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http://www.ncbi.nlm.nih.gov/pubmed/16986122 | 1. Hum Mutat. 2007 Feb;28(2):168-76. doi: 10.1002/humu.20397.
A common variant located in the 3'UTR of the RET gene is associated with
protection from Hirschsprung disease.
Griseri P(1), Lantieri F, Puppo F, Bachetti T, Di Duca M, Ravazzolo R,
Ceccherini I.
Author information:
(1)Laboratory of Molecular Genetics, Institute G. Gaslini, Genova, Italy.
Complex diseases are common genetic disorders showing familial aggregation but
no typical Mendelian inheritance. Hirschsprung disease (HSCR), a developmental
disorder characterized by the absence of enteric neurons in distal segments of
the gut, shows a complex pattern of inheritance, with the RET protooncogene
acting as a major gene and additional susceptibility loci playing minor roles.
In the last years, we have identified a "protective" RET haplotype, which is
underrepresented in HSCR patients with respect to controls. Here, we demonstrate
that the protective effect of this haplotype is due to a variant located in the
3' untranslated region (UTR) of the RET gene, which slows down the physiological
mRNA decay of the gene transcripts. Such a functional effect of this common RET
variant explains the under-representation of the whole haplotype and its role as
a modifying factor in HSCR pathogenesis.
(c) 2006 Wiley-Liss, Inc.
DOI: 10.1002/humu.20397
PMID: 16986122 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17415329 | 1. MedGenMed. 2006 Dec 7;8(4):48.
Bacterial pericarditis and tamponade due to nonencapsulated Haemophilus
influenzae complicating a case of adult community-acquired pneumonia.
Garg P(1), Gupta R, Szalados JE.
Author information:
(1)Department of Medicine, University of Florida, Jacksonville, USA.
[email protected]
We report a case of bacterial pericarditis in an immunologically competent adult
female caused by nonencapsulated Haemophilus influenzae (H influenzae) that was
complicated by the acute development of life-threatening pericardial tamponade.
H influenzae is a gram-negative coccobacillus, a pathogen most frequently
associated with childhood exanthema (otitis media, meningitis) and, less
frequently, adult pneumonia. Encapsulated, type b, or typable H influenzae is
the strain implicated in childhood infections. On the other hand,
nonencapsulated or nontypable H influenzae is the specific strain most often
associated with exacerbation of chronic obstructive airway disease. Bacterial
pericarditis caused by either subtype of H influenzae is exceedingly rare. We
have located only 15 previously reported cases of H influenzae pericarditis
occurring in adults in the world medical literature, the majority of which date
back to the pre-antibiotic era. In 12 of these 15 cases (the only cases in which
typing could be accomplished), the encapsulated strain of H influenzae was
cultured from the pericardial fluid. Thus, to the best of our knowledge, we are
reporting here the first case of bacterial pericarditis caused by
nonencapsulated H influenzae in an immunologically competent adult.
PMCID: PMC1868328
PMID: 17415329 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22332442 | 1. Isr Med Assoc J. 2011 Dec;13(12):735-9.
The clinical significance of ventricular arrhythmias during an exercise test in
non-competitive and competitive athletes.
Fuchs T(1), Torjman A, Galitzkaya L, Leitman M, Pilz-Burstein R.
Author information:
(1)Arrhythmia Service, Assaf Harofeh Medical Center, Zerifin, affiliated with
Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.
[email protected]
BACKGROUND: Sudden death in athletes can occur during sport activities and is
presumably related to ventricular arrhythmias. There are no guidelines
concerning athletes who develop ventricular arrhythmias during an exercise test.
It is unclear whether they should be allowed to continue with their competitive
activity or not.
OBJECTIVES: To investigate the long-term follow-up of athletes with ventricular
arrhythmias during an exercise test.
METHODS: From a database of 56,462 athletes we identified 192 athletes, less
than 35 years old, who had ventricular arrhythmias during an exercise test.
Ninety athletes had > or = 3 ventricular premature beats (group A) and 102
athletes had ventricular couplets or non-sustained ventricular tachycardia
during an exercise test (group B). A control group of 92 athletes without
ventricular arrhythmias was randomly selected from the database (group C).
RESULTS: All athletes, except one who died from a dilated cardiomyopathy, were
alive during a follow-up period of 70 +/- 25 months. An abnormal echocardiogram
was obtained in seven athletes from group A (10%), four from group B (5%), and
one from group C (3%) (not significant). An abnormal echocardiogram was more
likely to be present in competitive athletes (P = 0.001) and in female athletes
(P = 0.01).
CONCLUSIONS: Our results showed that ventricular arrhythmias during exercise are
more commonly associated with cardiovascular abnormalities in young competitive
athletes and in female athletes. When present, they necessitate a thorough
investigation and follow-up.
PMID: 22332442 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22231448 | 1. Oncogene. 2012 Sep 20;31(38):4245-54. doi: 10.1038/onc.2011.586. Epub 2012 Jan
9.
Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication
fork restart.
Hromas R(1), Williamson EA, Fnu S, Lee YJ, Park SJ, Beck BD, You JS, Leitao A,
Nickoloff JA, Lee SH.
Author information:
(1)Department of Medicine, University of Florida and Shands Health Care System,
Gainesville, FL 32610, USA. [email protected]
Erratum in
Oncogene. 2014 Jan 23;33(4):536. Laitao, A [corrected to Leitao, A].
Chk1 both arrests replication forks and enhances repair of DNA damage by
phosphorylating downstream effectors. Although there has been a concerted effort
to identify effectors of Chk1 activity, underlying mechanisms of effector action
are still being identified. Metnase (also called SETMAR) is a SET and
transposase domain protein that promotes both DNA double-strand break (DSB)
repair and restart of stalled replication forks. In this study, we show that
Metnase is phosphorylated only on Ser495 (S495) in vivo in response to DNA
damage by ionizing radiation. Chk1 is the major mediator of this phosphorylation
event. We had previously shown that wild-type (wt) Metnase associates with
chromatin near DSBs and methylates histone H3 Lys36. Here we show that a
Ser495Ala (S495A) Metnase mutant, which is not phosphorylated by Chk1, is
defective in DSB-induced chromatin association. The S495A mutant also fails to
enhance repair of an induced DSB when compared with wt Metnase. Interestingly,
the S495A mutant demonstrated increased restart of stalled replication forks
compared with wt Metnase. Thus, phosphorylation of Metnase S495 differentiates
between these two functions, enhancing DSB repair and repressing replication
fork restart. In summary, these data lend insight into the mechanism by which
Chk1 enhances repair of DNA damage while at the same time repressing stalled
replication fork restart.
DOI: 10.1038/onc.2011.586
PMCID: PMC3963179
PMID: 22231448 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23169561 | 1. Heredity (Edinb). 2013 Jan;110(1):10-8. doi: 10.1038/hdy.2012.46. Epub 2012
Nov 21.
The basis of antagonistic pleiotropy in hfq mutations that have opposite effects
on fitness at slow and fast growth rates.
Maharjan R(1), McKenzie C, Yeung A, Ferenci T.
Author information:
(1)School of Molecular Bioscience, University of Sydney, Sydney, New South
Wales, Australia.
Mutations beneficial in one environment may cause costs in different
environments, resulting in antagonistic pleiotropy. Here, we describe a novel
form of antagonistic pleiotropy that operates even within the same environment,
where benefits and deleterious effects exhibit themselves at different growth
rates. The fitness of hfq mutations in Escherichia coli affecting the RNA
chaperone involved in small-RNA regulation is remarkably sensitive to growth
rate. E. coli populations evolving in chemostats under nutrient limitation
acquired beneficial mutations in hfq during slow growth (0.1 h(-1)) but not in
populations growing sixfold faster. Four identified hfq alleles from parallel
populations were beneficial at 0.1 h(-1) and deleterious at 0.6 h(-1). The hfq
mutations were beneficial, deleterious or neutral at an intermediate growth rate
(0.5 h(-1)) and one changed from beneficial to deleterious within a 36 min
difference in doubling time. The benefit of hfq mutations was due to the greater
transport of limiting nutrient, which diminished at higher growth rates. The
deleterious effects of hfq mutations at 0.6 h(-1) were less clear, with
decreased viability a contributing factor. The results demonstrate distinct
pleiotropy characteristics in the alleles of the same gene, probably because the
altered residues in Hfq affected the regulation of expression of different genes
in distinct ways. In addition, these results point to a source of variation in
experimental measurement of the selective advantage of a mutation; estimates of
fitness need to consider variation in growth rate impacting on the magnitude of
the benefit of mutations and on their fitness distributions.
DOI: 10.1038/hdy.2012.46
PMCID: PMC3530959
PMID: 23169561 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17489946 | 1. Acta Neurol Scand. 2007 May;115(5):347-50. doi:
10.1111/j.1600-0404.2007.00796.x.
Pregabalin in restless legs syndrome with and without neuropathic pain.
Sommer M(1), Bachmann CG, Liebetanz KM, Schindehütte J, Tings T, Paulus W.
Author information:
(1)Department of Clinical Neurophysiology, University of Goettingen, Goettingen,
Germany. [email protected]
BACKGROUND: Restless legs syndrome (RLS) is a common neurological disorder
complicated in many patients by augmentation to dopaminergic therapy or
comorbidities such as neuropathic pain.
AIMS: To explore the effectiveness of pregabalin in RLS in a pragmatic clinical
setting.
METHODS: After observing improvement of restless legs symptoms in seven patients
treated with pregabalin for neuropathic pain, we extended the clinical
observation to a total of 16 patients with secondary RLS, in most of them due to
neuropathy, and to three patients with idiopathic RLS.
RESULTS: Three patients discontinued pregabalin because of side effects (rash,
fatigue, loss of efficacy). The other 16 patients self-rated a satisfactory or
good alleviation of RLS symptoms and maintained pregabalin, five with add-on
medication, on a mean daily dose of 305 mg (standard deviation, 185 mg), and
with a mean duration of 217 (standard deviation, 183) days.
CONCLUSION: These data propose pregabalin as a new option in the treatment of
secondary RLS for patients with neuropathic pain, which should be further
investigated with randomized, placebo-controlled trials.
DOI: 10.1111/j.1600-0404.2007.00796.x
PMID: 17489946 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16475235 | 1. Prenat Diagn. 2006 Mar;26(3):226-30. doi: 10.1002/pd.1385.
A novel heterozygous missense mutation 377T > C (V126A) of TGIF gene in a family
segregated with holoprosencephaly and moyamoya disease.
Chen M(1), Kuo SJ, Liu CS, Chen WL, Ko TM, Chen TH, Chang SP, Huang CH, Chang
YY, Wang BT.
Author information:
(1)Department of Obstetrics and Gynecology, Changhua Christian Hospital,
Changhua, Taiwan, Republic of China. [email protected]
OBJECTIVES: To identify whether any mutations of candidate genes including SHH,
ZIC2, SIX3, and TGIF exist in a Taiwanese family segregated with
holoprosencephaly (HPE) and moyamoya disease.
METHODS: Genotypes of the candidate genes SHH, ZIC2, SIX3, and TGIF were
determined in the family members who were available for analysis by sequencing.
In addition, genomic regions of another 50 unrelated Taiwanese (100 chromosomes)
were studied to verify whether the nucleotide changes we found were mutations or
polymorphisms.
RESULTS: A novel missense mutation 377T > C and two polymorphisms (420A > G and
487C > T) in the TGIF gene were identified. No mutations in SHH, ZIC2 and SIX3
were found. The mother of the three HPE fetuses was found to be afflicted with
moyamoya disease. A brief review of the mutations as well as polymorphisms
reported in the TGIF gene up to 2005 is given.
CONCLUSION: Molecular diagnosis can help genetic counseling in HPE, which is a
heterogeneous disorder with its phenotypic and genotypic spectrum highly widened
and variable. The possible association between TGIF mutation and moyamoya
disease noted in our study also appeared to be novel.
2006 John Wiley & Sons, Ltd.
DOI: 10.1002/pd.1385
PMID: 16475235 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18926777 | 1. J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Nov 15;875(2):478-86. doi:
10.1016/j.jchromb.2008.09.029. Epub 2008 Oct 2.
Proteomic analysis optimization: selective protein sample on-column retention in
reverse-phase liquid chromatography.
Winnik WM(1), Ortiz PA.
Author information:
(1)National Health and Environmental Effects Research Laboratory, Environmental
Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle
Park, NC 27711, United States. [email protected]
In an effort to optimize reverse-phase liquid chromatography (RPLC) for
proteomics, we studied the impact of composition of the sample injection
solution on protein on-column selection and retention. All the proteins studied
were retained on-column when injections were made in 50% formic acid, 0.1% TFA
or 8.3M urea. When formic acid was increased to 80%, the superoxide dismutase
standard (MW 26,159) and 58 mouse microsomal proteins that possessed low-range
molecular weights, high pIs or basic amino acid clusters were non-retained,
resulting in retention selectivity during sample injection. Introducing to the
80% formic acid injection solution an organic solvent such as acetonitrile or
acetonitrile-DMSO induced further retention selectivity, and increasing levels
of organic solvents reduced on-column retention. The proteome was split into the
proteins that were retained on-column which eluted at higher retention times
(RTs), vs the proteins that collected in the injection flow-through which
normally eluted at lower RTs. This protein selectivity was confirmed after
fraction collection, 1D-GE and nano-LC-MS/MS. The significance of this procedure
is that it can be exploited for fast extraction of small basic proteins from the
bulk of the proteome and for on-column enrichment of hydrophobic proteins.
DOI: 10.1016/j.jchromb.2008.09.029
PMID: 18926777 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16332963 | 1. Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18075-80. doi:
10.1073/pnas.0503676102. Epub 2005 Dec 6.
The SET domain protein Metnase mediates foreign DNA integration and links
integration to nonhomologous end-joining repair.
Lee SH(1), Oshige M, Durant ST, Rasila KK, Williamson EA, Ramsey H, Kwan L,
Nickoloff JA, Hromas R.
Author information:
(1)Department of Biochemistry and Molecular Biology, Indiana University School
of Medicine, Indianapolis, 46202, USA.
The molecular mechanism by which foreign DNA integrates into the human genome is
poorly understood yet critical to many disease processes, including retroviral
infection and carcinogenesis, and to gene therapy. We hypothesized that the
mechanism of genomic integration may be similar to transposition in lower
organisms. We identified a protein, termed Metnase, that has a SET domain and a
transposase/nuclease domain. Metnase methylates histone H3 lysines 4 and 36,
which are associated with open chromatin. Metnase increases resistance to
ionizing radiation and increases nonhomologous end-joining repair of DNA
doublestrand breaks. Most significantly, Metnase promotes integration of
exogenous DNA into the genomes of host cells. Therefore, Metnase is a
nonhomologous end-joining repair protein that regulates genomic integration of
exogenous DNA and establishes a relationship among histone modification, DNA
repair, and integration. The data suggest a model wherein Metnase promotes
integration of exogenous DNA by opening chromatin and facilitating joining of
DNA ends. This study demonstrates that eukaryotic transposase domains can have
important cell functions beyond transposition of genetic elements.
DOI: 10.1073/pnas.0503676102
PMCID: PMC1312370
PMID: 16332963 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20674333 | 1. Eur J Cancer. 2010 Oct;46(15):2726-38. doi: 10.1016/j.ejca.2010.06.118. Epub
2010 Jul 30.
An international validation study of the EORTC QLQ-INFO25 questionnaire: an
instrument to assess the information given to cancer patients.
Arraras JI(1), Greimel E, Sezer O, Chie WC, Bergenmar M, Costantini A, Young T,
Vlasic KK, Velikova G.
Author information:
(1)Oncology Department, Hospital de Navarra, Pamplona, Spain.
[email protected]
AIM: The EORTC Quality of Life (QOL) Group has developed an instrument to
evaluate the information received by cancer patients. This study assessed the
psychometric characteristics of the EORTC INFO module in a large
international/multi-cultural sample of cancer patients.
METHODS: The provisional 26-item information module (EORTC INFO26) was
administered with the EORTC QLQ-C30 and the information scales of the inpatient
satisfaction module EORTC IN-PATSAT32 on two occasions during the patients'
treatment and follow-up period. Questionnaire-hypothesised scale structure,
reliability, validity and responsiveness to changes were evaluated through
standard psychometric analyses. Patient acceptability was assessed with a
debriefing questionnaire.
RESULTS: The study comprised 509 patients from 8 countries (7 European countries
and Taiwan) with different cancers and disease stages. Multi-trait scaling
analysis led to the deletion of one item but confirmed the hypothesised 4
multi-item scales (information about disease, medical tests, treatment and other
services) and eight single items. Internal consistency for all scales was good
(α>0.70), as was test-retest reliability (intraclass correlations>0.70). All
items can be combined to generate a single score (α>0.90). Convergent validity
was supported by significant correlations with related areas of IN-PATSAT32
(r>0.40). Low correlations with EORTC QLQ-C30 scales confirmed divergent
validity (r<0.30) The EORTC INFO-25 module discriminated among groups based on
gender, age, education, levels of anxiety and depression, information wishes and
satisfaction. Only one scale captured changes over time.
CONCLUSIONS: The EORTC QLQ-INFO 25 is a reliable and valid self-reported
instrument. The module can be used in cross-cultural observational and
intervention studies.
Copyright © 2010 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ejca.2010.06.118
PMID: 20674333 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23150934 | 1. N Engl J Med. 2013 Jan 10;368(2):117-27. doi: 10.1056/NEJMoa1211851. Epub 2012
Nov 14.
TREM2 variants in Alzheimer's disease.
Guerreiro R(1), Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E,
Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J,
Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K,
Powell J, St George-Hyslop P, Singleton A, Hardy J; Alzheimer Genetic Analysis
Group.
Collaborators: Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E,
Majounie E, Cruchaga C, Sassi C, Kauwe JS, Lupton MK, Ryten M, Brown K, Lowe J,
Ridge PG, Hammer MB, Wakutani Y, Hazrati L, Proitsi P, Newhouse S, Lohmann E,
Erginel-Unaltuna N, Medway C, Hanagasi H, Troakes C, Gurvit H, Bilgic B,
Al-Sarraj S, Benitez B, Cooper B, Carrell D, Emre M, Zou F, Ma L, Murray M,
Dickson D, Younkin S, Petersen RC, Corcoran CD, Cai Y, Oliveira C, Ribeiro MH,
Santana I, Tschanz JT, Gibbs J, Norton MC, Kloszewska I, Mecocci P, Soininen H,
Tsolaki M, Vellas B, Munger RG, Mann DM, Pickering-Brown S, Lovestone S, Beck J,
Mead S, Collinge J, Parsons L, Pocock J, Morris JC, Revesz T, Lashley T, Fox NC,
Rossor MN, Grenier-Boley B, Bellenguez C, Moskvina V, Sims R, Harold D, Williams
J, Lambert JC, Amouyel P, Graff-Radford N, Goate A, Rademakers R, Morgan K,
Powell J, St George-Hyslop P, Singleton A, Hardy J, Gerrish A, Chapman J,
Abraham R, Hollingworth P, Hamshere M, Pahwa JS, Dowzell K, Williams A, Jones N,
Thomas C, Stretton A, Morgan A, Williams K, Thomas S, Brayne C, Rubinsztein DC,
Gill M, Lawlor B, Lynch A, Passmore P, Craig D, McGuinness B, Johnston JA, Todd
S, Holmes C, Smith A, Love S, Kehoe PG, Maier W, Jessen F, Heun R, Kölsch H,
Schürmann B, Ramirez A, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J,
Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Nowotny P, Mayo K,
Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Nöthen
MM, Holmans P, O'Donovan M, Owen MJ, Zelenika D, Epelbaum J, Dartigues JF,
Tzourio C, Berr C, Boland A, Campion D, Alpérovitch A, Lathrop M, Smith C,
Trabzuni D, Walker R, Weale M.
Author information:
(1)University College London (UCL) Institute of Neurology, London, United
Kingdom.
Comment in
N Engl J Med. 2013 Jan 10;368(2):182-4. doi: 10.1056/NEJMe1213157.
Nat Rev Neurol. 2013 Jan;9(1):5. doi: 10.1038/nrneurol.2012.254.
Clin Genet. 2013 Jun;83(6):525-6. doi: 10.1111/cge.12108.
N Engl J Med. 2013 Oct 17;369(16):1564-5. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1565. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1568. doi: 10.1056/NEJMc1306509.
N Engl J Med. 2013 Oct 17;369(16):1569-70. doi: 10.1056/NEJMc1306509.
BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the
triggering receptor expressed on myeloid cells 2 protein, have previously been
associated with an autosomal recessive form of early-onset dementia.
METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic
variability in TREM2 in a series of 1092 patients with Alzheimer's disease and
1107 controls (the discovery set). We then performed a meta-analysis on imputed
data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution)
from three genomewide association studies of Alzheimer's disease and tested for
the association of the variant with disease. We genotyped the R47H variant in an
additional 1887 cases and 4061 controls. We then assayed the expression of TREM2
across different regions of the human brain and identified genes that are
differentially expressed in a mouse model of Alzheimer's disease and in control
mice.
RESULTS: We found significantly more variants in exon 2 of TREM2 in patients
with Alzheimer's disease than in controls in the discovery set (P=0.02). There
were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant
alleles in 1107 controls (P<0.001). The most commonly associated variant,
rs75932628 (encoding R47H), showed highly significant association with
Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed
from genomewide association studies confirmed this association (P=0.002), as did
direct genotyping of an additional series of 1887 patients with Alzheimer's
disease and 4061 controls (P<0.001). Trem2 expression differed between control
mice and a mouse model of Alzheimer's disease.
CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a
significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's
Research UK and others.).
DOI: 10.1056/NEJMoa1211851
PMCID: PMC3631573
PMID: 23150934 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12851688 | 1. Int J Oncol. 2003 Aug;23(2):389-400.
Non-small and small cell lung carcinoma cell lines exhibit cell type-specific
sensitivity to edelfosine-induced cell death and different cell line-specific
responses to edelfosine treatment.
Shafer SH(1), Williams CL.
Author information:
(1)Molecular Pharmacology Laboratory, Guthrie Research Institute, Sayre, PA
18840, USA.
The unique signal transduction pathways that distinguish non-small cell lung
carcinoma (NSCLC) from small cell lung carcinoma (SCLC) are poorly understood.
We investigated the ability of edelfosine, an inhibitor of
phosphatidylinositol-specific phospholipase C (PLC) to inhibit cell viability
among four NSCLC cell lines and four SCLC cell lines. The differential
sensitivity of cells to edelfosine's cytostatic and cytotoxic effects has been
attributed to edelfosine-induced changes in the activities of many enzymes,
including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated
kinases (ERK), p38 kinase, and poly(ADP-ribose) polymerase (PARP). To
investigate the role of these enzymes in edelfosine-induced cytotoxicity, we
correlated edelfosine-induced changes in enzyme activity and cell viability
among the different NSCLC and SCLC cell lines. We found that NSCLC cells are
much more susceptible to the cytotoxic effects of this drug than are SCLC cells.
Three out of the four edelfosine-sensitive NSCLC cell lines (NCI-H157, NCI-H520,
NCI-H522) exhibit G2/M arrest, significant apoptosis and some degree of JNK
activation in response to drug treatment. In contrast, none of the SCLC cell
lines exhibit edelfosine-induced G2/M arrest or significant apoptosis. A
comparison of the edelfosine-induced effects among the sensitive and resistant
lung cancer lines indicates that there is little correlation between
edelfosine-induced cytotoxicity and altered activities of JNK, ERK, p38, or
cleavage of PARP. These results demonstrate that edelfosine-induced changes in
JNK, ERK, p38, or PARP are not good predictors of cell susceptibility to
edelfosine-induced cytotoxicity. Thus, edelfosine-induced inactivation of PLC
may disrupt signaling cascades downstream of PLC that are unique to individual
cellular environments. These findings also identify edelfosine as one of the few
potential chemotherapeutic agents that has a greater cytotoxic effect against
NSCLC cells than SCLC cells.
PMID: 12851688 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21932936 | 1. Hemoglobin. 2011;35(5-6):450-62. doi: 10.3109/03630269.2011.613506. Epub 2011
Sep 20.
Milestones in the history of hemoglobin research (in memory of professor Titus
H.J. Huisman).
Thein SL(1).
Author information:
(1)Department of Molecular Haematology, King's College London, London, UK.
[email protected]
Professor Titus H.J. Huisman is best known for his work on hemoglobin (Hb)
variants. To date, more than 1,000 Hb variants have been discovered and
characterized, of which about one-third were discovered in Titus Huisman's
laboratory at the Medical College of Georgia, Augusta, GA, USA. A registry of
these Hb variants and other information, a legacy from Professor Huisman, is now
available online, at HbVar database (hhtp://globin.bx.psu.edu/hbvar). During the
last century, major developments in Hb research have been made using physical,
chemical, physiological and genetic methods. This review highlights the
milestones and key developments in Hb research most relevant to hematologists,
and that have impacted our understanding and management of the thalassemias and
sickle cell disease.
DOI: 10.3109/03630269.2011.613506
PMID: 21932936 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19170108 | 1. J Cell Physiol. 2009 Jun;219(3):634-41. doi: 10.1002/jcp.21708.
Mitochondrial localization, ELK-1 transcriptional regulation and growth
inhibitory functions of BRCA1, BRCA1a, and BRCA1b proteins.
Maniccia AW(1), Lewis C, Begum N, Xu J, Cui J, Chipitsyna G, Aysola K, Reddy V,
Bhat G, Fujimura Y, Henderson B, Reddy ES, Rao VN.
Author information:
(1)Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine,
Georgia Cancer Center for Excellence, Atlanta, Georgia, USA.
BRCA1 is a tumor suppressor gene that is mutated in families with breast and
ovarian cancer. Several BRCA1 splice variants are found in different tissues,
but their subcellular localization and functions are poorly understood at the
moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis
and function as a tumor suppressor of triple negative breast, ovarian and
prostate cancers. In this study we have analyzed the function of BRCA1 isoforms
(BRCA1a and BRCA1b) and compared them to the wild-type BRCA1 protein using
several criteria like studying expression in normal and tumor cells by RNase
protection assays, subcellular localization/fractionation by immunofluorescence
microscopy and Western blot analysis, transcription regulation of biological
relevant proteins and growth suppression in breast cancer cells. We are
demonstrating for the first time that ectopically expressed GFP-tagged BRCA1,
BRCA1a, and BRCA1b proteins are localized to the mitochondria, repress ELK-1
transcriptional activity and possess antiproliferative activity on breast cancer
cells. These results suggest that the exon 9, 10, and 11 sequences (aa 263-1365)
which contain two nuclear localization signals, p53, Rb, c-Myc, gamma-tubulin,
Stat, Rad51, Rad50 binding domains, angiopoietin-1 repression domain are not
absolutely required for mitochondrial localization and growth suppressor
function of these proteins. Since mitochondrial dysfunction is a hallmark of
cancer, we can speculate that the mitochondrial localization of BRCA1 proteins
may be functionally significant in regulating both the mitochondrial DNA damage
as well as apoptotic activity of BRCA1 proteins and mislocalization causes
cancer. J. Cell. Physiol. 219: 634-641, 2009. (c) 2009 Wiley-Liss, Inc.
DOI: 10.1002/jcp.21708
PMCID: PMC3693557
PMID: 19170108 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10823953 | 1. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6085-90. doi:
10.1073/pnas.97.11.6085.
Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic
pulmonary lymphangioleiomyomatosis.
Carsillo T(1), Astrinidis A, Henske EP.
Author information:
(1)Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia PA
19111, USA.
Lymphangioleiomyomatosis (LAM) is a progressive and often fatal interstitial
lung disease characterized by a diffuse proliferation of abnormal smooth muscle
cells in the lungs. LAM is of unusual interest biologically because it affects
almost exclusively young women. LAM can occur as an isolated disorder (sporadic
LAM) or in association with tuberous sclerosis complex. Renal angiomyolipomas,
which are found in most tuberous sclerosis patients, also occur in 60% of
sporadic LAM patients. We previously found TSC2 loss of heterozygosity in 7 of
13 (54%) of angiomyolipomas from sporadic LAM patients, suggesting that LAM and
TSC could have a common genetic basis. In this study, we report the
identification of somatic TSC2 mutations in five of seven angiomyolipomas from
sporadic LAM patients. In all four patients from whom lung tissue was available,
the same mutation found in the angiomyolipoma was present in the abnormal
pulmonary smooth muscle cells. In no case was the mutation present in normal
kidney, morphologically normal lung, or lymphoblastoid cells. Our data
demonstrate that somatic mutations in the TSC2 gene occur in the angiomyolipomas
and pulmonary LAM cells of women with sporadic LAM, strongly supporting a direct
role of TSC2 in the pathogenesis of this disease.
DOI: 10.1073/pnas.97.11.6085
PMCID: PMC18562
PMID: 10823953 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19690168 | 1. J Biol Chem. 2009 Dec 4;284(49):34189-200. doi: 10.1074/jbc.M109.008417. Epub
2009 Aug 18.
NF-YC complexity is generated by dual promoters and alternative splicing.
Ceribelli M(1), Benatti P, Imbriano C, Mantovani R.
Author information:
(1)Dipartimento di Scienze Biomolecolari e Biotecnologie, Università degli Studi
di Milano, Via Celoria 26, 20133 Milano, Italy.
The CCAAT box is a DNA element present in the majority of human promoters, bound
by the trimeric NF-Y, composed of NF-YA, NF-YB, and NF-YC subunits. We describe
and characterize novel isoforms of one of the two histone-like subunits, NF-YC.
The locus generates a minimum of four splicing products, mainly located within
the Q-rich activation domain. The abundance of each isoform is cell-dependent;
only one major NF-YC isoform is present in a given cell type. The 37- and 50-kDa
isoforms are mutually exclusive, and preferential pairings with NF-YA isoforms
possess different transcriptional activities, with specific combinations being
more active on selected promoters. The transcriptional regulation of the NF-YC
locus is also complex, and mRNAs arise from the two promoters P1 and P2.
Transient transfections, chromatin immunoprecipitations, and reverse
transcription-PCRs indicate that P1 has a robust housekeeping activity; P2
possesses a lower basal activity, but it is induced in response to DNA damage in
a p53-dependent way. Alternative promoter usage directly affects NF-YC splicing,
with the 50-kDa transcript being excluded from P2. Specific functional
inactivation of the 37-kDa isoform affects the basal levels of G(1)/S blocking
and pro-apoptotic genes but not G(2)/M promoters. In summary, our data highlight
an unexpected degree of complexity and regulation of the NF-YC gene,
demonstrating the existence of a discrete cohort of NF-Y trimer subtypes
resulting from the functional diversification of Q-rich transactivating subunits
and a specific role of the 37-kDa isoform in suppression of the DNA
damage-response under growing conditions.
DOI: 10.1074/jbc.M109.008417
PMCID: PMC2797189
PMID: 19690168 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20598273 | 1. Am J Hum Genet. 2010 Jul 9;87(1):60-74. doi: 10.1016/j.ajhg.2010.06.007.
Differential contributions of rare and common, coding and noncoding Ret
mutations to multifactorial Hirschsprung disease liability.
Emison ES(1), Garcia-Barcelo M, Grice EA, Lantieri F, Amiel J, Burzynski G,
Fernandez RM, Hao L, Kashuk C, West K, Miao X, Tam PK, Griseri P, Ceccherini I,
Pelet A, Jannot AS, de Pontual L, Henrion-Caude A, Lyonnet S, Verheij JB,
Hofstra RM, Antiñolo G, Borrego S, McCallion AS, Chakravarti A.
Author information:
(1)Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic
Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine
kinase RET. In a study of 690 European- and 192 Chinese-descent probands and
their parents or controls, we demonstrate the ubiquity of a >4-fold
susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European
ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within
the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T
variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET
transactivation. The T allele, with a control frequency of 20%-30%/47% and case
frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved
in all forms of HSCR. It is marginally associated with proband gender (p = 0.13)
and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and
familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the
common forms of male, short-segment, and simplex families whereas multiple,
rare, coding mutations are the norm in the less common and more severe forms of
female, long-segment, and multiplex families. The T variant also increases
penetrance in patients with rare RET coding mutations. Thus, both rare and
common mutations, individually and together, make contributions to the risk of
HSCR. The distribution of RET variants in diverse HSCR patients suggests a
"cellular-recessive" genetic model where both RET alleles' function is
compromised. The RET allelic series, and its genotype-phenotype correlations,
shows that success in variant identification in complex disorders may strongly
depend on which patients are studied.
Copyright 2010 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2010.06.007
PMCID: PMC2896767
PMID: 20598273 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23372769 | 1. PLoS One. 2013;8(1):e54800. doi: 10.1371/journal.pone.0054800. Epub 2013 Jan
23.
Mutational spectrum of semaphorin 3A and semaphorin 3D genes in Spanish
Hirschsprung patients.
Luzón-Toro B(1), Fernández RM, Torroglosa A, de Agustín JC, Méndez-Vidal C,
Segura DI, Antiñolo G, Borrego S.
Author information:
(1)Department of Genetics, Reproduction and Fetal Medicine, Institute of
Biomedicine of Seville, University Hospital Virgen del Rocío/Consejo Superior de
Investigaciones Científicas/University of Seville, Seville, Spain.
Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder
characterized by the absence of ganglion cells along variable lengths of the
distal gastrointestinal tract, which results in tonic contraction of the
aganglionic colon segment and functional intestinal obstruction. The RET
proto-oncogene is the major gene associated to HSCR with differential
contributions of its rare and common, coding and noncoding mutations to the
multifactorial nature of this pathology. In addition, many other genes have been
described to be associated with this pathology, including the semaphorins class
III genes SEMA3A (7p12.1) and SEMA3D (7q21.11) through SNP array analyses and by
next-generation sequencing technologies. Semaphorins are guidance cues for
developing neurons implicated in the axonal projections and in the determination
of the migratory pathway for neural-crest derived neural precursors during
enteric nervous system development. In addition, it has been described that
increased SEMA3A expression may be a risk factor for HSCR through the
upregulation of the gene in the aganglionic smooth muscle layer of the colon in
HSCR patients. Here we present the results of a comprehensive analysis of SEMA3A
and SEMA3D in a series of 200 Spanish HSCR patients by the mutational screening
of its coding sequence, which has led to find a number of potentially
deleterious variants. RET mutations have been also detected in some of those
patients carrying SEMAs variants. We have evaluated the A131T-SEMA3A,
S598G-SEMA3A and E198K-SEMA3D mutations using colon tissue sections of these
patients by immunohistochemistry. All mutants presented increased protein
expression in smooth muscle layer of ganglionic segments. Moreover, A131T-SEMA3A
also maintained higher protein levels in the aganglionic muscle layers. These
findings strongly suggest that these mutants have a pathogenic effect on the
disease. Furthermore, because of their coexistence with RET mutations, our data
substantiate the additive genetic model proposed for this rare disorder and
further support the association of SEMAs genes with HSCR.
DOI: 10.1371/journal.pone.0054800
PMCID: PMC3553056
PMID: 23372769 [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/12581156 | 1. Genes Cells. 2003 Feb;8(2):131-44. doi: 10.1046/j.1365-2443.2003.00620.x.
Mitogen-activated protein kinase p38 defines the common senescence-signalling
pathway.
Iwasa H(1), Han J, Ishikawa F.
Author information:
(1)Laboratory of Molecular and Cellular Assembly, Department of Biological
Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of
Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan.
BACKGROUND: Cellular senescence is a state of irreversible growth arrest shown
by normal cells, and has been most extensively studied in replicative senescence
caused by telomere shortening. Several conditions, including oncogenic Ras
over-expression and inappropriate culture conditions, also induce senescence
without telomere shortening. However, it remains unclear how a common set of
senescence phenotypes is indistinguishably induced in various types of
senescence.
RESULTS: We demonstrate that p38 mitogen-activated protein kinase (MAPK) plays
important causative roles in senescent cells following telomere shortening,
Ras-Raf activation, oxidative stress or inappropriate culture conditions. By
monitoring the kinetics of p38 activation, we suggest that p38 is activated not
directly by the initial stimuli, but in response to unidentified cellular
conditions caused by these stimuli. Importantly, this p38-activating condition
appears to be defined quantitatively as a sum of continuous and low-level
stresses, and remains even after the initial stimuli are withdrawn, which may
explain the well-known irreversible nature of cellular senescence. We also show
that papilloma virus E7 abolishes the p38-induced growth arrest but not other
senescence-associated phenotypes, indicating the differential role of pRb in the
downstream of p38.
CONCLUSION: These results indicate that p38 comprises the senescence-executing
pathway in response to diverse stimuli.
DOI: 10.1046/j.1365-2443.2003.00620.x
PMID: 12581156 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9482835 | 1. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2044-9. doi:
10.1073/pnas.95.5.2044.
Multiple evolutionary origins of the fungus causing Panama disease of banana:
concordant evidence from nuclear and mitochondrial gene genealogies.
O'Donnell K(1), Kistler HC, Cigelnik E, Ploetz RC.
Author information:
(1)National Center for Agricultural Utilization Research, U.S. Department of
Agriculture-Agricultural Research Service, 1815 North University Street, Peoria,
IL 61604, USA. [email protected]
Panama disease of banana, caused by the fungus Fusarium oxysporum f. sp.
cubense, is a serious constraint both to the commercial production of banana and
cultivation for subsistence agriculture. Previous work has indicated that F.
oxysporum f. sp. cubense consists of several clonal lineages that may be
genetically distant. In this study we tested whether lineages of the Panama
disease pathogen have a monophyletic origin by comparing DNA sequences of
nuclear and mitochondrial genes. DNA sequences were obtained for translation
elongation factor 1alpha and the mitochondrial small subunit ribosomal RNA genes
for F. oxysporum strains from banana, pathogenic strains from other hosts and
putatively nonpathogenic isolates of F. oxysporum. Cladograms for the two genes
were highly concordant and a partition-homogeneity test indicated the two
datasets could be combined. The tree inferred from the combined dataset resolved
five lineages corresponding to "F. oxysporum f. sp. cubense" with a large
dichotomy between two taxa represented by strains most commonly isolated from
bananas with Panama disease. The results also demonstrate that the latter two
taxa have significantly different chromosome numbers. F. oxysporum isolates
collected as nonpathogenic or pathogenic to other hosts that have very similar
or identical elongation factor 1alpha and mitochondrial small subunit genotypes
as banana pathogens were shown to cause little or no disease on banana. Taken
together, these results indicate Panama disease of banana is caused by fungi
with independent evolutionary origins.
DOI: 10.1073/pnas.95.5.2044
PMCID: PMC19243
PMID: 9482835 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14720367 | 1. Ai Zheng. 2004 Jan;23(1):8-14.
[Expression and structure of BNIP3L in lung cancer].
[Article in Chinese]
Sun JL(1), He XS, Yu YH, Chen ZC.
Author information:
(1)Cancer Research Institute, Xiangya School of Medicine, Central South
University, Changsha, Hunan, 410078, P.R.China.
BACKGROUND & OBJECTIVE: Bcl-2/E1B 19kDa interacting protein3-like (BNIP3L) gene
is a tumor suppressor gene cloned from a human fetal liver cDNA library, which
is located at 8p21, one of the high frequent regions of loss of heterozygosity
(LOH) in lung carcinoma. BNIP3L protein can interact with antiapoptotic
proteins, such as Bcl-2, Bcl-x(L), E1B19K, which promotes apoptosis. This study
was designed to explore the correlation of alteration of expression and
structure of BNIP3L gene with the progression of lung cancer.
METHODS: The expression and structure of BNIP3L gene in 4 lung cancer cell
strains and 30 tissues were determined by SP immunohistochemistry, immunoblot,
semi-quantitative reverse transcription-PCR (RT-PCR), PCR-single strain
conformation polymorphism (PCR-SSCP).
RESULTS: (1) In 4 lung cancer cell strains, BNIP3L protein was not detected in
A549, NCI-H460, NCI-H446, except for NCI-H520, in which the protein expression
level was slightly lower than that in immortal bronchial epithelial cell strain
HBE4-E6/E7. BNIP3L protein was observed in 46.7% (14/30) lung cancer tissues,
while 100% (12/12) in normal lung tissues. The difference was significant in
statistics (P< 0.05). (2) BNIP3L mRNA was detected in 4 lung cancer cell
strains; and there existed no obvious discrepancy of the amount between these
cell strains and HBE4-E6/E7. Absence or decrease of BNIP3L mRNA was observed in
26.7%(8/30) of lung cancer tissues. The average quantity of BNIP3L mRNA was
0.404+/-0.070 in lung cancer tissues, while 0.575+/-0.065 in paired normal lung
tissues. The difference was significant in statistics (P< 0.05). In all the
cancerous cell strains and tissues with BNIP3L mRNA, the products of RT-PCR were
as long as those from their control samples in size, including the entire coding
region, and no variation of BNIP3L gene structure such as absence,
rearrangement, aberrant splicing were detected.(3) No point mutation was
detected in all 6 exons of BNIP3L gene in 4 lung cancer cell strains and 30
tissues.
CONCLUSION: BNIP3L protein expression was down-regulated in lung cancer, which
might be involved in the occurrence and/or development of lung cancer. The
down-regulation of BNIP3L protein expression in lung cancer was partly caused by
the down-regulation of its transcription. The variation of gene structure may be
not the reason of BNIP3L inactivity in lung cancer.
PMID: 14720367 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10963640 | 1. J Clin Oncol. 2000 Sep;18(17):3115-24. doi: 10.1200/JCO.2000.18.17.3115.
Epirubicin-based chemotherapy in metastatic breast cancer patients: role of
dose-intensity and duration of treatment.
French Epirubicin Study Group.
PURPOSE: To determine whether the duration and the dose of epirubicin modify the
long-term outcome of patients with metastatic breast cancer (MBC).
PATIENTS AND METHODS: Four hundred seventeen anthracycline-naive MBC patients
were randomized to receive one of the following regimens: arm A: 11 cycles of
fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500
mg/m(2) (FEC 75) every 21 days; arm B: four cycles of FEC 100 (same regimen but
with epirubicin 100 mg/m(2)) then eight cycles of FEC 50 (epirubicin 50
mg/m(2)); and arm C: four cycles of FEC 100 then restart the same regimen at
disease progression in case of prior response or stabilization.
RESULTS: Hematologic toxicity was similar. Nausea/vomiting and stomatitis were
significantly less frequent in arm A as was left ventricular ejection fraction
decrease in arm C (A = six patients, B = five patients, and C = one patient).
Six patients died of infections (A = four patients and C = two patients). After
four cycles, the objective response rate (ORR) was better with FEC 100 than with
FEC 75 (49.2% v 40%, respectively; P: =.07). The ORR was better with the longer
regimens (arm A, 56.9%; B, 64%; and C, 47.6%; P: =.06) and was 41% after
second-line FEC 100. After a median follow-up of 41 months, the response
duration and time to progression (TTP) were significantly better with arm B, the
longer regimen (P: =.012 and P: < 10(-3), respectively). The median survival
times for arms A, B, and C were similar (17.9, 18.9, and 16. 3 months,
respectively; P: =.49).
CONCLUSION: In MBC, longer epirubicin-based regimens are better in terms of
response duration and TTP. FEC 100 regimens improve the ORR. However, four
initial cycles of FEC 100 and identical retreatment at disease progression
yielded equivalent overall survival to longer regimens.
DOI: 10.1200/JCO.2000.18.17.3115
PMID: 10963640 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21873567 | 1. Mol Cell Proteomics. 2011 Nov;10(11):M111.009183. doi:
10.1074/mcp.M111.009183. Epub 2011 Aug 26.
Quantitative proteomic analysis of cellular protein modulation upon inhibition
of the NEDD8-activating enzyme by MLN4924.
Liao H(1), Liu XJ, Blank JL, Bouck DC, Bernard H, Garcia K, Lightcap ES.
Author information:
(1)Discovery, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Cullin-RING ubiquitin ligases (CRLs) are responsible for the ubiquitination of
many cellular proteins, thereby targeting them for proteasomal degradation. In
most cases the substrates of the CRLs have not been identified, although many of
those that are known have cancer relevance. MLN4924, an investigational small
molecule that is a potent and selective inhibitor of the Nedd8-activating enzyme
(NAE), is currently being explored in Phase I clinical trials. Inhibition of
Nedd8-activating enzyme by MLN4924 prevents the conjugation of cullin proteins
with NEDD8, resulting in inactivation of the entire family of CRLs. We have
performed stable isotope labeling with amino acids in cell culture analysis of
A375 melanoma cells treated with MLN4924 to identify new CRL substrates,
confidently identifying and quantitating 5122-6012 proteins per time point.
Proteins such as MLX, EID1, KLF5, ORC6L, MAGEA6, MORF4L2, MRFAP1, MORF4L1, and
TAX1BP1 are rapidly stabilized by MLN4924, suggesting that they are novel CRL
substrates. Proteins up-regulated at later times were also identified and siRNA
against their corresponding genes were used to evaluate their influence on
MLN4924-induced cell death. Thirty-eight proteins were identified as being
particularly important for the cytotoxicity of MLN4924. Strikingly, these
proteins had roles in cell cycle, DNA damage repair, and ubiquitin transfer.
Therefore, the combination of RNAi with stable isotope labeling with amino acids
in cell culture provides a paradigm for understanding the mechanism of action of
novel agents affecting the ubiquitin proteasome system and a path to identifying
mechanistic biomarkers.
DOI: 10.1074/mcp.M111.009183
PMCID: PMC3226404
PMID: 21873567 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8822090 | 1. Jpn J Pharmacol. 1996 Jan;70(1):65-72. doi: 10.1254/jjp.70.65.
Antitumor effect of CGP41251, a new selective protein kinase C inhibitor, on
human non-small cell lung cancer cells.
Ikegami Y(1), Yano S, Nakao K.
Author information:
(1)Drug Discovery Research Unit, Ciba-Geigy Japan Ltd., Takarazuka.
The antitumor effect of CGP41251 (4'-N-benzoyl staurosporine), a selective
protein kinase C (PKC) inhibitor, was examined on two kinds of human non-small
cell lung cancer (NSCLC) cell lines (adenocarcinoma: A549 and squamous cell
carcinoma: NCI-H520). CGP41251 at 0.5 or 1.0 microM inhibited the proliferation
of these tumor cell lines significantly; However, at 0.1 microM, it did not show
any significant inhibition. Cell cycle analysis indicated that CGP41251 at 0.5
or 1.0 microM arrested the cell cycle progression at the G2/M phase up to 24 hr,
but 0.1 microM did not. It seems that the antiproliferative action of CGP41251
against human NSCLC is related to G2/M accumulation. In NCI-H520, CGP41251
caused DNA re-replication without mitosis. In a nude mice xenograft, CGP41251 at
a dose of 200 mg/kg showed antitumor activity against these cell lines.
Histopathologically, expansion of central necrosis was observed, although no
destruction of tumor nests was seen by CGP41251 administration. In both tumor
tissues, the PKC activity of the particulate fraction was significantly
decreased by CGP41251 treatment. From these results, it is thought that the
antitumor activity of CGP41251 against human NSCLS is accompanied by the
decrease of PKC activity in the particulate fraction. Moreover, the G2/M arrest
of the cell cycle induced by CGP41251 might be important for the growth
inhibitory action of this compound.
DOI: 10.1254/jjp.70.65
PMID: 8822090 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19256341 | 1. Sheng Wu Gong Cheng Xue Bao. 2008 Nov;24(11):1931-6.
[One-step ethanol fermentation with Kluyveromyces marxianus YX01 from Jerusalem
artichoke].
[Article in Chinese]
Yuan W(1), Ren J, Zhao X, Bai F.
Author information:
(1)Department of Bioscience and Bioengineering, Dalian University of Technology,
Dalian 116023, China.
A unique one-step ethanol fermentation process was developed with the
inulinase-producing strain Kluyveromyces marxianus YX01. Firstly, the impact of
temperature on ethanol fermentation was investigated through flask fermentation,
and the temperature of 35 degrees C was observed to be the optimum to coordinate
inulinase production, inulin saccharification and ethanol fermentation. And
then, the impact of aeration and substrate concentration was studied through
batch fermentation in the 2.5 L fermentor, and the experimental data indicated
that the average ethanol fermentation time was decreased at the aeration rates
of 50 mL/min and 100 mL/min, but higher ethanol yield was obtained under
non-aeration conditions with more substrate directed to ethanol production. The
ethanol concentration of 92.2 g/L was achieved with the substrate containing 235
g/L inulin, and the ethanol yield was calculated to be 0.436, equivalent to
85.5% of its theoretical value. Finally, Jerusalem artichoke grown in salina and
irrigated with seawater was fermented without sterilization treatment, 84.0 g/L
ethanol was obtained with the substrate containing 280 g/L dry Jerusalem
artichoke meal, and the ethanol yield was calculated to be 0.405, indicating the
Jerusalem artichoke could be an alternative feedstock for grain-based fuel
ethanol production.
PMID: 19256341 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18652574 | 1. Biochem J. 2008 Dec 15;416(3):327-35. doi: 10.1042/BJ20071720.
The 5'-3' exoribonuclease Pacman is required for normal male fertility and is
dynamically localized in cytoplasmic particles in Drosophila testis cells.
Zabolotskaya MV(1), Grima DP, Lin MD, Chou TB, Newbury SF.
Author information:
(1)Brighton and Sussex Medical School, Medical Research Building, University of
Sussex, Brighton BN1 9PS, UK.
The exoribonuclease Xrn1 is widely recognised as a key component in the 5'-3'
RNA degradation pathway. This enzyme is highly conserved between yeast and
humans and is known to be involved in RNA interference and degradation of
microRNAs as well as RNA turnover. In yeast and human tissue culture cells, Xrn1
has been shown to be a component of P-bodies (processing bodies), dynamic
cytoplasmic granules where RNA degradation can take place. In this paper we show
for the first time that Pacman, the Drosophila homologue of Xrn1, is localized
in cytoplasmic particles in Drosophila testis cells. These particles are present
in both the mitotically dividing spermatogonia derived from primordial stem
cells and in the transcriptionally active spermatocytes. Pacman is co-localized
with the decapping activator dDcp1 and the helicase Me31B (a Dhh1 homologue) in
these particles, although this co-localization is not completely overlapping,
suggesting that there are different compartments within these granules.
Particles containing Pacman respond to stress and depletion of 5'-3' decay
factors in the same way as yeast P-bodies, and therefore are likely to be sites
of mRNA degradation or storage. Pacman is shown to be required for normal
Drosophila spermatogenesis, suggesting that control of mRNA stability is crucial
in the testis differentiation pathway.
DOI: 10.1042/BJ20071720
PMID: 18652574 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17664422 | 1. Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13028-33. doi:
10.1073/pnas.0701953104. Epub 2007 Jul 30.
Cellular senescence is an important mechanism of tumor regression upon c-Myc
inactivation.
Wu CH(1), van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW.
Author information:
(1)Department of Medicine, Division of Oncology, Stanford University School of
Medicine, CA 94305, USA.
Oncogene-induced senescence is an important mechanism by which normal cells are
restrained from malignant transformation. Here we report that the suppression of
the c-Myc (MYC) oncogene induces cellular senescence in diverse tumor types
including lymphoma, osteosarcoma, and hepatocellular carcinoma. MYC inactivation
was associated with prototypical markers of senescence, including acidic
beta-gal staining, induction of p16INK4a, and p15INK4b expression. Moreover, MYC
inactivation induced global changes in chromatin structure associated with the
marked reduction of histone H4 acetylation and increased histone H3 K9
methylation. Osteosarcomas engineered to be deficient in p16INK4a or Rb
exhibited impaired senescence and failed to exhibit sustained tumor regression
upon MYC inactivation. Similarly, only after lymphomas were repaired for p53
expression did MYC inactivation induce robust senescence and sustained tumor
regression. The pharmacologic inhibition of signaling pathways implicated in
oncogene-induced senescence including ATM/ATR and MAPK did not prevent
senescence associated with MYC inactivation. Our results suggest that cellular
senescence programs remain latently functional, even in established tumors, and
can become reactivated, serving as a critical mechanism of oncogene addiction
associated with MYC inactivation.
DOI: 10.1073/pnas.0701953104
PMCID: PMC1941831
PMID: 17664422 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23216904 | 1. Genes Cells. 2013 Jan;18(1):32-41. doi: 10.1111/gtc.12015. Epub 2012 Dec 6.
ROS-generating oxidases Nox1 and Nox4 contribute to oncogenic Ras-induced
premature senescence.
Kodama R(1), Kato M, Furuta S, Ueno S, Zhang Y, Matsuno K, Yabe-Nishimura C,
Tanaka E, Kamata T.
Author information:
(1)Department of Molecular Biology and Biochemistry, Shinshu University Graduate
School of Medicine, Matsumoto, Nagano, 390-8621, Japan.
Activated oncogenes induce premature cellular senescence, a permanent state of
proliferative arrest in primary rodent and human fibroblasts. Recent studies
suggest that generation of reactive oxygen species (ROS) is involved in
oncogenic Ras-induced premature senescence. However, the signaling mechanism
controlling this oxidant-mediated irreversible growth arrest is not fully
understood. Here, we show that through the Ras/MEK pathway, Ras oncogene
up-regulated the expression of superoxide-generating oxidases, Nox1 in rat REF52
cells and Nox4 in primary human lung TIG-3 cells, leading to an increase in
intracellular level of ROS. Ablation of Nox1 and Nox4 by small interfering RNAs
(siRNAs) blocked the RasV12 senescent phenotype including β-galactosidase
activity, growth arrest and accumulation of tumor suppressors such as p53 and
p16Ink4a. This suggests that Nox-generated ROS transduce senescence signals by
activating the p53 and p16Ink4a pathway. Furthermore, Nox1 and Nox4 siRNAs
inhibited both Ras-induced DNA damage response and p38MAPK activation, whereas
overexpression of Nox1 and Nox4 alone was able to induce senescence. The
involvement of Nox1 in Ras-induced senescence was also confirmed with embryonic
fibroblasts derived from Nox1 knockout mice. Together, these findings suggest
that Nox1- and Nox4-generated ROS play an important role in Ras-induced
premature senescence, which may involve DNA damage response and p38MAPK
signaling pathways.
© 2012 The Authors Genes to Cells © 2012 by the Molecular Biology Society of
Japan and Wiley Publishing Asia Pty Ltd.
DOI: 10.1111/gtc.12015
PMID: 23216904 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22901103 | 1. BJOG. 2012 Dec;119(13):1583-90. doi: 10.1111/j.1471-0528.2012.03470.x. Epub
2012 Aug 20.
Vaccination against H1N1 influenza with Pandemrix(®) during pregnancy and
delivery outcome: a Swedish register study.
Källén B(1), Olausson PO.
Author information:
(1)Tornblad Institute, University of Lund, Lund, Sweden. [email protected]
OBJECTIVE: To describe a large study on pregnancy outcome after vaccination
against H1N1 during the 2009/10 pandemic.
DESIGN: A cohort study of women vaccinated with Pandemrix(®) during pregnancy.
SETTING: The Swedish Medical Birth Register was used for the analysis.
Information on vaccination and pregnancy week when vaccination was made was
obtained from antenatal care documents.
POPULATION: All women who gave birth during 2009 and 2010 in Sweden.
METHODS: Characteristics of the vaccinated women and their delivery outcome were
compared with two groups of women: women without a known vaccination who gave
birth in 2009/10 after 1 October 2009, and women who gave birth during 2009
before 1 October. Adjustment was made for year of delivery, maternal age,
parity, smoking habits and body mass index.
OUTCOME MEASURES: Stillbirth, congenital malformations, preterm birth, low
birthweight, small for gestational age.
RESULTS: A total of 18 612 vaccinated women having 18 844 infants were studied.
The risk for stillbirth, preterm birth and low birthweight was lower than in the
comparison groups whereas the risk for small for gestational age and a
congenital malformation (after vaccination during the first trimester) did not
differ from the comparison groups. No clear-cut explanation to the 'protective'
effect of vaccination was found.
CONCLUSIONS: Vaccination during pregnancy with Pandemrix(®) appeared to have no
ill effects on the pregnancy. On the contrary, the rate of preterm birth and low
birthweight was lower than expected, which agrees with some previous results.
© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology ©
2012 RCOG.
DOI: 10.1111/j.1471-0528.2012.03470.x
PMID: 22901103 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21969368 | 1. J Biol Chem. 2011 Nov 25;286(47):40867-77. doi: 10.1074/jbc.M111.279984. Epub
2011 Oct 3.
Mechanistic studies of substrate-assisted inhibition of ubiquitin-activating
enzyme by adenosine sulfamate analogues.
Chen JJ(1), Tsu CA, Gavin JM, Milhollen MA, Bruzzese FJ, Mallender WD, Sintchak
MD, Bump NJ, Yang X, Ma J, Loke HK, Xu Q, Li P, Bence NF, Brownell JE, Dick LR.
Author information:
(1)Discovery, Millennium Pharmaceuticals Inc., Cambridge, Massachusetts 02139,
USA. [email protected]
Ubiquitin-activating enzyme (UAE or E1) activates ubiquitin via an adenylate
intermediate and catalyzes its transfer to a ubiquitin-conjugating enzyme (E2).
MLN4924 is an adenosine sulfamate analogue that was identified as a selective,
mechanism-based inhibitor of NEDD8-activating enzyme (NAE), another E1 enzyme,
by forming a NEDD8-MLN4924 adduct that tightly binds at the active site of NAE,
a novel mechanism termed substrate-assisted inhibition (Brownell, J. E.,
Sintchak, M. D., Gavin, J. M., Liao, H., Bruzzese, F. J., Bump, N. J., Soucy, T.
A., Milhollen, M. A., Yang, X., Burkhardt, A. L., Ma, J., Loke, H. K., Lingaraj,
T., Wu, D., Hamman, K. B., Spelman, J. J., Cullis, C. A., Langston, S. P.,
Vyskocil, S., Sells, T. B., Mallender, W. D., Visiers, I., Li, P., Claiborne, C.
F., Rolfe, M., Bolen, J. B., and Dick, L. R. (2010) Mol. Cell 37, 102-111). In
the present study, substrate-assisted inhibition of human UAE (Ube1) by another
adenosine sulfamate analogue,
5'-O-sulfamoyl-N(6)-[(1S)-2,3-dihydro-1H-inden-1-yl]-adenosine (Compound I), a
nonselective E1 inhibitor, was characterized. Compound I inhibited UAE-dependent
ATP-PP(i) exchange activity, caused loss of UAE thioester, and inhibited E1-E2
transthiolation in a dose-dependent manner. Mechanistic studies on Compound I
and its purified ubiquitin adduct demonstrate that the proposed
substrate-assisted inhibition via covalent adduct formation is entirely
consistent with the three-step ubiquitin activation process and that the adduct
is formed via nucleophilic attack of UAE thioester by the sulfamate group of
Compound I after completion of step 2. Kinetic and affinity analysis of Compound
I, MLN4924, and their purified ubiquitin adducts suggest that both the rate of
adduct formation and the affinity between the adduct and E1 contribute to the
overall potency. Because all E1s are thought to use a similar mechanism to
activate their cognate ubiquitin-like proteins, the substrate-assisted
inhibition by adenosine sulfamate analogues represents a promising strategy to
develop potent and selective E1 inhibitors that can modulate diverse biological
pathways.
DOI: 10.1074/jbc.M111.279984
PMCID: PMC3220466
PMID: 21969368 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17005986 | 1. Microbiology (Reading). 2006 Oct;152(Pt 10):3061-3073. doi:
10.1099/mic.0.29051-0.
Database mining and transcriptional analysis of genes encoding inulin-modifying
enzymes of Aspergillus niger.
Yuan XL(1), Goosen C(2)(3), Kools H(4), van der Maarel MJEC(5)(2), van den
Hondel CAMJJ(1), Dijkhuizen L(2)(3), Ram AFJ(6)(1).
Author information:
(1)Institute of Biology Leiden, Leiden University, Fungal Genetics Research
Group, Wassenaarseweg 64, 2333 AL Leiden, The Netherlands.
(2)Centre for Carbohydrate Bioprocessing TNO-University of Groningen, Kerklaan
30, 9751 NN Haren, The Netherlands.
(3)Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology
Institute (GBB), University of Groningen, Kerklaan 30, 9751 NN Haren, The
Netherlands.
(4)Microbiology, Fungal Genomics Group, Wageningen University, Dreijenlaan 2,
6703 HA Wageningen, The Netherlands.
(5)TNO Quality of Life, Business Unit Innovative Ingredients and Products,
Rouaanstraat 27, 9723 CC Groningen, The Netherlands.
(6)TNO Quality of Life, Business Unit Microbiology, Utrechtseweg 48, 3500 AJ
Zeist, The Netherlands.
As a soil fungus, Aspergillus niger can metabolize a wide variety of carbon
sources, employing sets of enzymes able to degrade plant-derived
polysaccharides. In this study the genome sequence of A. niger strain CBS 513.88
was surveyed, to analyse the gene/enzyme network involved in utilization of the
plant storage polymer inulin, and of sucrose, the substrate for inulin synthesis
in plants. In addition to three known activities, encoded by the genes suc1
(invertase activity; designated sucA), inuE (exo-inulinase activity) and
inuA/inuB (endo-inulinase activity), two new putative invertase-like proteins
were identified. These two putative proteins lack N-terminal signal sequences
and therefore are expected to be intracellular enzymes. One of these two genes,
designated sucB, is expressed at a low level, and its expression is up-regulated
when A. niger is grown on sucrose- or inulin-containing media. Transcriptional
analysis of the genes encoding the sucrose- (sucA) and inulin-hydrolysing
enzymes (inuA and inuE) indicated that they are similarly regulated and all
strongly induced on sucrose and inulin. Analysis of a DeltacreA mutant strain of
A. niger revealed that expression of the extracellular inulinolytic enzymes is
under control of the catabolite repressor CreA. Expression of the inulinolytic
enzymes was not induced by fructose, not even in the DeltacreA background,
indicating that fructose did not act as an inducer. Evidence is provided that
sucrose, or a sucrose-derived intermediate, but not fructose, acts as an inducer
for the expression of inulinolytic genes in A. niger.
DOI: 10.1099/mic.0.29051-0
PMID: 17005986 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18723672 | 1. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13027-32. doi:
10.1073/pnas.0805038105. Epub 2008 Aug 22.
Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29
in cardiac fibrosis.
van Rooij E(1), Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS,
Hill JA, Olson EN.
Author information:
(1)Department of Molecular Biology, University of Texas Southwestern Medical
Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied
by a pathological remodeling response that includes hypertrophic cardiac growth
and fibrosis, which impair cardiac contractility. Previously, we showed that
cardiac hypertrophy and heart failure are accompanied by characteristic changes
in the expression of a collection of specific microRNAs (miRNAs), which act as
negative regulators of gene expression. Here, we show that MI in mice and humans
also results in the dysregulation of specific miRNAs, which are similar to but
distinct from those involved in hypertrophy and heart failure. Among the
MI-regulated miRNAs are members of the miR-29 family, which are down-regulated
in the region of the heart adjacent to the infarct. The miR-29 family targets a
cadre of mRNAs that encode proteins involved in fibrosis, including multiple
collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be
predicted to derepress the expression of these mRNAs and enhance the fibrotic
response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo
induces the expression of collagens, whereas over-expression of miR-29 in
fibroblasts reduces collagen expression. We conclude that miR-29 acts as a
regulator of cardiac fibrosis and represents a potential therapeutic target for
tissue fibrosis in general.
DOI: 10.1073/pnas.0805038105
PMCID: PMC2529064
PMID: 18723672 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest statement: E.v.R., W.S.M.,
and E.N.O. are cofounders of MiRagen Therapeutics. |
http://www.ncbi.nlm.nih.gov/pubmed/17622371 | 1. Tex Heart Inst J. 2007;34(2):209-13.
The TandemHeart pVAD in the treatment of acute fulminant myocarditis.
Khalife WI(1), Kar B.
Author information:
(1)Department of Cardiology, Division of Heart Failure/Cardiac Transplantation,
Texas Heart Institute at St. Luke's Episcopal Hospital, Houston, Texas 77030,
USA. [email protected]
Acute fulminant myocarditis commonly manifests itself as severe, rapidly
progressive hemodynamic deterioration and circulatory collapse that may be
resistant to high doses of inotropic agents and steroids and to mechanical
support by intra-aortic balloon pump. Acute myocarditis has a high mortality
rate and may necessitate heart transplantation. The best short-term therapy
available to support the patient may be a percutaneous left ventricular assist
device. One such unit, the TandemHeart percutaneous ventricular assist device,
can enable patients to recover in a few days. Two of our patients who
experienced profound, therapy-resistant heart failure arising from acute
myocarditis were successfully supported by the TandemHeart. To the best of our
knowledge, these are the 1st reported cases in which the TandemHeart
percutaneous ventricular assist device served as a bridge to recovery from acute
fulminant myocarditis.
PMCID: PMC1894709
PMID: 17622371 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24031675 | 1. Braz J Microbiol. 2011 Apr;42(2):633-49. doi:
10.1590/S1517-838220110002000028. Epub 2011 Jun 1.
Comparative study of two purified inulinases from thermophile Thielavia
Terrestris NRRL 8126 and mesophile Aspergillus Foetidus NRRL 337 grown on
Cichorium Intybus l.
Fawzi EM(1).
Author information:
(1)Biological and Geological Sciences Department, Faculty of Education, Ain
Shams University , Roxy, Heliopolis, P.C.11757, Cairo , Egypt.
Thirty fungal species grown on Cichorium intybus L. root extract as a sole
carbon source, were screened for the production of exo-inulinase activities. The
thermophile Thielavia terrestris NRRL 8126 and mesophile Aspergillus foetidus
NRRL 337 gave the highest production levels of inulinases I & II at 50 and 24 ºC
respectively. Yeast extract and peptone were the best nitrogen sources for
highest production of inulinases I & II at five and seven days of incubation
respectively. The two inulinases I & II were purified to homogeneity by
gel-filtration and ion-exchange chromatography with 66.0 and 42.0 fold of
purification respectively. The optimum temperatures of purified inulinases I &
II were 75 and 50 ºC respectively. Inulinase I was more thermostable than the
other one. The optimum pH for activity was found to be 4.5 and 5.5 for
inulinases I & II respectively. A comparatively lower Michaelis-Menten constant
(2.15 mg/ml) and higher maximum initial velocity (115 µmol/min/mg of protein)
for inulinase I on inulin demonstrated the exoinulinase's greater affinity for
inulin substrate. These findings are significant for its potential industrial
application. The molecular mass of the inulinases I & II were estimated to be 72
& 78 kDa respectively by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis.
DOI: 10.1590/S1517-838220110002000028
PMCID: PMC3769809
PMID: 24031675 |
http://www.ncbi.nlm.nih.gov/pubmed/12055771 | 1. Arch Mal Coeur Vaiss. 2002 Apr;95(4):305-9.
[Fulminating myocarditis: myocardial recovery after circulatory assistance].
[Article in French]
Leprince P(1), Combes A, Bonnet N, Espinosa T, Levasseur JP, Léger P, Bors V,
Rama A, Vaissier E, Pavie A.
Author information:
(1)Service de chirurgie thoracique et cardiovasculaire, groupe hospitalier La
Pitié-La Salpêtrière, 75013 Paris. [email protected]
The clinical expression of acute myocarditis is variable from paucisymptomatic
to fulminating forms which are usually lethal within days. The latter
presentation takes the form of very acute cardiac failure. During this phase,
the severity of myocardial dysfunction may be such that death ensues. However,
if the patient survives, paradoxically, these forms have a better long-term
prognosis with complete recovery of myocardial function being possible after the
acute phase. The authors report a typical case of fulminating myocarditis with
electromechanical dissociation, which recovered completely after a period of
circulatory assistance. This case illustrates the rapidity of deterioration of
the haemodynamic status and the importance of organ dysfunction despite early
management. In a review of the literature, the authors found about 150 reported
cases of acute myocarditis treated with circulatory assistance. In the best
series, about half the patients were weaned off the circulatory assistance
without having to undergo cardiac transplantation. However, the potential
recovery of myocardial function is difficult to predict.
PMID: 12055771 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23963659 | 1. Breast Cancer Res Treat. 2013 Aug;141(1):67-78. doi:
10.1007/s10549-013-2668-x. Epub 2013 Aug 21.
Effects of sorafenib on energy metabolism in breast cancer cells: role of
AMPK-mTORC1 signaling.
Fumarola C(1), Caffarra C, La Monica S, Galetti M, Alfieri RR, Cavazzoni A,
Galvani E, Generali D, Petronini PG, Bonelli MA.
Author information:
(1)Department of Clinical and Experimental Medicine, University of Parma, Via
Volturno, 39, Parma 43125, Italy. [email protected]
In this study, we investigated the effects and the underlying molecular
mechanisms of the multi-kinase inhibitor sorafenib in a panel of breast cancer
cell lines. Sorafenib inhibited cell proliferation and induced apoptosis through
the mitochondrial pathway. These effects were neither correlated with modulation
of MAPK and AKT pathways nor dependent on the ERα status. Sorafenib promoted an
early perturbation of mitochondrial function, inducing a deep depolarization of
mitochondrial membrane, associated with drop of intracellular ATP levels and
increase of ROS generation. As a response to this stress condition, the energy
sensor AMPK was rapidly activated in all the cell lines analyzed. In MCF-7 and
SKBR3 cells, AMPK enhanced glucose uptake by up-regulating the expression of
GLUT-1 glucose transporter, as also demonstrated by AMPKα1 RNA interference, and
stimulated aerobic glycolysis thus increasing lactate production. Moreover, the
GLUT-1 inhibitor fasentin blocked sorafenib-induced glucose uptake and
potentiated its cytotoxic activity in SKBR3 cells. Persistent activation of AMPK
by sorafenib finally led to the impairment of glucose metabolism both in MCF-7
and SKBR3 cells as well as in the highly glycolytic MDA-MB-231 cells, resulting
in cell death. This previously unrecognized long-term effect of sorafenib was
mediated by AMPK-dependent inhibition of the mTORC1 pathway. Suppression of
mTORC1 activity was sufficient for sorafenib to hinder glucose utilization in
breast cancer cells, as demonstrated by the observation that the mTORC1
inhibitor rapamycin induced a comparable down-regulation of GLUT-1 expression
and glucose uptake. The key role of AMPK-dependent inhibition of mTORC1 in
sorafenib mechanisms of action was confirmed by AMPKα1 silencing, which restored
mTORC1 activity conferring a significant protection from cell death. This study
provides insights into the molecular mechanisms driving sorafenib anti-tumoral
activity in breast cancer, and supports the need for going on with clinical
trials aimed at proving the efficacy of sorafenib for breast cancer treatment.
DOI: 10.1007/s10549-013-2668-x
PMID: 23963659 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19767749 | 1. Nat Struct Mol Biol. 2009 Oct;16(10):1101-8. doi: 10.1038/nsmb.1668. Epub 2009
Sep 20.
Structural and kinetic determinants of protease substrates.
Timmer JC(1), Zhu W, Pop C, Regan T, Snipas SJ, Eroshkin AM, Riedl SJ, Salvesen
GS.
Author information:
(1)Apoptosis and Cell Death Research Program at the Burnham Institute for
Medical Research, La Jolla, California, USA.
Two fundamental questions with regard to proteolytic networks and pathways
concern the structural repertoire and kinetic threshold that distinguish
legitimate signaling substrates. We used N-terminal proteomics to address these
issues by identifying cleavage sites within the Escherichia coli proteome that
are driven by the apoptotic signaling protease caspase-3 and the bacterial
protease glutamyl endopeptidase (GluC). Defying the dogma that proteases cleave
primarily in natively unstructured loops, we found that both caspase-3 and GluC
cleave in alpha-helices nearly as frequently as in extended loops. Notably,
biochemical and kinetic characterization revealed that E. coli caspase-3
substrates are greatly inferior to natural substrates, suggesting protease and
substrate coevolution. Engineering an E. coli substrate to match natural
catalytic rates defined a kinetic threshold that depicts a signaling event. This
unique combination of proteomics, biochemistry, kinetics and substrate
engineering reveals new insights into the structure-function relationship of
protease targets and their validation from large-scale approaches.
DOI: 10.1038/nsmb.1668
PMCID: PMC4042863
PMID: 19767749 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16397222 | 1. Cancer Res. 2006 Jan 1;66(1):107-12. doi: 10.1158/0008-5472.CAN-05-2485.
Consistent rearrangement of chromosomal band 6p21 with generation of fusion
genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma.
Micci F(1), Panagopoulos I, Bjerkehagen B, Heim S.
Author information:
(1)Department of Cancer Genetics, The Norwegian Radium Hospital, Oslo.
[email protected]
Endometrial stromal sarcomas (ESS) represent <10% of all uterine sarcomas.
Cytogenetic data on this tumor type are limited to 32 cases, and the karyotypes
are often complex, but the pattern of rearrangement is nevertheless clearly
nonrandom with particularly frequent involvement of chromosome arms 6p and 7p.
Recently, a specific translocation t(7;17)(p15;q21) leading to the fusion of two
zinc finger genes, juxtaposed with another zinc finger (JAZF1) and joined to
JAZF1 (JJAZ1), was described in a subset of ESS. We present three ESS whose
karyotypes were without the disease-specific t(7;17) but instead showed
rearrangement of chromosomal band 6p21, twice as an unbalanced t(6p;7p) and once
as a three-way 6;10;10 translocation. All three tumors showed specific
rearrangement of the PHD finger protein 1 (PHF1) gene, located in chromosomal
band 6p21. In the two tumors with t(6;7), PHF1 was recombined with the JAZF1
gene from 7p15, leading to the formation of a JAZF1/PHF1 fusion gene. The third
tumor showed a t(6p;10q;10p) as the sole karyotypic abnormality, leading to the
fusion of PHF1 with another partner, the enhancer of polycomb (EPC1) gene from
10p11; EPC1 has hitherto not been associated with neoplasia. The PHF1 gene
encodes a protein with two zinc finger motifs whose involvement in tumorigenesis
and/or tumor progression has not been reported before, but its rearrangement
clearly defines a new pathogenetic subgroup of ESS.
DOI: 10.1158/0008-5472.CAN-05-2485
PMID: 16397222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16781216 | 1. Am Heart J. 2006 Jun;151(6):1186.e1-9. doi: 10.1016/j.ahj.2006.01.004.
Evaluation of a novel anti-ischemic agent in acute coronary syndromes: design
and rationale for the Metabolic Efficiency with Ranolazine for Less Ischemia in
Non-ST-elevation acute coronary syndromes (MERLIN)-TIMI 36 trial.
Morrow DA(1), Scirica BM, Karwatowska-Prokopczuk E, Skene A, McCabe CH,
Braunwald E; MERLIN-TIMI 36 Investigators.
Author information:
(1)TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham
and Women's Hospital, Boston, MA 02115, USA.
BACKGROUND: Despite advances in antithrombotic therapies and invasive
technology, the risk of recurrent ischemic complications in patients with
non-ST-elevation acute coronary syndromes (NSTE-ACSs) remains substantial.
Ranolazine is a novel agent that inhibits the late sodium current thereby
reducing cellular sodium and calcium overload and has been shown to reduce
ischemia in patients with chronic stable angina.
STUDY DESIGN: MERLIN-TIMI 36 is a phase III, randomized, double-blind,
parallel-group, placebo-controlled, multinational clinical trial to evaluate the
efficacy and safety of ranolazine during long-term treatment of patients with
NSTE-ACS receiving standard therapy (N = 6500). Eligible patients are randomized
1:1 to ranolazine or matched placebo, initiated as 200 mg intravenously over 1
hour, followed by an 80-mg/h infusion (40 mg/h for patients with severe renal
insufficiency) for up to 96 hours and oral ranolazine ER 1000 mg BID or matched
placebo until the end of study. The primary end point is the time to first
occurrence of any element of the composite of cardiovascular death, myocardial
infarction, or recurrent ischemia. Secondary end points include ischemia on
Holter monitoring, hospitalization for new or worsening heart failure, quality
of life measures, and exercise performance. The evaluation of long-term safety
will include death from any cause and symptomatic documented arrhythmia.
Recruitment began in October 2004. The trial will continue until 730 major
cardiovascular events and 310 deaths are recorded with expected completion in 24
to 28 months.
CONCLUSIONS: MERLIN-TIMI 36 will evaluate the role of ranolazine in the acute
and chronic management of patients presenting with NSTE-ACS.
DOI: 10.1016/j.ahj.2006.01.004
PMID: 16781216 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20562527 | 1. Cell Cycle. 2010 Jun 15;9(12):2412-22. doi: 10.4161/cc.9.12.11989. Epub 2010
Jun 15.
Glycolytic cancer associated fibroblasts promote breast cancer tumor growth,
without a measurable increase in angiogenesis: evidence for stromal-epithelial
metabolic coupling.
Migneco G(1), Whitaker-Menezes D, Chiavarina B, Castello-Cros R, Pavlides S,
Pestell RG, Fatatis A, Flomenberg N, Tsirigos A, Howell A, Martinez-Outschoorn
UE, Sotgia F, Lisanti MP.
Author information:
(1)Department of Stem Cell Biology & Regenerative Medicine, Thomas Jefferson
University, Philadelphia, PA, USA.
Previously, we proposed a new model for understanding the Warburg effect in
tumorigenesis and metastasis. In this model, the stromal fibroblasts would
undergo aerobic glycolysis (a.k.a., the Warburg effect)--producing and secreting
increased pyruvate/lactate that could then be used by adjacent epithelial cancer
cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and
ATP production. To test this model more directly, here we used a matched set of
metabolically well-characterized immortalized fibroblasts that differ in a
single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have
an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift
towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated
these differences in CL3 and CL4 fibroblasts by performing an unbiased
proteomics analysis, showing the functional upregulation of 4 glycolytic
enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the
proteins that were upregulated in CL4 fibroblasts, as seen by unbiased
proteomics, were also transcriptionally upregulated in the stroma of human
breast cancers, especially in the patients that were prone to metastasis.
Importantly, when CL4 fibroblasts were co-injected with human breast cancer
cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced.
CL4 fibroblasts induced a > 4-fold increase in tumor mass, and a near 8-fold
increase in tumor volume, without any measurable increases in tumor
angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors
when they were injected alone, without epithelial cancer cells. Mechanistically,
under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial
activity in adjacent breast cancer cells (relative to CL3 cells), consistent
with the "Reverse Warburg Effect". Notably, Western blot analysis of CL4
fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein
levels. In human breast cancer patients, a loss of stromal Cav-1 is associated
with an increased risk of early tumor recurrence, metastasis,
tamoxifen-resistance, and poor clinical outcome. Thus, loss of stromal Cav-1 may
be an effective marker for predicting the "Reverse Warburg Effect" in the stroma
of human breast cancer patients. As such, CL4 fibroblasts are a new attractive
model for mimicking the "glycolytic phenotype" of cancer-associated fibroblasts.
Nutrients derived from glycolytic cancer associated fibroblasts could provide an
escape mechanism to confer drug-resistance during anti-angiogenic therapy, by
effectively reducing the dependence of cancer cells on a vascular blood supply.
DOI: 10.4161/cc.9.12.11989
PMID: 20562527 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12926878 | 1. J Agric Food Chem. 2003 Aug 27;51(18):5326-8. doi: 10.1021/jf0300689.
Effect of menadione sodium bisulfite, an inducer of plant defenses, on the
dynamic of banana phytoalexin accumulation during pathogenesis.
Borges AA(1), Borges-Perez A, Fernandez-Falcon M.
Author information:
(1)Instituto de Productos Naturales y Agrobiología--CSIC. Avda Astrofísico
Francisco Sánchez 3, P.O. Box 195, 38206 La Laguna, Tenerife, Canary Islands,
Spain. [email protected]
Using an authentic sample of 2-hydroxy-9-(p-hydroxyphenyl)-phenalen-1-one, a
banana phenalenone-type phytoalexin, we studied its dynamic of accumulation
during pathogenesis of banana plants (Musa acuminata (AAA), Grand Nain)
inoculated with Fusarium oxysporum f.sp. cubense (FOC), Race 4, the causal agent
of Panama disease. The results obtained demonstrate that banana plants treated
prior inoculation with menadione sodium bisulfite (MSB), an inducer of plant
defenses, are capable of changing the dynamic of accumulation (higher amount and
speed of biosynthesis) of this banana phytoalexin, biosynthesized by the banana
plant during pathogenesis.
DOI: 10.1021/jf0300689
PMID: 12926878 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22166400 | 1. Parkinsonism Relat Disord. 2012 Jan;18 Suppl 1:S1-3. doi:
10.1016/S1353-8020(11)70003-7.
Autosomal dominant parkinsonism: its etiologies and differential diagnoses.
Hattori N(1).
Author information:
(1)Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo,
Bunkyo, Tokyo 113-8421, Japan.
Recently, several genes for parkinsonism have been identified. Among them,
familial Parkinson's disease (PD) could be assigned for PARK disorders. PARK
disorders consist of three different inherited modes such as autosomal
recessive, autosomal dominant modes and susceptible genes. Some of them manifest
not only typical parkinsonism, but also dystonia, pyramidal sign, and mental
dysfunctions. While the monogenic forms of PARK disorders have been reviewed
extensively, it is not easy to do differential diagnosis of PARK disorders due
to the additional features except for typical parkinsonism. In this
presentation, we focus on two different scenarios of patients with autosomal
dominant parkinsonism: (1) parkinsonism with mutations in one of the PARK genes;
(2) parkinsonism with mutations other than PARK genes or yet other genes where
parkinsonism is a well recognized, concomitant, or even an isolated feature.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1353-8020(11)70003-7
PMID: 22166400 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16230785 | 1. Endocrine. 2005 Aug;27(3):283-8. doi: 10.1385/endo:27:3:283.
Influence of low protein diet on nonthyroidal illness syndrome in chronic renal
failure.
Rosolowska-Huszcz D(1), Kozlowska L, Rydzewski A.
Author information:
(1)Department of Dietetics, Warsaw Agricultural University, Warsaw, Poland.
[email protected]
Renal failure causes alterations in thyroid hormone metabolism known as
nonthyroidal illness syndrome. In the present study we have examined the effect
of a low protein diet (LPD) on circulating levels of hormones of the
pituitary-thyroid axis, and tumor necrosis factor alpha (TNF-alpha) in patients
with chronic renal failure. Seventeen subjects with conservatively treated
chronic renal failure (estimated creatinine clearance 39.5+/-11.1 mL/min) were
studied before and after 8 wk of dietary intervention (0.6 g/kg of ideal body
mass protein, 30% of calories derived from fat, 62% of calories derived from
carbohydrates, and 10 mg/kg of phosphorus). Body fat and fat-free mass remained
unchanged. Urea and TNF-alpha serum concentrations significantly decreased,
whereas T3 and total and free T4 serum concentrations increased significantly.
Triiodothyronine level after treatment correlated negatively with baseline urea
level. Changes in T3, T4, and fT4 serum concentrations as well as calculated
peripheral deiodinase activity correlated negatively with their baseline values.
Alterations in TNF-alpha correlated positively with protein intake, whereas
changes in T4 and T4/TSH were inversely related to vegetal protein intake. In
conclusion, low protein, low phosphorus diet, which is often prescribed to
patients with moderate impairment of renal function, exerts a beneficial effect
on low T3 syndrome coexisting with renal failure. The effect of low protein diet
on the pituitary-thyroid axis is dependent on the degree of renal functional
impairment and LPD-induced decrease in TNF-alpha may also contribute to the
observed effects of dietary treatment.
DOI: 10.1385/endo:27:3:283
PMID: 16230785 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16757427 | 1. Int J Hematol. 2006 May;83(4):294-300. doi: 10.1532/IJH97.06025.
The second generation of BCR-ABL tyrosine kinase inhibitors.
Tauchi T(1), Ohyashiki K.
Author information:
(1)First Department of Internal Medicine, Tokyo Medical University, Tokyo,
Japan. [email protected]
Imatinib was developed as the first molecularly targeted therapy to specifically
inhibit the BCR-ABL kinase in Philadelphia chromosome (Ph)-positive chronic
myeloid leukemia (CML). Because of the excellent hematologic and cytogenetic
responses, imatinib has moved toward first-line treatment for newly diagnosed
CML. However, the emergence of resistance to imatinib remains a major problem in
the treatment of Ph-positive leukemia. Several mechanisms of imatinib resistance
have been identified, including BCR-ABL gene amplification that leads to
overexpression of the BCR-ABL protein, point mutations in the BCR-ABL kinase
domain that interfere with imatinib binding, and point mutations outside of the
kinase domain that allosterically inhibit imatinib binding to BCR-ABL. The need
for alternative or additional treatment for imatinib-resistant BCR-ABL-positive
leukemia has guided the way to the design of a second generation of targeted
therapies, which has resulted mainly in the development of novel small-molecule
inhibitors such as AMN107, dasatinib, NS-187, and ON012380. The major goal of
these efforts is to create new compounds that are more potent than imatinib
and/or more effective against imatinib-resistant BCR-ABL clones. In this review,
we discuss the next generation of BCR-ABL kinase inhibitors for overcoming
imatinib resistance.
DOI: 10.1532/IJH97.06025
PMID: 16757427 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22427796 | 1. PLoS One. 2012;7(3):e28787. doi: 10.1371/journal.pone.0028787. Epub 2012 Mar
12.
Cooperative genome-wide analysis shows increased homozygosity in early onset
Parkinson's disease.
Simón-Sánchez J(1), Kilarski LL, Nalls MA, Martinez M, Schulte C, Holmans P;
International Parkinson's Disease Genomics Consortium; Wellcome Trust Case
Control Consortium; Gasser T, Hardy J, Singleton AB, Wood NW, Brice A, Heutink
P, Williams N, Morris HR.
Author information:
(1)Section of Medical Genomics, Department of Clinical Genetics, VU University
Medical Centre, Amsterdam, The Netherlands.
Parkinson's disease (PD) occurs in both familial and sporadic forms, and both
monogenic and complex genetic factors have been identified. Early onset PD
(EOPD) is particularly associated with autosomal recessive (AR) mutations, and
three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading
to AR disease. Since mutations in these genes account for less than 10% of EOPD
patients, we hypothesized that further recessive genetic factors are involved in
this disorder, which may appear in extended runs of homozygosity.We carried out
genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in
1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an
increased level of genomic homozygosity in EOPD cases compared to controls.
These differences are larger for ROH of 9 Mb and above, where there is a more
than three-fold increase in the proportion of cases carrying a ROH. These
differences are not explained by occult recessive mutations at existing loci.
Controlling for genome wide homozygosity in logistic regression analyses
increased the differences between cases and controls, indicating that in EOPD
cases ROHs do not simply relate to genome wide measures of inbreeding.
Homozygosity at a locus on chromosome19p13.3 was identified as being more common
in EOPD cases as compared to controls. Sequencing analysis of genes and
predicted transcripts within this locus failed to identify a novel mutation
causing EOPD in our cohort.There is an increased rate of genome wide
homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a
signature of inbreeding and do not necessarily harbour disease-causing genetic
variants. Although there might be other regions of interest apart from
chromosome 19p13.3, we lack the power to detect them with this analysis.
DOI: 10.1371/journal.pone.0028787
PMCID: PMC3299635
PMID: 22427796 [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/17379100 | 1. Exp Hematol. 2007 Apr;35(4 Suppl 1):144-54. doi: 10.1016/j.exphem.2007.01.023.
Optimizing therapy of chronic myeloid leukemia.
Deininger MW(1).
Author information:
(1)Oregon Health and Science University, Cancer Institute, Portland, OR 97239,
USA. [email protected]
Chronic myeloid leukemia (CML) is caused by Bcr-Abl, a constitutively active
tyrosine kinase that is the result of a reciprocal translocation between
chromosomes 9 and 22 and cytogenetically evident as the Philadelphia chromosome.
Imatinib (Glivec, Gleevec), a specific small molecule inhibitor of Bcr-Abl, has
become the standard drug therapy for CML, and has dramatically diminished the
use of allogeneic stem cell transplantation. Despite unprecedented rates of
complete cytogenetic response, residual disease remains detectable in the
majority of patients, suggesting that imatinib fails to eradicate leukemic stem
cells. In this publication, the current perspectives for CML patients treated
with imatinib are reviewed, focusing on the results of both standard and
high-dose therapy. Monitoring of time-dependent prognostic factors is reviewed.
The reasons imatinib may not be able to eradicate the disease are discussed, and
potential strategies to achieve disease elimination are presented. Lastly,
resistance to imatinib and the potential of second-generation Abl kinase
inhibitors in the setting of clinical resistance are considered.
DOI: 10.1016/j.exphem.2007.01.023
PMID: 17379100 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17341613 | 1. Ann N Y Acad Sci. 2006 Dec;1091:184-90. doi: 10.1196/annals.1378.065.
Multiple levels of control of the expression of the human A beta H-J-J locus
encoding aspartyl-beta-hydroxylase, junctin, and junctate.
Feriotto G(1), Finotti A, Breveglieri G, Treves S, Zorzato F, Gambari R.
Author information:
(1)Department of Biochemistry and Molecular Biology, Section of Molecular
Biology, Via Fossato di Mortara 74, 44100 Ferrara, Italy.
The human AbetaH-J-J locus is a genomic sequence which generates three
functionally distinct proteins, the enzyme aspartyl-beta-hydroxylase (AbetaH),
the structural protein of sarcoplasmic reticulum junctin, and the membrane-bound
calcium binding protein junctate. The first and second exons are mutually
exclusive when mature mRNAs are produced. Moreover, the use of different splice
donors has been shown to be involved in the generation of protein diversity by
alternative splicing. As to transcriptional regulation, two promoters (P1 and
P2) were identified. When the P1 and P2 promoter sequences are compared,
important differences are clearly detectable. The most interesting result
emerging from studies focused on the P2 promoter is that the calcium-dependent
transcriptional factor MEF-2 activates the transcription of junctin, junctate,
and AbetaH in excitable tissues and, to a lesser extent, in kidney. No Sp1
binding sites are present in the P2 promoter. In contrast, P1 promoter contains
GC-rich sequences, which have homologies with the Sp1 consensus binding site.
DOI: 10.1196/annals.1378.065
PMID: 17341613 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24167038 | 1. Mov Disord. 2014 Jan;29(1):41-53. doi: 10.1002/mds.25724. Epub 2013 Oct 25.
PINK1 heterozygous mutations induce subtle alterations in dopamine-dependent
synaptic plasticity.
Madeo G(1), Schirinzi T, Martella G, Latagliata EC, Puglisi F, Shen J, Valente
EM, Federici M, Mercuri NB, Puglisi-Allegra S, Bonsi P, Pisani A.
Author information:
(1)Department of System Medicine, University of Rome "Tor Vergata", Rome, Italy.
Homozygous or compound heterozygous mutations in the phosphatase and tensin
homolog-induced putative kinase 1 (PINK1) gene are causative of autosomal
recessive, early onset Parkinson's disease. Single heterozygous mutations have
been detected repeatedly both in a subset of patients and in unaffected
individuals, and the significance of these mutations has long been debated.
Several neurophysiological studies from non-manifesting PINK1 heterozygotes have
demonstrated the existence of neural plasticity abnormalities, indicating the
presence of specific endophenotypic traits in the heterozygous state. We
performed a functional analysis of corticostriatal synaptic plasticity in
heterozygous PINK1 knockout (PINK1(+/-) ) mice using a multidisciplinary
approach and observed that, despite normal motor behavior, repetitive activation
of cortical inputs to striatal neurons failed to induce long-term potentiation
(LTP), whereas long-term depression was normal. Although nigral dopaminergic
neurons exhibited normal morphological and electrophysiological properties with
normal responses to dopamine receptor activation, a significantly lower dopamine
release was measured in the striatum of PINK1(+/-) mice compared with control
mice, suggesting that a decrease in stimulus-evoked dopamine overflow acts as a
major determinant for the LTP deficit. Accordingly, pharmacological agents
capable of increasing the availability of dopamine in the synaptic cleft
restored normal LTP in heterozygous mice. Moreover, monoamine oxidase B
inhibitors rescued physiological LTP and normal dopamine release. Our results
provide novel evidence for striatal plasticity abnormalities, even in the
heterozygous disease state. These alterations might be considered an
endophenotype to this monogenic form of Parkinson's disease and a valid tool
with which to characterize early disease stage and design possible
disease-modifying therapies.
Copyright © 2013 Movement Disorder Society.
DOI: 10.1002/mds.25724
PMCID: PMC4022284
PMID: 24167038 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: nothing to report. |
http://www.ncbi.nlm.nih.gov/pubmed/21672900 | 1. Ann Pharmacother. 2011 Jun;45(6):787-97. doi: 10.1345/aph.1P784. Epub 2011 Jun
13.
Use of tyrosine kinase inhibitors for chronic myeloid leukemia: management of
patients and practical applications for pharmacy practitioners.
Wong SF(1), Mirshahidi H.
Author information:
(1)Department of Pharmacotherapy and Outcomes Science, Loma Linda University,
Loma Linda, CA, USA. [email protected]
OBJECTIVE: To summarize the use of tyrosine kinase inhibitors (TKIs) for
treatment of patients with chronic myeloid leukemia (CML) and provide practical
information for patient management.
DATA SOURCES: Literature was retrieved from PubMed (2000-January 2011), using
the search terms chronic myeloid leukemia and tyrosine kinase inhibitor.
Abstracts presented at the 2008-2010 annual meetings of the American Society of
Hematology and the American Society of Clinical Oncology, reference citations
from identified publications, as well as the manufacturers' full prescribing
information for cited drugs, also were reviewed.
STUDY SELECTION AND DATA EXTRACTION: Articles evaluating the efficacy and safety
of the TKIs imatinib, nilotinib, and dasatinib were evaluated. Focus was placed
on publications supporting management of patients with CML in the chronic phase.
Reports presenting clinical trial information of TKIs in development also were
included.
DATA SYNTHESIS: The discovery of targeted tyrosine kinase inhibition of BCR-ABL
kinase dramatically changed the treatment of CML. Imatinib, the first TKI
approved for treatment of patients with Philadelphia chromosome--positive CML,
demonstrated significant superiority over the previous standard of care:
interferon plus cytarabine. The newer, more potent TKIs, nilotinib and
dasatinib, have demonstrated improved efficacy over imatinib as first-line
therapy and provide an effective option for patients with resistance or
intolerance to imatinib.
CONCLUSIONS: To maximize efficacy of TKI therapy, close patient management,
involving frequent monitoring of patient response, is essential. Given the
importance of continuing TKI therapy, early recognition and management of
adverse events are critical to optimizing outcomes in patients with CML. In
addition to the safety profile and considerations of comorbidities, additional
factors can affect therapeutic selection, including drug-drug and drug-food
interactions. Research investigating new therapies, particularly for patients
harboring the T315I mutation-which remains refractory to current TKIs-continues
in the quest to improve outcomes in patients with CML.
DOI: 10.1345/aph.1P784
PMID: 21672900 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25712444 | 1. Ann Pharmacother. 2015 May;49(5):582-98. doi: 10.1177/1060028015573564. Epub
2015 Feb 23.
Empagliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes mellitus:
a review of the evidence.
White JR Jr(1).
Author information:
(1)Washington State University, Spokane, WA, USA [email protected].
OBJECTIVE: To review available studies of empagliflozin, a sodium glucose
co-transporter-2 (SGLT2) inhibitor approved in 2014 by the European Commission
and the United States Food and Drug Administration for the treatment of type 2
diabetes mellitus (T2DM).
DATA SOURCES: PubMed was searched using the search terms empagliflozin, BI
10773, and BI10773, for entries between January 1, 2000, and December 1, 2014.
Reference lists from retrieved articles were searched manually for additional
peer-reviewed publications.
STUDY SELECTION AND DATA EXTRACTION: All publications reporting clinical trials
of empagliflozin were eligible for inclusion.
DATA SYNTHESIS: Empagliflozin is a new once-daily oral SGLT2 inhibitor with a
mechanism of action that is independent of β-cell function and the insulin
pathway. Data from a comprehensive phase III clinical trial program have
demonstrated its efficacy as monotherapy, as add-on to other glucose-lowering
agents, and in different patient populations. In these studies, empagliflozin
resulted in improvements in blood glucose levels as well as reductions in body
weight and blood pressure. Empagliflozin was well tolerated and was not
associated with an increased risk of hypoglycemia versus placebo.
CONCLUSION: The oral antidiabetes agent, empagliflozin, can be used as
monotherapy or alongside other glucose-lowering treatments, including insulin,
to treat T2DM.
© The Author(s) 2015.
DOI: 10.1177/1060028015573564
PMID: 25712444 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16689455 | 1. Ther Umsch. 2006 Apr;63(4):249-54. doi: 10.1024/0040-5930.63.4.249.
[Tyrosine kinase inhibitors for the treatment of CML].
[Article in German]
Heim D(1).
Author information:
(1)Hämatologie, Innere Medizin, Universitätsspital Basel, Basel. [email protected]
Chronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a
shortened chromosome 22 which is the result of a reciprocal translocation
between chromosome 9 and 22. The fusion gene is called BCR-ABL. After
transcription and translation the constitutively activated p210 BCR-ABL
oncoprotein is formed. This leads to uncontrolled activation of the ABL tyrosin
kinase. Deregulated cellular proliferation and diminished apoptosis of BCR-ABL
transformed cells is the result. Expression of the BCR-ABL oncoprotein is
sufficient and necessary for the development of a CML phenotype. Imatinib
mesylate (Glivec) is a small molecule that binds to the ATP pocket of ABL and
blocks downstream signalling events. Imatinib is very effective in the treatment
of CML in all stages of the disease. Patients with newly diagnosed chronic phase
CML were randomized to imatinib or to interferon plus cytarabine in the IRIS
trial. Imatinib showed significantly superior tolerability, hematologic and
cytogenetic resposes and increased time to progression. In patients with
advanced phase CML, imatinib is less effective and response duration is short.
Median overall survival of blast crisis patients is 6.9 months only. Additional
BCR-ABL independent chromosomal abnormalities are common in advanced phase CML
and result in resistance to imatinib. BCR-ABL kinase-domaine mutations are
frequently found in imatinib resistant patients and confer diminished
sensitivity to imatinib. Second generation, more powerful ABL kinase inhibitors,
which are effective against most of the known mutations are currently tested in
clinical trials.
DOI: 10.1024/0040-5930.63.4.249
PMID: 16689455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20578184 | 1. Stem Cells. 2010 Sep;28(9):1457-64. doi: 10.1002/stem.469.
Nanog regulates primordial germ cell migration through Cxcr4b.
Sánchez-Sánchez AV(1), Camp E, Leal-Tassias A, Atkinson SP, Armstrong L,
Díaz-Llopis M, Mullor JL.
Author information:
(1)Instituto de Investigación Sanitaria, Fundación para la Investigación
Hospital La Fe, Valencia, Spain.
Gonadal development in vertebrates depends on the early determination of
primordial germ cells (PGCs) and their correct migration to the sites where the
gonads develop. Several genes have been implicated in PGC specification and
migration in vertebrates. Additionally, some of the genes associated with
pluripotency, such as Oct4 and Nanog, are expressed in PGCs and gonads,
suggesting a role for these genes in maintaining pluripotency of the germ
lineage, which may be considered the only cell type that perpetually maintains
stemness properties. Here, we report that medaka Nanog (Ol-Nanog) is expressed
in the developing PGCs. Depletion of Ol-Nanog protein causes aberrant migration
of PGCs and inhibits expression of Cxcr4b in PGCs, where it normally serves as
the receptor of Sdf1a to guide PGC migration. Moreover, chromatin
immunoprecipitation analysis demonstrates that Ol-Nanog protein binds to the
promoter region of Cxcr4b, suggesting a direct regulation of Cxcr4b by Ol-Nanog.
Simultaneous overexpression of Cxcr4b mRNA and depletion of Ol-Nanog protein in
PGCs rescues the migration defective phenotype induced by a loss of Ol-Nanog,
whereas overexpression of Sdf1a, the ligand for Cxcr4b, does not restore proper
PGC migration. These results indicate that Ol-Nanog mediates PGC migration by
regulating Cxcr4b expression.
DOI: 10.1002/stem.469
PMID: 20578184 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23090888 | 1. Am J Hematol. 2012 Nov;87(11):1037-45. doi: 10.1002/ajh.23282.
Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management.
Jabbour E(1), Kantarjian H.
Author information:
(1)Department of Leukemia, The University of Texas M.D. Anderson Cancer Center,
Houston, TX 77030, USA. [email protected]
DISEASE OVERVIEW: Chronic Myeloid Leukemia (CML) is a myeloproliferative
neoplasm with an incidence of one-two cases per 100,000 adults and accounts for
∼15% of newly diagnosed cases of leukemia in adults.
DIAGNOSIS: CML is characterized by a balanced genetic translocation,
t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from
chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome
22q11.2. This rearrangement is known as the Philadelphia chromosome. The
molecular consequence of this translocation is the generation of a BCR-ABL
fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein.
FRONTLINE THERAPY: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib,
and dasatinib, have been approved by the US Food and Drug Administration for the
first-line treatment of patients with newly diagnosed CML in chronic phase
(CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper
and faster responses; their impact on long-term survival remains to be
determined.
SALVAGE THERAPY: For patients who fail standard-dose imatinib therapy, imatinib
dose escalation is a second-line option. Alternative second-line options include
2nd generation TKIs. Although both are potent and specific BCR-ABL TKIs,
dasatinib and nilotinib exhibit unique pharmacological profiles and response
patterns relative to different patient characteristics, such as disease stage
and BCR-ABL mutational status. Patients who develop the T315I "gatekeeper"
mutation display resistance to all currently available TKIs and are candidate
for clinical trials. Allogeneic transplantation remains an important therapeutic
option for CML-CP harboring the T315I mutation, patients who fail 2nd generation
TKIs, and for all patients in advanced phase disease.
Copyright © 2012 Wiley Periodicals, Inc.
DOI: 10.1002/ajh.23282
PMID: 23090888 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12454739 | 1. Leukemia. 2002 Dec;16(12):2349-57. doi: 10.1038/sj.leu.2402775.
Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with
other chemotherapeutic drugs.
Tipping AJ(1), Mahon FX, Zafirides G, Lagarde V, Goldman JM, Melo JV.
Author information:
(1)Dept of Haematology, Imperial College of Science, Technology and Medicine,
Hammersmith Hospital, London, UK.
Imatinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the
tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic
myeloid leukemia (CML). The drug shows great efficacy in chronic phase, but is
less effective in maintaining hematologic remissions in blast crisis patients.
Our group has previously described several cell lines made resistant to
imatinib. We now examine the question of cross-resistance to other
chemotherapeutic drugs used in CML. Four paired imatinib-sensitive/resistant CML
cell lines were assessed by caspase-3 and MTS assays for their proliferative
response to cytosine arabinoside (Ara-C), daunorubicin (DNR), homoharringtonine
(HHT) and hydroxyurea (HU), either alone or in combination with imatinib.
Primary blasts from advanced-stage CML patients refractory to imatinib therapy
were studied by semi-solid media clonogenic assays. We found that these drugs
are generally capable of major inhibition of proliferation of the CML cell
lines, although differential responses to DNR and HHT were noted between some
sensitive and resistant cell line pairs, implying that resistance to imatinib
may confer a growth advantage under such conditions. The four drugs were also
effective in preventing the formation of progenitor cell colonies from CML
patients both before treatment with imatinib, and after relapse on the drug.
Isobolographic analysis implied that these drugs will generally combine well
with imatinib, and in some cases will be synergistic. We conclude that Ara-C,
DNR or HHT, either alone or in combination with imatinib, are likely to be the
best therapeutic alternatives in the management of patients who become resistant
to imatinib monotherapy.
DOI: 10.1038/sj.leu.2402775
PMID: 12454739 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19139263 | 1. J Cell Biol. 2009 Jan 12;184(1):67-82. doi: 10.1083/jcb.200801009.
A role for NANOG in G1 to S transition in human embryonic stem cells through
direct binding of CDK6 and CDC25A.
Zhang X(1), Neganova I, Przyborski S, Yang C, Cooke M, Atkinson SP, Anyfantis G,
Fenyk S, Keith WN, Hoare SF, Hughes O, Strachan T, Stojkovic M, Hinds PW,
Armstrong L, Lako M.
Author information:
(1)NorthEast England Stem Cell Institute, Institute of Human Genetics, Newcastle
University, International Centre for Life, Newcastle upon Tyne, England, UK.
In this study, we show that NANOG, a master transcription factor, regulates
S-phase entry in human embryonic stem cells (hESCs) via transcriptional
regulation of cell cycle regulatory components. Chromatin immunoprecipitation
combined with reporter-based transfection assays show that the C-terminal region
of NANOG binds to the regulatory regions of CDK6 and CDC25A genes under normal
physiological conditions. Decreased CDK6 and CDC25A expression in hESCs suggest
that both CDK6 and CDC25A are involved in S-phase regulation. The effects of
NANOG overexpression on S-phase regulation are mitigated by the down-regulation
of CDK6 or CDC25A alone. Overexpression of CDK6 or CDC25A alone can rescue the
impact of NANOG down-regulation on S-phase entry, suggesting that CDK6 and
CDC25A are downstream cell cycle effectors of NANOG during the G1 to S
transition.
DOI: 10.1083/jcb.200801009
PMCID: PMC2615089
PMID: 19139263 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16843101 | 1. Cancer Genet Cytogenet. 2006 Jul 15;168(2):120-3. doi:
10.1016/j.cancergencyto.2006.02.002.
Random aneuploidy in CML patients at diagnosis and under imatinib treatment.
Amiel A(1), Yukla M, Gaber E, Leopold L, Josef G, Fejgin M, Lishner M.
Author information:
(1)Genetic Institute, Meir Medical Center, Tshernichovski St., Kfar-Saba 44281,
Israel. [email protected]
Chronic myeloid leukemia (CML) is characterized by the presence of a BCR-ABL
fusion gene, which is the result of a reciprocal translocation between
chromosomes 9 and 22, and is cytogenetically visible as a shortened chromosome
22 (Philadelphia). Research during the past two decades has established that
BCR-ABL is probably the pathogenetic pathway leading to CML, and that
constitutive tyrosine kinase activity is central to BCR-ABL capacity to
transform hematopoietic cells in vitro and in vivo. The tyrosine kinase
inhibitor imatinib mesylate was introduced into the treatment regimen for CML in
1998. During the last few years, reports on chromosomal changes during imatinib
treatment have been described. In this study, we evaluated the random aneuploidy
rate with chromosomes 9 and 18 in bone marrow from treated and untreated
patients. We found higher aneuploidy rates in both treated and untreated
patients compared to the control group. In three patients who were treated with
imatinib mesylate for more than 1.5 years, triploidy also appeared in some
nuclei. To our knowledge, this is the first report on new chromosomal changes
such as random aneuploidy and triploidy under imatinib treatment, but more
studies are needed to investigate the long-term effect of the imatinib treatment
on genetic instability.
DOI: 10.1016/j.cancergencyto.2006.02.002
PMID: 16843101 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17364993 | 1. Hematology. 2007 Feb;12(1):49-53. doi: 10.1080/10245330600937929.
Imatinib-induced immune hepatitis: case report and literature review.
Al Sobhi E(1), Zahrani Z, Zevallos E, Zuraiki A.
Author information:
(1)Department of Pathology and Laboratory Medicine, King Khalid National Guard
Hospital, Jeddah, Saudi Arabia. [email protected]
Imatinib is one of the most recent medications used for the treatment of chronic
myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). It is an
orally administered protein-tyrosine kinase inhibitor, an enzyme which is
produced by BCR-ABL fusion which results from translocation of 9:22 chromosome
(Philadelphia chromosome). Imatinib blocks proliferation and induces apoptosis
of BCR-ABL-expression in CML. Many side effects produced by imatinib have been
documented but its induction of hepatotoxcity has been rarely reported. Only a
few cases so far have been reported in the literature and almost all were in
females. We describe another case of hepatotoxicity due to imatinib in a 17-year
old female with clinical, laboratory and histopathological changes. The case
described here suggests that imatinib may also induce immune hepatitis, in some
patients.
DOI: 10.1080/10245330600937929
PMID: 17364993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22315219 | 1. J Biol Chem. 2012 Apr 6;287(15):12417-24. doi: 10.1074/jbc.M111.333856. Epub
2012 Feb 7.
CtBP-interacting BTB zinc finger protein (CIBZ) promotes proliferation and G1/S
transition in embryonic stem cells via Nanog.
Nishii T(1), Oikawa Y, Ishida Y, Kawaichi M, Matsuda E.
Author information:
(1)Division of Gene Function in Animals, Nara Institute of Science and
Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan.
Mouse embryonic stem cells (ESCs) require transcriptional regulation to ensure
rapid proliferation that allows for self-renewal. However, the molecular
mechanism by which transcriptional factors regulate this rapid proliferation
remains largely unknown. Here we present data showing that CIBZ, a BTB domain
zinc finger transcriptional factor, is a key transcriptional regulator for
regulation of ESC proliferation. Here we show that deletion or siRNA knockdown
of CIBZ inhibits ESC proliferation. Cell cycle analysis shows that loss of CIBZ
delays the progression of ESCs through the G1 to S phase transition. Conversely,
constitutive ectopic expression of exogenous CIBZ in ESCs promotes proliferation
and accelerates G1/S transition. These findings suggest that regulation of the
G1/S transition explains, in part, CIBZ-associated ESC proliferation. Our data
suggest that CIBZ acts through the post-transcriptionally regulates the
expression of Nanog, a positive regulator of ESC proliferation and G1/S
transition, but does not affect Oct3/4 and Sox2 protein expression. Notably,
constitutive overexpression of Nanog partially rescued the proliferation defect
caused by CIBZ knockdown, indicating the role of CIBZ in ESC proliferation and
G1/S transition at least in part depends on the Nanog protein level.
DOI: 10.1074/jbc.M111.333856
PMCID: PMC3320991
PMID: 22315219 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19323652 | 1. Clin Sci (Lond). 2009 May;116(9):697-712. doi: 10.1042/CS20080508.
Autophagy in disease: a double-edged sword with therapeutic potential.
Martinet W(1), Agostinis P, Vanhoecke B, Dewaele M, De Meyer GR.
Author information:
(1)Division of Pharmacology, University of Antwerp, B-2610 Antwerp, Belgium.
[email protected]
Autophagy is a catabolic trafficking pathway for bulk destruction and turnover
of long-lived proteins and organelles via regulated lysosomal degradation. In
eukaryotic cells, autophagy occurs constitutively at low levels to perform
housekeeping functions, such as the destruction of dysfunctional organelles.
Up-regulation occurs in the presence of external stressors (e.g. starvation,
hormonal imbalance and oxidative stress) and internal needs (e.g. removal of
protein aggregates), suggesting that the process is an important survival
mechanism. However, the occurrence of autophagic structures in dying cells of
different organisms has led to the hypothesis that autophagy may also have a
causative role in stress-induced cell death. The identification within the last
decade of a full set of genes essential for autophagy in yeast, the discovery of
human orthologues and the definition of signalling pathways regulating autophagy
have accelerated our molecular understanding and interest in this fundamental
process. A growing body of evidence indicates that autophagy is associated with
heart disease, cancer and a number of neurodegenerative disorders, such as
Alzheimer's, Parkinson's and Huntington's diseases. Furthermore, it has been
demonstrated that autophagy plays a role in embryogenesis, aging and immunity.
Recently, it has been shown that autophagy can be intensified by specific drugs.
The pharmacological modulation of the autophagic pathway represents a major
challenge for clinicians to treat human disease.
DOI: 10.1042/CS20080508
PMID: 19323652 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12200353 | 1. Blood. 2002 Sep 15;100(6):1965-71. doi: 10.1182/blood-2001-12-0181.
A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia
chromosome-positive acute lymphoid leukemias.
Ottmann OG(1), Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S,
Fischer T, Deininger MW, Schiffer CA, Baccarani M, Gratwohl A, Hochhaus A,
Hoelzer D, Fernandes-Reese S, Gathmann I, Capdeville R, O'Brien SG.
Author information:
(1)Medizinische Klinik III/Abteilung Haematologie, Johann Wolfgang Goethe
Universität, 60590 Frankfurt, Germany. [email protected]
The translocation (9;22) gives rise to the p190(Bcr-Abl) and p210(Bcr-Abl)
tyrosine kinase proteins, considered sufficient for leukemic transformation.
Philadelphia-positive (Ph(+)) acute leukemia patients failing to respond to
initial induction therapy have a poor prognosis with few effective treatment
options. Imatinib is an orally administered, potent inhibitor of the Bcr-Abl
tyrosine kinase. We conducted a clinical trial in 56 patients with relapsed or
refractory Ph(+) acute lymphoblastic leukemia (ALL; 48 patients) or chronic
myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was
given once daily at 400 mg or 600 mg. Imatinib induced complete hematologic
responses (CHRs) and complete marrow responses (marrow-CRs) in 29% of ALL
patients (CHR, 19%; marrow-CR, 10%), which were sustained for at least 4 weeks
in 6% of patients. Median estimated time to progression and overall survival for
ALL patients were 2.2 and 4.9 months, respectively. CHRs were reported for 3
(38%) of the patients with LyBC (one sustained CHR). Grade 3 or 4
treatment-related nonhematologic toxicity was reported for 9% of patients; none
of the patients discontinued therapy because of nonhematologic adverse
reactions. Grade 4 neutropenia and thrombocytopenia occurred in 54% and 27% of
patients, respectively. Imatinib therapy resulted in a clinically relevant
hematologic response rate in relapsed or refractory Ph(+) acute lymphoid
leukemia patients, but development of resistance and subsequent disease
progression were rapid. Further studies are warranted to test the effects of
imatinib in combination with other agents and to define the mechanisms of
resistance to imatinib.
DOI: 10.1182/blood-2001-12-0181
PMID: 12200353 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24213377 | 1. Nucleus. 2013 Nov-Dec;4(6):424-30. doi: 10.4161/nucl.26865. Epub 2013 Nov 8.
Nuclear lamins: making contacts with promoters.
Lund E(1), Collas P(1).
Author information:
(1)Stem Cell Epigenetics Laboratory; Institute of Basic Medical Sciences;
Faculty of Medicine; University of Oslo, and Norwegian Center for Stem Cell
Research; Oslo, Norway.
Comment on
Genome Res. 2013 Oct;23(10):1580-9. doi: 10.1101/gr.159400.113.
The nuclear lamina guards the genome and in many ways contributes to regulating
nuclear function. Increasing evidence indicates that the lamina dynamically
interacts with chromatin mainly through large repressive domains, and recent
data suggest that at least some of the lamin-genome contacts may be
developmentally significant. In an attempt to provide an additional meaning to
lamin-genome contacts, a recent study characterized the association of gene
promoters with A-type lamins in progenitor and differentiated cells. Here, we
discuss how A-type lamins interact with spatially defined promoter regions, and
the relationship between these interactions, associated chromatin marks and gene
expression outputs. We discuss the impact of A-type lamins on nucleus-wide and
local chromatin organization. We also address how lamin-promoter interactions
are redistributed during differentiation of adipocyte progenitors into
adipocytes. Finally, we propose a model of lineage-specific "unlocking" of
developmentally regulated loci and its significance in cellular differentiation.
DOI: 10.4161/nucl.26865
PMCID: PMC3925686
PMID: 24213377 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23439366 | 1. RNA Biol. 2013 May;10(5):679-86. doi: 10.4161/rna.24022. Epub 2013 Feb 25.
CRISPR-Cas: evolution of an RNA-based adaptive immunity system in prokaryotes.
Koonin EV(1), Makarova KS.
Author information:
(1)National Center for Biotechnology Information, NLM, National Institutes of
Health, Bethesda, MD, USA. [email protected]
The CRISPR-Cas (clustered regularly interspaced short palindromic repeats,
CRISPR-associated genes) is an adaptive immunity system in bacteria and archaea
that functions via a distinct self-non-self recognition mechanism that is
partially analogous to the mechanism of eukaryotic RNA interference (RNAi). The
CRISPR-Cas system incorporates fragments of virus or plasmid DNA into the CRISPR
repeat cassettes and employs the processed transcripts of these spacers as guide
RNAs to cleave the cognate foreign DNA or RNA. The Cas proteins, however, are
not homologous to the proteins involved in RNAi and comprise numerous, highly
diverged families. The majority of the Cas proteins contain diverse variants of
the RNA recognition motif (RRM), a widespread RNA-binding domain. Despite the
fast evolution that is typical of the cas genes, the presence of diverse
versions of the RRM in most Cas proteins provides for a simple scenario for the
evolution of the three distinct types of CRISPR-cas systems. In addition to
several proteins that are directly implicated in the immune response, the cas
genes encode a variety of proteins that are homologous to prokaryotic toxins
that typically possess nuclease activity. The predicted toxins associated with
CRISPR-Cas systems include the essential Cas2 protein, proteins of COG1517 that,
in addition to a ligand-binding domain and a helix-turn-helix domain, typically
contain different nuclease domains and several other predicted nucleases. The
tight association of the CRISPR-Cas immunity systems with predicted toxins that,
upon activation, would induce dormancy or cell death suggests that adaptive
immunity and dormancy/suicide response are functionally coupled. Such coupling
could manifest in the persistence state being induced and potentially providing
conditions for more effective action of the immune system or in cell death being
triggered when immunity fails.
DOI: 10.4161/rna.24022
PMCID: PMC3737325
PMID: 23439366 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23334424 | 1. Nature. 2013 Feb 14;494(7436):266-70. doi: 10.1038/nature11835. Epub 2013 Jan
20.
A complete mass-spectrometric map of the yeast proteome applied to quantitative
trait analysis.
Picotti P(1), Clément-Ziza M, Lam H, Campbell DS, Schmidt A, Deutsch EW, Röst H,
Sun Z, Rinner O, Reiter L, Shen Q, Michaelson JJ, Frei A, Alberti S, Kusebauch
U, Wollscheid B, Moritz RL, Beyer A, Aebersold R.
Author information:
(1)Department of Biology, Institute of Molecular Systems Biology, ETH Zurich,
Zurich CH-8093, Switzerland. [email protected]
Comment in
Nat Methods. 2013 Mar;10(3):192. doi: 10.1038/nmeth.2392.
Experience from different fields of life sciences suggests that accessible,
complete reference maps of the components of the system under study are highly
beneficial research tools. Examples of such maps include libraries of the
spectroscopic properties of molecules, or databases of drug structures in
analytical or forensic chemistry. Such maps, and methods to navigate them,
constitute reliable assays to probe any sample for the presence and amount of
molecules contained in the map. So far, attempts to generate such maps for any
proteome have failed to reach complete proteome coverage. Here we use a strategy
based on high-throughput peptide synthesis and mass spectrometry to generate an
almost complete reference map (97% of the genome-predicted proteins) of the
Saccharomyces cerevisiae proteome. We generated two versions of this
mass-spectrometric map, one supporting discovery-driven (shotgun) and the other
supporting hypothesis-driven (targeted) proteomic measurements. Together, the
two versions of the map constitute a complete set of proteomic assays to support
most studies performed with contemporary proteomic technologies. To show the
utility of the maps, we applied them to a protein quantitative trait locus (QTL)
analysis, which requires precise measurement of the same set of peptides over a
large number of samples. Protein measurements over 78 S. cerevisiae strains
revealed a complex relationship between independent genetic loci, influencing
the levels of related proteins. Our results suggest that selective pressure
favours the acquisition of sets of polymorphisms that adapt protein levels but
also maintain the stoichiometry of functionally related pathway members.
DOI: 10.1038/nature11835
PMCID: PMC3951219
PMID: 23334424 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14728807 | 1. Cell Res. 2003 Dec;13(6):499-502. doi: 10.1038/sj.cr.7290193.
Identification of two distinct transactivation domains in the pluripotency
sustaining factor nanog.
Pan GJ(1), Pei DQ.
Author information:
(1)Institute of Pharmacology, Department of Biological Sciences and
Biotechnology and State Key Laboratory of Biomembrane and Membrane
Biotechnology, Tsinghua Institutes of Biomedicine, Tsinghua University, 100084
Beijing, China.
Nanog is a newly identified homeodomain gene that functions to sustain the
pluripotency of embryonic stem cells. However, the molecular mechanism through
which nanog regulates stem cell pluripotency remains unknown. Mouse nanog
encodes a polypeptide of 305 residues with a divergent homeodomain similar to
those in the NK-2 family. The rest of nanog contains no apparent homology to any
known proteins characterized so far. It is hypothesized that nanog encodes a
transcription factor that regulates stem cell pluripotency by switching on or
off target genes. To test this hypothesis, we constructed fusion proteins
between nanog and DNA binding domains of the yeast transcription factor Gal4 and
tested the transactivation potentials of these constructs. Our data demonstrate
that both regions N- and C- terminal to the homeodomain have transcription
activities. Despite the fact that it contains no apparent transactivation
motifs, the C-terminal domain is about 7 times as active as the N-terminal one.
This unique arrangement of dual transactivators may confer nanog the flexibility
and specificity to regulate downstream genes critical for both pluripotency and
differentiation of stem cells.
DOI: 10.1038/sj.cr.7290193
PMID: 14728807 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24903420 | 1. Bioinformatics. 2014 Oct;30(19):2808-10. doi: 10.1093/bioinformatics/btu379.
Epub 2014 Jun 5.
Sushi.R: flexible, quantitative and integrative genomic visualizations for
publication-quality multi-panel figures.
Phanstiel DH(1), Boyle AP(1), Araya CL(1), Snyder MP(1).
Author information:
(1)Department of Genetics, Stanford University School of Medicine, Stanford, CA
94305, USA.
Interpretation and communication of genomic data require flexible and
quantitative tools to analyze and visualize diverse data types, and yet, a
comprehensive tool to display all common genomic data types in publication
quality figures does not exist to date. To address this shortcoming, we present
Sushi.R, an R/Bioconductor package that allows flexible integration of genomic
visualizations into highly customizable, publication-ready, multi-panel figures
from common genomic data formats including Browser Extensible Data (BED),
bedGraph and Browser Extensible Data Paired-End (BEDPE). Sushi.R is open source
and made publicly available through GitHub (https://github.com/dphansti/Sushi)
and Bioconductor
(http://bioconductor.org/packages/release/bioc/html/Sushi.html).
© The Author 2014. Published by Oxford University Press.
DOI: 10.1093/bioinformatics/btu379
PMCID: PMC4173017
PMID: 24903420 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22151181 | 1. BMC Cancer. 2011 Dec 9;11:512. doi: 10.1186/1471-2407-11-512.
Regulation of hTERT by BCR-ABL at multiple levels in K562 cells.
Chai JH(1), Zhang Y, Tan WH, Chng WJ, Li B, Wang X.
Author information:
(1)Department of Biochemistry, Yong Loo Lin School of Medicine, National
University of Singapore, 8 Medical Drive, 117597 Singapore, Singapore.
BACKGROUND: The cytogenetic characteristic of Chronic Myeloid Leukemia (CML) is
the formation of the Philadelphia chromosome gene product, BCR-ABL. Given that
BCR-ABL is the specific target of Gleevec in CML treatment, we investigated the
regulation of the catalytic component of telomerase, hTERT, by BCR-ABL at
multiple levels in K562 cells.
METHODS: Molecular techniques such as over expression, knockdown, real-time PCR,
immunoprecipitation, western blotting, reporter assay, confocal microscopy,
telomerase assays and microarray were used to suggest that hTERT expression and
activity is modulated by BCR-ABL at multiple levels.
RESULTS: Our results suggest that BCR-ABL plays an important role in regulating
hTERT in K562 (BCR-ABL positive human leukemia) cells. When Gleevec inhibited
the tyrosine kinase activity of BCR-ABL, phosphorylation of hTERT was
downregulated, therefore suggesting a positive correlation between BCR-ABL and
hTERT. Gleevec treatment inhibited hTERT at mRNA level and significantly reduced
telomerase activity (TA) in K562 cells, but not in HL60 or Jurkat cells (BCR-ABL
negative cells). We also demonstrated that the transcription factor STAT5a plays
a critical role in hTERT gene regulation in K562 cells. Knockdown of STAT5a, but
not STAT5b, resulted in a marked downregulation of hTERT mRNA level, TA and
hTERT protein level in K562 cells. Furthermore, translocation of hTERT from
nucleoli to nucleoplasm was observed in K562 cells induced by Gleevec.
CONCLUSIONS: Our data reveal that BCR-ABL can regulate TA at multiple levels,
including transcription, post-translational level, and proper localization.
Thus, suppression of cell growth and induction of apoptosis by Gleevec treatment
may be partially due to TA inhibition. Additionally, we have identified STAT5a
as critical mediator of the hTERT gene expression in BCR-ABL positive CML cells,
suggesting that targeting STAT5a may be a promising therapeutic strategy for
BCR-ABL positive CML patients.
DOI: 10.1186/1471-2407-11-512
PMCID: PMC3259104
PMID: 22151181 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11827928 | 1. Circulation. 2002 Feb 5;105(5):614-20. doi: 10.1161/hc0502.103012.
Accelerated cardiomyopathy in mice with overexpression of cardiac G(s)alpha and
a missense mutation in the alpha-myosin heavy chain.
Hardt SE(1), Geng YJ, Montagne O, Asai K, Hong C, Yang GP, Bishop SP, Kim SJ,
Vatner DE, Seidman CE, Seidman JG, Homcy CJ, Vatner SF.
Author information:
(1)Cardiovascular Research Institute, Department of Cell Biology, University of
Medicine and Dentistry New Jersey, New Jersey Medical School, Newark, USA.
BACKGROUND: To understand further the pathogenesis of familial hypertrophic
cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403-->Gln
missense mutation in the alpha-myosin heavy chain (403) is affected by
chronically enhancing sympathetic drive by mating the mice with those
overexpressing G(s)alpha (G(s)alpha x403).
METHODS AND RESULTS: Heart rate in 3-month-old conscious mice was elevated
similarly (P<0.05) in mice overexpressing G(s)alpha (G(s)alpha mice; 746 +/- 14
bpm) and G(s)alpha x403 mice (718+/- 19 bpm) compared with littermate wild-type
mice (WT; 623+/- 18 bpm) and 403 mice (594+/- 16 bpm). Left ventricular ejection
fraction (LVEF), as determined by echocardiography, was enhanced in G(s)alpha
x403 mice (88+/- 1%, P<0.001) compared with WT (69+/- 1%), 403 (75+/- 1%), and
G(s)alpha (69 +/- 2%) mice. Isolated cardiomyocytes from G(s)alpha x403 mice
also exhibited higher (P<0.001) baseline percent contraction (11.9+/- 0.5%) than
WT (7.0+/- 0.5%), 403 (5.5+/- 0.5%), and G(s)alpha (7.8+/- 0.3%) cardiomyocytes.
Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in
G(s)alpha and normalized in G(s)alpha x403 mice. This was also observed in vivo.
In vivo isoproterenol (0.1 microgram . kg(-1) . min(-1)) increased LVEF to
maximal levels in G(s)alpha x403 and G(s)alpha, whereas in 403, the response was
attenuated compared with WT. At 10 months of age, G(s)alpha x403 had
significantly depressed LVEF (57 +/- 4%). Histopathological examination
demonstrated that myocyte hypertrophy and fibrosis were already present in young
G(s)alpha x403 mice and that old animals had severe cardiomyopathy. By 15 months
of age, the survival of G(s)alpha x403 was 0% compared with 100% for WT, 71% for
G(s)alpha, and 100% for 403 mice (P<0.05).
CONCLUSIONS: These results show that the cardiomyopathy developed by G(s)alpha
x403 mice is synergistic rather than additive, most likely owing to the elevated
baseline function combined with enhanced responsiveness to sympathetic
stimulation.
DOI: 10.1161/hc0502.103012
PMID: 11827928 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16271306 | 1. Cell Biol Int. 2006 Feb;30(2):133-7. doi: 10.1016/j.cellbi.2005.09.002. Epub
2005 Nov 2.
Dexamethasone has pro-apoptotic effects on non-activated fresh peripheral blood
mononuclear cells.
Totino PR(1), Riccio EK, Corte-Real S, Daniel-Ribeiro CT, de Fátima
Ferreira-da-Cruz M.
Author information:
(1)Department of Immunology, WHO Collaborating Center for Research and Training
in the Immunology of Parasitic Diseases, Instituto Oswaldo Cruz, Fiocruz, RJ,
Brazil.
Apoptosis is a physiological method of cell death commonly referred to as
programmed cell death. However, non-apoptotic programmed cell death, such as
autophagy and programmed necrosis, has been characterized by morphological
criteria. In view of the human therapeutic use of DEX, and considering that no
difference in the number and/or affinity of glucocorticoid receptors in
activated and non-activated lymphocytes has been reported, we decided to
evaluate the effect of DEX on fresh peripheral blood mononuclear cells (PBMC).
Transmission electron microscopy showed that DEX can significantly induce
apoptosis in non-activated PBMC. It was also observed by transmission electron
microscopy that, independently of DEX treatment, PBMC also died by a process
marked by extreme vacuolization and increase in cellular volume; these cells
were erroneously classified as viable by flow cytometry using the 7-AAD assay.
It is concluded that the DEX pro-apoptotic effect is not restricted to activated
PBMC and, therefore, DEX-induced apoptosis could play either homeostatic
(activated PBMC) or immunosuppressive (non-activated PBMC) roles.
DOI: 10.1016/j.cellbi.2005.09.002
PMID: 16271306 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2326195 | 1. Nucleic Acids Res. 1990 Mar 25;18(6):1565-9. doi: 10.1093/nar/18.6.1565.
Role of GC-biased mutation pressure on synonymous codon choice in Micrococcus
luteus, a bacterium with a high genomic GC-content.
Ohama T(1), Muto A, Osawa S.
Author information:
(1)Department of Biology, School of Science, Nagoya University, Japan.
The GC (G + C, or G or C)-contents of codon silent positions in all two-codon
sets and three codons AUY/A (IIe), and in most of the family boxes of
Micrococcus luteus (genomic GC-content: 74%) are 95% to 100% in both the highly
and weakly expressed genes. In some family boxes, there is a decrease in NNC
codons and an increase in NNG codons from the highly expressed to weakly
expressed genes without apparent involvement of NNU and NNA codons. From these
observations, we conclude that the selective use of synonymous codons in M.
luteus may be largely determined by GC-biased mutation pressure and that in the
highly expressed genes tRNAs would act as a weak selection pressure in some
family boxes. Available data suggest that the effect of selection pressure by
tRNAs on the synonymous codon choice becomes more apparent in the highly
expressed genes in eubacteria with intermediate GC-contents such as Escherichia
coli and Bacillus subtilis, and that the U/C ratio of the codon third positions
in NNU/C-type two-codon sets in the weakly expressed genes would represent the
approximate magnitude of directional mutation pressure throughout eubacteria.
DOI: 10.1093/nar/18.6.1565
PMCID: PMC330526
PMID: 2326195 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20232788 | 1. Verh K Acad Geneeskd Belg. 2009;71(6):335-71.
Cardiovascular characteristics in Marfan syndrome and their relation to the
genotype.
De Backer J(1).
Author information:
(1)Dienst Cardiologie, Centrum voor Medische Genetica Vakgroep Pediatrie en
Genetica, Fac. Geneeskunde en Gezondheidswetenschappen, UGent De Pintelaan 185,
B 9000 Gent.
Marfan syndrome (MFS) is a systemic disorder of connective tissue with autosomal
dominant inheritance. The diagnosis of MFS is based on the identification of a
combination of clinical manifestations in the ocular, musculoskeletal, and
cardiovascular organ systems defined in the Ghent Nosology (De Paepe et al,
1996). Confirmation of the diagnosis in an individual requires the presence of
major clinical manifestations in at least two organ systems associated with
involvement of a third organ system. In relatives of an affected proband, major
involvement of one organ system and involvement of a second organ system
confirms the diagnosis. Major clinical criteria are very specific for MFS and
include a combination of (4 out of 8) skeletal manifestations, ectopia lentis,
dural ectasia and dilatation or dissection of the ascending aorta. The
prevalence of- and the guidelines for the assessment of each of these major
criteria are well established. Minor clinical criteria are less typical, but
their importance in the diagnostic process should not be underestimated.
Unfortunately, figures on the prevalence as well as practical guidelines for the
assessment of most minor criteria are lacking, especially for those involving
the cardiovascular system. The major cardiovascular manifestation in MFS is a
progressive dilatation of the ascending aorta, leading to aortic aneurysm
formation and eventually to fatal aortic rupture or dissection. Aortic
dissection in early adult life is the leading cause of death in MFS. Early
diagnosis of individuals at risk of the disease is extremely important as timely
treatment of cardiovascular complications has greatly improved life expectancy
in MFS. Despite progress in medical and surgical treatment of aortic aneurysms,
MFS continues to be associated with significant morbidity and mortality. This
may be related to inadequate diagnosis or treatment, but also to the occurrence
of cardiovascular problems in ageing MFS patients that were unrecognised until
now, such as left ventricular (LV) dysfunction.This thesis is focused on the
study of cardiovascular manifestations of MFS which localize beyond the aortic
root and on the presently unknown relationship between the severity of the
cardiovascular phenotype and the genotype. In the first part, we have studied
the prevalence and diagnostic value of the following cardiovascular
manifestations of MFS: mitral valve prolapse (MVP) and calcification of the
mitral valve annulus, dilatation of the main pulmonary artery (MPA) and
dilatation or dissection of the descending aorta. We found a significantly
higher prevalence of MVP in MFS patients compared to normal controls, indicating
that this feature is useful in the diagnostic evaluation of the condition. In
contrast, calcification of the mitral valve annulus appears to be very uncommon,
difficult to quantify and therefore not useful in the diagnosis of MFS. We also
studied the dimension of the MPA in a series of MFS patients and defined a
cut-of value that can be used in the diagnostic evaluation of adult MFS
patients. In addition, we showed that diameters of the aorta measured at
different levels beyond the aortic root are increased in MFS patients compared
to controls. Unfortunately, there was too much overlap with the values obtained
in the normal control population to provide cut-off values for the descending
aorta. Based on these findings, we developed practical guidelines for the
cardiovascular evaluation of patients referred for MFS. In the second part, we
studied LV function in MFS patients free of valvular heart disease using a
combination of echocardiography (both conventional echocardiography and tissue
Doppler imaging) and Magnetic Resonance Imaging. We could demonstrate that MFS
patients present a combination of systolic and diastolic dysfunction that is not
related to valvular heart disease. This may be attributed to a primary
contractile dysfunction of the myocardium and is likely related to the
underlying alterations in the elastic features of the myocardium, resulting from
the microfibrillar defect. This observation is important in the development of
new therapeutic strategies for MFS. Affected individuals may benefit from a
treatment with agents that support myocardial function such as angiotensin
converting enzyme--inhibitors or angiotensin II type-1 receptor blockers.
Furthermore, since MFS patients survive longer thanks to improved medical and
surgical treatments, LV dysfunction may become an important issue in the
follow-up of these patients. In the third part, we have studied aspects of local
and global wave reflection in the aorta of MFS patients. Early return of
reflected waves boosts systolic pressure and presents an extra load for the
heart and the central vessels. As such, these wave reflections are regarded as
one of the important determinants of central blood pressure and can contribute
to the development of aortic dilatation in MFS. However, we were unable to
demonstrate clear differences in both local and global parameters of wave
reflection between MFS patients and normal controls. This could be explained by
the fact that increased length of the aorta on the one hand and increased aortic
stiffness on the other hand counterbalance each other in MFS patients without
yielding any net effect on wave reflection. In the last part of this thesis, we
investigated the correlation between the severity of the cardiovascular
phenotype in MFS and the type of FBN1 mutation. First, we investigated the
correlation between parameters of aortic stiffness (distensibility and pulse
wave velocity measured by Magnetic Resonance Imaging) and the type of FBN1
mutation (missense or in-frame deletions/insertions versus nonsense or
out-of-frame deletions/insertions). We could not demonstrate any significant
differences between these different mutation types, indicating that the FBN1
genotype is not the sole determinant of aortic stiffness. Second, we provided a
detailed description of clinical findings in three unrelated MFS families in
which an FBN1 mutation was identified and which demonstrate striking
intrafamilial phenotypic variability as another illustration of the absence of
genotype/phenotype correlations in MFS. This study also illustrated several
important issues in MFS. First, repeated clinical examination of suspected
patients can be necessary in order to establish a correct and final diagnosis.
Second, extensive family history taking and clinical examination of first degree
relatives can be highly contributory to the diagnosis. Third, patients with an
'atypical' MFS phenotype may show substantial clinical overlap with other
connective tissue disorders such as Weill-Marchesani syndrome or Ehlers-Danlos
syndrome and represent a diagnostic challenge. We demonstrated that additional
mutational analysis of the FBN1 gene can be a valuable aid to the diagnosis and
help to outline medical management options in these challenging cases. In
conclusion, we have refined diagnostic guidelines for the assessment of minor
cardiovascular manifestations in MFS, shown that LV dysfunction is part of the
cardiovascular spectrum and should be followed in the management of MFS
patients, and demonstrated that aortic wave reflection is not elevated in MFS.
In this work, we also investigated genotype/phenotype correlations, illustrated
the marked (intrafamilial) variability in phenotypic expression of the
condition, and the value of molecular testing in the diagnosis of MFS. Overall,
this thesis nicely illustrates that close interaction and collaboration between
cardiology and genetics is an added value to the study of disease pathogenesis
of MFS and aortic aneurysms in general.
PMID: 20232788 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23438854 | 1. Mol Cell. 2013 Feb 21;49(4):583-90. doi: 10.1016/j.molcel.2013.01.029.
The coming age of complete, accurate, and ubiquitous proteomes.
Mann M(1), Kulak NA, Nagaraj N, Cox J.
Author information:
(1)Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
[email protected]
High-resolution mass spectrometry (MS)-based proteomics has progressed
tremendously over the years. For model organisms like yeast, we can now quantify
complete proteomes in just a few hours. Developments discussed in this
Perspective will soon enable complete proteome analysis of mammalian cells, as
well, with profound impact on biology and biomedicine.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.molcel.2013.01.029
PMID: 23438854 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15768030 | 1. Nat Biotechnol. 2005 Apr;23(4):463-8. doi: 10.1038/nbt1076. Epub 2005 Mar 13.
Enrichment and analysis of peptide subsets using fluorous affinity tags and mass
spectrometry.
Brittain SM(1), Ficarro SB, Brock A, Peters EC.
Author information:
(1)Genomics Institute of the Novartis Research Foundation, 10675 John Jay
Hopkins Drive, San Diego, CA 92121, USA.
Although mass spectrometry has become a powerful tool for the functional
analysis of biological systems, complete proteome characterization cannot yet be
achieved. Instead, the sheer complexity of living organisms demands
fractionation of cellular extracts to enable more targeted analyses. Here, we
introduce the concept of "fluorous proteomics," whereby specific peptide subsets
from samples of biological origin are tagged with perfluorinated moieties and
subsequently enriched by solid-phase extraction over a fluorous-functionalized
stationary phase. This approach is extremely selective, yet can readily be
tailored to enrich different subsets of peptides. Additionally, this methodology
overcomes many of the limitations of traditional bioaffinity-based enrichment
strategies, while enabling new affinity enrichment schemes impossible to
implement with bioaffinity reagents. The potential of this methodology is
demonstrated by the facile enrichment of peptides bearing particular side-chain
functionalities or post-translational modifications from tryptic digests of
individual proteins as well as whole cell lysates.
DOI: 10.1038/nbt1076
PMID: 15768030 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19945378 | 1. Cell. 2009 Nov 25;139(5):945-56. doi: 10.1016/j.cell.2009.07.040.
RNA-guided RNA cleavage by a CRISPR RNA-Cas protein complex.
Hale CR(1), Zhao P, Olson S, Duff MO, Graveley BR, Wells L, Terns RM, Terns MP.
Author information:
(1)Department of Biochemistry, University of Georgia, Athens, GA 30602, USA.
Comment in
Cell. 2009 Nov 25;139(5):863-5. doi: 10.1016/j.cell.2009.11.018.
Compelling evidence indicates that the CRISPR-Cas system protects prokaryotes
from viruses and other potential genome invaders. This adaptive prokaryotic
immune system arises from the clustered regularly interspaced short palindromic
repeats (CRISPRs) found in prokaryotic genomes, which harbor short
invader-derived sequences, and the CRISPR-associated (Cas) protein-coding genes.
Here, we have identified a CRISPR-Cas effector complex that is comprised of
small invader-targeting RNAs from the CRISPR loci (termed prokaryotic silencing
(psi)RNAs) and the RAMP module (or Cmr) Cas proteins. The psiRNA-Cmr protein
complexes cleave complementary target RNAs at a fixed distance from the 3' end
of the integral psiRNAs. In Pyrococcus furiosus, psiRNAs occur in two size forms
that share a common 5' sequence tag but have distinct 3' ends that direct
cleavage of a given target RNA at two distinct sites. Our results indicate that
prokaryotes possess a unique RNA silencing system that functions by
homology-dependent cleavage of invader RNAs.
DOI: 10.1016/j.cell.2009.07.040
PMCID: PMC2951265
PMID: 19945378 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8433382 | 1. J Mol Evol. 1993 Feb;36(2):121-6. doi: 10.1007/BF00166247.
Accumulation of adenine and thymine in a groE-homologous operon of an
intracellular symbiont.
Ohtaka C(1), Ishikawa H.
Author information:
(1)Zoological Institute, Faculty of Science, University of Tokyo, Japan.
As a result of the nucleotide sequence analysis of an aphid endosymbiont's
operon homologous to the Escherichia coli groE, we noted that directional base
substitutions tending toward an increase of A + T content represent an obvious
evolutionary trend in this prokaryotic operon, housed for a long period by an
eukaryotic cell. This result, when taken together with previous reports, raised
the possibility that genomic DNA of prokaryotes residing in an eukaryotic cell
is subject to A/T-biased directional mutation pressure and/or both negative and
positive selection operating under conditions specific to the intracellular
environments.
DOI: 10.1007/BF00166247
PMID: 8433382 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17157688 | 1. Am J Emerg Med. 2007 Jan;25(1):72-9. doi: 10.1016/j.ajem.2006.04.017.
Hypertrophic cardiomyopathy: electrocardiographic manifestations and other
important considerations for the emergency physician.
Kelly BS(1), Mattu A, Brady WJ.
Author information:
(1)Department of Emergency Medicine, Mount Carmel Health System, Columbus, OH
43123, USA.
Hypertrophic cardiomyopathy (HCM) is one of the most common inherited primary
cardiac disorders and the most common cause of sudden cardiac death in young
athletes. With advances in technology, it is now recognized that HCM affects
individuals of all ages. Many patients with HCM will have a benign course with
few symptoms. Some patients, however, possess risk factors that greatly increase
the likelihood of sudden death if their disease remains undiagnosed. Therefore,
it is imperative that emergency physicians be familiar with the symptoms and
typical electrocardiogram manifestations of HCM. Three illustrative cases are
presented with a review of the disease.
DOI: 10.1016/j.ajem.2006.04.017
PMID: 17157688 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6686529 | 1. Eur Heart J. 1983 Nov;4 Suppl F:135-44. doi: 10.1093/eurheartj/4.suppl_f.135.
Hypertrophic cardiomyopathy: a common cause of sudden death in the young
competitive athlete.
Maron BJ, Epstein SE, Roberts WC.
The causes of sudden, unexpected death in highly-conditioned competitive
athletes are summarized. In the vast majority of young athletes (less than 35
years of age) sudden death is due to underlying structural cardiovascular
disease. Hypertrophic cardiomyopathy appears to be the most common cause of such
deaths and may account for about one-half of the sudden deaths in a youthful
athletic population. Cardiovascular abnormalities that appear to be less
frequent important causes of sudden death include anomalous origin of the left
coronary artery from the anterior sinus of Valsalva, ruptured aorta (due to
cystic medial necrosis), idiopathic concentric left ventricular hypertrophy and
coronary artery atherosclerosis. Other diseases which are probably particularly
uncommon causes of sudden death in the young athlete include mitral valve
prolapse, aortic valvular stenosis, acute myocarditis, QT interval prolongation
syndromes, hypoplasia of the coronary arteries or sarcoidosis. Cardiovascular
disease in young athletes is usually unsuspected during life. In only about 25%
of those competitive athletes who die suddenly is underlying disease identified
prior to participation and rarely is the correct clinical diagnosis made. In
contrast, when sudden death occurs in older competitive or recreational athletes
(over 35 years of age) it is usually due to coronary artery disease.
DOI: 10.1093/eurheartj/4.suppl_f.135
PMID: 6686529 [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/10798028 | 1. Indian J Pediatr. 1999 Jan-Feb;66(1):1-5. doi: 10.1007/BF02752340.
Sudden cardiac death in the young athlete.
Goble MM(1).
Author information:
(1)Michigan State University, Department of Pediatrics and Human Development,
East Lansing, USA.
Sudden cardiac death in athletes is usually due to underlying cardiovascular
disease. In the young less than 30 years of age, the most common abnormality is
hypertrophic cardiomyopathy, followed by congenital coronary artery anomalies.
The final common pathway is usually ventricular fibrillation. Sudden cardiac
death in the young is rare but remains a source of concern. A careful screening
history and physical examination, especially for potential athletes, should
identify the majority of young people at risk.
DOI: 10.1007/BF02752340
PMID: 10798028 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21160605 | 1. World J Cardiol. 2010 Sep 26;2(9):289-98. doi: 10.4330/wjc.v2.i9.289.
Hypertrophic cardiomyopathy and sudden cardiac death.
Stroumpoulis KI(1), Pantazopoulos IN, Xanthos TT.
Author information:
(1)Konstantinos I Stroumpoulis, Department of Experimental Surgery and Surgical
Research, Medical School, University of Athens, 11527, Athens, Greece.
Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease
that affects the left ventricle. HCM can appear at any age, with the majority of
the patients remaining clinically stable. When patients complain of symptoms,
these include: dyspnea, dizziness, syncope and angina. HCM can lead to sudden
cardiac death (SCD), mainly due to ventricular tachyarrhythmia or ventricular
tachycardia. High-risk patients benefit from implantable
cardioverter-defibrillators. Left ventricular outflow tract obstruction is not a
rare feature in HCM, especially in symptomatic patients, and procedures that
abolish that obstruction provide positive and consistent results that can
improve long-term survival. HCM is the most common cause of sudden death in
young competitive athletes and preparticipation screening programs have to be
implemented to avoid these tragic fatalities. The structure of these programs is
a matter of large debate. Worldwide registries are necessary to identify the
full extent of HCM-related SCD.
DOI: 10.4330/wjc.v2.i9.289
PMCID: PMC2998829
PMID: 21160605 |
http://www.ncbi.nlm.nih.gov/pubmed/17853713 | 1. Med Pregl. 2007 Jan-Feb;60(1-2):61-5. doi: 10.2298/mpns0702061p.
[Causes of sudden cardiac death in athletes].
[Article in Serbian]
Popović D(1), Ostojić MC, Popović N, Stojiljković S, Sćepanović L.
Author information:
(1)Medicinski fakultet, Beograd, Institut za fiziologiju. [email protected]
INTRODUCTION: Sudden cardiac death in athletes is a growing problem, despite the
huge existing knowledge in medicine and sports.
EFFECTS OF VIGOROUS PHYSICAL ACTIVITY: In response to vigorous physical
activity, the body undergoes profound morphologic and functional changes. These
changes are usually healthy, but sometimes may gravitate to some cardiac
diseases. But still, most saudden cardiac deaths are due to previous unknown
diseases.
CAUSES OF SUDDEN CARDIAC DEATH: The most common cause of sudden cardiac death in
athletes is hypertrophic cardiomyopathy. Other reasons are congenital coronary
artery anomalies, nivocarditis, dilatative cardiomyopathy, arrhythmogenic
cardiomyopathy of the right ventricle, sarcoidosis, mitral valve prolapse,
aortic valve stenosis, atherosclerosis, long QT syndrome, and blunt impact to
the chest.
CONCLUSION: Bearing in mind the above mentioned, more frequent physical
examinations of athletes are recommended.
DOI: 10.2298/mpns0702061p
PMID: 17853713 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20404488 | 1. Autophagy. 2010 May;6(4):555-7. doi: 10.4161/auto.6.4.11812. Epub 2010 May 16.
Quality control autophagy: a joint effort of ubiquitin, protein deacetylase and
actin cytoskeleton.
Lee JY(1), Yao TP.
Author information:
(1)Department of Pharmacology and Cancer Biology, Duke University, Durham, NC,
USA.
Autophagy has been predominantly studied as a nonselective self-digestion
process that recycles macromolecules and produces energy in response to
starvation. However, autophagy independent of nutrient status has long been
known to exist. Recent evidence suggests that this form of autophagy enforces
intracellular quality control by selectively disposing of aberrant protein
aggregates and damaged organelles--common denominators in various forms of
neurodegenerative diseases. By definition, this form of autophagy, termed
quality-control (QC) autophagy, must be different from nutrient-regulated
autophagy in substrate selectivity, regulation and function. We have recently
identified the ubiquitin-binding deacetylase, HDAC6, as a key component that
establishes QC. HDAC6 is not required for autophagy activation per se; rather,
it is recruited to ubiquitinated autophagic substrates where it stimulates
autophagosome-lysosome fusion by promoting F-actin remodeling in a
cortactin-dependent manner. Remarkably, HDAC6 and cortactin are dispensable for
starvation-induced autophagy. These findings reveal that autophagosomes
associated with QC are molecularly and biochemically distinct from those
associated with starvation autophagy, thereby providing a new molecular
framework to understand the emerging complexity of autophagy and therapeutic
potential of this unique machinery.
DOI: 10.4161/auto.6.4.11812
PMCID: PMC3752377
PMID: 20404488 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11159287 | 1. Arch Dis Child. 2001 Feb;84(2):129-37. doi: 10.1136/adc.84.2.129.
Natural history of cardiovascular manifestations in Marfan syndrome.
van Karnebeek CD(1), Naeff MS, Mulder BJ, Hennekam RC, Offringa M.
Author information:
(1)Department of Paediatrics H3-150, Emma Children's Hospital, Academic Medical
Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
AIMS: To investigate the natural history of mitral valve and aortic
abnormalities in patients with Marfan syndrome during childhood and adolescence.
METHODS: Fifty two patients with Marfan syndrome were followed for a mean of 7.9
years. Occurrence of adverse cardiovascular outcomes was measured clinically and
by ultrasound examination.
RESULTS: Mitral valve prolapse (MVP) was diagnosed in 46 patients at a mean age
of 9.7 years, more than 80% of whom presented as "silent MVP". Mitral
regurgitation (MR) occurred in 25 patients, aortic dilatation in 43, and aortic
regurgitation (AR) in 13. Both MVP and aortic dilatation developed at a constant
rate during the age period 5-20 years. In 23 patients MVP was diagnosed before
aortic dilatation, in 18 the reverse occurred, and in 11 patients the two
abnormalities were diagnosed simultaneously. During follow up, 21 patients
showed progression of mitral valve dysfunction; progression of aortic
abnormalities occurred in 13. Aortic surgery was performed in 10; two died of
subsequent complications. Mitral valve surgery was performed in six. In sporadic
female Marfan patients the age at initial diagnosis of MVP, MR, aortic
dilatation, and AR was lowest, the grade of MR and AR most severe, the time
lapse between the occurrence of MVP and subsequent MR as well as between
dilatation and subsequent AR shortest, and the risk for cardiovascular
associated morbidity and mortality highest.
CONCLUSIONS: During childhood and adolescence in Marfan syndrome, mitral valve
dysfunction as well as aortic abnormalities develop and progress gradually,
often without symptoms, but may cause considerable morbidity and mortality by
the end of the second decade, especially in female sporadic patients.
DOI: 10.1136/adc.84.2.129
PMCID: PMC1718664
PMID: 11159287 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12651044 | 1. J Am Coll Cardiol. 2003 Mar 19;41(6):974-80. doi:
10.1016/s0735-1097(02)02976-5.
Relationship of race to sudden cardiac death in competitive athletes with
hypertrophic cardiomyopathy.
Maron BJ(1), Carney KP, Lever HM, Lewis JF, Barac I, Casey SA, Sherrid MV.
Author information:
(1)Minneapolis Heart Institute Foundation, 920 East 28th Street, Suite 60,
Minneapolis, MN 55407, USA. [email protected]
OBJECTIVES: The goal of this study was to determine the impact of race on
identification of hypertrophic cardiomyopathy (HCM).
BACKGROUND: Sudden death in young competitive athletes is due to a variety of
cardiovascular diseases (CVDs) and, most commonly, HCM. These catastrophes have
become an important issue for African Americans, although HCM has been
previously regarded as rare in this segment of the U.S. population.
METHODS: We studied the relationship of race to the prevalence of CVDs causing
sudden death in our national athlete registry, and compared these findings with
a representative multicenter hospital-based cohort of patients with HCM.
RESULTS: Of 584 athlete deaths, 286 were documented to be due to CVD at ages 17
+/- 3 years; 156 (55%) were white, and 120 (42%) were African American. Most
were male (90%), and 67% participated in basketball and football. Among the 286
cardiovascular deaths, most were due to HCM (n = 102; 36%) or anomalous coronary
artery of wrong sinus origin (n = 37; 13%). Of the athletes who died of HCM, 42
(41%) were white, but 56 (55%) were African American. In contrast, of 1,986
clinically identified HCM patients, only 158 (8%) were African American (p <
0.001).
CONCLUSIONS: In this autopsy series, HCM represented a common cause of sudden
death in young and previously undiagnosed African American male athletes, in
sharp contrast with the infrequent clinical identification of HCM in a
hospital-based population (i.e., by seven-fold). This discrepancy suggests that
many HCM cases go unrecognized in the African American community, underscoring
the need for enhanced clinical recognition of HCM to create the opportunity for
preventive measures to be employed in high-risk patients with this complex
disease.
DOI: 10.1016/s0735-1097(02)02976-5
PMID: 12651044 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17965226 | 1. J Med Genet. 2008 Jan;45(1):1-14. doi: 10.1136/jmg.2007.053959. Epub 2007 Oct
26.
Hirschsprung disease, associated syndromes and genetics: a review.
Amiel J(1), Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego
S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L,
Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A,
Tam PK, Ceccherini I, Hofstra RM, Fernandez R; Hirschsprung Disease Consortium.
Author information:
(1)Université Paris 5-Descartes, Faculté de Médecine, INSERM U-781, AP-HP,
Hôpital Necker-Enfant Malades, Paris, France. [email protected]
Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic
cause of functional intestinal obstruction with an incidence of 1/5000 live
births. This developmental disorder is a neurocristopathy and is characterised
by the absence of the enteric ganglia along a variable length of the intestine.
In the last decades, the development of surgical approaches has importantly
decreased mortality and morbidity which allowed the emergence of familial cases.
Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent
penetrance, and variable expression according to the length of the aganglionic
segment. While all Mendelian modes of inheritance have been described in
syndromic HSCR, isolated HSCR stands as a model for genetic disorders with
complex patterns of inheritance. The tyrosine kinase receptor RET is the major
gene with both rare coding sequence mutations and/or a frequent variant located
in an enhancer element predisposing to the disease. Hitherto, 10 genes and five
loci have been found to be involved in HSCR development.
DOI: 10.1136/jmg.2007.053959
PMID: 17965226 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22348088 | 1. PLoS One. 2012;7(2):e31443. doi: 10.1371/journal.pone.0031443. Epub 2012 Feb
14.
Empirical evaluation of bone extraction protocols.
Cleland TP(1), Voegele K, Schweitzer MH.
Author information:
(1)Department of Marine, Earth, Atmospheric Sciences, North Carolina State
University, Raleigh, North Carolina, United States of America. [email protected]
The application of high-resolution analytical techniques to characterize ancient
bone proteins requires clean, efficient extraction to obtain high quality data.
Here, we evaluated many different protocols from the literature on ostrich
cortical bone and moa cortical bone to evaluate their yield and relative purity
using the identification of antibody-antigen complexes on enzyme-linked
immunosorbent assay and gel electrophoresis. Moa bone provided an ancient
comparison for the effectiveness of bone extraction protocols tested on ostrich
bone. For the immunological part of this study, we focused on collagen I,
osteocalcin, and hemoglobin because collagen and osteocalcin are the most
abundant proteins in the mineralized extracellular matrix and hemoglobin is
common in the vasculature. Most of these procedures demineralize the bone first,
and then the remaining organics are chemically extracted. We found that the use
of hydrochloric acid, rather than ethylenediaminetetraacetic acid, for
demineralization resulted in the cleanest extractions because the acid was
easily removed. In contrast, the use of ethylenediaminetetraacetic acid resulted
in smearing upon electrophoretic separation, possibly indicating these samples
were not as pure. The denaturing agents sodium dodecyl sulfate, urea, and
guanidine HCl have been used extensively for the solubilization of proteins in
non-biomineralized tissue, but only the latter has been used on bone. We show
that all three denaturing agents are effective for extracting bone proteins. One
additional method tested uses ammonium bicarbonate as a solubilizing buffer that
is more appropriate for post-extraction analyses (e.g., proteomics) by removing
the need for desalting. We found that both guanidine HCl and ammonium
bicarbonate were effective for extracting many bone proteins, resulting in
similar electrophoretic patterns. With the increasing use of proteomics, a new
generation of scientists are now interested in the study of proteins from not
only extant bone but also from ancient bone.
DOI: 10.1371/journal.pone.0031443
PMCID: PMC3279360
PMID: 22348088 [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/19076295 | 1. New Phytol. 2009;181(3):588-600. doi: 10.1111/j.1469-8137.2008.02701.x. Epub
2008 Dec 8.
Role of Lon1 protease in post-germinative growth and maintenance of
mitochondrial function in Arabidopsis thaliana.
Rigas S(1), Daras G, Laxa M, Marathias N, Fasseas C, Sweetlove LJ, Hatzopoulos
P.
Author information:
(1)Department of Agricultural Biotechnology, Agricultural University of Athens,
Iera Odos 75, Athens 118 55, Greece.
Comment in
New Phytol. 2009;181(3):505-8. doi: 10.1111/j.1469-8137.2009.02731.x.
Plant Signal Behav. 2009 Mar;4(3):221-4. doi: 10.4161/psb.4.3.7863.
Maintenance of protein quality control and turnover is essential for cellular
homeostasis. In plant organelles this biological process is predominantly
performed by ATP-dependent proteases. Here, a genetic screen was performed that
led to the identification of Arabidopsis thaliana Lon1 protease mutants that
exhibit a post-embryonic growth retardation phenotype. Translational fusion to
yellow fluorescent protein revealed AtLon1 subcellular localization in plant
mitochondria, and the AtLon1 gene could complement the respiratory-deficient
phenotype of the yeast PIM1 gene homolog. AtLon1 is highly expressed in rapidly
growing plant organs of embryonic origin, including cotyledons and primary
roots, and in inflorescences, which have increased mitochondria numbers per cell
to fulfill their high energy requirements. In lon1 mutants, the expression of
both mitochondrial and nuclear genes encoding respiratory proteins was normal.
However, mitochondria isolated from lon1 mutants had a lower capacity for
respiration of succinate and cytochrome c via complexes II and IV, respectively.
Furthermore, the activity of key enzymes of the tricarboxylic acid (TCA) cycle
was significantly reduced. Additionally, mitochondria in lon1 mutants had an
aberrant morphology. These results shed light on the developmental mechanisms of
selective proteolysis in plant mitochondria and suggest a critical role for
AtLon1 protease in organelle biogenesis and seedling establishment.
DOI: 10.1111/j.1469-8137.2008.02701.x
PMID: 19076295 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18720427 | 1. Rapid Commun Mass Spectrom. 2008 Sep;22(18):2751-67. doi: 10.1002/rcm.3679.
Species identification of Oetzi's clothing with matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry based on peptide pattern
similarities of hair digests.
Hollemeyer K(1), Altmeyer W, Heinzle E, Pitra C.
Author information:
(1)Biochemical Engineering Institute, Saarland University, Saarbruecken,
Germany. [email protected]
Identification of ancient biological samples from the 1991-discovered and more
than 5300-year-old Tyrolean mummy, also called iceman or Oetzi, is very
difficult. The species of origins of four animal-hair-bearing samples of the
accoutrement of the mummy not yet diagnosed were identified by a special
proteomics method. Ha 43/91/130 and Ha 6/91, two samples from his coat, and Ha
5/91, a sample from his leggings, were assigned to sheep. The upper leather of
his moccasins, Ha 2/91, was made from cattle. Despite the enormous age of these
samples with partial (bio)chemical alterations, reliable identification was
possible using a recently developed matrix-assisted laser desorption/ionization
time-of-flight mass spectrometric ((MALDI-TOF MS)-based analytical method. The
method is exclusively based on the analysis of proteins and uses minute amounts
of peptides directly derived from tryptic hair digests without any separation or
enrichment steps. Unknown species are identified by comparison of their peptide
ion patterns with known spectra stored in existing databases. Hereby, the
correlation distance, a form of Euclidean distance, and deduced parameters are
used to measure similarities. If more than one potential hit remains, specific
diagnostic peptide ions are used to stepwise exclude incorrect matches. These
ions are specific for orders, families, subfamilies/genera and/or even species.
Peptide mass fingerprinting data combined with those from collision-induced
dissociation spectra (combined MS & MS/MS) were used for interpretation with the
MASCOT search engine and the NCBI database to find the potential parentage of
hair proteins. For this technique, selected precursor ions were identified as
specific diagnostic peptide ions.
Copyright (c) 2008 John Wiley & Sons, Ltd.
DOI: 10.1002/rcm.3679
PMID: 18720427 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22159580 | 1. Development. 2012 Jan;139(2):325-34. doi: 10.1242/dev.074260. Epub 2011 Dec 7.
The kinase Sgg modulates temporal development of macrochaetes in Drosophila by
phosphorylation of Scute and Pannier.
Yang M(1), Hatton-Ellis E, Simpson P.
Author information:
(1)Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2
3EJ, UK.
Evolution of novel structures is often made possible by changes in the timing or
spatial expression of genes regulating development. Macrochaetes, large sensory
bristles arranged into species-specific stereotypical patterns, are an
evolutionary novelty of cyclorraphous flies and are associated with changes in
both the temporal and spatial expression of the proneural genes achaete (ac) and
scute (sc). Changes in spatial expression are associated with the evolution of
cis-regulatory sequences, but it is not known how temporal regulation is
achieved. One factor required for ac-sc expression, the expression of which
coincides temporally with that of ac-sc in the notum, is Wingless (Wg; also
known as Wnt). Wingless downregulates the activity of the serine/threonine
kinase Shaggy (Sgg; also known as GSK-3). We demonstrate that Scute is
phosphorylated by Sgg on a serine residue and that mutation of this residue
results in a form of Sc with heightened proneural activity that can rescue the
loss of bristles characteristic of wg mutants. We suggest that the
phosphorylated form of Sc has reduced transcriptional activity such that sc is
unable to autoregulate, an essential function for the segregation of bristle
precursors. Sgg also phosphorylates Pannier, a transcriptional activator of
ac-sc, the activity of which is similarly dampened when in the phosphorylated
state. Furthermore, we show that Wg signalling does not act directly via a
cis-regulatory element of the ac-sc genes. We suggest that temporal control of
ac-sc activity in cyclorraphous flies is likely to be regulated by permissive
factors and might therefore not be encoded at the level of ac-sc gene sequences.
DOI: 10.1242/dev.074260
PMCID: PMC3243096
PMID: 22159580 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12793636 | 1. J Indian Med Assoc. 2002 Dec;100(12):708-9.
Study of sudden cardiac deaths in young athletes.
Kahali B(1), Roy DG, Batabyal S, Bose TK.
Author information:
(1)Department of FSM, Burdwan Medical College, Burdwan 713104.
Sudden cardiac deaths in athletes are usually due to underlying cardiovascular
disease. The final pathway is usually ventricular fibrillation following
hypertrophic cardiomyopathy and coronary artery anomalies in young persons below
the age of 30 years. Sudden cardiac death in young is rare but remains as a
source of concern. A postmortem study was conducted to ascertain the cardiac
causes of sudden death in persons below the age group 30 years following
exercise in games or otherwise. Out of 15 cases in autopsy finding, hypertrophic
cardiomyopathy (n=7) was the commonest cause followed by coronary artery
anomalies (n=4). Sudden unexpected death is a source of concern and careful
screening of history and physical examination for potential athletes should
identify majority of people at risk.
PMID: 12793636 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18480046 | 1. J Biol Chem. 2008 Jul 18;283(29):20579-89. doi: 10.1074/jbc.M800554200. Epub
2008 May 13.
Functional effects of the hypertrophic cardiomyopathy R403Q mutation are
different in an alpha- or beta-myosin heavy chain backbone.
Lowey S(1), Lesko LM, Rovner AS, Hodges AR, White SL, Low RB, Rincon M, Gulick
J, Robbins J.
Author information:
(1)Department of Molecular Physiology and Biophysics, University of Vermont,
Burlington, VT 05405, USA. [email protected]
The R403Q mutation in the beta-myosin heavy chain (MHC) was the first mutation
to be linked to familial hypertrophic cardiomyopathy (FHC), a primary disease of
heart muscle. The initial studies with R403Q myosin, isolated from biopsies of
patients, showed a large decrease in myosin motor function, leading to the
hypothesis that hypertrophy was a compensatory response. The introduction of the
mouse model for FHC (the mouse expresses predominantly alpha-MHC as opposed to
the beta-isoform in larger mammals) created a new paradigm for FHC based on
finding enhanced motor function for R403Q alpha-MHC. To help resolve these
conflicting mechanisms, we used a transgenic mouse model in which the endogenous
alpha-MHC was largely replaced with transgenically encoded beta-MHC. A His(6)
tag was cloned at the N terminus of the alpha-and beta-MHC to facilitate protein
isolation by Ni(2+)-chelating chromatography. Characterization of the R403Q
alpha-MHC by the in vitro motility assay showed a 30-40% increase in actin
filament velocity compared with wild type, consistent with published studies. In
contrast, the R403Q mutation in a beta-MHC backbone showed no enhancement in
velocity. Cleavage of the His-tagged myosin by chymotrypsin made it possible to
isolate homogeneous myosin subfragment 1 (S1), uncontaminated by endogenous
myosin. We find that the actin-activated MgATPase activity for R403Q alpha-S1 is
approximately 30% higher than for wild type, whereas the enzymatic activity for
R403Q beta-S1 is reduced by approximately 10%. Thus, the functional consequences
of the mutation are fundamentally changed depending upon the context of the
cardiac MHC isoform.
DOI: 10.1074/jbc.M800554200
PMCID: PMC2459289
PMID: 18480046 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1456297 | 1. Am J Med Genet. 1992 Sep 15;44(2):233-6. doi: 10.1002/ajmg.1320440222.
Child with manifestations of dermotrichic syndrome and ichthyosis
follicularis-alopecia-photophobia (IFAP) syndrome.
Martino F(1), D'Eufemia P, Pergola MS, Finocchiaro R, Celli M, Giampà G,
Frontali M, Giardini O.
Author information:
(1)Istituto di Clinica Pediatrica, Università La Sapienza, Roma, Italy.
We report on a boy with short stature, mental retardation, seizures, follicular
ichthyosis, generalized alopecia, hypohydrosis, enamel dysplasia, photophobia,
congenital aganglionic megacolon, inguinal hernia, vertebral, renal and other
anomalies, and a normal chromosome constitution. The clinical findings include
all the features that dermotrichic and ichthyosis
follicularis-alopecia-photophobia (IFAP) syndrome have in common and in addition
those that characterize IFAP syndrome (photophobia, recurrent respiratory
infections, etc.), those that are present only in dermotrichic syndrome (nail
anomalies, hypohydrosis, megacolon, vertebral defects, etc.) and additional ones
(enamel dysplasia, renal anomalies, inguinal hernia, etc.). Two maternal uncles
were referred as being affected by alopecia and ichthyosis suggesting X-linked
recessive transmission. Various hypotheses concerning the relationship between
the 2 syndromes and the present case are discussed.
DOI: 10.1002/ajmg.1320440222
PMID: 1456297 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24440309 | 1. Arch Biochem Biophys. 2014 Mar 1;545:83-91. doi: 10.1016/j.abb.2014.01.006.
Epub 2014 Jan 15.
CK2 involvement in ESCRT-III complex phosphorylation.
Salvi M(1), Raiborg C(2), Hanson PI(3), Campsteijn C(2), Stenmark H(2), Pinna
LA(4).
Author information:
(1)Department of Biomedical Sciences, University of Padova, V.le G. Colombo 3,
Padova, Italy. Electronic address: [email protected].
(2)Department of Biochemistry, Institute for Cancer Research, Oslo University
Hospital, Montebello, Norway.
(3)Department of Cell Biology and Physiology, Washington University School of
Medicine, St. Louis, MO, USA.
(4)Department of Biomedical Sciences, University of Padova, V.le G. Colombo 3,
Padova, Italy; CNR Institute of Neurosciences, V.le G. Colombo 3, Padova, Italy;
Venetian Institute for Molecular Medicine (VIMM), via Orus 2, 35129 Padova,
Italy.
The multivesicular body (MVB) sorting pathway is a mechanism for delivering
transmembrane proteins into the lumen of the lysosome for degradation. ESCRT-III
is the final complex in the pathway that assembles on endosomes and executes
membrane scission of intraluminal vesicles. In addition, proteins of this
complex are involved in other topologically similar processes such as
cytokinesis, virus egress and autophagy. Here we show that protein kinase CK2α
is involved in the phosphorylation of the ESCRT-III subunits CHMP3 and CHMP2B,
as well as of VPS4B/SKD1, an ATPase that mediates ESCRT-III disassembly. This
phosphorylation is observed both in vitro and in cells. While we do not observe
recruitment of CK2α to endosomes, we demonstrate the localization of CK2α to
midbodies during cytokinesis. Phosphomimetic and non-phosphorylatable mutants of
ESCRT-III proteins can still bind endosomes and localize to midbodies,
indicating that CK2α does not regulate ESCRT-III localization. Finally, we
analyzed two cellular functions where CHMP3, CHMP2B and VPS4 are known to be
involved, epidermal growth factor degradation and cytokinetic abscission. We
demonstrate that the former is impaired by CK2α downregulation whereas the
latter is not affected. Taken together, our results indicate that CK2α regulates
the function of ESCRT-III proteins in MVB sorting.
Copyright © 2014 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.abb.2014.01.006
PMID: 24440309 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19383720 | 1. J Cell Sci. 2009 May 15;122(Pt 10):1574-83. doi: 10.1242/jcs.044354. Epub 2009
Apr 21.
Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A.
Fernandez-Martinez J(1), Vela EM, Tora-Ponsioen M, Ocaña OH, Nieto MA, Galceran
J.
Author information:
(1)Instituto de Neurociencias, CSIC-UMH, Sant Joan d'Alacant, Alicante, Spain.
Notch signalling is used throughout the animal kingdom to spatially and
temporally regulate cell fate, proliferation and differentiation. Its importance
is reflected in the dramatic effects produced on both development and health by
small variations in the strength of the Notch signal. The
Down-syndrome-associated kinase DYRK1A is coexpressed with Notch in various
tissues during embryonic development. Here we show that DYRK1A moves to the
nuclear transcription compartment where it interacts with the intracellular
domain of Notch promoting its phosphorylation in the ankyrin domain and reducing
its capacity to sustain transcription. DYRK1A attenuates Notch signalling in
neural cells both in culture and in vivo, constituting a novel mechanism capable
of modulating different developmental processes that can also contribute to the
alterations observed during brain development in animal models of Down syndrome.
DOI: 10.1242/jcs.044354
PMID: 19383720 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23474818 | 1. Hum Mol Genet. 2013 Jul 1;22(13):2676-88. doi: 10.1093/hmg/ddt117. Epub 2013
Mar 7.
ALS mutant FUS disrupts nuclear localization and sequesters wild-type FUS within
cytoplasmic stress granules.
Vance C(1), Scotter EL, Nishimura AL, Troakes C, Mitchell JC, Kathe C, Urwin H,
Manser C, Miller CC, Hortobágyi T, Dragunow M, Rogelj B, Shaw CE.
Author information:
(1)Department of Clinical Neuroscience, King’s College London, UK.
Mutations in the gene encoding Fused in Sarcoma (FUS) cause amyotrophic lateral
sclerosis (ALS), a fatal neurodegenerative disorder. FUS is a predominantly
nuclear DNA- and RNA-binding protein that is involved in RNA processing. Large
FUS-immunoreactive inclusions fill the perikaryon of surviving motor neurons of
ALS patients carrying mutations at post-mortem. This sequestration of FUS is
predicted to disrupt RNA processing and initiate neurodegeneration. Here, we
demonstrate that C-terminal ALS mutations disrupt the nuclear localizing signal
(NLS) of FUS resulting in cytoplasmic accumulation in transfected cells and
patient fibroblasts. FUS mislocalization is rescued by the addition of the
wild-type FUS NLS to mutant proteins. We also show that oxidative stress
recruits mutant FUS to cytoplasmic stress granules where it is able to bind and
sequester wild-type FUS. While FUS interacts with itself directly by
protein-protein interaction, the recruitment of FUS to stress granules and
interaction with PABP are RNA dependent. These findings support a two-hit
hypothesis, whereby cytoplasmic mislocalization of FUS protein, followed by
cellular stress, contributes to the formation of cytoplasmic aggregates that may
sequester FUS, disrupt RNA processing and initiate motor neuron degeneration.
DOI: 10.1093/hmg/ddt117
PMCID: PMC3674807
PMID: 23474818 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17947214 | 1. Eur Heart J. 2007 Nov;28(22):2732-7. doi: 10.1093/eurheartj/ehm429. Epub 2007
Oct 17.
Cardiac beta-myosin heavy chain defects in two families with non-compaction
cardiomyopathy: linking non-compaction to hypertrophic, restrictive, and dilated
cardiomyopathies.
Hoedemaekers YM(1), Caliskan K, Majoor-Krakauer D, van de Laar I, Michels M,
Witsenburg M, ten Cate FJ, Simoons ML, Dooijes D.
Author information:
(1)Department of Clinical Genetics, Erasmus Medical Centre, Dr Molewaterplein
50, 3015GE Rotterdam, The Netherlands.
Comment in
Eur Heart J. 2008 Apr;29(7):949-50; author reply 950-1. doi:
10.1093/eurheartj/ehn029.
Cardiomyopathies are classified according to distinct morphological
characteristics. They occur relatively frequent and are an important cause of
mortality and morbidity. Isolated ventricular non-compaction or non-compaction
cardiomyopathy (NCCM) is characterized by an excessively thickened endocardial
layer with deep intertrabecular recesses, reminiscent of the myocardium during
early embryogenesis. Aims Autosomal-dominant as well as X-linked inheritance for
NCCM has been described and several loci have been associated with the disease.
Nevertheless, a major genetic cause for familial NCCM remains to be identified.
Methods and Results We describe, in two separate autosomal-dominant NCCM
families, the identification of mutations in the sarcomeric cardiac beta-myosin
heavy chain gene (MYH7), known to be associated with hypertrophic cardiomyopathy
(HCM), restricted cardiomyopathy (RCM), and dilated cardiomyopathy (DCM).
Conclusion These results confirm the genetic heterogeneity of NCCM and suggest
that the molecular classification of cardiomyopathies includes an
MYH7-associated spectrum of NCCM with HCM, RCM, and DCM.
DOI: 10.1093/eurheartj/ehm429
PMID: 17947214 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12235210 | 1. J Exp Med. 2002 Sep 16;196(6):765-80. doi: 10.1084/jem.20020179.
DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is
up-regulated in human tumors.
Zaika AI(1), Slade N, Erster SH, Sansome C, Joseph TW, Pearl M, Chalas E, Moll
UM.
Author information:
(1)Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA.
p73 has significant homology to p53. However, tumor-associated up-regulation of
p73 and genetic data from human tumors and p73-deficient mice exclude a
classical Knudson-type tumor suppressor role. We report that the human TP73 gene
generates an NH(2) terminally truncated isoform. DeltaNp73 derives from an
alternative promoter in intron 3 and lacks the transactivation domain of
full-length TAp73. DeltaNp73 is frequently overexpressed in a variety of human
cancers, but not in normal tissues. DeltaNp73 acts as a potent transdominant
inhibitor of wild-type p53 and transactivation-competent TAp73. DeltaNp73
efficiently counteracts transactivation function, apoptosis, and growth
suppression mediated by wild-type p53 and TAp73, and confers drug resistance to
wild-type p53 harboring tumor cells. Conversely, down-regulation of endogenous
DeltaNp73 levels by antisense methods alleviates its suppressive action and
enhances p53- and TAp73-mediated apoptosis. DeltaNp73 is complexed with
wild-type p53, as demonstrated by coimmunoprecipitation from cultured cells and
primary tumors. Thus, DeltaNp73 mediates a novel inactivation mechanism of p53
and TAp73 via a dominant-negative family network. Deregulated expression of
DeltaNp73 can bestow oncogenic activity upon the TP73 gene by functionally
inactivating the suppressor action of p53 and TAp73. This trait might be
selected for in human cancers.
DOI: 10.1084/jem.20020179
PMCID: PMC2194062
PMID: 12235210 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24101600 | 1. Hum Mol Genet. 2014 Feb 1;23(3):602-17. doi: 10.1093/hmg/ddt448. Epub 2013 Sep
18.
Differential, dominant activation and inhibition of Notch signalling and APP
cleavage by truncations of PSEN1 in human disease.
Newman M(1), Wilson L, Verdile G, Lim A, Khan I, Moussavi Nik SH, Pursglove S,
Chapman G, Martins RN, Lardelli M.
Author information:
(1)Discipline of Genetics, School of Molecular and Biomedical Science,
University of Adelaide, Adelaide, SA 5005, Australia.
PRESENILIN1 (PSEN1) is the major locus for mutations causing familial
Alzheimer's disease (FAD) and is also mutated in Pick disease of brain, familial
acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch
signalling and many other signalling pathways and protein cleavage events
including production of the Amyloidβ (Aβ) peptide from the AMYLOID BETA A4
PRECURSOR PROTEIN (APP). We previously reported that interference with splicing
of transcripts of the zebrafish orthologue of PSEN1 creates dominant negative
effects on Notch signalling. Here, we extend this work to show that various
truncations of human PSEN1 (or zebrafish Psen1) protein have starkly
differential effects on Notch signalling and cleavage of zebrafish Appa (a
paralogue of human APP). Different truncations can suppress or stimulate Notch
signalling but not Appa cleavage and vice versa. The G183V mutation possibly
causing Pick disease causes production of aberrant transcripts truncating the
open reading frame after exon 5 sequence. We show that the truncated protein
potentially translated from these transcripts avidly incorporates into very
stable Psen1-dependent higher molecular weight complexes and suppresses cleavage
of Appa but not Notch signalling. In contrast, the truncated protein potentially
produced by the P242LfsX11 acne inversa mutation has no effect on Appa cleavage
but, unexpectedly, enhances Notch signalling. Our results suggest novel
hypotheses for the pathological mechanisms underlying these diseases and
illustrate the importance of investigating the function of dominant mutations at
physiologically relevant expression levels and in the normally heterozygous
state in which they cause human disease rather than in isolation from healthy
alleles.
DOI: 10.1093/hmg/ddt448
PMID: 24101600 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14634023 | 1. J Biol Chem. 2004 Feb 27;279(9):8076-83. doi: 10.1074/jbc.M307469200. Epub
2003 Nov 21.
p73 Induces apoptosis via PUMA transactivation and Bax mitochondrial
translocation.
Melino G(1), Bernassola F, Ranalli M, Yee K, Zong WX, Corazzari M, Knight RA,
Green DR, Thompson C, Vousden KH.
Author information:
(1)Biochemistry Laboratory, Instituto Dermopatico Dell'Immacolata-Istituto di
Ricovero e Cura a Carattere Scientifico, Department of Experimental Medicine and
Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy.
[email protected]
p73, an important developmental gene, shares a high sequence homology with p53
and induces both G(1) cell cycle arrest and apoptosis. However, the molecular
mechanisms through which p73 induces apoptosis are unclear. We found that
p73-induced apoptosis is mediated by PUMA (p53 up-regulated modulator of
apoptosis) induction, which, in turn, causes Bax mitochondrial translocation and
cytochrome c release. Overexpression of p73 isoforms promotes cell death and bax
promoter transactivation in a time-dependent manner. However, the kinetics of
apoptosis do not correlate with the increase of Bax protein levels. Instead,
p73-induced mitochondrial translocation of Bax is kinetically compatible with
the induction of cell death. p73 is localized in the nucleus and remains nuclear
during the induction of cell death, indicating that the effect of p73 on Bax
translocation is indirect. The ability of p73 to directly transactivate PUMA and
the direct effect of PUMA on Bax conformation and mitochondrial relocalization
suggest a molecular link between p73 and the mitochondrial apoptotic pathway.
Our data therefore indicate that PUMA-mediated Bax mitochondrial translocation,
rather than its direct transactivation, correlates with cell death. Finally,
human DeltaNp73, an isoform lacking the amino-terminal transactivation domain,
inhibits TAp73-induced as well as p53-induced apoptosis. The DeltaNp73 isoforms
seem therefore to act as dominant negatives, repressing the PUMA/Bax system and,
thus, finely tuning p73-induced apoptosis. Our findings demonstrate that p73
elicits apoptosis via the mitochondrial pathway using PUMA and Bax as mediators.
DOI: 10.1074/jbc.M307469200
PMID: 14634023 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24753582 | 1. Proc Natl Acad Sci U S A. 2014 May 6;111(18):E1872-9. doi:
10.1073/pnas.1400749111. Epub 2014 Apr 21.
Control of MT1-MMP transport by atypical PKC during breast-cancer progression.
Rossé C(1), Lodillinsky C, Fuhrmann L, Nourieh M, Monteiro P, Irondelle M,
Lagoutte E, Vacher S, Waharte F, Paul-Gilloteaux P, Romao M, Sengmanivong L,
Linch M, van Lint J, Raposo G, Vincent-Salomon A, Bièche I, Parker PJ, Chavrier
P.
Author information:
(1)Research Center, Institut Curie, 75005 Paris, France.
Dissemination of carcinoma cells requires the pericellular degradation of the
extracellular matrix, which is mediated by membrane type 1-matrix
metalloproteinase (MT1-MMP). In this article, we report a co-up-regulation and
colocalization of MT1-MMP and atypical protein kinase C iota (aPKCι) in hormone
receptor-negative breast tumors in association with a higher risk of metastasis.
Silencing of aPKC in invasive breast-tumor cell lines impaired the delivery of
MT1-MMP from late endocytic storage compartments to the surface and inhibited
matrix degradation and invasion. We provide evidence that aPKCι, in association
with MT1-MMP-containing endosomes, phosphorylates cortactin, which is present in
F-actin-rich puncta on MT1-MMP-positive endosomes and regulates cortactin
association with the membrane scission protein dynamin-2. Thus, cell line-based
observations and clinical data reveal the concerted activity of aPKC, cortactin,
and dynamin-2, which control the trafficking of MT1-MMP from late endosome to
the plasma membrane and play an important role in the invasive potential of
breast-cancer cells.
DOI: 10.1073/pnas.1400749111
PMCID: PMC4020077
PMID: 24753582 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/18342333 | 1. J Mol Biol. 2008 Apr 18;378(1):20-30. doi: 10.1016/j.jmb.2008.02.021. Epub
2008 Feb 20.
Molecular mechanism of p73-mediated regulation of hepatitis B virus core
promoter/enhancer II: implications for hepatocarcinogenesis.
Buhlmann S(1), Racek T, Schwarz A, Schaefer S, Pützer BM.
Author information:
(1)Department of Vectorology and Experimental Gene Therapy, Biomedical Research
Center, University of Rostock, Schillingallee 69, D-18057 Rostock, Germany.
Hepatitis B virus (HBV) is a causative agent of chronic hepatitis and
hepatocellular carcinoma. Recent findings demonstrating p73 and specifically
N-terminally truncated p73 (DeltaTAp73) accumulation in hepatocellular carcinoma
suggest that p73 plays a role in the malignant phenotype. Here, we investigated
the mechanism of HBV pregenomic core promoter/enhancer II (cp/EII) regulation by
full-length TAp73 and its oncogenic counterpart DeltaTAp73. Ectopic and
endogenous expression of TAp73 leads to a significant downregulation of cp/EII
activity in p53-deficient hepatoma cell lines. In contrast, overexpression of
DeltaTAp73 results in significant cp/EII activation and increased HBV core (HBc)
expression. TAp73-mediated repression of HBV transcription was substantially
abolished by DeltaTAp73. We show that both TAp73 and DeltaTAp73 proteins
directly bind to the Sp1 transcription factor, a key stimulator of HBV gene
expression. However, only TAp73 abolishes Sp1 binding to cp/EII, whereas the
DeltaTAp73-Sp1 complex further persists on the DNA. The inhibitory effect of
p53/p73 on HBc expression is associated with the inhibition of viral
replication, while DeltaTAp73 is not. These data strongly support the fact that
the p73-isoform-related interaction with Sp1 is the underlying mechanism of the
diverse outcome on HBc expression, suggesting a new mechanism by which oncogenic
DeltaTAp73 could enhance the carcinogenic process in liver cells.
DOI: 10.1016/j.jmb.2008.02.021
PMID: 18342333 [Indexed for MEDLINE] |