tbuckley/cabot-search huggingface dataset:
Effect of dutasteride on clinical progression of benign prostatic hyperplasia in asymptomatic men with enlarged prostate: a post hoc analysis of the REDUCE study
Authors: P. Toren, D. Margel, G. Kulkarni, A. Finelli, A. Zlotta, N. Fleshner
Journal: BMJ (2013)

To assess the role of dutasteride in preventing clinical progression of benign prostatic hyperplasia in asymptomatic men with larger prostates.Post hoc analysis of four year, double blind Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study1617 men randomised to dutasteride or placebo with a prostate size >40 mL and baseline International Prostate Symptom Score (IPSS) <8. Subjects who took medications for benign prostatic hyperplasia were excluded at study entry.Placebo or dutasteride 0.5 mg daily.Comparison of risk of clinical progression of benign prostatic hyperplasia at four years (defined as a ≥ 4 point worsening on IPSS, acute urinary retention, urinary tract infection, or surgery related to benign prostatic hyperplasia).825 participants took placebo, 792 took dutasteride. A total of 464 (29%) experienced clinical progression benign prostatic hyperplasia, 297(36%) taking placebo, 167 (21%) taking dutasteride (P<0.001). The relative risk reduction was 41% and the absolute risk reduction 15%, with a number needed to treat (NNT) of 7. Among men who had acute urinary retention and surgery related to benign prostatic hyperplasia, the absolute risk reduction for dutasteride was 6.0% and 3.8%, respectively. On multivariable regression analysis adjusting for covariates, dutasteride significantly reduced clinical progression of benign prostatic hyperplasia with an odds ratio of 0.47 (95% CI 0.37 to 0.59, P<0.001). Analysis of time to first event yielded a hazard ratio of 0.673 (P<0.001) for those taking dutasteride. Sexual adverse events were most common and similar to prior reports.Further prospective studies may be warranted to demonstrate generalisability of these results.This study is the first to explore the benefit of treating asymptomatic or mildly symptomatic men with an enlarged prostate. Dutasteride significantly decreased the incidence of benign prostatic hyperplasia clinical progression.
Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (<i>THBD</i>) Predict Mortality in Patients With Graft-Versus-Host Disease
Authors: Sivaramakrishna P. Rachakonda, Olaf Penack, Sascha Dietrich, Olga Blau, Igor Wolfgang Blau, Aleksandar Radujkovic, Berend Isermann, Anthony D. Ho, Lutz Uharek, Peter Dreger, Rajiv Kumar, Thomas Luft
Journal: Journal of Clinical Oncology (2014)

Steroid-refractory graft-versus-host disease (GVHD) is a major and often fatal complication after allogeneic stem-cell transplantation (alloSCT). Although the pathophysiology of steroid refractoriness is not fully understood, evidence is accumulating that endothelial cell stress is involved, and endothelial thrombomodulin (THBD) plays a role in this process. Here we assess whether single-nucleotide polymorphisms (SNPs) within the THBD gene predict outcome after alloSCT.Seven SNPs within the THBD gene were studied (rs1962, rs1042579, rs1042580, rs3176123, rs3176124, rs3176126, and rs3176134) in a training cohort of 306 patients. The relevant genotypes were then validated in an independent cohort (n = 321).In the training cohort, an increased risk of nonrelapse mortality (NRM) was associated with three of seven SNPs tested: rs1962, rs1042579 (in linkage disequilibrium with rs3176123), and rs1042580. When patients were divided into risk groups (one v no high-risk SNP), a strong correlation with NRM was observed (hazard ratio [HR], 2.31; 95% CI, 1.36 to 3.95; P = .002). More specifically, NRM was predicted by THBD SNPs in patients who later developed GVHD (HR, 3.03; 95% CI, 1.61 to 5.68; P < .001) but not in patients without GVHD. In contrast, THBD SNPs did not predict incidence of acute GVHD. Multivariable analyses adjusting for clinical variables confirmed the independent effect of THBD SNPs on NRM. All findings could be reproduced in the validation cohort.THBD SNPs predict mortality of manifest GVHD but not the risk of acquiring GVHD, supporting the hypothesis that endothelial vulnerability contributes to GVHD refractoriness.
Isolation and Molecular Evolution of the Selenocysteine tRNA (Cf TRSP) and RNase P RNA (Cf RPPH1) Genes in the Dog Family, Canidae
Authors: Carolyne Bardeleben, Rachael L. Moore, Robert K. Wayne
Journal: Molecular Biology and Evolution (2004)

In an effort to identify rapidly evolving nuclear sequences useful for phylogenetic analyses of closely related species, we isolated two genes transcribed by RNA polymerase III (pol III), the selenocysteine tRNA gene (TRSP) and an RNase P RNA (RPPH1) gene from the domestic dog (Canis familiaris). We focus on genes transcribed by pol III because their coding regions are small (generally 100–300 base pairs [bp]) and their essential promoter elements are located within a couple of hundred bps upstream of the coding region. Therefore, we predicted that regions flanking the coding region and outside of the promoter elements would be free of constraint and would evolve rapidly. We amplified TRSP from 23 canids and RPPH1 from 12 canids and analyzed the molecular evolution of these genes and their utility as phylogenetic markers for resolving relationships among species in Canidae. We compared the rate of evolution of the gene-flanking regions to other noncoding regions of nuclear DNA (introns) and to the mitochondrial encoded COII gene. Alignment of TRSP from 23 canids revealed that regions directly adjacent to the coding region display high sequence variability. We discuss this pattern in terms of functional mechanisms of transcription. Although the flanking regions evolve no faster than introns, both genes were found to be useful phylogenetic markers, in part, because of the synapomorphic indels found in the flanking regions. Gene trees generated from the TRSP and RPPH1 loci were generally in agreement with the published mtDNA phylogeny and are the first phylogeny of Canidae based on nuclear sequences.
DOTS-Finder: a comprehensive tool for assessing driver genes in cancer genomes
Authors: Giorgio EM Melloni, Alessandro GE Ogier, Stefano de Pretis, Luca Mazzarella, Mattia Pelizzola, Pier Pelicci, Laura Riva
Journal: Genome Medicine (2014)

A key challenge in the analysis of cancer genomes is the identification of driver genes from the vast number of mutations present in a cohort of patients. DOTS-Finder is a new tool that allows the detection of driver genes through the sequential application of functional and frequentist approaches, and is specifically tailored to the analysis of few tumor samples. We have identified driver genes in the genomic data of 34 tumor types derived from existing exploratory projects such as The Cancer Genome Atlas and from studies investigating the usefulness of genomic information in the clinical settings. DOTS-Finder is available at https://cgsb.genomics.iit.it/wiki/projects/DOTS-Finder/ .
Evaluating the impact of genotype on the relationship between impaired lung growth and chronic exposure to traffic derived pollutants
Authors: Jeenath Jamaludin, Nadine Marlin, Helen Wood, Chris Griffiths, Jonathon Grigg, Robert Walton, Isobel Dundas, Ian Mudway, Frank Kelly
Journal: European Respiratory Journal (2013)

Background : Small deficits in lung growth have been reported in children with high exposures to traffic-related pollutants.

Aim : To investigate the relationship between lung volume (FVC) and long term exposures to NOx, NO2, PM2.5 and PM10 and establish whether polymorphisms in xenobiotic metabolism genes modify this association.

Methods : FVC was measured in 887 8-9 year-old children in East London during the Winter periods 2008–2012 and related to annual pollutant exposures modeled at the residential address. 18 SNPs were investigated, either reflecting previously published, or hypothesized susceptibility loci, including the following genes: glutathione S-transferase pi 1 (GSTP1), glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase theta (GSTT1) and cytochrome P450 1A1 (CYP1A1).

Results : We found significant negative associations (P=0.05) between FVC and each of the examined pollutants: using NO2 as an illustration: -3.0 (-5.0-0.0) mL per μg/m3. Polymorphisms in GSTP1 and possession of the GSTM1 and GSTT1 null genotype did not modify this relationship. Of the remaining polymorphisms we found evidence of effect modification associated with snps in CYP1A1 (rs2606345 and rs2198843), with losses of FVC in heterozygotes and homozygotes compared with wild type.

Conclusions: These data demonstrate decreased lung volumes in children with high pollutant exposures. We were unable to replicate previously reported modification of the air pollutant, lung function interaction by polymorphisms in GST genes, but provide preliminary evidence that polymorphisms CYP1A1 may modify this effect.
Cell therapy for autoimmune diseases: does it have a future?
Authors: A Radbruch
Journal: Annals of the Rheumatic Diseases (2004)

Almost all current therapeutic concepts in autoimmune diseases are based on the systemic suppression of immune functions and are not curative. The recent introduction of biologicals such as tumour necrosis factor blocking antibodies or receptors has added greater specificity to efficient management of disease by targeted suppression of rheumatic inflammation. It is evident, however, that only the elimination of the cells secreting inflammatory mediators, rather than the blockade of secreted molecules, will offer real specific therapeutic advantages in the future. Merely the elimination of such cells and also cells controlling the secreting effector cells could be curative and induce true long term remissions. We review here the state of the art and future therapeutic concepts that are based on the specific modulation of pathogenic cells that induce and sustain autoimmune inflammation. This sounds visionary, however, a variety of basic tools are at hand now. Thus, direct and specific cell therapy of rheumatic diseases will become a true alternative to conventional therapies.
Quantitative and Qualitative Changes in V-J α Rearrangements During Mouse Thymocytes Differentiation
Authors: Nicolas Pasqual, Maighréad Gallagher, Catherine Aude-Garcia, Mélanie Loiodice, Florence Thuderoz, Jacques Demongeot, Rod Ceredig, Patrice Noël Marche, Evelyne Jouvin-Marche
Journal: The Journal of Experimental Medicine (2002)

Knowledge of the complete nucleotide sequence of the mouse TCRAD locus allows an accurate determination V-J rearrangement status. Using multiplex genomic PCR assays and real time PCR analysis, we report a comprehensive and systematic analysis of the V-J recombination of TCR α chain in normal mouse thymocytes during development. These respective qualitative and quantitative approaches give rise to four major points describing the control of gene rearrangements. (a) The V-J recombination pattern is not random during ontogeny and generates a limited TCR α repertoire; (b) V-J rearrangement control is intrinsic to the thymus; (c) each V gene rearranges to a set of contiguous J segments with a gaussian-like frequency; (d) there are more rearrangements involving V genes at the 3′ side than 5′ end of V region. Taken together, this reflects a preferential association of V and J gene segments according to their respective positions in the locus, indicating that accessibility of both V and J regions is coordinately regulated, but in different ways. These results provide a new insight into TCR α repertoire size and suggest a scenario for V usage during differentiation.
T Cell Development and T Cell Responses in Mice with Mutations Affecting Tyrosines 292 or 315 of the Zap-70 Protein Tyrosine Kinase
Authors: Antoine Magnan, Vincenzo Di Bartolo, Anne-Marie Mura, Claude Boyer, Mireille Richelme, Yea-Lih Lin, Agnès Roure, Anne Gillet, Cécile Arrieumerlou, Oreste Acuto, Bernard Malissen, Marie Malissen
Journal: The Journal of Experimental Medicine (2001)

After stimulation of the T cell receptor (TCR), the tyrosine residues 292 and 315 in interdomain B of the protein tyrosine kinase ZAP-70 become phosphorylated and plausibly function as docking sites for Cbl and Vav1, respectively. The two latter proteins have been suggested to serve as substrates for ZAP-70 and to fine-tune its function. To address the role of these residues in T cell development and in the function of primary T cells, we have generated mice that express ZAP-70 molecules with Tyr to Phe substitution at position 292 (Y292F) or 315 (Y315F). When analyzed in a sensitized TCR transgenic background, the ZAP-70 Y315F mutation reduced the rate of positive selection and delayed the occurrence of negative selection. Furthermore, this mutation unexpectedly affected the constitutive levels of the CD3-ζ p21 phosphoisoform. Conversely, the ZAP-70 Y292F mutation upregulated proximal events in TCR signaling and allowed more T cells to produce interleukin 2 and interferon γ in response to a given dose of antigen. The observation that ZAP-70 Y292F T cells have a slower rate of ligand-induced TCR downmodulation suggests that Y292 is likely involved in regulating the duration activated TCR reside at the cell surface. Furthermore, we showed that Y292 and Y315 are dispensable for the TCR-induced tyrosine phosphorylation of Cbl and Vav1, respectively. Therefore, other molecules present in the TCR signaling cassette act as additional adaptors for Cbl and Vav1. The present in vivo analyses extend previous data based on transformed T cell lines and suggest that residue Y292 plays a role in attenuation of TCR signaling, whereas residue Y315 enhances ZAP-70 function.
Preventing fatal diseases increases healthcare costs: cause elimination life table approach
Authors: L. Bonneux, J. J Barendregt, W. J Nusselder, P. J Van der Maas
Journal: BMJ (1998)

<h3>Abstract</h3> <b>Objectives:</b> To examine whether elimination of fatal diseases will increase healthcare costs. <b>Design:</b> Mortality data from vital statistics combined with healthcare spending in a cause elimination life table. Costs were allocated to specific diseases through the various healthcare registers. <b>Setting and subjects:</b> The population of the Netherlands, 1988. <b>Main outcome measures</b>: Healthcare costs of a synthetic life table cohort, expressed as life time expected costs. <b>Results:</b> The life time expected healthcare costs for 1988 in the Netherlands were £56 600 for men and £80 900 for women. Elimination of fatal diseases—such as coronary heart disease, cancer, or chronic obstructive lung disease—increases health- care costs. Major savings will be achieved only by elimination of non-fatal disease—such as musculoskeletal diseases and mental disorders. <b>Conclusion:</b> The aim of prevention is to spare people from avoidable misery and death not to save money on the healthcare system. In countries with low mortality, elimination of fatal diseases by successful prevention increases healthcare spending because of the medical expenses during added life years. <h3>Key messages</h3> In countries with low mortality prevention of fatal diseases adds life years predominantly to old age, when disabling conditions are prevalent If fatal diseases are eliminated, the medical costs of life extension at old age will generally be higher than the costs prevented. Prevention of disabling conditions, particularly mental disorders and musculoskeletal conditions, might both lower healthcare costs and improve public health The aim of prevention is to save people from preventable morbidity and mortality not to save money For the time being, prevention of disability should have the highest priority for future research
Effects of TNF antagonists on sperm characteristics in patients with spondyloarthritis
Authors: P. M. Villiger, G. Caliezi, V. Cottin, F. Forger, A. Senn, M. Ostensen
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> To study the influence of tumour necrosis factor (TNF) antagonists on spermatogenesis in a cohort of patients with spondyloarthritis (SpA). <h3>Patients and methods</h3> Semen samples of 26 patients with SpA were analysed according to WHO 1999 guidelines with and without TNF blocking agents (infliximab, etanercept or adalimumab). Results were compared with semen samples of 102 healthy volunteers. <h3>Results</h3> Sperm abnormalities were found in 10/11 patients without anti-TNF therapy. The sperm of these 11 patients had significantly poorer motility (p=0.001) and vitality (p=0.001) than found in 15 patients tested during longstanding anti-TNF therapy, but sperm concentration and morphology were similar in the two groups. There was no significant difference of sperm quality between healthy controls and anti-TNF treated patients with SpA. Notably, sperm abnormalities were also found in 102 healthy controls. <h3>Conclusion</h3> Sperm abnormalities are a common finding in healthy men, they are more pronounced in patients with active SpA. The sperm quality of patients with SpA with inactive disease receiving long-term TNF inhibition is comparable to that in healthy controls. The data support continuation of anti-TNF treatment when fatherhood is planned.
Effect of Mycobacterium tuberculosis and its components on macrophages and the release of matrix metalloproteinases.
Authors: J C Chang, A Wysocki, K M Tchou-Wong, N Moskowitz, Y Zhang, W N Rom
Journal: Thorax (1996)

BACKGROUND: Pulmonary tuberculosis is associated with caseating necrosis, parenchymal lung destruction, and cavity formation. It was hypothesised that tuberculous lung destruction is mediated, at least in part, by the participation of matrix metalloproteinases released by mononuclear phagocytes. METHODS: Cells of the myelomonocytic leukaemia cell line THP-1 were incubated with lipoarabinomannan (LAM), the major antigenic cell wall component, and with Mycobacterium tuberculosis and analysed by Northern blot analysis. Two patients with active cavitary tuberculosis also underwent bronchoalveolar lavage and the cells were analysed by Northern blotting. RESULTS: Incubation of THP-1 cells with LAM resulted in the stimulated release of matrix metalloproteinase-9 (MMP-9), a 92 kDa gelatinase, by 24 hours in a dose-dependent fashion. In addition, Northern analysis revealed that LAM upregulated the gene for MMP-9 by 24 hours, but not the gene for the 72 kDa gelatinase MMP-2. Heat killed M tuberculosis H37Ra also upregulated the MMP-9 gene. Bronchoalveolar lavage of the two patients with active cavitary tuberculosis showed striking upregulation of the MMP-9 gene compared with a normal control using Northern analysis. LAM also upregulated the type I interstitial collagenase (MMP-1) gene by 24 hours in both THP-1 cells and peripheral blood monocytes. CONCLUSIONS: These data suggest that M tuberculosis and its major cell antigenic component, LAM, stimulate the release of MMP-9 and upregulate the expression of genes for MMP-1 and MMP-9. It is possible that M tuberculosis and its components contribute directly to cavity formation by their ability to stimulate macrophages to release matrix metallo-proteinases that digest collagens I-IV, and indirectly by stimulating the release of the cytokines interleukin 1 beta and tumour necrosis factor alpha that induce fibroblasts to amplify the release of matrix metalloproteinases.
Rosuvastatin in Older Patients with Systolic Heart Failure
Authors: John Kjekshus, Eduard Apetrei, Vivencio Barrios, Michael Böhm, John G.F. Cleland, Jan H. Cornel, Peter Dunselman, Cândida Fonseca, Assen Goudev, Peer Grande, Lars Gullestad, Åke Hjalmarson, Jaromir Hradec, András Jánosi, Gabriel Kamenský, Michel Komajda, Jerzy Korewicki, Timo Kuusi, François Mach, Vyacheslav Mareev, John J.V. McMurray, Naresh Ranjith, Maria Schaufelberger, Johan Vanhaecke, Dirk J. van Veldhuisen, Finn Waagstein, Hans Wedel, John Wikstrand
Journal: New England Journal of Medicine (2007)

Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients.A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations.As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group.Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)
Renal amyloidosis complicating sarcoidosis.
Authors: M Rainfray, A Meyrier, D Valeyre, A Tazi, J P Battesti
Journal: Thorax (1988)

Amyloidosis of the AA type is a well known complication of several granulomatoses.Its association with tuberculosis is well known, and it has also been reported in leprosy, ileocolitis, and coccidioidomycosis.In contrast, it is exceedingly rare in sarcoidosis, with only three cases published so far.We have observed the occurrence of nephrotic syndrome due to renal deposits of amyloid in a case of sarcoidosis with a prolonged and active course.Case report