tbuckley/cabot-search huggingface dataset:
Lack of Phospholipase A <sub>2</sub> Receptor Increases Susceptibility to Cardiac Rupture After Myocardial Infarction
Authors: Hideto Mishina, Kazuhiro Watanabe, Shun Tamaru, Yosuke Watanabe, Daisuke Fujioka, Soichiro Takahashi, Koji Suzuki, Takamitsu Nakamura, Jun-ei Obata, Kenichi Kawabata, Yasunori Yokota, Osamu Inoue, Makoto Murakami, Kohji Hanasaki, Kiyotaka Kugiyama
Journal: Circulation Research (2013)

Recent evidence indicates that the biological effects of secretory phospholipase A2 (sPLA2) cannot be fully explained by its catalytic activity. A cell surface receptor for sPLA2 (PLA2 receptor 1 [PLA2R]) and its high-affinity ligands (including sPLA2-IB, sPLA2-IIE, and sPLA2-X) are expressed in the infarcted myocardium.This study asked whether PLA2R might play a pathogenic role in myocardial infarction (MI) using mice lacking PLA2R (PLA2R(-/-)).MI was induced by permanent ligation of the left coronary artery. PLA2R(-/-) mice exhibited higher rates of cardiac rupture after MI compared with PLA2R wild-type (PLA2R(+/+)) mice (46% versus 21%, respectively; P=0.015). PLA2R(-/-) mice had a 31% decrease in collagen content and a 45% decrease in the number of α-smooth muscle actin-positive fibroblasts in the infarcted region compared with PLA2R(+/+) mice. PLA2R was primarily found in myofibroblasts in the infarcted region. PLA2R(-/-) myofibroblasts were impaired in collagen-dependent migration, proliferation, and activation of focal adhesion kinase in response to sPLA2-IB. Binding of sPLA2-IB to PLA2R promoted migration and proliferation of myofibroblasts through functional interaction with integrin β1, independent of the catalytic activity of sPLA2-IB. In rescue experiments, the injection of PLA2R(+/+) myofibroblasts into the infarcted myocardium prevented post-MI cardiac rupture and reversed the decrease in collagen content in the infarcted region in PLA2R(-/-) mice.PLA2R deficiency increased the susceptibility to post-MI cardiac rupture through impaired healing of the infarcted region. This might be partly explained by a reduction in integrin β1-mediated migratory and proliferative responses of PLA2R(-/-) myofibroblasts.
VITAMIN A INTOXICATION AS A CAUSE OF PSEUDOTUMOR CEREBRI
Authors: George Morrice
Journal: JAMA (1960)

Three girls aged 14, 15, and 16 years had diplopia, papilledema, and other symptoms suggesting brain tumor. In addition to various individual complaints, each had hypomenorrhea, alopecia, and rhagades or other marked forms of dermatosis. They had been taking, respectively, 200,000; 200,000, and 90,000 units of vitamin A per day. Treatment consisted in stopping the intake of vitamin A; in addition the oldest patient received acetazolamide as a diuretic. The symptoms subsided rapidly, but in the oldest patient slight blurring of the margins of the optic disks were still present six months later. Alopecia, rhagades, nonspecific dermatitis, migratory arthralgia, hepatosplenomegaly, and hypomenorrhea are important in the differential diagnosis between the pseudotumor cerebri of chronic vitamin A intoxication and true intracranial tumor.
Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis
Authors: Sanae Ben Mkaddem, Gilles Hayem, Friederike Jönsson, Elisabetta Rossato, Erwan Boedec, Tarek Boussetta, Jamel El Benna, Pierre Launay, Jean-Michel Goujon, Marc Benhamou, Pierre Bruhns, Renato C. Monteiro
Journal: Journal of Clinical Investigation (2014)

Rheumatoid arthritis–associated (RA-associated) inflammation is mediated through the interaction between RA IgG immune complexes and IgG Fc receptors on immune cells. Polymorphisms within the gene encoding the human IgG Fc receptor IIA (hFcγRIIA) are associated with an increased risk of developing RA. Within the hFcγRIIA intracytoplasmic domain, there are 2 conserved tyrosine residues arranged in a noncanonical immunoreceptor tyrosine–based activation motif (ITAM). Here, we reveal that inhibitory engagement of the hFcγRIIA ITAM either with anti-hFcγRII F(ab′)2 fragments or intravenous hIgG (IVIg) ameliorates RA-associated inflammation, and this effect was characteristic of previously described inhibitory ITAM (ITAMi) signaling for hFcαRI and hFcγRIIIA, but only involves a single tyrosine. In hFcγRIIA-expressing mice, arthritis induction was inhibited following hFcγRIIA engagement. Moreover, hFcγRIIA ITAMi-signaling reduced ROS and inflammatory cytokine production through inhibition of guanine nucleotide exchange factor VAV-1 and IL-1 receptor–associated kinase 1 (IRAK-1), respectively. ITAMi signaling was mediated by tyrosine 304 (Y304) within the hFcγRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcγRII F(ab′)2 treatment of inflammatory synovial cells from RA patients inhibited ROS production through induction of ITAMi signaling. These data suggest that shifting constitutive hFcγRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation.
Self management for men with lower urinary tract symptoms: randomised controlled trial
Authors: Christian T Brown, Tet Yap, David A Cromwell, Lorna Rixon, Liz Steed, Kathleen Mulligan, Anthony Mundy, Stanton P Newman, Jan van der Meulen, Mark Emberton
Journal: BMJ (2006)

<b>Objective</b> To evaluate the effectiveness of self management as a first line intervention for men with lower urinary tract symptoms. <b>Design</b> Randomised controlled trial. <b>Setting</b> A teaching hospital and a district general hospital in London. <b>Participants</b> 140 men (mean age 63 (SD 10.7) years), recruited between January 2003 and April 2004, referred by general practitioners to urological outpatient departments with uncomplicated lower urinary tract symptoms. <b>Interventions</b> Self management and standard care (n=73) or standard care alone (n=67). The self management group took part in three small group sessions comprising education, lifestyle advice, and training in problem solving and goal setting skills. <b>Main outcome measures</b> The primary outcome measure was treatment failure measured at 3, 6, and 12 months. Symptom severity (international prostate symptom score; higher scores represent a poorer outcome) was used as a secondary outcome. <b>Results</b> At three months, treatment failure had occurred in 7 (10%) of the self management group and in 27 (42%) of the standard care group (difference=32%, 95% confidence interval 18% to 46%). Corresponding differences in the frequency of treatment failure were 42% (27% to 57%) at six months and 48% (32% to 64%) at 12 months. At three months, the mean international prostate symptom score was 10.7 in the self management group and 16.4 in the standard care group (difference=5.7, 3.7 to 7.7). Corresponding differences in score were 6.5 (4.3 to 8.7) at six months and 5.1 (2.7 to 7.6) at 12 months. <b>Conclusions</b> Self management significantly reduced the frequency of treatment failure and reduced urinary symptoms. Because of the large observed benefit of self management, the results of this study support the case for a large multicentre trial to confirm whether self management could be considered as first line treatment for men with lower urinary tract symptoms. <b>Trial registration</b> National Research Register N0263115137; Clinical trials NCT00270309.
Intermediacy and Gene–Environment Interaction: The Example of CHRNA5-A3 Region, Smoking, Nicotine Dependence, and Lung Cancer
Authors: Sholom Wacholder, Nilanjan Chatterjee, Neil Caporaso
Journal: JNCI Journal of the National Cancer Institute (2008)

During the “candidate gene era,” many studies with a small number of cases investigated a small number of variants in a limited number of genes chosen on the basis of partial knowledge of their function. These studies established only a few genetic risk factors for cancer (1) and other diseases. Remarkably, recent genome-wide association (GWA) studies have produced strong evidence that variation in a number of genomic regions affects risk of disease (2). Successful GWA studies most often used an agnostic approach to interrogating as many of the more common genetic variants as feasible (up to a million now) and large numbers of cases. They adopted a de facto criterion for genome-wide statistical significance of P values below 10−7 (3), thus guaranteeing a low chance of reporting a false positive even for quite low prior probabilities of association and weak effects (4), and they used statistical methods, such as principal components analysis (5), which protects not only against population stratification but also against poor control selection (6).
Neuroimmune regulation of allergic asthma: A tripeptide regulates lung immune responses in a rat model of allergic asthma
Authors: Rene Dery, Lakshmi Puttagunta, Marina Ulanova, Deborah James, Ron Mathison, Joe Davison, Grant Stenton, Shaheed Merani, A Dean Befus
Journal: Journal of Allergy and Clinical Immunology (2002)
Towards a data sharing Code of Conduct for international genomic research
Authors: Bartha Knoppers, Jennifer R Harris, Anne Tassé, Isabelle Budin-Ljøsne, Jane Kaye, Mylène Deschênes, Ma'n H Zawati
Journal: Genome Medicine (2011)

Data sharing is increasingly regarded as an ethical and scientific imperative that advances knowledge and thereby respects the contributions of the participants. Because of this and the ever-increasing amount of data access requests currently filed around the world, three groups have decided to develop data sharing principles specific to the context of collaborative international genomics research. These groups are: the international Public Population Project in Genomics (P3G), an international consortium of projects partaking in large-scale genetic epidemiological studies and biobanks; the European Network for Genetic and Genomic Epidemiology (ENGAGE), a research project aiming to translate data from large-scale epidemiological research initiatives into relevant clinical information; and the Centre for Health, Law and Emerging Technologies (HeLEX). We propose seven different principles and a preliminary international data sharing Code of Conduct for ongoing discussion.
On the Composition of the Preimmune Repertoire of T Cells Specific for Peptide–Major Histocompatibility Complex Ligands
Authors: Marc K. Jenkins, H. Hamlet Chu, James B. McLachlan, James J. Moon
Journal: Annual Review of Immunology (2010)

Millions of T cells are produced in the thymus, each expressing a unique α/β T cell receptor (TCR) capable of binding to a foreign peptide in the binding groove of a host major histocompatibility complex (MHC) molecule. T cell–mediated immunity to infection is due to the proliferation and differentiation of rare clones in the preimmune repertoire that by chance express TCRs specific for peptide-MHC (pMHC) ligands derived from the microorganism. Here we review recent findings that have altered our understanding of how the preimmune repertoire is established. Recent structural studies indicate that a germline-encoded tendency of TCRs to bind MHC molecules contributes to the MHC bias of T cell repertoires. It has also become clear that the preimmune repertoire contains functionally heterogeneous subsets including recent thymic emigrants, mature naive phenotype cells, memory phenotype cells, and natural regulatory T cells. In addition, sensitive new detection methods have revealed that the repertoire of naive phenotype T cells consists of distinct pMHC-specific populations that consistently vary in size in different individuals. The implications of these new findings for the clonal selection theory, self-tolerance, and immunodominance are discussed.
Recognition of Human Histocompatibility Leukocyte Antigen (HLA)-E Complexed with HLA Class I Signal Sequence–derived Peptides by CD94/NKG2 Confers Protection from Natural Killer Cell–mediated Lysis
Authors: Francisco Borrego, Matthias Ulbrecht, Elisabeth H. Weiss, John E. Coligan, Andrew G. Brooks
Journal: The Journal of Experimental Medicine (1998)

Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical HLA class I molecule, the gene for which is transcribed in most tissues. It has recently been reported that this molecule binds peptides derived from the signal sequence of HLA class I proteins; however, no function for HLA-E has yet been described. We show that natural killer (NK) cells can recognize target cells expressing HLA-E molecules on the cell surface and this interaction results in inhibition of the lytic process. Furthermore, HLA-E recognition is mediated primarily through the CD94/NKG2-A heterodimer, as CD94-specific, but not killer cell inhibitory receptor (KIR)–specific mAbs block HLA-E–mediated protection of target cells. Cell surface HLA-E could be increased by incubation with synthetic peptides corresponding to residues 3–11 from the signal sequences of a number of HLA class I molecules; however, only peptides which contained a Met at position 2 were capable of conferring resistance to NK-mediated lysis, whereas those having Thr at position 2 had no effect. Interestingly, HLA class I molecules previously correlated with CD94/NKG2 recognition all have Met at residue 4 of the signal sequence (position 2 of the HLA-E binding peptide), whereas those which have been reported not to interact with CD94/NKG2 have Thr at this position. Thus, these data show a function for HLA-E and suggest an alternative explanation for the apparent broad reactivity of CD94/NKG2 with HLA class I molecules; that CD94/NKG2 interacts with HLA-E complexed with signal sequence peptides derived from “protective” HLA class I alleles rather than directly interacting with classical HLA class I proteins.
The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation
Authors: Daniel E. Singer
Journal: Annals of Internal Medicine (2009)

Guidelines recommend warfarin use in patients with atrial fibrillation solely on the basis of risk for ischemic stroke without antithrombotic therapy. These guidelines rely on ischemic stroke rates observed in older trials and do not explicitly account for increased risk for hemorrhage.To quantify the net clinical benefit of warfarin therapy in a cohort of patients with atrial fibrillation.Mixed retrospective and prospective cohort study of patients with atrial fibrillation between 1996 and 2003.An integrated health care delivery system.13 559 adults with nonvalvular atrial fibrillation.Warfarin exposure, patient characteristics, CHADS(2) score (1 point for each of congestive heart failure, hypertension, age, and diabetes and 2 points for stroke), and outcome events were ascertained from health plan records and databases. Net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by warfarin minus intracranial hemorrhages attributable to warfarin, multiplied by an impact weight. The base-case impact weight was 1.5, reflecting the greater clinical impact of intracranial hemorrhage versus thromboembolism.Patients accumulated more than 66 000 person-years of follow-up. The adjusted net clinical benefit of warfarin for the cohort overall was 0.68% per year (95% CI, 0.34% to 0.87%). Adjusted net clinical benefit was greatest for patients with a history of ischemic stroke (2.48% per year [CI, 0.75% to 4.22%]) and for those 85 years or older (2.34% per year [CI, 1.29% to 3.30%]). The net clinical benefit of warfarin increased from essentially zero in CHADS(2) stroke risk categories 0 and 1 to 2.22% per year (CI, 0.58% to 3.75%) in CHADS(2) categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used.Residual confounding is a possibility. Some outcome events were probably missed by the screening algorithm or when medical records were unavailable.Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. Risk assessment that incorporates both risk for thromboembolism and risk for intracranial hemorrhage provides a more quantitatively informed basis for the decision on antithrombotic therapy in patients with atrial fibrillation.National Institute on Aging; National Heart, Lung, and Blood Institute; and Massachusetts General Hospital.
Protein Insertions and Deletions Enabled by Neutral Roaming in Sequence Space
Authors: Ágnes Tóth-Petróczy, Dan S. Tawfik
Journal: Molecular Biology and Evolution (2013)

Backbone modifications via insertions and deletions (InDels) may exert dramatic effects, for better (mediating new functions) and for worse (causing loss of structure and/or function). However, contrary to point mutations (substitutions), our knowledge of the evolution and structural-functional effects of InDels is limited and so is our capability to engineer them. We sought to assess how deleterious InDels are relative to point mutations and understand the mechanisms that mediate their acceptance. Analysis of the evolution of InDels in orthologous protein phylogenies indicated that their rate of purging is 9- to 100-fold higher than for point mutations. In yeast, for example, the substitutions-to-InDels ratio is approximately 14-fold higher in protein coding than in noncoding regions. The incorporation of InDels relative to substitutions is not only slow but also nonlinear. On average, ≥50 substitutions accumulate before the appearance of the first InDel. We also found enriched substitutions in sequential and spatial proximity to InDels, suggesting that certain substitutions are correlated with InDels. As indicated by the lag in InDels accumulation, some of these correlated substitutions may have occurred first, as apparently neutral mutations, and later enabled the accumulation of InDels that would be otherwise purged. Thus, compensatory substitutions may follow InDels in an "adaptive walk" as traditionally assumed, but might also accumulate first, by "neutral roaming." The dynamics of InDels accumulation also depends on their genomic frequencies-InDels in flies are 4-fold more frequent than in yeast and tend to be compensated rather than enabled.
DEVELOPMENT AND APPLICATION OF POLYMER-MATRIX DEVICE TO REMODEL LEFT VENTRICULAR – MITRAL VALVE APPARATUS IN ISCHEMIC MITRAL REGURGITATION
Authors: Akihisa Kataoka, Xin Zeng, Michael Garcia, Margo Seybolt, Suzanne Sullivan, Jose Guerrero, Maryanne Muriuki, Adam Kozak, Gavin Braithwaite, Mark Handschumacher, Robert Levine, Judy Hung
Journal: Journal of the American College of Cardiology (2014)
Somatic<i>SF3B1</i>Mutation in Myelodysplasia with Ring Sideroblasts
Authors: E. Papaemmanuil, M. Cazzola, J. Boultwood, L. Malcovati, P. Vyas, D. Bowen, A. Pellagatti, J.S. Wainscoat, E. Hellstrom-Lindberg, C. Gambacorti-Passerini, A.L. Godfrey, I. Rapado, A. Cvejic, R. Rance, C. McGee, P. Ellis, L.J. Mudie, P.J. Stephens, S. McLaren, C.E. Massie, P.S. Tarpey, I. Varela, S. Nik-Zainal, H.R. Davies, A. Shlien, D. Jones, K. Raine, J. Hinton, A.P. Butler, J.W. Teague, E.J. Baxter, J. Score, A. Galli, M.G. Della Porta, E. Travaglino, M. Groves, S. Tauro, N.C. Munshi, K.C. Anderson, A. El-Naggar, A. Fischer, V. Mustonen, A.J. Warren, N.C.P. Cross, A.R. Green, P.A. Futreal, M.R. Stratton, P.J. Campbell
Journal: New England Journal of Medicine (2011)

Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies.We used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers.We identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations.Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes. (Funded by the Wellcome Trust and others.).
OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway
Authors: Ya-Ching Lu, Joseph T Chang, Chun-Ta Liao, Chung-Jan Kang, Shiang-Fu Huang, I-How Chen, Chi-Che Huang, Yu-Chen Huang, Wen-Ho Chen, Chi-Ying Tsai, Hung-Ming Wang, Tzu-Chen Yen, Guo-Rung You, Chang-Hsu Chiang, Ann-Joy Cheng
Journal: Molecular Cancer (2014)

MicroRNA-196 (miR-196), which is highly up-regulated in oral cancer cells, has been reported to be aberrantly expressed in several cancers; however, the significance of miR-196 in oral cancer has not yet been addressed. Cellular functions in response to miR-196 modulation were examined, including cell growth, migration, invasion and radio/chemosensitivity. Algorithm-based studies were used to identify the regulatory target of miR-196. The miR-196 target gene and downstream molecular mechanisms were confirmed by RT-qPCR, western blot, luciferase reporter and confocal microscopy analyses. miR-196 expression was determined in paired cancer and adjacent normal tissues from oral cancer patients. Both miR-196a and miR-196b were highly over-expressed in the cancer tissue and correlated with lymph node metastasis (P = 0.001 and P = 0.006, respectively). Functionally, miR-196 actively promoted cell migration and invasion without affecting cell growth. Mechanistically, miR-196 performed it's their function by inhibiting NME4 expression and further activating p-JNK, suppressing TIMP1, and augmenting MMP1/9. miR-196 contributes to oral cancer by promoting cell migration and invasion. Clinically, miR-196a/b was significantly over-expressed in the cancer tissues and correlated with lymph node metastasis. Thus, our findings provide new knowledge of the underlying mechanism of cancer metastasis. miR-196 may serve as a promising marker for better oral cancer management.
All duplicates are not equal: the difference between small-scale and genome duplication
Authors: Luke Hakes, John W Pinney, Simon C Lovell, Stephen G Oliver, David L Robertson
Journal: Genome biology (2007)

Abstract Background Genes in populations are in constant flux, being gained through duplication and occasionally retained or, more frequently, lost from the genome. In this study we compare pairs of identifiable gene duplicates generated by small-scale (predominantly single-gene) duplications with those created by a large-scale gene duplication event (whole-genome duplication) in the yeast Saccharomyces cerevisiae . Results We find a number of quantifiable differences between these data sets. Whole-genome duplicates tend to exhibit less profound phenotypic effects when deleted, are functionally less divergent, and are associated with a different set of functions than their small-scale duplicate counterparts. At first sight, either of these latter two features could provide a plausible mechanism by which the difference in dispensability might arise. However, we uncover no evidence suggesting that this is the case. We find that the difference in dispensability observed between the two duplicate types is limited to gene products found within protein complexes, and probably results from differences in the relative strength of the evolutionary pressures present following each type of duplication event. Conclusion Genes, and the proteins they specify, originating from small-scale and whole-genome duplication events differ in quantifiable ways. We infer that this is not due to their association with different functional categories; rather, it is a direct result of biases in gene retention.