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http://www.ncbi.nlm.nih.gov/pubmed/22480286
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1. Cardiovasc Hematol Agents Med Chem. 2012 Jun;10(2):116-23. doi:
10.2174/187152512800388911.
Dabigatran: a new chapter in anticoagulation.
Ahmed S(1), Levin V, Malacoff R, Martinez MW.
Author information:
(1)Division of Cardiology, Lehigh Valley Health Network, Allentown, PA 18103,
USA.
For the last 60 years warfarin has been the cornerstone for chronic
anticoagulation in prevention of ischemic strokes and systemic embolization.
Warfarin therapy has several limitations including frequent monitoring and
various food and significant drug interactions, which make it a less than ideal
chronic oral anticoagulant. The continued search for safe, effective,
medications with predictable pharmacokinetic profiles has led to newer
alternatives. Dabigatran is a potent reversible, competitive direct thrombin
inhibitor which is available as the prodrug, Dabigatran etexilate. It was first
approved in Europe and recently in October 2010, the US food and drug
administration (FDA) has approved the use of this novel oral anticoagulation for
prevention of stroke in those with non valvular atrial fibrillation. This review
will cover the chemical structure, mechanism of action, pharmacokinetic profile,
clinical trials, dosage, clinical implication and adverse effects of dabigatran.
DOI: 10.2174/187152512800388911
PMID: 22480286 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23328389
|
1. J Cardiovasc Pharmacol. 2013 Jun;61(6):474-81. doi:
10.1097/FJC.0b013e31828685da.
Pharmacokinetics of oral treprostinil sustained release tablets during chronic
administration to patients with pulmonary arterial hypertension.
White RJ(1), Torres F, Allen R, Jerjes C, Pulido T, Yehle D, Howell M, Laliberte
K, Marier JF, Tapson VF.
Author information:
(1)Division of Pulmonary & Critical Care Medicine, University of Rochester,
Rochester, NY 14623, USA. jim_white@urmc.rochester.edu
Comment in
J Cardiovasc Pharmacol. 2013 Jun;61(6):471-3. doi:
10.1097/FJC.0b013e318294980e.
Pulmonary arterial hypertension (PAH) is a progressive vascular disease that
ultimately leads to right ventricular failure and death. Treprostinil diolamine
is an oral prostacyclin analogue; sustained release tablets of oral treprostinil
are currently being evaluated for efficacy and safety as a potential therapy in
patients with PAH. Previous attempts at developing an oral prostanoid have been
limited by rapid absorption and short plasma half-life; thus, the aim of this
study was to characterize the pharmacokinetic profile of treprostinil diolamine
in PAH patients after chronic dosing. The study enrolled 74 PAH patients who had
been taking treprostinil diolamine for a minimum of 4 weeks (range: 0.5-16 mg).
We collected plasma samples over 12 hours and estimated pharmacokinetic
parameters using noncompartmental methods. Seventy patients had complete data.
After chronic twice-daily oral dosing of treprostinil diolamine, mean area under
the curve (AUC0-12) of treprostinil increased from 5244 to 20,4086 pg·hr-·mL-
and mean maximum observed plasma concentration (Cmax) increased from 1383 to
33588 pg/mL. The apparent clearance (CL/F) was similar across all doses,
indicating a linear dose-exposure relationship after twice-daily dosing. We
conclude that twice-daily oral treprostinil provides sustained and proportional
treprostinil concentrations over a wide range of doses during chronic
administration to PAH patients.
DOI: 10.1097/FJC.0b013e31828685da
PMID: 23328389 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15831522
|
1. Mol Endocrinol. 2005 Jun;19(6):1618-28. doi: 10.1210/me.2004-0503. Epub 2005
Apr 14.
Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone
receptor alpha1-specific manner that requires TAK1 and p38 mitogen-activated
protein kinase.
Kinugawa K(1), Jeong MY, Bristow MR, Long CS.
Author information:
(1)Denver Health Medical Center, Colorado 80204, USA.
Alterations in TR [thyroid hormone (TH) receptor]1 isoform expression have been
reported in models of both physiologic and pathologic cardiac hypertrophy as
well as in patients with heart failure. In this report, we demonstrate that TH
induces hypertrophy as a direct result of binding to the TRalpha1 isoform and,
moreover, that overexpression of TRalpha1 alone is also associated with a
hypertrophic phenotype, even in the absence of ligand. The mechanism of TH and
TRalpha1-specific hypertrophy is novel for a nuclear hormone receptor and
involves the transforming growth factor beta-activated kinase (TAK1) and p38.
Mitigating TRalpha1 effects, both TRalpha2 and TRbeta1 attenuate
TRalpha1-induced myocardial growth and gene expression by diminishing TAK1 and
p38 activities, respectively. These findings refine our previous observations on
TR expression in the hypertrophied and failing heart and suggest that
manipulation of thyroid hormone signaling in an isoform-specific manner may be a
relevant therapeutic target for altering the pathologic myocardial program.
DOI: 10.1210/me.2004-0503
PMCID: PMC1237131
PMID: 15831522 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21988948
|
1. Crit Pathw Cardiol. 2011 Jun;10(2):84-6. doi: 10.1097/HPC.0b013e318224df28.
Dabigatran: a new option for anticoagulation in atrial fibrillation and venous
thromboembolism.
Acharjee S(1), Cannon CP.
Author information:
(1)Department of Medicine, SUNY at Buffalo School of Medicine, NY, USA.
For several decades now, oral anticoagulation with warfarin has represented the
cornerstone of measures to prevent occurrence of ischemic stroke in high-risk
patients with atrial fibrillation. However, the mechanism of action and
pharmacokinetic profile of this vitamin K antagonist confers a narrow
therapeutic range and makes it prone to drug and dietary interactions, requiring
frequent monitoring of its effectiveness. The recently introduced oral direct
thrombin antagonist, dabigatran, has been shown in phase III clinical trials to
be noninferior in efficacy to warfarin for the prevention of thromboembolic
events in patients with atrial fibrillation, as well as in treatment of acute
venous thromboembolism. In this article, we review the factors necessitating the
development of dabigatran, summarize key clinical trial evidence leading to its
approval, and discuss its potential role as an alternative to warfarin in
current clinical practice.
DOI: 10.1097/HPC.0b013e318224df28
PMID: 21988948 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17103451
|
1. Am J Med Genet A. 2006 Dec 15;140(24):2730-41. doi: 10.1002/ajmg.a.31530.
Clinical features and management issues in Mowat-Wilson syndrome.
Adam MP(1), Schelley S, Gallagher R, Brady AN, Barr K, Blumberg B, Shieh JT,
Graham J, Slavotinek A, Martin M, Keppler-Noreuil K, Storm AL, Hudgins L.
Author information:
(1)Department of Human Genetics, Emory University School of Medicine, Atlanta,
Georgia, USA. madam@genetics.emory.edu
Comment in
Am J Med Genet A. 2007 Jul 1;143A(13):1528-30. doi: 10.1002/ajmg.a.31801.
Mowat-Wilson syndrome (MWS) is a relatively newly described multiple congenital
anomaly/mental retardation syndrome. Haploinsufficiency of a gene termed ZFHX1B
(also known as SIP1) on chromosome 2 is responsible for this condition, and
clinical genetic testing for MWS recently became available. The majority of
reports in the literature originate from Northern Europe and Australia. Here we
report our clinical experience with 12 patients diagnosed with MWS within a
2-year period of time in the United States, with particular emphasis on clinical
characteristics and management strategies. Individuals with this condition have
characteristic facial features, including microcephaly, hypertelorism, medially
flared and broad eyebrows, prominent columella, pointed chin, and uplifted
earlobes, which typically prompt the clinician to consider the diagnosis.
Medical issues in our cohort of patients included seizures (75%) with no
predeliction for any particular seizure type; agenesis of the corpus callosum
(60% of our patients studied); congenital heart defects (75%), particularly
involving the pulmonary arteries and/or valves; hypospadias (55% of males);
severely impaired or absent speech (100% of individuals over 1 year of age) with
relatively spared receptive language; and Hirschsprung disease (50%) or chronic
constipation (25%). The incidence of MWS is unknown, but based on the number of
patients identified in a short period of time within the US, it is likely
greatly under recognized. MWS should be considered in any individual with
severely impaired or absent speech, especially in the presence of seizures and
anomalies involving the pulmonary arteries (particularly pulmonary artery sling)
or pulmonary valves.
(c) 2006 Wiley-Liss, Inc.
DOI: 10.1002/ajmg.a.31530
PMID: 17103451 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/3931221
|
1. Science. 1985 Nov 1;230(4725):550-3. doi: 10.1126/science.3931221.
Cyanobacterial light-harvesting complex subunits encoded in two red
light-induced transcripts.
Conley PB, Lemaux PG, Grossman AR.
The major light-harvesting complex in cyanobacteria and red algae, the
phycobilisome, is composed of chromophoric and nonchromophoric polypeptides. Two
linked genes encoding major chromophoric components, the polypeptide subunits of
phycocyanin, were isolated from the cyanobacterium Fremyella diplosiphon.
Transcripts from this phycocyanin subunit gene cluster were present as major
species in the cyanobacterium grown in red light, but not in cultures maintained
in green light. The genes for the subunits of the red light-induced phycocyanin
were transcribed together (beta-phycocyanin followed by alpha-phycocyanin) on
two messenger RNA species; one contained 1600 bases while the other had 3800
bases. The latter, which encompassed the smaller transcript, contained
additional sequences extending from the 3' end of the coding region of the
alpha-phycocyanin gene. It may encode other light-induced components of the
phycobilisome. Since phycocyanin, which effectively absorbs red light, becomes a
dominant constituent of the phycobilisome in red light, these different levels
may reflect an important adaptive mechanism of these organisms to their
environment.
DOI: 10.1126/science.3931221
PMID: 3931221 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7678762
|
1. Plant Mol Biol. 1993 Jan;21(1):27-38. doi: 10.1007/BF00039615.
Characterization and transcript analysis of the major phycobiliprotein subunit
genes from Aglaothamnion neglectum (Rhodophyta).
Apt KE(1), Grossman AR.
Author information:
(1)Carnegie Institution of Washington, Department of Plant Biology, Stanford, CA
94305-1297.
The genes encoding the alpha and beta subunits of allophycocyanin, phycocyanin
and phycoerythrin from the red alga Aglaothamnion neglectum were isolated and
characterized. While the operons containing the different phycobiliprotein genes
are dispersed on the plastid genome, the genes encoding the alpha and beta
subunits for each phycobiliprotein are contiguous. The beta subunit gene is 5'
for both the phycocyanin and phycoerythrin operons, while the alpha subunit gene
is 5' for the allophycocyanin operon. The amino acid sequences of A. neglectum
phycobiliproteins, as deduced from the nucleotide sequences of the genes, are
65-85% identical to analogous proteins from other red algae and cyanobacteria.
The conserved nature of the plastid-encoded red algal and cyanobacterial
phycobiliprotein genes supports the proposed origin of red algal plastids from
cyanobacterial endosymbionts. Many environmental factors effect phycobilisome
biosynthesis. The effect of both nutrient availability and light quantity on the
level of A. neglectum phycobiliprotein subunits and the mRNA species encoding
those subunits is described.
DOI: 10.1007/BF00039615
PMID: 7678762 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20074983
|
1. Blood Cells Mol Dis. 2010 Mar 15;44(3):181-7. doi: 10.1016/j.bcmd.2009.12.006.
Epub 2010 Jan 13.
Spontaneous regression of disease manifestations can occur in type 1 Gaucher
disease; results of a retrospective cohort study.
Boomsma JM(1), van Dussen L, Wiersma MG, Groener JE, Aerts JM, Maas M, Hollak
CE.
Author information:
(1)Department of Internal Medicine, Academic Medical Center, Amsterdam, The
Netherlands.
Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient
activity of the enzyme glucocerebrosidase. GD is classically divided into three
major phenotypes. The most prevailing form is type 1, which presents with
variable hepatosplenomegaly, cytopenia, and/or bone disease. In adult patients
with mild manifestations, progress of disease might be slow or even absent. As a
consequence, treatment with intravenous enzyme replacement or substrate
reduction is not always necessary. In the Netherlands, the follow-up of GD
patients is centralized, which allows detailed investigation of untreated
patients. A retrospective study was conducted in 18 type 1 GD patients, (2
teenagers: 15 and 16 years of age at first visit) who were not treated for at
least one year. The chitotriosidase activity, platelet count, hemoglobin level,
lumbar bone marrow fat content measured with quantitative chemical shift imaging
(QCSI), liver ratio (ml/kg body weight), and spleen volume were recorded.
Criteria were developed to score regression, stability or progression of
disease. During a mean follow up of 4.5 years (range 1.1-12.2) seven patients
(39%) showed spontaneous regression of GD. Eight patients (44%) were stable. Two
patients had progressive disease, solely based upon a sustained increase in
chitotriosidase activity. A pediatric patient had an increase in splenomegaly
but an improvement in bone marrow fat fraction, probably due to aging. Nine
patients fulfilled the local criteria to start treatment at first visit, of whom
six started treatment within 1.1 to 6.8 years. The other three refused therapy,
but nevertheless showed stability or even regression of the disease during a
follow up of 4.6, 9.5 and 11.4 years respectively. None of the parameters was
predictive of progression or regression of disease. In conclusion, GD in adults
can, in some cases, regress spontaneously. No parameters for accurately
predicting future disease course exist.
2009 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.bcmd.2009.12.006
PMID: 20074983 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21526168
|
1. PLoS One. 2011 Apr 22;6(4):e17626. doi: 10.1371/journal.pone.0017626.
Evaluation of the efficacy and safety of rivaroxaban using a computer model for
blood coagulation.
Burghaus R(1), Coboeken K, Gaub T, Kuepfer L, Sensse A, Siegmund HU, Weiss W,
Mueck W, Lippert J.
Author information:
(1)Bayer Schering Pharma AG, Wuppertal, Germany.
Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European
Union and several other countries for the prevention of venous thromboembolism
in adult patients undergoing elective hip or knee replacement surgery and is in
advanced clinical development for the treatment of thromboembolic disorders. Its
mechanism of action is antithrombin independent and differs from that of other
anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an
indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin
inhibitor). A blood coagulation computer model has been developed, based on
several published models and preclinical and clinical data. Unlike previous
models, the current model takes into account both the intrinsic and extrinsic
pathways of the coagulation cascade, and possesses some unique features,
including a blood flow component and a portfolio of drug action mechanisms. This
study aimed to use the model to compare the mechanism of action of rivaroxaban
with that of warfarin, and to evaluate the efficacy and safety of different
rivaroxaban doses with other anticoagulants included in the model. Rather than
reproducing known standard clinical measurements, such as the prothrombin time
and activated partial thromboplastin time clotting tests, the anticoagulant
benchmarking was based on a simulation of physiologically plausible clotting
scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity
for tissue factor concentration inducing clotting, and a steep
concentration-effect relationship, rapidly flattening towards higher inhibitor
concentrations, both suggesting a broad therapeutic window. The predicted dosing
window is highly accordant with the final dose recommendation based upon
extensive clinical studies.
DOI: 10.1371/journal.pone.0017626
PMCID: PMC3081290
PMID: 21526168 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: All authors are Bayer AG
subsidiary employees and own stocks of Bayer AG. 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/2502578
|
1. J Immunol Methods. 1989 Jul 6;121(1):9-18. doi: 10.1016/0022-1759(89)90414-6.
A novel and inexpensive source of allophycocyanin for multicolor flow cytometry.
Jung TM(1), Dailey MO.
Author information:
(1)Department of Pathology, University of Iowa, College of Medicine, Iowa City
52242.
Allophycocyanin (APC) belongs to a family of phycobiliproteins that are well
suited as fluorescent reagents for flow cytometric analysis, since they have a
broad excitation spectrum, a large Stoke's shift and they fluoresce with a high
quantum yield. The widespread use of APC has been limited by the availability of
raw material and high cost of the purified phycobiliprotein. We have assessed
the suitability of dry, powdered Spirulina platensis, available at health food
stores, as an inexpensive source of APC. APC was extracted from Spirulina
platensis by overnight treatment with lysozyme, followed by ammonium sulfate
precipitation. APC was then separated from phycocyanin (the only other major
phycobiliprotein in Spirulina) by elution of bound material from an
hydroxylapatite column using an increasing continuous phosphate gradient. APC
isolated in this manner retained its normal trimeric structure. The absorbance
and fluorescence excitation and emission spectra of the purified
phycobiliproteins were identical to those previously shown for C-PC and APC. APC
can be stored concentrated at 4 degrees C, frozen at -70 degrees C, or as a
saturated ammonium sulfate precipitate, with no subunit dissociation or change
in spectral properties. Moreover, APC has been conjugated to monoclonal and
polyclonal antibodies for use in multicolor FACS analysis, with the conjugated
antibody activity remaining stable for at least 2 years. Thus, this procedure is
a simple, cost-effective method for preparing reagents for multicolor
immunofluorescence and flow cytometry.
DOI: 10.1016/0022-1759(89)90414-6
PMID: 2502578 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17010801
|
1. J Am Coll Cardiol. 2006 Oct 3;48(7):1396-8. doi: 10.1016/j.jacc.2006.07.016.
Epub 2006 Sep 12.
Phospholamban R14 deletion results in late-onset, mild, hereditary dilated
cardiomyopathy.
DeWitt MM(1), MacLeod HM, Soliven B, McNally EM.
Author information:
(1)Department to Medicine, Section of Cardiology, The University of Chicago,
Chicago, Illinois, USA.
OBJECTIVES: The purpose of this research was to determine the phenotypic
spectrum associated with phospholamban gene (PLN) mutations.
BACKGROUND: Inheritance contributes to the development of dilated
cardiomyopathy. Mutations in the gene encoding PLN have been associated with
dilated cardiomyopathy characterized by early onset and the presence of lethal
ventricular arrhythmias.
METHODS: We screened a cohort of 260 unrelated dilated cardiomyopathy patients
from a tertiary care referral center for mutations in the PLN gene.
RESULTS: Family history of cardiomyopathy was present in approximately one-half
the individuals in this cohort. We identified 1 family with a deletion of
arginine 14 in the PLN. Interestingly, unlike other individuals reported with
the identical PLN mutation, these individuals were not diagnosed with dilated
cardiomyopathy until their seventh decade when they were only mildly symptomatic
with congestive heart failure.
CONCLUSIONS: The identical PLN mutation can be associated with both mild and
severe forms of dilated cardiomyopathy. Additionally, PLN mutations should be
considered in late onset cardiomyopathy. (Genetics of Cardiovascular and
Neuromuscular Disease;
http://www.clinicaltrials.gov/ct/show/NCT00138931?order=1; NCT00138931)
DOI: 10.1016/j.jacc.2006.07.016
PMID: 17010801 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18989393
|
1. PLoS Comput Biol. 2008 Nov;4(11):e1000213. doi: 10.1371/journal.pcbi.1000213.
Epub 2008 Nov 7.
Transmembrane topology and signal peptide prediction using dynamic bayesian
networks.
Reynolds SM(1), Käll L, Riffle ME, Bilmes JA, Noble WS.
Author information:
(1)Department of Electrical Engineering, University of Washington, Seattle,
Washington, United States of America.
Hidden Markov models (HMMs) have been successfully applied to the tasks of
transmembrane protein topology prediction and signal peptide prediction. In this
paper we expand upon this work by making use of the more powerful class of
dynamic Bayesian networks (DBNs). Our model, Philius, is inspired by a
previously published HMM, Phobius, and combines a signal peptide submodel with a
transmembrane submodel. We introduce a two-stage DBN decoder that combines the
power of posterior decoding with the grammar constraints of Viterbi-style
decoding. Philius also provides protein type, segment, and topology confidence
metrics to aid in the interpretation of the predictions. We report a relative
improvement of 13% over Phobius in full-topology prediction accuracy on
transmembrane proteins, and a sensitivity and specificity of 0.96 in detecting
signal peptides. We also show that our confidence metrics correlate well with
the observed precision. In addition, we have made predictions on all 6.3 million
proteins in the Yeast Resource Center (YRC) database. This large-scale study
provides an overall picture of the relative numbers of proteins that include a
signal-peptide and/or one or more transmembrane segments as well as a valuable
resource for the scientific community. All DBNs are implemented using the
Graphical Models Toolkit. Source code for the models described here is available
at http://noble.gs.washington.edu/proj/philius. A Philius Web server is
available at http://www.yeastrc.org/philius, and the predictions on the YRC
database are available at http://www.yeastrc.org/pdr.
DOI: 10.1371/journal.pcbi.1000213
PMCID: PMC2570248
PMID: 18989393 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/21297619
|
1. Nat Methods. 2011 Mar;8(3):260-6. doi: 10.1038/nmeth.1567. Epub 2011 Feb 6.
Flybow: genetic multicolor cell labeling for neural circuit analysis in
Drosophila melanogaster.
Hadjieconomou D(1), Rotkopf S, Alexandre C, Bell DM, Dickson BJ, Salecker I.
Author information:
(1)Medical Research Council National Institute for Medical Research, Division of
Molecular Neurobiology, London, UK.
Comment in
Nat Methods. 2011 Mar;8(3):217-8. doi: 10.1038/nmeth0311-217.
To facilitate studies of neural network architecture and formation, we generated
three Drosophila melanogaster variants of the mouse Brainbow-2 system, called
Flybow. Sequences encoding different membrane-tethered fluorescent proteins were
arranged in pairs within cassettes flanked by recombination sites. Flybow
combines the Gal4-upstream activating sequence binary system to regulate
transgene expression and an inducible modified Flp-FRT system to drive
inversions and excisions of cassettes. This provides spatial and temporal
control over the stochastic expression of one of two or four reporters within
one sample. Using the visual system, the embryonic nervous system and the wing
imaginal disc, we show that Flybow in conjunction with specific Gal4 drivers can
be used to visualize cell morphology with high resolution. Finally, we
demonstrate that this labeling approach is compatible with available
Flp-FRT-based techniques, such as mosaic analysis with a repressible cell
marker; this could further support the genetic analysis of neural circuit
assembly and function.
DOI: 10.1038/nmeth.1567
PMID: 21297619 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9548282
|
1. Electrophoresis. 1998 Feb;19(2):215-9. doi: 10.1002/elps.1150190213.
Electrophoretic applications of phycobiliproteins.
Aráoz R(1), Lebert M, Häder DP.
Author information:
(1)Institut für Botanik und Pharmazeutische Biologie,
Friedrich-Alexander-Universität, Erlangen, Germany.
Phycobiliproteins are homologous chromoproteins which constitute the
phycobilisomes, the light harvesting complexes of the photosynthetic apparatus
in cyanobacteria, rhodophyta and cryptophyta. In the present work, phycocyanin
(PC) and phycoerythrin (PE) from a Nostoc species are proposed as protein
markers for electrophoretic techniques. Phycocyanin is a blue-colored
phycobiliprotein; it carries phycocyanobilin as chromophoric group and is
composed of two subunits, alpha and beta, with Mr of 14000 and 17000,
respectively. In contrast, the PE subunits, having a similar Mr of 21000, are
deep rose chromoproteins and carry phycoerythrobilin residues. Both low
molecular weight phycobiliproteins are also suitable for monitoring protein
blotting and the focusing time of protein samples during isoelectric focusing as
internal markers. The PE subunits which form a single broad band after sodium
dodecyl sulfate-polyacrylamide gel electrophoresis have different isoelectric
points, and they form two visible bands when they reach their isoelectric point.
The phycobilisomes constitute up to 50% of the total protein in cyanobacteria
and their content in PC or PE can be up- or down-regulated by using different
light conditions (chromatic adaptation).
DOI: 10.1002/elps.1150190213
PMID: 9548282 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15302727
|
1. Chest. 2004 Aug;126(2):420-7. doi: 10.1378/chest.126.2.420.
Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension
associated with connective tissue disease.
Oudiz RJ(1), Schilz RJ, Barst RJ, Galié N, Rich S, Rubin LJ, Simonneau G;
Treprostinil Study Group.
Author information:
(1)Research and Education Institute, Harbor-UCLA Medical Center, Torrance, CA
90502, USA. oudiz@humc.edu
Comment in
Chest. 2005 Sep;128(3):1888. doi: 10.1378/chest.128.3.1888.
STUDY OBJECTIVES: To assess the efficacy and safety of continuous subcutaneous
infusion of treprostinil, a stable prostacyclin analogue, for treating pulmonary
arterial hypertension (PAH) in patients with connective tissue disease (CTD).
DESIGN: Two multicenter, randomized, double-blind, placebo-controlled,
prospective trials of treprostinil vs placebo in 470 patients with PAH.
PATIENTS: A subset of 90 patients with PAH and CTD, including systemic lupus
erythematosus, diffuse scleroderma, limited scleroderma, and mixed CTD/overlap
syndrome.
INTERVENTIONS: Patients received either treprostinil (initiated at 1.25
ng/kg/min, and titrated upward) or placebo via continuous subcutaneous infusion.
The maximum dose of treprostinil allowed was 22.5 ng/kg/min.
MEASUREMENTS: Six-minute walk (6MW) distance and dyspnea-fatigue scores were
determined at baseline, and at 6 weeks and 12 weeks. Hemodynamic measures were
obtained at baseline and at 12 weeks.
RESULTS: At baseline, most patients had New York Heart Association class III
symptoms. The mean baseline 6MW distance was 289 m (range, 60 to 448 m). The
mean dose of treprostinil at week 12 was 8.4 ng/kg/min (range, 1.25 to 17.5
ng/kg/min). After 12 weeks, the change in cardiac index from baseline was + 0.2
+/- 0.08 L/min/m(2) in the treprostinil group and - 0.07 +/- 0.07 L/min/m(2) in
the placebo group (p = 0.007). The pulmonary vascular resistance index decreased
by 4 +/- 2 U x m(2) in the treprostinil group and increased by 1 +/- 1 U x m(2)
in the placebo group (p = 0.006). The placebo-corrected median improvement from
baseline in 6MW distance was 25 m in treprostinil-treated patients (p = 0.055);
this improvement appeared to be dose related. Dyspnea fatigue scores also
improved in the treprostinil group compared with the placebo group (p = 0.014).
Adverse events included infusion site pain and typical side effects related to
prostaglandins, and were tolerated by most patients.
CONCLUSIONS: Continuous subcutaneous infusion of treprostinil in patients with
PAH associated with CTD improved exercise capacity, symptoms of PAH, and
hemodynamics.
DOI: 10.1378/chest.126.2.420
PMID: 15302727 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1859661
|
1. Eur J Cardiothorac Surg. 1991;5(5):230-4. doi: 10.1016/1010-7940(91)90169-k.
Coronary artery bypass surgery in patients with angina pectoris and
hypothyroidism.
Kawasuji M(1), Sawa S, Tsujiguchi H, Iwa T.
Author information:
(1)Department of Surgery I, Kanazawa University School of Medicine, Japan.
The treatment of hypothyroidism in patients undergoing coronary artery bypass
surgery is a difficult clinical problem. To determine perioperative thyroid
replacement therapy in patients with hypothyroidism, plasma total thyroxine
(T4), total triiodothyroxine (T3), free T4, free T3 and thyroid-stimulating
hormone levels were measured preoperatively and at 1, 2, 3, 7, and 14 days after
operation in 9 patients with hypothyroidism and were compared with levels in 14
patients with normal thyroid function who underwent coronary bypass surgery. In
the normal control group, total T4 decreased to its lowest level on the 1st
postoperative day and then increased gradually to the preoperative level at 7
days. Total T4 remained within the normal range throughout the entire
postoperative course. In 6 patients with hypothyroidism who were treated with
thyroid hormone before surgery, total T4 decreased immediately after operation
and only increased after starting thyroid replacement therapy. In 3 hypothyroid
patients without prior thyroid replacement, total T4 showed a change similar to
patients in the control group but remained below the normal range until starting
thyroid replacement therapy. Coronary bypass surgery was performed safely in
patients with hypothyroidism. Preoperative thyroid replacement with suboptimal
doses was safe in patients with severe hypothyroidism. Adequate postoperative
thyroid replacement was achieved in all patients without complications.
DOI: 10.1016/1010-7940(91)90169-k
PMID: 1859661 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23827424
|
1. Pediatr Neurol. 2013 Jul;49(1):31-39.e2. doi:
10.1016/j.pediatrneurol.2013.02.015.
Cerebrospinal fluid brain injury biomarkers in children: a multicenter study.
Shahim P(1), Darin N, Andreasson U, Blennow K, Jennions E, Lundgren J, Månsson
JE, Naess K, Törnhage CJ, Zetterberg H, Mattsson N.
Author information:
(1)Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology,
Department of Neurochemistry, Sahlgrenska University Hospital/Mölndal, Sweden.
pashtun.shahim@neuro.gu.se
BACKGROUND: Cerebrospinal fluid (CSF) biomarkers reflecting neuronal and
astroglial injury, such as total tau (T-tau), glial fibrillary acidic protein
(GFAP), and neurofilament light (NFL), have been extensively investigated in
neurologic diseases in adults, but no large study has investigated these
biomarkers in children.
METHODS: This study presents a detailed evaluation of CFS T-tau, GFAP, NFL, and
CSF:albumin ratio in a large cohort of pediatric patients. This is a
retrospective multicenter study on pediatric patients aged <16 years (n = 607),
where neuronal injury biomarkers T-tau, GFAP, NFL, and CSF albumin ratio were
analyzed during 2000-2010 at the Clinical Neurochemistry Laboratory, Sahlgrenska
University Hospital, Sweden. The patients were grouped into eight categories:
epilepsy, infectious and inflammatory central nervous system disorders,
progressive encephalopathy, static encephalopathy, tumors, movement disorders,
miscellaneous disorders, and a control group.
RESULTS: T-tau, GFAP, and NFL were increased in progressive encephalopathy (P <
0.001), epilepsy (P < 0.001), and infectious and inflammatory central nervous
system disorders (P < 0.001) compared with controls. T-tau was the biomarker
with the highest diagnostic accuracy with the area under the curve of 0.83 (95%
confidence interval (CI), 0.77-0.90; P < 0.0001) for progressive encephalopathy
followed by epilepsy 0.80 (95% CI, 0.75-0.87; P < 0.0001). The combination of
all four biomarkers further improved the area under the curve for the
progressive encephalopathy 0.87 (95% CI, 0.77-0.89; P < 0.0001), followed by
epilepsy 0.81 (95% CI, 0.74-0.80; P = 0.030). The combination of the biomarkers
also separated progressive from static encephalopathy 0.88 (95% CI, 0.83-0.93; P
< 0.0001).
CONCLUSIONS: CSF T-tau, GFAP, and NFL are differently altered across different
neurologic diseases in children. Importantly, the biomarker pattern
distinguishes between progressive and static neurologic disorders.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.pediatrneurol.2013.02.015
PMID: 23827424 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10339434
|
1. Curr Biol. 1999 May 20;9(10):531-4. doi: 10.1016/s0960-9822(99)80237-1.
Thermostable uracil-DNA glycosylase from Thermotoga maritima a member of a novel
class of DNA repair enzymes.
Sandigursky M(1), Franklin WA.
Author information:
(1)Departments of Radiology and Radiation Oncology, Albert Einstein College of
Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
Uracil-DNA glycosylase (UDG) is a ubiquitous enzyme found in eukaryotes and
prokaryotes [1][2][3]. This enzyme removes uracil bases that are present in DNA
as a result of either deamination of cytosine or misincorporation of dUMP
instead of dTMP [4] [5], and it is the primary activity in the DNA base excision
repair pathway. Although UDG activities have been shown to be present in several
thermophiles [6][7][8], no sequences have been found that are complementary to
the Escherichia coli ung gene, which encodes UDG [9]. Here, we describe a UDG
from the thermophile Thermotoga maritima. The T. maritima UDG gene has a low
level of homology to the E. coli G-T/U mismatch-specific DNA glycosylase gene
(mug). The expressed protein is capable of removing uracil from DNA containing
either a U-A or a U-G base pair and is heat-stable up to 75 degrees C. The
enzyme is also active on single-stranded DNA containing uracil. Analogous genes
appear to be present in several prokaryotic organisms, including thermophilic
and mesophilic eubacteria as well as archaebacteria, the human-disease pathogens
Treponema palladium and Rickettsia prowazekii, and the extremely radioresistant
organism Deinococcus radiodurans. These findings suggest that the T. maritima
UDG is a member of a new class of DNA repair enzymes.
DOI: 10.1016/s0960-9822(99)80237-1
PMID: 10339434 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/26052092
|
1. Cancer Lett. 2015 Sep 1;365(2):141-8. doi: 10.1016/j.canlet.2015.06.003. Epub
2015 Jun 5.
Circular RNA: A new star of noncoding RNAs.
Qu S(1), Yang X(1), Li X(1), Wang J(1), Gao Y(1), Shang R(1), Sun W(1), Dou
K(1), Li H(2).
Author information:
(1)Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military
Medical University, Xi'an, 710032, China.
(2)Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military
Medical University, Xi'an, 710032, China. Electronic address:
lihaim@fmmu.edu.cn.
Comment in
BJOG. 2016 Dec;123(13):2119. doi: 10.1111/1471-0528.13965.
Circular RNAs (circRNAs) are a novel type of RNA that, unlike linear RNAs, form
a covalently closed continuous loop and are highly represented in the eukaryotic
transcriptome. Recent studies have discovered thousands of endogenous circRNAs
in mammalian cells. CircRNAs are largely generated from exonic or intronic
sequences, and reverse complementary sequences or RNA-binding proteins (RBPs)
are necessary for circRNA biogenesis. The majority of circRNAs are conserved
across species, are stable and resistant to RNase R, and often exhibit
tissue/developmental-stage-specific expression. Recent research has revealed
that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing
and transcription, and modifiers of parental gene expression. Emerging evidence
indicates that circRNAs might play important roles in atherosclerotic vascular
disease risk, neurological disorders, prion diseases and cancer; exhibit
aberrant expression in colorectal cancer (CRC) and pancreatic ductal
adenocarcinoma (PDAC); and serve as diagnostic or predictive biomarkers of some
diseases. Similar to miRNAs and long noncoding RNAs (lncRNAs), circRNAs are
becoming a new research hotspot in the field of RNA and could be widely involved
in the processes of life. Herein, we review the formation and properties of
circRNAs, their functions, and their potential significance in disease.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
DOI: 10.1016/j.canlet.2015.06.003
PMID: 26052092 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24523921
|
1. PLoS One. 2014 Feb 11;9(2):e88591. doi: 10.1371/journal.pone.0088591.
eCollection 2014.
Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients.
Jessen Krut J(1), Mellberg T(1), Price RW(2), Hagberg L(1), Fuchs D(3),
Rosengren L(4), Nilsson S(5), Zetterberg H(6), Gisslén M(1).
Author information:
(1)Institute of Biomedicine, Department of Infectious Diseases, University of
Gothenburg, Gothenburg, Sweden.
(2)Department of Neurology, University of California San Francisco, San
Francisco, California, United States of America.
(3)Division of Biological Chemistry, Biocenter, Innsbruck Medical University,
Innsbruck, Austria.
(4)Institute of Neuroscience and Physiology, Department of Neurology, the
Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
(5)Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
(6)Institute of Neuroscience and Physiology, Department of Psychiatry and
Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg,
Gothenburg, Sweden ; UCL Institute of Neurology, Queen Square, London, United
Kingdom.
BACKGROUND: Prevalence of neurocognitive impairment in HIV-1 infected patients
is reported to be high. Whether this is a result of active HIV-related
neurodegeneration is unclear. We examined axonal injury in HIV-1 patients by
measuring the light subunit of neurofilament protein (NFL) in CSF with a novel,
sensitive method.
METHODS: With a cross-sectional design, CSF concentrations of neurofilament
protein light (NFL) (marker of neuronal injury), neopterin (intrathecal
immunoactivation) and CSF/Plasma albumin ratio (blood-brain barrier integrity)
were analyzed on CSF from 252 HIV-infected patients, subdivided into untreated
neuroasymptomatics (n = 200), HIV-associated dementia (HAD) (n = 14) and on
combinations antiretroviral treatment (cART) (n = 85), and healthy controls (n =
204). 46 HIV-infected patients were included in both treated and untreated
groups, but sampled at different timepoints. Furthermore, 78 neuroasymptomatic
patients were analyzed before and after treatment initiation.
RESULTS: While HAD patients had the highest NFL concentrations, elevated CSF NFL
was also found in 33% of untreated neuroasymptomatic patients, mainly in those
with blood CD4+ cell counts below 250 cells/μL. CSF NFL concentrations in the
untreated neuroasymptomatics and treated groups were equivalent to controls 18.5
and 3.9 years older, respectively. Neopterin correlated with NFL levels in
untreated groups while the albumin ratio correlated with NFL in both untreated
and treated groups.
CONCLUSIONS: Increased CSF NFL indicates ongoing axonal injury in many
neuroasymptomatic patients. Treatment decreases NFL, but treated patients retain
higher levels than controls, indicating either continued virus-related injury or
an aging-like effect of HIV infection. NFL correlates with neopterin and albumin
ratio, suggesting an association between axonal injury, neuroinflammation and
blood-brain barrier permeability. NFL appears to be a sensitive biomarker of
subclinical and clinical brain injury in HIV and warrants further assessment for
broader clinical use.
DOI: 10.1371/journal.pone.0088591
PMCID: PMC3921217
PMID: 24523921 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: Dr Jan Krut, Dr Tomas
Mellberg, Dr Dietmar Fuchs, Dr Lars Rosengren, Dr Staffan Nilsson and Dr Henrik
Zetterberg have all declared that no competing interests exist. Dr Richard W
Price has the following conflicts: Serving as a Consultant to Merck & Co and
receiving honoraria and travel reimbursement for meeting presentations from
AbbVie. Dr Lars Hagberg has the following conflicts: Payment for lecture for
infectious specialists and GP:s from Roche, Meda. Dr Magnus Gisslén has the
following conflicts: Money paid by BMS, Gilead, Janssen, GSK and Abbott for
scientific advisory board and educational lectures. 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/19433372
|
1. Bull Cancer. 2009;96 Suppl 1:S35-43. doi: 10.1684/bdc.2008.0774.
[Targeting HER pathway in head and neck and thoracic cancers].
[Article in French]
Barlesi F(1), Breen D.
Author information:
(1)Service d'Oncologie Thoracique, Pôle thorax, Faculté de Médecine, Université
de la Méditerranée, Hôpital Sainte-Marguerite, Assistance Publique-Hôpitaux de
Marseille, Marseille, France. fabrice.barlesi@mail.ap-hm.fr
Bronchial and head and neck (HN) cancers share similarities especially regarding
the HER pathway. Therapeutic progresses targeting the HER pathway are based on
monoclonal antibodies, especially cetuximab, and tyrosine kinase (TK)
inhibitors, targeting HER only, as gefitinib and erlotinib, or HER and other
receptor(s), as VEGFR for the ZD6474. The results obtained already led to the
registration of cetuximab (combined with radiotherapy) for management of locally
advanced HN cancers, and the registration of erlotinib (and gefitinib in some
countries) for management of non-small-cell lung cancer (NSCLC) in the second or
third line setting. Therefore, these first successes led to the development of
several drugs including monoclonal antibodies (trastuzumab, panitumumab,
matuzumab), TK inhibitors targeting one receptor as well as TK pan-inhibitors
(lapatinib, HKI 272, PKI 166, EKB-569, AEE-788), currently assessed through
clinical trials worldwide. In the same time, progresses regarding the HER
pathway also focused on a better selection of patients who clearly beneficiate
from these drugs (EGFR gene mutations, EGFR gene amplification by FISH) allowing
the first steps in tailoring anticancer treatments in lung cancer. In
conclusion, therapeutic progresses targeting the HER pathway have improve
management of HN and NSCLC patients and rise hopes for the future.
DOI: 10.1684/bdc.2008.0774
PMID: 19433372 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17975102
|
1. Stroke. 2007 Dec;38(12):3205-12. doi: 10.1161/STROKEAHA.107.489351. Epub 2007
Nov 1.
Shift analysis versus dichotomization of the modified Rankin scale outcome
scores in the NINDS and ECASS-II trials.
Savitz SI(1), Lew R, Bluhmki E, Hacke W, Fisher M.
Author information:
(1)Department of Neurology, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, MA, USA. sean.i.savitz@uth.tmc.edu
BACKGROUND AND PURPOSE: The SAINT I trial that showed a significant benefit of
the neuroprotectant NXY-059 used a novel outcome for acute ischemic stroke
trials: a shift toward good functional outcome on the 7-category modified Rankin
scale (mRS).
METHODS: We used the Cochran-Mantel-Haenszel shift test to analyze the
distribution of the 90-day mRS outcomes in the NINDS and ECASS-II databases and
compared the results with a dichotomized mRS outcome by logistic regression (0
to 2 vs 3 to 6, or 0 to 1 vs 2 to 6). We also stratified each dataset based on
National Institutes of Health Stroke Scale baseline severity.
RESULTS: Each dataset showed a statistically significant shift in the 90-day mRS
distributions favoring tissue plasminogen activator (odds ratio, 1.6 for NINDS,
1.3 for ECASS-II). For ECASS-II, larger shift effects appeared in National
Institutes of Health Stroke Scale 0 to 6 and 16 to 40 strata. Similarly, the mRS
0 to 2 analysis but not mRS 0 to 1 found similar treatment effects in both
datasets (odds ratio, 1.6 for NINDS, 1.5 for ECASS-II) and similar variations in
the low and high strata in the ECASS-II trial. NINDS found no significant
treatment effects across the strata. After removing the strata at the fringes,
the shift test lost significance in both datasets.
CONCLUSIONS: Tissue plasminogen activator causes a beneficial shift toward
wellness on the mRS in both the NINDS and ECASS-II trials, and ECASS-II would
have been a positive trial according to the shift approach. However, the shift
effect is not global for all treated patients and does not outperform the
dichotomized 0 to 2 outcome. Patients with mild and severe deficits also shifted
favorably on the mRS in the ECASS-II trial.
DOI: 10.1161/STROKEAHA.107.489351
PMID: 17975102 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23419732
|
1. Free Radic Biol Med. 2013 Sep;62:145-156. doi:
10.1016/j.freeradbiomed.2013.01.033. Epub 2013 Feb 16.
Nitrone-based therapeutics for neurodegenerative diseases: their use alone or in
combination with lanthionines.
Floyd RA(1), Castro Faria Neto HC(2), Zimmerman GA(3), Hensley K(4), Towner
RA(5).
Author information:
(1)Experimental Therapeutics, Oklahoma Medical Research Foundation, Oklahoma
City, OK 73104, USA. Electronic address: robert-floyd@omrf.ouhsc.edu.
(2)Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz, IOC, Fiocruz, Rio
de Janeiro, Brazil.
(3)Laboratorio de Immunofarmacologia, Instituto Oswaldo Cruz, IOC, Fiocruz, Rio
de Janeiro, Brazil; Department of Medicine, University of Utah School of
Medicine, Salt Lake City, Utah, USA.
(4)Department of Pathology and Department of Neurosciences, University of Toledo
Medical Center, Toledo, OH.
(5)Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation,
Oklahoma City, OK 73104, USA.
The possibility of free radical reactions occurring in biological processes led
to the development and employment of novel methods and techniques focused on
determining their existence and importance in normal and pathological
conditions. For this reason the use of nitrones for spin trapping free radicals
became widespread in the 1970s and 1980s, when surprisingly the first evidence
of their potent biological properties was noted. Since then widespread
exploration and demonstration of the potent biological properties of
phenyl-tert-butylnitrone (PBN) and its derivatives took place in preclinical
models of septic shock and then in experimental stroke. The most extensive
commercial effort made to capitalize on the potent properties of the
PBN-nitrones was for acute ischemic stroke. This occurred during 1993-2006, when
the 2,4-disulfonylphenyl PBN derivative, called NXY-059 in the stroke studies,
was shown to be safe in humans and was taken all the way through clinical phase
3 trials and then was deemed to be ineffective. As summarized in this review,
because of its excellent human safety profile, 2,4-disulfonylphenyl PBN, now
called OKN-007 in the cancer studies, was tested as an anti-cancer agent in
several preclinical glioma models and shown to be very effective. Based on these
studies this compound is now scheduled to enter into early clinical trials for
astrocytoma/glioblastoma multiforme this year. The potential use of OKN-007 in
combination with neurotropic compounds such as the lanthionine ketamine esters
is discussed for glioblastoma multiforme as well as for various other
indications leading to dementia, such as aging, septic shock, and malaria
infections. There is much more research and development activity ongoing for
various indications with the nitrones, alone or in combination with other active
compounds, as briefly noted in this review.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.freeradbiomed.2013.01.033
PMCID: PMC3715559
PMID: 23419732 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest. Some of the authors
(RAF,RAT and KH) are inventors on issued or pending US patents and RAF is a
co-founder of Otologic Pharmaceutics, INC which has in commercial development a
treatment consisting of a nitrone combined with an antioxidant for noise-induced
hearing loss.
|
http://www.ncbi.nlm.nih.gov/pubmed/25686607
|
1. Nature. 2015 Apr 23;520(7548):558-62. doi: 10.1038/nature14154. Epub 2015 Feb
16.
Super-enhancers delineate disease-associated regulatory nodes in T cells.
Vahedi G(1), Kanno Y(1), Furumoto Y(2), Jiang K(1), Parker SC(3), Erdos MR(3),
Davis SR(4), Roychoudhuri R(4), Restifo NP(4), Gadina M(2), Tang Z(5), Ruan
Y(5), Collins FS(3), Sartorelli V(6), O'Shea JJ(1).
Author information:
(1)Lymphocyte Cell Biology Section, National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH),
Bethesda, Maryland 20892, USA.
(2)Translational Immunology Section, NIAMS, NIH, Bethesda, Maryland 20892, USA.
(3)Medical Genomics and Metabolic Genetics Branch, National Human Genome
Research Institute, NIH, Bethesda, Maryland 20892, USA.
(4)Center for Cancer Research, National Cancer Institute, NIH, Bethesda,
Maryland 20892, USA.
(5)The Jackson Laboratory for Genomic Medicine and Department of Genetic and
Development Biology, University of Connecticut, Farmington, Connecticut 06030,
USA.
(6)Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda,
Maryland 20892, USA.
Enhancers regulate spatiotemporal gene expression and impart cell-specific
transcriptional outputs that drive cell identity. Super-enhancers (SEs), also
known as stretch-enhancers, are a subset of enhancers especially important for
genes associated with cell identity and genetic risk of disease. CD4(+) T cells
are critical for host defence and autoimmunity. Here we analysed maps of mouse
T-cell SEs as a non-biased means of identifying key regulatory nodes involved in
cell specification. We found that cytokines and cytokine receptors were the
dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the
locus encoding Bach2, a key negative regulator of effector differentiation,
emerged as the most prominent T-cell SE, revealing a network in which
SE-associated genes critical for T-cell biology are repressed by BACH2.
Disease-associated single-nucleotide polymorphisms for immune-mediated
disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs
versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment
of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately
altered the expression of rheumatoid arthritis risk genes with SE structures.
Together, these results indicate that genes with SE architecture in T cells
encompass a variety of cytokines and cytokine receptors but are controlled by a
'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of
SEs allows the unbiased determination of key regulatory nodes in T cells, which
are preferentially modulated by pharmacological intervention.
DOI: 10.1038/nature14154
PMCID: PMC4409450
PMID: 25686607 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24941067
|
1. PLoS One. 2014 Jun 18;9(6):e99870. doi: 10.1371/journal.pone.0099870.
eCollection 2014.
Neurological assessment and its relationship to CSF biomarkers in amateur
boxers.
Neselius S(1), Brisby H(1), Marcusson J(2), Zetterberg H(3), Blennow K(4),
Karlsson T(5).
Author information:
(1)Department of Orthopaedics, Sahlgrenska University Hospital, Gothenburg,
Sweden; Institute for Clinical Sciences, the Sahlgrenska Academy at the
University of Gothenburg, Gothenburg, Sweden.
(2)Geriatric Section, University Hospital in Linköping, Linköping, Sweden;
Institution of Clinical and Experimental Medicine, Linköping University,
Linköping, Sweden.
(3)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal,
Sweden; Institute of Neuroscience and Physiology, Department of Psychiatry and
Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg,
Gothenburg, Sweden; UCL Institute of Neurology, Queen Square, London, United
Kingdom.
(4)Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal,
Sweden; Institute of Neuroscience and Physiology, Department of Psychiatry and
Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg,
Gothenburg, Sweden.
(5)Disability Research, Department of Behavioral Sciences and Learning,
Linköping University, Linköping, Sweden; Linnaeus Centre HEAD, Linköping
University, Linköping, Sweden.
BACKGROUND: Mild traumatic brain injury (TBI) or concussion is common in many
sports. Today, neuropsychological evaluation is recommended in the monitoring of
a concussion and in return-to-play considerations. To investigate the
sensitivity of neuropsychological assessment, we tested amateur boxers post bout
and compared with controls. Further the relationship between neuropsychological
test results and brain injury biomarkers in the cerebrospinal fluid (CSF) were
investigated.
METHOD: Thirty amateur boxers on high elite level with a minimum of 45 bouts and
25 non-boxing matched controls were included. Memory tests (Rey Osterrieth
Complex Figure, Listening Span, Digit Span, Controlled Word Association Test,
and computerized testing of episodic memory), tests of processing speed and
executive functions (Trail Making, Reaction Time, and Finger Tapping) were
performed and related to previously published CSF biomarker results for the
axonal injury marker neurofilament light (NFL).
RESULTS: The neurological assessment showed no significant differences between
boxers and controls, although elevated CSF NFL, as a sign of axonal injury, was
detected in about 80% of the boxers 1-6 days post bout. The investigation of the
relationship between neuropsychological evaluation and CSF NFL concentrations
revealed that boxers with persisting NFL concentration elevation after at least
14 days resting time post bout, had a significantly poorer performance on Trail
Making A (p = 0.041) and Simple Reaction Time (p = 0.042) compared to other
boxers.
CONCLUSION: This is the first study showing traumatic axonal brain injury can be
present without measureable cognitive impairment. The repetitive, subconcussive
head trauma in amateur boxing causes axonal injury that can be detected with
analysis of CSF NFL, but is not sufficient to produce impairment in memory
tests, tests of processing speed, or executive functions. The association of
prolonged CSF NFL increase in boxers with impairment of processing speed is an
interesting observation, which needs to be verified in larger studies.
DOI: 10.1371/journal.pone.0099870
PMCID: PMC4062456
PMID: 24941067 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/21619633
|
1. BMC Genomics. 2011 May 27;12:270. doi: 10.1186/1471-2164-12-270.
Genomic features and computational identification of human microRNAs under
long-range developmental regulation.
Sheng Y(1), Previti C.
Author information:
(1)Computational Biology Unit, Bergen Center for Computational Science, and Sars
International Centre for Marine Molecular Biology, University of Bergen, Bergen,
5008, Norway. Ying.Sheng@medisin.uio.no
BACKGROUND: Recent functional studies have demonstrated that many microRNAs
(miRNAs) are expressed by RNA polymerase II in a specific spatiotemporal manner
during the development of organisms and play a key role in cell-lineage
decisions and morphogenesis. They are therefore functionally related to a number
of key protein coding developmental genes, that form genomic regulatory blocks
(GRBs) with arrays of highly conserved non-coding elements (HCNEs) functioning
as long-range enhancers that collaboratively regulate the expression of their
target genes. Given this functional similarity as well as recent zebrafish
transgenesis assays showing that the miR-9 family is indeed regulated by HCNEs
with enhancer activity, we hypothesized that this type of miRNA regulation is
prevalent. In this paper, we therefore systematically investigate the regulatory
landscape around conserved self-transcribed miRNAs (ST miRNAs), with their own
known or computationally inferred promoters, by analyzing the hallmarks of GRB
target genes. These include not only the density of HCNEs in their vicinity but
also the presence of large CpG islands (CGIs) and distinct patterns of histone
modification marks associated with developmental genes.
RESULTS: Our results show that a subset of the conserved ST miRNAs we studied
shares properties similar to those of protein-coding GRB target genes: they are
located in regions of significantly higher HCNE/enhancer binding density and are
more likely to be associated with CGIs. Furthermore, their putative promoters
have both activating as well as silencing histone modification marks during
development and differentiation. Based on these results we used both an elevated
HCNE density in the genomic vicinity as well as the presence of a bivalent
promoter to identify 29 putative GRB target miRNAs/miRNA clusters, over
two-thirds of which are known to play a role during development and
differentiation. Furthermore these predictions include miRNAs of the miR-9
family, which are the only experimentally verified GRB target miRNAs.
CONCLUSIONS: A subset of the conserved miRNA loci we investigated exhibits
typical characteristics of GRB target genes, which may partially explain their
complex expression profiles during development.
DOI: 10.1186/1471-2164-12-270
PMCID: PMC3123655
PMID: 21619633 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22435031
|
1. Hippokratia. 2011 Jul;15(3):278-9.
Identification of a mutation in the MTM1 gene, associated with X-linked
myotubular myopathy, in a Greek family.
Fidani L, Karagianni P, Tsakalidis C, Mitsiakos G, Hatziioannidis I, Biancalana
V, Nikolaidis N.
Erratum in
Hippokratia. 2021 Apr-Jun;25(2):99.
X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy, usually
characterized by severe hypotonia and respiratory insufficiency at birth, in
affected, male infants. The disease is causally associated with mutations in the
MTM1 gene, coding for phosphatase myotubularin. We report a severe case of XLMTM
with a novel mutation, at a donor splicing site (c.1467+1G) previously
associated with severe phenotype. The mutation was also identified in the
patient's mother, providing an opportunity for sound genetic counseling.
PMCID: PMC3306040
PMID: 22435031
|
http://www.ncbi.nlm.nih.gov/pubmed/15373777
|
1. J Invest Dermatol. 2004 Oct;123(4):715-32. doi:
10.1111/j.0022-202X.2004.23213.x.
Stratum corneum keratin structure, function, and formation: the cubic
rod-packing and membrane templating model.
Norlén L(1), Al-Amoudi A.
Author information:
(1)Group of Applied Physics-Biomedical, Department of Physics, University of
Geneva, Geneva, Switzerland. lars.norlen@physics.unige.ch
Comment in
J Invest Dermatol. 2004 Oct;123(4):ix-x. doi:
10.1111/j.0022-202X.2004.23242.x.
A new model for stratum corneum keratin structure, function, and formation is
presented. The structural and functional part of the model, which hereafter is
referred to as "the cubic rod-packing model", postulates that stratum corneum
keratin intermediate filaments are arranged according to a cubic-like
rod-packing symmetry with or without the presence of an intracellular lipid
membrane with cubic-like symmetry enveloping each individual filament. The new
model could account for (i) the cryo-electron density pattern of the native
corneocyte keratin matrix, (ii) the X-ray diffraction patterns, (iii) the
swelling behavior, and (iv) the mechanical properties of mammalian stratum
corneum. The morphogenetic part of the model, which hereafter is referred to as
"the membrane templating model", postulates the presence in cellular space of a
highly dynamic small lattice parameter (<30 nm) membrane structure with
cubic-like symmetry, to which keratin is associated. It further proposes that
membrane templating, rather than spontaneous self-assembly, is responsible for
keratin intermediate filament formation and dynamics. The new model could
account for (i) the cryo-electron density patterns of the native keratinocyte
cytoplasmic space, (ii) the characteristic features of the keratin network
formation process, (iii) the dynamic properties of keratin intermediate
filaments, (iv) the close lipid association of keratin, (v) the insolubility in
non-denaturating buffers and pronounced polymorphism of keratin assembled in
vitro, and (vi) the measured reduction in cell volume and hydration level
between the stratum granulosum and stratum corneum. Further, using
cryo-transmission electron microscopy on native, fully hydrated, vitreous
epidermis we show that the subfilametous keratin electron density pattern
consists, both in corneocytes and in viable keratinocytes, of one axial
subfilament surrounded by an undetermined number of peripheral subfilaments
forming filaments with a diameter of approximately 8 nm.
DOI: 10.1111/j.0022-202X.2004.23213.x
PMID: 15373777 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23822165
|
1. Dis Esophagus. 2014 Apr;27(3):294-302. doi: 10.1111/dote.12100. Epub 2013 Jul
4.
CXCR4 heterogeneous expression in esophageal squamous cell cancer and stronger
metastatic potential with CXCR4-positive cancer cells.
Lu CL(1), Guo J, Gu J, Ge D, Hou YY, Lin ZW, Ding JY.
Author information:
(1)Department of Thoracic Surgery, Zhongshan Hospital, Fudan University,
Shanghai, China.
CXCR4 belongs to a family of G protein-coupled cell surface receptors and has
been proved to a prognostic marker in a various tumors, including esophageal
squamous cell cancer. In this study, we analyzed CXCR4 expression in tumor
tissue and metastatic tumor tissues of lymph node by immunohistochemistry. CXCR4
was found to be an independent factor of patients' survival and heterogeneously
expressed in tumor tissues. Compared with the primary tumor tissues, the scores
of CXCR4 expression were significantly higher in corresponding metastatic tumor
tissues of lymph nodes (P < 0.01). It was suggested CXCR4-positive cells were
prone to migrate to lymph nodes. In the further experiments in vitro, we
confirmed heterogeneous expression of CXCR4 in esophageal squamous cell cancer
cell lines (KYSE70, Ec109, and CaES17) by flow cytometry analysis. Meanwhile,
two subpopulations were isolated from Ec109 based on CXCR4 membrane expression
by fluorescence-activated cell sorting. CXCR4-positive cells showed stronger
migration ability in Boyden chamber assay than CXCR4 negative ones (P < 0.01).
However, no significant difference of cell proliferation was found between the
two subpopulations in colony formation assay (P > 0.05). We concluded that CXCR4
might be a key molecule in esophageal squamous cell cancer metastasis.
© 2013 Wiley Periodicals, Inc. and the International Society for Diseases of the
Esophagus.
DOI: 10.1111/dote.12100
PMID: 23822165 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8779840
|
1. Am J Physiol. 1996 Feb;270(2 Pt 2):H638-44. doi:
10.1152/ajpheart.1996.270.2.H638.
Regulation of SERCA 2 expression by thyroid hormone in cultured chick embryo
cardiomyocytes.
Fisher DJ(1), Phillips S, McQuinn T.
Author information:
(1)Lillie Frank Abercrombie Section of Pediatric Cardiology, Department of
Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
We investigated the role of thyroid hormone in the physiological perinatal
increase in cardiac sarcoplasmic reticulum (SR) Ca(2+)-adenosinetriphosphatase
(ATPase) expression. We isolated and cultured the cardiomyocytes in 10(-8) M
triiodothyronine (T3) for 48 h and then measured SR Ca(2+)-ATPase mRNA and
immunodetectable protein contents as well as SR-dependent 45Ca2+ uptake rate. We
also examined the effect of T3 on expression of the same gene in monkey kidney
CV-1 cells, which do not express thyroid hormone receptors. T3 increased
cardiomyocyte SR Ca2+ pump mRNA content by 289 +/- 35%, and immunodetectable SR
Ca2+ pump protein content by 255 +/- 44%, and SR-specific 45Ca2+ uptake rate by
189 +/- 22% (P < 0.01 for each). In contrast, T3 had no significant effect on
the total cellular RNA or protein contents in the cardiomyocyte, and there was
no effect of T3 on Ca(2+)-ATPase mRNA content in the thyroid hormone
receptor-negative CV-1 cells. These data demonstrate that T3 increases
expression of the cardiac SR Ca2+ pump, that the effect can be localized to the
cardiomyocyte, and that the effect is dependent on thyroid hormone receptors.
These data are consistent with pretranslational and possibly transcriptional
level effect of thyroid hormone on the cardiac SR Ca2+ pump gene (SERCA 2). The
gestation-associated increase in thyroid hormone may be at least partially
responsible for the previously demonstrated perinatal increase in cardiac SR
Ca2+ pump expression.
DOI: 10.1152/ajpheart.1996.270.2.H638
PMID: 8779840 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24339831
|
1. Front Genet. 2013 Dec 10;4:283. doi: 10.3389/fgene.2013.00283. eCollection
2013.
Circ2Traits: a comprehensive database for circular RNA potentially associated
with disease and traits.
Ghosal S(1), Das S, Sen R, Basak P, Chakrabarti J.
Author information:
(1)Computational Biology Group, Theory Department, Indian Association for the
Cultivation of Science Kolkata, India.
Circular RNAs are new players in regulation of post transcriptional gene
expression. Animal genomes express many circular RNAs from diverse genomic
locations. A recent study has validated a fairly large number of circular RNAs
in human, mouse, and nematode. Circular RNAs play a crucial role in fine tuning
the level of miRNA mediated regulation of gene expression by sequestering the
miRNAs. Their interaction with disease associated miRNAs indicates that circular
RNAs are important for disease regulation. In this paper we studied the
potential association of circular RNAs (circRNA) with human diseases in two
different ways. Firstly, the interactions of circRNAs with disease associated
miRNAs were identified, following which the likelihood of a circRNA being
associated with a disease was calculated. For the miRNAs associated with
individual diseases, we constructed a network of predicted interactions between
the miRNAs and protein coding, long non-coding and circular RNA genes. We
carried out gene ontology (GO) enrichment analysis on the set of protein coding
genes in the miRNA- circRNA interactome of individual diseases to check the
enrichment of genes associated with particular biological processes. Secondly,
disease associated SNPs were mapped on circRNA loci, and Argonaute (Ago)
interaction sites on circular RNAs were identified. We compiled a database of
disease-circRNA association in Circ2Traits (http://gyanxet-beta.com/circdb/),
the first comprehensive knowledgebase of potential association of circular RNAs
with diseases in human.
DOI: 10.3389/fgene.2013.00283
PMCID: PMC3857533
PMID: 24339831
|
http://www.ncbi.nlm.nih.gov/pubmed/15047890
|
1. Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5069-74. doi:
10.1073/pnas.0400913101. Epub 2004 Mar 26.
Gene discovery in genetically labeled single dopaminergic neurons of the retina.
Gustincich S(1), Contini M, Gariboldi M, Puopolo M, Kadota K, Bono H, LeMieux J,
Walsh P, Carninci P, Hayashizaki Y, Okazaki Y, Raviola E.
Author information:
(1)Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue,
Boston, MA 02115, USA.
In the retina, dopamine plays a central role in neural adaptation to light.
Progress in the study of dopaminergic amacrine (DA) cells has been limited
because they are very few (450 in each mouse retina, 0.005% of retinal neurons).
Here, we applied transgenic technology, single-cell global mRNA amplification,
and cDNA microarray screening to identify transcripts present in DA cells. To
profile gene expression in single neurons, we developed a method (SMART7) that
combines a PCR-based initial step (switching mechanism at the 5' end of the RNA
transcript or SMART) with T7 RNA polymerase amplification. Single-cell targets
were synthesized from genetically labeled DA cells to screen the RIKEN 19k mouse
cDNA microarrays. Seven hundred ninety-five transcripts were identified in DA
cells at a high level of confidence, and expression of the most interesting
genes was confirmed by immunocytochemistry. Twenty-one previously undescribed
proteins were found in DA cells, including a chloride channel, receptors and
other membrane glycoproteins, kinases, transcription factors, and secreted
neuroactive molecules. Thirty-eight percent of transcripts were ESTs or coding
for hypothetical proteins, suggesting that a large portion of the DA cell
proteome is still uncharacterized. Because cryptochrome-1 mRNA was found in DA
cells, immunocytochemistry was extended to other components of the circadian
clock machinery. This analysis showed that DA cells contain the most common
clock-related proteins.
DOI: 10.1073/pnas.0400913101
PMCID: PMC387375
PMID: 15047890 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20683334
|
1. Eur J Anaesthesiol. 2010 Oct;27(10):874-81. doi: 10.1097/EJA.0b013e32833d56b7.
Reversal of rocuronium-induced neuromuscular blockade with sugammadex compared
with neostigmine during sevoflurane anaesthesia: results of a randomised,
controlled trial.
Blobner M(1), Eriksson LI, Scholz J, Motsch J, Della Rocca G, Prins ME.
Author information:
(1)Klinik für Anästhesiologie der Technischen Universität München, Munich,
Germany. Blobner@lrz.tum.de
BACKGROUND AND OBJECTIVE: Sugammadex, a modified gamma-cyclodextrin, is a
selective relaxant-binding agent designed to reverse the effects of the
steroidal neuromuscular blocking agents rocuronium or vecuronium. This study
compared the efficacy of sugammadex and neostigmine for reversal of
neuromuscular blockade induced by rocuronium for facilitating elective surgery.
METHODS: This randomised, multicentre, parallel-group trial included 98 adult
patients. Patients received intravenous propofol for induction followed by
sevoflurane maintenance anaesthesia. Neuromuscular blockade was monitored using
acceleromyography and a train-of-four (TOF) mode of stimulation. Patients were
randomly allocated to receive sugammadex 2.0 mg kg(-1) or neostigmine 50 microg
kg (-1) (with glycopyrrolate 10 microg kg(-1)) at reappearance of the second
response of the TOF (mean 16% twitch height of first response) after the last
dose of rocuronium. Safety was evaluated by assessing adverse events, laboratory
variables and vital signs.
RESULTS: Time to recovery of the TOF ratio of 0.9 after sugammadex compared with
neostigmine was significantly shorter (P < 0.0001), being 1.5 versus 18.6 min
(geometric means). Predictability of response was greater with sugammadex than
neostigmine: with 98% of sugammadex patients versus 11% of neostigmine patients
recovering to a TOF ratio of 0.9 within 5 min. There were no clinical events
related to residual neuromuscular blockade or reoccurrence of blockade. Serious
adverse events were observed in two sugammadex-treated patients and in three
neostigmine-treated patients, respectively, but none were considered related to
study drugs.
CONCLUSION: Sugammadex achieved significantly faster recovery of neuromuscular
function after rocuronium to a TOF ratio of 0.9 compared with neostigmine
(Clinicaltrials.gov identifier: NCT00451217).
DOI: 10.1097/EJA.0b013e32833d56b7
PMID: 20683334 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17289402
|
1. J Struct Biol. 2007 Jun;158(3):378-85. doi: 10.1016/j.jsb.2006.12.007. Epub
2006 Dec 28.
Dissecting the 3-D structure of vimentin intermediate filaments by cryo-electron
tomography.
Goldie KN(1), Wedig T, Mitra AK, Aebi U, Herrmann H, Hoenger A.
Author information:
(1)Structural and Computational Biology Unit, European Molecular Biology Lab,
Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
Vimentin polymerizes via complex lateral interactions of coiled-coil dimers into
long, flexible filaments referred to as intermediate filaments (IFs).
Intermediate in diameter between microtubules and microfilaments, IFs constitute
the third cytoskeletal filament system of metazoan cells. Here we investigated
the molecular basis of the 3-D architecture of vimentin IFs by cryo-electron
microscopy (cryo-EM) as well as cryo-electron tomography (Cryo-ET) 3-D
reconstruction. We demonstrate that vimentin filaments in cross-section exhibit
predominantly a four-stranded protofibrilar organization with a right-handed
supertwist with a helical pitch of about 96 nm. Compact filaments imaged by
cryo-EM appear surprisingly straight and hence appear very stiff. In addition,
IFs exhibited an increased flexibility at sites of partial unraveling. This is
in strong contrast to chemically fixed, negatively stained preparations of
vimentin filaments that generally exhibit smooth bending without untwisting. At
some point along the filament unraveling may be triggered and propagates in a
cooperative manner so that long stretches of filaments appear to have unraveled
rapidly in a coordinated fashion.
DOI: 10.1016/j.jsb.2006.12.007
PMID: 17289402 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16061665
|
1. Cancer Res. 2005 Aug 1;65(15):6828-34. doi: 10.1158/0008-5472.CAN-05-1119.
Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer.
Gauger MA(1), Sancar A.
Author information:
(1)Department of Biochemistry and Biophysics, University of North Carolina
School of Medicine, Chapel Hill, North Carolina 27599, USA.
It has been reported that disruption of the circadian clock may lead to
increased risk of breast cancer in humans and to a high rate or ionizing
radiation-induced tumors and mortality in mice. Cryptochrome 1 and cryptochrome
2 proteins are core components of the mammalian circadian clock and mice mutated
in both genes are arrhythmic. We tested Cry1-/- Cry2-/- mice and fibroblasts
derived from these mice for radiation-induced cancer and killing and DNA damage
checkpoints and killing, respectively. We find that the mutant mice are
indistinguishable from the wild-type controls with respect to radiation-induced
morbidity and mortality. Similarly, the Cry1-/- Cry2-/-mutant fibroblasts are
indistinguishable from the wild-type controls with respect to their sensitivity
to ionizing radiation and UV radiation and ionizing radiation-induced DNA damage
checkpoint response. Our data suggest that disruption of the circadian clock in
itself does not compromise mammalian DNA repair and DNA damage checkpoints and
does not predispose mice to spontaneous and ionizing radiation-induced cancers.
We conclude that the effect of circadian clock disruption on cellular response
to DNA damage and cancer predisposition in mice may depend on the mechanism by
which the clock is disrupted.
DOI: 10.1158/0008-5472.CAN-05-1119
PMID: 16061665 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20880963
|
1. Endocr Rev. 2011 Feb;32(1):64-80. doi: 10.1210/er.2009-0040. Epub 2010 Sep 29.
Thyronamines--past, present, and future.
Piehl S(1), Hoefig CS, Scanlan TS, Köhrle J.
Author information:
(1)Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin
Berlin, Charité Campus Virchow-Klinikum (Südring 10), Augustenburger Platz 1,
13353 Berlin, Germany.
Thyronamines (TAMs) are a newly identified class of endogenous signaling
compounds. Their structure is identical to that of thyroid hormone and
deiodinated thyroid hormone derivatives, except that TAMs do not possess a
carboxylate group. Despite some initial publications dating back to the 1950s,
TAMs did not develop into an independent area of research until 2004, when they
were rediscovered as potential ligands to a class of G protein-coupled receptors
called trace-amine associated receptors. Since this discovery, two
representatives of TAMs, namely 3-iodothyronamine (3-T(1)AM) and thyronamine
(T(0)AM), have been detected in vivo. Intraperitoneal or central injection of
3-T(1)AM or T(0)AM into mice, rats, or Djungarian hamsters caused various prompt
effects, such as metabolic depression, hypothermia, negative chronotropy,
negative inotropy, hyperglycemia, reduction of the respiratory quotient,
ketonuria, and reduction of fat mass. Although their physiological function
remains elusive, 3-T(1)AM and T(0)AM have already revealed promising therapeutic
potential because they represent the only endogenous compounds inducing
hypothermia as a prophylactic or acute treatment of stroke and might thus be
expected to cause fewer side effects than synthetic compounds. This review
article summarizes the still somewhat scattered data on TAMs obtained both
recently and more than 20 yr ago to yield a complete and updated picture of the
current state of TAM research.
DOI: 10.1210/er.2009-0040
PMID: 20880963 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23737378
|
1. Laryngoscope. 2013 Aug;123(8):1889-95. doi: 10.1002/lary.23884. Epub 2013 Jun
4.
Is there a "July effect" for head and neck cancer surgery?
Hennessey PT(1), Francis HW, Gourin CG.
Author information:
(1)Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University,
Baltimore, Maryland 21287, USA.
OBJECTIVES/HYPOTHESIS: A "July effect" of increased complications when new
trainees begin residency has been reported widely by the media. We sought to
determine the effect of admission month on in-hospital mortality, complications,
length of hospitalization, and costs for patients undergoing head and neck
cancer (HNCA) surgery.
STUDY DESIGN: Retrospective cross-sectional study.
METHODS: Discharge data from the Nationwide Inpatient Sample for 48,263 patients
who underwent an ablative procedure for a malignant oral cavity, laryngeal,
hypopharyngeal, or oropharyngeal neoplasm in 2005 to 2008 were analyzed using
cross-tabulations and multivariate regression modeling.
RESULTS: There were 3,812 cases admitted in July (8%). July admission was
significantly associated with Medicaid (RRR 1.40, P = 0.011) or self-pay payor
status (RRR 1.40, P = 0.022), medium hospital bed size (RRR 1.63, P = 0.033) and
large hospital bed size (RRR 1.73, P = 0.013). There was no association between
July admission and other patient or hospital demographic characteristics. Major
procedures and comorbidity were significantly associated with in-hospital death,
surgical and medical complications, length of hospitalization, and costs, but no
association was found for July admission, July through September discharge, or
teaching hospital status and short-term morbidity or mortality. Teaching
hospitals and large hospital bed size were predictors of increased length of
hospitalization and costs; and private, for profit hospitals were additionally
associated with increased costs. No interaction between July admission and
teaching hospitals was found for any of the outcome variables studied.
CONCLUSIONS: These data do not support evidence of a "July effect" or an
increase in morbidity or mortality at teaching hospitals providing HNCA surgical
care.
© 2013 The American Laryngological, Rhinological and Otological Society, Inc.
DOI: 10.1002/lary.23884
PMID: 23737378 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8389710
|
1. Eur Heart J. 1993 May;14(5):629-33. doi: 10.1093/eurheartj/14.5.629.
Triiodothyronine therapy in open-heart surgery: from hope to disappointment.
Teiger E(1), Menasché P, Mansier P, Chevalier B, Lajeunie E, Bloch G, Piwnica A.
Author information:
(1)Department of Cardiovascular Surgery, Hopital Lariboisière, Paris, France.
A controversy persists as to whether cardiopulmonary bypass (CPB) decreases
plasma levels of triiodothyronine (T3), thereby justifying peri-operative
administration of T3 to improve haemodynamic recovery. To examine the effects of
T3 therapy on post-CPB haemodynamics and to determine whether the potential
inotropic effects of T3 are mediated by an increase in beta-adrenergic
responsiveness, a prospective, randomized, double-blind, placebo-controlled
study was performed in 20 patients undergoing cardiac surgery with CPB. T3 or
placebo solution (10 patients in each group) was given intravenously at the time
of aortic unclamping and 4, 8, 12 and 20 h thereafter. End points included (1)
thyroid hormone levels measured by radioimmunoassay (2) standard haemodynamic
parameters (3) the density of lymphocyte beta-adrenoceptors measured by a
radioligand (125I-iodocyanopindolol) binding technique. Post-CPB values (cross
clamp removal) of T3 (pg.ml-1) were not significantly decreased compared with
pre-CPB values: 3.3 +/- 0.2 vs 3.1 +/- 0.2 in controls and 3.3 +/- 0.4 vs 3.7
+/- 0.6 in T3-treated patients, respectively. The haemodynamic parameters were
no different between the two groups at any postoperative time point. Likewise,
density and affinity of lymphocyte beta-adrenoceptors were not significantly
different from pre-operative values in either group. Thus, there seems to be no
sound justification for a routine use of T3 in patients undergoing open-heart
procedures.
DOI: 10.1093/eurheartj/14.5.629
PMID: 8389710 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/1415533
|
1. Am J Physiol. 1992 Sep;263(3 Pt 1):E534-40. doi:
10.1152/ajpendo.1992.263.3.E534.
Thyroid hormone effects on cardiac gene expression independent of cardiac growth
and protein synthesis.
Ojamaa K(1), Samarel AM, Kupfer JM, Hong C, Klein I.
Author information:
(1)Department of Medicine, North Shore University Hospital, Manhasset, New York
11030.
Prior studies have demonstrated the importance of hemodynamic loading in
mediating thyroxine (T4)-induced cardiac hypertrophy. Direct cellular effects of
thyroid hormone have been implicated in modulating the expression of the myosin
heavy chain (MHC) genes and the slow sarcoplasmic reticulum calcium adenosine
triphosphatase (SR Ca(2+)-ATPase) gene. In the present report, administration of
T4 for 72 h did not stimulate growth of the hemodynamically unloaded heterotopic
isograft. The synthetic rates of total cardiac proteins and MHC in the isograft
remained significantly lower at 64 and 53% of the respective rates measured
simultaneously in the in situ working heart. Although total left ventricle RNA
content in the isograft was unchanged by T4, alpha-MHC and SR Ca(2+)-ATPase mRNA
concentrations were increased 181 and 208%, respectively, and the previously
observed beta-MHC expression was completely prevented. These data indicate that,
although T4 requires an increased hemodynamic load to stimulate cardiac protein
synthesis, it is capable of directly altering the expression of at least two
myocyte-specific genes. Therefore some of the phenotypic alterations observed
with thyroid hormone treatment are the result of direct effects of the hormones
on specific cardiac genes and independent of changes in cardiac growth.
DOI: 10.1152/ajpendo.1992.263.3.E534
PMID: 1415533 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9781038
|
1. Eur J Hum Genet. 1998 Jul-Aug;6(4):325-30. doi: 10.1038/sj.ejhg.5200189.
Genomic organization of the MTM1 gene implicated in X-linked myotubular
myopathy.
Laporte J(1), Guiraud-Chaumeil C, Tanner SM, Blondeau F, Hu LJ, Vicaire S,
Liechti-Gallati S, Mandel JL.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS,
Illkirch, France.
X-linked recessive myotubular myopathy (XLMTM) is a very severe congenital
muscular disease characterised by an impaired maturation of muscle fibres, and
caused by defects in the MTM1 gene. This gene defines a new family of putative
tyrosine phosphatases conserved through evolution. We have determined intronic
flanking sequences for all the 15 exons to facilitate the detection of mutations
in patients and genetic counselling. We characterised a new polymorphic marker
in the immediate vicinity of the gene, which might prove useful for linkage
analysis. Sequencing of the TATA-less predicted promoter provides the basis for
transcriptional regulatory studies.
DOI: 10.1038/sj.ejhg.5200189
PMID: 9781038 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9309268
|
1. Pathol Biol (Paris). 1997 Jun;45(6):500-5.
Genetics of ageing.
Macieira-Coelho A(1).
Author information:
(1)INSERM Génétique et Vieillissement, Université de Paris VI, Versailles,
France.
The classical arguments favouring a genetic basis of ageing are reviewed
emphasizing the questions that remain unanswered. Genes cannot be the sole
genetic determinants of ageing. Mendel's paradigm cannot anymore explain all the
results recently obtained. Different aspects of the organization of the genome
must also play a role in ageing. The functions of the largest part of the human
genome remain unknown. Moreover the different genetic theories of ageing are
based on natural selection. However, other paradigms are being proposed that can
complement or replace Darwin's paradigm. They are based on the spontaneous
organization of complex systems. They must be considered in the reappraisal of
the ageing phenomenon.
PMID: 9309268 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22855832
|
1. Genes Dev. 2012 Aug 1;26(15):1714-28. doi: 10.1101/gad.194209.112.
Cfp1 integrates both CpG content and gene activity for accurate H3K4me3
deposition in embryonic stem cells.
Clouaire T(1), Webb S, Skene P, Illingworth R, Kerr A, Andrews R, Lee JH,
Skalnik D, Bird A.
Author information:
(1)Wellcome Trust Centre for Cell Biology, University of Edinburgh, United
Kingdom.
Trimethylation of histone H3 Lys 4 (H3K4me3) is a mark of active and poised
promoters. The Set1 complex is responsible for most somatic H3K4me3 and contains
the conserved subunit CxxC finger protein 1 (Cfp1), which binds to unmethylated
CpGs and links H3K4me3 with CpG islands (CGIs). Here we report that Cfp1 plays
unanticipated roles in organizing genome-wide H3K4me3 in embryonic stem cells.
Cfp1 deficiency caused two contrasting phenotypes: drastic loss of H3K4me3 at
expressed CGI-associated genes, with minimal consequences for transcription, and
creation of "ectopic" H3K4me3 peaks at numerous regulatory regions. DNA binding
by Cfp1 was dispensable for targeting H3K4me3 to active genes but was required
to prevent ectopic H3K4me3 peaks. The presence of ectopic peaks at enhancers
often coincided with increased expression of nearby genes. This suggests that
CpG targeting prevents "leakage" of H3K4me3 to inappropriate chromatin
compartments. Our results demonstrate that Cfp1 is a specificity factor that
integrates multiple signals, including promoter CpG content and gene activity,
to regulate genome-wide patterns of H3K4me3.
DOI: 10.1101/gad.194209.112
PMCID: PMC3418589
PMID: 22855832 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23395387
|
1. Cytokine. 2013 Mar;61(3):792-800. doi: 10.1016/j.cyto.2013.01.003. Epub 2013
Feb 8.
Differences are evident within the CXCR4-CXCL12 axis between ethnically
divergent South African populations.
Shalekoff S(1), Schramm DB, Lassaunière R, Picton AC, Tiemessen CT.
Author information:
(1)Centre for HIV and STIs, National Institute for Communicable Diseases, and
Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South
Africa.
The G-protein-coupled receptor, CXCR4, is highly expressed on a number of cell
types, and together with its ligand, CXCL12, plays an important role in immune
development and trafficking of cells. CXCR4 promotes tumor growth, angiogenesis
and metastasis, and is a prognostic marker in a number of different types of
tumors. Additionally, CXCR4 is utilized, together with CD4, for entry of
T-tropic HIV viruses. Ethnic differences in incidence and mortality of various
cancers, and in the response to highly active antiretroviral treatment (HAART)
of HIV-1 infected individuals have been reported. The aim of this study was to
establish if differences in the CXCR4-CXCL12 axis exist between ethnically
divergent uninfected South Africans. CXCR4 density was significantly higher on
CD4(+) and CD8(+) T cells, B cells and CD56(dim) NK cells, and CXCL12 levels
lower in Black compared with Caucasian individuals. Furthermore, an inverse
correlation was observed between CXCR4 density on CD56(+) and CD3(+) cells and
age, only in Black individuals. CXCL12-3'A heterozygosity (AG) found in 28% of
Caucasians did not explain the higher plasma levels of CXCL12 compared to Black
individuals who were all GG genotypes, suggesting that other factors influence
homeostatic levels of CXCL12. In conclusion, this study demonstrates that
ethnically divergent populations show clear differences in both CXCR4 density
and CXCL12 plasma levels which may influence the course of cancer and HIV-1
infection.
Copyright © 2013 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.cyto.2013.01.003
PMID: 23395387 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18207470
|
1. Semin Fetal Neonatal Med. 2008 Apr;13(2):57-62. doi:
10.1016/j.siny.2007.11.001. Epub 2008 Jan 22.
Recent progress in non-invasive prenatal diagnosis.
Hahn S(1), Zhong XY, Holzgreve W.
Author information:
(1)University Women's Hospital/Department of Biomedicine, University Hospital
Basel, Switzerland. shahn@uhbs.ch
Although the first finding that fetal cells can enter the maternal circulation
was made more than a century ago, it is still unclear if this finding will be
translated into a clinically useful diagnostic tool in the foreseeable future.
However, significant progress has been made via the analysis of cell-free fetal
DNA in maternal plasma/serum and clinical services are now already being offered
for the determination of fetal rhesus D status and sex. Currently, however, this
technology is really only suited for the analysis of fetal genetic loci
completely absent from the maternal genome. The detection of more subtle fetal
genetic traits, such as point mutations involved in Mendelian disorders
(thalassaemia, cystic fibrosis), is considerably more complex. Preliminary
reports indicate that the detection of fetal aneuploidies might be possible
using epigenetically modified genes, e.g. maspin on chromosome 18. Additionally,
an exiting recent development is that it might be feasible to detect Down
syndrome via the quantitative assessment of placentally derived cell-free mRNA
of chromosome-21-specific genes such as PLAC4.
DOI: 10.1016/j.siny.2007.11.001
PMID: 18207470 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/10802345
|
1. Neurosci Res. 2000 May;37(1):67-78. doi: 10.1016/s0168-0102(00)00102-4.
Characterization of the subventricular zone of the adult human brain: evidence
for the involvement of Bcl-2.
Bernier PJ(1), Vinet J, Cossette M, Parent A.
Author information:
(1)Laboratoire de Neurobiologie, Centre de Recherche Université Laval
Robert-Giffard, 2601 Chemin de la Canardière, Local F-6500, Beauport, Canada.
The subventricular zone (SVZ) is an embryonic remnant that persists and remains
mitotically active throughout adulthood. The rodent SVZ harbors neuronal
precursors, principally in its anterior part, and generates neuroblasts that
migrate tangentially into the olfactory bulb, thus forming the so-called rostral
migratory stream. This study aimed at characterizing the SVZ in the human brain.
Antibodies raised against the widely used SVZ molecular markers nestin, glial
fibrillary acidic protein, beta-tubulin-III and polysialylated neural cell
adhesion molecule, have allowed us to characterize in detail a zone similar to
the rodent SVZ in humans. Virtually all portions of the lateral ventricle, as
well as the ventral (hypothalamic) sector of the third ventricle, displayed
immunoreactivity for most of the molecular markers. The midline region of the
septum (septal recess) and the ventral portion of the SVZ displayed a
particularly intense immunostaining for all SVZ markers. These two regions may
represent zones of adult neurogenesis that are unique to primates. Furthermore,
the anti-apoptotic protein Bcl-2 was found to be actively synthesized and
co-expressed with all the other markers throughout the entire SVZ. This study
reveals that a well-developed SVZ exists in the adult human brain and suggests
that Bcl-2 might play an important role in the functional organization of such a
system.
DOI: 10.1016/s0168-0102(00)00102-4
PMID: 10802345 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22140039
|
1. Am J Physiol Heart Circ Physiol. 2012 Feb 1;302(3):H621-33. doi:
10.1152/ajpheart.00825.2011. Epub 2011 Dec 2.
Altered clock gene expression and vascular smooth muscle diurnal contractile
variations in type 2 diabetic db/db mice.
Su W(1), Xie Z, Guo Z, Duncan MJ, Lutshumba J, Gong MC.
Author information:
(1)Departments of Physiology, University of Kentucky Medical Center, Lexington,
KY 40536, USA.
This study was designed to determine whether the 24-h rhythms of clock gene
expression and vascular smooth muscle (VSM) contractile responses are altered in
type 2 diabetic db/db mice. Control and db/db mice were euthanized at 6-h
intervals throughout the day. The aorta, mesenteric arteries, heart, kidney, and
brain were isolated. Clock and target gene mRNA levels were determined by either
real-time PCR or in situ hybridization. Isometric contractions were measured in
isolated aortic helical strips, and pressor responses to an intravenous
injection of vasoconstrictors were determined in vivo using radiotelemetry. We
found that the 24-h mRNA rhythms of the following genes were suppressed in db/db
mice compared with control mice: the clock genes period homolog 1/2 (Per1/2) and
cryptochrome 1/2 (Cry1/2) and their target genes D site albumin promoter-binding
protein (Dbp) and peroxisome proliferator-activated receptor-γ (Pparg) in the
aorta and mesenteric arteries; Dbp in the heart; Per1, nuclear receptor
subfamily 1, group D, member 1 (Rev-erba), and Dbp in the kidney; and Per1 in
the suprachiasmatic nucleus. The 24-h contractile variations in response to
phenylephrine (α(1)-agonist), ANG II, and high K(+) were significantly altered
in the aortas from db/db mice compared with control mice. The diurnal variations
of the in vivo pressor responses to phenylephrine and ANG II were lost in db/db
mice. Moreover, the 24-h mRNA rhythms of the contraction-related proteins Rho
kinase 1/2, PKC-potentiated phosphatase inhibitory protein of 17 kDa,
calponin-3, tropomyosin-1/2, and smooth muscle protein 22-α were suppressed in
db/db mice compared with control mice. Together, our data demonstrated that the
24-h rhythms of clock gene mRNA, mRNA levels of several contraction-related
proteins, and VSM contraction were disrupted in db/db mice, which may contribute
to the disruption of their blood pressure circadian rhythm.
DOI: 10.1152/ajpheart.00825.2011
PMCID: PMC3353796
PMID: 22140039 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11470472
|
1. Cardiovasc Res. 2001 Aug 1;51(2):322-30. doi: 10.1016/s0008-6363(01)00287-5.
3,5,3'-Triiodothyronine deprivation affects phenotype and intracellular [Ca2+]i
of human cardiomyocytes in culture.
Forini F(1), Paolicchi A, Pizzorusso T, Ratto GM, Saviozzi M, Vanini V, Iervasi
G.
Author information:
(1)Istituto di Fisiologia Clinica C.N.R., via Moruzzi 1, 56100, Pisa, Italy.
simona@ifc.cnr.it
OBJECTIVE: A decrease in plasma T3 concentration is a frequent finding in
patients with heart failure. However, the role of this 'low T3 syndrome' on
disease evolution has never been clarified. As phenotypic and functional
cardiomyocyte impairments are alterations that correlate with the failing
myocardium, we studied the long-term effects of T3 deprivation on human
cardiomyocyte structure and calcium handling.
METHODS: Atrial cardiomyocytes and myocardial tissue were cultured with or
without 3 nM T3. Microscopical examination of structural features was followed
by analysis of alpha-sarcomeric actinin and sarcoplasmic reticulum calcium
ATP-ase (SERCA-2) content. Calcium handling was studied by [Ca2+](i) imaging.
RESULTS: When stimulated with cyclopiazonic acid, a SERCA-2 inhibitor,
T3-deprived cardiomyocytes showed significantly faster (P=0.03) and more
transient (P=0.04) increases in [Ca(2+)](i) than T3-supplemented cells.
Moreover, in the T3-free cultures a significantly lower number of cells
(P=0.003) responded to caffeine, a typical activator of sarcoplasmic reticulum
Ca(2+)-release channel. T3-deprived cardiomyocytes also presented altered
morphology with larger dimensions than T3-supplemented cells (P < 0.0001).
Additionally, in T3-deprived samples alpha-sarcomeric actinin and SERCA-2
protein levels were reduced to 65.6 +/- 3% (P < 0.0001) and 74.1 +/- 4%
(P=0.005), respectively, when compared with the T3-supplemented group.
CONCLUSIONS: Our data show that human cardiomyocyte calcium handling and
phenotype are strongly influenced by T3 suggesting important implications of the
'low T3 syndrome' on the progression of heart failure.
DOI: 10.1016/s0008-6363(01)00287-5
PMID: 11470472 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24578770
|
1. West J Emerg Med. 2014 Feb;15(1):88-93. doi: 10.5811/westjem.2013.10.18123.
The July Effect: is emergency department length of stay greater at the beginning
of the hospital academic year?
Riguzzi C(1), Hern HG(1), Vahidnia F(1), Herring A(1), Alter H(1).
Author information:
(1)Highland Hospital, Alameda Health System, Oakland, California.
INTRODUCTION: There has been concern of increased emergency department (ED)
length of stay (LOS) during the months when new residents are orienting to their
roles. This so-called "July Effect" has long been thought to increase LOS, and
potentially contribute to hospital overcrowding and increased waiting time for
patients. The objective of this study is to determine if the average ED LOS at
the beginning of the hospital academic year differs for teaching hospitals with
residents in the ED, when compared to other months of the year, and as compared
to non-teaching hospitals without residents.
METHODS: We performed a retrospective analysis of a nationally representative
sample of 283,621 ED visits from the National Hospital Ambulatory Medical Care
Survey (NHAMCS), from 2001 to 2008. We stratified the sample by proportion of
visits seen by a resident, and compared July to the rest of the year, July to
June, and July and August to the remainder of the year. We compared LOS for
teaching hospitals to non-teaching hospitals. We used bivariate statistics, and
multivariable regression modeling to adjust for covariates.
RESULTS: Our findings show that at teaching hospitals with residents, there is
no significant difference in mean LOS for the month of July (275 minutes) versus
the rest of the year (259 min), July and August versus the rest of the year, or
July versus June. Non-teaching hospital control samples yielded similar results
with no significant difference in LOS for the same time periods. There was a
significant difference found in mean LOS at teaching hospitals (260 minutes) as
compared to non-teaching hospitals (185 minutes) throughout the year (p<0.0001).
CONCLUSION: Teaching hospitals with residents in the ED have slower throughput
of patients, no matter what time of year. Thus, the "July Effect" does not
appear to a factor in ED LOS. This has implications as overcrowding and patient
boarding become more of a concern in our increasingly busy EDs. These results
question the need for additional staffing early in the academic year. Teaching
hospitals may already institute more robust staffing during this time,
preventing any significant increase in LOS. Multiple factors contribute to long
stays in the ED. While patients seen by residents stay longer in the ED, there
is little variability throughout the academic year.
DOI: 10.5811/westjem.2013.10.18123
PMCID: PMC3935791
PMID: 24578770 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22952936
|
1. PLoS One. 2012;7(8):e44237. doi: 10.1371/journal.pone.0044237. Epub 2012 Aug
29.
Diurnal variation of hepatic antioxidant gene expression in mice.
Xu YQ(1), Zhang D, Jin T, Cai DJ, Wu Q, Lu Y, Liu J, Klaassen CD.
Author information:
(1)Zunyi Medical College, Zunyi, China.
BACKGROUND: This study was aimed to examine circadian variations of hepatic
antioxidant components, including the Nrf2- pathway, the glutathione (GSH)
system, antioxidant enzymes and metallothionein in mouse liver.
METHODS AND RESULTS: Adult mice were housed in light- and temperature-controlled
facilities for 2 weeks, and livers were collected every 4 h during the 24 h
period. Total RNA was isolated, purified, and subjected to real-time RT-PCR
analysis. Hepatic mRNA levels of Nrf2, Keap1, Nqo1 and Gclc were higher in the
light-phase than the dark-phase, and were female-predominant. Hepatic GSH
presented marked circadian fluctuations, along with glutathione S-transferases
(GST-α1, GST-µ, GST-π) and glutathione peroxidase (GPx1). The expressions of
GPx1, GST-µ and GST-π mRNA were also higher in females. Antioxidant enzymes
Cu/Zn superoxide dismutase (Sod1), catalase (CAT), cyclooxygenase-2 (Cox-2) and
heme oxygenase-1 (Ho-1) showed circadian rhythms, with higher expressions of
Cox-2 and CAT in females. Metallothionein, a small non-enzymatic antioxidant
protein, showed dramatic circadian variation in males, but higher expression in
females. The circadian variations of the clock gene Brain and Muscle Arnt-like
Protein-1(Bmal1), albumin site D-binding protein (Dbp), nuclear receptor
Rev-Erbα (Nr1d1), period protein (Per1 and Per2) and cryptochrome 1(Cry1) were
in agreement with the literature. Furthermore, acetaminophen hepatotoxicity is
more severe when administered in the afternoon when hepatic GSH was lowest.
CONCLUSIONS: Circadian variations and gender differences in transcript levels of
antioxidant genes exist in mouse liver, which could affect body responses to
oxidative stress at different times of the day.
DOI: 10.1371/journal.pone.0044237
PMCID: PMC3430632
PMID: 22952936 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/20512532
|
1. J Gen Intern Med. 2010 Aug;25(8):774-9. doi: 10.1007/s11606-010-1356-3. Epub
2010 May 29.
A July spike in fatal medication errors: a possible effect of new medical
residents.
Phillips DP(1), Barker GE.
Author information:
(1)Department of Sociology, University of California at San Diego, 0533, 9500
Gilman Drive, La Jolla, CA 92093-0533, USA. dphillips@ucsd.edu
Comment in
J Gen Intern Med. 2010 Aug;25(8):760-1. doi: 10.1007/s11606-010-1421-y.
J Gen Intern Med. 2011 Jan;26(1):10; author reply 11. doi:
10.1007/s11606-010-1532-5.
BACKGROUND: Each July thousands begin medical residencies and acquire increased
responsibility for patient care. Many have suggested that these new medical
residents may produce errors and worsen patient outcomes-the so-called "July
Effect;" however, we have found no U.S. evidence documenting this effect.
OBJECTIVE: Determine whether fatal medication errors spike in July.
DESIGN: We examined all U.S. death certificates, 1979-2006 (n = 62,338,584),
focusing on medication errors (n = 244,388). We compared the observed number of
deaths in July with the number expected, determined by least-squares regression
techniques. We compared the July Effect inside versus outside medical
institutions. We also compared the July Effect in counties with versus without
teaching hospitals.
OUTCOME MEASURE: JR = Observed number of July deaths / Expected number of July
deaths.
RESULTS: Inside medical institutions, in counties containing teaching hospitals,
fatal medication errors spiked by 10% in July and in no other month [JR = 1.10
(1.06-1.14)]. In contrast, there was no July spike in counties without teaching
hospitals. The greater the concentration of teaching hospitals in a region, the
greater the July spike (r = .80; P = .005). These findings held only for
medication errors, not for other causes of death.
CONCLUSIONS: We found a significant July spike in fatal medication errors inside
medical institutions. After assessing competing explanations, we concluded that
the July mortality spike results at least partly from changes associated with
the arrival of new medical residents.
DOI: 10.1007/s11606-010-1356-3
PMCID: PMC2896592
PMID: 20512532 [Indexed for MEDLINE]
Conflict of interest statement: None disclosed.
|
http://www.ncbi.nlm.nih.gov/pubmed/18208360
|
1. Biol Chem. 2008 Mar;389(3):279-83. doi: 10.1515/BC.2008.033.
FoxO transcription factors in oxidative stress response and ageing--a new fork
on the way to longevity?
Sedding DG(1).
Author information:
(1)Department of Cardiology, Justus-Liebig University, D-35392 Giessen, Germany.
daniel.sedding@innere.med.uni-giessen.de
Forkhead box O (FoxO) transcription factors are important downstream targets of
the PI3K/Akt signaling pathway and crucial regulators of cell fate. This
function of FoxOs relies on their ability to control diverse cellular functions,
including proliferation, differentiation, apoptosis, DNA repair, defense against
oxidative stress and ageing. FoxOs are regulated by a variety of different
growth factors and hormones, and their activity is tightly controlled by
post-translational modifications, including phosphorylation, acetylation,
ubiquitination and interaction with different proteins and transcription
factors. This brief review focuses on the molecular mechanisms, cellular effects
and resulting organismal phenotypes generated by differentially regulated FoxO
proteins and discusses our current understanding of the role of FoxOs in disease
and ageing processes.
DOI: 10.1515/BC.2008.033
PMID: 18208360 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19468253
|
1. Pathobiology. 2009 May;76(3):136-40. doi: 10.1159/000209391. Epub 2009 May 19.
Immunolocalization of DNMT1 and DNMT3a in salivary gland neoplasms.
Cavaliéri Gomes C(1), da Silveira e Oliveira C, Santos Pimenta LG, De Marco L,
Santiago Gomez R.
Author information:
(1)School of Dentistry, Pontifícia Universidade Católica de Minas Gerais, Belo
Horizonte, Brazil.
OBJECTIVE: Salivary gland neoplasms pathogenesis has not been well established.
DNA methylation occurs when methyl groups are added to cytosine nucleotides in
specific areas of the gene by the enzyme DNA methyltransferase (DNMT). This
chemical modification can alter gene expression without altering DNA sequence.
While DNMT3a is mostly involved in de novo methylation, DNMT1 acts as a
maintenance methyltransferase. We aimed to investigate the immunoexpression of
DNMT3a and DNMT1 in minor salivary gland neoplasms, comparing it with normal
tissue.
MATERIAL: Forty-four formalin-fixed and paraffin-embedded samples of pleomorphic
adenoma, adenoid cystic carcinoma, mucoepidermoid carcinoma and polymorphous
low-grade adenocarcinoma were included in the study. The DNMT1 and DNMT3a
proteins were identified by using a highly sensitive polymer-based system.
RESULTS: Positive nuclear and cytoplasmic labeling for DNMT1 was observed in all
samples, including the controls. Positive nuclear labeling for DNMT3a was found
only in few neoplasms: 1 pleomorphic adenoma (9.0%), 2 adenoid cystic carcinoma
(16.6%) and 1 mucoepidermoid (9.0%) cases.
CONCLUSION: Our results were not able to demonstrate a clear correlation between
DNMT1 and DNMT3a immunoexpression and salivary gland neoplasms development.
Copyright 2009 S. Karger AG, Basel.
DOI: 10.1159/000209391
PMID: 19468253 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19778587
|
1. Neuroscience. 2009 Dec 29;164(4):1531-7. doi:
10.1016/j.neuroscience.2009.09.039. Epub 2009 Sep 22.
5-Lipoxygenase and epigenetic DNA methylation in aging cultures of cerebellar
granule cells.
Imbesi M(1), Dzitoyeva S, Ng LW, Manev H.
Author information:
(1)Department of Psychiatry, The Psychiatric Institute,University of Illinois at
Chicago, Chicago, IL 60612, USA.
5-Lipoxygenase (5-Lox), an enzyme involved in the metabolism of arachidonic acid
participates in the modulation of the proliferation and differentiation of
neural stem cells and cerebellar granule cell (CGC) precursors. Since epigenetic
mechanisms including DNA methylation regulate 5-LOX expression and have been
suggested as possible modulators of stem cell differentiation and aging, using
primary cultures of mouse CGC (1, 5, 10, 14, 30 days in vitro; DIV), we studied
DNA methylation patterns of the 5-LOX promoter and 5-LOX mRNA levels. We also
measured the mRNA and protein content of the DNA methyltransferases DNMT1 and
DNMT3a. 5-LOX, DNMT1, and DNMT3a mRNA levels were measured by real-time PCR. We
observed that 5-LOX expression and the expression of maintenance DNMT1 is
maximal at 1 DIV (proliferating neuronal precursors), whereas the expression of
the de novo DNA methyltransferase DNMT3a mRNA increased in aging cultures. We
analyzed the methylation status of the 5-LOX promoter using the
methylation-sensitive restriction endonucleases AciI, BstUI, HpaII, and HinP1I,
which digest unmethylated CpGs while leaving methylated CpGs intact. The 5-LOX
DNA methylation increased with the age of the cells. Taken together, our data
show that as cultured CGC mature and age in vitro, a decrease in 5-LOX mRNA
content is accompanied by an increase in the methylation of the gene DNA. In
addition, an increase in DNMT3a but not DNMT1 expression accompanies an increase
of 5-LOX methylation during in vitro maturation.
DOI: 10.1016/j.neuroscience.2009.09.039
PMCID: PMC2783316
PMID: 19778587 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/9624150
|
1. J Biol Chem. 1998 Jun 19;273(25):15590-7. doi: 10.1074/jbc.273.25.15590.
Type XIII collagen is identified as a plasma membrane protein.
Hägg P(1), Rehn M, Huhtala P, Väisänen T, Tamminen M, Pihlajaniemi T.
Author information:
(1)Collagen Research Unit, Biocenter and Department of Medical Biochemistry,
University of Oulu, FIN-90220 Oulu, Finland.
The complete primary structure of the mouse type XIII collagen chain was
determined by cDNA cloning. Comparison of the mouse amino acid sequences with
the previously determined human sequences revealed a high identity of 90%.
Surprisingly, the mouse cDNAs extended further in the 5' direction than the
previously identified human clones. The 5' sequences contained a new in-frame
ATG codon for translation initiation which resulted in elongation of the
N-terminal noncollagenous domain by 81 residues. These N-terminal sequences lack
a typical signal sequence but include a highly hydrophobic segment that clearly
fulfills the criteria for a transmembrane domain. The sequence data thus
unexpectedly suggested that type XIII collagen may be located on the plasma
membrane, with a short cytosolic N-terminal portion and a long collagenous
extracellular portion. These sequence data prompted us to generate antipeptide
antibodies against type XIII collagen in order to study the protein and its
subcellular location. Western blotting of human tumor HT-1080 cell extract
revealed bands of over 180 kDa. These appeared to represent disulfide-bonded
multimeric polypeptide forms that resolved upon reduction into 85-95-kDa bands
that are likely to represent a mixture of splice forms of monomeric type XIII
collagen chains. These chains were shown to contain the predicted N-terminal
extension and thus also the putative transmembrane segment. Immunoprecipitation
of biotinylated type XIII collagen from surface-labeled HT-1080 cells,
subcellular fractionation, and immunofluorescence staining were used to
demonstrate that type XIII collagen molecules are indeed located in the plasma
membranes of these cells.
DOI: 10.1074/jbc.273.25.15590
PMID: 9624150 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8187356
|
1. Clin Nephrol. 1994 Mar;41(3):144-9.
Effect of enalapril on the microvascular albumin leakage in patients with
diabetic microangiopathy and normal or mildly elevated blood pressure.
Chagnac A(1), Korzets A, Zevin D, Wender T, Carmon G, Hirsh J, Gafter U, Levi J.
Author information:
(1)Department of Nephrology, Golda Medical Center, Hasharon Hospital,
Petach-Tikva, Israel.
The transcapillary escape rate of albumin (TERalb) is often elevated in patients
with diabetic microangiopathy. The objective of this study was to examine the
effect of enalapril on the TERalb of diabetic patients with albuminuria and
normal or mildly elevated blood pressure. Seventeen diabetic patients with
diabetic retinopathy, albuminuria, a diastolic blood pressure below 100 mmHg and
increased TERalb participated in the study. Blood pressure and TERalb were
measured before and after 14 days of therapy with enalapril, 20 mg daily for 14
days. Systolic and diastolic blood pressure fell from 168 +/- 6 to 155 +/- 6 (p
< 0.001) and from 87 +/- 2 to 81 +/- 2 mmHg (p < 0.005) respectively. Mean
arterial pressure declined from 114 +/- 3 to 105 +/- 3 mmHg (p < 0.0001). The
elevated TERalb decreased from 9.5 +/- 0.5 to 7.2 +/- 0.5%/hr (p < 0.005). In
the hypertensive subset, systolic, diastolic and mean arterial pressure
decreased significantly by 15, 7 and 10 mmHg (p < 0.005, p < 0.005 and p < 0.005
respectively); TERalb decreased from 9.5 +/- 0.6 to 7.3 +/- 0.6 (p < 0.03). In
the normotensive subset, arterial pressure remained unchanged and TERalb
decreased from 9.0 +/- 0.8 to 6.8 +/- 1.0%/hr (p < 0.03). Plasma fructosamine
decreased from 373 +/- 23 to 347 +/- 20 (p < 0.05) in the hypertensive group and
remained unchanged in the normotensive patients. No correlation could be
demonstrated between variation in TERalb and changes in blood pressure. In
conclusion, enalapril decreases microvascular albumin leakage in patients with
diabetic microangiopathy and normal or mildly elevated blood pressure.
PMID: 8187356 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20592766
|
1. Oxid Med Cell Longev. 2009 Jul-Aug;2(3):119-29. doi: 10.4161/oxim.2.3.8916.
A fork in the path: Developing therapeutic inroads with FoxO proteins.
Maiese K(1), Hou J, Chong ZZ, Shang YC.
Author information:
(1)Division of Cellular and Molecular Cerebral Ischemia, Wayne State University
School of Medicine, Detroit, MI 48201, USA. kmaiese@med.wayne.edu
Advances in clinical care for disorders involving any system of the body
necessitates novel therapeutic strategies that can focus upon the modulation of
cellular proliferation, metabolism, inflammation and longevity. In this respect,
members of the mammalian forkhead transcription factors of the O class (FoxOs)
that include FoxO1, FoxO3, FoxO4 and FoxO6 are increasingly being recognized as
exciting prospects for multiple disorders. These transcription factors govern
development, proliferation, survival and longevity during multiple cellular
environments that can involve oxidative stress. Furthermore, these transcription
factors are closely integrated with several novel signal transduction pathways,
such as erythropoietin and Wnt proteins, that may influence the ability of FoxOs
to act as a "double-edge sword" to sometimes promote cell survival, but at other
times lead to cell injury. Here we discuss the fascinating but complex role of
FoxOs during cellular injury and oxidative stress, progenitor cell development,
fertility, angiogenesis, cardiovascular function, cellular metabolism and
diabetes, cell longevity, immune surveillance and cancer.
DOI: 10.4161/oxim.2.3.8916
PMCID: PMC2763237
PMID: 20592766 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22413869
|
1. BMC Med. 2012 Mar 13;10:26. doi: 10.1186/1741-7015-10-26.
Insufficient maintenance DNA methylation is associated with abnormal embryonic
development.
Yin LJ(1), Zhang Y, Lv PP, He WH, Wu YT, Liu AX, Ding GL, Dong MY, Qu F, Xu CM,
Zhu XM, Huang HF.
Author information:
(1)Department of Reproductive Endocrinology, Women's Hospital, School of
Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou, Zhejiang 310006, China.
BACKGROUND: Early pregnancy loss (EPL) is a frustrating clinical problem, whose
mechanisms are not completely understood. DNA methylation, which includes
maintenance methylation and de novo methylation directed by DNA
methyltransferases (DNMTs), is important for embryo development. Abnormal
function of these DNMTs may have serious consequences for embryonic development.
METHODS: To evaluate the possible involvement of DNA methylation in human EPL,
the expression of DNMT proteins and global methylation of DNA were assessed in
villous or decidua from EPL patients. The association of maintenance methylation
with embryo implantation and development was also examined.
RESULTS: We found that DNMT1 and DNMT3A were both expressed in normal human
villous and decidua. DNMT1 expression and DNA global methylation levels were
significantly down-regulated in villous of EPL. DNMT3A expression was not
significantly changed in the EPL group compared to controls in either villous or
decidua. We also found that disturbance of maintenance methylation with a DNMT1
inhibitor may result in a decreased global DNA methylation level and impaired
embryonic development in the mouse model, and inhibit in vitro embryo attachment
to endometrial cells.
CONCLUSIONS: Our results demonstrate that defects in DNA maintenance methylation
in the embryo, not in the mother, are associated with abnormal embryonic
implantation and development. The findings of the current study provide new
insights into the etiology of EPL.
DOI: 10.1186/1741-7015-10-26
PMCID: PMC3355050
PMID: 22413869 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8712223
|
1. Am J Kidney Dis. 1996 Jul;28(1):62-6. doi: 10.1016/s0272-6386(96)90131-6.
Accumulation of glycated albumin in end-stage renal failure: evidence for the
principle of "physiological microalbuminuria".
Donnelly SM(1).
Author information:
(1)Department of Medicine, Mount Sinai Hospital, University of Toronto, Ontario,
Canada.
In light of the growing understanding of the toxic effects of glycated albumin
and of the preferential excretion of this substance, the excretion of glycated
albumin could be considered a physiologic function of the kidney. Furthermore,
if the increased load of glycated albumin in diabetic patients results in
glycated albumin excretion rates in the range of 20 to 200 microg/min, might
this not be considered "physiologic microalbuminuria"? The hypothesis is
presented that microalbuminuria composed of glycated albumin is a homeostatic
renal function. Although some proteins are glycosylated for their normal
physiologic function, many proteins are glycated nonenzymatically according to
ambient blood glucose. Albumin is subject to nonenzymatic glycation in all
humans, but at increased rates in diabetic patients. Glycated albumin induces
changes in the microvasculature and glomerulus that may lead to endothelial
dysfunction and diabetic nephropathy, respectively. Renal excretion of glycated
albumin is enhanced compared with native albumin. To explore this potential
homeostatic function of the kidney, patients with impaired renal function were
studied to determine whether glycated albumin accumulates. Plasma levels of
glycated albumin were determined in diabetic and nondiabetic patients on
hemodialysis. Hemoglobin A1c was used as an index of the rate of nonenzymatic
glycation of proteins. Hemoglobin A1c was increased in the diabetic subjects but
was normal in the nondiabetic group (7.9% +/- 0.5% v 6.2% +/- 0.2%,
respectively; P < 0.01). On the other hand, the glycated albumin was elevated in
both groups and was not significantly different between them (1.95% +/- 0.15% in
the diabetic patients v 1.75% +/- 0.14% in the nondiabetic patients; P = NS).
The results of this study provide the first clinical evidence supporting the
hypothesis that the excretion of glycated albumin is a homeostatic renal
function.
DOI: 10.1016/s0272-6386(96)90131-6
PMID: 8712223 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18388640
|
1. Disaster Med Public Health Prep. 2007 Nov;1(2):122-34. doi:
10.1097/DMP.0b013e318158c5fd.
Botulism: cause, effects, diagnosis, clinical and laboratory identification, and
treatment modalities.
Dembek ZF(1), Smith LA, Rusnak JM.
Author information:
(1)US Army Medical Research Institute of Infectious Diseases, 1425 Porter St, Ft
Detrick, MD 21702, USA. zygmunt.dembek@det.amedd.army.mil
Botulism is a neuroparalytic disease caused by neurotoxins produced by the
bacteria Clostridium botulinum. Botulinum neurotoxins (BoNTs) are among the most
potent naturally occurring toxins and are a category A biological threat agent.
The 7 toxin serotypes of BoNTs (serotypes A-G) have different toxicities, act
through 3 different intracellular protein targets, and exhibit different
durations of effect. Botulism may follow ingestion of food contaminated with
BoNT, from toxin production of C botulinum present in the intestine or wounds,
or from inhalation of aerosolized toxin. Intoxication classically presents as an
acute, symmetrical, descending flaccid paralysis. Early diagnosis is important
because antitoxin therapy is most effective when administered early.
Confirmatory testing of botulism with BoNT assays or C botulinum cultures is
time-consuming, and may be insensitive in the diagnosis of inhalational botulism
and in as many as 32% of food-borne botulism cases. Therefore, the decision to
initiate botulinum antitoxin therapy is primarily based on symptoms and physical
examination findings that are consistent with botulism, with support of
epidemiological history and electrophysiological testing. Modern clinical
practice and antitoxin treatment has reduced botulism mortality rates from
approximately 60% to < or =10%. The pentavalent botulinum toxoid is an
investigational product and has been used for more than 45 years in at-risk
laboratory workers to protect against toxin serotypes A to E. Due to declining
immunogenicity and potency of the pentavalent botulinum toxoid, novel vaccine
candidates are being developed.
DOI: 10.1097/DMP.0b013e318158c5fd
PMID: 18388640 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/7796616
|
1. Cutis. 1995 Apr;55(4):233-6.
Acrokeratosis paraneoplastica (Bazex syndrome) with oropharyngeal squamous cell
carcinoma.
Estrela F(1), Pinto GM, Pinto LM, Afonso A.
Author information:
(1)Department of Dermatology, Curry Cabral Hospital, Lisboa, Portugal.
A 65-year-old white man presented with all the clinical features of
acrokeratosis paraneoplastica of Bazex, characterized by violaceous erythema and
scaling of the nose, aural helices, fingers, and toes, with keratoderma and
severe nail dystrophy. Examination of the patient for possible associated
malignancy disclosed an asymptomatic squamous cell carcinoma at the
oropharyngeal region. The skin lesions resolved almost completely following
radiation therapy of the neoplasm, but the onychodystrophy persisted. This case
report illustrates the importance of early recognition of Bazex syndrome.
PMID: 7796616 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24114694
|
1. Paediatr Drugs. 2014 Feb;16(1):21-8. doi: 10.1007/s40272-013-0051-3.
Giant cell tumor of bone in childhood: clinical aspects and novel therapeutic
targets.
Federman N(1), Brien EW, Narasimhan V, Dry SM, Sodhi M, Chawla SP.
Author information:
(1)Department of Pediatrics, Hematology/Oncology, Mattel Children's Hospital at
University of California, Los Angeles, USA, nfederman@mednet.ucla.edu.
Giant cell tumor of bone (GCTB) is a rare primary bone tumor that primarily
affects young adults, but can be seen in children. The primary modality of
treatment is surgical resection; however, this is not always possible given the
location and extent of the neoplasm. Recent developments in the understanding of
the underlying molecular pathogenesis of disease have pointed to interactions
between the stromal component producing receptor activator of nuclear
factor-kappaB (RANK) and RANK-ligand (RANKL) causing the formation of
osteoclast-like giant cells that drive bone destruction. The development of a
monoclonal humanized antibody to RANKL, denosumab, has been shown to reduce
skeletal-related events from osteoporosis and from bony metastases from solid
tumors. Recent phase II clinical trials with denosumab in skeletally mature
adolescents over age 12 years and adults with GCTB, have shown both safety and
efficacy, leading to its accelerated US FDA approval on 13 June 2013. In
children who are skeletally immature, safety and efficacy has not been
established, and there has been only published anecdotal use.
DOI: 10.1007/s40272-013-0051-3
PMID: 24114694 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/14570904
|
1. J Biol Chem. 2004 Jan 9;279(2):892-900. doi: 10.1074/jbc.M306615200. Epub 2003
Oct 21.
Suppression of adriamycin-induced apoptosis by sustained activation of the
phosphatidylinositol-3'-OH kinase-Akt pathway.
Takeuchi K(1), Ito F.
Author information:
(1)Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan
University, Hirakata, Osaka 573-0101, Japan.
The mechanisms by which growth factors trigger signal transduction pathways
leading to protection against apoptosis are of great interest. In this study, we
investigated the effect of hepatocyte growth factor (HGF/SF) and epidermal
growth factor (EGF) on adriamycin (ADR)-induced apoptosis. Treatment of human
epithelial MKN74 cells with ADR, a DNA topoisomerase IIalpha inhibitor, caused
apoptosis. However, cells pretreated with HGF/SF, but not those pretreated with
EGF, were resistant to this apoptosis. The protective effect of HGF/SF against
the ADR-induced apoptosis was abolished in the presence of either LY294002, an
inhibitor of phosphatidylinositol-3'-OH kinase (PI3-K) or
1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, an
inhibitor of Akt, thus implicating the activation of PI3-K-Akt signaling in the
antiapoptotic action of HGF/SF. Immunoblotting analysis revealed that HGF/SF
stimulated the sustained phosphorylation of Akt for several hours but that EGF
stimulated the phosphorylation only transiently. Furthermore, ADR-induced
activation of caspase-9, a downstream molecule of Akt, was inhibited for at
least 24 h after HGF/SF stimulation, but it was not affected by EGF stimulation.
Cell-surface biotin-labeling analysis showed that the HGF/SF receptor remained
on the cell surface until at least 30 min after HGF/SF addition but that the EGF
receptor level on the cell surface was attenuated at an earlier time after EGF
addition. These results indicate that HGF/SF, but not EGF, transmitted
protective signals against ADR-induced apoptosis by causing sustained activation
of the PI3-K-Akt signaling pathway. Furthermore, the difference in antiapoptotic
capacity between HGF/SF and EGF is explained, at least in part, by the delayed
down-regulation of the HGF/SF receptor.
DOI: 10.1074/jbc.M306615200
PMID: 14570904 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11818019
|
1. J Biomed Opt. 2002 Jan;7(1):109-22. doi: 10.1117/1.1428292.
Morphological spot counting from stacked images for automated analysis of gene
copy numbers by fluorescence in situ hybridization.
Grigoryan AM(1), Dougherty ER, Kononen J, Bubendorf L, Hostetter G, Kallioniemi
O.
Author information:
(1)University of Texas at San Antonio, College of Engineering, San Antonio,
Texas, USA.
Fluorescence in situ hybridization (FISH) is a molecular diagnostic technique in
which a fluorescent labeled probe hybridizes to a target nucleotide sequence of
deoxyribose nucleic acid. Upon excitation, each chromosome containing the target
sequence produces a fluorescent signal (spot). Because fluorescent spot counting
is tedious and often subjective, automated digital algorithms to count spots are
desirable. New technology provides a stack of images on multiple focal planes
throughout a tissue sample. Multiple-focal-plane imaging helps overcome the
biases and imprecision inherent in single-focal-plane methods. This paper
proposes an algorithm for global spot counting in stacked three-dimensional
slice FISH images without the necessity of nuclei segmentation. It is designed
to work in complex backgrounds, when there are agglomerated nuclei, and in the
presence of illumination gradients. It is based on the morphological top-hat
transform, which locates intensity spikes on irregular backgrounds. After
finding signals in the slice images, the algorithm groups these together to form
three-dimensional spots. Filters are employed to separate legitimate spots from
fluorescent noise. The algorithm is set in a comprehensive toolbox that provides
visualization and analytic facilities. It includes simulation software that
allows examination of algorithm performance for various image and algorithm
parameter settings, including signal size, signal density, and the number of
slices.
DOI: 10.1117/1.1428292
PMID: 11818019 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18450745
|
1. J Biol Chem. 2008 Jul 11;283(28):19626-35. doi: 10.1074/jbc.M802655200. Epub
2008 May 1.
Specificity of the chromodomain Y chromosome family of chromodomains for
lysine-methylated ARK(S/T) motifs.
Fischle W(1), Franz H, Jacobs SA, Allis CD, Khorasanizadeh S.
Author information:
(1)Department of Biochemistry and Molecular Genetics, University of Virginia
Health System, Charlottesville, Virginia 22908-0733, USA. wfischl@gwdg.de
Previous studies have shown two homologous chromodomain modules in the HP1 and
Polycomb proteins exhibit discriminatory binding to related methyllysine
residues (embedded in ARKS motifs) of the histone H3 tail. Methylated ARK(S/T)
motifs have recently been identified in other chromatin factors (e.g. linker
histone H1.4 and lysine methyltransferase G9a). These are thought to function as
peripheral docking sites for the HP1 chromodomain. In vertebrates, HP1-like
chromodomains are also present in the chromodomain Y chromosome (CDY) family of
proteins adjacent to a putative catalytic motif. The human genome encodes three
CDY family proteins, CDY, CDYL, and CDYL2. These have putative functions ranging
from establishment of histone H4 acetylation during spermiogenesis to regulation
of transcription co-repressor complexes. To delineate the biochemical functions
of the CDY family chromodomains, we analyzed their specificity of methyllysine
recognition. We detected substantial differences among these factors. The CDY
chromodomain exhibits discriminatory binding to lysine-methylated ARK(S/T)
motifs, whereas the CDYL2 chromodomain binds with comparable strength to
multiple ARK(S/T) motifs. Interestingly, subtle amino acid changes in the CDYL
chromodomain prohibit such binding interactions in vitro and in vivo. However,
point mutations can rescue binding. In support of the in vitro binding
properties of the chromodomains, the full-length CDY family proteins exhibit
substantial variability in chromatin localization. Our studies underscore the
significance of subtle sequence differences in a conserved signaling module for
diverse epigenetic regulatory pathways.
DOI: 10.1074/jbc.M802655200
PMCID: PMC2443675
PMID: 18450745 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20305384
|
1. Epigenetics. 2010 Apr;5(3):229-40. doi: 10.4161/epi.5.3.11409. Epub 2010 Apr
1.
5-azacytidine treatment reorganizes genomic histone modification patterns.
Komashko VM, Farnham PJ.
Methylation of DNA in combination with histone modifications establishes an
epigenetic code that ensures the proper control of gene expression. Although DNA
methyltransferases have been shown to interact with histone methyltransferases
such as EZH2 (which methylates histone H3 on lysine 27) and G9a (which
methylates histone H3 on lysine 9), the relationship between DNA methylation and
repressive histone marks has not been fully studied. In cancer cells, promoters
of genes are often aberrantly methylated. Accordingly, 5-azacytidine (a DNA
demethylating drug) is used for treating patients with myelodysplastic syndrome.
However, no genome-scale studies of the effects of this drug have been reported.
In this work, we report the effects of 5-azacytidine on global gene expression
and analyze ~24,000 human promoters using ChIP-chip to determine how
5-azacytidine treatment effects H3K27me3 and H3K9me3 levels. We found that (1)
5-azacytidine treatment results in large changes in gene regulation with
distinct functional categories of genes showing increased (e.g. C2H2 zinc finger
transcription factors) and decreased (e.g. genes involved in regulation of
mitochondria and oxidoreductase activity) levels; (2) most genes that show
altered expression are not regulated by promoters that display DNA methylation
prior to the treatment; (3) certain gene classes switch their repression mark
upon treatment with 5-azacytidine (from H3K27me3 to H3K9me3 and vice versa); and
(4) most changes in gene expression are not due to relief of repression mediated
by DNA or histone methylation.
DOI: 10.4161/epi.5.3.11409
PMID: 20305384 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20959496
|
1. Physiol Genomics. 2011 May 1;43(10):534-42. doi:
10.1152/physiolgenomics.00130.2010. Epub 2010 Oct 19.
The role of microRNA in modulating myocardial ischemia-reperfusion injury.
Ye Y(1), Perez-Polo JR, Qian J, Birnbaum Y.
Author information:
(1)Department of Biochemistry and Molecular Biology, University of Texas Medical
Branch, Galveston, TX 77555, USA. yumye@utmb
MicroRNAs (miRNAs) are small (∼22 nt) noncoding single-stranded RNA molecules
that downregulate gene expression. Studies have shown that miRNAs control
diverse aspects of heart disease, including hypertrophy, remodeling, heart
failure, and arrhythmia. Recently, several studies have suggested that miRNAs
contribute to ischemia-reperfusion injury by altering key signaling elements,
thus making them potential therapeutic targets. By altering the expression of
various key elements in cell survival and apoptosis [such as phosphoinositide
3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN),
Bcl-2, Mcl-1, heat shock protein (HSP)60, HSP70, HSP20, programmed cell death 4
(Pdcd4), LRRFIP1, Fas ligand (FasL), Sirt-1, etc.], miRNAs alter the response to
ischemia-reperfusion injury. Studies using various in vivo, ex vivo, and in
vitro models have suggested the possible involvement of miR-1, miR-21, miR-29,
miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or
remodeling after myocardial infarction. Thus miRNAs could be potential
therapeutic targets for the treatment of heart disease. Inhibiting miRNAs by
antisense strategies or pharmacological approaches is likely to emerge as an
alternative and safe method for conferring short- and intermediate-term
protection against ischemia-reperfusion injury.
DOI: 10.1152/physiolgenomics.00130.2010
PMID: 20959496 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8894691
|
1. Hum Mol Genet. 1996 Oct;5(10):1577-80. doi: 10.1093/hmg/5.10.1577.
Mechanism of ret dysfunction by Hirschsprung mutations affecting its
extracellular domain.
Iwashita T(1), Murakami H, Asai N, Takahashi M.
Author information:
(1)Department of Pathology, Nagoya University School of Medicine, Japan.
Hirschsprung disease (HSCR) is a congenital disorder associated with the absence
of intrinsic ganglion cells in the distal gastrointestinal tract. Recently, many
missense, nonsense and frameshift mutations of the ret proto-oncogene were found
in familial and sporadic cases of HSCR. Consistent with the view that the HSCR
phenotype is the result of inactivation of Ret, the missense mutations detected
in the tyrosine kinase domain were demonstrated to result in a marked decrease
of the kinase activity of Ret. However, the effects of missense mutations found
in the extracellular domain remain unknown. We now report that five mutations in
the extracellular domain examined inhibit transport of the Ret protein to the
plasma membrane. As a consequence, they significantly decreased the transforming
activity of Ret with multiple endocrine neoplasia (MEN) 2A mutation for which
cell surface expression is required. Our results also demonstrated that long
segment HSCR mutations more severely impair transport of Ret to the plasma
membrane than a short segment HSCR mutation, suggesting that the level of its
cell surface expression may correlate to the HSCR phenotype.
DOI: 10.1093/hmg/5.10.1577
PMID: 8894691 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17825502
|
1. Drug Alcohol Depend. 2008 Jan 1;92(1-3):3-8. doi:
10.1016/j.drugalcdep.2007.06.017. Epub 2007 Sep 6.
Cytisine for smoking cessation: a research agenda.
Etter JF(1), Lukas RJ, Benowitz NL, West R, Dresler CM.
Author information:
(1)Institute of Social and Preventive Medicine, University of Geneva, CMU, Case
Postale, CH-1211 Geneva 4, Switzerland. jean-francois.etter@imsp.unige.ch
Comment in
Drug Alcohol Depend. 2008 Jan 1;92(1-3):1-2. doi:
10.1016/j.drugalcdep.2007.07.010.
Cytisine has a molecular structure somewhat similar to that of nicotine and
varenicline. The concept for the new smoking cessation drug varenicline was
based partly on cytisine. Like varenicline, cytisine is a partial agonist of
nicotinic acetylcholine receptors, with high affinity for alpha4beta2 receptors.
Cytisine has been used since the 1960s as a smoking cessation drug in Eastern
and Central Europe, but has remained largely unnoticed elsewhere. Three
placebo-controlled trials, conducted in East and West Germany in the 1960s and
1970s, suggest that cytisine, even with minimal behavioural support, may be
effective in aiding smoking cessation. Cytisine tablets are very inexpensive to
produce and could be a more affordable treatment than nicotine replacement,
bupropion and varenicline. There is however a dearth of scientific research on
the properties of cytisine, including safety, abuse liability and efficacy. This
paper seeks to identify research priorities for molecular, animal and clinical
studies. In particular, new studies are necessary to define the nicotinic
receptor interaction profile of cytisine, to establish its pharmacokinetics and
pharmacodynamics in humans, to determine whether animals self-administer
cytisine, and to ascertain whether cytisine is safe and effective as a smoking
cessation drug. Potentially, this research effort, contributing to wider use of
an inexpensive drug, could save many lives.
DOI: 10.1016/j.drugalcdep.2007.06.017
PMID: 17825502 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16465592
|
1. Mamm Genome. 2006 Feb;17(2):119-28. doi: 10.1007/s00335-005-0098-8. Epub 2006
Feb 7.
Neuronal expression of the Ccm2 gene in a new mouse model of cerebral cavernous
malformations.
Plummer NW(1), Squire TL, Srinivasan S, Huang E, Zawistowski JS, Matsunami H,
Hale LP, Marchuk DA.
Author information:
(1)Department of Molecular Genetics and Microbiology, Duke University Medical
Center, Durham, North Carolina 27710, USA.
Cerebral cavernous malformations are vascular defects of the central nervous
system consisting of clusters of dilated vessels that are subject to frequent
hemorrhaging. The genes mutated in three forms of autosomal dominant cerebral
cavernous malformations have been cloned, but it remains unclear which cell type
is ultimately responsible for the lesion. In this article we describe mice with
a gene trap insertion in the Ccm2 gene. Consistent with the human phenotype,
heterozygous animals develop cerebral vascular malformations, although
penetrance is low. Beta-galactosidase activity in heterozygous brain and in situ
hybridization in wild-type brain revealed Ccm2 expression in neurons and choroid
plexus but not in vascular endothelium of small vessels in the brain. The
expression pattern of Ccm2 is similar to that of the Ccm1 gene and its
interacting protein ICAP1 (Itgb1bp1). These data suggest that cerebral cavernous
malformations arise as a result of defects in the neural parenchyma surrounding
the vascular endothelial cells in the brain.
DOI: 10.1007/s00335-005-0098-8
PMID: 16465592 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23866358
|
1. Prescrire Int. 2013 Jun;22(139):155-9.
Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little
clinical experience.
[No authors listed]
Dabigatran, rivaroxaban and apixaban are oral anticoagulants used to prevent or
treat thrombosis in a variety of situations. Like all anticoagulants, these
drugs can provoke bleeding. How should patients be managed if bleeding occurs
during dabigatran, rivaroxaban or apixaban therapy? How can the risk of bleeding
be reduced in patients who require surgery or other invasive procedures? To
answer these questions, we reviewed the available literature, using the standard
Prescrire methodology. In clinical trials, warfarin, enoxaparin, dabigatran,
rivaroxaban and apixaban were associated with a similar frequency of severe
bleeding. Numerous reports of severe bleeding associated with dabigatran have
been recorded since this drug was first marketed. Some situations are associated
with a particularly high bleeding risk, including: even mild renal failure,
advanced age, extremes in body weight and drug-drug interactions, particularly
with antiplatelet agents (including aspirin), nonsteroidal antiinflammatory
drugs, and many drugs used in cardiovascular indications. In patients treated
with dabigatran, rivaroxaban or apixaban, changes in the INR (international
normalised ratio) and activated partial thromboplastin time (aPTT) do not
correlate with the dose. In early 2013, there is still no routine coagulation
test suitable for monitoring these patients; specific tests are only available
in specialised laboratories. In early 2013 there is no antidote for dabigatran,
rivaroxaban or apixaban, nor any specific treatment with proven efficacy for
severe bleeding linked to these drugs. Recommendations on the management of
bleeding in this setting are based mainly on pharmacological parameters and on
scarce experimen-Haemodialysis reduces the plasma concentration of dabigatran,
while rivaroxaban and apixaban cannot be eliminated by dialysis. Prothrombin
complex concentrates and recombinant activated factor VII seem to have little or
no efficacy, and they carry a poorly documented risk of thrombosis. For patients
undergoing surgery or other invasive procedures, clinical practice guidelines
are primarily based on pharmacokinetic parameters and on extrapolation of data
on vitamin K antagonists. The decision on whether or not to discontinue
anticoagulation before the procedure mainly depends on the likely risk of
bleeding. In patients at high risk of thrombosis, heparin can be proposed when
the anticoagulant is withdrawn. In early 2013, difficulties in the management of
bleeding and of situations in which there is a risk of bleeding weigh heavily in
the balance of potential harm versus potential benefit of dabigatran,
rivaroxaban and apixaban. When an oral anticoagulant is required, it is best to
choose warfarin, a vitamin K antagonist, and the drug with which we have the
most experience, except in those rare situations in which the INR cannot be
maintained within the therapeutic range.
PMID: 23866358 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20219102
|
1. Mol Cancer. 2010 Mar 10;9:56. doi: 10.1186/1476-4598-9-56.
Specific effects of bortezomib against experimental malignant pleural effusion:
a preclinical study.
Psallidas I(1), Karabela SP, Moschos C, Sherrill TP, Kollintza A, Magkouta S,
Theodoropoulou P, Roussos C, Blackwell TS, Kalomenidis I, Stathopoulos GT.
Author information:
(1)Applied Biomedical Research & Training Center "Marianthi Simou", Department
of Critical Care & Pulmonary Services, General Hospital "Evangelismos", National
and Kapodistrian University of Athens, Greece.
BACKGROUND: We have previously shown that nuclear factor (NF)-kappaB activation
of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of
malignant pleural effusions (MPE) by these cells. In the present studies we
hypothesized that treatment of immunocompetent mice with bortezomib tailored to
inhibit cancer cell NF-kappaB activation and not proliferation specifically
inhibits MPE formation by LLC cells.
RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100
ng/ml) inhibited NF-kappaB activation and NF-kappaB-dependent transcription, but
not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice
bearing LLC-induced subcutaneous tumors and MPEs significantly blocked
tumor-specific NF-kappaB activation. However, bortezomib treatment did not
impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced
MPE. This specific effect was evidenced by significant reductions in effusion
accumulation and the associated mortality and was observed with both preventive
(beginning before MPE formation) and therapeutic (beginning after MPE
establishment) bortezomib treatment. The favorable impact of bortezomib on MPE
was associated with suppression of cardinal MPE-associated phenomena, such as
inflammation, vascular hyperpermeability, and angiogenesis. In this regard,
therapeutic bortezomib treatment had identical favorable results on MPE compared
with preventive treatment, indicating that the drug specifically counteracts
effusion formation.
CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block
NF-kappaB activation of lung adenocarcinoma specifically targets the
effusion-inducing phenotype of this tumor. Although the drug has limited
activity against advanced solid lung cancer, it may prove beneficial for
patients with MPE.
DOI: 10.1186/1476-4598-9-56
PMCID: PMC2841124
PMID: 20219102 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/17212618
|
1. Acta Neurol Scand. 2007 Feb;115(2):129-31. doi:
10.1111/j.1600-0404.2006.00727.x.
Motor neuron disease recovery associated with IV ceftriaxone and anti-Babesia
therapy.
Harvey WT(1), Martz D.
Author information:
(1)Rocky Mountain Chronic Disease Specialists, L.L.C., North Circle Drive,
Colorado Springs, CO 80909, USA. wth928@aol.com
Comment in
Acta Neurol Scand. 2008 Mar;117(3):217. doi:
10.1111/j.1600-0404.2007.00952.x.
This report summarizes what we believe to be the first verifiable case of a
significant and progressive motor neuron disease (MND) consistent with
amyotrophic lateral sclerosis that resolved during treatment with i.v.
ceftriaxone plus oral atovaquone and mefloquine. The rationale for use of these
antibiotics was (i) positive testing for Borrelia burgdorferi and (ii) red blood
cell ring forms consistent with Babesia species infection. The patient has
continued to be free of MND signs and symptoms for 15 months, although some
symptoms consistent with disseminated Borreliosis remain.
DOI: 10.1111/j.1600-0404.2006.00727.x
PMID: 17212618 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/22527616
|
1. Pituitary. 2012 Dec;15 Suppl 1:S61-7. doi: 10.1007/s11102-012-0391-y.
Genetic analysis in a patient presenting with meningioma and familial isolated
pituitary adenoma (FIPA) reveals selective involvement of the R81X mutation of
the AIP gene in the pathogenesis of the pituitary tumor.
Guaraldi F(1), Corazzini V, Gallia GL, Grottoli S, Stals K, Dalantaeva N,
Frohman LA, Korbonits M, Salvatori R.
Author information:
(1)Division of Endocrinology, Department of Internal Medicine, University of
Turin, 10126, Turin, Italy.
Familial isolated pituitary adenoma (FIPA), defined as the occurrence of at
least two cases of pituitary adenoma in a family that does not exhibit features
of syndromic diseases, such as Carney complex or Multiple Endocrine Neoplasia
type 1 or 4, is a rare autosomal dominant disease with low penetrance. About 20
% of the families with FIPA harbor inactivating mutation in aryl hydrocarbon
receptor-interacting protein gene (AIP) associated with loss of heterozygosity
of the same genetic locus (11q13) in the tumor. Rarely different types of
extra-pituitary tumors have been described in the setting of AIP
mutation-positive FIPA. We present the case of a patient who was diagnosed with
acromegaly due to the AIP mutation c.241C>T (p.R81X) at the age of 34 years, and
treated by transsphenoidal surgery. At the age of 43 years she was diagnosed
with a meningioma, and at age 46 had recurrence of the somatotropinoma. Genetic
studies demonstrated loss of the normal allele (by sequencing and microsatellite
analysis) in DNA from the pituitary adenoma but not from the meningioma,
suggesting a selective involvement of AIP mutation in the pathogenesis of the
pituitary adenoma, and a casual association with the meningioma. Further
investigations are required to define the exact role of AIP in non-pituitary
tumorigenesis.
DOI: 10.1007/s11102-012-0391-y
PMID: 22527616 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16083281
|
1. J Proteome Res. 2005 Jul-Aug;4(4):1310-7. doi: 10.1021/pr050028f.
Quantitative protein expression analysis of CLL B cells from mutated and
unmutated IgV(H) subgroups using acid-cleavable isotope-coded affinity tag
reagents.
Barnidge DR(1), Jelinek DF, Muddiman DC, Kay NE.
Author information:
(1)Mayo Proteomics Research Center, Department of Biochemistry and Molecular
Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
barnidge.david@mayo.edu
Relative protein expression levels were compared in leukemic B cells from two
patients with chronic lymphocytic leukemia (CLL) having either mutated (M-CLL)
or unmutated (UM-CLL) immunoglobulin variable heavy chain genes (IgV(H)). Cells
were separated into cytosol and membrane protein fractions then labeled with
acid-cleavable ICAT reagents (cICAT). Labeled proteins were digested with
trypsin then subjected to SCX and affinity chromatography followed by
LC-ESI-MS/MS analysis on a linear ion trap mass spectrometer. A total of 9
proteins from the cytosol fraction and 4 from the membrane fraction showed a
3-fold or greater difference between M-CLL and UM-CLL and a subset of these were
examined by Western blot where results concurred with cICAT abundance ratios.
The abundance of one of the proteins in particular, the mitochondrial membrane
protein cytochrome c oxidase subunit COX G was examined in 6 M-CLL and 6 UM-CLL
patients using western blot and results showed significantly greater levels (P <
0.001) in M-CLL patients vs UM-CLL patients. These results demonstrate that
stable isotope labeling and mass spectrometry can complement 2D gel
electrophoresis and gene microarray technologies for identifying putative and
perhaps unique prognostic markers in CLL.
DOI: 10.1021/pr050028f
PMCID: PMC1403294
PMID: 16083281 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16409643
|
1. Retrovirology. 2006 Jan 13;3:5. doi: 10.1186/1742-4690-3-5.
SUV39H1 interacts with HTLV-1 Tax and abrogates Tax transactivation of HTLV-1
LTR.
Kamoi K(1), Yamamoto K, Misawa A, Miyake A, Ishida T, Tanaka Y, Mochizuki M,
Watanabe T.
Author information:
(1)Department of Medical Genome Sciences, Graduate School of Frontier Sciences,
The University of Tokyo, 4-6-1 Shirokanedai, Tokyo 108-8639, Japan.
koju1030@ims.u-tokyo.ac.jp
BACKGROUND: Tax is the oncoprotein of HTLV-1 which deregulates signal
transduction pathways, transcription of genes and cell cycle regulation of host
cells. Transacting function of Tax is mainly mediated by its protein-protein
interactions with host cellular factors. As to Tax-mediated regulation of gene
expression of HTLV-1 and cellular genes, Tax was shown to regulate histone
acetylation through its physical interaction with histone acetylases and
deacetylases. However, functional interaction of Tax with histone
methyltransferases (HMTase) has not been studied. Here we examined the ability
of Tax to interact with a histone methyltransferase SUV39H1 that methylates
histone H3 lysine 9 (H3K9) and represses transcription of genes, and studied the
functional effects of the interaction on HTLV-1 gene expression.
RESULTS: Tax was shown to interact with SUV39H1 in vitro, and the interaction is
largely dependent on the C-terminal half of SUV39H1 containing the SET domain.
Tax does not affect the methyltransferase activity of SUV39H1 but tethers
SUV39H1 to a Tax containing complex in the nuclei. In reporter gene assays,
co-expression of SUV39H1 represses Tax transactivation of HTLV-1 LTR promoter
activity, which was dependent on the methyltransferase activity of SUV39H1.
Furthermore, SUV39H1 expression is induced along with Tax in JPX9 cells.
Chromatin immunoprecipitation (ChIP) analysis shows localization of SUV39H1 on
the LTR after Tax induction, but not in the absence of Tax induction, in JPX9
transformants retaining HTLV-1-Luc plasmid. Immunoblotting shows higher levels
of SUV39H1 expression in HTLV-1 transformed and latently infected cell lines.
CONCLUSION: Our study revealed for the first time the interaction between Tax
and SUV39H1 and apparent tethering of SUV39H1 by Tax to the HTLV-1 LTR. It is
speculated that Tax-mediated tethering of SUV39H1 to the LTR and induction of
the repressive histone modification on the chromatin through H3 K9 methylation
may be the basis for the dose-dependent repression of Tax transactivation of LTR
by SUV39H1. Tax-induced SUV39H1 expression, Tax-SUV39H1 interaction and
tethering to the LTR may provide a support for an idea that the above sequence
of events may form a negative feedback loop that self-limits HTLV-1 viral gene
expression in infected cells.
DOI: 10.1186/1742-4690-3-5
PMCID: PMC1363732
PMID: 16409643 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/2358611
|
1. J Am Coll Cardiol. 1990 Jul;16(1):91-5. doi: 10.1016/0735-1097(90)90462-x.
Altered thyroid hormone metabolism in advanced heart failure.
Hamilton MA(1), Stevenson LW, Luu M, Walden JA.
Author information:
(1)Division of Cardiology, University of California, Los Angeles School of
Medicine 90024-1679.
To determine the prevalence and significance of abnormal thyroid hormone
metabolism in congestive heart failure, free thyroxine (T4) index, free
triiodothyronine (T3) index, reverse T3 and thyrotropin levels were obtained in
84 hospitalized patients with chronic advanced heart failure. Free T4 index was
normal in all patients. Free T3 index was reduced or reverse T3 elevated, or
both, leading to a low free T3 index/reverse T3 ratio in 49 (58%) of the 84
patients. A low free T3 index/reverse T3 ratio was associated with higher right
atrial, pulmonary artery and pulmonary capillary wedge pressures and lower
ejection fraction, cardiac index, serum sodium, albumin and total lymphocyte
count. In multivariate analysis, the free T3 index/reverse T3 ratio was the only
independent predictor of poor 6 week outcome (p less than 0.001); the actuarial
1 year survival rate was 100% for patients with a normal ratio and only 37% for
those with a low ratio (p less than 0.0001). A low free T3 index/reverse T3
ratio is associated with poor ventricular function and nutritional status and is
the strongest predictor yet identified for short-term outcome in patients with
advanced heart failure.
DOI: 10.1016/0735-1097(90)90462-x
PMID: 2358611 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/25619277
|
1. FEBS J. 2015 Apr;282(7):1225-41. doi: 10.1111/febs.13211. Epub 2015 Feb 13.
How pyridoxal 5'-phosphate differentially regulates human cytosolic and
mitochondrial serine hydroxymethyltransferase oligomeric state.
Giardina G(1), Brunotti P, Fiascarelli A, Cicalini A, Costa MG, Buckle AM, di
Salvo ML, Giorgi A, Marani M, Paone A, Rinaldo S, Paiardini A, Contestabile R,
Cutruzzolà F.
Author information:
(1)Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università
di Roma, Italy.
Adaptive metabolic reprogramming gives cancer cells a proliferative advantage.
Tumour cells extensively use glycolysis to sustain anabolism and produce serine,
which not only refuels the one-carbon units necessary for the synthesis of
nucleotide precursors and for DNA methylation, but also affects the cellular
redox homeostasis. Given its central role in serine metabolism, serine
hydroxymethyltransferase (SHMT), a pyridoxal 5'-phosphate (PLP)-dependent
enzyme, is an attractive target for tumour chemotherapy. In humans, the
cytosolic isoform (SHMT1) and the mitochondrial isoform (SHMT2) have distinct
cellular roles, but high sequence identity and comparable catalytic properties,
which may complicate development of successful therapeutic strategies. Here, we
investigated how binding of the cofactor PLP controls the oligomeric state of
the human isoforms. The fact that eukaryotic SHMTs are tetrameric proteins while
bacterial SHMTs function as dimers may suggest that the quaternary assembly in
eukaryotes provides an advantage to fine-tune SHMT function and differentially
regulate intertwined metabolic fluxes, and may provide a tool to address the
specificity problem. We determined the crystal structure of SHMT2, and compared
it to the apo-enzyme structure, showing that PLP binding triggers a
disorder-to-order transition accompanied by a large rigid-body movement of the
two cofactor-binding domains. Moreover, we demonstrated that SHMT1 exists in
solution as a tetramer, both in the absence and presence of PLP, while SHMT2
undergoes a dimer-to-tetramer transition upon PLP binding. These findings
indicate an unexpected structural difference between the two human SHMT
isoforms, which opens new perspectives for understanding their differing
behaviours, roles or regulation mechanisms in response to PLP availability
in vivo.
© 2015 FEBS.
DOI: 10.1111/febs.13211
PMID: 25619277 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19689438
|
1. J Am Acad Nurse Pract. 2009 Aug;21(8):423-9. doi:
10.1111/j.1745-7599.2009.00424.x.
Burning mouth syndrome: Identification, diagnosis, and treatment.
Rivinius C(1).
Author information:
(1)Jacobson Memorial Hospital Care Center, Inc., Elgin, North Dakota 58533, USA.
crivinius2@yahoo.com
PURPOSE: To provide an overview of burning mouth syndrome (BMS), describe the
role of the clinician when a patient presents with the burning mouth complaint,
offer guidance in differentiating the cause of the complaint, and identify
potential treatment options for the patient suffering from BMS.
DATA SOURCES: A search of MD Consult, Medline, and EBSCO Host Research Databases
with the terms "burning mouth" and "BMS."
CONCLUSIONS: BMS is a common, chronic disorder of unknown etiology with no
underlying or systemic causes or oral signs identified. It affects more than 1
million people in the United States, predominantly postmenopausal women. Despite
the common nature of the disorder, it is often misunderstood. Palliative
treatment, education, and support should be offered to the patient with
idiopathic BMS. A variety of treatment options exist, including benzodiazepines,
tricyclic antidepressants, anticonvulsants, alpha-lipoic acid, topical
capsaicin, and cognitive therapy can be added to the medication regimen for
greater benefit.
IMPLICATIONS FOR PRACTICE: The role of the clinician is to obtain a meticulous
history and physical examination of the patient, order relevant diagnostic
tests, and rule out treatable conditions that may be causing the burning mouth
symptom. If secondary causes of BMS are ruled out, the clinician should present
treatment options to the patient and consider referral to specialists as
necessary. A combination of medications may be more effective than a single
medication.
DOI: 10.1111/j.1745-7599.2009.00424.x
PMID: 19689438 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15249207
|
1. Biochem Biophys Res Commun. 2004 Aug 6;320(4):1133-8. doi:
10.1016/j.bbrc.2004.06.066.
Blockage of RNA polymerase II at a cyclobutane pyrimidine dimer and 6-4
photoproduct.
Mei Kwei JS(1), Kuraoka I, Horibata K, Ubukata M, Kobatake E, Iwai S, Handa H,
Tanaka K.
Author information:
(1)Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka,
Suita, Osaka 565-0871, Japan.
The blockage of transcription elongation by RNA polymerase II (pol II) at a DNA
damage site on the transcribed strand triggers a transcription-coupled DNA
repair (TCR), which rapidly removes DNA damage on the transcribed strand of the
expressed gene and allows the resumption of transcription. To analyze the effect
of UV-induced DNA damage on transcription elongation, an in vitro transcription
elongation system using pol II and oligo(dC)-tailed templates containing a
cyclobutane pyrimidine dimer (CPD) or 6-4 photoproduct (6-4PP) at a specific
site was employed. The results showed that pol II incorporated nucleotides
opposite the CPD and 6-4PP and then stalled. Pol II formed a stable ternary
complex consisting of pol II, the DNA damage template, and the nascent
transcript. Furthermore, atomic force microscopy imaging revealed that pol II
stalled at the damaged region. These findings may provide the basis for analysis
of the initiation step of TCR.
DOI: 10.1016/j.bbrc.2004.06.066
PMID: 15249207 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18326497
|
1. J Biol Chem. 2008 May 9;283(19):13116-23. doi: 10.1074/jbc.M707697200. Epub
2008 Mar 7.
Mechanism of ceftriaxone induction of excitatory amino acid transporter-2
expression and glutamate uptake in primary human astrocytes.
Lee SG(1), Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, Volsky DJ, Fisher PB.
Author information:
(1)Department of Urology, Neurosurgery, and Pathology, Herbert Irving
Comprehensive Cancer Center, Columbia University Medical Center, New York, New
York 10032, USA.
Glutamate is an essential neurotransmitter regulating brain functions.
Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate
transporters primarily expressed in astroglial cells. Dysfunction of EAAT2 is
implicated in acute and chronic neurological disorders, including
stroke/ischemia, temporal lobe epilepsy, amyotrophic lateral sclerosis,
Alzheimer disease, human immunodeficiency virus 1-associated dementia, and
growth of malignant gliomas. Ceftriaxone, one of the beta-lactam antibiotics, is
a stimulator of EAAT2 expression with neuroprotective effects in both in vitro
and in vivo models based in part on its ability to inhibit neuronal cell death
by glutamate excitotoxicity. Based on this consideration and its lack of
toxicity, ceftriaxone has potential to manipulate glutamate transmission and
ameliorate neurotoxicity. We investigated the mechanism by which ceftriaxone
enhances EAAT2 expression in primary human fetal astrocytes (PHFA). Ceftriaxone
elevated EAAT2 transcription in PHFA through the nuclear factor-kappaB
(NF-kappaB) signaling pathway. The antibiotic promoted nuclear translocation of
p65 and activation of NF-kappaB. The specific NF-kappaB binding site at the -272
position of the EAAT2 promoter was responsible for ceftriaxone-mediated EAAT2
induction. In addition, ceftriaxone increased glutamate uptake, a primary
function of EAAT2, and EAAT2 small interference RNA completely inhibited
ceftriaxone-induced glutamate uptake activity in PHFA. Taken together, our data
indicate that ceftriaxone is a potent modulator of glutamate transport in PHFA
through NF-kappaB-mediated EAAT2 promoter activation. These findings suggest a
mechanism for ceftriaxone modulation of glutamate transport and for its
potential effects on ameliorating specific neurodegenerative diseases through
modulation of extracellular glutamate.
DOI: 10.1074/jbc.M707697200
PMCID: PMC2442320
PMID: 18326497 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/8898827
|
1. Stroke. 1996 Nov;27(11):2131-5. doi: 10.1161/01.str.27.11.2131.
Moyamoya and Down syndrome. Clinical and radiological features.
Cramer SC(1), Robertson RL, Dooling EC, Scott RM.
Author information:
(1)Neurology Service, Massachusetts General Hospital, Boston 02114, USA.
BACKGROUND AND PURPOSE: Moyamoya disease is a chronic occlusive cerebrovascular
disorder characterized by progressive stenosis of the supraclinoid internal
carotid artery, with the secondary development of enlarged basal collateral
vessels. It may occur as a primary disease or as a syndrome in association with
a variety of conditions, and its pathogenesis remains unexplained. There are
relatively few reports describing the occurrence of moyamoya in Down syndrome.
The aim of this study is to describe the clinical and radiological features of
moyamoya syndrome associated with Down syndrome (MM-DS) and to explore theories
of moyamoya pathogenesis in these patients.
METHODS: Seven children with MM-DS underwent brain imaging, transfemoral
angiography, and serial neurological exams. Neurological deficits, poststroke
recovery, radiographic infarct characteristics, and angiographic abnormalities
were reviewed.
RESULTS: The clinical and radiological features of primary moyamoya disease
overlap with those of MM-DS. Hemiplegia and aphasia were the most common
presentations. Motor recovery was excellent in five of seven cases. Cerebral
infarcts were superficial or deep and can occur in a watershed distribution.
Angiography demonstrated involvement of the internal carotid artery and its
branches bilaterally in all seven cases and the posterior cerebral arteries in
four cases.
CONCLUSIONS: The clinical and radiological features of MM-DS overlap with
primary moyamoya disease. We postulate that a protein encoded on chromosome 21
may be related to the pathogenesis of moyamoya disease. Although the neuronal
substrate is abnormal in Down syndrome patients, recovery from hemiplegic stroke
in patients with MM-DS is comparable to recovery in patients with primary
moyamoya.
DOI: 10.1161/01.str.27.11.2131
PMID: 8898827 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19582169
|
1. PLoS One. 2009 Jul 2;4(7):e6133. doi: 10.1371/journal.pone.0006133.
Multiple horizontal gene transfer events and domain fusions have created novel
regulatory and metabolic networks in the oomycete genome.
Morris PF(1), Schlosser LR, Onasch KD, Wittenschlaeger T, Austin R, Provart N.
Author information:
(1)Department of Biological Sciences, Bowling Green State University, Bowling
Green, OH, USA. pmorris@bgsu.edu
Complex enzymes with multiple catalytic activities are hypothesized to have
evolved from more primitive precursors. Global analysis of the Phytophthora
sojae genome using conservative criteria for evaluation of complex proteins
identified 273 novel multifunctional proteins that were also conserved in P.
ramorum. Each of these proteins contains combinations of protein motifs that are
not present in bacterial, plant, animal, or fungal genomes. A subset of these
proteins were also identified in the two diatom genomes, but the majority of
these proteins have formed after the split between diatoms and oomycetes.
Documentation of multiple cases of domain fusions that are common to both
oomycetes and diatom genomes lends additional support for the hypothesis that
oomycetes and diatoms are monophyletic. Bifunctional proteins that catalyze two
steps in a metabolic pathway can be used to infer the interaction of orthologous
proteins that exist as separate entities in other genomes. We postulated that
the novel multifunctional proteins of oomycetes could function as potential
Rosetta Stones to identify interacting proteins of conserved metabolic and
regulatory networks in other eukaryotic genomes. However ortholog analysis of
each domain within our set of 273 multifunctional proteins against 39 sequenced
bacterial and eukaryotic genomes, identified only 18 candidate Rosetta Stone
proteins. Thus the majority of multifunctional proteins are not Rosetta Stones,
but they may nonetheless be useful in identifying novel metabolic and regulatory
networks in oomycetes. Phylogenetic analysis of all the enzymes in three
pathways with one or more novel multifunctional proteins was conducted to
determine the probable origins of individual enzymes. These analyses revealed
multiple examples of horizontal transfer from both bacterial genomes and the
photosynthetic endosymbiont in the ancestral genome of Stramenopiles. The
complexity of the phylogenetic origins of these metabolic pathways and the
paucity of Rosetta Stones relative to the total number of multifunctional
proteins suggests that the proteome of oomycetes has few features in common with
other Kingdoms.
DOI: 10.1371/journal.pone.0006133
PMCID: PMC2705460
PMID: 19582169 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.
|
http://www.ncbi.nlm.nih.gov/pubmed/23181572
|
1. Curr Pharm Des. 2013;19(22):4025-38. doi: 10.2174/1381612811319220012.
From bortezomib to other inhibitors of the proteasome and beyond.
Buac D(1), Shen M, Schmitt S, Kona FR, Deshmukh R, Zhang Z, Neslund-Dudas C,
Mitra B, Dou QP.
Author information:
(1)Department of Oncology and Barbara Ann Karmanos Cancer Institute, Wayne State
University School of Medicine, 4100 John R Street Hudson Webber Cancer Research
Center Room 540.1, Detroit Michigan 48201 USA. doup@karmanos.org.
The cancer drug discovery field has placed much emphasis on the identification
of novel and cancer-specific molecular targets. A rich source of such targets
for the design of novel anti-tumor agents is the ubiqutin-proteasome system
(UP-S), a tightly regulated, highly specific pathway responsible for the vast
majority of protein turnover within the cell. Because of its critical role in
almost all cell processes that ensure normal cellular function, its inhibition
at one point in time was deemed non-specific and therefore not worth further
investigation as a molecular drug target. However, today the proteasome is one
of the most promising anti-cancer drug targets of the century. The discovery
that tumor cells are in fact more sensitive to proteasome inhibitors than normal
cells indeed paved the way for the design of its inhibitors. Such efforts have
led to bortezomib, the first FDA approved proteasome inhibitor now used as a
frontline treatment for newly diagnosed multiple myeloma (MM),
relapsed/refractory MM and mantle cell lymphoma. Though successful in improving
clinical outcomes for patients with hematological malignancies, relapse often
occurs in those who initially responded to bortezomib. Therefore, the
acquisition of bortezomib resistance is a major issue with its therapy.
Furthermore, some neuro-toxicities have been associated with bortezomib
treatment and its efficacy in solid tumors is lacking. These observations have
encouraged researchers to pursue the next generation of proteasome inhibitors,
which would ideally overcome bortezomib resistance, have reduced toxicities and
a broader range of anti-cancer activity. This review summarizes the success and
limitations of bortezomib, and describes recent advances in the field,
including, and most notably, the most recent FDA approval of carfilzomib in
July, 2012, a second generation proteasome inhibitor. Other proteasome
inhibitors currently in clinical trials and those that are currently
experimental grade will also be discussed.
DOI: 10.2174/1381612811319220012
PMCID: PMC3657018
PMID: 23181572 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18558051
|
1. Actas Dermosifiliogr. 2008 Jul-Aug;99(6):431-40.
[Burning mouth syndrome].
[Article in Spanish]
Brufau-Redondo C(1), Martín-Brufau R, Corbalán-Velez R, de Concepción-Salesa A.
Author information:
(1)Servicio de Dermatología, Hospital General Universitario Reina Sofía, Murcia,
Spain. Cbrufau@terra.es
Burning mouth syndrome is characterized by a painful burning or stinging
sensation affecting the tongue or other areas of the mouth without obvious signs
of an organic cause on physical examination. A burning mouth sensation can occur
in several cutaneous or systemic diseases that must be ruled out prior to making
a diagnosis of burning mouth syndrome, since this term is used exclusively to
refer to idiopathic forms and is included within the cutaneous sensory
disorders. In most cases, patients with burning mouth syndrome have accompanying
psychologic or psychiatric conditions. Consequently, the syndrome has
traditionally been included among the psychogenic dermatoses. However, it is
currently unclear whether psychologic factors are a cause or a consequence of
the syndrome, or whether each exacerbates the other. Recent studies propose the
etiology to be neurologic, either neuropathic or related to taste.
PMID: 18558051 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/20635402
|
1. Am J Med Genet A. 2010 Aug;152A(8):2085-9. doi: 10.1002/ajmg.a.33539.
Aortic dissection and moyamoya disease in Turner syndrome.
Jagannath AD(1), Rastogi U, Spooner AE, Lin AE, Agnihotri AK.
Author information:
(1)Division of Cardiac Surgery, Massachusetts General Hospital, Boston,
Massachusetts, USA.
Aortic dilation and dissection are well-recognized cardiac abnormalities in
women with Turner syndrome (TS), although the underlying pathophysiology is not
fully understood. We report on a 46-year-old Hispanic woman who was previously
diagnosed with moyamoya disease on magnetic resonance imaging after a
presentation with stroke-like symptoms. Her features were consistent with TS and
chromosome analysis revealed mosaicism in which 17% of the cells showed a
pseudoisodicentric Y chromosome: 45,X (25)/46,X psu idic (Y)(11.2) (5). A
preceding screening transthoracic echocardiogram had shown a bicuspid aortic
valve (BAV) with an aortic diameter of 3.2 cm; at the time of moyamoya
diagnosis, the aorta was 3.5 cm with mild aortic stenosis and mild aortic
regurgitation. Four years later, the patient had had an acute aortic dissection,
Stanford type A, which was repaired successfully. This case report is the third
individual with TS associated with moyamoya disease and the first associated
with dissection. The small number of cases does not allow detailed analysis
other than noting patient age (two older than 40 years), karyotype (two others
associated with isochrome Xq), and associated cardiac risk factors (one with
BAV). Although this may be a chance occurrence, we hypothesize that moyamoya
disease could be a manifestation of the vasculopathy in TS.
DOI: 10.1002/ajmg.a.33539
PMID: 20635402 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/24694531
|
1. J Am Coll Cardiol. 2014 Jun 17;63(23):2541-2548. doi:
10.1016/j.jacc.2014.03.019. Epub 2014 Mar 30.
Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin
intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial
of evolocumab.
Stroes E(1), Colquhoun D(2), Sullivan D(3), Civeira F(4), Rosenson RS(5), Watts
GF(6), Bruckert E(7), Cho L(8), Dent R(9), Knusel B(9), Xue A(9), Scott R(9),
Wasserman SM(9), Rocco M(10); GAUSS-2 Investigators.
Author information:
(1)Department of Vascular Medicine, Academic Medical Center, Amsterdam, the
Netherlands. Electronic address: e.s.stroes@amc.uva.nl.
(2)Wesley Medical Centre, Auchenflower, Australia.
(3)Department of Clinical Biochemistry, Royal Prince Alfred Hospital,
Camperdown, Australia.
(4)Hospital Universitario Miguel Servet, Zaragoza, Spain.
(5)Cardiometabolic Disorders Department, Icahn School of Medicine at Mount
Sinai, New York, New York.
(6)Lipid Disorders Clinic, Royal Perth Hospital, School of Medicine and
Pharmacology, University of Western Australia, Perth, Australia.
(7)Hopital Pitie-Salpetriere, Paris, France.
(8)Preventive Cardiology and Rehabilitation, Cleveland Clinic, Cleveland, Ohio.
(9)Amgen, Thousand Oaks, California.
(10)Cardiovascular Medicine Department, Cleveland Clinic, Cleveland, Ohio.
OBJECTIVES: This study sought to evaluate the efficacy and safety of
subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic
patients who are unable to tolerate effective statin doses.
BACKGROUND: Statin intolerance, which is predominantly due to muscle-related
side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully
human monoclonal antibody to proprotein convertase subtilisin/kexin type 9
(PCSK9), demonstrated marked reductions in plasma low-density lipoprotein
cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients.
METHODS: The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in
Statin Intolerant Subjects) trial was a 12-week, double-blind study of
randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or
evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous
placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints
were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and
at week 12.
RESULTS: Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl)
were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%,
corresponding to treatment differences versus ezetimibe of 37% to 39%
(p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients
and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and
laboratory abnormalities were comparable across treatment groups.
CONCLUSIONS: Robust efficacy combined with favorable tolerability makes
evolocumab a promising therapy for addressing the largely unmet clinical need in
high-risk patients with elevated cholesterol who are statin intolerant. (Goal
Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant
Subjects-2; NCT01763905).
Copyright © 2014 American College of Cardiology Foundation. Published by
Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jacc.2014.03.019
PMID: 24694531 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21867529
|
1. Respir Res. 2011 Aug 25;12(1):115. doi: 10.1186/1465-9921-12-115.
Altered surfactant homeostasis and recurrent respiratory failure secondary to
TTF-1 nuclear targeting defect.
Peca D(1), Petrini S, Tzialla C, Boldrini R, Morini F, Stronati M, Carnielli VP,
Cogo PE, Danhaive O.
Author information:
(1)Department of Medical and Surgical Neonatology, Bambino Gesù Children's
Hospital IRCCS, Rome, Italy.
BACKGROUND: Mutations of genes affecting surfactant homeostasis, such as SFTPB,
SFTPC and ABCA3, lead to diffuse lung disease in neonates and children.
Haploinsufficiency of NKX2.1, the gene encoding the thyroid transcription
factor-1 (TTF-1)--critical for lung, thyroid and central nervous system
morphogenesis and function--causes a rare form of progressive respiratory
failure designated brain-lung-thyroid syndrome. Molecular mechanisms involved in
this syndrome are heterogeneous and poorly explored. We report a novel TTF-1
molecular defect causing recurrent respiratory failure episodes in an infant.
METHODS: The subject was an infant with severe neonatal respiratory distress
syndrome followed by recurrent respiratory failure episodes, hypopituitarism and
neurological abnormalities. Lung histology and ultrastructure were assessed by
surgical biopsy. Surfactant-related genes were studied by direct genomic DNA
sequencing and array chromatine genomic hybridization (aCGH). Surfactant protein
expression in lung tissue was analyzed by confocal immunofluorescence
microscopy. For kinetics studies, surfactant protein B and disaturated
phosphatidylcholine (DSPC) were isolated from serial tracheal aspirates after
intravenous administration of stable isotope-labeled (2)H(2)O and (13)C-leucine;
fractional synthetic rate was derived from gas chromatography/mass spectrometry
(2)H and (13)C enrichment curves. Six intubated infants with no primary lung
disease were used as controls.
RESULTS: Lung biopsy showed desquamative interstitial pneumonitis and lamellar
body abnormalities suggestive of genetic surfactant deficiency. Genetic studies
identified a heterozygous ABCA3 mutation, L941P, previously unreported. No
SFTPB, SFTPC or NKX2.1 mutations or deletions were found. However,
immunofluorescence studies showed TTF-1 prevalently expressed in type II cell
cytoplasm instead of nucleus, indicating defective nuclear targeting. This
pattern has not been reported in human and was not found in two healthy controls
and in five ABCA3 mutation carriers. Kinetic studies demonstrated a marked
reduction of SP-B synthesis (43.2 vs. 76.5 ± 24.8%/day); conversely, DSPC
synthesis was higher (12.4 vs. 6.3 ± 0.5%/day) compared to controls, although
there was a marked reduction of DSPC content in tracheal aspirates (29.8 vs.
56.1 ± 12.4% of total phospholipid content).
CONCLUSION: Defective TTF-1 signaling may result in profound surfactant
homeostasis disruption and neonatal/pediatric diffuse lung disease. Heterozygous
ABCA3 missense mutations may act as disease modifiers in other genetic
surfactant defects.
DOI: 10.1186/1465-9921-12-115
PMCID: PMC3179724
PMID: 21867529 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21551164
|
1. Eur J Endocrinol. 2011 Jul;165(1):167-70. doi: 10.1530/EJE-11-0101. Epub 2011
May 6.
Life-threatening metabolic alkalosis in Pendred syndrome.
Kandasamy N(1), Fugazzola L, Evans M, Chatterjee K, Karet F.
Author information:
(1)Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
INTRODUCTION: Pendred syndrome, a combination of sensorineural deafness,
impaired organification of iodide in the thyroid and goitre, results from
biallelic defects in pendrin (encoded by SLC26A4), which transports chloride and
iodide in the inner ear and thyroid respectively. Recently, pendrin has also
been identified in the kidneys, where it is found in the apical plasma membrane
of non-α-type intercalated cells of the cortical collecting duct. Here, it
functions as a chloride-bicarbonate exchanger, capable of secreting bicarbonate
into the urine. Despite this function, patients with Pendred syndrome have not
been reported to develop any significant acid-base disturbances, except a single
previous reported case of metabolic alkalosis in the context of Pendred syndrome
in a child started on a diuretic.
CASE REPORT: We describe a 46-year-old female with sensorineural deafness and
hypothyroidism, who presented with severe hypokalaemic metabolic alkalosis
during inter-current illnesses on two occasions, and who was found to be
homozygous for a loss-of-function mutation (V138F) in SLC26A4. Her acid-base
status and electrolytes were unremarkable when she was well.
CONCLUSION: This case illustrates that, although pendrin is not usually required
to maintain acid-base homeostasis under ambient condition, loss of renal
bicarbonate excretion by pendrin during a metabolic alkalotic challenge may
contribute to life-threatening acid-base disturbances in patients with Pendred
syndrome.
DOI: 10.1530/EJE-11-0101
PMCID: PMC3118492
PMID: 21551164 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/19648386
|
1. Mayo Clin Proc. 2009 Aug;84(8):694-701. doi: 10.4065/84.8.694.
Validity of the FOUR score coma scale in the medical intensive care unit.
Iyer VN(1), Mandrekar JN, Danielson RD, Zubkov AY, Elmer JL, Wijdicks EF.
Author information:
(1)Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN
55905, USA.
OBJECTIVE: To evaluate the validity of the FOUR (Full Outline of
UnResponsiveness) score (ranging from 0 to 16), a new coma scale consisting of 4
components (eye response, motor response, brainstem reflexes, and respiration
pattern), when used by the staff members of a medical intensive care unit (ICU).
PATIENTS AND METHODS: This interobserver agreement study prospectively evaluated
the use of the FOUR score to describe the condition of 100 critically ill
patients from May 1, 2007, to April 30, 2008. We compared the FOUR score to the
Glasgow Coma Scale (GCS) score. For each patient, the FOUR score and the GCS
score were determined by a randomly selected staff pair (nurse/fellow,
nurse/consultant, fellow/fellow, or fellow/consultant). Pair wise weighted kappa
values were calculated for both scores for each observer pair.
RESULTS: The interrater agreement with the FOUR score was excellent (weighted
kappa: eye response, 0.96; motor response, 0.97; brainstem reflex, 0.98;
respiration pattern, 1.00) and similar to that obtained with the GCS (weighted
kappa: eye response, 0.96; motor response, 0.97; verbal response, 0.98). In
terms of the predictive power for poor neurologic outcome (Modified Rankin Scale
score, 3-6), the area under the receiver operating characteristic curve was 0.75
for the FOUR score and 0.76 for the GCS score. The mortality rate for patients
with the lowest FOUR score of 0 (89%) was higher than that for patients with the
lowest GCS score of 3 (71%).
CONCLUSION: The interrater agreement of FOUR score results was excellent among
medical intensivists. In contrast to the GCS, all components of the FOUR score
can be rated even when patients have undergone intubation. The FOUR score is a
good predictor of the prognosis of critically ill patients and has important
advantages over the GCS in the ICU setting.
DOI: 10.4065/84.8.694
PMCID: PMC2719522
PMID: 19648386 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23822094
|
1. Anat Histol Embryol. 2014 Jun;43(3):239-44. doi: 10.1111/ahe.12074. Epub 2013
Jul 4.
3D printing of rat salivary glands: The submandibular-sublingual complex.
Cecchini MP(1), Parnigotto M, Merigo F, Marzola P, Daducci A, Tambalo S, Boschi
F, Colombo L, Sbarbati A.
Author information:
(1)Department of Neurological, Neuropsychological, Morphological and Movement
Sciences, Anatomy and Histology Section, University of Verona, Strada Le Grazie
8, 37134, Verona, Italy.
The morphology and the functionality of the murid glandular complex, composed of
the submandibular and sublingual salivary glands (SSC), were the object of
several studies conducted mainly using magnetic resonance imaging (MRI). Using a
4.7 T scanner and a manganese-based contrast agent, we improved the
signal-to-noise ratio of the SSC relating to the surrounding anatomical
structures allowing to obtain high-contrast 3D images of the SSC. In the last
few years, the large development in resin melting techniques opened the way for
printing 3D objects starting from a 3D stack of images. Here, we demonstrate the
feasibility of the 3D printing technique of soft tissues such as the SSC in the
rat with the aim to improve the visualization of the organs. This approach is
useful to preserve the real in vivo morphology of the SCC in living animals
avoiding the anatomical shape changes due to the lack of relationships with the
surrounding organs in case of extraction. It is also harmless, repeatable and
can be applied to explore volumetric changes occurring during body growth,
excretory duct obstruction, tumorigenesis and regeneration processes. 3D
printing allows to obtain a solid object with the same shape of the organ of
interest, which can be observed, freely rotated and manipulated. To increase the
visibility of the details, it is possible to print the organs with a selected
zoom factor, useful as in case of tiny organs in small mammalia. An immediate
application of this technique is represented by educational classes.
© 2013 Blackwell Verlag GmbH.
DOI: 10.1111/ahe.12074
PMID: 23822094 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21995290
|
1. BMC Med Genet. 2011 Oct 13;12:138. doi: 10.1186/1471-2350-12-138.
Comprehensive analysis of RET common and rare variants in a series of Spanish
Hirschsprung patients confirms a synergistic effect of both kinds of events.
Núñez-Torres R(1), Fernández RM, Acosta MJ, Enguix-Riego Mdel V, Marbá M, Carlos
de Agustín J, Castaño L, Antiñolo G, Borrego S.
Author information:
(1)Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal,
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del
Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
BACKGROUND: RET is the major gene associated to Hirschsprung disease (HSCR) with
differential contributions of its rare and common, coding and noncoding
mutations to the multifactorial nature of this pathology. In the present study,
we have performed a comprehensive study of our HSCR series evaluating the
involvement of both RET rare variants (RVs) and common variants (CVs) in the
context of the disease.
METHODS: RET mutational screening was performed by dHPLC and direct sequencing
for the identification of RVs. In addition Taqman technology was applied for the
genotyping of 3 RET CVs previously associated to HSCR, including a variant lying
in an enhancer domain within RET intron 1 (rs2435357). Statistical analyses were
performed using the SPSS v.17.0 to analyze the distribution of the variants.
RESULTS: Our results confirm the strongest association to HSCR for the
"enhancer" variant, and demonstrate a significantly higher impact of it in male
versus female patients. Integration of the RET RVs and CVs analysis showed that
in 91.66% of cases with both kinds of mutational events, the enhancer allele is
in trans with the allele bearing the RET RV.
CONCLUSIONS: A gender effect exists on both the transmission and distribution of
rare coding and common HSCR causing mutations. In addition, these RET CVs and
RVs seem to act in a synergistic way leading to HSCR phenotype.
DOI: 10.1186/1471-2350-12-138
PMCID: PMC3210088
PMID: 21995290 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/15254679
|
1. Oncol Rep. 2004 Aug;12(2):207-11.
Ectopic expression of DICE1 suppresses tumor cell growth.
Wieland I(1), Sell C, Weidle UH, Wieacker P.
Author information:
(1)Institute of Human Genetics, Otto-von-Guericke-Universität, Magdeburg,
Germany. ilse.wieland@medizin.uni-magdeburg.de
The tumor suppressor gene DICE1 is located within a previously reported critical
region of loss of heterozygosity on chromosome 13q14.3. Expression of the
remaining DICE1 allele is down-regulated in non-small cell lung carcinomas.
Ectopic expression of DICE1 cDNA by DICE1-green fluorescent protein fusion
constructs resulted in inhibition of colony formation of human non-small cell
lung carcinoma cell line SK-MES-1 and NCI-H520 and prostate carcinoma cell line
DU145. In IGF-IR transformed Balb/c 3T3, DICE1 substantially sup-pressed growth
in soft agar. These results demonstrate that DICE1 has a growth-suppressing
activity and interferes with anchorage-independent growth of IGF-IR transformed
tumor cells dependent upon IGF-I signaling.
PMID: 15254679 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/16549820
|
1. J Clin Oncol. 2006 Apr 10;24(11):1672-8. doi: 10.1200/JCO.2005.04.4339. Epub
2006 Mar 20.
Association of the PDCD5 locus with lung cancer risk and prognosis in smokers.
Spinola M(1), Meyer P, Kammerer S, Falvella FS, Boettger MB, Hoyal CR,
Pignatiello C, Fischer R, Roth RB, Pastorino U, Haeussinger K, Nelson MR,
Dierkesmann R, Dragani TA, Braun A.
Author information:
(1)Department of Experimental Oncology and Laboratories, Thoracic Surgery,
Istituto Nazionale Tumori, Milan, Italy.
Comment in
J Clin Oncol. 2006 Apr 10;24(11):1651-2. doi: 10.1200/JCO.2005.05.4114.
PURPOSE: Whole-genome scan association analysis was carried out to identify
genetic variants predictive of lung cancer risk in smokers and to confirm the
identified variants in an independent sample.
PATIENTS AND METHODS: A case-control study was performed using two pools
consisting of DNA from 322 German smoking lung cancer patients and 273 healthy
smoking controls, respectively. A replication study was carried out using 254
Italian lung adenocarcinoma (ADCA) patients and 235 healthy controls.
RESULTS: Patients with genotypes GG or CG for the rs1862214 single nucleotide
polymorphism, 5' upstream of the programmed cell death 5 (PDCD5) gene, compared
with those with the common genotype CC showed an increased risk of lung cancer
(odds ratio, 1.6; 95% CI, 1.2 to 2.1) and a higher incidence of poor clinical
stage disease (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.4; P = .023), nodal
involvement (HR, 1.9; 95% CI, 1.1 to 3.6; P = .033), and short-term survivorship
(HR, 1.8; 95% CI, 1.2 to 2.6, P = .003). PDCD5 mRNA expression levels were
approximately 2.4-fold lower in lung ADCA as compared to normal lung tissue.
Human NCI-H520 cancer cells transfected with PDCD5 cDNA showed decreased
colony-forming ability.
CONCLUSION: These results suggest that the rs1862214 polymorphism in PDCD5 is
predictive for lung cancer risk and prognosis, and that PDCD5 may represent a
novel tumor suppressor gene influencing lung cancer.
DOI: 10.1200/JCO.2005.04.4339
PMID: 16549820 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/18427804
|
1. Appl Microbiol Biotechnol. 2008 Jun;79(3):339-54. doi:
10.1007/s00253-008-1458-6. Epub 2008 Apr 22.
The yeast Kluyveromyces marxianus and its biotechnological potential.
Fonseca GG(1), Heinzle E, Wittmann C, Gombert AK.
Author information:
(1)Department of Chemical Engineering, University of São Paulo, São Paulo, São
Paulo, Brazil.
Strains belonging to the yeast species Kluyveromyces marxianus have been
isolated from a great variety of habitats, which results in a high metabolic
diversity and a substantial degree of intraspecific polymorphism. As a
consequence, several different biotechnological applications have been
investigated with this yeast: production of enzymes (beta-galactosidase,
beta-glucosidase, inulinase, and polygalacturonases, among others), of
single-cell protein, of aroma compounds, and of ethanol (including
high-temperature and simultaneous saccharification-fermentation processes);
reduction of lactose content in food products; production of bioingredients from
cheese-whey; bioremediation; as an anticholesterolemic agent; and as a host for
heterologous protein production. Compared to its congener and model organism,
Kluyveromyces lactis, the accumulated knowledge on K. marxianus is much smaller
and spread over a number of different strains. Although there is no publicly
available genome sequence for this species, 20% of the CBS 712 strain genome was
randomly sequenced (Llorente et al. in FEBS Lett 487:71-75, 2000). In spite of
these facts, K. marxianus can envisage a great biotechnological future because
of some of its qualities, such as a broad substrate spectrum, thermotolerance,
high growth rates, and less tendency to ferment when exposed to sugar excess,
when compared to K. lactis. To increase our knowledge on the biology of this
species and to enable the potential applications to be converted into industrial
practice, a more systematic approach, including the careful choice of (a)
reference strain(s) by the scientific community, would certainly be of great
value.
DOI: 10.1007/s00253-008-1458-6
PMID: 18427804 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21903771
|
1. Clin Cancer Res. 2011 Nov 1;17(21):6812-21. doi:
10.1158/1078-0432.CCR-11-0396. Epub 2011 Sep 8.
BCR-ABL transcript dynamics support the hypothesis that leukemic stem cells are
reduced during imatinib treatment.
Stein AM(1), Bottino D, Modur V, Branford S, Kaeda J, Goldman JM, Hughes TP,
Radich JP, Hochhaus A.
Author information:
(1)Oncology, Novartis Institutes for BioMedical Research, Inc., Cambridge,
Massachusetts 02139, USA. andrew.stein@novartis.com
Comment in
Clin Cancer Res. 2011 Nov 1;17(21):6605-7. doi:
10.1158/1078-0432.CCR-11-2240.
PURPOSE: Imatinib induces a durable response in most patients with Philadelphia
chromosome-positive chronic myeloid leukemia, but it is currently unclear
whether imatinib reduces the leukemic stem cell (LSC) burden, which may be an
important step toward enabling safe discontinuation of therapy. In this article,
we use mathematical models of BCR-ABL levels to make inferences on the dynamics
of LSCs.
EXPERIMENTAL DESIGN: Patients with at least 1 BCR-ABL transcript measurement on
imatinib were included (N = 477). Maximum likelihood methods were used to test 3
potential hypotheses of the dynamics of BCR-ABL transcripts on imatinib therapy:
(i) monoexponential, in which there is little, if any, decline in BCR-ABL
transcripts; (ii) biexponential, in which patients have a rapid initial decrease
in BCR-ABL transcripts followed by a more gradual response; and (iii)
triexponential, in which patients first exhibit a biphasic decline but then have
a third phase when BCR-ABL transcripts increase rapidly.
RESULTS: We found that most patients treated with imatinib exhibit a biphasic
decrease in BCR-ABL transcript levels, with a rapid decrease during the first
few months of treatment, followed by a more gradual decrease that often
continues over many years.
CONCLUSIONS: We show that the only hypothesis consistent with current data on
progenitor cell turnover and with the long-term, gradual decrease in the BCR-ABL
levels seen in most patients is that these patients exhibit a continual, gradual
reduction of the LSCs. This observation may explain the ability to discontinue
imatinib therapy without relapse in some cases.
©2011 AACR
DOI: 10.1158/1078-0432.CCR-11-0396
PMID: 21903771 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/11685733
|
1. Semin Oncol. 2001 Aug;28(4 Suppl 15):71-6. doi: 10.1016/s0093-7754(01)90159-9.
Docetaxel, estramustine, plus trastuzumab in patients with metastatic
androgen-independent prostate cancer.
Small EJ(1), Bok R, Reese DM, Sudilovsky D, Frohlich M.
Author information:
(1)Urologic Oncology Program, University of California, San Francisco
Comprehensive Cancer Center, San Francisco, CA 94143-1711, USA.
The incidence of human epidermal growth factor receptor 2 (HER2) protein
overexpression and its prognostic value are not well characterized in patients
with prostate cancer. A phase I study was designed to evaluate
docetaxel/estramustine plus trastuzumab, a humanized monoclonal antibody that
binds to the HER2 receptor, in patients with metastatic androgen-independent
prostate cancer (AIPC). HER2 positivity was not required because safety was the
primary endpoint. Patients received oral estramustine 280 mg three times daily
(days 1 to 5); docetaxel, 70 mg/m(2) intravenously (day 2); and trastuzumab, 2
mg/kg intravenously (days 2, 9, and 19), every 21 days until the disease
progressed or toxicity became unacceptable. This regimen was well tolerated
among the first 13 treated patients. Grade 4 neutropenia was seen in 10% of
administered cycles. There were two episodes of febrile neutropenia and two
thrombembolic events. Of the 13 patients evaluable for prostate-specific antigen
(PSA) response, nine (69%) experienced a decrease in PSA level of >50%. Two
(33%) of six patients with measurable disease had objective responses, and one
complete response was seen on bone scan. Docetaxel/estramustine/trastuzumab
appears to be a safe combination when used in the treatment of metastatic AIPC.
The response data are too preliminary for speculation about the relative
benefits of this 3-drug regimen compared with the combination of only docetaxel
and estramustine in this clinical setting.
Copyright 2001 by W.B. Saunders Company.
DOI: 10.1016/s0093-7754(01)90159-9
PMID: 11685733 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21878041
|
1. Expert Rev Cardiovasc Ther. 2011 Aug;9(8):959-73. doi: 10.1586/erc.11.99.
Selective and specific I(f) inhibition with ivabradine: new perspectives for the
treatment of cardiovascular disease.
Ferrari R(1), Ceconi C.
Author information:
(1)Department of Cardiology, University of Ferrara, Salvatore Maugeri
Foundation, IRCCS, Lumezzane, Italy. fri@unife.it
Heart rate is a major determinant of myocardial oxygen demand and supply, and
increased heart rate adversely affects the pathophysiology of myocardial
ischemia. High resting heart rate is a risk factor in cardiovascular disease.
The development of the heart rate-lowering agent ivabradine showed that heart
rate was also an important treatment target, notably in coronary artery disease
and heart failure. Indeed, heart rate reduction with ivabradine, a selective and
specific I(f) inhibitor, reduces myocardial oxygen demand, increases diastolic
perfusion time and improves energetics in ischemic myocardium. Ivabradine
protects the myocardium during ischemia, improves left ventricular function in
heart failure and reduces remodeling following myocardial infarction. It
improves prognosis in patients with coronary artery disease, left ventricular
dysfunction and heart rate ≥70 beats per minute, as well as in patients with
heart failure and left ventricular dysfunction. Ivabradine is safe, well
tolerated and can be used in combination with the main drugs for cardiovascular
disease.
DOI: 10.1586/erc.11.99
PMID: 21878041 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23380391
|
1. Clin Nephrol. 2014 Aug;82(2):144-8. doi: 10.5414/CN107796.
Adult hemolytic uremic syndrome associated with Streptococcus pneumoniae.
Allen JC, McCulloch T, Kolhe NV.
Erratum in
Clin Nephrol. 2015 Feb;83(2):130. Kolh, Nitin V [corrected to Kolhe, Nitin
V].
Hemolyitic uremic syndrome (HUS), characterized by triad of acute kidney injury,
thrombocytopenia, and hemolytic anemia, has considerable morbidity and mortality
and is known to be associated with diarrheal illness. It usually occurs after a
diarrheal illness due to Shiga-toxin-producing Escherichia coli. Streptococcus
pneumoniae is a rare but well recognized trigger for non-diarrhea associated HUS
in children, but has not been reported in adults. We report a case of an adult
presenting with pneumococcal pneumonia complicated by HUS and required renal
replacement therapy.
DOI: 10.5414/CN107796
PMID: 23380391 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/23498937
|
1. Cell. 2013 Mar 14;152(6):1285-97. doi: 10.1016/j.cell.2013.02.029.
CTCF and cohesin: linking gene regulatory elements with their targets.
Merkenschlager M(1), Odom DT.
Author information:
(1)Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College
London, Du Cane Road, London W12 0NN, UK. matthias.merkenschlager@csc.mrc.ac.uk
Current epigenomics approaches have facilitated the genome-wide identification
of regulatory elements based on chromatin features and transcriptional regulator
binding and have begun to map long-range interactions between regulatory
elements and their targets. Here, we focus on the emerging roles of CTCF and the
cohesin in coordinating long-range interactions between regulatory elements. We
discuss how species-specific transposable elements may influence such
interactions by remodeling the CTCF binding repertoire and suggest that
cohesin's association with enhancers, promoters, and sites defined by CTCF
binding has the potential to form developmentally regulated networks of
long-range interactions that reflect and promote cell-type-specific
transcriptional programs.
Copyright © 2013 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.cell.2013.02.029
PMID: 23498937 [Indexed for MEDLINE]
|
http://www.ncbi.nlm.nih.gov/pubmed/21170699
|
1. Wien Med Wochenschr. 2010 Dec;160(21-22):586-9. doi:
10.1007/s10354-010-0840-z.
[Austrian guidance for the pharmacologic treatment of osteoporosis in
postmenopausal women: Addendum 2010].
[Article in German]
Dimai HP(1), Pietschmann P, Resch H, Preisinger E, Fahrleitner-Pammer A, Dobnig
H, Klaushofer K; Austrian Society for Bone and Mineral Research (AuSBMR).
Author information:
(1)Klinische Abteilung für Endokrinologie und Stoffwechsel, Universitätsklinik
für Innere Medizin, Medizinische Universität Graz, Graz, Austria.
hans.dimai@medunigraz.at
The Austrian Society for Bone and Mineral Research routinely publishes
evidence-based guidelines for the treatment of postmenopausal osteoporosis. The
fully human monoclonal antibody denosumab (Prolia(®)) has been recently approved
by the European Medical Agency (EMEA) and the Food and Drug Administration (FDA)
for the treatment of postmenopausal osteoporosis. Denosumab has been shown to
reduce vertebral, non-vertebral,and hip-fracture risk effectively. Together with
alendronate, risedronate, zoledronate, ibandronate, strontium ranelate, and
raloxifene, denosumab constitutes an effective option in the treatment of
postmenopausal osteoporosis.
DOI: 10.1007/s10354-010-0840-z
PMID: 21170699 [Indexed for MEDLINE]
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