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http://www.ncbi.nlm.nih.gov/pubmed/23871674 | 1. Am J Cardiol. 2013 Oct 15;112(8):1197-206. doi: 10.1016/j.amjcard.2013.06.017.
Epub 2013 Jul 19.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised
2010 task force criteria with inclusion of non-desmosomal phospholamban mutation
carriers.
Groeneweg JA(1), van der Zwaag PA, Olde Nordkamp LR, Bikker H, Jongbloed JD,
Jongbloed R, Wiesfeld AC, Cox MG, van der Heijden JF, Atsma DE, de Boer K,
Doevendans PA, Vink A, van Veen TA, Dooijes D, van den Berg MP, Wilde AA, van
Tintelen JP, Hauer RN.
Author information:
(1)Department of Cardiology, University Medical Center Utrecht, Utrecht, The
Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht,
The Netherlands. Electronic address: j.groeneweg-4@umcutrecht.nl.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently
associated with desmosomal mutations. However, nondesmosomal mutations may be
involved. The aim of this study was to assess the contribution of a
phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised
2010 task force criteria (TFC). In 142 Dutch patients (106 men, mean age 51 ± 13
years) with proven ARVD/C (fulfillment of 2010 TFC for diagnosis), 5 known
desmosomal genes (PKP2, DSP, DSC2, DSG2, and JUP) and the nondesmosomal PLN gene
were screened. After genetic analysis, phenotypic characteristics of desmosomal
versus PLN mutation carriers were compared. In 59 of 142 patients with ARVD/C
(42%), no desmosomal mutation was found. In 19 of 142 patients (13%), the PLN
founder mutation c.40_42delAGA (p.Arg14del) was identified. PLN mutation
carriers more often had low-voltage electrocardiograms (p = 0.004), inverted T
waves in leads V4 to V6 (p <0.001), and additional structural (p = 0.007) or
functional (p = 0.017) left ventricular impairment, whereas desmosomal mutation
carriers had more solitary right ventricular abnormalities. The revised TFC
included 21 of 142 patients with proven ARVD/C who did not meet the 1994 TFC,
including 7 PLN mutation carriers. In conclusion, there is a substantial
contribution of PLN mutation to ARVD/C diagnosis by the 2010 TFC. In 32% of
patients (19 of 59) with genetically unexplained proven ARVD/C, this
nondesmosomal mutation was found. PLN mutation carriers have ARVD/C
characteristics, including important right ventricular involvement, and
additionally more often low-voltage electrocardiograms, inverted T waves in the
left precordial leads, and left ventricular involvement.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.amjcard.2013.06.017
PMID: 23871674 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23568436 | 1. Neth Heart J. 2013 Jun;21(6):286-93. doi: 10.1007/s12471-013-0401-3.
Recurrent and founder mutations in the Netherlands-Phospholamban p.Arg14del
mutation causes arrhythmogenic cardiomyopathy.
van der Zwaag PA(1), van Rijsingen IA, de Ruiter R, Nannenberg EA, Groeneweg JA,
Post JG, Hauer RN, van Gelder IC, van den Berg MP, van der Harst P, Wilde AA,
van Tintelen JP.
Author information:
(1)Department of Genetics, University of Groningen, University Medical Center
Groningen, P.O. Box: 30.001, 9700 RB, Groningen, the Netherlands,
p.a.van.der.zwaag@umcg.nl.
BACKGROUND: Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in
the phospholamban (PLN) gene can be identified in 10-15 % of Dutch patients with
dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic
burden of the p.Arg14del mutation was illustrated by the high rate of
appropriate ICD discharges and a positive family history for sudden cardiac
death.
METHODS: Our goal was to evaluate the geographical distribution and the origin
of this specific mutation in the Netherlands and to get an estimation of the
prevalence in a Dutch population cohort. Therefore, we investigated the postal
codes of the places of residence of PLN p.Arg14del mutation carriers and places
of birth of their ancestors. In addition, a large population-based cohort
(PREVEND) was screened for the presence of this mutation.
RESULTS: By April 2012, we had identified 101 probands carrying the PLN
p.Arg14del mutation. A total of 358 family members were also found to carry this
mutation, resulting in a total of 459 mutation carriers. The majority of
mutation carriers live in the northern part of the Netherlands and analysing
their grandparents' places of birth indicated that the mutation likely
originated in the eastern part of the province of Friesland. In the PREVEND
cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of
8,267 subjects (0.07 %).
CONCLUSION: The p.Arg14del mutation in the PLN gene is the most frequently
identified mutation in Dutch cardiomyopathy patients. The mutation that arose
575-825 years ago is likely to have originated from the eastern part of the
province of Friesland and is highly prevalent in the general population in the
northern part of the Netherlands.
DOI: 10.1007/s12471-013-0401-3
PMCID: PMC3661879
PMID: 23568436 |
http://www.ncbi.nlm.nih.gov/pubmed/26052092 | 1. Cancer Lett. 2015 Sep 1;365(2):141-8. doi: 10.1016/j.canlet.2015.06.003. Epub
2015 Jun 5.
Circular RNA: A new star of noncoding RNAs.
Qu S(1), Yang X(1), Li X(1), Wang J(1), Gao Y(1), Shang R(1), Sun W(1), Dou
K(1), Li H(2).
Author information:
(1)Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military
Medical University, Xi'an, 710032, China.
(2)Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military
Medical University, Xi'an, 710032, China. Electronic address:
lihaim@fmmu.edu.cn.
Comment in
BJOG. 2016 Dec;123(13):2119. doi: 10.1111/1471-0528.13965.
Circular RNAs (circRNAs) are a novel type of RNA that, unlike linear RNAs, form
a covalently closed continuous loop and are highly represented in the eukaryotic
transcriptome. Recent studies have discovered thousands of endogenous circRNAs
in mammalian cells. CircRNAs are largely generated from exonic or intronic
sequences, and reverse complementary sequences or RNA-binding proteins (RBPs)
are necessary for circRNA biogenesis. The majority of circRNAs are conserved
across species, are stable and resistant to RNase R, and often exhibit
tissue/developmental-stage-specific expression. Recent research has revealed
that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing
and transcription, and modifiers of parental gene expression. Emerging evidence
indicates that circRNAs might play important roles in atherosclerotic vascular
disease risk, neurological disorders, prion diseases and cancer; exhibit
aberrant expression in colorectal cancer (CRC) and pancreatic ductal
adenocarcinoma (PDAC); and serve as diagnostic or predictive biomarkers of some
diseases. Similar to miRNAs and long noncoding RNAs (lncRNAs), circRNAs are
becoming a new research hotspot in the field of RNA and could be widely involved
in the processes of life. Herein, we review the formation and properties of
circRNAs, their functions, and their potential significance in disease.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.canlet.2015.06.003
PMID: 26052092 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12639993 | 1. J Clin Invest. 2003 Mar;111(6):869-76. doi: 10.1172/JCI17892.
Human phospholamban null results in lethal dilated cardiomyopathy revealing a
critical difference between mouse and human.
Haghighi K(1), Kolokathis F, Pater L, Lynch RA, Asahi M, Gramolini AO, Fan GC,
Tsiapras D, Hahn HS, Adamopoulos S, Liggett SB, Dorn GW 2nd, MacLennan DH,
Kremastinos DT, Kranias EG.
Author information:
(1)Department of Pharmacology and Cell Biophysics, University of Cincinnati,
College of Medicine, Cincinnati, Ohio 45267, USA.
Comment in
J Clin Invest. 2003 Mar;111(6):801-3. doi: 10.1172/JCI18153.
In human disease and experimental animal models, depressed Ca(2+) handling in
failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum
(SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN)
or expression of dominant-negative PLN mutants enhances SR and cardiac function,
but effects of PLN mutations in humans are unknown. Here, a T116G point
mutation, substituting a termination codon for Leu-39 (L39stop), was identified
in two families with hereditary heart failure. The heterozygous individuals
exhibited hypertrophy without diminished contractile performance. Strikingly,
both individuals homozygous for L39stop developed dilated cardiomyopathy and
heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50%
reduction in PLN mRNA and no detectable PLN protein were noted in one explanted
heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK)
293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR
Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was
expressed, it was misrouted to the cytosol or plasma membrane. These findings
describe a naturally-occurring loss-of-function human PLN mutation (PLN null).
In contrast to reported benefits of PLN ablation in mouse heart failure, humans
lacking PLN develop lethal dilated cardiomyopathy.
DOI: 10.1172/JCI17892
PMCID: PMC153772
PMID: 12639993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22820313 | 1. Eur J Heart Fail. 2012 Nov;14(11):1199-207. doi: 10.1093/eurjhf/hfs119. Epub
2012 Jul 20.
Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy
or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the
concept of arrhythmogenic cardiomyopathy.
van der Zwaag PA(1), van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen
DJ, Wiesfeld AC, Cox MG, van Lochem LT, de Boer RA, Hofstra RM, Christiaans I,
van Spaendonck-Zwarts KY, Lekanne dit Deprez RH, Judge DP, Calkins H, Suurmeijer
AJ, Hauer RN, Saffitz JE, Wilde AA, van den Berg MP, van Tintelen JP.
Author information:
(1)Department of Genetics, University of Groningen, University Medical Center
Groningen, The Netherlands.
AIMS: To investigate whether phospholamban gene (PLN) mutations underlie
patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy
(ARVC) or idiopathic dilated cardiomyopathy (DCM).
METHODS AND RESULTS: We screened a cohort of 97 ARVC and 257 DCM unrelated index
patients for PLN mutations and evaluated their clinical characteristics. PLN
mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM
patients. Haplotype analysis revealed a common founder, estimated to be between
575 and 825 years old. A low voltage electrocardiogram was present in 46 % of
R14del carriers. Compared with R14del- DCM patients, R14del+ DCM patients more
often demonstrated appropriate implantable cardioverter defibrillator discharge
(47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001),
and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 %
, P = 0.007). We observed a similar pattern in the ARVC patients although this
was not statistically significant. The average age of 26 family members who died
of SCD was 37.7 years. Immunohistochemistry in available myocardial samples
revealed absent/depressed plakoglobin levels at intercalated disks in five of
seven (71 %) R14del+ ARVC samples, but in only one of nine (11 %) R14del+ DCM
samples (P = 0.03).
CONCLUSIONS: The PLN R14del founder mutation is present in a substantial number
of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed
with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the
presenting symptom. These findings support the concept of 'arrhythmogenic
cardiomyopathy'.
DOI: 10.1093/eurjhf/hfs119
PMCID: PMC3475434
PMID: 22820313 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21282613 | 1. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2735-40. doi:
10.1073/pnas.1013987108. Epub 2011 Jan 31.
Lethal Arg9Cys phospholamban mutation hinders Ca2+-ATPase regulation and
phosphorylation by protein kinase A.
Ha KN(1), Masterson LR, Hou Z, Verardi R, Walsh N, Veglia G, Robia SL.
Author information:
(1)Department of Biochemistry, Molecular Biology, and Biophysics, University of
Minnesota, Minneapolis, MN 55455, USA.
The regulatory interaction of phospholamban (PLN) with Ca(2+)-ATPase controls
the uptake of calcium into the sarcoplasmic reticulum, modulating heart muscle
contractility. A missense mutation in PLN cytoplasmic domain (R9C) triggers
dilated cardiomyopathy in humans, leading to premature death. Using a
combination of biochemical and biophysical techniques both in vitro and in live
cells, we show that the R9C mutation increases the stability of the PLN
pentameric assembly via disulfide bridge formation, preventing its binding to
Ca(2+)-ATPase as well as phosphorylation by protein kinase A. These effects are
enhanced under oxidizing conditions, suggesting that oxidative stress may
exacerbate the cardiotoxic effects of the PLN(R9C) mutant. These results reveal
a regulatory role of the PLN pentamer in calcium homeostasis, going beyond the
previously hypothesized role of passive storage for active monomers.
DOI: 10.1073/pnas.1013987108
PMCID: PMC3041113
PMID: 21282613 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20638444 | 1. Neurosci Lett. 2010 Oct 4;482(3):188-92. doi: 10.1016/j.neulet.2010.07.020.
Epub 2010 Jul 16.
Screening for inhibitors of the SOD1 gene promoter: pyrimethamine does not
reduce SOD1 levels in cell and animal models.
Wright PD(1), Huang M, Weiss A, Matthews J, Wightman N, Glicksman M, Brown RH
Jr.
Author information:
(1)University of Massachusetts Medical School, Department of Neurology,
Worcester, MA 01655, USA. paul.wright@umassmed.edu
Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are detected in 20% of
familial and 3% of sporadic amyotrophic lateral sclerosis (ALS) cases. Although
mutant SOD1 is known to induce motor neuron death via multiple adverse acquired
functions, its exact pathogenic mechanism is not well defined. SOD1 toxicity is
dose dependent; levels of mutant SOD1 protein in transgenic mice determine
disease susceptibility, onset and rate of progression. We therefore sought to
identify small molecules that reduce SOD1 levels by inhibiting the SOD1
promoter. We tested pyrimethamine (previously reported to suppress SOD1
expression), several compounds currently in trials in human and murine ALS, and
a set of 1040 FDA-approved compounds. In a PC12 cell-based assay, no compounds
reduced SOD1 promoter activity without concomitant cytotoxicity. Additionally,
pyrimethamine failed to repress levels of SOD1 protein in HeLa cells or
homogenates of liver, spinal cord and brain of wild-type mice. Thirty-four
compounds (including riluzole, ceftriaxone, minocyclin, PBA, lithium,
acetylcysteine) in human and mouse ALS trials and an additional set of 1040
FDA-approved compounds also showed no effect on SOD1 promoter activity. This
present study thus failed to identify small molecule inhibitors of SOD1 gene
expression.
(c) 2010 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.neulet.2010.07.020
PMCID: PMC2962987
PMID: 20638444 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25240289 | 1. Eur J Cancer. 2014 Nov;50(16):2763-70. doi: 10.1016/j.ejca.2014.08.002. Epub
2014 Sep 15.
The impact of Oncotype DX testing on breast cancer management and chemotherapy
prescribing patterns in a tertiary referral centre.
McVeigh TP(1), Hughes LM(2), Miller N(2), Sheehan M(3), Keane M(4), Sweeney
KJ(3), Kerin MJ(2).
Author information:
(1)Discipline of Surgery, National University of Ireland Galway, Ireland.
Electronic address: terri.mcveigh@gmail.com.
(2)Discipline of Surgery, National University of Ireland Galway, Ireland.
(3)BreastCheck, Western Unit, Ireland.
(4)Department of Oncology, Galway University Hospital, Ireland.
INTRODUCTION: The use of chemotherapy in node-negative, (O)Estrogen Receptor
(ER)-positive breast cancer has changed significantly since the introduction of
Oncotype DX to determine systemic recurrence risk based on tumour genomic
signature.
AIMS: This study aims to
METHODS: A cohort study was undertaken, including consecutive patients with
early node-negative, ER-positive breast cancer diagnosed between 2006 and May
2013, including a period of prospective clinical trial (Trial Assigning
Individualised Options for Treatment (TAILORx)) recruitment. Data were collected
regarding patient demographics, tumour clinico-pathological features, Oncotype
DX use and recurrence score and chemotherapy use. All therapeutic decisions were
made following multidisciplinary discussion, with adherence to guidelines and
consideration of trial protocol and Oncotype DX recurrence scores.
RESULTS: 479 consecutive patients were included in the study, of whom 241 (50%)
underwent Oncotype DX testing, 97 as part of the TAILORx clinical trial.
Oncotype DX testing began on a trial basis in 2007 and until October 2011, only
patients enrolled on TAILORx availed of genomic profiling. From October 2011,
Oncotype DX was used in all eligible patients as per National Cancer Control
Programme (NCCP) guidelines. A total of 216 (45%) patients received
chemotherapy. The use of chemotherapy changed in inverse proportion to the
availability of the genomic assay. Of those patients in whom Oncotype DX was
utilised, 138 (57%) were spared chemotherapy.
CONCLUSION: This study validates the use of molecular testing in the
rationalisation of systemic therapy.
Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ejca.2014.08.002
PMCID: PMC4204201
PMID: 25240289 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19597720 | 1. Biol Trace Elem Res. 2010 Apr;134(1):55-63. doi: 10.1007/s12011-009-8457-z.
Epub 2009 Jul 14.
Effect of zinc supplementation on antioxidant activity in young wrestlers.
Kara E(1), Gunay M, Cicioglu I, Ozal M, Kilic M, Mogulkoc R, Baltaci AK.
Author information:
(1)Faculty of Education, Department of Physical Fitness and Sport, Karabuk
University, Karabuk, Turkey.
This study aims to examine the effect of zinc supplementation on free-radical
formation and antioxidant system in individuals who are actively engaged in
wrestling as a sport. The study registered a total of 40 male subjects, of whom
20 were wrestlers and 20 were sedentary individuals. The subjects were equally
allocated to four groups: group 1, zinc-supplemented sportsmen group; group 2,
sportsmen group without supplementation; group 3, zinc-supplemented sedentary
group; group 4, sedentary group without supplementation. Blood samples were
collected from all subjects twice, once at the beginning of the study and once
again at the end of 8-week procedures. The blood samples collected were analyzed
to determine the levels of malondialdehyde (MDA), serum glutathione (GSH), serum
glutathione peroxidase (GPx) activity, serum superoxide dismutase (SOD) activity
(ELISA colorimetric method) and zinc (colorimetric method). No difference was
found between MDA levels of the study groups in the beginning of the study. The
highest MDA value at the end of the study was obtained in group 4 (p < 0.01).
MDA levels in group 2 were established to be significantly higher than those in
groups 1 and 3 (p < 0.01). GSH level, GPx, and SOD activities and zinc level
measured in the beginning of the study were not different between groups.
Measurements performed at the end of the study showed that groups 1 and 3
(zinc-supplemented groups) had the highest GSH level, GPx, and SOD activities
and zinc level (p < 0.01). These parameters were not different in the groups
without supplementation (groups 2 and 4). Results obtained at the end of the
study indicate that zinc supplementation prevents production of free radicals by
activating the antioxidant system. In conclusion, physiologic doses of zinc
supplementation to athletes may beneficially contribute to their health and
performance.
DOI: 10.1007/s12011-009-8457-z
PMID: 19597720 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23436649 | 1. Int J Sports Physiol Perform. 2013 Sep;8(5):565-72. doi:
10.1123/ijspp.8.5.565. Epub 2013 Feb 20.
Effect of dietary antioxidants, training, and performance correlates on
antioxidant status in competitive rowers.
Braakhuis AJ(1), Hopkins WG, Lowe TE.
Author information:
(1)Faculty of Medical and Health Sciences, University of Auckland, Auckland, New
Zealand.
The beneficial effects of exercise and a healthy diet are well documented in the
general population but poorly understood in elite athletes. Previous research in
subelite athletes suggests that regular training and an antioxidant-rich diet
enhance antioxidant defenses but not performance.
PURPOSE: To investigate whether habitual diet and/or exercise (training status
or performance) affect antioxidant status in elite athletes.
METHODS: Antioxidant blood biomarkers were assessed before and after a 30-min
ergometer time trial in 28 male and 34 female rowers. The antioxidant blood
biomarkers included ascorbic acid, uric acid, total antioxidant capacity (TAC),
erythrocyte- superoxide dismutase, glutathione peroxidase (GPx), and catalase.
Rowers completed a 7-d food diary and an antioxidant-intake questionnaire.
Effects of diet, training, and performance on resting biomarkers were assessed
with Pearson correlations, and their effect on exercise-induced changes in blood
biomarkers was assessed by a method of standardization.
RESULTS: With the exception of GPx, there were small to moderate increases with
exercise for all markers. Blood resting TAC had a small correlation with total
antioxidant intake (correlation .29; 90% confidence limits, ±.27), and the
exercise-induced change in TAC had a trivial to small association with dietary
antioxidant intake from vitamin C (standardized effect .19; ±.22), vegetables
(.20; ±.23), and vitamin A (.25; ±.27). Most other dietary intakes had trivial
associations with antioxidant biomarkers. Years of training had a small inverse
correlation with TAC (-.32; ±.19) and a small association with the
exercise-induced change in TAC (.27; ±.24).
CONCLUSION: Training status correlates more strongly with antioxidant status
than diet does.
DOI: 10.1123/ijspp.8.5.565
PMID: 23436649 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22080314 | 1. J Strength Cond Res. 2011 Dec;25(12):3448-55. doi:
10.1519/JSC.0b013e3182162f2b.
Creatine supplementation decreases oxidative DNA damage and lipid peroxidation
induced by a single bout of resistance exercise.
Rahimi R(1).
Author information:
(1)Department of Physical Education and Sport Science, University of Kurdistan,
Sanandaj, Iran. rahman.rahimi@yahoo.com
Rahimi, R. Creatine supplementation decreases oxidative DNA damage and lipid
peroxidation induced by a single bout of resistance exercise. J Strength Cond
Res 25(12): 3448-3455, 2011-Creatine (Cr), or methyl guanidine-acetic acid, can
be either ingested from exogenous sources, such as fish or meat, or produced
endogenously by the body, primarily in the liver. It is used as an ergogenic aid
to improve muscle mass, strength, and endurance. Heretofore, Cr's positive
therapeutic benefits in various oxidative stress-associated diseases have been
reported in the literature and, recently, Cr has also been shown to exert direct
antioxidant effects. Therefore, the purpose of this study was to investigate the
effects of an acute bout of resistance exercise (RE) on oxidative stress
response and oxidative DNA damage in male athletes and whether supplementation
with Cr could negate any observed differences. Twenty-seven resistance-trained
men were randomly divided into a Cr supplementation group (the Cr group [21.6 ±
3.6 years], taking 4 × 5 g Cr monohydrate per day) or a placebo (PL)
supplementation group (the PL group [21.2 ± 3.2 years], taking 4 × 5 g
maltodextrin per day). A double-blind research design was employed for a 7-day
supplementation period. Before and after the seventh day of supplementation, the
subjects performed an RE protocol (7 sets of 4 exercises using 60-90 1
repetition maximum) in the flat pyramid loading pattern. Blood and urine samples
taken before, immediately, and 24-hour postexercise were analyzed for plasma
malondialdehyde (MDA) and urinary 8-hydroxy-2-deoxyguanosine (8-OHdG) excretion.
Before the supplementation period, a significant increase in the urinary 8-OHdG
excretion and plasma MDA levels was observed after RE. The Cr supplementation
induces a significant increase in athletics performance, and it attenuated the
changes observed in the urinary 8-OHdG excretion and plasma MDA. These results
indicate that Cr supplementation reduced oxidative DNA damage and lipid
peroxidation induced by a single bout of RE.
DOI: 10.1519/JSC.0b013e3182162f2b
PMID: 22080314 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16575496 | 1. Eur J Nutr. 2006 Aug;45(5):259-66. doi: 10.1007/s00394-006-0593-z. Epub 2006
Mar 30.
Effect of soy- and whey protein-isolate supplemented diet on the redox
parameters of trained mice.
Elia D(1), Stadler K, Horváth V, Jakus J.
Author information:
(1)Institute of Biomolecular Chemistry Chemical Research Center, Hungarian
Academy of Sciences, Budapest, Hungary.
BACKGROUND: A number of clinical trials have successfully been performed using
whey and/or soy proteins in the treatment of many diseases. They both have
antioxidant properties, which appears to be a factor in aerobic physical
performance as well. In addition, these are the most often used supplements that
sportsmen take to increase their performance.
AIM OF THE STUDY: To investigate the effect of whey and soy protein
supplementation on redox parameters in the muscle, on body weight, and body
composition in swimming-trained and non-trained animals.
METHODS: The effect of whey and soy protein-isolate supplementation on muscle
redox parameters, body weight, and body composition in trained and non-trained
mice was investigated after a single exhaustive bout of exercise. Steady state
free radical concentration measured using electron spin resonance (ESR)
spectroscopy, reduced and oxidized glutathione ratio, thiobarbituric
acid-reactive substances (TBARS), and protein carbonyl levels of the red leg
muscle were measured.
RESULTS: Free radical concentrations and glutathione composition of the tissue
indicated that whey protein supplementation of the regular diet was able to
prevent oxidative stress regardless of training. Soy protein supplementation
decreased TBARS only in the muscle of untrained animals, while training per se
lowered protein damage in all investigated groups. A mixture of soy and whey
protein supplementation resulted in leaner animals after training, but had no
synergistic effect on either of the measured redox parameters.
CONCLUSIONS: Athletes consuming these supplements could train with higher
exercise intensity. The antioxidant effect of the two proteins is based on
different mechanisms of action.
DOI: 10.1007/s00394-006-0593-z
PMID: 16575496 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23717765 | 1. Int J Prev Med. 2013 Apr;4(Suppl 1):S24-30.
The effect of vitamins C and e supplementation on muscle damage, performance,
and body composition in athlete women: a clinical trial.
Taghiyar M(1), Ghiasvand R, Askari G, Feizi A, Hariri M, Mashhadi NS, Darvishi
L.
Author information:
(1)Food Security Research Center, Isfahan University of Medical Sciences,
Isfahan, Iran ; Department of Community Nutrition, School of Nutrition and Food
Science, Isfahan University of Medical Sciences, Isfahan, Iran.
BACKGROUND: Due to the special training conditions and lifestyle athletes
require an antioxidant system that is more efficient than others. To keep this
system optimal, many of them use antioxidant supplements. This study aimed to
investigate the effects of vitamins C and E supplementation on muscle damage,
performance, and body composition in athlete women.
METHODS: The study was a 4-week randomized, double-blind clinical trial
conducted on 64 trained female athletes recruited in Isfahan sports club. They
were randomly assigned to one of the following four groups; A: vitamin C (250
mg/day), B: vitamin E (400 IU), C: vitamin C + vitamin E and control (placebo).
Harvard Step Test was used to measure maximal oxygen consumption for
performance, body composition, and damage marker (myoglobin) were measured
before and after the intervention.
RESULTS: Comparing the result of the test in performance of sport, there was no
significant difference between groups in VO2 max. Also, vitamin supplements had
no significant effect on subcutaneous fat between the groups, however, in the
intergroup comparison, were significantly increased in group control (P = 0.03).
But, there were no significant differences, change in myoglobin between the
groups. There was a significant increase in group A (P = 0.04).
CONCLUSIONS: Vitamins C and E supplementation had no significant effect on any
of the studied parameters.
PMCID: PMC3665021
PMID: 23717765
Conflict of interest statement: Conflict of Interest: None declared |
http://www.ncbi.nlm.nih.gov/pubmed/23800565 | 1. Nutrition. 2013 Sep;29(9):1127-32. doi: 10.1016/j.nut.2013.03.003. Epub 2013
Jun 22.
Effects of creatine supplementation on oxidative stress and inflammatory markers
after repeated-sprint exercise in humans.
Deminice R(1), Rosa FT, Franco GS, Jordao AA, de Freitas EC.
Author information:
(1)Department of Physical Education, Faculty of Physical Education and
Sport-State University of Londrina, Paraná, Brazil. deminice@ig.com.br
OBJECTIVE: The goal of this study was to evaluate the effects of creatine (Cr)
supplementation on oxidative stress and inflammation markers after acute
repeated-sprint exercise in humans.
METHODS: Twenty-five players under age 20 y were randomly assigned to two
groups: Cr supplemented and placebo. Double-blind controlled supplementation was
performed using Cr (0.3 g/kg) or placebo tablets for 7 d. Before and after 7 d
of supplementation, the athletes performed two consecutive Running-based
Anaerobic Sprint Tests (RAST). RAST consisted of six 35-m sprint runs at maximum
speed with 10 sec rest between them. Blood samples were collected just prior to
start of test (pre), just after the completion (0 h), and 1 h after completion.
RESULTS: Average, maximum, and minimum power values were greater in the
Cr-supplemented group compared with placebo (P < 0.05). There were significant
increases (P < 0.05) in plasma tumor necrosis factor alpha (TNF-α) and
C-reactive protein (CRP) up to 1 h after acute sprint exercise in the
placebo-supplemented group. Malondialdehyde, lactate dehydrogenase (LDH),
catalase, and superoxide dismutase enzymes also were increased after exercise in
both groups. Red blood cell glutathione was lower after exercise in both groups.
Cr supplementation reversed the increase in TNF-α and CRP as well as LDH induced
by acute exercise. Controversially, Cr supplementation did not inhibit the rise
in oxidative stress markers. Also, antioxidant enzyme activity was not different
between placebo and Cr-supplemented groups.
CONCLUSION: Cr supplementation inhibited the increase of inflammation markers
TNF-α and CRP, but not oxidative stress markers, due to acute exercise.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nut.2013.03.003
PMID: 23800565 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17010801 | 1. J Am Coll Cardiol. 2006 Oct 3;48(7):1396-8. doi: 10.1016/j.jacc.2006.07.016.
Epub 2006 Sep 12.
Phospholamban R14 deletion results in late-onset, mild, hereditary dilated
cardiomyopathy.
DeWitt MM(1), MacLeod HM, Soliven B, McNally EM.
Author information:
(1)Department to Medicine, Section of Cardiology, The University of Chicago,
Chicago, Illinois, USA.
OBJECTIVES: The purpose of this research was to determine the phenotypic
spectrum associated with phospholamban gene (PLN) mutations.
BACKGROUND: Inheritance contributes to the development of dilated
cardiomyopathy. Mutations in the gene encoding PLN have been associated with
dilated cardiomyopathy characterized by early onset and the presence of lethal
ventricular arrhythmias.
METHODS: We screened a cohort of 260 unrelated dilated cardiomyopathy patients
from a tertiary care referral center for mutations in the PLN gene.
RESULTS: Family history of cardiomyopathy was present in approximately one-half
the individuals in this cohort. We identified 1 family with a deletion of
arginine 14 in the PLN. Interestingly, unlike other individuals reported with
the identical PLN mutation, these individuals were not diagnosed with dilated
cardiomyopathy until their seventh decade when they were only mildly symptomatic
with congestive heart failure.
CONCLUSIONS: The identical PLN mutation can be associated with both mild and
severe forms of dilated cardiomyopathy. Additionally, PLN mutations should be
considered in late onset cardiomyopathy. (Genetics of Cardiovascular and
Neuromuscular Disease;
http://www.clinicaltrials.gov/ct/show/NCT00138931?order=1; NCT00138931)
DOI: 10.1016/j.jacc.2006.07.016
PMID: 17010801 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16432188 | 1. Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1388-93. doi:
10.1073/pnas.0510519103. Epub 2006 Jan 23.
A mutation in the human phospholamban gene, deleting arginine 14, results in
lethal, hereditary cardiomyopathy.
Haghighi K(1), Kolokathis F, Gramolini AO, Waggoner JR, Pater L, Lynch RA, Fan
GC, Tsiapras D, Parekh RR, Dorn GW 2nd, MacLennan DH, Kremastinos DT, Kranias
EG.
Author information:
(1)Department of Pharmacology and Cell Biophysics, University of Cincinnati
College of Medicine, Cincinnati, OH 45267, USA.
The sarcoplasmic reticulum Ca(2+)-cycling proteins are key regulators of cardiac
contractility, and alterations in sarcoplasmic reticulum Ca(2+)-cycling
properties have been shown to be causal of familial cardiomyopathies. Through
genetic screening of dilated cardiomyopathy patients, we identified a previously
uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the
phospholamban (PLN) gene in a large family with hereditary heart failure. No
homozygous individuals were identified. By middle age, heterozygous individuals
developed left ventricular dilation, contractile dysfunction, and episodic
ventricular arrhythmias, with overt heart failure in some cases. Transgenic mice
overexpressing the mutant PLN-R14Del recapitulated human cardiomyopathy
exhibiting similar histopathologic abnormalities and premature death.
Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in
sarcoplasmic reticulum Ca(2+)-ATPase superinhibition. The dominant effect of the
PLN-R14Del mutation could not be fully removed, even upon phosphorylation by
protein kinase A. Thus, by chronic suppression of sarcoplasmic reticulum
Ca(2+)-ATPase activity, the nonreversible superinhibitory function of mutant
PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in
both humans and mice.
DOI: 10.1073/pnas.0510519103
PMCID: PMC1360586
PMID: 16432188 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21830999 | 1. J Sports Sci. 2011;29 Suppl 1:S47-55. doi: 10.1080/02640414.2011.602098. Epub
2011 Aug 11.
Antioxidant and Vitamin D supplements for athletes: sense or nonsense?
Powers S(1), Nelson WB, Larson-Meyer E.
Author information:
(1)Department of Applied Physiology and Kinesiology, University of Florida,
Gainesville, Florida 32611-8208, USA. spowers@hhp.ufl.edu
The idea that dietary supplements can improve athletic performance is popular
among athletes. The use of antioxidant supplements is widespread among endurance
athletes because of evidence that free radicals contribute to muscle fatigue
during prolonged exercise. Furthermore, interest in vitamin D supplementation is
increasing in response to studies indicating that vitamin D deficiency exists in
athletic populations. This review explores the rationale for supplementation
with both antioxidants and vitamin D and discusses the evidence to support and
deny the benefits of these dietary supplements. The issue of whether athletes
should use antioxidant supplements remains highly controversial. Nonetheless, at
present there is limited scientific evidence to recommend antioxidant
supplements to athletes or other physically active individuals. Therefore,
athletes should consult with their health care professional and/or nutritionist
when considering antioxidant supplementation. The issue of whether athletes
should supplement with vitamin D is also controversial. While arguments for and
against vitamin D supplementation exist, additional research is required to
determine whether vitamin D supplementation is beneficial to athletes.
Nevertheless, based upon the growing evidence that many athletic populations are
vitamin D deficient or insufficient, it is recommended that athletes monitor
their serum vitamin D concentration and consult with their health care
professional and/or nutritionist to determine if they would derive health
benefits from vitamin D supplementation.
DOI: 10.1080/02640414.2011.602098
PMID: 21830999 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25580223 | 1. F1000Res. 2014 Apr 11;3:90. doi: 10.12688/f1000research.3872.2. eCollection
2014.
Does the linear Sry transcript function as a ceRNA for miR-138? The sense of
antisense.
Granados-Riveron JT(1), Aquino-Jarquin G(1).
Author information:
(1)Laboratorio de Investigación en Genómica, Genética y Bioinformática, Hospital
Infantil de México Federico Gómez, Mexico City, 06720, Mexico.
Recently, the sex determining region Y ( Sry) and the cerebellar
degeneration-related protein 1 ( CDR1as) RNA transcripts have been described to
function as a new class of post-transcriptional regulatory RNAs that behave as
circular endogenous RNA sponges for the micro RNAs (miRNAs) miR-138 and miR-7,
respectively. A special feature of the Sry gene is its ability to generate
linear and circular transcripts, both transcribed in the sense orientation. Here
we remark that both sense (e.g. Sry RNA) and antisense (e.g. CDR1as) transcripts
could circularize and behave as miRNAs sponges, and importantly, that also
protein-coding segments of mRNAs could also assume this role. Thus, it is
reasonable to think that the linear Sry sense transcript could additionally act
as a miRNA sponge, or as an endogenous competing RNA for miR-138.
DOI: 10.12688/f1000research.3872.2
PMCID: PMC4288412
PMID: 25580223
Conflict of interest statement: Competing interests: No competing interests were
disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/19777560 | 1. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):619-628. doi:
10.1002/ajmg.b.31031.
The effect of smoking on MAOA promoter methylation in DNA prepared from
lymphoblasts and whole blood.
Philibert RA(1)(2), Beach SRH(3), Gunter TD(1), Brody GH(3), Madan A(4), Gerrard
M(5).
Author information:
(1)Department of Psychiatry, The University of Iowa, Iowa City, Iowa.
(2)Neuroscience and Genetics Programs, The University of Iowa, Iowa City, Iowa.
(3)Institute for Behavioral Research, The University of Georgia, Athens,
Georgia.
(4)The Swedish Hospital Institute for Neuroscience, Seattle, Washington.
(5)Norris Cotton Cancer Center, Dartmouth Medical Center, Lebanon, New
Hampshire.
Prior work using lymphoblast DNA prepared from 192 subjects from the Iowa
Adoption Studies (IAS) demonstrated that decreased MAOA promoter methylation was
associated with lifetime symptom count for nicotine dependence (ND) and provided
suggestive evidence that the amount of methylation is genotype dependent. In the
current investigation, we replicate and extend these prior findings in three
ways using another 289 IAS subjects and the same methodologies. First, we show
that methylation is dependent on current smoking status. Second, we introduce a
factor analytic approach to DNA methylation, highlighting three distinct regions
of the promoter that may function in somewhat different ways for males and
females. Third, we directly compare the methylation signatures in DNA prepared
from whole blood and lymphoblasts from a subset of these subjects and provide
suggestive evidence favoring the use of lymphoblast DNA. We conclude that
smoking reliably decreases MAOA methylation, but exact characterization of
effects on level of methylation depend on genotype, smoking history, current
smoking status, gender, and region of the promoter-associated CpG Island
examined.
(c) 2009 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.b.31031
PMCID: PMC3694401
PMID: 19777560 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22906985 | 1. Lab Invest. 2012 Oct;92(10):1451-60. doi: 10.1038/labinvest.2012.110. Epub
2012 Aug 20.
Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via
coordinated epigenetic and IL-6-driven events.
Huang L(1), Frampton G, Rao A, Zhang KS, Chen W, Lai JM, Yin XY, Walker K,
Culbreath B, Leyva-Illades D, Quinn M, McMillin M, Bradley M, Liang LJ, DeMorrow
S.
Author information:
(1)Department of Internal Medicine, Texas A&M Health Science Center College of
Medicine, Scott and White Hospital, Central Texas Veterans Health Care System,
Temple, TX 76504, USA.
The secretion of dopamine and serotonin is increased in cholangiocarcinoma,
which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation
enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an
unknown mechanism. The aims of this study were to (i) correlate MAOA
immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii)
determine the mechanism by which MAOA expression is suppressed and (iii)
evaluate the consequences of restored MAOA expression in cholangiocarcinoma.
MAOA expression was assessed in cholangiocarcinoma and nonmalignant controls.
The control of MAOA expression by promoter hypermethylation was evaluated and
the contribution of interleukin-6 (IL-6) signaling to the suppression of MAOA
expression was determined. The effects of MAOA overexpression on
cholangiocarcinoma growth and invasion were also assessed. MAOA expression is
correlated with differentiation, invasion and survival in cholangiocarcinoma.
The MAOA promoter was hypermethylated immediately upstream of the start codon in
cholangiocarcinoma samples and cell lines but not in nonmalignant counterparts.
IL-6 signaling also decreased MAOA expression via a mechanism independent of
hypermethylation, involving the regulation of the balance between SP-1
transcriptional activity and its inhibitor, R1 repressor. Inhibition of both
IL-6 signaling and DNA methylation restored MAOA levels to those observed in
cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth
and invasion. MAOA expression is suppressed by the coordinated control of
promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic
marker in the management of cholangiocarcinoma, and therapies designed to
increase MAOA expression might prove beneficial in the treatment of
cholangiocarcinoma.
DOI: 10.1038/labinvest.2012.110
PMCID: PMC3959781
PMID: 22906985 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20026581 | 1. Nucleic Acids Res. 2010 Apr;38(6):1796-804. doi: 10.1093/nar/gkp1152. Epub
2009 Dec 21.
The multi-domain protein Np95 connects DNA methylation and histone modification.
Rottach A(1), Frauer C, Pichler G, Bonapace IM, Spada F, Leonhardt H.
Author information:
(1)Ludwig Maximilians University Munich, Department of Biology II and Center for
Integrated Protein Science Munich, Grosshaderner Str. 2, 82152
Planegg-Martinsried, Germany.
DNA methylation and histone modifications play a central role in the epigenetic
regulation of gene expression and cell differentiation. Recently, Np95 (also
known as UHRF1 or ICBP90) has been found to interact with Dnmt1 and to bind
hemimethylated DNA, indicating together with genetic studies a central role in
the maintenance of DNA methylation. Using in vitro binding assays we observed a
weak preference of Np95 and its SRA (SET- and Ring-associated) domain for
hemimethylated CpG sites. However, the binding kinetics of Np95 in living cells
was not affected by the complete loss of genomic methylation. Investigating
further links with heterochromatin, we could show that Np95 preferentially binds
histone H3 N-terminal tails with trimethylated (H3K9me3) but not acetylated
lysine 9 via a tandem Tudor domain. This domain contains three highly conserved
aromatic amino acids that form an aromatic cage similar to the one binding
H3K9me3 in the chromodomain of HP1ss. Mutations targeting the aromatic cage of
the Np95 tandem Tudor domain (Y188A and Y191A) abolished specific H3 histone
tail binding. These multiple interactions of the multi-domain protein Np95 with
hemimethylated DNA and repressive histone marks as well as with DNA and histone
methyltransferases integrate the two major epigenetic silencing pathways.
DOI: 10.1093/nar/gkp1152
PMCID: PMC2847221
PMID: 20026581 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17468742 | 1. Nature. 2007 May 31;447(7144):601-5. doi: 10.1038/nature05823. Epub 2007 Apr
29.
The histone H3K4 demethylase SMCX links REST target genes to X-linked mental
retardation.
Tahiliani M(1), Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, Li J, Rao A,
Shi Y.
Author information:
(1)Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine
and BCMP, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood
Avenue Boston, Massachusetts 02115, USA.
Gene transcription is critically influenced by chromatin structure and the
modification status of histone tails. Methylation of lysine residues in histone
tails is dynamically regulated by the opposing activities of histone
methyltransferases and histone demethylases. Here we show that JARID1C/SMCX, a
JmjC-domain-containing protein implicated in X-linked mental retardation and
epilepsy, possesses H3K4 tri-demethylase activity and functions as a
transcriptional repressor. An SMCX complex isolated from HeLa cells contains
additional chromatin modifiers (the histone deacetylases HDAC1 and HDAC2, and
the histone H3K9 methyltransferase G9a) and the transcriptional repressor REST,
suggesting a direct role for SMCX in chromatin dynamics and REST-mediated
repression. Chromatin immunoprecipitation reveals that SMCX and REST co-occupy
the neuron-restrictive silencing elements in the promoters of a subset of REST
target genes. RNA-interference-mediated depletion of SMCX derepresses several of
these targets and simultaneously increases H3K4 trimethylation at the sodium
channel type 2A (SCN2A) and synapsin I (SYN1) promoters. We propose that loss of
SMCX activity impairs REST-mediated neuronal gene regulation, thereby
contributing to SMCX-associated X-linked mental retardation.
DOI: 10.1038/nature05823
PMID: 17468742 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18058811 | 1. Mol Reprod Dev. 2008 May;75(5):731-43. doi: 10.1002/mrd.20816.
Messenger RNA expression patterns of histone-associated genes in bovine
preimplantation embryos derived from different origins.
Nowak-Imialek M(1), Wrenzycki C, Herrmann D, Lucas-Hahn A, Lagutina I, Lemme E,
Lazzari G, Galli C, Niemann H.
Author information:
(1)Department of Biotechnology, Institute for Animal Breeding (FAL), Mariensee,
Neustadt, Germany.
Histone modification genes in bovine embryos: The mRNA expression pattern of
histone-related genes was determined in bovine oocytes and embryos. We compared
immature and in vitro-matured oocytes, either before or after enucleation and
activation, in vitro produced embryos (zygotes, 8-16 cell stages, blastocysts),
embryos cloned with female or male donor cells; parthenogenetic embryos, and in
vivo-derived blastocysts to detect deviations from the normal expression
pattern. A sensitive semi-quantitative endpoint RT-PCR assay was used to reveal
differences in histone deacetylation [histone deacetylase 2 (HDAC2)]; histone
acetylation [histone acetyltransferase 1 (HAT1)]; histone methylation [histone
methyltransferases (SUV39H1, G9A)]; heterochromatin formation [heterochromatin
protein 1 (HP1)]; and chromatin-mediated transcription regulation [zygote arrest
1 (ZAR1)]. With the exception of ZAR1, these mRNAs were present throughout
preimplantation development. The relative abundance of mRNAs for histone
methyltransferases (SUV39H1 and G9A) and for heterochromatin-associated protein
(HP1) differed significantly before and after activation of the bovine embryonic
genome. The similarity of HAT1 gene expression in 8-16 cell embryos and
blastocysts suggests that histone acetylation is primarily affected by in vitro
culture only prior to embryonic genome activation. HDAC2 gene mRNA expression
was not affected by in vitro culture and/or cloning before and after activation
of the embryonic genome. The donor cell line affected mRNA expression patterns
of genes involved in reprogramming cloned embryos suggesting epigenetic
dysregulation. Results show that both in vitro production and somatic cloning
alter the mRNA expression of histone modifying genes in bovine embryos.
(c) 2007 Wiley-Liss, Inc.
DOI: 10.1002/mrd.20816
PMID: 18058811 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19838998 | 1. Int J Vitam Nutr Res. 2009 Jan;79(1):5-13. doi: 10.1024/0300-9831.79.1.5.
Antioxidant effect on urinary excretion of malondialdehyde in non-athletes
during aerobic training.
Hadley M(1), Visser MF, Vander Steen T.
Author information:
(1)Department of Chemistry and Geology, Minnesota State University, Mankato,
Mankato, MN 56001, USA. mary.hadley@mnsu.edu
Conditions in the body during aerobic exercise increase the level of lipid
peroxidation (LP). LP is associated with elevated concentration of modified
low-density lipoproteins that are implicated in development of cardiovascular
disease. Supplementation with antioxidant vitamin E to athletes at 267 mg (400
IUs) or greater has been reported to reduce levels of LP associated with
exercise. Little is currently known about the effects of modest supplementation
of vitamin E on previously sedentary adults who initiate an aerobic fitness
program. In the present study, sedentary subjects (n = 14) kept 24-hour diet
records to establish antioxidant intake of vitamins E and C and collected
24-hour urine samples that were used to determine baseline urinary
malondialdehyde (MDA) concentrations, one measure of in vivo LP. No significant
differences were noted in the parameters between groups. Seven subjects were
randomly selected and supplemented daily with 133 mg (200 IUs) of vitamin E. All
subjects participated in moderate-intensity aerobic training for 8 weeks.
Post-training, non-supplemented subjects excreted significantly more MDA
(p<0.05) and consumed significantly fewer antioxidants than the supplemented
group. Vitamin E supplementation appears to suppress elevated LP associated with
beginning an aerobic exercise regimen in previously sedentary subjects.
DOI: 10.1024/0300-9831.79.1.5
PMID: 19838998 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16829191 | 1. Eur J Heart Fail. 2007 Jan;9(1):37-43. doi: 10.1016/j.ejheart.2006.04.007.
Epub 2006 Jul 7.
Mutational screening of phospholamban gene in hypertrophic and idiopathic
dilated cardiomyopathy and functional study of the PLN -42 C>G mutation.
Medin M(1), Hermida-Prieto M, Monserrat L, Laredo R, Rodriguez-Rey JC, Fernandez
X, Castro-Beiras A.
Author information:
(1)Hospital Universitario Juan Canalejo, Spain.
BACKGROUND: Phospholamban is an endogenous sarcoplasmic reticulum calcium ATPase
inhibitor with a regulatory effect on cardiac contraction/relaxation coupling.
Mutations in the phospholamban gene (PLN) have been associated with primary
cardiomyopathies.
AIMS: To screen for PLN mutations in our population of patients with primary
cardiomyopathies and to perform functional analysis of the mutations identified.
METHODS: We performed SSCP mutational screening and DNA sequencing of the PLN
gene in 186 patients with either hypertrophic or dilated cardiomyopathy. To
study promoter strength we constructed reporter plasmids containing the
luciferase gene and performed transient transfection analysis in C6 and C2C12
cell lines.
RESULTS: The PLN -42 C>G mutation was found in one patient with late onset
familial apical hypertrophic cardiomyopathy. This mutation decreased
phospholamban promoter activity by 43% and 47%, in C6 and C2C12 cell lines
respectively. One son had mild apical hypertrophic cardiomyopathy and carried
the mutation, another son with normal ECG and echocardiogram also had the
mutation.
CONCLUSION: The PLN -42 C>G mutation is associated with a benign form of apical
hypertrophic cardiomyopathy in this family, though the presence of a healthy
adult carrier suggests that other genetic and environmental factors could be
involved. Otherwise, mutations in the PLN gene are not a frequent cause of
cardiomyopathies in our population.
DOI: 10.1016/j.ejheart.2006.04.007
PMID: 16829191 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21332051 | 1. Kardiol Pol. 2011;69(2):134-7.
Phospholamban gene mutations are not associated with hypertrophic cardiomyopathy
in patients from southern Poland.
Petkow-Dimitrow P(1), Kieć-Wilk B, Kwaśniak M, Mikołajczyk M, Dembińska-Kieć A.
Author information:
(1)2nd Department of Cardiology, Collegium Medicum, Jagiellonian University,
Krakow, Poland. dimitrow@mp.pl
Comment in
Kardiol Pol. 2011;69(2):138.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic disease. The role of
phospholamban (PLN) gene mutations is the development of HCM has not been
established.
AIM: To screen for PLN gene mutations in a group of HCM patients from the
southern Poland.
METHODS: We included 50 consecutive patients (31 males, mean age 42 ± 14 years)
diagnosed with HCM on the basis of typical clinical, echocardiographic, and
haemodynamic features. The control group consisted of 50 (sex-, age-matched)
healthy subjects with normal echocardiograms.
RESULTS: The genetic analysis was focused on R9C mutation with the ability to
block PLN phosphorylation leading to chronic inhibition of SERCA2a activity.
Another analysed mutation causing the alteration of PLN level in cells was
related to the substitution of a leucine residue at position 39 with a premature
stop codon (L39X). The sequence analysis of selected coding regions of the PLN
gene did not show the presence of mutations in either the patients or the
control subpopulations.
CONCLUSIONS: Systematic mutation screening did not reveal any mutation in the
selected regions of the PLN gene. Additionally, no polymorphisms were detected
in any patients. Therefore, PLN gene mutations were not found to be associated
with HCM in the study group.
PMID: 21332051 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17035524 | 1. J Neurosci. 2006 Oct 11;26(41):10397-406. doi: 10.1523/JNEUROSCI.1671-06.2006.
Functional analyses of glycyl-tRNA synthetase mutations suggest a key role for
tRNA-charging enzymes in peripheral axons.
Antonellis A(1), Lee-Lin SQ, Wasterlain A, Leo P, Quezado M, Goldfarb LG, Myung
K, Burgess S, Fischbeck KH, Green ED.
Author information:
(1)Genome Technology Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, Maryland 20892, USA.
Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy
type V (dSMA-V) are axonal neuropathies characterized by a phenotype that is
more severe in the upper extremities. We previously implicated mutations in the
gene encoding glycyl-tRNA synthetase (GARS) as the cause of CMT2D and dSMA-V.
GARS is a member of the family of aminoacyl-tRNA synthetases responsible for
charging tRNA with cognate amino acids; GARS ligates glycine to tRNA(Gly). Here,
we present functional analyses of disease-associated GARS mutations and show
that there are not any significant mutation-associated changes in GARS
expression levels; that the majority of identified GARS mutations modeled in
yeast severely impair viability; and that, in most cases, mutant GARS protein
mislocalizes in neuronal cells. Indeed, four of the five mutations studied show
loss-of-function features in at least one assay, suggesting that tRNA-charging
deficits play a role in disease pathogenesis. Finally, we detected endogenous
GARS-associated granules in the neurite projections of cultured neurons and in
the peripheral nerve axons of normal human tissue. These data are particularly
important in light of the recent identification of CMT-associated mutations in
another tRNA synthetase gene [YARS (tyrosyl-tRNA synthetase gene)]. Together,
these findings suggest that tRNA-charging enzymes play a key role in maintaining
peripheral axons.
DOI: 10.1523/JNEUROSCI.1671-06.2006
PMCID: PMC6674701
PMID: 17035524 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25168514 | 1. Hum Mutat. 2014 Nov;35(11):1363-71. doi: 10.1002/humu.22681.
Impaired function is a common feature of neuropathy-associated glycyl-tRNA
synthetase mutations.
Griffin LB(1), Sakaguchi R, McGuigan D, Gonzalez MA, Searby C, Züchner S, Hou
YM, Antonellis A.
Author information:
(1)Cellular and Molecular Biology Program, University of Michigan Medical
School, Ann Arbor, Michigan; Medical Scientist Training Program, University of
Michigan Medical School, Ann Arbor, Michigan.
Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal-dominant axonal
peripheral neuropathy characterized by impaired motor and sensory function in
the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene
cause CMT2D. GARS is a member of the ubiquitously expressed aminoacyl-tRNA
synthetase (ARS) family and is responsible for charging tRNA with glycine. To
date, 13 GARS mutations have been identified in patients with CMT disease. While
functional studies have revealed loss-of-function characteristics, only four
GARS mutations have been rigorously studied. Here, we report the functional
evaluation of nine CMT-associated GARS mutations in tRNA charging, yeast
complementation, and subcellular localization assays. Our results demonstrate
that impaired function is a common characteristic of CMT-associated GARS
mutations. Additionally, one mutation previously associated with CMT disease
(p.Ser581Leu) does not demonstrate impaired function, was identified in the
general population, and failed to segregate with disease in two newly identified
families with CMT disease. Thus, we propose that this variant is not a
disease-causing mutation. Together, our data indicate that impaired function is
a key component of GARS-mediated CMT disease and emphasize the need for careful
genetic and functional evaluation before implicating a variant in disease onset.
© 2014 WILEY PERIODICALS, INC.
DOI: 10.1002/humu.22681
PMCID: PMC4213347
PMID: 25168514 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21310746 | 1. Bioinformatics. 2011 Apr 1;27(7):933-8. doi: 10.1093/bioinformatics/btr053.
Epub 2011 Feb 9.
FISH Finder: a high-throughput tool for analyzing FISH images.
Shirley JW(1), Ty S, Takebayashi S, Liu X, Gilbert DM.
Author information:
(1)Department of Biological Science, Florida State University, Tallahassee, FL
32306, USA.
MOTIVATION: Fluorescence in situ hybridization (FISH) is used to study the
organization and the positioning of specific DNA sequences within the cell
nucleus. Analyzing the data from FISH images is a tedious process that invokes
an element of subjectivity. Automated FISH image analysis offers savings in time
as well as gaining the benefit of objective data analysis. While several FISH
image analysis software tools have been developed, they often use a
threshold-based segmentation algorithm for nucleus segmentation. As fluorescence
signal intensities can vary significantly from experiment to experiment, from
cell to cell, and within a cell, threshold-based segmentation is inflexible and
often insufficient for automatic image analysis, leading to additional manual
segmentation and potential subjective bias. To overcome these problems, we
developed a graphical software tool called FISH Finder to automatically analyze
FISH images that vary significantly. By posing the nucleus segmentation as a
classification problem, compound Bayesian classifier is employed so that
contextual information is utilized, resulting in reliable classification and
boundary extraction. This makes it possible to analyze FISH images efficiently
and objectively without adjustment of input parameters. Additionally, FISH
Finder was designed to analyze the distances between differentially stained FISH
probes.
AVAILABILITY: FISH Finder is a standalone MATLAB application and platform
independent software. The program is freely available from:
http://code.google.com/p/fishfinder/downloads/list.
DOI: 10.1093/bioinformatics/btr053
PMCID: PMC3065689
PMID: 21310746 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22665392 | 1. IEEE Trans Nanobioscience. 2012 Jun;11(2):111-8. doi:
10.1109/TNB.2012.2189414.
Classification of multicolor fluorescence in situ hybridization (M-FISH) images
with sparse representation.
Cao H(1), Deng HW, Li M, Wang YP.
Author information:
(1)Department of Biomedical Engineering, Tulane University, New Orleans, LA
70118, USA. hcao3@tulane.edu
There has been a considerable interest in sparse representation and compressive
sensing in applied mathematics and signal processing in recent years but with
limited success to medical image processing. In this paper we developed a sparse
representation-based classification (SRC) algorithm based on L1-norm
minimization for classifying chromosomes from multicolor fluorescence in situ
hybridization (M-FISH) images. The algorithm has been tested on a comprehensive
M-FISH database that we established, demonstrating improved performance in
classification. When compared with other pixel-wise M-FISH image classifiers
such as fuzzy c-means (FCM) clustering algorithms and adaptive fuzzy c-means
(AFCM) clustering algorithms that we proposed earlier the current method gave
the lowest classification error. In order to evaluate the performance of
different SRC for M-FISH imaging analysis, three different sparse representation
methods, namely, Homotopy method, Orthogonal Matching Pursuit (OMP), and Least
Angle Regression (LARS), were tested and compared. Results from our statistical
analysis have shown that Homotopy based method is significantly better than the
other two methods. Our work indicates that sparse representations based
classifiers with proper models can outperform many existing classifiers for
M-FISH classification including those that we proposed before, which can
significantly improve the multicolor imaging system for chromosome analysis in
cancer and genetic disease diagnosis.
DOI: 10.1109/TNB.2012.2189414
PMCID: PMC4165853
PMID: 22665392 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20925138 | 1. J Pathol. 2010 Dec;222(4):345-9. doi: 10.1002/path.2777.
Dyskerin and cancer: more than telomerase. The defect in mRNA translation helps
in explaining how a proliferative defect leads to cancer.
Montanaro L(1).
Author information:
(1)Department of Experimental Pathology, Alma Mater Studiorum--Università di
Bologna, Bologna, Italy. lorenzo.montanaro@unibo.it
Point mutations in the DKC1 gene that encodes dyskerin cause the rare inherited
syndrome called X-linked dyskeratosis congenita, characterized by a failure of
proliferating tissues and increased susceptibility to cancer. Dyskerin is a
nucleolar protein with different functions, all fundamental to basic cellular
events such as protein expression, growth, and proliferation. The two
best-characterized dyskerin activities are the stabilization of the telomerase
RNA component, allowing the proper function telomerase enzymatic complex, and
the modification of specific uridine residues of ribosomal RNA by converting
them to pseudouridine, thus allowing proper ribosome processing and function. In
light of the recent findings, this review focuses on the molecular pathogenesis
of dyskeratosis congenita, discussing how a defect in ribosomal function might
impact on the translation of a subset of mRNAs encoding for tumour suppressors,
thus providing an explanation for the apparent paradox of dyskeratosis congenita
in which reduced cell proliferation is associated with cancer susceptibility. In
addition, the current evidence pointing to a role played by dyskerin in tumours
in the general population is also discussed.
Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by
John Wiley & Sons, Ltd.
DOI: 10.1002/path.2777
PMID: 20925138 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18054794 | 1. Mech Ageing Dev. 2008 Jan-Feb;129(1-2):48-59. doi: 10.1016/j.mad.2007.10.006.
Epub 2007 Oct 30.
Dyskeratosis Congenita: a historical perspective.
Walne AJ(1), Dokal I.
Author information:
(1)Academic Unit of Paediatrics, Institute of Cell and Molecular Science, Barts
and The London, Queen Mary's School of Medicine and Dentistry, The Blizard
Building, 4 Newark Street, London E1 2AT, UK. a.walne@qmul.ac.uk
"Dyskeratosis Congenita (DC) also known as Zinsser-Engman-Cole syndrome is a
rare multi-system bone marrow failure syndrome characterised by mucocutaneous
abnormalities and an increased predisposition to cancer". This is a common
definition of DC but how did this definition arise? The aim of this review is to
follow the development of DC and associated diseases from its first reported
description in the early 20th century to the current understanding of the genes
involved and its pathophysiology in 2007 in a chronological order. Although this
review is not intended to be an exhaustive citation of the literature available
it does provide a summary of the key developments, citing particularly the
earlier reports of each development.
DOI: 10.1016/j.mad.2007.10.006
PMID: 18054794 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12690580 | 1. Am J Hum Genet. 2003 May;72(5):1293-9. doi: 10.1086/375039. Epub 2003 Apr 10.
Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and
distal spinal muscular atrophy type V.
Antonellis A(1), Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ,
Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu
V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED.
Author information:
(1)Genome Technology Branch, National Human Genome Research Institute, National
Institutes of Health, Bethesda, MD 20892, USA.
Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy
type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal
dominant fashion. Our previous genetic and physical mapping efforts localized
the responsible gene(s) to a well-defined region on human chromosome 7p. Here,
we report the identification of four disease-associated missense mutations in
the glycyl tRNA synthetase gene in families with CMT2D and dSMA-V. This is the
first example of an aminoacyl tRNA synthetase being implicated in a human
genetic disease, which makes genes that encode these enzymes relevant candidates
for other inherited neuropathies and motor neuron diseases.
DOI: 10.1086/375039
PMCID: PMC1180282
PMID: 12690580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20507306 | 1. Br J Haematol. 2010 Jul;150(2):179-88. doi: 10.1111/j.1365-2141.2010.08212.x.
Epub 2010 Apr 30.
Malignancies and survival patterns in the National Cancer Institute inherited
bone marrow failure syndromes cohort study.
Alter BP(1), Giri N, Savage SA, Peters JA, Loud JT, Leathwood L, Carr AG, Greene
MH, Rosenberg PS.
Author information:
(1)Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, Rockville, MD 20852-7231, USA. alterb@mail.nih.gov
Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia
(DBA), and Shwachman-Diamond syndrome (SDS) comprise major inherited bone marrow
failure syndromes (IBMFS). Adverse events include severe bone marrow failure
(BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid
tumours (ST). The natural history of FA is well characterised; hazard rates in
the other syndromes have not yet been quantified. An open cohort was established
at the National Cancer Institute (NCI) in 2002. Patients enrolled prior to
December, 2007 were followed up to December, 2008. Diagnoses were confirmed with
standard tests. Age-associated risks of adverse events were calculated. Most
patients in each syndrome survived to young adulthood. Patients with FA had
earlier onset of cancers, need for stem cell transplant, and death; followed by
DC; DBA and SDS were mildest. While FA and DC patients had markedly increased
risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS
patients. The NCI cohort provides the first direct quantitative comparison of
timing and magnitude of cancer risk in the IBMFS. The findings demonstrate that
both FA and DC are major cancer susceptibility syndromes. The IBMFS,
historically considered paediatric disorders, have important management
implications for physicians treating adult patients.
DOI: 10.1111/j.1365-2141.2010.08212.x
PMCID: PMC3125983
PMID: 20507306 [Indexed for MEDLINE]
Conflict of interest statement: Conflict-of-interest All authors declare no
competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/17548343 | 1. J Biol Chem. 2007 Jul 20;282(29):21024-31. doi: 10.1074/jbc.M703883200. Epub
2007 Jun 4.
Purification and characterization of cellular proteins associated with histone
H4 tails.
Choi J(1), Kim B, Heo K, Kim K, Kim H, Zhan Y, Ranish JA, An W.
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Southern
California (USC)/Norris Comprehensive Cancer Center, USC Keck School of
Medicine, Los Angeles, California 90033, USA.
The histone H4 N-terminal tail has long been regarded as a major regulator in
chromatin structure and function. Although the underlying mechanism has not been
unraveled, an emerging body of evidence supports that H4 tail and its
post-translational modification function as a recruitment motif for key factors
required for proper regulation of chromatin transcription. To investigate these
aspects, we have generated HeLa cell lines that constitutively express ectopic
H4 tail domain for biochemical purification of proteins associated with H4 tail.
We found that expressed H4 tails stably associate with sets of transcription
regulatory factors and histone methyltransferases distinct from those that
associate with histone H3 tails. Importantly, point mutations of four major
lysine substrates to block cellular acetylation of ectopic H4 tail significantly
inhibited the association of histone methyltransferases and sets of
transcription-activating factors, supporting a major role of acetylation on
recruitmentbased action of H4 tail during transcription. Further, our
transcription analysis revealed that the proteins associated with
wild-type/acetylated H4 tail, but not with mutant/unacetylated H4 tail, can
enhance p300-dependent chromatin transcription. Taken together, these findings
demonstrate novel roles for H4 tail and its acetylation in mediating recruitment
of multiple regulatory factors that can change chromatin states for
transcription regulation.
DOI: 10.1074/jbc.M703883200
PMID: 17548343 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25420567 | 1. Rinsho Shinkeigaku. 2014;54(11):911-5. doi: 10.5692/clinicalneurol.54.911.
[A novel mutation in glycyl-tRNA synthetase caused Charcot-Marie-Tooth disease
type 2D with facial and respiratory muscle involvement].
[Article in Japanese]
Kawakami N(1), Komatsu K, Yamashita H, Uemura K, Oka N, Takashima H, Takahashi
R.
Author information:
(1)Department of Neurology, Shizuoka General Hospital.
BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral
neuropathy; symptoms include distal wasting and weakness, usually with some
sensory impairment. The clinical course is typically benign and the disease is
not life threatening; however, in some cases, severe phenotypes include serious
respiratory distress.
CASE REPORT: Here we describe a 45-year-old woman with a long course of
motor-dominant neuropathy. Distal weakness appeared in childhood and became
worse with age. After a diagnosis of CMT type 2, the symptoms progressed, and in
her fourth decade, facial and respiratory muscle weakness appeared, ultimately
requiring non-invasive mechanical ventilation. There was no family history of
CMT. Comprehensive analysis of known CMT-related genes revealed a novel
heterozygous c.815T>A, p.L218Q mutation in glycyl-tRNA synthetase (GARS), a
causative gene for both CMT type 2D (CMT2D) and distal spinal muscular atrophy
type V (dSMA-V). This mutation was considered pathogenic based on molecular
evidence; notably, it was unique in that all other reported GARS mutations
associated with severe phenotypes are located in an anticodon-binding domain,
while in this case in an apparently non-functional region of the GARS gene. Not
a simple loss-of-function mechanism, but rather gain-of-function mechanisms have
also been reported in GARS mutations. This case provided useful information for
understanding the mechanism of CMT2D/dSMA-V.
DOI: 10.5692/clinicalneurol.54.911
PMID: 25420567 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16982418 | 1. Neuron. 2006 Sep 21;51(6):715-26. doi: 10.1016/j.neuron.2006.08.027.
An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a
Charcot-Marie-Tooth 2D mouse model.
Seburn KL(1), Nangle LA, Cox GA, Schimmel P, Burgess RW.
Author information:
(1)The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
Comment in
Neuron. 2006 Sep 21;51(6):672-4. doi: 10.1016/j.neuron.2006.09.008.
Of the many inherited Charcot-Marie-Tooth peripheral neuropathies, type 2D
(CMT2D) is caused by dominant point mutations in the gene GARS, encoding glycyl
tRNA synthetase (GlyRS). Here we report a dominant mutation in Gars that causes
neuropathy in the mouse. Importantly, both sensory and motor axons are affected,
and the dominant phenotype is not caused by a loss of the GlyRS aminoacylation
function. Mutant mice have abnormal neuromuscular junction morphology and
impaired transmission, reduced nerve conduction velocities, and a loss of
large-diameter peripheral axons, without defects in myelination. The mutant
GlyRS enzyme retains aminoacylation activity, and a loss-of-function allele,
generated by a gene-trap insertion, shows no dominant phenotype in mice. These
results indicate that the CMT2D phenotype is caused not by reduction of the
canonical GlyRS activity and insufficiencies in protein synthesis, but instead
by novel pathogenic roles for the mutant GlyRS that specifically affect
peripheral neurons.
DOI: 10.1016/j.neuron.2006.08.027
PMID: 16982418 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23352883 | 1. Arch Pediatr. 2013 Mar;20(3):299-306. doi: 10.1016/j.arcped.2012.12.003. Epub
2013 Jan 23.
[Dyskeratosis congenita: an update].
[Article in French]
Mialou V(1), Leblanc T, Peffault de Latour R, Dalle JH, Socié G.
Author information:
(1)Institut d'hématologie et oncologie pédiatrique (IHOP), 1, place
Professeur-J.-Renaut, 69008 Lyon, France. valerie.mialou@chu-lyon.fr
Dyskeratosis congenita is a rare inherited bone marrow failure characterized by
excessively short telomeres in highly proliferative tissues. These abnormalities
are due to disturbance of the telomere maintenance machinery. The clinical
presentation is characterized by skin pigmentation, nail dystrophy, and mucosal
leukoplakia. All these mucocutaneous features are rare in childhood: they
usually appear between 5 and 10 years of age. In young children, the initial
presentation can associate bone marrow failure and neurological or ocular
problems: Hoyeraal-Hreidarsson and Revesz syndromes, respectively. Clinical
progression of the disease can lead to aplastic anemia (86% of all patients) and
to pulmonary or hepatic complications. These patients also have an increased
risk of cancer. Diagnosis is often suspected on bone marrow failure with no
clinical or biological abnormalities compatible with Fanconi anemia diagnosis.
The telomere length study can be helpful for diagnosis in case of aplastic
anemia in children before studying gene mutations. Until now, 6 genes (DKC1,
TERT, TERC, NOLA2, NOLA3, TINF2) have been identified in dyskeratosis congenita.
Transmission of the disease can be autosomal recessive, autosomal dominant, or
X-linked. In half of the cases, the genetic abnormality is unknown. Treatment of
DC has to be adapted to each patient, from symptomatic or androgenic treatment
to hematopoietic stem cell transplantation.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.arcped.2012.12.003
PMID: 23352883 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18562771 | 1. Int J Sport Nutr Exerc Metab. 2008 Jun;18(3):301-12. doi:
10.1123/ijsnem.18.3.301.
High-protein-PUFA supplementation, red blood cell membranes, and plasma
antioxidant activity in volleyball athletes.
Malaguti M(1), Baldini M, Angeloni C, Biagi P, Hrelia S.
Author information:
(1)Dept. of Biochemistry, University of Bologna, Italy.
The authors evaluated the role of a high-protein, low-calorie, polyunsaturated
fatty-acid (PUFA) -supplemented diet on anthropometric parameters,
erythrocyte-membrane fatty-acid composition, and plasma antioxidant defenses of
nonprofessional volleyball athletes. The athletes were divided in two groups:
One (n = 5) followed the Mediterranean diet, and the other (n = 6) followed a
high-protein, low-calorie diet with a 3-g/day fish-oil supplementation. All the
athletes had anthropometric measurements taken, both at the beginning and at the
end of the study, which lasted for 2 months. Body-mass index and total body fat
were significantly diminished in the second group, while they remained unchanged
in the first. Plasma total antioxidant activity (TAA) was significantly
increased in the plasma of both groups, with no differences between the groups,
suggesting that physical activity, not the different diets, is the main
contributor to the increase of plasma TAA. The second group showed a significant
increase in erythrocyte-membrane PUFA content and in the unsaturation index
value (UI) because of the fish-oil supplementation.A high-protein,
low-carbohydrate, fish-oil-supplemented diet seems to be useful only when the
aim of the diet is to obtain weight loss in a short-term period. The significant
increase in the UI of erythrocyte membranes indicates the potential for harm,
because a high intake of PUFA might increase susceptibility to lipid
peroxidation not counterbalanced by a higher increase in TAA. Adherence to the
Mediterranean diet seems to be the better choice.
DOI: 10.1123/ijsnem.18.3.301
PMID: 18562771 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17545306 | 1. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):9976-81. doi:
10.1073/pnas.0703908104. Epub 2007 Jun 1.
Long-range structural effects of a Charcot-Marie-Tooth disease-causing mutation
in human glycyl-tRNA synthetase.
Xie W(1), Nangle LA, Zhang W, Schimmel P, Yang XL.
Author information:
(1)The Skaggs Institute for Chemical Biology and Department of Molecular
Biology, The Scripps Research Institute, BCC-379, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA.
Functional expansion of specific tRNA synthetases in higher organisms is well
documented. These additional functions may explain why dominant mutations in
glycyl-tRNA synthetase (GlyRS) and tyrosyl-tRNA synthetase cause
Charcot-Marie-Tooth (CMT) disease, the most common heritable disease of the
peripheral nervous system. At least 10 disease-causing mutant alleles of GlyRS
have been annotated. These mutations scatter broadly across the primary sequence
and have no apparent unifying connection. Here we report the structure of wild
type and a CMT-causing mutant (G526R) of homodimeric human GlyRS. The mutation
is at the site for synthesis of glycyl-adenylate, but the rest of the two
structures are closely similar. Significantly, the mutant form diffracts to a
higher resolution and has a greater dimer interface. The extra dimer
interactions are located approximately 30 A away from the G526R mutation. Direct
experiments confirm the tighter dimer interaction of the G526R protein. The
results suggest the possible importance of subtle, long-range structural effects
of CMT-causing mutations at the dimer interface. From analysis of a third
crystal, an appended motif, found in higher eukaryote GlyRSs, seems not to have
a role in these long-range effects.
DOI: 10.1073/pnas.0703908104
PMCID: PMC1891255
PMID: 17545306 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/21712654 | 1. RNA Biol. 2011 Sep-Oct;8(5):706-13. doi: 10.4161/rna.8.5.16154. Epub 2011 Jul
7.
Regulation and function of miRNA-21 in health and disease.
Kumarswamy R(1), Volkmann I, Thum T.
Author information:
(1)Institute of Molecular and Translational Therapeutic Strategies (IMTTS),
Hannover Medical School, Hannover, Germany.
The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora
of biological functions and diseases including development, cancer,
cardiovascular diseases and inflammation. The gene coding for pri-miR-21
(primary transcript containing miR-21) is located within the intronic region of
the TMEM49 gene. Despite pri-miR-21 and TMEM49 are overlapping genes in the same
direction of transcription, pri-miR-21 is independently transcribed by its own
promoter regions and terminated with its own poly(A) tail. After transcription,
primiR- 21 is finally processed into mature miR-21. Expression of miR-21 has
been found to be deregulated in almost all types of cancers and therefore was
classified as an oncomiR. During recent years, additional roles of miR-21 in
cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis
as well as myocardial infarction have been described. MiR-21 additionally
regulates various immunological and developmental processes. Due to the critical
functions of its target proteins in various signaling pathways, miR-21 has
become an attractive target for genetic and pharmacological modulation in
various disease conditions.
DOI: 10.4161/rna.8.5.16154
PMCID: PMC3256347
PMID: 21712654 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22859901 | 1. Int J Med Sci. 2012;9(6):413-23. doi: 10.7150/ijms.4514. Epub 2012 Jul 21.
MicroRNA 21 inhibits left ventricular remodeling in the early phase of rat model
with ischemia-reperfusion injury by suppressing cell apoptosis.
Qin Y(1), Yu Y, Dong H, Bian X, Guo X, Dong S.
Author information:
(1)Department of Emergency, Third Hospital of Hebei Medical University,
Shijiazhuang 050051, China.
OBJECTIVE: To determine the role of microRNA 21(miR-21) on left ventricular
remodeling of rat heart with ischemia-reperfusion (I/R) injury and to
investigate the underlying mechanism of miR-21 mediated myocardium protection.
METHODS: Rats were randomly divided into three groups: an I/R model group with
Ad-GFP (Ad-GFP group), an I/R model group with Ad-miR-21 (Ad-miR-21 group) and a
sham-surgery group. Changes in hemodynamic parameters were recorded at 1 week
after I/R. Histological diagnosis was achieved by hematoxylin and eosin (H&E).
Left ventricular (LV) dimensions, myocardial infarct size, LV/BW, collagen type
Ⅰ, type Ⅲ and PCNA positive cells were measured. Primary cultures of neonatal
rat cardiac ventricular myocytes were performed and cell ischemic injury was
induced by hypoxia in a serum- and glucose-free medium, and reoxygenation (H/R).
MiR-21 inhibitor and pre-miR-21 were respectively added to the culture medium
for the miR-21 knockdown and for the miR-21 up-regulation. qRT-PCR was used to
determine the miR-21 levels in cultured cells. Flow cytometry was performed to
examine the cell apoptosis.
RESULTS: In the Ad-miR-21 group, LV dimensions, myocardial infarct size, LV/BW,
collagen type Ⅰ, type Ⅲ and PCNA positive cells all significantly decreased
compared with the Ad-GFP group. At 1 week after I/R, the Ad-miR-21 significantly
improved LVSP, LV +dp/dt(max), LV - dp/dt(min), and decreased heart rate (HR)
and LVEDP compared with the Ad-GFP group. Compared with the Ad-GFP, the cell
apoptotic rate significantly decreased in the Ad-miR-21 group. The miR-21
inhibitor exacerbated cardiac myocyte apoptosis and the pre-miR-21 decreased
hypoxia/reoxygenation- induced cardiac myocyte apoptosis.
CONCLUSIONS: Ad-miR-21 improves LV remodeling and decreases the apoptosis of
myocardial cells, suggesting the possible mechanism by which Ad-miR-21 functions
in protecting against I/R injury.
DOI: 10.7150/ijms.4514
PMCID: PMC3410360
PMID: 22859901 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interest exists. |
http://www.ncbi.nlm.nih.gov/pubmed/12154089 | 1. J Biol Chem. 2002 Oct 18;277(42):39195-201. doi: 10.1074/jbc.M205166200. Epub
2002 Aug 1.
Postsynthetic trimethylation of histone H4 at lysine 20 in mammalian tissues is
associated with aging.
Sarg B(1), Koutzamani E, Helliger W, Rundquist I, Lindner HH.
Author information:
(1)Department of Medical Chemistry and Biochemistry, University of Innsbruck,
Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
Methylation of the N-terminal region of histones was first described more than
35 years ago, but its biological significance has remained unclear. Proposed
functions range from transcriptional regulation to the higher order packing of
chromatin in progress of mitotic condensation. Primarily because of the recent
discovery of the SET domain-depending H3-specific histone methyltransferases
SUV39H1 and Suv39h1, which selectively methylate lysine 9 of the H3 N terminus,
this posttranslational modification has regained scientific interest. In the
past, investigations concerning the biological significance of histone
methylation were largely limited because of a lack of simple and sensitive
analytical procedures for detecting this modification. The present work
investigated the methylation pattern of histone H4 both in different mammalian
organs of various ages and in cell lines by applying mass spectrometric analysis
and a newly developed hydrophilic-interaction liquid chromatographic method
enabling the simultaneous separation of methylated and acetylated forms, which
obviates the need to work with radioactive materials. In rat kidney and liver
the dimethylated lysine 20 was found to be the main methylation product, whereas
the monomethyl derivative was present in much smaller amounts. In addition, for
the first time a trimethylated form of lysine 20 of H4 was found in mammalian
tissue. A significant increase in this trimethylated histone H4 was detected in
organs of animals older than 30 days, whereas the amounts of mono- and
dimethylated forms did not essentially change in organs from young (10 days old)
or old animals (30 and 450 days old). Trimethylated H4 was also detected in
transformed cells; although it was present in only trace amounts in
logarithmically growing cells, we found an increase in trimethylated lysine 20
in cells in the stationary phase.
DOI: 10.1074/jbc.M205166200
PMID: 12154089 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12893173 | 1. Methods. 2003 Sep;31(1):49-58. doi: 10.1016/s1046-2023(03)00087-2.
Methods and tips for the purification of human histone methyltransferases.
Nishioka K(1), Reinberg D.
Author information:
(1)Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology,
Department of Biochemistry, University of Medicine and Dentistry of New Jersey,
Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
knishiok@lab.nig.ac.jp
Recently developed biochemical techniques have enabled researchers to study
histone modifications more easily and accurately. One of these modifications,
histone lysine methylation, has been shown to be highly stable and to represent
an epigenetic alteration. Extensive biochemical analyses have led to discoveries
about the nature and functions of this modification, thus accelerating our
understanding of this crucial epigenetic event. Here we describe basic methods
for purification and biochemical analysis of lysine-directed, histone
methyltransferases from HeLa cell-derived extracts. In the section on substrate
preparation, we describe a simple method for the preparation of recombinant
substrates, although we recommend using native substrates for initial detection
of the activities. The purification protocols for several histone
methyltransferases have been streamlined so that those researchers with a basic
understanding of biochemistry can perform them. We also describe many tips and
provide suggestions to avoid common pitfalls in the biochemical analysis of
histone methyltransferases.
DOI: 10.1016/s1046-2023(03)00087-2
PMID: 12893173 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22882958 | 1. Int J Cardiol. 2013 Sep 10;167(6):2875-81. doi: 10.1016/j.ijcard.2012.07.021.
Epub 2012 Aug 9.
Myocardial and circulating levels of microRNA-21 reflect left ventricular
fibrosis in aortic stenosis patients.
Villar AV(1), García R, Merino D, Llano M, Cobo M, Montalvo C, Martín-Durán R,
Hurlé MA, Nistal JF.
Author information:
(1)Universidad de Cantabria, Santander, Spain.
BACKGROUND: Various human cardiovascular pathophysiological conditions associate
aberrant expression of microRNAs (miRNAs) and circulating miRNAs are emerging as
promising biomarkers. In mice, myocardial miR-21 overexpression is related to
cardiac fibrosis elicited by pressure overload. This study was designed to
determine the role of myocardial and plasmatic miR-21 in the maladaptive
remodeling of the extracellular matrix induced by pressure overload in aortic
stenosis (AS) patients and the clinical value of miR-21 as a biomarker for
pathological myocardial fibrosis.
METHODS: In left ventricular biopsies from 75 AS patients and 32 surgical
controls, we quantified the myocardial transcript levels of miR-21,
miR-21-targets and ECM- and TGF-β-signaling-related elements. miR-21 plasma
levels were determined in 25 healthy volunteers and in AS patients. In situ
hybridization of miR-21 was performed in myocardial sections.
RESULTS: The myocardial and plasma levels of miR-21 were significantly higher in
the AS patients compared with the controls and correlated directly with the
echocardiographic mean transvalvular gradients. miR-21 overexpression was
confined to interstitial cells and absent in cardiomyocytes. Using bootstrap
validated multiple linear regression, the variance in myocardial collagen
expression was predicted by myocardial miR-21 (70% of collagen variance) or
plasma miR-21 (52% of collagen variance), together with the miR-21 targets RECK
and PDCD4, and effectors of TGF-ß signaling.
CONCLUSIONS: Our results support the role of miR-21 as a regulator of the
fibrotic process that occurs in response to pressure overload in AS patients and
underscore the value of circulating miR-21 as a biomarker for myocardial
fibrosis.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.ijcard.2012.07.021
PMID: 22882958 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17846168 | 1. J Cell Biol. 2007 Sep 10;178(6):925-36. doi: 10.1083/jcb.200703081.
Suv4-20h deficiency results in telomere elongation and derepression of telomere
recombination.
Benetti R(1), Gonzalo S, Jaco I, Schotta G, Klatt P, Jenuwein T, Blasco MA.
Author information:
(1)Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National
Cancer Centre, Madrid, Spain.
Mammalian telomeres have heterochromatic features, including trimethylated
histone H3 at lysine 9 (H3K9me3) and trimethylated histone H4 at lysine 20
(H4K20me3). In addition, subtelomeric DNA is hypermethylated. The enzymatic
activities responsible for these modifications at telomeres are beginning to be
characterized. In particular, H4K20me3 at telomeres could be catalyzed by the
novel Suv4-20h1 and Suv4-20h2 histone methyltransferases (HMTases). In this
study, we demonstrate that the Suv4-20h enzymes are responsible for this histone
modification at telomeres. Cells deficient for Suv4-20h2 or for both Suv4-20h1
and Suv4-20h2 show decreased levels of H4K20me3 at telomeres and subtelomeres in
the absence of changes in H3K9me3. These epigenetic alterations are accompanied
by telomere elongation, indicating a role for Suv4-20h HMTases in telomere
length control. Finally, cells lacking either the Suv4-20h or Suv39h HMTases
show increased frequencies of telomere recombination in the absence of changes
in subtelomeric DNA methylation. These results demonstrate the importance of
chromatin architecture in the maintenance of telomere length homeostasis and
reveal a novel role for histone lysine methylation in controlling telomere
recombination.
DOI: 10.1083/jcb.200703081
PMCID: PMC2064618
PMID: 17846168 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11316813 | 1. J Biol Chem. 2001 Jul 6;276(27):25309-17. doi: 10.1074/jbc.M101914200. Epub
2001 Apr 20.
Set domain-containing protein, G9a, is a novel lysine-preferring mammalian
histone methyltransferase with hyperactivity and specific selectivity to lysines
9 and 27 of histone H3.
Tachibana M(1), Sugimoto K, Fukushima T, Shinkai Y.
Author information:
(1)Department of Cell Biology, Institute for Virus Research, Kyoto University,
Shogoin Kawara-cho, Kyoto 606-8507, Japan.
The covalent modification of histone tails has regulatory roles in various
nuclear processes, such as control of transcription and mitotic chromosome
condensation. Among the different groups of enzymes known to catalyze the
covalent modification, the most recent additions are the histone
methyltransferases (HMTases), whose functions are now being characterized. Here
we show that a SET domain-containing protein, G9a, is a novel mammalian
lysine-preferring HMTase. Like Suv39 h1, the first identified lysine-preferring
mammalian HMTase, G9a transfers methyl groups to the lysine residues of histone
H3, but with a 10-20-fold higher activity. It was reported that lysines 4, 9,
and 27 in H3 are methylated in mammalian cells. G9a was able to add methyl
groups to lysine 27 as well as 9 in H3, compared with Suv39 h1, which was only
able to methylate lysine 9. Our data clearly demonstrated that G9a has an
enzymatic nature distinct from Suv39 h1 and its homologue h2. Finally,
fluorescent protein-labeled G9a was shown to be localized in the nucleus but not
in the repressive chromatin domains of centromeric loci, in which Suv39 h1
family proteins were localized. This finding indicates that G9a may contribute
to the organization of the higher order chromatin structure of non-centromeric
loci.
DOI: 10.1074/jbc.M101914200
PMID: 11316813 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19706597 | 1. J Biol Chem. 2009 Oct 23;284(43):29514-25. doi: 10.1074/jbc.M109.027896. Epub
2009 Aug 25.
MicroRNA expression signature and the role of microRNA-21 in the early phase of
acute myocardial infarction.
Dong S(1), Cheng Y, Yang J, Li J, Liu X, Wang X, Wang D, Krall TJ, Delphin ES,
Zhang C.
Author information:
(1)Department of Anesthesiology, RNA and Cardiovascular Research Laboratory, New
Jersey Medical School, University of Medicine and Dentistry of New Jersey,
Newark, New Jersey 07101, USA.
Several recent reports have suggested that microRNAs (miRNAs) might play
critical roles in acute myocardial infarction (AMI). However, the miRNA
expression signature in the early phase of AMI has not been identified. In this
study, the miRNA expression signature was investigated in rat hearts 6 h after
AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs
were differentially expressed in infarcted areas and 33 miRNAs were aberrantly
expressed in the border areas. Remarkably, miR-21 expression was significantly
down-regulated in infarcted areas, but was up-regulated in border areas. The
down-regulation of miR-21 in the infarcted areas was inhibited by ischemic
preconditioning, a known cardiac protective method. Overexpression of miR-21 via
adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by
29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI.
Using both gain-of-function and loss-of-function approaches in cultured cardiac
myocytes, we identified that miR-21 had a protective effect on ischemia-induced
cell apoptosis that was associated with its target gene programmed cell death 4
and activator protein 1 pathway. The protective effect of miR-21 against
ischemia-induced cardiac myocyte damage was further confirmed in vivo by
decreased cell apoptosis in the border and infarcted areas of the infarcted rat
hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as
miR-21 may play critical roles in the early phase of AMI.
DOI: 10.1074/jbc.M109.027896
PMCID: PMC2785585
PMID: 19706597 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17584191 | 1. Hepatol Res. 2007 Nov;37(11):974-83. doi: 10.1111/j.1872-034X.2007.00141.x.
Epub 2007 Jun 20.
Alterations of DNA methylation and histone modifications contribute to gene
silencing in hepatocellular carcinomas.
Kondo Y(1), Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, Kato H, Mizuno Y,
Yokoe M, Sugauchi F, Hirashima N, Orito E, Osada H, Ueda R, Guo Y, Chen X, Issa
JP, Sekido Y.
Author information:
(1)Division of Molecular Oncology, Aichi Cancer Center Research Institute,
Aichi, Japan.
AIM: The aim of the present study was to examine DNA methylation and histone
modification changes in hepatocellular carcinomas (HCC).
METHODS: DNA methylation in the P16, RASSF1a, progesterone receptor (PGR) and
estrogen receptor alpha (ERalpha) promoters was determined by quantitative
bisulfite-pyrosequencing technique in HCC patients. Histone H3-lysine (K) 4,
H3-K9 and H3-K27 modifications in all these four genes were examined by
chromatin immunoprecipitation (ChIP) assay in HCC cell lines. Expression of two
DNA methyltransferases (DNMT1 and DNMT3b) and three histone methyltransferases
(SUV39H1, G9a and EZH2) in HCC patients was measured by real-time polymerase
chain reaction.
RESULTS: Aberrant DNA methylation was detected in all the HCC. Patients with DNA
methylation in the RASSF1a, PGR andERalpha promoters in cancers also had
substantial DNA methylation in their non-cancerous liver tissues, whereas DNA
methylation in the P16 promoter was cancer specific. Epigenetic states in HCC
cell lines showed that silencing of P16 and RASSF1a depended on DNA methylation
and histone H3-K9 methylation. However, silencing of the PGR and ERalpha genes
was more closely related to H3-K27 methylation rather than DNA methylation.
Consistent with the alteration of histone status, higher expression of G9a and
EZH2 was found in HCC than in non-cancerous liver tissues (P < 0.01).
CONCLUSION: These data suggest that multiple epigenetic silencing mechanisms are
inappropriately active in HCC cells.
DOI: 10.1111/j.1872-034X.2007.00141.x
PMID: 17584191 |
http://www.ncbi.nlm.nih.gov/pubmed/15254397 | 1. Cancer Biol Ther. 2004 Jun;3(6):528-33. doi: 10.4161/cbt.3.6.843. Epub 2004
Jun 24.
BRCA1 and transcription.
Lane TF(1).
Author information:
(1)David Geffen School of Medicine at University of California, Los Angele, CA
90095-1740, USA. tlane@mednet.ucla.edu
The BRCA1 tumor suppressor gene is expressed in all mammalian cells. Within
these cells, the BRCA1 protein product interacts with several seemingly distinct
nuclear complexes. Proteins within these complexes are potential targets for the
E3-ubiquitin ligase activity associated with BRCA1:BARD1 complexes. Recent
breakthroughs have centered on elucidating critical DNA repair and
chromatin-remodeling functions associated with BRCA1 activity. During both DNA
replication and DNA repair, BRCA1 appears to serve both adaptor and enzymatic
functions. Roles include transient physical recruitment of NBS1, gammaH2AX,
FANCD2 and other proteins in specific repair associated complexes, and enzymatic
activity as an E3-ubiquitin ligase against a subset of these proteins. BRCA1 has
also been implicated as a regulator of transcription. It is in this second
capacity that progress has been much more difficult to assess. In particular,
unambiguous adaptor and enzymatic functions have yet to be demonstrated in
transcriptional machinery. Addressing the critical gap in our understanding of
enzymatic targets of BRCA1 will be required for significant future progress in
this field. The following review puts forward a model for BRCA1 interactions
with the transcriptional complex in undamaged cells, and a potential mechanism
for substrate switching between transcription and DNA-repair complexes following
exposure of cells to proliferative or genotoxic stress. This model incorporates
recent evidence that BRCA1 interacts predominantly with hyper-phosphorylated,
enzymatically active, RNA polymerase II (RNAPII) in undamaged cells. The model
proposes that BRCA1 binds processive RNA polymerase as part of a genome
surveillance function, upstream of critical roles in DNA repair.
DOI: 10.4161/cbt.3.6.843
PMID: 15254397 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22870189 | 1. PLoS One. 2012;7(8):e39573. doi: 10.1371/journal.pone.0039573. Epub 2012 Aug
3.
ChIPnorm: a statistical method for normalizing and identifying differential
regions in histone modification ChIP-seq libraries.
Nair NU(1), Sahu AD, Bucher P, Moret BM.
Author information:
(1)Laboratory for Computational Biology and Bioinformatics, School of Computer
and Communication Sciences, École Polytechnique Fédérale de Lausanne (EPFL),
Lausanne, Switzerland.
The advent of high-throughput technologies such as ChIP-seq has made possible
the study of histone modifications. A problem of particular interest is the
identification of regions of the genome where different cell types from the same
organism exhibit different patterns of histone enrichment. This problem turns
out to be surprisingly difficult, even in simple pairwise comparisons, because
of the significant level of noise in ChIP-seq data. In this paper we propose a
two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and
to find differential regions in the genome, given two libraries of histone
modifications of different cell types. We show that the ChIPnorm method removes
most of the noise and bias in the data and outperforms other normalization
methods. We correlate the histone marks with gene expression data and confirm
that histone modifications H3K27me3 and H3K4me3 act as respectively a repressor
and an activator of genes. Compared to what was previously reported in the
literature, we find that a substantially higher fraction of bivalent marks in ES
cells for H3K27me3 and H3K4me3 move into a K27-only state. We find that most of
the promoter regions in protein-coding genes have differential
histone-modification sites. The software for this work can be downloaded from
http://lcbb.epfl.ch/software.html.
DOI: 10.1371/journal.pone.0039573
PMCID: PMC3411705
PMID: 22870189 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21094032 | 1. Curr Opin Immunol. 2010 Dec;22(6):706-14. doi: 10.1016/j.coi.2010.10.014. Epub
2010 Nov 18.
The role of SLAM/CD2 polymorphisms in systemic autoimmunity.
Wang A(1), Batteux F, Wakeland EK.
Author information:
(1)Department of Immunology and the Walter M. and Helen D. Bader Center for
Research on Arthritis and Autoimmune Disease, University of Texas Southwestern
Medical Center, Dallas, TX 75390, USA.
The SLAM/CD2 gene family encodes receptors that play important roles in
regulating multiple cellular interactions in the adaptive and innate immune
systems. Three members of this gene family, Ly108, Ly9, and CD84, exhibit
polymorphisms that strongly influence susceptibility to systemic autoimmunity,
notably in mice, but also in some human populations. Polymorphisms of Ly108 in
mice strongly impact central tolerance in both B and T cell development,
predominantly by modulating apoptosis, anergy, and cell-cycle progression. In
addition, Ly108 and CD84, together with their downstream signaling adaptor
SLAM-associated protein (SAP), have emerged as key players in B-T interactions
during the formation of germinal centers. Interestingly, several independent
lines of research have now associated variations in B-T interactions during
germinal center formation with systemic autoimmunity, suggesting that
susceptibility to systemic lupus erythematosus (SLE) may involve in part the
impairment of this peripheral tolerance checkpoint. These new insights into the
multiplicity of roles played by the SLAM/CD2 family and its potential importance
in human autoimmunity positions the SLAM/CD2 family as an excellent target for
immunotherapy.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.coi.2010.10.014
PMID: 21094032 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17420471 | 1. Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6614-9. doi:
10.1073/pnas.0610481104. Epub 2007 Apr 9.
A mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin
ligase.
Horwitz AA(1), Affar el B, Heine GF, Shi Y, Parvin JD.
Author information:
(1)Department of Pathology, Harvard Medical School and Brigham and Women's
Hospital, Boston, MA 02115, USA.
Loss of function of the tumor suppressor protein BRCA1 is responsible for a high
percentage of familial and also sporadic breast cancers. Early work identified a
stimulatory transcriptional coactivator function for the BRCA1 protein, and more
recently, BRCA1 has been implicated in transcriptional repression, although few
examples of repressed genes have been characterized. We recently used an in
vitro transcription assay to identify a biochemical mechanism that explained the
BRCA1 stimulatory activity. In this study, we identified an ubiquitin-dependent
mechanism by which BRCA1 inhibits transcription. BRCA1 ubiquitinates the
transcriptional preinitiation complex, preventing stable association of TFIIE
and TFIIH, and thus blocks the initiation of mRNA synthesis. What is striking
about this mechanism of regulation by BRCA1 is that the ubiquitination of the
preinitiation complex is not targeting proteins for degradation by the
proteasome, nor are ubiquitin receptors modifying the activity, but rather the
ubiquitin moiety itself interferes with the assembly of basal transcription
factors at the promoter. Using RNAi to knockdown expression of the endogenous
BRCA1 protein, we assessed the level of repression dependent on BRCA1 in the
cell, and we found that BRCA1 is at least as significant a transcriptional
repressor as it is an activator. These results define a biochemical mechanism by
which the BRCA1 enzymatic activity regulates a key cellular process.
DOI: 10.1073/pnas.0610481104
PMCID: PMC1871834
PMID: 17420471 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/17825470 | 1. Biochimie. 2008 Jan;90(1):122-30. doi: 10.1016/j.biochi.2007.07.017. Epub 2007
Jul 31.
Dyskeratosis congenita: the diverse clinical presentation of mutations in the
telomerase complex.
Vulliamy TJ(1), Dokal I.
Author information:
(1)Academic Unit of Paediatrics, Institute of Cell and Molecular Science, Barts
and the London, Queen Mary School of Medicine and Dentistry, 4 Newark Street,
London E1 2AT, UK. t.vulliamy@qmul.ac.uk <t.vulliamy@qmul.ac.uk>
Dyskeratosis congenita is an inherited syndrome characterised by mucocutaneous
features, bone marrow failure, an increased risk of malignancy and other somatic
abnormalities. There is a considerable range of clinical severity and in its
occult form the disease may present as idiopathic aplastic anaemia. Genes
responsible for X-linked, autosomal dominant and autosomal recessive forms of
the disease have been identified and been found to encode products involved in
telomere maintenance. Premature shortening of telomeres could account for the
pathology, affecting the tissues that turn over most rapidly. However, the
protein that is mutated in the X-linked disease, dyskerin, also plays a
fundamental role in ribosome biogenesis, directing the pseudouridylation of
ribosomal RNA using H/ACA small nucleolar RNAs as guides. Heterozygous mutations
in the RNA component of telomerase (TERC) cause the autosomal dominant form of
the disease through haploinsufficiency. Disease anticipation described in these
families is associated with progressive telomere shortening through the
generations. Heterozygous mutations in the reverse transcriptase component of
telomerase (TERT) have a more variable role, often displaying incomplete
penetrance and diverse clinical presentation. The autosomal recessive form of
the disease is genetically heterogeneous, although one sub-type has been
described in which NOP10 is mutated. This small protein is also associated with
the maturation of ribosomal RNA and the telomerase complex.
DOI: 10.1016/j.biochi.2007.07.017
PMID: 17825470 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25124893 | 1. Immunogenetics. 2014 Nov;66(11):671-4. doi: 10.1007/s00251-014-0795-0. Epub
2014 Aug 16.
Parallel evolution of a self-signal: humans and new world monkeys independently
lost the cell surface sugar Neu5Gc.
Springer SA(1), Diaz SL, Gagneux P.
Author information:
(1)Glycobiology Research and Training Center, Department of Cellular and
Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Human sialic acid biology is unusual and thought to be unique among mammals.
Humans lack a functional cytidine monophosphate-N-acetylneuraminic acid
hydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate
mammalian signal of self. Losing this sugar changed how humans interact with
some of our deadliest pathogens: malaria, influenza, and streptococcus among
others. We show that the New World monkeys, comprising the third of all primate
species, have human-like sialic acid biology. They have lost Neu5Gc because of
an independent CMAH inactivation ~30 million years ago (mya) (compared to ~3 mya
in hominids). This parallel loss of Neu5Gc opens sialic acid biology to
comparative phylogenetic analysis and reveals an unexpected conservation
priority. New World monkeys risk infection by human pathogens that can recognize
cells in the absence of Neu5Gc. This striking molecular convergence provides a
mechanism that could explain the long-standing observation that New World
monkeys are susceptible to some human diseases that cannot be transmitted to
other primates.
DOI: 10.1007/s00251-014-0795-0
PMCID: PMC4198446
PMID: 25124893 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24278741 | 1. Scientifica (Cairo). 2012;2012:796808. doi: 10.6064/2012/796808. Epub 2012 Oct
18.
The BRCA1 Breast Cancer Suppressor: Regulation of Transport, Dynamics, and
Function at Multiple Subcellular Locations.
Henderson BR(1).
Author information:
(1)Westmead Institute for Cancer Research, Westmead Millennium Institute at
Westmead Hospital, University of Sydney, Darcy Road, P.O. Box 412, Westmead, NSW
2145, Australia.
Inherited mutations in the BRCA1 gene predispose to a higher risk of
breast/ovarian cancer. The BRCA1 tumor suppressor is a 1863 amino acid protein
with multiple protein interaction domains that facilitate its roles in
regulating DNA repair and maintenance, cell cycle progression, transcription,
and cell survival/apoptosis. BRCA1 was first identified as a nuclear
phosphoprotein, but has since been shown to contain different transport
sequences including nuclear export and nuclear localization signals that enable
it to shuttle between specific sites within the nucleus and cytoplasm, including
DNA repair foci, centrosomes, and mitochondria. BRCA1 nuclear transport and
ubiquitin E3 ligase enzymatic activity are tightly regulated by the BRCA1
dimeric binding partner BARD1 and further modulated by cancer mutations and
diverse signaling pathways. This paper will focus on the transport, dynamics,
and multiple intracellular destinations of BRCA1 with emphasis on how regulation
of these events has impact on, and determines, a broad range of important
cellular functions.
DOI: 10.6064/2012/796808
PMCID: PMC3820561
PMID: 24278741 |
http://www.ncbi.nlm.nih.gov/pubmed/23520510 | 1. PLoS One. 2013;8(3):e58443. doi: 10.1371/journal.pone.0058443. Epub 2013 Mar
8.
A simple method for assessment of human anti-Neu5Gc antibodies applied to
Kawasaki disease.
Padler-Karavani V(1), Tremoulet AH, Yu H, Chen X, Burns JC, Varki A.
Author information:
(1)Glycobiology Research and Training Center, Department of Medicine, University
of California San Diego, La Jolla, California, United States of America.
N-glycolylneuraminic acid (Neu5Gc) is an immunogenic sugar of dietary origin
that metabolically incorporates into diverse native glycoconjugates in humans.
Anti-Neu5Gc antibodies are detected in all human sera, though with variable
levels and epitope-recognition profiles. These antibodies likely play a role in
several inflammation-mediated pathologies including cardiovascular diseases and
cancer. In cancer, they have dualistic and opposing roles, either stimulating or
repressing disease, as a function of their dose, and some of these antibodies
serve as carcinoma biomarkers. Thus, anti-Neu5Gc antibodies may signify risk of
inflammation-mediated diseases, and changes in their levels could potentially be
used to monitor disease progression and/or response to therapy. Currently, it is
difficult to determine levels of anti-Neu5Gc antibodies in individual human
samples because these antibodies recognize multiple Neu5Gc-epitopes. Here we
describe a simple and specific method for detection and overall estimation of
human anti-Neu5Gc antibodies. We exploit the difference between two mouse models
that differ only by Neu5Gc-presence (wild-type) or Neu5Gc-absence (Cmah(-/-)
knockout). We characterize mouse serum from both strains by HPLC, lectin and
mass-spectrometry analysis and show the target Neu5Gc-epitopes. We then use
Cmah(-/-) knockout sera to inhibit all non-Neu5Gc-reactivity followed by binding
to wild-type sera to detect overall anti-Neu5Gc response in a single assay. We
applied this methodology to characterize and quantify anti-Neu5Gc IgG and IgA in
sera of patients with Kawasaki disease (KD) at various stages compared to
controls. KD is an acute childhood febrile disease characterized by inflammation
of coronary arteries that untreated may lead to coronary artery aneurysms with
risk of thrombosis and myocardial infarction. This estimated response is
comparable to the average of detailed anti-Neu5Gc IgG profile analyzed by a
sialoglycan microarray. Both assays revealed an elevated response in acute KD
patients with normal coronaries compared to patients with aneurysm or dilated
coronaries. Implications of these findings are discussed.
DOI: 10.1371/journal.pone.0058443
PMCID: PMC3592828
PMID: 23520510 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have read the
journal’s policy and have the following conflicts: A.V. is co-founder of and
Scientific Advisor to Sialix Inc, a startup biotech company interested in the
practical relevance of anti-Neu5Gc antibodies to human disease. The submission
is related to US Patent No: 7,682,794 entitled “Methods for detecting and
analyzing N-glycolylneuraminic acid (Neu5Gc) in biological materials”.
Additional patent applications may be made in relation to the content of the
current paper. There are no further patents, products in development or marketed
products to declare. This does not alter the authors' adherence to all the PLOS
ONE policies on sharing data and materials, as detailed online in the guide for
authors. |
http://www.ncbi.nlm.nih.gov/pubmed/22058220 | 1. Haematologica. 2012 Mar;97(3):353-9. doi: 10.3324/haematol.2011.055269. Epub
2011 Nov 4.
Telomere length is associated with disease severity and declines with age in
dyskeratosis congenita.
Alter BP(1), Rosenberg PS, Giri N, Baerlocher GM, Lansdorp PM, Savage SA.
Author information:
(1)Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, National Institutes of Health, Department of Health
and Human Services, Rockville, MD 20852-7231, USA. alterb@mail.nih.gov
BACKGROUND: Dyskeratosis congenita is a cancer-prone bone marrow failure
syndrome caused by aberrations in telomere biology.
DESIGN AND METHODS: We studied 65 patients with dyskeratosis congenita and 127
unaffected relatives. Telomere length was measured by automated multicolor flow
fluorescence in situ hybridization in peripheral blood leukocyte subsets. We
age-adjusted telomere length using Z-scores (standard deviations from the mean
for age).
RESULTS: We confirmed that telomere lengths below the first percentile for age
are very sensitive and specific for the diagnosis of dyskeratosis congenita. We
provide evidence that lymphocytes alone and not granulocytes may suffice for
clinical screening, while lymphocyte subsets may be required for challenging
cases, including identification of silent carriers. We show for the first time
using flow fluorescence in situ hybridization that the shortest telomeres are
associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes),
mutations in DKC1, TINF2, or unknown genes, and moderate or severe aplastic
anemia. In the first longitudinal follow up of dyskeratosis congenita patients,
we demonstrate that telomere lengths decline with age, in contrast to the
apparent stable telomere length observed in cross-sectional data.
CONCLUSIONS: Telomere length by flow fluorescence in situ hybridization is an
important diagnostic test for dyskeratosis congenita; age-adjusted values
provide a quantitative measure of disease severity (clinical subset, mutated
gene, and degree of bone marrow failure). Patients with dyskeratosis congenita
have accelerated telomere shortening. This study is registered at
www.clinicaltrials.gov (identifier: NCT00027274).
DOI: 10.3324/haematol.2011.055269
PMCID: PMC3291588
PMID: 22058220 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16710298 | 1. EMBO J. 2006 Jun 7;25(11):2465-74. doi: 10.1038/sj.emboj.7601144. Epub 2006
May 18.
Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins
Bmi1 and Ring1b.
Buchwald G(1), van der Stoop P, Weichenrieder O, Perrakis A, van Lohuizen M,
Sixma TK.
Author information:
(1)Division of Molecular Carcinogenesis and Center for Biomedical Genetics,
Netherlands Cancer Institute, Amsterdam, Netherlands.
Polycomb group proteins Ring1b and Bmi1 (B-cell-specific Moloney murine
leukaemia virus integration site 1) are critical components of the chromatin
modulating PRC1 complex. Histone H2A ubiquitination by the PRC1 complex strongly
depends on the Ring1b protein. Here we show that the E3-ligase activity of
Ring1b on histone H2A is enhanced by Bmi1 in vitro. The N-terminal Ring-domains
are sufficient for this activity and Ring1a can replace Ring1b. E2 enzymes
UbcH5a, b, c or UbcH6 support this activity with varying processivity and
selectivity. All four E2s promote autoubiquitination of Ring1b without affecting
E3-ligase activity. We solved the crystal structure of the Ring-Ring
heterodimeric complex of Ring1b and Bmi1. In the structure the arrangement of
the Ring-domains is similar to another H2A E3 ligase, the BRCA1/BARD1 complex,
but complex formation depends on an N-terminal arm of Ring1b that embraces the
Bmi1 Ring-domain. Mutation of a critical residue in the E2/E3 interface shows
that catalytic activity resides in Ring1b and not in Bmi1. These data provide a
foundation for understanding the critical enzymatic activity at the core of the
PRC1 polycomb complex, which is implicated in stem cell maintenance and cancer.
DOI: 10.1038/sj.emboj.7601144
PMCID: PMC1478191
PMID: 16710298 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18669916 | 1. Glycobiology. 2008 Oct;18(10):818-30. doi: 10.1093/glycob/cwn072. Epub 2008
Jul 31.
Diversity in specificity, abundance, and composition of anti-Neu5Gc antibodies
in normal humans: potential implications for disease.
Padler-Karavani V(1), Yu H, Cao H, Chokhawala H, Karp F, Varki N, Chen X, Varki
A.
Author information:
(1)Glycobiology Research and Training Center and Department of Medicine,
University of California, San Diego, La Jolla, CA 92093, USA.
Human heterophile antibodies that agglutinate animal erythrocytes are known to
detect the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc). This
monosaccharide cannot by itself fill the binding site (paratope) of an antibody
and can also be modified and presented in various linkages, on diverse
underlying glycans. Thus, we hypothesized that the human anti-Neu5Gc antibody
response is diverse and polyclonal. Here, we use a novel set of natural and
chemoenzymatically synthesized glycans to show that normal humans have an
abundant and diverse spectrum of such anti-Neu5Gc antibodies, directed against a
variety of Neu5Gc-containing epitopes. High sensitivity and specificity assays
were achieved by using N-acetylneuraminic acid (Neu5Ac)-containing probes
(differing from Neu5Gc by one less oxygen atom) as optimal background controls.
The commonest anti-Neu5Gc antibodies are of the IgG class. Moreover, the range
of reactivity and Ig classes of antibodies vary greatly amongst normal humans,
with some individuals having remarkably large amounts, even surpassing levels of
some well-known natural blood group and xenoreactive antibodies. We purified
these anti-Neu5Gc antibodies from individual human sera using a newly developed
affinity method and showed that they bind to wild-type but not Neu5Gc-deficient
mouse tissues. Moreover, they bind back to human carcinomas that have
accumulated Neu5Gc in vivo. As dietary Neu5Gc is primarily found in red meat and
milk products, we suggest that this ongoing antigen-antibody reaction may
generate chronic inflammation, possibly contributing to the high frequency of
diet-related carcinomas and other diseases in humans.
DOI: 10.1093/glycob/cwn072
PMCID: PMC2586336
PMID: 18669916 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21255096 | 1. Exp Dermatol. 2011 Feb;20(2):154-6. doi: 10.1111/j.1600-0625.2010.01193.x.
New targets of pemphigus vulgaris antibodies identified by protein array
technology.
Kalantari-Dehaghi M, Molina DM, Farhadieh M, Morrow WJ, Liang X, Felgner PL,
Grando SA.
We performed partial evaluation of pemphigus vulgaris (PV) autoantibody profile
using the protein array technology. The sera from seven patients with acute PV
and five healthy donors were probed for the presence of autoantibodies
characteristic of the organ-non-specific autoimmune disorders rheumatoid
arthritis, lupus erythematosus, scleroderma, diabetes and some other autoimmune
disorders, but not to desmosomal proteins. The array targeted 785 human genes
amplified using Mammalian Gene Clone Collection with gene-specific primers
containing 20-bp nucleotide extension complementary to ends of linear pXT7
vector. The array identified PV antibodies significantly (P<0.05) differentially
reactive with 16 antigens, most of which were cell-surface proteins, such as
CD2, CD31, CD33, CD36, CD37, CD40, CD54, CD66c and CD84 molecules,
nicotinamide/nicotinic acid mononucleotide adenylyltransferase, immunoglobulin
heavy chain constant region gamma 2 and others. Reactivity with Fc-IgG helps
explain an ability of the chimeric desmoglein constructs to absorb out all
disease-causing PV antibodies. Anti-M(1) muscarinic receptor antibody was also
identified, consistent with the facts that while blockade of this receptor
causes keratinocyte detachment, its activation is therapeutic in PV. Further
proteomics analysis of PV antibodies should help elucidate the immunopathogenic
mechanisms underlying keratinocyte detachment and blistering.
© 2011 John Wiley & Sons A/S.
DOI: 10.1111/j.1600-0625.2010.01193.x
PMID: 21255096 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23790307 | 1. J Mal Vasc. 2013 Jul;38(4):259-70. doi: 10.1016/j.jmv.2013.05.005. Epub 2013
Jun 20.
[Hemorrhagic accidents of the new oral anticoagulants and coagulation assays].
[Article in French]
Samama MM(1), Conard J, Lillo-Le Louët A.
Author information:
(1)Service d'hématologie biologique, groupe hospitalier Broca-Cochin-Hôtel-Dieu,
27, rue du Faubourg-Saint-Jacques, 75679 Paris cedex 14, France.
meyermichel.samama@biomnis.com
New oral anticoagulants which specifically inhibit factor Xa (FXa) or thrombin
(FIIa) do not require routine laboratory monitoring. However, they induce a
state of hypocoagulation and increase the risk of bleeding. In some clinical
situations, such as emergency surgery, hemorrhagic episodes, or recurrent
stroke, coagulation monitoring may be useful. A significant number of
publications have reported uncontrollable hemorrhagic complications and deaths
in patients treated with these new anticoagulants. The selection of the most
appropriate clotting assay is based on the drug used and the availability of the
test. The new anticoagulants influence all global clot-based tests. Prothrombin
time and partial thromboplastin time measured before and after treatment are
considered as qualitative tests since they are not specific. Specific anti-Xa
and anti-IIa assays are available and results can be expressed in nanogram per
milliliter of plasma using calibrated plasmas containing well-established
amounts of drug. The fact that there is no specific antidote to reverse the
anticoagulant action of the new anticoagulants can impair management of
hemorrhagic complications; clinical experience is still limited. Pro-hemostatic
treatment with non-activated or activated prothrombin complexes (FEIBA(®)), or
as a last recourse with FVIIa concentrates (NovoSeven(®)), has been used with
variable results. Some suggestions for the management of patients with bleeding
have been published but there is still little clinical evidence for these
interventions.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.
DOI: 10.1016/j.jmv.2013.05.005
PMID: 23790307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25003133 | 1. Biomed Res Int. 2014;2014:963230. doi: 10.1155/2014/963230. Epub 2014 Jun 9.
Prevalence of anti-Neu5Gc antibodies in patients with hypothyroidism.
Eleftheriou P(1), Kynigopoulos S(1), Giovou A(1), Mazmanidi A(1), Yovos J(2),
Skepastianos P(1), Vagdatli E(1), Petrou C(1), Papara D(1), Efterpiou M(1).
Author information:
(1)Department of Medical Laboratory Studies, School of Health and Medical Care,
Alexander Technological Educational Institute of Thessaloniki, TEI Campus
Sindos, 57400 Thessaloniki, Greece.
(2)1st Internal Medicine Department, AHEPA University General Hospital of
Thessaloniki, St. Kyriakidi 1, 54636 Thessaloniki, Greece ; Aristotle University
of Thessaloniki, St. Kyriakidi 1, 54636 Thessaloniki, Greece.
BACKGROUND: N-Glycolylneuraminic acid (Neu5Gc) is a sialic acid synthesized by
animals, but not by humans or birds. However, it can be incorporated in human
cells and can trigger immune response. In the present study, we detected
anti-Neu5Gc antibodies in samples of the general population and of patients
suffering from hypothyroidism/Hashimoto's disease, which is known to have
autoimmune origin.
METHODS: Antibodies were measured using enzyme-immunosorbent techniques.
RESULTS: Serum anti-Neu5Gc IgG antibodies were higher in patients with
hypothyroidism (mean: 14.8 ± 15.9 μg/mL, median: 10.0 μg/mL, P = 0.0003,
Mann-Whitney) and even higher in the group with Hashimoto's thyroiditis (mean:
31.1 ± 16.3 μg/mL, median: 27.2 μg/mL, P = 0.0000, Mann-Whitney) compared to the
general population (mean: 5.3 ± 4.7 μg/mL, median : 4 μg/mL). All anti-TPO
positive samples had anti-Neu5Gc antibody concentration higher than the mean
value of the general population while anti-TPO concentration was increased as
anti-Neu5Gc concentration increased. Low concentrations of IgA and IgM
antibodies were measured in both general population and patient groups.
CONCLUSION: The increased values of anti-Neu5Gc antibodies in patients with
hypothyroidism/Hashimoto's disease and the correlation of anti-TPO incidence
with increased anti-Neu5Gc concentration raise the possibility of an association
between anti-Neu5Gc antibody development and autoimmune hypothyroidism.
DOI: 10.1155/2014/963230
PMCID: PMC4070528
PMID: 25003133 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23634925 | 1. Neurosurg Focus. 2013 May;34(5):E6. doi: 10.3171/2013.2.FOCUS1328.
The role of anticoagulants, antiplatelet agents, and their reversal strategies
in the management of intracerebral hemorrhage.
James RF(1), Palys V, Lomboy JR, Lamm JR Jr, Simon SD.
Author information:
(1)Division of Neurosurgery, Department of Surgery, East Carolina University
Brody School of Medicine, Greenville, North Carolina, USA. jamesro@ecu.edu
New anticoagulant and antiplatelet medications have been approved and are
prescribed with increased frequency. Intracranial hemorrhage is associated with
the use of these medications. Therefore, neurosurgeons need to be aware of these
new medications, how they are different from their predecessors, and the
strategies for the urgent reversal of their effects. Utilization of intraluminal
stents by endovascular neurosurgeons has resulted in the need to have a thorough
understanding of antiplatelet agents. Increased use of dabigatran, rivaroxaban,
and apixaban as oral anticoagulants for the treatment of atrial fibrillation and
acute deep venous thrombosis has increased despite the lack of known antidotes
to these medications.
DOI: 10.3171/2013.2.FOCUS1328
PMID: 23634925 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22308807 | 1. Rev Prat. 2011 Nov;61(9):1239-43.
[New anticoagulants].
[Article in French]
Godier A(1), Martin AC, Lakhdari M, Samama CM.
Author information:
(1)Service d'anesthésie-réanimation, université Paris-Descartes, Hôtel-Dieu,
AP-HP 75181 PARIS Cedex 4. anne.godier@htd.aphp.fr
The range of anticoagulants has been very active recently with the development
of new compounds including injectable anti-Xa such as fondaparinux, and new oral
drugs which can be divided into anti-IIa with dabigatran, and anti-Xa, such as
rivaroxaban and apixaban still in the development stage. Others are coming
forward. They are more convenient to use and do not require routine coagulation
monitoring. However, several points need to be clarified and the place for each
drug remains to be determined. In case of massive bleeding, management is
unclear and none of these newer agents has a specific antidote that completely
reverses its anticoagulant effect.
PMID: 22308807 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23737395 | 1. Int J Cancer. 2013 Dec 15;133(12):2781-90. doi: 10.1002/ijc.28301. Epub 2013
Jul 16.
Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy.
Leng S(1), Hao Y, Du D, Xie S, Hong L, Gu H, Zhu X, Zhang J, Fan D, Kung HF.
Author information:
(1)Department of Human Anatomy, Guangzhou Medical University, Guangzhou,
Guangdong, People's Republic of China.
Ursolic acid (UA) has been reported to possess anticancer activities. Although
some of the anticancer activities of UA have been explained by its
apoptosis-inducing properties, the mechanisms underlying its anticancer actions
are largely unknown. We have found that UA-activated autophagy induced
cytotoxicity and reduced tumor growth of cervical cancer cells TC-1 in a
concentration-dependent manner. UA did not induce apoptosis of TC-1 cells in
vitro as determined by annexin V/propidium iodide staining, DNA fragmentation,
and Western blot analysis of the apoptosis-related proteins. We found that UA
increased punctate staining of light chain 3 (LC3), which is an autophagy
marker. LC3II, the processed form of LC3I which is formed during the formation
of double membranes, was induced by UA treatment. These results were further
confirmed by transmission electron microscopy. Wortmannin, an inhibitor of
autophagy, and a small interfering RNA (siRNA) for autophagy-related genes
(Atg5) reduced LC3II and simultaneously increased the survival of TC-1 cells
treated with UA. We also found that LC3II was significantly reduced and that
survival was increased in Atg5-/- mouse embryonic fibroblast (MEF) cells
compared to Atg5+/+ MEF cells under UA treatment. However, silencing BECN1 by
siRNA affected neither the expression of LC3II nor the survival of TC-1 cells
under UA treatment. These results suggest that autophagy is a major mechanism by
which UA kills TC-1 cells. It is Atg5 rather than BECN1 that plays a crucial
role in UA-induced autophagic cell death in TC-1 cells. The activation of
autophagy by UA may become a potential cancer therapeutic strategy complementing
the apoptosis-based therapies. Furthermore, regulation of Atg5 may improve the
efficacy of UA in cancer treatment.
Copyright © 2013 UICC.
DOI: 10.1002/ijc.28301
PMID: 23737395 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23555300 | 1. PLoS Genet. 2013 Mar;9(3):e1003394. doi: 10.1371/journal.pgen.1003394. Epub
2013 Mar 28.
Genome-wide association study and gene expression analysis identifies CD84 as a
predictor of response to etanercept therapy in rheumatoid arthritis.
Cui J(1), Stahl EA, Saevarsdottir S, Miceli C, Diogo D, Trynka G, Raj T, Mirkov
MU, Canhao H, Ikari K, Terao C, Okada Y, Wedrén S, Askling J, Yamanaka H,
Momohara S, Taniguchi A, Ohmura K, Matsuda F, Mimori T, Gupta N, Kuchroo M,
Morgan AW, Isaacs JD, Wilson AG, Hyrich KL, Herenius M, Doorenspleet ME, Tak PP,
Crusius JB, van der Horst-Bruinsma IE, Wolbink GJ, van Riel PL, van de Laar M,
Guchelaar HJ, Shadick NA, Allaart CF, Huizinga TW, Toes RE, Kimberly RP, Bridges
SL Jr, Criswell LA, Moreland LW, Fonseca JE, de Vries N, Stranger BE, De Jager
PL, Raychaudhuri S, Weinblatt ME, Gregersen PK, Mariette X, Barton A, Padyukov
L, Coenen MJ, Karlson EW, Plenge RM.
Author information:
(1)Division of Rheumatology, Immunology, and Allergy, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts, United States of
America.
Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used
treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail
to respond adequately to anti-TNF therapy, which limits the development of
clinical biomarkers to predict response or new drugs to target refractory cases.
To understand the biological basis of response to anti-TNF therapy, we conducted
a genome-wide association study (GWAS) meta-analysis of more than 2 million
common variants in 2,706 RA patients from 13 different collections. Patients
were treated with one of three anti-TNF medications: etanercept (n = 733),
infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528)
at the 1q23 locus that was associated with change in disease activity score
(ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the
infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt
transcription factor binding site motifs in the 3' UTR of an immune-related
gene, CD84, and the allele associated with better response to etanercept was
associated with higher CD84 gene expression in peripheral blood mononuclear
cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients).
Consistent with the genetic findings, higher CD84 gene expression correlated
with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant
trend for better ΔDAS in a subset of RA patients with gene expression data (n =
31, etanercept-treated). A small, multi-ethnic replication showed a
non-significant trend towards an association among etanercept-treated RA
patients of Portuguese ancestry (n = 139, P = 0.4), but no association among
patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an
allele associated with response to etanercept therapy is also associated with
CD84 gene expression, and further that CD84 expression correlates with disease
activity. These findings support a model in which CD84 genotypes and/or
expression may serve as a useful biomarker for response to etanercept treatment
in RA patients of European ancestry.
DOI: 10.1371/journal.pgen.1003394
PMCID: PMC3610685
PMID: 23555300 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/16479151 | 1. Cancer Biol Ther. 2006 Feb;5(2):137-41. doi: 10.4161/cbt.5.2.2479. Epub 2006
Feb 4.
Substrates of the BRCA1-dependent ubiquitin ligase.
Starita LM(1), Parvin JD.
Author information:
(1)Department of Pathology, Brigham and Women's Hospital and Harvard Medical
School, Boston, Massachusetts 02115, USA.
Discovering the precise function of the breast and ovarian specific tumor
suppressor, BRCA1, has proven to be quite complicated. It has been determined
that BRCA1, together with BARD1, comprise an E3 ubiquitin ligase. Since it is
now known that BRCA1 is an enzyme, the challenge for BRCA1 research is to learn
how this enzymatic activity functions in normal breast and ovarian cells in
order to suppress cancerous transformation. This review will survey the known
ubiquitination substrates of BRCA1 and suggest how these reactions may influence
the genomic stability and proliferation of breast cells.
DOI: 10.4161/cbt.5.2.2479
PMID: 16479151 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23945141 | 1. J Immunol. 2013 Sep 15;191(6):2907-15. doi: 10.4049/jimmunol.1301195. Epub
2013 Aug 14.
Long-term IgG response to porcine Neu5Gc antigens without transmission of PERV
in burn patients treated with porcine skin xenografts.
Scobie L(1), Padler-Karavani V, Le Bas-Bernardet S, Crossan C, Blaha J,
Matouskova M, Hector RD, Cozzi E, Vanhove B, Charreau B, Blancho G, Bourdais L,
Tallacchini M, Ribes JM, Yu H, Chen X, Kracikova J, Broz L, Hejnar J, Vesely P,
Takeuchi Y, Varki A, Soulillou JP.
Author information:
(1)Department of Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA,
United Kingdom.
Acellular materials of xenogenic origin are used worldwide as xenografts, and
phase I trials of viable pig pancreatic islets are currently being performed.
However, limited information is available on transmission of porcine endogenous
retrovirus (PERV) after xenotransplantation and on the long-term immune response
of recipients to xenoantigens. We analyzed the blood of burn patients who had
received living pig-skin dressings for up to 8 wk for the presence of PERV as
well as for the level and nature of their long term (maximum, 34 y) immune
response against pig Ags. Although no evidence of PERV genomic material or
anti-PERV Ab response was found, we observed a moderate increase in anti-αGal
Abs and a high and sustained anti-non-αGal IgG response in those patients. Abs
against the nonhuman sialic acid Neu5Gc constituted the anti-non-αGal response
with the recognition pattern on a sialoglycan array differing from that of burn
patients treated without pig skin. These data suggest that anti-Neu5Gc Abs
represent a barrier for long-term acceptance of porcine xenografts. Because
anti-Neu5Gc Abs can promote chronic inflammation, the long-term safety of living
and acellular pig tissue implants in recipients warrants further evaluation.
DOI: 10.4049/jimmunol.1301195
PMCID: PMC3782708
PMID: 23945141 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20681793 | 1. Radiat Res. 2010 Jul;174(1):1-13. doi: 10.1667/RR1290.1.
Impact of RING and BRCT domain mutations on BRCA1 protein stability,
localization and recruitment to DNA damage.
Nelson AC(1), Holt JT.
Author information:
(1)Department of Pathology and Program in Cancer Biology, University of Colorado
Denver, Aurora, Colorado 80045, USA.
Mutations within the tumor suppressor BRCA1 cause the majority of hereditary
breast and ovarian cancers. The BRCA1 protein is an important regulator of DNA
double-strand break repair, and BRCA1-deficient cells are highly sensitive to
ionizing radiation. Furthermore, BRCA1 function may contribute to enforcement of
the G(2) cell cycle checkpoint. E3-ubiquitin ligase activity is the only known
enzymatic activity of BRCA1, which is mediated by the N-terminal RING finger
domain. The C-terminal BRCT repeat domain, which mediates protein-protein
interactions, is the only other identified structural domain. By investigating
cancer-linked mutations within each domain, we demonstrate that truncation of
the BRCT domain greatly impairs the stability and nuclear localization of BRCA1
protein. A missense mutation within the RING domain does not affect these
biochemical properties. However, both mutant forms of BRCA1 fail to colocalize
in nuclear foci with the known BRCA1-interacting proteins BARD1 and BACH1, which
are important for DNA repair. This failure occurs despite the continued ability
of the RING mutant protein to interact with BACH1 and the ability of the BRCT
mutant to interact with BARD1. Furthermore, neither mutant form of BRCA1 is
recruited into DNA damage-associated foci marked by gamma-H2AX. Therefore, our
data suggest that both the RING and BRCT domains of BRCA1 are required for an
early step in the function of BRCA1 during DNA repair: recruitment to the sites
of DNA damage.
DOI: 10.1667/RR1290.1
PMCID: PMC4550207
PMID: 20681793 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21464712 | 1. Curr Opin Cardiol. 2011 May;26(3):181-9. doi: 10.1097/HCO.0b013e328345983d.
MicroRNAs in the cardiovascular system.
Han M(1), Toli J, Abdellatif M.
Author information:
(1)Department of Cell Biology and Molecular Medicine, Cardiovascular Research
Institute, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103,
USA.
PURPOSE OF REVIEW: Reprogramming of gene expression underlies the mechanisms
involved in cardiac pathogenesis. MicroRNAs (miRNAs) are unique
posttranscriptional regulators of gene expression whose function in cardiac
development and disease has recently begun to unravel. In addition, they are
potentially highly effective therapeutic tools. In this review, we will
summarize the recent advancements in the field.
RECENT FINDINGS: The cardiac-enriched miRNAs, including miR-1, miR-133, and
miR-208, as well as the ubiquitous miR-23a and miR-199b, play major roles in the
development of cardiac hypertrophy. On the other hand, miR-21, miR-199a,
miR-210, and miR-494 have been proven critical for the myocytes' adaptation and
survival during hypoxia/ischemia. Using depletion or replacement strategies
against some of these miRNAs has proven very effective in preventing or even
reversing some disorders. These findings and more will be detailed in this
review.
SUMMARY: In general, the discovery of miRNAs has uncovered a new dimension of
gene regulation that provides us with unique mechanistic insights into cardiac
diseases, in addition to which they can be utilized for new diagnostics and
therapeutic strategies.
DOI: 10.1097/HCO.0b013e328345983d
PMID: 21464712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11786991 | 1. Am J Phys Anthropol. 2001;Suppl 33(Suppl ):54-69. doi: 10.1002/ajpa.10018.abs.
Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and
implications for hominid evolution.
Varki A(1).
Author information:
(1)Glycobiology Research and Training Center and Department of Medicine and
University of California, San Diego, La Jolla, California 92093, USA.
The surface of all mammalian cells is covered with a dense and complex array of
sugar chains, which are frequently terminated by members of a family of
molecules called sialic acids. One particular sialic acid called
N-glycolylneuraminic acid (Neu5Gc) is widely expressed on most mammalian
tissues, but is not easily detectable on human cells. In fact, it provokes an
immune response in adult humans. The human deficiency of Neu5Gc is explained by
an inactivating mutation in the gene encoding CMP-N-acetylneuraminic acid
hydroxylase, the rate-limiting enzyme in generating Neu5Gc in cells of other
mammals. This deficiency also results in an excess of the precursor sialic acid
N-acetylneuraminic acid (Neu5Ac) in humans. This mutation appears universal to
modern humans, occurred sometime after our last common ancestor with the great
apes, and happens to be one of the first known human-great ape genetic
differences with an obvious biochemical readout. While the original selection
mechanisms and major biological consequences of this human-specific mutation
remain uncertain, several interesting clues are currently being pursued. First,
there is evidence that the human condition can explain differences in
susceptibility or resistance to certain microbial pathogens. Second, the
functions of some endogenous receptors for sialic acids in the immune system may
be altered by this difference. Third, despite the lack of any obvious alternate
pathway for synthesis, Neu5Gc has been reported in human tumors and possibly in
human fetal tissues, and traces have even been detected in normal human tissues.
One possible explanation is that this represents accumulation of Neu5Gc from
dietary sources of animal origin. Finally, a markedly reduced expression of
hydroxylase in the brains of other mammals raises the possibility that the
human-specific mutation of this enzyme could have played a role in human brain
evolution.
Copyright 2001 Wiley-Liss, Inc.
DOI: 10.1002/ajpa.10018.abs
PMCID: PMC7159735
PMID: 11786991 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23626658 | 1. Transl Stroke Res. 2012 Jun;3(2):296-304. doi: 10.1007/s12975-012-0158-9.
Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected
to cerebral ischemia and reperfusion.
Kumari S(1), Anderson L, Farmer S, Mehta SL, Li PA.
Author information:
(1)Department of Pharmaceutical Sciences, Biomanufacturing, Research Institute
and Technology Enterprise (BRITE), North Carolina Central University, BRITE
Building 2025, 302 East Lawson Street, Durham, NC 27707, USA.
Preischemic hyperglycemia exacerbates brain damage caused by cerebral ischemia.
In the present experiment, we studied the effects of preischemic hyperglycemia
on protein markers that are related to mitochondrial fission and fusion,
mitochondrial biogenesis, and autophagy in mice subjected to 30-min transient
focal ischemia. The fission proteins dynamin-related protein 1 (Drp1) and
fission 1 (Fis1), fusion proteins optic atrophy 1 (Opa1) and mitofusin 2 (Mfn2),
mitochondrial biogenesis regulators nuclear respiratory factor 1 (NRF1) and
peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α),
and autophagy marker beclin 1 and microtubule-associated protein light chain 3
(LC3) were analyzed in control, 30 min middle cerebral artery occlusion (MCAO)
plus 6-, 24-, and 72 h of reperfusion in normo- and hyperglycemic conditions.
Cerebral ischemia increased the levels of Drp1 and decreased Fis1 after
reperfusion. Preischemic hyperglycemia further augmented the increase of Drp1
and induced elevation in Fis1. Ischemia inhibited the levels of Opa1 and Mfn2
and hyperglycemia further decreased the level of Opa1. Further, NRF1 increased
after reperfusion in both normo- and hyperglycemic animals. However, such
increase was caused by reperfusion rather than glucose level. Finally, ischemia
increased beclin 1 level at 6 and 24 h of reperfusion and hyperglycemia further
increased the beclin 1 level and caused LC3-II increase as well. Hyperglycemia
enhances the ischemia-induced mitochondrial dynamic imbalance towards fission
that may favor mitochondrial fragmentation and subsequent damage. Hyperglycemia
elevated autophagy markers may represent an adapting reaction to the severe
damage incurred in hyperglycemic animals or a third pathway of cell death.
DOI: 10.1007/s12975-012-0158-9
PMCID: PMC3636536
PMID: 23626658
Conflict of interest statement: Conflict of Interest The authors declare that
there are no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20040957 | 1. Indian J Pharmacol. 2008 Oct;40(5):191-6. doi: 10.4103/0253-7613.44150.
Partial nicotinic acetylcholine (alpha4beta2) agonists as promising new
medications for smoking cessation.
Singh J(1), Budhiraja S.
Author information:
(1)Department of Pharmacology, Pt. B. D. Sharma PGIMS, Haryana, India.
OBJECTIVE: To review the pharmacology, clinical efficacy and safety of partial
agonists of alpha4beta2 nicotinic acetylcholine receptor.
DATA SOURCES: Primary literature and review articles were obtained via a PUBMED
search (1988-August 2006) using the key terms smoking cessation, partial agonist
alpha4beta2 nicotinic acetylcholine receptor, varenicline, cytisine and
SSR591813. Additional studies and abstracts were identified from the
bibliographies of reviewed literature.
STUDY SELECTION AND DATA EXTRACTION: Studies and review articles related to
varenicline, cytisine and the partial agonist alpha4beta2 nicotinic
acetylcholine receptor were reviewed.
DATA SYNTHESIS: Smoking is widely recognized as a serious health problem.
Smoking cessation has major health benefits. According to the US Public Health
Services, all patients attempting to quit smoking should be encouraged to use
one or more effective pharmacotherapy. Currently, along with nicotine
replacement therapy, bupropion, nortriptyline and clonidine, are the mainstay of
pharmacotherapy. More than (3/4) of patients receiving treatment for smoking
cessation return to smoking within the first year. Nicotine, through stimulating
alpha4beta2 nAChR, releases dopamine in the reward pathway. Partial agonist of
alpha4beta2 nAChR elicits moderate and sustained release of dopamine, which is
countered during the cessation attempts; it simultaneously blocks the effects of
nicotine by binding with alpha4beta2 receptors during smoking. Recently,
varenicline, a partial agonist at alpha4beta2 nAChR, has been approved by the
FDA (Food and Drug Administration) for smoking cessation.
CONCLUSION: Partial agonist alpha4beta2 nAChR appears to be a promising target
in smoking cessation. Varenicline of this group is approved for treatment of
smoking cessation by the FDA in May 2006.
DOI: 10.4103/0253-7613.44150
PMCID: PMC2792622
PMID: 20040957 |
http://www.ncbi.nlm.nih.gov/pubmed/17220536 | 1. Pharmacol Rep. 2006 Nov-Dec;58(6):777-98.
Cytisine for the treatment of nicotine addiction: from a molecule to therapeutic
efficacy.
Tutka P(1), Zatoński W.
Author information:
(1)Department of Experimental and Clinical Pharmacology, Medical University of
Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland. tutka@am.lublin.pl
Cytisine, a natural plant alkaloid, has been marketed in Central and Eastern
Europe for over 40 years for the clinical management of smoking cessation.
Despite the fact that cytisine has been used by millions of smokers, its
characteristics have not been reviewed in scientific literature in English, and
presently existing clinical studies on its effectiveness and safety are
insufficient to warrant licensing by modern standards. Understanding of the
mechanism of cytisine action as a smoking cessation aid provides a necessary
basis for conducting clinical trials to confirm its efficacy as an optimal
antismoking therapy. Hereafter, we present a review of current knowledge about
the pharmacokinetics, pharmacodynamics, toxicity, therapeutic efficacy and
safety of cytisine, and about its derivatives that are under development. Recent
pharmacological research has elucidated that the drug is a low efficacy partial
agonist of alpha4beta2 nicotinic acetylcholine receptors, which are believed to
be central to the effect of nicotine (NIC) on the reward pathway. The drug
reduces the effects of NIC on dopamine release in the mesolimbic system when
given alone, while simultaneously attenuating NIC withdrawal symptoms that
accompany cessation attempts. Clinical studies on cytisine as a smoking
cessation aid have demonstrated that the drug is effective and safe. Our recent
uncontrolled trial has shown that a 12-month carbon monoxide-verified continuous
abstinence rate following a standard course of treatment with cytisine with
minimal behavioral support is similar (13.8%; N = 436) to that observed
following treatment with NIC replacement therapy. Since cytisine exhibits a
desirable pharmacological profile which makes it an attractive smoking cessation
drug, it should be advanced to randomized clinical trials. However, more
detailed preclinical studies on its pharmacokinetics and safety profile are
required.
PMID: 17220536 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24831822 | 1. Health Technol Assess. 2014 May;18(33):1-120. doi: 10.3310/hta18330.
What is the clinical effectiveness and cost-effectiveness of cytisine compared
with varenicline for smoking cessation? A systematic review and economic
evaluation.
Leaviss J(1), Sullivan W(1), Ren S(1), Everson-Hock E(1), Stevenson M(1),
Stevens JW(1), Strong M(1), Cantrell A(1).
Author information:
(1)School of Health and Related Research (ScHARR), University of Sheffield,
Sheffield, UK.
BACKGROUND: Tobacco smoking is one of the leading causes of deaths worldwide.
Nearly one-fifth of adults in the UK regularly smoke cigarettes. The ill-health
associated with smoking costs the NHS over £3B every year. A number of
pharmacological interventions are available that can help people to quit
smoking. These include nicotinic receptor partial agonists such as varenicline
or cytisine. Varenicline is a synthetic product licensed for use in the UK,
while cytisine is derived naturally from the seeds of the plant Cytisus
laborinum L. (golden rain acacia).
OBJECTIVES: To review the evidence on the clinical effectiveness and safety of
cytisine from smoking cessation compared with varenicline; to develop an
economic model to estimate the cost-effectiveness of cytisine and varenicline;
and to provide recommendations based on value of information analyses as to
whether or not a head-to-head trial of cytisine and varenicline would represent
effective use of resources.
DATA SOURCES: Efficacy and adverse events data were sourced from a recent
Cochrane review. These data were supplemented with an updated search of twelve
electronic databases, including MEDLINE, EMBASE, Cumulative Index to Nursing and
Allied Health Literature and The Cochrane Library, for the period from December
2011 to January 2013. The review included randomised controlled trials (RCTs) of
adult smokers attempting to quit using varenicline or cytisine. Further
interventions were considered (placebo, nicotine replacement therapy, bupropion)
to allow an indirect comparison between varenicline and cytisine. The primary
outcome was abstinence at a minimum of 6 months' follow-up. Secondary outcomes
were common adverse events such as abnormal dreams, headache, nausea, insomnia
and serious adverse events.
REVIEW METHODS: A systematic review and network meta-analysis of the clinical
evidence was undertaken. A random-effects model was used to allow for
heterogeneity between studies. The economic model structure was based on a
published model. Probabilistic sensitivity analyses were undertaken to estimate
the treatment expected to be most cost-effective given current information.
Formal expected value of perfect information, perfect partial information and of
sample information were performed.
RESULTS: Twenty-three (RCTs) were included in the systematic review, comprising
a total of 10,610 participants. Twenty-one trials of varenicline of differing
dosing schedules and two trials of cytisine at standard dose met the inclusion
criteria. No head-to-head trials comparing varenicline with cytisine were
identified. The methodological quality of the studies was judged to be moderate
to good. Cytisine was more efficacious than placebo [hazard ratio (HR) 4.27, 95%
credible interval (CrI) 2.05 to 10.05], as was standard-dose varenicline (HR
2.58, 95% Crl 2.16 to 3.15). Standard-dose varenicline treatment was associated
with significantly higher rates of headache, insomnia and nausea than placebo;
there was no significant difference in the rates of abnormal dreams. There were
no significant differences in the rates of headache or nausea between cytisine
and placebo; data were identified for neither abnormal dreams nor insomnia.
Using expected values, cytisine is anticipated to dominate varenicline, in that
it produces more quality-adjusted life-years at a lower associated cost. This
occurred in approximately 90% of the scenarios performed. However, owing to the
large number of people who wish to quit smoking (estimated to be 3 million over
a 10-year period), the implications of making an incorrect decision is large.
The expected value of sample information indicated that conducting a
head-to-head trial of cytisine and varenicline was worthwhile, and that 1000
smokers per arm was an appropriate number to recruit.
CONCLUSIONS: On the basis of the evidence included in this review, varenicline
and cytisine are both effective interventions to aid smoking cessation when
compared with placebo. Cytisine is estimated to be both more clinically
effective and cost-effective than varenicline. However, there is uncertainty in
the decision, and a head-to-head trial of cytisine and varenicline would appear
to be an effective use of resources.
STUDY REGISTRATION: The study was registered as PROSPERO CRD42012003455.
FUNDING DETAILS: The National Institute for Health Research Health Technology
Assessment programme.
DOI: 10.3310/hta18330
PMCID: PMC4780997
PMID: 24831822 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17253581 | 1. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD006103. doi:
10.1002/14651858.CD006103.pub2.
Nicotine receptor partial agonists for smoking cessation.
Cahill K(1), Stead LF, Lancaster T.
Author information:
(1)Department of Primary Health Care, Old Road Campus, University of Oxford,
Oxford, UK, OX3 7LF. kate.cahill@dphpc.ox.ac.uk
Update in
Cochrane Database Syst Rev. 2008 Jul 16;(3):CD006103. doi:
10.1002/14651858.CD006103.pub3.
BACKGROUND: Nicotine receptor partial agonists may help smokers to quit by a
combination of maintaining moderate levels of dopamine to counteract withdrawal
symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an
antagonist). Varenicline was developed as a nicotine receptor partial agonist
from cytisine, a drug widely used in central and eastern Europe for smoking
cessation. The first trial reports of varenicline were released in 2006, and
further trials are underway.
OBJECTIVES: The primary objective of this review is to assess the efficacy and
tolerability of nicotine receptor partial agonists, including varenicline and
cytisine, for smoking cessation.
SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group's specialised
register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or
'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or
as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH
terms and free text, and we contacted authors of trial reports for additional
information where necessary. The last search was in October 2006.
SELECTION CRITERIA: We included randomized controlled trials which compared the
treatment drug with placebo. We also included comparisons with bupropion where
available. We excluded trials which did not report a minimum follow-up period of
six months from start of treatment.
DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of
participants, the dose and duration of treatment, the outcome measures, the
randomization procedure, concealment of allocation, and completeness of follow
up. The main outcome measured was abstinence from smoking after at least six
months from the beginning of treatment. We used the most rigorous definition of
abstinence, and preferred biochemically validated rates where they were
reported. Where appropriate we performed meta-analysis using the Mantel-Haenszel
fixed-effect model.
MAIN RESULTS: We found five trials of varenicline compared with placebo for
smoking cessation; three of these also included a bupropion experimental arm. We
also found one relapse prevention trial, comparing varenicline with placebo. The
six trials covered 4924 participants, 2451 of whom used varenicline. We
identified one trial of cytisine (Tabex) for inclusion. The pooled odds ratio
(OR) for continuous abstinence at 12 months for varenicline versus placebo was
3.22 (95% confidence interval [CI] 2.43 to 4.27). The pooled OR for varenicline
versus bupropion was 1.66 (95% CI 1.28 to 2.16). The main adverse effect of
varenicline was nausea, which was mostly at mild to moderate levels and usually
subsided over time. The two trials which tested the use of varenicline beyond
the 12-week standard regimen found the drug to be well-tolerated and effective
during long-term use. The one cytisine trial included in this review found that
more participants taking cytisine stopped smoking compared with placebo at
two-year follow up, with an OR of 1.77 (95% CI 1.30 to 2.40).
AUTHORS' CONCLUSIONS: Varenicline increased the odds of successful long-term
smoking cessation approximately threefold compared with pharmacologically
unassisted quit attempts. In trials reported so far, more participants quit
successfully with varenicline than with bupropion. The effectiveness of
varenicline as an aid to relapse prevention has not been clearly established.
The main adverse effect of varenciline is nausea, but this is mostly at mild to
moderate levels and tends to reduce with habituation. There is a need for
independent trials of varenicline versus placebo, to test the early findings.
There is also a need for direct comparisons with nicotine replacement therapy,
and for further trials with bupropion, to establish the relative efficacy of the
treatments.Cytisine may also increase the chances of quitting, but the evidence
at present is inconclusive.
DOI: 10.1002/14651858.CD006103.pub2
PMID: 17253581 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23728690 | 1. Cochrane Database Syst Rev. 2013 May 31;2013(5):CD009329. doi:
10.1002/14651858.CD009329.pub2.
Pharmacological interventions for smoking cessation: an overview and network
meta-analysis.
Cahill K(1), Stevens S, Perera R, Lancaster T.
Author information:
(1)Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
kate.cahill@phc.ox.ac.uk.
Comment in
Evid Based Med. 2013 Dec;18(6):212-3. doi: 10.1136/eb-2013-101462.
JAMA. 2014 Jan 8;311(2):193-4. doi: 10.1001/jama.2013.283787.
BACKGROUND: Smoking is the leading preventable cause of illness and premature
death worldwide. Some medications have been proven to help people to quit, with
three licensed for this purpose in Europe and the USA: nicotine replacement
therapy (NRT), bupropion, and varenicline. Cytisine (a treatment
pharmacologically similar to varenicline) is also licensed for use in Russia and
some of the former socialist economy countries. Other therapies, including
nortriptyline, have also been tested for effectiveness.
OBJECTIVES: How do NRT, bupropion and varenicline compare with placebo and with
each other in achieving long-term abstinence (six months or longer)? How do the
remaining treatments compare with placebo in achieving long-term abstinence? How
do the risks of adverse and serious adverse events (SAEs) compare between the
treatments, and are there instances where the harms may outweigh the benefits?
METHODS: The overview is restricted to Cochrane reviews, all of which include
randomised trials. Participants are usually adult smokers, but we exclude
reviews of smoking cessation for pregnant women and in particular disease groups
or specific settings. We cover nicotine replacement therapy (NRT),
antidepressants (bupropion and nortriptyline), nicotine receptor partial
agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid
receptor antagonists (rimonabant), clonidine, lobeline, dianicline,
mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver
acetate. Our outcome for benefit is continuous or prolonged abstinence at least
six months from the start of treatment. Our outcome for harms is the incidence
of serious adverse events associated with each of the treatments. We searched
the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for
any reviews with 'smoking' in the title, abstract or keyword fields. The last
search was conducted in November 2012. We assessed methodological quality using
a revised version of the AMSTAR scale. For NRT, bupropion and varenicline we
conducted network meta-analyses, comparing each with the others and with placebo
for benefit, and varenicline and bupropion for risks of serious adverse events.
MAIN RESULTS: We identified 12 treatment-specific reviews. The analyses covered
267 studies, involving 101,804 participants. Both NRT and bupropion were
superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71
to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively). Varenicline increased
the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47).
Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR
0.99; 95% CredI 0.86 to 1.13). Varenicline was superior to single forms of NRT
(OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to
1.96). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI
1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than
'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to
1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75
to 1.48). Combination NRT also outperformed single formulations. The four
categories of NRT performed similarly against each other, apart from 'other'
NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01
to 1.46). Cytisine (a nicotine receptor partial agonist) returned positive
findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant
adverse events or SAEs. Across the 82 included and excluded bupropion trials,
our estimate of six seizures in the bupropion arms versus none in the placebo
arms was lower than the expected rate (1:1000), at about 1:1500. SAE
meta-analysis of the bupropion studies demonstrated no excess of
neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR
0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no
difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to
1.55), and subgroup analyses detected no significant excess of neuropsychiatric
events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI
0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI
1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the
effect of NRT compared with NRT alone. Clonidine increased the chances of
quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent
rise in adverse events. Mecamylamine in combination with NRT may increase the
chances of quitting, but the current evidence is inconclusive. Other treatments
failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not
yet licensed for use as an aid to smoking cessation or relapse prevention.
Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant,
taranabant and dianicline are no longer supporting the development or testing of
these treatments.
AUTHORS' CONCLUSIONS: NRT, bupropion, varenicline and cytisine have been shown
to improve the chances of quitting. Combination NRT and varenicline are equally
effective as quitting aids. Nortriptyline also improves the chances of quitting.
On current evidence, none of the treatments appear to have an incidence of
adverse events that would mitigate their use. Further research is warranted into
the safety of varenicline and into cytisine's potential as an effective and
affordable treatment, but not into the efficacy and safety of NRT.
DOI: 10.1002/14651858.CD009329.pub2
PMCID: PMC8406789
PMID: 23728690 [Indexed for MEDLINE]
Conflict of interest statement: Three authors of this overview (KC, RP, TL) have
contributed to many of the included reviews. |
http://www.ncbi.nlm.nih.gov/pubmed/23978314 | 1. Expert Opin Pharmacother. 2013 Oct;14(14):1959-67. doi:
10.1517/14656566.2013.818978. Epub 2013 Aug 26.
Pharmacotherapies and harm-reduction options for the treatment of tobacco
dependence.
Le Houezec J(1), Aubin HJ.
Author information:
(1)Consultant in Public Health, Tobacco dependence, Amzer Glas , 176 rue de
Brest, 35000 Rennes , France +332 99 33 72 67 ;
jacques.lehouezec@amzer-glas.com.
INTRODUCTION: Tobacco dependence, a chronic relapsing condition, requires
repeated interventions and multiple attempts to quit.
AREAS COVERED: Strategies for assisting smoking cessation include behavioural
counselling and pharmacotherapy. Three drugs are currently used as first-line
pharmacotherapy: nicotine replacement therapy (NRT), bupropion and varenicline.
Compared to placebo, the drug effect varies from RR = 2.27 for varenicline, to
1.69 for bupropion, and 1.60 for any form of NRT. Cytisine (similar to
varenicline) has a RR = 3.98 compared to placebo (two trials). Second-line
pharmacotherapies include nortriptyline and clonidine. This review also offers
an overview of pipeline developments.
EXPERT OPINION: Effective medications exist, and clinicians should encourage and
offer treatment to every smoker. However, most smokers try to quit by
themselves, with only about 3% quitting successfully each year. Alternative
interventions are needed. Harm reduction has not received much support to date.
Safer alternative to tobacco smoking (smoke-free products, long-term use of
cessation drugs, or electronic cigarettes) could save lives and reduce the
burden of tobacco-related deaths and diseases. Despite some encouragement to
develop a research agenda for e-cigarettes, particularly on the safety issues,
too little attention has been brought to this area of research.
DOI: 10.1517/14656566.2013.818978
PMID: 23978314 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24086431 | 1. PLoS One. 2013 Sep 23;8(9):e75035. doi: 10.1371/journal.pone.0075035.
eCollection 2013.
NOTCH3 variants and risk of ischemic stroke.
Ross OA(1), Soto-Ortolaza AI, Heckman MG, Verbeeck C, Serie DJ, Rayaprolu S,
Rich SS, Nalls MA, Singleton A, Guerreiro R, Kinsella E, Wszolek ZK, Brott TG,
Brown RD Jr, Worrall BB, Meschia JF.
Author information:
(1)Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States
of America.
BACKGROUND: Mutations within the NOTCH3 gene cause cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
CADASIL mutations appear to be restricted to the first twenty-four exons,
resulting in the gain or loss of a cysteine amino acid. The role of other exonic
NOTCH3 variation not involving cysteine residues and mutations in exons 25-33 in
ischemic stroke remains unresolved.
METHODS: All 33 exons of NOTCH3 were sequenced in 269 Caucasian probands from
the Siblings With Ischemic Stroke Study (SWISS), a 70-center North American
affected sibling pair study and 95 healthy Caucasian control subjects. Variants
identified by sequencing in the SWISS probands were then tested for association
with ischemic stroke using US Caucasian controls collected at the Mayo Clinic
(n=654), and further assessed in a Caucasian (n=802) and African American
(n=298) patient-control series collected through the Ischemic Stroke Genetics
Study (ISGS).
RESULTS: Sequencing of the 269 SWISS probands identified one (0.4%) with small
vessel type stroke carrying a known CADASIL mutation (p.R558C; Exon 11). Of the
19 common NOTCH3 variants identified, the only variant significantly associated
with ischemic stroke after multiple testing adjustment was p.R1560P (rs78501403;
Exon 25) in the combined SWISS and ISGS Caucasian series (Odds Ratio [OR] 0.50,
P=0.0022) where presence of the minor allele was protective against ischemic
stroke. Although only significant prior to adjustment for multiple testing,
p.T101T (rs3815188; Exon 3) was associated with an increased risk of
small-vessel stroke (OR: 1.56, P=0.008) and p.P380P (rs61749020; Exon 7) was
associated with decreased risk of large-vessel stroke (OR: 0.35, P=0.047) in
Caucasians. No significant associations were observed in the small African
American series.
CONCLUSION: Cysteine-affecting NOTCH3 mutations are rare in patients with
typical ischemic stroke, however our observation that common NOTCH3 variants may
be associated with risk of ischemic stroke warrants further study.
DOI: 10.1371/journal.pone.0075035
PMCID: PMC3781028
PMID: 24086431 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: Owen A. Ross is a PLOS ONE
Editorial Board member. This does not alter the authors' adherence to all the
PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/22623959 | 1. PLoS One. 2012;7(5):e36590. doi: 10.1371/journal.pone.0036590. Epub 2012 May
18.
Identification of a known mutation in Notch 3 in familiar CADASIL in China.
Tan ZX(1), Li FF, Qu YY, Liu J, Liu GR, Zhou J, Zhu YL, Liu SL.
Author information:
(1)Genomics Research Center, Harbin Medical University, Harbin, China.
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) is an inherited disease leading to recurrent
ischemic stroke and vascular dementia. Numerous mutations in the 23 exons of the
NOTCH3 gene have been reported to cause CADASIL in Caucasian populations, but
the full spectrum of genetic changes leading to this disease is yet to be known
and, especially, very few reports are available on CADASIL in Asian populations.
METHODS AND RESULTS: We genotyped members of a 5-generational Han Chinese family
with CADASIL patients and identified an R133C mutation in the NOTCH3 gene.
Clinical analysis demonstrated that the penetrance of the mutation was not
complete. Five of the mutation carriers, not exposed to the known vascular risk
factors, did not show any clinical feature of CADASIL, suggesting the importance
of environmental factors to the development of this disease.
CONCLUSIONS: Members of a 5-generational Han Chinese family with CADASIL
patients had an R133C mutation in the NOTCH3 gene but only individuals exposed
to known vascular risk factors developed CADASIL.
DOI: 10.1371/journal.pone.0036590
PMCID: PMC3356370
PMID: 22623959 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/21038489 | 1. Cephalalgia. 2010 Nov;30(11):1284-9. doi: 10.1177/0333102410370870.
CADASIL and migraine: A narrative review.
Liem MK(1), Oberstein SA, van der Grond J, Ferrari MD, Haan J.
Author information:
(1)Leiden University Medical Center, Netherlands. m.k.liem@lumc.nl
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene and is
clinically characterized by recurrent stroke, cognitive decline, psychiatric
disturbances and migraine. The prevalence of migraine in CADASIL is slightly
higher than in the general population, and the proportion of migraine with aura
is much higher. The pathophysiological mechanism that leads to increased aura
prevalence in CADASIL is unknown. Possible mechanisms of the excess of migraine
with aura are an increased susceptibility to cortical spreading depression (CSD)
or a different expression of CSD. It is also possible that the brainstem
migraine area is involved in CADASIL. Last, it is possible that the NOTCH3
mutation acts as a migraine aura susceptibility gene by itself. In this
narrative review we summarize the literature about migraine in CADASIL, with a
special focus on what CADASIL might teach us about the pathophysiology of
migraine.
DOI: 10.1177/0333102410370870
PMID: 21038489 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21772710 | 1. J Anaesthesiol Clin Pharmacol. 2011 Apr;27(2):293-4. doi:
10.4103/0970-9185.81853.
Cerebral autosomal dominant arteriopathy with subcortical infarct and
leukoencephalopathy: A rare syndrome raising anesthetic concerns!
Singh GP(1), Mahajan C, Prabhakar H, Bindra A.
Author information:
(1)Department of Neuroanaesthesiology, All India Institute of Medical Sciences,
New Delhi - 110 029, India.
DOI: 10.4103/0970-9185.81853
PMCID: PMC3127329
PMID: 21772710 |
http://www.ncbi.nlm.nih.gov/pubmed/11706120 | 1. Neurology. 2001 Nov 13;57(9):1714-7. doi: 10.1212/wnl.57.9.1714.
NOTCH3 mutation involving three cysteine residues in a family with typical
CADASIL.
Dichgans M(1), Herzog J, Gasser T.
Author information:
(1)Department of Neurology, Klinikum Grosshadern,
Ludwig-Maximilians-Universität, Munich, Germany.
mdichgans@nefo.med.uni-muenchen.de
Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary
angiopathy causing stroke and vascular dementia. All CADASIL mutations
identified so far result in the loss or gain of one cysteine residue within
epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion
causing a loss of three cysteine residues within EGF repeat 6 is reported. These
data are consistent with the hypothesis that the change toward an odd number of
cysteine residues within a given EGF repeat and therefore an unpaired, reactive
cysteine residue is the common and critical molecular event in CADASIL.
DOI: 10.1212/wnl.57.9.1714
PMID: 11706120 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21154363 | 1. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD006103. doi:
10.1002/14651858.CD006103.pub4.
Nicotine receptor partial agonists for smoking cessation.
Cahill K(1), Stead LF, Lancaster T.
Author information:
(1)Department of Primary Health Care, University of Oxford, Rosemary Rue
Building, Old Road Campus, Oxford, UK, OX3 7LF.
Update in
Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006103. doi:
10.1002/14651858.CD006103.pub5.
Comment in
Evid Based Med. 2011 Aug;16(4):113-4. doi: 10.1136/ebm1200.
Update of
Cochrane Database Syst Rev. 2008 Jul 16;(3):CD006103. doi:
10.1002/14651858.CD006103.pub3.
BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking
by a combination of maintaining moderate levels of dopamine to counteract
withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction
(acting as an antagonist). Varenicline was developed as a nicotine receptor
partial agonist from cytisine, a drug widely used in central and eastern Europe
for smoking cessation. The first trial reports of varenicline were released in
2006, and further trials have now been published or are currently underway.
OBJECTIVES: The primary objective of this review is to assess the efficacy and
tolerability of nicotine receptor partial agonists, including varenicline and
cytisine, for smoking cessation.
SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group's specialised
register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or
'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or
as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH
terms and free text, and we contacted authors of trial reports for additional
information where necessary. The latest search was in September 2010.
SELECTION CRITERIA: We included randomized controlled trials which compared the
treatment drug with placebo. We also included comparisons with bupropion and
nicotine patches where available. We excluded trials which did not report a
minimum follow-up period of six months from start of treatment.
DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the
dose and duration of treatment, the outcome measures, the randomization
procedure, concealment of allocation, and completeness of follow up.The main
outcome measured was abstinence from smoking after at least six months from the
beginning of treatment. We used the most rigorous definition of abstinence, and
preferred biochemically validated rates where they were reported. Where
appropriate we performed meta-analysis to produce a risk ratio, using the
Mantel-Haenszel fixed-effect model.
MAIN RESULTS: We found 11 trials of varenicline compared with placebo for
smoking cessation; three of these included a bupropion experimental arm. We also
found one relapse prevention trial, comparing varenicline with placebo, and two
open-label trials comparing varenicline with nicotine replacement therapy (NRT).
We also include one trial in which all the participants were given varenicline,
but received behavioural support either online or by phone calls, or by both
methods. This trial is not included in the analyses, but contributes to the data
on safety and tolerability. The included studies covered >10,300 participants,
6892 of whom used varenicline. We identified one trial of cytisine (Tabex) for
inclusion.The pooled risk ratio (RR) (10 trials, 4443 people, excluding one
trial evaluating long term safety) for continuous abstinence at six months or
longer for varenicline at standard dosage versus placebo was 2.31 (95%
confidence interval [CI] 2.01 to 2.66). Varenicline at lower or variable doses
was also shown to be effective, with an RR of 2.09 (95% CI 1.56 to 2.78; 4
trials, 1272 people). The pooled RR for varenicline versus bupropion at one year
was 1.52 (95% CI 1.22 to 1.88; 3 trials, 1622 people). The RR for varenicline
versus NRT for point prevalence abstinence at 24 weeks was 1.13 (95% CI 0.94 to
1.35; 2 trials, 778 people). The two trials which tested the use of varenicline
beyond the 12-week standard regimen found the drug to be well-tolerated during
long-term use. The main adverse effect of varenicline was nausea, which was
mostly at mild to moderate levels and usually subsided over time. Post-marketing
safety data raised questions about a possible association between varenicline
and depressed mood, agitation, and suicidal behaviour or ideation. The labelling
of varenicline was amended in 2008, and the manufacturers produced a Medication
Guide. Thus far, surveillance reports and secondary analyses of trial data lend
little support to a causal relationship.The one cytisine trial included in this
review found that more participants taking cytisine stopped smoking compared
with placebo at two-year follow up, with an RR of 1.61 (95% CI 1.24 to 2.08).
AUTHORS' CONCLUSIONS: Varenicline at standard dose increased the chances of
successful long-term smoking cessation between two- and threefold compared with
pharmacologically unassisted quit attempts. Lower dose regimens also conferred
benefits for cessation, while reducing the incidence of adverse events. More
participants quit successfully with varenicline than with bupropion. Two
open-label trials of varenicline versus NRT suggested a modest benefit of
varenicline but confidence intervals did not rule out equivalence. Limited
evidence suggests that varenicline may have a role to play in relapse
prevention. The main adverse effect of varenicline is nausea, but mostly at mild
to moderate levels and tending to subside over time. Possible links with serious
adverse events, including depressed mood, agitation and suicidal thoughts, have
been reported but are so far not substantiated.There is a need for further
independent community-based trials of varenicline, to test its efficacy and
safety in smokers with varying co-morbidities and risk patterns. There is a need
for further trials of the efficacy of treatment extended beyond 12 weeks.
Cytisine may also increase the chances of quitting, but the evidence at present
is inconclusive.
DOI: 10.1002/14651858.CD006103.pub4
PMID: 21154363 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23592277 | 1. Am J Med Genet C Semin Med Genet. 2013 May;163C(2):86-91. doi:
10.1002/ajmg.c.31359. Epub 2013 Apr 16.
The NSD1 and EZH2 overgrowth genes, similarities and differences.
Tatton-Brown K(1), Rahman N.
Author information:
(1)Institute of Cancer Research, St George's University of London and the Royal
Marsden Hospital, London, UK. kate.tatton-brown@icr.ac.uk
NSD1 and EZH2 are SET domain-containing histone methyltransferases that play key
roles in the regulation of transcription through histone modification and
chromatin modeling: NSD1 preferentially methylates lysine residue 36 of histone
3 (H3K36) and is primarily associated with active transcription, while EZH2
shows specificity for lysine residue 27 (H3K27) and is associated with
transcriptional repression. Somatic dysregulation of NSD1 and EZH2 have been
associated with tumorigenesis. NSD1, as a fusion transcript with NUP98, plays a
key role in leukemogenesis, particularly childhood acute myeloid leukemia. EZH2
is a major proto-oncogene and mono- and biallelic activating and inactivating
somatic mutations occur as early events in the development of tumors,
particularly poor prognosis hematopoietic malignancies. Constitutional NSD1 and
EZH2 mutations cause Sotos and Weaver syndromes respectively, overgrowth
syndromes with considerable phenotypic overlap. NSD1 mutations that cause Sotos
syndrome are loss-of-function, primarily truncating mutations or missense
mutations at key residues in functional domains. EZH2 mutations that cause
Weaver syndrome are primarily missense variants and the rare truncating
mutations reported to date are in the last exon, suggesting that simple
haploinsufficiency is unlikely to be generating the overgrowth phenotype
although the exact mechanism has not yet been determined. Many additional
questions about the molecular and clinical features of NSD1 and EZH2 remain
unanswered. However, studies are underway to address these and, as more cases
are ascertained and technology improves, it is hoped that these will, in time,
be answered.
Copyright © 2013 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.c.31359
PMCID: PMC4845886
PMID: 23592277 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24852293 | 1. J Med Genet. 2014 Aug;51(8):512-7. doi: 10.1136/jmedgenet-2014-102402. Epub
2014 May 22.
Mutations in SETD2 cause a novel overgrowth condition.
Luscan A(1), Laurendeau I(1), Malan V(2), Francannet C(3), Odent S(4), Giuliano
F(5), Lacombe D(6), Touraine R(7), Vidaud M(1), Pasmant E(1), Cormier-Daire
V(8).
Author information:
(1)EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences
Pharmaceutiques et Biologiques, Paris, France Service de Biochimie et de
Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin,
Paris, France.
(2)Service d'Histo-Embryo-Cytogénétique, Université Paris Descartes, Sorbonne
Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
(3)Service de Génétique Médicale, CHU Estaing, Clermont-Ferrand, France.
(4)Université de Rennes 1, CNRS UMR6290, Service de Génétique Clinique, CHU
Hôpital Sud, Rennes, France.
(5)Service de Génétique Médicale, CHU Hôpital l'Archet 2, Nice, France.
(6)Service de Génétique Médicale, CHU de Bordeaux et EA4576, Université de
Bordeaux, Bordeaux, France.
(7)Service de Génétique, CHU de Saint-Etienne, hôpital Nord, Saint-Etienne,
France.
(8)INSERM UMR_1163, Département de génétique, Université Paris Descartes
Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades,
Assistance Publique-Hôpitaux de Paris, Paris, France.
BACKGROUND: Overgrowth conditions are a heterogeneous group of disorders
characterised by increased growth and variable features, including macrocephaly,
distinctive facial appearance and various degrees of learning difficulties and
intellectual disability. Among them, Sotos and Weaver syndromes are clinically
well defined and due to heterozygous mutations in NSD1 and EZH2, respectively.
NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers
catalyse two specific post-translational modifications of histones: methylation
of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that
mutations in writers of these two chromatin marks could cause overgrowth
conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or
EZH2 abnormalities.
METHODS: We analysed the coding sequences of 14 H3K27 methylation-related genes
and eight H3K36 methylation-related genes using a targeted next-generation
sequencing approach in three Sotos, 11 'Sotos-like' and two Weaver syndrome
patients.
RESULTS: We identified two heterozygous mutations in the SETD2 gene in two
patients with 'Sotos-like' syndrome: one missense p.Leu1815Trp de novo mutation
in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is
non-redundantly responsible for H3K36 trimethylation. The two probands shared
similar clinical features, including postnatal overgrowth, macrocephaly,
obesity, speech delay and advanced carpal ossification.
CONCLUSIONS: Our results illustrate the power of targeted next-generation
sequencing to identify rare disease-causing variants. We provide a compelling
argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by
loss-of-function mutations of epigenetic writers of the H3K36 histone mark.
Published by the BMJ Publishing Group Limited. For permission to use (where not
already granted under a licence) please go to
http://group.bmj.com/group/rights-licensing/permissions.
DOI: 10.1136/jmedgenet-2014-102402
PMID: 24852293 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22177091 | 1. Am J Hum Genet. 2012 Jan 13;90(1):110-8. doi: 10.1016/j.ajhg.2011.11.018. Epub
2011 Dec 15.
Mutations in EZH2 cause Weaver syndrome.
Gibson WT(1), Hood RL, Zhan SH, Bulman DE, Fejes AP, Moore R, Mungall AJ, Eydoux
P, Babul-Hirji R, An J, Marra MA; FORGE Canada Consortium; Chitayat D, Boycott
KM, Weaver DD, Jones SJ.
Author information:
(1)Department of Medical Genetics, University of British Columbia, Vancouver,
Canada. wtgibson@cfri.ubc.ca
We used trio-based whole-exome sequencing to analyze two families affected by
Weaver syndrome, including one of the original families reported in 1974.
Filtering of rare variants in the affected probands against the parental
variants identified two different de novo mutations in the enhancer of zeste
homolog 2 (EZH2). Sanger sequencing of EZH2 in a third classically-affected
proband identified a third de novo mutation in this gene. These data show that
mutations in EZH2 cause Weaver syndrome.
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2011.11.018
PMCID: PMC3257956
PMID: 22177091 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19006080 | 1. J Neurosci Res. 2009 Apr;87(5):1162-7. doi: 10.1002/jnr.21935.
CADASIL: extended polymorphisms and mutational analysis of the NOTCH3 gene.
Ungaro C(1), Mazzei R, Conforti FL, Sprovieri T, Servillo P, Liguori M, Citrigno
L, Gabriele AL, Magariello A, Patitucci A, Muglia M, Quattrone A.
Author information:
(1)Institute of Neurological Sciences, National Research Council, Mangone,
Italy.
CADASIL is a cerebrovascular disease caused by mutations in the NOTCH3 gene.
Most mutations result in a gain or loss of cysteine residue in one of the 34
epidermal growth factor-like repeats in the extracellular domain of the Notch3
protein, thus sparing the number of cysteine residues. To date, more than 130
different mutations in the NOTCH3 gene have been reported in CADASIL patients,
of which 95% are missense point mutations. Many polymorphisms have also been
identified in the NOTCH3 coding sequence, some of them leading to amino acid
substitutions. The aim of the present study was to analyze the NOTCH3 gene in a
large group of patients affected by leukoencephalopathy and to investigate the
presence of genetic variants. The molecular analysis revealed several nucleotide
alterations. In particular, we identified 20 different mutations, 22
polymorphisms, and 8 genetic variants of unknown pathological significance never
reported previously. We hope that this NOTCH3 gene mutational analysis,
performed in such a significant number of unrelated and related patients
affected by leukoencephalopathy, will help in molecular screening for the NOTCH3
gene, thus contributing to enlargement of the NOTCH3 gene variation database.
DOI: 10.1002/jnr.21935
PMID: 19006080 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23099237 | 1. Leuk Res. 2013 Mar;37(3):305-11. doi: 10.1016/j.leukres.2012.10.004. Epub 2012
Oct 23.
TET2, ASXL1 and EZH2 mutations in Chinese with myelodysplastic syndromes.
Wang J(1), Ai X, Gale RP, Xu Z, Qin T, Fang L, Zhang H, Pan L, Hu N, Zhang Y,
Xiao Z.
Author information:
(1)MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital,
Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin,
China.
Somatic mutations of epigenetic gene regulators are common in patients with
myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory
features. We studied mutations in TET2, ASXL1 and EZH2 in 153 Chinese patients
with MDS. TET2 mutations were detected in 35 patients (23%), ASXL1 in 33
patients (22%) and EZH2 in 8 (5%). ASXL1 mutations were associated with
increased colony formation of BFU-E, CFU-E and CFU-GM (P-values, 0.049, 0.011
and 0.006). EZH2 mutations were common in patients with poor IPSS cytogenetics
(P=0.001) and in patients in the IPSS intermediate-2/high-risk cohorts (P=0.06).
In uni- but not multi-variate analyses, mutated TET2 was associated with longer
survival (P=0.044) whereas EZH2 mutations were associated with an increased risk
of transformation to acute myeloid leukemia (AML; P=0.039). These data suggest
ASXL1 mutations might results in dominance of the mutant clone in Chinese with
MDS whereas EZH2 mutations might predict an increased risk of transformation to
AML.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.leukres.2012.10.004
PMID: 23099237 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21923765 | 1. Mol Microbiol. 2011 Nov;82(3):634-47. doi: 10.1111/j.1365-2958.2011.07843.x.
Epub 2011 Oct 10.
Bacillus anthracis virulence regulator AtxA: oligomeric state, function and
CO(2) -signalling.
Hammerstrom TG(1), Roh JH, Nikonowicz EP, Koehler TM.
Author information:
(1)Department of Microbiology and Molecular Genetics, The University of Texas -
Houston Health Science Center, Medical School, Houston, TX, USA.
AtxA, a unique regulatory protein of unknown molecular function, positively
controls expression of the major virulence genes of Bacillus anthracis. The 475
amino acid sequence of AtxA reveals DNA binding motifs and regions similar to
proteins associated with the phosphoenolpyruvate: carbohydrate
phosphotransferase system (PTS). We used strains producing native and functional
epitope-tagged AtxA proteins to examine protein-protein interactions in cell
lysates and in solutions of purified protein. Co-affinity purification,
non-denaturing polyacrylamide gel electrophoresis and bis(maleimido)hexane (BMH)
cross-linking experiments revealed AtxA homo-multimers. Dimers were the most
abundant species. BMH cross-links available cysteines within 13 Å. To localize
interaction sites, six AtxA mutants containing distinct Cys→Ser substitutions
were tested for multimerization and cross-linking. All mutants multimerized, but
one mutation, C402S, prevented cross-linking. Thus, BMH uses C402 to make the
inter-molecular bond between AtxA proteins, but C402 is not required for
protein-protein interaction. C402 is in a region bearing amino acid similarity
to Enzyme IIB proteins of the PTS. The AtxA EIIB motif may function in protein
oligomerization. Finally, cultures grown with elevated CO(2) /bicarbonate
exhibited increased AtxA dimer/monomer ratios and increased AtxA activity,
relative to cultures grown without added CO(2) /bicarbonate, suggesting that
this host-associated signal enhances AtxA function by shifting the dimer/monomer
equilibrium towards the dimeric state.
© 2011 Blackwell Publishing Ltd.
DOI: 10.1111/j.1365-2958.2011.07843.x
PMCID: PMC3211139
PMID: 21923765 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2579060 | 1. J Bacteriol. 1985 Mar;161(3):1162-70. doi: 10.1128/jb.161.3.1162-1170.1985.
Escherichia coli 6S RNA gene is part of a dual-function transcription unit.
Hsu LM, Zagorski J, Wang Z, Fournier MJ.
The gene coding for the metabolically stable 6S RNA of Escherichia coli has been
cloned, sequenced, and partially characterized in expression analyses. The DNA
sequence results confirm the accuracy of the previously established RNA sequence
and, with genomic hybridization data, reveal that there is only one copy of the
6S DNA in the chromosome. Consistent with its relaxed mode of expression, the
promoter region of the 6S RNA gene was found to lack the hypothetical GC-rich
discriminator domain common to other stable RNA genes under stringent control.
The sequence results also revealed the occurrence of a 540-base-pair open
reading frame immediately downstream from the 6S RNA coding region. Results from
the expression analyses show that the protein and RNA coding regions are
cotranscribed in vitro and that the open reading frame is translated in vivo.
DOI: 10.1128/jb.161.3.1162-1170.1985
PMCID: PMC215021
PMID: 2579060 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25177364 | 1. Mol Cytogenet. 2014 May 27;7:35. doi: 10.1186/1755-8166-7-35. eCollection
2014.
Submicroscopic deletion of 5q involving tumor suppressor genes (CTNNA1, HSPA9)
and copy neutral loss of heterozygosity associated with TET2 and EZH2 mutations
in a case of MDS with normal chromosome and FISH results.
Hemmat M(1), Chen W(2), Anguiano A(1), Naggar ME(1), Racke FK(1), Jones D(3),
Wang Y(3), Strom CM(1), Chang K(1), Boyar FZ(1).
Author information:
(1)Cytogenetics Department, Quest Diagnostics Nichols Institute, 33608 Ortega
Hwy, 92675 San Juan Capistrano, CA, USA.
(2)University of Texas southwestern Medical Center, 5323 Harry Hines Blvd, 75235
Dallas, TX, USA.
(3)Quest Diagnostics Nichols Institute, 14225 Newbrook Drive, 20151 Chantilly,
VA, USA.
Advances in genome-wide molecular cytogenetics allow identification of novel
submicroscopic DNA copy number alterations (aCNAs) and copy-neutral loss of
heterozygosity (cnLOH) resulting in homozygosity for known gene mutations in
myeloid neoplasms. We describe the use of an oligo-SNP array for genomic
profiling of aCNA and cnLOH, together with sequence analysis of recurrently
mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with
normal karyotype and FISH results. Oligo-SNP array analysis revealed a
hemizygous deletion of 896 kb at chromosome 5q31.2, representing the smallest 5q
deletion reported to date. The deletion involved multiple genes, including two
tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with
MDS/AML. The SNP-array study also detected 3 segments of somatic cnLOH: one
involved the entire long arm of chromosome 4; the second involved the distal
half of the long arm of chromosome 7, and the third encompassed the entire
chromosome 22 (UPD 22). Sequence analysis revealed mutations in TET2 (4q), EZH2
(7q), ASXL1 (20q11.21), and RUNX1 (21q22.3). Coincidently, TET2 and EZH2 were
located at segments of cnLOH resulting in their homozygosity. Loss of
heterozygosity affecting these two chromosomes and mutations in TET2 and EZH2
are indicative of a myelodysplastic syndrome with a poor prognosis. Deletion of
the tumor suppressor genes CTNNA1 and HSPA9 is also likely to contribute to a
poor prognosis. Furthermore, the original cnLOHs in multiple chromosomes and
additional cnLOH 14q in the follow-up study suggest genetic evolution of the
disease and poor prognosis. This study attests to the fact that some patients
with a myelodysplastic syndrome who exhibit a normal karyotype may have
underlying genetic abnormalities detectable by chromosomal microarray and/or
targeted mutation analyses.
DOI: 10.1186/1755-8166-7-35
PMCID: PMC4149311
PMID: 25177364 |
http://www.ncbi.nlm.nih.gov/pubmed/16717210 | 1. Neurology. 2006 May 23;66(10):1511-6. doi: 10.1212/01.wnl.0000216259.99811.50.
Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation.
Kim Y(1), Choi EJ, Choi CG, Kim G, Choi JH, Yoo HW, Kim JS.
Author information:
(1)Department of Biochemistry, School of Medicine, Wonkwang University, Iksan,
Chonbuk, Korea.
OBJECTIVE: To elucidate the phenotype, genotype, and MRI findings of Korean
patients with cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL) and mutation carriers.
METHODS: The authors studied 40 members of nine unrelated Korean CADASIL
families. After genetic analysis of Notch3, clinical and MRI findings were
correlated in 27 mutation carriers.
RESULT: Notch3 mutation sites were C174R (one family, n = 3), R133C (one family,
n = 3), R587C (one family, n = 1), R544C (two families, n = 5), and R75P (four
families, n = 15). The clinical features were typical of CADASIL, but the
frequency of migraine in the Korean population appears low. MRI abnormalities
were found in 54% of the mutant carriers, the most common being white matter
hyperintensities. The prevalence of lacunes and microbleeds increased with
patient age. Anterior temporal areas were less often involved in subjects with
R75P mutations than in those where mutations occurred in other sites (p = 0.02).
Gradient echo imaging identified microbleedings in 33% of mutation carriers (64%
of those with abnormal MRI), whereas diffusion-weighted MRI showed abnormal
findings in only one patient. Neurologic disability was related to the number of
lacunar infarcts and the lesion volume of white matter hyperintensities (p <
0.001) whereas MMSE score was related to the number of lacunar infarcts (p <
0.005).
CONCLUSIONS: Although Korean cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL) mutation carriers show
similar clinical and MRI findings, these abnormalities appear less frequently
than in other populations. Relatively frequent microbleedings on gradient echo
imaging suggest that treatment should be individualized according to MRI
findings. The novel mutation of R75P, not involving a cysteine residue, is
related to less frequent involvement of the anterior temporal area, thus
broadening the spectrum of CADASIL.
DOI: 10.1212/01.wnl.0000216259.99811.50
PMID: 16717210 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15149039 | 1. Int J Med Microbiol. 2004 Apr;293(7-8):619-24. doi: 10.1078/1438-4221-00306.
In vivo Bacillus anthracis gene expression requires PagR as an intermediate
effector of the AtxA signalling cascade.
Mignot T(1), Couture-Tosi E, Mesnage S, Mock M, Fouet A.
Author information:
(1)Unité Toxines et Pathogénie Bactérienne, CNRS URA 2172, Institut Pasteur,
Paris, France.
Transcription of the major Bacillus anthracis virulence genes is triggered by
CO2, a signal mimicking the host environment. A 182-kb plasmid, pXO1, carries
the anthrax toxin genes and the genes responsible for their regulation of
transcription, namely atxA and, pagR, the second gene of the pag operon. AtxA
has major effects on the physiology of B. anthracis. It coordinates the
transcription activation of the toxin genes with that of the capsule
biosynthetic enzyme operon, located on the second virulence plasmid, pXO2. In
rich medium, B. anthracis synthesises alternatively two S-layer proteins (Sap
and EA1). An exponential phase "Sap-layer" is subsequently replaced by a
stationary phase "EA1-layer". S-layer gene transcription is controlled by
alternative sigma factors and by Sap acting as a transcriptional repressor of
eag. Furthermore, in vitro in presence of CO2 and in vivo, AtxA is part of the
sap and eag regulatory network. Only eag is significantly expressed in these
conditions and this is due to AtxA activating eag and repressing sap
transcription. PagR, and not AtxA itself, is the direct effector of this
regulation by binding to sap and eag promoter regions. Therefore, PagR mediates
the effect of AtxA on eag and sap and is the most downstream element of a
signalling cascade initiated by AtxA. Taken together, these results indicate
that the B. anthracis transcriptional regulator AtxA is controlling the
synthesis of the three toxin components and of the surface elements (capsule and
S-layer). Thus, AtxA is a master regulator that coordinates the response to host
signals by orchestrating positive and negative controls over genes located on
all genetic elements.
DOI: 10.1078/1438-4221-00306
PMID: 15149039 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23587639 | 1. Neurobiol Aging. 2013 Sep;34(9):2234.e9-12. doi:
10.1016/j.neurobiolaging.2013.03.005. Epub 2013 Apr 12.
First deep intronic mutation in the NOTCH3 gene in a family with late-onset
CADASIL.
Bianchi S(1), Dotti MT, Gallus GN, D'Eramo C, Di Donato I, Bernardi L, Maletta
R, Puccio G, Bruni AC, Federico A.
Author information:
(1)Department of Medical, Surgical and Neurological Sciences, University of
Siena, Siena, Italy.
CADASIL is the most prominent inherited form of vascular dementia. The main
clinical features include migraine with aura, stroke, mood disturbances, and
cognitive decline, with a mid-life (30s-60s) adult onset. Genetic testing is the
gold standard for the diagnosis. CADASIL is caused mostly by missense mutations
in the NOTCH3 gene, invariably involving a cysteine residue. Only a couple of
splice site mutations have been reported. In a few pathologically defined
patients, genetic mutations remain unidentified. We report a family with
late-onset CADASIL phenotype carrying a novel intronic deletion in the NOTCH3
gene (c.341-26_24delAAC). Transcript analysis revealed a splicing alteration,
with the complete intron 3 retention. The insertion was in-frame and encoded an
extra 25 amino acids, including 1 cysteine. This is the first report of an
aberrant splicing event of the NOTCH3 gene associated with a mutation far away
from the canonical splice site. Our finding suggests that the assays used to
evaluate splicing should be mandatory in the diagnostic setting of genetically
undefined CADASIL cases.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2013.03.005
PMID: 23587639 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22475286 | 1. Expert Rev Hematol. 2012 Apr;5(2):177-85. doi: 10.1586/ehm.12.5.
The role of histone methyltransferase EZH2 in myelodysplastic syndromes.
Xu F(1), Li X.
Author information:
(1)Department of Hematology, the Sixth People's Hospital affiliated to Shanghai
Jiaotong University, Shanghai, China.
Previous epigenetics research in myelodysplastic syndromes (MDS) mainly focused
on the DNA methylation of tumor suppressor genes. Recent studies reported that
around 6% of MDS patients have several EZH2 mutations including missense,
frameshift and truncated mutations. Histone methyltransferase EZH2 plays a
critical role in epigenetic regulation as a bridge between histone
methylation/deacetylation and DNA methylation. EZH2 is frequently overexpressed
and considered to be an oncogene in cancers; nevertheless, EZH2 is considered as
a candidate tumor suppressor gene in MDS due to EZH2 mutations associated with
poor survival. Many questions still need further discussion. Moreover,
3-deazaneplanocin can reduce EZH2 levels and H3K27 trimethylation, and
synergistic effects are seen in combination with DNA demethylation agents or
histone deacetylation inhibitors. All of the above give us more chances to
improve epigenetic therapy in MDS. Therefore, the molecular mechanisms of EZH2
in tumorigenesis and the role of EZH2 in MDS are studied.
DOI: 10.1586/ehm.12.5
PMID: 22475286 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7116934 | 1. Cytogenet Cell Genet. 1982;33(1-2):133-8. doi: 10.1159/000131737.
Cytogenetic and flow cytometric studies of cells from patients with Fanconi's
anemia.
Latt SA, Kaiser TN, Lojewski A, Dougherty C, Juergens L, Brefach S, Sahar E,
Gustashaw K, Schreck RR, Powers M, Lalande M.
Cells from patients wtih Fanconi's anemia are unusually sensitive to agents
which are capable of crosslinking DNA. This increased sensitivity can be
detected both by cytogenetic and flow cytometric methods. An elevated frequency
of chromosome aberrations, which is further exaggerated by exposure of cells to
DNA crosslinking agents, is a general feature of Fanconi's anemia. Information
about the formation of sister chromatid exchanges in this disease is less
consistent. Cytogenetic analysis of cells from patients with Fanconi's anemia
can be compromised by a low mitotic index. This is reflected in an accumulation
of cells In the G2 phase of the cycle, after exposure to the bifunctional
alkylating agent, mitomycin C. New methods for differentiating individuals with
Fanconi's anemia from unaffected individuals should be of empirical use and
might also facilitate mechanistic studies of this disease.
DOI: 10.1159/000131737
PMID: 7116934 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7011307 | 1. Basic Life Sci. 1980;15:245-65. doi: 10.1007/978-1-4684-3842-0_17.
Relationship of DNA lesions and their repair to chromosomal aberration
production.
Bender MA.
Though the roles of some specific DNA lesions in the production of chromosomal
aberrations is clearly established, those of others remain unclear. While the
study of aberration production in human genetic DNA repair deficiency diseases
has been extremely rewarding already, eukaryotic repair systems are obviously
complex, and one is tempted to feel that such studies may have raised as many
questions as they have provided answers. For example, the "standard" sort of
xeroderma pigmentosum is chromosomally sensitive to ultraviolet light and to
those chemical agents inducing ultraviolet-type DNA repair. But both it and the
variant form have been reported to also be sensitive to the crosslinking agent
mitomycin C in one study [18], implying a common step or steps in the repair of
pyrimidine cyclobutane dimers and DNA crosslinks. However, just to complicate
matters, another study of chromosomal aberration production in xeroderma
pigmentosum cells had found them no more sensitive to mitomycin C than normal
cells [50]. Similarly, Fanconi's anemia cells, which are chromosomally sensitive
to crosslinking agents, and appear to be defective in the "unhooking" of linked
polynucleotide strands [15, 16, 49, 51], are reported to be chromosomally
sensitive to ethyl methanesulfonate as well [29], and to be sensitive to
ionizing radiation [7, 19, ]0], again implying overlapping repair systems. It
seems certain that further study of chromosomal aberration production in repair
deficient cells by agents inducing various DNA lesions will reveal even greater
complexity in eukaryotic DNA repair systems and their role in chromosomal
aberration production. Nevertheless, there seems hope, at least, that such
studies may also ultimately lead to a complete understanding of the molecular
mechanisms involved.
DOI: 10.1007/978-1-4684-3842-0_17
PMID: 7011307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21568838 | 1. Biochemistry (Mosc). 2011 Jan;76(1):36-48. doi: 10.1134/s0006297911010068.
Fanconi anemia: at the crossroads of DNA repair.
Deakyne JS(1), Mazin AV.
Author information:
(1)Department of Biochemistry and Molecular Biology, Drexel University College
of Medicine, Philadelphia, Pennsylvania 19102, USA.
Fanconi anemia (FA) is an autosomal disorder that causes genome instability. FA
patients suffer developmental abnormalities, early-onset bone marrow failure,
and a predisposition to cancer. The disease is manifested by defects in DNA
repair, hypersensitivity to DNA crosslinking agents, and a high degree of
chromosomal aberrations. The FA pathway comprises 13 disease-causing genes
involved in maintaining genomic stability. The fast pace of study of the novel
DNA damage network has led to the constant discovery of new FA-like genes
involved in the pathway that when mutated lead to similar disorders. A majority
of the FA proteins act as signal transducers and scaffolding proteins to employ
other pathways to repair DNA. This review discusses what is known about the FA
proteins and other recently linked FA-like proteins. The goal is to clarify how
the proteins work together to carry out interstrand crosslink repair and
homologous recombination-mediated repair of damaged DNA.
DOI: 10.1134/s0006297911010068
PMID: 21568838 [Indexed for MEDLINE] |