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http://www.ncbi.nlm.nih.gov/pubmed/23096376
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1. G Ital Cardiol (Rome). 2012 Oct;13(10 Suppl 2):50S-54S. doi:
10.1714/1167.12921.
[New pharmacological approaches to ischemic heart disease].
[Article in Italian]
Raddino R(1), Della Pina P, Gorga E, Brambilla G, Regazzoni V, Gavazzoni M, Dei
Cas L.
Author information:
(1)Dipartimento di Medicina Sperimentale ed Applicata, Universita degli Studi e
Spedali Civili, Brescia. riccardo.raddino@libero.it
Major steps have been made in the treatment of ischemic heart disease from the
discovery of nitrates as antianginal medication to the techniques of
percutaneous angioplasty. This incredible therapeutic progress has resulted in a
reduced incidence of ischemic heart disease and related mortality and morbidity.
However, statistical and epidemiological data indicate that in ischemic heart
disease, despite the achievement of great success, there is a necessity for a
further step toward treatment, considering the fact that the characteristics of
this population are changing (increased prevalence of subendocardial infarction
compared with classic transmural infarction, especially in the elderly
population). Furthermore, the need for alternative therapeutic approaches to
traditional ones is recognized. Ranolazine is a selective inhibitor of Na
channels that prevents pathological extension of late Na current developing in
the ischemic myocardial cell. This current is responsible for calcium overload,
with consequent impairment of diastolic relaxation. Ranolazine reduces Na
overload induced by calcium and improves diastolic relaxation and coronary
subendocardial flow, without affecting hemodynamic parameters such as blood
pressure, heart rate, or inotropic state of the heart, avoiding undesirable side
effects. Efficacy of ranolazine has been evaluated in several trials, using
clinical and instrumental endpoints (MARISA and CARISA) or, more recently, using
endpoints such as mortality and reinfarction (ERICA and MERLIN-TIMI 36).
Ivabradine acts through the inhibition of late Na current (also known as If),
which controls the spontaneous diastolic depolarization of sinus node cells. The
partial inhibition of these channels reduces the frequency of sinus node action
potential initiation, resulting in decreased heart rate without effects on
contractility, atrio-ventricular conduction, or repolarization. The BEAUTIFUL
trial has tested whether the effect of ivabradine in lowering heart rate is able
to reduce mortality and cardiovascular morbidity in patients with coronary
artery disease and left ventricular systolic dysfunction. The most significant
results were obtained in the subgroup of patients with life-limiting exertional
angina. In this group, ivabradine significantly reduced the primary endpoint, a
composite of cardiovascular death, hospitalization for fatal and nonfatal acute
myocardial infarction (AMI) or heart failure, by 24%, and hospitalizations for
AMI by 42%. In the subgroup of patients with baseline heart rate >70 bpm,
hospitalizations for AMI and revascularization were reduced by 73% and 59%,
respectively.
DOI: 10.1714/1167.12921
PMID: 23096376 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/14722917
|
1. Hum Mutat. 2004 Feb;23(2):134-146. doi: 10.1002/humu.10305.
Characterization of the somatic mutational spectrum of the neurofibromatosis
type 1 (NF1) gene in neurofibromatosis patients with benign and malignant
tumors.
Upadhyaya M(1), Han S(1), Consoli C(1), Majounie E(1), Horan M(1), Thomas NS(1),
Potts C(1), Griffiths S(1), Ruggieri M(2), von Deimling A(3), Cooper DN(1).
Author information:
(1)Institute of Medical Genetics, University of Wales College of Medicine,
Cardiff, UK.
(2)Institute of Bioimaging and Pathology of the Central Nervous System, National
Research Council, Catania, Italy.
(3)Institut für Neuropathologie, Charité, Humboldt-Universität, Berlin, Germany.
One of the main features of neurofibromatosis type 1 (NF1) is benign
neurofibromas, 10-20% of which become transformed into malignant peripheral
nerve sheath tumors (MPNSTs). The molecular basis of NF1 tumorigenesis is,
however, still unclear. Ninety-one tumors from 31 NF1 patients were screened for
gross changes in the NF1 gene using microsatellite/restriction fragment length
polymorphism (RFLP) markers; loss of heterozygosity (LOH) was found in 17 out of
91 (19%) tumors (including two out of seven MPNSTs). Denaturing high performance
liquid chromatography (DHPLC) was then used to screen 43 LOH-negative and 10
LOH-positive tumors for NF1 microlesions at both RNA and DNA levels. Thirteen
germline and 12 somatic mutations were identified, of which three germline
(IVS7-2A>G, 3731delT, 6117delG) and eight somatic (1888delG, 4374-4375delCC,
R2129S, 2088delG, 2341del18, IVS27b-5C>T, 4083insT, Q519P) were novel. A mosaic
mutation (R2429X) was also identified in a neurofibroma by DHPLC analysis and
cloning/sequencing. The observed somatic and germline mutational spectra were
similar in terms of mutation type, relative frequency of occurrence, and
putative underlying mechanisms of mutagenesis. Tumors lacking mutations were
screened for NF1 gene promoter hypermethylation but none were found.
Microsatellite instability (MSI) analysis revealed MSI in five out of 11 MPNSTs
as compared to none out of 70 neurofibromas (p=1.8 x 10(-5)). The screening of
seven MPNSTs for subtle mutations in the CDKN2A and TP53 genes proved negative,
although the screening of 11 MPNSTs detected LOH involving either the TP53 or
the CDKN2A gene in a total of four tumors. These findings are consistent with
the view that NF1 tumorigenesis is a complex multistep process involving a
variety of different types of genetic defect at multiple loci.
Copyright 2003 Wiley-Liss, Inc.
DOI: 10.1002/humu.10305
PMID: 14722917 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16158195
|
1. Biosci Rep. 2004 Dec;24(6):559-76. doi: 10.1007/s10540-005-2792-x.
Pre-UV-treatment of cells results in enhanced host cell reactivation of a UV
damaged reporter gene in CHO-AA8 chinese hamster ovary cells but not in
transcription-coupled repair deficient CHO-UV61 cells.
Liu L(1), Rainbow AJ.
Author information:
(1)Department of Biology, McMaster University, L8S 4K1, Hamilton, Ontario,
Canada, rainbow@mcmaster.ca.
We have used a non-replicating recombinant adenovirus, Ad5MCMVlacZ, which
expresses the beta-galactosidase reporter gene, to examine both constitutive and
inducible repair of UV-damaged DNA in repair proficient CHO-AA8 Chinese hamster
ovary cells and in mutant CHO-UV61 cells which are deficient in the
transcription-coupled repair (TCR) pathway of nucleotide excision repair. Host
cell reactivation (HCR) of beta-galactosidase activity for UV-irradiated
Ad5MCMVlacZ was significantly reduced in non-irradiated CHO-UV61 cells compared
to that in non-irradiated CHO-AA8 cells suggesting that repair in the
transcribed strand of the UV-damaged reporter gene in untreated cells utilizes
TCR. Prior UV-irradiation of cells with low UV fluences resulted in a transient
enhancement of HCR for expression of the UV-damaged reporter gene in CHO-AA8
cells but not in TCR deficient CHO-UV61 cells. These results suggest the
presence of an inducible DNA pathway in CHO cells that results from an
enhancement of TCR or a mechanism that involves the TCR pathway.
DOI: 10.1007/s10540-005-2792-x
PMID: 16158195 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12142466
|
1. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10571-4. doi:
10.1073/pnas.162278199. Epub 2002 Jul 25.
Clusters of transcription-coupled repair in the human genome.
Surrallés J(1), Ramírez MJ, Marcos R, Natarajan AT, Mullenders LH.
Author information:
(1)Department of Genetics and Microbiology, Universitat Autònoma de Barcelona,
08193 Bellaterra, Barcelona, Spain. jordi.surralles@uab.es
A specialized nucleotide excision repair pathway known as transcription-coupled
repair (TCR) counteracts the toxic effects of DNA damage in transcriptionally
active genes. The clustering of active genes into gene-rich chromosomal domains
predicts that the sites of TCR are unevenly distributed through the genome. To
elucidate the genomic organization and chromosomal localization of TCR, we
isolated DNA fragments encompassing TCR-mediated repair sites from UV-C
irradiated xeroderma pigmentosum group C cells, which can only repair the
transcribed strand of active genes. This DNA was used as a molecular probe to
visualize TCR in normal metaphase spreads by reverse fluorescence in situ
hybridization. Whereas DNA repair sites in normal human cells are evenly
distributed through the genome, TCR is highly localized at specific chromosomal
domains. Particularly, clusters of TCR sites were identified at
early-replicating gene-rich bands and telomeric regions of several chromosomes.
High gene-density chromosomes such as chromosome 19 and the GC-rich domains of
several chromosomes (T bands) are preferential locations of TCR. Our results
demonstrate that the intragenomic localization of TCR resembles the uneven
distribution of the human transcriptome, CpG islands, and hyperacetylated
histones, enforcing the basic link between DNA repair, transcription, and
nuclear organization in a complex genome.
DOI: 10.1073/pnas.162278199
PMCID: PMC124978
PMID: 12142466 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7957102
|
1. EMBO J. 1994 Nov 15;13(22):5361-9. doi: 10.1002/j.1460-2075.1994.tb06871.x.
RAD26, the functional S. cerevisiae homolog of the Cockayne syndrome B gene
ERCC6.
van Gool AJ(1), Verhage R, Swagemakers SM, van de Putte P, Brouwer J, Troelstra
C, Bootsma D, Hoeijmakers JH.
Author information:
(1)MGC Department of Cell Biology and Genetics, Erasmus University Rotterdam,
The Netherlands.
Transcription-coupled repair (TCR) is a universal sub-pathway of the nucleotide
excision repair (NER) system that is limited to the transcribed strand of active
structural genes. It accomplishes the preferential elimination of
transcription-blocking DNA lesions and permits rapid resumption of the vital
process of transcription. A defect in TCR is responsible for the rare hereditary
disorder Cockayne syndrome (CS). Recently we found that mutations in the ERCC6
repair gene, encoding a putative helicase, underly the repair defect of CS
complementation group B. Here we report the cloning and characterization of the
Saccharomyces cerevisiae homolog of CSB/ERCC6, which we designate RAD26. A rad26
disruption mutant appears viable and grows normally, indicating that the gene
does not have an essential function. In analogy with CS, preferential repair of
UV-induced cyclobutane pyrimidine dimers in the transcribed strand of the active
RBP2 gene is severely impaired. Surprisingly, in contrast to the human CS
mutant, yeast RAD26 disruption does not induce any UV-, cisPt- or X-ray
sensitivity, explaining why it was not isolated as a mutant before. Recovery of
growth after UV exposure was somewhat delayed in rad26. These findings suggest
that TCR in lower eukaryotes is not very important for cell survival and that
the global genome repair pathway of NER is the major determinant of cellular
resistance to genotoxicity.
DOI: 10.1002/j.1460-2075.1994.tb06871.x
PMCID: PMC395493
PMID: 7957102 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24920614
|
1. J Neurosci. 2014 Jun 11;34(24):8083-97. doi: 10.1523/JNEUROSCI.0543-14.2014.
Profilin 1 associates with stress granules and ALS-linked mutations alter stress
granule dynamics.
Figley MD(1), Bieri G(1), Kolaitis RM(2), Taylor JP(2), Gitler AD(3).
Author information:
(1)Department of Genetics and Neuroscience Graduate Program, Stanford University
School of Medicine, Stanford, California 94305, and.
(2)Department of Cell and Molecular Biology, St Jude Children's Research
Hospital, Memphis, Tennessee 38105.
(3)Department of Genetics and agitler@stanford.edu.
Mutations in the PFN1 gene encoding profilin 1 are a rare cause of familial
amyotrophic lateral sclerosis (ALS). Profilin 1 is a well studied actin-binding
protein but how PFN1 mutations cause ALS is unknown. The budding yeast,
Saccharomyces cerevisiae, has one PFN1 ortholog. We expressed the ALS-linked
profilin 1 mutant proteins in yeast, demonstrating a loss of protein stability
and failure to restore growth to profilin mutant cells, without exhibiting
gain-of-function toxicity. This model provides for simple and rapid screening of
novel ALS-linked PFN1 variants. To gain insight into potential novel roles for
profilin 1, we performed an unbiased, genome-wide synthetic lethal screen with
yeast cells lacking profilin (pfy1Δ). Unexpectedly, deletion of several stress
granule and processing body genes, including pbp1Δ, were found to be synthetic
lethal with pfy1Δ. Mutations in ATXN2, the human ortholog of PBP1, are a known
ALS genetic risk factor and ataxin 2 is a stress granule component in mammalian
cells. Given this genetic interaction and recent evidence linking stress granule
dynamics to ALS pathogenesis, we hypothesized that profilin 1 might also
associate with stress granules. Here we report that profilin 1 and related
protein profilin 2 are novel stress granule-associated proteins in mouse primary
cortical neurons and in human cell lines and that ALS-linked mutations in
profilin 1 alter stress granule dynamics, providing further evidence for the
potential role of stress granules in ALS pathogenesis.
Copyright © 2014 the authors 0270-6474/14/348083-15$15.00/0.
DOI: 10.1523/JNEUROSCI.0543-14.2014
PMCID: PMC4051967
PMID: 24920614 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24090136
|
1. Mol Neurodegener. 2013 Aug 31;8:30. doi: 10.1186/1750-1326-8-30.
Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and
dynamics.
Baron DM(1), Kaushansky LJ, Ward CL, Sama RR, Chian RJ, Boggio KJ, Quaresma AJ,
Nickerson JA, Bosco DA.
Author information:
(1)Department of Neurology, University of Massachusetts Medical School,
Worcester, MA, USA. Daryl.Bosco@umassmed.edu.
BACKGROUND: Amyotrophic lateral sclerosis (ALS)-linked fused in
sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within
cytoplasmic stress granules under conditions of induced stress. Since only the
mutants, but not the endogenous wild-type FUS, are associated with stress
granules under most of the stress conditions reported to date, the relationship
between FUS and stress granules represents a mutant-specific phenotype and thus
may be of significance in mutant-induced pathogenesis. While the association of
mutant-FUS with stress granules is well established, the effect of the mutant
protein on stress granules has not been examined. Here we investigated the
effect of mutant-FUS on stress granule formation and dynamics under conditions
of oxidative stress.
RESULTS: We found that expression of mutant-FUS delays the assembly of stress
granules. However, once stress granules containing mutant-FUS are formed, they
are more dynamic, larger and more abundant compared to stress granules lacking
FUS. Once stress is removed, stress granules disassemble more rapidly in cells
expressing mutant-FUS. These effects directly correlate with the degree of
mutant-FUS cytoplasmic localization, which is induced by mutations in the
nuclear localization signal of the protein. We also determine that the RGG
domains within FUS play a key role in its association to stress granules. While
there has been speculation that arginine methylation within these RGG domains
modulates the incorporation of FUS into stress granules, our results demonstrate
that this post-translational modification is not involved.
CONCLUSIONS: Our results indicate that mutant-FUS alters the dynamic properties
of stress granules, which is consistent with a gain-of-toxic mechanism for
mutant-FUS in stress granule assembly and cellular stress response.
DOI: 10.1186/1750-1326-8-30
PMCID: PMC3766239
PMID: 24090136 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1832527
|
1. Am Rev Respir Dis. 1991 Sep;144(3 Pt 1):564-9. doi:
10.1164/ajrccm/144.3_Pt_1.564.
Activity of clarithromycin against Mycobacterium avium infection in patients
with the acquired immune deficiency syndrome. A controlled clinical trial.
Dautzenberg B(1), Truffot C, Legris S, Meyohas MC, Berlie HC, Mercat A, Chevret
S, Grosset J.
Author information:
(1)Pulmonary Department Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
Comment in
Am Rev Respir Dis. 1992 May;145(5):1241-2. doi: 10.1164/ajrccm/145.5.1241b.
Disseminated Mycobacterium avium infection is common in patients with acquired
immune deficiency syndrome (AIDS), but no drug studies have been reported
establishing antimicrobial activity against this organism in a controlled,
randomized trial. Clarithromycin, a new macrolide, has activity against M. avium
in vitro and in animals, but it has not been studied in humans. In this
randomized, double-blind, placebo-controlled trial, we measured the ability of
clarithromycin to reduce M. avium bacteremia in patients with AIDS and
disseminated infection. Of 23 patients initially enrolled, 15 men with
late-stage AIDS qualified for the study. One group received clarithromycin alone
for 6 wk, then placebo plus rifampin, isoniazid, ethambutol, and clofazimine for
6 wk. The other group received placebo alone, then clarithromycin plus the other
four drugs. Colony-forming units (CFU) of M. avium per milliliter of blood were
determined by quantitative cultures taken at baseline and every 2 wk thereafter.
Minimum inhibitory concentration of clarithromycin for 90% of the strains
isolated from patients at baseline, as measured on 7H11 agar at pH 6.6, was 8
micrograms/ml. Eight eligible patients with initial positive cultures who were
initially receiving clarithromycin alone had marked declines in blood M. avium
CFU; in six cases, CFU decreased to zero. When seven patients were switched to
placebo plus the other four drugs, CFU rose in four patients and remained
undetectable in three. The five eligible patients initially treated with placebo
had progressive CFU increases; when three were switched to clarithromycin plus
the four drugs, their CFU declined.(ABSTRACT TRUNCATED AT 250 WORDS)
DOI: 10.1164/ajrccm/144.3_Pt_1.564
PMID: 1832527 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11073759
|
1. Clin Infect Dis. 2000 Nov;31(5):1245-52. doi: 10.1086/317468. Epub 2000 Nov 6.
A randomized, double-blind trial comparing azithromycin and clarithromycin in
the treatment of disseminated Mycobacterium avium infection in patients with
human immunodeficiency virus.
Dunne M(1), Fessel J, Kumar P, Dickenson G, Keiser P, Boulos M, Mogyros M, White
AC Jr, Cahn P, O'Connor M, Lewi D, Green S, Tilles J, Hicks C, Bissett J,
Schneider MM, Benner R.
Author information:
(1)Pfizer Central Research, Groton, CT 06340, USA. dunnemw@groton.pfizer.com
Erratum in
Clin Infect Dis 2001 May 1;32(9):1386.
Two hundred and forty-six patients infected with human immunodeficiency virus
(HIV) who also had disseminated Mycobacterium avium complex received either
azithromycin 250 mg every day, azithromycin 600 mg every day, or clarithromycin
500 mg twice a day, each combined with ethambutol, for 24 weeks. Samples drawn
from patients were cultured and clinically assessed every 3 weeks up to week 12,
then monthly thereafter through week 24 of double-blind therapy and every 3
months while on open-label therapy through the conclusion of the trial. The
azithromycin 250 mg arm of the study was dropped after an interim analysis
showed a lower rate of clearance of bacteremia. At 24 weeks of therapy, the
likelihood of patients' developing 2 consecutive negative cultures (46% vs. 56%,
P=.24) or 1 negative culture (59% vs. 61%, P=.80) was similar for azithromycin
600 mg (n=68) and clarithromycin (n=57), respectively. The likelihood of relapse
was 39% versus 27% (P=.21) on azithromycin compared with clarithromycin,
respectively. Of the 6 patients who experienced relapse, none of those
randomized to receive azithromycin developed isolates resistant to macrolides,
compared with 2 of 3 patients randomized to receive clarithromycin [corrected].
Mortality was similar in patients comprising each arm of the study (69% vs. 63%;
hazard, 95.1% confidence interval, 1.1 [0.7, 1.7]). Azithromycin 600 mg, when
given in combination with ethambutol, is an effective agent for the treatment of
disseminated M. avium disease in patients infected with HIV.
DOI: 10.1086/317468
PMID: 11073759 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9875582
|
1. AIDS. 1998 Dec 24;12(18):2439-46. doi: 10.1097/00002030-199818000-00013.
A phase II/III trial of antimicrobial therapy with or without amikacin in the
treatment of disseminated Mycobacterium avium infection in HIV-infected
individuals. AIDS Clinical Trials Group Protocol 135 Study Team.
Parenti DM(1), Williams PL, Hafner R, Jacobs MR, Hojczyk P, Hooton TM, Barber
TW, Simpson G, van der Horst C, Currier J, Powderly WG, Limjoco M, Ellner JJ.
Author information:
(1)George Washington University Medical Center, Washington, DC 20037, USA.
OBJECTIVE: To determine the clinical and microbiologic benefit of adding
amikacin to a four-drug oral regimen for treatment of disseminated Mycobacterium
avium infection in HIV-infected patients.
DESIGN: A randomized, open-labeled, comparative trial.
SETTING: Outpatient clinics.
PATIENTS: Seventy-four patients with HIV and symptomatic bacteremic M. avium
infection.
INTERVENTIONS: Rifampin 10 mg/kg daily, ciprofloxacin 500 mg twice daily,
clofazimine 100 mg every day, and ethambutol 15 mg/kg orally daily for 24 weeks,
with or without amikacin 10 mg/kg intravenously or intramuscularly 5 days weekly
for the first 4 weeks.
MAIN OUTCOME MEASURE: Clinical and microbiologic response at 4 weeks;
quantitative level of bacteremia with M. avium.
RESULTS: No difference in clinical response was noted with the addition of
amikacin to the four-drug oral regimen, and only 25% in either group had a
complete or partial response at 4 weeks. A comparable quantitative decrease in
bacteremia was noted in both treatment groups, with 16% of patients being
culture-negative at 4 weeks and 38% at 12 weeks. Toxicities were mainly
gastrointestinal. Amikacin was well tolerated. Median survival was 30 weeks in
both groups.
CONCLUSIONS: The addition of amikacin to a four-drug oral regimen of rifampin,
ciprofloxacin, clofazimine, and ethambutol did not provide clinical or
microbiologic benefit.
DOI: 10.1097/00002030-199818000-00013
PMID: 9875582 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23152885
|
1. PLoS One. 2012;7(11):e49267. doi: 10.1371/journal.pone.0049267. Epub 2012 Nov
13.
The effect of PRMT1-mediated arginine methylation on the subcellular
localization, stress granules, and detergent-insoluble aggregates of FUS/TLS.
Yamaguchi A(1), Kitajo K.
Author information:
(1)Department of Neurobiology, Graduate School of Medicine, Chiba University,
Chiba, Japan.
Fused in sarcoma/translocated in liposarcoma (FUS/TLS) is one of causative genes
for familial amyotrophic lateral sclerosis (ALS). In order to identify binding
partners for FUS/TLS, we performed a yeast two-hybrid screening and found that
protein arginine methyltransferase 1 (PRMT1) is one of binding partners
primarily in the nucleus. In vitro and in vivo methylation assays showed that
FUS/TLS could be methylated by PRMT1. The modulation of arginine methylation
levels by a general methyltransferase inhibitor or conditional over-expression
of PRMT1 altered slightly the nucleus-cytoplasmic ratio of FUS/TLS in cell
fractionation assays. Although co-localized primarily in the nucleus in normal
condition, FUS/TLS and PRMT1 were partially recruited to the cytoplasmic
granules under oxidative stress, which were merged with stress granules (SGs)
markers in SH-SY5Y cell. C-terminal truncated form of FUS/TLS (FUS-dC), which
lacks C-terminal nuclear localization signal (NLS), formed cytoplasmic
inclusions like ALS-linked FUS mutants and was partially co-localized with
PRMT1. Furthermore, conditional over-expression of PRMT1 reduced the
FUS-dC-mediated SGs formation and the detergent-insoluble aggregates in HEK293
cells. These findings indicate that PRMT1-mediated arginine methylation could be
implicated in the nucleus-cytoplasmic shuttling of FUS/TLS and in the SGs
formation and the detergent-insoluble inclusions of ALS-linked FUS/TLS mutants.
DOI: 10.1371/journal.pone.0049267
PMCID: PMC3496700
PMID: 23152885 [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/17431895
|
1. Am J Med Genet A. 2007 May 1;143A(9):999-1008. doi: 10.1002/ajmg.a.31689.
Smith-Magenis syndrome and Moyamoya disease in a patient with
del(17)(p11.2p13.1).
Girirajan S(1), Mendoza-Londono R, Vlangos CN, Dupuis L, Nowak NJ, Bunyan DJ,
Hatchwell E, Elsea SH.
Author information:
(1)Department of Human Genetics, Medical College of Virginia Campus, Virginia
Commonwealth University, Richmond, VA 23298, USA.
Chromosomal rearrangements causing microdeletions and microduplications are a
major cause of congenital malformation and mental retardation. Because they are
not visible by routine chromosome analysis, high resolution whole-genome
technologies are required for the detection and diagnosis of small chromosomal
abnormalities. Recently, array-comparative genomic hybridization (aCGH) and
multiplex ligation-dependent probe amplification (MLPA) have been useful tools
for the identification and mapping of deletions and duplications at higher
resolution and throughput. Smith-Magenis syndrome (SMS) is a multiple congenital
anomalies/mental retardation syndrome caused by deletion or mutation of the
retinoic acid induced 1 (RAI1) gene and is often associated with a chromosome
17p11.2 deletion. We report here on the clinical and molecular analysis of a
10-year-old girl with SMS and moyamoya disease (occlusion of the circle of
Willis). We have employed a combination of aCGH, FISH, and MLPA to characterize
an approximately 6.3 Mb deletion spanning chromosome region 17p11.2-p13.1 in
this patient, with the proximal breakpoint within the RAI1 gene. Further,
investigation of the genomic architecture at the breakpoint intervals of this
large deletion documented the presence of palindromic repeat elements that could
potentially form recombination substrates leading to unequal crossover.
DOI: 10.1002/ajmg.a.31689
PMID: 17431895 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23121133
|
1. Dev Med Child Neurol. 2013 Feb;55(2):167-172. doi: 10.1111/dmcn.12013. Epub
2012 Nov 2.
Brain magnetic resonance imaging and motor and intellectual functioning in 86
patients born at term with spastic diplegia.
Numata Y(1)(2), Onuma A(1), Kobayashi Y(3), Sato-Shirai I(1)(2), Tanaka S(1),
Kobayashi S(1), Wakusawa K(1), Inui T(1), Kure S(2), Haginoya K(1).
Author information:
(1)Department of Pediatric Neurology, Takuto Rehabilitation Center for Children,
Sendai.
(2)Department of Pediatrics, Tohoku University School of Medicine, Sendai.
(3)Department of Pediatrics, Nishitaga National Hospital, Sendai, Japan.
Comment in
Dev Med Child Neurol. 2013 Feb;55(2):103-104. doi: 10.1111/dmcn.12047.
AIM: To investigate the association between magnetic resonance imaging (MRI)
patterns and motor function, epileptic episodes, and IQ or developmental
quotient in patients born at term with spastic diplegia.
METHOD: Eighty-six patients born at term with cerebral palsy (CP) and spastic
diplegia (54 males, 32 females; median age 20 y, range 7-42 y) among 829
patients with CP underwent brain MRI between 1990 and 2008. The MRI and clinical
findings were analysed retrospectively. Intellectual disability was classified
according to the Enjoji developmental test or the Wechsler Intelligence Scale
for Children (3rd edition).
RESULTS: The median ages at diagnosis of CP, assignment of Gross Motor Function
Classification System (GMFCS) level, cognitive assessment, and MRI were 2 years
(range 5 mo-8 y), 6 years (2 y 8 mo-19 y), 6 years (1 y 4 mo-19 y), and 7 years
(10 mo-30 y) respectively. MRI included normal findings (41.9%), periventricular
leukomalacia, hypomyelination, and porencephaly/periventricular venous
infarction. The frequency of patients in GMFCS levels III to V and intellectual
disability did not differ between those with normal and abnormal MRI findings.
Patients with normal MRI findings had significantly fewer epileptic episodes
than those with abnormal ones (p=0.001).
INTERPRETATION: Varied MRI findings, as well as the presence of severe motor
dysfunction and intellectual disability (despite normal MRI), suggest that
patients born at term with spastic diplegia had heterogeneous and unidentified
pathophysiology.
© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.
DOI: 10.1111/dmcn.12013
PMID: 23121133 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19765185
|
1. J Neurochem. 2009 Nov;111(4):1051-61. doi: 10.1111/j.1471-4159.2009.06383.x.
Epub 2009 Sep 16.
TDP-43 is recruited to stress granules in conditions of oxidative insult.
Colombrita C(1), Zennaro E, Fallini C, Weber M, Sommacal A, Buratti E, Silani V,
Ratti A.
Author information:
(1)Department of Neurology and Laboratory of Neuroscience, Dino Ferrari Center,
Università degli Studi di Milano - IRCCS Istituto Auxologico Italiano, Milan,
Italy.
Transactive response DNA-binding protein 43 (TDP-43) forms abnormal
ubiquitinated and phosphorylated inclusions in brain tissues from patients with
amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.
TDP-43 is a DNA/RNA-binding protein involved in RNA processing, such as
transcription, pre-mRNA splicing, mRNA stabilization and transport to dendrites.
We found that in response to oxidative stress and to environmental insults of
different types TDP-43 is capable to assemble into stress granules (SGs),
ribonucleoprotein complexes where protein synthesis is temporarily arrested. We
demonstrated that a specific aminoacidic interval (216-315) in the C-terminal
region and the RNA-recognition motif 1 domain are both implicated in TDP-43
participation in SGs as their deletion prevented the recruitment of TDP-43 into
SGs. Our data show that TDP-43 is a specific component of SGs and not of
processing bodies, although we proved that TDP-43 is not necessary for SG
formation, and its gene silencing does not impair cell survival during stress.
The analysis of spinal cord tissue from ALS patients showed that SG markers are
not entrapped in TDP-43 pathological inclusions. Although SGs were not evident
in ALS brains, we speculate that an altered control of mRNA translation in
stressful conditions may trigger motor neuron degeneration at early stages of
the disease.
DOI: 10.1111/j.1471-4159.2009.06383.x
PMID: 19765185 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15563017
|
1. J Child Neurol. 2004 Sep;19(9):699-709. doi: 10.1177/08830738040190091101.
Molecular genetic basis of tuberous sclerosis complex: from bench to bedside.
Au KS(1), Williams AT, Gambello MJ, Northrup H.
Author information:
(1)Department of Pediatrics, Division of Medical Genetics, The University of
Texas Medical School at Houston, Houston, TX 77030, USA.
Tuberous sclerosis complex is an autosomal dominant disease of benign tumors
occurring in multiple organ systems of the body. Either of two genes, TSC1 or
TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype. The
protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and
tuberin (TSC2), have been discovered to play important roles in several
cell-signaling pathways. Knowledge regarding the function of the
tuberin-hamartin complex has led to therapeutic intervention trials. Numerous
pathogenic mutations have been elucidated in individuals affected with tuberous
sclerosis complex. Information on the type and distribution of nearly 1000
mutations in the two genes is discussed. Mosaicism for tuberous sclerosis
complex mutations has been documented, complicating provision of genetic
counseling to families. Emerging genotype-phenotype correlations should provide
guidance for better medical care of individuals with tuberous sclerosis complex.
DOI: 10.1177/08830738040190091101
PMID: 15563017 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21177652
|
1. Nucleic Acids Res. 2011 Apr;39(8):3103-15. doi: 10.1093/nar/gkq1298. Epub 2010
Dec 21.
The chromodomains of CHD1 are critical for enzymatic activity but less important
for chromatin localization.
Morettini S(1), Tribus M, Zeilner A, Sebald J, Campo-Fernandez B, Scheran G,
Wörle H, Podhraski V, Fyodorov DV, Lusser A.
Author information:
(1)Division of Molecular Biology, Biocenter, Innsbruck Medical University,
Fritz-Pregl Strasse 3, 6020 Innsbruck, Austria.
The molecular motor protein CHD1 has been implicated in the regulation of
transcription and in the transcription-independent genome-wide incorporation of
H3.3 into paternal chromatin in Drosophila melanogaster. A key feature of CHD1
is the presence of two chromodomains, which can bind to histone H3 methylated at
lysine 4 and thus might serve to recruit and/or maintain CHD1 at the chromatin.
Here, we describe genetic and biochemical approaches to the study of the
Drosophila CHD1 chromodomains. We found that overall localization of CHD1 on
polytene chromosomes does not appreciably change in chromodomain-mutant flies.
In contrast, the chromodomains are important for transcription-independent
activities of CHD1 during early embryonic development as well as for
transcriptional regulation of several heat shock genes. However, neither CHD1
nor its chromodomains are needed for RNA polymerase II localization and H3K4
methylation but loss of CHD1 decreases transcription-induced histone eviction at
the Hsp70 gene in vivo. Chromodomain mutations negatively affect the chromatin
assembly activities of CHD1 in vitro, and they appear to be involved in linking
the ATP-dependent motor to the chromatin assembly function of CHD1.
DOI: 10.1093/nar/gkq1298
PMCID: PMC3082874
PMID: 21177652 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16468993
|
1. Mol Microbiol. 2006 Mar;59(5):1531-41. doi: 10.1111/j.1365-2958.2005.05031.x.
The ISWI and CHD1 chromatin remodelling activities influence ADH2 expression and
chromatin organization.
Xella B(1), Goding C, Agricola E, Di Mauro E, Caserta M.
Author information:
(1)Istituto Pasteur-Fondazione Cenci Bolognetti, c/o Dipartmento di Genetica e
Biologia Molecolare, Universita La Sapienza, 00185 Rome, Italy.
Nucleosome remodelling complexes play a key role in gene activation in response
to environmental changes by driving promoter chromatin to reach an accessible
configuration. They also mediate genome-wide chromatin organization, although
their role in processes other than activation-related chromatin remodelling are
poorly understood. The Saccharomyces cerevisiae ADH2 gene represents an
excellent model for understanding the role of chromatin structure and
remodelling in gene regulation. Following glucose depletion, highly positioned
promoter nucleosomes are destabilized leading to strictly regulated kinetics of
transcriptional activation. Nevertheless, no chromatin remodelling activities
responsible for establishing or remodelling ADH2 chromatin structure have been
identified to date. Here we show that the absence of the Isw1 and Chd1
ATP-dependent chromatin remodelling activities delays the maximal expression of
ADH2 without impairing the chromatin remodelling that occurs upon activation.
Instead, a destabilized chromatin structure on the ADH2 coding and termination
region is observed in the absence of Isw1 or Chd1 in repressing conditions. The
specific Isw1 complex involved in this nucleosome repositioning is Isw1b because
the deletion of Ioc2 and Ioc4, but not of Ioc3, causes the same phenotype as the
deletion of Isw1. Moreover, the lack of Chd1 combined with the absence of Isw1
and Isw2 impairs nucleosome spacing along the ADH2 gene, and genome-wide in S.
cerevisiae. Thus, the ISWI and Chd1 remodelling factors are not only involved in
transcription-related chromatin remodelling, but also are required to maintain a
specific chromatin configuration across the yeast genome.
DOI: 10.1111/j.1365-2958.2005.05031.x
PMID: 16468993 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18576213
|
1. Int J Neurosci. 2008 Aug;118(8):1157-63. doi: 10.1080/00207450801898279.
Neurofibromatosis type 1 association with moyamoya disease.
Koc F(1), Yerdelen D, Koc Z.
Author information:
(1)Department of Neurology, Cukurova University Medical School, Adana, Turkey.
kocfiliz@gmail.com
The neurofibromatoses are genetic disorders of the nervous system that primarily
affect the development and growth of neural (nerve) cell tissues. The
neurofibromatoses are classified as neurofibromatosis type 1 (NF1) and
neurofibromatosis type 2 (NF2). NF1 is the more common type of the
neurofibromatoses. The gene responsible for NF1 is located on the chromosome
region 17q11.2 and for familial moyamoya disease on chromosome 17q25. This
article reports on a 20-year-old female with neurofibromatosis-1 who developed
moyamoya syndrome. More extensive reports and further investigations of such
families having this combination will certainly provide a better understanding
of this link in the near future.
DOI: 10.1080/00207450801898279
PMID: 18576213 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16263726
|
1. J Biol Chem. 2005 Dec 23;280(51):41789-92. doi: 10.1074/jbc.C500395200. Epub
2005 Oct 31.
Human but not yeast CHD1 binds directly and selectively to histone H3 methylated
at lysine 4 via its tandem chromodomains.
Sims RJ 3rd(1), Chen CF, Santos-Rosa H, Kouzarides T, Patel SS, Reinberg D.
Author information:
(1)Howard Hughes Medical Institute and Robert Wood Johnson Medical School,
Piscataway, New Jersey 08854, USA.
Defining the protein factors that directly recognize post-translational,
covalent histone modifications is essential toward understanding the impact of
these chromatin "marks" on gene regulation. In the current study, we identify
human CHD1, an ATP-dependent chromatin remodeling protein, as a factor that
directly and selectively recognizes histone H3 methylated on lysine 4. In vitro
binding studies identified that CHD1 recognizes di- and trimethyl H3K4 with a
dissociation constant (Kd) of approximately 5 microm, whereas monomethyl H3K4
binds CHD1 with a 3-fold lower affinity. Surprisingly, human CHD1 binds to
methylated H3K4 in a manner that requires both of its tandem chromodomains. In
vitro analyses demonstrate that unlike human CHD1, yeast Chd1 does not bind
methylated H3K4. Our findings indicate that yeast and human CHD1 have diverged
in their ability to discriminate covalently modified histones and link histone
modification-recognition and non-covalent chromatin remodeling activities within
a single human protein.
DOI: 10.1074/jbc.C500395200
PMCID: PMC1421377
PMID: 16263726 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17098252
|
1. J Mol Biol. 2007 Jan 26;365(4):1047-62. doi: 10.1016/j.jmb.2006.10.039. Epub
2006 Oct 14.
Structural polymorphism of chromodomains in Chd1.
Okuda M(1), Horikoshi M, Nishimura Y.
Author information:
(1)Graduate School of Supramolecular Biology, Yokohama City University,
Tsurumi-ku, Yokohama 230-0045, Japan.
Chromodomain from heterochromatin protein 1 and polycomb protein is known to be
a lysine-methylated histone H3 tail-binding module. Chromo-helicase/ATPase
DNA-binding protein 1 (CHD1) is an ATP-dependent chromatin remodeling factor,
containing two tandem chromodomains. In human CHD1, both chromodomains are
essential for specific binding to a K4 methylated histone H3 (H3 MeK4) peptide
and are found to bind cooperatively in the crystal structure. For the budding
yeast homologue, Chd1, the second but not the first chromodomain was once
reported to bind to an H3 MeK4 peptide. Here, we reveal that neither the second
chromodomain nor a region containing tandem chromodomains from yeast Chd1 bind
to any lysine-methylated or arginine-methylated histone peptides that we
examined. In addition, we examined the structures of the chromodomains from Chd1
by NMR. Although the tertiary structure of the region containing tandem
chromodomains could not be obtained, the secondary structure deduced from NMR is
well conserved in the tertiary structures of the corresponding first and second
chromodomains determined individually by NMR. Both chromodomains of Chd1
demonstrate a structure similar to that of the corresponding part of CHD1,
consisting of a three-stranded beta-sheet followed by a C-terminal alpha-helix.
However, an additional helix between the first and second beta-strands, which is
found in both of the first chromodomains of Chd1 and CHD1, is positioned in an
entirely different manner in Chd1 and CHD1. In human CHD1 this helix forms the
peptide-binding site. The amino acid sequences of the chromodomains could be
well aligned on the basis of these structures. The alignment showed that yeast
Chd1 lacks several key functional residues, which are responsible for specific
binding to a methylated lysine residue in other chromodomains. Chd1 is likely to
have no binding affinity for any H3 MeK peptide, as found in other chromodomain
proteins.
DOI: 10.1016/j.jmb.2006.10.039
PMID: 17098252 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8733409
|
1. Tuber Lung Dis. 1996 Feb;77(1):19-26. doi: 10.1016/s0962-8479(96)90070-2.
Clarithromycin against Mycobacterium avium complex infections.
Heifets LB(1).
Author information:
(1)Department of Microbiology, University of Colorado Health Sciences Center,
USA.
The turning point in antimicrobial therapy of Mycobacterium avium infections
came with the development of two new macrolides, clarithromycin and
azithromycin. Controlled clinical trials, the first ever conducted with any
agent among patients with M. avium infection, indicated the high efficiency of
clarithromycin, in either acquired immune deficiency syndrome (AIDS) patients
having a disseminated infection or non-AIDS patients with localized pulmonary
disease. Monotherapy with clarithromycin resulted in elimination of bacteremia
in almost all patients with disseminated infection, which is inevitably followed
by a relapse of bacteremia in patients who survived long enough to reach this
event. The strains susceptible to clarithromycin isolated before therapy
contained 10(-8) or 10(-9) resistant mutants, and the relapses of bacteremia
were caused by multiplication of these pre-existing mutants.
Clarithromycin-resistance was associated with a mutation in the 23S rRNA gene.
Cross-resistance between clarithromycin and azithromycin was confirmed with
laboratory mutants and clinical isolates. At least two methods for determining
the susceptibility of the M. avium isolates to clarithromycin are available: one
is minimum inhibitory concentration (MIC) determination on Mueller-Hinton agar
(pH 7.4) supplemented with 10% Oleic acid-albumin-dextrose catalase, the other
is MIC determination in 7H12 broth, also at pH 7.4. The breakpoints for
'susceptible' for these methods are < or = 8.0 micrograms/ml and < or = 2.0
micrograms/ml, respectively. The breakpoints for 'resistant' are > 128
micrograms/ml for the agar method and > 32.0 micrograms/ml for the broth method.
The predictability value of MIC determination was confirmed by comparing the
test results with the patients' clinical and bacteriological response to
therapy. The remaining major problem in the therapy of the M. avium infections
is a selection of companion drugs to be used in combination with clarithromycin
(or azithromycin) to prevent the emergence of the macrolide-resistance. A number
of clinical trials are now in progress to find a solution to this problem.
DOI: 10.1016/s0962-8479(96)90070-2
PMID: 8733409 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19335127
|
1. Neurosurg Focus. 2009 Apr;26(4):E11. doi: 10.3171/2009.1.FOCUS08310.
Moyamoya disease: a summary.
Burke GM(1), Burke AM, Sherma AK, Hurley MC, Batjer HH, Bendok BR.
Author information:
(1)New York Medical College, Valhalla, New York, USA.
Moyamoya, meaning a "hazy puff of smoke" in Japanese, is a chronic, occlusive
cerebrovascular disease involving bilateral stenosis or occlusion of the
terminal portion of the internal carotid arteries (ICAs) and/or the proximal
portions of the anterior cerebral arteries and middle cerebral arteries (MCAs).
The Ministry of Health and Welfare of Japan has defined 4 types of moyamoya
disease (MMD): ischemic, hemorrhagic, epileptic, and "other." The ischemic type
has been shown to predominate in childhood, while the hemorrhagic type is more
often observed in the adult population. The highest prevalence of MMD is found
in Japan, with a higher female to male ratio. Studies have shown a possible
genetic association of MMD linked to chromosome 17 in Japanese cases as well as
in cases found in other demographics. During autopsy, intracerebral hematoma is
found and most commonly serves as the major cause of death in patients with MMD.
Moyamoya vessels at the base of the brain are composed of medium-sized or small
muscular arteries emanating from the circle of Willis, mainly the intracranial
portions of ICAs, anterior choroidal arteries, and posterior cerebral arteries,
forming complex channels that connect with distal positions of the MCAs. Off of
these channels are small tortuous and dilated vessels that penetrate into the
base of the brain at the site of the thalamoperforate and lenticulostriate
arteries. On angiography, there is the characteristic stenosis or occlusion
bilaterally at the terminal portion of the ICAs as well as the moyamoya vessels
at the base of the brain. Six angiographic stages have been described, from
Stage 1, which reveals a narrowing of the carotid forks, to Stage 6, in which
the moyamoya vessels disappear and collateral circulation is produced solely
from the external carotid arteries. Cases with milder symptoms are usually
treated conservatively; however, more severe symptomatic cases are treated using
revascularization procedures. Surgical treatments are divided into 3 types:
direct, indirect, and combined/other methods. Direct bypass includes superficial
temporal artery-MCA bypass or use of other graft types. Indirect procedures
bring in circulation to the intracranial regions by introducing newly developed
vasculature from newly approximated tissues. These procedures may not be enough
to prevent further ischemia; therefore, a combination of direct and indirect
procedures is more suitable. This article will give a review of the
epidemiology, natural history, pathology, pathophysiology, and diagnostic
criteria, including imaging, and briefly describe the surgical treatment of MMD.
DOI: 10.3171/2009.1.FOCUS08310
PMID: 19335127 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16584300
|
1. Microb Drug Resist. 2006 Spring;12(1):1-6. doi: 10.1089/mdr.2006.12.1.
In vivo efficacy of phage therapy for Mycobacterium avium infection as delivered
by a nonvirulent mycobacterium.
Danelishvili L(1), Young LS, Bermudez LE.
Author information:
(1)Department of Biomedical Sciences, College of Veterinary Medicine, Department
of Microbiology, College of Science, Oregon State University, 105 Magruder Hall,
Corvallis, OR 97331-8797, USA.
The emergence of mycobacteria resistant to currently available antimicrobial
agents has become an important problem in modern medicine. Mycobacterium avium
and M. tuberculosis are intracellular pathogens that replicate and survive
within the mononuclear phagocytes. TM4 is a lytic mycobacteriophage that kills
both extracellular M. avium and M. tuberculosis. When delivered by M. smegmatis
transiently infected with TM4, it kills both M. avium and M. tuberculosis within
RAW 264.7 macrophages. To evaluate the treatment of M. avium infection with
phage in vivo, C57 BL/6 mice were infected with M. avium 109 and, 7 days later,
treated either once or twice with TM4 phage (7.9 x 10(10) PFU/ml), M. smegmatis
(4 x 10(8) cFU/ml), or M. smegmatis with TM4 phage delivered intravenously
(i.v.). Treatment with TM4 phage alone or M. smegmatis without TM4 did not show
a significant decrease in number of intracellular bacteria in the spleen
compared with untreated control. In contrast, administration of M. smegmatis-TM4
resulted in a significant decrease in the number of M. avium in the spleen.
However, 23% of bacteria recovered from treated mice were resistant to TM4.
These in vivo studies confirmed the in vitro findings that an avirulent
mycobacterium can be used as a carrier to deliver antimycobacterial phage
intracellularly.
DOI: 10.1089/mdr.2006.12.1
PMID: 16584300 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1387133
|
1. J Antimicrob Chemother. 1992 Jun;29(6):693-9. doi: 10.1093/jac/29.6.693.
TLC G-65 in combination with other agents in the therapy of Mycobacterium avium
infection in beige mice.
Cynamon MH(1), Klemens SP, Swenson CE.
Author information:
(1)Veterans Affairs Medical Center, Syracuse, New York.
The activity of TLC G-65 (a liposomal gentamicin preparation), alone and in
combination with rifapentine, clarithromycin, clofazimine and ethambutol, was
evaluated in the beige mouse (C57BL/6J--bgj/bgj) model of disseminated
Mycobacterium avium infection. TLC G-65 was found to be more active than
amikacin. The combination of rifapentine and TLC G-65 was more active than
either agent alone. The activity of clarithromycin in combination with TLC G-65
was similar to that of either agent alone. Clofazimine improved the activity of
TLC G-65 with respect to the spleen, while ethambutol improved the activity with
respect to the liver. Clofazimine and ethambutol enhanced the activity of TLC
G-65 against bacteria in the lungs. TLC G-65 in combination with rifapentine
appears to be an attractive regimen for the treatment of infections caused by
bacteria in the M. avium complex.
DOI: 10.1093/jac/29.6.693
PMID: 1387133 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19948887
|
1. Genetics. 2010 Feb;184(2):321-34. doi: 10.1534/genetics.109.111526. Epub 2009
Nov 30.
Histone H3K4 and K36 methylation, Chd1 and Rpd3S oppose the functions of
Saccharomyces cerevisiae Spt4-Spt5 in transcription.
Quan TK(1), Hartzog GA.
Author information:
(1)Department of Molecular, Cell, and Developmental Biology, University of
California, Santa Cruz, California 95064, USA.
Spt4-Spt5, a general transcription elongation factor for RNA polymerase II, also
has roles in chromatin regulation. However, the relationships between these
functions are not clear. Previously, we isolated suppressors of a Saccharomyces
cerevisiae spt5 mutation in genes encoding members of the Paf1 complex, which
regulates several cotranscriptional histone modifications, and Chd1, a chromatin
remodeling enzyme. Here, we show that this suppression of spt5 can result from
loss of histone H3 lysines 4 or 36 methylation, or reduced recruitment of Chd1
or the Rpd3S complex. These spt5 suppressors also rescue the synthetic growth
defects observed in spt5 mutants that also lack elongation factor TFIIS. Using a
FLO8 reporter gene, we found that a chd1 mutation caused cryptic initiation of
transcription. We further observed enhancement of cryptic initiation in chd1
isw1 mutants and increased histone acetylation in a chd1 mutant. We suggest
that, as previously proposed for H3 lysine 36 methylation and the Rpd3S complex,
H3 lysine 4 methylation and Chd1 function to maintain normal chromatin
structures over transcribed genes, and that one function of Spt4-Spt5 is to help
RNA polymerase II overcome the repressive effects of these histone modifications
and chromatin regulators on transcription.
DOI: 10.1534/genetics.109.111526
PMCID: PMC2828714
PMID: 19948887 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18924029
|
1. Kardiol Pol. 2008 Sep;66(9):982-6; discussion 986.
[Myopericarditis complicated with cardiogenic shock mimicking acute coronary
syndrome with ST elevation in a patient with hyperthyroidism and diabetes
mellitus].
[Article in Polish]
Kukla P(1), Bryniarski L, Bromblik A, Szczuka K, Kawecka-Jaszcz K.
Author information:
(1)Oddział Wewnetrzny, Szpital Specjalistyczny im. H. Klimontowicza, Gorlice.
kukla_piotr@poczta.onet.pl
We describe a case of a 56 year old man with myopericarditis complicated with
cardiogenic shock within first 3 days, mimicking on admission acute myocardial
infarction with ST elevation in inferior ECG leads. Additionally, patient
presented hyperthyroidism and totally decompensated diabetes mellitus. He
required during the first 3 days intravenous infusion of inotropic agents.
Cardiac enzymes levels were elevated. Akinesia in mid-inferior and mid-posterior
regions in ECHO was observed. On the 10th day ST segment elevation in I, II,
V3-V6 and ST depression in aVR was observed in ECG. After stabilisation patient
underwent coronarography which showed normal coronary arteries. The final
diagnosis was acute myopericarditis complicated with acute heart failure and
cardiogenic shock.
PMID: 18924029 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22422841
|
1. Nucleic Acids Res. 2012 Jul;40(12):e90. doi: 10.1093/nar/gks237. Epub 2012 Mar
15.
Unveiling combinatorial regulation through the combination of ChIP information
and in silico cis-regulatory module detection.
Sun H(1), Guns T, Fierro AC, Thorrez L, Nijssen S, Marchal K.
Author information:
(1)Department of Microbial and Molecular Systems, Katholieke Universiteit
Leuven, Leuven, Belgium.
Computationally retrieving biologically relevant cis-regulatory modules (CRMs)
is not straightforward. Because of the large number of candidates and the
imperfection of the screening methods, many spurious CRMs are detected that are
as high scoring as the biologically true ones. Using ChIP-information allows not
only to reduce the regions in which the binding sites of the assayed
transcription factor (TF) should be located, but also allows restricting the
valid CRMs to those that contain the assayed TF (here referred to as applying
CRM detection in a query-based mode). In this study, we show that exploiting
ChIP-information in a query-based way makes in silico CRM detection a much more
feasible endeavor. To be able to handle the large datasets, the query-based
setting and other specificities proper to CRM detection on ChIP-Seq based data,
we developed a novel powerful CRM detection method 'CPModule'. By applying it on
a well-studied ChIP-Seq data set involved in self-renewal of mouse embryonic
stem cells, we demonstrate how our tool can recover combinatorial regulation of
five known TFs that are key in the self-renewal of mouse embryonic stem cells.
Additionally, we make a number of new predictions on combinatorial regulation of
these five key TFs with other TFs documented in TRANSFAC.
DOI: 10.1093/nar/gks237
PMCID: PMC3384348
PMID: 22422841 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7995828
|
1. J Cardiovasc Surg (Torino). 1994 Oct;35(5):383-9.
Triiodothyronine administration in coronary artery bypass surgery: effect on
hemodynamics.
Vavouranakis I(1), Sanoudos G, Manios A, Kalogeropoulou K, Sitaras K, Kokkinos
C.
Author information:
(1)Division of Cardiovascular Surgery, NIMTS Hospital, Athens, Greece.
OBJECTIVE: The purpose of this study was to investigate any potential
hemodynamic effect of intravenously administered triiodothyronine in patients
undergoing coronary artery bypass surgery.
EXPERIMENTAL DESIGN: Thirty patients were randomized in this single-blind,
placebo-controlled trial. Hemodynamic parameters including heart rate, stroke
volume index, cardiac index, pulmonary wedge pressure, pulmonary vascular
resistances, systemic vascular resistances, and mean blood pressure, were
compared between the two groups preoperatively, before the initiation of
cardiopulmonary bypass (CPB), 5 minutes after the end of CPB, and 2, 4, 10, 16,
and 22 hours thereafter.
INTERVENTION: Triiodothyronine was administered as a bolus infusion over a 1 min
period after removal of the aortic cross-clamp, (0.15 microgram/kg), before the
end of CPB (0.1 microgram/kg), 4 hours after the end of CPB (0.1 microgram/kg),
9 hours after CPB (0.1 microgram/kg), and 14 hours after CPB (0.1 microgram/kg).
Patients received inotropes, vasodilators, and diuretics only if specifically
indicated.
RESULTS: Plasma FT3 levels were higher in the T3 group, but within the normal
range. No significant differences were noted in the pre and post CPB
hemodynamics between the two groups for the most part of the study except that
heart rate was increased in T3 group. A greater number of patients in the
control group received vasodilators. No adverse reactions were noted with
triiodothyronine administration.
CONCLUSION: Triiodothyronine administration in patients undergoing
cardiopulmonary bypass surgery is safe, may lessen the need for pharmacological
(vasodilator) therapy, but may increase heart rate.
PMID: 7995828 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12213743
|
1. Asian Cardiovasc Thorac Ann. 2002 Sep;10(3):219-22. doi:
10.1177/021849230201000306.
Effects of intravenous triiodothyronine during coronary artery bypass surgery.
Güden M(1), Akpinar B, Sagğbaş E, Sanisoğlu I, Cakali E, Bayindir O.
Author information:
(1)Department of Cardiovascular Surgery Kadir Has University, Florence
Nightingale Hospital Istanbul, Turkey.
A prospective randomized and double-blind study was performed to evaluate
whether perioperative triiodothyronine administration has any effect on
cardiovascular performance after coronary artery bypass surgery. Sixty patients
were assigned to 2 groups of 30 each. When crossclamping ended, group A received
an intravenous bolus of triiodothyronine, followed by infusion for 6 hours.
Group B received a placebo. Serum triiodothyronine levels and hemo-dynamic
parameters were serially measured. Mean postoperative cardiac index was
slightly, but not significantly, higher in group A, whereas systemic vascular
resistance was significantly lower in group A. Compared with preoperative
values, serum triiodothyronine levels dropped significantly in group B at the
end of cardiopulmonary bypass and remained low 12 hours postoperatively, while
levels rose significantly in group A. No significant differences were detected
between the groups in the incidence of arrhythmia, the need for inotropic
support, intensive care unit stay, mortality, and morbidity. Perioperative
administration of triiodothyronine increased cardiac output slightly and
decreased systemic vascular resistance, but it had no effect on operative
outcome. Routine use after coronary surgery is thus not recommended.
DOI: 10.1177/021849230201000306
PMID: 12213743 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20671200
|
1. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14615-20. doi:
10.1073/pnas.1002876107. Epub 2010 Jul 29.
Genome-wide identification of cis-regulatory motifs and modules underlying gene
coregulation using statistics and phylogeny.
Rouault H(1), Mazouni K, Couturier L, Hakim V, Schweisguth F.
Author information:
(1)Laboratoire de Physique Statistique, Centre National de la Recherche
Scientifique, Université Pierre et Marie Curie, Ecole Normale Supérieure, 75231,
Paris Cedex 05, France.
Cell fate determination depends in part on the establishment of specific
transcriptional programs of gene expression. These programs result from the
interpretation of the genomic cis-regulatory information by sequence-specific
factors. Decoding this information in sequenced genomes is an important issue.
Here, we developed statistical analysis tools to computationally identify the
cis-regulatory elements that control gene expression in a set of coregulated
genes. Starting with a small number of validated and/or predicted cis-regulatory
modules (CRMs) in a reference species as a training set, but with no a priori
knowledge of the factors acting in trans, we computationally predicted
transcription factor binding sites (TFBSs) and genomic CRMs underlying
coregulation. This method was applied to the gene expression program active in
Drosophila melanogaster sensory organ precursor cells (SOPs), a specific type of
neural progenitor cells. Mutational analysis showed that four, including one
newly characterized, out of the five top-ranked families of predicted TFBSs were
required for SOP-specific gene expression. Additionaly, 19 out of the 29
top-ranked predicted CRMs directed gene expression in neural progenitor cells,
i.e., SOPs or larval brain neuroblasts, with a notable fraction active in SOPs
(11/29). We further identified the lola gene as the target of two SOP-specific
CRMs and found that the lola gene contributed to SOP specification. The
statistics and phylogeny-based tools described here can be more generally
applied to identify the cis-regulatory elements of specific gene regulatory
networks in any family of related species with sequenced genomes.
DOI: 10.1073/pnas.1002876107
PMCID: PMC2930411
PMID: 20671200 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
|
http://www.ncbi.nlm.nih.gov/pubmed/23958074
|
1. J Cardiothorac Vasc Anesth. 2013 Dec;27(6):1218-23. doi:
10.1053/j.jvca.2013.01.027. Epub 2013 Aug 16.
Efficacy of perioperative oral triiodothyronine replacement therapy in patients
undergoing off-pump coronary artery bypass grafting.
Choi YS(1), Shim JK, Song JW, Song Y, Yang SY, Kwak YL.
Author information:
(1)Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research
Institute, Yonsei University College of Medicine.
OBJECTIVE: The aim of this study was to assess the effects of oral
triiodothyronine (T3) therapy on postoperative thyroid hormone concentrations,
hemodynamic variables, and outcomes.
DESIGN: A prospective, randomized, controlled, double-blind study.
SETTING: Cardiac operating room at a single institution.
PARTICIPANTS: One hundred patients undergoing elective off-pump coronary artery
bypass graft surgery.
INTERVENTIONS: Patients received either 20 μg of oral T3 or placebo every 12
hours starting 20 minutes before anesthetic induction, for a total of 4 doses.
MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of thyroid hormones were
measured serially before surgery, upon arrival in the intensive care unit, and
12, 24, and 36 hours after surgery. Hemodynamic variables also were recorded
serially. Postoperative inotrope requirement and major morbidity endpoints were
assessed. Serum T3 concentrations were significantly higher with fewer patients
having T3 concentrations below the normal range in the T3 group than the placebo
group throughout the postoperative period. Hemodynamic variables, postoperative
inotrope requirement, and outcome variables showed no differences between the
groups.
CONCLUSIONS: Oral T3 therapy significantly attenuated the postoperative decline
in T3 concentrations in patients undergoing off-pump coronary artery bypass
graft surgery. The lack of apparent clinical benefit merits further
investigations in patients with reduced cardiac performance.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1053/j.jvca.2013.01.027
PMID: 23958074 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10343261
|
1. J Thorac Cardiovasc Surg. 1999 Jun;117(6):1128-34. doi:
10.1016/s0022-5223(99)70249-7.
A randomized double-blind study of the effect of triiodothyronine on cardiac
function and morbidity after coronary bypass surgery.
Mullis-Jansson SL(1), Argenziano M, Corwin S, Homma S, Weinberg AD, Williams M,
Rose EA, Smith CR.
Author information:
(1)Departments of Anesthesiology, Surgery,and Medicine, Columbia University
College of Physicians and Surgeons, New York, NY, USA.
BACKGROUND: Although triiodothyronine deficiency has been described after
cardiopulmonary bypass, data supporting its use have been conflicting. A
double-blind, randomized, placebo-controlled study was undertaken to further
define the effect of triiodothyronine on hemodynamics and outcome after coronary
artery bypass grafting.
METHODS: A total of 170 patients undergoing elective coronary artery bypass
grafting were enrolled and completed the study from November 1996 through March
1998. On removal of the aortic crossclamp, patients were randomized to receive
either intravenous triiodothyronine (0.4 microgram/kg bolus plus 0.1
microgram/kg infusion administered over a 6-hour period, n = 81) or placebo (n =
89). Outcome variables included hemodynamic profile and inotropic drug/pressor
requirements at several time points (mean +/- standard error of the mean),
perioperative morbidity (arrhythmia/ischemia/infarction), and mortality.
RESULTS: Despite similar baseline characteristics, patients randomized to
triiodothyronine had a higher cardiac index and lower inotropic requirements
after the operation. Subjects receiving triiodothyronine demonstrated a
significantly lower incidence of postoperative myocardial ischemia (4% vs 18%, P
=.007) and pacemaker dependence (14% vs 25%, P =.013). Seven patients in the
placebo group required postoperative mechanical assistance (intra-aortic balloon
pump, n = 4; left ventricular assist device, n = 3), compared with none in the
triiodothyronine group (P =.01). There were 2 deaths in the placebo group and no
deaths in the triiodothyronine group.
CONCLUSIONS: Parenteral triiodothyronine given after crossclamp removal during
elective coronary artery bypass grafting significantly improved postoperative
ventricular function, reduced the need for treatment with inotropic agents and
mechanical devices, and decreased the incidence of myocardial ischemia. The
incidence of atrial fibrillation was slightly decreased, and the need for
postoperative pacemaker support was reduced.
DOI: 10.1016/s0022-5223(99)70249-7
PMID: 10343261 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18606616
|
1. Nucleic Acids Res. 2008 Aug;36(13):4488-97. doi: 10.1093/nar/gkn407. Epub 2008
Jul 7.
MOPAT: a graph-based method to predict recurrent cis-regulatory modules from
known motifs.
Hu J(1), Hu H, Li X.
Author information:
(1)Division of Biostatistics, School of Informatics, Indiana University, 410
West 10th Street, Indianapolis, IN 46202, USA.
The identification of cis-regulatory modules (CRMs) can greatly advance our
understanding of eukaryotic regulatory mechanism. Current methods to predict
CRMs from known motifs either depend on multiple alignments or can only deal
with a small number of known motifs provided by users. These methods are
problematic when binding sites are not well aligned in multiple alignments or
when the number of input known motifs is large. We thus developed a new CRM
identification method MOPAT (motif pair tree), which identifies CRMs through the
identification of motif modules, groups of motifs co-occurring in multiple CRMs.
It can identify 'orthologous' CRMs without multiple alignments. It can also find
CRMs given a large number of known motifs. We have applied this method to mouse
developmental genes, and have evaluated the predicted CRMs and motif modules by
microarray expression data and known interacting motif pairs. We show that the
expression profiles of the genes containing CRMs of the same motif module
correlate significantly better than those of a random set of genes do. We also
show that the known interacting motif pairs are significantly included in our
predictions. Compared with several current methods, our method shows better
performance in identifying meaningful CRMs.
DOI: 10.1093/nar/gkn407
PMCID: PMC2490743
PMID: 18606616 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/6966005
|
1. Johns Hopkins Med J. 1980 Apr;146(4):133-6.
Haemophilus influenzae sepsis leading to pericarditis despite antimicrobial
therapy.
Leggiadro RJ, Balsam D.
Acute purulent pericarditis is a well-recognized, though infrequently seen,
manifestation of systemic Haemophilus influenzae type b disease. We recently
studied two pediatric patients who developed signs of this septic complication
during appropriate antibiotic treatment for bacteremia. These case reports
should alert physicians to the possibility that pericarditis may become
clinically evident in patients with systemic H. influenzae infections many days
after initiation of appropriate therapy. The pathophysiology, diagnostic
modalities and therapy are briefly reviewed.
PMID: 6966005 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16315865
|
1. Gan To Kagaku Ryoho. 2005 Oct;32(11):1550-2.
[Evaluation of host immunity and side effects in breast cancer patients treated
with adjuvant chemotherapy (FEC therapy)].
[Article in Japanese]
Nagashima Y(1), Sanpei N, Yamamoto S, Yoshino S, Tangoku A, Oka M.
Author information:
(1)Dept. of Surgery II, Yamaguchi University School of Medicine.
BACKGROUND: FEC (5-FU+epirubicin+cyclophosphamide) therapy has been used as
adjuvant chemotherapy for breast cancer patients with nodes positive. The aim of
this study was to evaluate host immunity and side effects of the FEC therapy.
The effect of oral administration of Lentinus edodes mycelia (LEM) was also
observed.
METHODS: Ten patients were enrolled in this study. The treatment with 5-FU (500
mg/m2), epirubicin (75 mg/m2) and cyclophosphamide (500 mg/m2) was administered
every 21 days for 2 cycles, and LEM (9 g/day po) was administered during the 2nd
cycle.
RESULTS: NK cell activity and the number of white blood cells decreased on the
7th day after the therapy, and they recovered on the 21st day. However, this NK
cell activity and the number of white blood cells didn't decrease when the FEC
therapy was used with LEM po.
CONCLUSIONS: FEC 75 therapy has made some impacts on host immunity, and LEM with
the FEC 75 therapy might have prevented host immunity.
PMID: 16315865 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12525522
|
1. J Clin Oncol. 2003 Jan 15;21(2):298-305. doi: 10.1200/JCO.2003.04.148.
Randomized trial comparing six versus three cycles of epirubicin-based adjuvant
chemotherapy in premenopausal, node-positive breast cancer patients: 10-year
follow-up results of the French Adjuvant Study Group 01 trial.
Fumoleau P(1), Kerbrat P, Romestaing P, Fargeot P, Brémond A, Namer M, Schraub
S, Goudier MJ, Mihura J, Monnier A, Clavère P, Serin D, Seffert P, Pourny C,
Facchini T, Jacquin JP, Sztermer JF, Datchary J, Ramos R, Luporsi E.
Author information:
(1)Département d'Oncologie Médicale, Centre René Gauducheau, Nantes, France.
fumoleau@gauducheau-nantes.fnclcc.fr
PURPOSE: To evaluate the duration and dose intensity of epirubicin-based
regimens in premenopausal patients with lymph node-positive breast cancer.
PATIENTS AND METHODS: Between 1986 and 1990, 621 patients with operable breast
cancer were randomly assigned to receive fluorouracil (Roche SA, Basel,
Switzerland) 500 mg/m2, epirubicin (Pharmacia SA, Milan, Italy) 50 mg/m2, and
cyclophosphamide (Asta Medica AG, Frankfurt, Germany) 500 mg/m2 every 21 days
(FEC 50) for six cycles (6 FEC 50); FEC 50 for three cycles (3 FEC 50); or the
same regimen with epirubicin 75 mg/m2 (FEC 75) for three cycles (3 FEC 75). All
patients in the three arms received chest wall irradiation at the end of the
third cycle.
RESULTS: After a 131-month median follow-up, the 10-year disease-free survival
(DFS) was 53.4%, 42.5%, and 43.6% (P =.05) in the three arms, respectively.
Pairwise comparisons demonstrate that 6 FEC 50 was superior both to 3 FEC 50 (P
=.02) and to 3 FEC 75 (P =.05). The 10-year overall survival (OS) for the 6 FEC
50 arm was 64.3%, for the 3 FEC 50 arm it was 56.6%, and for the 3 FEC 75 arm,
it was 59.7% (P =.25), respectively. Pairwise comparisons demonstrate that 6 FEC
50 was more effective than 3 FEC 50 (P =.10). Cox regression analysis
demonstrates that OS was significantly better in the 6 FEC 50 than in the 3 FEC
50 arm (P =.046). No severe infections (grade 3 to 4), acute cardiac toxicity,
or deaths from toxicity have been observed. Only five patients developed delayed
cardiac dysfunctions, and three patients developed acute myeloblastic leukemia.
CONCLUSION: After a long-term follow-up in an adjuvant setting, the benefit of
six cycles of FEC 50 compared with three cycles, whatever the dose, is highly
significant in terms of DFS. As regards OS, the group receiving six cycles of
FEC 50 has significantly better results than the group receiving three cycles of
FEC 50.
DOI: 10.1200/JCO.2003.04.148
PMID: 12525522 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8808724
|
1. J Chemother. 1996 Jun;8(3):237-42. doi: 10.1179/joc.1996.8.3.237.
Prevention of delayed emesis by a single intravenous bolus dose of
5-HT3-receptor-antagonist in moderately emetogenic chemotherapy.
Massidda B(1), Ionta MT.
Author information:
(1)Division of Medical Oncology, University of Cagliari, Italy.
While the use of 5-HT3 receptor antagonists is clearly justified in patients
receiving cisplatin, their role with less emetic drugs is still not defined. The
aim of our randomized study was to verify the efficacy of the single standard
dose of three 5-HT3-receptor-antagonists in moderately emetic chemotherapies.
Sixty chemotherapy-naive breast cancer patients of 30 to 71 years in age, P.S. =
0-1, receiving 5-fluorouracil-epirubicin-cyclophosphamide (FEC 75) q 21 days or
cyclophosphamide-methotrexate-5-fluorouracil (CMF) or 120 mg/m2 epirubicin or
high dose mitomycin-methotrexate-mitoxantrone (MMM) q 14 days (+ G-CSF) or 100
mg/m2 epirubicin (+ G-CSF) were randomized to receive, 15 min before
chemotherapy, 8 mg i.v. bolus of ondansetron or 3 mg i.v. granisetron or 5 mg
i.v. tropisetron and no further antiemetic therapy in the following days. 180
cycles were evaluable. Complete protection, (the absence of vomiting episodes,)
was respectively 75%, 70% and 70% in the acute and 70%, 82%, 72% in the delayed
phases, and an absence of nausea was 56%, 37% and 20% in the acute phase and
50%, 35% and 27% in the delayed, respectively. Complete response, (absence of
vomiting and absence or mild nausea,) was 74%, 58.6% and 50.8% in the acute and
64%, 63.7%, 47.3% in the delayed phases, respectively. At the statistical
analysis no significant differences between the three drugs were found regarding
acute vomiting while ondansetron was superior to granisetron and tropisetron in
acute (p = 0.018; p < 0.05) and delayed nausea (P = 0.104; p < 0.01). This
activity is practically the same as that we reported (Ann Oncol 1994; 6, suppl
8: 204) with a loading dose on day 1 and maintenance for the following 2-5 days,
but with a significantly favorable cost-benefit ratio.
DOI: 10.1179/joc.1996.8.3.237
PMID: 8808724 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22874562
|
1. Autophagy. 2012 Nov;8(11):1677-9. doi: 10.4161/auto.21484. Epub 2012 Aug 9.
Inactivation of the Cullin (CUL)-RING E3 ligase by the NEDD8-activating enzyme
inhibitor MLN4924 triggers protective autophagy in cancer cells.
Luo Z(1), Pan Y, Jeong LS, Liu J, Jia L.
Author information:
(1)Department of Immunology, Shanghai Medical College, Fudan University,
Shanghai, China.
Comment on
Luo Z, Yu G, Lee HW, Li L, Wang L, Yang D, et al. The Nedd8-activating
enzyme inhibitor MLN4924 induces autophagy and apoptosis to suppress liver
cancer cell growth. Cancer Res. 2012;72:3360–71. doi:
10.1158/0008-5472.CAN-12-0388.
The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological
processes by targeting a mass of substrates for ubiquitination and degradation,
whereas its dysfunction causes carcinogenesis. Post-translational neddylation of
CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is
required for CRL activation. Recently, MLN4924 was discovered via a
high-throughput screen as a specific NAE1 inhibitor and first-in-class
anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes
the accumulation of CRL substrates that trigger cell cycle arrest, senescence
and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo.
Recently, we found that MLN4924 also triggers protective autophagy in response
to CRL inactivation. MLN4924-induced autophagy is attributed partially to the
inhibition of mechanistic target of rapamycin (also known as mammalian target of
rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein
DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the
blockage of autophagy response enhances apoptosis in MLN4924-treated cells.
Together, our findings not only reveal autophagy as a novel cellular response to
CRL inactivation by MLN4924, but also provide a piece of proof-of-concept
evidence for the combination of MLN4924 with autophagy inhibitors to enhance
therapeutic efficacy.
DOI: 10.4161/auto.21484
PMCID: PMC3494597
PMID: 22874562 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11875727
|
1. Br J Cancer. 2002 Mar 4;86(5):692-7. doi: 10.1038/sj.bjc.6600165.
Sequential or alternating administration of docetaxel (Taxotere) combined with
FEC in metastatic breast cancer: a randomised phase II trial.
Spielmann M(1), Tubiana-Hulin M, Namer M, Mansouri H, Bougnoux Ph,
Tubiana-Mathieu N, Lotz V, Eymard JC.
Author information:
(1)Institut Gustave Roussy, 39-53 rue Camille Desmoulins, 94805 Villejuif,
France. spielman@igr.fr
The aim of this study, using a Fleming single-stage design, was to explore the
efficacy and safety of Taxotere 100 x mg x m(-2) docetaxel and FEC 75
cyclophosphamide 500 mg x m(-2), fluorouracil 500 x mg x m(-2) and epirubicin 75
mg x m(-2), in alternating and sequential schedules for the first-line treatment
of metastatic breast cancer. One hundred and thirty-six women were randomly
allocated, to one of three treatment regimens: DTX 100 plus FEC 75, alternated
for eight courses (ALT); four courses of DTX 100 followed by four courses of FEC
75 (SEQ T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ
F). One hundred and thirty-one women were evaluable for tumour response.
Although the treatment outcome was equivalent in the two sequential arms and the
alternating regimen (P=0.110, not significant), the response rate was less
encouraging in the SEQ F arm (52.3%) than in the other two arms (71.1% for ALT
and 70.5% for SEQ T), in which docetaxel was administered first. Time to
progression was similar in the ALT, SEQ T and SEQ F arms (9.5, 9.3 and 10.4
months respectively). Grade 3-4 neutropenia was observed in nearly all patients;
febrile neutropenia occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of
patients. Few patients (< or =9%) developed grade 3-4 non-haematological
toxicities. Relative dose intensity was 97-99% for all regimens. All treatment
regimens were active and well tolerated.
Copyright 2002 Cancer Research UK
DOI: 10.1038/sj.bjc.6600165
PMCID: PMC2375306
PMID: 11875727 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22072567
|
1. Cancer Res. 2012 Jan 1;72(1):282-93. doi: 10.1158/0008-5472.CAN-11-2866. Epub
2011 Nov 9.
Radiosensitization of human pancreatic cancer cells by MLN4924, an
investigational NEDD8-activating enzyme inhibitor.
Wei D(1), Li H, Yu J, Sebolt JT, Zhao L, Lawrence TS, Smith PG, Morgan MA, Sun
Y.
Author information:
(1)Division of Radiation and Cancer Biology, Department of Radiation Oncology,
University of Michigan, Ann Arbor, Michigan 48109, USA.
Radiotherapy is used in locally advanced pancreatic cancers in which it can
improve survival in combination with gemcitabine. However, prognosis is still
poor in this setting in which more effective therapies remain needed. MLN4924 is
an investigational small molecule currently in phase I clinical trials. MLN4924
inhibits NAE (NEDD8 Activating Enzyme), a pivotal regulator of the E3 ubiquitin
ligase SCF (SKP1, Cullins, and F-box protein), that has been implicated recently
in DNA damage and repair. In this study, we provide evidence that MLN4924 can be
used as an effective radiosensitizer in pancreatic cancer. Specifically, MLN4924
(20-100 nmol/L) effectively inhibited cullin neddylation and sensitized
pancreatic cancer cells to ionizing radiation in vitro with a sensitivity
enhancement ratio of approximately 1.5. Mechanistically, MLN4924 treatment
stimulated an accumulation of several SCF substrates, including CDT1, WEE1, and
NOXA, in parallel with an enhancement of radiation-induced DNA damage,
aneuploidy, G(2)/M phase cell-cycle arrest, and apoptosis. RNAi-mediated
knockdown of CDT1 and WEE1 partially abrogated MLN4924-induced aneuploidy,
G(2)/M arrest, and radiosensitization, indicating a causal effect. Furthermore,
MLN4924 was an effective radiosensitizer in a mouse xenograft model of human
pancreatic cancer. Our findings offer proof-of-concept for use of MLN4924 as a
novel class of radiosensitizer for the treatment of pancreatic cancer.
©2011 AACR.
DOI: 10.1158/0008-5472.CAN-11-2866
PMCID: PMC3251739
PMID: 22072567 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19360080
|
1. Nature. 2009 Apr 9;458(7239):732-6. doi: 10.1038/nature07884.
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.
Soucy TA(1), Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell
JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin
JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ,
Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S,
Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB,
Langston SP.
Author information:
(1)Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge,
Massachusetts 02139, USA. teresa.soucy@mpi.com
Comment in
Nature. 2009 Apr 9;458(7239):709-10. doi: 10.1038/458709a.
The clinical development of an inhibitor of cellular proteasome function
suggests that compounds targeting other components of the ubiquitin-proteasome
system might prove useful for the treatment of human malignancies.
NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation
pathway that controls the activity of the cullin-RING subtype of ubiquitin
ligases, thereby regulating the turnover of a subset of proteins upstream of the
proteasome. Substrates of cullin-RING ligases have important roles in cellular
processes associated with cancer cell growth and survival pathways. Here we
describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts
cullin-RING ligase-mediated protein turnover leading to apoptotic death in human
tumour cells by a new mechanism of action, the deregulation of S-phase DNA
synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at
compound exposures that were well tolerated. Our data suggest that NAE
inhibitors may hold promise for the treatment of cancer.
DOI: 10.1038/nature07884
PMID: 19360080 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24672057
|
1. Mol Cancer Ther. 2014 Jun;13(6):1625-35. doi: 10.1158/1535-7163.MCT-13-0634.
Epub 2014 Mar 26.
Nedd8-activating enzyme inhibitor MLN4924 provides synergy with mitomycin C
through interactions with ATR, BRCA1/BRCA2, and chromatin dynamics pathways.
Garcia K(1), Blank JL(1), Bouck DC(1), Liu XJ(1), Sappal DS(1), Hather G(1),
Cosmopoulos K(1), Thomas MP(1), Kuranda M(1), Pickard MD(1), Liu R(1), Bandi
S(1), Smith PG(1), Lightcap ES(2).
Author information:
(1)Authors' Affiliations: Departments of Discovery, Clinical Biostatistics, and
Information Technology, Takeda Pharmaceuticals International Co., Cambridge,
Massachusetts.
(2)Authors' Affiliations: Departments of Discovery, Clinical Biostatistics, and
Information Technology, Takeda Pharmaceuticals International Co., Cambridge,
Massachusetts eric.lightcap@takeda.com.
MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating
enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via
rereplication in most cell lines. This distinct mechanism of DNA damage may
affect its ability to combine with standard-of-care agents and may affect the
clinical development of MLN4924. As such, we studied its interaction with other
DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38,
and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The
combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse
xenograft model. Importantly, depletion of genes within the ataxia
telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin
modification, and transcription-coupled repair reduced the synergy between
mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA
strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest
that mitomycin C causes stalled replication forks, which when combined with
rereplication induced by MLN4924 results in frequent replication fork
collisions, leading to cell death. This study provides a straightforward
approach to understand the mechanism of synergy, which may provide useful
information for the clinical development of these combinations.
©2014 American Association for Cancer Research.
DOI: 10.1158/1535-7163.MCT-13-0634
PMID: 24672057 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21417215
|
1. J Org Chem. 2011 May 6;76(9):3557-61. doi: 10.1021/jo2001897. Epub 2011 Mar
21.
Stereoselective synthesis of MLN4924, an inhibitor of NEDD8-activating enzyme.
Lee HW(1), Nam SK, Choi WJ, Kim HO, Jeong LS.
Author information:
(1)Department of Bioinspired Science and Laboratory of Medicinal Chemistry,
College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
Erratum in
J Org Chem. 2011 May 6;76(9):3614.
MLN4924 (1), which is in clinical trials as an anticancer agent, was
stereoselectively synthesized from d-ribose via a route involving
stereoselective reduction, regioselective cleavage of an isopropylidene moiety,
and selective displacement of a cyclic sulfate moiety as key steps.
© 2011 American Chemical Society
DOI: 10.1021/jo2001897
PMID: 21417215 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/21463634
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1. J Mol Biol. 2011 Jun 3;409(2):136-45. doi: 10.1016/j.jmb.2011.03.023. Epub
2011 Apr 2.
Neddylation-induced conformational control regulates cullin RING ligase activity
in vivo.
Boh BK(1), Smith PG, Hagen T.
Author information:
(1)NUS Graduate School for Integrative Sciences and Engineering (NGS), National
University of Singapore, Singapore 117456, Singapore.
Cullin RING ligases (CRLs) constitute the largest family of ubiquitin ligases
with diverse cellular functions. Conjugation of the ubiquitin-like molecule
Nedd8 to a conserved lysine residue on the cullin scaffold is essential for the
activity of CRLs. Using structural studies and in vitro assays, it has been
demonstrated that neddylation stimulates CRL activity through conformational
rearrangement of the cullin C-terminal winged-helix B domain and Rbx1 RING
subdomain from a closed architecture to an open and dynamic structure, thus
promoting ubiquitin transfer onto the substrate. Here, we tested whether the
proposed mechanism operates in vivo in intact cells and applies to other CRL
family members. To inhibit cellular neddylation, we used a cell line with
tetracycline-inducible expression of a dominant-negative form of the Nedd8 E2
enzyme or treatment of cells with the Nedd8 E1 inhibitor MLN4924. Using these
cellular systems, we show that different mutants of Cul2 and Cul3 and of Rbx1
that confer increased Rbx1 flexibility mimic neddylation and rescue CRL activity
in intact cells. Our findings indicate that in vivo neddylation functions by
inducing conformational changes in the C-terminal domain of Cul2 and Cul3 that
free the RING domain of Rbx1 and bridge the gap for ubiquitin transfer onto the
substrate.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jmb.2011.03.023
PMID: 21463634 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/22246439
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1. Mol Cancer Ther. 2012 Apr;11(4):942-51. doi: 10.1158/1535-7163.MCT-11-0563.
Epub 2012 Jan 12.
Molecular and cellular effects of NEDD8-activating enzyme inhibition in myeloma.
McMillin DW(1), Jacobs HM, Delmore JE, Buon L, Hunter ZR, Monrose V, Yu J, Smith
PG, Richardson PG, Anderson KC, Treon SP, Kung AL, Mitsiades CS.
Author information:
(1)Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center,
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
The NEDD8-activating enzyme is upstream of the 20S proteasome in the
ubiquitin/proteasome pathway and catalyzes the first step in the neddylation
pathway. NEDD8 modification of cullins is required for ubiquitination of
cullin-ring ligases that regulate degradation of a distinct subset of proteins.
The more targeted impact of NEDD8-activating enzyme on protein degradation
prompted us to study MLN4924, an investigational NEDD8-activating enzyme
inhibitor, in preclinical multiple myeloma models. In vitro treatment with
MLN4924 led to dose-dependent decrease of viability (EC(50) = 25-150 nmol/L) in
a panel of human multiple myeloma cell lines. MLN4924 was similarly active
against a bortezomib-resistant ANBL-6 subline and its bortezomib-sensitive
parental cells. MLN4924 had submicromolar activity (EC(50) values <500 nmol/L)
against primary CD138(+) multiple myeloma patient cells and exhibited at least
additive effect when combined with dexamethasone, doxorubicin, and bortezomib
against MM.1S cells. The bortezomib-induced compensatory upregulation of
transcripts for ubiquitin/proteasome was not observed with MLN4924 treatment,
suggesting distinct functional roles of NEDD8-activating enzyme versus 20S
proteasome. MLN4924 was well tolerated at doses up to 60 mg/kg 2× daily and
significantly reduced tumor burden in both a subcutaneous and an orthotopic
mouse model of multiple myeloma. These studies provide the framework for the
clinical investigation of MLN4924 in multiple myeloma.
DOI: 10.1158/1535-7163.MCT-11-0563
PMCID: PMC3755358
PMID: 22246439 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of Potential Conflicts of Interest
DWM is a founder and equity holder in Axios Biosciences. HMJ, JD, LB, ZH, VM,
ALK have nothing to disclose. JY, PG are employees of Millennium Pharmaceuticals
(The Takeda Oncology company); P.G.R. has received honoraria from Millennium,
Celgene and Novartis; as well as research support from Johnson & Johnson and
Bristol-Myers Squibb. K.C.A. has received research grants and honoraria from
Millennium and Celgene, has been a consultant for Millennium, Celgene, Novartis,
Bristol-Myers Squibb, Merck and Onyx and is a founder of Acetylon
Pharmaceutials. SPT has received honoraria from and is consultant/member of
advisory board for Millennium. CSM has received in the past Consultant honoraria
from Millennium Pharmaceuticals, Novartis Pharmaceuticals, Bristol-Myers Squibb,
Merck & Co., Kosan Pharmaceuticals, Pharmion, Johnson & Johnson and Amnis
Therapeutics, licensing royalties from PharmaMar, and research funding from
Amgen Pharmaceuticals, AVEO Pharma, EMD Serono, Sunesis, Gloucester
Pharmaceuticals and Johnson & Johnson.
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http://www.ncbi.nlm.nih.gov/pubmed/19920172
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1. Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20776-81. doi:
10.1073/pnas.0906998106. Epub 2009 Nov 17.
The anti-apoptotic protein HAX-1 is a regulator of cardiac function.
Zhao W(1), Waggoner JR, Zhang ZG, Lam CK, Han P, Qian J, Schroder PM, Mitton B,
Kontrogianni-Konstantopoulos A, Robia SL, Kranias EG.
Author information:
(1)Department of Pharmacology and Cell Biophysics, University of Cincinnati
College of Medicine, Cincinnati, OH 45267-0575, USA.
The HS-1 associated protein X-1 (HAX-1) is a ubiquitously expressed protein that
protects cardiomyocytes from programmed cell death. Here we identify HAX-1 as a
regulator of contractility and calcium cycling in the heart. HAX-1
overexpression reduced sarcoplasmic reticulum Ca-ATPase (SERCA2) pump activity
in isolated cardiomyocytes and in vivo, leading to depressed myocyte calcium
kinetics and mechanics. Conversely, downregulation of HAX-1 enhanced calcium
cycling and contractility. The inhibitory effects of HAX-1 were abolished upon
phosphorylation of phospholamban, which plays a fundamental role in controlling
basal contractility and constitutes a key downstream effector of the
beta-adrenergic signaling cascade. Mechanistically, HAX-1 promoted formation of
phospholamban monomers, the active/inhibitory units of the calcium pump. Indeed,
ablation of PLN rescued HAX-1 inhibition of contractility in vivo. Thus, HAX-1
represents a regulatory mechanism in cardiac calcium cycling and its responses
to sympathetic stimulation, implicating its importance in calcium homeostasis
and cell survival.
DOI: 10.1073/pnas.0906998106
PMCID: PMC2791603
PMID: 19920172 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/18971376
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1. Mol Biol Cell. 2009 Jan;20(1):306-18. doi: 10.1091/mbc.e08-06-0587. Epub 2008
Oct 29.
The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein
levels to promote cell survival.
Vafiadaki E(1), Arvanitis DA, Pagakis SN, Papalouka V, Sanoudou D,
Kontrogianni-Konstantopoulos A, Kranias EG.
Author information:
(1)Molecular Biology Division, Biomedical Research Foundation, Academy of
Athens, Greece.
Cardiac contractility is regulated through the activity of various key
Ca(2+)-handling proteins. The sarco(endo)plasmic reticulum (SR) Ca(2+) transport
ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of
Ca(2+) by SR membranes during relaxation. Recently, the antiapoptotic
HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN,
and this interaction was postulated to regulate cell apoptosis. In the current
study, we determined that HAX-1 can also bind to SERCA2. Deletion mapping
analysis demonstrated that amino acid residues 575-594 of SERCA2's nucleotide
binding domain are required for its interaction with the C-terminal domain of
HAX-1, containing amino acids 203-245. In transiently cotransfected human
embryonic kidney 293 cells, recombinant SERCA2 was specifically targeted to the
ER, whereas HAX-1 selectively concentrated at mitochondria. On triple
transfections with PLN, however, HAX-1 massively translocated to the ER
membranes, where it codistributed with PLN and SERCA2. Overexpression of SERCA2
abrogated the protective effects of HAX-1 on cell survival, after
hypoxia/reoxygenation or thapsigargin treatment. Importantly, HAX-1
overexpression was associated with down-regulation of SERCA2 expression levels,
resulting in significant reduction of apparent ER Ca(2+) levels. These findings
suggest that HAX-1 may promote cell survival through modulation of SERCA2
protein levels and thus ER Ca(2+) stores.
DOI: 10.1091/mbc.e08-06-0587
PMCID: PMC2613088
PMID: 18971376 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/20129059
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1. Mol Cell. 2010 Jan 15;37(1):102-11. doi: 10.1016/j.molcel.2009.12.024.
Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the
NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ.
Brownell JE(1), Sintchak MD, Gavin JM, Liao H, Bruzzese FJ, Bump NJ, Soucy TA,
Milhollen MA, Yang X, Burkhardt AL, Ma J, Loke HK, Lingaraj T, Wu D, Hamman KB,
Spelman JJ, Cullis CA, Langston SP, Vyskocil S, Sells TB, Mallender WD, Visiers
I, Li P, Claiborne CF, Rolfe M, Bolen JB, Dick LR.
Author information:
(1)Discovery, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge,
MA 02139, USA.
The NEDD8-activating enzyme (NAE) initiates a protein homeostatic pathway
essential for cancer cell growth and survival. MLN4924 is a selective inhibitor
of NAE currently in clinical trials for the treatment of cancer. Here, we show
that MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent
NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles
NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be
further utilized in subsequent intraenzyme reactions. The stability of the
NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby
accounting for the potent inhibition of the NEDD8 pathway by MLN4924.
Importantly, we have determined that compounds resembling MLN4924 demonstrate
the ability to form analogous adducts with other ubiquitin-like proteins (UBLs)
catalyzed by their cognate-activating enzymes. These findings reveal insights
into the mechanism of E1s and suggest a general strategy for selective
inhibition of UBL conjugation pathways.
Copyright 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2009.12.024
PMID: 20129059 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/24213570
|
1. Oncogene. 2014 Oct 30;33(44):5211-20. doi: 10.1038/onc.2013.473. Epub 2013 Nov
11.
Endothelial deletion of Sag/Rbx2/Roc2 E3 ubiquitin ligase causes embryonic
lethality and blocks tumor angiogenesis.
Tan M(1), Li H(1), Sun Y(1).
Author information:
(1)Division of Radiation and Cancer Biology, Department of Radiation Oncology,
University of Michigan, Ann Arbor, MI, USA.
SAG (Sensitive to Apoptosis Gene), also known as RBX2 or ROC2, is a RING protein
required for the activity of Cullin-RING ligase (CRL). Our recent study showed
that Sag total knockout caused embryonic lethality at E11.5-12.5 days with
associated defects in vasculogenesis. Whether Sag is required for de novo
vasculogenesis in embryos and angiogenesis in tumors is totally unknown. Here,
we report that Sag endothelial deletion also causes embryonic lethality at E15.5
with poor vasculogenesis. Sag deletion in primary endothelial cells (ECs) or
knockdown in MS-1 ECs inhibits migration, proliferation and tube formation, with
p27 accumulation being responsible for the suppression of migration and
proliferation. Furthermore, Sag deletion significantly inhibits angiogenesis in
an in vivo Matrigel plug assay, and tumor angiogenesis and tumorigenesis in a
B16F10 melanoma model. Finally, MLN4924, an investigational small molecule
inhibitor of NEDD8-activating enzyme (NAE) that inhibits CRL, suppresses in
vitro migration, proliferation and tube formation, as well as in vivo
angiogenesis and tumorigenesis. Taken together, our study, using both genetic
and pharmaceutical approaches, demonstrates that Sag is essential for embryonic
vasculogenesis and tumor angiogenesis, and provides the proof-of-concept
evidence that targeting Sag E3 ubiquitin ligase may have clinical value for
anti-angiogenesis therapy of human cancer.
DOI: 10.1038/onc.2013.473
PMCID: PMC4016996
PMID: 24213570 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest The authors declare no
conflict of interest.
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http://www.ncbi.nlm.nih.gov/pubmed/18415121
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1. Pflugers Arch. 2009 Jan;457(3):687-700. doi: 10.1007/s00424-008-0506-5. Epub
2008 Apr 16.
The role of SERCA2a/PLN complex, Ca(2+) homeostasis, and anti-apoptotic proteins
in determining cell fate.
Vafiadaki E(1), Papalouka V, Arvanitis DA, Kranias EG, Sanoudou D.
Author information:
(1)Molecular Biology Division, Biomedical Research Foundation, Academy of
Athens, Soranou Efesiou 4, Athens 115 27, Greece.
Intracellular calcium is a major coordinator of numerous aspects of cellular
physiology, including muscle contractility and cell survival. In cardiac muscle,
aberrant Ca(2+) cycling has been implicated in a range of pathological
conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic
reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator
phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and,
therefore, cardiac function. Herein, we discuss the mechanisms through which
SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis
is placed on our newly identified PLN-binding partner HS-1-associated protein
X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous
similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2
family can influence ER Ca(2+) content, a critical determinant of cellular
sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore
unveils an important new link between Ca(2+) homeostasis and cell survival, with
significant therapeutic potential.
DOI: 10.1007/s00424-008-0506-5
PMID: 18415121 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23624319
|
1. Anal Biochem. 2013 Aug 15;439(2):109-15. doi: 10.1016/j.ab.2013.04.016. Epub
2013 Apr 25.
Quantifiable analysis of cellular pathway inhibition of a Nedd8-activating
enzyme inhibitor, MLN4924, using AlphaScreen.
Yan ZH(1), Burkhardt A, Loke HK, Chen J, Xu Q, Brauer P, Ma J, Lin Y, Garcia K,
Dick LR, Bembenek ME.
Author information:
(1)Millennium Pharmaceuticals: The Takeda Oncology Company, Cambridge, MA 02139,
USA.
Cellular effects of a Nedd8-activating enzyme (NAE) inhibitor, MLN4924, using
the AlphaScreen format were explored. MLN4924 acts as a substrate-assisted
inhibitor of NAE by forming a tight binding Nedd8-MLN4924 adduct. The inhibited
enzyme can no longer transfer Nedd8 downstream to modify and activate the E3
cullin-RING ligases. This results in the stabilization of proteins regulated by
the proteasome, leading to cell death. These studies monitored the endogenous
cellular changes to NAE∼Nedd8 thioester, the formation of the Nedd8-MLN4924
adduct, and the reduction in the Cul1-Nedd8. Lysates derived from
MLN4924-treated HCT116 cells showed that whereas the β-subunit of NAE remained
constant, reductions of both NAE∼Nedd8 thioester and Cul1-Nedd8 levels occurred
with a concomitant rise of the adduct. Moreover, the formation of the
Nedd8-MLN4924 adduct was approximately stoichiometric with the concentration of
NAEβ. Higher density 384-well cell-based assays illustrated the kinetics of
enzyme inactivation across a wider range of MLN4924 concentrations, showing a
rapid loss of NAE∼Nedd8 thioester and Cul1-Nedd8. The reduction of NAE∼Nedd8
thioester precedes the loss of Cul1-Nedd8 at twice the rate. Finally, these
results clearly demonstrate the utility of the homogeneous assay for
quantitative assessment of these endogenous cellular components in a 384-well
plate in response to inhibition of NAE by MLN4924.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ab.2013.04.016
PMID: 23624319 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/17726868
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1. Wiad Lek. 2007;60(3-4):155-7.
[Sudden death in competitive athletes].
[Article in Polish]
Juszczyk Z(1).
Author information:
(1)Szpitala im. Swietej Elzbiety w Białej. szpitalbiala@pro.onet.pl
In athletes under the age of 35 years the incidence of sudden death is low, most
causes to be due to ventricular arrhythmias, usually provoked by exertion, and
nearly always occur in the presence of structural heart disease or abnormalities
in the conduction system. The most common structural disease is hypertrophic
cardiomyopathy followed by coronary artery anomalies, idiopathic dilated
cardiomyopathy, arrhythmogenic right ventricular dysplasia, aortic stenosis,
myocarditis, the Wolff-Parkinson-White syndrome, and long QT syndrome. The
evaluation of athletes with symptoms of cardiac arrhythmias, syncope, family
history of sudden death require a complete cardiac workup. If they have
documented hypertrophic cardiomyopathy, arrhythmogenic right ventricular
dysplasia, idiopathic dilated cardiomyopathy, long QT syndrome, family history
presentation with sudden death, and septal thickness greater than 20 mm
competitive athletics are generally prohibited. In athletes with asymptomatic
bradyarrhythmia, supraventricular tachycardias and atrial premature contractions
without structural heart disease all competitive sports are allowed if heart
rate in bradyarrhythmia appropriately increases with exercise. Athletes with
premature ventricular contraction, nonsustained ventricular tachycardia and non
structural heart disease are without athletic restriction as long as the
arrhythmia does not worsen on exertion and cause dyspnea, presyncope or syncope.
PMID: 17726868 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16672832
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1. Med Sci Sports Exerc. 2006 May;38(5):816-25. doi:
10.1249/01.mss.0000218130.41133.cc.
The congenital long QT syndrome and implications for young athletes.
Kapetanopoulos A(1), Kluger J, Maron BJ, Thompson PD.
Author information:
(1)Hartford Hospital, University of Connecticut School of Medicine, Farmington,
06102, USA.
The congenital long QT syndrome (LQTS) is caused by cardiac ion channel
mutations, which predispose young individuals to sudden cardiac death often
related to exercise. The issue of LQTS and sports participation has received
significant publicity due to reports of sudden death in young competitive
athletes. This article reviews the pathophysiology, clinical characteristics,
and management of LQTS in the physically active and athletic population.
DOI: 10.1249/01.mss.0000218130.41133.cc
PMID: 16672832 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/24634471
|
1. Clin Cancer Res. 2014 Mar 15;20(6):1576-89. doi:
10.1158/1078-0432.CCR-13-0987.
The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven
NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells.
Godbersen JC(1), Humphries LA, Danilova OV, Kebbekus PE, Brown JR, Eastman A,
Danilov AV.
Author information:
(1)Authors' Affiliations: Departments of Medicine and Pathology,
Dartmouth-Hitchcock Medical Center, Lebanon; Department of Pharmacology and
Toxicology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; and
Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Erratum in
Clin Cancer Res. 2016 Aug 15;22(16):4274. doi:
10.1158/1078-0432.CCR-16-1475.
BACKGROUND: Stromal-mediated signaling enhances NF-κB pathway activity in
chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and
chemoresistance. Ubiquitination of IκBα may partially account for constitutive
activation of NF-κB. MLN4924 is an investigational agent that inhibits the
Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and
preventing degradation of their substrates.
EXPERIMENTAL DESIGN: We conducted a preclinical assessment of MLN4924 in CLL.
Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic
the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on
CLL cell apoptosis, NF-κB pathway activity, Bcl-2 family members, and cell cycle
was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry.
RESULTS: CD40L-expressing stroma protected CLL cells from spontaneous apoptosis
and induced resistance to multiple drugs, accompanied by NF-κB activation and
Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and
circumvented stroma-mediated resistance. This was accompanied by accumulation of
phospho-IκBα, decreased nuclear translocation of p65 and p52 leading to
inhibition of both the canonical and noncanonical NF-κB pathways, and reduced
transcription of their target genes, notably chemokines. MLN4924 promoted
induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2
family members toward the proapoptotic BH3-only proteins. siRNA-mediated
knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the
antitumor activity of the inhibitors of B-cell receptor (BCR)-associated
kinases.
CONCLUSIONS: MLN4924 disrupts NF-κB activation and induces Bim expression in CLL
cells, thereby preventing stroma-mediated resistance. Our data provide rationale
for further evaluation of MLN4924 in CLL.
©2014 AACR.
DOI: 10.1158/1078-0432.CCR-13-0987
PMCID: PMC3960291
PMID: 24634471 [Indexed for MEDLINE]
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http://www.ncbi.nlm.nih.gov/pubmed/24198575
|
1. Open Access J Sports Med. 2011 Jul 21;2:85-97. doi: 10.2147/OAJSM.S10675.
Sudden cardiac death in young athletes.
Ostman-Smith I(1).
Author information:
(1)Division of Paediatric Cardiology, Institute of Clinical Sciences,
Sahlgrenska Academy, Gothenburg University, Sweden.
Athletic activity is associated with an increased risk of sudden death for
individuals with some congenital or acquired heart disorders. This review
considers in particular the causes of death affecting athletes below 35 years of
age. In this age group the largest proportion of deaths are caused by diseases
with autosomal dominant inheritance such as hypertrophic cardiomyopathy,
arrhythmogenic right ventricular cardiomyopathy, long QT-syndrome, and Marfan's
syndrome. A policy of early cascade-screening of all first-degree relatives of
patients with these disorders will therefore detect a substantial number of
individuals at risk. A strictly regulated system with preparticipation screening
of all athletes following a protocol pioneered in Italy, including school-age
children, can also detect cases caused by sporadic new mutations and has been
shown to reduce excess mortality among athletes substantially. Recommendations
for screening procedure are reviewed. It is concluded that ECG screening ought
to be part of preparticipation screening, but using criteria that do not cause
too many false positives among athletes. One such suggested protocol will show
positive in approximately 5% of screened individuals, among whom many will be
screened for these diseases. On this point further research is needed to define
what kind of false-positive and false-negative rate these new criteria result
in. A less formal system based on cascade-screening of relatives, education of
coaches about suspicious symptoms, and preparticipation questionnaires used by
athletic clubs, has been associated over time with a sizeable reduction in
sudden cardiac deaths among Swedish athletes, and thus appears to be worth
implementing even for junior athletes not recommended for formal
preparticipation screening. It is strongly argued that in families with
autosomal dominant disorders the first screening of children should be carried
out no later than 6 to 7 years of age.
DOI: 10.2147/OAJSM.S10675
PMCID: PMC3781887
PMID: 24198575
|
http://www.ncbi.nlm.nih.gov/pubmed/19535269
|
1. Cardiovasc Pathol. 2010 Jul-Aug;19(4):207-17. doi:
10.1016/j.carpath.2009.04.001. Epub 2009 Jun 16.
Prevention of sudden cardiac death in the young and in athletes: dream or
reality?
Thiene G(1), Carturan E, Corrado D, Basso C.
Author information:
(1)Pathology Department of Medical Diagnostic Sciences and Special Therapies,
University of Padua Medical School, Padua, Italy. gaetano.thiene@unipd.it
Cardiovascular diseases account for 40% of all deaths in the Western countries,
and nearly two thirds of them occur suddenly. Young people (<35 years) are not
spared from sudden death (SD) with a rate of 1/100,000 per year. Effort is a
trigger with a threefold risk in athletes vs. nonathletes, and sports
disqualification is by itself life-saving in people with underlying concealed
cardiovascular diseases. Several culprits of cardiac SD may be identified at
postmortem and atherosclerotic coronary artery disease is the leading cause (25%
of SD cases in the young), mostly consisting of a single obstructive plaque with
fibrocellular intimal proliferation. However, the spectrum of cardiovascular
substrates is wide and include also congenital diseases of the coronary arteries
(mainly anomalous origin), myocardium (arrhythmogenic and hypertrophic
cardiomyopathies, myocarditis), valves (aortic stenosis and mitral valve
prolapse), and conduction system (ventricular preexcitation, accelerated
atrioventricular conduction and block). In up to 20% of cases, the heart is
grossly and histologically normal at autopsy (unexplained SD or "mors sine
materia"), and inherited ion channel diseases have been implicated (long and
short QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular
tachycardia). Targets to treat and prevent SD in the young consist of the
following: (a) avoid triggers like effort or emotion, (b) inhibit the onset of
arrhythmias with drugs or ablation, (c) switch off arrhythmias with
defibrillator, and (d) hinder the recurrence of the disease with genetic
counseling and/or therapy. In vivo detection of cardiomyopathies is nowadays
feasible by electrocardiogram and/or echocardiography, which resulted in a sharp
decline of SD in the athletes in Italy, thanks to obligatory preparticipation
screening for sport activity. Genetic screening could play a pivotal role in
early detection of asymptomatic mutation carriers of cardiovascular diseases at
risk of SD.
DOI: 10.1016/j.carpath.2009.04.001
PMID: 19535269 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15074012
|
1. Pol Merkur Lekarski. 2004 Jan;16(91):5-7.
[Cardiovascular diseases as a cause of sudden death in athletes].
[Article in Polish]
Halawa B.
Cardiac arrhythmias are the reason of the most sudden deaths in athletes. The
annual risk of sudden death at athletes is between 5 to 10 per one million.
Benign arrhythmia including bradyarrhythmias, atrial and ventricular premature
contractions are common in the athletes. Supraventricular arrhythmias such as
atrial fibrillation, nodal reciprocal entrant tachycardia and
Wolff-Parkinson-White syndrome are less common. Perhaps the rarest and the most
dangerous arrhythmias are ventricular arrhythmias, among them arrhythmias
secondary to hypertrophic cardiomyopathy, arrhythmogenic right ventricular
dysplasia, long QT syndrome, and anomalous origin of coronary arteries.
Asymptomatic bradyarrhythmias (if the heart rate in bradyarrhythmia appropriate
increases with exercise), supraventricularis tachycardias, and atrial premature
contractions without structural heart disease are not the contraindication to
sports Athletes with premature ventricular contraction, nonsustained ventricular
tachycardia and non structural heart disease are without athletic restrictions
as long as the arrhythmias do not worsen and they not cause dyspnea or
presyncope during exertion. Frequent or multiform premature ventricular
contraction or sustained ventricular tachycardia indicate a higher risk, and all
participation in athletic should be restricted.
PMID: 15074012 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23986575
|
1. J Virol. 2013 Nov;87(21):11741-50. doi: 10.1128/JVI.02002-13. Epub 2013 Aug
28.
Inhibition of CUL4A Neddylation causes a reversible block to SAMHD1-mediated
restriction of HIV-1.
Hofmann H(1), Norton TD, Schultz ML, Polsky SB, Sunseri N, Landau NR.
Author information:
(1)Microbiology Department, New York University School of Medicine, New York,
New York, USA.
The deoxynucleoside triphosphohydrolase SAMHD1 restricts retroviral replication
in myeloid cells. Human immunodeficiency virus type 2 (HIV-2) and a simian
immunodeficiency virus from rhesus macaques (SIVmac) encode Vpx, a
virion-packaged accessory protein that counteracts SAMHD1 by inducing its
degradation. SAMHD1 is thought to work by depleting the pool of intracellular
deoxynucleoside triphosphates but has also been reported to have exonuclease
activity that could allow it to degrade the viral genomic RNA or viral
reverse-transcribed DNA. To induce the degradation of SAMHD1, Vpx co-opts the
cullin4a-based E3 ubiquitin ligase, CRL4. E3 ubiquitin ligases are regulated by
the covalent attachment of the ubiquitin-like protein Nedd8 to the cullin
subunit. Neddylation can be prevented by MLN4924, a drug that inhibits the
nedd8-activating enzyme. We report that MLN4924 inhibits the neddylation of
CRL4, blocking Vpx-induced degradation of SAMHD1 and maintaining the
restriction. Removal of the drug several hours postinfection released the block.
Similarly, Vpx-containing virus-like particles and deoxynucleosides added to the
cells more than 24 h postinfection released the SAMHD1-mediated block. Taken
together, these findings support deoxynucleoside triphosphate pool depletion as
the primary mechanism of SAMHD1 restriction and argue against a nucleolytic
mechanism, which would not be reversible.
DOI: 10.1128/JVI.02002-13
PMCID: PMC3807335
PMID: 23986575 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15184297
|
1. Circulation. 2004 Jun 8;109(22):2807-16. doi:
10.1161/01.CIR.0000128363.85581.E1.
Recommendations for physical activity and recreational sports participation for
young patients with genetic cardiovascular diseases.
Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A, Corrado D, Crosson JE, Deal
BJ, Driscoll DJ, Estes NA 3rd, Araújo CG, Liang DH, Mitten MJ, Myerburg RJ,
Pelliccia A, Thompson PD, Towbin JA, Van Camp SP; Working Groups of the American
Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention;
Councils on Clinical Cardiology and Cardiovascular Disease in the Young.
A group of relatively uncommon but important genetic cardiovascular diseases
(GCVDs) are associated with increased risk for sudden cardiac death during
exercise, including hypertrophic cardiomyopathy, long-QT syndrome, Marfan
syndrome, and arrhythmogenic right ventricular cardiomyopathy. These conditions,
characterized by diverse phenotypic expression and genetic substrates, account
for a substantial proportion of unexpected and usually arrhythmia-based fatal
events during adolescence and young adulthood. Guidelines are in place governing
eligibility and disqualification criteria for competitive athletes with these
GCVDs (eg, Bethesda Conference No. 26 and its update as Bethesda Conference No.
36 in 2005). However, similar systematic recommendations for the much larger
population of patients with GCVD who are not trained athletes, but nevertheless
wish to participate in any of a variety of recreational physical activities and
sports, have not been available. The practicing clinician is frequently
confronted with the dilemma of designing noncompetitive exercise programs for
athletes with GCVD after disqualification from competition, as well as for those
patients with such conditions who do not aspire to organized sports. Indeed,
many asymptomatic (or mildly symptomatic) patients with GCVD desire a physically
active lifestyle with participation in recreational and leisure-time activities
to take advantage of the many documented benefits of exercise. However, to date,
no reference document has been available for ascertaining which types of
physical activity could be regarded as either prudent or inadvisable in these
subgroups of patients. Therefore, given this clear and present need, this
American Heart Association consensus document was constituted, based largely on
the experience and insights of the expert panel, to offer recommendations
governing recreational exercise for patients with known GCVDs.
DOI: 10.1161/01.CIR.0000128363.85581.E1
PMID: 15184297 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20675977
|
1. Postgrad Med. 2010 Jul;122(4):144-57. doi: 10.3810/pgm.2010.07.2181.
Causes of sudden cardiac arrest in young athletes.
Westrol MS(1), Kapitanyan R, Marques-Baptista A, Merlin MA.
Author information:
(1)University of Medicine and Dentistry of New Jersey-Robert Wood Johnson
Medical School, Piscataway, NJ, USA.
Knowledge of sudden cardiac death in young athletes is imperative for all
physicians and allied health professionals. The complete differential diagnosis
of a young patient with sudden cardiac arrest will result in proper work-up and
treatment. In this article, we review several etiologies of sudden cardiac
death, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular
cardiomyopathy, Wolff-Parkinson-White syndrome, long QT syndrome, Brugada
syndrome, and commotio cordis. Clinical findings, work-up, treatment, long-term
management, and athlete preparticipation screening guidelines are discussed.
DOI: 10.3810/pgm.2010.07.2181
PMID: 20675977 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12831662
|
1. Curr Sports Med Rep. 2003 Apr;2(2):72-8. doi:
10.1249/00149619-200304000-00005.
The long QT syndrome: considerations in the athletic population.
Schulze-Bahr E(1), Mönnig G, Eckardt L, Wedekind H, Wichter T, Breithardt G.
Author information:
(1)Department Molekular-Kardiologie, Institut für Arterioskleroseforschung an
der Westfälischen, Wilhelms-Universität Münster, Domagkstrasse 3, D-48149
Münster, Germany. heart@uni-muenster.de
In athletes, ventricular arrhythmias and sudden cardiac death are rare and
unpredictable events. Often, an underlying heart disease is present, but
pre-existing clinical signs or symptoms may not be recognized. Primary
electrical disorders (such as the long QT syndrome) are rarely present in
athletes but, so far, are a considerable reason for disqualification from sport
activity. These disorders are mostly inherited, and patients should be referred
to a cardiologist with special experience. Through the efforts of molecular
genetics and cellular electrophysiology, an increasing understanding of the
underlying mechanisms of arrhythmogenesis is being gathered. During the past
decade, evidence has grown that establishing accurate genetic diagnoses and
dissection of molecular disease mechanisms can have an impact on prognosis, and
help direct therapy in a range of cardiovascular diseases. Further achievements
in the areas of clinical and molecular research, improvement of medical
education, and expansion of genotyping facilities will facilitate the correct
and immediate identification of affected patients.
DOI: 10.1249/00149619-200304000-00005
PMID: 12831662 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11475927
|
1. Rev Med Liege. 2001 May;56(5):318-25.
[Sudden death in athletes].
[Article in French]
Kulbertus H(1).
Author information:
(1)Service de Cardiologie, Université de Liège.
Sudden death is rare in the young athlete. The causes may vary. In the US,
hypertrophic cardiomyopathy plays the predominant role whereas in Europe right
ventricular arrhythmogenic dysplasia and atherosclerosis of the coronary
arteries are more frequent. Other causes such as congenital anomalies of the
coronary vessels, myocarditis, Marfan's disease, the long QT, the Brugada and
the Wollf-Parkinson-White syndromes exist, but are rare. Attentive
preparticipation screening (clinical history and medical examination) is
mandatory in all future young athletes.
PMID: 11475927 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20975745
|
1. Nat Rev Clin Oncol. 2010 Dec;7(12):725-32. doi: 10.1038/nrclinonc.2010.170.
Epub 2010 Oct 26.
Breast cancer assessment tools and optimizing adjuvant therapy.
Oakman C(1), Santarpia L, Di Leo A.
Author information:
(1)Sandro Pitigliani Medical Oncology Unit, Department of Oncology, Hospital of
Prato, Istituto Toscano Tumori, Piazza Ospedale 2, 59100 Prato, Italy.
Recommendation of systemic adjuvant therapy and choice of optimal agents for
early-stage breast cancer remains a challenge. Adjuvant therapy is indicated on
the assumption of residual micrometastatic disease. Adjuvant assessment tools
for prognosis and prediction of treatment benefit, including Adjuvant! Online,
the St Gallen Consensus, Oncotype DX(®) and MammaPrint(®), aid clinical decision
making. However, all of these tools have limitations that must be considered in
their judicious application. Clinicopathological based tools are critically
dependent on accurate, standardized measurement of parameters. Multigene tools
are appealing for their objectivity and reproducibility, particularly regarding
analysis of proliferation, but these approaches still overlook the biological
heterogeneity within tumors evidenced by distinct cell subpopulations with
different genomic patterns and function. The greatest treatment challenge
remains for patients assessed as intermediate risk of relapse, a problem not
overcome by multigene tools. Remarkable diversity in breast cancer dictates that
adjuvant management must be biologically driven. Future identification of
predictive biomarkers for specific chemotherapy sensitivity may allow targeted
use of available agents, including anthracyclines, taxanes and DNA damaging
agents. The presence of drug targets and targetable signaling pathways, rather
than molecularly defined subgroups, may ultimately drive treatment decisions.
DOI: 10.1038/nrclinonc.2010.170
PMID: 20975745 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18159035
|
1. Am J Health Syst Pharm. 2008 Jan 1;65(1):23-8. doi: 10.2146/ajhp060352.
Gene-expression assays: new tools to individualize treatment of early-stage
breast cancer.
Dobbe E(1), Gurney K, Kiekow S, Lafferty JS, Kolesar JM.
Author information:
(1)School of Pharmacy, University of Wisconsin, Madison, WI 53705-2222, USA.
PURPOSE: The clinical and economic data for the two currently available
gene-expression assays are reviewed.
SUMMARY: Two gene-expression assays, used to determine the risk of breast cancer
recurrence in patients with stage I or II node-negative breast cancer, are
currently available. Oncotype DX is an assay performed on RNA extracted from
paraffin-embedded tumor tissue. It analyzes the expression of 21 genes: 16
cancer-related genes and 5 reference genes. The results are used to calculate a
recurrence score to identify the likelihood of cancer recurrence in patients
treated with tamoxifen. The results of two studies evaluating the ability of
Oncotype DX to predict the risk of breast cancer recurrence suggest that
patients with ER-positive, node-negative breast cancer and a low recurrence
score may need only adjuvant treatment with tamoxifen, while intermediate- and
high-risk patients may require additional treatment with adjuvant chemotherapy.
MammaPrint, an oligonucleotide microassay performed on fresh-frozen tumor
samples, analyzes the expression of 70 genes. Studies have found that MammaPrint
allows young patients (<61 years) with early-stage breast cancer to be
categorized as having a high or low risk of distant metastasis. High-risk
patients may then be managed with more aggressive therapy.
CONCLUSION: Two gene-expression assays, Oncotype DX and MammaPrint, have been
developed to determine the risk of breast cancer recurrence in patients with
stage I or II node-negative breast cancer. In the future, these tests may be
useful in determining the need for systemic adjuvant therapy in such patients.
DOI: 10.2146/ajhp060352
PMID: 18159035 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19825882
|
1. Ann Oncol. 2010 Apr;21(4):717-722. doi: 10.1093/annonc/mdp388. Epub 2009 Oct
13.
The 70-gene prognosis signature predicts early metastasis in breast cancer
patients between 55 and 70 years of age.
Mook S(1), Schmidt MK(2), Weigelt B(3), Kreike B(4), Eekhout I(1), van de Vijver
MJ(1), Glas AM(5), Floore A(5), Rutgers EJT(6), van 't Veer LJ(7).
Author information:
(1)Department of Pathology.
(2)Department of Epidemiology.
(3)Department of Experimental Therapy.
(4)Department of Radiation Oncology, The Netherlands Cancer Institute.
(5)Department of Agendia BV.
(6)Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam,
The Netherlands.
(7)Department of Pathology; Department of Agendia BV. Electronic address:
l.vt.veer@nki.nl.
BACKGROUND: The majority of breast cancer patients are postmenopausal women who
are increasingly being offered adjuvant chemotherapy. Since the beneficial
effect of chemotherapy in postmenopausal patients predominantly occurs in the
first 5 years after diagnosis, a prognostic marker for early events can be of
use for adjuvant treatment decision making. The aim of this study was to
evaluate the prognostic value of the 70-gene prognosis signature for early
events in postmenopausal patients.
METHODS: Frozen tumor samples from 148 patients aged 55-70 years were selected
(T1-2, N0) and classified by the 70-gene prognosis signature (MammaPrint) into
good or poor prognosis. Eighteen percent received hormonal therapy.
RESULTS: Breast cancer-specific survival (BCSS) at 5 years was 99% for the
good-prognosis signature versus 80% for the poor-prognosis signature group (P =
0.036). The 70-gene prognosis signature was a significant and independent
predictor of BCCS during the first 5 years of follow-up with an adjusted hazard
ratio of 14.4 (95% confidence interval 1.7-122.2; P = 0.01) at 5 years.
CONCLUSION: The 70-gene prognosis signature can accurately select postmenopausal
patients at low risk of breast cancer-related death within 5 years of diagnosis
and can be of clinical use in selecting postmenopausal women for adjuvant
chemotherapy.
DOI: 10.1093/annonc/mdp388
PMID: 19825882 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19214742
|
1. Breast Cancer Res Treat. 2010 Feb;119(3):551-8. doi:
10.1007/s10549-009-0333-1. Epub 2009 Feb 13.
The 70-gene signature as a response predictor for neoadjuvant chemotherapy in
breast cancer.
Straver ME(1), Glas AM, Hannemann J, Wesseling J, van de Vijver MJ, Rutgers EJ,
Vrancken Peeters MJ, van Tinteren H, Van't Veer LJ, Rodenhuis S.
Author information:
(1)Department of Surgical Oncology, The Netherlands Cancer Institute - Antoni
van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
m.straver@nki.nl
The 70-gene signature (MammaPrint) is a prognostic tool used to guide adjuvant
treatment decisions. The aim of this study was to assess its value to predict
chemosensitivity in the neoadjuvant setting. We obtained the 70-gene profile of
stage II-III patients prior to neoadjuvant chemotherapy and classified the
prognosis-signatures. Pathological complete remission (pCR) was used to measure
chemosensitivity. Among 167 patients, 144 (86%) were having a poor and 23 (14%)
a good prognosis-signature. None of the good prognosis-signature patients
achieved a pCR (0/23), whereas 29/144 patients (20%) in the poor
prognosis-signature group did (P = 0.015). All triple-negative tumors (n = 38)
had a poor prognosis-signature. Within the non triple-negative subgroup, the
response of the primary tumor remained associated with the classification of the
prognosis-signature (P = 0.023). A pCR is unlikely to be achieved in tumors that
have a good prognosis-signature. Tumors with a poor prognosis-signature are more
sensitive to chemotherapy.
DOI: 10.1007/s10549-009-0333-1
PMID: 19214742 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19125125
|
1. Genet Med. 2009 Jan;11(1):66-73. doi: 10.1097/GIM.0b013e3181928f56.
Recommendations from the EGAPP Working Group: can tumor gene expression
profiling improve outcomes in patients with breast cancer?
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working
Group(1).
Collaborators: Berg AO, Armstrong K, Botkin J, Calonge N, Haddow J, Hayes M,
Kaye C, Phillips KA, Piper M, Richards CS, Scott JA, Strickland OL, Teutsch S.
Author information:
(1)egappinfo@egappreviews.org
SUMMARY OF RECOMMENDATIONS: The EGAPP Working Group (EWG) found insufficient
evidence to make a recommendation for or against the use of tumor gene
expression profiles to improve outcomes in defined populations of women with
breast cancer. For one test, the EWG found preliminary evidence of potential
benefit of testing results to some women who face decisions about treatment
options (reduced adverse events due to low risk women avoiding chemotherapy),
but could not rule out the potential for harm for others (breast cancer
recurrence that might have been prevented). The evidence is insufficient to
assess the balance of benefits and harms of the proposed uses of the tests. The
EWG encourages further development and evaluation of these technologies.
RATIONALE: The measurement of gene expression in breast tumor tissue is proposed
as a way to estimate the risk of distant disease recurrence in order to provide
additional information beyond current clinicopathological risk stratification
and to influence decisions about treatment in order to improve health outcomes.
Based on their review of the EGAPP-commissioned evidence report, Impact of Gene
Expression Profiling Tests on Breast Cancer Outcomes and other data summaries,
the EWG found no direct evidence linking tumor gene expression profiling of
women with breast cancer to improved outcomes, and inadequate evidence to
construct an evidence chain. However, further evaluation on the clinical utility
of some tests and management algorithms, including well-designed randomized
controlled trials, is warranted.
ANALYTIC VALIDITY: Some data on technical performance of assays were identified
for MammaPrint and Oncotype DX, though estimates of analytic sensitivity and
specificity could not be made. Published performance data on the laboratory
developed Quest H:I Test were limited. Overall, the EWG found the evidence to be
inadequate.
CLINICAL VALIDITY: The EWG found adequate evidence regarding the association of
the Oncotype DX Recurrence Score with disease recurrence and adequate evidence
for response to chemotherapy. The EWG found adequate evidence to characterize
the association of MammaPrint with future metastases, but inadequate evidence to
assess the added value to standard risk stratification, and could not determine
the population to which the test would best apply. The evidence was inadequate
to characterize the clinical validity of the Quest H:I Test.
CLINICAL UTILITY: The EWG found no evidence regarding the clinical utility of
the MammaPrint and Quest H:I Ratio tests, and inadequate evidence regarding
Oncotype DX. These technologies have potential for both benefit and harm.
CONTEXTUAL ISSUES: The EWG reviewed economic studies that used modeling to
predict potential effects of using gene profiling, and judged the evidence
inadequate.
DOI: 10.1097/GIM.0b013e3181928f56
PMCID: PMC2743614
PMID: 19125125 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21847392
|
1. J Breast Cancer. 2011 Mar;14(1):33-8. doi: 10.4048/jbc.2011.14.1.33. Epub 2011
Mar 31.
The 70-gene prognostic signature for korean breast cancer patients.
Na KY(1), Kim KS, Lee JE, Kim HJ, Yang JH, Ahn SH, Moon BI, Kim RM, Ko SM, Jung
YS.
Author information:
(1)Department of Surgery, Ajou University School of Medicine, Suwon, Korea.
PURPOSE: A 70-gene prognostic signature has prognostic value in patients with
node-negative breast cancer in Europe. This diagnostic test known as
"MammaPrint™ (70-gene prognostic signature)" was recently validated and
implementation was feasible. Therefore, we assessed the 70-gene prognostic
signature in Korean patients with breast cancer. We compared the risk predicted
by the 70-gene prognostic signature with commonly used clinicopathological
guidelines among Korean patients with breast cancer. We also analyzed the
70-gene prognostic signature and clinicopathological feature of the patients in
comparison with a previous validation study.
METHODS: Forty-eight eligible patients with breast cancer (clinical T1-2N0M0)
were selected from four hospitals in Korea. Fresh tumor samples were analyzed
with a customized microarray for the 70-gene prognostic signature. Concordance
between the risk predicted by the 70-gene prognostic signature and risk
predicted by commonly used clinicopathological guidelines (St. Gallen
guidelines, National Institutes of Health [NIH] guideline, and Adjuvant! Online)
was evaluated.
RESULTS: Prognosis signatures were assessed in 36 patients. No significant
differences were observed in the clinicopathological features of patients
compared with previous studies. The 70-gene prognosis signature identified five
(13.9%) patients with a low-risk prognosis signature and 31 (86.1%) patients
with a high-risk prognosis signature. Clinical risk was concordant with the
prognosis signature for 29 patients (80.6%) according to the St. Gallen
guidelines; 30 patients (83.4%) according to the NIH guidelines; and 23 patients
(63.8%) according to the Adjuvant! Online. Our results were different from
previous validation studies in Europe with about a 40% low-risk prognosis and
about a 60% high-risk prognosis. The high incidence in the high-risk group was
consistent with data in Japan.
CONCLUSION: The results of 70-gene prognostic signature of Korean patients with
breast cancer were somewhat different from those identified in Europe. This
difference should be studied as whether there is a gene disparity between Asians
and Europeans. Further large-scale studies with a follow-up evaluation are
required to assess whether the use of the 70-gene prognostic signature can
predict the prognosis of Korean patients with breast cancer.
DOI: 10.4048/jbc.2011.14.1.33
PMCID: PMC3148507
PMID: 21847392
Conflict of interest statement: The authors declare that they have no competing
interests.
|
http://www.ncbi.nlm.nih.gov/pubmed/23679081
|
1. Int J Neurosci. 2013 Nov;123(11):802-9. doi: 10.3109/00207454.2013.803477.
Epub 2013 May 23.
Involvement of the dual-specificity phosphatase M3/6 in c-Jun N-terminal kinase
inactivation following cerebral ischemia in the rat hippocampus.
Huang Z(1), Liu Y, Zhu J, Wu H, Guo J.
Author information:
(1)1Laboratory Center for Basic Medical Sciences, Nanjing Medical University ,
Nanjing , P.R. China.
The c-Jun N-terminal kinase (JNK) undergoes complete inactivation following the
intense activation induced by cerebral ischemia and reperfusion in rat
hippocampi. This study examines the molecular mechanism underlying JNK
dephosphorylation and inactivation evoked by dual-specificity phosphates
following cerebral ischemia. The results revealed upregulation of
dual-specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat
hippocampi. This was accompanied by the dephosphorylation of JNK. The M3/6
inhibitor, anisomycin, was found to enhance JNK activity following postischemic
reperfusion, suggesting that M3/6 is closely associated with JNK inactivation
following cerebral ischemia. Cerebral ischemia also induced an increase in heat
shock protein (HSP70) levels, which is involved in the upregulation of soluble
cytoplasmic M3/6 levels. The inhibition of HSP70 using quercetin resulted in an
elevation of JNK activity by decreasing the cytoplasmic solubility of M3/6. The
findings of the current study suggest that M3/6 is implicated in the
inactivation of JNK in response to cerebral ischemia, which requires the
molecular chaperone HSP70 to facilitate the correction of folding defects.
DOI: 10.3109/00207454.2013.803477
PMID: 23679081 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8910287
|
1. J Biol Chem. 1996 Nov 1;271(44):27205-8. doi: 10.1074/jbc.271.44.27205.
The dual specificity phosphatases M3/6 and MKP-3 are highly selective for
inactivation of distinct mitogen-activated protein kinases.
Muda M(1), Theodosiou A, Rodrigues N, Boschert U, Camps M, Gillieron C, Davies
K, Ashworth A, Arkinstall S.
Author information:
(1)Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development
S. A., CH-1228 Plan-les-Ouates, Geneva, Switzerland. SA7182@GGR.CO.UK
The mitogen-activated protein (MAP) kinase family includes extracellular
signal-regulated kinase (ERK), c-Jun NH2-terminal kinase/stress-activated
protein kinase (JNK/SAPK) and p38/RK/CSBP (p38) as structurally and functionally
distinct enzyme classes. Here we describe two new dual specificity phosphatases
of the CL100/MKP-1 family that are selective for inactivating ERK or JNK/SAPK
and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase
of this family to display highly specific inactivation of JNK/SAPK and p38 MAP
kinases. Although stress-induced activation of p54 SAPKbeta, p46 SAPKgamma
(JNK1) or p38 MAP kinases is abolished upon co-transfection with increasing
amounts of M3/6 plasmid, epidermal growth factor-stimulated ERK1 is remarkably
insensitive even to the highest levels of M3/6 expression obtained. In contrast
to M3/6, the dual specificity phosphatase MKP-3 is selective for inactivation of
ERK family MAP kinases. Low level expression of MKP-3 blocks totally epidermal
growth factor-stimulated ERK1, whereas stress-induced activation of p54 SAPKbeta
and p38 MAP kinases is inhibited only partially under identical conditions.
Selective regulation by M3/6 and MKP-3 was also observed upon chronic MAP kinase
activation by constitutive p21(ras) GTPases. Hence, although M3/6 expression
effectively blocked p54 SAPKbeta activation by p21(rac) (G12V), ERK1 activated
by p21(ras) (G12V) was insensitive to this phosphatase. ERK1 activation by
oncogenic p21(ras) was, however, blocked totally by co-expression of MKP-3. This
is the first report demonstrating reciprocally selective inhibition of different
MAP kinases by two distinct dual specificity phosphatases.
DOI: 10.1074/jbc.271.44.27205
PMID: 8910287 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11566103
|
1. Curr Biol. 2001 Sep 18;11(18):1439-43. doi: 10.1016/s0960-9822(01)00426-2.
The JNK phosphatase M3/6 is inhibited by protein-damaging stress.
Palacios C(1), Collins MK, Perkins GR.
Author information:
(1)The Department of Immunology, University College London Medical School,
Windeyer Building, 46 Cleveland Street, London W1P6DB, United Kingdom.
Cells respond to stresses such as osmotic shock and heat shock by activating
stress-activated protein kinases (SAPKs), including c-Jun N-terminal kinase
(JNK) [1]. Activation of JNK requires phosphorylation of threonine and tyrosine
residues in the TPY activation loop motif [2, 3] and can be reversed by the
removal of either phosphate group. Numerous JNK phosphatases including
dual-specificity phosphatases [4, 5], have been identified. Many stimuli
activate JNK by increasing its rate of phosphorylation; however, JNK
dephosphorylation is inhibited in cells after heat shock [6], suggesting that a
JNK phosphatase(s) is inactivated. M3/6 is a dual-specificity phosphatase
selective for JNK [7, 8]. We have previously expressed M3/6 in the mouse bone
marrow cell line BAF3 in order to show that JNK activation by IL-3 is necessary
for cell survival and proliferation [9]. Here we report that M3/6 dissociates
from JNK and appears in an insoluble fraction after heat shock. These data
identify M3/6 as a JNK phosphatase that is inactivated by heat shock and provide
a molecular mechanism for the activation of JNK by heat shock.
DOI: 10.1016/s0960-9822(01)00426-2
PMID: 11566103 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22100391
|
1. Cell Signal. 2012 Mar;24(3):664-76. doi: 10.1016/j.cellsig.2011.10.015. Epub
2011 Nov 9.
Phosphorylation of the M3/6 dual-specificity phosphatase enhances the activation
of JNK by arsenite.
Cotsiki M(1), Oehrl W, Samiotaki M, Theodosiou A, Panayotou G.
Author information:
(1)Institute of Molecular Oncology, Biomedical Sciences Research Center
Alexander Fleming, Vari, Greece.
Specific outcomes upon activation of the c-Jun N-terminal kinase (JNK) pathway
critically depend on the intensity and duration of signal transmission.
Dual-specificity phosphatases (DUSPs) play a very important role in these events
by modulating the extent of JNK phosphorylation and activation and thus
regulating cellular responses to stress. M3/6 (DUSP8) is one of the
dual-specificity protein phosphatases with distinct specificity towards JNK. It
has been shown that M3/6 itself is phosphorylated by JNK upon stimulation with
arsenite, but the role of this phosphorylation has not been investigated. In
this study, we mapped JNK-induced phosphorylation sites on M3/6 using mass
spectrometry. Phosphorylated residues Ser 515, Thr 518 and Ser 520 were
identified and site-directed mutagenesis was employed to investigate their role.
Upon arsenite stimulation, M3/6 mutated at these sites exhibited decreased
phosphorylation compared to the wild-type protein. No difference was observed in
terms of the enzyme's in vitro phosphatase activity, its substrate specificity
towards JNK isoforms, its interactions with JNK and the scaffold family of
JNK-interacting proteins (JIPs), its stability or its subcellular localization.
Interestingly, expression of M3/6 phosphorylation mutants delayed the
time-course of JNK phosphorylation and activation by arsenite. We propose that
phosphorylation of the M3/6 phosphatase by JNK in response to stress stimuli
results in attenuation of phosphatase activity and acceleration of JNK
activation.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cellsig.2011.10.015
PMID: 22100391 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12598532
|
1. J Biol Chem. 2003 May 9;278(19):16957-67. doi: 10.1074/jbc.M212049200. Epub
2003 Feb 21.
Polyglutamine expansion induces a protein-damaging stress connecting heat shock
protein 70 to the JNK pathway.
Merienne K(1), Helmlinger D, Perkin GR, Devys D, Trottier Y.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM,
Université Louis Pasteur, BP 10142, Illkirch C U de Strasbourg, 67404 cedex,
France. merienne@igbmc.u-strasbg.fr
Polyglutamine diseases, including Huntington's disease, designate a group of
nine neurodegenerative disorders characterized by the presence of a toxic
polyglutamine expansion in specific target proteins. Using cell and mouse
models, we have shown that expanded polyglutamine led to activation of the
stress kinase JNK and the transcription factor AP-1, which are implicated in
neuronal death. Polyglutamine expansion-induced stress shared common features
with protein-damaging stress such as heat shock, because activation of JNK
involved inhibition of JNK phosphatase activities. Indeed, expanded
polyglutamine impaired the solubility of the dual-specificity JNK phosphatase
M3/6. Aggregation of M3/6 by polyglutamine expansion appeared to be indirect,
because M3/6 was not recruited into polyglutamine inclusions. The heat shock
protein HSP70, which is known to inhibit JNK during the heat shock response,
suppressed polyglutamine-mediated aggregation of M3/6 and activation of JNK.
Interestingly, levels of HSP70 were down-regulated by polyglutamine expansion.
We suggest that reduction of HSP70 by expanded polyglutamine is implicated in
aggregation and inhibition of M3/6 and in activation of JNK and AP-1.
DOI: 10.1074/jbc.M212049200
PMID: 12598532 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11948422
|
1. Oncogene. 2002 Apr 4;21(15):2387-97. doi: 10.1038/sj.onc.1205309.
Differential effects of stress stimuli on a JNK-inactivating phosphatase.
Theodosiou A(1), Ashworth A.
Author information:
(1)CRC Gene Function and Regulation Group, The Breakthrough Toby Robins Breast
Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3
6JB, UK.
Stress signals elicit a wide variety of cellular responses, many of which
converge on the phosphorylation of JNK and p38 kinases, the activation of which
has been well-characterized. How these kinases are switched off by
dephosphorylation is not well understood. Here we describe how diverse cellular
stresses affect differently the stability and activity of a JNK-inactivating
dual-specificity threonine-tyrosine phosphatase M3/6. Both anisomycin and
arsenite activate the JNK pathway and, in addition, inactivate the M3/6
phosphatase. However, while anisomycin treatment of cells leads to M3/6 protein
degradation, arsenite appears to inactivate M3/6 directly. These results might
have implications for the mechanism of tumour promotion by arsenic.
DOI: 10.1038/sj.onc.1205309
PMID: 11948422 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21234187
|
1. Ann Pediatr Cardiol. 2010 Jul;3(2):107-12. doi: 10.4103/0974-2069.74035.
Sudden cardiac death in children and adolescents (excluding Sudden Infant Death
Syndrome).
Gajewski KK(1), Saul JP.
Author information:
(1)Department of Pediatrics, Louisiana State University School of Medicine, New
Orleans, Louisiana, USA.
Sudden death in the young is rare. About 25% of cases occur during sports. Most
young people with sudden cardiac death (SCD) have underlying heart disease, with
hypertrophic cardiomyopathy and coronary artery anomalies being commonest in
most series. Arrhythmogenic right ventricular dysplasia and long QT syndrome are
the most common primary arrhythmic causes of SCD. It is estimated that early
cardiopulmonary resuscitation and widespread availability of automatic external
defibrillators could prevent about a quarter of pediatric sudden deaths.
DOI: 10.4103/0974-2069.74035
PMCID: PMC3017912
PMID: 21234187
Conflict of interest statement: Conflict of Interest: None declared.
|
http://www.ncbi.nlm.nih.gov/pubmed/10915787
|
1. J Biol Chem. 2000 Oct 13;275(41):31755-62. doi: 10.1074/jbc.M004182200.
Regulation of dual-specificity phosphatases M3/6 and hVH5 by phorbol esters.
Analysis of a delta-like domain.
Johnson TR(1), Biggs JR, Winbourn SE, Kraft AS.
Author information:
(1)Department of Medical Oncology, University of Colorado Health Sciences
Center, Denver, Colorado 80262, USA.
Treatment of leukemic cells with phorbol 12-myristate 13-acetate (PMA) induces a
short-lived phosphorylation and activation of stress-activated protein kinase
(SAPK) and cellular differentiation. To investigate whether the rapid
deactivation of SAPK results from dephosphorylation by dual-specificity
phosphatases (DSPs), we studied regulation of the DSP hVH5 and its murine
orthologue M3/6 in K562 human leukemia cells. PMA treatment rapidly induced hVH5
transcripts in these cells, and induced expression of M3/6 completely inhibited
PMA-stimulated phosphorylation of SAPK, suggesting a feedback loop to control
SAPK activity. Using both stable cell lines and transient transfection we
demonstrate that activation of SAPK rapidly stimulated phosphorylation of M3/6.
This phosphorylation did not regulate the half-life of total cellular M3/6. hVH5
and M3/6 shares with all sequenced mammalian DSPs an amino acid motif, XILPXLXL,
located approximately 80 amino acids from the active site. The hVH5-M3/6
sequence, RILPHLYL, shares significant homology with the SAPK binding site of
the c-Jun protein, called the delta domain. This motif was found to be important
for DSP function, because deletion of RILPHLYL inhibits SAPK-mediated
phosphorylation of M3/6, and deletion of this sequence or mutation of the LYL
portion blocks the ability of this phosphatase to dephosphorylate SAPK.
DOI: 10.1074/jbc.M004182200
PMID: 10915787 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15888437
|
1. J Biol Chem. 2005 Jul 8;280(27):25651-8. doi: 10.1074/jbc.M501926200. Epub
2005 May 10.
Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3
scaffold protein beta-arrestin 2.
Willoughby EA(1), Collins MK.
Author information:
(1)Division of Infection and Immunity, University College London, Windeyer
Building, 46 Cleveland Street, London W1T 4JF, United Kingdom.
JNK scaffold proteins bind JNK and upstream kinases to activate subsets of JNK
and localize activated JNK to specific subcellular sites. We previously
demonstrated that the dual specificity phosphatases (DSPs) MKP7 and M3/6 bind
the scaffold JNK-interacting protein-1 (JIP-1) and inactivate the bound subset
of JNK (1). The G protein-coupled receptor (GPCR) adaptor beta-arrestin 2 is
also a JNK3 scaffold. It binds the upstream kinases ASK1 and MKK4 and couples
stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic
pool of JNK3. Here we report that MKP7 also binds beta-arrestin 2 via amino
acids 394-443 of MKP7, the same region that interacts with JIP-1. This region of
MKP7 interacts with beta-arrestin 2 at a central region near the JNK binding
domain. MKP7 dephosphorylates JNK3 bound to beta-arrestin 2, either following
activation by ASK1 overexpression or following AT1aR stimulation. Initial AT1aR
stimulation causes a rapid (within 5 min) dissociation of MKP7 from
beta-arrestin 2. MKP7 then reassociates with beta-arrestin 2 on endocytic
vesicles 30-60 min after initial receptor stimulation. This dynamic interaction
between phosphatase and scaffold permits signal transduction through a module
that binds both positive and negative regulators.
DOI: 10.1074/jbc.M501926200
PMID: 15888437 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23159405
|
1. Cell Signal. 2013 Feb;25(2):429-38. doi: 10.1016/j.cellsig.2012.11.010. Epub
2012 Nov 15.
Differential regulation of M3/6 (DUSP8) signaling complexes in response to
arsenite-induced oxidative stress.
Oehrl W(1), Cotsiki M, Panayotou G.
Author information:
(1)Biomedical Sciences Research Center "Alexander Fleming", Vari 166 72, Greece.
Mitogen-activated protein kinase (MAPK) cascades are involved in the regulation
of cellular proliferation, differentiation, survival, apoptosis, as well as in
inflammatory responses. Signal intensity and duration have been recognized as
crucial parameters determining MAPK signaling output. Phosphatases play a
particularly important role in this respect, by tightly controlling MAPK
phosphorylation and activation. M3/6 (DUSP8) is a dual-specificity phosphatase
implicated in the dephosphorylation and inactivation of JNK and, to a lesser
extent, p38 MAPKs and is found in a complex with these kinases, along with other
pathway components, held together by scaffold proteins. The JNK family consists
of three genes, giving rise to at least ten different splice variants. Some
functional differences between these gene products have been demonstrated, but
the underlying molecular mechanisms and the roles of individual splice variants
are still incompletely understood. We have investigated the interaction of M3/6
with JNK isoforms, as well as scaffold proteins of the JNK interacting protein
(JIP) family, in order to elucidate the contribution of M3/6 to the regulation
of distinct JNK signaling modules. M3/6 exhibited stronger binding towards JNK1β
and JNK2α isoforms and this was reflected in higher enzymatic activity towards
JNK2α2 when compared to JNK1α1 in vitro. After activation of the pathway by
exposure of cells to arsenite, the interaction of M3/6 with JNK1α and JNK3 was
enhanced, whereas that with JNK1β or JNK2α decreased. The modulation of binding
affinities was found to be independent of JNK-mediated M3/6 phosphorylation.
Furthermore, arsenite treatment resulted in an inducible recruitment of M3/6 to
JNK-interacting protein 3 (JIP3) scaffold complexes, while its interaction with
JIP1 or JIP2 was constitutive. The presented data suggest an isoform-specific
role for the M3/6 phosphatase and the dynamic targeting of M3/6 towards distinct
JNK-containing signaling complexes.
Copyright © 2012 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cellsig.2012.11.010
PMID: 23159405 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20616184
|
1. Mol Cell Proteomics. 2010 Nov;9(11):2424-37. doi: 10.1074/mcp.M110.001917.
Epub 2010 Jul 8.
Naturally occurring human urinary peptides for use in diagnosis of chronic
kidney disease.
Good DM(1), Zürbig P, Argilés A, Bauer HW, Behrens G, Coon JJ, Dakna M, Decramer
S, Delles C, Dominiczak AF, Ehrich JH, Eitner F, Fliser D, Frommberger M, Ganser
A, Girolami MA, Golovko I, Gwinner W, Haubitz M, Herget-Rosenthal S, Jankowski
J, Jahn H, Jerums G, Julian BA, Kellmann M, Kliem V, Kolch W, Krolewski AS,
Luppi M, Massy Z, Melter M, Neusüss C, Novak J, Peter K, Rossing K, Rupprecht H,
Schanstra JP, Schiffer E, Stolzenburg JU, Tarnow L, Theodorescu D, Thongboonkerd
V, Vanholder R, Weissinger EM, Mischak H, Schmitt-Kopplin P.
Author information:
(1)Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706,
USA.
Because of its availability, ease of collection, and correlation with physiology
and pathology, urine is an attractive source for clinical
proteomics/peptidomics. However, the lack of comparable data sets from large
cohorts has greatly hindered the development of clinical proteomics. Here, we
report the establishment of a reproducible, high resolution method for peptidome
analysis of naturally occurring human urinary peptides and proteins, ranging
from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by
capillary electrophoresis coupled to MS. All processed data were deposited in an
Structured Query Language (SQL) database. This database currently contains 5,010
relevant unique urinary peptides that serve as a pool of potential classifiers
for diagnosis and monitoring of various diseases. As an example, by using this
source of information, we were able to define urinary peptide biomarkers for
chronic kidney diseases, allowing diagnosis of these diseases with high
accuracy. Application of the chronic kidney disease-specific biomarker set to an
independent test cohort in the subsequent replication phase resulted in 85.5%
sensitivity and 100% specificity. These results indicate the potential
usefulness of capillary electrophoresis coupled to MS for clinical applications
in the analysis of naturally occurring urinary peptides.
DOI: 10.1074/mcp.M110.001917
PMCID: PMC2984241
PMID: 20616184 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/12524447
|
1. J Biol Chem. 2003 Mar 21;278(12):10731-6. doi: 10.1074/jbc.M207324200. Epub
2003 Jan 10.
The JNK-interacting protein-1 scaffold protein targets MAPK phosphatase-7 to
dephosphorylate JNK.
Willoughby EA(1), Perkins GR, Collins MK, Whitmarsh AJ.
Author information:
(1)Department of Immunology and Molecular Pathology, University College London
and Royal Free Medical School, Windeyer Institute, United Kingdom.
The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases
(MAPKs) are activated by pleiotropic signals including environmental stresses,
growth factors, and hormones. A subset of JNK can bind to distinct scaffold
proteins that also bind upstream kinases of the JNK pathway, allowing sequential
kinase activation within a signaling module. The JNK-interacting protein-1
(JIP-1) scaffold protein specifically binds JNK, MAP kinase kinase 7, and
members of the MLK family and is essential for stress-mediated JNK activation in
neurones. Here we report that JIP-1 also binds the dual-specificity phosphatases
MKP7 and M3/6 via a region independent of its JNK binding domain. The C-terminal
region of MKP7, homologous to that of M3/6 but not other DSPs, is required for
interaction with JIP-1. When MKP7 is bound to JIP-1 it reduces JNK activation
leading to reduced phosphorylation of the JNK target c-Jun. These results
indicate that the JIP-1 scaffold protein modulates JNK signaling via association
with both protein kinases and protein phosphatases that target JNK.
DOI: 10.1074/jbc.M207324200
PMID: 12524447 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21143788
|
1. BMC Genomics. 2010 Dec 1;11 Suppl 3(Suppl 3):S6. doi:
10.1186/1471-2164-11-S3-S6.
Cross-domain neurobiology data integration and exploration.
Xuan W(1), Dai M, Buckner J, Mirel B, Song J, Athey B, Watson SJ, Meng F.
Author information:
(1)Psychiatry Department and Molecular and Behavioral Neuroscience Institute,
University of Michigan, USA. wxuan@umich.edu
BACKGROUND: Understanding the biomedical implications of data from high
throughput experiments requires solutions for effective cross-scale and
cross-domain data exploration. However, existing solutions do not provide
sufficient support for linking molecular level data to neuroanatomical
structures, which is critical for understanding high level neurobiological
functions.
RESULTS: Our work integrates molecular level data with high level biological
functions and we present results using anatomical structure as a scaffold. Our
solution also allows the sharing of intermediate data exploration results with
other web applications, greatly increasing the power of cross-domain data
exploration and mining.
CONCLUSIONS: The Flex-based PubAnatomy web application we developed enables
highly interactive visual exploration of literature and experimental data for
understanding the relationships between molecular level changes, pathways, brain
circuits and pathophysiological processes. The prototype of PubAnatomy is freely
accessible at:
[http://brainarray.mbni.med.umich.edu/Brainarray/prototype/PubAnatomy].
DOI: 10.1186/1471-2164-11-S3-S6
PMCID: PMC2999351
PMID: 21143788 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19604367
|
1. BMC Genomics. 2009 Jul 15;10:316. doi: 10.1186/1471-2164-10-316.
Genomic resources of Magnaporthe oryzae (GROMO): a comprehensive and integrated
database on rice blast fungus.
Thakur S(1), Jha S, Roy-Barman S, Chattoo B.
Author information:
(1)Centre for Genome Research, Department of Microbiology and Biotechnology
Centre, Faculty of Science, The M, S, University of Baroda, Vadodara - 390002,
India. bharat.chattoo@bcmsu.ac.in
BACKGROUND: Magnaporthe oryzae, rice blast fungus, is the most devastating
pathogen of rice. It has emerged as a model phytopathogen for the study of
host-pathogen interactions. A large body of data has been generated on different
aspects of biology of this fungus and on host-pathogen interactions. However,
most of the data is scattered and is not available as a single resource for
researchers in this field.
DESCRIPTION: Genomic Resources of Magnaporthe oyzae (GROMO), is a specialized,
and comprehensive database for rice blast fungus, integrating information from
several resources. GROMO contains information on genomic sequence, mutants
available, gene expression, localization of proteins obtained from a variety of
repositories, as primary data. In addition, prediction of domains, pathways,
protein-protein interactions, sumolyation sites and biochemical properties that
were obtained after computational analysis of protein sequences have also been
included as derived data. This database has an intuitive user interface that
shall prompt the user to explore various possible information resources
available on a given gene or a protein, from a single source.
CONCLUSION: Currently, information on M. oryzae is available from different
resources like BROAD MIT Magnaporthe database, Agrobacterium
tumefaciens-mediated transformation (ATMT) M. oryzae database, Magnaporthe
grisea--Oryza sativa (MGOS) and Massive Parallel Signature Sequencing (MPSS)
databases. In the GROMO project, an effort has been made to integrate
information from all these databases, derive some new data based on the
available information analyzed by relevant programs and make more insightful
predictions to better understand the biology of M. oryzae. The database is
currently available at: http://gromo.msubiotech.ac.in/
DOI: 10.1186/1471-2164-10-316
PMCID: PMC2721851
PMID: 19604367 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23593176
|
1. PLoS One. 2013 Apr 4;8(4):e60213. doi: 10.1371/journal.pone.0060213. Print
2013.
Microarray analyses of glucocorticoid and vitamin D3 target genes in
differentiating cultured human podocytes.
Cheng X(1), Zhao X, Khurana S, Bruggeman LA, Kao HY.
Author information:
(1)Department of Biochemistry, School of Medicine, Case Western Reserve
University (CWRU) and the Comprehensive Cancer Center of CWRU, Cleveland, Ohio,
United States of America.
Erratum in
PLoS One. 2013;8(6).
doi:10.1371/annotation/ce9027f6-dbf9-4fc9-af40-9e244edf6a6e.
Glomerular podocytes are highly differentiated epithelial cells that are key
components of the kidney filtration units. Podocyte damage or loss is the
hallmark of nephritic diseases characterized by severe proteinuria. Recent
studies implicate that hormones including glucocorticoids (ligand for
glucocorticoid receptor) and vitamin D3 (ligand for vitamin D receptor) protect
or promote repair of podocytes from injury. In order to elucidate the mechanisms
underlying hormone-mediated podocyte-protecting activity from injury, we carried
out microarray gene expression studies to identify the target genes and
corresponding pathways in response to these hormones during podocyte
differentiation. We used immortalized human cultured podocytes (HPCs) as a model
system and carried out in vitro differentiation assays followed by dexamethasone
(Dex) or vitamin D3 (VD3) treatment. Upon the induction of differentiation,
multiple functional categories including cell cycle, organelle dynamics,
mitochondrion, apoptosis and cytoskeleton organization were among the most
significantly affected. Interestingly, while Dex and VD3 are capable of
protecting podocytes from injury, they only share limited target genes and
affected pathways. Compared to VD3 treatment, Dex had a broader and greater
impact on gene expression profiles. In-depth analyses of Dex altered genes
indicate that Dex crosstalks with a broad spectrum of signaling pathways, of
which inflammatory responses, cell migration, angiogenesis, NF-κB and TGFβ
pathways are predominantly altered. Together, our study provides new information
and identifies several new avenues for future investigation of hormone signaling
in podocytes.
DOI: 10.1371/journal.pone.0060213
PMCID: PMC3617172
PMID: 23593176 [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/21044771
|
1. Adv Chronic Kidney Dis. 2010 Nov;17(6):487-92. doi:
10.1053/j.ackd.2010.09.005.
Proteomics database in chronic kidney disease.
Yamamoto T(1).
Author information:
(1)Institute of Nephrology, Structural Pathology, Chuo-ku Niigata, Niigata,
Japan. tdsymmt@med.niigata-u.ac.jp
Databases which are useful for proteomic analysis of human kidney tissue and
urine have been discussed in this article. Integration of the gene-centric and
protein-centric general databases with those of human kidney tissue and urine
proteomes may open a new window for research in nephrology. Proteins present in
the kidney and urine provide basic tools for investigation of kidney function
and disease. By comparing such databases between the healthy and diseased
populations, we may be able to identify the following: proteins involved in the
development of renal disease, proteins involved in progression of CKD, or new
biomarker candidate proteins for either the development of renal disease or the
progression of CKD.
Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1053/j.ackd.2010.09.005
PMID: 21044771 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19728071
|
1. Behav Genet. 2009 Nov;39(6):605-15. doi: 10.1007/s10519-009-9294-8. Epub 2009
Sep 3.
Born to be happy? The etiology of subjective well-being.
Bartels M(1), Boomsma DI.
Author information:
(1)Department of Biological Psychology, VU University, Van der Boechorststraat
1, 1081 BT, Amsterdam, The Netherlands. m.bartels@psy.vu.nl
Subjective Wellbeing (SWB) can be assessed with distinct measures that have been
hypothesized to represent different domains of SWB. The current study assessed
SWB with four different measures in a genetically informative sample of
adolescent twins and their siblings aged 13-28 years (N = 5,024 subjects from
2,157 families). Multivariate genetic modeling was applied to the data to
explore the etiology of individual differences in SWB measures and the
association among them. Developmental trends and sex differences were examined
for mean levels and the variance-covariance structure. Mean SWB levels were
equal in men and women. A small negative effect of age on mean levels of SWB was
found. Individual differences in SWB were accounted for by additive and
non-additive genetic influences, and non-shared environment. The broad-sense
heritabilities were estimated between 40 and 50%. The clustering of the four
different measures (quality of life in general, satisfaction with life, quality
of life at present, and subjective happiness) was explained by an underlying
additive genetic factor and an underlying non-additive genetic factor. The
effect of these latent genetic factors on the phenotypes was not moderated by
either age or sex.
DOI: 10.1007/s10519-009-9294-8
PMCID: PMC2780680
PMID: 19728071 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2687698
|
1. Nature. 1989 Dec 21-28;342(6252):877-83. doi: 10.1038/342877a0.
Conformations of immunoglobulin hypervariable regions.
Chothia C(1), Lesk AM, Tramontano A, Levitt M, Smith-Gill SJ, Air G, Sheriff S,
Padlan EA, Davies D, Tulip WR, et al.
Author information:
(1)MRC Laboratory of Molecular Biology, Cambridge, UK.
Comment in
Nature. 1990 Feb 1;343(6257):411-2. doi: 10.1038/343411a0.
On the basis of comparative studies of known antibody structures and sequences
it has been argued that there is a small repertoire of main-chain conformations
for at least five of the six hypervariable regions of antibodies, and that the
particular conformation adopted is determined by a few key conserved residues.
These hypotheses are now supported by reasonably successful predictions of the
structures of most hypervariable regions of various antibodies, as revealed by
comparison with their subsequently determined structures.
DOI: 10.1038/342877a0
PMID: 2687698 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8227075
|
1. J Biol Chem. 1993 Nov 25;268(33):25124-31.
Identification of a secondary Fc gamma RI binding site within a genetically
engineered human IgG antibody.
Chappel MS(1), Isenman DE, Oomen R, Xu YY, Klein MH.
Author information:
(1)Department of Immunology, University of Toronto, Ontario, Canada.
Although human IgG2 is not cytophilic, we have shown previously that an IgG2
antibody expressing the sequence PLLGG (underline = substitution) spanning CH2
domain residues 233-237 (Eu numbering) displayed IgG1-like Fc gamma RI binding
activity. In contrast, IgG1 PLLGG exhibited 3-fold less affinity, whereas IgG2
ELLGG was 3-fold more active than native IgG1. These results suggested that
additional site(s) conferred enhanced binding properties to the engineered,
cytophilic IgG2 variant. These sites were shown to reside in the IgG2 CH2
domain, since the IgG1 CH2 module did not have enhanced activity in a panel of
hybrid IgG1/IgG2 antibodies. To map these sites further, human IgG1 and IgG2
constant region gene segments were modified to allow reciprocal COOH-terminal
half segment exchanges of CH2 exons. These were cloned into a pSV2neo expression
vector bearing a rearranged MOPC 315 heavy chain variable region gene and
transfected into a MOPC 315 heavy chain deletion mutant. The dinitrophenol
affinity-purified IgGs were radiolabeled and assessed for Fc gamma RI binding
activity in direct binding assays using U937 cells. The COOH terminus of the
IgG2 CH2 domain was found to contain accessory site(s) since it enhanced the
binding properties of both IgG1 PLLGG and native IgG1. In contrast, grafting of
the COOH terminus of the IgG1 CH2 domain onto IgG2 PLLGG and IgG2 ELLGG
diminished their cytophilic activity. The amino acid responsible for the
enhancing properties of the COOH terminus of the IgG2 CH2 domain was shown to be
threonine 339, since IgG1 PLLGG/Thr339 displayed increased Fc gamma RI binding
affinity. Kinetics studies revealed that this is accomplished through an
increase in the forward rate constant of the IgG-Fc gamma RI interaction.
PMID: 8227075 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22665257
|
1. Methods Mol Biol. 2012;882:605-33. doi: 10.1007/978-1-61779-842-9_33.
IMGT/DomainGapAlign: the IMGT® tool for the analysis of IG, TR, MH, IgSF, and
MhSF domain amino acid polymorphism.
Ehrenmann F(1), Lefranc MP.
Author information:
(1)IMGT®, The International ImMunoGeneTics Information System®, Université
Montpellier 2, Laboratoire d'ImmunoGénétique Moléculaire (LIGM), Institut de
Génétique Humaine (IGH), UPR CNRS 1142, Montpellier, France.
IMGT/DomainGapAlign is the online tool of IMGT(®), the international
ImMunoGeneTics information system(®), for the analysis of amino acid sequences
and two-dimensional (2D) structures of domains. IMGT/DomainGapAlign allows the
analysis of the closest variable (V) and constant (C) domains of immunoglobulins
(IG) or antibodies, T cell receptors (TR), and immunoglobulin superfamily (IgSF)
proteins, and of the groove (G) domains of major histocompatibility (MH; in
humans, HLA for human leukocyte antigen) and MH superfamily proteins.
IMGT/DomainGapAlign aligns the user own sequences against the IMGT domain
reference directory, displays amino acid changes, creates IMGT gaps, and
delimits the domain strands and loops (and helix for G domain) according to the
IMGT unique numbering. IMGT/DomainGapAlign is coupled to the
IMGT/Collier-de-Perles tool that draws standardized IMGT Colliers de Perles. The
analysis is based on the IMGT-ONTOLOGY concepts of identification,
classification, description, and numerotation generated from the axioms of the
Formal IMGT-ONTOLOGY or IMGT-Kaleidoscope. IMGT/DomainGapAlign provides an
invaluable help for antibody engineering and antibody humanization as it
precisely defines the standardized framework regions (FR-IMGT) and
complementarity determining regions (CDR-IMGT) to be grafted.
IMGT/DomainGapAlign is freely available at http://www.imgt.org.
DOI: 10.1007/978-1-61779-842-9_33
PMID: 22665257 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/308705
|
1. Surgery. 1978 Oct;84(4):471-5.
Purulent pericarditis in children.
Garvin PJ, Danis RK, Lewis JE Jr, Willman VL.
Acute purulent pericarditis was treated successfully in five children between
the ages of 27 months and 11 1/2 years during the past 5 years. The responsible
organism was Hemophilus influenzae, type b, in two cases and Meningococcus,
Pneumococcus, and coagulase-positive Staphylococcus aureus in one case each. No
primary source of infection could be identified in two patients. A high index of
suspicion, combined with immediate echocardiograms and pericardiocentesis, led
to the diagnosis. Immediate antibiotic therapy was instituted on the basis of
the gram stain of the pericardial fluid. All five patients had a pericardial
window established--four through subxyphoid approach and the fifth, because of a
left pleural effusion, through a left thoracotomy. When the subxyphoid approach
was used, sump drains were left for postoperative suction and irrigation. All
five patients survived without sequalae during follow-up periods of from 18
months to 5 years. We advocate an aggressive approach to the diagnosis and
treatment of this problem. This report documents the safety, ease, and
effectiveness of the subxyphoid approach as a means of drainage.
PMID: 308705 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24105488
|
1. J Child Neurol. 2014 Nov;29(11):1562-71. doi: 10.1177/0883073813501870. Epub
2013 Oct 7.
Subependymal giant cell astrocytomas in patients with tuberous sclerosis
complex: considerations for surgical or pharmacotherapeutic intervention.
Wheless JW(1), Klimo P Jr(2).
Author information:
(1)Department of Pediatric Neurology, Neuroscience Institute and Tuberous
Sclerosis Clinic, Le Bonheur Children's Hospital, University of Tennessee Health
Science Center, Memphis, TN, USA jwheless@uthsc.edu.
(2)Department of Neurosurgery, Neuroscience Institute and Tuberous Sclerosis
Clinic, Le Bonheur Children's Hospital, University of Tennessee Health Science
Center, Memphis, TN, USA Semmes-Murphey Neurologic & Spine Institute, Memphis,
TN, USA St. Jude Children's Research Hospital, Memphis, TN, USA.
Tuberous sclerosis complex is a genetic disorder caused by mutations in either
the TSC1 or TSC2 gene that can result in the growth of hamartomas in multiple
organ systems. Subependymal giant cell astrocytomas are slow-growing brain
tumors associated primarily with tuberous sclerosis complex. They are usually
located in the ventricles, often near the foramen of Monro, where they can cause
an obstruction if they grow too large, leading to increased intracranial
pressure. Surgery to remove a tumor has been the mainstay of treatment but can
be associated with postoperative morbidity and mortality. Not all tumors and/or
patients are suitable for surgery. The recent development of mammalian target of
rapamycin inhibitors that target the pathway affected by TSC1/TSC2 mutations
offers a novel pharmacotherapeutic option for these patients. We review the
timing and use of surgery versus pharmacotherapy for the treatment of
subependymal giant cell astrocytoma in patients with tuberous sclerosis complex.
© The Author(s) 2013.
DOI: 10.1177/0883073813501870
PMID: 24105488 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18503082
|
1. Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W503-8. doi:
10.1093/nar/gkn316. Epub 2008 May 24.
IMGT/V-QUEST: the highly customized and integrated system for IG and TR
standardized V-J and V-D-J sequence analysis.
Brochet X(1), Lefranc MP, Giudicelli V.
Author information:
(1)IMGT, the international ImMunoGeneTics information system, Laboratoire
d'ImmunoGénétique Moléculaire LIGM, Université Montpellier 2, Institut de
Génétique Humaine IGH, UPR CNRS 1142, 141 rue de la Cardonille, 34396
Montpellier cedex 5, France.
IMGT/V-QUEST is the highly customized and integrated system for the standardized
analysis of the immunoglobulin (IG) and T cell receptor (TR) rearranged
nucleotide sequences. IMGT/V-QUEST identifies the variable (V), diversity (D)
and joining (J) genes and alleles by alignment with the germline IG and TR gene
and allele sequences of the IMGT reference directory. New functionalities were
added through a complete rewrite in Java. IMGT/V-QUEST analyses batches of
sequences (up to 50) in a single run. IMGT/V-QUEST describes the V-REGION
mutations and identifies the hot spot positions in the closest germline V gene.
IMGT/V-QUEST can detect insertions and deletions in the submitted sequences by
reference to the IMGT unique numbering. IMGT/V-QUEST integrates
IMGT/JunctionAnalysis for a detailed analysis of the V-J and V-D-J junctions,
and IMGT/Automat for a full V-J- and V-D-J-REGION annotation. IMGT/V-QUEST
displays, in 'Detailed view', the results and alignments for each submitted
sequence individually and, in 'Synthesis view', the alignments of the sequences
that, in a given run, express the same V gene and allele. The 'Advanced
parameters' allow to modify default parameters used by IMGT/V-QUEST and
IMGT/JunctionAnalysis according to the users' interest. IMGT/V-QUEST is freely
available for academic research at http://imgt.cines.fr.
DOI: 10.1093/nar/gkn316
PMCID: PMC2447746
PMID: 18503082 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19900967
|
1. Nucleic Acids Res. 2010 Jan;38(Database issue):D301-7. doi:
10.1093/nar/gkp946. Epub 2009 Nov 9.
IMGT/3Dstructure-DB and IMGT/DomainGapAlign: a database and a tool for
immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF.
Ehrenmann F(1), Kaas Q, Lefranc MP.
Author information:
(1)IMGT, the International imMunoGeneTics Information System, Université
Montpellier 2, Laboratoire d'ImmunoGénétique Moléculaire LIGM, Institut de
Génétique Humaine IGH, UPR CNRS 1142, 141 rue de la Cardonille, 34396
Montpellier cedex 5, France.
IMGT/3Dstructure-DB is the three-dimensional (3D) structure database of IMGT,
the international ImMunoGenetics information system that is acknowledged as the
global reference in immunogenetics and immunoinformatics. IMGT/3Dstructure-DB
contains 3D structures of immunoglobulins (IG) or antibodies, T cell receptors
(TR), major histocompatibility complex (MHC) proteins, antigen receptor/antigen
complexes (IG/Ag, TR/peptide/MHC) of vertebrates; 3D structures of related
proteins of the immune system (RPI) of vertebrates and invertebrates, belonging
to the immunoglobulin and MHC superfamilies (IgSF and MhcSF, respectively) and
found in complexes with IG, TR or MHC. IMGT/3Dstructure-DB data are annotated
according to the IMGT criteria, using IMGT/DomainGapAlign, and based on the
IMGT-ONTOLOGY concepts and axioms. IMGT/3Dstructure-DB provides IMGT gene and
allele identification (CLASSIFICATION), region and domain delimitations
(DESCRIPTION), amino acid positions according to the IMGT unique numbering
(NUMEROTATION) that are used in IMGT/3Dstructure-DB cards, results of contact
analysis and renumbered flat files. In its Web version, the IMGT/DomainGapAlign
tool analyses amino acid sequences, per domain. Coupled to the
IMGT/Collier-de-Perles tool, it provides an invaluable help for antibody
engineering and humanization design based on complementarity determining region
(CDR) grafting as it precisely defines the standardized framework regions
(FR-IMGT) and CDR-IMGT. IMGT/3Dstructure-DB and IMGT/DomainGapAlign are freely
available at http://www.imgt.org.
DOI: 10.1093/nar/gkp946
PMCID: PMC2808948
PMID: 19900967 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17877839
|
1. BMC Bioinformatics. 2007 Sep 19;8:348. doi: 10.1186/1471-2105-8-348.
PADB: published association database.
Rhee H(1), Lee JS.
Author information:
(1)Department of Clinical Genetics, Yonsei University College of Medicine,
Seoul, Korea. hwanseok@yonsei.ac.kr
BACKGROUND: Although molecular pathway information and the International HapMap
Project data can help biomedical researchers to investigate the aetiology of
complex diseases more effectively, such information is missing or insufficient
in current genetic association databases. In addition, only a few of the
environmental risk factors are included as gene-environment interactions, and
the risk measures of associations are not indexed in any association databases.
DESCRIPTION: We have developed a published association database (PADB;
http://www.medclue.com/padb) that includes both the genetic associations and the
environmental risk factors available in PubMed database. Each genetic risk
factor is linked to a molecular pathway database and the HapMap database through
human gene symbols identified in the abstracts. And the risk measures such as
odds ratios or hazard ratios are extracted automatically from the abstracts when
available. Thus, users can review the association data sorted by the risk
measures, and genetic associations can be grouped by human genes or molecular
pathways. The search results can also be saved to tab-delimited text files for
further sorting or analysis. Currently, PADB indexes more than 1,500,000 PubMed
abstracts that include 3442 human genes, 461 molecular pathways and about
190,000 risk measures ranging from 0.00001 to 4878.9.
CONCLUSION: PADB is a unique online database of published associations that will
serve as a novel and powerful resource for reviewing and interpreting huge
association data of complex human diseases.
DOI: 10.1186/1471-2105-8-348
PMCID: PMC2039752
PMID: 17877839 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17241641
|
1. J Mol Biol. 2007 Mar 16;367(1):65-79. doi: 10.1016/j.jmb.2006.10.057. Epub
2006 Oct 21.
Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic
function.
Vafiadaki E(1), Sanoudou D, Arvanitis DA, Catino DH, Kranias EG,
Kontrogianni-Konstantopoulos A.
Author information:
(1)Molecular Biology Division, Center for Basic Research, Foundation for
Biomedical Research of the Academy of Athens, Soranou Efesiou 4, Athens 115 27,
Greece.
Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility
in the heart. Its regulatory effects are mediated through its interaction with
the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of
its Ca(2+)-affinity. To identify additional proteins that may interact with PLN,
we used the yeast-two-hybrid system to screen an adult human cardiac cDNA
library. HS-1 associated protein X-1 (HAX-1) was identified as a PLN-binding
partner. The minimal binding regions were mapped to amino acid residues 203-245
for HAX-1 and residues 16-22 for PLN. The interaction between the two proteins
was confirmed using GST-HAX-1, bound to the glutathione-matrix, which
specifically adsorbed native PLN from human or mouse cardiac homogenates, while
in reciprocal binding studies, recombinant His-HAX-1 bound GST-PLN. Kinetic
studies using surface plasmon resonance yielded a K(D) of approximately 1 muM as
the binding affinity for the PLN/HAX-1 complex. Phosphorylation of PLN by
cAMP-dependent protein kinase reduced binding to HAX-1, while increasing
concentrations of Ca(2+) diminished the PLN/HAX-1 interaction in a
dose-dependent manner. HAX-1 concentrated to mitochondria, but upon transient
co-transfection of HEK 293 cells with PLN, HAX-1 redistributed and co-localized
with PLN at the endoplasmic reticulum. Analysis of the anti-apoptotic function
of HAX-1 revealed that the presence of PLN enhanced the HAX-1 protective effects
from hypoxia/reoxygenation-induced cell death. These findings suggest a possible
link between the Ca(2+) handling by the sarcoplasmic reticulum and cell survival
mediated by the PLN/HAX-1 interaction.
DOI: 10.1016/j.jmb.2006.10.057
PMID: 17241641 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9367782
|
1. J Mol Biol. 1997 Nov 7;273(4):927-48. doi: 10.1006/jmbi.1997.1354.
Standard conformations for the canonical structures of immunoglobulins.
Al-Lazikani B(1), Lesk AM, Chothia C.
Author information:
(1)University of Cambridge Clinical School, Hills Road, Cambridge, CB2 2QH,
England.
A comparative analysis of the main-chain conformation of the L1, L2, L3, H1 and
H2 hypervariable regions in 17 immunoglobulin structures that have been
accurately determined at high resolution is described. This involves 79
hypervariable regions in all. We also analysed a part of the H3 region in 12 of
the 15 VH domains considered here. On the basis of the residues at key sites the
79 hypervariable regions can be assigned to one of 18 different canonical
structures. We show that 71 of these hypervariable regions have a conformation
that is very close to what can be defined as a "standard" conformation of each
canonical structure. These standard conformations are described in detail. The
other eight hypervariable regions have small deviations from the standard
conformations that, in six cases, involve only the rotation of a single peptide
group. Most H3 hypervariable regions have the same conformation in the part that
is close to the framework and the details of this conformation are also
described here.
Copyright 1997 Academic Press Limited
DOI: 10.1006/jmbi.1997.1354
PMID: 9367782 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20505370
|
1. Plant Signal Behav. 2010 Oct;5(10):1167-70. doi: 10.4161/psb.5.10.11905. Epub
2010 Oct 1.
A role for CHROMOMETHYLASE3 in mediating transposon and euchromatin silencing
during egg cell reprogramming in Arabidopsis.
Pillot M(1), Autran D, Leblanc O, Grimanelli D.
Author information:
(1)Laboratoire Génome et Développement des Plantes (LGDP), UMR 5096
IRD-CNRS-Université de Perpignan, Montpellier, France.
During embryogenesis there is a major switch from dependence upon
maternally-deposited products to reliance on products of the zygotic genome. In
animals, this so-called maternal-to-zygotic transition occurs following a period
of transcriptional quiescence. Recently, we have shown that the early embryo in
Arabidopsis is also quiescent, a state inherited from the female gamete and
linked to specific patterns of H3K9 dimethylation and TERMINAL FLOWER2 (TFL2)
localization. We also demonstrated that CHROMOMETHYLASE 3 (CMT3) is required for
H3K9 dimethylation in the egg cell and for normal embryogenesis during the first
few divisions of the zygote. Subsequent analysis of CMT3 mutants points to a key
role in egg cell reprogramming by controlling silencing in both transposon and
euchromatic regions. A speculative model of the CMT3-induced egg cell silencing
is presented here, based on these results and current data from the literature
suggesting the potential involvement of small RNAs targeted to the egg cell, a
process conceptually similar to the division of labor described in the male
gametophyte for which we show that H3K9 modifications and TFL2 localization are
reminiscent of the female gametophyte.
© 2010 Landes Bioscience
DOI: 10.4161/psb.5.10.11905
PMCID: PMC3115342
PMID: 20505370 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16820580
|
1. Circulation. 2006 Jul 4;114(1 Suppl):I245-50. doi:
10.1161/CIRCULATIONAHA.105.000786.
Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic
performance and are associated with reduced troponin I release after on-pump
coronary artery bypass grafting.
Ranasinghe AM(1), Quinn DW, Pagano D, Edwards N, Faroqui M, Graham TR, Keogh BE,
Mascaro J, Riddington DW, Rooney SJ, Townend JN, Wilson IC, Bonser RS.
Author information:
(1)Department of Cardiothoracic Surgery, University Hospital Birmingham,
Edgbaston, Birmingham, B15 2TH, UK.
BACKGROUND: Both glucose-insulin-potassium (GIK) and tri-iodothyronine (T3) may
improve cardiovascular performance after coronary artery surgery (CABG) but
their effects have not been directly compared and the effects of combined
treatment are unknown.
METHODS AND RESULTS: In 2 consecutive randomized double-blind placebo-controlled
trials, in patients undergoing first time isolated on-pump CABG between January
2000 and September 2004, 440 patients were recruited and randomized to either
placebo (5% dextrose) (n=160), GIK (40% dextrose, K+ 100 mmol.L(-1), insulin 70
u.L(-1)) (0.75 mL.kg(-1) h(-1)) (n=157), T3 (0.8 microg.kg(-1) followed by 0.113
microg.kg(-1) h(-1)) (n=63) or GIK+T3 (n=60). GIK/placebo therapy was
administered from start of operation until 6 hours after removal of aortic
cross-clamp (AXC) and T3/placebo was administered for a 6-hour period from
removal of AXC. Serial hemodynamic measurements were taken up to 12 hours after
removal of AXC and troponin I (cTnI) levels were assayed to 72 hours. Cardiac
index (CI) was significantly increased in both the GIK and GIK/T3 group in the
first 6 hours compared with placebo (P<0.001 for both) and T3 therapy (P=0.009
and 0.029, respectively). T3 therapy increased CI versus placebo between 6 and
12 hours after AXC removal (P=0.01) but combination therapy did not. Release of
cTnI was lower in all treatment groups at 6 and 12 hours after removal of AXC.
CONCLUSIONS: Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance
and results in reduced cTnI release in patients undergoing on-pump CABG surgery.
Combination therapy does not provide added hemodynamic effect.
DOI: 10.1161/CIRCULATIONAHA.105.000786
PMID: 16820580 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15946751
|
1. Biochim Biophys Acta. 2005 Jun 30;1729(2):118-25. doi:
10.1016/j.bbaexp.2005.04.001.
Isolation and expression analysis of genes encoding DNA methyltransferase in
wheat (Triticum aestivum L.).
Dai Y(1), Ni Z, Dai J, Zhao T, Sun Q.
Author information:
(1)Department of Plant Genetics and Breeding, State Key Laboratory for
Agrobiotechnology, China Agricultural University, Beijing.
DNA methylation of cytosine residues, catalyzed by DNA methyltransferases, is
suggested to play important roles in regulating gene expression and plant
development. In this study, we isolated four wheat cDNA fragments and one cDNA
with open reading frame encoding putative DNA methyltransferase and designated
TaMET1, TaMET2a, TaMET2b, TaCMT, TaMET3, respectively. BLASTX searches and
phylogenetic analysis suggested that five cDNAs belonged to four classes (Dnmt1,
Dnmt2, CMT and Dnmt3) of DNA methyltransferase genes. TaMET2a encoded a protein
of 376 aa and contained eight of ten conserved motifs characteristic of DNA
methyltransferase. Genomic sequence of TaMET2a was obtained and found to contain
ten introns and eleven exons. The expression analysis of the five genes revealed
that they were expressed in developing seed, during germination and various
vegetative tissues, but in quite different abundance. It was interesting to note
that TaMET1 and TaMET3 mRNAs were clearly detected in dry seeds. Moreover, the
differential expression patterns of five genes were observed between wheat
hybrid and its parents in leaf, stem and root of jointing stage, some were
up-regulated while some others were down-regulated in the hybrid. We concluded
that multiple wheat DNA methyltransferase genes were present and might play
important roles in wheat growth and development.
DOI: 10.1016/j.bbaexp.2005.04.001
PMID: 15946751 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21930502
|
1. Database (Oxford). 2011 Sep 19;2011:bar026. doi: 10.1093/database/bar026.
Print 2011.
International Cancer Genome Consortium Data Portal--a one-stop shop for cancer
genomics data.
Zhang J(1), Baran J, Cros A, Guberman JM, Haider S, Hsu J, Liang Y, Rivkin E,
Wang J, Whitty B, Wong-Erasmus M, Yao L, Kasprzyk A.
Author information:
(1)Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
The International Cancer Genome Consortium (ICGC) is a collaborative effort to
characterize genomic abnormalities in 50 different cancer types. To make this
data available, the ICGC has created the ICGC Data Portal. Powered by the
BioMart software, the Data Portal allows each ICGC member institution to manage
and maintain its own databases locally, while seamlessly presenting all the data
in a single access point for users. The Data Portal currently contains data from
24 cancer projects, including ICGC, The Cancer Genome Atlas (TCGA), Johns
Hopkins University, and the Tumor Sequencing Project. It consists of 3478
genomes and 13 cancer types and subtypes. Available open access data types
include simple somatic mutations, copy number alterations, structural
rearrangements, gene expression, microRNAs, DNA methylation and exon junctions.
Additionally, simple germline variations are available as controlled access
data. The Data Portal uses a web-based graphical user interface (GUI) to offer
researchers multiple ways to quickly and easily search and analyze the available
data. The web interface can assist in constructing complicated queries across
multiple data sets. Several application programming interfaces are also
available for programmatic access. Here we describe the organization,
functionality, and capabilities of the ICGC Data Portal.
DOI: 10.1093/database/bar026
PMCID: PMC3263593
PMID: 21930502 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20089483
|
1. Anadolu Kardiyol Derg. 2009 Dec;9 Suppl 2:17-23.
Sudden cardiac death in young competitive athletes due to genetic cardiac
abnormalities.
Wever-Pinzon OE(1), Myerson M, Sherrid MV.
Author information:
(1)Division of Cardiology, St Luke's - Roosevelt Hospital Center Columbia
University, College of Physicians & Surgeons New York City, NY 10019, USA.
Sudden cardiac death (SCD) in young athletes is generally caused by inherited
cardiac disorders. While these events are relatively few compared to other
cardiac deaths, they are tragic in that death occurs in a young, otherwise
healthy person. The genetic abnormalities most associated with SCD are
hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy,
long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic
ventricular tachycardia. As a result of growing awareness that these deaths can
be prevented, guidelines have been issued in both Europe and the United States
to help screen and determine qualification for young persons who want to
participate in competitive athletics. There remains debate on the how extensive
screening should be, in particular over the use of the 12-lead electrocardiogram
(ECG), with European guidelines mandating ECG and United States guidelines not
recommending routine use of the ECG.
PMID: 20089483 [Indexed for MEDLINE]
|
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