tbuckley/cabot-search huggingface dataset:
The Cardiac Fas (APO-1/CD95) Receptor/Fas Ligand System
Authors: Kai C. Wollert, Jörg Heineke, Jürgen Westermann, Mark Lüdde, Beate Fiedler, Wolfgang Zierhut, Didier Laurent, Manuel K. A. Bauer, Klaus Schulze-Osthoff, Helmut Drexler
Journal: Circulation (2000)

Background —Fas (APO-1/CD95) is a transmembrane receptor belonging to the tumor necrosis factor receptor superfamily. Cross-linking of Fas by Fas ligand (FasL), a tumor necrosis factor-α–related cytokine, promotes apoptosis and/or transcription factor activation in a highly cell-type–specific manner. The biological consequences of Fas activation in cardiomyocytes and the regulation of Fas and FasL abundance in the myocardium in vivo remain largely unknown. Methods and Results —As shown by immunohistochemistry, Fas was expressed on the sarcolemma of cardiomyocytes in left ventricular tissue sections. Moreover, FasL was constitutively expressed in the myocardium and in isolated cardiomyocytes, as revealed by reverse transcription polymerase chain reaction and Western blotting. Left ventricular abundance of Fas but not FasL was upregulated in a rat model of compensated volume-overload hypertrophy and was closely related to diastolic but not systolic wall stress as determined by MRI. Cardiomyocyte apoptosis was not enhanced in volume-overload hypertrophy despite the increased expression of Fas and the presence of FasL in the myocardium. Moreover, injection of mice with an agonistic anti-Fas antibody promoted hepatocyte but not cardiomyocyte apoptosis in vivo. Stimulation of isolated cardiomyocytes with recombinant FasL promoted an activation of the transcription factor AP-1 as shown by electrophoretic mobility shift assays but did not induce cell death. Conclusions —Fas and FasL are constitutively expressed in the myocardium and in cardiomyocytes. Myocardial expression of Fas is closely related to diastolic loading conditions in vivo. Signaling pathways emanating from Fas are coupled to an activation of the transcription factor AP-1 in cardiomyocytes.
The activation of plasminogen by Hageman factor (Factor XII) and Hageman factor fragments.
Authors: G H Goldsmith, H Saito, O S Ratnoff
Journal: Journal of Clinical Investigation (1978)

Activation of plasminogen through surface-mediated reactions is well recognized. In the presence of kaolin, purified Hageman factor (Factor XII) changed plasminogen to plasmin, as assayed upon a synthetic amide substrate and by fibrinolysis. Kinetic studies suggested an enzymatic action of Hageman factor upon its substrate, plasminogen. Hageman factor fragments, at a protein concentration equivalent to whole Hageman factor, activated plasminogen to a lesser extent. These protein preparations were not contaminated with other agents implicated in surface-mediated fibrinolysis. Diisopropyl fluorophosphate treatment of plasminogen did not inhibit its activation by Hageman factor. These studies indicate that Hageman factor has a hitherto unsuspected function, the direct activation of plasminogen.
Sudden infant death syndrome: How significant are the cardiac channelopathies?
Authors: D TESTER, M ACKERMAN
Journal: Cardiovascular Research (2005)

Having an apparently healthy, thriving infant fail to reach his/her first birthday is profoundly tragic. This tragedy is compounded when the infant's death is unexpected and unexplained, signed out as sudden infant death syndrome (SIDS). Despite impressive success and welcome reductions in these tragic deaths due in large measure to "Back-to-Sleep" campaigns, the fundamental pathogenic mechanisms precipitating such deaths remain dimly exposed. Here, we review the causal link between SIDS and mutations involving the SCN5A-encoded cardiac sodium channel, provide new findings following extensive postmortem genetic testing of long QT syndrome (LQTS)-associated potassium channel genes in a population-based cohort of SIDS, and summarize the current understanding regarding the spectrum and prevalence of cardiac channelopathies in the pathogenesis of SIDS.
A Randomized Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus
Authors: Maria Grazia Revello, Tiziana Lazzarotto, Brunella Guerra, Arsenio Spinillo, Enrico Ferrazzi, Alessandra Kustermann, Secondo Guaschino, Patrizia Vergani, Tullia Todros, Tiziana Frusca, Alessia Arossa, Milena Furione, Vanina Rognoni, Nicola Rizzo, Liliana Gabrielli, Catherine Klersy, Giuseppe Gerna
Journal: New England Journal of Medicine (2014)

Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40% to 16%.We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study. A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth or by means of amniocentesis.A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, -3 to 31; P=0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%).In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.).
Functional analysis of transcription factor binding sites in human promoters
Authors: Troy W Whitfield, Jie Wang, Patrick J Collins, E Christopher Partridge, Shelley Force Aldred, Nathan D Trinklein, Richard M Myers, Zhiping Weng
Journal: Genome biology (2012)

Abstract Background The binding of transcription factors to specific locations in the genome is integral to the orchestration of transcriptional regulation in cells. To characterize transcription factor binding site function on a large scale, we predicted and mutagenized 455 binding sites in human promoters. We carried out functional tests on these sites in four different immortalized human cell lines using transient transfections with a luciferase reporter assay, primarily for the transcription factors CTCF, GABP, GATA2, E2F, STAT, and YY1. Results In each cell line, between 36% and 49% of binding sites made a functional contribution to the promoter activity; the overall rate for observing function in any of the cell lines was 70%. Transcription factor binding resulted in transcriptional repression in more than a third of functional sites. When compared with predicted binding sites whose function was not experimentally verified, the functional binding sites had higher conservation and were located closer to transcriptional start sites (TSSs). Among functional sites, repressive sites tended to be located further from TSSs than were activating sites. Our data provide significant insight into the functional characteristics of YY1 binding sites, most notably the detection of distinct activating and repressing classes of YY1 binding sites. Repressing sites were located closer to, and often overlapped with, translational start sites and presented a distinctive variation on the canonical YY1 binding motif. Conclusions The genomic properties that we found to associate with functional TF binding sites on promoters -- conservation, TSS proximity, motifs and their variations -- point the way to improved accuracy in future TFBS predictions.
Amplification of the BRCA2 Pathway Gene <b> <i>EMSY</i> </b> in Sporadic Breast Cancer Is Related to Negative Outcome
Authors: Carmen Rodriguez, Luke Hughes-Davies, Hélène Vallès, Béatrice Orsetti, Marguerite Cuny, Lisa Ursule, Tony Kouzarides, Charles Theillet
Journal: Clinical Cancer Research (2004)

Abstract DNA amplification at band q13 of chromosome 11 is common in breast cancer, and CCND1 and EMS1 remain the strongest candidate genes. However, amplification patterns are consistent with the existence of four cores of amplification, suggesting the involvement of additional genes. Here we present evidence strongly suggesting the involvement of the recently characterized EMSY gene in the formation of the telomeric amplicon. EMSY maps at 11q13.5, 100 kb centromeric to the GARP gene, which has been mapped within the core of the distal amplicon. The EMSY protein was shown to interact with BRCA2 and has a role in chromatin remodeling. This makes EMSY a strong candidate oncogene for the 11q13.5 amplicon. DNA amplification was studied in a total of 940 primary breast tumors and 39 breast cancer cell lines. Amplification profiles were consistent with the EMSY-GARP locus being amplified independently of CCND1 and/or EMS1. EMSY RNA expression levels were studied along with those of five other genes located at 11q13.5 by real-time quantitative PCR in the 39 cell lines and a subset of 65 tumors. EMSY overexpression correlated strongly with DNA amplification in both primary tumors and cell lines. In a subset of 296 patients, EMSY amplification was found by both uni- and multivariate analyses to correlate with shortened disease-free survival. These data indicate that EMSY is a strong candidate oncogene for the 11q13.5 amplicon.
The Behavioral Response to Personalized Genetic Information: Will Genetic Risk Profiles Motivate Individuals and Families to Choose More Healthful Behaviors?
Authors: Colleen M. McBride, Laura M. Koehly, Saskia C. Sanderson, Kimberly A. Kaphingst
Journal: Annual Review of Public Health (2010)

This report describes the use of information emerging from genetic discovery to motivate risk-reducing health behaviors. Most research to date has evaluated the effects of information related to rare genetic variants on screening behaviors, in which genetic risk feedback has been associated consistently with improved screening adherence. The limited research with common genetic variants suggests that genetic information, when based on single-gene variants with low-risk probabilities, has little impact on behavior. The effect on behavioral outcomes of more realistic testing scenarios in which genetic risk is based on numerous genetic variants is largely unexplored. Little attention has been directed to matching genetic information to the literacy levels of target audiences. Another promising area for research is consideration of using genetic information to identify risk shared within kinship networks and to expand the influence of behavior change beyond the individual.
Comprehensive analysis of lymph node stroma-expressed Ig superfamily members reveals redundant and nonredundant roles for ICAM-1, ICAM-2, and VCAM-1 in lymphocyte homing
Authors: Rémy T. Boscacci, Friederike Pfeiffer, Kathrin Gollmer, Ana Isabel Checa Sevilla, Ana Maria Martin, Silvia Fernandez Soriano, Daniela Natale, Sarah Henrickson, Ulrich H. von Andrian, Yoshinori Fukui, Mario Mellado, Urban Deutsch, Britta Engelhardt, Jens V. Stein
Journal: Blood (2010)
Rapid detection of<i>HLA-A*31:01</i>allele in DNA and blood samples using loop-mediated isothermal amplification
Authors: Y.K. Cheung, M. Kwok, E. Chan, P. Kwan
Journal: British Journal of Dermatology (2014)

The human leucocyte antigen (HLA) allele, HLA-A*31:01, is a biomarker for adverse cutaneous reactions to carbamazepine, a first-line antiepileptic drug.To develop a platform that can rapidly detect the HLA-A*31:01 allele in blood samples to facilitate pretreatment screening.A novel protocol based on loop-mediated isothermal amplification (LAMP) was designed and optimized. It was applied to purified genomic DNA samples derived from B-cell lines with known HLA genotypes, and to DNA and whole blood samples collected from patients with epilepsy, in whom HLA-A genotypes were determined by sequence-based typing.The turnaround time for the LAMP-based protocol was < 45 min. In the DNA samples derived from B-cell lines (n = 66), the sensitivity, specificity, positive predictive value and negative predictive value of the LAMP-based protocol for detecting HLA-A*31:01 were 1·00 [95% confidence interval (CI) 0·88-1·00], 0·95 (95% CI 0·82-0·99), 0·94 and 1·00, respectively. The LAMP-based protocol produced the same results in the DNA and whole blood samples collected from patients (n = 34). Its sensitivity, specificity, positive predictive value and negative predictive value in detecting HLA-A*31:01 in the patient samples were 1·00 (95% CI 0·57-1·00), 0·97 (95% CI 0·83-0·99), 0·83 and 1·00, respectively.The findings demonstrated the feasibility of accurately detecting HLA-A*31:01 in DNA and whole blood samples using a LAMP-based protocol. Given its rapid turnaround time, this novel platform has the potential to be adapted into a point-of-care screening test.
Change in CA 125 levels after the first cycle of induction chemotherapy is an independent predictor of epithelial ovarian tumour outcome
Authors: J.M. Riedinger, F. Bonnetain, J.P. Basuyau, N. Eche, H. Larbre, I. Dalifard, J. Wafflart, G. Ricolleau, M.F. Pichon
Journal: Annals of Oncology (2007)
Hydroxy-Methylglutaryl–Coenzyme A Reductase Inhibition Promotes Endothelial Nitric Oxide Synthase Activation Through a Decrease in Caveolin Abundance
Authors: Olivier Feron, Chantal Dessy, Jean-Pierre Desager, J.-L. Balligand
Journal: Circulation (2001)

Background —Hypercholesterolemia is causally associated with defects of endothelial nitric oxide (NO)–dependent vasodilation. Increased uptake of cholesterol by endothelial cells (ECs) upregulates the abundance of the structural protein caveolin-1 and impairs NO release through the stabilization of the inhibitory heterocomplex between caveolin-1 and endothelial NO synthase (eNOS). Therefore, we examined whether the hydroxy-methylglutaryl–coenzyme A reductase inhibitor atorvastatin modulates caveolin abundance, eNOS activity, and NO release through a reduction in endogenous cholesterol levels. Methods and Results —ECs were incubated with increasing doses of atorvastatin in the absence or in the presence of human LDL cholesterol (LDL-Chol) fractions in the presence of antioxidants. Our results show that atorvastatin (10 nmol/L to 1 μmol/L) reduced caveolin-1 abundance in the absence (−75%) and in the presence (−20% to 70%) of LDL-Chol. This was paralleled by a decreased inhibitory interaction between caveolin-1 and eNOS and a restoration and/or potentiation of the basal (+45%) and agonist-stimulated (+107%) eNOS activity. These effects were observed in the absence of changes in eNOS abundance and were reversed with mevalonate. In the presence of LDL-Chol, atorvastatin also promoted the agonist-induced association of eNOS and the chaperone Hsp90, resulting in the potentiation of eNOS activation. Conclusions —We provide biochemical and functional evidence that atorvastatin promotes NO production by decreasing caveolin-1 expression in ECs, regardless of the level of extracellular LDL-Chol. These findings highlight the therapeutic potential of inhibiting cholesterol synthesis in peripheral cells to correct NO-dependent endothelial dysfunction associated with hypercholesterolemia and possibly other diseases.
ANTIDEPRESSANTS IN LONG-TERM TREATMENT
Authors: Stuart A. Montgomery, M.D
Journal: Annual Review of Medicine (1994)

▪ Abstract One of the most important recent developments in the management of depression is the recognition of the need for long-term treatment. Treatment of an episode of depression must continue after apparent response in order to consolidate response and prevent relapse. A continuation treatment period of at least four months after response of the acute episode is required in all patients with depression. Most depression is recurrent, and prophylactic treatment with antidepressants reduces the risk of new episodes. This treatment needs to be continued over very long periods, because the risk of new episodes does not appear to diminish with time. In selecting an antidepressant for long-term treatment efficacy, safety and tolerability in the long term should be taken into account since not all antidepressants have been adequately tested, and some do not appear to be effective. The most thoroughly tested antidepressants are the tricyclic imipramine and the new selective serotonin reuptake inhibitors.
Prevalence of Complicated Carotid Atheroma as Detected by Magnetic Resonance Direct Thrombus Imaging in Patients With Suspected Carotid Artery Stenosis and Previous Acute Cerebral Ischemia
Authors: Rachael E. Murphy, Alan R. Moody, Paul S. Morgan, Anne L. Martel, G.S. Delay, Steve Allder, Shane T. MacSweeney, William G. Tennant, John Gladman, John Lowe, Beverley J. Hunt
Journal: Circulation (2003)

Background— It is recognized that complicated plaque largely accounts for the morbidity and mortality from atherosclerosis. Ideally, investigation of symptomatic and asymptomatic patients would identify atheromatous plaques independently of stenosis. We have previously shown that a magnetic resonance direct thrombus imaging (MRDTI) technique demonstrates complicated atheroma as high signal within the carotid arterial wall. We used this technique to examine the prevalence of complicated carotid plaque in vivo in the ipsilateral arteries of recently symptomatic patients with suspected carotid artery stenosis and to compare this with their contralateral arteries and with those of healthy age- and sex-matched controls. Methods and Results— The carotid arteries of 120 patients with suspected severe carotid artery stenosis and previous acute cerebral ischemia were imaged using MRDTI, as were 28 control arteries. High signal was not seen in any control artery. However, there was a 60% prevalence of high signal, suggestive of complicated plaque in the patients’ ipsilateral arteries. The prevalence of high signal was significantly greater in the patients’ ipsilateral vessels compared with the contralateral, asymptomatic side (60% versus 36%, χ 2 P &lt;0.001), particularly for vessels of only moderate stenosis. Conclusions— MRDTI high signal suggestive of complicated plaque is prevalent in the ipsilateral carotid arteries of patients with carotid stenosis and recent cerebral ischemic events. MRDTI has a potential role in identifying “at risk” plaque, studying atherogenesis and the effects of plaque-modifying strategies.
Cell cycle-dependent regulation of the bi-directional overlapping promoter of human BRCA2/ZAR2 genes in breast cancer cells
Authors: Smita Misra, Shvetank Sharma, Anupriya Agarwal, Sheetal V Khedkar, Manish K Tripathi, Mukul K Mittal, Gautam Chaudhuri
Journal: Molecular Cancer (2010)

Abstract Background BRCA2 gene expression is tightly regulated during the cell cycle in human breast cells. The expression of BRCA2 gene is silenced at the G0/G1 phase of cell growth and is de-silenced at the S/G2 phase. While studying the activity of BRCA2 gene promoter in breast cancer cells, we discovered that this promoter has bi-directional activity and the product of the reverse activity (a ZAR1-like protein, we named ZAR2) silences the forward promoter at the G0/G1 phase of the cell. Standard techniques like cell synchronization by serum starvation, flow cytometry, N-terminal or C-terminal FLAG epitope-tagged protein expression, immunofluorescence confocal microscopy, dual luciferase assay for promoter evaluation, and chromatin immunoprecipitation assay were employed during this study. Results Human BRCA2 gene promoter is active in both the forward and the reverse orientations. This promoter is 8-20 fold more active in the reverse orientation than in the forward orientation when the cells are in the non-dividing stage (G0/G1). When the cells are in the dividing state (S/G 2 ), the forward activity of the promoter is 5-8 folds higher than the reverse activity. The reverse activity transcribes the ZAR2 mRNA with 966 nt coding sequence which codes for a 321 amino acid protein. ZAR2 has two C4 type zinc fingers at the carboxyl terminus. In the G0/G1 growth phase ZAR2 is predominantly located inside the nucleus of the breast cells, binds to the BRCA2 promoter and inhibits the expression of BRCA2. In the dividing cells, ZAR2 is trapped in the cytoplasm. Conclusions BRCA2 gene promoter has bi-directional activity, expressing BRCA2 and a novel C4-type zinc finger containing transcription factor ZAR2. Subcellular location of ZAR2 and its expression from the reverse promoter of the BRCA2 gene are stringently regulated in a cell cycle dependent manner. ZAR2 binds to BRCA2/ZAR2 bi-directional promoter in vivo and is responsible, at least in part, for the silencing of BRCA2 gene expression in the G0/G1 phase in human breast cells.
Hyperventilation in Postural Hypotension
Authors: JOHN F. BURNUM, JOHN B. HICKAM, EUGENE A. STEAD
Journal: Circulation (1954)

In normal subjects hyperventilation causes a drop in arterial blood pressure, apparently because of the direct effect of hypocapnia on the peripheral vessels. In persons with disease of the autonomic nervous system, the drop in blood pressure is much greater because it is not effectively opposed by reflex vasoconstriction. Consequently, hyperventilation caused by anxiety may greatly intensify postural hypotension in such patients and contribute significantly to their disability. A pertinent case is reported.
Development and treatment of fresh lung carcinoma after successful lobectomy.
Authors: R A Smith
Journal: Thorax (1966)

A close follow-up of all patients treated surgically for lung carcinoma has been carried out.The follow-up was designed to give as much informa- tion as possible on the cause of death following operation, particularly over the long term.During this study it became clear that many patients developed fresh evidence, primarily radiological, of lung carcinoma at varying times after opera- tion.This appeared to be more frequent than the literature suggested and to be a problem of sufficient size to consider the possibility of further operative treatment in an attempt to arrest the progress of the disease.This and other aspects considered in this paper have already been fully discussed by Hughes and Blades (1961) in their report.By concentrating principally on patients for whom further surgery seemed justifiable, much information on the natural history of other aspects of the disease after operation has probably been lost.This paper describes the different patterns of development of fresh carcinoma and adds information on the important matter of the development of fresh primary lung tumour or tumours, properly described by Le Gal and Bauer (1961) as a complication of successful lung cancer surgery.It would be simpler to discuss only those patients thought to have developed further primary tumours.By including all the manifesta- tions of extension it may be easier to form an opinion on the evidence put forward that a pro- portion of patients develop fresh primaries rather than metastases.Chest radiographs at four-monthly intervals on every patient operated upon, from the date of operation to death, provide the basis for this study.When a fresh radiological shadow, presumably due to lung carcinoma, appeared, the origin of the shadow and its treatment comprise the clinical problems. METHOD OF FOLLOW-UPThe following requirements were considered necessary for an adequate follow-up.The followup had to be complete, it had to include every B