tbuckley/cabot-search huggingface dataset:
Mismatch repair polymorphisms and risk of colon cancer, tumour microsatellite instability and interactions with lifestyle factors
Authors: P T Campbell, K Curtin, C M Ulrich, W S Samowitz, J Bigler, C M Velicer, B Caan, J D Potter, M L Slattery
Journal: Gut (2008)

<h3>Background:</h3> Germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome colon cancers. Less understood is the risk of colon cancer associated with common polymorphisms in MMR genes and the potential interacting role of lifestyle factors known to damage DNA. <h3>Methods:</h3> A study was conducted to examine whether <i>MLH1</i> (<i>-93G&gt;A</i> and <i>Ile219Val</i>) and <i>MSH6</i> (<i>Gly39Glu</i>) polymorphisms were associated with risk of colon cancer in data from 1609 colon cancer cases and 1972 controls. Genotype data were further stratified by microsatellite instability status, smoking, alcohol, Western diet, alcohol and obesity, to investigate potential heterogeneity. <h3>Results:</h3> The <i>MSH6 39Glu</i> allele was associated with increased risk of colon cancer among men (<i>Gly/Glu</i> or <i>Glu/Glu</i> vs <i>Gly/Gly</i>, OR 1.27; 95% CI 1.04 to 1.54). Neither <i>MLH1</i> polymorphism was associated with colon cancer risk overall. When stratified by microsatellite stability status, however, the <i>MLH1 -93A</i> allele was associated with a more than doubling in microsatellite instability (MSI)-positive colon cancer risk (<i>AA</i> vs <i>GG</i>, OR 2.47; 95% CI 1.48 to 4.11); no associations were observed between the MMR polymorphisms examined and MSI-negative colon cancer. Statistically significant interactions were observed between: <i>MLH1 -93G&gt;A</i> and smoking (MSI-negative colon cancer only, p value interaction: 0.005); and <i>MLH1 Ile219Val</i> and Western diet (p value interaction: 0.03). <h3>Conclusions:</h3> The <i>MSH6 Gly39Glu</i> and <i>MLH1 -93G&gt;A</i> polymorphisms were associated with risk of overall colon and MSI-positive colon cancers, respectively. Risk for colon cancer, stratified by MMR genotype, was further modified by smoking and Western diet.
Severe Peripheral Arterial Disease During Nilotinib Therapy
Authors: P. Le Coutre, D. Rea, E. Abruzzese, H. Dombret, M. M. Trawinska, S. Herndlhofer, B. Dorken, P. Valent
Journal: JNCI Journal of the National Cancer Institute (2011)

(36.4%) had a history of nicotine abuse, seven (63.6%) had arterial hypertension, three (27.3%) had diabetes mellitus, five (45.5%) had dyslipidemia, three (27.3%) were obese, six (54.5%) were male, and seven (63.6%) were older than 60 years (all cardiovascular risk factors). All 11 PAD patients had at least a cytogenetic remission while on nilotinib. One patient with hyper eosinophilic syndrome and one patient with CML received nilotinib as first-line treatment. Previous treatments for the remaining patients were hydroxyurea (nine patients), interferon alpha (seven patients), imatinib (nine patients), dasatinib (one patient), or another agent (four patients). In these 11 patients, the mean time from CML diagnosis to initiation of nilotinib was 347 weeks (range = 8–651 weeks) and the mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16–212 weeks) (Table 1). In all cases, the lower limbs were affected; in nine patients, the femoral superficial artery was involved. These patients were treated with angioplasty (eight patients), stent implantation (eight patients), and/or amputation (four patients).
CCL20 mediates lipopolysaccharide induced liver injury and is a potential driver of inflammation and fibrosis in alcoholic hepatitis
Authors: Silvia Affò, Oriol Morales-Ibanez, Daniel Rodrigo-Torres, José Altamirano, Delia Blaya, Dianne H Dapito, Cristina Millán, Mar Coll, Jorge M Caviglia, Vicente Arroyo, Juan Caballería, Robert F Schwabe, Pere Ginès, Ramón Bataller, Pau Sancho-Bru
Journal: Gut (2014)

Objective Chemokines are known to play an important role in the pathophysiology of alcoholic hepatitis (AH), a form of acute-on-chronic liver injury frequently mediated by gut derived lipopolysaccharide (LPS). In our study, we hypothesise that chemokine CCL20, one of the most upregulated chemokines in patients with AH, is implicated in the pathogenesis of AH by mediating LPS induced liver injury. Design CCL20 gene expression and serum levels and their correlation with disease severity were assessed in patients with AH. Cellular sources of CCL20 and its biological effects were evaluated in vitro and in vivo in chronic, acute and acute-on-chronic experimental models of carbon tetrachloride and LPS induced liver injury. RNA interference technology was used to knockdown CCL20 in vivo. Results CCL20 hepatic and serum levels were increased in patients with AH and correlated with the degree of fibrosis, portal hypertension, endotoxaemia, disease severity scores and short term mortality. Moreover, CCL20 expression was increased in animal models of liver injury and particularly under acute-on-chronic conditions. Macrophages and hepatic stellate cells (HSCs) were identified as the main CCL20 producing cell types. Silencing CCL20 in vivo reduced LPS induced aspartate aminotransferase and lactate dehydrogenase serum levels and hepatic proinflammatory and profibrogenic genes. CCL20 induced proinflammatory and profibrogenic effects in cultured primary HSCs. Conclusions Our results suggest that CCL20 upregulation is strongly associated with LPS and may not only represent a new potential biomarker to predict outcome in patients with AH but also an important mediator linking hepatic inflammation, injury and fibrosis in AH.
Immunity and other defenses in pea aphids, Acyrthosiphon pisum
Authors: Nicole M Gerardo, Boran Altincicek, Caroline Anselme, Hagop Atamian, Seth M Barribeau, Martin de Vos, Elizabeth J Duncan, Jay D Evans, Toni Gabaldón, Murad Ghanim, Adelaziz Heddi, Isgouhi Kaloshian, Amparo Latorre, Andres Moya, Atsushi Nakabachi, Benjamin J Parker, Vincente Pérez-Brocal, Miguel Pignatelli, Yvan Rahbé, John S Ramsey, Chelsea J Spragg, Javier Tamames, Daniel Tamarit, Cecilia Tamborindeguy, Caroline Vincent-Monegat, Andreas Vilcinskas
Journal: Genome biology (2010)

Abstract Background Recent genomic analyses of arthropod defense mechanisms suggest conservation of key elements underlying responses to pathogens, parasites and stresses. At the center of pathogen-induced immune responses are signaling pathways triggered by the recognition of fungal, bacterial and viral signatures. These pathways result in the production of response molecules, such as antimicrobial peptides and lysozymes, which degrade or destroy invaders. Using the recently sequenced genome of the pea aphid ( Acyrthosiphon pisum ), we conducted the first extensive annotation of the immune and stress gene repertoire of a hemipterous insect, which is phylogenetically distantly related to previously characterized insects models. Results Strikingly, pea aphids appear to be missing genes present in insect genomes characterized to date and thought critical for recognition, signaling and killing of microbes. In line with results of gene annotation, experimental analyses designed to characterize immune response through the isolation of RNA transcripts and proteins from immune-challenged pea aphids uncovered few immune-related products. Gene expression studies, however, indicated some expression of immune and stress-related genes. Conclusions The absence of genes suspected to be essential for the insect immune response suggests that the traditional view of insect immunity may not be as broadly applicable as once thought. The limitations of the aphid immune system may be representative of a broad range of insects, or may be aphid specific. We suggest that several aspects of the aphid life style, such as their association with microbial symbionts, could facilitate survival without strong immune protection.
Lack of enhanced T-helper cell function in uremic patients with circulating alloreactive antibodies.
Authors: A Shoker, R Miller, R Uldall, E Friedman, S Angra, C J Cardella
Journal: Journal of the American Society of Nephrology (1995)

Some uremic patients with a history of blood transfusion, pregnancy, and previous transplantation maintain high levels of alloreactive cytotoxic antibodies in the absence of continuous exogenous allogenic stimuli and are thus considered sensitized to the major histocompatibility proteins. To differentiate into antibody-producing cells, B lymphocytes must interact with T-helper (CD4+) cells. Whether ongoing help from these cells is necessary for the B cells to continue producing cytotoxic alloreactive antibodies in these sensitized uremic patients is unknown. To gain insight into the cellular mechanisms that are associated with sustained alloantibody production, T cell activation markers were measured and specific and nonspecific T-helper cell function was studied in three uremic groups with different levels of panel reactive antibodies: 10 patients whose sera reacted to more than 80% of a panel of normal lymphocytes for at least 6 months before the study were highly sensitized, 20 patients whose sera reacted to less than 80% of the panel were moderately sensitized, and 10 nonsensitized patients whose sera did not react to any cell on the panel. The number of total and activated T-helper cells was similar in the highly sensitized and nonsensitized patients. Peripheral blood lymphocyte proliferation in response to plant lectins, soluble OKT3, or alloantigens was similar in the three uremic groups. The spontaneous proliferation of pure T-helper cells and proliferative responses to immobilized OKT3 or alloantigens were also similar in highly sensitized and nonsensitized patients. Alloreactive interleukin-2-producing cell frequencies with pure CD4+ cells as responding cells were 771 +/- 77.9/10(6) cells in highly sensitized, 945 +/- 252/10(6) cells in nonsensitized, and 973 +/- 114/10(6) cells in controls (P = not significant). Panel reactive antibody levels did not correlate with any of the measures of T helper responses. There was a significant decrease of peripheral blood lymphocyte responses to alloantigens and anti-CD3 antibody in all uremic patients as compared with normals, suggesting a dysfunction in accessory cells that was quantitatively similar in sensitized and nonsensitized patients. In spite of the continuous production of alloantibodies by B cells, there is no evidence of either specific or nonspecific enhancement of T-helper cell function in sensitized patients. The absence of T cell immunity to alloantigens suggests that sustained activation of T-helper cells with subsequent interleukin-2 production is not necessary to maintain alloreactive B cell function.
Association of <i>XPD</i> Polymorphisms with Severe Toxicity in Non–Small Cell Lung Cancer Patients in a Chinese Population
Authors: Wenting Wu, Wei Zhang, Rong Qiao, Dan Chen, Huibo Wang, Yi Wang, Shuyu Zhang, Ge Gao, Aiqin Gu, Jie Shen, Ji Qian, Weiwei Fan, Li Jin, Baohui Han, Daru Lu
Journal: Clinical Cancer Research (2009)

Platinum agents cause DNA cross-linking and adducts. Xeroderma pigmentosum group D (XPD) plays a key role in the nucleotide excision repair pathway of DNA repair. Genetic polymorphisms of XPD may affect the capacity to remove the deleterious DNA lesions in normal tissues and lead to greater treatment-related toxicity. This study aimed to investigate the association of three polymorphisms of XPD at codons 156, 312, and 711, with the occurrence of grade 3 or 4 toxicity in advanced non-small cell lung cancer patients.We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to genotype the three polymorphisms in 209 stage III and IV non-small cell lung cancer patients treated with platinum-based chemotherapy.The variant homozygotes of XPD p.Arg(156)Arg (rs238406) polymorphism were associated with a significantly increased risk of grade 3 or 4 hematologic toxicity (adjusted odds ratios, 3.24; 95% confidence interval, 1.35-7.78; P for trend = 0.009), and, more specifically, severe leukopenia toxicity (P for trend = 0.005). No statistically significant association was found for the three polymorphisms and grade 3 or 4 gastrointestinal toxicity. Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype "CG" (in the order of p.Arg(156)Arg-p.Asp(312)Asn) on the risk of grade 3 or 4 hematologic toxicity.This investigation, for the first time, provides suggestive evidence of an effect of XPD p.Arg(156)Arg polymorphism on severe toxicity variability among platinum-treated non-small cell lung cancer patients.
Pleural effusion as a presenting symptom of ovarian hyperstimulation syndrome
Authors: A Man, Y Schwarz, J Greif
Journal: European Respiratory Journal (1997)

Pharmacological ovarian stimulation is an accepted technique for amplifying the normal process of follicular development and maturation. It has been in use for the past decade, especially in cases of infertility. Pleural effusion associated with ovarian hyperstimulation syndrome (OHSS), a complication of this therapy, may be more prevalent than is commonly accepted. Four young women presented to our department with dyspnoea caused by pleural effusion as a result of ovarian hyperstimulation syndrome (OHSS). The diagnosis of OHSS was based on a history of pharmacological ovarian stimulation, clinical and laboratory evidence of ovarian enlargement and exclusion of other potential causes of pleural effusion in young women, such as infections, malignancy, pulmonary embolism and collagen vascular diseases. The fluid characteristics in all cases were exudative, with low to normal LDH. All of these patients required fluid evacuation for symptomatic relief. Resolution was achieved with supportive measures and rest. Ovarian hyperstimulation syndrome may be common enough to warrant routine consideration in the differential diagnosis of pleural effusion in young women.
Health status measured with the CRQ does not predict mortality in COPD
Authors: T. Oga, K. Nishimura, M. Tsukino, S. Sato, T. Hajiro, A. Ikeda, M. Mishima
Journal: European Respiratory Journal (2002)

One purpose of measuring health status is to predict future outcomes. The aim of this study was to investigate the ability of health status derived from the Chronic Respiratory Disease Questionnaire (CRQ) to predict mortality in chronic obstructive pulmonary disease (COPD). One-hundred and forty-three patients with COPD were recruited. Health status, using the CRQ, and pulmonary function were measured at entry. Mortality after 7 yrs was then assessed. Univariate and multivariate Cox proportional hazards analyses were performed to predict those factors related to mortality. Of all the patients, 13 could not be followed up and 40 had died. The survival rate was 69% at 7 yrs. Univariate regression analyses revealed that the dyspnoea and emotional function domains and the total score of the CRQ were weakly but significantly correlated with mortality from all causes. However, multivariate regression analyses revealed that age and forced expiratory volume in one second were the strongest predictors of mortality, and health status was not a significant factor. Although there was a weak but significant relationship between health status and subsequent mortality in chronic obstructive pulmonary disease, it was not significant after an adjustment for age and pulmonary function. Mortality cannot be predicted from Chronic Respiratory Disease Questionnaire scores.
Methacholine challenge in preschool children: methacholine-induced wheeze versus transcutaneous oximetry
Authors: SC Yong, CM Smith, R Wach, M Kurian, RA Primhak
Journal: European Respiratory Journal (1999)

Tracheal/chest auscultation for wheeze and transcutaneous oximetry have both been suggested as measures of outcome in bronchial provocation tests in young children. This study aimed to compare the sensitivity and safety of these two techniques as end-points for methacholine challenge in children aged <4 yrs. Seventy-two methacholine challenges were performed in 39 children aged <4 yrs with recurrent wheeze. Arterial oxygen saturation (Sa,O2) and transcutaneous oxygen pressure tcPO2 continuously, and the test was terminated when wheeze was heard or at Sa,O2 <91%. tcPO2 was not used as an end-point. Wheeze or desaturation occurred at < or =8 mg x mL(-1) methacholine in every test. One child had transient clinical cyanosis, but no other ill-effects were seen. Fifty-six tests (78%) were terminated for wheeze, seven (10%) for fall in Sa,O2 and nine (12%) showed simultaneous responses in both parameters. Twenty-eight tests (39%) contained a fall in tcPO2 >3 kPa but six of these also showed a significant rise. Fifty-three tests (75%) contained a fall in tcPO2 >15%, but 20 of these also showed a significant rise. Tracheal/chest auscultation with Sa,O2 monitoring is a sensitive and relatively safe end-point for bronchial challenges in preschool children. The erratic pattern of transcutaneous oxygen pressure response in some children casts doubt on its reliability as a proxy measure of bronchial obstruction.
Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene
Authors: R.M. Tuder, M.E. Yeager, M. Geraci, H.A. Golpon, N.F. Voelkel
Journal: European Respiratory Journal (2001)

The recent discoveries of the familial primary pulmonary hypertension gene and somatic mutations in key cell growth and cell death regulatory genes in primary pulmonary hypertension have added a new dimension to severe pulmonary hypertension research. These findings have already impacted on how the disease is viewed, and ultimately, how severe pulmonary hypertension is diagnosed and treated. However, this new information raises several fundamental questions related to the role of bone morphogenetic protein receptor signalling in the control of lung vascular cell function. Furthermore, additional genes and gene products may also be involved in the pathogenesis of the disease. The way severe pulmonary hypertension is viewed and studied is on the verge of shifting from a vasoconstrictive to a cell growth paradigm.
Abstract B38: Whole exome sequencing of 101 neuroblastomas with distinct genomic subgroups identified significantly mutated pathways in aggressive tumor subtypes
Authors: Miki Ohira, Yuanyuan Li, Yong Zhou, Xiangchun Li, Zhibo Gao, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Yohko Nakamura, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara
Journal: Cancer Research (2014)

Abstract Neuroblastoma is known to exhibit wide ranges of clinical behavior, from spontaneous regression to highly resistant to chemotherapy. Previously, we have established the risk classification system based on the copy number profiles of the tumor determined by array CGH analysis. The two most major subclasses with aggressive phenotype are P1a (with partial chromosomal gains/losses, MYCN amplification, 1p loss and 17q gain, but no 11q loss) and P3s (with partial chromosomal gains/losses, 11q loss and 17q gain, but no 1p loss nor MYCN amplification), whose 8-year survival rates were 33% and 31%, respectively, in our database. On the other hand, Ss subgroup, categorized as few chromosomal gains/losses, showed favorable prognosis (8-year survival rate was 82%). To determine and compare the spectrum of genetic alterations in each tumor subtype, we have so far conducted whole-exome sequencing of 101 cases (P1a:17, P3s:44, Ss:20, others including metastasized or relapsed:20). On average, P1a and P3s subgroups had approximately 14 and 19 somatic alterations in coding genes, respectively, while Ss had very few alterations with only 1.2. Few recurrent non-silent mutations were found in all subgroups, however, pathway analysis by David with KEGG database indicated that a part of these novel somatic mutations were concentrated in cancer-related signaling pathways, such as those of MAPK (14 genes, adjusted p&amp;lt;0.001) and Wnt (7 genes, p&amp;lt;0.001), significantly in P1a subtype. Ongoing efforts will validate mutation candidates in a larger scale sample set by independent analysis platforms as well as the correlations with prognosis of each tumor subset. Citation Format: Miki Ohira, Yuanyuan Li, Yong Zhou, Xiangchun Li, Zhibo Gao, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Yohko Nakamura, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara. Whole exome sequencing of 101 neuroblastomas with distinct genomic subgroups identified significantly mutated pathways in aggressive tumor subtypes. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B38.
Na+/H+ exchanger inhibitor, FR183998, has protective effect in lethal acute liver failure and prevents iNOS induction in rats
Authors: Hironori Tanaka, Yoichiro Uchida, Masaki Kaibori, Takeshi Hijikawa, Morihiko Ishizaki, Masanori Yamada, Kosuke Matsui, Takashi Ozaki, Katsuji Tokuhara, Yasuo Kamiyama, Mikio Nishizawa, Seiji Ito, Tadayoshi Okumura
Journal: Journal of Hepatology (2007)
The Inexact Use of Fisher's Exact Test in Six Major Medical Journals
Authors: W. Paul McKinney
Journal: JAMA (1989)

We reviewed the use of Fisher's Exact Test in 71 articles published between 1983 and 1987 in six medical journals. Thirty-three of 56 selected articles did not specify use of a one- or two-tailed test, and 12 (36%) of these actually used the one-tailed test. Five (42%) of these 12 articles contained at least one table in which the standard significance level of P less than .05 was no longer met when a two-tailed analysis was run instead. Eleven (65%) of 17 articles with a statistical consultant compared with 10 (28%) of 36 articles without a consultant specified use of a one- or two-sided test. The use of Fisher's Exact Test without specification as a one- or two-tailed version may misrepresent the statistical significance of data. A uniform specification statement should be required for all manuscripts to correct such potential errors in interpretation.
Chronic SR Ca <sup>2+</sup> -ATPase Inhibition Causes Adaptive Changes in Cellular Ca <sup>2+</sup> Transport
Authors: Angela G. Brittsan, Kenneth S. Ginsburg, Guoxiang Chu, Atsuko Yatani, Beata M. Wolska, Albrecht G. Schmidt, Michio Asahi, David H. MacLennan, Donald M. Bers, Evangelia G. Kranias
Journal: Circulation Research (2003)

Phospholamban, the critical regulator of the cardiac SERCA2a Ca2+ affinity, is phosphorylated at Ser16 and Thr17 during beta-adrenergic stimulation (eg, isoproterenol). To assess the impact of nonphosphorylatable phospholamban, a S16A, T17A double-mutant (DM) was introduced into phospholamban knockout mouse hearts. Transgenic lines expressing DM phospholamban at levels similar to wild types (WT) were identified. In vitro phosphorylation confirmed that DM phospholamban could not be phosphorylated, but produced the same shift in EC50 of SERCA2a for Ca2+ as unphosphorylated WT phospholamban. Rates of basal twitch [Ca2+]i decline were not different in DM versus WT cardiomyocytes. Isoproterenol increased the rates of twitch [Ca2+]i decline in WT, but not DM myocytes, confirming the prominent role of phospholamban phosphorylation in this response. Increased L-type Ca2+ current (ICa) density, with unaltered characteristics, was the major compensation in DM myocytes. Consequently, the normal beta-adrenergic-induced increase in ICa caused larger dynamic changes in absolute ICa density. Isoproterenol increased Ca2+ transients to a comparable amplitude in DM and WT. There were no changes in myofilament Ca2+ sensitivity, or the expression levels and Ca2+ removal activities of other Ca2+-handling proteins. Nor was there evidence of cardiac remodeling up to 10 months of age. Thus, chronic inhibition of SERCA2a by ablation of phospholamban phosphorylation (abolishing its adrenergic regulation) results in a unique cellular adaptation involving greater dynamic ICa modulation. This ICa modulation may partly compensate for the loss in SERCA2a responsiveness and thereby partially normalize beta-adrenergic inotropy in DM phospholamban mice.