tbuckley/cabot-search huggingface dataset:
MHC2TA is associated with rheumatoid arthritis in Japanese patients
Authors: N. Iikuni, K. Ikari, S. Momohara, T. Tomatsu, M. Hara, H. Yamanaka, H. Okamoto, N. Kamatani
Journal: Annals of the Rheumatic Diseases (2006)

Ten single-nucleotide polymorphisms (SNPs) were selected for genotyping.These included the tagging SNP (rs1248696) marking the haplotype over-represented in Crohn's disease and an additional nine SNPs selected to provide 100% gene coverage across the DLG5 gene using the available HapMap Phase1 data (r 2 .0.8 and minor allele frequencies .5%;http://www.broad.mit.edu/mpg/tagger/; table 1). 7 The sample size was calculated to ensure that the study had 80% power to detect the same effect size of 1.62 reported in the original inflammatory bowel disease study at the 5% significance level.Allele and genotype frequencies were compared between patients with PsA (n = 356) and population controls (n = 356).All were Caucasians, and PsA was defined as the presence of both psoriasis and inflammatory arthritis regardless of the rheumatoid factor status.Both the case and control cohorts have been described previously. 6Genotyping was performed using the Sequenom MassArray platform (Sequenom, San Diego, California, USA).This study was approved by the North West Multicentre Research Ethics Committee (MREC 99/8/84), and all subjects provided informed consent.Genotype frequencies for both PsA cases and controls conformed to Hardy-Weinberg expectations and allele frequencies were similar to those reported previously in European populations where data were available.Genotype frequencies between PsA cases and controls were not significantly different for any of the SNPs tested (table 1).Stratifying by the presence or absence of rheumatoid factor, by sex or by performing subset analysis on those with type 1 psoriasis did not show evidence of an association in subgroups of patients (data not shown).Strong linkage disequilibrium existed across the gene (D9 .0.9).Haplotype analysis showed no difference in haplotype distributions between cases and controls (data not shown).The association of the DLG5 gene with Crohn's disease has been replicated, but not in all populations and not always with the same SNP found in the original study. 8To ensure that an effect with another variant was not missed in this study, comprehensive genotyping across the gene and haplotype analysis was undertaken, but no association with PsA was found.We conclude that the DLG5 gene does not seem to be a major susceptibility gene for PsA in the UK population.
A multicenter randomized clinical trial comparing paclitaxel–cisplatin–etoposide versus cisplatin–etoposide as first-line treatment in patients with small-cell lung cancer
Authors: D. Mavroudis, E. Papadakis, M. Veslemes, X. Tsiafaki, J. Stavrakakis, C. Kouroussis, S. Kakolyris, E. Bania, J. Jordanoglou, M. Agelidou, J. Vlachonicolis, V. Georgoulias
Journal: Annals of Oncology (2001)
The Underside of the Silver Tsunami — Older Adults and Mental Health Care
Authors: Stephen J. Bartels, John A. Naslund
Journal: New England Journal of Medicine (2013)

By 2030, the United States will have less than one geriatric psychiatrist per 6000 older adults with mental health or substance-use disorders. Perhaps innovations in other types of workforce expansion, use of technology, and federal policy can help to fill the gap.
Ribosomal Protein S27-like, a p53-Inducible Modulator of Cell Fate in Response to Genotoxic Stress
Authors: Jingsong Li, Jing Tan, Li Zhuang, Birendranath Banerjee, Xiaojing Yang, Jenny Fung Ling Chau, Puay Leng Lee, Manoor Prakash Hande, Baojie Li, Qiang Yu
Journal: Cancer Research (2007)

Abstract Activation of the p53 tumor suppressor upon DNA damage elicits either cell cycle arrest or apoptosis, and the precise mechanism governing cell fate after p53 response has not been well defined. Through genomic analysis, we have identified the ribosomal protein S27-like (RPS27L) as a novel p53 transcriptional target gene. Although RPS27L mRNA levels were consistently induced after diverse p53 activating signals, its change in protein level was stimuli-dependent: it was up-regulated when cells were arrested in response to DNA-damaging agents Adriamycin or VP16 but was down-regulated when cells underwent apoptosis in response to antimetabolite agent 5-fluorouracil. RPS27L is a nuclear protein that forms nuclear foci upon DNA damage. Depletion of RPS27L resulted in deficiency in DNA damage checkpoints, leading to conversion of DNA damage–induced p53 response from cell cycle arrest to apoptosis. We further show that RPS27L positively regulates p21 protein expression. Through this mechanism, RPS27L induction by p53 facilitates p21-mediated cell cycle arrest and protects against DNA damage–induced apoptosis. Thus, RPS27L modulates DNA damage response and functions as a part of the control switch to determine cell fate to DNA damage–p53 response. [Cancer Res 2007;67(23):11317–26]
Treatment of pyoderma gangrenosum with intravenous immunoglobulin
Authors: D.L. Cummins, G.J. Anhalt, T. Monahan, J.H. Meyerle
Journal: British Journal of Dermatology (2007)

Intravenous immunoglobulin (IVIG) is increasingly being used to treat inflammatory and autoimmune disease.To elucidate the efficacy of IVIG as an adjunct treatment for pyoderma gangrenosum (PG).Ten patients with PG were treated with IVIG at Johns Hopkins Department of Dermatology. All patients had severe mutilating and/or refractory disease requiring multi-agent therapy. The charts were reviewed retrospectively.Seven of the ten patients had clearance of PG lesions in the setting of IVIG and six of these patients maintained efficacy with repeated IVIG treatment. Five patients complained of nausea with treatment, and in one case nausea was severe and intractable. One patient developed an immune reaction requiring diphenhydramine and methylprednisolone and another experienced aseptic meningitis.IVIG may be an effective adjuvant in the treatment of PG and has an acceptable side-effect profile. Randomized, placebo-controlled, double-blinded trials are needed to confirm this hypothesis.
Multichain Interleukin-2 Receptor: A Target for Immunotherapy in Lymphoma
Authors: T. A. Waldmann
Journal: JNCI Journal of the National Cancer Institute (1989)

Activation of resting T cells induces synthesis of interleukin-2 (IL-2) and expression of its specific high-affinity receptor. We proposed a multichain model for the high-affinity IL-2 receptor in which both a 55-kilodalton IL-2-binding peptide identified by the anti-Tac monoclonal antibody and a 70/75-kilodalton IL-2-binding peptide are associated in a receptor complex. The IL-2 receptor is proving to be an extraordinarily versatile therapeutic target, since it is expressed by the abnormal T cells in patients with certain lymphoid malignancies or autoimmune disorders and in individuals rejecting allografts, whereas it is not expressed by normal resting cells. Monoclonal antibodies and toxin-lymphokine conjugates directed toward IL-2 receptors represent novel therapeutic agents for these clinical conditions. [J Natl Cancer Inst 81:914-923, 1989]
Myeloid-Derived Suppressor Cells as a Vehicle for Tumor-Specific Oncolytic Viral Therapy
Authors: Samuel Eisenstein, Brian A. Coakley, Karen Briley-Saebo, Ge Ma, Hui-ming Chen, Marcia Meseck, Stephen Ward, Celia Divino, Savio Woo, Shu-Hsia Chen, Ping-Ying Pan
Journal: Cancer Research (2013)

One of the several impediments to effective oncolytic virus therapy of cancer remains a lack of tumor-specific targeting. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells induced by tumor factors in tumor-bearing hosts. The biodistribution kinetics of MDSC and other immune cell types in a murine hepatic colon cancer model was investigated through the use of tracking markers and MRI. MDSCs were superior to other immune cell types in preferential migration to tumors in comparison with other tissues. On the basis of this observation, we engineered a strain of vesicular stomatitis virus (VSV), an oncolytic rhabdovirus that bound MDSCs and used them as a delivery vehicle. Improving VSV-binding efficiency to MDSCs extended the long-term survival of mice bearing metastatic colon tumors compared with systemic administration of wild-type VSV alone. Survival was further extended by multiple injections of the engineered virus without significant toxicity. Notably, direct tumor killing was accentuated by promoting MDSC differentiation towards the classically activated M1-like phenotype. Our results offer a preclinical proof-of-concept for using MDSCs to facilitate and enhance the tumor-killing activity of tumor-targeted oncolytic therapeutics.
Genetic Manipulation of Periostin Expression Reveals a Role in Cardiac Hypertrophy and Ventricular Remodeling
Authors: Toru Oka, Jian Xu, Robert A. Kaiser, Jaime Melendez, Michael Hambleton, Michelle A. Sargent, Angela Lorts, Eric W. Brunskill, Gerald W. Dorn, Simon J. Conway, Bruce J. Aronow, Jeffrey Robbins, Jeffery D. Molkentin
Journal: Circulation Research (2007)

The cardiac extracellular matrix is a dynamic structural support network that is both influenced by, and a regulator of, pathological remodeling and hypertrophic growth. In response to pathologic insults, the adult heart reexpresses the secreted extracellular matrix protein periostin (Pn). Here we show that Pn is critically involved in regulating the cardiac hypertrophic response, interstitial fibrosis, and ventricular remodeling following long-term pressure overload stimulation and myocardial infarction. Mice lacking the gene encoding Pn ( Postn ) were more prone to ventricular rupture in the first 10 days after a myocardial infarction, but surviving mice showed less fibrosis and better ventricular performance. Pn −/− mice also showed less fibrosis and hypertrophy following long-term pressure overload, suggesting an intimate relationship between Pn and the regulation of cardiac remodeling. In contrast, inducible overexpression of Pn in the heart protected mice from rupture following myocardial infarction and induced spontaneous hypertrophy with aging. With respect to a mechanism underlying these alterations, Pn −/− hearts showed an altered molecular program in fibroblast function. Indeed, fibroblasts isolated from Pn −/− hearts were less effective in adherence to cardiac myocytes and were characterized by a dramatic alteration in global gene expression (7% of all genes). These are the first genetic data detailing the function of Pn in the adult heart as a regulator of cardiac remodeling and hypertrophy.
Altered Phenotype of Peripheral Blood Dendritic Cells in Pediatric Type 1 Diabetes
Authors: Janne K. Nieminen, Jukka Vakkila, Harri M. Salo, Nina Ekström, Taina Härkönen, Jorma Ilonen, Mikael Knip, Outi Vaarala
Journal: Diabetes Care (2012)

Dendritic cells (DCs) are largely responsible for the activation and fine-tuning of T-cell responses. Altered numbers of blood DCs have been reported in type 1 diabetes (T1D). We aimed at characterizing the less well-known phenotypic properties of DCs in T1D.In a case-control setting, samples from a total of 90 children were studied by flow cytometry or by quantitative real-time PCR (qPCR).We found decreased numbers of myeloid DCs (mDCs) (8.97 vs. 13.4 cells/μL, P = 0.009, n = 31) and plasmacytoid DCs (pDCs) (9.47 vs. 14.6 cells/μL, P = 0.018, n = 30) in recent-onset T1D. Using a panel of antibodies against functionally important DC markers, we detected a decreased expression of CC chemokine receptor 2 (CCR2) on mDCs (percentage above negative control, P = 0.002, n = 29) and pDCs (median intensity, P = 0.003, n = 30) from T1D patients. In an independent series of children, the reduced expression of CCR2 was confirmed by qPCR in isolated mDCs (P = 0.043, n = 20). Serum concentrations of CCR2 ligands monocyte chemotactic protein-1 and -3 did not differ between the groups. A trend for an enhanced responsiveness of the nuclear factor-κB pathway (P = 0.063, n = 39) was seen in mDCs from children with β-cell autoantibodies, which is possibly related to the reduced CCR2 expression, since CCR2 on mDCs was downregulated by nuclear factor-κB-activating agents.Given the role of CCR2 in DC chemotaxis and in DC-elicited Th1 differentiation, our results may indicate a functionally important DC abnormality in T1D affecting the initiation and quality of immune responses.
Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci
Authors: A. Zhernakova, E. A. Stahl, G. Trynka, S. Raychaudhuri, E. Festen, L. Franke, R. S. N. Fehrmann, F. A. S. Kurreeman, B. Thomson, N. Gupta, J. Romanos, R. McManus, A. W. Ryan, G. Turner, E. F. Remmers, L. Greco, R. Toes, E. Grandone, M. C. Mazzilli, A. Rybak, B. Cukrowska, Y. Li, P. I. W. de Bakker, P. K. Gregersen, J. Worthington, K. A. Siminovitch, L. Klareskog, T. W. J. Huizinga, C. Wijmenga, R. M. Plenge
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-human leucocyte antigen (HLA) CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. The authors hypothesised that there are additional shared risk alleles, and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. <h3>Materials and methods</h3> The authors performed a meta-analysis of two published GWAS on CD (4533 cases and 10 750 controls) and RA (5539 cases and 17 231 controls), and genotyping the top associated single-nucleotide polymorphisms (SNPs) in independent set of 2169 CD cases and 2255 controls, and 2845 RA cases and 4944 controls. The authors used the gene-expression dataset of peripheral blood mononuclear cell of 1469 individuals to investigate the genotype-expression correlation of associated variants. The authors also analysed the results using various pathway analysis tools. <h3>Results</h3> Above already established six shared loci, eight additional SNPs demonstrated p&lt;5×10<sup>−8</sup> in a combined analysis of all 50 266 samples. From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium block around the SNP. Pathway analysis tools indicate remarkable overrepresentation of T cell signalling molecules among the shared genes. <h3>Conclusions</h3> The authors identified 14 shared CD-RA risk loci. These associations implicate antigen presentation and T cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
The risk of atrial fibrillation in patients with rheumatoid arthritis
Authors: Seoyoung C Kim, Jun Liu, Daniel H Solomon
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Prior research suggests an important role of systemic inflammation in pathogenesis of atrial fibrillation (AF). It is well known that rheumatoid arthritis (RA), a chronic, systemic inflammatory disorder, increases the risk of cardiovascular disease (CVD), but little evidence exists whether the risk of AF is increased in RA. <h3>Methods</h3> Using data from a large US commercial insurance plan, we examined the incidence rate (IR) of hospitalisation for AF in patients with RA compared with non-RA. RA patients were identified with ≥2 separate visits coded for RA and ≥1 disease-modifying antirheumatic drug dispensing. The IR of AF in RA patients was also compared with those with osteoarthritis, a chronic non-inflammatory condition. <h3>Results</h3> There were 20 852 RA and 104 260 non-RA patients, matched on age, sex and index date. The mean follow-up was 2 years. The IR per 1000 person-years of AF was 4.0 (95% CI 3.4 to 4.7) in RA and 2.8 (95% CI 2.6 to 3.0) in non-RA patients. The IR ratio for AF was 1.4 (95% CI 1.2 to 1.7) in RA compared with non-RA patients. In a multivariable Cox model adjusting for a number of risk factors such as diabetes, CVD, medications and healthcare utilisation, the risk of AF was no longer increased in RA (HR 1.1, 95% CI 0.9 to 1.4) compared with non-RA patients. There was also no difference in the AF risk between RA and osteoarthritis patients. <h3>Conclusions</h3> Our results show no increased risk of AF associated with RA, after adjusting for various comorbidities, medications and healthcare use.
Interleukin-1 and Interleukin-6 Gene Polymorphisms and the Risk of Breast Cancer in Caucasian Women
Authors: Lukas A. Hefler, Christoph Grimm, Tilmann Lantzsch, Dieter Lampe, Sepp Leodolter, Heinz Koelbl, Georg Heinze, Alexander Reinthaller, Dan Tong-Cacsire, Clemens Tempfer, Robert Zeillinger
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. Interleukin (IL)-1 and IL-6 are crucially involved in breast carcinogenesis. Whether polymorphisms of the genes encoding IL-1 (IL1) and IL-6 (IL6) also influence breast cancer risk is unknown. Experimental Design: In the present case-control study, we ascertained three polymorphisms of the IL1 gene cluster [−889 C/T polymorphism of the IL1α gene (IL1A), −511 C/T polymorphism of the IL1β promoter (IL1B promoter), a polymorphism of IL1β exon 5 (IL1B exon 5)], an 86-bp repeat in intron 2 of the IL1 receptor antagonist gene (IL1RN), and the −174 G/C polymorphism of the IL6 gene (IL6) in 269 patients with breast cancer and 227 healthy controls using PCR and pyrosequencing. Results: Polymorphisms within the IL1 gene cluster and the respective haplotypes were not associated with the presence and the phenotype of breast cancer. The IL6 polymorphism was significantly associated with breast cancer. Odds ratios for women with one or two high-risk alleles versus women homozygous for the low-risk allele were 1.5 (95% confidence interval, 1.04-2.3; P = 0.04) and 2.0 (95% confidence interval, 1.1-3.6; P = 0.02), respectively. No association was ascertained between presence of the IL6 polymorphism and various clinicopathologic variables. Conclusions: Although polymorphisms within the IL1 gene cluster do not seem to influence breast cancer risk or phenotype, presence of the −174C IL6 allele increases the risk of breast cancer in Caucasian women in a dose-dependent fashion.
Measurements of nitric oxide concentration and hyporeactivity in rat superior mesenteric artery exposed to endotoxin
Authors: R Hernanz
Journal: Cardiovascular Research (2004)

Objective: The present study was designed to relate nitric oxide (NO) concentration to changes in vascular reactivity in rat superior mesenteric arteries treated with lipopolysaccharide (LPS, 10 μg ml−1, 1–8 h). Methods: In rat mesenteric arteries, isometric tension was recorded in wire myographs, protein expression was evaluated by Western blot and/or immunohistochemistry and NO concentration was measured by application of a NO specific electrode. Results: Incubation with LPS (5 h) resulted in inducible NO synthase (iNOS) expression and enhanced superoxide dismutase (Cu/Zn–SOD and Mn–SOD) expression, but it did not modify endothelial NO synthase (eNOS) expression. Noradrenaline (0.5 μM) evoked increases in NO concentration and tension by, respectively, 5.0±2.0 nM and 4.4±0.1 N m−1 (n=6). While NO concentration was unaltered, incubation with LPS reduced noradrenaline contraction to 3.5±0.2 N m−1 (n=39, P<0.05). In contrast to indomethacin, 1400 W (10 μM) restored noradrenaline contraction, while the combination of noradrenaline and oxyhaemoglobin (10 μM) evoked less contraction in LPS compared to control segments. Polyethylene glycol (PEG)-catalase in combination with oxyhaemoglobin reversed noradrenaline hyporeactivity in LPS-treated segments. LPS did not increase, but reduced basal NO concentration, an effect which was reversed by 1400 W and tempol (100 μM). In LPS-treated segments contracted with noradrenaline, the NO synthase substrate, l-arginine (100 μM), relaxed and increased NO concentration with, respectively, 73±9% and 19.5±6.5 nM (n=5). 1400 W and oxyhaemoglobin reversed l-arginine relaxation and increases in NO concentration. In contrast to tempol and PEG-catalase, N-acetylcysteine (0.1–1 mM), which is able to release NO from intracellular stores, relaxed LPS-treated tissue, an effect that was abolished by long-term, but not by short-term, incubation with 1400 W. Conclusions: The present study provides direct evidence that exposure to LPS results in induction of iNOS and SOD associated with noradrenaline hyporeactivity, while increased NO is only measured when l-arginine is present. A catalase-sensitive mechanism and release of NO from N-acetylcysteine-sensitive stores could also contribute to the vascular hyporeactivity.
Sildenafil Effects on Exercise, Neurohormonal Activation, and Erectile Dysfunction in Congestive Heart Failure
Authors: Edimar Alcides Bocchi, Guilherme Guimarães, Amilcar Mocelin, Fernando Bacal, Giovanni Bellotti, José Franchini Ramires
Journal: Circulation (2002)

Background— Erectile dysfunction (ED) is common in patients with congestive heart failure (CHF). ED reduces quality of life, and it may affect compliance, thereby impairing the success of CHF treatment. Methods and Results— In the first phase (fixed-dose double-blind, randomized, placebo-controlled, two-way crossover study), we studied in 23 men with CHF the effects of 50 mg sildenafil on exercise and neurohormonal activation. Patients underwent a treadmill 6-minute cardiopulmonary walking (6′WT) test followed by a maximal cardiopulmonary exercise test (ET). In the second phase, patients received sildenafil, taken as required for ED. Sildenafil reduced the heart rate (HR) (bpm) before the 6′WT (from 75±15 to 71±14, P =0.02) and ET (from 75±15 to 71±15, P =0.02); the systolic blood pressure (mm Hg) before the 6′WT (from 116±18 to 108±18, P =0.004) and ET (from 116±15 to 108±17, P =0.001); the diastolic blood pressure before the 6′WT (from 69±9 to 63±11, P =0.01) and ET (from 70±8 to 65±10, P =0.004); and the Ve/V co 2 slope during the 6′WT (from 32±7 to 31±6, P =0.04) and ET (from 33±8 to 31±5, P =0.03). Sildenafil attenuated the HR increment during the 6′WT ( P =0.003) and ET ( P =0.000). Sildenafil increased the peak · o 2 from 16.6±3.4 to 17.7±3.4 mL/kg per min ( P =0.025) and the exercise time from 12.3±3.4 to 13.7±3.2 minutes ( P =0.003). Sildenafil improved most scores of International Index of Erectile Function. Conclusions— Sildenafil was tolerated and effective for ED treatment in CHF, and improved the exercise capacity. The reduction of HR during exercise with sildenafil could theoretically decrease the myocardial oxygen consumption during sexual activity.