tbuckley/cabot-search huggingface dataset:
Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice
Authors: D. Jauch, M. Martin, G. Schiechl, R. Kesselring, H. J. Schlitt, E. K. Geissler, S. Fichtner-Feigl
Journal: Gut (2011)

<h3>Background and aims</h3> Colitis-associated tumorigenesis is a balance between proliferation of tumour cells and tumour immunosurveillance. The role of T-helper-cell-derived cytokines in tumour growth is not fully understood. In this study the authors investigated the influence of interleukin (IL) 21 on intestinal tumorigenesis. <h3>Methods</h3> Chronic colitis was induced in IL-21<sup>−/−</sup> and littermate control wild-type mice with three cycles of 1.5% dextran sulphate sodium (DSS) over 7 days followed by 7 days of drinking water. Mice received an azoxymethane injection on day 0 of DSS-colitis to induce tumorigenesis. Immunohistochemistry was performed on inflamed and tumour-bearing areas of colons. Cytokine expression of isolated colonic CD4 T cells was determined by ELISA. Cytotoxic capacity of isolated colonic CD8 T cells targeting tumour cells was evaluated by flow cytometry and quantitative cytotoxicity assay. Apoptosis of tumour cells was determined by TUNEL assay of colonic sections. <h3>Results</h3> Increasing expression of IL-21 was observed in chronic colitis, which showed functional importance, since IL-21 deficiency prevented chronic DSS-colitis development. Further, in the absence of IL-21, significantly fewer tumour nodules were detected, despite a similar extent of intestinal inflammation. In wild-type mice, 8.6±1.9 tumour nodules were found compared with 1.0±1.2 in IL-21-deficient mice. In tumour-bearing IL-21-deficient mice, intestinal inflammation was restored and partly dependent on interferon (IFN)-γ, whereas the inflammation in wild-type mice showed high IL-17A concentrations. In these rare tumours in IL-21-deficient mice, tumour cell proliferation (Ki-67) was decreased, while cell apoptosis was increased, compared with wild-type mice. Increased IFNγ expression in tumour-bearing IL-21-deficient mice led to increased tumour immunosurveillance mediated by cytotoxic CD8CD103 T cells targeting E-cadherin<sup>+</sup> colonic tumour cells and therefore limited tumour growth. <h3>Conclusion</h3> These results indicate that IL-21 orchestrates colitis-associated tumorigenesis, leading to the hypothesis that high IFNγ and low IL-17A expression reduces tumour cell proliferation and increases tumour immunosurveillance.
The Potential of HDAC Inhibitors as Cognitive Enhancers
Authors: Johannes Gräff, Li-Huei Tsai
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Histone acetylation is a prominent epigenetic modification of the central nervous system that is unequivocally associated with an increase in the rate of gene transcription. Because gene transcription, in turn, plays an important role in long-lasting forms of memory, histone acetylation generally favors long-term memory, whereas histone deacetylation impinges on it. Histone acetylation is also amenable to pharmacological interventions—predominantly by the use of histone deacetylase (HDAC) inhibitors—and has therefore spurred considerable interest as a putative target of cognitive enhancement. Because of the ubiquitous presence of histone acetylation, HDAC inhibitors have great potential not only to treat cognitive impairment resulting from neurodevelopmental and neurodegenerative disorders but also to serve as cognitive enhancers for the cognitively healthy. In this review, we summarize the state of the art of HDAC inhibitors as cognitive treatments or cognitive enhancers; describe a new model of their mode of action, epigenetic priming; and caution against their unsupervised usage, despite their overall great promise.
Oxygen in the home.
Authors: P Howard
Journal: Thorax (1983)

Oxygen in the homeThe importance of oxygen as a therapeutic agent was established by JS Haldane in 1917' and by Bar- croft in 1920.2The latter divided anoxia into three types: anoxic, anaemic, and stagnant.Breathing of oxygen-enriched air was described as palliative; it enabled tissues to be vitalised while recovery occurred.Both Haldane' and in 1931 Barach3 noticed that high inspired oxygen concentrations sometimes caused a rise in the arterial carbon dioxide tension (Paco2).Excessive stimulation of metabolism was erroneously considered to be the cause of the raised Paco2 and this led to the establishment of intermittent oxygen treatment.Much criticism was levelled at this technique, which only occasionally relieved hypoxic tissue.Comroe and others in 19504 described some of the harmful effects of oxygen when used to treat hypoxia in patients with bron- chitis and emphysema.Suker and Hickman in 19565 related the rise of Paco2 to respiratory depression caused by high inspired oxygen concentrations in patients with chronic bronchitis, which is the basis of our present understanding.It became clear that high inspired oxygen concentrations could not safely be administered to patients with chronic airways obs- truction with any degree of carbon dioxide retention for fear of a further sharp rise in Paco2, leading to coma through cerebral acidosis.5But patients with hypoxaemia from other causes, such as acute or
Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease
Authors: A. M. Muise, T. D. Walters, W. K. Glowacka, A. M. Griffiths, B.-Y. Ngan, H. Lan, W. Xu, M. S. Silverberg, D. Rotin
Journal: Gut (2009)

<h3>Background:</h3> Patients with Crohn's disease have defects in intestinal epithelial permeability that are inadequately explained by known inflammatory bowel disease (IBD) susceptibility genes. E-cadherin (<i>CDH1</i>) plays a vital role in maintaining the integrity of the intestinal barrier and its cellular localisation is disrupted in patients with Crohn's disease. <h3>Aim:</h3> To determine if polymorphisms in the <i>CDH1</i> gene are associated with Crohn's disease and to determine the function associated with these polymorphisms. <h3>Methods:</h3> The hypothesis was tested using a candidate gene approach using 20 Tag SNPs derived from the HapMap and Crohn's disease trios. Functional studies were carried out using HapMap cell lines and polarised epithelial cell lines (MDCK-1 and Caco2). <h3>Results:</h3> Here we show that <i>CDH1</i> is associated with Crohn's disease in 327 trios (rs10431923 excess transmission of "TT" genotype; p = 0.0020) and is replicated in the Wellcome Trust Case Control Consortium CD data set (TT risk allele; OR 1.2, p = 0.005). Patients with the Crohn's disease risk haplotype (rs12597188, rs10431923 and rs9935563; GTC allelic frequency 21%; p = 0.000016) exhibited increased E-cadherin cytoplasmic accumulation in their intestinal epithelium which may be explained by the presence of a novel truncated form of E-cadherin. Accordingly, expression of this truncated E-cadherin in cultured polarised epithelial cells resulted in abnormal intracellular accumulation and impaired plasma membrane localisation of both E-cadherin and β-catenin. <h3>Conclusion:</h3> The mis-localisation of E-cadherin and β-catenin may explain the increased permeability seen in some patients with Crohn's disease. Thus, the polymorphisms identified in <i>CDH1</i> are important for understanding the pathogenesis of Crohn's disease and point to a defect in barrier defence.
The prevalence of congenital uterine anomalies in unselected and high-risk populations: a systematic review
Authors: Y.Y. Chan, K. Jayaprakasan, J. Zamora, J.G. Thornton, N. Raine-Fenning, A. Coomarasamy
Journal: Human Reproduction Update (2011)

and in women with infertility, including those undergoing IVF treatment, women with a history of miscarriage, women with infertility and recurrent miscarriage combined, and women with a history of preterm delivery.methods: Searches of MEDLINE, EMBASE, Web of Science and the Cochrane register were performed.Study selection and data extraction were conducted independently by two reviewers.Studies were grouped into those that used 'optimal' and 'suboptimal' tests for uterine anomalies.Meta-analyses were performed to establish the prevalence of uterine anomalies and their subtypes within the various populations.results: We identified 94 observational studies comprising 89 861 women.The prevalence of uterine anomalies diagnosed by optimal tests was 5.5% [95% confidence interval (CI), 3.5-8.5] in the unselected population, 8.0% (95% CI, 5.3-12) in infertile women, 13.3% (95% CI, 8.9-20.0) in those with a history of miscarriage and 24.5% (95% CI, 18.3 -32.8) in those with miscarriage and infertility.Arcuate uterus is most common in the unselected population (3.9%; 95% CI, 2.1 -7.1), and its prevalence is not increased in high-risk groups.In contrast, septate uterus is the most common anomaly in high-risk populations.conclusions: Women with a history of miscarriage or miscarriage and infertility have higher prevalence of congenital uterine anomalies compared with the unselected population.
Complete heart block and bowel infarction secondary to rheumatoid disease.
Authors: M Wilsher, W M Smeeton, T D Koelmeyer, A H Roche
Journal: Annals of the Rheumatic Diseases (1985)

A case of complete heart block secondary to rheumatoid involvement of the conduction system is presented. The same patient died after infarction of the colon as a consequence of arterial spasm superimposed upon pre-existing rheumatoid changes in the mesenteric arteries. The coexistence of rheumatoid involvement of the heart and of the bowel vasculature has not previously been reported.
ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells
Authors: Lukas Niederreiter, Teresa M.J. Fritz, Timon E. Adolph, Anna-Maria Krismer, Felix A. Offner, Markus Tschurtschenthaler, Magdalena B. Flak, Shuhei Hosomi, Michal F. Tomczak, Nicole C. Kaneider, Edina Sarcevic, Sarah L. Kempster, Tim Raine, Daniela Esser, Philip Rosenstiel, Kenji Kohno, Takao Iwawaki, Herbert Tilg, Richard S. Blumberg, Arthur Kaser
Journal: The Journal of Experimental Medicine (2013)

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box–binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)–mediated increase in Lgr5+ and Olfm4+ ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)–related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors.
A study on tinea gladiatorum in young wrestlers and dermatophyte contamination of wrestling mats from Sari, Iran
Authors: Mohammad T Hedayati, Parvaneh Afshar, Tahereh Shokohi, Reza Aghili
Journal: British Journal of Sports Medicine (2006)

To study the prevalence of tinea gladiatorum among young wrestlers and dermatophyte contamination of wrestling mats from Sari city, the capital of Mazandaran, a northern province of Iran.324 wrestlers (aged 9-20 years) from 7 active clubs in Sari city were examined, and skin scrapings were obtained from 135 wrestlers suspected of having tinea gladiatorum. The scraped skin samples were evaluated with potassium hydroxide. Pleated carpet sterile fragments (5 x 5 cm) were used for to survey of wrestling mat contamination. Sabouraud's dextrose agar with and without chloramphenicole and cyclohexamide was used to culture scrapings and wrestling mat samples. The dermatophytes were identified by routine laboratory techniques.Our study showed that of the 324 wrestlers, 65 (20.1%) had tinea gladiatorum. Most lesions were on the trunk and head. All the wrestling mat samples were positive for dermatophytes. Trichophyton tonsurans was isolated from all the scrapings and wrestling mat samples.Considering that several colonies of T tonsurans were isolated from all the wrestling mats and from wrestlers with tinea gladiatorum (as the only dermatophyte species) we think that the contamination of wrestling mats with T tonsurans has a crucial role in the injection of wrestlers.
A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action
Authors: Vincenzo Damiano, Sonia Garofalo, Roberta Rosa, Roberto Bianco, Rosa Caputo, Teresa Gelardi, Gerardina Merola, Luigi Racioppi, Corrado Garbi, Ekambar R. Kandimalla, Sudhir Agrawal, Giampaolo Tortora
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel toll-like receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment. Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers. Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between toll-like receptor 9 and HER receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling. Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a toll-like receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):692130)
Serotyping, multilocus sequence typing and antibiotic resistance of Streptococcus pneumoniae isolates in China
Authors: Yijie Zhang, Yusheng Chen, Yuqian Li, Zhanwei Wang, Machao Li, Daxuan Wang, Ying Shang, Rongrong Fu, Zhancheng Gao
Journal: European Respiratory Journal (2012)

Introduction Streptococcus pneumoniae is a major causative agent of severe infections, which has become a major public health concern.

Objectives A prospective study was performed to investigate the serotype distribution, genetic relationship and antimicrobial resistance in Streptococcus pneumoniae ( S. pneumoniae ) isolates from patients in China.

Methods 21 Blood/cerebrospinal fluid (CSF) isolates and 18 sputum isolates were collected from patients admitted to the Peking University People's Hospital and Fujian Provincial Hospital were analyzed for investigating the serotypes, the multilocus sequence typing (MLST), and their susceptibilities to antibiotics.

Results The most frequent serotypes of blood/CSF isolates were 14 (38.1%), 19A (14.3%), 23F (9.5%), 18C (9.5%), and in the sputum isolates the most frequent serotypes were 19F(33.3%), 23F(16.7%), 19A(11.1%), 3(11.1%). The coverage rates of the blood/CSF and sputum isolates for the 7-valent pneumococcal conjugate vaccine (PCV7) were 66.7% and 61.1%, respectively. 4 of 5 isolates determined as 19A were collected from patients <5 years old. The MLST analysis showed that all the 5 isolates were ST320. All the 21 blood/CSF isolates, the resistance rates of erythromycin and penicillin were 90.5% and 61.9%. Of the 18 sputum isolates, the resistance rates of erythromycin and penicillin were 83.3% and 66.7%. All of the isolates of serotype 19A were resistant to both penicillin and erythromycin.

Conclusions The introduction of PCV13, in which the 19A conjugate is included, will be necessary in China because of the high rates and severe antibiotic resistance of 19A.
Comparison of Endoscopic Ultrasonography and Multidetector Computed Tomography for Detecting and Staging Pancreatic Cancer
Authors: John DeWitt, Benedict Devereaux, Melissa Chriswell, Kathleen McGreevy, Thomas Howard, Thomas F. Imperiale, Donato Ciaccia, Kathleen A. Lane, Dean Maglinte, Kenyon Kopecky, Julia LeBlanc, Lee McHenry, James Madura, Alex Aisen, Harvey Cramer, Oscar Cummings, Stuart Sherman
Journal: Annals of Internal Medicine (2004)

Background: Accurate preoperative detection and staging of pancreatic cancer may identify patients with locoregional disease that is amenable to surgical resection. Objective: To compare endoscopic ultrasonography and multidetector computed tomography (CT) for the detection, staging, and resectability of known or suspected locoregional pancreatic cancer. Design: Prospective, observational, cohort study. Setting: Single, tertiary referral hospital in Indianapolis, Indiana. Patients: 120 participants with known or suspected locoregional pancreatic cancer. Interventions: Endoscopic ultrasonography followed by multidetector CT was performed in all patients. Patients with known or suspected pancreatic cancer deemed potentially resectable by 1 or both tests were considered for surgery. Measurements: Detection, staging, and resectability of pancreatic cancer. Surgically resected pancreatic cancer with negative microscopic histologic margins was considered resectable. Results: Of 120 patients enrolled, 104 (87%) underwent endoscopic ultrasonography and CT. Of the 80 patients with pancreatic cancer, 27 (34%) were managed nonoperatively, and 53 (66%) treated surgically had resectable (n = 25) or unresectable (n = 28) cancer. For the 80 patients with cancer, the sensitivity of endoscopic ultrasonography (98% [95% CI, 91% to 100%]) for detecting a pancreatic mass was greater than that of CT (86% [CI, 77% to 93%]; P = 0.012). For the 53 surgical patients, endoscopic ultrasonography was superior to CT for tumor staging accuracy (67% vs. 41%; P < 0.001) but equivalent for nodal staging accuracy (44% vs. 47%; P > 0.2). Of the 25 resectable pancreatic tumors in patients recommended for surgery, endoscopic ultrasonography and CT correctly identified 88% and 92%, respectively, as resectable. Of the 28 unresectable pancreatic tumors in patients recommended for surgery, endoscopic ultrasonography and CT correctly identified 68% and 64%, respectively, as unresectable. Limitations: Radiologists who read the scans and endosonographers were not blinded to previous radiographic information. Because of the modest sample size, CIs of the sensitivity estimates were sometimes wide. Conclusion: Compared with multidetector CT, endoscopic ultrasonography is superior for tumor detection and staging but similar for nodal staging and resectability of preoperatively suspected nonmetastatic pancreatic cancer.
Long-Term Remissions of Severe Pemphigus After Rituximab Therapy Are Associated with Prolonged Failure of Desmoglein B Cell Response
Authors: Natacha Colliou, Damien Picard, Frédérique Caillot, Sébastien Calbo, Stéphanie Le Corre, Annick Lim, Brigitte Lemercier, Brigitte Le Mauff, Maud Maho-Vaillant, Serge Jacquot, Christophe Bedane, Philippe Bernard, Frédéric Caux, Catherine Prost, Emmanuel Delaporte, Marie-Sylvie Doutre, Brigitte Dreno, Nathalie Franck, Saskia Ingen-Housz-Oro, Olivier Chosidow, Christine Pauwels, Catherine Picard, Jean-Claude Roujeau, Michèle Sigal, Emmanuelle Tancrede-Bohin, Isabelle Templier, Rüdiger Eming, Michael Hertl, Michel D’Incan, Pascal Joly, Philippe Musette
Journal: Science Translational Medicine (2013)

Changes in the B cell repertoire mediate long-lasting therapeutic effects of rituximab in pemphigus patients.
Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients
Authors: Francisco Chung, Jun Lu, Brian D. Palmer, Philip Kestell, Peter Browett, Bruce C. Baguley, Malcolm Tingle, Lai-Ming Ching
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Thalidomide has a variety of biological effects that vary considerably according to the species tested. We sought to establish whether differences in pharmacokinetics could form a basis for the species-specific effects of thalidomide. Experimental Design: Mice and rabbits were administered thalidomide (2 mg/kg) p.o. or i.v., and plasma concentrations of thalidomide were measured after drug administration using high performance liquid chromotography. Plasma samples from five multiple myeloma patients over 24 hours after their first dose of thalidomide (200 mg) were similarly analyzed and all data were fitted to a one-compartment model. Metabolites of thalidomide in plasma were identified simultaneously using liquid chromatography-mass spectrometry. Results: Plasma concentration-time profiles for the individual patients were very similar to each other, but widely different pharmacokinetic properties were found between patients compared with those in mice or rabbits. Area under the concentration curve values for mice, rabbits, and multiple myeloma patients were 4, 8, and 81 μmol/L · hour, respectively, and corresponding elimination half-lives were 0.5, 2.2, and 7.3 hours, respectively. Large differences were also observed between the metabolite profiles from the three species. Hydrolysis products were detected for all species, and the proportion of hydroxylated metabolites was higher in mice than in rabbits and undetectable in patients. Conclusions: Our results show major interspecies differences in the pharmacokinetics of thalidomide that are related to the altered degree of metabolism. We suggest that the interspecies differences in biological effects of thalidomide may be attributable, at least in part, to the differences in its metabolism and hence pharmacokinetics.