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http://www.ncbi.nlm.nih.gov/pubmed/24225132 | 1. Biochim Biophys Acta. 2014 Feb;1844(2):316-22. doi:
10.1016/j.bbapap.2013.11.001. Epub 2013 Nov 10.
HMMpTM: improving transmembrane protein topology prediction using
phosphorylation and glycosylation site prediction.
Tsaousis GN(1), Bagos PG(2), Hamodrakas SJ(3).
Author information:
(1)Department of Cell Biology and Biophysics, Faculty of Biology, University of
Athens, Panepistimiopolis, Athens 15701, Greece.
(2)Department of Computer Science and Biomedical Informatics, University of
Thessaly, Papasiopoulou 2-4, Lamia 35100, Greece.
(3)Department of Cell Biology and Biophysics, Faculty of Biology, University of
Athens, Panepistimiopolis, Athens 15701, Greece. Electronic address:
[email protected].
During the last two decades a large number of computational methods have been
developed for predicting transmembrane protein topology. Current predictors rely
on topogenic signals in the protein sequence, such as the distribution of
positively charged residues in extra-membrane loops and the existence of
N-terminal signals. However, phosphorylation and glycosylation are
post-translational modifications (PTMs) that occur in a compartment-specific
manner and therefore the presence of a phosphorylation or glycosylation site in
a transmembrane protein provides topological information. We examine the
combination of phosphorylation and glycosylation site prediction with
transmembrane protein topology prediction. We report the development of a Hidden
Markov Model based method, capable of predicting the topology of transmembrane
proteins and the existence of kinase specific phosphorylation and N/O-linked
glycosylation sites along the protein sequence. Our method integrates a novel
feature in transmembrane protein topology prediction, which results in improved
performance for topology prediction and reliable prediction of phosphorylation
and glycosylation sites. The method is freely available at
http://bioinformatics.biol.uoa.gr/HMMpTM.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.bbapap.2013.11.001
PMID: 24225132 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10599057 | 1. Neurochirurgie. 1999 Nov;45(4):293-300.
[Cerebral tumors and neoangiogenesis ].
[Article in French]
Jouanneau E(1), Bachelot T.
Author information:
(1)Service de Neurochirurgie A, Hôpital Pierre Wertheimer, Université Lyon I.
Angiogenesis, which is the development of new vessels arising from the
preestablished arborization, plays a fundamental role in tumor growth.
Angiogenesis is the combination of antagonistic factors: proangiogenesis and
antiangiogenesis factors. On the basis of the concept of relationship between
angiogenesis and tumor growth, a promising new way of research is developing
with the aim to control angiogenesis with an antitumor goal. The results of the
preclinical trials point out the potential of antiangiogenesis agents in the
fight against cancer. So, it was showed that tumor growth in animal models of
syngenic or human tumors is inhibited by inhibitors of proangiogenic factors
(like VEGF or FGF antibody ...) or by antiangiogenic factors. Endostatin, which
is a natural inhibitor of angiogenesis, seems to be the most powerful molecule,
able to achieve total and final regression of preestablished tumors. However,
there are only preliminary data. Clinical trials are on the way. They should
bring some answers concerning the place of these antiangiogenesis agents in the
traditional therapeutic strategy. In neurooncology, just like in general
cancerology, clinical trials have began with different molecules like
Marismastat or Thalidomid. A review of the principal actors, preclinical and
clinical trials in progress is presented.
PMID: 10599057 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18416999 | 1. Curr Cardiol Rep. 2008 Feb;10(1):37-42. doi: 10.1007/s11886-008-0008-2.
Neuroprotection in cerebral ischemia: emphasis on the SAINT trial.
Chacon MR(1), Jensen MB, Sattin JA, Zivin JA.
Author information:
(1)Department of Neurosciences, University of California San Diego, 9500 Gilman
Drive, La Jolla, CA 92093-0624, USA.
Acute ischemic stroke (AIS) is a significant cause of death and disability in
the United States. It has been 10 years since tissue plasminogen activator
became the first medication approved by the US Food and Drug Administration for
treatment for AIS. However, this treatment simply reopens arteries. The
identification of deleterious cellular reactions that occur secondary to
cerebral ischemia has led investigators to search for neuroprotection strategies
to complement reperfusion. More than 100 human trials, including a handful of
phase III trials, had failed to produce an efficacious neuroprotective agent. In
2006, the first positive trial of neuroprotection was published: the SAINT I
(Stroke-Acute Ischemic NXY Treatment) study. In February 2008, the SAINT II
study was published, indicating that NXY-059 was not effective for AIS
treatment.
DOI: 10.1007/s11886-008-0008-2
PMID: 18416999 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20089864 | 1. J Biol Chem. 2010 Mar 26;285(13):9493-9505. doi: 10.1074/jbc.M109.093609. Epub
2010 Jan 19.
Influence of the human cohesion establishment factor Ctf4/AND-1 on DNA
replication.
Bermudez VP(1), Farina A(1), Tappin I(1), Hurwitz J(2).
Author information:
(1)Program of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New
York, New York 10065.
(2)Program of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New
York, New York 10065. Electronic address: [email protected].
Ctf4/AND-1 is a highly conserved gene product required for both DNA replication
and the establishment of sister chromatid cohesion. In this report, we examined
the mechanism of action of human Ctf4 (hCtf4) in DNA replication both in vitro
and in vivo. Our findings show that the purified hCtf4 exists as a dimer and
that the hCtf4 SepB domain likely plays a primary role determining the dimeric
structure. hCtf4 binds preferentially to DNA template-primer structures,
interacts directly with the replicative DNA polymerases (alpha, delta, and
epsilon), and markedly stimulates the polymerase activities of DNA polymerases
alpha and epsilon in vitro. Depletion of hCtf4 in HeLa cells by small
interfering RNA resulted in G(1)/S phase arrest. DNA fiber analysis revealed
that cells depleted of hCtf4 exhibited a rate of DNA replication slower than
cells treated with control small interfering RNA. These findings suggest that in
human cells, hCtf4 plays an essential role in DNA replication and its ability to
stimulate the replicative DNA polymerases may contribute to this effect.
DOI: 10.1074/jbc.M109.093609
PMCID: PMC2843200
PMID: 20089864 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18954857 | 1. Ann Endocrinol (Paris). 2008 Sep;69 Suppl 1:S33-6. doi:
10.1016/S0003-4266(08)73966-0.
[Thyroid hormone analogs: an important biological supply and new therapeutic
possibilities].
[Article in French]
Josseaume C(1), Lorcy Y.
Author information:
(1)Service d'Endocrinologie, Diabète, Maladie de la nutrition, Médecine Interne,
CHU Rennes, Hôpital Sud, 16, boulevard de Bulgarie, 35000 Rennes.
[email protected]
Thyroid hormones [predominantly 3, 5, 3 -I- iodothyronine (T3)] regulate
cholesterol and lipoprotein metabolism but cardiac effects restrict their use as
hypolipidemic drugs. New molecules have been developped which target
specifically the thyroid hormone receptor ss, predominant isoform in liver. The
first thyroid hormone agonist, called GC1, has selective actions compared to T3.
In animals, GC1 reduced serum cholesterol and serum triglycerides, probably by
stimulation important steps in reverse cholesterol transport. Other selective
thyromimetic, KB- 2115 and KB - 141 have similar effects. Another class of
thyroid hormone analogs, the thyronamines have emerged recently but the basic
biology of this new class of endogenous thyroid hormone remains to better
understood. Therefore, these molecules may be a potentially treatment for
obesity and reduction cholesterol, triglycerides and lipoprotein (a). To date
the studies in human are preliminary. Tolerance and efficacy of these drugs are
still under investigation.
DOI: 10.1016/S0003-4266(08)73966-0
PMID: 18954857 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10581234 | 1. EMBO J. 1999 Dec 1;18(23):6599-609. doi: 10.1093/emboj/18.23.6599.
Crystal structure of a thwarted mismatch glycosylase DNA repair complex.
Barrett TE(1), Schärer OD, Savva R, Brown T, Jiricny J, Verdine GL, Pearl LH.
Author information:
(1)Department of Biochemistry and Molecular Biology, University College London,
Gower Street, London WC1E 6BT.
The bacterial mismatch-specific uracil-DNA glycosylase (MUG) and eukaryotic
thymine-DNA glycosylase (TDG) enzymes form a homologous family of DNA
glycosylases that initiate base-excision repair of G:U/T mismatches. Despite low
sequence homology, the MUG/TDG enzymes are structurally related to the
uracil-DNA glycosylase enzymes, but have a very different mechanism for
substrate recognition. We have now determined the crystal structure of the
Escherichia coli MUG enzyme complexed with an oligonucleotide containing a
non-hydrolysable deoxyuridine analogue mismatched with guanine, providing the
first structure of an intact substrate-nucleotide productively bound to a
hydrolytic DNA glycosylase. The structure of this complex explains the
preference for G:U over G:T mispairs, and reveals an essentially non-specific
pyrimidine-binding pocket that allows MUG/TDG enzymes to excise the alkylated
base, 3, N(4)-ethenocytosine. Together with structures for the free enzyme and
for an abasic-DNA product complex, the MUG-substrate analogue complex reveals
the conformational changes accompanying the catalytic cycle of substrate
binding, base excision and product release.
DOI: 10.1093/emboj/18.23.6599
PMCID: PMC1171723
PMID: 10581234 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14694036 | 1. Neurology. 2003 Dec 23;61(12):1720-5. doi: 10.1212/01.wnl.0000098880.19793.b6.
Neurofilament light protein and glial fibrillary acidic protein as biological
markers in MS.
Malmeström C(1), Haghighi S, Rosengren L, Andersen O, Lycke J.
Author information:
(1)Institute of Clinical Neuroscience, Department of Neurology, Göteborg
University, Sahlgrenska University Hospital, Sweden.
Comment in
Neurology. 2004 Aug 10;63(3):599; author reply 599. doi:
10.1212/wnl.63.3.599.
OBJECTIVE: To determine if CNS-derived proteins present in the CSF of multiple
sclerosis (MS) patients reflect different pathologic processes of MS and if
these proteins could be useful as biologic markers of disease activity.
METHODS: Concentrations of the neurofilament light protein (NFL), glial
fibrillary acidic protein (GFAP), S100B, and the neuron-specific enolase protein
(NSE) were determined in the CSF of 66 MS patients and 50 healthy control
subjects with immunoassays.
RESULTS: The mean levels of the NFL were increased during all stages of MS
compared with controls (p < 0.001), peaking almost 10 times higher during acute
relapses. The highest levels of GFAP were found during the secondary progressive
course (p < 0.001) with a strong correlation with neurologic deficits (Expanded
Disability Status Scale score, r = 0.73, p < 0.001). No increase of S100B or NSE
protein was found in the CSF of MS patients compared with control subjects.
CONCLUSIONS: Increased level of NFL is a general feature of MS, indicating
continuous axonal damage during the entire course of the disease with the most
profound damage during acute relapses. GFAP may serve as a biomarker for disease
progression, probably reflecting the increasing rate of astrogliosis.
DOI: 10.1212/01.wnl.0000098880.19793.b6
PMID: 14694036 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20531305 | 1. Oncogene. 2010 Aug 26;29(34):4741-51. doi: 10.1038/onc.2010.215. Epub 2010 Jun
7.
EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war
on cancer.
Singh A(1), Settleman J.
Author information:
(1)Massachusetts General Hospital Cancer Center and Harvard Medical School,
Charlestown, MA, USA.
Tumors are cellularly and molecularly heterogeneous, with subsets of
undifferentiated cancer cells exhibiting stem cell-like features (CSCs).
Epithelial to mesenchymal transitions (EMT) are transdifferentiation programs
that are required for tissue morphogenesis during embryonic development. The EMT
process can be regulated by a diverse array of cytokines and growth factors,
such as transforming growth factor (TGF)-beta, whose activities are dysregulated
during malignant tumor progression. Thus, EMT induction in cancer cells results
in the acquisition of invasive and metastatic properties. Recent reports
indicate that the emergence of CSCs occurs in part as a result of EMT, for
example, through cues from tumor stromal components. Recent evidence now
indicates that EMT of tumor cells not only causes increased metastasis, but also
contributes to drug resistance. In this review, we will provide potential
mechanistic explanations for the association between EMT induction and the
emergence of CSCs. We will also highlight recent studies implicating the
function of TGF-beta-regulated noncoding RNAs in driving EMT and promoting CSC
self-renewal. Finally we will discuss how EMT and CSCs may contribute to drug
resistance, as well as therapeutic strategies to overcome this clinically.
DOI: 10.1038/onc.2010.215
PMCID: PMC3176718
PMID: 20531305 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16772121 | 1. Cancer Genet Cytogenet. 2006 Jul 1;168(1):50-8. doi:
10.1016/j.cancergencyto.2005.12.009.
Balanced t(11;15)(q23;q15) in a TP53+/+ breast cancer patient from a Li-Fraumeni
syndrome family.
Sherif ZA(1), Danielsen M.
Author information:
(1)Department of Biochemistry and Molecular Biology, Georgetown University
Medical Center, Basic Science Building, Rm. 337, 3900 Reservoir Road, NW,
Washington, DC 20057, USA. [email protected]
Li-Fraumeni Syndrome (LFS) is characterized by early-onset carcinogenesis
involving multiple tumor types and shows autosomal dominant inheritance.
Approximately 70% of LFS cases are due to germline mutations in the TP53 gene on
chromosome 17p13.1. Mutations have also been found in the CHEK2 gene on
chromosome 22q11, and others have been mapped to chromosome 11q23. While
characterizing an LFS family with a documented defect in TP53, we found one
family member who developed bilateral breast cancer at age 37 yet was homozygous
for wild-type TP53. Her mother also developed early-onset primary bilateral
breast cancer, and a sister had unilateral breast cancer and a soft tissue
sarcoma. Cytogenetic analysis using fluorescence in situ hybridization of a
primary skin fibroblast cell line revealed that the patient had a novel balanced
reciprocal translocation between the long arms of chromosomes 11 and 15:
t(11;15)(q23;q15). This translocation was not present in a primary skin
fibroblast cell line from a brother with neuroblastoma, who was heterozygous for
the TP53 mutation. There was no evidence of acute lymphoblastic leukemia in
either the patient or her mother, although a nephew did develop leukemia and
died in childhood. These data may implicate the region at breakpoint 11q23
and/or 15q15 as playing a significant role in predisposition to breast cancer
development.
DOI: 10.1016/j.cancergencyto.2005.12.009
PMID: 16772121 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21303301 | 1. Clin Chem Lab Med. 2011 Apr;49(4):641-6. doi: 10.1515/CCLM.2011.099. Epub 2011
Feb 9.
Non-invasive prenatal diagnosis of trisomy 21 by reverse transcriptase multiplex
ligation-dependent probe amplification.
Deng YH(1), Yin AH, He Q, Chen JC, He YS, Wang HQ, Li M, Chen HY.
Author information:
(1)Daan Gene Diagnostic Center, Sun Yet-Sen University, Guangzhou, Guangdong, PR
China.
BACKGROUND: Obtaining fetal DNA or RNA by either chorionic villus sampling (CVS)
or amniocentesis is currently, the gold standard prenatal diagnosis. However,
these invasive procedures carry risk of miscarriage. A reliable method for
non-invasive prenatal diagnosis (NIPD) has long been sought to reduce the risk
of miscarriage.
METHODS: Cell-free fetal RNA was extracted from the plasma of peripheral blood
from 121 women 9-20 weeks of pregnancy. Five single nucleotide polymorphism
(SNP) loci in PLAC4 gene were analyzed by reverse transcriptase multiplex
ligation-dependent probe amplification (RT-MLPA), followed by capillary
electrophoresis. Karyotype analysis was used for confirmation of prenatal
diagnosis of trisomy 21.
RESULTS: Of 121 samples, 23 were diagnosed with trisomy 21, 87 with normal
ploidy, nine had all five SNP loci homozygous and two had one heterozygous SNP
locus. Comparing with karyotype analysis, the diagnostic sensitivity and
specificity of RT-MLPA were 92% and 100%, respectively.
CONCLUSIONS: RT-MLPA is a convenient and reliable method for the diagnosis of
trisomy 21. We have shown that this method has good specificity, high
sensitivity, and high throughput, making this technique applicable for NIPD in
clinical practice.
DOI: 10.1515/CCLM.2011.099
PMID: 21303301 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18369171 | 1. Stroke. 2008 Jun;39(6):1751-8. doi: 10.1161/STROKEAHA.107.503334. Epub 2008
Mar 27.
NXY-059 for the treatment of acute stroke: pooled analysis of the SAINT I and II
Trials.
Diener HC(1), Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Shuaib A, Ashwood
T, Wasiewski W, Alderfer V, Hårdemark HG, Rodichok L; SAINT I and II
Investigators.
Collaborators: Lees KR, Shuaib A, Ashwood T, Davalos A, Davis S, Diener HC,
Grotta J, Lyden P, Wasiewski W, Pocock S, Adams H, Bath P, Oakes D, Wahlgren NG,
Collier T, Alderfer V, Emeribe U, Stoltenberg A.
Author information:
(1)Department of Neurology, University of Duisburg-Essen, Hufelandstrasse 55,
45122 Essen, Germany. [email protected]
Comment in
Stroke. 2008 Jun;39(6):1659-60. doi: 10.1161/STROKEAHA.107.505024.
BACKGROUND AND PURPOSE: In animal models of acute ischemic stroke (AIS), the
free radical-trapping agent NXY-059 showed promise as a neuroprotectant. SAINT I
and II were randomized, placebo-controlled, double-blind trials to investigate
the efficacy of NXY-059 in patients with AIS.
METHODS: Patients with AIS received an infusion of intravenous NXY-059 or
placebo within 6 hours from the onset of stroke symptoms. A pooled individual
patient analysis was prespecified to assess the overall efficacy and to examine
subgroups. The primary end point was the distribution of disability scores
measured on the modified Rankin scale (mRS) at 90 days. Neurologic and
activities of daily living scores were investigated as secondary end points. We
also evaluated whether treatment with NXY-059 would reduce alteplase-related
intracranial hemorrhages. Finally, we evaluated possible predictors of good or
poor outcome.
RESULTS: An intent-to-treat efficacy analysis was based on 5028 patients.
Baseline parameters and prognostic factors were well balanced between treatment
groups. The distribution of scores on the mRS was not different in the group
treated with NXY-059 (n=2438) compared with the placebo group (n=2456): odds
ratio for limiting disability=1.02; 95% CI, 0.92 to 1.13 (P=0.682,
Cochran-Mantel-Haenszel test). Comparisons at each level of the mRS confirmed an
absence of benefit. There was no evidence of efficacy in prespecified subgroups
or from the secondary outcome analyses. Mortality was equal in the 2 groups
(16.7% vs 16.5%), and adverse event rates were similar. Among patients treated
with alteplase, there was no decrease in rates of symptomatic or asymptomatic
hemorrhage associated with NXY-059 treatment versus placebo. Subgroup analyses
identified National Institutes of Health Stroke Scale score, age, markers of
inflammation, blood glucose, and right-sided infarct as predictors of poor
outcome.
CONCLUSIONS: NXY-059 is ineffective for treatment of AIS within 6 hours of
symptom onset. This is also true for subgroups and the prevention of
alteplase-associated hemorrhage.
DOI: 10.1161/STROKEAHA.107.503334
PMID: 18369171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9445490 | 1. Pediatrics. 1998 Feb;101(2):185-93. doi: 10.1542/peds.101.2.185.
Effect of allopurinol on postasphyxial free radical formation, cerebral
hemodynamics, and electrical brain activity.
Van Bel F(1), Shadid M, Moison RM, Dorrepaal CA, Fontijn J, Monteiro L, Van De
Bor M, Berger HM.
Author information:
(1)Department of Pediatrics, Leiden University Hospital, The Netherlands.
OBJECTIVE: Free radical-induced postasphyxial reperfusion injury has been
recognized as an important cause of brain tissue damage. We investigated the
effect of high-dose allopurinol (ALLO; 40 mg/kg), a xanthine-oxidase inhibitor
and free radical scavenger, on free radical status in severely asphyxiated
newborns and on postasphyxial cerebral perfusion and electrical brain activity.
METHODS: Free radical status was assessed by serial plasma determination of
nonprotein-bound iron (microM), antioxidative capacity, and malondialdehyde
(MDA; microM). Cerebral perfusion was investigated by monitoring changes in
cerebral blood volume (delta CBV; mL/100 g brain tissue) with near infrared
spectroscopy; electrocortical brain activity (ECBA) was assessed in microvolts
by cerebral function monitor. Eleven infants received 40 mg/kg ALLO
intravenously, and 11 infants served as controls (CONT). Plasma nonprotein-bound
iron, antioxidative capacity, and MDA were measured before 4 hours, between 16
and 20 hours, and at the second and third days of age. Changes in CBV and ECBA
were monitored between 4 and 8, 16 and 20, 58 and 62, and 104 and 110 hours of
age.
RESULTS: Six CONT and two ALLO infants died after neurologic deterioration. No
toxic side effects of ALLO were detected. Nonprotein-bound iron (mean +/- SEM)
in the CONT group showed an initial rise (18.7 +/- 4.6 microM to 21.3 +/- 3.4
microM) but dropped to 7.4 +/- 3.5 microM at day 3; in the ALLO group it dropped
from 15.5 +/- 4.6 microM to 0 microM at day 3. Uric acid was significantly lower
in ALLO-treated infants from 16 hours of life on. MDA remained stable in the
ALLO group, but increased in the CONT group at 8 to 16 hours versus < 4 hours
(mean +/- SEM; 0.83 +/- 0.31 microM vs 0.50 +/- 0.14 microM). During 4 to 8
hours, delta CBV-CONT showed a larger drop than delta CBV-ALLO from baseline.
During the subsequent registrations CBV remained stable in both groups.
ECBA-CONT decreased, but ECBA-ALLO remained stable during 4 to 8 hours of age.
Neonates who died had the largest drops in CBV and ECBA.
CONCLUSION: This study suggests a beneficial effect of ALLO treatment on free
radical formation, CBV, and electrical brain activity, without toxic side
effects.
DOI: 10.1542/peds.101.2.185
PMID: 9445490 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19324998 | 1. Endocrinology. 2009 Jul;150(7):3417-24. doi: 10.1210/en.2009-0059. Epub 2009
Mar 26.
Carbohydrate response element binding protein gene expression is positively
regulated by thyroid hormone.
Hashimoto K(1), Ishida E, Matsumoto S, Okada S, Yamada M, Satoh T, Monden T,
Mori M.
Author information:
(1)Department of Medicine and Molecular Science, Graduate School of Medicine,
Gunma University, 3-39-15 Showa-machi Maebashi, Gunma, Japan.
[email protected]
The molecular mechanism of thyroid hormone (TH) effects to fatty acid metabolism
in liver is yet to be clear. The carbohydrate response element-binding protein
(ChREBP) as well as sterol response element-binding protein (SREBP)-1c plays a
pivotal role in hepatic lipogenesis. Both SREBP-1c and ChREBP are target genes
of liver X receptors (LXRs). Because LXRs and TH receptors (TRs) cross talk
mutually in many aspects of transcription, we examined whether TRs regulate the
mouse ChREBP gene expression. In the current study, we demonstrated that TH
up-regulated mouse ChREBP mRNA and protein expression in liver. Run-on and
luciferase assays showed that TH and TR-beta1 positively regulated the ChREBP
gene transcription. The mouse ChREBP gene promoter contains two direct repeat-4
sites (LXRE1 and LXRE2) and EMSAs demonstrated that LXR-alpha and TR-beta1
prefer to bind LXRE1 and LXRE2, respectively. The direct repeat-4 deletion and
LXRE2 mutants of the promoter deteriorate the positive regulation by TR-beta1,
indicating that LXRE2 is functionally important for the regulation. We also
showed that human ChREBP gene expression and promoter activities were
up-regulated by TH. These data suggest that ChREBP mRNA expression is positively
regulated by TR-beta1 and TH at the transcriptional level in mammals. This novel
observation indicates that TH fine-tunes hepatic lipogenesis via regulating
SREBP-1c and ChREBP gene expression reciprocally.
DOI: 10.1210/en.2009-0059
PMCID: PMC2703542
PMID: 19324998 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1547928 | 1. Diabetologia. 1992 Feb;35(2):99-103. doi: 10.1007/BF00402539.
Dual effect of insulin on plasma volume and transcapillary albumin transport.
Hilsted J(1), Christensen NJ.
Author information:
(1)Department of Internal Medicine and Endocrinology, Hvidovre Hospital,
Denmark.
During the past decade it has been demonstrated that insulin, apart from its
effects on metabolism and ion fluxes, has acute effects on the cardiovascular
system and capillary permeability. Intravenous infusion of insulin in doses
which increase plasma insulin to physiological levels, induced vascular
dilatation and increased muscle sympathetic nerve activity during a euglycaemic
glucose clamp. During similar conditions insulin increased the transcapillary
escape rate of albumin and reduced plasma volume. Insulin has also an indirect
effect on vascular permeability during hypoglycaemia, which is mediated by the
increase in plasma adrenaline. Adrenaline infusion increased haematocrit and
decreased plasma volume and intravascular albumin mass. In contrast to insulin
adrenaline did not increase the transcapillary escape rate of albumin. Total
autonomic blockade during insulin-induced hypoglycaemia abolished the increase
in haematocrit, but did not influence the decrease in plasma volume and the
increase in the transcapillary escape rate of albumin. Insulin administration
may also increase urinary albumin excretion, and this effect was observed during
a euglycaemic clamp. The mechanism of the increase in capillary permeability
after insulin has not been elucidated. A number of morphological studies
indicate that insulin may have effects on endothelial cell morphology and
paraendothelial cell permeability. These results indicate that insulin, apart
from its effect on peripheral blood flow, may play a role in a normal transfer
of macromolecules from the blood to the extracellular space after food intake.
This process may be greatly disturbed in insulin-dependent diabetic patients.
DOI: 10.1007/BF00402539
PMID: 1547928 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2060321 | 1. Dan Med Bull. 1991 Apr;38(2):134-44.
Albuminuria--a marker of renal and generalized vascular disease in
insulin-dependent diabetes mellitus.
Jensen T(1).
Author information:
(1)Steno Memorial Hospital, Gentofte.
Atherosclerotic vascular disease is a major cause of morbidity and mortality in
insulin-dependent diabetes mellitus. The frequent coexistence in these patients
of microangiopathy and coronary artery disease was observed more than 30 years
ago and later verified in large epidemiological studies. Thus, the subgroup
(30-40%) of patients who develop clinical nephropathy, also are at extremely
high risk of early cardiovascular death. A number of established cardiovascular
risk factors are present not only in advanced clinical nephropathy but also in
its earliest stages. These include elevated blood pressure, atherogenic changes
in the plasma concentrations of lipids and lipoproteins, elevated plasma levels
of fibrinogen and probably hyperreactivity of platelets. However, it seems
unlikely that these risk factors fully explain the excess cardiovascular
morbidity and mortality in insulin-dependent diabetic patients with clinical
nephropathy. Patients with slightly elevated urinary albumin excretion are at
increased risk of developing not only clinical nephropathy and coronary heart
disease but also proliferative retinopathy and cardiomyopathy. We have,
therefore, hypothesised that elevated urinary albumin excretion is a marker of
generalized disease in the vascular wall of small and large blood vessels.
Findings of elevated transcapillary escape rate of albumin, elevated plasma
concentration of von Willebrand factor and impaired fibrinolytic capacity in
early diabetic nephropathy have supported this hypothesis. However, the initial
pathophysiological mechanisms involved are still hypothetical and largely
unknown. During recent years the incidence of clinical nephropathy has declined
and the prognosis of insulin-dependent diabetic patients has improved. Whether
intervention directed against the often clustered cardiovascular risk factors
will further improve the prognosis in proteinuric patients is suggested but
still unknown. However, the key question is still, why is the vascular wall, in
small and large blood vessels, vulnerable in some but not all diabetic patients?
In the future more studies of the initial pathophysiological mechanisms involved
in this vulnerability are needed.
PMID: 2060321 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14712914 | 1. Novartis Found Symp. 2003;253:56-66; discussion 66-72, 102-9.
Light signalling in cryptochrome-deficient mice.
Bonnefont X(1), Albus H, Meijer JH, van der Horst GT.
Author information:
(1)MGC, Department of Cell Biology and Genetics, Erasmus MC, PO Box 1738, 3000
DR Rotterdam, The Netherlands.
The mammalian master clock driving circadian rhythmicity in physiology,
metabolism, and behaviour resides within the suprachiasmatic nuclei (SCN) of the
anterior hypothalamus and is composed of intertwined negative and positive
autoregulatory transcription-translation feedback loops. The Cryptochrome 1 and
2 gene products act in the negative feedback loop and are indispensable for
molecular core oscillator function, as evident from the arrhythmic wheel running
behaviour and absence of cyclic clock gene expression in mCry1/mCry2 double
mutant mice in constant darkness. Recently, we have measured real-time
multi-unit electrode activity recordings in hypothalamic slices from
mCry-deficient mice kept in constant darkness and observed a complete lack of
circadian oscillations in firing patterns. This proves that CRY proteins, and
thus an intact circadian clock, are prerequisite for circadian rhythmicity in
membrane excitability in SCN neurons. Strikingly, when mCry-deficient mice are
housed in normal light-dark cycles, a single non-circadian peak in neuronal
activity can be detected in SCN slices prepared two hours after the beginning of
the day. This light-induced increase in electric activity of the SCN suggests
that deletion of the mCry genes converts the core oscillator in an
hour-glass-like timekeeper and may explain why in normal day-night cycles
mCry-deficient mice show apparently normal behaviour.
PMID: 14712914 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12800543 | 1. Endocrinol Metab Clin North Am. 2003 Jun;32(2):503-18. doi:
10.1016/s0889-8529(03)00007-0.
Perioperative management of patients with hypothyroidism.
Stathatos N(1), Wartofsky L.
Author information:
(1)Department of Medicine, Washington Hospital Center, 110 Irving Street NW,
Washington, DC 20010, USA.
Hypothyroidism is a common disorder affecting the cardiovascular, respiratory,
hematopoietic, and renal organ systems--each of which is particularly germane in
the management of the surgical patient. In general, treatment of recognized
hypothyroidism is recommended before any surgical procedure whenever possible
and euthyroidism should be documented by measurement of serum TSH as part of the
preoperative evaluation. Such a strategy is likely to result in better surgical
outcomes with improved morbidity and mortality. One exception to treating first
with thyroid hormone is the patient with angina or coronary artery disease
requiring bypass grafting, angioplasty or stenting. In this setting,
preoperative thyroid hormone therapy could tax the ischemic myocardium. The
coronary blood flow should be addressed first, and thyroid hormone therapy
initiated afterwards. The authors have emphasized the need for caution in the
interpretation of low serum thyroid hormones in sick or surgical patients
because of the importance of distinguishing between hypothyroidism and the
"euthyroid sick syndrome." There is no clear evidence at this point to support
thyroid hormone replacement in the latter patients, and it may be potentially
harmful. Rather, we hold that T3 treatment of various surgical and other
patients with nonthyroidal illness should be deferred until proof of its
therapeutic efficacy is demonstrated.
DOI: 10.1016/s0889-8529(03)00007-0
PMID: 12800543 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22427649 | 1. J Biol Chem. 2012 May 11;287(20):16521-9. doi: 10.1074/jbc.M112.360859. Epub
2012 Mar 16.
Hydrophobic imbalance in the cytoplasmic domain of phospholamban is a
determinant for lethal dilated cardiomyopathy.
Ceholski DK(1), Trieber CA, Young HS.
Author information:
(1)Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7,
Canada.
The sarco(endo)plasmic reticulum calcium ATPase (SERCA) and its regulatory
partner phospholamban (PLN) are essential for myocardial contractility. Arg(9) →
Cys (R9C) and Arg(14) deletion (R14del) mutations in PLN are associated with
lethal dilated cardiomyopathy in humans. To better understand these mutations,
we made a series of amino acid substitutions in the cytoplasmic domain of PLN
and tested their ability to inhibit SERCA. R9C is a complete loss-of-function
mutant of PLN, whereas R14del is a mild loss-of-function mutant. When combined
with wild-type PLN to simulate heterozygous conditions, the mutants had a
dominant negative effect on SERCA function. A series of targeted mutations in
this region of the PLN cytoplasmic domain ((8)TRSAIRR(14)) demonstrated the
importance of hydrophobic balance in proper PLN regulation of SERCA. We found
that Arg(9) → Leu and Thr(8) → Cys substitutions mimicked the behavior of the
R9C mutant, and an Arg(14) → Ala substitution mimicked the behavior of the
R14del mutant. The results reveal that the change in hydrophobicity resulting
from the R9C and R14del mutations is sufficient to explain the loss of function
and persistent interaction with SERCA. Hydrophobic imbalance in the cytoplasmic
domain of PLN appears to be a predictor for the development and progression of
dilated cardiomyopathy.
DOI: 10.1074/jbc.M112.360859
PMCID: PMC3351288
PMID: 22427649 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20035856 | 1. Exp Gerontol. 2010 Apr;45(4):312-22. doi: 10.1016/j.exger.2009.12.008. Epub
2009 Dec 24.
Age-dependent decreases in DNA methyltransferase levels and low transmethylation
micronutrient levels synergize to promote overexpression of genes implicated in
autoimmunity and acute coronary syndromes.
Li Y(1), Liu Y, Strickland FM, Richardson B.
Author information:
(1)Dept. of Medicine, University of Michigan, Ann Arbor, 48109, USA.
T cell DNA methylation levels decline with age, activating genes such as KIR and
TNFSF7 (CD70), implicated in lupus-like autoimmunity and acute coronary
syndromes. The mechanisms causing age-dependent DNA demethylation are unclear.
Maintenance of DNA methylation depends on DNA methyltransferase 1 (Dnmt1) and
intracellular S-adenosylmethionine (SAM) levels, and is inhibited by
S-adenosylhomocysteine (SAH). SAM levels depend on dietary micronutrients
including folate and methionine. SAH levels depend on serum homocysteine
concentrations. T cell Dnmt1 levels also decline with age. We hypothesized that
age-dependent Dnmt1 decreases synergize with low folate, low methionine or high
homocysteine levels to demethylate and activate methylation-sensitive genes. T
cells from healthy adults ages 22-81, stimulated and cultured with low folate,
low methionine, or high homocysteine concentrations showed demethylation and
overexpression of KIR and CD70 beginning at age approximately 50 and increased
further with age. The effects were reproduced by Dnmt1 knockdowns in T cells
from young subjects. These results indicate that maintenance of T cell DNA
methylation patterns is more sensitive to low folate and methionine levels in
older than younger individuals, due to low Dnmt1 levels, and that homocysteine
further increases aberrant gene expression. Thus, attention to proper nutrition
may be particularly important in the elderly.
Published by Elsevier Inc.
DOI: 10.1016/j.exger.2009.12.008
PMCID: PMC2838973
PMID: 20035856 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11555290 | 1. Mol Microbiol. 2001 Sep;41(5):1101-11. doi: 10.1046/j.1365-2958.2001.02559.x.
Escherichia coli DNA glycosylase Mug: a growth-regulated enzyme required for
mutation avoidance in stationary-phase cells.
Mokkapati SK(1), Fernández de Henestrosa AR, Bhagwat AS.
Author information:
(1)Department of Chemistry, 463 Chemistry Building, Wayne State University,
Detroit, MI 48202, USA.
The Escherichia coli DNA glycosylase Mug excises 3,N(4)-ethenocytosines (epsilon
C) and uracils from DNA, but its biological function is obscure. This is because
epsilon C is not found in E. coli DNA, and uracil-DNA glycosylase (Ung), a
distinct enzyme, is much more efficient at removing uracils from DNA than Mug.
We find that Mug is overexpressed as cells enter stationary phase, and it is
maintained at a fairly high level in resting cells. This is true of cells grown
in rich or minimal media, and the principal regulation of mug is at the level of
mRNA. Although the expression of mug is strongly dependent on the
stationary-phase sigma factor, sigma(S), when cells are grown in minimal media,
it shows only a modest dependence on sigma(S) when cells are grown in rich
media. When mug cells are maintained in stationary phase for several days, they
acquire many more mutations than their mug(+) counterparts. This is true in ung
as well as ung(+) cells, and a majority of new mutations may not be C to T. Our
results show that the biological role of Mug parallels its expression in cells.
It is expressed poorly in exponentially growing cells and has no apparent role
in mutation avoidance in these cells. In contrast, Mug is fairly abundant in
stationary-phase cells and has an important anti-mutator role at this stage of
cell growth. Thus, Mug joins a very small coterie of DNA repair enzymes whose
principal function is to avoid mutations in stationary-phase cells.
DOI: 10.1046/j.1365-2958.2001.02559.x
PMID: 11555290 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9312172 | 1. J Clin Invest. 1997 Oct 1;100(7):1742-9. doi: 10.1172/JCI119699.
Thyroid hormone improves function and Ca2+ handling in pressure overload
hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and
alpha-myosin heavy chain in rat hearts.
Chang KC(1), Figueredo VM, Schreur JH, Kariya K, Weiner MW, Simpson PC, Camacho
SA.
Author information:
(1)Department of Medicine, University of California, San Francisco, California
94143, USA.
We asked whether thyroid hormone (T4) would improve heart function in left
ventricular hypertrophy (LVH) induced by pressure overload (aortic banding).
After banding for 10-22 wk, rats were treated with T4 or saline for 10-14 d.
Isovolumic LV pressure and cytosolic [Ca2+] (indo-1) were assessed in perfused
hearts. Sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, and alpha-
and beta-myosin heavy chain (MHC) proteins were assayed in homogenates of
myocytes isolated from the same hearts. Of 14 banded hearts treated with saline,
8 had compensated LVH with normal function (LVHcomp), whereas 6 had abnormal
contraction, relaxation, and calcium handling (LVHdecomp). In contrast, banded
animals treated with T4 had no myocardial dysfunction; these hearts had
increased contractility, and faster relaxation and cytosolic [Ca2+] decline
compared with LVHcomp and LVHdecomp. Myocytes from banded hearts treated with T4
were hypertrophied but had increased concentrations of alpha-MHC and SERCA
proteins, similar to physiological hypertrophy induced by exercise. Thus thyroid
hormone improves LV function and calcium handling in pressure overload
hypertrophy, and these beneficial effects are related to changes in myocyte gene
expression. Induction of physiological hypertrophy by thyroid hormone-like
signaling might be a therapeutic strategy for treating cardiac dysfunction in
pathological hypertrophy and heart failure.
DOI: 10.1172/JCI119699
PMCID: PMC508357
PMID: 9312172 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19405859 | 1. Photomed Laser Surg. 2009 Jun;27(3):493-8. doi: 10.1089/pho.2008.2343.
Blue laser irradiation enhances extracellular calcification of primary
mesenchymal stem cells.
Kushibiki T(1), Awazu K.
Author information:
(1)Frontier Research Base for Global Young Researchers, Frontier Research
Center, Graduate School of Engineering, Osaka University, Osaka, Japan.
[email protected]
BACKGROUND DATA AND OBJECTIVE: Mesenchymal stem cells (MSCs) are multipotent
cells present in adult bone marrow that replicate as undifferentiated cells and
can differentiate to lineages of mesenchymal tissues. Homeostatic control of
bone remodeling maintains bone mass by ensuring that bone resorption and bone
formation occur sequentially and in a balanced manner. As most homeostatic
functions occur in a circadian manner, a circadian clock could control bone
mass. Here we show that laser irradiation can direct the extracellular
calcification of mouse MSCs by altering the intracellular localization of the
circadian rhythm protein cryptochrome 1 (CRY1).
MATERIALS AND METHODS: MSCs were irradiated with a blue laser (wavelength 405
nm) for 180 sec via a fiber attached to the bottom of the culture dish. After
laser irradiation, the MSCs were incubated in osteogenic differentiation medium
for 5 d. After laser irradiation, circadian rhythm protein CRY1 was
immunostained and histochemical staining for extracellular calcification was
observed.
RESULTS: Laser irradiation promoted extracellular calcification of MSCs, induced
the translocation of CRY1 protein from the cytoplasm to the nucleus, and
decreased CRY1 mRNA levels quantified by real-time PCR. Since the timing of
nuclear accumulation of clock proteins constitutes an important step in the
transcription-translation feedback loop driving the circadian core oscillator,
laser irradiation could provide a simple and effective technology for clock
protein localization and turnover. Our results also indicate that CRY1 is a
master regulator of circadian rhythm that regulates the extracellular
calcification of MSCs.
CONCLUSION: Laser irradiation could provide a simple and effective means of
controlling the fate of MSCs as a therapeutic strategy, and act as a "molecular
switch" of regulatory proteins by suppressing CRY transcription. Furthermore,
this model system may be useful for exploring the cross-talk between circadian
rhythm and cell function.
DOI: 10.1089/pho.2008.2343
PMID: 19405859 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22768981 | 1. Genomics Proteomics Bioinformatics. 2012 Apr;10(2):74-81. doi:
10.1016/j.gpb.2012.05.001. Epub 2012 Jun 9.
The association between H3K4me3 and antisense transcription.
Cui P(1), Liu W, Zhao Y, Lin Q, Ding F, Xin C, Geng J, Song S, Sun F, Hu S, Yu
J.
Author information:
(1)CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of
Genomics, Chinese Academy of Sciences, Beijing 100029, China.
Histone H3 lysine 4 trimethylation (H3K4me3) is well known to occur in the
promoter region of genes for transcription activation. However, when
investigating the H3K4me3 profiles in the mouse cerebrum and testis, we
discovered that H3K4me3 also has a significant enrichment at the 3' end of
actively transcribed (sense) genes, named as 3'-H3K4me3. 3'-H3K4me3 is
associated with ~15% of protein-coding genes in both tissues. In addition, we
examined the transcriptional initiation signals including RNA polymerase II
(RNAPII) binding sites and 5'-CAGE-tag that marks transcriptional start sites.
Interestingly, we found that 3'-H3K4me3 is associated with the initiation of
antisense transcription. Furthermore, 3'-H3K4me3 modification levels correlate
positively with the antisense expression levels of the associated sense genes,
implying that 3'-H3K4me3 is involved in the activation of antisense
transcription. Taken together, our findings suggest that H3K4me3 may be involved
in the regulation of antisense transcription that initiates from the 3' end of
sense genes. In addition, a positive correlation was also observed between the
expression of antisense and the associated sense genes with 3'-H3K4me3
modification. More importantly, we observed the 3'-H3K4me3 enrichment among
genes in human, fruitfly and Arabidopsis, and found that the sequences of
3'-H3K4me3-marked regions are highly conserved and essentially indistinguishable
from known promoters in vertebrate. Therefore, we speculate that these
3'-H3K4me3-marked regions may serve as potential promoters for antisense
transcription and 3'-H3K4me3 appear to be a universal epigenetic feature in
eukaryotes. Our results provide a novel insight into the epigenetic roles of
H3K4me3 and the regulatory mechanism of antisense transcription.
Copyright © 2012. Published by Elsevier Ltd.
DOI: 10.1016/j.gpb.2012.05.001
PMCID: PMC5054153
PMID: 22768981 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22103571 | 1. Acta Anaesthesiol Scand. 2012 Apr;56(4):482-90. doi:
10.1111/j.1399-6576.2011.02570.x. Epub 2011 Nov 21.
Sevoflurane vs. propofol in patients with coronary disease undergoing mitral
surgery: a randomised study.
Bignami E(1), Landoni G, Gerli C, Testa V, Mizzi A, Fano G, Nuzzi M, Franco A,
Zangrillo A.
Author information:
(1)Department of Anesthesia and Intensive Care, Università Vita-Salute San
Raffaele, Milan, Italy.
BACKGROUND: Myocardial ischemic damage is reduced by volatile anaesthetics in
patients undergoing low-risk coronary artery bypass graft surgery; few and
discordant results exist in other settings. We therefore performed a randomised
controlled trial (sevoflurane vs. propofol) to compare cardiac troponin release
in patients with coronary disease undergoing mitral surgery.
METHODS: Patients with coronary artery disease undergoing mitral surgery were
randomly allocated to receive either sevoflurane (50 patients) or propofol (50
patients) as main hypnotic. The primary endpoint of the study was peak
post-operative cardiac troponin release defined as the maximum value among the
post-operative values measured at intensive care unit arrival, 4 h later, on the
first and second post-operative day.
RESULTS: There was no significant difference in post-operative peak troponin
release, the median (25th-75th percentiles) values being 14.9 (10.1-22.1) ng/ml
and 14.5 (8.8-17.6) ng/ml in the sevoflurane and propofol groups, respectively
(P = 0.4). Fentanyl administration was different between the two groups: 1347 ±
447 μg in patients receiving sevoflurane and 1670 ± 469 μg in those receiving
propofol, P = 0.002. The 1-year follow-up identified two patients who died in
the propofol group (one myocardial infarction and one low cardiac output
syndrome) and one in the sevoflurane group (myocardial infarction).
CONCLUSION: In this study, patients with coronary artery disease undergoing
mitral surgery did not benefit from the cardioprotective properties of
halogenated anaesthetics. Sevoflurane anaesthesia was not associated to lower
cardiac troponin release when compared with propofol anaesthesia.
© 2011 The Authors Acta Anaesthesiologica Scandinavica © 2011 The Acta
Anaesthesiologica Scandinavica Foundation.
DOI: 10.1111/j.1399-6576.2011.02570.x
PMID: 22103571 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25218787 | 1. Clin Chim Acta. 2015 Jan 1;438:309-15. doi: 10.1016/j.cca.2014.09.002. Epub
2014 Sep 8.
Potential of syncytiotrophoblasts isolated from the cervical mucus for early
non-invasive prenatal diagnosis: evidence of a vanishing twin.
Mantzaris D(1), Cram DS(2).
Author information:
(1)Genetic Technologies Ltd, Melbourne, Australia.
(2)Department of Anatomy and Developmental Biology, Monash University,
Melbourne, Australia; Berry Genomics, Beijing, China. Electronic address:
[email protected].
BACKGROUND: Non-invasive methods to assess the foetal genome during pregnancy
will provide new opportunities to offer pregnant women a more comprehensive
genetic diagnosis of their established foetus. The aim of this study was to
determine the presence and frequency of foetal cells in transcervical cell (TCC)
mucus samples from pregnant women and determine their suitability for early
prenatal diagnosis.
METHODS: Syncytiotrophoblasts in aspirated TCC mucus samples were identified by
immunostaining with the foetal-specific antibody NDOG1. Genetic analysis of
foetal cells was performed by laser capture microdissection and quantitative
fluorescent PCR (QF-PCR).
RESULTS: In 116 of 207 (56%) TCC samples, abundant syncytiotrophoblasts were
retrieved. However, when TCC samples were stratified for the presence of
chorionic villous fragments, syncytiotrophoblasts were identified in 85 of 109
(78%) samples. Significant numbers of syncytiotrophoblasts were found in TCC
samples collected between 6 and 9weeks of gestation (mean 741, range 25-2884).
QF-PCR analysis of NDOG1 positive syncytiotrophoblasts and matching maternal DNA
confirmed their foetal origin and correct foetal cell sexing was achieved in 97%
of TCC samples. The one discordant sex diagnosis was associated with a dizygotic
dichorionic twin pregnancy resulting from the implantation of a female T21
embryo and a normal male embryo, where the female T21 foetus had succumbed at
6weeks of gestation and was vanishing.
CONCLUSIONS: Syncytiotrophoblasts can be successfully isolated from TCC samples
and represent a suitable source of cells for genetic analysis of the established
foetus in early pregnancy. The study highlights a vanishing twin as a potential
cause for discordant non-invasive prenatal test results.
Copyright © 2014 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.cca.2014.09.002
PMID: 25218787 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23284292 | 1. PLoS Genet. 2012;8(12):e1003111. doi: 10.1371/journal.pgen.1003111. Epub 2012
Dec 20.
ATX1-generated H3K4me3 is required for efficient elongation of transcription,
not initiation, at ATX1-regulated genes.
Ding Y(1), Ndamukong I, Xu Z, Lapko H, Fromm M, Avramova Z.
Author information:
(1)School of Life Sciences, University of Science and Technology of China,
Hefei, Anhui, China.
Tri-methylated H3 lysine 4 (H3K4me3) is associated with transcriptionally active
genes, but its function in the transcription process is still unclear. Point
mutations in the catalytic domain of ATX1 (ARABIDOPSIS TRITHORAX1), a H3K4
methyltransferase, and RNAi knockdowns of subunits of the AtCOMPASS-like
(Arabidopsis Complex Proteins Associated with Set) were used to address this
question. We demonstrate that both ATX1 and AtCOMPASS-like are required for high
level accumulation of TBP (TATA-binding protein) and Pol II at promoters and
that this requirement is independent of the catalytic histone modifying
activity. However, the catalytic function is critically required for
transcription as H3K4me3 levels determine the efficiency of transcription
elongation. The roles of H3K4me3, ATX1, and AtCOMPASS-like may be of a general
relevance for transcription of Trithorax-activated eukaryotic genes.
DOI: 10.1371/journal.pgen.1003111
PMCID: PMC3527332
PMID: 23284292 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/11577024 | 1. Circ Res. 2001 Sep 28;89(7):591-8. doi: 10.1161/hh1901.096706.
Regulation of thyroid hormone receptor isoforms in physiological and
pathological cardiac hypertrophy.
Kinugawa K(1), Yonekura K, Ribeiro RC, Eto Y, Aoyagi T, Baxter JD, Camacho SA,
Bristow MR, Long CS, Simpson PC.
Author information:
(1)Division of Cardiology, University of Colorado Health Sciences Center,
Denver, CO, USA.
Physiological and pathological cardiac hypertrophy have directionally opposite
changes in transcription of thyroid hormone (TH)-responsive genes, including
alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum
Ca(2+)-ATPase (SERCA), and TH treatment can reverse molecular and functional
abnormalities in pathological hypertrophy, such as pressure overload. These
findings suggest relative hypothyroidism in pathological hypertrophy, but serum
levels of TH are usually normal. We studied the regulation of TH receptors (TRs)
beta1, alpha1, and alpha2 in pathological and physiological rat cardiac
hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH
target genes, alpha- and beta-MyHC and SERCA. All 3 TR subtypes in myocytes were
downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype,
phenylephrine in culture and pressure overload in vivo. Myocyte TRbeta1 was
upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine,
T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or
excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and
promoters. In addition, TR cotransfection and treatment with the
TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR
isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and
TRalpha1 to alpha-MyHC transcription and increased myocyte size. We conclude
that TR isoforms have distinct regulation and function in rat cardiac myocytes.
Changes in myocyte TR levels can explain in part the characteristic molecular
phenotypes in physiological and pathological cardiac hypertrophy.
DOI: 10.1161/hh1901.096706
PMID: 11577024 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22773950 | 1. Open Biol. 2012 Jun;2(6):120086. doi: 10.1098/rsob.120086.
Non-invasive prenatal diagnosis by massively parallel sequencing of maternal
plasma DNA.
Lo YM(1).
Author information:
(1)Li Ka Shing Institute of Health Sciences, The Chinese University of Hong
Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, People's
Republic of China. [email protected]
The presence of foetal DNA in the plasma of pregnant women has opened up new
possibilities for non-invasive prenatal diagnosis. The use of circulating foetal
DNA for the non-invasive prenatal detection of foetal chromosomal aneuploidies
is challenging as foetal DNA represents a minor fraction of maternal plasma DNA.
In 2007, it was shown that single molecule counting methods would allow the
detection of the presence of a trisomic foetus, as long as enough molecules were
counted. With the advent of massively parallel sequencing, millions or billions
of DNA molecules can be readily counted. Using massively parallel sequencing,
foetal trisomies 21, 13 and 18 have been detected from maternal plasma.
Recently, large-scale clinical studies have validated the robustness of this
approach for the prenatal detection of foetal chromosomal aneuploidies. A
proof-of-concept study has also shown that a genome-wide genetic and mutational
map of a foetus can be constructed from the maternal plasma DNA sequencing data.
These developments suggest that the analysis of foetal DNA in maternal plasma
would play an increasingly important role in future obstetrics practice. It is
thus a priority that the ethical, social and legal issues regarding this
technology be systematically studied.
DOI: 10.1098/rsob.120086
PMCID: PMC3390796
PMID: 22773950 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24205972 | 1. AIDS Res Hum Retroviruses. 2014 Apr;30(4):389-93. doi: 10.1089/aid.2013.0234.
Epub 2014 Jan 4.
Genome sequence of a novel HIV-1 circulating recombinant form (CRF64_BC)
identified from Yunnan, China.
Hsi J(1), Wei H, Xing H, Feng Y, He X, Liao L, Jia M, Wang N, Ning C, Shao Y.
Author information:
(1)1 State Key Laboratory for Infectious Disease Prevention and Control,
National Center for AIDS/STD Control and Prevention , Chinese Center for Disease
Control and Prevention, Beijing, China .
We report a novel HIV-1 circulating recombinant form (CRF64_BC) that was
isolated from five epidemiologically unlinked HIV-infected persons in Yunnan
province. CRF64_BC was composed of subtype B and subtype C, with five short
subtype B segments inserted into the subtype C backbone. Phylogenetic analysis
demonstrated that the C subregion was correlated with the India C lineage, which
was transmitted into China in the early 1990s. The evolutionary history of the B
subregion was not as clear as the C subregion, as the short length of this
region yielded poor phylogenetic results. Dehong is considered the epicenter of
HIV-1 in China, and recombinant strains such as CRF07_BC and CRF08_BC, which
also originated from this region, have spread widely in China. The newly emerged
CRF64_BC increases the complexity of the HIV epidemic in China and complicates
the development of subtype-specific tools against HIV transmission.
DOI: 10.1089/aid.2013.0234
PMCID: PMC3976579
PMID: 24205972 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26155468 | 1. J Clin Diagn Res. 2015 May;9(5):AD01-2. doi: 10.7860/JCDR/2015/12733.5884.
Epub 2015 May 1.
Agnathia Holoprosencephaly and Situs Inversus in A Neonate Born to an Alcoholic
Mother.
Goswami D(1), Kusre G(2).
Author information:
(1)Post Graduate Trainee, Department of Anatomy, Assam Medical College and
Hospital , Dibrugarh, Assam, India .
(2)Associate Professor, Department of Anatomy, Assam Medical College and
Hospital , Dibrugarh, Assam, India .
Agnathia, holoprosencephaly and situs inversus complex is an extremely rare form
of congenital malformation. Though a few cases have been reported from other
parts of the world, to the best of our knowledge none has been reported from
India so far. Maternal alcoholism is regarded as an important factor causing
holoprosencephaly. Disruption of the Shh gene signaling pathway is also said to
be a factor for the occurrence of holoprosencephaly as well as left right
asymmetry. Though several factors are suspected as a cause of this deformity,
the precise aetiopathogenesis is still under debate. Lack of knowledge might be
due to paucity of data from cases due to its rarity. Hereby, we are presenting a
case of agnathia, holoprosencephaly and situs inversus born at 32 wk of
gestation by an alcoholic mother. Externally the child had agnathia and
cyclopia. There was no mandible or any oral cavity. It was accompanied by
noticeable limb deformity. Internally there was holoprosencephaly, situs
inversus totalis with several visceral abnormalities. To the best of our
knowledge this is the first case of agnathia, holoprosencephaly and situs
inversus complex to be reported in an indexed literature from India. This report
also strengthens the association of maternal alcoholism with occurrence of
holoprosencephaly.
DOI: 10.7860/JCDR/2015/12733.5884
PMCID: PMC4484060
PMID: 26155468 |
http://www.ncbi.nlm.nih.gov/pubmed/21577144 | 1. J Immunother. 2011 Jun;34(5):409-18. doi: 10.1097/CJI.0b013e31821ca6ce.
PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses
to autologous dendritic cell/myeloma fusion vaccine.
Rosenblatt J(1), Glotzbecker B, Mills H, Vasir B, Tzachanis D, Levine JD, Joyce
RM, Wellenstein K, Keefe W, Schickler M, Rotem-Yehudar R, Kufe D, Avigan D.
Author information:
(1)Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
[email protected]
We have developed a cancer vaccine in which autologous tumor is fused with
dendritic cells (DCs) resulting in the presentation of tumor antigens in the
context of DC-mediated costimulation. In clinical trials, immunologic responses
have been observed, however responses may be muted by inhibitory pathways. The
PD1/PDL1 pathway is an important element contributing to tumor-mediated immune
suppression. In this study, we demonstrate that myeloma cells and DC/tumor
fusions strongly express PD-L1. Compared with a control population of normal
volunteers, increased PD-1 expression was observed on T cells isolated from
patients with myeloma. It is interesting to note that after autologous
transplantation, T-cell expression of PD-1 returned to levels seen in normal
controls. We examined the effect of PD-1 blockade on T-cell response to DC/tumor
fusions ex vivo. Presence of CT-011, an anti-PD1 antibody, promoted the
vaccine-induced T-cell polarization towards an activated phenotype expressing
Th1 compared with Th2 cytokines. A concomitant decrease in regulatory T cells
and enhanced killing in a cytotoxicity assay was observed. In summary, we
demonstrate that PD-1 expression is increased in T cells of patients with active
myeloma, and that CT-011 enhances activated T-cell responses after DC/tumor
fusion stimulation.
DOI: 10.1097/CJI.0b013e31821ca6ce
PMCID: PMC3142955
PMID: 21577144 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18283404 | 1. J Neurol. 2008 Feb;255(2):231-8. doi: 10.1007/s00415-008-0696-y. Epub 2008 Feb
20.
Campath 1-H treatment in patients with aggressive relapsing remitting multiple
sclerosis.
Hirst CL(1), Pace A, Pickersgill TP, Jones R, McLean BN, Zajicek JP, Scolding
NJ, Robertson NP.
Author information:
(1)Department of Neurology, University Hospital of Wales, Heath Park, Cardiff,
UK.
Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the
CD52 antigen, a low molecular weight glycoprotein present on the surface of most
lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T
lymphocyte depletion. Following encouraging initial data from other centres we
report our open label experience of using Campath 1-H as a treatment in
aggressive relapsing multiple sclerosis in a consecutive series of 39 highly
selected patients treated across three regional centres and followed for a mean
of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to
0.19 post treatment with 29% of documented relapses observed in the 12 weeks
following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in
those patients completing > or =1 year of follow- up. Eighty-three per cent of
patients had stable or improved disability following treatment. Infusion related
side effects were common including rash, headache and pyrexia but were usually
mild and self limiting. Transient worsening of pre-existing neurological
deficits during infusion was observed in 3 patients. 12 patients developed
biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid
disease and 1 patient autoimmune skin disease. We conclude that relapse rates
fall following Campath 1-H. Whilst side effects were common these were normally
self limiting or easily managed, suggesting Campath 1-H may be of use in the
treatment of very active relapsing remitting multiple sclerosis.
DOI: 10.1007/s00415-008-0696-y
PMID: 18283404 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18227705 | 1. Melanoma Res. 2008 Feb;18(1):29-35. doi: 10.1097/CMR.0b013e3282f32517.
Mutation analysis of the EGFR-NRAS-BRAF pathway in melanomas from black Africans
and other subgroups of cutaneous melanoma.
Akslen LA(1), Puntervoll H, Bachmann IM, Straume O, Vuhahula E, Kumar R, Molven
A.
Author information:
(1)Section for Pathology, The Gade Institute, University of Bergen, Haukeland
University Hospital, Bergen, Norway. [email protected]
Earlier studies have shown frequent mutations in the BRAF and NRAS genes in
cutaneous melanoma, but these alterations have not been examined in the rare
category of melanoma from black Africans. Moreover, the frequency of epidermal
growth factor receptor (EGFR) mutations in melanocytic tumors is not known. We
therefore examined 165 benign and malignant melanocytic lesions (including 118
invasive melanomas and 18 metastases collected as consecutive cases from various
time periods and from two different pathology departments; the 51 nodular
melanomas were randomly selected from a larger, consecutive, population-based
series of nodular melanomas) with respect to alterations in the EGFR, BRAF and
NRAS genes. Mutations in EGFR (exons 18-21) were not detected. EGFR protein
expression was observed in a subgroup of melanomas, but without associations
with clinicopathologic phenotype or prognosis. Cytoplasmic EGFR expression was,
however, significantly increased from benign nevi to melanomas. Mutations in
BRAF and NRAS were detected in superficial melanoma (25 and 29%, respectively),
nodular melanoma (29 and 28%, respectively) and lentigo maligna melanoma (15 and
16%, respectively). In a series of melanomas from black Africans (n=26), only
two BRAF mutations (8%) were found, both being different from the common T1799A
substitution. Moreover, melanomas from black Africans exhibited mutations in
NRAS exon 1 only (12%), whereas NRAS exon 2 mutations were predominant in
melanomas from Caucasians. Thus, the frequencies of BRAF and NRAS mutations were
particularly low in melanomas from black Africans, supporting a different
pathogenesis of these tumors.
DOI: 10.1097/CMR.0b013e3282f32517
PMID: 18227705 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22719898 | 1. PLoS One. 2012;7(6):e38513. doi: 10.1371/journal.pone.0038513. Epub 2012 Jun
12.
Oxytocin and vasopressin are dysregulated in Williams Syndrome, a genetic
disorder affecting social behavior.
Dai L(1), Carter CS, Ying J, Bellugi U, Pournajafi-Nazarloo H, Korenberg JR.
Author information:
(1)Center for Integrated Neuroscience and Human Behavior, and Department of
Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.
The molecular and neural mechanisms regulating human social-emotional behaviors
are fundamentally important but largely unknown; unraveling these requires a
genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a
condition caused by deletion of ~28 genes, is associated with a gregarious
personality, strong drive to approach strangers, difficult peer interactions,
and attraction to music. WS provides a unique opportunity to identify endogenous
human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and
arginine vasopressin (AVP) regulate reproductive and social behaviors in
mammals, and we reasoned that these might mediate the features of WS. Here we
established blood levels of OT and AVP in WS and controls at baseline, and at
multiple timepoints following a positive emotional intervention (music), and a
negative physical stressor (cold). We also related these levels to standardized
indices of social behavior. Results revealed significantly higher median levels
of OT in WS versus controls at baseline, with a less marked increase in AVP.
Further, in WS, OT and AVP increased in response to music and to cold, with
greater variability and an amplified peak release compared to controls. In WS,
baseline OT but not AVP, was correlated positively with approach, but negatively
with adaptive social behaviors. These results indicate that WS deleted genes
perturb hypothalamic-pituitary release not only of OT but also of AVP,
implicating more complex neuropeptide circuitry for WS features and providing
evidence for their roles in endogenous regulation of human social behavior. The
data suggest a possible biological basis for amygdalar involvement, for
increased anxiety, and for the paradox of increased approach but poor social
relationships in WS. They also offer insight for translating genetic and
neuroendocrine knowledge into treatments for disorders of social behavior.
DOI: 10.1371/journal.pone.0038513
PMCID: PMC3373592
PMID: 22719898 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: All authors have declared
that no competing interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/10882637 | 1. Eur J Med Res. 2000 Jun 20;5(6):231-5.
Co-morbidity in Gaucher's disease results of a nationwide enquiry in Spain.
Pérez-Calvo J(1), Bernal M, Giraldo P, Torralba MA, Civeira F, Giralt M, Pocovi
M.
Author information:
(1)Servicio de Medicina Interna B, Hospital Clínico Universitario, Avda S. Juan
Bosco no 15, 50009 Zaragoza, Spain. [email protected].
SHORT INTRODUCTION: Gaucher's disease (GD) is an autosomal recessive disease
produced by mutations of the Glucocerebrosidase gene. Carriers are considered to
be healthy subjects because there is no manifestation of the disease, but they
show signs of macrophage disfunction. The aim of the study was to determine if
GD patients and non affected carriers risk suffering other diseases when
compared to healthy non-carrier relatives.
DESIGN: Epidemiologic study of historic cohorts. The fact that they have one or
two mutated alleles has been considered to be the risk factor leading to other
conditions (Dementia, Parkinson disease, Ischemic stroke, Ischemic heart
disease, Non rheumatic valvular disease, Cancer hematological and
non-hematological, Pulmonary fibrosis, Tuberculosis, Gallstones and
Schizophrenia). All people, patients, carriers and healthy controls shared the
same genetical background and environmental influence. - Patients and relatives
enrolled on the Spanish Gaucher Disease Registry were evaluated.
STATISTICS: For the Relative-Risk calculation the Mantel-Haenszel test was
applied. Yates' correction was used when size sample was too small. A value of p
<0.05 was accepted for statistical significance.
RESULTS: 370 people, from 79 different families, were surveyed. We received
evaluable information from 45 families (56%), totalling 258 people (69%): 59
healthy subjects (Mean age 32. 20, RANGE: 10-85; M 57.63%/F 42.37%), 132
carriers (Mean age 35.91, RANGE: 1-79; M 56.82%/F 43.18%) and 67 patients (Mean
age 32.16, Range: 1-76; M 44.78%/F 55.22%. - Relative Risk of suffering any
disease with regard to Gaucher's status: Patient vs Healthy 9.69 (95% Confidence
interval [CI] 2.00-63.99; p 0.0006). Patient vs Carrier 3.74 (CI 1.53-9.27; p
0.001); Carrier vs Healthy 2.59 (CI 0. 52-12.50; p 0.21). Relative Risk of
suffering any disease with regard to sex was 3.96 for female patients (CI
1.01-16.75; p 0.02) and 1.34 for female carriers (CI 0.27-6.75; p = 0.68).
CONCLUSION: As a group, Gaucher's patients seem to have a greater risk of
suffering other common unrelated diseases than carriers or healthy relatives.
This excess of risk is particularly higher among female patients and can not be
explained in terms of differences in age. Carrier status doesn't seem to highten
the risk of suffering other diseases.
PMID: 10882637 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23342320 | 1. Ann Rehabil Med. 2012 Dec;36(6):857-60. doi: 10.5535/arm.2012.36.6.857. Epub
2012 Dec 28.
CYP2C9 Mutation Affecting the Individual Variability of Warfarin Dose
Requirement.
Kim YB(1), Ko MJ, Lee DG, Do JG, Hwang JH.
Author information:
(1)Department of Rehabilitation Medicine, Pusan National University Yangsan
Hospital, Yangsan 626-770, Korea.
Warfarin is a frequently prescribed anticoagulant in rehabilitation patients.
Adverse drug reactions of warfarin were reported as bleeding and cutaneous
microvascular thrombosis. Major bleeding, such as intracranial hemorrhage and
psoas hematoma, in patients receiving anticoagulation therapy is a rare
condition, but sometimes very serious complication that can even be fatal.
Patient-specific factors (eg, age, body size, race, concurrent diseases, and
medications) explain some of the individual variability in warfarin dose, but
genetic factors, which influence warfarin response, explain a significantly
higher proportion of the variability in the dose. There are two identified genes
that are responsible for the main proportion of the genetic effect: CYP2C9,
which codes for the enzyme cytochrome P450 2C9 that metabolizes S-warfarin, and
VKORC1, which codes for warfarin's target, vitamin K epoxide reductase. We
report a case of intolerance to warfarin dosing, due to impaired drug metabolism
in a patient with CYP2C9(*)1/(*)3 and VKORC 1173TT. Fortunately, there are no
severe complications.
DOI: 10.5535/arm.2012.36.6.857
PMCID: PMC3546190
PMID: 23342320 |
http://www.ncbi.nlm.nih.gov/pubmed/20854800 | 1. Clin Chim Acta. 2011 Jan 14;412(1-2):79-85. doi: 10.1016/j.cca.2010.09.014.
Epub 2010 Sep 18.
Genotyping three SNPs affecting warfarin drug response by isothermal real-time
HDA assays.
Li Y(1), Jortani SA, Ramey-Hartung B, Hudson E, Lemieux B, Kong H.
Author information:
(1)BioHelix Corporation, Beverly MA 01915, USA. [email protected]
BACKGROUND: The response to the anticoagulant drug warfarin is greatly affected
by genetic polymorphisms in the VKORC1 and CYP2C9 genes. Genotyping these
polymorphisms has been shown to be important in reducing the time of the trial
and error process for finding the maintenance dose of warfarin thus reducing the
risk of adverse effects of the drug.
METHOD: We developed a real-time isothermal DNA amplification system for
genotyping three single nucleotide polymorphisms (SNPs) that influence warfarin
response. For each SNP, real-time isothermal Helicase Dependent Amplification
(HDA) reactions were performed to amplify a DNA fragment containing the SNP.
Amplicons were detected by fluorescently labeled allele specific probes during
real-time HDA amplification.
RESULTS: Fifty clinical samples were analyzed by the HDA-based method,
generating a total of 150 results. Of these, 148 were consistent between the
HDA-based assays and a reference method. The two samples with unresolved
HDA-based test results were repeated and found to be consistent with the
reference method.
CONCLUSION: The HDA-based assays demonstrated a clinically acceptable
performance for genotyping the VKORC1 -1639G>A SNP and two SNPs (430C>T and
1075A>C) for the CYP2C9 enzyme (CYP2C9*2 and CYP2C9*3), all of which are
relevant in warfarin pharmacogenentics.
Copyright © 2010 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.cca.2010.09.014
PMCID: PMC2991486
PMID: 20854800 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17849147 | 1. Planta. 2008 Jan;227(2):331-9. doi: 10.1007/s00425-007-0620-1. Epub 2007 Sep
12.
Plant defensins and virally encoded fungal toxin KP4 inhibit plant root growth.
Allen A(1), Snyder AK, Preuss M, Nielsen EE, Shah DM, Smith TJ.
Author information:
(1)The Donald Danforth Plant Science Center, 975 North Warson Road, St Louis, MO
63132, USA.
Plant defensins are small, highly stable, cysteine-rich antimicrobial proteins
that are thought to constitute an important component of plant defense against
fungal pathogens. There are a number of such defensins expressed in various
plant tissues with differing antifungal activity and spectrum. Relatively little
is known about the modes of action and biological roles of these proteins. Our
previous work on a virally encoded fungal toxin, KP4, from Ustilago maydis and
subsequently with the plant defensin, MsDef1, from Medicago sativa demonstrated
that some of these proteins specifically blocked calcium channels in both fungi
and animals. The results presented here demonstrate that KP4 and three plant
defensins, MsDef1, MtDef2, and RsAFP2, all inhibit root growth in germinating
Arabidopsis seeds at low micromolar concentrations. We have previously
demonstrated that a fusion protein composed of Rab GTPase (RabA4b) and enhanced
yellow fluorescent protein (EYFP) is dependent upon calcium gradients for
localization to the tips of the growing root hairs in Arabidopsis thaliana.
Using this tip-localized fusion protein, we demonstrate that all four proteins
rapidly depolarize the growing root hair and block growth in a reversible
manner. This inhibitory activity on root and root hair is not directly
correlated with the antifungal activity of these proteins and suggests that
plants apparently express targets for these antifungal proteins. The data
presented here suggest that plant defensins may have roles in regulating plant
growth and development.
DOI: 10.1007/s00425-007-0620-1
PMID: 17849147 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24618127 | 1. J Pharmacol Exp Ther. 2014 May;349(2):288-96. doi: 10.1124/jpet.113.211334.
Epub 2014 Mar 11.
5-hydroxytryptamine-mediated neurotransmission modulates spontaneous and
vagal-evoked glutamate release in the nucleus of the solitary tract effect of
uptake blockade.
Hosford PS(1), Mifflin SW, Ramage AG.
Author information:
(1)Department of Integrative Physiology, University of North Texas Health
Science Center, Fort Worth, Texas (P.S.H., S.W.M.); and Department of
Neuroscience, Physiology and Pharmacology, University College London, London,
United Kingdom (P.S.H., A.G.R.).
The effect of blockade of either 5-hydroxytryptamine (5-HT)/serotonin
transporter (SERT) with citalopram or the organic cation transporter 3
(OCT3)/plasma membrane monoamine transporter (PMAT) with decynium-22 (D-22) on
spontaneous and evoked release of 5-HT in the nucleus tractus solitarius (NTS)
was investigated in rat brainstem slices treated with gabazine. 5-HT release was
measured indirectly by changes in the frequency and amplitude of glutamatergic
miniature excitatory postsynaptic currents (mEPSCs) [in the presence of
tetrodotoxin (TTX)] and evoked EPSCs. Blockade of 5-HT3 receptors with
granisetron reduced, whereas the 5-HT3 agonist phenylbiguanide increased, the
frequency of mEPSCs. 5-HT decreased mEPSC frequency at low concentrations and
increased frequency at high concentrations. This inhibition was blocked by the
5-HT1A antagonist
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide
(WAY-100635), which was ineffective on its own, whereas the excitation was
reversed by granisetron. The addition of citalopram or D-22 caused inhibition,
which was prevented by 5-HT1A blockade. Thus, in the NTS, the spontaneous
release of 5-HT is able to activate 5-HT3 receptors, but not 5-HT1A receptors,
as the release in their vicinity is removed by uptake. The ineffectiveness of
corticosterone suggests that the low-affinity, high-capacity transporter is
PMAT, not OCT3. For evoked 5-HT release, only D-22 caused an increase in the
amplitude of EPSCs, with a decrease in the paired pulse ratio, and increased the
number of spontaneous EPSCs after 20-Hz stimulation. Thus, for the evoked
release of 5-HT, the low-affinity, high-capacity transporter PMAT, but not 5-HT
transporter (5-HTT)/SERT, is important in the regulation of changes in 5-HT
extracellular concentration.
DOI: 10.1124/jpet.113.211334
PMID: 24618127 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21419134 | 1. J Mol Biol. 2011 May 20;408(5):807-14. doi: 10.1016/j.jmb.2011.03.018. Epub
2011 Mar 23.
Structural insights for MPP8 chromodomain interaction with histone H3 lysine 9:
potential effect of phosphorylation on methyl-lysine binding.
Chang Y(1), Horton JR, Bedford MT, Zhang X, Cheng X.
Author information:
(1)Department of Biochemistry, Emory University School of Medicine, Atlanta, GA
30322, USA.
M-phase phosphoprotein 8 (MPP8) harbors an N-terminal chromodomain and a
C-terminal ankyrin repeat domain. MPP8, via its chromodomain, binds histone H3
peptide tri- or di-methylated at lysine 9 (H3K9me3/H3K9me2) in submicromolar
affinity. We determined the crystal structure of MPP8 chromodomain in complex
with H3K9me3 peptide. MPP8 interacts with at least six histone H3 residues from
glutamine 5 to serine 10, enabling its ability to distinguish
lysine-9-containing peptide (QTARKS) from that of lysine 27 (KAARKS), both
sharing the ARKS sequence. A partial hydrophobic cage with three aromatic
residues (Phe59, Trp80 and Tyr83) and one aspartate (Asp87) encloses the
methylated lysine 9. MPP8 has been reported to be phosphorylated in vivo,
including the cage residue Tyr83 and the succeeding Thr84 and Ser85. Modeling a
phosphate group onto the side-chain hydroxyl oxygen of Tyr83 suggests that the
negatively charged phosphate group could enhance the binding of positively
charged methyl-lysine or create a regulatory signal by allowing or inhibiting
binding of other protein(s).
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jmb.2011.03.018
PMCID: PMC3081990
PMID: 21419134 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20204499 | 1. Breast Cancer Res Treat. 2010 Apr;120(3):655-61. doi:
10.1007/s10549-010-0814-2. Epub 2010 Mar 5.
The predictive value of the 70-gene signature for adjuvant chemotherapy in early
breast cancer.
Knauer M(1), Mook S, Rutgers EJ, Bender RA, Hauptmann M, van de Vijver MJ,
Koornstra RH, Bueno-de-Mesquita JM, Linn SC, van 't Veer LJ.
Author information:
(1)Division of Diagnostic Oncology, Netherlands Cancer Institute, Plesmanlaan,
Amsterdam, The Netherlands. [email protected]
Multigene assays have been developed and validated to determine the prognosis of
breast cancer. In this study, we assessed the additional predictive value of the
70-gene MammaPrint signature for chemotherapy (CT) benefit in addition to
endocrine therapy (ET) from pooled study series. For 541 patients who received
either ET (n = 315) or ET + CT (n = 226), breast cancer-specific survival (BCSS)
and distant disease-free survival (DDFS) at 5 years were assessed separately for
the 70-gene high and low risk groups. The 70-gene signature classified 252
patients (47%) as low risk and 289 (53%) as high risk. Within the 70-gene low
risk group, BCSS was 97% for the ET group and 99% for the ET + CT group at 5
years with a non-significant univariate hazard ratio (HR) of 0.58 (95% CI
0.07-4.98; P = 0.62). In the 70-gene high risk group, BCSS was 81% (ET group)
and 94% (ET + CT group) at 5 years with a significant HR of 0.21 (95% CI
0.07-0.59; P < 0.01). DDFS was 93% (ET) versus 99% (ET + CT), respectively, in
the 70-gene low risk group, HR 0.26 (95% CI 0.03-2.02; P = 0.20). In the high
risk group DDFS was 76 versus 88%, HR of 0.35 (95% CI 0.17-0.71; P < 0.01).
Results were similar in multivariate analysis, showing significant survival
benefit by adding CT in the 70-gene high risk group. A significant and
clinically meaningful benefit was observed by adding chemotherapy to endocrine
treatment in 70-gene high risk patients. This benefit was not significant in low
risk patients, who were at such low risk for recurrence and cancer-related
death, that adding CT does not appear to be clinically meaningful.
DOI: 10.1007/s10549-010-0814-2
PMID: 20204499 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11532175 | 1. Plant J. 2001 Aug;27(4):297-304. doi: 10.1046/j.1365-313x.2001.01094.x.
Association of the NADPH:protochlorophyllide oxidoreductase (POR) with isolated
etioplast inner membranes from wheat.
Engdahl S(1), Aronsson H, Sundqvist C, Timko MP, Dahlin C.
Author information:
(1)Department of Plant Physiology, Göteborg University, Box 461, SE-405 30
Göteborg, Sweden.
Membrane association of NADPH:protochlorophyllide oxidoreductase (POR, EC:
1.6.99.1) with isolated prolamellar bodies (PLBs) and prothylakoids (PTs) from
wheat etioplasts was investigated. In vitro-expressed radiolabelled POR, with or
without transit peptide, was used to characterize membrane association
conditions. Proper association of POR with PLBs and PTs did not require the
presequence, whereas NADPH and hydrolysable ATP were vital for the process.
After treating the membranes with thermolysin, sodium hydroxide or carbonate, a
firm attachment of the POR protein to the membrane was found. Although the PLBs
and PTs differ significantly in their relative amount of POR in vivo, no major
differences in POR association capacity could be observed between the two
membrane systems when exogenous NADPH was added. Experiments run with only an
endogenous NADPH source almost abolished association of POR with both PLBs and
PTs. In addition, POR protein carrying a mutation in the putative
nucleotide-binding site (ALA06) was unable to bind to the inner membranes in the
presence of NADPH, which further demonstrates that the co-factor is essential
for proper membrane association. POR protein carrying a mutation in the
substrate-binding site (ALA24) showed less binding to the membranes as compared
to the wild type. The results presented here introduce studies of a novel area
of protein-membrane interaction, namely the association of proteins with a
paracrystalline membrane structure, the PLB.
DOI: 10.1046/j.1365-313x.2001.01094.x
PMID: 11532175 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23449779 | 1. Am J Epidemiol. 2013 Apr 1;177(7):683-9. doi: 10.1093/aje/kws301. Epub 2013
Feb 28.
Longevity in male and female joggers: the Copenhagen City Heart Study.
Schnohr P(1), Marott JL, Lange P, Jensen GB.
Author information:
(1)The Copenhagen City Heart Study, Epidemiologic Research Unit, Bispebjerg
University Hospital, DK-2400 Copenhagen NV, Denmark. [email protected]
Comment in
Am J Epidemiol. 2013 Jul 15;178(2):319. doi: 10.1093/aje/kwt106.
Am J Epidemiol. 2013 Jul 15;178(2):319-20. doi: 10.1093/aje/kwt107.
Since 1970, jogging has become an increasingly popular form of exercise, but
concern about harmful effects has been raised following reports of deaths during
jogging. The purpose of this study was to investigate if jogging, which can be
very vigorous, is associated with increased all-cause mortality in men and
women. Jogging habits were recorded in a random sample of 17,589 healthy men and
women aged 20-98 years, invited between 1976 and 2003 to the Copenhagen City
Heart Study. The expected lifetime was calculated by integrating the predicted
survival curve estimated in the Cox model. In this study 1,878 persons (1,116
men and 762 women) were classified as joggers. During the 35-year maximum
follow-up period, we registered 122 deaths among joggers and 10,158 deaths among
nonjoggers. The age-adjusted hazard ratio of death among joggers was 0.56 (95%
confidence interval: 0.46, 0.67) for men and 0.56 (95% confidence interval:
0.40, 0.80) for women. The age-adjusted increase in survival with jogging was
6.2 years in men and 5.6 years in women. This long-term study of joggers showed
that jogging was associated with significantly lower all-cause mortality and a
substantial increase in survival for both men and women.
DOI: 10.1093/aje/kws301
PMID: 23449779 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23990368 | 1. J Mol Histol. 2014 Apr;45(2):121-8. doi: 10.1007/s10735-013-9537-0. Epub 2013
Aug 30.
A novel adenoviral vector-mediated mouse model of Charcot-Marie-Tooth type 2D
(CMT2D).
Seo AJ(1), Shin YH, Lee SJ, Kim D, Park BS, Kim S, Choi KH, Jeong NY, Park C,
Jang JY, Huh Y, Jung J.
Author information:
(1)Department of Anatomy and Neurobiology, School of Medicine, Kyung Hee
University, Heogi-Dong 1, Dongdaemun-Gu, Seoul, 130-701, Republic of Korea.
Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA
synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS.
Here, we report a novel GARS-associated mouse neuropathy model using an
adenoviral vector system that contains a neuronal-specific promoter. In this
model, we found that wild-type GARS is distributed to peripheral axons, dorsal
root ganglion (DRG) cell bodies, central axon terminals, and motor neuron cell
bodies. In contrast, GARS containing a G240R mutation was localized in DRG and
motor neuron cell bodies, but not axonal regions, in vivo. Thus, our data
suggest that the disease-causing G240R mutation may result in a distribution
defect of GARS in peripheral nerves in vivo. Furthermore, a distributional
defect may be associated with axonal degradation in GARS-associated
neuropathies.
DOI: 10.1007/s10735-013-9537-0
PMID: 23990368 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10781108 | 1. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4979-84. doi:
10.1073/pnas.97.9.4979.
Conserved plant genes with similarity to mammalian de novo DNA
methyltransferases.
Cao X(1), Springer NM, Muszynski MG, Phillips RL, Kaeppler S, Jacobsen SE.
Author information:
(1)Department of Molecular, Cell and Developmental Biology, University of
California, Los Angeles, CA 90095-1606, USA.
DNA methylation plays a critical role in controlling states of gene activity in
most eukaryotic organisms, and it is essential for proper growth and
development. Patterns of methylation are established by de novo
methyltransferases and maintained by maintenance methyltransferase activities.
The Dnmt3 family of de novo DNA methyltransferases has recently been
characterized in animals. Here we describe DNA methyltransferase genes from both
Arabidopsis and maize that show a high level of sequence similarity to Dnmt3,
suggesting that they encode plant de novo methyltransferases. Relative to all
known eukaryotic methyltransferases, these plant proteins contain a novel
arrangement of the motifs required for DNA methyltransferase catalytic activity.
The N termini of these methyltransferases contain a series of
ubiquitin-associated (UBA) domains. UBA domains are found in several ubiquitin
pathway proteins and in DNA repair enzymes such as Rad23, and they may be
involved in ubiquitin binding. The presence of UBA domains provides a possible
link between DNA methylation and ubiquitin/proteasome pathways.
DOI: 10.1073/pnas.97.9.4979
PMCID: PMC18343
PMID: 10781108 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10049571 | 1. Dev Biol. 1999 Mar 1;207(1):150-62. doi: 10.1006/dbio.1998.9149.
Wingless signaling leads to an asymmetric response to decapentaplegic-dependent
signaling during sense organ patterning on the notum of Drosophila melanogaster.
Phillips RG(1), Warner NL, Whittle JR.
Author information:
(1)School of Biological Sciences, University of Sussex, Falmer, Brighton, BN1
9QG, United Kingdom. [email protected]
Wnt and Decapentaplegic cell signaling pathways act synergistically in their
contribution to macrochaete (sense organ) patterning on the notum of Drosophila
melanogaster. The Wingless-signaling pathway was ectopically activated by
removing Shaggy activity (the homologue of vertebrate glycogen synthase kinase
3) in mosaics. Proneural activity is asymmetric within the Shaggy-deficient
clone of cells and shows a fixed "polarity" with respect to body axis,
independent of the precise location of the clone. This asymmetric response
indicates the existence in the epithelium of a second signal, which we suggest
is Decapentaplegic. Ectopic expression of Decapentaplegic induces extra
macrochaetes only in cells which also receive the Wingless signal. Activation of
Hedgehog signaling generates a long-range signal which can promote macrochaete
formation in the Wingless activity domain. This signal depends upon
decapentaplegic function. Autonomous activation of the Wingless signal response
in cells causes them to attenuate or sequester this signal. Our results suggest
a novel patterning mechanism which determines sense organ positioning in
Drosophila.
Copyright 1999 Academic Press.
DOI: 10.1006/dbio.1998.9149
PMID: 10049571 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17553932 | 1. Mol Biol Cell. 2007 Aug;18(8):3105-18. doi: 10.1091/mbc.e05-11-1027. Epub 2007
Jun 6.
Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the
activity of acid-sensing ion channels.
Joch M(1), Ase AR, Chen CX, MacDonald PA, Kontogiannea M, Corera AT, Brice A,
Séguéla P, Fon EA.
Author information:
(1)Centre for Neuronal Survival and Cell Biology of Excitable Tissues, Montreal
Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
Mutations in the parkin gene result in an autosomal recessive juvenile-onset
form of Parkinson's disease. As an E3 ubiquitin-ligase, parkin promotes the
attachment of ubiquitin onto specific substrate proteins. Defects in the
ubiquitination of parkin substrates are therefore believed to lead to
neurodegeneration in Parkinson's disease. Here, we identify the
PSD-95/Discs-large/Zona Occludens-1 (PDZ) protein PICK1 as a novel parkin
substrate. We find that parkin binds PICK1 via a PDZ-mediated interaction, which
predominantly promotes PICK1 monoubiquitination rather than polyubiquitination.
Consistent with monoubiquitination and recent work implicating parkin in
proteasome-independent pathways, parkin does not promote PICK1 degradation.
However, parkin regulates the effects of PICK1 on one of its other PDZ partners,
the acid-sensing ion channel (ASIC). Overexpression of wild-type, but not PDZ
binding- or E3 ubiquitin-ligase-defective parkin abolishes the previously
described, protein kinase C-induced, PICK1-dependent potentiation of ASIC2a
currents in non-neuronal cells. Conversely, the loss of parkin in hippocampal
neurons from parkin knockout mice unmasks prominent potentiation of native ASIC
currents, which is normally suppressed by endogenous parkin in wild-type
neurons. Given that ASIC channels contribute to excitotoxicity, our work
provides a mechanism explaining how defects in parkin-mediated PICK1
monoubiquitination could enhance ASIC activity and thereby promote
neurodegeneration in Parkinson's disease.
DOI: 10.1091/mbc.e05-11-1027
PMCID: PMC1949385
PMID: 17553932 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9623916 | 1. Microbiol Immunol. 1998;42(4):289-97. doi: 10.1111/j.1348-0421.1998.tb02285.x.
The 21-kDa polypeptide (VAP21) in the rabies virion is a CD99-related host cell
protein.
Sagara J(1), Tochikura TS, Tanaka H, Baba Y, Tsukita S, Tsukita S, Kawai A.
Author information:
(1)Department of Molecular Microbiology, Graduate School of Pharmaceutical
Sciences, Kyoto University, Japan.
In our monoclonal antibody (MAb) stocks prepared against the BHK-21 cell
antigens, two (#11875 and 28276) recognized a 21-kDa polypeptide (referred to as
VAP21) which is efficiently incorporated into the rabies virion. By using these
MAbs, we isolated the cDNA clones that encoded a polypeptide of 144 amino acids
from our BHK-21 cell cDNA library. Based on the following evidence, the cDNA was
assumed to encode a full-length sequence of VAP21 antigen: i) expression of the
cDNA in animal cells resulted in the production of a polypeptide recognized by
the two MAbs, and its electrophoretic mobility was the same as that of authentic
VAP21 antigen; and ii) immunization with the products from the cDNA-transformed
E. coli cells raised specific antibodies in rabbits that recognized a 21-kDa
polypeptide in the virion. From the deduced amino acid sequence, it is suggested
that the VAP21 antigen has a molecular structure of type-I transmembrane protein
containing characteristic proline-rich and glycine-rich regions in its
ectodomain. Homology searches resulted in finding homologous sequences (totally
about 40% homology) in the human MIC2 gene product (CD99; 32-kDa) of T
lymphocytes. These results suggest that the VAP21 antigen in the rabies virion
is a cellular CD99-related transmembrane protein.
DOI: 10.1111/j.1348-0421.1998.tb02285.x
PMID: 9623916 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23291270 | 1. J Med Internet Res. 2013 Jan 7;15(1):e5. doi: 10.2196/jmir.2249.
A smartphone-based intervention with diaries and therapist-feedback to reduce
catastrophizing and increase functioning in women with chronic widespread pain:
randomized controlled trial.
Kristjánsdóttir OB(1), Fors EA, Eide E, Finset A, Stensrud TL, van Dulmen S,
Wigers SH, Eide H.
Author information:
(1)Institute of Nursing, Faculty of Health, Oslo and Akershus University College
of Applied Sciences, Oslo, Norway. [email protected]
BACKGROUND: Internet-based interventions using cognitive behavioral approaches
can be effective in promoting self-management of chronic pain conditions.
Web-based programs delivered via smartphones are increasingly used to support
the self-management of various health disorders, but research on smartphone
interventions for persons with chronic pain is limited.
OBJECTIVE: The aim of this trial was to study the efficacy of a 4-week
smartphone-delivered intervention with written diaries and therapist feedback
following an inpatient chronic pain rehabilitation program.
METHODS: A total of 140 women with chronic widespread pain who participated in a
4-week inpatient rehabilitation program were randomized into 2 groups: with or
without a smartphone intervention after the rehabilitation. The smartphone
intervention consisted of 1 face-to-face session and 4 weeks of written
communication via a smartphone. Participants received 3 smartphone diary entries
daily to support their awareness of and reflection on pain-related thoughts,
feelings, and activities. The registered diaries were immediately available to a
therapist who submitted personalized written feedback daily based on cognitive
behavioral principles. Both groups were given access to a noninteractive website
after discharge to promote constructive self-management. Outcomes were measured
with self-reported questionnaires. The primary outcome measure of
catastrophizing was determined using the pain catastrophizing scale (score range
0-52). Secondary outcomes included acceptance of pain, emotional distress,
functioning, and symptom levels.
RESULTS: Of the 140 participants, 112 completed the study: 48 in the
intervention group and 64 in the control group. Immediately after the
intervention period, the intervention group reported less catastrophizing (mean
9.20, SD 5.85) than the control group (mean 15.71, SD 9.11, P<.001), yielding a
large effect size (Cohen's d=0.87) for study completers. At 5-month follow-up,
the between-group effect sizes remained moderate for catastrophizing (Cohen's
d=0.74, P=.003), acceptance of pain (Cohen's d=0.54, P=.02), and functioning and
symptom levels (Cohen's d=0.75, P=.001).
CONCLUSIONS: The results suggest that a smartphone-delivered intervention with
diaries and personalized feedback can reduce catastrophizing and prevent
increases in functional impairment and symptom levels in women with chronic
widespread pain following inpatient rehabilitation.
TRIAL REGISTRATION: Clinicaltrials.gov NCT01236209;
http://www.clinicaltrials.gov/ct2/show/NCT01236209 (Archived by WebCite at
http://www.webcitation.org/6DUejLpPY).
DOI: 10.2196/jmir.2249
PMCID: PMC3636250
PMID: 23291270 [Indexed for MEDLINE]
Conflict of interest statement: Conflicts of Interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/25408124 | 1. J Back Musculoskelet Rehabil. 2015;28(4):681-7. doi: 10.3233/BMR-140567.
Lack of association between DSCAM gene polymorphisms and adolescent idiopathic
scoliosis susceptibility in a Chinese Han population.
Wu W(1)(2), Zhu Z(1), Mao S(1), Qiu X(1), Qian B(1), Liu Z(1), Qiu Y(1).
Author information:
(1)Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing
University Medical School, Nanjing, China.
(2)Department of Orthopedics, The People's Hospital of Three Gorges University,
The First Hospital of Yichang, Yichang, Hubei, China.
BACKGROUND: In a recent genome wide association study, polymorphisms in the
DSCAM and CNTNAP2 genes were reported to be related with susceptibility of AIS.
Consequently, further replication studies are warranted in other populations due
to ethnic difference in genetic background.
OBJECTIVE: To explore whether single nucleotide polymorphisms (SNPs) of DSCAM
(rs2222973) and CNTNAP2 (rs11770843) genes are associated with the
susceptibility and curve severity of AIS in a Chinese Han population.
METHODS: A total of 648 AIS patients and 573 age- and sex-matched healthy
adolescents in rs2222973 were recruited, and in rs11770843 there were 100 AIS
patients and 100 age- and sex-matched healthy adolescents included in present
study. Polymerase chain reaction-restriction fragment length polymorphism
(PCR-RFLP) analysis was repeatedly carried out to verify the linkage of AIS with
SNPs rs2222973 in the DSCAM gene and rs11770843 in the CNTNAP2 gene.
Case-control and case-only studies were respectively performed to define the
contribution of the DSCAM gene polymorphisms to predisposition and disease
severity of AIS.
RESULTS: Association analysis of the DSCAM SNP rs2222973 with AIS revealed no
significant differences both in genotype frequency (p= 0.280) and allelic
frequency (p= 0.643). The CNTNAP2 SNP rs11770843 (C/T) was not found in either
the AIS or control group; all 100 AIS patients and 100 normal controls had the
T/T genotype. Among skeletally matured AIS patients, the average maximal Cobb
angles were also comparable within different DSCAM genotypes.
CONCLUSION: Our study did not repeatedly confirm the association of the
rs2222973 or the rs11770843 with AIS in a Chinese Han population. We concluded
that the associations of rs2222973 with AIS predisposition and curve severity
are negative in a Chinese Han population.
DOI: 10.3233/BMR-140567
PMID: 25408124 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17885521 | 1. J Cardiovasc Med (Hagerstown). 2007 Oct;8(10):821-9. doi:
10.2459/JCM.0b013e3280101e3c.
Contrast-enhanced cardiovascular magnetic resonance in primary and ischemic
dilated cardiomyopathy.
Calore C(1), Cacciavillani L, Boffa GM, Silva C, Tiso E, Marra MP, Bacchiega E,
Corbetti F, Iliceto S.
Author information:
(1)Department of Cardiac, Thoracic and Vascular Sciences of the University of
Padua, Padua, Italy. [email protected]
OBJECTIVES: Differentiation between primary dilated cardiomyopathy and ischemic
cardiomyopathy has an important clinical significance. Contrast-enhanced
cardiovascular magnetic resonance can play a role in this task, identifying
myocardial scarring or fibrosis as presence of delayed enhancement. The aim of
the present study was to evaluate the diagnostic potential of contrast-enhanced
cardiovascular magnetic resonance in differentiating dilated cardiomyopathy from
ischemic cardiomyopathy.
METHODS: Contrast-enhanced cardiovascular magnetic resonance was performed in
100 patients with left ventricular dilatation and reduced systolic function: 24
had normal coronary arteries (dilated cardiomyopathy group) and 76 had
significant coronary artery disease (ischemic cardiomyopathy group), with or
without previous myocardial infarction.
RESULTS: In the dilated cardiomyopathy group, only seven (29%) patients showed
delayed enhancement and its pattern was characterized by mid-wall, patchy or
diffuse location. All patients with ischemic cardiomyopathy and prior myocardial
infarction (54 subjects) showed delayed enhancement with subendocardial (n = 4)
or transmural (n = 50) extension. Among the 22 patients with ischemic
cardiomyopathy but without previous myocardial infarction, 13 (59%) showed
either subendocardial (n = 4) or transmural (n = 9) delayed enhancement.
CONCLUSIONS: Patterns of delayed enhancement are different in dilated
cardiomyopathy and ischemic cardiomyopathy, reflecting the presence of scarring
or various degrees of fibrosis in left ventricular myocardium. The presence of
subendocardial or transmural delayed enhancement at contrast-enhanced
cardiovascular magnetic resonance allowed distinction between dilated
cardiomyopathy and ischemic cardiomyopathy with high sensitivity (88%) and
specificity (100%). Integration of cardiovascular magnetic resonance results
with angiographic information can be useful in the identification of pathogenic
mechanisms underlying left ventricular dysfunction.
DOI: 10.2459/JCM.0b013e3280101e3c
PMID: 17885521 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23871832 | 1. Biochim Biophys Acta. 2013 Dec;1833(12):2734-2744. doi:
10.1016/j.bbamcr.2013.07.008. Epub 2013 Jul 18.
The small GTPase N-Ras regulates extracellular matrix synthesis, proliferation
and migration in fibroblasts.
Fuentes-Calvo I(1), Crespo P(2), Santos E(3), López-Novoa JM(1),
Martínez-Salgado C(4).
Author information:
(1)Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de
Investigación Nefrológica, Departamento de Fisiología y Farmacología,
Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica
de Salamanca (IBSAL), Salamanca, Spain.
(2)Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo
Superior de Investigaciones Científicas (CSIC), IDICAN, Universidad de
Cantabria, Cantabria, Spain.
(3)Centro de Investigación del Cáncer, Universidad de Salamanca, Consejo
Superior de Investigaciones Científicas (CSIC), Salamanca, Spain.
(4)Unidad de Fisiopatología Renal y Cardiovascular, Instituto "Reina Sofía" de
Investigación Nefrológica, Departamento de Fisiología y Farmacología,
Universidad de Salamanca, Salamanca, Spain; Instituto de Investigación Biomédica
de Salamanca (IBSAL), Salamanca, Spain; Instituto de Estudios de Ciencias de la
Salud de Castilla y León (IECSCYL), Unidad de Investigación, Hospital
Universitario de Salamanca, Salamanca, Spain. Electronic address:
[email protected].
In addition to their role as oncogenes, Ras GTPases are key regulators of cell
function. There is a proven relationship between the signaling pathways of
transforming growth factor-β1 (TGF- β1) and Ras GTPases. Each of the Ras
isoforms (H, N and K) exhibits specific modulatory activity on different
cellular pathways. Our purpose has been to study some of the mechanisms involved
in the development of renal fibrosis, assessing the individual role of N-Ras in
basal and TGF-β1-mediated extracellular matrix (ECM) synthesis, proliferation,
and migration in immortalized N-Ras deficient fibroblasts (N-ras(-/-)). Compared
to normal counterparts, fibroblasts deficient for N-Ras exhibited higher basal
activity levels of phosphatidylinositol-3-kinase (PI3K)/Akt and MEK/Erk,
accompanied by upregulated collagen synthesis and diminished proliferation and
migration rates. We found that the absence of N-Ras did not affect
TGF-β1-induced proliferation and migration, which required PI3K/Akt but not
Erk1/2 activation. Similar effector pathway dependence was found for fibronectin
and collagen type I expression. Our results indicate that N-Ras might contribute
to renal fibrosis through the down-regulation of ECM synthesis and up-regulation
proliferation and migration modulating Akt activation. N-Ras also regulates
TGF-β1-induced collagen I and fibronectin expression through Erk-independent
pathways.
© 2013.
DOI: 10.1016/j.bbamcr.2013.07.008
PMID: 23871832 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23443971 | 1. Tumour Biol. 2013 Jun;34(3):1699-712. doi: 10.1007/s13277-013-0707-1. Epub
2013 Feb 27.
Metabolic phenotypes in triple-negative breast cancer.
Kim S(1), Kim DH, Jung WH, Koo JS.
Author information:
(1)Department of Pathology, Yonsei University Health System, Seoul, South Korea.
The aim of study was to investigate the metabolism of tumor and stromal cells
necessary to determine differential tumor-stroma metabolic interactions
according to the molecular subtypes of triple-negative breast cancer (TNBC).
Tissues from 132 patients of TNBC were prepared for use as tissue microarrays
(TMA). Expression of CK5/6, EGFR, claudin 3, claudin 4, claudin7, E-cadherin,
AR, GGT1, STAT1, and interleukin-8 was evaluated by immunohistochemical staining
using TMA to classify molecular subtypes of TNBC. In addition,
immunohistochemical staining for Glut1, CAIX, BNIP3, MCT4, Beclin-1, LC3A, LC3B,
and p62 was performed. According to glycolytic status determined by the
immunohistochemical expression of Glut-1 and CAIX in tumor and stroma, the
metabolic phenotypes of the TNBCs were defined as follows: Warburg type (tumor:
glycolysis, stroma: non-glycolysis), reverse Warburg type (tumor:
non-glycolysis, stroma: glycolysis), mixed metabolic type (tumor: glycolysis,
stroma: glycolysis), and metabolic null type (tumor: non-glycolysis, stroma:
non-glycolysis). TNBCs were classified as follows: 79 Warburg type (59.8 %), 7
reverse Warburg type (5.3 %), 24 mixed metabolic type (18.2 %), and 22 metabolic
null type (16.7 %). There was no statistical significance between the metabolic
phenotypes and molecular subtypes (P=0.706). Reverse Warburg type showed the
most dysfunctional mitochondrial status for stromal cells, while Warburg type
showed the most functional mitochondrial status (P=0.036). Regarding stromal
autophagy status, reverse Warburg type showed the most activated status, while
all of the Warburg and metabolic null types showed a non-activated status
(P<0.001). In conclusion, Warburg type was the most common metabolic phenotype
in TNBC, while reverse Warburg type was the most unusual. Metabolic phenotypes
did not differ among the molecular subtypes of TNBCs.
DOI: 10.1007/s13277-013-0707-1
PMID: 23443971 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17309171 | 1. J BUON. 2006 Oct-Dec;11(4):415-8.
AIDIT and IMPACT: building research collaborations in targeted prostate cancer
screening.
Doherty R(1), Lubinski J, Manguoglu E, Luleci G, Christie M, Craven P, Bancroft
E, Mitra A, Morgan S, Eeles R; IMPACT Steering Committee.
Author information:
(1)The Institute of Cancer Research, London, United Kingdom.
AIDIT (Advancing International Co-operation and Developing Infrastructure for
Targeted Screening of Prostate Cancer in Men with Genetic Predisposition) is a
project funded by the Sixth Framework Programme of the European Community which
is endeavouring to facilitate co-operation between European countries in the
field of cancer research. The project also aims to raise awareness of familial
prostate cancer among health professionals and the public within the associated
candidate countries (ACCs) and new member states of the European Union (EU).
AIDIT will focus on linking clinical and research teams in the ACCs and new
member states with the IMPACT Consortium (Identification of Men with a genetic
predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation
carriers and controls), an international team investigating screening and
diagnosis for men with a genetic risk of prostate cancer predisposition genes
BRCA1 or BRCA2). Cancer research has been targeted as a high priority for the
European Community; however, research is most successful when centralised and
well coordinated, avoiding the duplication and fragmentation associated with
smaller, isolated studies. AIDIT will consolidate the current IMPACT consortium
and allow research partners from across the world to benefit from shared
knowledge and experience. To date, the AIDIT team has established a website to
facilitate communication between project collaborators (www.impact-study.co.uk),
has been represented at several international meetings and has facilitated a
conference for the IMPACT study to bring together international research teams,
clinicians and policy makers.
PMID: 17309171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11564050 | 1. Br J Clin Pharmacol. 2001;52 Suppl 1(Suppl 1):21S-34S. doi:
10.1046/j.1365-2125.2001.0520s1021.x.
Therapeutic drug monitoring: antiarrhythmic drugs.
Campbell TJ(1), Williams KM.
Author information:
(1)Department of Medicine, University of New South Wales and St Vincent's
Hospital, Darlinghurst, NSW 2010, Australia.
Antiarrhythmic agents are traditionally classified according to Vaughan Williams
into four classes of action. Class I antiarrhythmic agents include most of the
drugs traditionally thought of as antiarrhythmics, and have as a common action,
blockade of the fast-inward sodium channel on myocardium. These agents have a
very significant toxicity, and while they are being used less, therapeutic drug
monitoring (TDM) does significantly increase the safety with which they can be
administered. Class II agents are antisympathetic drugs, particularly the
b-adrenoceptor blockers. These are generally safe agents which do not normally
require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM
can be useful in the case of amiodarone to monitor compliance and toxicity but
is generally of little value for sotalol. Class IV antiarrhythmic drugs are the
calcium channel blockers verapamil and diltiazem. These are normally monitored
by haemodynamic effects, rather than using TDM. Other agents which do not fall
neatly into the Vaughan Williams classification include digoxin and perhexiline.
TDM is very useful for monitoring the administration (and particularly the
safety) of both of these agents.
DOI: 10.1046/j.1365-2125.2001.0520s1021.x
PMCID: PMC2014627
PMID: 11564050 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/876685 | 1. Pathology. 1977 Apr;9(2):105-9. doi: 10.3109/00313027709085246.
Malignant melanoma with adjacent Hutchinson's melanotic freckle in Black
Africans.
Rippey JJ, Rippey E.
Hutchinson's melanotic freckle (lentigo maligna) is a well-known pigmented
lesion, usually seen on the face of white patients. It may be associated with
invasive malignant melanoma. This paper reports the incidence of this lesion in
association with invasive malignant melanomas of the feet and hands of Black
Africans. In Blacks, as in Whites, malignant melanoma with adjacent Hutchinson's
melanotic freckle carries a considerably better prognosis than other
histogenetic patterns of malignant melanoma.
DOI: 10.3109/00313027709085246
PMID: 876685 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10682690 | 1. Br J Cancer. 2000 Feb;82(3):731-6. doi: 10.1054/bjoc.1999.0988.
Adding free to total prostate-specific antigen levels in trials of prostate
cancer screening.
Wald NJ(1), Watt HC, George L, Knekt P, Helzlsouer KJ, Tuomilehto J.
Author information:
(1)Department of Environmental and Preventive Medicine, Wolfson Institute of
Preventive Medicine, St Bartholomew's and the Royal London School of Medicine
and Dentistry, UK.
We used a nested case-control design on data from men in four prospective
studies (from the UK, Maryland in the USA, and two from Finland) with available
stored serum samples to determine whether there was an advantage in measuring
both free prostate-specific antigen (PSA) and total PSA as a potential screening
test for prostate cancer. Of these men, 247 were verified through national vital
statistics offices as having died of prostate cancer, or having developed the
disease, and 953 men who did not develop prostate cancer (controls) were
selected, matched to cases for age, study centre and sample storage duration.
Fixing the false-positive rate at 1%, the prostate cancer detection rate
(sensitivity) over the 3 years following serum collection (based on 14 cancers)
increased from an estimated 95% using total PSA to 97% using free and bound PSA
(that is, bound to alpha-antichymotrypsin which together with the free form is
total PSA). Over a 6-year period (based on 41 cancers) a similar difference
occurred (52% and 56% detection rates respectively). We conclude that there is
no material advantage in adding free to total PSA in prostate cancer screening
trials.
DOI: 10.1054/bjoc.1999.0988
PMCID: PMC2363306
PMID: 10682690 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9709961 | 1. J Clin Endocrinol Metab. 1998 Aug;83(8):2868-74. doi: 10.1210/jcem.83.8.5032.
Ontogeny of iodothyronine deiodinases in human liver.
Richard K(1), Hume R, Kaptein E, Sanders JP, van Toor H, De Herder WW, den
Hollander JC, Krenning EP, Visser TJ.
Author information:
(1)Department of Internal Medicine III, Erasmus University Medical School,
Rotterdam, The Netherlands.
The role of the deiodinases D1, D2, and D3 in the tissue-specific and
time-dependent regulation of thyroid hormone bioactivity during fetal
development has been investigated in animals but little is known about the
ontogeny of these enzymes in humans. We analyzed D1, D2, and D3 activities in
liver microsomes from 10 fetuses of 15-20 weeks gestation and from 8 apparently
healthy adult tissue transplant donors, and in liver homogenates from 2 fetuses
(20 weeks gestation), 5 preterm infants (27-32 weeks gestation), and 13 term
infants who survived up to 39 weeks postnatally. D1 activity was determined
using 1 microM [3',5'-125I]rT3 as substrate and 10 mM dithiothreitol (DTT) as
cofactor, D2 activity using 1 nM [3',5'-125I]T4 and 25 mM DTT in the presence of
1 mM 6-propyl-2-thiouracil (to block D1 activity) and 1 microM T3 (to block D3
activity), and D3 activity using 10 nM [3,5-125I]T3 and 50 mM DTT, by
quantitation of the release of 125I. The assays were validated by high
performance liquid chromatography of the products, and kinetic analysis
[Michaelis-Menten constant (Km) of rT3 for D1: 0.5 microM; Km of T3 for D3: 2
nM]. In liver homogenates, D1 activity was not correlated with age, whereas D3
activity showed a strong negative correlation with age (r -0.84), with high D3
activities in preterm infants and (except in 1 infant of 35 weeks) absent D3
activity in full-term infants. In microsomes, D1 activities amounted to 4.3-60
pmol/min/mg protein in fetal livers and to 170-313 pmol/min/mg protein in adult
livers, whereas microsomal D3 activities were 0.15-1.45 pmol/min/mg protein in
fetuses and <0.1 pmol/min/mg protein in all but one adult. In the latter sample,
D3 activity amounted to 0.36 pmol/min/mg protein. D2 activity was negligible in
both fetal and adult livers. These findings indicate high D1 and D3 activities
in fetal human liver, and high D1 and mostly absent D3 activities in adult human
liver. Therefore, the low serum T3 levels in the human fetus appear to be caused
by high hepatic (and placental) D3 activity rather than caused by low hepatic D1
activity. The occasional expression of D3 in adult human liver is intriguing and
deserves further investigation.
DOI: 10.1210/jcem.83.8.5032
PMID: 9709961 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22373002 | 1. BMC Complement Altern Med. 2012 Feb 28;12:11. doi: 10.1186/1472-6882-12-11.
Effect of self-administered auricular acupressure on smoking cessation--a pilot
study.
Leung L(1), Neufeld T, Marin S.
Author information:
(1)Department of Family Medicine, Queen's University, 220 Bagot Street,
Kingston, ON K7L 5E9, Canada. [email protected]
BACKGROUND: Tobacco smoking is still a worldwide health risk. Current
pharmacotherapies have at best, a success rate of no more than 50%. Auricular
(ear) acupressure has been purported to be beneficial in achieving smoking
cessation in some studies, while in others has been deemed insignificant. We
hereby describe the protocol for a three-arm randomised controlled trial to
examine the possible benefits of self-administered acupressure for smoking
cessation.
METHODS: Sixty consenting participants with confirmed habit of tobacco smoking
will be recruited and randomized into three arms to receive either auricular
acupressure at five true acupoints (NADA protocol), auricular acupressure at
five sham points, or no auricular acupressure at all. Participants having
auricular acupressure will exert firm pressure to each acupoint bilaterally via
the bead in the attached plasters whenever they feel the urge to smoke. The
treatment phase will last for six weeks during which all participants will be
assessed weekly to review their smoking log, state of abstinence, end-exhalation
carbon monoxide levels and possible adverse effects including withdrawal
reactions and stress levels. At any time, a successful quit date will be defined
with continuous abstinence for the following consecutive 7 days. From then on,
participants will be evaluated individually for continuous abstinence rate
(CAR), end-exhalation carbon monoxide levels and adverse effects of stress and
withdrawal at specified intervals up to 26 weeks. Expectancy of treatment will
be assessed with a four-item Borkovec and Nau self-assessment credibility scale
during and after intervention.
DISCUSSION: We incorporate validated outcome measures of smoking cessation into
our randomised controlled trial design with the objectives to evaluate the
feasibility and possible benefits of self-administered auricular acupressure as
a non-invasive alternative to pharmacotherapy for smoking cessation.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT01389622 (registered Jul 7 2011).
DOI: 10.1186/1472-6882-12-11
PMCID: PMC3328240
PMID: 22373002 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23955788 | 1. Curr Cardiol Rep. 2013 Oct;15(10):408. doi: 10.1007/s11886-013-0408-9.
Stem cell therapy for electrophysiological disorders.
Pokushalov E(1), Romanov A, Steinberg JS.
Author information:
(1)State Research Institute of Circulation Pathology, 15 Rechkunovskaya St.,
Novosibirsk, Russia, 630055. [email protected]
Cardiovascular diseases are a leading cause of mortality worldwide. Terminally
differentiated adult cardiomyocytes lack the innate ability to regenerate. Cell-
and gene-based therapies are emerging as exciting new experimental strategies
for myocardial repair and treatment of a variety of cardiovascular diseases. The
potential advantages and shortcomings of each strategy for electrophysiological
disorders are discussed. Since the first description of human induced
pluripotent stem cell-derived cardiomyocytes, these cells have garnered
tremendous interest for their potential use in patient-specific analysis and
therapy. However, a full understanding of their electrophysiological and
contractile function is necessary before this potential can be realized. This
review focuses on the mechanisms by which stem cell therapy may function as an
antiarrhythmic treatment and early clinical results.
DOI: 10.1007/s11886-013-0408-9
PMID: 23955788 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9794474 | 1. Endocrinology. 1998 Nov;139(11):4626-33. doi: 10.1210/endo.139.11.6323.
Direct measurement of the contributions of type I and type II 5'-deiodinases to
whole body steady state 3,5,3'-triiodothyronine production from thyroxine in the
rat.
Nguyen TT(1), Chapa F, DiStefano JJ 3rd.
Author information:
(1)Department of Computer Science, University of California, Los Angeles
90095-1596, USA.
Production of T3 from T4 in tissues is catalyzed by two 5'-deiodinases, type I
(D1) and type II (D2), but the quantitative contribution of each pathway to
whole body T3 production is not well established. In the presence of
propylthiouracil (PTU), D1, but not D2, can be effectively blocked, providing an
experimental probe for addressing this problem. Decades ago, this approach
provided indirect estimates ranging from 23-44% contribution by D2, based on
plasma T3 appearance rate comparisons (PAR3 = PCR3 [T3]p) in periodically
T4-injected athyreotic rats vs. controls. Two, more recent studies, using
constant infusions of T4 for replacement, achieved 22% and 65% estimates,
respectively, from PAR3 comparisons. We have revisited this problem more
directly and precisely, with two major differences in experiment design. We used
direct whole body steady state measurements of T3 production, instead of
indirect plasma-only data (PAR3). We also used (euthyroid) physiological doses
of both T4 (0.9 microg/day x 100 g BW) and T3 (0.15 microg/day x 100 g BW) for
replacement in two thyroidectomized rat groups, instead of T4 only, in a 7-day
constant steady state, dual tracer infusion protocol. The first group also had
chronically implanted 150-mg PTU pellets (TXR-PTU); the other had implanted 0.1
N NaOH placebo pellets (TXR-EU); each delivered their product at constant rates.
A third euthyroid intact group was used as the controls. The completeness of D1
inhibition was ascertained in a fourth group, identically treated with 150-mg
PTU pellets, in which negligible D1 activity was found in liver and kidney using
labeled rT3 as substrate for the 5'-D assays and minimal (1 mM) dithiothreitol
as cofactor. In the TXR-PTU group, the percentage of T4 converted to T3 was
11.8%, compared with 23.4% (P < 0.0005) in the TXR-EU group, and 22.7% (P = NS)
in controls. Thus, in euthyroid steady state, D2 contributes about half of the
T3 produced from T4.
DOI: 10.1210/endo.139.11.6323
PMID: 9794474 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23936319 | 1. PLoS One. 2013 Aug 2;8(8):e69147. doi: 10.1371/journal.pone.0069147. Print
2013.
Expression of human Gaucher disease gene GBA generates neurodevelopmental
defects and ER stress in Drosophila eye.
Suzuki T(1), Shimoda M, Ito K, Hanai S, Aizawa H, Kato T, Kawasaki K, Yamaguchi
T, Ryoo HD, Goto-Inoue N, Setou M, Tsuji S, Ishida N.
Author information:
(1)National Institute of Advanced Industrial Science and Technology, Tsukuba,
Ibaraki, Japan.
Erratum in
PLoS One. 2015 Aug 19;10(8):e0135619. doi: 10.1371/journal.pone.0135619.
Gaucher disease (GD) is the most common of the lysosomal storage disorders and
is caused by defects in the GBA gene encoding glucocerebrosidase (GlcCerase).
The accumulation of its substrate, glucocylceramide (GlcCer) is considered the
main cause of GD. We found here that the expression of human mutated GlcCerase
gene (hGBA) that is associated with neuronopathy in GD patients causes
neurodevelopmental defects in Drosophila eyes. The data indicate that
endoplasmic reticulum (ER) stress was elevated in Drosophila eye carrying
mutated hGBAs by using of the ER stress markers dXBP1 and dBiP. We also found
that Ambroxol, a potential pharmacological chaperone for mutated hGBAs, can
alleviate the neuronopathic phenotype through reducing ER stress. We demonstrate
a novel mechanism of neurodevelopmental defects mediated by ER stress through
expression of mutants of human GBA gene in the eye of Drosophila.
DOI: 10.1371/journal.pone.0069147
PMCID: PMC3732251
PMID: 23936319 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: This work was funded in
part by a grant from Nihon Advanced Agri Corporation. This does not alter the
authors' adherence to all the PLOS ONE policies on sharing data and materials. |
http://www.ncbi.nlm.nih.gov/pubmed/12723987 | 1. Arthritis Res Ther. 2003;5(3):R158-62. doi: 10.1186/ar750. Epub 2003 Mar 24.
Smoking-gender interaction and risk for rheumatoid arthritis.
Krishnan E(1), Sokka T, Hannonen P.
Author information:
(1)Department of Medicine, Stanford University, Palo Alto, California, USA.
[email protected]
The present case-control study was conducted to investigate the relationship
between smoking and rheumatoid arthritis, and to investigate formally the
interaction between sex, smoking, and risk for developing rheumatoid arthritis.
The study was performed in the Central District of Finland. Cases were patients
with rheumatoid arthritis and the control group was a random sample of the
general population. Logistic regression models were used to evaluate the effect
of smoking on risk for rheumatoid arthritis, after adjusting for the effects of
age, education, body mass index, and indices of general health and pain.
Overall, 1095 patients with rheumatoid arthritis and 1530 control individuals
were included. Patients were older, less well educated, more disabled, and had
poorer levels of general health as compared with control individuals (all P <
0.01). Preliminary analyses revealed the presence of substantial statistical
interaction between smoking and sex (P < 0.001). In separate multivariable
analyses, past history of smoking was associated with increased risk for
rheumatoid arthritis overall in men (odds ratio 2.0, 95% confidence interval
1.2-3.2) but not in women. Among men, this effect was seen only for rheumatoid
factor-positive rheumatoid arthritis. There were significant interactions
between smoking and age among women but not among men. We conclude that sex is a
biologic effect modifier in the association between smoking and rheumatoid
arthritis. The role of menopause in the etiology of rheumatoid arthritis merits
further research.
DOI: 10.1186/ar750
PMCID: PMC165046
PMID: 12723987 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14638695 | 1. J Biol Chem. 2004 Feb 13;279(7):6087-97. doi: 10.1074/jbc.M307087200. Epub
2003 Nov 24.
Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved
Rac-dependent cell migration.
Grimsley CM(1), Kinchen JM, Tosello-Trampont AC, Brugnera E, Haney LB, Lu M,
Chen Q, Klingele D, Hengartner MO, Ravichandran KS.
Author information:
(1)Beirne Carter Center for Immunology Research and the Department of
Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Cell migration is essential throughout embryonic and adult life. In numerous
cell systems, the small GTPase Rac is required for lamellipodia formation at the
leading edge and movement ability. However, the molecular mechanisms leading to
Rac activation during migration are still unclear. Recently, a mammalian
superfamily of proteins related to the prototype member Dock180 has been
identified with homologues in Drosophila and Caenorhabditis elegans. Here, we
addressed the role of Dock180 and ELMO1 proteins, which function as a complex to
mediate Rac activation, in mammalian cell migration. Using mutants of Dock180
and ELMO1 in a Transwell assay as well as transgenic rescue of a C. elegans
mutant lacking CED-5 (Dock180 homologue), we identified specific regions of
Dock180 and ELMO1 required for migration in vitro and in a whole animal model.
In both systems, the Dock180.ELMO1 complex formation and the ability to activate
Rac were required. We also found that ELMO1 regulated multiple Dock180
superfamily members to promote migration. Interestingly, deletion mutants of
ELMO1 missing their first 531 or first 330 amino acids that can still bind and
cooperate with Dock180 in Rac activation failed to promote migration, which
correlated with the inability to localize to lamellipodia. This finding suggests
that Rac activation by the ELMO.Dock180 complex at discrete intracellular
locations mediated by the N-terminal 330 amino acids of ELMO1 rather than
generalized Rac activation plays a role in cell migration.
DOI: 10.1074/jbc.M307087200
PMID: 14638695 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23248098 | 1. Cancer Prev Res (Phila). 2013 Jan;6(1):27-39. doi:
10.1158/1940-6207.CAPR-12-0349. Epub 2012 Dec 17.
Dietary resveratrol prevents development of high-grade prostatic intraepithelial
neoplastic lesions: involvement of SIRT1/S6K axis.
Li G(1), Rivas P, Bedolla R, Thapa D, Reddick RL, Ghosh R, Kumar AP.
Author information:
(1)Department of Urology, The University of Texas Health Science Center, San
Antonio, TX 78229, USA.
SIRT1 (mammalian ortholog of the yeast silent information regulator 2) is a
NAD-dependent histone deacetylase belonging to the multigene family of sirtuins.
Anecdotal and epidemiologic observations provide evidence for beneficial effects
of the calorie restriction mimetic resveratrol (RES), a SIRT1 activator in
preventing cardiovascular diseases and cancer. Although SIRT1 possesses both
tumorigenic and antitumorigenic potential, the molecular mechanisms underlying
SIRT1-mediated tumor progression or inhibition are poorly understood. In this
study, we investigated the role of SIRT1 in multiple human prostate cancer cell
lines and prostate-specific PTEN knockout mouse model using resveratrol.
Androgen-independent prostate cancer cell lines (C42B, PC3, and DU145) express
higher levels of SIRT1 than androgen-responsive (LNCaP) and nontumorigenic
prostate cells (RWPE-1). Resveratrol enhanced this expression without any
significant effect on SIRT1 enzymatic activity. Inhibition of SIRT1 expression
using shRNA enhanced cell proliferation and inhibited autophagy by repressing
phosphorylation of S6K and 4E-BP1. These biologic correlates were reversed in
the presence of resveratrol. Analysis of prostates from dietary intervention
with resveratrol showed a significant reduction in prostate weight and reduction
in the incidence of high-grade prostatic intraepithelial neoplastic (HGPIN)
lesions by approximately 54% with no significant change in body weight.
Consistent with the in vitro findings, resveratrol intervention in the PTEN
knockout mouse model was associated with reduction in the prostatic levels of
mTOR complex 1 (mTORC1) activity and increased expression of SIRT1. These data
suggest that SIRT1/S6K-mediated inhibition of autophagy drives prostate
tumorigenesis. Therefore, modulation of SIRT1/S6K signaling represents an
effective strategy for prostate cancer prevention.
©2012 AACR.
DOI: 10.1158/1940-6207.CAPR-12-0349
PMCID: PMC3536933
PMID: 23248098 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure of potential conflicts of interest:
No potential conflicts of interest were identified by any authors of this
manuscript |
http://www.ncbi.nlm.nih.gov/pubmed/22583331 | 1. Expert Opin Ther Pat. 2012 May;22(5):483-94. doi:
10.1517/13543776.2012.680437.
Sodium glucose co-transporter 2 (SGLT2) inhibitors: novel antidiabetic agents.
Washburn WN(1).
Author information:
(1)Metabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb
Co., P.O. Box 5400, Princeton, NJ 08543, USA. [email protected]
INTRODUCTION: Maintenance of glucose homeostasis in healthy individuals involves
SGLT2 (sodium glucose co-transporter 2)-mediated recovery of glucose from the
glomerular filtrate which otherwise would be excreted in urine. Clinical studies
indicate that SGLT2 inhibitors provide an insulin-independent means to reduce
the hyperglycemia that is the hallmark of type 2 diabetes mellitus (T2DM) with
minimal risk of hypoglycemia.
AREAS COVERED: The pharmacophore common to the SGLT2 inhibitors currently in
development is a diarylmethane C-glucoside which is discussed in this review.
The focus is how this pharmacophore was further modified as inferred from the
patents publishing from 2009 to 2011. The emphasis is on the strategy that each
group employed to circumvent the constraints imposed by prior art and how the
resulting SGLT2 potency and selectivity versus SGLT1 compared with that of the
lead clinical compound dapagliflozin.
EXPERT OPINION: SGLT2 inhibitors offer a new fundamentally different approach
for treatment of diabetes. To date, the clinical results suggest that for
non-renally impaired patients this class of inhibitors could be safely used at
any stage of T2DM either alone or in combination with other marketed
antidiabetic medications.
DOI: 10.1517/13543776.2012.680437
PMID: 22583331 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15362510 | 1. Mol Cell Biochem. 2004 Jun;261(1-2):245-9. doi:
10.1023/b:mcbi.0000028762.97754.26.
Increased inhibition of SERCA2 by phospholamban in the type I diabetic heart.
Vasanji Z(1), Dhalla NS, Netticadan T.
Author information:
(1)Institute of Cardiovascular Sciences, St. Boniface General Hospital Research
Centre, and Department of Physiology, University of Manitoba, Winnipeg,
Manitoba, Canada.
The sarcoplasmic reticulum (SR) plays a critical role in mediating cardiac
contractility and its function is abnormal in the diabetic heart. However, the
mechanisms underlying SR dysfunction in the diabetic heart are not clear.
Because protein phosphorylation regulates SR function, this study examined the
phosphorylation state of phospholamban, a key SR protein that regulates SR
calcium (Ca2+) uptake in the heart. Diabetes was induced in male Sprague-Dawley
rats by an injection of streptozotocin (STZ; 65 mg kg(-1) i.v.), and the animals
were humanely killed after 6 weeks and cardiac SR function was examined.
Depressed cardiac performance was associated with reduced SR Ca2+-uptake
activity in diabetic animals. The reduction in SR Ca2+-uptake was consistent
with a significant decrease in the level of SR Ca2+-pump ATPase (SERCA2a)
protein. The level of phospholamban (PLB) protein was also decreased, however,
the ratio of PLB to SERCA2a was increased in the diabetic heart. Depressed SR
Ca2+-uptake was also due to a reduction in the phosphorylation of PLB by the
Ca2+-calmodulin-dependent protein kinase (CaMK) and cAMP-dependent protein
kinase (PKA). Although the activities of the SR-associated
Ca2+-calmodulin-dependent protein kinase (CaMK), cAMP-dependent protein kinase
(PKA) were increased in the diabetic heart, depressed phosphorylation of PLB
could partly be attributed to an increase in the SR-associated protein
phosphatase activities. These results suggest that there is increased inhibition
of SERCA2a by PLB and this appears to be a major defect underlying SR
dysfunction in the diabetic heart.
DOI: 10.1023/b:mcbi.0000028762.97754.26
PMID: 15362510 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8000657 | 1. J Am Coll Surg. 1995 Jan;180(1):65-71.
Melanoma in black South Africans.
Hudson DA(1), Krige JE.
Author information:
(1)Department of Plastic and Reconstructive Surgery, University of Cape Town,
South Africa.
BACKGROUND: Scant data exists on melanoma in blacks from Africa. This study was
undertaken to define factors affecting outcome of blacks from South Africa with
melanoma.
STUDY DESIGN: A retrospective analysis of the management and outcome of 63 black
patients with malignant melanoma treated at a major referral center during a 14
year period is presented. Data evaluated included patient demographic and
clinical characteristics, stage at presentation, tumor site, histologic type,
treatment, and subsequent cure. Survival curves were calculated for stage and
site of disease.
RESULT: The mean age at presentation of the 39 women and 24 men was 60.5 years
(range of 30 to 85 years), with a peak incidence in the sixth decade. The foot
was the most common site of disease (45 patients). Seven patients had subungual
melanoma, seven had primary mucosal lesions, and in six, the primary lesion
could not be found. Thirty patients presented with stage I disease, two with
stage II, 23 with stage III, and nine with disseminated metastatic disease.
Acral lentiginous melanoma was the most common histogenetic type (34 patients),
nodular melanoma occurred in ten patients, and superficial spreading melanoma
occurred in three patients. The mean Breslow depth was 6.15 mm (range of 1 to 25
mm). Patients with localized disease were treated by wide local excision and
split skin graft, while patients with melanoma in the nailbed were treated by
amputation of the involved digit. Sixteen patients are alive after a mean
follow-up period of 82.1 months, 44 have died after a mean of 12.7 months, and
five patients have been unavailable for follow-up evaluation.
CONCLUSIONS: The poor prognosis in black patients in South Africa is the result
of delayed presentation with thick primary lesions and advanced disease. An
active education program may reduce mortality by detecting the disease earlier.
PMID: 8000657 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21248360 | 1. J Dent Res. 2011 May;90(5):665-71. doi: 10.1177/0022034510393516. Epub 2011
Jan 19.
Influence of experimental esophageal acidification on sleep bruxism: a
randomized trial.
Ohmure H(1), Oikawa K, Kanematsu K, Saito Y, Yamamoto T, Nagahama H, Tsubouchi
H, Miyawaki S.
Author information:
(1)Department of Orthodontics, Kagoshima University Graduate School of Medical
and Dental Sciences, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
Comment in
J Dent Res. 2011 Oct;90(10):1253; author reply 1254. doi:
10.1177/0022034511415276.
The aim of this cross-over, randomized, single-blinded trial was to examine
whether intra-esophageal acidification induces sleep bruxism (SB).
Polysomnography with electromyogram (EMG) of masseter muscle, audio-video
recording, and esophageal pH monitoring were performed in a sleep laboratory.
Twelve healthy adult males without SB participated. Intra-esophageal infusions
of 5-mL acidic solution (0.1 N HCl) or saline were administered. The frequencies
of EMG bursts, rhythmic masticatory muscle activity (RMMA) episodes, grinding
noise, and the RMMA/microarousal ratio were significantly higher in the
20-minute period after acidic infusion than after saline infusion. RMMA episodes
including SB were induced by esophageal acidification. This trial is registered
with the UMIN Clinical Trials Registry, UMIN000002923.
ABBREVIATIONS: ASDA, American Sleep Disorders Association; EMG, electromyogram;
GER, gastroesophageal reflux; LES, lower esophageal sphincter; NREM, non-rapid
eye movement; REM, rapid eye movement; RMMA, rhythmic masticatory muscle
activity; SB, sleep bruxism; SD, standard deviation; UES, upper esophageal
sphincter.
DOI: 10.1177/0022034510393516
PMID: 21248360 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11901234 | 1. Mol Pharmacol. 2002 Apr;61(4):936-44. doi: 10.1124/mol.61.4.936.
The virally encoded fungal toxin KP4 specifically blocks L-type voltage-gated
calcium channels.
Gage MJ(1), Rane SG, Hockerman GH, Smith TJ.
Author information:
(1)Donald Danforth Plant Science Center, St. Louis, Missouri 63132, USA.
KP4 is a virally encoded fungal toxin secreted by the P4 killer strain of
Ustilago maydis. Previous studies demonstrated that this toxin inhibits growth
of the target fungal cells by blocking calcium uptake rather than forming
channels, as had been suggested previously. Unexpectedly, this toxin was also
shown to inhibit voltage-gated calcium channel activity in mammalian cells. We
used whole-cell patch-clamp techniques to further characterize this activity
against mammalian cells. KP4 is shown to specifically block L-type calcium
channels with weak voltage dependence to the block. Because KP4 activity is
abrogated by calcium, KP4 probably binds competitively with calcium to the
channel exterior. Finally, it is shown that chemical reagents that modify lysine
residues reduce KP4 activity in both patch-clamp experiments on mammalian cells
and in fungal killing assays. Because the only lysine residue is K42, this
residue seems to be crucial for both mammalian and fungal channel activity. Our
results defining the type of mammalian channel affected by this fungal toxin
further support our contention that KP4 inhibits fungal growth by blocking
transmembrane calcium flux through fungal calcium channels, and imply a high
degree of structural homology between these fungal and mammalian calcium
channels.
DOI: 10.1124/mol.61.4.936
PMID: 11901234 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21613270 | 1. Hum Mol Genet. 2011 Aug 15;20(16):3227-40. doi: 10.1093/hmg/ddr235. Epub 2011
May 25.
The PINK1/Parkin pathway regulates mitochondrial dynamics and function in
mammalian hippocampal and dopaminergic neurons.
Yu W(1), Sun Y, Guo S, Lu B.
Author information:
(1)Department of Pathology, Stanford University School of Medicine, Stanford, CA
94305, USA.
PTEN-induced putative kinase 1 (PINK1) and Parkin act in a common pathway to
regulate mitochondrial dynamics, the involvement of which in the pathogenesis of
Parkinson's disease (PD) is increasingly being appreciated. However, how the
PINK1/Parkin pathway influences mitochondrial function is not well understood,
and the exact role of this pathway in controlling mitochondrial dynamics remains
controversial. Here we used mammalian primary neurons to examine the function of
the PINK1/Parkin pathway in regulating mitochondrial dynamics and function. In
rat hippocampal neurons, PINK1 or Parkin overexpression resulted in increased
mitochondrial number, smaller mitochondrial size and reduced mitochondrial
occupancy of neuronal processes, suggesting that the balance of mitochondrial
fission/fusion dynamics is tipped toward more fission. Conversely, inactivation
of PINK1 resulted in elongated mitochondria, indicating that the balance of
mitochondrial fission/fusion dynamics is tipped toward more fusion. Furthermore,
overexpression of the fission protein Drp1 (dynamin-related protein 1) or
knocking down of the fusion protein OPA1 (optical atrophy 1) suppressed PINK1
RNAi-induced mitochondrial morphological defect, and overexpression of PINK1 or
Parkin suppressed the elongated mitochondria phenotype caused by Drp1 RNAi.
Functionally, PINK1 knockdown and overexpression had opposite effects on
dendritic spine formation and neuronal vulnerability to excitotoxicity. Finally,
we found that PINK1/Parkin similarly influenced mitochondrial dynamics in rat
midbrain dopaminergic neurons. These results, together with previous findings in
Drosophila dopaminergic neurons, indicate that the PINK1/Parkin pathway plays
conserved roles in regulating neuronal mitochondrial dynamics and function.
DOI: 10.1093/hmg/ddr235
PMCID: PMC3140825
PMID: 21613270 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24311433 | 1. Am J Med Genet A. 2014 Feb;164A(2):425-31. doi: 10.1002/ajmg.a.36307. Epub
2013 Dec 5.
Small mosaic deletion encompassing the snoRNAs and SNURF-SNRPN results in an
atypical Prader-Willi syndrome phenotype.
Anderlid BM(1), Lundin J, Malmgren H, Lehtihet M, Nordgren A.
Author information:
(1)Department of Molecular Medicine and Surgery, Clinal Genetic Unit, Centre of
Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of
Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
Genetic analyses were performed in a male patient with suspected Prader-Willi
syndrome who presented with hypogonadism, excessive eating, central obesity,
small hands and feet and cognition within the low normal range. However, he had
no neonatal hypotonia or feeding problems during infancy. Chromosome analysis
showed a normal male karyotype. Further analysis with array-CGH identified a
mosaic 847 kb deletion in 15q11-q13, including SNURF-SNRPN, the snoRNA gene
clusters SNORD116 (HBII-85), SNORD115, (HBII-52), SNORD109 A and B (HBII-438A
and B), SNORD64 (HBII-13), and NPAP1 (C15ORF2). MLPA confirmed the deletion and
the results were compatible with a paternal origin. Metaphase-FISH verified the
mosaicism with the deletion present in 58% of leukocytes analyzed. Three smaller
deletions in this region have previously been reported in patients with
Prader-Willi syndrome phenotype. All three deletions included SNORD116, but only
two encompassed parts of SNURF-SNRPN, implicating SNORD116 as the major
contributor to the Prader-Willi phenotype. Our case adds further information
about genotype-phenotype correlation and supports the hypothesis that SNORD116
plays a major role in the pathogenesis of Prader-Willi syndrome. Furthermore, it
examplifies diagnostic difficulties in atypical cases and illustrates the need
for additional testing methods when Prader-Willi syndrome is suspected.
© 2013 Wiley Periodicals, Inc.
DOI: 10.1002/ajmg.a.36307
PMID: 24311433 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19257836 | 1. J Med Food. 2009 Apr;12(2):259-70. doi: 10.1089/jmf.2008.0196.
Role of cranberry on bacterial adhesion forces and implications for Escherichia
coli-uroepithelial cell attachment.
Pinzón-Arango PA(1), Liu Y, Camesano TA.
Author information:
(1)Department of Chemical Engineering, Worcester Polytechnic Institute,
Worcester, Massachusetts 01609, USA.
Previous clinical research has suggested that the consumption of cranberry
products prevents the adhesion of Escherichia coli to uroepithelial cells by
causing changes in bacterial fimbriae. Atomic force microscopy was used to probe
the adhesion forces between E. coli (nonfimbriated strain HB101 and the
P-fimbriated variant HB101pDC1) and a model surface (silicon nitride), to
determine the effect of growth in cranberry products on bacterial adhesion.
Bacteria were grown in tryptic soy broth supplemented with either light
cranberry juice cocktail (L-CJC) or cranberry proanthocyanidins (PACs). Growth
of E. coli HB101pDC1 and HB101 in L-CJC or PACs resulted in a decrease in
adhesion forces with increasing number of cultures. In a macroscale
bacteria-uroepithelial cell adhesion assay a decrease in bacterial attachment
was observed for E. coli HB101pDC1 grown in L-CJC or PACs. This effect was
reversible because bacteria that were regrown in cranberry-free medium regained
their ability to attach to uroepithelial cells, and their adhesion forces
reverted to the values observed in the control condition. Exposure to increasing
concentrations of L-CJC resulted in a decrease of bacterial attachment to
uroepithelial cells for the P-fimbriated strain after L-CJC treatment (27% by
weight) and after PACs treatment (345.8 microg/mL). Cranberry products affect
the surface properties, such as fimbriae and lipopolysaccharides, and adhesion
of fimbriated and nonfimbriated E. coli. The concentration of cranberry products
and the number of cultures the bacteria were exposed to cranberry determines how
much the adhesion forces and attachment are altered.
DOI: 10.1089/jmf.2008.0196
PMID: 19257836 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19301936 | 1. Clin Drug Investig. 2009;29(4):215-29. doi: 10.2165/00044011-200929040-00001.
Flushing ASsessment Tool (FAST): psychometric properties of a new measure
assessing flushing symptoms and clinical impact of niacin therapy.
Kawata AK(1), Revicki DA, Thakkar R, Jiang P, Krause S, Davidson MH, Punzi HA,
Padley RJ.
Author information:
(1)United BioSource Corporation, Bethesda, Maryland 20814, USA.
[email protected]
BACKGROUND AND OBJECTIVE: A common adverse effect of niacin therapy is flushing,
manifested by cutaneous warmth, redness, itching and/or tingling. The Flushing
ASsessment Tool (FAST) was developed to assess flushing symptoms and their
impact on patients receiving niacin therapy. This study evaluated the
reliability, validity and responsiveness of the FAST. The minimal important
difference (MID) of the FAST was also examined.
METHODS: This was a prospective, randomized, double-blind, placebo-controlled,
parallel-group 8-week study conducted to evaluate the psychometric
characteristics of the FAST. The instrument is administered daily using an
electronic patient diary. The study was conducted at 41 clinical sites in the
US. 276 patients with dyslipidaemia were randomized to treatment and were at
least 18 years of age, with fasting laboratory values of low-density lipoprotein
cholesterol (LDL-C) <250 mg/dL and one of the following: high-density
lipoprotein cholesterol (HDL-C) <40 mg/dL for males or <50 mg/dL for females; or
triglycerides (TG) > or = 150 and < or = 400 mg/dL; or LDL-C > or = 70 mg/dL for
patients with a history of coronary heart disease (CHD) or CHD risk equivalents,
or > or = 100 mg/dL for subjects with two risk factors, or > or = 160 mg/dL for
subjects with 0-1 risk factors. Patients were randomized (1 : 1 : 1) to receive
niacin extended-release (NER) 500 mg/day in week 1, 1000 mg/day in week 2 and
2000 mg/day in weeks 3-6/aspirin (acetylsalicylic acid [ASA]), NER/ASA placebo,
or NER placebo/ASA placebo.
RESULTS: FAST test-retest reliability in stable patients during the first 2
weeks was demonstrated for overall flushing severity using patient and physician
overall treatment effect (OTE) ratings (intraclass correlation coefficients of
>0.7 for mean overall and individual flushing severity scores). Over the 6-week
treatment period, FAST scores demonstrated significant correlations with
individual symptoms, impact on daily activities and sleep, and dissatisfaction
related to flushing (p < 0.01). Changes in FAST scores were associated with
treatment satisfaction (p < 0.01) and patient- and physician-rated OTE (p <
0.01). Using patient-rated OTE, the mean maximum flushing severity scores
improved 1.85 points in responders and only 0.18 points in non-responders (p <
0.001); responders were defined by improved patient- or physician-rated OTE.
Among patients with flushing, mean maximum overall flushing scores differed
between patients who subsequently discontinued due to flushing (7.9 points) and
those who did not discontinue (4.7 points; p < 0.001). The probable range in
this study for a detectable change in flushing symptoms (MID) was 0.29-0.38
points for mean flushing severity and 0.66-0.86 points for maximum flushing
severity.
CONCLUSION: The FAST exhibited test-retest reliability, good evidence of
construct validity, and, overall, flushing severity was responsive to change
over time. The FAST is a reliable and valid instrument for assessing the impact
of niacin-induced flushing in patients with dyslipidaemia.
DOI: 10.2165/00044011-200929040-00001
PMID: 19301936 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9797 | 1. Acta Virol. 1976 Jun;20(3):183-8.
Morphological, cytological and biological observations on viruses isolated from
patients with subacute thyroiditis de Quervain.
Stancek D, Ciampor F, Mucha V, Hnilica P, Stancekova M.
New data on viruses isolated from patients with subacute thyroiditis de Quervain
are reported. Characteristic morphological, cytological, some physico-chemical
and biological features of the isolated viruses are described. A possible role
of these viruses in human and animal health disorders is discussed. The isolated
viruses remain unclassified so far.
PMID: 9797 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23821651 | 1. Bioinformatics. 2013 Sep 15;29(18):2292-9. doi: 10.1093/bioinformatics/btt381.
Epub 2013 Jul 2.
TIGAR: transcript isoform abundance estimation method with gapped alignment of
RNA-Seq data by variational Bayesian inference.
Nariai N(1), Hirose O, Kojima K, Nagasaki M.
Author information:
(1)Department of Integrative Genomics, Tohoku Medical Megabank Organization,
Tohoku University, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
[email protected]
MOTIVATION: Many human genes express multiple transcript isoforms through
alternative splicing, which greatly increases diversity of protein function.
Although RNA sequencing (RNA-Seq) technologies have been widely used in
measuring amounts of transcribed mRNA, accurate estimation of transcript isoform
abundances from RNA-Seq data is challenging because reads often map to more than
one transcript isoforms or paralogs whose sequences are similar to each other.
RESULTS: We propose a statistical method to estimate transcript isoform
abundances from RNA-Seq data. Our method can handle gapped alignments of reads
against reference sequences so that it allows insertion or deletion errors
within reads. The proposed method optimizes the number of transcript isoforms by
variational Bayesian inference through an iterative procedure, and its
convergence is guaranteed under a stopping criterion. On simulated datasets, our
method outperformed the comparable quantification methods in inferring
transcript isoform abundances, and at the same time its rate of convergence was
faster than that of the expectation maximization algorithm. We also applied our
method to RNA-Seq data of human cell line samples, and showed that our
prediction result was more consistent among technical replicates than those of
other methods.
AVAILABILITY: An implementation of our method is available at
http://github.com/nariai/tigar
CONTACT: [email protected]
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics
online.
DOI: 10.1093/bioinformatics/btt381
PMID: 23821651 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12029088 | 1. J Biol Chem. 2002 Aug 2;277(31):28238-46. doi: 10.1074/jbc.M202783200. Epub
2002 May 23.
Identification of novel SH3 domain ligands for the Src family kinase Hck.
Wiskott-Aldrich syndrome protein (WASP), WASP-interacting protein (WIP), and
ELMO1.
Scott MP(1), Zappacosta F, Kim EY, Annan RS, Miller WT.
Author information:
(1)Department of Physiology and Biophysics, School of Medicine, State University
of New York, Stony Brook, New York 11794-8661, USA.
The importance of the SH3 domain of Hck in kinase regulation, substrate
phosphorylation, and ligand binding has been established. However, few in vivo
ligands are known for the SH3 domain of Hck. In this study, we used mass
spectrometry to identify approximately 25 potential binding partners for the SH3
domain of Hck from the monocyte cell line U937. Two major interacting proteins
were the actin binding proteins Wiskott-Aldrich syndrome protein (WASP) and
WASP-interacting protein (WIP). We also focused on a novel interaction between
Hck and ELMO1, an 84-kDa protein that was recently identified as the mammalian
ortholog of the Caenorhabditis elegans gene, ced-12. In mammalian cells, ELMO1
interacts with Dock180 as a component of the CrkII/Dock180/Rac pathway
responsible for phagocytosis and cell migration. Using purified proteins, we
confirmed that WASP-interacting protein and ELMO1 interact directly with the SH3
domain of Hck. We also show that Hck and ELMO1 interact in intact cells and that
ELMO1 is heavily tyrosine-phosphorylated in cells that co-express Hck,
suggesting that it is a substrate of Hck. The binding of ELMO1 to Hck is
specifically dependent on the interaction of a polyproline motif with the SH3
domain of Hck. Our results suggest that these proteins may be novel
activators/effectors of Hck.
DOI: 10.1074/jbc.M202783200
PMID: 12029088 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24525673 | 1. Plant Physiol. 2014 Apr;164(4):1879-92. doi: 10.1104/pp.113.233031. Epub 2014
Feb 13.
Processing-body movement in Arabidopsis depends on an interaction between
myosins and DECAPPING PROTEIN1.
Steffens A(1), Jaegle B, Tresch A, Hülskamp M, Jakoby M.
Author information:
(1)Botanical Institute, Biocenter, Cologne University, Cologne 50674, Germany.
Processing (P)-bodies are cytoplasmic RNA protein aggregates responsible for the
storage, degradation, and quality control of translationally repressed messenger
RNAs in eukaryotic cells. In mammals, P-body-related RNA and protein exchanges
are actomyosin dependent, whereas P-body movement requires intact microtubules.
In contrast, in plants, P-body motility is actin based. In this study, we show
the direct interaction of the P-body core component DECAPPING PROTEIN1 (DCP1)
with the tails of different unconventional myosins in Arabidopsis (Arabidopsis
thaliana). By performing coexpression studies with AtDCP1, dominant-negative
myosin fragments, as well as functional full-length myosin XI-K, the association
of P-bodies and myosins was analyzed in detail. Finally, the combination of
mutant analyses and characterization of P-body movement patterns showed that
myosin XI-K is essential for fast and directed P-body transport. Together, our
data indicate that P-body movement in plants is governed by myosin XI members
through direct binding to AtDCP1 rather than through an adapter protein, as
known for membrane-coated organelles. Interspecies and intraspecies interaction
approaches with mammalian and yeast protein homologs suggest that this mechanism
is evolutionarily conserved among eukaryotes.
DOI: 10.1104/pp.113.233031
PMCID: PMC3982750
PMID: 24525673 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11712796 | 1. Anticancer Res. 2001 Jul-Aug;21(4B):2973-8.
High dose daily amifostine and hypofractionated intensively accelerated
radiotherapy for locally advanced breast cancer. A phase I/II study and report
on early and late sequellae.
Koukourakis MI(1), Yannakakis D.
Author information:
(1)Department of Radiotherapy and Oncology, Democritus University of Thrace,
Alexandroupolis, Greece. [email protected]
Intrinsic radioresistance, tumor hypoxia and ability of cancer cells to undergo
rapid repopulation during radiotherapy are associated with failure of
radiotherapy. Tumors with low alpha/beta-ratio values or hypoxic tumors unable
to undergo re-oxygenation, are unlikely to be eradicated with standard
radiotherapy. Although the therapeutic efficacy of accelerated regimens based on
low-dose per fraction may be high since they minimize the adverse role of rapid
tumor repopulation, the cellular compartment with low alpha/beta-ratio values
(i.e. hypoxic cells) remains a limiting factor. Accelerated hypofractionation,
which may be more effective in such tumors, cannot be safely applied unless
normal tissues are protected. In the present study we assessed the feasibility
of hypofractionated and accelerated radiotherapy supported by cytoprotection
(HypoARC) with high dose daily amifostine. Fifteen breast cancer patients with
locally advanced disease entered radiation-dose escalation protocoL Twelve
consecutive fractions of 3.5-4Gy (5 fractions/week) were given to the
breast/chest wall, supraclavicular and axillary area, within 17 days. A high
dose of amifostine, at 1,000 mg flat dose, was given 20 minutes before each
radiotherapy fraction. Amifostine administration was well- tolerated with minor
side-effects (vomiting in 6 out of 15 and hypotention in 2 out of 15 patients).
Radiation induced acute skin toxicity was negligible (grade 3 in 1 out of 15
patients). Ten out of 15 patients survived more than 12 months and 7 out of 15
more than 18 months following HypoARC. None of these patients showed any signs
of late sequellae, such as lung and myoskeletal fibrosis, or brachial
plexopathy. Complete and partial responses were obtained in 11 out of 15 (73%)
and in 4 out of 15 (27%) patients, respectively. High dose daily amifostine
during hypofractionated radiotherapy is feasible. HypoARC regimen is
well-tolerated, effective and has minimal acute and late toxicity to normal
breast, chest and axillary tissues.
PMID: 11712796 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25127231 | 1. Lancet Neurol. 2014 Sep;13(9):875-84. doi: 10.1016/S1474-4422(14)70143-7. Epub
2014 Aug 7.
Pallidal neurostimulation in patients with medication-refractory cervical
dystonia: a randomised, sham-controlled trial.
Volkmann J(1), Mueller J(2), Deuschl G(3), Kühn AA(4), Krauss JK(5), Poewe W(2),
Timmermann L(6), Falk D(7), Kupsch A(4), Kivi A(4), Schneider GH(8), Schnitzler
A(6), Südmeyer M(6), Voges J(9), Wolters A(10), Wittstock M(10), Müller JU(11),
Hering S(2), Eisner W(12), Vesper J(13), Prokop T(13), Pinsker M(14), Schrader
C(15), Kloss M(16), Kiening K(17), Boetzel K(18), Mehrkens J(19), Skogseid
IM(20), Ramm-Pettersen J(21), Kemmler G(22), Bhatia KP(23), Vitek JL(24),
Benecke R(10); DBS study group for dystonia.
Author information:
(1)Department of Neurology, Christian Albrechts University, Kiel, Germany.
Electronic address: [email protected].
(2)Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
(3)Department of Neurology, Christian Albrechts University, Kiel, Germany.
(4)Department of Neurology, Charité Universitätsmedizin Berlin, Campus Virchow,
Berlin, Germany.
(5)Department of Neurosurgery, Medical School Hannover, Hannover, Germany.
(6)Department of Neurology and Institute of Clinical Neuroscience and Medical
Psychology, Heinrich Heine University, Düsseldorf, Germany.
(7)Department of Neurosurgery, Christian Albrechts University, Kiel, Germany.
(8)Department of Neurosurgery, Charité Universitätsmedizin Berlin, Campus
Virchow, Berlin, Germany.
(9)Department of Stereotactic and Functional Neurosurgery, University of
Cologne, Cologne, Germany.
(10)Department of Neurology, University of Rostock, Rostock, Germany.
(11)Department of Neurosurgery, Ernst Moritz Arndt University, Greifswald,
Germany.
(12)Department of Neurosurgery, Medical University Innsbruck, Innsbruck,
Austria.
(13)Division of Stereotactic and Functional Neurosurgery, University of
Freiburg, Freiburg, Germany.
(14)Department of Neurosurgery, Christian Albrechts University, Kiel, Germany;
Division of Stereotactic and Functional Neurosurgery, University of Freiburg,
Freiburg, Germany.
(15)Department of Neurology, Medical School Hannover, Hannover, Germany.
(16)Department of Neurology, University of Heidelberg, Heidelberg, Germany.
(17)Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
(18)Department of Neurology, Ludwig Maximilians University, Munich, Germany.
(19)Department of Neurosurgery, Ludwig Maximilians University, Munich, Germany.
(20)Department of Neurology, University of Oslo, Oslo, Norway.
(21)Department of Neurosurgery, University of Oslo, Oslo, Norway.
(22)Section of Biostatistics, Department of Psychiatry, Medical University
Innsbruck, Innsbruck, Austria.
(23)Institute of Neurology, University College London, London, UK.
(24)Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
Comment in
Lancet Neurol. 2014 Sep;13(9):856-7. doi: 10.1016/S1474-4422(14)70178-4.
BACKGROUND: Cervical dystonia is managed mainly by repeated botulinum toxin
injections. We aimed to establish whether pallidal neurostimulation could
improve symptoms in patients not adequately responding to chemodenervation or
oral drug treatment.
METHODS: In this randomised, sham-controlled trial, we recruited patients with
cervical dystonia from centres in Germany, Norway, and Austria. Eligible
patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western
Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were
randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz;
pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham
stimulation (amplitude 0 V) by computer-generated randomisation lists with
randomly permuted block lengths stratified by centre. All patients, masked to
treatment assignment, were implanted with a deep brain stimulation device and
received their assigned treatment for 3 months. Neurostimulation was activated
in the sham group at 3 months and outcomes were reassessed in all patients after
6 months of active treatment. Treating physicians were not masked. The primary
endpoint was the change in the TWSTRS severity score from baseline to 3 months,
assessed by two masked dystonia experts using standardised videos, analysed by
intention to treat. This trial is registered with ClinicalTrials.gov, number
NCT00148889.
FINDINGS: Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of
whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation.
Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%)
patients at 6 months. At 3 months, the reduction in dystonia severity was
significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0
to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean
between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat
population. Over the course of the study, 21 adverse events (five serious) were
reported in 11 (34%) of 32 patients in the neurostimulation group compared with
20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group.
Serious adverse events were typically related to the implant procedure or the
implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four
patients assigned to neurostimulation vs three patients assigned to sham
stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia;
five vs one), and depression (one vs two) were the most common non-serious
adverse events reported during the course of the study.
INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than
sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up
is needed to ascertain the magnitude and stability of chronic neurostimulation
effects before this treatment can be recommended as routine for patients who are
not responding to conventional medical therapy.
FUNDING: Medtronic.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(14)70143-7
PMID: 25127231 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19805216 | 1. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15628-32. doi:
10.1073/pnas.0908039106. Epub 2009 Sep 8.
Assembly of the Cdc45-Mcm2-7-GINS complex in human cells requires the
Ctf4/And-1, RecQL4, and Mcm10 proteins.
Im JS(1), Ki SH, Farina A, Jung DS, Hurwitz J, Lee JK.
Author information:
(1)Department of Biology Education, Seoul National University, Seoul, 151-748,
Korea.
In eukaryotes, the activation of the prereplicative complex and assembly of an
active DNA unwinding complex are critical but poorly understood steps required
for the initiation of DNA replication. In this report, we have used bimolecular
fluorescence complementation assays in HeLa cells to examine the interactions
between Cdc45, Mcm2-7, and the GINS complex (collectively called the CMG
complex), which seem to play a key role in the formation and progression of
replication forks. Interactions between the CMG components were observed only
after the G(1)/S transition of the cell cycle and were abolished by treatment of
cells with either a CDK inhibitor or siRNA against the Cdc7 kinase. Stable
association of CMG required all three components of the CMG complex as well as
RecQL4, Ctf4/And-1, and Mcm10. Surprisingly, depletion of TopBP1, a homologue of
Dpb11 that plays an essential role in the chromatin loading of Cdc45 and GINS in
yeast cells, did not significantly affect CMG complex formation. These results
suggest that the proteins involved in the assembly of initiation complexes in
human cells may differ somewhat from those in yeast systems.
DOI: 10.1073/pnas.0908039106
PMCID: PMC2747170
PMID: 19805216 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/12481988 | 1. Neurogenetics. 2002 Oct;4(2):93-6. doi: 10.1007/s10048-002-0138-4.
A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian
family.
Georgiou DM(1), Zidar J, Korosec M, Middleton LT, Kyriakides T, Christodoulou K.
Author information:
(1)The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and
sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is
currently subdivided into seven types based on genetic localization. These are
CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21),
HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for
autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3).
Mutations in four genes (connexin 32, myelin protein zero, neurofilament-light,
and kinesin) have been associated with the CMT2 phenotype. We identified a novel
neurofilament-light missense mutation (C64T) that causes the disease in a large
Slovenian CMT2 family. This novel mutation shows complete co-segregation with
the dominantly inherited CMT2 phenotype in our family.
DOI: 10.1007/s10048-002-0138-4
PMID: 12481988 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23742015 | 1. Allergy. 2013 Jul;68(7):829-35. doi: 10.1111/all.12169. Epub 2013 Jun 6.
The consequences of not having eosinophils.
Gleich GJ(1), Klion AD, Lee JJ, Weller PF.
Author information:
(1)University of Utah Health Sciences Center, Salt Lake City, UT 84132-2409,
USA. [email protected]
Several lines of evidence suggest that deficiency of eosinophils is not
associated with any characteristic abnormality. Patients lacking eosinophils, in
the setting of immunodeficiency or as a consequence of IgG-mediated eosinophil
precursor destruction, do not display any distinguishing abnormalities related
to eosinophil reduction. The observation that eosinophil-deficient mice do not
display any distinctive syndrome or failure of their health is evidence that,
under ordinary laboratory conditions, the eosinophil does not play a critical
role in the well-being of mammals. Observations that monoclonal antibodies to
interleukin-5 (IL-5) are well tolerated appear unsurprising in light of these
findings. For example, patients with the hypereosinophilic syndrome have
received mepolizumab, an anti-IL-5 monoclonal antibody, for as long as 6 years
and have not developed any characteristic set of adverse events. Safety data for
reslizumab, another anti-IL-5 monoclonal antibody, and benralizumab, a
monoclonal antibody to the IL-5 receptor α-chain, are comparatively limited,
especially for benralizumab, although reports of administration of these
antibodies to humans suggest that they are well tolerated. Thus, data to the
present suggest that reduction of eosinophils appears to have no characteristic
ill effects on normal health, and monoclonal antibodies that deplete eosinophils
have the potential to be widely employed in the treatment of
eosinophil-associated diseases.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
DOI: 10.1111/all.12169
PMCID: PMC3915877
PMID: 23742015 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest: GJG is a consultant to
GlaxoSmithKline and receives honoraria, is a board member of the American
Partnership for Eosinophilic Diseases (APFED), holds equity in Immune Design
Corporation, is a founder of ImmViz, and can receive royalties from
Teva/Cephalon; K.M. Leiferman, GJG’s wife, is a consultant to Beiersdorf AG and
receives honoraria. ADK has no conflicts. JJL has no conflicts. PFW is
consultant to GlaxoSmithKline and receives honoraria. |
http://www.ncbi.nlm.nih.gov/pubmed/12655635 | 1. Int J Eat Disord. 2003 Apr;33(3):364-6. doi: 10.1002/eat.10146.
Echocardiographic investigation of pericardial effusion in a case of anorexia
nervosa.
Inagaki T(1), Yamamoto M, Tsubouchi K, Miyaoka T, Uegaki J, Maeda T, Horiguchi
J, Yamane Y, Kato Y.
Author information:
(1)Department of Psychiatry, Shimane Medical University, 89-1 Enya, Izumo,
Shimane 693-8501, Japan. [email protected]
Pericardial effusion has recently been reported as a complication of anorexia
nervosa. A distinct pathophysiological cause of it could not be revealed. In
some reports, there was a probable correlation between weight gain and reduction
of pericardial effusion in anorexia nervosa cases. We encountered a case in
which pericardial effusion remitted completely along with body weight increase
and normalization of low T3 syndrome. These findings suggest that the reduction
of pericardial effusion may correlate with both weight gain and low T3
normalization. Plasma brain natriuretic peptide (BNP) levels were increased in
this case despite heart failure, and plasma BNP decreased as pericardial
effusion remitted. The measurement of serum BNP level may be a clinical
parameter in such a case of pericardial effusion.
Copyright 2003 by Wiley Periodicals, Inc.
DOI: 10.1002/eat.10146
PMID: 12655635 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24764190 | 1. Dis Model Mech. 2014 Jun;7(6):723-30. doi: 10.1242/dmm.016162. Epub 2014 Apr
24.
Contribution of neural cell death to depressive phenotypes of
streptozotocin-induced diabetic mice.
Chen C(1), Wang Y(2), Zhang J(1), Ma L(3), Gu J(4), Ho G(5).
Author information:
(1)Department of Pediatrics, The Second Affiliated Hospital of Shantou
University Medical College, Shantou 515041, China.
(2)Department of Molecular Pathology, Shantou University Medical College,
Shantou 515041, China.
(3)Department of Pediatrics, The Second Affiliated Hospital of Shantou
University Medical College, Shantou 515041, China. Laboratory of Translational
Medicine, The Second Affiliated Hospital of Shantou University Medical College,
Shantou 515041, China.
(4)Department of Molecular Pathology, Shantou University Medical College,
Shantou 515041, China. Laboratory of Translational Medicine, The Second
Affiliated Hospital of Shantou University Medical College, Shantou 515041,
China.
(5)Department of Pediatrics, The Second Affiliated Hospital of Shantou
University Medical College, Shantou 515041, China. Laboratory of Translational
Medicine, The Second Affiliated Hospital of Shantou University Medical College,
Shantou 515041, China. [email protected].
Major depression disorder (MDD) or depression is highly prevalent in individuals
with diabetes, and the depressive symptoms are more severe and less responsive
to antidepressant therapies in these patients. The underlying mechanism is
little understood. We hypothesized that the pathophysiology of comorbid
depression was more complex than that proposed for MDD and that neural cell
death played a role in the disease severity. To test this hypothesis, we
generated streptozotocin (STZ)-induced diabetic mice. These mice had blood
glucose levels threefold above controls and exhibited depressive phenotypes as
judged by a battery of behavioral tests, thus confirming the comorbidity in
mice. Immunohistological studies showed markedly increased TUNEL-positive cells
in the frontal cortex and hippocampus of the comorbid mice, indicating
apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2
proteins in these brain regions. In addition, the serum brain-derived
neurotrophic factor (BDNF) level of comorbid mice was reduced compared with
controls, further supporting the neurodegenerative change. Mechanistic analyses
showed an increased expression of mitochondrial fission genes fission protein 1
(Fis1) and dynamin-related protein 1 (Drp1), and a decreased expression of
mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optical
atrophy 1 (Opa1). Representative assessment of the proteins Drp1 and Mfn2
mirrored the mRNA changes. The data demonstrated that neural cell death was
associated with the depressive phenotype of comorbid mice and that a
fission-dominant expression of genes and proteins mediating mitochondrial
dynamics played a role in the hyperglycemia-induced cell death. The study
provides new insight into the disease mechanism and could aid the development of
novel therapeutics aimed at providing neuroprotection by modulating
mitochondrial dynamics to treat comorbid depression with diabetes.
© 2014. Published by The Company of Biologists Ltd.
DOI: 10.1242/dmm.016162
PMCID: PMC4036479
PMID: 24764190 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16457589 | 1. J Proteome Res. 2006 Feb;5(2):248-53. doi: 10.1021/pr050269n.
Precise characterization of human histones in the H2A gene family by top down
mass spectrometry.
Boyne MT 2nd(1), Pesavento JJ, Mizzen CA, Kelleher NL.
Author information:
(1)Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana,
Illinois 61801, USA.
Top Down analysis revealed that at least fourteen genes encoding histone H2A are
coexpressed in HeLa cells. Characterization of these species revealed that all
except H2A.Z and H2A.F/Z were alpha-N-acetylated, H2A.O and H2A.C,D,I,N,P were
the most abundant, and those exceeding approximately 10% abundance lacked
post-translational modifications. This unequivocal identification of H2A forms
illustrates the advantages of Top Down Mass Spectrometry and provides a global
perspective of H2A regulation through the cell cycle.
DOI: 10.1021/pr050269n
PMID: 16457589 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20588305 | 1. Eur J Hum Genet. 2010 Nov;18(11):1196-201. doi: 10.1038/ejhg.2010.102. Epub
2010 Jun 30.
Paternally inherited microdeletion at 15q11.2 confirms a significant role for
the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome.
Duker AL(1), Ballif BC, Bawle EV, Person RE, Mahadevan S, Alliman S, Thompson R,
Traylor R, Bejjani BA, Shaffer LG, Rosenfeld JA, Lamb AN, Sahoo T.
Author information:
(1)Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan,
Detroit, MI, USA.
Prader-Willi syndrome (PWS) is a neurobehavioral disorder manifested by
infantile hypotonia and feeding difficulties in infancy, followed by morbid
obesity secondary to hyperphagia. It is caused by deficiency of paternally
expressed transcript(s) within the human chromosome region 15q11.2. PWS patients
harboring balanced chromosomal translocations with breakpoints within small
nuclear ribonucleoprotein polypeptide N (SNRPN) have provided indirect evidence
for a role for the imprinted C/D box containing small nucleolar RNA (snoRNA)
genes encoded downstream of SNRPN. In addition, recently published data provide
strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85)
in PWS etiology. In this study, we performed detailed phenotypic, cytogenetic,
and molecular analyses including chromosome analysis, array comparative genomic
hybridization (array CGH), expression studies, and single-nucleotide
polymorphism (SNP) genotyping for parent-of-origin determination of the 15q11.2
microdeletion on an 11-year-old child expressing the major components of the PWS
phenotype. This child had an ∼236.29 kb microdeletion at 15q11.2 within the
larger Prader-Willi/Angelman syndrome critical region that included the SNORD116
cluster of snoRNAs. Analysis of SNP genotypes in proband and mother provided
evidence in support of the deletion being on the paternal chromosome 15. This
child also met most of the major PWS diagnostic criteria including infantile
hypotonia, early-onset morbid obesity, and hypogonadism. Identification and
characterization of this case provide unequivocal evidence for a critical role
for the SNORD116 snoRNA molecules in PWS pathogenesis. Array CGH testing for
genomic copy-number changes in cases with complex phenotypes is proving to be
invaluable in detecting novel alterations and enabling better genotype-phenotype
correlations.
DOI: 10.1038/ejhg.2010.102
PMCID: PMC2987474
PMID: 20588305 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17475706 | 1. Br J Ophthalmol. 2007 Sep;91(9):1183-9. doi: 10.1136/bjo.2007.114769. Epub
2007 May 2.
Matrix metalloproteinases in human choroidal neovascular membranes excised
following verteporfin photodynamic therapy.
Tatar O(1), Adam A, Shinoda K, Eckert T, Scharioth GB, Klein M, Yoeruek E,
Bartz-Schmidt KU, Grisanti S.
Author information:
(1)University Eye Hospital, Centre for Ophthalmology, Eberhard-Karls University,
Tuebingen, Germany.
AIM: To evaluate expression of proangiogenic matrix metalloproteinases (MMP) 2
and 9 at distinct intervals after verteporfin photodynamic therapy (PDT) in
human choroidal neovascular membranes (CNV) secondary to age-related macular
degeneration (AMD).
METHODS: Retrospective review of an interventional case series of 49 patients
who underwent removal of CNV. Twenty-six patients were treated with PDT 3 to 383
days prior to surgery. Twenty-three CNV without previous treatment were used as
controls. CNV were stained for CD34, cytokeratin 18, endostatin, MMP-2 and MMP-9
by immunohistochemistry.
RESULTS: CNV without previous therapy disclosed MMP-2, MMP-9 in RPE-Bruch's
membrane, vessels and stroma in different intensities. Three days after PDT,
MMP-9 expression was significantly weaker in stroma (p = 0.0019). Endostatin was
significantly reduced in vessels (p<0.001). At longer post-PDT intervals, a
significant increase of MMP-9 in stroma (p = 0.037) and of endostatin in
RPE-Bruch's membrane (p = 0.02), vessels (p = 0.005) and stroma (p<0.001) were
disclosed. No significant changes in MMP-2 expression were detected.
CONCLUSIONS: PDT induced an early, temporary decrease in MMP-9 and endostatin
expression. At longer intervals, MMP-9 increase is possibly associated with the
angiogenic process responsible for recurrence after PDT. MMP-9, however, acts as
a double-edged sword by concomitant induction of endostatin, an endogenous
inhibitor of angiogenesis.
DOI: 10.1136/bjo.2007.114769
PMCID: PMC1954910
PMID: 17475706 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None. |
http://www.ncbi.nlm.nih.gov/pubmed/15610702 | 1. Curr Treat Options Neurol. 2005 Jan;7(1):3-14. doi: 10.1007/s11940-005-0001-7.
Autoimmune Myasthenia Gravis: Recommendations for Treatment and Immunologic
Modulation.
Juel VC(1), Massey JM.
Author information:
(1)Duke University Medical Center, DUMC 3403, Durham, NC 27710, USA.
[email protected].
Treatment for myasthenia gravis should be individualized to each patient based
on the clinical characteristics of myasthenia including the distribution,
duration, and severity of weakness and resulting functional impairment; the
risks for treatment complications related to age, gender, and medical
comorbidities; and the presence of thymoma. Acetylcholinesterase inhibitors
provide temporary, symptomatic treatment for all forms of myasthenia gravis.
Immune modulators address the underlying autoimmune process in myasthenia
gravis, but are associated with potential complications and side effects. Most
patients with generalized myasthenia who have significant weakness beyond the
ocular muscles and who remain symptomatic, despite treatment with cholinesterase
inhibitors, are candidates for immune modulation. Although corticosteroids are
effective for long-term immune modulation in myasthenia gravis, several more
contemporary immunomodulators including azathioprine, cyclosporine, and
mycophenolate mofetil have shown efficacy in myasthenia gravis and are used
increasingly as first-line treatments and as steroid-sparing agents. Plasma
exchange is used to achieve rapid improvement in patients with myasthenic crisis
or exacerbation, to improve strength before a surgical procedure or thymectomy,
and to minimize steroid-induced exacerbation in patients with oropharyngeal or
respiratory muscle weakness. Intravenous immunoglobulin represents an
alternative to plasma exchange in patients requiring relatively rapid short-term
improvement in the setting of poor venous access. Because of a lack of
controlled trials, the role of thymectomy in nonthymomatous myasthenia gravis is
unclear, although evidence suggests that thymectomy increases the probability
for myasthenic remission or improvement.
DOI: 10.1007/s11940-005-0001-7
PMID: 15610702 |
http://www.ncbi.nlm.nih.gov/pubmed/6727432 | 1. Mayo Clin Proc. 1984 Jun;59(6):415-22. doi: 10.1016/s0025-6196(12)61466-9.
Clinical and therapeutic aspects of Haemophilus influenzae pericarditis in
pediatric patients.
Fyfe DA, Hagler DJ, Puga FJ, Driscoll DJ.
Two cases of Haemophilus influenzae type B pericarditis are presented which
demonstrate the major clinical features and sequelae of this serious illness.
These cases are analyzed together with 77 others from the literature to
characterize the clinical features, natural history, and optimal therapy. H.
influenzae pericarditis is an increasingly frequent disease of young children. A
mild prodromal illness is often followed by rapid progression of cardiac
compromise until death ensues, unless pericarditis is diagnosed and treated
appropriately. The development of cardiomegaly in a febrile patient with a
Haemophilus infection is an indication for echocardiography, which is diagnostic
of the pericardial effusion. Initial cultures of pericardial aspirates will be
positive in 75% of cases even when antibiotic therapy has been initiated. Use of
appropriate parenterally administered antibiotics, in combination with early
surgical pericardial drainage or partial pericardiectomy, should minimize
morbidity and mortality and prevent acute constrictive sequelae.
DOI: 10.1016/s0025-6196(12)61466-9
PMID: 6727432 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17889539 | 1. Breast. 2008 Feb;17(1):80-4. doi: 10.1016/j.breast.2007.07.041. Epub 2007 Sep
21.
Evaluation of FISH image analysis system on assessing HER2 amplification in
breast carcinoma cases.
Theodosiou Z(1), Kasampalidis IN, Karayannopoulou G, Kostopoulos I, Bobos M,
Bevilacqua G, Aretini P, Starita A, Lyroudia K, Pitas I.
Author information:
(1)Department of Informatics, Aristotle University of Thessaloniki, Box 451,
54124 Thessaloniki, Greece.
HER2-positive breast cancer is characterized by aggressive growth and poor
prognosis. Women with metastatic breast cancer with over-expression of HER2
protein or excessive presence of HER2 gene copies are potential candidates for
Herceptin (Trastuzumab) targeted treatment that binds to HER2 receptors on tumor
cells and inhibits tumor cell growth. Fluorescence in situ hybridization (FISH)
is one of the most widely used methods to determine HER2 status. Typically,
evaluation of FISH images involves manual counting of FISH signals in multiple
images, a time consuming and error prone procedure. Recently, we developed novel
software for the automated evaluation of FISH images and, in this study, we
present the first testing of this software on images from two separate research
clinics. To our knowledge, this is the first concurrent evaluation of any FISH
image analysis software in two different clinics. The evaluation shows that the
developed FISH image analysis software can accelerate evaluation of HER2 status
in most breast cancer cases.
DOI: 10.1016/j.breast.2007.07.041
PMID: 17889539 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23558379 | 1. BioDrugs. 2013 Jun;27(3):181-9. doi: 10.1007/s40259-013-0028-3.
The outlook for alemtuzumab in multiple sclerosis.
Williams T(1), Coles A, Azzopardi L.
Author information:
(1)Department of Clinical Neurosciences, Addenbrooke's Hospital, University of
Cambridge, Box 165, Cambridge, CB2 0QQ, UK.
Alemtuzumab is a humanized anti-CD52 monoclonal antibody. Treatment in humans
results in a rapid, profound, and prolonged B- and T-cell lymphopenia.
Subsequently, lymphocyte reconstitution by homeostatic mechanisms alters the
composition, phenotype, and function of T-cell subsets, thus allowing the immune
system to be 'reset'. One phase II and two phase III randomized, multicenter,
single-blinded (outcomes assessor) clinical trials of alemtuzumab in
relapsing-remitting multiple sclerosis have now been completed. Against an
active comparator and the current first-line therapy for relapsing-remitting
multiple sclerosis (interferon-beta), alemtuzumab showed a significant reduction
in annualized relapse rate as well as a significant reduction in the
accumulation of disability. These outcomes are sustained over at least 5 years
following treatment. The most common adverse effects are mild infusion
reactions, an increased incidence of mild-to-moderate severity infections and
secondary autoimmunity. The latter is observed in a third of treated patients,
commonly thyroid disease but other target cells have been described including
cytopenias. Marketing authorization applications have been submitted for the use
of alemtuzumab in multiple sclerosis to the Food and Drug Administration and the
European Medicines Agency, with licensing expected in 2013. Here, we discuss the
outlook for alemtuzumab in multiple sclerosis in light of the currently
available therapies, outcomes of and lessons learnt from clinical trials, and
the overall position of monoclonal antibodies in modern treatment strategies.
DOI: 10.1007/s40259-013-0028-3
PMID: 23558379 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25128455 | 1. Eur J Cancer. 2014 Oct;50(15):2725-34. doi: 10.1016/j.ejca.2014.07.004. Epub
2014 Aug 12.
Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity
in HER2 overexpressing breast cancer.
García-Parra J(1), Dalmases A(1), Morancho B(2), Arpí O(1), Menendez S(1),
Sabbaghi M(1), Zazo S(3), Chamizo C(3), Madoz J(3), Eroles P(4), Servitja S(1),
Tusquets I(5), Yelamos J(6), Lluch A(7), Arribas J(8), Rojo F(9), Rovira A(1),
Albanell J(10).
Author information:
(1)Cancer Research Program, IMIM (Hospital del Mar Research Institute),
Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona,
Spain.
(2)Preclinical Research Program, Valld'Hebron Institute of Oncology (VHIO),
Barcelona, Spain.
(3)Pathology Department, IIS-Fundación Jiménez Díaz, Madrid, Spain.
(4)Institute of Health Research INCLIVA, Valencia, Spain.
(5)Cancer Research Program, IMIM (Hospital del Mar Research Institute),
Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona,
Spain; Autonomous University of Barcelona, Spain.
(6)Cancer Research Program, IMIM (Hospital del Mar Research Institute),
Barcelona, Spain; Immunology Department, Hospital del Mar, Barcelona, Spain.
(7)Oncology and Hematology Department, Hospital Clinico Universitario, Valencia,
Spain; Valencia Central University, Spain.
(8)Preclinical Research Program, Valld'Hebron Institute of Oncology (VHIO),
Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat
Autonoma de Barcelona, Bellaterra, Spain; Institució Catalana de Recerca I
Estudis Avançats (ICREA), Barcelona, Spain.
(9)Cancer Research Program, IMIM (Hospital del Mar Research Institute),
Barcelona, Spain; Pathology Department, IIS-Fundación Jiménez Díaz, Madrid,
Spain; Pathology Department, Hospital del Mar, Barcelona, Spain.
(10)Cancer Research Program, IMIM (Hospital del Mar Research Institute),
Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Barcelona,
Spain; Universitat Pompeu Fabra, Barcelona, Spain. Electronic address:
[email protected].
AIM: Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results
in Breast Cancer (BRCA) deficient breast cancer, but not in molecularly
unselected patient populations. Two lines of research in this field are needed:
the identification of novel subsets of patients that could potentially benefit
from PARP inhibitors and the discovery of suitable targeted therapies for
combination strategies.
METHODS: We tested PARP inhibition, alone or combined with the anti-HER2
antibody trastuzumab on HER2+ breast cancer. We used two PARP inhibitors in
clinical development, olaparib and rucaparib, as well as genetic downmodulation
of PARP-1 for in vitro studies. DNA damage was studied by the formation of γH2AX
foci and comet assay. Finally, the in vivo anti-tumour effect of olaparib and
trastuzumab was examined in nude mice subcutaneously implanted with BT474 cells.
RESULTS: In a panel of four HER2 overexpressing breast cancer cell lines, both
olaparib and rucaparib significantly decreased cell growth and enhanced
anti-tumour effects of trastuzumab. Cells exposed to olaparib and trastuzumab
had greater DNA damage than cells exposed to each agent alone. Mechanistic
exploratory assays showed that trastuzumab downmodulated the homologous
recombination protein proliferating cell nuclear antigen (PCNA). Combination
treatment in the BT474 xenograft model resulted in enhanced growth inhibition,
reduced tumour cell proliferation, and increased DNA damage and apoptosis.
CONCLUSION: Taken together, our results show that PARP inhibition has antitumour
effects and increases trastuzumab activity in HER2 overexpressing breast cancer.
These findings make this novel combination a promising strategy for clinical
development.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ejca.2014.07.004
PMID: 25128455 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23347730 | 1. Breast. 2013 Oct;22(5):682-90. doi: 10.1016/j.breast.2012.12.002. Epub 2013
Jan 21.
Additional prognostic value of the 70-gene signature (MammaPrint(®)) among
breast cancer patients with 4-9 positive lymph nodes.
Saghatchian M(1), Mook S, Pruneri G, Viale G, Glas AM, Guerin S, Cardoso F,
Piccart M, Tursz T, Delaloge S, van't Veer L.
Author information:
(1)Institut Gustave Roussy, Villejuif, France; Netherlands Cancer Institute,
Amsterdam, The Netherlands. Electronic address: [email protected].
BACKGROUND: The 70 gene-signature (MammaPrint(®)) is a prognostic profile of
distant recurrence and survival of primary breast cancer (BC). BC patients with
4-9 positive nodes (LN 4-9) are considered clinically at high-risk. Herein we
examined MammaPrint(®) added prognostic value in this group.
PATIENTS AND METHODS: MammaPrint(®) profiles were generated from frozen tumours
of patients operated from primary BC. Samples were classified as genomic Low
Risk (GLR) or genomic High Risk (GHR).
RESULTS: Among the 173 samples, 70 (40%) were classified as GLR and 103 (60%) as
GHR. Tumours in the GHR group were significantly more often ductal carcinomas
(93%), grade 3 (60%), oestrogen and progesterone-negative, Her2 positive (25%).
In the GLR category, the 5-year overall survival was 97% vs. 76% for in the GHR
group (p < 0.01); Distant Metastasis Free Survival (DMFS) at 5 years was 87% for
GLR patients and 63% for GHR patients (p < 0.01). In the Luminal A subgroup, the
genomic profile was the only independent risk factor for DM and BC specific
death.
CONCLUSION: In the Luminal A subgroup, MammaPrint(®) is an independent
prognostic marker in BC patients with LN 4-9 and may be integrated in a
selection strategy of patients candidate for more aggressive therapeutic
approaches.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.breast.2012.12.002
PMID: 23347730 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12524013 | 1. Semin Cell Dev Biol. 2003 Feb;14(1):101-10. doi:
10.1016/s1084-9521(02)00142-8.
Imprinting and disease.
Walter J(1), Paulsen M.
Author information:
(1)FR 8.2 Genetik, Universität des Saarlandes, Postfach 151150, 66041
Saarbrücken, Germany. [email protected]
Deregulation of imprinted genes has been observed in a number of human diseases
such as Beckwith-Wiedemann syndrome, Prader-Willi/Angelman syndromes and cancer.
Imprinting diseases are characterised by complex patterns of mutations and
associated phenotypes affecting pre- and postnatal growth and neurological
functions. Regulation of imprinted gene expression is mediated by
allele-specific epigenetic modifications of DNA and chromatin. These
modifications preferentially affect central regulatory elements that control in
cis over long distances allele-specific expression of several neighbouring
genes. Investigations of imprinting diseases have a strong impact on biomedical
research and provide interesting models for function and mechanisms of
epigenetic gene control.
DOI: 10.1016/s1084-9521(02)00142-8
PMID: 12524013 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11502465 | 1. Urology. 2001 Aug;58(2 Suppl 1):114-22. doi: 10.1016/s0090-4295(01)01253-5.
Growth factors and their receptors: new targets for prostate cancer therapy.
Barton J(1), Blackledge G, Wakeling A.
Author information:
(1)AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, United
Kingdom.
Stimulation of the signal transduction pathway of the epidermal growth-factor
receptor (EGFR) tyrosine kinase family of receptors in tumor cells enhances
cellular proliferation, prevents apoptosis, and promotes tumor-cell mobility,
adhesion, and invasion. Therapeutic approaches used to target the EGFR and its
signal transduction cascade include (1) monoclonal antibodies (eg, cetuximab
[IMC-C225]) directed against the extracellular binding domain of the receptor;
and (2) trastuzumab, a monoclonal antibody binding to the HER2 receptor;
immunotoxin conjugates use an antibody directed against EGFR joined to a cell
toxin. All are in clinical trials for a number of cancers, including prostate
cancer. Antisense strategies are in preclinical development.
Low-molecular-weight inhibitors of the EGFR tyrosine kinase also in clinical
development include OSI-774, PD182905, PKI-166, CI-1033, and ZD1839. ZD1839 has
shown encouraging results in patients with prostate cancer in phase 1 trials. mn
DOI: 10.1016/s0090-4295(01)01253-5
PMID: 11502465 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21572407 | 1. Nat Methods. 2011 May 15;8(7):559-64. doi: 10.1038/nmeth.1608.
A quantitative analysis of CLIP methods for identifying binding sites of
RNA-binding proteins.
Kishore S(1), Jaskiewicz L, Burger L, Hausser J, Khorshid M, Zavolan M.
Author information:
(1)Biozentrum, University of Basel and Swiss Institute of Bioinformatics, Basel,
Switzerland.
Cross-linking and immunoprecipitation (CLIP) is increasingly used to map
transcriptome-wide binding sites of RNA-binding proteins. We developed a method
for CLIP data analysis, and applied it to compare CLIP with photoactivatable
ribonucleoside-enhanced CLIP (PAR-CLIP) and to uncover how differences in
cross-linking and ribonuclease digestion affect the identified sites. We found
only small differences in accuracies of these methods in identifying binding
sites of HuR, which binds low-complexity sequences, and Argonaute 2, which has a
complex binding specificity. We found that cross-link-induced mutations led to
single-nucleotide resolution for both PAR-CLIP and CLIP. Our results confirm the
expectation from original CLIP publications that RNA-binding proteins do not
protect their binding sites sufficiently under the denaturing conditions used
during the CLIP procedure, and we show that extensive digestion with
sequence-specific RNases strongly biases the recovered binding sites. This bias
can be substantially reduced by milder nuclease digestion conditions.
DOI: 10.1038/nmeth.1608
PMID: 21572407 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18392595 | 1. Methods Mol Biol. 2008;384:783-801. doi: 10.1007/978-1-59745-376-9_33.
Multi-dimensional capillary electrophoresis and chromatography for proteomic
analysis.
Gao M(1), Zhang X.
Author information:
(1)Department of Chemistry & Research Center for Proteome, Fudan University,
Shanghai, China.
Comprehensive two-dimensional liquid chromatography-capillary electrophoresis
systems are summarized in this chapter. A variety of combinations of capillary
electrophoresis and liquid chromatography modes as well as interfaces and
detection technologies are discussed. A typical, comprehensive two-dimensional
system coupled with reverse-phase liquid chromatography with fast capillary
electrophoresis and hyphenated to mass spectrometry was demonstrated for
proteomic analysis. A two-dimensional capillary electrophoresis system of
coupling capillary sieving electrophoresis with micellar electrokinetic
chromatography and its application in single cell analysis for protein
expression profiling are presented.
DOI: 10.1007/978-1-59745-376-9_33
PMID: 18392595 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23099994 | 1. J Cancer Res Clin Oncol. 2013 Mar;139(3):367-78. doi:
10.1007/s00432-012-1340-x. Epub 2012 Oct 26.
A novel predictive strategy by immunohistochemical analysis of four EGFR ligands
in metastatic colorectal cancer treated with anti-EGFR antibodies.
Yoshida M(1), Shimura T, Sato M, Ebi M, Nakazawa T, Takeyama H, Joh T.
Author information:
(1)Department of Gastroenterology and Metabolism, Nagoya City University
Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya
467-8601, Japan.
PURPOSE: Although KRAS mutation has been identified as a negative predictive
biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the
efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR
antibodies work by blocking ligand binding, but the significance of EGFR ligands
in mCRC has not been completely described. This study was conducted to identify
the correlation between all seven EGFR ligands and clinical outcomes in mCRC
treated with anti-EGFR antibodies. Furthermore, we determined an appropriate
predictive strategy for anti-EGFR antibodies using these EGFR ligands.
METHODS: Among 36 mCRC patients who had been treated with cetuximab or
panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated
properly as the second and further lines and analyzed the relationship between
immunoreactivity to seven EGFR ligands and clinical outcomes.
RESULTS: Good clinical outcomes were associated with immunoreactivity against
amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF),
transforming growth factor-α (TGF-α), and epiregulin (EREG). Further, patients
with immunoreactivity to greater than two of these four ligands (AR, HB-EGF,
TGF-α, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p =
0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer
progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when
compared with patients with immunoreactivity against zero or one ligand.
CONCLUSIONS: Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF,
TGF-α, and EREG) might be a novel predictive biomarker and may help optimize
patient selection for cetuximab and panitumumab therapy in patients with mCRC.
DOI: 10.1007/s00432-012-1340-x
PMID: 23099994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23836442 | 1. Int J Mol Med. 2013 Sep;32(3):647-52. doi: 10.3892/ijmm.2013.1433. Epub 2013
Jul 5.
Polymorphisms and expression of the WNT8A gene in Hirschsprung's disease.
Gao H(1), Chen D, Liu X, Wu M, Mi J, Wang W.
Author information:
(1)Laboratory of Pediatric Congenital Malformation, Ministry of Public Health,
Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004,
P.R. China.
Hirschsprung's disease (HSCR) is a congenital disorder characterized by an
absence of intrinsic ganglion cells in the nerves forming the plexus of the
lower intestine. The WNT signaling pathway is considered to play an important
role in embryonic development. In the present study, we analyzed 2 polymorphisms
of the WNT8A gene (rs78301778 and rs6596422) to determine their association with
the risk and development of HSCR. Allele frequencies and genotype distributions
were analyzed by sequence analysis in patients with HSCR and normal controls.
Using real-time PCR, western blot analysis and immunohistochemistry, we detected
the mRNA and protein expression of WNT8A in patients with HSCR. The data
indicated that the differences in genotype distributions and allele frequencies
of rs78301778 and rs6596422 between various clinical classifications were
statistically significant. The analysis of the mRNA and protein expression of
WNT8A revealed that the expression of WNT8A was increased in the stenotic colon
segments compared with the normal colon segments. In conclusion, the data
presented in this study suggest that the WNT8A gene is involved in the
susceptibility to HSCR, and plays an important role in the occurrence and
development of HSCR. These findings warrant further investigation.
DOI: 10.3892/ijmm.2013.1433
PMID: 23836442 [Indexed for MEDLINE] |