tbuckley/cabot-search huggingface dataset:
Acute Endothelin A Receptor Blockade Causes Selective Pulmonary Vasodilation in Patients With Chronic Heart Failure
Authors: Michael M. Givertz, Wilson S. Colucci, Thierry H. LeJemtel, Stephen S. Gottlieb, Joshua M. Hare, Mara T. Slawsky, Carl V. Leier, Evan Loh, John M. Nicklas, Bruce E. Lewis
Journal: Circulation (2000)

Background —Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET A receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET A receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. Methods and Results —This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21±1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure ≥15 mm Hg and a cardiac index ≤2.5 L · min −1 · m −2 were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure ( P ≤0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan. Conclusions —In patients with moderate to severe heart failure receiving conventional therapy, acute ET A receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure.
ANTIGENIC RELATIONSHIPS OF BENCE JONES PROTEINS, MYELOMA GLOBULINS, AND NORMAL HUMAN γ-GLOBULIN
Authors: Shunsuke Migita, Frank W. Putnam
Journal: The Journal of Experimental Medicine (1963)

By means of immunodiffusion and immunoelectrophoresis study has been made of antigenic relationships of Bence Jones proteins, and the three classes of normal and pathological immunoglobulins, 7S γ, ß2A, and ß2M. All thirty-nine Bence Jones proteins studied could be classified into either one of two distinct antigenic types, A or B. Both types are related to the immunoelectrophoretically slow (S) fragment of a papain digest of normal γ-globulin; B is related more closely than A, but neither has antigenic determinants in common with the fast (F) fragment. The 7S γ myeloma globulins were either immunological type I or II. The papain digests of these proteins produced the S and F precipitin lines in immunoelectrophoresis but multiple bands in starch gel electrophoresis, especially in the F region. The S fraction of type I myeloma globulins is antigenically similar to Bence Jones protein of type B, and the S component of type II myeloma globulins has antigenic determinants in common with type A Bence Jones protein. Correspondingly, myeloma patients with type I globulins and proteinuria usually excrete type B Bence Jones proteins, whereas patients with type II excrete type A proteins. The F fragment is the part common to normal 7S γ-globulin and types I and II myeloma globulins but is absent in ß2A and ß2M pathological globulins and in both types of Bence Jones proteins. Papain digests of ß2A myeloma globulins produced a single precipitin line in immunoelectrophoresis. ß2A myeloma globulins appeared to have two antigenic units, one in common with type B Bence Jones protein and normal γ-globulin, and another specific to ß2A. The ß2A myeloma patients excreted type B Bence Jones protein. The papain digest of a macroglobulin produced two precipitin lines, the faster of which had antigenic determinants in common with type B Bence Jones protein, the slower seemed specific for the macroglobulin. Five serum micromolecular globulins proved to be either type A or B Bence Jones proteins. From the above results, an antigenic map was constructed showing which determinants are shared and which are specific for normal 7S γ-globulin, types I and II myeloma globulins, ß2A myeloma globulins, a macroglobulin, and types A and B Bence Jones proteins.
The Varieties of Immunological Experience: Of Pathogens, Stress, and Dendritic Cells
Authors: Bali Pulendran
Journal: Annual Review of Immunology (2015)

In the 40 years since their discovery, dendritic cells (DCs) have been recognized as central players in immune regulation. DCs sense microbial stimuli through pathogen-recognition receptors (PRRs) and decode, integrate, and present information derived from such stimuli to T cells, thus stimulating immune responses. DCs can also regulate the quality of immune responses. Several functionally specialized subsets of DCs exist, but DCs also display functional plasticity in response to diverse stimuli. In addition to sensing pathogens via PRRs, emerging evidence suggests that DCs can also sense stress signals, such as amino acid starvation, through ancient stress and nutrient sensing pathways, to stimulate adaptive immunity. Here, I discuss these exciting advances in the context of a historic perspective on the discovery of DCs and their role in immune regulation. I conclude with a discussion of emerging areas in DC biology in the systems immunology era and suggest that the impact of DCs on immunity can be usefully contextualized in a hierarchy-of-organization model in which DCs, their receptors and signaling networks, cell-cell interactions, tissue microenvironment, and the host macroenvironment represent different levels of the hierarchy. Immunity or tolerance can then be represented as a complex function of each of these hierarchies.
Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial
Authors: J. C. Figueiredo, M. V. Grau, R. W. Haile, R. S. Sandler, R. W. Summers, R. S. Bresalier, C. A. Burke, G. E. McKeown-Eyssen, J. A. Baron
Journal: JNCI Journal of the National Cancer Institute (2009)

Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting.We studied prostate cancer occurrence in the Aspirin/ Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006.Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0 -7.8) years and asked periodically to report all illnesses and hospitalizations.Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment.Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01).In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses.These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid -containing supplements vs natural sources of folate.
Molecular Signatures of the Three Stem Cell Lineages in Hydra and the Emergence of Stem Cell Function at the Base of Multicellularity
Authors: Georg Hemmrich, Konstantin Khalturin, Anna-Marei Boehm, Malte Puchert, Friederike Anton-Erxleben, Jörg Wittlieb, Ulrich C. Klostermeier, Philip Rosenstiel, Hans-Heinrich Oberg, Tomislav Domazet-Lošo, Toshimi Sugimoto, Hitoshi Niwa, Thomas C.G. Bosch
Journal: Molecular Biology and Evolution (2012)

How distinct stem cell populations originate and whether there is a clear stem cell "genetic signature" remain poorly understood. Understanding the evolution of stem cells requires molecular profiling of stem cells in an animal at a basal phylogenetic position. In this study, using transgenic Hydra polyps, we reveal for each of the three stem cell populations a specific signature set of transcriptions factors and of genes playing key roles in cell type-specific function and interlineage communication. Our data show that principal functions of stem cell genes, such as maintenance of stemness and control of stem cell self-renewal and differentiation, arose very early in metazoan evolution. They are corroborating the view that stem cell types shared common, multifunctional ancestors, which achieved complexity through a stepwise segregation of function in daughter cells.
Similar Effectiveness of Paroxetine, Fluoxetine, and Sertraline in Primary Care
Authors: Kurt Kroenke, Suzanne L. West, Ralph Swindle, Alicia Gilsenan, George J. Eckert, Rowena Dolor, Paul Stang, Xiao-Hua Zhou, Ron Hays, Morris Weinberger
Journal: JAMA (2001)

ContextSelective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressant, yet it is not known whether one SSRI is more effective than another.ObjectiveTo compare the effectiveness of 3 SSRIs (paroxetine, fluoxetine, and sertraline) in depressed primary care patients.DesignOpen-label, randomized, intention-to-treat trial, with patient enrollment occurring in April-November 1999.SettingThirty-seven clinics in 2 US primary care research networks.PatientsA total of 573 depressed adult patients for whom their primary care physician thought that antidepressant therapy was warranted and who completed a baseline interview.InterventionsPatients were randomly assigned to receive paroxetine (n = 189), fluoxetine (n = 193), or sertraline (n = 191) for 9 months. Primary care physicians were allowed to switch patients to a different SSRI or non-SSRI antidepressant if they did not adequately respond to or tolerate the initial SSRI.Main Outcome MeasuresThe primary outcome measure was change in the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) Mental Component Summary score (range, 0-100), compared across treatment groups at 1, 3, 6, and 9 months. Secondary outcomes included other depression and psychological measures, multiple measures of social and work functioning, and other domains of health-related quality of life, such as physical functioning, concentration and memory, vitality, bodily pain, sleep, and sexual functioning.ResultsFollow-up interviews were successfully completed in 94% of patients at 1 month, 87% at 3 months, 84% at 6 months, and 79% at 9 months. Responses to the 3 SSRIs were comparable on all measures and at all time points. The mean change in the SF-36 Mental Component Summary score at 9 months was + 15.8 in the paroxetine group, + 15.1 in the fluoxetine group, and + 17.4 in the sertraline group. The drugs were also associated with similar incidences of adverse effects and discontinuation rates.ConclusionsThe SSRI antidepressants paroxetine, fluoxetine, and sertraline were similar in effectiveness for depressive symptoms as well as multiple domains of health-related quality of life over the entire 9 months of this trial.
Theoretic Analysis of the Influence of Heart-Dipole Eccentricity on Limb Leads, Wilson Central-Terminal Voltage and the Frontal-Plane Vectorcardiogram
Authors: ERNEST FRANK
Journal: Circulation Research (1953)

This is a theoretic investigation of the influence of the position of a current dipole on the electric potential produced at the boundary of a homogeneous conducting sphere. Thirty different eccentric dipole positions are selected within the sphere to bear analogy to locations of the equivalent dipole of the human heart within the chest, and boundary-potential calculations are made from points selected to bear analogy with body-surface points utilized in limb leads, Wilson centralterminal and frontal-plane electrocardiography. The point of view taken differs completely from the scalene-triangle geometric representation of eccentricity; instead, an equilateral triangle is used in conjunction with assigned strength and orientation time-variations for the eccentric dipole. It is concluded that if electrocardiography were subject to no other limitation of the application of field analysis, eccentricity of dipole position alone can produce very significant deviations between the manifest heart vector and the true heart vector in both direction and magnitude. The dependence of the Wilson central-terminal voltage on dipole eccentricity is likewise appreciable and of the same order of magnitude as reported by several experimenters; however, the effects of eccentricity on the Wilson central-terminal voltage are generally less pronounced than on the manifest heart vector.
THE PROGNOSTIC VALUE OF THE THROMBOLYSIS IN MYOCARDIAL INFARCTION (TIMI) RISK INDEX AFTER PRIMARY PERCUTANEOUS CORONARY INTERVENTION FOR ST-ELEVATION MYOCARDIAL INFARCTION AT LONG-TERM FOLLOW-UP
Authors: Pier Woudstra, Peter Damman, Karel T. Koch, José P.S. Henriques, Jan Baan, Marije M. Vis, Jan J. Piek, Jan G.P. Tijssen, Robbert J. de Winter
Journal: Journal of the American College of Cardiology (2011)
Fluoride and Calcium Therapy for Myeloma Bone Lesions
Authors: Phin Cohen
Journal: JAMA (1966)

Skeletal fluorosis has been induced in eight cases of multiple myeloma. In seven of the eight cases, radiological fluorosis developed, four patients showing stage I changes and three, stage II changes by the criteria of Roholm. The five patients who had bone biopsies before and after fluoride-calcium therapy all showed marked thickening of trabeculae posttherapy. Five of the six patients who had severe pain experienced pain relief coincident with the fluorotic changes.
Severe Respiratory Disease Concurrent with the Circulation of H1N1 Influenza
Authors: Gerardo Chowell, Stefano M. Bertozzi, M. Arantxa Colchero, Hugo Lopez-Gatell, Celia Alpuche-Aranda, Mauricio Hernandez, Mark A. Miller
Journal: New England Journal of Medicine (2009)

In the spring of 2009, an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of a novel swine-origin influenza A (H1N1) virus (S-OIV), widely known as swine flu, in Mexico. Influenza A (H1N1) subtype viruses have rarely predominated since the 1957 pandemic. The analysis of epidemic pneumonia in the absence of routine diagnostic tests can provide information about risk factors for severe disease from this virus and prospects for its control.From March 24 to April 29, 2009, a total of 2155 cases of severe pneumonia, involving 821 hospitalizations and 100 deaths, were reported to the Mexican Ministry of Health. During this period, of the 8817 nasopharyngeal specimens that were submitted to the National Epidemiological Reference Laboratory, 2582 were positive for S-OIV. We compared the age distribution of patients who were reported to have severe pneumonia with that during recent influenza epidemics to document an age shift in rates of death and illness.During the study period, 87% of deaths and 71% of cases of severe pneumonia involved patients between the ages of 5 and 59 years, as compared with average rates of 17% and 32%, respectively, in that age group during the referent periods. Features of this epidemic were similar to those of past influenza pandemics in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population.During the early phase of this influenza pandemic, there was a sudden increase in the rate of severe pneumonia and a shift in the age distribution of patients with such illness, which was reminiscent of past pandemics and suggested relative protection for persons who were exposed to H1N1 strains during childhood before the 1957 pandemic. If resources or vaccine supplies are limited, these findings suggest a rationale for focusing prevention efforts on younger populations.
Effects of Chronic Jet Lag on Tumor Progression in Mice
Authors: Elisabeth Filipski, Franck Delaunay, Verdun M. King, Ming-Wei Wu, Bruno Claustrat, Aline Gréchez-Cassiau, Catherine Guettier, Michael H. Hastings, Lévi Francis
Journal: Cancer Research (2004)

Abstract Frequent transmeridian flights or predominant work at night can increase cancer risk. Altered circadian rhythms also predict for poor survival in cancer patients, whereas physical destruction of the suprachiasmatic nuclei (SCN), the hypothalamic circadian pacemaker, accelerates tumor growth in mice. Here we tested the effect of functional disruption of circadian system on tumor progression in a novel experimental model of chronic jet lag. B6D2F1 mice were synchronized with 12 hours of light and 12 hours of darkness or underwent repeat 8-hour advances of the light/dark cycle every 2 days before inoculation of Glasgow osteosarcoma. The 24-hour changes were assessed for plasma corticosterone, clock protein mPER1 expression in the SCN, and mRNA expression of clock genes mPer2 and mRev-erbα in liver and tumor. Time series were analyzed by spectral analysis and/or Cosinor. Differences were compared with analysis of variance (ANOVA). The 24-hour rest/activity cycle was ablated, and the rhythms of body temperature, serum corticosterone, and mPER1 protein expression in the SCN were markedly altered in jet-lagged mice as compared with controls (ANOVA, P &amp;lt; 0.001 for corticosterone and P = 0.01 for mPER1). Tumor grew faster in the jet-lagged animals as compared with controls (ANOVA, P &amp;lt; 0.001), whereas exposure to constant light or darkness had no effect (ANOVA, P = 0.66 and P = 0.8, respectively). The expression of mPer2 and mRev-erbα mRNAs in controls showed significant circadian rhythms in the liver (P = 0.006 and P = 0.003, respectively, Cosinor) and in the tumor (P = 0.04 and P &amp;lt; 0.001). Both rhythms were suppressed in the liver (P = 0.2 and P = 0.1, respectively, Cosinor) and in the tumor (P = 0.5) of jet-lagged mice. Altered environmental conditions can disrupt circadian clock molecular coordination in peripheral organs including tumors and play a significant role in malignant progression.
Biased accumulation of T lymphocytes with "memory"-type CD45 leukocyte common antigen gene expression on the epithelial surface of the human lung.
Authors: C Saltini, M Kirby, B C Trapnell, N Tamura, R G Crystal
Journal: The Journal of Experimental Medicine (1990)

Expression of alternatively spliced products of the CD45 leukocyte common antigen gene identifies two populations of blood T cells: "naive" T cells (containing CD45R-IV mRNA transcripts, CD45 220, 205 kD surface proteins detected with antibody 2H4) that respond poorly to recall antigens, and "memory" T cells (containing CD45R-0 mRNA transcripts, expressing CD45 180 kD protein, detected with antibody UCHL1) that respond promptly to recall antigens. While blood contains approximately equal numbers of "naive" and "memory" T cells, it is known that UCHL1+ "memory" T cells accumulate at sites of chronic inflammation. To test the concept that "memory" T cells are a feature of the T lymphocyte populations present in tissues chronically exposed to antigens in normals as well as in individuals with chronic inflammation, we evaluated T lymphocytes obtained from blood and the epithelial surface of the lower respiratory tract of normal individuals for the expression of specific CD45 surface protein isoforms and corresponding mRNA transcripts. Flow cytometric analysis of CD45 220, 205, and 180 kD surface proteins demonstrated that lung T cells of normals are dominated by UCHL1+ "memory" cells (86 +/- 2%) while autologous blood T cells have equal proportions of "memory" UCHL1+ and "naive" 2H4+ T cells. In addition, polymerase chain reaction analysis of CD45 mRNA transcripts revealed that the lung cells expressed CD45R-0 mRNA transcripts but 17-fold fewer CD45R-IV mRNA transcripts than autologous blood T cells (p less than 0.01). The pattern of lung T cells being dominated by CD45R-0 mRNA+, UCHL1+ "memory" T cells was also observed in individuals with chronic beryllium disease, an example of a chronic inflammatory disease in which antigen-specific T cells accumulate on the pulmonary epithelial surface. Like the normals, the lung T cells of the beryllium disease patients were dominated by CD45R-0 mRNA transcript+, UCHL1+, T cells. However, on a quantitative basis, the beryllium patients contained far greater numbers of T cells, i.e., the T cell populations on the surface of the normal and inflamed lung are similar in character ("memory" T cells) but differ in numbers (there are far more in the chronic inflammatory state). Thus, T cell populations on the epithelial surface of the normal lung likely reflect the chronic exposure to a diverse set of antigens, with a pattern that is qualitatively similar to that observed among T cells accumulating in response to a single antigen.
Amplification and Overexpression of <i>CACNA1E</i> Correlates with Relapse in Favorable Histology Wilms' Tumors
Authors: Rachael Natrajan, Suzanne E. Little, Jorge S. Reis-Filho, Lara Hing, Boo Messahel, Paul E. Grundy, Jeffrey S. Dome, Toni Schneider, Gordan M. Vujanic, Kathy Pritchard-Jones, Chris Jones
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The most well established molecular markers of poor outcome in Wilms' tumor are loss of heterozygosity at chromosomes 1p and/or 16q, although to date no specific genes at these loci have been identified. We have previously shown a link between genomic gain of chromosome 1q and tumor relapse and sought to further elucidate the role of genes on 1q in treatment failure. Experimental Design: Microarray-based comparative genomic hybridization identified a microamplification harboring a single gene (CACNA1E) at 1q25.3 in 6 of 76 (7.9%) Wilms' tumors, correlating with a shorter relapse-free survival (P = 0.0044, log-rank test). Further characterization of this gene was carried out by measuring mRNA and protein expression as well as stable transfection of HEK293 cells. Results: Overexpression of the CACNA1E transcript was associated with DNA copy number (P = 0.0204, ANOVA) and tumor relapse (P = 0.0851, log-rank test). Immunohistochemistry against the protein product CaV2.3 revealed expression localized to the apical membrane in the distal tubules of normal kidney but not to the metanephric blastemal cells of fetal kidney from which Wilms' tumors arise. Nuclear localization in 99 of 160 (61.9%) Wilms' tumor cases correlated with a reduced relapse-free survival, particularly in cases treated with preoperative chemotherapy (P = 0.009, log-rank test). Expression profiling of stably transfected HEK293 cells revealed specific up-regulation of the immediate early response genes EGR1/EGR2/EGR3 and FOS/FOSB, mediated by activation of the MEK/ERK5/Nur77 pathway. Conclusions: These data identify a unique genetic aberration with direct clinical relevance in Wilms' tumor relapse and provide evidence for a potential novel mechanism of treatment resistance in these tumors.