tbuckley/cabot-search huggingface dataset:
Anti–Factor H Autoantibodies Associated with Atypical Hemolytic Uremic Syndrome
Authors: Marie-Agne[Combining Grave Accent]s Dragon-Durey, Chantal Loirat, Sylvie Cloarec, Marie-Alice Macher, Jacques Blouin, Hubert Nivet, Laurence Weiss, Wolf Herman Fridman, Véronique Frémeaux-Bacchi
Journal: Journal of the American Society of Nephrology (2004)

Several studies have demonstrated genetic predisposition in non-shigatoxin-associated hemolytic uremic syndrome (HUS), involving regulatory proteins of the complement alternative pathway: Factor H (FH) and membrane co-factor protein (CD46). Regarding the observations of thrombotic thrombocytopenic purpura patients, in whom a von Willebrand factor protease (ADAMST-13) deficiency may be inherited or acquired secondary to IgG antibodies, it was speculated that HUS might occur in a context of an autoimmune disease with the development of anti-FH antibodies leading to an acquired FH deficiency. The presence of FH autoantibodies was investigated by an ELISA method using coated purified human FH in a series of 48 children who presented with atypical HUS and were recruited from French university hospitals. Anti-FH IgG antibodies were detected in the plasma of three children who presented with recurrent HUS. The anti-FH specificity was conserved by the Fab'2 fraction. The plasma FH activity was found to be decreased, whereas plasma FH antigenic levels and FH gene analysis were normal, indicating that the presence of anti-FH antibodies led to an acquired functional FH deficiency. This report supports for the first time that HUS may occur in a context of an autoimmune disease with the development of anti-FH-specific antibody leading to an acquired FH deficiency. This new mechanism of functional FH deficiency may lead to the design of new approaches of diagnosis and treatment with a particular interest in plasma exchanges or immunosuppressive therapies.
Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A
Authors: Gregory F. Sonnenberg, Meera G. Nair, Thomas J. Kirn, Colby Zaph, Lynette A. Fouser, David Artis
Journal: The Journal of Experimental Medicine (2010)

IL-22 has both proinflammatory and tissue-protective properties depending on the context in which it is expressed. However, the factors that influence the functional outcomes of IL-22 expression remain poorly defined. We demonstrate that after administration of a high dose of bleomycin that induces acute tissue damage and airway inflammation and is lethal to wild-type (WT) mice, Th17 cell–derived IL-22 and IL-17A are expressed in the lung. Bleomycin-induced disease was ameliorated in Il22−/− mice or after anti–IL-22 monoclonal antibody (mAb) treatment of WT mice, indicating a proinflammatory/pathological role for IL-22 in airway inflammation. However, despite increased bleomycin-induced IL-22 production, Il17a−/− mice were protected from airway inflammation, suggesting that IL-17A may regulate the expression and/or proinflammatory properties of IL-22. Consistent with this, IL-17A inhibited IL-22 production by Th17 cells, and exogenous administration of IL-22 could only promote airway inflammation in vivo by acting in synergy with IL-17A. Anti–IL-22 mAb was delivered to Il17a−/− mice and was found to exacerbate bleomycin-induced airway inflammation, indicating that IL-22 is tissue protective in the absence of IL-17A. Finally, in an in vitro culture system, IL-22 administration protected airway epithelial cells from bleomycin-induced apoptosis, and this protection was reversed after coadministration of IL-17A. These data identify that IL-17A can regulate the expression, proinflammatory properties, and tissue-protective functions of IL-22, and indicate that the presence or absence of IL-17A governs the proinflammatory versus tissue-protective properties of IL-22 in a model of airway damage and inflammation.
Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke
Authors: Eric Jüttler, Andreas Unterberg, Johannes Woitzik, Julian Bösel, Hemasse Amiri, Oliver W. Sakowitz, Matthias Gondan, Petra Schiller, Ronald Limprecht, Steffen Luntz, Hauke Schneider, Thomas Pinzer, Carsten Hobohm, Jürgen Meixensberger, Werner Hacke
Journal: New England Journal of Medicine (2014)

Early decompressive hemicraniectomy reduces mortality without increasing the risk of very severe disability among patients 60 years of age or younger with complete or subtotal space-occupying middle-cerebral-artery infarction. Its benefit in older patients is uncertain.
Sphingosine-1-phosphate receptor-2 deficiency leads to inhibition of macrophage proinflammatory activities and atherosclerosis in apoE-deficient mice
Authors: Fei Wang, Yasuo Okamoto, Isao Inoki, Kazuaki Yoshioka, Wa Du, Xun Qi, Noriko Takuwa, Koichi Gonda, Yasuhiko Yamamoto, Ryunosuke Ohkawa, Takumi Nishiuchi, Naotoshi Sugimoto, Yutaka Yatomi, Kunitoshi Mitsumori, Masahide Asano, Makoto Kinoshita, Yoh Takuwa
Journal: Journal of Clinical Investigation (2010)

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that has pleiotropic effects in a variety of cell types including ECs, SMCs, and macrophages, all of which are central to the development of atherosclerosis. It may therefore exert stimulatory and inhibitory effects on atherosclerosis. Here, we investigated the role of the S1P receptor S1PR2 in atherosclerosis by analyzing S1pr2–/– mice with an Apoe–/– background. S1PR2 was expressed in macrophages, ECs, and SMCs in atherosclerotic aortas. In S1pr2–/–Apoe–/– mice fed a high-cholesterol diet for 4 months, the area of the atherosclerotic plaque was markedly decreased, with reduced macrophage density, increased SMC density, increased eNOS phosphorylation, and downregulation of proinflammatory cytokines compared with S1pr2+/+Apoe–/– mice. Bone marrow chimera experiments indicated a major role for macrophage S1PR2 in atherogenesis. S1pr2–/–Apoe–/– macrophages showed diminished Rho/Rho kinase/NF-κB (ROCK/NF-κB) activity. Consequently, they also displayed reduced cytokine expression, reduced oxidized LDL uptake, and stimulated cholesterol efflux associated with decreased scavenger receptor expression and increased cholesterol efflux transporter expression. S1pr2–/–Apoe–/– ECs also showed reduced ROCK and NF-κB activities, with decreased MCP-1 expression and elevated eNOS phosphorylation. Pharmacologic S1PR2 blockade in S1pr2+/+Apoe–/– mice diminished the atherosclerotic plaque area in aortas and modified LDL accumulation in macrophages. We conclude therefore that S1PR2 plays a critical role in atherogenesis and may serve as a novel therapeutic target for atherosclerosis.
Transcriptional features of genomic regulatory blocks
Authors: Altuna Akalin, David Fredman, Erik Arner, Xianjun Dong, Jan Christian Bryne, Harukazu Suzuki, Carsten O Daub, Yoshihide Hayashizaki, Boris Lenhard
Journal: Genome biology (2009)

Genomic regulatory blocks (GRBs) are chromosomal regions spanned by highly conserved non-coding elements (HCNEs), most of which serve as regulatory inputs of one target gene in the region. The target genes are most often transcription factors involved in embryonic development and differentiation. GRBs often contain extensive gene deserts, as well as additional 'bystander' genes intertwined with HCNEs but whose expression and function are unrelated to those of the target gene. The tight regulation of target genes, complex arrangement of regulatory inputs, and the differential responsiveness of genes in the region call for the examination of fundamental rules governing transcriptional activity in GRBs. Here we use extensive CAGE tag mapping of transcription start sites across different human tissues and differentiation stages combined with expression data and a number of sequence and epigenetic features to discover these rules and patterns.We show evidence that GRB target genes have properties that set them apart from their bystanders as well as other genes in the genome: longer CpG islands, a higher number and wider spacing of alternative transcription start sites, and a distinct composition of transcription factor binding sites in their core/proximal promoters. Target gene expression correlates with the acetylation state of HCNEs in the region. Additionally, target gene promoters have a distinct combination of activating and repressing histone modifications in mouse embryonic stem cell lines.GRB targets are genes with a number of unique features that are the likely cause of their ability to respond to regulatory inputs from very long distances.
Listeriolysin O is a target of the immune response to Listeria monocytogenes.
Authors: H G Bouwer, C S Nelson, B L Gibbins, D A Portnoy, D J Hinrichs
Journal: The Journal of Experimental Medicine (1992)

The immunologic mechanism of protective immunity to the intracellular parasite Listeria monocytogenes (Lm) is not well understood, however, antilisterial immunity can be adoptively transferred with T lymphocytes from Lm-immune donors. The Lm-immune cells are believed to produce macrophage-activating lymphokines, which leads to the eventual macrophage-dependent eradication of the bacterium. Increasing evidence suggests that immunity to Lm resides exclusively within the CD8+ T cell subset. It is possible that the Lm-immune CD8+ T cells function to release sequestered Lm from nonprofessional phagocytes to awaiting activated macrophage populations. This study was conducted to determine if listeriolysin O (LLO), which is an essential determinant of Lm pathogenicity, is also a target of the antilisterial immune response. We have found that target cells infected with a LLO+ Lm strain are lysed by Lm-immune cytotoxic cells, whereas target cells infected with a LLO- Lm mutant, or pulsed with a heat-killed Lm preparation, are not lysed by the Lm-immune effector cells. We have used a Bacillus subtilis (Bs) construct that expresses the LLO gene product and found that target cells infected with the LLO+ Bs construct are lysed by antilisterial cytotoxic cells. The antilisterial cytotoxic response is targeted against LLO, in that we have also used a Bs construct that expresses the perfringolysin (PLO) gene product and found that target cells infected with the PLO+ Bs are not lysed by antilisterial cytotoxic effector cells. These data strongly suggest that LLO is a target antigen of antilisterial immunity and may represent the dominant target during the expression of the immune response to Lm.
Drug repositioning for personalized medicine
Authors: Yvonne Y Li, Steven JM Jones
Journal: Genome Medicine (2012)

Human diseases can be caused by complex mechanisms involving aberrations in numerous proteins and pathways. With recent advances in genomics, elucidating the molecular basis of disease on a personalized level has become an attainable goal. In many cases, relevant molecular targets will be identified for which approved drugs already exist, and the potential repositioning of these drugs to a new indication can be investigated. Repositioning is an accelerated route for drug discovery because existing drugs have established clinical and pharmacokinetic data. Personalized medicine and repositioning both aim to improve the productivity of current drug discovery pipelines, which expend enormous time and cost to develop new drugs, only to have them fail in clinical trials because of lack of efficacy or toxicity. Here, we discuss the current state of research in these two fields, focusing on recent large-scale efforts to systematically find repositioning candidates and elucidate individual disease mechanisms in cancer. We also discuss scenarios in which personalized drug repositioning could be particularly rewarding, such as for diseases that are rare or have specific mutations, as well as current challenges in this field. With an increasing number of drugs being approved for rare cancer subtypes, personalized medicine and repositioning approaches are poised to significantly alter the way we diagnose diseases, infer treatments and develop new drugs.
Effect of pentagastrin on histamine output from the stomach in patients with duodenal ulcer.
Authors: W K Man, J H Saunders, C Ingoldby, J Spencer
Journal: Gut (1981)

The role of histamine in acid secretion is controversial. Improvements in the techniques of histamine assay allow a better assessment of the relationship of histamine to acid secretion. Patients with duodenal ulcers were studied to determine the mucosal histamine responses to pentagastrin stimulation to relate the appearance of histamine in the gastric juice to acid production during stimulation, and to detect changes in the plasma histamine concentration during pentagastrin stimulation. There was a mean 27% fall (range 0-60%) in mucosal histamine concentration after pentagastrin. The output of histamine into gastric juice closely paralleled acid output in peak output acid duration. The histogram profiles of acid and histamine were similar in shape. In contrast with previous studies, plasma histamine concentration was found to rise during peak acid secretion (mean rise 65%). There was no relationship between initial mucosal histamine concentration and acid secretion or maximal gastric juice histamine. The association of histamine and gastric acid release found in these studies was so close that a functional relationship may be presumed. Our data are compatible with the hypothesis that pentagastrin acts on the parietal cell indirectly by causing histamine release in the gastric mucosa, which in turn releases acid from the parietal cells.
S2 Occupational exposure, breathlessness and COPD in a general population of older UK men
Authors: E. Pickles, J. Szram, S. J. Schofield, A. P. M. Woods, P. Cullinan
Journal: Thorax (2011)

<h3></h3> Most COPD is attributable to smoking, however evidence from workforce and general population studies suggest that occupational exposure is also associated with the disease. This study examines the relationship between respiratory symptoms, doctor-diagnosed COPD and occupational exposure in a general UK population. Lifetime occupational and smoking history, doctor-diagnosed disease and current respiratory symptoms were collected by postal questionnaire in a cohort of subjects aged 51–60, recruited from 33 general practices in Kent; here we present the results in men (n=3011). Occupations were defined <i>a priori</i> as being associated with an increased risk of COPD using 13 job categories as defined for the European Community Respiratory Health Survey1; all other occupations were designated low risk (referent). Logistic regression in men with complete data and no history of asthma (n=2452) demonstrated a statistically significant increase in both the odds of breathlessness (modified MRC score 1 or greater, Abstract S2 table 1) and breathlessness reported along with symptoms of chronic bronchitis (data not shown) in subjects who had a history of ever having been employed in a risky job, compared to other referent (mainly white collar) workers. This association, between work in occupations with an <i>a priori</i> risk of COPD and chronic respiratory symptoms, remained after adjustment for age and smoking status, using pack year history. The strength of the relationship between symptoms and work varied by occupational type; cleaners, painters and agricultural workers had the highest risk of breathlessness when compared to the referent population (Abstract S2 table 1). An increased risk of doctor-diagnosed COPD (COPD, chronic bronchitis or emphysema) was also found in cleaners, transport workers, wood and construction workers (data not shown); in comparison with the prevalence of respiratory symptoms, the number of men declaring doctor-diagnosed disease was small (21% vs 5%). This study demonstrates an association between occupational exposure, chronic respiratory symptoms and doctor-diagnosed COPD within a general population of older males in the UK independent of smoking history. Further characterisation of the cohort, using the results of spirometry, will allow the relationship between risky job exposure and disease to be examined in more detail.
Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer
Authors: Fabrice André, Thomas Bachelot, Mario Campone, Florence Dalenc, Jose M. Perez-Garcia, Sara A. Hurvitz, Nicholas Turner, Hope Rugo, John W. Smith, Stephanie Deudon, Michael Shi, Yong Zhang, Andrea Kay, Diana Graus Porta, Alejandro Yovine, José Baselga
Journal: Clinical Cancer Research (2013)

Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers.Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR).Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer.Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.
Oral Uracil and Tegafur Compared With Classic Cyclophosphamide, Methotrexate, Fluorouracil As Postoperative Chemotherapy in Patients With Node-Negative, High-Risk Breast Cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial
Authors: Toru Watanabe, Muneaki Sano, Shigemitsu Takashima, Tomoki Kitaya, Yutaka Tokuda, Masataka Yoshimoto, Norio Kohno, Kazuhiko Nakagami, Hiroji Iwata, Kojiro Shimozuma, Hiroshi Sonoo, Hitoshi Tsuda, Goi Sakamoto, Yasuo Ohashi
Journal: Journal of Clinical Oncology (2009)

Purpose The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative adjuvant treatment to women with node-negative, high-risk breast cancer. Patients and Methods Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS. Results Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF. Conclusion RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.
The Relationship Between Knowledge of Recent HbA1c Values and Diabetes Care Understanding and Self-Management
Authors: Michele Heisler, John D. Piette, Michael Spencer, Edie Kieffer, Sandeep Vijan
Journal: Diabetes Care (2005)

OBJECTIVE—Knowledge of one’s actual and target health outcomes (such as HbA1c values) is hypothesized to be a prerequisite for effective patient involvement in managing chronic diseases such as diabetes. We examined 1) the frequency and correlates of knowing one’s most recent HbA1c test result and 2) whether knowing one’s HbA1c value is associated with a more accurate assessment of diabetes control and better diabetes self-care understanding, self-efficacy, and behaviors related to glycemic control. RESEARCH DESIGN AND METHODS—We conducted a cross-sectional survey of a sample of 686 U.S. adults with type 2 diabetes in five health systems who had HbA1c checked in the previous 6 months. Independent variables included patient characteristics, health care provider communication, and health system type. We examined bivariate and multivariate associations between each variable and the respondents’ knowledge of their last HbA1c values and assessed whether knowledge of HbA1c was associated with key diabetes care attitudes and behaviors. RESULTS—Of the respondents, 66% reported that they did not know their last HbA1c value and only 25% accurately reported that value. In multivariate analyses, more years of formal education and high evaluations of provider thoroughness of communication were independently associated with HbA1c knowledge. Respondents who knew their last HbA1c value had higher odds of accurately assessing their diabetes control (adjusted odds ratio 1.59, 95% CI 1.05–2.42) and better reported understanding of their diabetes care (P &amp;lt; 0.001). HbA1c knowledge was not associated with respondents’ diabetes care self-efficacy or reported self-management behaviors. CONCLUSIONS—Respondents who knew their HbA1c values reported better diabetes care understanding and assessment of their glycemic control than those who did not. Knowledge of one’s HbA1c level alone, however, was not sufficient to translate increased understanding of diabetes care into the increased confidence and motivation necessary to improve patients’ diabetes self-management. Strategies to provide information to patients must be combined with other behavioral strategies to motivate and help patients effectively manage their diabetes.
You Can’t Get What You Want: Innovation for End-of-Life Communication in the Intensive Care Unit
Authors: Margaret L. Schwarze, Toby C. Campbell, Thomas V. Cunningham, Douglas B. White, Robert M. Arnold
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Family meetings to establish care goals for patients in the intensive care unit (ICU) are inherently challenging due to asymmetries of information between physicians and families, complicated family dynamics, mixed messages from providers, and uncertainty about prognosis and preferences (1, 2). How we communicate during these meetings—specifically the words we choose—may interfere with our ability to determine patient preferences and goals. One word that may be particularly problematic is the use of the word “want.”