tbuckley/cabot-search huggingface dataset:
Crohn's Disease Loci Are Common Targets of Protozoa-Driven Selection
Authors: Rachele Cagliani, Uberto Pozzoli, Diego Forni, Andrea Cassinotti, Matteo Fumagalli, Matteo Giani, Maria Fichera, Marta Lombardini, Sandro Ardizzone, Rosanna Asselta, Roberto de Franchis, Stefania Riva, Mara Biasin, Giacomo P. Comi, Nereo Bresolin, Mario Clerici, Manuela Sironi
Journal: Molecular Biology and Evolution (2013)

Previous studies indicated that a few risk variants for autoimmune diseases are subject to pathogen-driven selection. Nonetheless, the proportion of risk loci that has been targeted by pathogens and the type of infectious agent(s) that exerted the strongest pressure remain to be evaluated. We assessed whether different pathogens exerted a pressure on known Crohn's disease (CD) risk variants and demonstrate that these single-nucleotide polymorphisms (SNPs) are preferential targets of protozoa-driven selection (P = 0.008). In particular, 19% of SNPs associated with CD have been subject to protozoa-driven selective pressure. Analysis of P values from genome-wide association studies (GWASs) and meta-analyses indicated that protozoan-selected SNPs display significantly stronger association with CD compared with nonselected variants. This same behavior was not observed for GWASs of other autoimmune diseases. Thus, we integrated selection signatures and meta-analysis results to prioritize five genic SNPs for replication in an Italian cohort. Three SNPs were significantly associated with CD risk, and combination with meta-analysis results yielded P values < 4 × 10(-6). The bona fide risk alleles are located in ARHGEF2, an interactor of NOD2, NSF, a gene involved in autophagy, and HEBP1, encoding a possible mediator of inflammation. Pathway analysis indicated that ARHGEF2 and NSF participate in a molecular network, which also contains VAMP3 (previously associated to CD) and is centered around miR-31 (known to be disregulated in CD). Thus, we show that protozoa-driven selective pressure had a major role in shaping predisposition to CD. We next used this information for the identification of three bona fide novel susceptibility loci.
The effect of octreotide on gastric emptying at a dosage used to prevent complications after pancreatic surgery: a randomised, placebo controlled study in volunteers
Authors: M I van Berge Henegouwen, Th M van Gulik, L M A Akkermans, J B M J Jansen, D J Gouma
Journal: Gut (1997)

Background —Octreotide is used in many centres to prevent complications after pancreatic surgery. Delayed gastric emptying is a another complication occurring in around 30% of patients after pancreatoduodenectomy (PD) and causes prolonged hospital stay. The influence of octreotide on this complication is doubtful. Aims —To assess the effect of octreotide, at the clinical dosage used after pancreatic surgery, on gastric emptying in healthy volunteers. Subjects and methods —Eight healthy male volunteers (mean age 22.5 years) participated in this double blind, placebo controlled study. On day 1 subjects received 100 μg of octreotide or placebo subcutaneously, three times daily and on day 2, one hour after the fourth injection, gastric emptying, postprandial cholecystokinin (CCK) release, and mouth to caecum transit time (MCTT) were measured. This protocol was repeated after one week, in a crossover design. On the test day subjects received a liquid test meal (1.57 MJ/300 ml) and gastric emptying measurements were performed with applied potential tomography, a non-invasive, validated technique which measures gastric emptying through impedance differences. From the gastric emptying curves, lag time, t 50 , and postlag emptying rate were measured. MCTT was measured using the hydrogen breath test. Results —Lag time decreased from 29.6 (6.3) (mean (SEM)) to 12.2 (4.6) minutes (p&lt;0.05) during octreotide treatment; t 50 decreased from 87.8 (12.0) to 47.5 (8.2) minutes (p&lt;0.02) and there was a trend towards an increased postlag emptying rate (0.8 to 1.6% per minute; p=0.07). MCTT increased from 150 (12.7) to 229 (17.9) minutes during octreotide treatment (p&lt;0.01). Octreotide suppressed postprandial CCK release (p&lt;0.05). Conclusions —MCTT was delayed by octreotide, suggesting impairment of small bowel transit. Octreotide administered at the clinical dosage for pancreatic surgery accelerates gastric emptying, mainly by shortening the lag time. Suppression of postprandial CCK release may be involved in this process. Octreotide administration is therefore not a contributing factor in the pathogenesis of delayed postoperative gastric emptying after PD and might even play a role in preventing this complication.
Increased CDC20 expression is associated with pancreatic ductal adenocarcinoma differentiation and progression
Authors: David Z Chang, Ying Ma, Baoan Ji, Yan Liu, Patrick Hwu, James L Abbruzzese, Craig Logsdon, Huamin Wang
Journal: Journal of Hematology & Oncology (2012)

Cell division cycle 20 (CDC20) homolog is an anaphase-promoting complex activator that is essential for cell division, but whether its expression in pancreatic ductal adenocarcinoma (PDAC) is significant is unknown. In this retrospective study, we determined whether aberrant CDC20 expression can be used as a biomarker in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and whether its expression reflects clinical progression. We compared CDC20 expression levels in normal, cancerous, and inflamed pancreatic tissues from stage II PDAC patients with clinical outcomes and determined CDC20 levels in seven PDAC cell lines. CDC20 was identified using a cDNA microarray database containing gene expression profiles for PDAC tissues and cell lines and chronic pancreatitis and normal pancreas tissues. Its expression was confirmed by real-time quantitative reverse-transcriptase-polymerase chain reaction (qRT-PCR). An immunohistochemical analysis of tissue microarrays from resected PDAC tumors and paired benign pancreatic tissues was done and CDC20 levels were correlated with clinical outcome. Fifty-six patients were included in this study. A microarray analysis revealed 5-fold higher CDC20 expression in PDAC tissue than in chronic pancreatitis tissue. A qRT-PCR analysis confirmed a mean 20-fold higher CDC20 level in PDAC tissue than in normal pancreas and pancreatitis tissue. RNA and protein CDC20 expression was detected in several PDAC cell lines. An immunohistochemical analysis revealed higher CDC20 protein expression levels in PDAC tissue than in normal pancreas tissue, and high CDC20 expression was associated with poor differentiation (P = 0.020) and a significantly lower 5-year recurrence-free survival rate (P = 0.039); we also found a trend toward a shorter overall survival duration. Aberrant CDC20 expression may play an important role in PDAC tumorigenesis and progression and may thus be useful as a marker of disease progression and prognosis and as a therapeutic target.
Oxidative Stress Induces NF- B Nuclear Translocation Without Degradation of I B 
Authors: T. G. Canty, E. M. Boyle, A. Farr, E. N. Morgan, E. D. Verrier, T. H. Pohlman
Journal: Circulation (1999)

Rel/NF-kappaB, an oxidative stress-responsive transcription factor, participates transiently in the control of gene expression. The cellular mechanisms that mediate NF-kappaB activation during ischemia (and during reperfusion in the course of treating ischemia) are not known.To investigate the NF-kappaB activation induced during oxidative stress, we examined human cardiac tissue obtained during surgical procedures requiring cardiopulmonary bypass. In vitro, we examined human umbilical vein endothelial cells (HUVECs) exposed to hypoxia, reoxygenation after hypoxia, or a reactive oxygen intermediate (H(2)O(2)). Electrophoretic mobility shift assays performed on right atrial tissue revealed prominent NF-kappaB activation after hearts had been exposed to ischemia and reperfusion. The assays also showed that NF-kappaB activation was observed in hypoxic HUVECs after reoxygenation and in cultures treated with H(2)O(2) (500 micromol/L). Pervanadate (200 micromol/L) also induced marked NF-kappaB activation in HUVECs, indicating that H(2)O(2)-induced NF-kappaB activation is potentiated by the inhibition of tyrosine phosphatases. Western blotting of cytoplasmic IkappaBalpha demonstrated that NF-kappaB activation induced by oxidative stress was not associated with IkappaBalpha degradation. In contrast, tumor necrosis factor-alpha-induced NF-kappaB activation occurred in concert with degradation of IkappaBalpha. Inhibition of IkappaBalpha degradation with a proteasome inhibitor, MG-115, blocked NF-kappaB activation induced by tumor necrosis factor-alpha; however, MG-115 had no effect on NF-kappaB activation during oxidative stress.This study demonstrated a stimulus-specific mechanism of NF-kappaB activation in endothelial cells that acts independently of IkappaBalpha degradation and may require tyrosine phosphorylation.
Study quality on groin injury management remains low: a systematic review on treatment of groin pain in athletes
Authors: Andreas Serner, Casper H van Eijck, Berend R Beumer, Per Hölmich, Adam Weir, Robert-Jan de Vos
Journal: British Journal of Sports Medicine (2015)

Background Groin pain in athletes is frequent and many different treatment options have been proposed. The current level of evidence for the efficacy of these treatments is unknown. Objective Systematically review the literature on the efficacy of treatments for groin pain in athletes. Methods Nine medical databases were searched in May 2014. Inclusion criteria: treatment studies in athletes with groin pain; randomised controlled trials, controlled clinical trials or case series; n&gt;10; outcome measures describing number of recovered athletes, patient satisfaction, pain scores or functional outcome scores. One author screened search results, and two authors independently assessed study quality. A best evidence synthesis was performed. Relationships between quality score and outcomes were evaluated. Review registration number CRD42014010262. Results 72 studies were included for quality analysis. Four studies were high quality. There is moderate evidence that, for adductor-related groin pain, active exercises compared with passive treatments improve success, multimodal treatment with a manual therapy technique shortens the time to return to sports compared with active exercises and adductor tenotomy improves treatment success over time. There is moderate evidence that for athletes with sportsman's hernia, surgery results in better treatment success then conservative treatment. There was a moderate and inverse correlation between study quality and treatment success (p&lt;0.001, r=−0.41), but not between study quality and publication year (p=0.09, r=0.20). Conclusions Only 6% of publications were high quality. Low-quality studies showed significantly higher treatment success and study quality has not improved since 1985. There is moderate evidence for the efficacy of conservative treatment (active exercises and multimodal treatments) and for surgery in patients with adductor-related groin pain. There is moderate evidence for efficacy of surgical treatment in sportsman's hernia.
Association Between Osteosarcoma and Deleterious Mutations in the RECQL4 Gene in Rothmund-Thomson Syndrome
Authors: L. L. Wang, A. Gannavarapu, C. A. Kozinetz, M. L. Levy, R. A. Lewis, M. M. Chintagumpala, R. Ruiz-Maldanado, J. Contreras-Ruiz, C. Cunniff, R. P. Erickson, D. Lev, M. Rogers, E. H. Zackai, S. E. Plon
Journal: JNCI Journal of the National Cancer Institute (2003)

Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene.We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein.Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test).Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.
Nonhomogeneous Model of Sequence Evolution Indicates Independent Origins of Primary Endosymbionts Within the Enterobacteriales (γ-Proteobacteria)
Authors: Joshua T. Herbeck, Patrick H. Degnan, Jennifer J. Wernegreen
Journal: Molecular Biology and Evolution (2004)

Standard methods of phylogenetic reconstruction are based on models that assume homogeneity of nucleotide composition among taxa. However, this assumption is often violated in biological data sets. In this study, we examine possible effects of nucleotide heterogeneity among lineages on the phylogenetic reconstruction of a bacterial group that spans a wide range of genomic nucleotide contents: obligately endosymbiotic bacteria and free-living or commensal species in the γ-Proteobacteria. We focus on AT-rich primary endosymbionts to better understand the origins of obligately intracellular lifestyles. Previous phylogenetic analyses of this bacterial group point to the importance of accounting for base compositional variation in estimating relationships, particularly between endosymbiotic and free-living taxa. Here, we develop an approach to compare susceptibility of various phylogenetic reconstruction methods to the effects of nucleotide heterogeneity. First, we identify candidate trees of γ-Proteobacteria groEL and 16S rRNA using approaches that assume homogeneous and stationary base composition, including Bayesian, maximum likelihood, parsimony, and distance methods. We then create permutations of the resulting candidate trees by varying the placement of the AT-rich endosymbiont Buchnera. These permutations are evaluated under the nonhomogeneous and nonstationary maximum likelihood model of Galtier and Gouy, which allows equilibrium base content to vary among examined lineages. Our results show that commonly used phylogenetic methods produce incongruent trees of the Enterobacteriales, and that the placement of Buchnera is especially unstable. However, under a nonhomogeneous model, various groEL and 16S rRNA phylogenies that separate Buchnera from other AT-rich endosymbionts (Blochmannia and Wigglesworthia) have consistently and significantly higher likelihood scores. Blochmannia and Wigglesworthia appear to have evolved from secondary endosymbionts, and represent an origin of primary endosymbiosis that is independent from Buchnera. This application of a nonhomogeneous model offers a computationally feasible way to test specific phylogenetic hypotheses for taxa with heterogeneous and nonstationary base composition.
Asbestos Exposure, Pleural Plaques, and the Risk of Death from Lung Cancer
Authors: Jean-Claude Pairon, Pascal Andujar, Mickael Rinaldo, Jacques Ameille, Patrick Brochard, Soizick Chamming’s, Bénédicte Clin, Gilbert Ferretti, Antoine Gislard, François Laurent, Amandine Luc, Pascal Wild, Christophe Paris
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Although asbestos is a well-known lung carcinogen, the pleural plaque-lung cancer link remains controversial.This study was designed to examine this link in asbestos-exposed workers.A 6-year follow-up was conducted to study lung cancer mortality in the 5,402 male subjects participating in an asbestos-related disease screening program conducted from October 2003 to December 2005 in four French regions. Chest computed tomography (CT) scan was performed in all subjects with randomized, independent, double reading of CT scans focusing on benign asbestos-related abnormalities. Cox model survival regression analysis was used to model lung cancer mortality according to the presence of pleural plaques, with age as the main time variable, adjusting for smoking and asbestos cumulative exposure index. All statistical tests were two-sided.Thirty-six deaths from lung cancer were recorded. Lung cancer mortality was significantly associated with pleural plaques in the follow-up study in terms of both the unadjusted hazard ratio of 2.91 (95% confidence interval = 1.49-5.70) and the adjusted hazard ratio of 2.41 (95% confidence interval = 1.21-4.85) after adjustment for smoking and asbestos cumulative exposure index.Pleural plaques may be an independent risk factor for lung cancer death in asbestos-exposed workers and could be used as an additional criterion in the definition of high-risk populations eligible for CT screening.
High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia A patients not undergoing immunotolerance
Authors: Giuseppe Tagariello, Alfonso Iorio, Davide Matino, Donata Belvini, Roberta Salviato, Roberto Sartori, Paolo Radossi
Journal: Journal of Hematology & Oncology (2013)

The natural history of inhibitors in patients with haemophilia A not undergoing immune tolerance induction (ITI) is largely unknown. A recent randomized controlled trial suggests that the higher the FVIII dose used for ITI, the faster the clearance and the lower the rate of bleeding, without any difference in the rate of tolerance. We aimed at assessing the rate of spontaneous inhibitor clearance in a large cohort of patients not undergoing ITI. A retrospective analysis of anti-FVIII inhibitors of long-term registry data in a single centre cohort of 524 haemophilia A patients considered for synovectomy was performed. Patients were tested for inhibitors before and 15 days after any and each surgical episode and thereafter did not undergo immune tolerance at any time. The cumulative incidence of inhibitors overall was 34% (180 out of 524) with the highest percentage of 39% (168 out of 434) in severe patients which represented 83% of the cohort. Among the 180 inhibitor patients: 63 had permanent inhibitors; 70 fulfilled current criteria for transient inhibitors but a third category of 47 additional patients cleared the alloantibody spontaneously in >6 months. At logistic regression, both the inhibitor titre and the gene mutation were shown to predict time to clearance. Spontaneous clearance of inhibitors over variable time in the absence of ITI treatment was found in up to 2/3 of the cases.
Chronic Suppression of Angiogenesis following Radiation Exposure Is Independent of Hematopoietic Reconstitution
Authors: Taturo Udagawa, Amy E. Birsner, Mark Wood, Robert J. D'Amato
Journal: Cancer Research (2007)

Abstract Radiation can potentially suppress neovascularization by inhibiting the incorporation of hematopoietic precursors as well as damaging mature endothelial cells. The purpose of these studies was to quantify the effect of radiation on angiogenesis and to examine the relationship between bone marrow reconstitution and neovascularization. Immune competent, severe combined immunodeficient, RAG1-deficient, and green fluorescence protein transgenic mice in the C57 genetic background, as well as the highly angiogenic 129S1/SvlmJ strain of mice, underwent whole-body or localized exposure to radiation. The hematopoietic systems in the irradiated recipients were restored by bone marrow transfer. Hematopoietic reconstitution was assessed by doing complete blood counts. Angiogenesis was induced in the mouse cornea using 80 ng of purified basic fibroblast growth factor, and the neovascular response was quantified using a slit lamp biomicroscope. Following whole-body exposure and bone marrow transplantation, the hematopoietic system was successfully reconstituted over time, but the corneal angiogenic response was permanently and significantly blunted up to 66%. Localized exposure of the eyes to radiation suppressed corneal angiogenesis comparably to whole-body exposure. Whole-body irradiation with ocular shielding induced bone marrow suppression but did not inhibit corneal neovascularization. In mice exposed to radiation before tumor implantation, the reduced local angiogenic response correlated with significantly reduced growth of tumor cells in vivo. These results indicate that bone marrow suppression does not suppress neovascularization in the mouse cornea and that although hematopoietic stem cells can readily reconstitute peripheral blood, they do not restore a local radiation-induced deficit in neovascular response. [Cancer Res 2007;67(5):2040–5]
Evaluation of the efficacy and safety of etoricoxib compared with naproxen in two, 138-week randomised studies of patients with osteoarthritis
Authors: J Y Reginster, K Malmstrom, A Mehta, G Bergman, A T Ko, S P Curtis, A S Reicin
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objectives:</b> To assess the efficacy and safety of etoricoxib 60 mg once daily and naproxen 500 mg twice daily over a 138-week treatment period in patients with osteoarthritis (OA). <b>Methods:</b> Two 1-year randomised, double blind, parallel group two-part base studies (part I 12 weeks; part II 40 weeks), followed by an 86-week extension, in patients with OA (hip or knee) were conducted at 80 clinical centres (19 countries). The studies had identical designs. Patients taking placebo in part I received etoricoxib or naproxen (1:1 ratio) in part II and the extension; patients taking etoricoxib or naproxen in part I continued to receive the same treatment throughout the entire length of the studies. Co-primary efficacy end points were patient global assessment of disease status, and WOMAC questionnaire pain subscale and physical function subscale (100 mm VAS). Efficacy over 138 weeks was assessed by graphical analysis. Safety was assessed by observation of adverse experiences and laboratory and physical evaluations. <b>Results:</b> 997 patients entered (615 completed) the base studies. Of these patients, 463 patients entered the extensions. A total of 161 and 152 patients in the etoricoxib and naproxen groups, respectively, completed 138 treatment weeks. Etoricoxib and naproxen showed similar efficacy throughout the 138 weeks of treatment. For etoricoxib and naproxen, respectively, WOMAC pain assessments were 67 and 67 mm (baseline); 28 and 29 mm (1 year), and 34 and 33 mm (138 weeks). Results for the other efficacy end points were similar to those seen with the WOMAC pain assessments. Both etoricoxib and naproxen were generally well tolerated. <b>Conclusion:</b> Both etoricoxib and naproxen demonstrated long-term clinical efficacy for the treatment of OA. Etoricoxib and naproxen were generally well tolerated.