin XY, Quackenbush J, Rackham O,
Ramilowski J, Ravasi T, Rehli M, Rennie S, Rito T, Rizzu P, Robert C, Roos M,
Rost B, Roudnicky F, Roy R, Rye MB, Sachenkova O, Saetrom P, Sai H, Saiki S,
Saito M, Saito A, Sakaguchi S, Sakai M, Sakaue S, Sakaue-Sawano A, Sandelin A,
Sano H, Sasamoto Y, Sato H, Saxena A, Saya H, Schafferhans A, Schmeier S,
Schmidl C, Schmocker D, Schneider C, Schueler M, Schultes EA, Schulze-Tanzil G,
Semple CA, Seno S, Seo W, Sese J, Severin J, Sheng G, Shi J, Shimoni Y, Shin JW,
SimonSanchez J, Sivertsson A, Sjostedt E, Soderhall C, Laurent GS 3rd, Stoiber
MH, Sugiyama D, Summers KM, Suzuki AM, Suzuki H, Suzuki K, Suzuki M, Suzuki N,
Suzuki T, Swanson DJ, Swoboda RK, Tagami M, Taguchi A, Takahashi H, Takahashi M,
Takamochi K, Takeda S, Takenaka Y, Tam KT, Tanaka H, Tanaka R, Tanaka Y, Tang D,
Taniuchi I, Tanzer A, Tarui H, Taylor MS, Terada A, Terao Y, Testa AC, Thomas M,
Thongjuea S, Tomii K, Torlai Triglia E, Toyoda H, Tsang HG, Tsujikawa M, Uhlén
M, Valen E, van de Wetering M, van Nimwegen E, Velmeshev D, Verardo R, Vitezic
M, Vitting-Seerup K, von Feilitzen K, Voolstra CR, Vorontsov IE, Wahlestedt C,
Wasserman WW, Watanabe K, Watanabe S, Wells CA, Winteringham LN, Wolvetang E,
Yabukami H, Yagi K, Yamada T, Yamaguchi Y, Yamamoto M, Yamamoto Y, Yamamoto Y,
Yamanaka Y, Yano K, Yasuzawa K, Yatsuka Y, Yo M, Yokokura S, Yoneda M, Yoshida
E, Yoshida Y, Yoshihara M, Young R, Young RS, Yu NY, Yumoto N, Zabierowski SE,
Zhang PG, Zucchelli S, Zwahlen M. |
What is the use of the Canadian C-Spine Rule? | The Canadian C-spine rule clinically clears cervical spine fracture without imaging. | The Canadian c-spine rule (CCR) allows safe, reproducible use of radiography in
alert, stable patients with potential c-spine injury in the emergency setting
[Stiell, I., Clement, C., McKnight, R., Brison, R., Schull, M., Lowe, B.,
Worthington, J., Eisenhauer, M., Cass, D., Greenberg, G., MacPhail, I., Dreyer,
J., Lee, J., Bandiera, G., Reardon, M., Holroyd, B., Lesiuk, H., G. Wells, 2003.
The Canadian c-spine rule versus the nexus low-risk criteria in patients with
trauma. The New England journal of medicine 349 (26), 2510-2518; Stiell, I.,
Wells, G., Vandemheen, K., Clement, C., 2001. The Canadian c-spine rule for
radiography in alert and stable trauma patients. JAMA 286 (15), 1841]. This
paper reports on a study of emergency nurses' ability to identify patients
requiring immobilisation using the CCR. Emergency department triage nurses (N =
112) were trained in the use of the CCR and then asked to use the tool over the
following 14 months in the assessment of 460 patients who presented with
potential c-spine injury. Trained medical staff repeated 55% of the clinical
assessments independently using the rule. The level of agreement between nurse
and medical judgement was calculated. The inter-rater reliability using the
kappa statistic was 0.6 (95% CI 0.50-0.62 N = 254) indicating a 'good' level of
agreement. The majority of nurses indicated they were comfortable using the
rule. The results suggest that UK emergency department nurses were able to use
the Canadian c-spine rule to successfully guide selective immobilisation. A 25%
reduction in immobilisation rates would have been achieved if the rule had been
followed. Further studies are needed to test the reduction in levels of
immobilisation that could be achieved in clinical practice. INTRODUCTION: The Canadian C-Spine Rule (CCR) is a clinical decision aid to
facilitate the safe removal of cervical collars in the alert, orientated,
low-risk adult trauma patient. Few health care settings have assessed
initiatives to train charge nurses to use the CCR. This practice improvement
project conducted in a secondary trauma center in Canada aimed to (1) train
charge nurses of the emergency room to use the CCR, (2) monitor its use
throughout the project period, and (3) compare the assessments of the charge
nurses with those of emergency physicians.
METHODS: The project began with the creation of an interdisciplinary team.
Clinical guidelines were established by the interdisciplinary project team. Nine
charge nurses of the emergency room were then trained to use the CCR (3 on each
8-hour shift). The use of the CCR was monitored throughout the project period,
from June 1 to October 5, 2016.
RESULTS: The 3 aims of this practice improvement project were attained
successfully. Over a 5-month period, 114 patients were assessed with the CCR.
Charge nurses removed the cervical collars for 54 of 114 patients (47%). A
perfect agreement rate (114 of 114 patients, 100%) was attained between the
assessments of the nurses and those of physicians.
DISCUSSION: This project shows that the charge nurses of a secondary trauma
center can use the CCR safely on alert, orientated, and low-risk adult trauma
patients as demonstrated by the agreement in the assessments of emergency room
nurses and physicians. Author information:
(1)Department of Emergency Medicine, University of Iowa, Iowa City, IA. Author information:
(1)Department of Intensive Care Nursing, School of Nursing and Midwifery, Tehran
University of Medical Sciences, Tehran, Iran.
(2)Road Traffic Injury Research Center, Tabriz University of Medical Sciences,
Tabriz, Iran.
(3)Department of Clinical Pharmacy (Pharmacotherapy), Drug Applied Research
Center, Tabriz University of Medical Sciences, Tabriz, Iran.
(4)Tuberculosis and Lung Research Center, Tabriz University of Medical Sciences,
Tabriz, Iran.
(5)Pre-Hospital and Hospital Research Center, Tehran University of Medical
Sciences, Tehran, Iran.
(6)Department of Emergency Medicine, Sina Hospital, Tehran University of Medical
Sciences, Tehran, Iran.
(7)Community Medicine, College of Medicine, University of Sulaimani, Sulaimani,
Iraq.
(8)Department of Emergency Medicine, Maragheh University of Medical Sciences,
Maragheh, Iran.
(9)Community Health Department, Technical College of Health, Sulaimani
Polytechnic University, Sulaimani, Iraq.
(10)Emergency Department, 9-Day Hospital, Torbat Heydariyeh University of
Medical Sciences, Torbat Heydariyeh, Iran.
(11)Department of Epidemiology and Biostatistics School of Public Health, Tehran
University of Medical Sciences, Poursina Ave, Tehran, Iran.
(12)Department of Emergency Medicine, Shahid Sadoughi University of Medical
Sciences, Yazd, Iran.
(13)Division of Genetics and Epidemiology, The Institute of Cancer Research,
London, UK.
(14)Physiology Research Center, School of Medicine, Iran University of Medical
Sciences, Hemmat Highway, Tehran, Iran.
(15)Physiology Research Center, School of Medicine, Iran University of Medical
Sciences, Hemmat Highway, Tehran, Iran. [email protected].
(16)Department of Epidemiology and Biostatistics School of Public Health, Tehran
University of Medical Sciences, Poursina Ave, Tehran, Iran.
[email protected].
(17)Pediatric Chronic Kidney Disease Research Center, University of Medical
Sciences, Tehran, Iran. [email protected]. The unique anatomy and flexibility of the cervical spine predispose it to a risk
of injury. Trauma to the cervical spine encompasses a wide range of injuries
from minor muscular strains to life-threatening fracture-dislocations associated
with spinal cord lesions. Initial assessment and management should follow the
Advanced Trauma Life Support (ATLS) protocols with adequate protection of the
cervical spine through triple immobilisation to prevent any unnecessary
movement, which can make the patient susceptible to further neurological
injuries. Although the presence of cervical spine injury is very often overt,
reliance on clinical examination alone is sometimes not sufficient and
potentially requires further imaging. Clinical decision rules such as the
Canadian C-Spine Rule are frequently used to risk-stratify patients needing
radiography. The level of cervical spine instability and knowledge of their
unique classification systems is of paramount importance and assists in the
decision-making process to guide definitive management. In this review, we also
propose an algorithm to aid the initial management of a patient with suspected
cervical spine injury in the emergency department. BACKGROUND: A consistent approach to cervical spine injury (CSI) clearance for
patients 65 and older remains a challenge. Clinical clearance algorithms like
the National Emergency X-Radiography Utilisation Study (NEXUS) criteria have
variable accuracy and the Canadian C-spine rule excludes older patients. Routine
CT of the cervical spine is performed to rule out CSI but at an increased cost
and low yield. Herein, we aimed to identify predictive clinical variables to
selectively screen older patients for CSI.
METHODS: The University of Iowa's trauma registry was interrogated to
retrospectively identify all patients 65 years and older who presented with
trauma from a ground-level fall from January 2012 to July 2017. The relationship
between predictive variables (demographics, NEXUS criteria and distracting
injuries) and presence of CSI was examined using the generalised linear
modelling (GLM) framework. A training set was used to build the statistical
models to identify clinical variables that can be used to predict CSI and a
validation set was used to assess the reliability and consistency of the model
coefficients estimated from the training set.
RESULTS: Overall, 2312 patients ≥65 admitted for ground-level falls were
identified; 253 (10.9%) patients had a CSI. Using the GLM framework, the best
predictive model for CSI included midline tenderness, focal neurological deficit
and signs of trauma to the head/face, with midline tenderness highly predictive
of CSI (OR=22.961 (15.178-34.737); p<0.001). The negative predictive value (NPV)
for this model was 95.1% (93.9%-96.3%). In the absence of midline tenderness,
the best model included focal neurological deficit (OR=2.601 (1.340-5.049);
p=0.005) and signs of trauma to the head/face (OR=3.024 (1.898-4.815); p<0.001).
The NPV was 94.3% (93.1%-95.5%).
CONCLUSION: Midline tenderness, focal neurological deficit and signs of trauma
to the head/face were significant in this older population. The absence of all
three variables indicates lower likelihood of CSI for patients≥65. Future
observational studies are warranted to prospectively validate this model. OBJECTIVE: The Canadian C-Spine Rule (CCR) and the National Emergency
X-Radiography Utilization Study (NEXUS) criteria are two commonly used clinical
decision rules which use midline cervical spine (c-spine) tenderness on
palpation as an indication for c-spine imaging post-trauma. This study was
undertaken to determine the prevalence and location of midline c-spine
tenderness in the non-trauma population.
METHODS: We prospectively evaluated consenting adult patients presenting to an
urban ED or university sport medicine clinic in Montreal, Canada between 2018
and 2020 for atraumatic non-head and neck-related reports over a 20-month
period. The presence and location of pain during midline c-spine palpation as
assessed by two examiners during separate evaluations was recorded. Patient
information such as age, neck length and circumference, gender, body mass index
(BMI) and scaphoid tenderness was also collected.
RESULTS: Of 478 patients enrolled, 286 (59.8%) had midline c-spine tenderness on
palpation with both examiners. The majority of those with tenderness were female
(70.6%). When examining all patients, tenderness was present in the upper third
of the c-spine in 128 (26.8%) patients, middle third in 270 (56.5%) patients and
lower third in 6 (1.3%) patients. Factors associated with having increased odds
of midline c-spine tenderness on palpation included a lower BMI and the presence
of scaphoid tenderness on palpation.
CONCLUSIONS: There is a high prevalence of c-spine tenderness on palpation in
patients who have not undergone head or neck trauma. This finding may help
explain the low specificity in some of the validation studies examining the CCR
and the NEXUS criteria. |
What is the Daughterless gene? | The daughterless (da) gene in Drosophila encodes a broadly expressed transcriptional regulator whose specific functions in the control of sex determination and neurogenesis have been extensively examined. | The daughterless (da) gene in Drosophila encodes a broadly expressed
transcriptional regulator whose specific functions in the control of sex
determination and neurogenesis have been extensively examined. We describe here
a third major developmental role for this regulatory gene: follicle formation
during oogenesis. A survey of da RNA and protein distribution during oogenesis
reveals a multiphasic expression pattern that includes both germline and soma.
Whereas the germline expression reflects da's role in progeny sex determination,
the somatic ovary expression of da correlates with the gene's role during egg
chamber morphogenesis. Severe, but viable, hypomorphic da mutant genotypes
exhibit dramatic defects during oogenesis, including aberrantly defined
follicles and loss of interfollicular stalks. The follicular defects observed in
da mutant ovaries are qualitatively very similar to those described in Notch (N)
or Delta (Dl) mutant ovaries. Moreover, in the ovary da- alleles exhibit
domit synergistic interactions with N or Dl mutations. We propose that all
three of these genes function in the same regulatory pathway to control follicle
formation. The daughterless (da) gene in Drosophila functions in the regulation of at least
three significant developmental pathways: sex determination, neurogenesis and
oogenesis. As a member of the helix-loop-helix (HLH) family of DNA binding
proteins, the da gene product appears to act as a transcription factor. Based on
the genetic and molecular characterization of da, it has been proposed that the
da protein (Da) functions as a generic member of this family, serving throughout
development as a necessary binding partner for an assortment of other HLH
proteins. As a result of temporally and/or spatially restricted expression,
these binding partners would provide some regulatory specificity to the
functional transcription complex. In order to participate in this way in the
regulation of multiple genes, Da must be expressed in numerous times and places
during development. Using anti-Da antibodies, we validate two predictions of
this scenario of Da function: (1) Da protein is not only nuclear localized, but
also associated with chromosomes in vivo; and (2) Da protein is widely
distributed, both spatially and temporally, throughout development. With regard
to the essential role of maternal da+ in progeny sex determination, little, if
any, Da protein is synthesized in the maternal germline. This suggests that the
female-specific germline function of da+ is provided to the zygote as maternally
synthesized RNA that becomes translated early in embryogenesis. As the only class I helix-loop-helix transcription factor in Drosophila,
Daughterless (Da) has generally been regarded as a ubiquitously expressed
binding partner for other developmentally regulated bHLH transcription factors.
From analysis of a novel tissue-specific allele, da(lyh), we show that da
expression is not constitutive, but is dynamically regulated. This
transcriptional regulation includes somatic ovary-specific activation,
autoregulation and negative regulation. Unexpectedly, the diverse functions of
da may require that expression levels be tightly controlled in a cell and/or
tissue-specific manner. Our analysis of da(lyh) identifies it as the first
springer insertion that functions as an insulating element, with its disruptive
activity mediated by the product of a fourth chromosome gene, Suppressor of lyh
[Su(lyh)]. |
Is telomestatin, a novel statin drug used to treat high cholesterol? | Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor and is used to treat cancer. | Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4
and has been shown to be a very potent telomerase inhibitor. The structural
similarity between telomestatin and a G-tetrad suggested to us that the
telomerase inhibition might be due to its ability either to facilitate the
formation of or trap out preformed G-quadruplex structures, and thereby
sequester single-stranded d[T(2)AG(3)](n) primer molecules required for
telomerase activity. Significantly, telomestatin appears to be a more potent
inhibitor of telomerase (5 nM) than any of the previously described
G-quadruplex-interactive molecules. In this communication we provide the first
experimental evidence that telomestatin selectively facilitates the formation of
or stabilizes intramolecular G-quadruplexes, in particular, that produced from
the human telomeric sequence d[T(2)AG(3)](4). A simulated annealing (SA) docking
approach was used to study the binding interactions of telomestatin with the
intramolecular antiparallel G-quadruplex structure. Each intramolecular
G-quadruplex molecule was found to bind two telomestatin molecules (unpublished
results). A 2:1 model for the telomestatin bound in the external stacking mode
in an energy minimized complex with the human telomeric basket-type G-quadruplex
was constructed. Our observation that a G-quadruplex-interactive molecule
without significant groove interactions is able to reorient in a G-quadruplex
structure proints to the importance of core interaction with an asymmetric
G-quadruplex structure in producing selective binding. Furthermore, the
G-quadruplex interactions of telomestatin are more selective for the
intramolecular structure in contrast to other G-quadruplex-interactive agents,
such as TMPyP4. The telomerase complex is responsible for telomere maintece and represents a
promising neoplasia therapeutic target. In order to determine whether
G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might
have effects on telomere dynamics and to evaluate the clinical utility, we
assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells.
We found that treatment with telomestatin reproducibly inhibited telomerase
activity in the BCR-ABL-positive leukemic cell lines OM9;22 and K562, resulting
in telomere shortening. Inhibition of telomerase activity by telomestatin
disrupts telomere maintece and ultimately results in telomere dysfunction.
Telomestatin completely suppressed the plating efficiency of K562 cells at 1
microM; however, telomestatin had less effects on BFU-Es and CFU-GMs colony
formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity
toward imatinib and chemotherapeutic agents was also observed in
telomestatin-treated K562 cells. Further, the combination of telomestatin plus
imatinib more effectively inhibited hematopoietic colony formation by primary
human chronic myelogenous leukemia cells. Last, telomestatin induced the
activation of ATM and Chk2, and subsequently increased the expression of
p21(CIP1) and p27(KIP1). These results demonstrate that telomere dysfunction
induced by telomestatin activates the ATM-dependent DNA damage response. We
conclude that telomerase inhibitors combined with the use of imatinib and other
chemotherapeutic agents may be very useful for the treatment of human leukemia. A novel telomerase inhibitor, telomestatin, isolated from Streptomyces anulatus
is the most potent telomerase inhibitor so far. Telomestatin specifically
inhibited telomerase without affecting reverse transcriptases and polymerases.
In addition, telomestatin induced telomere shortening, but its ratio was
extremely faster than that observed in physiological telomere shortening. These
results suggested the existence of other mechanisms to inhibit telomerase.
Telomeres consist of guanine rich sequences which compose a characteristic
three-dimensional structure designated as G-quadruplex. Stabilization of
G-quadruplex structure inhibited the catalysis of not only telomerase but also
other DNA interacting molecules. Telomestatin potently stabilized G-quadruplex
structure in a specific manner. G-quadruplex structure is also involved in a lot
of oncogene promoters. Thus, telomestatin provide the novel therapeutic
molecular target for cancer chemotherapy. The telomerase complex is responsible for telomere maintece and represents a
promising neoplasia therapeutic target. Recently, we have demonstrated that
treatment with a G-quadruplex-interactive agent, telomestatin reproducibly
inhibited telomerase activity in the BCR-ABL-positive leukemic cell lines. In
the present study, we investigated the mechanisms of apoptosis induced by
telomerase inhibition in acute leukemia. We have found the activation of
caspase-3 and poly-(ADP-ribose) polymerase in telomestatin-treated U937 cells
(PD20) and domit-negative DN-hTERT-expressing U937 cells (PD25). Activation
of p38 mitogen-activated protein (MAP) kinase and MKK3/6 was also found in
telomestatin-treated U937 cells (PD20) and domit-negative DN-hTERT-expressing
U937 cells (PD25); however, activation of JNK and ASK1 was not detected in these
cells. To examine the effect of p38 MAP kinase inhibition on growth properties
and apoptosis in telomerase-inhibited cells, we cultured DN-hTERT-expressing
U937 cells with or without SB203580. Domit-negative-hTERT-expressing U937
cells stopped proliferation on PD25; however, a significant increase in growth
rate was observed in the presence of SB203580. Treatment of SB203580 also
reduced the induction of apoptosis in DN-hTERT-expressing U937 cells (PD25).
These results suggest that p38 MAP kinase has a critical role for the induction
of apoptosis in telomerase-inhibited leukemia cells. Further, we evaluated the
effect of telomestatin on the growth of U937 cells in xenograft mouse model.
Systemic intraperitoneal administration of telomestatin in U937 xenografts
decreased tumor telomerase levels and reduced tumor volumes. Tumor tissue from
telomestatin-treated animals exhibited marked apoptosis. None of the mice
treated with telomestatin displayed any signs of toxicity. Taken together, these
results lay the foundations for a program of drug development to achieve the
dual aims of efficacy and selectivity in vivo. Guanine-rich human telomeric DNA can adopt secondary structures known as
G-quadruplexes, which can be targeted by small molecules to achieve anticancer
effects. So far, the structural information on complexes between human telomeric
DNA and ligands is limited to the parallel G-quadruplex conformation, despite
the high structural polymorphism of human telomeric G-quadruplexes. No structure
has been yet resolved for the complex with telomestatin, one of the most
promising G-quadruplex-targeting anticancer drug candidates. Here we present the
first high-resolution structure of the complex between an intramolecular (3 + 1)
human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic
hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the
G-quadruplex through π-stacking and electrostatic interactions. This structural
information provides a platform for the design of topology-specific
G-quadruplex-targeting compounds and is valuable for the development of new
potent anticancer drugs. Author information:
(1)Technology Research Association for Next Generation Natural Products
Chemistry, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan.
(2)RIKEN Center for Sustainable Resource Science, Natural Product Biosynthesis
Research Unit, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
(3)Kitasato Institute for Life Sciences, Kitasato University, 1-15-1 Kitasato,
Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.
(4)Japan Biological Informatics Consortium, 2-4-7 Aomi, Koto-ku, Tokyo,
135-0064, Japan.
(5)Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama,
Meguro-ku, Tokyo, 152-8551, Japan.
(6)RIKEN Center for Sustainable Resource Science, Molecular Structure
Characterization Unit, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
(7)RIKEN Center for Sustainable Resource Science, Chemical Biology Research
Group, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
(8)RIKEN Center for Sustainable Resource Science, Natural Product Biosynthesis
Research Unit, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
[email protected].
(9)National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi,
Koto-ku, Tokyo, 135-0064, Japan. [email protected]. |
What is amphiregulin a ligand of? | Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. | Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The
aim of this study was to investigate the effects of baseline plasma AREG levels
in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on
treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy.
Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The
clinical findings were further validated using an in vitro model of CRC. Among
35 patients, the progression-free survival (PFS) was significantly inferior in
patients with high AREG than in those with low AREG levels: 10.9 vs.
24.2 months, respectively (p = 0.008). However, after failure of first-line
chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months;
p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and
Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC
cell lines tested, AREG significantly decreased the anti-proliferative effect of
cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring
cetuximab resistance with gradual exposure for more than 6 months, AREG neither
increased colony formation nor activated AKT and ERK after cetuximab treatment.
Our results suggest that plasma AREG is a potential biomarker to predict
clinical outcomes after cetuximab-based chemotherapy. |
Which genetic susceptibility loci are implicated in irritable bowel syndrome (IBS)? | There have been six genetic susceptibility loci identified and confirmed for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. | Author information:
(1)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery,
University of Oxford, Oxford, UK.
(2)Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
(3)Center for Molecular Medicine & Clinical Epidemiology Unit, Department of
Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
(4)School of Biological Sciences, Monash University, Clayton, Victoria,
Australia.
(5)IBD Pharmacogenetics, College of Medicine and Health, University of Exeter,
Exeter, UK.
(6)Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
(7)William Harvey Research Institute, Barts & The London School of Medicine &
Dentistry, Queen Mary University of London, London, UK.
(8)Nuffield Department of Population Health, University of Oxford, Oxford, UK.
(9)23andMe, Inc., Sunnyvale, CA, USA.
(10)Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
(11)Saint Edmund Hall, University of Oxford, Oxford, UK.
(12)Enteric NeuroScience Program, Division of Gastroenterology and Hepatology,
Department of Medicine, Mayo Clinic, Rochester, MN, USA.
(13)Institute of Clinical Molecular Biology, Christian-Albrechts-University of
Kiel, Kiel, Germany.
(14)Department of Dermatology, Quincke Research Center, University Hospital
Schleswig-Holstein, Kiel, Germany.
(15)Department of Biostatistics, University of Michigan, School of Public
Health, Ann Arbor, MI, USA.
(16)Department of Laboratory Medicine, Children's and Women's Health, Norwegian
University of Science and Technology, Trondheim, Norway.
(17)Department of Public Health and Nursing, Norwegian University of Science and
Technology, Trondheim, Norway.
(18)Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust,
Levanger, Norway.
(19)Department of Molecular Medicine and Surgery, Karolinska Institutet,
Karolinska University Hospital, Stockholm, Sweden.
(20)Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu,
Estonia.
(21)Department of Genetics, University Medical Center Groningen, Groningen, the
Netherlands.
(22)Clinical Enteric Neuroscience Translational and Epidemiological Research and
Division of Gastroenterology and Hepatology, Department of Medicine, Mayo
Clinic, Rochester, MN, USA.
(23)David Geffen School of Medicine, University of California, Los Angeles, Los
Angeles, CA, USA.
(24)Neurogastroenterology Unit, Wythenshawe Hospital, Centre for
Gastrointestinal Sciences, University of Manchester, Manchester, UK.
(25)Nottingham Digestive Diseases Centre, National Institute for Health Research
Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust
and the University of Nottingham, Nottingham, UK.
(26)Center for Molecular Medicine & Clinical Epidemiology Unit, Department of
Medicine Solna, Karolinska Institutet, Stockholm, Sweden. [email protected].
(27)School of Biological Sciences, Monash University, Clayton, Victoria,
Australia. [email protected].
(28)Institute of Clinical Molecular Biology, Christian-Albrechts-University of
Kiel, Kiel, Germany. [email protected].
(29)Biodonostia Health Research Institute, San Sebastian, Spain.
[email protected].
(30)Gastrointestinal Genetics Lab, CIC bioGUNE - Basque Research and Technology
Alliance, Derio, Spain. [email protected].
(31)IKERBASQUE, The Basque Science Foundation, Bilbao, Spain.
[email protected].
(32)Big Data Institute, Li Ka Shing Centre for Health Information and Discovery,
University of Oxford, Oxford, UK. [email protected].
(33)Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
[email protected].
(34)Christ Church, University of Oxford, Oxford, UK.
[email protected].
(35)Division of Gastroenterology and Hepatology, Department of Medicine,
University of Cambridge, Cambridge, UK. [email protected].
(36)Department of Gastroenterology, Cambridge University Hospital, Cambridge,
UK. [email protected].
(#)Contributed equally |
Is there an association between Guillain–Barré syndrome and covid vaccine? | Yes. There series reporting Guillain–Barré syndrome after COVID-19 vaccination. | Safety monitoring is of paramount importance for vaccines authorized for
emergent use (EUA) by the US Food and Drug Administration (FDA) against
SARS-CoV-2. Mass immunization is an essential tool to end the current pandemic,
but vaccine surveillance is necessary to identify any potentially associated
harms. At the same time, probability of temporal bias should be borne in mind
before making conclusions about causality between the vaccine and an
attributable undesired effect. We report a case of Guillain-Barré syndrome after
the first dose of SARS-CoV-2 vaccine and believe this is a temporal, rather than
causal association. We report a case of Guillain-Barré syndrome (GBS) following the first dose of
Oxford/AstraZeneca COVID-19 vaccine with papilledema as atypical onset. As the
COVID-19 vaccination campaign progresses worldwide, GBSs vaccine-related have
been increasingly reported. After reviewing the available literature,
considering the annual incidence of GBS, in this historical moment, the public
health systems cannot afford an unjustified distrust in vaccines, caused by
misinterpretation of epidemiological data. Nonetheless, it is important for
clinicians to promptly recognize neurological complications potentially
associated with COVID-19 vaccinations and report them to pharmacovigilance
agencies. Patients with neurological symptoms should be enquired about recent vaccination
history. It is important after the COVID-19 mRNA vaccine, which is newly
introduced as it might link to the development of a wider variety of
neurological diseases. BACKGROUND: Guillain-Barré Syndrome (GBS) is a rapidly progressive
immune-mediated polyneuropathy often associated with an antecedent infectious
illness or vaccination. The classic presentation of GBS is characterized by
ascending limb weakness and numbness with loss of reflexes. However, atypical
variants involving the face and arms or with purely sensory symptoms also exist.
In up to 30% of cases, GBS progresses to respiratory failure, with patients
requiring mechanical ventilation.
CASE REPORT: We report a case of atypical GBS occurring after Coronavirus
disease 2019 (COVID-19) vaccination in an otherwise healthy 38-year-old man. The
patient's clinical presentation was characterized by bilateral hand and foot
paresthesias, dysarthria, bilateral facial weakness, and an absence of classic
ascending limb weakness. Albuminocytological dissociation within the
cerebrospinal fluid was suggestive of GBS. The patient received intravenous
immunoglobulin therapy, with modest improvement in his symptoms at the time of
his discharge from the hospital. Why Should an Emergency PhysicianBe Aware of
This? Patients with GBS are at risk for life-threatening complications,
including respiratory failure requiring mechanical ventilation. It is critical
for emergency physicians to be aware of the manifold presentations of GBS for
early recognition and treatment. This may be of particular importance in the
context of a worldwide vaccination campaign in response to the COVID-19
pandemic. ChAdOx1 nCoV-19 is an effective and well-tolerated coronavirus disease 2019
(COVID-19) vaccine. Rare cases of serious adverse events have been reported with
this vaccine. We report three patients who developed Guillain-Barré syndrome
following ChAdOx1 nCoV-19 vaccination, who did not have active or prior COVID-19
infection. The neurological illness in all patients had an onset of 11-13 days
after the first dose of vaccine. All were characterized by sensorimotor weakness
of the upper and lower limbs, with facial diplegia in one and dysautonomia in
the other. Nerve conduction studies were consistent with demyelination in two
and axonopathy in one. Cerebrospinal fluid analysis showed albuminocytological
dissociation in two patients. All patients had moderate-to-severe disability.
They were treated with intravenous immunoglobulin, with stabilization of the
disease. Proper monitoring and prompt reporting of such cases is required to
ensure safety of the vaccine. The emergence of the coronavirus 2019 (COVID-19) pandemic has presented an
unprecedented global challenge. Vaccines against COVID have been developed to
date. Covid-19 has been linked with the development of Guillain-Barre Syndrome
(GBS), a rare immune-mediated demyelinating neuropathy. We report three cases of
Guillain-Barre Syndrome and one case of Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP), presenting to a Tasmanian hospital, and review 15 other
reported cases and discuss likely immunopathology. Nearly all reported cases of
post-COVID-19 vacciation inflammatory demyelinating polyneuropathy are linked to
AstraZeneca vaccination and a variant with bifacial weakness is the most
reported form of GBS globally. IMPORTANCE: As part of postauthorization safety surveillance, the US Food and
Drug Administration (FDA) has identified a potential safety concern for
Guillain-Barré syndrome (GBS) following receipt of the Ad26.COV2.S
(Janssen/Johnson & Johnson) COVID-19 vaccine.
OBJECTIVE: To assess reports of GBS received in the Vaccine Adverse Event
Reporting System (VAERS) following Ad26.COV2.S vaccination.
DESIGN, SETTING, AND PARTICIPANTS: Reports of presumptive GBS were identified in
a US passive reporting system (VAERS) February-July 2021 and characterized,
including demographics, clinical characteristics, and relevant medical history.
EXPOSURES: Receipt of the Ad26.COV2.S vaccine; the comparator was the background
rate of GBS in the general (unvaccinated) population that had been estimated and
published based on a standardized case definition.
MAIN OUTCOMES AND MEASURES: Presumptive GBS; the reporting rate was analyzed,
including calculation of the observed to expected ratio based on background
rates and vaccine administration data. Because of limited availability of
medical records, cases were not assessed according to the Brighton Collaboration
criteria for GBS.
RESULTS: As of July 24, 2021, 130 reports of presumptive GBS were identified in
VAERS following Ad26.COV2.S vaccination (median age, 56 years; IQR, 45-62 years;
111 individuals [86.0%] were < 65 years; 77 men [59.7%]). The median time to
onset of GBS following vaccination was 13 days (IQR, 10-18 days), with 105 cases
(81.4%) beginning within 21 days and 123 (95.3%) within 42 days. One hundred
twenty-one reports (93.1%) were serious, including 1 death. With approximately
13 209 858 doses of vaccine administered to adults in the US, the estimated
crude reporting rate was 1 case of GBS per 100 000 doses administered. The
overall estimated observed to expected rate ratio was 4.18 (95% CI, 3.47-4.98)
for the 42-day window, and in the worst-case scenario analysis for adults 18
years or older, corresponded to an estimated absolute rate increase of 6.36 per
100 000 person-years (based on a rate of approximately 8.36 cases per 100 000
person-years [123 cases per 1 472 162 person-years] compared with a background
rate of approximately 2 cases per 100 000 person-years). For both risk windows,
the observed to expected rate ratio was elevated in all age groups except
individuals aged 18 through 29 years.
CONCLUSIONS AND RELEVANCE: These findings suggest a potential small but
statistically significant safety concern for Guillain-Barré syndrome following
receipt of the Ad26.COV2.S vaccine. However, the findings are subject to the
limitations of passive reporting systems and presumptive case definition, and
they must be considered preliminary pending analysis of medical records to
establish a definitive diagnosis. We conducted a multi-institutional study in Taiwan and a systematic review of
the literature for reports of Guillain-Barré syndrome after coronavirus disease
vaccination. This condition, mostly the classic form and the acute inflammatory
demyelinating polyneuropathy subtype, has been reported in 39 cases and has
occurred within 2 weeks of vaccine administration. In March 2020, the WHO declared COVID-19 to be a global pandemic and since
December 2020, millions of vaccines have been administered. To date, cases of
Guillain-Barré syndrome (GBS) following a COVID vaccine (Pfizer, Johnson &
Johnson, Janssen, AstraZeneca) have been reported. A 61-year-old woman developed
bilateral asymmetrical lower motor neuron (LMN) facial weakness followed by limb
symptoms, 10 days after receiving the first dose of AstraZeneca COVID vaccine.
The second patient was a 56-year-old man who, 9 days after receiving first dose
of AstraZeneca COVID vaccine, developed bilateral asymmetrical LMN facial
weakness with limb symptoms. Intravenous immunoglobulin was administered with
rapid recovery. These cases of GBS following the AstraZeneca COVID vaccine add
to cohort of patients reported. We flag up to raise awareness of this condition
post-COVID-19 vaccine and highlight the prominent bifacial involvement. Early
diagnosis and prompt treatment with intravenous immunoglobulin led to rapid
recovery. |
What is the function of the protein calreticulin? | Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca2+ buffer to assist correct protein folding within the ER. | The lectin chaperones calnexin (CNX) and calreticulin (CRT) localized in the
endoplasmic reticulum play important roles in glycoprotein quality control.
Although the interaction between these lectin chaperones and ERp57 is well
known, it has been recently reported that endoplasmic reticulum protein 29
(ERp29), a member of PDI family, interacts with CNX and CRT. The biochemical
function of ERp29 is unclear because it exhibits no ERp57-like redox activity.
In this study, we addressed the possibility that ER chaperones CNX and CRT are
connected via ERp29, based on our observation that ERp29 exists as a dimer. As a
result, we showed that CNX dimerizes through ERp29. These results endorse the
hypothesis that ERp29 serves as a bridge that links two molecules of CNX. Also,
we showed that similar complexes such as CNX-CRT were formed via ERp29. BACKGROUND: Calreticulin (CRT), an endoplasmic reticulum-resident protein
generally overexpressed in cancer cells, is associated with radiation
resistance. CRT shows higher transacetylase activity, as shown by us earlier, in
the presence of the polyphenolic acetates (like 7, 8-diacetoxy-4-methylcoumarin,
DAMC) and modifies the activity of a number of proteins, thereby influencing
cell signaling.
AIM: To investigate the relationship between CRT expression and radiation
response in a human glioma cell line and to evaluate the radiomodifying effects
of DAMC.
METHODS AND RESULTS: Studies were carried out in an established human glioma
cell line (BMG-1) and its isogenic clone overexpressing CRT (CROE,
CRT-overexpressing cells) by analyzing clonogenic survival, cell proliferation,
micronuclei analysis, and protein levels by Western blotting as parameters of
responses. CRT overexpression conferred resistance against radiation-induced
cell death in CROE cells (D37 = 7.35 Gy, D10 = 12.6 Gy and D0 = 7.25 Gy) as
compared to BMG-1 cells (D37 = 5.70 Gy, D10 = 9.2 Gy and D0 = 5.6 Gy). A
lower level of radiation-induced micronuclei formation observed in CROE cells
suggested that reduced induction and/or enhanced DNA repair partly contributed
to the enhanced radioresistance. Consistent with this suggestion, we noted that
CRT-mediated radioresistance was coupled with enhanced grp78 level and reduced
P53 activation-mediated prodeath signaling, while no changes were noted in
acetylation of histone H4. DAMC-enhanced radiation-induced delayed (secondary)
apoptosis, which was higher in CROE cells.
CONCLUSION: CRT overexpression confers resistance against radiation-induced
death of human glioma cells, which can be overcome by the polyphenolic acetate
DAMC. N-glycosylation is a highly conserved glycan modification, and more than 7000
proteins are N-glycosylated in humans. N-glycosylation has many biological
functions such as protein folding, trafficking, and signal transduction. Thus,
glycan modification to proteins is profoundly involved in numerous physiological
and pathological processes. The N-glycan precursor is biosynthesized in the
endoplasmic reticulum (ER) from dolichol phosphate by sequential enzymatic
reactions to generate the dolichol-linked oligosaccharide composed of 14 sugar
residues, Glc3Man9GlcNAc2. The oligosaccharide is then en bloc transferred to
the consensus sequence N-X-S/T (X represents any amino acid except proline) of
nascent proteins. Subsequently, the N-glycosylated nascent proteins enter the
folding step, in which N-glycans contribute largely to attaining the correct
protein fold by recruiting the lectin-like chaperones, calnexin, and
calreticulin. Despite the N-glycan-dependent folding process, some glycoproteins
do not fold correctly, and these misfolded glycoproteins are destined to
degradation by proteasomes in the cytosol. Properly folded proteins are
transported to the Golgi, and N-glycans undergo maturation by the sequential
reactions of glycosidases and glycosyltransferases, generating complex-type
N-glycans. N-Acetylglucosaminyltransferases (GnT-III, GnT-IV, and GnT-V) produce
branched N-glycan structures, affording a higher complexity to N-glycans. In
this chapter, we provide an overview of the biosynthetic pathway of N-glycans in
the ER and Golgi. |
Atlanto-axial rotary instability (Fielding type 1) is common to what diseases? | Atlanto-axial instability (AAI) is common in the connective tissue disorders, such as rheumatoid arthritis, and increasingly recognized in the heritable disorders of Stickler, Loeys-Dietz, Marfan, Morquio, and Ehlers-Danlos (EDS) syndromes as well as infectious disease. | We report a 15-year-old boy with mucopolysaccharidosis (MPS) Type VII (Sly
disease) who was found to have atlantoaxial instability with quadriparesis.
Subluxation of C1 on C2 has also been documented in patients with Type I and
Type IV MPS. Routine screening of the cervical spine is recommended in patients
with "MPS Type VII" so that delayed diagnosis of instability, which may lead to
neurologic compromise, is avoided. Grisel's syndrome is a unilateral or bilateral subluxation of C1 on C2,
associated with an infectious condition in the head or neck. Anatomic studies
have demonstrated the existence of a periodontoidal vascular plexus that drains
the posterior superior pharyngeal region. No lymph nodes are present in this
plexus, so septic exudates may be freely transferred from the pharynx to the
C1-C2 articulation. The resulting synovial and vascular engorgements may cause
mechanical and chemical damage to the transverse and facet capsular ligaments
leading to subluxation. The primary treatment of Grisel's syndrome is medical:
the underlying infectious organism must be isolated and appropriate antibiotics
prescribed. The subluxation is reduced in halter or skeletal traction. The
authors use the classification scheme of rotary subluxation proposed by
Fielding, so that treatment appropriate to the specific type of subluxation is
used. Based on biomechanical data predicting articular instability and canal
compromise proportional to the extent of ligamentous injury, the following
specific forms of immobilization are recommended to ensure ligamentous healing:
Fielding Type I (transverse ligament intact and bilateral facet capsular injury)
soft collar; Type II (transverse ligament and unilateral facet capsular injury)
Philadelphia collar or SOMI brace; and Type III (transverse ligament and
bilateral facet capsular ligament injury) halo. Following six to eight weeks of
immobilization, stability is assessed by the study of flexion-extension
roentgenograms. Should residual instability be demonstrated, arthrodesis is
indicated. Spondyloepiphyseal dysplasia congenita (SED) is a rare form of skeletal systemic
disease, characterized by congenital dwarfism with a short trunk and epiphysial
dysplasia in the long bones and vertebral bodies. Patients also frequently
suffer from atlanto-axial instability due to os odontoideum. Compression of the
spinal cord caused by atlanto-axial instability is a common, serious
complication in SED patients, and causes severe spinal cord symptoms or
occasionally sudden death. We present an SED patient who underwent a posterior
fusion of the occiput to the cervical spine for severe spinal cord symptoms due
to atlanto-axial instability. Atlanto-axial rotatory fixation (AARF) is a rare cause of childhood torticollis
that may occur spontaneously or in association with trauma and upper respiratory
infections. We describe the clinical findings, as well as the effectiveness of
imaging in the diagnosis and the treatment of 4 children with AARF, in whom
acute fixed non-dystonic torticollis was the presenting symptom. Onset of
torticollis was spontaneous in Case 1, after general anesthesia for
cholesteatoma surgery in Case 2, after a trauma in Case 3, and during
hypersomnia in Case 4. Duration of torticollis prior to diagnosis was 3 months
in the first two patients and 20 days in the other two. All the patients
underwent cervical X-rays examinations, which were not contributory to the
diagnosis, followed by CT, which demonstrated C1-C2 rotatory fixation. One
patient had a spontaneous resolution; treatment with Gardner's tongs and soft
collar permitted restoration of the normal alignment in the other 3 patients.
AARF must be considered in all the patients with persistent painful torticollis. The cervical spine often becomes involved early in the course of rheumatoid
arthritis, leading to three different patterns of instability: atlantoaxial
subluxation, atlantoaxial impaction, and subaxial subluxation. Although
radiographic changes are common, the prevalence of neurologic injury is
relatively low. The primary goal of treatment is to prevent permanent neurologic
injury while avoiding potentially dangerous and unnecessary surgery. Strategies
include patient education, lifestyle modification, regular radiographic
follow-up, and early surgical intervention, when indicated. Magnetic resoce
imaging is indicated when neurologic deficit (myelopathy) occurs or when plain
radiographs show atlantoaxial subluxation with a posterior atlantodental
interval < or =14 mm, any degree of atlantoaxial impaction, or subaxial stenosis
with a canal diameter < or =14 mm. Surgery should be considered promptly for any
of the following: progressive neurologic deficit, chronic neck pain in the
setting of radiographic instability that does not respond to nonnarcotic pain
medication, any degree of atlantoaxial impaction or cord stenosis, a posterior
atlantodental interval < or =14 mm, atlantoaxial impaction represented by
odontoid migration > or =5 mm rostral to McGregor's line, sagittal canal
diameter <14 mm, or a cervicomedullary angle <135 degrees. L’instabilité de la charnière occipito atloïdienne affecte 10 à 20% des sujets
présentant un Down syndrome (trisomie 21). Cette instabilité est souvent
asymptomatique et seulement diagnostiquée sur les radiographies qui montrent un
élargissement de la distance antérieure atloïdo-odontoide. L’asymptologie de
l’instabilité occipito atloïdienne affecte 1 à 2% des sujets présentant un Down
syndrome avec des signes manifestes de compression médullaire. La spondylose
cervicale qui est habituelle dans le Down syndrome peut potentialiser des
lésions de la moelle. 44 sujets Koweitis présentant un Down syndrome dont l’âge
était supérieur à 15 ans ont été évalués cliniquement et radiographiquement. Des
radiographies de la colonne cervicale de profil ont été effectuées en position
neutre et en position de flexion. Une instabilité occipito atloïdienne a été
diagnostiquée chez 8 sujets (18%) avec des anomalies congénitales de C1 C2, chez
5 sujets (12%). 5 patients présentaient une instabilité uniquement en flexion et
3 patients présentaient une telle instabilité sur tous les clichés. 3 patients
avec une instabilité occipito atloïdienne présentaient des anomalies de
l’odontoide aggravant encore les conditions locales. Lorsqu’il existe une
instabilité occipito atloïdienne, la distance C1 odontoide doit être évaluée car
elle indique l’espace possible pour la moelle. Une spondylolyse cervicale a été
relevée chez 16 patients (36% des sujets). Avec l’âge, les lésions dégénératives
peuvent évoluer, survet plus tôt que dans la population normale et peuvent
léser les différents niveaux de la colonne cervicale. La moitié des patients
avec une instabilité occipito atloïdienne ont une spondylolyse cervicale, avec
une co-morbidité entraît une moelle à risque. Atlantoaxial rotatory fixation (AARF) resulting from drug-induced cervical
dystonia (DICD) represents an extremely rare complication of antipsychotic
treatment, requiring a comprehensive assessment of pharmacologic therapy and
timely radiologic workup. We report a chronic case of Fielding type I, Pang type
I AARF secondary to schizophrenia treatment in a 16-year-old girl, along with a
review of the literature on the management challenges posed in this condition.
In this scenario, torticollis may just represent the tip of the iceberg, and
only an effective multidisciplinary approach increases the chances of
satisfactory correction with closed reduction, hence avoiding the burden of more
invasive treatment options. A relatively rare report of an 8-year-old girl with Maroteaux-Lamy syndrome that
is Type VI mucopolysaccharidosis who presented with symptoms of spastic
quadriparesis related to atlantoaxial instability is presented. Atlantoaxial
stabilization resulted in rapid and sustained neurological recovery. |
What is the effect of epiregulin on leptin secretion? | Epiregulin induces leptin secretion. | |
Which JASPAR release is JASPAR 2022? | JASPAR (http://jaspar.genereg.net/) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups. In JASPAR 2022, JASPAR's 9th release, the CORE collection was expanded with 341 new profiles (148 for plants, 101 for vertebrates, 85 for urochordates, and 7 for insects), which corresponds to a 19% expansion over the previous release. | |
Is Erythropoietin effective for neuroprotection of Preterm Infants. | No. High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. | BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective
effect in preclinical models of neonatal brain injury, and phase 2 trials have
suggested possible efficacy; however, the benefits and safety of this therapy in
extremely preterm infants have not been established.
METHODS: In this multicenter, randomized, double-blind trial of high-dose
erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27
weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours
after birth. Erythropoietin was administered intravenously at a dose of 1000 U
per kilogram of body weight every 48 hours for a total of six doses, followed by
a maintece dose of 400 U per kilogram three times per week by subcutaneous
injection through 32 completed weeks of postmenstrual age. Placebo was
administered as intravenous saline followed by sham injections. The primary
outcome was death or severe neurodevelopmental impairment at 22 to 26 months of
postmenstrual age. Severe neurodevelopmental impairment was defined as severe
cerebral palsy or a composite motor or composite cognitive score of less than 70
(which corresponds to 2 SD below the mean, with higher scores indicating better
performance) on the Bayley Scales of Infant and Toddler Development, third
edition.
RESULTS: A total of 741 infants were included in the per-protocol efficacy
analysis: 376 received erythropoietin and 365 received placebo. There was no
significant difference between the erythropoietin group and the placebo group in
the incidence of death or severe neurodevelopmental impairment at 2 years of age
(97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence
interval, 0.81 to 1.32; P = 0.80). There were no significant differences between
the groups in the rates of retinopathy of prematurity, intracranial hemorrhage,
sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in
the frequency of serious adverse events.
CONCLUSIONS: High-dose erythropoietin treatment administered to extremely
preterm infants from 24 hours after birth through 32 weeks of postmenstrual age
did not result in a lower risk of severe neurodevelopmental impairment or death
at 2 years of age. (Funded by the National Institute of Neurological Disorders
and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.). Despite improvements in viability, the long-term neurodevelopmental outcomes of
preterm babies remain serious concern as a significant percentage of these
infants develop neurological and/or intellectual impairment, and they are also
at increased risk of psychiatric illnesses later in life. The current challenge
is to develop neuroprotective approaches to improve adverse outcomes in preterm
survivors. The purpose of this review was to provide an overview of the current
evidence on pharmacological agents targeting the neuroprotection of the preterm
brain. Among them, magnesium sulfate, given antenatally to pregt women with
imminent preterm birth before 30 to 34 weeks of gestation, as well as caffeine
administered to preterm infants after birth, exhibited neuroprotective effects
for human preterm brain. Erythropoietin treatment of preterm infants did not
result in neuroprotection at 2 years of age in two out of three published large
randomized controlled trials; however, long-term follow-up of these infants is
needed to come to definite conclusions. Further studies are also required to
assess whether melatonin, neurosteroids, inhaled nitric oxide, allopurinol, or
dietary supplements (omega-3 fatty acids, choline, curcumin, etc.) could be
implemented as neuroprotectants in clinical practice. Furthermore, other
pharmacological agents showing promising signs of neuroprotective efficacy in
preclinical studies (growth factors, hyaluronidase inhibitors or treatment,
antidiabetic drugs, cannabidiol, histamine-H3 receptor antagonists, etc.), as
well as stem cell- or exosomal-based therapies and omedicine, may prove
useful in the future as potential neuroprotective approaches for human preterm
brain. KEY POINTS: · Magnesium and caffeine have neuroprotective effects for the
preterm brain.. · Follow-up of infants treated with erythropoietin is needed.. ·
Neuroprotective efficacy of several drugs in animals needs to be shown in
humans.. Preterm infants are at high risk of brain injury. With more understanding of the
preterm brain injury's pathogenesis, neuroscientists are looking for more
effective methods to prevent and treat it, among which erythropoietin (Epo) is
considered as a prime candidate. This review tries to clarify the possible
mechanisms of Epo in preterm neuroprotection and summarize updated evidence
considering Epo as a pharmacological neuroprotective strategy in animal models
and clinical trials. To date, various animal models have validated that Epo is
an anti-apoptotic, antiinflammatory, anti-oxidant, anti-excitotoxic,
neurogenetic, erythropoietic, angiogenetic, and neurotrophic agent, thus
preventing preterm brain injury. However, although the scientific rationale and
preclinical data for Epo's neuroprotective effect are promising, when translated
to bedside, the results vary in different studies, especially in its long-term
efficacy. Based on existing evidence, it is still too early to recommend Epo as
the standard treatment for preterm brain injury. |
What is the SPRTN protein function? | The protease SPRTN emerged as the essential enzyme for DNA-protein crosslink proteolysis repair. | Author information:
(1)Medical Research Council Oxford Institute for Radiation Oncology, Department
of Oncology, University of Oxford, Roosevelt Drive, OX3 7DQ, Oxford, UK.
(2)Medical Research Council Oxford Institute for Radiation Oncology, Department
of Oncology, University of Oxford, Roosevelt Drive, OX3 7DQ, Oxford, UK.
Electronic address: [email protected]. Repair of covalent DNA-protein crosslinks (DPCs) by the metalloprotease SPRTN
prevents genome instability, premature aging and carcinogenesis. SPRTN is
specifically activated by DNA structures containing single- and double-stranded
features, but degrades the protein components of DPCs promiscuously and
independent of amino acid sequence. This lack of specificity is useful to target
diverse protein adducts, however, it requires tight control in return, in order
to prohibit uncontrolled proteolysis of chromatin proteins. Here, we discover
the components and principles of a ubiquitin switch, which negatively regulates
SPRTN. We demonstrate that monoubiquitylation is induced in an E3
ligase-independent manner and, in contrast to previous assumptions, does not
control chromatin access of the enzyme. Data obtained in cells and in vitro
reveal that monoubiquitylation induces inactivation of the enzyme by triggering
autocatalytic cleavage in trans while also priming SPRTN for proteasomal
degradation in cis. Finally, we show that the deubiquitylating enzyme USP7
antagonizes this negative control of SPRTN in the presence of DPCs. The antitumor activity of poly(ADP-ribose) polymerase inhibitors (PARPis) has
been ascribed to PARP trapping, which consists in tight DNA-protein complexes.
Here we demonstrate that the cytotoxicity of talazoparib and olaparib results
from DNA replication. To elucidate the repair of PARP1-DNA complexes associated
with replication in human TK6 and chicken DT40 lymphoblastoid cells, we explored
the role of Spartan (SPRTN), a metalloprotease associated with DNA replication,
which removes proteins forming DPCs. We find that SPRTN-deficient cells are
hypersensitive to talazoparib and olaparib, but not to veliparib, a weak PARP
trapper. SPRTN-deficient cells exhibit delayed clearance of trapped PARP1 and
increased replication fork stalling upon talazoparib and olaparib treatment. We
also show that SPRTN interacts with PARP1 and forms nuclear foci that colocalize
with the replicative cell division cycle 45 protein (CDC45) in response to
talazoparib. Additionally, SPRTN is deubiquitinated and epistatic with
translesion synthesis (TLS) in response to talazoparib. Our results demonstrate
that SPRTN is recruited to trapped PARP1 in S-phase to assist in the excision
and replication bypass of PARP1-DNA complexes. |
What part of the body is associated with Cauda equina | The cauda equina is the sack of nerve roots (nerves that leave the spinal cord between spaces in the bones of the spine to connect to other parts of the body) at the lower end of the spinal cord. | Using a variety of neuroanatomical and histological techniques, we compare the
spinal cord and peripheral nerve distribution in the tails of larvae from
Xenopus laevis and three species of Rana. The relatively large, postsacral
spinal cord of Xenopus contains abundant motoneurons and their axons. Spinal
nerves exit from the spinal cord in a regular array, one nerve per myotome, from
the cervical region to near the end of the tail. Somata of motoneurons
innervating caudal myotomes are found along the entire length of the tail. In
contrast, the caudal cord of Rana is reduced to a filum terminale consisting of
little more than an ependymal tube; spinal nerves to all caudal myotomes leave
the cord in the sacral region and reach their motor targets via a cauda equina
and caudal plexus. Motoneuron cell bodies innervating caudal myotomes are found
only in the sacral region. The Rana larval pattern is similar to that of adult
frogs and mammals, whereas the Xenopus larval pattern is more like that of
salamanders and reptiles. These gross neuroanatomical differences are not due to
differences in the size or developmental stage of the tadpoles, but instead are
associated with differences in the swimming behavior of the larvae. The presence
of motoneurons in the caudal spinal cord of Xenopus may provide local
intermyotomal control within the tail; the elongated topography of the cord
appears to permit finer, rostral-to-caudal regulation of neuromuscular activity.
The Rana spinal cord, on the other hand--with motoneurons clustered
anteriorly--may produce concurrent firing of adjacent ipsilateral myotomes, but
at the expense of fine intermyotomal regulation. The fact that nerves in the
tail of Xenopus enter and exit from the spinal cord locally, as opposed to far
anteriorly as in Rana, means that for tadpoles of the same size, reflex arc
lengths are many times shorter in Xenopus. The spinal cord of two tetraodontiform fishes, the Japanese file fish (Navodon
modestus) and the panther puffer (Takifugu pardalis), are unusual among
vertebrates in having a markedly abbreviated spinal cord with a long and
flattened filum terminale. Only the rostral short part of the cord of both
species is cylindrical; the greater part of the cord is markedly flat. The
majority of the spinal nerve roots leave the short cylindrical part. The
flattened part of the cord contains the central canal, myelinated nerve fibers,
and a few motoneurons surrounding the cauda equina, and it is histologically
similar to the filum terminale of amphibians and mammals. The spinal cords of
other teleosts, the sun-fish and angler, also are abbreviated and possess a
filum terminale and cauda equina. These orders possess an enormous head and
short trunk. However, the correlation between this body form and an abbreviated
cord is not causal, since the tetraodontiform species described here show
ordinary body proportions. The spinal cord may be abbreviated in tetraodontiform
fishes in general. Penetrating spinal cord injuries (P.S.C.I.) are rarely described in Sub Saharian
countries in spite of an increasing number of wars. To study epidemiology
management and prognosis of P.S.C.I. in Senegal, population of 16 patients
collected from Fann Hospital in Dakar has been studied. 9 cases were related on
gunshot or shrapnel injuries and 6 were stab-wounded. 8 came from war practice
and 7 from civilian practice. The point of entry was at the posterior or lateral
part of the body and continuous leaking of cerebral spinal fluid from this point
was founded only in one patient. Patients showed a clinical picture of a
complete spinal cord section syndrome, 3 spinal cord hemisection Brown Sequard
syndromes, 3 cauda equina syndromes and 1 monoradicular syndrome. Spinal X-rays
or myelography may lead to an accurate evaluation of the extent of bone tissue
destruction. Anatomical evaluation of roots and spinal cord lesions were more
difficult when C.T. scan or R.M.I. is not available. Penetrating spinal cord
injury with foreign body included or myelography stop or showing cauda equina
syndrome should be operated on. 9 of our patients has benefited of spine
surgical posterior approach (laminectomy). Immediate vital prognosis is good
regarding the fact that visceral associated lesions were rare (2 cases).
Functional recovery is fair only 46.6% of patients expressed partial or complete
recovery. Prognosis factors such as injuring agent and initial neurological
status has been discussed. Prognosis of penetrating spinal cord injuries could
be improved by immediate and multidisciplinary management. Single or double-level compression of the lumbosacral nerve roots located in the
dural sac results in a polyradicular symptomatology clinically diagnosed as
cauda equina syndrome. The cauda equina nerve roots provide the sensory and
motor innervation of most of the lower extremities, the pelvic floor and the
sphincters. Therefore, in a fully developed cauda equina syndrome, multiple
signs of sensory disorders may appear. These disorders include low-back pain,
saddle anesthesia, bilateral sciatica, then motor weakness of the lower
extremities or chronic paraplegia and, bladder dysfunction. Multiple etiologies
can cause the cauda equina syndrome. Among them, non-neoplastic compressive
etiologies such as herniated lumbosacral discs and spinal stenosis and spinal
neoplasms play a significant role in the development of the cauda equina
syndrome. Non-compressive etiologies of the cauda equina syndrome include
ischemic insults, inflammatory conditions, spinal arachnoiditis and other
infectious etiologies. The use of canine, porcine and rat models mimicking the
cauda equina syndrome enabled discovery of the effects of the compression on
nerve root neural and vascular anatomy, the impairment of impulse propagation
and the changes of the neurotransmitters in the spinal cord after compression of
cauda equina. The involvement of intrinsic spinal cord neurons in the
compression-induced cauda equina syndrome includes anterograde, retrograde and
transneuronal degeneration in the lumbosacral segments. Prominent changes of
NADPH diaphorase exhibiting, Fos-like immunoreactive and heat shock protein
HSP72 were detected in the lumbosacral segments in a short-and long-lasting
compression of the cauda equina in the dog. Developments in the diagnosis and
treatment of patients with back pain, sciatica and with a herniated lumbar disc
are mentioned, including many treatment options available. Cauda equina syndrome is a relatively uncommon condition typically associated
with a large, space-occupying lesion within the canal of the lumbosacral spine.
The syndrome is characterized by varying patterns of low back pain, sciatica,
lower extremity sensorimotor loss, and bowel and bladder dysfunction. The
pathophysiology remains unclear but may be related to damage to the nerve roots
composing the cauda equina from direct mechanical compression and venous
congestion or ischemia. Early diagnosis is often challenging because the initial
signs and symptoms frequently are subtle. Classically, the full-blown syndrome
includes urinary retention, saddle anesthesia of the perineum, bilateral lower
extremity pain, numbness, and weakness. Decreased rectal tone may be a
relatively late finding. Early signs and symptoms of a developing postoperative
cauda equina syndrome are often attributed to common postoperative findings.
Therefore, a high index of suspicion is necessary in the postoperative spine
patient with back and/or leg pain refractory to analgesia, especially in the
setting of urinary retention. Regardless of the setting, when cauda equina
syndrome is diagnosed, the treatment is urgent surgical decompression of the
spinal canal. Intradural extramedullary type of spinal hydatid disease is a rare variety of
hydatid disease, and is even rarer in paediatric age group. Spinal hydatid
disease should be considered in the differential diagnosis of spinal cord
compression syndrome in endemic countries and should be evaluated with imaging
and serological investigations. Our case was a 9- year-old boy who presented
with lower back pain lasting for 8 months and progressive bilateral lower
extremities weakness lasting for 2 month. Neurological examination was
suggestive of lower motor neuron type of paraperesis. Magnetic resoce images
of the lumbar spine showed an intradural cystic lesion displacing and
compressing the lower cord and cauda equina. The cystic mass was explored with
L1-L4 laminectomy and after durotomy; it was separated from cord and dura mater
by hydrodissection. It contained a clear fluid. The pathological diagnosis was
hydatid disease. Cauda equina syndrome is a well described state of neurologic compromise due to
lumbosacral root compression. In most cases, it is due to a herniated disc,
tumor, infection, or hematoma. We report a case of rapid lumbar synovial cyst
expansion leading to acute cauda equina syndrome and compare it to similar cases
in the literature. The patient is a 49-year-old woman with a history of chronic
low back pain who developed cauda equina syndrome. Serial lumbar magnetic
resoce imaging studies demonstrated a significant increase in the size of a
lumbar synovial cyst over a 2 week interval. After an unsuccessful attempt to
relieve her acute symptoms with computed tomography-guided cyst aspiration, an
L4-5 posterior spinal decompression with excision of the synovial cyst was
performed. Postoperatively the patient's perineal numbness, bladder
incontinence, and associated pain complaints resolved. The only residual symptom
at one month follow-up was continued numbness in the right lower limb in an L5
distribution. This report adds to 6 other well described similar cases found in
the literature by illustrating several important points. First, a lumbar
synovial cyst is a rare but possible cause of acute cauda equina syndrome.
Second, magnetic resoce imaging is the test of choice to diagnose and
characterize lumbar synovial cysts; serial imaging can detect fluctuations in
cyst size. Third, percutaneous treatment of lumbar synovial cysts is variable in
efficacy and proved to be unsuccessful in our patient. Finally, surgical
management has shown high success rates for symptomatic cysts. Specifically, in
the setting of acute cauda equina syndrome secondary to a lumbar synovial cyst,
urgent surgical decompression has led to resolution of neurologic symptoms in
most reported cases. A lumbar synovial cyst is an uncommon cause of acute cauda
equina syndrome. Prompt diagnosis and treatment may lead to reduced morbidity
associated with this condition. Thermoesthesia-and-algesthesia disorders have been registered in the dermatomes
of cauda equina roots of patients with lumbar spine osteochondrosis in all the
cases. Negative changes in the sensitivity of this type are manifested
themselves as follows: 1) 2-8-degree increases of thresholds; 2) 3-6-degree
decreases of thresholds; 3) absence of thermal sense. In the presence of reflex
syndromes (lumbalgia and lumbar ischialgia) the disorders in L4, L5, S1
dermatomes have been determined to the greatest degree.
Thermoesthesia-and-algesthesia disorders are more pronounced in patients with
the radicular syndrome than in those with the reflex syndromes. The most
improvement ofthermoesthesia-and-algesthesia values is observed in L5 dermatome
of patients with lumbalgia and lumbar ischialgia after complex conservative
therapy. The treatment performed does not result in significant
thermoesthesia-and-algesthesia improvement for the limb with radiculopathy
events and in the dermatome of the root compressed in patients with the
radicular syndrome. Positive changes in contralateral limb are more pronounced. INTRODUCTION: Schwannoma is a relatively common benign spinal cord and/or cauda
equina tumor; however, giant cauda equina schwannoma with extensive scalloping
of the lumbar vertebral body is a rare pathology, and the treatment strategy,
including the use of surgical procedures, is controversial. In this report, we
present a rare case of a giant lumbar schwannoma of the cauda equina with
extremely large scalloping of the vertebral body, and we discuss the surgical
strategy we used to treat this pathology.
CASE PRESENTATION: A 42-year-old Japanese man presented to our department with
complaints of a gait disturbance and muscle weakness in the left lower limb. His
muscle strength in the proximal part of the left lower limb was grade 2 or 3/5,
and he exhibited a mild urinary disturbance on the first visit. X-ray and
computed tomography myelography of the lumbar spine showed an extremely large
erosive lesion at the L3 vertebral body. Magnetic resoce imaging of the
lumbar spine showed a large soft-tissue mass in the spinal canal at L2-L3 and
the vertebral body at L3. A one-stage complete tumor resection and instrumented
circumferential fusion were performed via a posterior approach, and a good
outcome was achieved after the surgery.
CONCLUSIONS: We performed one-stage posterior surgery in a patient with a giant
cauda equina schwannoma with extensive scalloping of the vertebral body, and a
good post-operative outcome was achieved. Maligt spinal cord compression(MSCC)is defined as a compression of the spinal
cord or cauda equina with neuropathy caused by tumor spreading to the vertebral
body. The common symptoms of MSCC are back pain, neck pain, muscle weakness,
sensory reduction, bladder and rectal disturbance. The risk of MSCC is
relatively high in patients with lung cancer, breast cancer, and prostate
cancer. MSCC is one of the oncologic emergencies that requires prompt diagnosis
and treatment to preserve and improve neurological function. Evaluation by
magnetic resoce imaging(MRI)and computed tomography( CT)are useful for the
diagnosis. The prognosis of these patients is often poor at the time of
diagnosis of MSCC, thus it is important for deciding the treatment strategy to
consider the prognosis and background of the patient in addition to the
objective findings including the degree of MSCC and spinal instability.
Treatment options consist of medical, surgical, and radiation therapy. We need a
multidisciplinary approach because the pathology of MSCC involves multiple
departments, such as medical oncology, orthopedics, and radiology. Supportive
care including rehabilitation and preventing skeletal related events are also
important. The cancer board, in which each physician and multidisciplinary
health care professionals regularly have a discussion and review the cases, is
required. |
What does RUNX1T1 stand for? | RUNX1T1 stands for runt-related transcription factor 1. | BACKGROUND: Runt-related transcription factor 1 (RUNX1T1) isoforms are involved
in adipogenesis. RUNX1T1 is mediated by the fat mass and obesity-associated
(FTO). However, the extent to which RUNX1T1 single-nucleotide polymorphisms
(SNPs) are associated with obesity risk or metabolic abnormalities in a
community population basis is unknown.
METHODS: Samples were obtained from the Australian Crossroads study bio-bank.
SNPs located in the coding region and 3'untranslated regions of RUNX1T1 with
minor allele frequency ≥0.05 were analysed using Taqman genotyping assays.
RESULTS: Eight candidate SNPs were genotyped successfully in 1440 participants.
Of these SNPs only rs34269950 located in the 'RRACH' motif, the most common
N6-methyladenosine (m6A) methylation modification site (recognized by FTO), was
significantly associated with obesity risk and metabolic abnormalities.
Specifically, compared to AA genotype, rs34269950 del/del genotype was
associated with a 1.47 [95% confidence interval (CI): 1.01-2.14, P = 0.042] fold
higher rate of obesity risk. Additionally, the del/del genotype was associated
with a 60% increased risk of metabolic syndrome (MetS) [odds ratio (OR) = 1.60,
95% CI: 1.10-2.32, P = 0.015], in comparison to the AA genotype. Finally,
rs34269950 del/del increased the risk of a larger waist circumference (OR =
1.65, 95% CI: 1.15-2.36, P = 0.007), but not other components of MetS.
CONCLUSION: Our study demonstrates that RUNX1T1 rs34269950, located in a
potential FTO recognition motif, is significantly associated with waist
circumference. This provides novel evidence to suggest SNPs located in RRACH
motif may be involved in RNA m6A modification and mechanistic pathways that
influence abdominal obesity. |
Describe InteractiveComplexHeatmap | InteractiveComplexHeatmap is designed with an easy-to-use interface where static complex heatmaps can be directly exported to an interactive Shiny web application only with one additional line of code. | |
What is the use of Brain Metastasis Velocity (BMV) Model? | Brain metastasis velocity (BMV) is a metric that describes the rate of development of new brain metastases (BM) after initial stereotactic radiosurgery. | PURPOSE: Prior statistical models attempted to identify risk factors for time to
distant brain failure (DBF) or time to salvage whole-brain radiation therapy
(WBRT) to predict the benefit of early WBRT versus stereotactic radiosurgery
(SRS) alone. We introduce a novel clinical metric, brain metastasis velocity
(BMV), for predicting clinical outcomes after initial DBF following upfront SRS
alone.
METHODS AND MATERIALS: BMV was defined as the cumulative number of new brain
metastases that developed over time since first SRS in years. Patients were
classified by BMV into low-, intermediate-, and high-risk groups, consisting of
<4, 4 to 13, and >13 new metastases per year, respectively. Histology, number of
metastases at the time of first SRS, and systemic disease status were assessed
for effect on BMV.
RESULTS: Of 737 patients treated at our institution with upfront SRS without
WBRT, 286 had ≥1 DBF event. A lower BMV predicted for improved overall survival
(OS) following initial DBF (log-rank P<.0001). Median OS for the low,
intermediate, and high BMV groups was 12.4 months (95% confidence interval [CI],
10.4-16.9 months), 8.2 months (95% CI, 5.0-9.7 months), and 4.3 months (95% CI,
2.6-6.7 months), respectively. Multivariate analysis showed that BMV remained
the domit predictor of OS, with a hazard ratio of 2.75 for the high BMV group
(95% CI, 1.94-3.89; P<.0001) and a hazard ratio of 1.65 for the intermediate BMV
group (95% CI, 1.18-2.30; P<.004). A lower BMV was associated with decreased
rates of salvage WBRT (P=.02) and neurologic death (P=.008). Factors predictive
for a higher BMV included ≥2 initial brain metastases (P=.004) and melanoma
histology (P=.008).
CONCLUSIONS: BMV is a novel metric associated with OS, neurologic death, and
need for salvage WBRT after initial DBF following upfront SRS alone. INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that
describes the recurrence rate of new brain metastases after initial treatment
with radiosurgery (SRS). We have previously risk stratified patients into high,
intermediate, and low-risk BMV groups, which correlates with overall survival
(OS). We sought to externally validate BMV in a multi-institutional setting.
METHODS: Patients from nine academic centers were treated with upfront SRS; the
validation cohort consisted of data from eight institutions not previously used
to define BMV. Patients were classified by BMV into low (<4 BMV), intermediate
(4-13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were
estimated using the Kaplan-Meier method. Cox proportional hazards methods were
used to estimate the effect of BMV and salvage modality on OS.
RESULTS: Of 2829 patients, 2092 patients were included in the validation
dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median
OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4-13, and BMV > 13
were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). After multivariate regression
modeling, melanoma histology (β: 10.10, SE: 1.89, p < 0.0001) and number of
initial brain metastases (β: 1.52, SE: 0.34, p < 0.0001) remained predictive of
BMV (adjusted R2 = 0.06).
CONCLUSIONS: This multi-institutional dataset validates BMV as a predictor of OS
following initial SRS. BMV is being utilized in upcoming multi-institutional
randomized controlled trials as a stratification variable for salvage whole
brain radiation versus salvage SRS after DBF. BACKGROUND: Brain metastasis velocity (BMV) predicts outcomes after initial
distant brain failure (DBF) following upfront stereotactic radiosurgery (SRS).
We developed an integrated model of clinical predictors and pre-SRS MRI-derived
radiomic scores (R-scores) to identify high-BMV (BMV-H) patients upon initial
identification of brain metastases (BMs).
METHODS: In total, 256 patients with BMs treated with upfront SRS alone were
retrospectively included. R-scores were built from 1246 radiomic features in 2
target volumes by using the Extreme Gradient Boosting algorithm to predict BMV-H
groups, as defined by BMV at least 4 or leptomeningeal disease at first DBF. Two
R-scores and 3 clinical predictors were integrated into a predictive
clinico-radiomic (CR) model.
RESULTS: The related R-scores showed significant differences between BMV-H and
low BMV (BMV-L), as defined by BMV less than 4 or no DBF (P < .001). Regression
analysis identified BMs number, perilesional edema, and extracranial progression
as significant predictors. The CR model using these 5 predictors achieved a
bootstrapping corrected C-index of 0.842 and 0.832 in the discovery and test
sets, respectively. Overall survival (OS) after first DBF was significantly
different between the CR-predicted BMV-L and BMV-H groups (median OS: 26.7 vs
13.0 months, P = .016). Among patients with a diagnosis-specific graded
prognostic assessment of 1.5-2 or 2.5-4, the median OS after initial SRS was
33.8 and 67.8 months for CR-predicted BMV-L, compared to 13.5 and 31.0 months
for CR-predicted BMV-H (P < .001 and <.001), respectively.
CONCLUSION: Our CR model provides a novel approach showing good performance to
predict BMV and clinical outcomes. OBJECTIVE: To provide a review of the current status of predictive nomograms and
brain metastasis velocity (BMV) in the prognostication of brain metastasis
outcomes.
BACKGROUND: Statistical analyses have been used for many years in an attempt to
predict clinical outcomes of brain metastasis patients. Such models have
attempted to predict such endpoints as survival and which patients would most
benefit from stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT).
METHODS: This narrative review includes documents the history of statistical
models and nomograms through the stage migration of the brain metastasis
population from a population with large symptomatic brain metastases to the
modern population with small asymptomatic metastases found on surveillance
imaging. It also tells the history of the derivation and validation of BMV, a
recently identified biomarker for survival and neurologic death in the brain
metastasis population treated with SRS.
CONCLUSIONS: Statistical models predicting brain metastasis behavior continue to
evolve with the changing landscape of systemic therapy and the more aggressive
use of SRS. Previous models with ultimately need to integrate biologic data and
will continue to be updated. |
What is "cell competition"? | Cell competition is a social cellular phenomenon in which unfit cells are selectively eliminated to maintain tissue homeostasis.
At the initial stage of carcinogenesis, cell competition often occurs between newly emerging transformed cells and the neighboring normal cells, leading to the elimination of transformed cells from the epithelial layer. | Cell competition is a social cellular phenomenon in which unfit cells are
selectively eliminated to maintain tissue homeostasis.1-3 Recent studies have
revealed that mechanical forces induce competitive cell-cell interactions in
Drosophila.4-6 This mechanical cell competition has also been reported to play
an important role in mammalian cells, using Madin-Darby canine kidney (MDCK)
cells depleted of a polarity regulator Scribble in a tetracycline-inducible
manner (scribKD cells).7scribKD cells are hypersensitive to crowding due to the
lower homeostatic density than wild-type (WT) cells,7,8 and in the context of
cell competition, scribKD cells are compacted and eliminated by WT cells.7-10
Although p38 and p53 are involved in this process,7,10 the molecular mechanism
by which WT cells recognize and mechanically eliminate scribKD cells remains
unclear. Here, we report that scribKD cells secrete fibroblast growth factor 21
(FGF21) to drive cell competition. Knockdown of FGF21 in scribKD cells or loss
of FGFR1 in WT cells suppresses cell competition, suggesting that WT cells
recognize scribKD cells through FGF21. FGF21-containing culture medium of
scribKD cells activates cell motility. Moreover, FGF21 promotes the compression
and elimination of scribKD cells by attracting surrounding WT cells. We also
demonstrate that activation of the apoptosis signal-regulating kinase 1
(ASK1)-p38 pathway in scribKD cells induces FGF21 to drive cell competition. Our
findings reveal a mechanism whereby WT cells mechanically eliminate scribKD
cells and propose a new function for FGF21 in cell-cell communication. Cell competition involves a conserved fitness-sensing process during which
fitter cells eliminate neighbouring less-fit but viable cells1. Cell competition
has been proposed as a surveillance mechanism to ensure normal development and
tissue homeostasis, and has also been suggested to act as a barrier to
interspecies chimerism2. However, cell competition has not been studied in an
interspecies context during early development owing to the lack of an in vitro
model. Here we developed an interspecies pluripotent stem cell (PSC) co-culture
strategy and uncovered a previously unknown mode of cell competition between
species. Interspecies competition between PSCs occurred in primed but not naive
pluripotent cells, and between evolutionarily distant species. By comparative
transcriptome analysis, we found that genes related to the NF-κB signalling
pathway, among others, were upregulated in less-fit 'loser' human cells. Genetic
inactivation of a core component (P65, also known as RELA) and an upstream
regulator (MYD88) of the NF-κB complex in human cells could overcome the
competition between human and mouse PSCs, thereby improving the survival and
chimerism of human cells in early mouse embryos. These insights into cell
competition pave the way for the study of evolutionarily conserved mechanisms
that underlie competitive cell interactions during early mammalian development.
Suppression of interspecies PSC competition may facilitate the generation of
human tissues in animals. At the initial stage of carcinogenesis, cell competition often occurs between
newly emerging transformed cells and the neighboring normal cells, leading to
the elimination of transformed cells from the epithelial layer. For instance,
when RasV12-transformed cells are surrounded by normal cells, RasV12 cells are
apically extruded from the epithelium. However, the underlying mechanisms of
this tumor-suppressive process still remain enigmatic. We first show by electron
microscopic analysis that characteristic finger-like membrane protrusions are
projected from both normal and RasV12 cells at their interface. In addition,
FBP17, a member of the F-BAR proteins, accumulates in RasV12 cells, as well as
surrounding normal cells, which plays a positive role in the formation of
finger-like protrusions and apical elimination of RasV12 cells. Furthermore,
cdc42 acts upstream of these processes. These results suggest that the
cdc42/FBP17 pathway is a crucial trigger of cell competition, inducing
"protrusion to protrusion response" between normal and RasV12-transformed cells. Complex multicellular organisms require quantitative and qualitative assessments
on each of their constitutive cell types to ensure coordinated and cooperative
behavior towards overall functional proficiency. Cell competition represents one
of the operating arms of such quality control mechanisms and relies on fitness
comparison among individual cells. However, what is exactly included in the
fitness equation for each cell type is still uncertain. Evidence will be
discussed to suggest that the ability of the cell to integrate and collaborate
within the organismal community represents an integral part of the best fitness
phenotype. Thus, under normal conditions, cell competition will select against
the emergence of altered cells with disruptive behavior towards tissue integrity
and/or tissue pattern formation. On the other hand, the winner phenotype
prevailing as a result of cell competition does not entail, by itself, any
degree of growth autonomy. While cell competition per se should not be
considered as a biological driving force towards the emergence of the neoplastic
phenotype, it is possible that the molecular machinery involved in the
winner/loser interaction could be hijacked by evolving cancer cell populations. |
What is IDD in relation to organ transplantation? | Imminent death donation (IDD) has been proposed as a separate category of organ donation: distinct from living donation and donation after cardiac death | |
Is METTL3 an m6A writer, reader or eraser? | The methyltransferase METTL3 is an m6A writer. | Author information:
(1)Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key
Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical
Sciences, Division of Life Sciences and Medicine, University of Science and
Technology of China, Hefei, Anhui, 230027, China.
(2)Institute of Immunology, University of Science and Technology of China,
Hefei, Anhui, 230027, China.
(3)Department of Clinical Laboratory, The First Affiliated Hospital of Anhui
Medical University, Hefei, Anhui, 230022, China.
(4)State Key Laboratory of Genetic Engineering, Human Phenome Institute,
Institutes of Biomedical Sciences, School of Life Sciences, Zhongshan Hospital,
Fudan University, Shanghai, 200032, China.
(5)Department of Immunobiology, Yale University School of Medicine, New Haven,
CT, 06520, USA.
(6)Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
(7)Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and
Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai,
200025, China.
(8)Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key
Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical
Sciences, Division of Life Sciences and Medicine, University of Science and
Technology of China, Hefei, Anhui, 230027, China. [email protected].
(9)Institute of Immunology, University of Science and Technology of China,
Hefei, Anhui, 230027, China. [email protected].
(10)Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key
Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical
Sciences, Division of Life Sciences and Medicine, University of Science and
Technology of China, Hefei, Anhui, 230027, China. [email protected].
(11)Institute of Immunology, University of Science and Technology of China,
Hefei, Anhui, 230027, China. [email protected].
(12)Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Hefei,
Anhui, 230027, China. [email protected]. |
What is the 4D nucleome project? | The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized and functions. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Validated experimental technologies will be combined with biophysical approaches to generate quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells. | Author information:
(1)Program in Systems Biology, Department of Biochemistry and Molecular
Pharmacology, University of Massachusetts Medical School, Howard Hughes Medical
Institute, Worcester, Massachusetts 01605, USA.
(2)Department of Cell and Developmental Biology, University of Illinois,
Urbana-Champaign, Illinois 61801, USA.
(3)Division of Biology and Biological Engineering, California Institute of
Technology, Pasadena, California 91125, USA.
(4)Department of Bioengineering, University of California San Diego, La Jolla,
California 92093, USA.
(5)Department of Molecular Biology and Genetics, Cornell University, Ithaca, New
York 14853, USA.
(6)Department of Biochemistry and Molecular Biophysics, Mortimer B. Zuckerman
Mind Brain and Behavior Institute, Columbia University, New York, New York
10027, USA.
(7)Institute for Medical Engineering and Science, and Department of Physics,
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
(8)Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies,
La Jolla, California 92037, USA.
(9)Department of Biomedical Informatics, Harvard Medical School, Boston,
Massachusetts 02115, USA.
(10)Ludwig Institute for Cancer Research, Department of Cellular and Molecular
Medicine, Institute of Genomic Medicine, Moores Cancer Center, University of
California San Diego, La Jolla California 92093, USA.
(11)Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue
North, Seattle, Washington 98109, USA.
(12)Department of Genome Sciences, University of Washington, Howard Hughes
Medical Institute, Seattle, Washington 98109, USA. |
Which drugs were included in the polypill that was tested in TIPS-3 trial? | Polypill tested in the TIPS-3 trial was comprised of atenolol, ramipril, hydrochlorothiazide, and a statin. | BACKGROUND: It is hypothesized that in individuals without clinical
cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction
in CVD risk could be achieved using fixed dose combination (FDC) therapy
(usually comprised of multiple blood-pressure agents and a statin [with or
without aspirin]) in a single "polypill". However, the impact of a polypill in
preventing clinical CV events has not been evaluated in a large randomized
controlled trial.
METHODS: TIPS-3 is a 2x2x2 factorial randomized controlled trial that will
examine the effect of a FDC polypill on major CV outcomes in a primary
prevention population. This study aims to determine whether the Polycap
(comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV
events in persons without a history of CVD, but who are at least at intermediate
CVD risk. Additional interventions in the factorial design of the study will
compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2)
vitamin D versus placebo on the risk of fractures, and (3) the combined effect
of aspirin and the Polycap on CV events.
RESULTS: The study has randomized 5713 participants across 9 countries. Mean age
of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk
score is 16.8, which is consistent with a study population at intermediate CVD
risk.
CONCLUSION: Results of the TIP-3 study will be key to determining the
appropriateness of FDC therapy as a strategy in the global prevention of CVD. |
What is the drug gantenerumab targeting? | Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. | Previous findings from the positron emission tomography (PET) substudy of the
SCarlet RoAD and Marguerite RoAD open-label extension (OLE) showed gantenerumab
doses up to 1200 mg every 4 weeks administered subcutaneously resulted in robust
beta-amyloid (Aβ) plaque removal over 24 months in people with
prodromal-to-moderate Alzheimer's disease (AD). In this 36-month update, we
demonstrate continued reduction, with mean (standard error) centiloid values at
36 months of -4.3 (7.5), 0.8 (6.7), and 4.7 (8.0) in the SCarlet RoAD
(double-blind pooled placebo and active groups), Marguerite RoAD double-blind
placebo, and Marguerite RoAD double-blind active groups respectively,
representing a change of -57.0 (10.3), -90.3 (9.0), and -74.9 (10.5) centiloids
respectively. These results demonstrate that prolonged gantenerumab treatment,
at doses up to 1200 mg, reduces amyloid plaque levels below the amyloid
positivity threshold. The ongoing GRADUATE Phase III trials will evaluate
potential clinical benefits associated with gantenerumab-induced
amyloid-lowering in people with early (prodromal-to-mild) AD. Author information:
(1)Warren Alpert Medical School of Brown University, Providence, RI, USA.
(2)Indiana University School of Medicine, Indianapolis, IN, USA.
(3)Washington University School of Medicine, St. Louis, MO, USA.
(4)Hitchcock Regulatory Consulting, Inc, Fishers, IN, USA.
(5)Icahn School of Medicine at Mount Sinai, New York, NY, USA.
(6)University College London, London, UK.
(7)Centre Hospitalier Universitaire de Rouen, Rouen, France.
(8)University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
(9)Emory University Medical Center, Atlanta, GA, USA.
(10)University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
(11)University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
(12)Yale University School of Medicine, New Haven, CT, USA.
(13)Columbia University Medical Center, New York, NY, USA.
(14)Hospital Clínic i Provincial de Barcelona, August Pi i Sunyer Biomedical
Research Institute-Universitat de Barcelona, Barcelona, Spain.
(15)Neuroscience Research Australia, University of New South Wales Medicine,
Randwick, New South Wales, Australia.
(16)McGill Center for Studies in Aging, McGill University, Montreal, Quebec,
Canada.
(17)University of California San Diego, San Diego, CA, USA.
(18)University of Melbourne, Melbourne, Victoria, Australia.
(19)University of British Columbia, Vancouver, British Columbia, Canada.
(20)University of Washington School of Medicine, Seattle, WA, USA.
(21)Hospices Civils de Lyon, Lyons, France.
(22)Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario,
Canada.
(23)Australian Alzheimer's Research Foundation, University of Western Australia,
Perth, Western Australia, Australia.
(24)Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
(25)Neurological Institute, Salpetriere University Hospital, Paris, France.
(26)Centre Hospitalier Régional Universitaire de Lille, Lille, France.
(27)Mayo Clinic, Rochester, MN, USA.
(28)University of Michigan, Ann Arbor, MI, USA.
(29)University of Rhode Island, Kingston, RI, USA.
(30)Keck School of Medicine, University of Southern California, San Diego, CA,
USA.
(31)Berry Consultants, LLC, Austin, TX, USA.
(32)Eli Lilly and Company, Indianapolis, IN, USA.
(33)F. Hoffmann-La Roche Ltd, Basel, Switzerland.
(34)Washington University School of Medicine, St. Louis, MO, USA.
[email protected].
(#)Contributed equally |
Is Ameloblastoma (AB) a common benign tumor occurring in the brain? | Ameloblastoma (AM) is a slow growing and aggressive benign tumor with an odontogenic epithelial origin arising from the mandible or maxilla. | Ameloblastoma is a histologically benign tumor derived from odontogenic
apparatus. The tumor can infiltrate into surrounding tissues. Although it is
benign, it presents symptoms of a maligt tumor, such as infiltration into the
lungs, pleura, regional and distant metastases, orbit, base of skull, brain and
has resulted in death. It also has a high incidence of recurrences, the
existence of regional or distant metastasis, showing a microscopic pattern of
ameloblastic carcinoma with cytologic features of an increasing
nuclear/cytoplastic ratio, nuclear hyperchromatism, and the presence of mitosis.
We report a study of 12 patients of ameloblastoma of the jaws between January
1992 and December 1996 consisting of 8 affected in the mandible and 4 in the
maxilla. One patient with a tumor in the maxilla was excluded from this study,
due to a different histological and clinical behaviour of the ameloblastoma. OBJECTIVE: Parathyroid hormone-related protein (PTHrP) production has been
demonstrated in a variety of tumor subtypes. Local production of PTHrP by
metastatic tumor cells in bone has been linked to bone destruction and tumor
growth. Ameloblastoma (AB) is a relatively common odontogenic epithelial
neoplasm that manifests local infiltrative intraosseous growth. AB recapitulates
the developing enamel epithelium, in which PTHrP recently has been demonstrated.
Yet PTHrP expression in a series of ABs has not been studied to date. The
purpose of this investigation is to assess the expression of PTHrP in
ameloblastoma.
STUDY DESIGN: Formalin-fixed, paraffin-embedded tissue sections of ameloblastoma
(n = 30; 24 conventional, 4 unicystic, and 2 arising in dentigerous cyst) were
immunostained with anti-PTHrP antibody using a multistep streptavidin-peroxidase
technique. Semiquantitative scoring of immunoreactivity was assessed as mild,
moderate, and intense.
RESULTS: All cases (100%) demonstrated positive immunoreactivity, with mild
reaction in 3 conventional ABs, 1 unicystic and 1 AB arising in dentigerous
cyst, and with moderate reaction in 12 conventional ABs, 3 unicystic and 1 AB
arising in dentigerous cyst. Intense immunoreactivity was seen in 9 cases of
conventional AB. This difference in immunostaining was not statistically
significant (Sigma2 = 4.41, df = 4, P = .358).
CONCLUSION: The results of this investigation suggest that PTHrP may play a
significant role in local bone resorption, offering at least partial explanation
for the tumor's infiltrative growth and destructive behavior. The uniformity of
PTHrP expression by AB, as detailed in this study, may harbor significant
therapeutic implications, particularly through PTHrP-blocking treatment
modalities. Ameloblastomas are histologically benign tumors derived from the odontogenic
apparatus. Although these tumors are locally invasive, they rarely invade the
paranasal sinuses, orbits, or intracranial cavity, and, thus, they rarely
produce ophthalmologic signs and symptoms. In this report, we describe the
neuro-ophthalmologic features of three patients with chronically aggressive
ameloblastoma. Two of the patients developed a progressive and recurrent orbital
apex and cavernous sinus syndromes. One of these patients is, to our knowledge,
the first patient described with orbital and cavernous simus involvement by an
ameloblastoma initially arising in the mandible. The other is only the second
case described with bilateral orbital involvement. The third patient in this
series developed a trigeminal sensory neuropathy as the only sign of the tumor.
Although ameloblastomas are benign, slowly growing tumors, they may, often over
a long period of time, cause significant neuro-ophthalmologic and orbital
manifestutions that can only be partially ameliorated by surgery. BACKGROUND: Ameloblastoma is a frequent odontogenic benign tumor characterized
by local invasiveness, high risk of recurrence and occasional metastasis and
maligt transformation. Matrix metalloproteinase-2 (MMP-2) promotes tumor
invasion and progression by destroying the extracellular matrix (ECM) and
basement membrane. For this proteolytic activity, the endogenous inhibitor is
reversion-inducing cysteine rich protein with Kazal motifs (RECK). The aim of
this study was to characterize the relationship between RECK and MMP-2
expression and the clinical manifestation of ameloblastoma.
METHODS: Immunohistochemistry and reverse transcription-polymerase chain
reaction (RT-PCR) were employed to detect the protein and mRNA expression of
RECK and MMP-2 in keratocystic odontogenic tumor (KCOT), ameloblastoma and
ameloblastic carcinoma.
RESULTS: RECK protein expression was significantly reduced in KCOT (87.5%),
ameloblastoma (56.5%) and ameloblastic carcinoma (0%) (P < 0.01), and was
significantly lower in recurrent ameloblastoma compared with primary
ameloblastoma (P < 0.01), but did not differ by histological type of
ameloblastoma. MMP-2 protein expression was significantly higher in
ameloblastoma and ameloblastic carcinoma compared with KCOT (P < 0.01). RECK
mRNA expression was significantly lower in ameloblastoma than in KCOT (P <
0.01), lower in recurrent ameloblastoma than in primary ameloblastoma, and was
negative in ameloblastic carcinoma. MMP-2 mRNA expression was significantly
higher in ameloblastoma compared with KCOT (P < 0.01), but was no different in
recurrent ameloblastoma versus primary ameloblastoma. RECK protein expression
was negatively associated with MMP-2 protein expression in ameloblastoma (r =
-0.431, P < 0.01).
CONCLUSION: Low or no RECK expression and increased MMP-2 expression may be
associated with negative clinical findings in ameloblastoma. RECK may
participate in the invasion, recurrence and maligt transformation of
ameloblastoma by regulating MMP-2 at the post-transcriptional level. BACKGROUND: Ameloblastoma is a benign odontogenic tumor, exhibiting local
invasiveness and high rate of recurrence. Metallothionein is a protein
associated with tumorigenesis, serving as prognostic factor in different
neoplasms. We are interested in mechanisms underlying ameloblastoma local
invasiveness. Thus, we decided to analyze expression of metallothionein in this
tumor.
MATERIALS AND METHODS: An immunohistochemical evaluation of metallothionein in
ameloblastoma was carried out. As control, we assessed expression of the same
molecule in calcifying cystic odontogenic tumor (CCOT), a non-invasive
odontogenic neoplasm with ameloblastomatous epithelium.
RESULTS: We studied 12 cases of solid/multicystic ameloblastomas.
Metallothionein was observed in all samples. This molecule was observed in
columnar cells in the periphery and in central polyhedral cells. CCOT (four
cases) also showed the presence of metallothionein. Morphometry of stained areas
showed that expression of metallothionein in ameloblastoma was significantly
higher compared to CCOT (P < 0.0001).
CONCLUSIONS: This protein may have an impact on ameloblastoma behavior.
Metallothionein would act as a zinc reservoir for important proteases related to
ameloblastoma biology, such as MMPs. This protein could also display pro-mitotic
and anti-apoptotic features in the tumor. Ameloblastoma (AB), which is the most common odontogenic tumor, may originate
from the dental lamina remts. The expression of CD56, which is a
transmembrane molecule, is associated with neuroectodermal differentiation of
the embryonal cells. The aim of this study was to evaluate the expression of
CD56 in AB, in comparison with other odontogenic cysts. We used formalin-fixed,
paraffi n-embedded specimens from 34 cases of AB, 10 cases of keratocystic
odontogenic tumor (KCOT), and 7 cases of dentigerous cyst (DC). We
immunohistochemically examined CD56, NeuroD1, and N-cadherin expression in these
tumors as compared with the expression patterns of various epithelial markers.
Seventy-four percent of AB showed immunopositivity for CD56, and both CD56 and
N-cadherin were diffusely positive in the outer columnar cells of AB. The
immunopositivities for NeuroD1 and N-cadherin were also observed in the outer
cells of AB. None of the DC cases was positive for CD56, whereas half the cases
of KCOT were positive. Because CD56 is expressed in the inner enamel epithelium
of enamel organs, the outer columnar cells of AB are likely to be the
differentiation phenotype of the inner enamel epithelium, which is associated
with neuroectodermal differentiation. The aberrant NeuroD1 expression may induce
CD56 expression in AB and KCOT. BACKGROUND: Ameloblastoma is a rare benign odontogenic tumor with locally
aggressive behavior and a high recurrence rate. When metastases occur, which are
uncommon, lungs constitute the most frequent site involved. Maligt
ameloblastomas are different from ameloblastic carcinomas. Maligt
ameloblastomas are tumors considered metastatic despite the appearance of
well-differentiated or benign histology, while ameloblastic carcinomas are
histologically maligt in both primary and metastatic sites.
CASE PRESENTATION: A 24-year-old Moroccan man presented a maligt
ameloblastoma of the mandible. The tumor was entirely resected. Five years
later, a local recurrence occurred. Our patient was treated by exclusive
radiotherapy with persistence of a residual disease. After two years he
developed multiple lung metastases. Our patient received a combination
chemotherapy using doxorubicin and cisplatin.
CONCLUSION: Less than 50 cases of ameloblastoma with metastases have been
reported. There is still no standard treatment for metastatic ameloblastoma.
Only through continuous reporting of such cases will clinicians be able to draw
an optimal strategy for management of this pathology. The ameloblastoma is a benign but aggressive neoplasm of odontogenic origin.
However, no enamel or hard tissue is formed by the tumor cells. Ameloblastomas
are infamous for their invasive growth and their tendency to recur. Robinson
(1937) as a benign tumor that is 'usually unicentric, nonfunctional,
intermittent in growth, anatomically benign and clinically persistent.' They may
occur at any age, even though nearly half of the tumors do occur between the
ages of 20 and 40 years. This is the most common neoplasm affecting the jaws,
yet only accounts for 1% of all tumors of the maxilla and mandible and 11% of
all odontogenic tumors. This report presents a case of ameloblastoma involving
entire ramus and part of body of mandible with resorption of the mesial and
distal root apices of second molar and distal root of mandibular first molar.
The lesion extending till the base of mandible surrounding the crown of the
unerupted third molar resembling the dentigerous cyst. This was surgically
resected followed by harvesting the contralateral sixth costochondral rib graft.
How to cite this article: Celur S, Babu KS. Plexiform Ameloblastoma. Int J Clin
Pediatr Dent 2012;5(1):78-83. Ameloblastoma or adamantinoma is the rarest of the three forms of tumor of the
odontogenic type. They are benign, locally aggressive neoplasms arising from
ameloblasts, which typically occur at the angle of the mandible, and are often
associated with an un-erupted tooth and must, therefore, be differentiated from
a dentigerous cyst which will be centered on the crown. When in the maxilla
(less common), they are located in the premolar region, and can extend up in the
maxillary sinus. Ameloblastoma is reported to constitute about 1-3% of tumors
and cysts of the jaws. The tumor is by far more common in the mandible than in
the maxilla and shows predilection for various parts of the mandible in
different racial groups. The relative frequency of the mandible to maxilla is
reported as varying from 80-20% to 99-1%. Here, we are representing a case of
ameloblastoma of anterior mandible which was considered as a rare site of
occurrence. Ameloblastoma is the most common aggressive benign odontogenic tumor of the
jaws. Ameloblastoma is a benign epithelial odontogenic tumor that typically
arises in the mandible or maxilla or, rarely, in the immediate adjacent soft
tissues. A clinical, radiographic and histopathological report is presented of a
case of acanthomatous ameloblastoma in relation to molar in the left mandible of
a 30-year-old healthy male. The histopathological examination of the removed
specimen revealed the histopathological pattern of an acanthomatous
ameloblastoma. The radiographic appearance of the lesion showed the presence of
multilocular radiolucencies, which were crossing the midline, which is rarely
found in ameloblastoma. Due to its rarity and lack of data, we take this
opportunity to present a world first case of acanthomatous ameloblastoma which
was crossing the midline. Ameloblastoma is a benign odontogenic tumor generally present in the jaw bone.
The tumor originates from the residual epithelium of the tooth germ, epithelium
of odontogenic cysts stratified squamous epithelium and epithelium of the enamel
organ. It represents approximately 1% of oral tumors. About 80% of
ameloblastomas occur in the mandible mainly the third molar region and the
remaining 20% in the upper jaw. Ameloblastoma clinically appears as an
aggressive odontogenic tumor, often asymptomatic and slow-growing, with no
evidence of swelling. This article deals with a complete review on
ameloblastoma. BACKGROUND: The ameloblastoma is the most common odontogenic epithelial tumor,
which belong to benign neoplasms that present a painless course, and usually
occur in the oromaxillo-facial region. Although the histopathological
manifestation of ameloblastoma is benign, it has unique biological behavior, for
example local invasion and recurrence repeatedly. A few case of ameloblastoma
was locally aggressive growth, and rarely metastasis to other tissue, for
example the lungs, lymph nodes, and spine.
CASE REPORT: A 64-year-old Chinese man, diagnosed with metastatic ameloblastoma,
was treated with palliative chemotherapy consisting of cyclophosphamide,
doxorubicin, and cisplatin for six cycles, and radiotherapy for 50 Gy after the
last cycle chemotherapy. During the surveillance CT scan after the therapy, the
tissues of the tumor were nearly complete response.
CONCLUSION: The purpose of this study was to report a case of a patient with a
right mandible ameloblastoma that recurred repeatedly and metastasized into
bilateral lung. After the chemotherapy and radiotherapy, the tissues of the
tumor were nearly complete response. This case is interesting because it
investigated the diagnosis and treatment of the maligcy ameloblastoma, as
this may help diagnose and treatment for clinician to the metastatic
ameloblastoma. Ameloblastoma is the most common epithelial odontogenic tumor. It may show
locally invasive behavior resulting in recurrence and maligcy. Therefore,
appropriate diagnosis of this tumor is necessary. The aim of this study was to
evaluate clinicopathological characteristics of ameloblastomas in an Iranian
population. We present a 40-year retrospective study of patients diagnosed from
1971 to 2010 in the Department of Oral and Maxillofacial Pathology, Faculty of
Dentistry, Mashhad, Iran. Information gathered from patient records included
age, gender, tumor location and histologic type. The frequency of odontogenic
tumors among all lesions was 2.08% and ameloblastoma with 88 samples
demonstrated the greatest prevalence (41.5%). Regarding gender, 60% of samples
occurred in males. The mean age of studied patients was 33.02± 15.74 years with
a peak of occurrence in the third decade of life. The most frequent location of
tumor was the mandibles (93.2%). Eighty five (96.6%) tumors were recorded as
benign and 3 (3.4%) as maligt. Of benign tumors, 62 (72.9%), 20 (23.5%) and 3
(3.6%) cases were of conventional, unicyctic and peripheral types, respectively.
In contrast to most previous studies, the most common histologic subtype in the
present study was plexiform. Knowledge of the incidence of ameloblastoma and its
clinicopathologic features including most common location, gender and age
distribution in different ethnogeographic backgrounds is necessary for accurate
diagnosis and proper treatment. BACKGROUND AND OVERVIEW: Ameloblastoma is an odontogenic tumor predomitly
occurring in patients who are in their 20s and 30s. Approximately 10% to 15% of
ameloblastomas occur in patients younger than 18 years. Although it is a benign
tumor, an ameloblastoma can have a devastating effect on children both
physically and emotionally. The aim of this case report is to demonstrate how
tissue engineering and surgical techniques can minimize morbidity and recovery
time after extirpation and immediate reconstruction of a mandibular
ameloblastoma.
CASE DESCRIPTION: An 11-year-old girl was referred for surgical evaluation of a
lesion found on a routine dental radiograph. Resection of a mandibular unicystic
ameloblastoma resulted, including immediate reconstruction using a costochondral
rib graft, allogeneic bone, bone marrow aspirate concentrate, and recombit
human morphogenetic protein-2. One year postoperatively, the patient had no
evidence of recurrence as well as excellent mandibular bone height and width
with good facial form. The patient has returned to her daily life without any
disabilities or disfigurement.
CONCLUSIONS AND PRACTICAL IMPLICATIONS: Dentists are typically the first health
care providers to discover oral pathology in patients. The coordination of care
by the dental care providers and the oral and maxillofacial specialist was key
to the successful outcome for this patient. With biotechnology and surgical
techniques, the dental surgeon can extirpate an ameloblastoma and reconstruct
the mandible defect to the ideal shape and size with minimal morbidity and
recovery time. Ameloblastoma is the second most common benign epithelial odontogenic tumor and
though it is of a benign nature, it is locally invasive, has a high recurrence
rate and could potentially become maligt. Many theories have been proposed to
explain the pathogenesis of ameloblastoma. Proper understanding of the
pathogenic mechanism involved in ameloblastoma and its proliferation aids in
constituting proper treatment of choice at an early stage, preventing morbidity
associated with extensive therapy. An attempt has been made to discuss the
current concepts related to molecular and genetic changes that occur in
ameloblastoma as these could affect treatment plan and prognosis. OBJECTIVE AND IMPORTANCE: Ameloblastoma is a locally aggressive benign tumor,
commonly occurring in the mandible. While giant ameloblastoma of multicystic or
plexiform variant have been reported, the authors report a rare case of giant
unicystic ameloblastoma of luminal variant, which was treated by compartmental
resection and planned for delayed reconstruction.
CLINICAL PRESENTATION: A 46 year old male patient reported to the oral surgery
out-patient department with a swelling of the left side mandible region of
2 years duration. He had undergone ayurvedic treatment for the same with no
improvement. The size of the lesion on presenting was approximately 9 × 12 cm.
INTERVENTION: Compartmental resection with plan for secondary reconstruction,
after adequate follow up period.
CONCLUSION: While conservative management is being explored as a treatment
option for unicystic ameloblastoma, resection is still the standard of care
regardless of the histopathological subtype for giant lesions. Ameloblastoma is a rare odontogenic tumor of the jaw. It is a benign neoplasm
but local recurrence is common. Metastasis from this tumor is all the more rare.
The commonest site for metastasis is lung. Brain is a very uncommon site of
involvement. Overall prognosis is good. We hereby discuss ameloblastoma of lower
jaw in a young adult which had metastasized to brain. Patient was operated for
the metastatic lesion of brain and is doing well on follow-up. Ameloblastoma is a locally aggressive tumor derived from odontogenic epithelium.
Although benign, its clinical behavior can often exhibit maligt
characteristics. It is marked by slow and persistent growth with infiltration of
adjacent tissues. Almost 70% occur in the mandible in patients older than
30 years. Recurrence of ameloblastoma from inadequate treatment is frequent.
Because of its slow growth, recurrences can present decades after primary
surgery. A primary ameloblastoma in an area outside the mandibular, maxillary,
and infratemporal fossa regions has not been described in detail to date, with
only 1 possible case mentioned in the literature. The authors present a case of
primary temporal bone ameloblastoma in a 17-year-old boy. The tumor originated
in the left mastoid, infiltrated the lateral semicircular canal, facial nerve,
and cochlea, and adhered to the sigmoid sinus and posterior cranial fossa dura.
Although invasion of multiple structures in the infratemporal fossa and temporal
bone leads to variable disease presentation, this case is unique because the
first symptom of disease was sudden and recurring unilateral sensorineural
hearing loss. Surgery required transection of the facial nerve. Histopathology
confirmed primary temporal bone ameloblastoma. The difficulties in achieving
wide surgical margins, diagnostics, and further management are addressed. BACKGROUND: Ameloblastoma is a neoplasm classified as a benign epithelial
odontogenic tumor of the jaws, grow slowly and are locally invasive. The aim of
the present study was to investigate the incidence, treatment, and complication
of patients with ameloblastoma in East-Indonesia during six years retrospective
study.
MATERIAL AND METHODS: This retrospective study included 84 patients who were
diagnosed with ameloblastoma from 2011 to 2016. There were 56 patients with
treatment data available. Data from each patient, including gender, age,
histologic type, the size of the tumor, radiologic form, tumor location, type of
treatment, and complication were reviewed and analyzed retrospectively.
RESULTS: Fourteen patients were diagnosed with unicystic ameloblastoma (25%),
thirty two patients with multicystic follicular ameloblastoma (57%) and ten
patients with an unspecified multicystic ameloblastoma (18%). A total of about
35 patients were treated conservatively (62.5%) and 21 patients were treated
radically (37.5%). Swelling was present as a pre-operative complication in all
56 cases (100%). There were no complaints concerning speech.
CONCLUSIONS: The majority findings of the histologic type were multicystic
ameloblastoma and their location were in the mandible. Most ameloblastoma were
treated conservatively and reconstructions were made with only titanium plates
and not bone graft. Ameloblastoma(AB) is an aggressive and slow-growing tumor with high recurrence
rate, which arises from odontogenic epithelium. AB mostly shows osteolytic
growth, but the specific pathogenesis is not yet clear. Periostin is a
considered a prominent oncogene, which was mainly produced by osteoblasts and
their precursors cells, it have been proved that Periostin play an important
role in bone lysis. However, the precise role of Periostin in AB progression
remains unknown. In this article, the surgical specimens from cases of AB were
collected, and the Periostin expression was tested and the results were analyzed
for possible correlations with clinical characteristics. In addition, the
proliferation、cell cycle and migration of AM-1 cells were evaluated after
transfection of siPeriostin. The results showed that Periostin levels were
significantly higher in patients with AB than in controls. Moreover, Periostin
levels in patients with AB were significantly associated with the number of
disease. Furthermore, the results suggested that Periostin expression
significantly promoted the proliferation and migration, in addition to cell
cycle progression of AM-1 cells. The present study demonstrated that Periostin
may be important in the pathogenesis and progression of AB and indicated its
potential therapeutic value. Author information:
(1)Professor & Head, Department of Oral Pathology, Faculty of Dental Sciences,
Sri Ramachandra Institute of Higher Education & Research (DU), Porur, Chennai,
India.
(2)Professor, Department of Oral & Maxillofacial Surgery, Faculty of Dental
Sciences, Sri Ramachandra Institute of Higher Education & Research (DU), Porur,
Chennai, India.
(3)Assoc. Professor, Department of Oral &Maxillofacial Surgery, Faculty of
Dental Sciences, Sri Ramachandra Institute of Higher Education & Research (DU),
Porur, Chennai, India.
(4)Senior Lecturer in Oral Pathology, Department of Oral &Maxillofacial Surgery,
Faculty of Dental Sciences, Sri Ramachandra Institute of Higher Education &
Research (DU), Porur, Chennai, India.
(5)Professor, Department of Oral Pathology, Faculty of Dental Sciences, Sri
Ramachandra Institute of Higher Education & Research (DU), Porur, Chennai,
India. Ameloblastic carcinoma (AC) is defined as a rare primary epithelial odontogenic
maligt neoplasm and the maligt counterpart of benign epithelial
odontogenic tumor of ameloblastoma (AB) by the WHO classification. AC develops
pulmonary metastasis in about one third of the patients and reveals a poor
prognosis. However, the mechanisms of AC oncogenesis remain unclear. In this
report, we aimed to clarify the mechanisms of maligt transformation of AB or
AC carcinogenesis. The relatively important genes in the maligt
transformation of AB were screened by DNA microarray analysis, and the
expression and localization of related proteins were examined by
immunohistochemistry using samples of AB and secondary AC. Two genes of
hypoxia-inducible factor 1 alpha subunit (HIF1A) and zinc finger E-box-binding
homeobox 1 (ZEB1) were significantly and relatively upregulated in AC than in
AB. Both genes were closely related in hypoxia and epithelial-mesenchymal
transition (EMT). In addition, expressions of HIF-1α and ZEB1 proteins were
significantly stronger in AC than in AB. In the cell assays using ameloblastoma
cell line, AM-1, hypoxia condition upregulated the expression of transforming
growth factor-β (TGF-β) and induced EMT. Furthermore, the hypoxia-induced
morphological change and cell migration ability were inhibited by an
antiallergic medicine tranilast. Finally, we concluded that hypoxia-induced
HIF-1α and ZEB1 were critical for the maligt transformation of AB via
TGF-β-dependent EMT. Then, both HIF-1α and ZEB1 could be potential biomarkers to
predict the maligt transformation of AB. BACKGROUND Ameloblastoma (AB) is a common odontogenic epithelial tumor, with
locally invasive behavior and high recurrence. In this study, we hypothesized
that miR-524-5p could be involved in the tumor microenvironment by targeting
interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) in AB. MATERIAL AND
METHODS The microRNA (miRNA) expression profile of AB tissues and normal oral
mucosa tissues (NOM; 6 paired samples) was analyzed. The miRNAs with fold change
≥2 and P<0.05 were considered to be differentially expressed. Among them,
downregulated miR-524-5p was verified by real-time qPCR. Potential targets of
miR-524-5p were predicted by bioinformatics analysis. The expression levels of
target genes were detected using real-time qPCR and Western blot, respectively.
Immunohistochemistry analysis of target genes was performed, and we also
assessed the correlation between miR-524-5p and its target. RESULTS Microarray
analysis results first indicated miR-524-5p is a downregulated miRNA in AB
tissues. Real-time qPCR results confirmed the expression pattern of miR-524-5p
in AB tissues. Moreover, IL-33 and its receptor ST2 were significantly
overexpressed. As shown in immunohistochemistry results, IL-33 was positively
expressed in lymphocytes and plasma cells, suggesting that IL-33/ST2
participates in tumor immune responses in the tumor microenvironment.
Correlation analysis suggested that miR-524-5p expression was negatively
correlated with IL-33/ST2. CONCLUSIONS Our findings reveal that downregulated
miR-524-5p can participate in the tumor microenvironment of AB by targeting the
IL-33/ST2 axis. Ameloblastoma is a benign odontogenic tumor which undergoes maligt
transformation to ameloblastic carcinoma. However, rarely it metastasizes
without undergoing cytological maligt changes, an entity referred to as
Metastasizing Ameloblastoma (MA). Through this study, we aimed to review cases
of MA reported since 2000 to explore the impact of clinico-demographic variables
on its prognosis. Based on PRISMA guidelines, a review of relevant literature
from PubMed/Medline, Science Direct and Cochrane database was performed from
January 2000 to March 2019. A total of 65 cases were considered for further
evaluation as per predefined inclusion and exclusion criteria. Results showed
that lungs followed by lymph nodes were the most common sites for benign
metastatic deposits. Multiple recurrences and inadequate surgical removal
increase the probability of distant metastatic spread. Despite having benign
cytological features, tumor recurrence and metastasis were associated with an
unfavorable clinical outcome in MA. Ameloblastoma is a benign locally invasive odontogenic tumor. It is the most
common odontogenic tumor [1]. Usually, in the middle-aged population, it is more
common in the mandible with about 5-20% occurring in the maxilla. We report a
case of maxillary unicystic ameloblastoma in a 3.5-year-old girl. Which
presented clinically as a large facial swelling causing severe facial
deformation and pressure symptoms on the left eye. CT scan showed that the
swelling extended to involve the orbital floor. The lesion was diagnosed and
confirmed by incisional biopsy then was successfully managed by maxillectomy and
immediate reconstruction using the buccal pad of fat. One year follow up with no
further complaints and no recurrence was observed. "Written informed consent was
obtained from the patient guardians for publication of this case report and
accompanying images. A copy of the written consent is available for review by
the Editor-in-Chief of this journal on request". Ameloblastoma (AB) is the most common benign epithelial odontogenic tumor
occurring in the jawbone. AB is a slowly growing tumor but sometimes shows a
locally invasive and an aggressive growth pattern with a marked bone resorption.
In addition, the local recurrence and distant metastasis of AB also sometimes
occurs, which resembles one of the typical maligt potentials. From these
points of view, to understand better the mechanisms of AB cell migration or
invasion is necessary for the better clinical therapy and improvements of the
patients' quality of life. Microtubules in eukaryotic cells reveal the shape of
hollow cylinders made up of polymerized alpha (α)- and beta (β)-tubulin dimers
and form the cytoskeleton together with microfilaments and intermediate
filaments. Microtubules play important roles in cell migration by undergoing
assembly and disassembly with post-translational modifications. Stability of
microtubules caused by their acetylation is involved in cell migration. In this
study, we investigated the expression and distribution of acetylated α-tubulin
and alpha-tubulin N-acetyltransferase 1 (αTAT1), an enzyme which acetylates
Lys-40 in α-tubulin, in AB specimens, and analyzed how tubulin was acetylated by
αTAT1 activation in a human AB cell line, AM-1. Finally, we clarified that
TGF-β-activated kinase1 (TAK1) was phosphorylated by TGF-β stimulation, then,
induced tubulin acetylation via αTAT1 activation, which subsequently activated
the migration and invasion of AB cells. Ameloblastomas are benign tumors that most commonly affecting the mandible. The
current standard of treatment for ameloblastomas is resection followed by
reconstruction that has historically been accomplished through the use of a
microsurgical vascularized flaps taken from the iliac crest or fibula.
Alloplastic reconstruction methods have gained popularity over recent years with
success reported in the reconstruction of many pathologies, including ankylosis,
condylar fracture, neoplasia involving extensive resection, severe
inflammatory/degenerative temporomandibular joint (TMJ) disease, and congenital
TMJ abnormalities. The authors present a patient who successfully underwent
ameloblastoma resection and TMJ reconstruction with a custom TMJ Concepts
alloplastic implant. The authors also present a review of the literature on
alloplastic TMJ reconstruction following ameloblastoma resection. To our
knowledge, this is the second report in the literature on the use of a TMJ
Concepts implant after ameloblastoma resection. Author information:
(1)Department of Oral Biology and Oral Pathology, School of Dentistry, Faculty
of Health Sciences, University of Pretoria, Pretoria, South Africa.
(2)Department of Oral Biology and Oral Pathology, School of Dentistry, Faculty
of Health Sciences, University of Pretoria, Pretoria, South Africa; Department
of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de
Minas Gerais, Belo Horizonte, Brazil.
(3)Department of Oral Surgery and Diagnosis, Odilon Behrens Hospital, Belo
Horizonte, Brazil.
(4)Department of Oral Biology and Oral Pathology, School of Dentistry, Faculty
of Health Sciences, University of Pretoria, Pretoria, South Africa. Electronic
address: [email protected]. |
In which aspects of the immune response is m6A methylation implicated? | m6A is a novel regulator of immune system homeostasis and activation. m6A modifications and m6A modifying proteins play a critical role in pathogen recognition, immune cell activation, immune cell fate decisions, and immune reactions. These modifications modulate the fate decisions of innate and adaptive immune cells and regulate immune responses in immune-associated diseases, including viral infections and cancer. | N6 -methyladenosine (m6 A) RNA methylation is a reversible posttranscriptional
modification in eukaryotes involving three types of functional proteins:
"writers", "erasers", and "readers". m6 A regulates the metabolism of messenger
RNAs and noncoding RNAs through RNA structure, splicing, stability, export, and
translation, thereby participating in various physiological and pathological
processes. Here, we summarize the current state of m6 A methylation researches,
focusing on how these modifications modulate the fate decisions of innate and
adaptive immune cells and regulate immune responses in immune-associated
diseases, including viral infections and cancer. These studies showed that m6 A
modifications and m6 A modifying proteins play a critical role in pathogen
recognition, immune cell activation, immune cell fate decisions, and immune
reactions. m6 A is a novel regulator of immune system homeostasis and
activation. |
Describe nextNEOpi | NextNEOpi is a comprehensive and fully-automated bioinformatic pipeline to predict tumor neoantigens from raw DNA and RNA sequencing data. In addition, nextNEOpi quantifies neoepitope- and patient-specific features associated with tumor immunogenicity and response to immunotherapy. | SUMMARY: Somatic mutations and gene fusions can produce immunogenic neoantigens
mediating anticancer immune responses. However, their computational prediction
from sequencing data requires complex computational workflows to identify
tumor-specific aberrations, derive the resulting peptides, infer patients' Human
Leukocyte Antigen types and predict neoepitopes binding to them, together with a
set of features underlying their immunogenicity. Here, we present nextNEOpi
(nextflow NEOantigen prediction pipeline) a comprehensive and fully automated
bioinformatic pipeline to predict tumor neoantigens from raw DNA and RNA
sequencing data. In addition, nextNEOpi quantifies neoepitope- and
patient-specific features associated with tumor immunogenicity and response to
immunotherapy.
AVAILABILITY AND IMPLEMENTATION: nextNEOpi source code and documentation are
available at https://github.com/icbi-lab/nextNEOpi.
CONTACT: [email protected] or [email protected].
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online. |
What is the use of the ATRIA score? | ATRIA score determines bleeding risk for patients on warfarin. | BACKGROUND: Clinical guidelines recommend oral anticoagulation for stroke
prevention in patients with atrial fibrillation (AF) at moderate or high risk
for stroke but not at high risk for bleeding; however, studies consistently
report suboptimal use of such therapy. This study used Medicare Part D claims
data to assess the use of warfarin in the Medicare population.
OBJECTIVES: To compare real-world warfarin utilization with current treatment
guideline recommendations, and to assess the effect of warfarin exposure level
on patient outcomes in Medicare beneficiaries with nonvalvular AF (NVAF).
METHODS: Patients who were recently diagnosed with NVAF were identified using a
random 5% sample of Research Identifiable Files of Medicare beneficiaries in
2006 or 2007. Individuals with moderate-to-high stroke risk per CHADS2 but not
at high bleeding risk per ATRIA (Anticoagulation and Risk Factors in Atrial
Fibrillation) bleeding risk score were evaluated for warfarin use, as identified
by the presence of ≥1 warfarin prescription claims within 12 months after the
index diagnosis. Warfarin exposure level was assessed by the proportion of days
covered during the 12-month follow-up period. The effect of warfarin exposure on
ischemic stroke and major bleeding event rates during the 12-month follow-up
period were assessed using multivariate logistic regression.
RESULTS: Data from 14,149 newly diagnosed patients with NVAF (mean age, 79
years; 58.7% female) were analyzed, and of these, 7524 (53.2%) patients were
identified as having moderate-to-high stroke risk and not being at high bleeding
risk. Of these patients, 3110 (41.3%) did not receive warfarin within 12 months
of the index diagnosis. The risk for ischemic stroke was significantly lower in
those with warfarin exposure versus no warfarin exposure (adjusted odds ratio
[OR], 0.51; confidence interval [CI], 0.43-0.61; P <.001) and in patients with
warfarin proportion of days covered ≥80% versus those with proportion of days
covered <80% (adjusted OR, 0.59; 95% CI, 0.48-0.72; P<.001). Warfarin exposure
was associated with a significantly higher major bleeding rate (adjusted OR,
1.19; 95% CI, 1.04-1.36; P = .013), with this significant difference being
driven by patients aged >65 years.
CONCLUSIONS: Based on a risk-stratification scheme composed of previously
published tools, such as CHADS2 and the ATRIA bleeding risk index, a significant
proportion of Medicare beneficiaries with AF are not receiving
guideline-recommended anticoagulation therapy, which leads to an excess rate of
ischemic stroke in this patient population. These findings highlight
quality-of-care issues for patients with AF and the need to improve compliance
with anticoagulation guidelines in the Medicare population. PURPOSE: To evaluate the outcome of patients with an established indication for
oral anticoagulation (OAC) undergoing coronary stent implantation (PCI-S) and
stratified by the baseline risk of bleeding.
MATERIAL AND METHODS: The database of the prospective, multicentre,
observational WAR-STENT registry (ClinicalTrials.gov identifier NCT00722319) was
analyzed and patients with atrial fibrillation and CHA2DS2-VASc score ≥2,
mechanical heart valve, prior cardiac embolism, intra-cardiac thrombus and
recent venous thromboembolism who were treated with either triple (warfarin,
aspirin and clopidogrel) or dual (warfarin and clopidogrel) or dual antiplatelet
(aspirin and clopidogrel) therapy, identified. Patients were then sorted into
two groups at non-low and low risk of bleeding, as defined by an ATRIA score >3
and ≤3 respectively, and compared regarding major adverse cardiac and vascular
events (MACVE) and bleeding.
RESULTS: At 12-month follow up, MACVE were comparable in the two groups, whereas
total, major and minor bleeding, as well as combined MACVE and total bleeding,
were significantly more frequent in the non-low bleeding risk group. Upon Cox
univariate and multivariable analysis, non-low bleeding risk category confirmed
as an independent predictor of major bleeding. The choice of antithrombotic
therapy however, appeared not to be influenced by the bleeding risk category at
baseline.
CONCLUSIONS: In patients with an established indication for OAC undergoing
PCI-S, non-low bleeding risk category is the most potent independent predictor
of major bleeding. Stratification of the bleeding risk at baseline should
therefore be regarded as an indispensable process to be carried out before
selection of the antithrombotic therapy. WHAT IS KNOWN AND OBJECTIVE: Bleeding risk scores (BRSs) aid in the assessment
of oral anticoagulant-related bleeding risk in patients with atrial
fibrillation. Ideally, the applicability of a BRS needs to be assessed, prior to
its routine use in a population other than the original derivation cohort.
Therefore, we evaluated the performance of 6 established BRSs to predict major
or clinically relevant bleeding (CRB) events associated with the use of oral
anticoagulant (OAC) among Malaysian patients.
METHODS: The pharmacy supply database and the medical records of patients with
non-valvular atrial fibrillation (NVAF) receiving warfarin, dabigatran or
rivaroxaban at two tertiary hospitals were reviewed. Patients who experienced an
OAC-associated major or CRB event within 12 months of follow-up, or who have
received OAC therapy for at least 1 year, were identified. The BRSs were fitted
separately into patient data. The discrimination and the calibration of these
BRSs as well as the factors associated with bleeding events were then assessed.
RESULTS: A total of 1017 patients with at least 1-year follow-up period, or
those who developed a bleeding event within 1 year of OAC use, were recruited.
Of which, 23 patients experienced a first major bleeding event, whereas 76
patients, a first CRB event. Multivariate logistic regression results show that
age of 75 or older, prior bleeding and male gender are associated with major
bleeding events. On the other hand, prior gastrointestinal bleeding, a
haematocrit value of less than 30% and renal impairment are independent
predictors of CRB events. All the BRSs show a satisfactory calibration for major
and CRB events. Among these BRSs, only HEMORR2 HAGES (C-statistic = 0.71, 95% CI
0.60-0.82, P < .001) and ATRIA score (C-statistic = 0.70, 95% CI 0.58-0.82,
P < .001) show acceptable discrimination performance for major bleeding events.
All the 6 BRSs, however, lack acceptable predictive performance for CRB events.
WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first
evaluation study of the predictive performance of these 6 BRSs on clinically
relevant bleeding events applied to the same cohort consisting of mainly Asian
novel oral anticoagulant users. These BRSs show poor to acceptable predictive
performance on OAC-induced major or CRB events. An improvement in the existing
BRSs for OAC users is warranted. BACKGROUND: Various bleeding risk scores have been proposed to assess the risk
of bleeding in patients with atrial fibrillation taking oral anticoagulants.
Limited data are available with these scores, in users of non-vitamin K
antagonist oral anticoagulants.
METHODS: Using the Danish registries, we evaluated and compared the risk
classification properties of the Hypertension, Age, Stroke, Bleeding
tendency/predisposition, Labile international normalized ratios, Elderly
age/frailty, Drugs such as concomitant aspirin/nonsteroidal anti-inflammatory
drugs or alcohol excess (HAS-BLED), Anticoagulation and Risk Factors in Atrial
Fibrillation (ATRIA), and Outcomes Registry for Better Informed Treatment of
Atrial Fibrillation (ORBIT) scores for predicting major bleeding in 57,930
atrial fibrillation patients (44.6% female; mean age 73.5 years, standard
deviation 11.4 years; mean CHA2DS2-VASc score 3.2, standard deviation 1.8).
RESULTS: At 1-year follow-up, C-statistics for ATRIA, HAS-BLED, and ORBIT were
approximately 0.59, with only minor differences between scores. Both ATRIA and
ORBIT categorized more patients as "low risk" (both >83%, when compared with
HAS-BLED, only 53%), and qualitatively, the receiver operating characteristic
curves revealed higher sensitivity (62.8%) for HAS-BLED compared with ATRIA
(29.7%) and ORBIT (37.1%). The clinical usefulness of scores was evaluated using
decision curve analyses at a 1-year perspective. If the intervention threshold
is low (<1.7%), the benefit is toward monitoring all patients. If preference is
for a major bleeding risk threshold between 1.7% and 2.0%, most benefit was
obtained by using HAS-BLED. The ORBIT and ATRIA scores provided better benefit
for thresholds between 2.0% and 6.0%.
CONCLUSION: This analysis of contemporary bleeding risk score stratification in
a "real-world" non-vitamin K antagonist oral anticoagulant users population with
atrial fibrillation showed modest predictive values using C-statistics. The
scores represent different risk thresholds, with HAS-BLED classifying least
patients at low risk and achieving the highest benefit if applying a major
bleeding intervention threshold of approximately 2%, whereas benefit from using
either ATRIA score or ORBIT score was only evident using higher intervention
thresholds. INTRODUCTION: Many patients with atrial fibrillation or atrial flutter (AF/FL)
who are high risk for ischemic stroke are not receiving evidence-based
thromboprophylaxis. We examined anticoagulant prescribing within 30 days of
receiving dysrhythmia care for non-valvular AF/FL in the emergency department
(ED).
METHODS: This prospective study included non-anticoagulated adults at high risk
for ischemic stroke (ATRIA score ≥7) who received emergency AF/FL care and were
discharged home from seven community EDs between May 2011 and August 2012. We
characterized oral anticoagulant prescribing patterns and identified predictors
of receiving anticoagulants within 30 days of the index ED visit. We also
describe documented reasons for withholding anticoagulation.
RESULTS: Of 312 eligible patients, 128 (41.0%) were prescribed anticoagulation
at ED discharge or within 30 days. Independent predictors of anticoagulation
included age (adjusted odds ratio [aOR] 0.89 per year, 95% confidence interval
[CI] 0.82-0.96); ED cardiology consultation (aOR 1.89, 95% CI [1.10-3.23]); and
failure of sinus restoration by time of ED discharge (aOR 2.65, 95% CI
[1.35-5.21]). Reasons for withholding anticoagulation at ED discharge were
documented in 139 of 227 cases (61.2%), the most common of which were deferring
the shared decision-making process to the patient's outpatient provider,
perceived bleeding risk, patient refusal, and restoration of sinus rhythm.
CONCLUSION: Approximately 40% of non-anticoagulated AF/FL patients at high risk
for stroke who presented for emergency dysrhythmia care were prescribed
anticoagulation within 30 days. Physicians were less likely to anticoagulate
older patients and those with ED sinus restoration. Opportunities exist to
improve rates of thromboprophylaxis in this high-risk population. BACKGROUND: The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA)
risk score used to detect the thromboembolic and hemorrhagic risk in atrial
fibrillation patients has been shown recently to predict poor clinical outcomes
in patients with acute myocardial infarction (ACS), regardless of having atrial
fibrillation (AF). We aimed to analyze the relationship between different risk
scores and contrast-induced nephropathy (CIN) development in patients with ACS
who underwent urgent percutaneous coronary intervention (PCI) and compare the
predictive ability of the ATRIA risk score with the MEHRAN risk score.
METHODS: We analyzed 429 patients having St-segment Elevation Myocardial
Infarction (STEMI) who underwent urgent PCI between January 2016 and February
2017. Patients were divided into two groups: those with and those without CIN
and both groups were compared according to clinical, laboratory, and demographic
features, including the CHA2DS2-VASc and ATRIA risk score. Predictors of CIN
were determined by multivariate regression analysis. Receiver operating
characteristics (ROC) curve analysis was used to analyze the prognostic value of
CHA2DS2-VASc and ATRIA risk score for CIN, following STEMI.
RESULTS: Multivariate regression analysis showed that Athe TRIA risk score,
Opaque/Creatinine Clearance ratio, and low left ventricular ejection fraction
was an independent predictor of CIN. The C-statistics for the ATRIA risk score
and CHA2DS2-VASC risk score were 0.66 and 0.64 (p<0.001, and p<0.001),
respectively. A pair-wise comparison of ROC curves showed that both scores were
not inferior to the MEHRAN score in predicting CIN.
CONCLUSION: The ATRIA and CHA2DS2-VASC scoring systems were useful for detecting
CIN following STEMI. |
Which protein is targeted by Herceptin? | Her2 is targeted by Herceptin. | BACKGROUND: On encountering a susceptible target, natural killer (NK) cells
mediate cytotoxicity through highly regulated steps of directed degranulation.
Cytotoxic granules converge at the microtubule organizing center and are
polarized toward the immunological synapse (IS), followed by granule exocytosis.
NK cell retargeting by chimeric antigen receptors (CARs) or mAbs represents a
promising strategy for overcoming tumor cell resistance. However, little is
known about the lytic granule dynamics of such retargeted NK cells toward
NK-cell-resistant tumors.
METHODS: Here, we used spinning disk confocal microscopy for live-cell imaging
to analyze granule-mediated NK cell cytotoxicity in ErbB2-targeted
CAR-expressing NK-92 cells (NK-92/5.28.z) and high-affinity FcR transgenic NK-92
cells plus Herceptin toward ErbB2-positive breast cancer cells (MDA-MB-453),
which are resistant to parental NK-92.
RESULTS: Unmodified NK-92 cells cocultured with resistant cancer cells showed
stable conjugate formation and granule clustering, but failed to polarize
granules to the IS. In contrast, retargeting by CAR or FcR+Herceptin toward the
MDA-MB-453 cells enabled granule polarization to the IS, resulting in highly
effective cytotoxicity. We found that in NK-92 the phosphoinositide 3-kinase
pathway was activated after contact with resistant MDA-MB-453, while
phospholipase C-γ (PLCγ) and mitogen-activated protein kinase
(MEK)/extracellular signal-regulated kinase (ERK) were not activated. In
contrast, retargeting by CAR or antibody-dependent cell-mediated cytotoxicity
(ADCC) provided the missing PLCγ and MEK/ERK signals.
CONCLUSIONS: These observations suggest that NK cells can create conjugates with
resistant cancer cells and respond by granule clustering, but the activation
signals are insufficient to induce granule polarization and consequent release
of lytic enzymes. Retargeting by CAR and/or the FcR/mAb (ADCC) axis provide the
necessary signals, leading to granule polarization and thereby overcoming tumor
cell resistance. BACKGROUND: ERBB2 is a proto-oncogene of multiple cancers including breast and
gastric cancers with HER2 protein overexpression or gene amplification and has
been proven clinically as a valid target for these cancers. HER2-targeting
agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA
for the treatment of breast cancer, but these drugs still face the challenge of
acquired resistance and/or severe adverse reactions in clinical use. Therefore,
there is significant unmet medical need for developing new agents that are more
effective and safer for patients with advanced HER2-positive solid tumors
including breast and gastric cancers.
METHODS: We report here the making of MRG002, a novel HER2-targeted antibody
drug conjugate (ADC), and preclinical characterization including pharmacology,
pharmacodynamics and toxicology and discuss its potential as a novel agent for
treating patients with HER2-positive solid tumors.
RESULTS: MRG002 exhibited similar antigen binding affinity but much reduced
antibody-dependent cellular cytotoxicity (ADCC) activity compared to
trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor
regression in both high- and medium-to-low HER2 expressing in vivo xenograft
models. Furthermore, MRG002 showed enhanced antitumor activity when used in
combination with an anti-PD-1 antibody. Main findings from toxicology studies
are related to the payload and are consistent with literature report of other
ADCs with monomethyl auristatinE.
CONCLUSION: MRG002 has demonstrated a favorable toxicity profile and potent
antitumor activities in the breast and gastric PDX models with varying levels of
HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical
study of MRG002 in patients with HER2-positive solid tumors is ongoing
(CTR20181778). |
What are the main clinical components of the brain death exam? | The three essential findings in brain death are coma, absence of brain stem reflexes by neurologic exam including ancillary testing, and apnea. Studies can highlight the variability in practice in regard to the AT and supports the use of ancillary tests to determine BD in patients. Coma and brain stem reflexes can be determined by several ancillary tests Ancillary tests include electroencephalography, brainstem auditory evoked potentials, included somatosensory evoked potentials, transcranial Doppler ultrasonography, conventional cerebral angiography, and nuclear medicine flow study | Forty years after the publication of a landmark paper by the Ad Hoc Committee of
the Harvard Medical School, the general concept of brain death has achieved
widespread acceptance. In the United States, irreversible dysfunction of the
brain and brainstem are required for the diagnosis of brain death. Although
primarily based on clinical evaluation, confirmatory examinations, including
radionuclide blood flow studies, play an important role in augmenting the
physical examination in special situations when some of its specific components
cannot be performed or reliably evaluated. The 2 main radionuclidic techniques
used in evaluation of brain death are radionuclide angiography with
nonlipophilic radiopharmaceuticals and parenchymal imaging with lipophilic
agents. Specific technical guidelines for determination of brain death have been
promulgated by professional medical societies. In the vast majority of cases,
blood flow examinations are useful in confirming brain death. Nonetheless, on
occasion patients clinically diagnosed with brain death will exhibit persistent
intracranial blood flow or electrical activity. Existence of these contradictory
cases reveals underlying inconsistencies in the definitions of brain death. We
hypothesize that the existence of these apparent contradictions is related to
differences in sensitivity of the physical examination and the confirmatory
examinations, differences in localization of the physical examination and
confirmatory tests, and differences between blood flow and cerebral function as
markers of brain death. BACKGROUND: In Canada, ancillary tests, such as selective four vessels
angiography (S4VA), are sometimes necessary for brain death (BD) diagnosis when
the clinical exam cannot be completed or confounding factors are present. Recent
Canadian guidelines assert that brain death is supported by the absence of
arterial blood flow at the surface of the brain and that venous return should
not be considered. However, neuropathologic and angiographic studies have
suggested that arteries might still be patent in BD patients. Current clinical
practices in BD diagnosis following S4VA need to be better understood.
METHODS: We conducted a retrospective study of all S4VA performed for the
determination of BD in a level 1 NeuroTrauma centre from 2003 to 2007. The
objective of the study was to describe the prevalence of intracranial arterial,
capillary (parenchymogram) and venous opacification in our study population. All
tests were reviewed independently by two neuroradiologists. Disagreements were
resolved by consensus.
RESULTS: Thirty two patients were declared BD following S4VA during the study
period. Nine of these patients (28%) presented some proximal opacification of
intracranial arteries (95% CI 15-45%). As opposed, none had a cerebral capillary
and deep venous drainage opacification (95% CI 0-10%).
CONCLUSION: The absence of cerebral deep venous drainage or parenchymogram might
represent a better objective marker of cerebral circulatory arrest for brain
death diagnosis when the use of S4VA is required. These findings open the path
for further research in enhancing our interpretation of angiographic studies for
brain death diagnosis. OBJECTIVE: To review practices of brain death (BD) determination in patients on
extracorporeal membrane oxygenation (ECMO).
METHODS: A systematic search was applied to PubMed and 6 electronic databases
from inception to May 22, 2019. Studies reporting methods of BD assessment in
adult patients (>18 years old) while on ECMO were included, after which data
regarding BD assessment were extracted.
RESULTS: Twenty-two studies (n = 177 patients) met the inclusion criteria.
Eighty-eight patients (50%) in 19 studies underwent the apnea test (AT); most
commonly through decreasing the ECMO sweep flow in 14 studies (n = 42, 48%),
followed by providing CO2 through the ventilator in 2 studies (n = 6, 7%), and
providing CO2 through the ECMO oxygenator in 1 study (n = 1, 1%). The details of
the AT were not reported in 2 studies (n = 39, 44%). In 19 patients (22%), the
AT was nonconfirmatory due to hemodynamic instability, hypoxia, insufficient CO2
rise, or unreliability of the AT. A total of 157 ancillary tests were performed,
including electroencephalogram (62%), computed tomography angiography (22%),
transcranial Doppler ultrasound (6%), cerebral blood flow nuclear study (5%),
cerebral angiography (4%), and other (1%). Forty-seven patients (53% of patients
with AT) with confirmatory AT still underwent additional ancillary for BD
confirmation. Only 21 patients (12% of all patients) were declared brain-dead
using confirmatory ATs alone without ancillary testing.
CONCLUSIONS: Performing AT for patients with ECMO was associated with high
failure rate and hemodynamic complications. Our study highlights the variability
in practice in regard to the AT and supports the use of ancillary tests to
determine BD in patients on ECMO. Apnea is one of the three cardinal findings in brain death (BD). Apnea testing
(AT) is physiologically and practically complex. We sought to review described
modifications of AT, safety and complication rates, monitoring techniques,
performance of AT on extracorporeal membrane oxygenation (ECMO), and other
relevant considerations regarding AT. We conducted a systematic scoping review
to answer these questions by searching the literature on AT in English language
available in PubMed or EMBASE since 1980. Pediatric or animal studies were
excluded. A total of 87 articles matched our inclusion criteria and were
qualitatively synthesized in this review. A large body of the literature on AT
since its inception addresses a variety of modifications, monitoring techniques,
complication rates, ways to perform AT on ECMO, and other considerations such as
variability in protocols, lack of uniform awareness, and legal considerations.
Only some modifications are widely used, especially methods to maintain
oxygenation, and most are not standardized or endorsed by brain death
guidelines. Future updates to AT protocols and strive for unification of such
protocols are desirable. OBJECTIVE: We sought to identify similarities and differences in the diagnostic
requirements for ancillary testing for determination of brain death/death by
neurologic criteria (BD/DNC) around the world.
METHODS: We reviewed diagnostic requirements for ancillary testing for BD/DNC in
78 unique official national BD/DNC protocols obtained from contacts worldwide
between January 2018 and April 2019.
RESULTS: Details provided on the performance and interpretation of ancillary
tests for determination of BD/DNC were variably provided and inconsistent.
Approximately half of all protocols that included each ancillary test provided
details about study performance: 63% of protocols that included conventional
cerebral angiography, 55% of protocols that included electroencephalography, 50%
of protocols that included somatosensory evoked potentials, 48% of protocols
that included transcranial Doppler ultrasonography, 43% of protocols that
included nuclear medicine flow study and 41% of protocols that included
brainstem auditory evoked potentials. Similarly, about half of all protocols
that included each ancillary test provided details about study interpretation:
66% of protocols that included electroencephalography, 59% of protocols that
included brainstem auditory evoked potentials, 56% of protocols that included
somatosensory evoked potentials, 55% of protocols that included transcranial
Doppler ultrasonography, 52% of protocols that included conventional cerebral
angiography and 49% of protocols that included nuclear medicine flow study.
INTERPRETATION: Diagnostic requirements for ancillary testing in BD/DNC
determination vary around the world. We hope that the World Brain Death Project
will improve worldwide consensus on the diagnostic requirements for ancillary
testing in BD/DNC, both for performance and interpretation. The apnea test, which involves disconnection from the mechanical ventilator,
presents risks during the determination of brain death, especially in hypoxemic
patients. We describe the performance of the apnea test without disconnection
from the mechanical ventilator in two patients. The first case involved an
8-year-old boy admitted with severe hypoxemia due to pneumonia. He presented
with cardiorespiratory arrest, followed by unresponsive coma due to
hypoxic-ischemic encephalopathy. Two clinical exams revealed the absence of
brainstem reflexes, and transcranial Doppler ultrasound revealed brain
circulatory arrest. Three attempts were made to perform the apnea test, which
were interrupted by hypoxemia; therefore, the apnea test was performed without
disconnection from the mechanical ventilator, adjusting the continuous airway
pressure to 10cmH2O and the inspired fraction of oxygen to 100%. The oxygen
saturation was maintained at 100% for 10 minutes. Posttest blood gas analysis
results were as follows: pH, 6.90; partial pressure of oxygen, 284.0mmHg;
partial pressure of carbon dioxide, 94.0mmHg; and oxygen saturation, 100%. The
second case involved a 43-year-old woman admitted with subarachnoid hemorrhage
(Hunt-Hess V and Fisher IV). Two clinical exams revealed unresponsive coma and
absence of all brainstem reflexes. Brain scintigraphy showed no radioisotope
uptake into the brain parenchyma. The first attempt at the apnea test was
stopped after 5 minutes due to hypothermia (34.9°C). After rewarming, the apnea
test was repeated without disconnection from the mechanical ventilator, showing
maintece of the functional residual volume with electrical bioimpedance.
Posttest blood gas analysis results were as follows: pH, 7.01; partial pressure
of oxygen, 232.0mmHg; partial pressure of carbon dioxide, 66.9mmHg; and oxygen
saturation, 99.0%. The apnea test without disconnection from the mechanical
ventilator allowed the preservation of oxygenation in both cases. The use of
continuous airway pressure during the apnea test seems to be a safe alternative
in order to maintain alveolar recruitment and oxygenation during brain death
determination. |
How does amphiregulin decrease the anti-proliferative effect of cetuximab? | In SNU-C4 and Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC cell lines tested, AREG significantly decreased the anti-proliferative effect of cetuximab (p < 0.05) via AKT and ERK activation. | Amphiregulin (AREG) is an epidermal growth factor receptor (EGFR) ligand. The
aim of this study was to investigate the effects of baseline plasma AREG levels
in KRAS, NRAS, and BRAF wild-type metastatic colorectal cancer (CRC) on
treatment outcome with palliative first-line cetuximab + FOLFIRI chemotherapy.
Chemotherapy outcomes were analyzed based on baseline plasma AREG levels. The
clinical findings were further validated using an in vitro model of CRC. Among
35 patients, the progression-free survival (PFS) was significantly inferior in
patients with high AREG than in those with low AREG levels: 10.9 vs.
24.2 months, respectively (p = 0.008). However, after failure of first-line
chemotherapy, AREG levels were associated with neither PFS (4.8 vs. 11.6 months;
p = 0.215) nor overall survival (8.4 vs. 13.3 months; p = 0.975). In SNU-C4 and
Caco-2 cells which were relatively sensitive to cetuximab among the seven CRC
cell lines tested, AREG significantly decreased the anti-proliferative effect of
cetuximab (p < 0.05) via AKT and ERK activation. However, after acquiring
cetuximab resistance with gradual exposure for more than 6 months, AREG neither
increased colony formation nor activated AKT and ERK after cetuximab treatment.
Our results suggest that plasma AREG is a potential biomarker to predict
clinical outcomes after cetuximab-based chemotherapy. |
Describe RCandy | RCandy is a platform-independent R package for rapid, simple, and flexible visualisation of recombination events in bacterial genomes. | |
What variables are included in the MuLBSTA score? | MuLBSTA score includes Multilobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension and Age. | Background: Despite an increase in the familiarity of the medical community with
the epidemiological and clinical characteristics of coronavirus disease 2019
(COVID-19), there is presently a lack of rapid and effective risk stratification
indicators to predict the poor clinical outcomes of COVID-19 especially in
severe patients. Methods: In this retrospective single-center study, we included
117 cases confirmed with COVID-19. The clinical, laboratory, and imaging
features were collected and analyzed during admission. The Multi-lobular
infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history,
hyper-Tension and Age (MuLBSTA) Score and Confusion, Urea, Respiratory rate,
Blood pressure, Age 65 (CURB65) score were used to assess the death and
intensive care unit (ICU) risks in all patients. Results: Among of all 117
hospitalized patients, 21 (17.9%) patients were admitted to the ICU care, and 5
(4.3%) patients were died. The median hospital stay was 12 (10-15) days. There
were 18 patients with MuLBSTA score ≥ 12 points and were all of severe type. In
severe type, ICU care and death patients, the proportion with MuLBSTA ≥ 12
points were greater than that of CURB65 score ≥ 3 points (severe type patients,
50 vs. 27.8%; ICU care, 61.9 vs. 19.0%; death, 100 vs. 40%). For the MuLBSTA
score, the ROC curve showed good efficiency of diagnosis death (area under the
curve [AUC], 0.956; cutoff value, 12; specificity, 89.5%; sensitivity, 100%) and
ICU care (AUC, 0.875; cutoff value, 11; specificity, 91.7%; sensitivity, 71.4%).
The K-M survival analysis showed that patients with MuLBSTA score ≥ 12 had
higher risk of ICU (log-rank, P = 0.001) and high risk of death (log-rank, P =
0.000). Conclusions: The MuLBSTA score is valuable for risk stratification and
could effectively screen high-risk patients at admission. The higher score at
admission have higher risk of ICU care and death in patients infected with
COVID. OBJECTIVES: The primary objectives of the study are to determine the
effectiveness of the Kaba Sura Kudineer (KSK) & Nilavembu Kudineer (NVK) along
with standard Allopathy Treatment to compared with Placebo (Decaffeinated Tea)
with standard Allopathy Treatment in the management of Symptomatic COVID 19
patients and also in reduction of Hospital Stay Time & Changes in Immunological
(IL6) and Bio Chemical Markers (Ferritin, CRP, D-Dimer and LDH). The secondary
objectives are to evaluate the safety of the trial medicines and their effects
in the reduce the risks of the disease. In addition, to document the profile of
Symptomatic COVID 19 patients as per Siddha Principles.
TRIAL DESIGN: A Double Blinded, Three arm, Single Centre, Placebo Controlled,
Exploratory and comparative Randomized Controlled Trial PARTICIPANTS: Patients
who were admitted to the COVID Care Centre at Govt. Institute of Medical
Sciences. Noida in India will be recruited. These will be patients with Mild and
Moderate symptoms with laboratory confirmed COVID 19 (RT - PCR Tested Positive)
aged 18-65, willing and consenting to participate.
INTERVENTION AND COMPARATOR: Arm I: Decaffeinated Tea (Placebo - similar in
taste and appearance to the other Two Decoctions), 60 Ml Morning and Night after
Food, along with standard Allopathy Treatment for 10 days. Arm II: Nilavembu
Kudineer (The Siddha Medicines which is used as a standard Anti-Viral drug for
the past Pandemics by Siddha Physicians) 60 Ml Morning and Night after Food,
along with standard Allopathy Treatment for 10 days. Arm III: Kaba Sura Kudineer
(The Siddha Medicine which is proposed to be used as a Treatment for COVID 19
based on Siddha Literature) 60 Ml Morning and Night after Food, along with
standard Allopathy Treatment for 10 days. The investigational drugs are
registered products under the Govt.of India and bought from GMP Certified
Manufacturing Units.
MAIN OUTCOMES: Primary outcomes: 1. Reduction in Viral load of SARS-CoV-2 at the
end of treatment (10 days). 2. Time taken to convert Patient from symptomatic to
Asymptomatic based on Reduction in clinical symptoms (10 days). 3. Effect of
drugs inflammatory markers (IL6,) at the end of treatment (10 days). 4.
Reduction in hospital stay time (20 days follow up). (Based on RT PCR CT Value
3rd, 6th if needed 10th day). (Based on IL 6 Value needed 10th day or IL6 value
on turning negative. (entry level/exit level). Secondary outcomes (10 days): 1.
Reduction in use of Intensive Supportive Care. 2. Reduction in incidence of
complications (Acute Respiratory Distress Syndrome, other systemic
complications). 3. MuLBSTA score for viral pneumonia (multinodular infiltration,
hypo-lymphocytosis, bacterial co infection, Total Leucocyte Count (TLC ≤ 0.8 x
109/L), smoking history, hyper-tension and age) score. 4. Laboratory markers
(Haematological & Biochemical Markers). 5. Adverse events/effects Siddha-based
measurements. 6. Siddha Udaliyal assessment by using Yakkai Ilakkanam (YI) Tool
to diagnose body condition for covid-19 patients.
RANDOMISATION: The assignment of the participants into 3 Groups will be
allocated in 1:1:1 Ratio through randomization Blocks in Microsoft Excel by a
Statistician who is not involved in the study. The allocation scheme will be
made by another statistician by using a closed envelope after the assessment of
eligibility and Informed consent procedures. The groups will be balanced for age
and sex with 3:1 Ratio in each group for mild: severe COVID-19 symptoms.
BLINDING: The Study is Double Blinded. Participants and Investigators were
blinded.
NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Sample size could not be calculated,
Since there are no prior trials on KSK and NVK as a comparative trial. In
addition, there are no prior trials on KSK and NVK in this region. A total
Number of 120 Patients, 40 each in 3 groups will be recruited in 1:1:1 Ratio.
TRIAL STATUS: Protocol Number : SCRUND GIMS Noida Study 1,Version: 2.0 Protocol
Date : 20.08.2020 The recruitment period is completed for the trial. The Trial
started its recruitment on 22.8.2020. We anticipate study including data
analysis will finish in January 2021. This is to state that it was a late
submission from authors for publication of the protocol to the BMC, after
enrolment in the study was over.
TRIAL REGISTRATION: The trial protocol was registered with CTRI (Clinical Trial
Registry of India) and number is CTRI/2020/08/027286 on 21.08.2020 FULL
PROTOCOL: The full Protocol is attached as an additional file, Accessible from
the Trials website (Additional file 1). In the interest in expediting
dissemination of this material, the familiar formatting has been eliminated.
This letter serves as a summary of the key elements of the full protocol. The
Study protocol has been reported in accordance with the SPIRIT guidelines. OBJECTIVE: To explore the correlation between early inflammation indicators and
the severity of coronavirus disease 2019 (COVID-19).
METHODS: A retrospective study was conducted. Patients with COVID-19 admitted to
Wenzhou Central Hospital from January 17 to February 14, 2020 were enrolled. The
general information, chest CT before admission, the first laboratory parameters
and chest CT within 24 hours after admission were collected. Patients were
followed up for 30 days after the first onset of dyspnea or pulmonary imaging
showed that the lesions progressed more than 50% within 24 to 48 hours
(according to the criteria for severe cases) as the study endpoint. According to
the endpoint, the patients were divided into two groups: mild type/common type
group and severe/critical group, and the differences in general information and
inflammation index of the two groups were compared. Logistic regression was used
to analyze the inflammation index and the severity of COVID-19. Receiver
operating characteristic (ROC) curve was draw to evaluate the predictive value
of early inflammation indicators for severe/critical in patients with COVID-19.
RESULTS: A total of 140 patients with COVID-19 were included, 74 males and 66
females; the average age was (45±14) years old; 6 cases (4.3%) of mild type, 107
cases (76.4%) of common type, and 22 cases (15.7%) of severe type, 5 cases
(3.6%) were critical. There were significantly differences in ages (years old:
43±13 vs. 57±13), the proportion of patients with one chronic disease (17.7% vs.
55.6%), C-reactive protein [CRP (mg/L): 7.3 (2.3, 21.0) vs. 40.1 (18.8, 62.6)],
lymphocyte count [LYM (×109/L): 1.3 (1.0, 1.8) vs. 0.8 (0.7, 1.1)], the
neutrophil/lymphocyte ratio [NLR: 2.1 (1.6, 3.0) vs. 3.1 (2.2, 8.8)] and
multilobularinltration, hypo-lymphocytosis, bacterial coinfection, smoking
history, hyper-tension and age [MuLBSTA score: 5.0 (3.0, 5.0) vs. 5.0 (5.0,
7.0)] between mild/common group and severe/critical group (all P < 0.05).
Univariate Logistic regression analysis showed that CRP, NLR, MuLBSTA score,
age, and whether chronic diseases were associated with the severity of COVID-19
[odds ratio (OR) and 95% confidence interval (95%CI) were 1.037 (1.020-1.055),
1.374 (1.123-1.680), 1.574 (1.296-1.911), 1.082 (1.042-1.125), 6.393
(2.551-16.023), respectively, all P < 0.01]. Further multivariate Logistic
regression analysis showed that CRP and MuLBSTA score were risk factors for the
development of COVID-19 to severe/critical cases [OR and 95%CI were 1.024
(1.002-1.048) and 1.321 (1.027-1.699) respectively, both P < 0.05]. ROC curve
analysis showed that the area under the curve for CRP and MuLBSTA score to
predict severe/critical cases were both 0.818, and the best cut-off points were
27.4 mg/L and 6.0 points, respectively.
CONCLUSIONS: CRP and MuLBSTA score are related to the severity of COVID-19, and
may have good independent predictive ability for the development of
severe/critical illness. |
Which organisms are the focus of the Wormbase? | WormBase continues to advance its practices on data acquisition, curation and retrieval to most effectively deliver comprehensive knowledge about Caenorhabditis elegans, and genomic information about other nematodes and parasitic flatworms. | WormBase ( www.wormbase.org ) provides the nematode research community with a
centralized database for information pertaining to nematode genes and genomes.
As more nematode genome sequences are becoming available and as richer data sets
are published, WormBase strives to maintain updated information, displays, and
services to facilitate efficient access to and understanding of the knowledge
generated by the published nematode genetics literature. This chapter aims to
provide an explanation of how to use basic features of WormBase, new features,
and some commonly used tools and data queries. Explanations of the curated data
and step-by-step instructions of how to access the data via the WormBase website
and available data mining tools are provided. WormBase (https://wormbase.org/) is a mature Model Organism Information Resource
supporting researchers using the nematode Caenorhabditis elegans as a model
system for studies across a broad range of basic biological processes. Toward
this mission, WormBase efforts are arranged in three primary facets: curation,
user interface and architecture. In this update, we describe progress in each of
these three areas. In particular, we discuss the status of literature curation
and recently added data, detail new features of the web interface and options
for users wishing to conduct data mining workflows, and discuss our efforts to
build a robust and scalable architecture by leveraging commercial cloud
offerings. We conclude with a description of WormBase's role as a founding
member of the nascent Alliance of Genome Resources. Biological knowledgebases rely on expert biocuration of the research literature
to maintain up-to-date collections of data organized in machine-readable form.
To enter information into knowledgebases, curators need to follow three steps:
(i) identify papers containing relevant data, a process called triaging; (ii)
recognize named entities; and (iii) extract and curate data in accordance with
the underlying data models. WormBase (WB), the authoritative repository for
research data on Caenorhabditis elegans and other nematodes, uses text mining
(TM) to semi-automate its curation pipeline. In addition, WB engages its
community, via an Author First Pass (AFP) system, to help recognize entities and
classify data types in their recently published papers. In this paper, we
present a new WB AFP system that combines TM and AFP into a single application
to enhance community curation. The system employs string-searching algorithms
and statistical methods (e.g. support vector machines (SVMs)) to extract
biological entities and classify data types, and it presents the results to
authors in a web form where they validate the extracted information, rather than
enter it de novo as the previous form required. With this new system, we lessen
the burden for authors, while at the same time receive valuable feedback on the
performance of our TM tools. The new user interface also links out to specific
structured data submission forms, e.g. for phenotype or expression pattern data,
giving the authors the opportunity to contribute a more detailed curation that
can be incorporated into WB with minimal curator review. Our approach is
generalizable and could be applied to additional knowledgebases that would like
to engage their user community in assisting with the curation. In the five
months succeeding the launch of the new system, the response rate has been
comparable with that of the previous AFP version, but the quality and quantity
of the data received has greatly improved. |
Is Ameloblastoma (AB) a benign tumor that never metastasizes? | Ameloblastomas are benign but locally invasive neoplasms which can be metastatic | Ameloblastoma is a locally invasive, histologically nonmaligt tumor that may
on very rare occasions give rise to metastases. A patient with a mandibular
ameloblastoma presenting typical histologic appearances developed a pulmonary
metastasis confirmed by histology as arising from the primary tumor. Two groups
of these extremely rare maligt ameloblastomas can be distinguished: those
without histologic signs of degeneration that give rise to metastases identical
to the primary lesion, and those with degenerative signs provoking metastases
with the histologic appearance of undifferentiated carcinoma. No relation
appears to exist between size of primary tumor, histologic type of
ameloblastoma, or its course and tendency to produce metastases. Ameloblastoma is an odontogenic tumor, usually benign, which rarely metastasizes
to distant organs. The case of a 27-year-old white woman is described, who
presented a metastatic pulmonary ameloblastoma 7 years after the removal of a
mandibular ameloblastoma. She presented no pulmonary symptoms, but a lung nodule
was found in a chest x-ray during a routine check-up for job admission. Computed
tomography (CT) revealed a 2-cm well-defined solitary round nodule without
calcifications, leading to the hypothesis of a metastatic tumor. Clinical and CT
investigation confirmed no ameloblastoma recurrence in the jaw and no other
primary tumor. The diagnosis of metastatic ameloblastoma was confirmed by
microscopic evaluation of the pulmonary nodule. Ameloblastoma of the maxilla is a rare odontogenic tumor that rarely
metastasizes. We report a patient who was diagnosed with ameloblastoma of the
maxilla 6 years ago and had undertaken the operation. However, the recurrence
occurred, and further pulmonary disease was discovered. He did not experience
chest pain and other respiratory systematic symptoms. Whether this metastasizing
ameloblastoma should be ranged among maligt or benign is discussed. The term
benign metastasizing ameloblastoma is suggested to describe this kind of tumor. Ameloblastoma is a locally aggressive, epithelial odontogenic tumor involving
mandibles and maxillas. Distant metastasis is a very rare condition and is
designated as metastasizing (maligt) ameloblastoma despite its benign
histological appearance. Up to now, only 27 well-documented cases of
metastasizing ameloblastomas are reported in the literature, and lung is the
most commonly involved organ. In previous reports of pulmonary metastasizing
ameloblastomas, there was little description of the histopathologic finding.
Here, the authors report 2 cases of pulmonary metastasizing ameloblastomas with
special emphasis on their interesting, interstitial spread along alveolar septa,
resulting in a unique 2-cell pattern under microscopic examination. Pulmonary
metastasizing ameloblastoma may pose difficulty in diagnosis if the pathologist
is not aware of patient's clinical history of ameloblastoma. Ameloblastic carcinoma (AC) is defined as a rare primary epithelial odontogenic
maligt neoplasm and the maligt counterpart of benign epithelial
odontogenic tumor of ameloblastoma (AB) by the WHO classification. AC develops
pulmonary metastasis in about one third of the patients and reveals a poor
prognosis. However, the mechanisms of AC oncogenesis remain unclear. In this
report, we aimed to clarify the mechanisms of maligt transformation of AB or
AC carcinogenesis. The relatively important genes in the maligt
transformation of AB were screened by DNA microarray analysis, and the
expression and localization of related proteins were examined by
immunohistochemistry using samples of AB and secondary AC. Two genes of
hypoxia-inducible factor 1 alpha subunit (HIF1A) and zinc finger E-box-binding
homeobox 1 (ZEB1) were significantly and relatively upregulated in AC than in
AB. Both genes were closely related in hypoxia and epithelial-mesenchymal
transition (EMT). In addition, expressions of HIF-1α and ZEB1 proteins were
significantly stronger in AC than in AB. In the cell assays using ameloblastoma
cell line, AM-1, hypoxia condition upregulated the expression of transforming
growth factor-β (TGF-β) and induced EMT. Furthermore, the hypoxia-induced
morphological change and cell migration ability were inhibited by an
antiallergic medicine tranilast. Finally, we concluded that hypoxia-induced
HIF-1α and ZEB1 were critical for the maligt transformation of AB via
TGF-β-dependent EMT. Then, both HIF-1α and ZEB1 could be potential biomarkers to
predict the maligt transformation of AB. Ameloblastomas are benign but locally invasive neoplasms which may grow to
massive proportions and cause significant morbidity. Although some types of
ameloblastoma can be treated predictably with aggressive surgical treatment,
recurrent ameloblastoma and metastasising ameloblastoma are still difficult to
treat. Recent studies have identified recurrent somatic and activating mutations
in the mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH)
signalling pathways in ameloblastoma. This development provided a possibility
that molecular targeted therapies can be used as neoadjuvant treatment. In this
review, we provide a summary of the latest WHO classification of ameloblastoma,
the current understanding of genetic mutations and novel molecular targeted
therapies arising from the recent developments. |
What does PCAT6 stand for? | PCAT6 stands for prostate cancer-associated transcript 6. | Breast cancer is an aggressive maligcy with high morbidity in females
worldwide. Extensive studies reveal that long noncoding RNAs (lncRNAs) are
abnormally expressed and act as key regulators in various cancers, including
breast cancer. In this work, we investigated the role and regulatory mechanism
of lncRNA prostate cancer-associated transcript 6 (PCAT6) in breast cancer
progression. Our findings revealed that PCAT6 was overexpressed in breast cancer
tissues and cell lines. Furthermore, elevation of PCAT6 reflected an adverse
prognosis of patients. Functional experiments indicated that PCAT6 knockdown
hampered cell proliferation, facilitated apoptosis and cell cycle arrest in
vitro, and inhibited tumor growth in vivo. We also found that the transcription
factor SP1 could bind to the PCAT6 promoter and promoted its expression.
Subsequently, it was verified that PCAT6 was a molecular sponge for microRNA-326
(miR-326), and the leucine-rich repeat containing the eight family member E
(LRRC8E) was a direct target of miR-326. Rescue assays revealed that LRRC8E
overexpression attenuated the suppressive effect of PCAT6 knockdown on cellular
progression of breast cancer. In summary, this study demonstrated that
SP1-activated PCAT6 promoted the maligt behaviors of breast cancer cells by
regulating the miR-326/LRRC8E axis. |
Is there any role of the 'Greek islands' in olfactory receptor choice? | Yes. 'Greek islands' first contribute to the formation of olfactory receptor compartments and then form a multi-chromosomal super-enhancer that associates with the single active olfactory receptor gene. The Greek-island-bound transcription factor LHX2 and adaptor protein LDB1 regulate the assembly and maintenance of olfactory receptor compartments, Greek island hubs and olfactory receptor transcription, providing mechanistic insights into and functional support for the role of trans interactions in gene expression. | The genome is partitioned into topologically associated domains and genomic
compartments with shared chromatin valence. This architecture is constrained by
the DNA polymer, which precludes interactions between genes on different
chromosomes. Here we report a marked divergence from this pattern of nuclear
organization that occurs in mouse olfactory sensory neurons. Chromatin
conformation capture using in situ Hi-C on fluorescence-activated cell-sorted
olfactory sensory neurons and their progenitors shows that olfactory receptor
gene clusters from 18 chromosomes make specific and robust interchromosomal
contacts that increase with differentiation of the cells. These contacts are
orchestrated by intergenic olfactory receptor enhancers, the 'Greek islands',
which first contribute to the formation of olfactory receptor compartments and
then form a multi-chromosomal super-enhancer that associates with the single
active olfactory receptor gene. The Greek-island-bound transcription factor LHX2
and adaptor protein LDB1 regulate the assembly and maintece of olfactory
receptor compartments, Greek island hubs and olfactory receptor transcription,
providing mechanistic insights into and functional support for the role of trans
interactions in gene expression. |
What is ASTRAL Score? | ASTRAL Score is used to predict prognosis of stroke patients. | BACKGROUND AND PURPOSE: The ASTRAL score was recently introduced as a prognostic
tool for acute ischemic stroke. It predicts 3-month outcome reliably in both the
derivation and the validation European cohorts. We aimed to validate the ASTRAL
score in a Chinese stroke population and moreover to explore its prognostic
value to predict 12-month outcome.
METHODS: We applied the ASTRAL score to acute ischemic stroke patients admitted
to 132 study sites of the China National Stroke Registry. Unfavorable outcome
was assessed as a modified Rankin Scale score >2 at 3 and 12 months. Areas under
the curve were calculated to quantify the prognostic value. Calibration was
assessed by comparing predicted and observed probability of unfavorable outcome
using Pearson correlation coefficient.
RESULTS: Among 3755 patients, 1473 (39.7%) had 3-month unfavorable outcome.
Areas under the curve for 3 and 12 months were 0.82 and 0.81, respectively.
There was high correlation between observed and expected probability of
unfavorable 3- and 12-month outcome (Pearson correlation coefficient: 0.964 and
0.963, respectively).
CONCLUSIONS: ASTRAL score is a reliable tool to predict unfavorable outcome at 3
and 12 months after acute ischemic stroke in the Chinese population. It is a
useful tool that can be readily applied in clinical practice to risk-stratify
acute stroke patients. BACKGROUND: Disability and mortality represent the most relevant clinical
outcomes after acute ischemic stroke. Recently, a number of prognostic models of
acute ischemic stroke have been developed, but they have not been extensively
validated. In this study, we evaluated the ability of 3 prognostic models
including the iScore, the PLAN score, and the ASTRAL score in predicting
clinical poor outcomes or mortality at 6 months in patients with acute ischemic
stroke.
METHODS: A total of 323 patients were divided into a good-prognosis group and a
poor-prognosis group based on the modified Rankin Scale. Model discrimination
was quantified by calculating the area under the receiver operating
characteristic (ROC) curve, and calibration was assessed by Hosmer-Lemeshow
goodness of fit test and Pearson correlation coefficient.
RESULTS: We identified 96 (29.7%) patients with poor prognosis, including 21 who
were dead. All 3 models showed good ability in predicting poor prognosis and
mortality in patients with acute ischemic stroke (all ROC > .70). There was no
difference between these 3 models in terms of sensitivity and accuracy (all
P > .05).
CONCLUSIONS: The results of this study suggest that the iScore, the PLAN score,
and the ASTRAL score were equal in predicting 6-month poor prognosis and
mortality in patients with acute ischemic stroke. Overall, there was a very high
correlation between observed and expected outcomes at the risk score level. BACKGROUND: Acute ischemic stroke (AIS) has a higher morbidity and mortality
rate. Many prediction tools have been developed to predict the risk of poor
outcomes in patients after AIS, such as the THRIVE score, the iScore score, and
the ASTRAL score. However, the predictive value of above 3 prediction tools in
Chinese patients with AIS need to be further verified. So, this study aimed to
determine the ability of the THRIVE score, the iScore score, and the ASTRAL
score in predicting clinical poor outcomes in Chinese patients with AIS at 1
year.
METHODS: A total of 772 patients with AIS were included in this study. The
baseline data of all patients were collected. The THRIVE score, the iScore
score, and the ASTRAL score were calculated. All patients were followed up at 1
year. The poor outcome was defined as death, moderate/severe disabilities
(modified Rankin scale, mRS > 2), most severe disability (mRS ≥ 5). Model
discrimination was quantified by calculating the area under the receiver
operating characteristic curve (AUC). The calibration was assessed using
Hosmer-Lemeshow goodness-of-fit test and Pearson correlation coefficient.
RESULTS: We identified 576 (74.6%) patients with good prognosis and 196 (25.4%)
patients with poor prognosis. AUC values of THRIVE score in predicting 1-year
poor prognosis was lower than the iScore score and the ASTRAL scores (P < .05).
The chi-square values of Hosmer-Lemeshow for the 3 prediction tools were 2.114,
4.877, 5.838 (all P < .05), respectively. There was a high correlation between
the observed and the expected poor prognosis (Pearson correlation coefficient,
.985, .693, and .620; all P < .05). AUC values of THRIVE score in predicting
1-year mortality and severe disability were lower than the iScore scores (all P
< .05).
CONCLUSIONS: The iScore score and the ASTRAL score reliably predict 1-year poor
outcomes in Chinese patients with AIS, and the iScore score can accurately
predict 1-year mortality and severe disability in Chinese AIS patients. BACKGROUND: : Various tools are currently available to quantify the risks of
adverse clinical outcomes after an ischemic stroke. This study aimed to validate
and compare prognostic scales among Chinese patients with ischemic stroke.
METHODS: : We compared three stroke prognostic scales (Stroke Prognostication
using Age and the National Institutes of Health Stroke Scale-100 [SPAN-100],
Totaled Health Risks in Vascular Events [THRIVE], and Acute Stroke Registry and
Analysis of Lausanne [ASTRAL]) in 3870 Chinese patients with ischemic stroke
from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). The
2-year primary outcome was a combination of death and major disability (modified
Rankin Scale score ≥3).
RESULTS: : Among all the scales, the ASTRAL score had the best accuracy for
predicting 2-year prognosis in Chinese patients with ischemic stroke. The
C-statistic of the ASTRAL score for the 2-year primary outcome was 0.79 (95%
confidence interval [CI]: 0.78-0.80), and the Hosmer-Lemeshow goodness-of-fit
test showed that the ASTRAL score fitted Chinese patients with ischemic stroke
well (χ2 = 9.83, P = 0.277). The incidences of the primary outcome in the <5%,
5%-9.9%, 10%-19.9%, and ≥20% risk groups based on the ASTRAL scores were 3.93%,
7.55%, 14.29%, and 41.81%, respectively (odds ratio: 1.23; 95% CI: 1.21-1.26; P
< 0.001).
CONCLUSION: : The ASTRAL score had higher efficacy than the SPAN-100 and THRIVE
scores in predicting 2-year adverse outcomes among Chinese patients with
ischemic stroke, suggesting that it could be a valuable risk assessment tool for
the 2-year prognosis of such patients. |
Is paxillin affected by RANKL? | Yes,
RANKL promotes paxillin serine and tyrosine phosphorylation. | Osteoclastic bone resorption depends upon the cell's ability to organize its
cytoskeleton via the αvβ3 integrin and osteoclastogenic cytokines. Because
paxillin associates with αvβ3, we asked if it participates in skeletal
degradation. Unlike deletion of other αvβ3-associated cytoskeleton-regulating
molecules, which impairs the cell's ability to spread, paxillin-deficient
(Pax(-/-) ) osteoclasts, generated from embryonic stem cells, "superspread" in
response to receptor activator of NF-κB ligand (RANKL) and form large, albeit
dynamically atypical, actin bands. Despite their increased size, Pax(-/-)
osteoclasts resorb bone poorly, excavating pits approximately one-third normal
depth. Ligand-occupied αvβ3 or RANKL promotes paxillin serine and tyrosine
phosphorylation, the latter via cellular sarcoma (c-Src). The abnormal Pax(-/-)
phenotype is rescued by wild-type (WT) paxillin but not that lacking its LD4
domain. In keeping with the appearance of mutant osteoclasts, WT paxillin,
overexpressed in WT cells, contracts the cytoskeleton. Most importantly, the
abnormal phenotype of Pax(-/-) osteoclasts likely represents failed
RANKL-mediated delivery of myosin IIA to the actin cytoskeleton via the paxillin
LD4 domain but is independent of tyrosine phosphorylation. Thus, in response to
RANKL, paxillin associates with myosin IIA to contract the osteoclast
cytoskeleton, thereby promoting its bone-degrading capacity. Proinflammatory cytokine production, cell chemotaxis, and osteoclastogenesis can
lead to inflammatory bone loss. Previously, we showed that
sphingosine-1-phosphate receptor 2 (S1PR2), a G protein coupled receptor,
regulates inflammatory cytokine production and osteoclastogenesis. However, the
signaling pathways regulated by S1PR2 in modulating inflammatory bone loss have
not been elucidated. Herein, we demonstrated that inhibition of S1PR2 by a
specific S1PR2 antagonist (JTE013) suppressed phosphoinositide 3-kinase (PI3K),
mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-B (NF-κB)
induced by an oral bacterial pathogen, Aggregatibacter actinomycetemcomitans,
and inhibited the release of IL-1β, IL-6, TNF-α, and S1P in murine bone marrow
cells. In addition, shRNA knockdown of S1PR2 or treatment by JTE013 suppressed
cell chemotaxis induced by bacteria-stimulated cell culture media. Furthermore,
JTE013 suppressed osteoclastogenesis and bone resorption induced by RANKL in
murine bone marrow cultures. ShRNA knockdown of S1PR2 or inhibition of S1PR2 by
JTE013 suppressed podosome components, including PI3K, Src, Pyk2, integrin β3,
filamentous actin (F-actin), and paxillin levels induced by RANKL in murine bone
marrow cells. We conclude that S1PR2 plays an essential role in modulating
proinflammatory cytokine production, cell chemotaxis, osteoclastogenesis, and
bone resorption. Inhibition of S1PR2 signaling could be a novel therapeutic
strategy for bone loss associated with skeletal diseases. As a crucial virulence factor of Porphyromonas gingivalis, gingipains play an
important role in periodontal destruction. This study aimed to investigate the
effect of gingipains on osteoclastogenesis. We used RAW264.7 cells as osteoclast
precursors in our study. In experimental groups, cells were treated with
gingipains and/or receptor activator of nuclear factor-κB ligand (RANKL).
Tartrate-resistant acid phosphatase (TRAP) activity staining assay showed
osteoclast precursors and RANKL-induced mature osteoclasts were increased in a
gingipains dose-dependent manner. Real-time reverse transcription polymerase
chain reaction analysis demonstrated that gingipains upregulated osteoclastic
genes including the protease cathepsin K (Ctsk), matrix metalloprotein 9 (Mmp9),
nuclear factor of activated T cells 1 (Nfatc1) and acid phosphatase 5, tartrate
resistant (Acp5) in a time-dependent manner. Western blotting assays presented
upregulated expressions of TNF receptor-activating factor 6 (TRAF6) and integrin
β3 induced by gingipains and RANKL compared to RANKL alone. Enhanced
integrin-related signaling was also demonstrated by elevated phosphorylations of
FAK and paxillin compared to control. Moreover, the pit resorption assays showed
that gingipains augmented bone resorptive function of osteoclasts induced by
RANKL. When we used Cilengitide to block integrin αvβ3, gingipains reversed the
reduction of formation and resorptive function in RANKL-induced osteoclasts, as
they enhanced integrin αvβ3 levels more than RANKL treatment alone. In
conclusion, our data suggest that gingipains augmented the differentiation and
function of mature osteoclasts induced by RANKL through the increase in integrin
αvβ3. |
What organ is associated with a Gleason pattern or Gleason Score? | The Gleason score is an important parameter for clinical outcome in prostate cancer patients | Cathepsin B (CB) is involved in degradation of extracellular matrix proteins
during tumor progression in human solid organ tumors (such as colorectal,
bladder, and breast cancers), including human prostate cancer. Its activities
are regulated by endogenous inhibitors (such as stefins or cystatins). Increased
expression of cathepsin B message, protein, and membrane association have been
linked to maligcy, but there are very few studies of their mRNA expression in
prostate cancer using in situ hybridization techniques. Our objective was to
determine the relationship of CB and stefin A (cystatin A) mRNA localization to
the Gleason grading system for histologic scores in the hope of distinguishing
aggressive and less aggressive variants of prostate cancer. We used a 25-base
biotinylated oligonucleotide CB cDNA antisense probe to localize CB message and
a 27-base biotinylated oligonucleotide stefin A cDNA antisense probe to localize
stefin A message. Prostate samples from 41 prostatectomy patients were collected
along with their pre-surgery serum PSA levels and clinical stage of the disease.
Sections prepared from frozen prostate tissue samples were hybridized with the
CB and stefin A and control pBR 322 probes using techniques reported by Sinha et
al. [1] and their distribution quantitated by an image analysis system. Prostate
sections treated with RNAse before hybridization or incubated with the pBR 322
control probe showed little or no reaction products, confirming that
localization of CB and stefin A probes was specific. In prostate cancer, the
reaction products were found in neoplastic and invasive cells and occasionally
in stromal cells. The ratios of CB to stefin A were similar in normal prostate
and benign prostatic hyperplasia (BPH) whereas they varied consistently within
and between Gleason histologic scores for prostate cancer. These variations
showed three localization patterns; namely, prostate cancers with higher levels
of CB than stefin A, lower levels of CB than stefin A, and similar levels of CB
and stefin A. All three patterns and ratios for CB and stefin A were found in
prostate samples (22/41) represented by the Gleason histologic score 6 tumors.
In these tumors, serum PSA levels ranged from 1 to 78 ng/ml and prostate cancers
showed B, C, and D clinical stages. There was no correlation of CB/stefin A
ratio and serum PSA values or clinical stage in a limited number of prostate
cancer cases. Our data showed that there were prostate cancer cases within
Gleason histologic scores which expressed high, similar, and low levels of CB
when compared to stefin A. We postulate that prostate cancer cases showing
higher levels of CB compared to stefin A probably represent an aggressive
variant of this cancer within any one Gleason histologic score. If this is the
case, aggressive variants of prostate cancer would occur within Gleason scores 3
to 10 even though higher scores are usually considered more aggressive forms of
prostate cancers. Since our study is based upon a very limited number of frozen
prostate samples, we emphasize that a larger series of archival prostate cancer
samples along with their survival data should be analyzed to establish any
relationship of CB/stefin A ratio and aggressive variants of this cancer.
Therefore, our conclusion is tentative. Our study provides a partial explanation
for differences in the clinical course of prostate cancer in patients. This is
the first study to show that determination of CB and stefin A mRNA ratios may
lead to identification of aggressive and less aggressive variants of prostate
cancer within a Gleason histologic score. OBJECTIVES: Most adenocarcinomas of the prostate with a Gleason score greater
than 8 at radical prostatectomy have extraprostatic extension and a high risk of
progression. With prostate-specific antigen screening, we have seen some cases
of earlier detected, organ-confined, high-grade adenocarcinoma. Few data are
available as to the likelihood of cure in these cases.
METHODS: We reviewed 27 cases of pathologically organ-confined adenocarcinoma
with a prostatectomy Gleason score of 8 to 10. To exclude cases with a
significant proportion of Gleason pattern 3, we excluded cases of Gleason score
3+5=8 and Gleason score 5+3=8. All cases of Gleason score 8 at radical
prostatectomy were Gleason score 4+4. The prognostic value of the clinical
parameters (clinical stage, serum prostate-specific antigen level, age) and
pathologic factors (biopsy Gleason score, radical prostatectomy Gleason score,
prostatectomy tumor volume) were tested to predict postoperative progression.
RESULTS: The mean age at diagnosis was 59.7 years (range 46 to 69) with
preoperative serum prostate-specific antigen levels ranging from 1.4 to 28 ng/mL
(mean 7.8). All tumors were classified as pathologic Stage T2N0Mx. Fifteen
patients (55.6%) had a Gleason score of 8, 11 patients (40.7%) had a Gleason
score of 9, and 1 had a Gleason score of 10 (3.7%). Tumor volumes ranged from
0.02 to 1.44 cm(3) (mean 0.56). Follow-up information was available for all men.
The mean follow-up for those without progression was 30.6 months (range 7 to 73)
and for those with progression was 23.6 months (range 9 to 44). The 33-month
actuarial risk of progression was 32%, with 10 men developing progression during
the study. None of the preoperative or postoperative variables predicted
progression.
CONCLUSIONS: Even when high-grade tumor is organ confined, it is associated with
a relatively unfavorable short-term outcome that is not predictable on the basis
of either preoperative clinicopathologic data or postoperative pathologic
information obtained from the radical prostatectomy specimen. If multiple biopsy cores contain prostate cancer with differing Gleason scores,
should an overall Gleason score be assigned, or should each core be graded
separately? We obtained data on 127 men with prostate cancer on needle biopsy
who underwent subsequent radical prostatectomy at our institution. We compared
the Gleason scores found on needle biopsy with the grade and stage
(organ-confined, extra-prostatic extension, positive seminal vesicles or lymph
nodes) at radical prostatectomy. On biopsy, 40 men had a pure Gleason score of 4
+ 3 = 7, 25 men had a Gleason score of 4 + 3 = 7 with a Gleason score of 3 + 3 =
6 on a separate core of the biopsy specimen, 27 men had a pure Gleason score of
4 + 4 = 8, and 35 men had a Gleason score of 4 + 4 = 8 with separate cores
containing Gleason pattern grade 3. A Gleason score of 4 + 4 = 8 with pattern
grade 3 in other cores had a more advanced stage than a pure Gleason score of 4
+ 3 = 7 (P = 0.008). There was no clear pattern analyzing pathological stage of
men with a pure Gleason score of 4 + 3 = 7 in comparison with those with Gleason
scores of 4 + 3 = 7 and 3 + 3 = 6 in other cores. The group with a Gleason score
of 4 + 4 = 8 and Gleason pattern grade 3 on other cores had a higher overall
grade on radical prostatectomy than the group with a pure Gleason score of 4 + 3
= 7 (P = 0.001). If one had assigned an overall Gleason score, then a biopsy
with Gleason score 4 + 4 = 8 on 1 or more cores and some pattern grade 3 in
other cores, would be designated as a Gleason score of 4 + 3 = 7. Based on our
findings, patients with a Gleason score of 4 + 4 = 8 on one or more cores with
pattern grade 3 in other cores should be given a final Gleason score of 4 + 4 =
8 instead of 4 + 3 = 7, because these patients are more likely to have higher
stage and grade on radical prostatectomy, comparable to a pure Gleason score of
4 + 4 = 8. Each core should be assigned a separate Gleason score, especially in
cases with high Gleason score cancer on at least 1 core. The Gleason score of prostate adenocarcinomas is an important preoperative
predictor of cancer behavior, and is used to help guide treatment. In the
setting of more than two positive biopsy sites, pathologists usually grade the
tumor at each site separately, and the Gleason score may differ from each
positive site. This study seeks to determine if the highest Gleason score in all
biopsy sites, or the Gleason score in the site with the highest tumor volume on
the needle biopsy is the best predictor of final Gleason score in the radical
prostatectomy specimens. Various preoperative biopsy findings were analyzed. All
151 patients had at least two positive biopsy sites and underwent radical
prostatectomy. Primary and secondary Gleason pattern grades were assigned for
each positive biopsy site. The tumor volume in the needle biopsy site was
defined by the percentage of areas of biopsy cores involved by cancer. The
radical prostatectomy specimens were completely embedded and processed in the
whole-mount method. The Gleason score from both the biopsy site with the highest
Gleason score and the biopsy site with the highest tumor volume on the needle
biopsy correlated equally well with final Gleason score at radical prostatectomy
(Spearman correlation coefficient =0.54 for both, P<0.001). The Gleason score
from both the biopsy site with the highest Gleason score and the biopsy site
with the highest tumor volume on the needle biopsy also correlated with primary
Gleason pattern grade at radical prostatectomy (Spearman correlation coefficient
=0.53 for both, P<0.001). Secondary Gleason pattern grade from the biopsy site
with the highest tumor volume on the needle biopsy correlated with secondary
Gleason pattern grade at radical prostatectomy slightly better than those from
the biopsy site with the highest Gleason score (Spearman correlation
coefficient, 0.32 vs 0.24; both P<0.001). Our data indicate that the highest
Gleason score from all sites and the Gleason score from the site with the
highest tumor volume on the needle biopsy are equally and significantly
predictive of final Gleason score on radical prostatectomy. Both methods of
prediction are significantly predictive of primary and secondary Gleason pattern
grade on radical prostatectomy. We recommend that the highest Gleason score from
all positive biopsy sites should be used when assigning an initial score using
needle biopsies. High Gleason score 8 to 10 adenocarcinoma is the most aggressive and potentially
lethal form of prostate cancer. The 2005 International Society of Urological
Pathology (ISUP)-modified Gleason grading scheme defines several gland
arrangements of high Gleason grade patterns 4 and 5. The aim of this
investigation was to quantitate the frequency of the ISUP-defined high Gleason
grade patterns in needle biopsy tissue, to determine the common admixtures and
to characterize patterns not presented in the 2005 ISUP report. For patients who
underwent radical prostatectomy, we analyzed for association of specific
high-grade patterns in needle biopsy with extraprostatic extension in radical
prostatectomy tissues. A total of 268 prostate needle biopsy cases with Gleason
score of 8 to 10 were examined. A mean of 3.6 patterns (range, 1 to 8) were
identified per case and only 12% of cases had a pure single pattern. Ill-defined
glands with poorly formed lumina (at 57%) and fused microacinar glands (at 53%)
comprised the predomit and most frequently admixed patterns. Single cells and
single signet ring cells were present in 53% and 31% of cases, respectively.
Additional patterns in order of frequency included cords (35%), cribriform
glands (25%), sheets of cells (19%), chains (4%), glomeruloid (3%),
comedonecrosis (2%), and hypernephromatoid (1 case=0.3%). Gleason score 8 to 10
carcinomas are typically extensive in needle core tissue, with a mean of 4.4
positive cores (range, 1 to 15 cores) per case. Only 14 cases (5%) had
high-grade minimal carcinoma measuring <1 mm in needle core tissue. Gleason
grade patterns not described in the 2005 ISUP report include single file growth,
solid cylinders, and nested patterns. The single file pattern was present in 40%
of cases, and the small solid nested pattern was detected in 24% of cases. One
case displayed solid cylinders. Only the single file pattern was associated with
extraprostatic extension at radical prostatectomy (P=0.005). These results show
that the 2005 ISUP-defined patterns of high Gleason score 8 to 10 prostatic
adenocarcinoma can be stratified on the basis of frequency of occurrence in
needle biopsy tissue. Three patterns not defined in the 2005 ISUP scheme have
been characterized, including single file, nested, and solid cylinder
arrangements. As aggressive and potentially lethal prostate cancer is most often
of Gleason score 8 to 10, it is important for diagnostic recognition purposes to
be aware of the frequency of various patterns encountered in high Gleason score
8 to 10 adenocarcinomas, the types of pattern admixtures, and the
histomorphologic presentation of unusual patterns. We propose that Gleason grade
assignments should incorporate single file, solid nested, and solid cylinder
arrangements as high-grade pattern 5 because of the absence of glandular luminal
space formation. Patients with Gleason score 7 prostate cancer on radical prostatectomy
demonstrate a wide range in clinical outcome. Gleason grade 4 prostate cancer
encompasses a heterogeneous group of tumor growth patterns including fused,
ill-defined, cribriform, and glomeruloid glandular structures. Our objective was
to determine the prognostic value of different Gleason grade 4 growth patterns.
We performed a nested case-control study among 535 patients with Gleason score 7
prostate cancer at radical prostatectomy, treated between March 1985 and July
2013 at a university hospital in the Netherlands. We analyzed 52 cases (with
metastasis, disease-specific mortality or both) and 109 controls, matched for
age, PSA level, and pT stage. Presence of the following Gleason grade 4 patterns
was recorded: fused, ill-defined, cribriform, and glomeruloid. Intraductal
carcinoma of the prostate and tertiary Gleason grade 5 were additionally
assessed. Outcomes were metastasis-free survival and disease-specific survival.
We used Cox proportional hazards regression to determine the predictive value of
Gleason grade 4 patterns for survival time. The overall prevalence of Gleason
grade 4 patterns was as follows: fused 75% (n=121), ill-defined 64% (n=102),
cribriform 48% (n=83), and glomeruloid 25% (n=40). Cribriform pattern was the
only pattern with an unequal distribution between cases and controls. Forty-two
out of 52 cases (81%) had cribriform growth pattern versus 41/109 controls
(38%). In multivariate analysis, presence of cribriform growth was an adverse
independent predictor for distant metastasis-free survival (HR 8.0, 95% CI
3.0-21; P<0.001) and disease-specific survival (HR 5.4, 95% CI 2.0-15, P=0.001).
In conclusion, cribriform growth in Gleason grade 4 is a strong prognostic
marker for distant metastasis and disease-specific death in patients with
Gleason score 7 prostate cancer at radical prostatectomy. Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma (PCa) on
core biopsy (NBX) is critical because it is associated with disease progression
and the worst clinical outcome. We evaluated 1557 consecutive and prospectively
collected NBXs to determine the frequency of diagnosis, morphologic subpatterns,
and their relation to the amount and pattern distribution of GP5 PCa based on
the 2005 modified Gleason grading system. Tertiary GP5 was upgraded to a
secondary pattern to derive the final Gleason score. GP5 accounted for 6% of all
NBXs and 14% of PCa cases. GP5 PCas were associated with high-risk preoperative
clinical and biopsy characteristics, regardless of the amount of GP5. Most
patients (85%) with % GP5 greater than 5% of PCa had the final Gleason score of
9 to 10, compared with % GP5 of 5% or less of PCa (P < .0001). The morphologic
subpatterns of GP5 PCas were as follows: infiltrating cords (96%), single cells
(76%), solid sheets (29%), and comedocarcinoma (2%). Infiltrating cords and
single-cell patterns frequently coexisted (76%). The GP5 was distributed in a
tertiary (66%), followed by secondary (32%) and primary (2%) components of PCa.
Infiltrating cords and single cells were the 2 most frequently encountered
patterns, specifically when GP5 involved 5% or less of PCa and represented
secondary or tertiary component of PCa. GP5 PCa is a relatively frequent
presentation in the contemporary NBX practice. Because of its important
prognostic and therapeutic implications, pathologists must be aware of its
varied morphologic presentations and to the fact that most cases with GP5
represent a tertiary component of PCa. The Gleason score remains the most reliable prognosticator in men with prostate
cancer. One of the recent important modifications in the Gleason grading system
recommended from the International Society of Urological Pathology consensus
conference is recording the percentage of Gleason pattern 4 in the pathology
reports of prostate needle biopsy and radical prostatectomy cases with Gleason
score 7 prostatic adenocarcinoma. Limited data have indeed suggested that the
percent Gleason pattern 4 contributes to stratifying the prognosis of patients
who undergo radical prostatectomy. An additional obvious benefit of reporting
percent pattern 4 includes providing critical information for treatment
decisions. This review summarizes and discusses available studies assessing the
utility of the percentage of Gleason pattern 4 in the management of prostate
cancer patients. The Gleason score is an important parameter for clinical outcome in prostate
cancer patients. Gleason score 8 is a heterogeneous disease including Gleason
score 3 + 5, 4 + 4, and 5 + 3 tumors, and encompasses a broad range of tumor
growth patterns. Our objective was to characterize individual growth patterns
and identify prognostic parameters in Gleason score 8 prostate cancer patients.
We reviewed 1064 radical prostatectomy specimens, recorded individual Gleason 4
and 5 growth patterns as well as presence of intraductal carcinoma, and
evaluated biochemical recurrence- and metastasis-free survival. Gleason score 8
disease was identified in 140 (13%) patients, of whom 76 (54%) had Gleason score
3 + 5, 46 (33%) 4 + 4, and 18 (13%) 5 + 3 disease. Invasive cribriform and/or
intraductal carcinoma (n = 87, 62%) was observed more frequently in Gleason
score 4 + 4 (93%) than 3 + 5 (47%; P < 0.001) and 5 + 3 (44%; P < 0.001)
patients. Gleason pattern 5 was present in 110 (79%) men: as single cells and/or
cords in 99 (90%) and solid fields in 32 (29%) cases. Solid field pattern 5
coexisted with cribriform architecture (23/32, 72%) more frequently than
nonsolid pattern 5 cases (36/78, 46%, P = 0.02). In multivariable analysis
including age, prostate-specific antigen, pT-stage, surgical margin status, and
lymph node metastases, presence of cribriform architecture was an independent
parameter for biochemical recurrence-free (hazard ratio (HR) 2.0, 95% confidence
interval (CI) 1.0-3.7; P = 0.04) and metastasis-free (HR 3.5, 95% CI 1.0-12.3;
P = 0.05) survival. In conclusion, invasive cribriform and/or intraductal
carcinoma occurs more frequently in Gleason score 4 + 4 prostate cancer patients
than in Gleason score 3 + 5 and 5 + 3, and is an independent parameter for
biochemical recurrence and metastasis. Therefore, cribriform architecture has
added value in risk stratification of Gleason score 8 prostate cancer patients. |
How does FTO suppress pancreatic tumorigenesis? | Reduced expression of the m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO demethylated the m6A modification of praja ring finger ubiquitin ligase 2 (PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and ultimately restraining the proliferation, invasion, and metastasis of pancreatic cancer cells. | Pancreatic cancer is the deadliest maligcy of the digestive system and is the
seventh most common cause of cancer-related deaths worldwide. The incidence and
mortality of pancreatic cancer continue to increase, and its 5-year survival
rate remains the lowest among all cancers. N6-methyladenine (m6A) is the most
abundant reversible RNA modification in various eukaryotic messenger and long
noncoding RNAs and plays crucial roles in the occurrence and development of
cancers. However, the role of m6A in pancreatic cancer remains unclear. The
present study aimed to explore the role of m6A and its regulators in pancreatic
cancer and assess its underlying molecular mechanism associated with pancreatic
cancer cell proliferation, invasion, and metastasis. Reduced expression of the
m6A demethylase, fat mass and obesity-associated protein (FTO), was responsible
for the high levels of m6A RNA modification in pancreatic cancer. Moreover, FTO
demethylated the m6A modification of praja ring finger ubiquitin ligase 2
(PJA2), thereby reducing its mRNA decay, suppressing Wnt signaling, and
ultimately restraining the proliferation, invasion, and metastasis of pancreatic
cancer cells. Altogether, this study describes new, potential molecular
therapeutic targets for pancreatic cancer that could pave the way to improve
patient outcome. |
Which tool has been developed to identify the glycan shielding of glycosylated proteins? | GLYCO (GLYcan COverage) is an in silico approach to quantify the glycan shielding of a protein surface. The software provides insights into glycan-dense/sparse regions of the entire protein surface or a subset of the protein surface. GLYCO calculates glycan shielding from a single coordinate file or from multiple coordinate files, for instance, as obtained from molecular dynamics simulations or by nuclear magnetic resonance spectroscopy structure determination, enabling analysis of glycan dynamics. | |
What are the targets of Tirbanibulin? | Tirbanibulin is Src kinase signaling inhibitor and tubulin polymerisation inhibitor that is being developed for the topical treatment of actinic keratosis, and psoriasis. | BACKGROUND: Current field-directed treatments of actinic keratosis (AK), a
pre-maligt condition, are often limited by severe local reactions and/or
complex treatment. Tirbanibulin, a novel potent anti-proliferative synthetic
agent that inhibits tubulin polymerization and Src kinase signalling, is being
developed as a convenient, safe, and effective field treatment of actinic
keratosis.
HYPOTHESIS: A short course of tirbanibulin ointment 1% safely reduces AK
lesions.
METHODS: In the Phase 1 study, 4 treatment cohorts with forearm lesions received
tirbanibulin ointment 1% over 25 or 100 cm2 once daily for 3 or 5 days and were
evaluated through day 45. In the Phase 2 study, 2 treatment cohorts with face or
scalp lesions received tirbanibulin ointment 1% once daily for 3 or 5 days over
25 cm2 and were evaluated through day 57. Lesion reductions, clearance rates,
safety, and pharmacokinetics were assessed.
RESULTS: Forearm AK lesions were reduced by day 45 in all Phase 1 cohorts
(N=30). Complete AK clearance at day 57 for face/scalp AK lesions in Phase 2
cohorts (N=168) was demonstrated in 43% and 32% of participants of the 5-day and
3-day cohorts, respectively. Adverse reactions were mainly transient mild local
erythema and flaking/scaling, pruritus, and pain. Tirbanibulin plasma
concentrations were low or undetectable.
CONCLUSION: Tirbanibulin ointment 1% was well tolerated and active in AK
reduction. Based on activity, the 5-day regimen was selected for Phase 3
development. Clinicaltrials.gov: NCT02337205; NCT02838628 J Drugs Dermatol.
2020;19(11):1093-1100. doi:10.36849/JDD.2020.5576THIS ARTICLE HAD BEEN MADE
AVAILABLE FREE OF CHARGE. PLEASE SCROLL DOWN TO ACCESS THE FULL TEXT OF THIS
ARTICLE WITHOUT LOGGING IN. NO PURCHASE NECESSARY. PLEASE CONTACT THE PUBLISHER
WITH ANY QUESTIONS. BACKGROUND: The tubulin polymerization and Src kinase signaling inhibitor
tirbanibulin is being investigated as a topical treatment for actinic keratosis,
a precursor of squamous-cell carcinoma.
METHODS: In two identically designed double-blind trials, we randomly assigned,
in a 1:1 ratio, adults with actinic keratoses on the face or scalp to receive
either topical tirbanibulin or vehicle (placebo) ointment. The ointment was
applied by the patients to a 25-cm2 contiguous area containing four to eight
lesions once daily for 5 consecutive days. The primary outcome was the
percentage of patients with a complete (100%) reduction in the number of lesions
in the application area at day 57. The secondary outcome was the percentage of
patients with a partial (≥75%) reduction in the number of lesions within the
application area at day 57. The incidence of recurrence was evaluated at 1 year.
Local reactions were scored with the use of 4-point scale (ranging from 0
[absent] to 3 [severe]).
RESULTS: A total of 702 patients were enrolled in the two trials (351 patients
per trial). Complete clearance in trial 1 occurred in 44% of the patients (77 of
175) in the tirbanibulin group and in 5% of those (8 of 176) in the vehicle
group (difference, 40 percentage points; 95% confidence interval [CI], 32 to 47;
P<0.001); in trial 2, the percentages were 54% (97 of 178 patients) and 13% (22
of 173), respectively (difference, 42 percentage points; 95% CI, 33 to 51;
P<0.001). The percentages of patients with partial clearance were significantly
higher in the tirbanibulin groups than in the vehicle groups. At 1 year, the
estimated percentage of patients with recurrent lesions was 47% among patients
who had had a complete response to tirbanibulin. The most common local reactions
to tirbanibulin were erythema in 91% of the patients and flaking or scaling in
82%. Adverse events with tirbanibulin were application-site pain in 10% of the
patients and pruritus in 9%, all of which resolved.
CONCLUSIONS: In two identically designed trials, tirbanibulin 1% ointment
applied once daily for 5 days was superior to vehicle for the treatment of
actinic keratosis at 2 months but was associated with transient local reactions
and recurrence of lesions at 1 year. Trials comparing tirbanibulin with
conventional treatments and that have longer follow-up are needed to determine
the effects of tirbanibulin therapy on actinic keratosis. (Funded by Athenex;
ClinicalTrials.gov numbers, NCT03285477 and NCT03285490.). Tirbanibulin (Klisyri®) is a first-in-class Src kinase signaling inhibitor and
tubulin polymerisation inhibitor being developed by Athenex in conjunction with
global partners for the topical treatment of actinic keratosis, and psoriasis.
Based on the data from two pivotal phase III trials the drug was recently
approved for marketing in the US as a topical treatment for actinic keratosis.
This article summarizes the milestones in the development of tirbanibulin
leading to this first approval. Tirbanibulin (KX-01) is the first clinical Src inhibitor of the novel
peptidomimetic class that targets the peptide substrate site of Src providing
more specificity toward the Src kinase. This study assessed the impact of KX-01
on cobalt chloride (CoCl2)-treated L929 cells and bleomycin (BLM)-induced
pulmonary fibrosis in rats to evaluate the efficacy of this compound in vitro
and in vivo, respectively. In CoCl2-treated L929 cells, KX-01 significantly
reduced the expression of smooth muscle actin (α-SMA), collagen I, collagen III,
hypoxia inducing factor (HIF-1α), signal transducers and transcriptional
activators (p-STAT3), and p-Src. In BLM-induced pulmonary fibrosis rats, KX-01
reduced pathological scores, collagen deposition, α-SMA, collagen I, collagen
III, p-Src, HIF-1α, and p-STAT3. Overall, these findings revealed that KX-01 can
alleviate experimental pulmonary fibrosis via suppressing the p-SRC/p-STAT3
signaling pathways. Tirbanibulin is a novel tubulin polymerization and Src kinase signaling
inhibitor. This study was designed to fully characterize tirbanibulin
pharmacokinetics (PK) when applied topically under maximal use conditions. This
was an open-label, parallel-group PK safety study of tirbanibulin ointment 1%
applied to 25 cm2 of the face or balding scalp in adults with actinic keratosis
(AK). Eligible subjects self-applied tirbanibulin once-daily for 5 days. PK
sampling occurred on days 1, 3 and 4 at 0 hour (before dosing), and on day 5 at
prespecified time points up to 24 hours after application. Safety assessments
included adverse events and local skin reactions were evaluated up to day 29.
Eighteen subjects (face or scalp, n = 9 each) completed the study. Subjects were
White (100%), of mean [range] age 66.4 [43-83] years, predomitly men (83.3%)
with Fitzpatrick skin type I to III (94.4%); baseline AK lesion count, mean
[range] 8.2 [6-14]. All subjects had quantifiable but low plasma concentrations
of tirbanibulin. On day 5, overall mean (standard deviation) maximum
concentration (Cmax ) was 0.26 (0.23) ng/mL (or 0.60 nM), median time to maximum
concentration was 6.91 hours, and mean (standard deviation) area under the
plasma concentration-time curve from time 0 to 24 hours was 4.09 (3.15) ng ∙
h/mL. Four subjects experienced a total of 5 treatment-emergent adverse events
that resolved. Mild to moderate erythema, flaking, or scaling in the treatment
area peaked around day 8 before resolving or returning to baseline by day 29. In
conclusion, under maximal use conditions, tirbanibulin ointment 1% for 5 days in
the treatment of AK on the face or scalp was well tolerated and resulted in low
systemic exposure with subomolar plasma concentrations. |
Is retinol binding protein 4 an adipokine? | Yes,
Retinol-binding protein 4 (RBP4) is a prominent adipokine. | Pancreatic β-cell dysfunction plays a decisive role in the progression of type 2
diabetes. Retinol-binding protein 4 (RBP4) is a prominent adipokine in type 2
diabetes, although its effect on β-cell function remains elusive, and the
underlying mechanisms are unknown. Here, we found that elevated circulating RBP4
levels were inversely correlated with pancreatic β-cell function in db/db mice
across different glycemic stages. RBP4 directly suppressed glucose-stimulated
insulin secretion (GSIS) in primary isolated islets and INS-1E cells in a dose-
and time-dependent manner. RBP4 transgenic (RBP4-Tg) overexpressing mice showed
a dynamic decrease of GSIS, which appeared as early as 8 weeks old, preceding
the impairment of insulin sensitivity and glucose tolerance. Islets isolated
from RBP4-Tg mice showed a significant decrease of GSIS. Mechanistically, we
demonstrated that the stimulated by retinoic acid 6 (STRA6), RBP4's only known
specific membrane receptor, is expressed in β-cells and mediates the inhibitory
effect of RBP4 on insulin synthesis through the Janus kinase 2/STAT1/ISL-1
pathway. Moreover, decreasing circulating RBP4 level could effectively restore
β-cell dysfunction and ameliorate hyperglycemia in db/db mice. These
observations revealed a role of RBP4 in pancreatic β-cell dysfunction, which
provides new insight into the diabetogenic effect of RBP4. CONTEXT: Data on the presence/quantification of the neurotrophic adipokines
retinol-binding protein-4 (RBP4), clusterin, and pigment epithelium-derived
factor (PEDF) in human cerebrospinal fluid (CSF) are scarce and migration of
these adipokines across of the blood-brain barrier (BBB) is uncertain.
OBJECTIVE: This work aimed to quantify RBP4, PEDF, and clusterin in paired serum
and CSF samples of patients undergoing neurological evaluation.
METHODS: A total of 268 patients (109 male, 159 female) were included. Adipokine
serum and CSF concentrations were measured by enzyme-linked immunosorbent assay
in duplicate.
RESULTS: RBP4 was abundant in serum (mean, 31.9 ± 24.2 μg/mL). The serum
concentrations were approximately 145 times higher than in CSF (CSF to serum
RBP4 ratio, 8.2 ± 4.3 × 10-3). PEDF was detectable in serum (mean, 30.2 ± 11.7
μg/mL) and concentrations were approximately 25 times higher than in CSF (CSF to
serum PEDF ratio, 42.3 ± 15.6 × 10-3). Clusterin serum concentrations were
abundant with mean levels of 346.0 ± 114.6 μg/mL, which were approximately 40
times higher than CSF levels (CSF to serum clusterin ratio, 29.6 ± 23.4 × 10-3).
RBP4 and PEDF serum levels correlated positively with CSF levels, which were
increased in overweight/obese patients and in type 2 diabetic patients. The CSF
concentrations of all 3 adipokines increased with BBB dysfunction. RBP4 in CSF
correlated positively with inflammatory parameters. In detail, only RBP4 showed
the kinetics and associations that are mandatory for a putative mediator of the
fat-brain axis.
CONCLUSION: RBP4, PEDF, and clusterin are permeable to the BBB and increase with
the measure of BBB dysfunction. RBP4 represents an inflammatory neurotrophic
adipokine and is a promising mediator of the fat-brain axis. |
What is the function of BACH1 | BACH1) is the first mammalian heme-binding transcription factor that belongs to the basic region leucine zipper (bZIP) family and a member of CNC (cap 'n' collar | BRCA1 interacts in vivo with a novel protein, BACH1, a member of the DEAH
helicase family. BACH1 binds directly to the BRCT repeats of BRCA1. A BACH1
derivative, bearing a mutation in a residue that was essential for catalytic
function in other helicases, interfered with normal double-strand break repair
in a manner that was dependent on its BRCA1 binding function. Thus, BACH1/BRCA1
complex formation contributes to a key BRCA1 activity. In addition, germline
BACH1 mutations affecting the helicase domain were detected in two early-onset
breast cancer patients and not in 200 matched controls. Thus, it is conceivable
that, like BRCA1, BACH1 is a target of germline cancer-inducing mutations. Heme oxygenase 1 (HO-1) catalyzes heme breakdown, eventually releasing iron,
carbon monoxide, and bilirubin IXalpha. HO-1 is induced by its substrate heme
and various environmental factors, which represents a protective response
against oxidative stresses. Here we show that hypoxia represses HO-1 expression
in three human cell types but induces it in rat, bovine, and monkey cells,
indicating the inter-species difference in the hypoxic regulation of HO-1
expression. The hypoxia-mediated repression of HO-1 expression is consistently
associated with the induction of Bach1, a heme-regulated transcriptional
repressor, in human cells. Bach1 is a basic leucine zipper protein, forming a
heterodimer with a small Maf protein. Expression of HO-1 was also reduced in
human cells when exposed to interferon-gamma or an iron chelator
desferrioxamine, each of which induced Bach1 expression. In contrast, induction
of HO-1 expression by CoCl(2) is associated with reduced expression of Bach1
mRNA. Thus, expression of HO-1 and Bach1 is inversely regulated. We have
identified a Maf recognition element in the human HO-1 gene that is required for
repression of a reporter gene by hypoxia and targeted by Bach1. Therefore, Bach1
functions as a hypoxia-inducible repressor for the HO-1 gene, thereby
contributing to fine-tuning of oxygen homeostasis in human cells. Bach1 is a transcriptional repressor of the cytoprotective enzyme heme
oxygenase-1 (HO-1). Although HO-1 protects against atherosclerosis, the function
of Bach1 in this process is poorly understood. We isolated peritoneal
macrophages and aortic smooth muscle cells (SMC) from wild-type and
bach1-deficient mice. bach1-Deficient macrophages expressed increased levels of
HO-1 and showed elevated phagocytic activity when incubated with 0.75 microm
microspheres. In SMC, bach1-ablation resulted in increased expression of HO-1
and decreased proliferation in bromodeoxyuridine incorporation assay as compared
with wild-type cells. The up-regulated phagocytic activity and reduced SMC
proliferation of bach1-deficient cells were not restored by Zinc (II)
protoporphyrin IX, an inhibitor of HO, suggesting that HO-independent mechanisms
are also involved in the regulation of phagocytosis of macrophages and
proliferation of SMC by Bach1. In wild-type mice, cuff placement around femoral
artery caused pronounced intimal proliferation without affecting the media, thus
resulting in intimal to medial (I/M) volume ratio of 65.6%. bach1-deficient mice
had less degree of intimal growth (I/M ratio of 45.6%). These results indicate
that Bach1 plays a critical role in the regulation of HO-1 expression,
macrophage function, SMC proliferation and neointimal formation. Bach1 may
regulate gene expression in these cells during inflammation and atherogenesis. Bach1 functions as a transcriptional repressor of heme oxygenase-1 (HO-1) and
the beta-globin genes. The enhancer regions of these genes contain multiple Maf
recognition elements (MAREs) to which Bach1 can bind. Previous studies have
shown that increased levels of heme and cadmium induce the nuclear export of
Bach1, resulting in cytoplasmic accumulation. By means of a yeast two hybrid
screening using Bach1 as bait, we identified the intracellular hyaluronic acid
binding protein (IHABP) as a potential regulator of Bach1. IHABP is a
microtubule-associated protein that may regulate the organization of the
cytoskeletal network. A series of domain analyses revealed that a region of
Bach1 previously implicated in cytoplasmic accumulation was necessary for
IHABP-binding. A C-terminal region of IHABP was necessary for Bach1-binding.
Overexpressed Bach1 colocalized with IHABP in the cytoplasm, forming fiber-like
structures on microtubules. Fluorescence recovery after photobleaching (FRAP)
analysis revealed a dynamic nature of the Bach1-IHABP interaction in living
cells. The repression of HO-1 reporter activity by Bach1 was attenuated by
co-transfecting IHABP in a dose-dependent manner. Moreover, the overexpression
of IHABP induced the endogenous HO-1 gene in NIH3T3 cells. The overall results
suggest that IHABP regulates the subcelluar localization of Bach1 in order to
fine-tune transactivation of Bach1 target genes such as HO-1. The link between defects in BRCA1 and breast cancer development may be best
understood by deciphering the role of associated proteins. BRCA1 associated
C-terminal helicase (BACH1) interacts directly with the BRCA1 C-terminal BRCT
repeats, which are important for BRCA1 DNA repair and are mutated in the
majority of BRCA1 familial cancers. Thus, BACH1 is a likely candidate for
mediating BRCA1 DNA repair and tumor suppression functions. Although previous
evidence using overexpression of a domit negative BACH1 has suggested that
BACH1 is involved in BRCA1-DNA repair function, our results using BACH1
deficient cells provide direct evidence for involvement of BACH1 in DNA repair
as well as for localizing BRCA1. Following DNA damage BACH1 is modified by
phosphorylation, displays a BRCA1-like nuclear foci pattern and colocalizes with
gamma-H2AX. Given that the BACH1/BRCA1 complex is unaltered by DNA damage and
the intensity of BRCA1 foci is diminished in BACH1 deficient cells, BACH1 may
serve to not only facilitate DNA repair, but also maintain BRCA1 in DNA damage
foci. The mammalian transcription factor Bach1 functions as a repressor of the
enhancers of heme oxygenase-1 (HO-1) gene (Hmox-1) by forming heterodimers with
the small Maf proteins such as MafK. The transcription of Hmox-1 is regulated by
the substrate of HO-1, heme. Heme induces expression of Hmox-1 in part by
inhibiting the binding of Bach1 to the enhancers and inducing the nuclear export
of Bach1. A dipeptide motif of cysteine and proline (CP motif) in Bach1 is
essential for the heme-mediated regulation. In this study, we show that five
molecules of heme bind to Bach1 by the heme-titration assay. The Bach1-heme
complex exhibits an absorption spectrum with a major Soret peak at 371 nm and
Raman band at 343 cm(-1) in high amounts of heme and a spectrum containing the
major Soret peak at 423 nm at low heme concentrations. The spectroscopic
characterization indicates that Bach1 has two kinds of heme-binding sites with
different coordination structures. Mutagenesis studies have established that
four molecules of heme bind to the cysteine residues of four CP motifs in the C
terminus of Bach1. These results raise the possibility that two separated
activities of Bach1, DNA-binding and nuclear export, are regulated by heme
binding at the different CP motifs of Bach1 respectively, but not by cooperative
heme-binding. Intracellular heme is a redox active molecule that can be detrimental to cells
at high concentrations or under oxidizing conditions. To prevent accumulation,
the inducible enzyme heme oxygenase-1 (HMOX1) catalyzes degradation of heme. In
the absence of elevated intracellular heme or oxidative stress, the basic region
leucine zipper transcriptional regulator BACH1 binds HMOX1 antioxidant response
elements and represses transcription. Conversely, increased intracellular heme
or sulfhydryl oxidation inactivate BACH1, permitting transcriptional induction
of HMOX1. Here, we investigate the effect of BACH1 inactivation on the induction
of HMOX1 and as a mechanism for broader gene induction. We show that BACH1 is
inactivated at low micromolar arsenite concentrations and that BACH1
inactivation is necessary and sufficient for transcriptional induction of HMOX1.
Because BACH1 is thought to interact with antioxidant response element motifs,
we further examined the role of BACH1 as a regulator of inducible antioxidant
gene expression by assessing the global profile of gene expression following
BACH1 knockdown using small interfering RNA. The loss of BACH1 function in human
keratinocytes results almost exclusively in HMOX1 induction, suggesting that
BACH1 may function as a rheostat regulating levels of intracellular free heme. Oxidative stress has been implicated in tissue damage from traumatic brain
injury. Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades prooxidant
heme to radical-scavenging biliverdin/bilirubin in order to protect cells from
oxidative stress. Although HO-1 is induced after induction of brain damage, the
regulatory mechanism of HO-1 in the brain is still unclear. Bach1 is a
transcriptional repressor of the HO-1 gene, and plays a critical role in tissue
protection from oxidative stress by reperfusion injury of the myocardium. In
this study, we examined the role of Bach1 in HO-1 regulation of the various
brain sites by investigating the expression of Bach1 and HO-1 in brain tissues
of mice bearing Bach1-deficient (Bach1(-/-)) or wild-type (Bach1(+/+)) genes.
While the expression levels of Bach1 mRNA in the olfactory bulb were
significantly higher than other brain areas, those at the cortex showed the
lowest activity. Bach1(-/-) mice showed significantly higher HO-1 mRNA
expression levels than Bach1(+/+) mice in all brain sites studied. Moreover,
higher induction of HO-1 was observed around damaged tissues after cold injury
in Bach1(-/-) than Bach1(+/+) mice. Thus, Bach1 plays an important role in
regulating the constitutive and inducible expression levels of HO-1 in the
brain. Although a significantly higher level of HO-1 was observed in Bach1(-/-)
than Bach1(+/+) mice, genetic ablation of the Bach1 gene failed to show any
tissue protective effect after cold injury was inflicted on the cortex. Bach1 is a transcriptional repressor of the heme oxygenase (HO)-1 gene.
Bach1-null (Bach1(-/-)) mice are reported to be protected from myocardial
ischemia/reperfusion injury; however, the effect of Bach1 disruption on another
oxidative stress model of hyperoxic lung injury has yet to be determined. To
investigate the role of Bach1 in hyperoxic lung injury, Bach1(-/-) mice and
wild-type (WT) mice were exposed to 90% O(2). During hyperoxic exposure, the
survival of Bach1(-/-) mice was significantly longer than that of WT mice.
However, the administration of zinc protoporphyrin, an inhibitor of HO-1
activity, did not change the mortality in either of the mice, thus suggesting
that this protective effect was not mediated by an HO-1 overexpression in
Bach1(-/-) mice. The indices of lung injury in the lungs of Bach1(-/-) mice were
lower than those of WT mice; unexpectedly, however, the levels of IL-6 in
bronchoalveolar lavage (BAL) fluid from Bach1(-/-) mice were significantly
higher than those of WT mice. Interestingly, the intrapulmonary administration
of small interfering RNA against IL-6 was shown to reduce the IL-6 levels in BAL
fluids and shorten the survival in Bach1(-/-) mice during hyperoxic exposure. In
addition, a chromatin immunoprecipitation analysis revealed the binding of Bach1
to the IL-6 promoter and its detachment after oxidative stress. Considering the
previous observation that the transgenic mice overexpressing IL-6 are protected
from hyperoxic lung injury, these results therefore indicate that IL-6 mediates
an increased survival in Bach1(-/-) mice during hyperoxic exposure. Bach1 is a member of the basic leucine zipper transcription factor family, and
the Bach1/small Maf heterodimer specifically represses transcriptional activity
directed by the Maf recognition element (MARE). Because Bach1 is a repressor of
the oxidative stress response, we examined the function(s) of Bach1 in
keratinocytes subjected to oxidative stress. Oxidative stress induced by
H(2)O(2) led to an increase in MARE activity and expression of heme oxygenase-1
(HO-1), an inducible antioxidant defense enzyme. Bach1 depletion by small
interfering RNAs or by deletion of Bach1 enhanced HO-1 expression in the absence
of H(2)O(2), indicating that Bach1 is a critical repressor of HO-1 in
keratinocytes. Although Bach1-deficient or -reduced keratinocytes expressed
higher levels of HO-1 than control cells in response to H(2)O(2), Bach1
down-regulation did not attenuate the production of reactive oxygen species by
H(2)O(2). In contrast, Bach1 overexpression abolished HO-1 induction by
H(2)O(2), which led to increased reactive oxygen species accumulation. HO-1 was
induced during keratinocyte differentiation, but MARE activity did not change
during differentiation. Furthermore, Bach1 overexpression did not inhibit
differentiation-associated induction of HO-1 expression, suggesting that HO-1
induction in differentiation is independent of Bach1. Thus, in response to
oxidative stress, Bach1 regulates the oxidation state through the negative
control of HO-1 expression prior to terminal keratinocyte differentiation.
However, Bach1-mediated repression is negated during keratinocyte
differentiation. A central mechanism in cellular defence against oxidative or electrophilic
stress is mediated by transcriptional induction of genes via the ARE
(antioxidant-response element), a cis-acting sequence present in the regulatory
regions of genes involved in the detoxification and elimination of reactive
oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine
zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid
2-related factor 2) that functions as a transcriptional activator via
heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is
relatively well understood, the mechanisms by which ARE-mediated signalling is
down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex,
tramtrack and bric-a-brac) and CNC (cap'n'collar protein) homology 1] binds to
ARE-like sequences, functioning as a transcriptional repressor in a subset of
ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the
present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it
is induced by Nrf2 overexpression and by Nrf2-activating agents in an
Nrf2-dependent manner. Furthermore, a functional ARE site was identified at
+1411 from the transcription start site of transcript variant 2 of BACH1. We
conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1
by Nrf2 may serve as a feedback-inhibitory mechanism for ARE-mediated gene
regulation. Up-regulation of heme oxygenase 1 (HO-1) by ultraviolet A (UVA; 320-380 nm)
irradiation of human skin cells protects them against oxidative stress. The role
of Nrf2 in up-regulation of HO-1 and other phase II genes is well established.
The mechanism underlying Bach1-mediated HO-1 repression is less well understood
although cellular localization seems to be crucial. Because prolonged HO-1
overexpression is likely to be detrimental, it is crucial that activation of the
gene is transient. We now show that UVA irradiation of cultured human skin
fibroblasts enhances accumulation of Bach1 mRNA and protein severalfold.
Endogenous Bach1 protein accumulates in the nucleus after 8h and may occupy MARE
sites after HO-1 activation thus providing a compensatory mechanism to control
HO-1 overexpression. Overexpression of Bach1, together with MafK, represses
basal and UVA-mediated HO-1 protein expression, whereas silencing of the Bach1
gene by Bach1-specific siRNAs causes robust enhancement of constitutive HO-1
levels. UVA treatment of cells in which Bach1 has been silenced leads to higher
levels of induction of the HO-1 protein. Although Bach1 protein is exported from
the nucleus 12h after UVA irradiation, the release of free cellular heme from
microsomal heme-containing proteins is immediate rather than delayed. Although
heme does promote the export of Bach1 via the Crm1/exportin 1 pathway and is
involved in the delayed UVA-mediated export of the protein, it is not clear how
this occurs. Cellular senescence prevents the aberrant proliferation of damaged cells. The
transcription factor Bach1 binds to p53 to repress cellular senescence, but it
is still unclear how the Bach1-p53 interaction is regulated. We found that the
Bach1-p53 interaction was inhibited by oncogenic Ras, bleomycin, and hydrogen
peroxide. Proteomics analysis of Bach1 complex revealed its interaction with
p19(ARF), a tumor suppressor that competitively inhibited the Bach1-p53
interaction when overexpressed within cells. Reduction of MDM2 expression in
wild-type murine embryonic fibroblasts (MEFs) did not result in slower
proliferation, showing that Bach1 plays a role in keeping the proliferation of
MEFs independent of MDM2. Consistent with this interpretation, expression of p21
was highly induced in MEFs when both Bach1 and MDM2 were abrogated. The level of
Bach1 protein was reduced on knockdown of p53. These results suggest that p53
activation involves its dissociation from Bach1, achieved in part by the
competitive binding of p19(ARF) to Bach1. The p19(ARF)-Bach1 interaction
constitutes a regulatory pathway of p53 in parallel with the p19(ARF)-MDM2
pathway. OBJECTIVE: The diverse clinical phenotype of hemoglobin E (HbE)/β-thalassemia
has not only confounded clinicians in matters of patient management but has also
led scientists to investigate the complex mechanisms involved in maintaining the
delicate red cell environment where, even with apparent similarities of α- and
β-globin genotypes, the phenotype tells a different story. The BTB and CNC
homology 1 (BACH1) protein is known to regulate α- and β-globin gene
transcriptions during the terminal differentiation of erythroid cells. With the
mutations involved in HbE/β-thalassemia disorder, we studied the role of BACH1
in compensating for the globin chain imbalance, albeit for fine-tuning purposes.
MATERIALS AND METHODS: A total of 47 HbE/β-thalassemia samples were analyzed
using real-time quantitative polymerase chain reaction and correlated with age,
sex, red blood cell parameters, globin gene expressions, and some clinical data.
RESULTS: The BACH1 expression among the β-thalassemia intermedia patients varied
by up to 2-log differences and was positively correlated to age; α-, β-, and
γ-globin gene expression level; and heme oxygenase 1 protein. BACH1 was also
negatively correlated to reticulocyte level and had a significant correlation
with splenectomy.
CONCLUSION: This study indicates that the expression of BACH1 could be elevated
as a compensatory mechanism to decrease the globin chain imbalance as well as to
reduce the oxidative stress found in HbE/β-thalassemia. Oxidative stress plays an essential role in inflammation and fibrosis. Bach1 is
an important transcriptional repressor that acts by modulating oxidative stress
and represents a potential target in the treatment of pulmonary fibrosis (PF).
In this study, we knocked down Bach1 using adenovirus-mediated small interfering
RNA (siRNA) to determine whether the use of Bach1 siRNA is an effective
therapeutic strategy in mice with bleomycin (BLM)‑induced PF. Mouse lung
fibroblasts (MLFs) were incubated with transforming growth
factor (TGF)-β1 (5 ng/ml) and subsequently infected with recombined
adenovirus-like Bach1 siRNA1 and Bach1 siRNA2, while an empty adenovirus vector
was used as the negative control. The selected Bach1 siRNA with higher
interference efficiency was used for the animal experiments. A mouse model of
BLM-induced PF was established, and Bach1 siRNA (1x109 pfu) was administered to
the mice via the tail vein. The results revealed that the Bach1 mRNA and protein
levels were significantly downregulated by Bach1 siRNA. Furthermore, the MLFs
infected with Bach1 siRNA exhibited increased mRNA and protein expression levels
of heme oxygenase-1 and glutathione peroxidase 1, but decreased levels of TGF-β1
and interleukin-6 in the cell supernatants compared with the cells exposed to
TGF-β1 alone. Bach1 knockdown by siRNA also enhanced the expression of
antioxidant factors, but suppressed that of fibrosis‑related cytokines in mice
compared with the BLM group. Finally, the inflammatory infiltration of alveolar
and interstitial cells and the destruction of lung structure were significantly
attenuated in the mide administered Bach1 siRNA compared with those in the BLM
group. On the whole, our findings demonstrate that Bach1 siRNA exerts protective
effects against BLM-induced PF in mice. Our data may provide the basis for the
development of novel targeted therapeutic strategies for PF. AIMS: The purpose of this study was to investigate the potential correlation
between metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and the
transcription factor BTB and CNC homology 1 (BACH1) and their
clinicopathological significance in triple-negative breast cancer (TNBC).
SUBJECTS AND METHODS: MALAT1 and BACH1 were detected by immunohistochemistry
using TNBC tissue microarrays of 240 patients. The association between MALAT1
and BACH1 expression levels was statistically analyzed. Moreover, the prognostic
roles as well as clinical and pathological significance of MALAT1 and BACH1
expression in TNBC were determined.
STATISTICAL ANALYSIS USED: Two-tailed Pearson correlation was used to examine
the correlation of BACH1 and MALA1 expression. Comparisons of
clinicopathological variables between different BACH1 and MALA1 expression
groups were performed using χ2 tests. Overall survival (OS) and disease-free
survival (DFS) curves were plotted with the Kaplan-Meier method and the
differences in OS and DFS between three groups were compared by the log-rank
test. Multiple comparisons were performed using χ2 tests for subsequent
individual group comparisons.
RESULTS: MALAT1 and BACH1 expression was significantly correlated with
tumor-node-metastasis stage, distant metastasis, pathological stage, and
survival outcomes of patients. Patients with high MALAT1 and BACH1 expression
exhibited shorter overall survival and disease-free survival.
CONCLUSIONS: These findings provide further insight into the expression pattern
of MALAT1 and BACH1 in TNBC and suggest them as prognostic biomarkers for TNBC. Bach1 is a known transcriptional repressor of the heme oxygenase-1 (HO-1) gene.
The purpose of this study was to determine whether angiogenesis is accelerated
by genetic ablation of Bach1 in a mouse ischemic hindlimb model. Hindlimb
ischemia was surgically induced in wild-type (WT) mice, Bach1-deficient
(Bach1-/-) mice, apolipoprotein E-deficient (ApoE-/-) mice, and Bach1/ApoE
double-knockout (Bach1-/-/ApoE-/-) mice. Blood flow recovery after hindlimb
ischemia showed significant improvement in Bach1-/- mice compared with that in
WT mice. Bach1-/-/ApoE-/- mice showed significantly improved blood flow recovery
compared with that in ApoE-/- mice to the level of that in WT mice. Migration of
endothelial cells in ApoE-/- mice was significantly decreased compared with that
in WT mice. Migration of endothelial cells significantly increased in
Bach1-/-/ApoE-/- mice compared with that in ApoE-/- mice to the level of that in
WT mice. The expression levels of HO-1, peroxisome proliferator-activated
receptor γ co-activator-1α, angiopoietin 1, and fibroblast growth factor 2 in
endothelial cells isolated from Bach1-/-/ApoE-/- mice were significantly higher
than those in ApoE-/- mice. Oxidative stress assessed by anti-acrolein antibody
staining in ischemic tissues and urinary 8-isoPGF2α excretion were significantly
increased in ApoE-/- mice compared with those in WT and Bach1-/- mice. Oxidative
stress was reduced in Bach1-/-/ApoE-/- mice compared with that in ApoE-/- mice.
These findings suggest that genetic ablation of Bach1 plays an important role in
ischemia-induced angiogenesis under the condition of increased oxidative stress.
Bach1 could be a potential therapeutic target to reduce oxidative stress and
potentially improve angiogenesis for patients with peripheral arterial disease. Maintece of stem-cell identity requires proper regulation of enhancer
activity. Both transcription factors OCT4/SOX2/NANOG and histone
methyltransferase complexes MLL/SET1 were shown to regulate enhancer activity,
but how they are regulated in embryonic stem cells (ESCs) remains further
studies. Here, we report a transcription factor BACH1, which directly interacts
with OCT4/SOX2/NANOG (OSN) and MLL/SET1 methyltransferase complexes and
maintains pluripotency in mouse ESCs (mESCs). BTB domain and bZIP domain of
BACH1 are required for these interactions and pluripotency maintece. Loss of
BACH1 reduced the interaction between NANOG and MLL1/SET1 complexes, and
decreased their occupancy on chromatin, and further decreased H3 lysine 4
trimethylation (H3K4me3) level on gene promoters and (super-) enhancers, leading
to decreased enhancer activity and transcription activity, especially on
stemness-related genes. Moreover, BACH1 recruited NANOG through chromatin
looping and regulated remote NANOG binding, fine-tuning enhancer-promoter
activity and gene expression. Collectively, these observations suggest that
BACH1 maintains pluripotency in ESCs by recruiting NANOG and MLL/SET1 complexes
to chromatin and maintaining the trimethylated state of H3K4 and
enhancer-promoter activity, especially on stemness-related genes. A limited number of overexpressed transcription factors are associated with
cancer progression in many types of cancer. BTB and CNC homology 1 (BACH1) is
the first mammalian heme-binding transcription factor that belongs to the basic
region leucine zipper (bZIP) family and a member of CNC (cap 'n' collar). It
forms heterodimers with the small musculoaponeurotic fibrosarcoma (MAF) proteins
and stimulates or suppresses the expression of target genes under a very low
intracellular heme concentration. It possesses a significant regulatory role in
heme homeostasis, oxidative stress, cell cycle, apoptosis, angiogenesis, and
cancer metastasis progression. This review discusses the current knowledge about
how BACH1 regulates cancer metastasis in various types of cancer and other
carcinogenic associated factors such as oxidative stress, cell cycle regulation,
apoptosis, and angiogenesis. Overall, from the reported studies and outcomes, it
could be realized that BACH1 is a potential pharmacological target for
discovering new therapeutic anticancer drugs. The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within
a topologically associated domain (TAD) in which multiple cis-regulatory
elements (CREs) and transcription factors (TFs) regulate its cell-specific
expression. The CREs are recruited to the gene promoter by a looping mechanism
that depends upon both architectural proteins and specific TFs. An siRNA screen
to identify TFs coordinating CFTR expression in airway epithelial cells
suggested an activating role for BTB domain and CNC homolog 1 (BACH1). BACH1 is
a ubiquitous master regulator of the cellular response to oxidative stress.
Here, we show that BACH1 may have a dual effect on CFTR expression by direct
occupancy of CREs at physiological oxygen (∼8%), while indirectly modulating
expression under conditions of oxidative stress. Hence BACH1, can activate or
repress the same gene, to fine tune expression in response to environmental cues
such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also
directly regulate CFTR gene expression by modulating locus architecture through
occupancy at known enhancers and structural elements, and depletion of BACH1
alters the higher order chromatin structure. |
What does the gene symbol EREG stand for? | The gene symbol EREG stands for the gene epiregulin. | Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell
migration by mediating cell-to-cell propagation of extracellular
signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR
ligands mediate the ERK activation waves. We found that epidermal growth factor
(EGF)-deficient cells exhibited lower basal ERK activity than the cells
deficient in heparin-binding EGF (HBEGF), transforming growth factor alpha
(TGFα) or epiregulin (EREG), but all cell lines deficient in a single EGFR
ligand retained the ERK activation waves. Surprisingly, ERK activation waves
were markedly suppressed, albeit incompletely, only when all four EGFR ligands
were knocked out. Re-expression of the EGFR ligands revealed that all but HBEGF
could restore the ERK activation waves. Aiming at complete elimination of the
ERK activation waves, we further attempted to knockout NRG1, a ligand for ErbB3
and ErbB4, and found that NRG1-deficiency induced growth arrest in the absence
of all four EGFR ligand genes. Collectively, these results showed that EGFR
ligands exhibit remarkable redundancy in the propagation of ERK activation waves
during collective cell migration. |
Which tool has been developed for proteome-wide detection of membrane lipid-binding proteins? | MBPpred is a profile Hidden Markov Model based method capable of detecting Membrane Binding Proteins (MBPs) from information encoded in their amino acid sequence. | A large number of modular domains that exhibit specific lipid binding properties
are present in many membrane proteins involved in trafficking and signal
transduction. These domains are present in either eukaryotic peripheral membrane
or transmembrane proteins and are responsible for the non-covalent interactions
of these proteins with membrane lipids. Here we report a profile Hidden Markov
Model based method capable of detecting Membrane Binding Proteins (MBPs) from
information encoded in their amino acid sequence, called MBPpred. The method
identifies MBPs that contain one or more of the Membrane Binding Domains (MBDs)
that have been described to date, and further classifies these proteins based on
their position in respect to the membrane, either as peripheral or
transmembrane. MBPpred is available online at
http://bioinformatics.biol.uoa.gr/MBPpred. This method was applied in selected
eukaryotic proteomes, in order to examine the characteristics they exhibit in
various eukaryotic kingdoms and phyla. |
What disease can be treated with Avacopan? | Avacopan is effective for ANCA-associated vasculitis. | Alternative C activation is involved in the pathogenesis of ANCA-associated
vasculitis. However, glucocorticoids used as treatment contribute to the
morbidity and mortality of vasculitis. We determined whether avacopan (CCX168),
an orally administered, selective C5a receptor inhibitor, could replace oral
glucocorticoids without compromising efficacy. In this randomized,
placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis
received placebo plus prednisone starting at 60 mg daily (control group),
avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or
avacopan (30 mg, twice daily) without prednisone. All patients received
cyclophosphamide or rituximab. The primary efficacy measure was the proportion
of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score
by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in
the control and 22 in each of the avacopan groups. Clinical response at week 12
was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in
the avacopan plus reduced-dose prednisone group (difference from control 16.4%;
two-sided 90% confidence limit, -4.3% to 37.1%; P=0.002 for noninferiority), and
17 of 21 (81.0%) patients in the avacopan without prednisone group (difference
from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P=0.01 for
noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19
of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21
of 22 (96%) patients in the avacopan without prednisone group. In conclusion,
C5a receptor inhibition with avacopan was effective in replacing high-dose
glucocorticoids in treating vasculitis. PURPOSE OF REVIEW: Vasculitides can affect small, medium and/or large vessels,
leading to end-organ damage, decreased quality of life and death.
Glucocorticoids remain the backbone of treatment for systemic vasculitis but are
associated with numerous toxicities. In recent years, the efficacy of
glucocorticoid-sparing biologic and novel small molecule therapies has been
demonstrated.
RECENT FINDINGS: In giant cell arteritis, tocilizumab was superior to
glucocorticoid monotherapy in maintece remission and cumulative
glucocorticoid exposure and is now approved for the treatment of giant cell
arteritis. In addition to the previously demonstrated efficacy of rituximab for
remission induction in antineutrophil cytoplasmic antibody (ANCA)-associated
vasculitis, recent trials have also demonstrated its superiority for remission
maintece compared to alternative approaches. Mepolizumab is superior to
standard of care alone with regard to remission rates and glucocorticoid-sparing
effect in refractory eosinophilic granulomatosis with polyangiitis. Avacopan has
shown significant promise in ANCA-associated vasculitis as part of a
glucocorticoid-free induction regimen in a recently completed phase 3 trial. Use
of biologics in rarer vasculitides remains guided by reports from small case
series.
SUMMARY: Biologics and other novel therapies have an increasingly important role
in the management of systemic vasculitis. Additional studies are needed to
define their optimal use and to guide their use in more rare forms of
vasculitis. Collaborators: Au Peh C, Chakera A, Cooper B, Kurtkoti J, Langguth D, Levidiotis
V, Luxton G, Mount P, Mudge D, Noble E, Phoon R, Ranganathan D, Ritchie A, Ryan
J, Suranyi M, Rosenkranz A, Lhotta K, Kronbichler A, Demoulin N, Bovy C,
Hellemans R, Hougardy J, Sprangers B, Wissing K, Pagnoux C, Barbour S, Brachemi
S, Cournoyer S, Girard L, Laurin L, Liang P, Philibert D, Walsh M, Tesar V,
Becvar R, Horak P, Rychlik I, Szpirt W, Dieperink H, Gregersen J, Ivarsen P,
Krarup E, Lyngsoe C, Rigothier C, Augusto J, Belot A, Chauveau D, Cornec D,
Jourde-Chiche N, Ficheux M, Karras A, Klein A, Maurier F, Mesbah R, Moranne O,
Neel A, Quemeneur T, Saadoun D, Terrier B, Zaoui P, Schaier M, Benck U, Bergner
R, Busch M, Floege J, Grundmann F, Haller H, Haubitz M, Hellmich B, Henes J,
Hohenstein B, Hugo C, Iking-Konert C, Arndt F, Kubacki T, Kotter I, Lamprecht P,
Lindner T, Halbritter J, Mehling H, Schönermarck U, Venhoff N, Vielhauer V,
Witzke O, Szombati I, Szucs G, Garibotto G, Alberici F, Brunetta E, Dagna L, De
Vita S, Emmi G, Gabrielli A, Manenti L, Pieruzzi F, Roccatello D, Salvarani C,
Dobashi H, Atsumi T, Fujimoto S, Hagino N, Ihata A, Kaname S, Kaneko Y, Katagiri
A, Katayama M, Kirino Y, Kitagawa K, Komatsuda A, Kono H, Kurasawa T, Matsumura
R, Mimura T, Morinobu A, Murakawa Y, Naniwa T, Nanki T, Ogawa N, Oshima H, Sada
K, Sugiyama E, Takeuchi T, Taki H, Tamura N, Tsukamoto T, Yamagata K, Yamamura
M, van Daele P, Rutgers A, Teng Y, Walker R, Chua I, Collins M, Rabindranath K,
de Zoysa J, Svensson M, Grevbo B, Kalstad S, Little M, Clarkson M, Molloy E,
Agraz Pamplona I, Anton J, Barrio Lucia V, Ciggaran S, Cinta Cid M, Diaz
Encarnacion M, Fulladosa Oliveras X, Soler JM, Rusinol MH, Praga M, Quintana
Porras L, Segarra A, Bruchfeld A, Segelmark M, Soveri I, Thomaidi E, Westman K,
Neumann T, Burnier M, Daikeler T, Dudler J, Hauser T, Seeger H, Vogt B, Jayne D,
Burton J, Al Jayyousi R, Amin T, Andrews J, Baines L, Brogan P, Dasgupta B,
Doulton T, Flossmann O, Griffin S, Harper J, Harper L, Kidder D, Klocke R,
Lanyon P, Luqmani R, McLaren J, Makanjuola D, McCann L, Nandagudi A, Selvan S,
O'Riordan E, Patel M, Patel R, Pusey C, Rajakariar R, Robson J, Robson M, Salama
A, Smyth L, Sznajd J, Taylor J, Merkel P, Sreih A, Belilos E, Bomback A, Carlin
J, Chang Chen Lin Y, Derebail V, Dragoi S, Dua A, Forbess L, Geetha D, Gipson P,
Gohh R, Greenwood GT, Hugenberg S, Jimenez R, Kaskas M, Kermani T, Kivitz A,
Koening C, Langford C, Marder G, Mohamed A, Monach P, Neyra N, Niemer G, Niles
J, Obi R, Owens C, Parks D, Podoll A, Rovin B, Sam R, Shergy W, Silva A, Specks
U, Spiera R, Springer J, Striebich C, Swarup A, Thakar S, Tiliakos A, Tsai Y,
Waguespack D, Chester Wasko M. Publisher: L’étude du complément bénéficie depuis quelques années d’un regain
d’intérêt dû en grande partie à la mise au point de nouveaux modulateurs du
complément, notamment le bloqueur du C5, l’éculizumab. Ce dernier a
significativement amélioré le pronostic de certaines pathologies rénales, comme
le syndrome hémolytique et urémique atypique. Cette avancée est un exemple
parfait d’une recherche translationnelle ayant débouché sur des applications
cliniques pour les patients. Actuellement, de nouvelles molécules sont en cours
de développement et certaines ont déjà démontré une efficacité clinique, comme
l’avacopan (bloqueur du C5aR) dans les vasculites à anticorps anticytoplasme des
polynucléaires neutrophiles. Du côté de la transplantation rénale, les
inhibiteurs du complément pourraient faire évoluer le traitement de certaines
complications comme le rejet humoral. Cependant, ces nouvelles thérapies ciblées
ont des effets secondaires, notamment infectieux, et un coût important. Introduction: Anti-neutrophil cytoplasm autoantibodies (ANCA)-associated
vasculitides (AAVs) are a group of rare heterogeneous diseases characterized by
blood vessel inflammation resulting in organ destruction and death. Although
various treatment strategies have resulted in marked improvement in
vasculitis-specific outcomes, many patients with AAV continue to suffer from
complications related to the prolonged use of glucocorticoids (GC) such as
infections, metabolic abnormalities, and increased cardiovascular morbidity.
Recently, activation of the alternative complement pathway has been implicated
in the augmentation of the damage caused by AAV via the complement C5a receptor
(C5aR1, CD88). Specifically targeting this pathway may lead to improved outcomes
in patients with AAV.Areas covered: In this article, we have summarized the
rationale for targeting the complement pathway in AAV. The relevant
pre-clinical, phase I, II and III findings with emphasis on the efficacy, and
safety of avacopan, a new oral competitive inhibitor that interferes with the
binding of C5a to C5aR1 (CD88), are reviewed.Expert opinion: These results are
encouraging, may led to major changes in the treatment approach for AAV, and
give rise to future studies utilizing complement inhibitors in AAV patients, and
potentially in other immune mediated diseases. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the treatment of
ANCA-associated vasculitis. N Engl J Med. 2021;384:599-609. 33596356. The antineutrophil cytoplasmic antibody (ANCA) vasculitides include several
closely related, often severe, multisystem autoimmune diseases characterized by
antibodies against serine proteinase 3 (PR3) or myeloperoxidase. Loss of
tolerance to these antigens triggers a cascade of events, beginning with the
priming of neutrophils by proinflammatory cytokines and complement activation,
translocation of ANCA-specific antigens to the plasma membrane, neutrophil
hyperactivation, and further activation of the alternative complement pathway,
leading to tissue damage and the clinical manifestations of ANCA vasculitis. Due
to the heterogeneity in presentation of these diseases, diagnosis is often
substantially delayed, leading to poor outcomes. The current treatment pathway
for most patients involves induction with cyclophosphamide or rituximab in
combination with glucocorticoids, followed by a maintece phase with
rituximab, azathioprine, or methotrexate, during which time glucocorticoids are
tapered. Current therapies are often effective in inducing and maintaining
remission but are associated with a range of toxicities. Several new therapies
are in development for ANCA vasculitis. Avacopan, an orally administered
inhibitor of the complement fragment 5a (C5a) receptor, has been assessed in a
phase 3 clinical trial and may play a role in reducing the cumulative
glucocorticoid dose. Preliminary data suggest that cluster of differentiation
(CD) 80 and CD86 blockade with abatacept may also have a role in the management
of ANCA vasculitis. There is an unmet need for additional therapeutic options
for patients with these diseases. Die Pathogenese von ANCA(antineutrophile zytoplasmatische
Antikörper)-assoziierten Vaskulitiden (AAV) ist komplex, das bessere Verständnis
der letzten Jahre hat jedoch neue therapeutische Ansätze ermöglicht. In den
letzten Jahren stand die Minimierung toxischer Therapieeffekte im Vordergrund.
In der Remissionsinduktion stehen für die schwere Granulomatose mit Polyangiitis
(GPA) und die mikroskopische Polyangiitis (MPA) neben Glukokortikoiden
Cyclophosphamid und Rituximab zur Verfügung. Die aktuellen Empfehlungen
ermöglichen eine raschere Reduktion der Steroiddosis und sehen den Einsatz der
Plasmapherese zurückhaltend. Zur Remissionserhaltung stehen Rituximab und
Azathioprin zur Verfügung. Medikamentenwahl und Dauer der Remissionserhaltung
richten sich insbesondere nach dem Rezidivrisiko. Der Stellenwert von niedrig
dosierten Steroiden ist nicht endgültig geklärt. Neue Therapieansätze wie der
C5a-Rezeptor-Inhibitor Avacopan könnten in Zukunft eine steroidminimierte
Therapie ermöglichen. Die Therapie der eosinophilen Granulomatose mit
Polyangiitis (EGPA) ist weniger evidenzbasiert und beinhaltet Glukokortikoide,
Immunsuppressiva je nach Erkrankungsschwere und zunehmend Biologika (z. B.
Interleukin[IL]-5-Blockade). Supportive Maßnahmen (Impfungen,
Infektionsprophylaxe, kardiovaskuläres Risikomanagement) gewinnen an Bedeutung.
Zukünftige Therapiestrategien müssen das individuelle Risiko (z. B. ANCA-Subtyp,
Rezidivrisiko) für Auswahl und Dauer der Therapien besser berücksichtigen. Publisher: REMISSIONSINDUKTION BEI GRANULOMATOSE MIT POLYANGIITIS
(GPA)/MIKROSKOPISCHER POLYANGIITIS (MPA): Das Komplementsystem spielt in der
Pathogenese, anders als früher vermutet, eine bedeutsame Rolle. Durch diese
Erkenntnis war es möglich, einen vollständig neuen Therapieansatz zu etablieren.
Die Blockade des C5a-Rezeptors mit Avacopan erwies sich in klinischen Studien
als effektiv und ermöglichte erstmals eine (fast) GC-freie Remissionsinduktion.
Avacopan ist eine kleines, gezielt eingreifendes Molekül und wird absehbar in
die Therapie der GPA/MPA Einzug halten. Die therapeutische Bedeutung der
Plasmapherese tritt weiter in den Hintergrund. Diese Therapieform bleibt aktuell
wenigen Ausnahmesituationen vorbehalten und kann nicht mehr generell bei
Glomerulonephritis oder pulmorenalem Syndrom empfohlen werden.
Therapieprotokolle mit vermindertem GC-Einsatz zeigen ähnlich gute Erfolge wie
Hochdosisprotokolle. Der GC-Einsatz kann daher weiter limitiert werden.
GPA/MPA-REMISSIONSERHALTUNG: Vor allem die MAINRITSAN-Studien zeigen, dass
Rituximab dem Azathioprin in der Remissionserhaltung überlegen ist und dass eine
längere Erhaltungstherapie, insbesondere bei Risikopatienten, mit klinisch
relevant geringeren Rezidivraten einhergeht.
GENETIK DER EOSINOPHILEN GRANULOMATOSE MIT POLYANGIITIS (EGPA): Trotz der
Seltenheit der EGPA konnte ein internationales Konsortium eine genomweite
Assoziationsstudie (GWAS) durchführen. Hierbei bestätigte sich auch auf der
genetischen Ebene der klinische Eindruck zweier distinkter Subgruppen. Es kann
ein mehr vaskulitisch geprägter Subtyp von einem durch die Eosinophilie
dominierten unterschieden werden. Diese Ergebnisse werden für zukünftige
Therapiekonzepte relevant sein.
EGPA-THERAPIE: Die bisher größte RCT bei EGPA wies eine verminderte Rezidivrate
sowie einen GC-einsparenden Effekt eines Anti-IL-5-Antikörpers (Mepolizumab)
nach. Der klinische Nutzen bestätigte sich in einer weiteren Analyse der Daten
und auch in der „Real Life“-Anwendung. |
Is HYDIN (Hydrocephalus-inducing protein homolog) an axonemal protein? | Yes,
HYDIN is a axonemal protein. | |
What disease is also known as Bechterew's Disease? | Ankylosing spondylitis (Bechterew's disease) is the most typical form of axial SpA whereby sacroiliitis can be found on X-rays of the SI joints. | The authors have used the modified method of the direct gene cloning suggested
by Nichols et al to isolate HLA-B27 gene from a patient suffering from
ankylosing spondylitis. Five restriction enzymes (ClaI, HindIII, SnaBI, PvuI,
SalGI) which had no recognition sites within the 6.0 kb EcoRI-BamHI-DNA fragment
supposedly containing the HLA-B27 gene have been chosen by
blotting-hybridization of the restriction fragments of the patients DNA with
HLA-B27-specific probe. The 6.0 +/- 0.5 kb DNA fragments were isolated and
cloned after the DNA treatment by 300 micrograms of all of these restriction
enzymes. The obtained mini-library containing 280 recombits has been screened
with the use of HLA-B27 specific oligonucleotide probe. The clone PB27-2 has
been isolated the restriction map of which is identical to HLA-B27k. The authors
are planning to determine the sequence of the isolated gene in order to find a
possible structural defect in it. Ankylosing spondylitis is a disease with clinically and radiologically very
variable features. It is the intention to direct the attention from the old by
orthopedists' influenced association of the stiff back to the polymorphism of
the disease especially to the early stages which still frequently are recognized
too late. The paper deals with the nosology, the various states of the clinical
course with the numerous radiological criteria including therapeutical
approaches. One hundred and twenty-two consecutive patients hospitalized for ankylosing
spondylitis (AS) were reexamined. The frequency of clinical signs and results of
tests for associations are presented. Psoriasis was associated with a distal
pattern of peripheral arthropathy. Spinal rigidity was predomitly seen in
males. Males with phalangeal arthropathy exhibited preserved spinal mobility.
This was the case also when HLA B27 positives and patients who did not have
psoriasis were considered separately. HLA B27 positive patients in this group
had frequently experienced acute anterior uveitis. It seems possible that the
disease in such males is the result of combined predisposition to ankylosing
spondylitis and psoriatic arthropathy. Hip arthropathy was frequently present in
males with spinal rigidity. The associations observed confirm that AS is a
heterogenous group of diseases. The term "syndrome" may be suitable for such a
heterogenous group, and we prefer the term "Bechterew's syndrome" as the name of
this group. When these new findings are added to the previous observations that
acute anterior uveitis probably is a clinical, sex-influenced characteristic of
HLA B27 positive Bechterew's syndrome, that HLA B27 negative patients with
Bechterew's syndrome frequently had psoriasis and were HLA B13 and B17 negative,
and that psoriasis was frequent in HLA B27 positive patients as well, we
tentatively conclude that different and interacting genetic mechanisms may be
involved in the etiology of Bechterew's syndrome. Cervical spine changed by Bechterew's disease is severely endangered with any
increased load. Even decent trauma is enough to produce a fracture with
affection of spinal cord. Because of little knowledge in these special items,
late diagnosis of overlooked injury is not rare, especially in two-level
injuries. Neurolesions following secondary fracture dislocations may occur
("fatal pause"). From january 1990 to february 2000 12 patients underwent
surgery (dorsoventral stabilisation, ventral stabilisation, laminectomy).
Diagnostic procedures, levels of injury, pre- and postoperative neurostatus
(following Frankel's score), operative technique, typical complications and
follow-up (Ø 17.8 months) were analyzed and compared with the literature. 11
patients showed preoperative neurodeficits. They were better in five cases and
disappeared at all in another five cases after surgery (83% positive
neurological outcome). There was no increase of neurology failure. Two patients
died (ARDS and cerebral ischemia with destruction of vertebral arteries). One
patient had to be reoperated because of implant dislocation. MRI is obvious in
diagnostic for these lesions. There is also an absolute need for total (both
clinical and radiological) examination of the whole spinal column, because there
is often injury of more than one level (three times in our study). Therapy
should be operative (dorsoventral stabilisation, in certain cases only anterior
procedure or laminectomy). Late diagnosis and therapy with secondary worsening
after fracture dislocation is not rare because of "overlooked injury". There
were four patients, that would not have suffered cervical spine fracture
(minimal injury force) without Bechterew's changes. There is often pulmonary
failure through limitation of thoracic movement and cerebral ischemia following
rupture of vertebral arteries as typical complications. Mortality (2 cases; 16%)
in our collective is less than literature's medium rates (35-57%). Although involvement of the temporomandibular joint in patients with ankylosing
spondylitis (AS, Bechterew disease) has been described previously, hyperplasia
of the mandibular coronoid process in those patients has not been reported yet.
Case notes were studied, and records were made of age, sex, clinical symptoms,
radiography, and treatment in all patients with a confirmed diagnosis of
coronoid hyperplasia presenting at the Department of Oral and Maxillofacial
Surgery, University of Bonn, between 1995 and 2007. Sixteen cases of coronoid
hyperplasia were recruited, of which 12 were bilateral and 4 were unilateral.
Four patients had AS, 3 of them were HLA-B27-positive. Temporomandibular joint
symptoms are frequently seen in patients with AS. Nevertheless, it must be
considered that a limitation of jaw mobility in those patients might also be
caused by an elongation of the mandibular coronoid process. Spondyloarthritis (SpA) is an umbrella term for a group of rheumatic diseases
characterised by inflammation of the sacroiliac (SI) joints and vertebral
column; today, differentiation is made between axial SpA and peripheral SpA.
Ankylosing spondylitis (Bechterew's disease) is the most typical form of axial
SpA whereby sacroiliitis can be found on X-rays of the SI joints. Axial SpA can,
however, also be present without radiographic evidence of sacroiliitis. A range
of SpA-related symptoms can also manifest themselves outside the musculoskeletal
system, for example, uveitis, psoriasis and inflammatory intestinal diseases.
Tumour necrosis factor (TNF)-α inhibitors play an important role in the
treatment of SpA. New classification criteria have recently been established in
which MRI of the SI joints and the presence of the HLA-B27 tissue antigen are
key. Axial and peripheral SpA should be recognized early in order to be able to
successfully treat these conditions. The term axial spondyloarthritis covers patients with established structural
changes visible on x-ray in sacroiliac joints and/or in the spine (classical
ankylosing spondylitis) but also patients with non-radiographic axial
spondyloarthritis in whom early inflammatory signs of the disease can only be
visualized with magnetic resoce imaging (MRI). The MRI technique plays an
important role in the diagnosis of this disease and an early diagnosis is
normally based on a combination of clinical, laboratory and imaging parameters.
Only non-steroidal anti-inflammatory drugs and TNF-α blockers are effective in
the treatment of axial spondyloarthritis. Patients with short disease duration
and elevated acute phase reactant levels demonstrate best therapy response and,
therefore, should be closely followed-up and consistently treated. Ankylosing spondylitis (AS) or Bechterew disease is a chronic, usually
progressive, systemic inflammatory joint disease, which predomitly affects
the spine and sacroiliac joints. In these joints, early inflammatory changes are
followed by lumbosacral pain and progressive restriction of spinal movement
associated with radiologically visible intervertebral ossification. Peripheral
joint involvement occurs in 10 to 30% of patients and shows a predilection for
the shoulders, knees, ankles, feet, and wrists. Temporomandibular joint (TMJ)
involvement has been described, and its reported frequency varies from 11 to
35%. However, ankylosis is uncommon with a single documented case utilizing an
alloplastic prosthesis for total joint replacement. A case report of bilateral
ankylosis of the jaw treated with alloplastic prostheses for total TMJ
replacement using a Brazilian system in a patient with AS is presented. Ankylosing spondylitis is an inflammatory rheumatic disease that is often
associated with back pain and restricted spinal movement. In the later stages of
the disease, complete ossification of the entire spine and severe deformity can
occur, often resulting in a marked reduction in quality of life and an increased
risk of loss of independence due to diminished visual field. Patients with
ankylosing spondylitis are at greater risk of spinal fractures. These are
generally complex fractures associated with high morbidity and mortality; in
addition, neurological deficits are not unusual. Conventional radiological
diagnosis is often insufficient to establish a diagnosis. Conservative treatment
of fractures of the spine in this patient group is unsatisfactory. Surgical
procedures, if necessary combined with decompression, are often the preferred
treatment of choice in the fractured or malaligned ankylosed spine. Rebalancing
of the sagittal profile with normalization of the visual axis and an improvement
of quality of life is achieved through corrective osteotomies. Despite the high
rate of complications, long-term results following spinal surgery in patients
with ankylosing spondylitis are good. Minimally invasive surgery is appropriate
for a further reduction in the complication rate. Meticulous preoperative
planning is essential in the treatment of patients with ankylosing spondylitis. |
Through which pathway does epiregulin promote leptin secretion? | EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. | |
Are there any R packages that help with visualizing data on spirals? | Yes. Spiralize is an R package for visualizing data on spirals. | |
Was ALVAC-HIV effective for HIV prevention in the HVTN 702 trial? | No. The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity | The RV144 HIV-1 vaccine trial results showed moderate reduction in viral
infections among vaccinees as well as induction of antibody-dependent cellular
cytotoxicity and vaccine-specific IgG and IgG3 responses directed at variable
loop regions 1 and 2 of the HIV envelope protein. However, with the recent
failure of the HVTN 702 clinical trial, comprehensive profiling of humoral
immune responses may provide insight for these disappointing results. One of the
changes included in the HVTN 702 study was the addition of a late boost, aimed
at augmenting peak immunity and durability. The companion vaccine trial RV305
was designed to permit the evaluation of the immunologic impact of late boosting
with either the boosting protein antigen alone, the canarypox viral vector ALVAC
alone, or a combination of both. Although previous data showed elevated levels
of IgG antibodies in both boosting arms, regardless of ALVAC-HIV vector
incorporation, the effect on shaping antibody effector function remains unclear.
Thus, here we analyzed the antibody and functional profile induced by RV305
boosting regimens and found that although IgG1 levels increased in both arms
that included protein boosting, IgG3 levels were reduced compared with the
original RV144 vaccine strategy. Most functional responses increased upon
protein boosting, regardless of the viral vector-priming agent incorporation.
These data suggest that the addition of a late protein boost alone is sufficient
to increase functionally potent vaccine-specific antibodies previously
associated with reduced risk of infection with HIV. Author information:
(1)From the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer
Research Center (G.E.G., Z.M., N. Grunenberg, Y.H., D.G., B.P., J.J.K., J.H.,
C.B., S.R., S.T., M.J., M. Sikhosana, M. Andrasik, J.G.K., M.J.M., P.B.G., H.J.,
L.C.), Seattle; the Perinatal HIV Research Unit, Faculty of Health Sciences,
University of the Witwatersrand (G.E.G., F.L., E.L., B.M., T.P., S.T.), the
National Institute for Communicable Diseases, National Health Laboratory Service
(A.P.), and Aurum Institute (C.I., M. Sebe, W.B., P.S., T.A., G. Kobane),
Johannesburg, Desmond Tutu HIV Centre (L.-G.B., S.K., C.N.N., M. Atujuna), the
Department of Medicine, Wellcome Centre for Infectious Diseases Research in
Africa, and Institute of Infectious Disease and Molecular Medicine (G.M.,
A.M.W.), and the Division of Clinical Pharmacology, Department of Medicine
(L.W.), University of Cape Town, Cape Town, Setshaba Research Centre, Soshanguve
(M.M., K.S.M.), Mecru Clinical Research Unit, Sefako Mkgatho Health Sciences
University, Ga-Rankuwa (M.N., M.P.M.), Nelson Mandela Academic Clinical Research
Unit and Department of Internal Medicine and Pharmacology, Walter Sisulu
University, Mthatha (T.D., P.M.), the School of Health Systems and Public
Health, Faculty of Health Sciences, University of Pretoria, Pretoria (S.T.), the
South African Medical Research Council (G.E.G., D.K., N.S., V.N., G. Kistnasami,
Z.G.) and the Centre for the AIDS Programme of Research in South Africa,
University of KwaZulu-Natal (N.N., N. Garrett), Durban, and Qhakaza Mbokodo
Research Clinic, Ladysmith (P.K., P.B.M.) - all in South Africa; the Vaccine
Research Program, Division of AIDS, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda (M. Allen), and
GlaxoSmithKline Vaccines, Rockville (N.K.-T.) - both in Maryland; the Department
of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory
University, Atlanta (D.B.); GSK Vaccines, Cambridge, MA (S.W.B.); Sanofi
Pasteur, Swiftwater, PA (S.P., C.D.G.); GlaxoSmithKline, Siena, Italy (S.P.);
GlaxoSmithKline, Wavre (M.K.), and GlaxoSmithKline, Rixensart (O.V.D.M.) - both
in Belgium; and the Graduate Group in Biostatistics and the Center for
Computational Biology, University of California, Berkeley (N.S.H.). The advanced-phase HIV prevention vaccine trials done in South Africa (HVTN 702)
and in Thailand (RV144), which both investigated canarypox vectors and
adjuvanted gp120 proteins, gave rise to different results. The South African
trial did not find vaccine efficacy, whereas the Thai trial had modest, but
statistically significant, success with the modified intention-to-treat analysis
prespecified in the protocols of both studies. An understanding of the
differences between the studies is required to avoid the possible, but
erroneous, conclusion that the results from the South African trial negatively
affect the results of the Thai trial. |
Do Afamin bind Vitamin E? | Yes,
Afamin is a plasma vitamin E-binding glycoprotein. | Author information:
(1)Division of Genetic Epidemiology, Department of Medical Genetics, Molecular
and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
(2)Institute of Epidemiology II, Helmholtz Zentrum München-German Research
Center for Environmental Health, Neuherberg, Germany.
(3)German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
(4)Department of Medicine, Internal Medicine, Lausanne University Hospital,
Lausanne, Switzerland.
(5)Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
(6)Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
(7)Department of Clinical Chemistry, University of Tampere School of Medicine,
Tampere, Finland.
(8)Centre for Cardiovascular Genetics, British Heart Foundation Laboratories,
University College London, London, U.K.
(9)Cardiovascular Genetics Division, University of Utah School of Medicine, Salt
Lake City, UT.
(10)Department of Genetic Medicine, Weill Cornell Medicine, Doha, Qatar.
(11)Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center
for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf,
Germany.
(12)First Department of Internal Medicine, Paracelsus Private Medical
University, Salzburg, Austria.
(13)Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine
University Düsseldorf, Düsseldorf, Germany.
(14)Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz
Center for Diabetes Research at Heinrich Heine University Düsseldorf,
Düsseldorf, Germany.
(15)German Centre for Cardiovascular Research (DZHK), partner site Munich Heart
Alliance, Munich, Germany.
(16)Department of Clinical Physiology, Tampere University Hospital, Tampere,
Finland.
(17)Department of Clinical Physiology, University of Tampere School of Medicine,
Tampere, Finland.
(18)Department of Clinical Physiology and Nuclear Medicine, Turku University
Hospital, Turku, Finland.
(19)Research Centre of Applied and Preventive Cardiovascular Medicine,
University of Turku, Turku, Finland.
(20)Vitateq Biotechnology GmbH, Innsbruck, Austria.
(21)Division of Genetic Epidemiology, Department of Medical Genetics, Molecular
and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria
[email protected]. PURPOSE: Oxidative stress is involved in the pathogenesis of hypertensive
disorders such as preeclampsia (PE) and associated with the human vitamin
E-binding protein afamin. The aim of this study was, therefore, to analyse
afamin in the first trimester of patients developing PE later in pregcy and
in control subjects without pregcy complications.
METHODS: In this retrospective study, 137 serum samples from the first trimester
of pregcy were analysed in a case-control study design. 39 patients developed
PE (10 patients with early-onset and 29 patients with late onset disease) and 98
women had an uncomplicated pregcy. Mann-Whitney U test, t test, logistic
regression and ROC analyses were performed for statistical evaluation.
RESULTS: Pregt women developing PE presented with higher afamin
concentrations in the first trimester [median 101.81 mg/L; interquartile range
(IQR) 88.94-113.26] compared to subjects with uncomplicated pregcy (median
86.40; IQR 75.26-96.92; p < 0.001). After adjusting for confounders, the odds
ratio per afamin standard deviation was 1.60 (95% CI: 1.04-2.58; p = 0.04). An
afamin threshold concentration of 87.8 mg/L exhibited the best sensitivity
(79.5%) and specificity (57.1%) in predicting PE. Subgroup analysis of early-
and late-onset disease resulted in substantially higher afamin concentrations in
women with developing late-onset PE compared to controls (p < 0.001) with an
odds ratio per afamin standard deviation of 1.62 (95% CI: 0.98-2.70; p = 0.06).
CONCLUSIONS: Serum afamin concentrations are elevated in the first trimester
among patients developing PE compared to controls. Substantial differences were
observed mainly among patients with late-onset PE. |
Is disruption of immune regulation mechanisms associated with adverse pregnancy outcomes, including preeclampsia (PE)? | Inflammation and oxidative stress at the maternal-fetal interface characterize the placental dysfunction that underlies the pregnancy disorder preeclampsia. | Maternal immunity undergoes subtle adjustment in order to tolerate the
semi-allogeneic embryo and maintain the host defense against potential
pathogens. Concomitantly, coagulation systems change from an anti-coagulant
state to a pro-coagulant state to meet the hemostatic challenge of placentation
and delivery. Innate immunity and blood coagulation systems are the first line
of defense to protect a host against exogenous challenges, including
alloantigens and mechanical insults, and preserve the integrity of an organism.
The interactions between coagulation and immune systems have been extensively
studied. Immune cells play a pivotal role in the initiation of the coagulation
cascade, whereas coagulation proteases display substantial immuno-modulatory
effects. Upon exogenous challenges, the immune and coagulation systems are
capable of potentiating each other leading to a vicious cycle. Natural killer
(NK) cells, macrophages (Mphis) and dendritic cells (DCs) are three major innate
immune cells that have been demonstrated to play essential roles in early
pregcy. However, immune maladaptation and hemostatic imbalance have been
suggested to be responsible for adverse pregt outcomes, such as preeclampsia
(PE), miscarriage, recurrent spontaneous abortion (RSA) and intrauterine growth
restriction (IUGR). In this review, we will summarize the mutual regulation
between blood coagulation and innate immune systems as well as their roles in
the maintece of normal pregcy and in the pathogenesis of adverse pregcy
outcomes. OBJECTIVE: Increased oxidative stress and immune dysfunction are implicated in
preeclampsia (PE) and may contribute to the two- to fourfold increase in PE
prevalence among women with type 1 diabetes. Prospective measures of fat-soluble
vitamins in diabetic pregcy are therefore of interest.
RESEARCH DESIGN AND METHODS: Maternal serum carotenoids (α- and β-carotene,
lycopene, and lutein) and vitamins A, D, and E (α- and γ-tocopherols) were
measured at first (12.2 ± 1.9 weeks [mean ± SD], visit 1), second (21.6 ± 1.5
weeks, visit 2), and third (31.5 ± 1.7 weeks, visit 3) trimesters of pregcy
in 23 women with type 1 diabetes who subsequently developed PE (DM PE+) and 24
women with type 1 diabetes, matched for age, diabetes duration, HbA(1c), and
parity, who did not develop PE (DM PE-). Data were analyzed without and with
adjustment for baseline differences in BMI, HDL cholesterol, and prandial
status.
RESULTS: In unadjusted analysis, in DM PE+ versus DM PE-, α-carotene and
β-carotene were 45 and 53% lower, respectively, at visit 3 (P < 0.05), before PE
onset. In adjusted analyses, the difference in β-carotene at visit 3 remained
significant. Most participants were vitamin D deficient (<20 ng/mL), and vitamin
D levels were lower in DM PE+ versus DM PE- throughout the pregcy, although
this did not reach statistical significance.
CONCLUSIONS: In pregt women with type 1 diabetes, low serum α- and β-carotene
were associated with subsequent development of PE, and vitamin D deficiency may
also be implicated. For many years, the innate immunity was of less interest than the adaptive
immunity because it was perceived to have secondary importance in the
functionality of the immune system. During the past decades, with the
advancement of knowledge about innate immune system, interest in innate immunity
has grown dramatically and thus its function has been extensively studied.
Innate immunity plays fundamental roles in the initiation and induction of
adaptive immune responses. It consists of several cells and receptors including
natural killer (NK) cells, macrophages (MQs), dendritic cells (DCs) and pattern
recognition receptors (PRRs). Two decades ago, Toll like receptors (TLRs) family
was known as one of the important PRRs with unique functions especially in
protection against invading pathogens. Since the female reproductive tract has
access to the outside environment and has a unique interaction with different
pathogens whether invading microorganisms or normal flora, allogenic sperm and
semi allogenic fetus, it has an essential need for effective immune responses.
It has therefore been suggested that TLRs may play important roles in the immune
regulation of the female reproductive tract. In addition, it has been
demonstrated that immune disturbance may be responsible for some adverse
pregcy outcomes such as preeclampsia (PE), recurrent spontaneous abortion
(RSA) and intrauterine growth restriction (IUGR). Our focus in this review is to
show the importance of TLRs in pregcy with emphasis on the expression of
these receptors in different tissues related to pregcy. PROBLEM: The lymphatic vasculature controls leukocytes trafficking and limits
the adaptive immune response. In previous models of preeclampsia (PE), defective
immune function caused by disruption of lymphangiogenesis was shown to be
involved in the disease pathophysiology. Especially, the dysfunction of
regulatory T cells (Treg) at the maternal-fetal interface may be one of the
causes of severe PE. In particular, activation of Tregs to obtain immune
tolerance requires adequate antigen presentation through the lymphatic system.
We hypothesized that impaired lymphangiogenesis and imbalanced Tregs at the
maternal-fetal interface are associated with the pathophysiology of severe PE.
However, the current research addressing this hypothesis is limited. Therefore,
to compare differences in lymphangiogenesis in severe PE and normal conditions,
we aimed to examine the location of lymphatics at the maternal-fetal interface
and to investigate the association between lymphangiogenesis and Tregs in severe
PE.
METHOD OF STUDY: We obtained entire uterus from normal pregt mice. Placental
and fetal membranes, including decidua, were obtained from 10 pregt women
with severe PE and 10 gestational age-matched controls. Immunohistochemistry for
LYVE1 was used to localize the distribution of lymphatic vessels and CD4, CD25,
and FOXP3 for Treg.
RESULTS: LYVE1-positive vessels were present in the uterine wall of mice.
LYVE1-positive lymphatic vessels were localized on the human decidua. Tubular
lymphatics were abundant in the control decidua, but significantly reduced in
severe PE. Furthermore, lymphatic vessel density correlated with the number of
decidual Tregs.
CONCLUSION: Abnormal decidual lymphangiogenesis is associated with reduced
numbers of decidual Tregs in severe PE. Fetomaternal immune tolerance is required to prevent fetal rejection during
pregcy; simultaneously, the maternal immune system must also protect the
fetus from harmful endogenous and exogenous antigens, including those associated
with viral and bacterial infections. Therefore, a delicate immune balance is
critical for the maintece of a successful pregcy, while disruption of this
balance can induce complications such as implantation failure, miscarriage,
preterm birth/labor, preeclampsia and fetal growth restriction. While the
adaptive immune system is critical for the development of tolerance, this review
summarizes evidence that modulation of the innate immunity is also essential for
achieving this delicate balance between tolerance and protection. Canonical
cells of the innate immune system, including dendritic cells, macrophages,
natural killer cells and invariant natural killer T cells, contribute to the
modulation of the immune balance at the fetomaternal interface. The newly
identified myeloid-derived suppressor cells and innate lymphoid cells also
appear important for successful reproduction. Moreover, it is possible that
sterile inflammation facilitates complications of pregcy via the innate
immune system. In this review, the characteristic features and functions of
innate immune cells in fetomaternal immunity and their contributions to
pregcy complications related to sterile inflammation are discussed. These
insights on innate immune system function in reproduction may provide new
perspectives for understanding the mechanisms of fetomaternal tolerance and the
etiology of pregcy complications. Preeclampsia is a pregcy-specific disorder, of which one of its major
subtypes, the placental subtype is considered a response to an ischemic
placental environment, impacting fetal growth and pregcy outcome.
Inflammatory immune responses have been linked to metabolic and inflammatory
disorders as well as reproductive failures. In healthy pregcy, immune
regulatory mechanisms prevent excessive systemic inflammation. However, in
preeclampsia, the regulation of immune responses is disrupted as a result of
aberrant activation of innate immune cells and imbalanced differentiation of
T-helper cell subsets creating a cytotoxic environment in utero. Recognition
events that facilitate immune interaction between maternal decidual T cells, NK
cells, and cytotrophoblasts are considered an indirect cause of the incomplete
remodeling of spiral arteries in preeclampsia. The mechanisms involved include
the activation of immune cells and the subsequent secretion of cytokines and
placental growth factors affecting trophoblast invasion, angiogenesis, and
eventually placentation. In this review, we focus on the role of excessive
systemic inflammation as the result of a dysregulated immune system in the
development of preeclampsia. These include insufficient control of inflammation,
failure of tolerance toward paternal antigens at the fetal-maternal interface,
and subsequent over- or insufficient activation of immune mediators. It is also
possible that external stimuli, such as bacterial endotoxin, may contribute to
the excessive systemic inflammation in preeclampsia by stimulating the release
of pro-inflammatory cytokines. In conclusion, a disrupted immune system might be
a predisposing factor or result of placental oxidative stress or excessive
inflammation in preeclampsia. Preeclampsia can thus be considered a
hyperinflammatory state associated with defective regulation of the immune
system proposed as a key element in the pathological events of the placental
subtype of this disorder. INTRODUCTION: Preeclampsia has the highest rate of obstetric morbidity and
mortality.
METHODS: We recruited 21 women with preeclampsia and 27 women with uncomplicated
pregcies. We used a quantitative protein macroarray that allowed for analysis
of 40 proteins.
RESULTS: We found a statistically significant increase in the concentration of
DR3, LIF and a significant decrease of VEGF, PlGF, syndecan-4 and galectin-2, in
the plasma of women with preeclampsia.
CONCLUSIONS: There are no previous studies assessing syndecan 4, galectin 2, and
DR3 concentrations in women with preeclampsia; Our results indicate these
proteins are new factors that play important roles in the immunological
pathomechanism of preeclampsia. Reproduction involves tightly regulated series of events and the immune system
is involved in an array of reproductive processes. Disruption of well-controlled
immune functions leads to infertility, placental inflammation, and numerous
pregcy complications, including preeclampsia (PE). Inflammasomes are involved
in the process of pathogen clearance and sterile inflammation. They are large
multi-protein complexes that are located in the cytosol and play key roles in
the production of the pivotal inflammatory cytokines, interleukin (IL)-1β and
IL-18, and pyroptosis. The nucleotide-binding oligomerization domain,
leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome is a
key mediator of sterile inflammation induced by various types of
damage-associated molecular patterns (DAMPs). Recent evidence indicates that the
NLRP3 inflammasome is involved in pregcy dysfunction, including PE. Many
DAMPs (uric acid, palmitic acid, high-mobility group box 1, advanced glycation
end products, extracellular vesicles, cell-free DNA, and free fatty acids) are
increased and associated with pregcy complications, especially PE. This
review focuses on the role of the NLRP3 inflammasome in the pathophysiology of
PE. Inflammation and oxidative stress at the maternal-fetal interface characterize
the placental dysfunction that underlies the pregcy disorder preeclampsia.
Specialized fetal trophoblasts directly interact with leukocytes at both sites
of the maternal-fetal interface; the uterine wall decidua; and the placenta.
TLR3 has been implicated in the harmful inflammation at the maternal-fetal
interface in preeclampsia, but the cellular involvement in the decidua and
placenta has not been determined. This study aimed to characterize and quantify
cell-specific TLR3 expression and function at the maternal-fetal interface in
normal and preeclamptic pregcies. TLR3 expression was assessed by
immunohistochemistry and quantified by a novel image-based and cell-specific
quantitation method. TLR3 was expressed at the maternal-fetal interface by all
decidual and placental trophoblast types and by maternal and fetal leukocytes.
Placental, but not decidual, TLR3 expression was significantly higher in
preeclampsia compared to normal pregcies. This increase was attributed to
placental intravillous tissue and associated with both moderate and severe
placental dysfunction. TLR3 pathway functionality in the decidua and placenta
was confirmed by TLR3 ligand-induced cytokine response, but the TLR3 expression
levels did not correlate between the two sites. In conclusion, functional TLR3
was broadly expressed by maternal and fetal cells at both sites of the
maternal-fetal interface and the placental intravillous expression was increased
in preeclampsia. This suggests TLR3-mediated inflammatory involvement with local
regulation at both sites of the maternal-fetal interface in normal and
preeclamptic pregcies. OBJECTIVES: Maternal systemic and placental inflammatory responses participate
in the pathogenesis of hypertensive disorders of pregcy including
preeclampsia, a pregcy-specific syndrome, although the role of inflammation
remains unclear. The NLRP3 inflammasome has been implicated in the control of
sterile inflammation involved in preeclampsia. In the present study, we
hypothesized that S100A9, as major alarmin, are associated with the pathogenesis
of preeclampsia and induction of a preeclampsia-like phenotype in pregt mice.
METHODS: Plasma were taken from normal pregt women and preeclampsia patients.
Human placental tissues, trophoblast cell line Sw.71 cells, and human umbilical
vein endothelial cells (HUVEC) were treated with S100A9 with or without
inhibitors associated with NLRP3 inflammasome. Pregt mice were administered
S100A9.
RESULTS: S100A9 was elevated in plasma and released from placentas of
preeclampsia patients. S100A9 activated the NLRP3 inflammasome, resulting in
IL-1β secretion, by human placental tissues and trophoblasts. In addition,
secretion of soluble endoglin, a main contributor to the pathogenesis of
preeclampsia, is regulated via S100A9-stimulated NLRP3 inflammasome activation
in the human placenta and HUVECs. S100A9 administration significantly elevated
maternal blood pressure and neutrophil accumulation within the placentas of
pregt mice, and both were significantly decreased in Nlrp3-knock out pregt
mice.
CONCLUSION: The results of this study demonstrated that S100A9 acts as a danger
signal to activate the NLRP3 inflammasome in the placenta, associating with
hypertension during pregcy. INTRODUCTION: Maternal immune system tolerance to the semi-allogeneic fetus is
critical to a successful pregcy. We previously reported that myeloid-derived
suppressor cells (MDSC) was associated with maternal immune imbalance. T cell
immunoglobulin and mucin-containing protein 3 (Tim-3)/Galectin-9 (Gal-9) pathway
modulates function of various immune cells in maternal-fetal interface. However,
the regulatory effects of Tim-3/Gal-9 signaling on MDSCs and its role in
preeclampsia (PE) remain unclear.
METHODS: In the current study we investigated the expression of Tim-3 on MDSC in
preeclampsia (PE) patients to further explore the pathogenesis of PE.
RESULTS: The proportion of Tim-3+ M-MDSC (monocytic MDSC) cells was higher in PE
patients than in healthy control. Meanwhile, the protein expression of Gal-9, as
the ligand of Tim-3, was increased in placenta of PE patients. M-MDSC also
expressed a higher level of interferon-γ (IFN-γ) and a lower level of
transforming growth factor-β (TGF-β) in PE. Furthermore, our study suggested
that blocking Tim-3 could attenuate the inhibitory function of MDSC.
DISCUSSION: The abnormal expression of Tim-3 on MDSC might be involved in the
pathogenesis of PE, and could be a marker to evaluate the immune function in PE. |
Can autophagy related lncRNAs be used for colorectal cancer prognosis? | Yes, a prognostic prediction model of CRC was built based on nine ARlncRNAs (NKILA, LINC00174, AC008760.1, LINC02041, PCAT6, AC156455.1, LINC01503, LINC00957, and CD27-AS1). The 5-year overall survival rate was significantly lower in the high-risk group than in the low-risk group among train set, validation set, and all patients (all p < 0.001). The model had high sensitivity and accuracy in predicting the 1-year overall survival rate (area under the curve = 0.717). The prediction model risk score was an independent predictor of CRC. | INTRODUCTION: Colorectal cancer (CRC) is the most common gastrointestinal cancer
and has a low overall survival rate. Tumor-node-metastasis staging alone is
insufficient to predict patient prognosis. Autophagy and long noncoding RNAs
play important roles in regulating the biological behavior of CRC. Therefore,
establishing an autophagy-related lncRNA (ARlncRNA)-based bioinformatics model
is important for predicting survival and facilitating clinical treatment.
METHODS: CRC data were retrieved from The Cancer Genome Atlas. The database was
randomly divided into train set and validation set; then, univariate and
multivariate Cox regression analyses were performed to screen prognosis-related
ARlncRNAs for prediction model construction. Interactive network and Sankey
diagrams of ARlncRNAs and messenger RNAs were plotted. We analyzed the survival
rate of high- and low-risk patients and plotted survival curves and determined
whether the risk score was an independent predictor of CRC. Receiver operating
characteristic curves were used to evaluate model sensitivity and specificity.
Then, the expression level of lncRNA was detected by quantitative real-time
polymerase chain reaction, and the location of lncRNA was observed by
fluorescence in situ hybridization. Additionally, the protein expression was
detected by Western blot.
RESULTS: A prognostic prediction model of CRC was built based on nine ARlncRNAs
(NKILA, LINC00174, AC008760.1, LINC02041, PCAT6, AC156455.1, LINC01503,
LINC00957, and CD27-AS1). The 5-year overall survival rate was significantly
lower in the high-risk group than in the low-risk group among train set,
validation set, and all patients (all p < 0.001). The model had high sensitivity
and accuracy in predicting the 1-year overall survival rate (area under the
curve = 0.717). The prediction model risk score was an independent predictor of
CRC. LINC00174 and NKILA were expressed in the nucleus and cytoplasm of normal
colonic epithelial cell line NCM460 and colorectal cancer cell lines HT29.
Additionally, LINC00174 and NKILA were overexpressed in HT29 compared with
NCM460. After autophagy activation, LINCC00174 expression was significantly
downregulated both in NCM460 and HT29, while NKILA expression was significantly
increased.
CONCLUSION: The new ARlncRNA-based model predicts CRC patient prognosis and
provides new research ideas regarding potential mechanisms regulating the
biological behavior of CRC. ARlncRNAs may play important roles in personalized
cancer treatment. |
Are there roles for cohesin mutations in AML? | Yes. Several landmark studies have shown that cohesin mutations perturb the balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data now begin to uncover the molecular mechanisms that underpin this phenotype. Among these mechanisms is a role for cohesin in the control of inflammatory responses in HSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and drive HSPC differentiation. Consistent with this, cohesin mutations promote resistance to inflammatory signals, and may provide a selective advantage for AML progression. |
Subsets and Splits
No saved queries yet
Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.