tbuckley/cabot-search huggingface dataset:
ATM and DNA-PK Function Redundantly to Phosphorylate H2AX after Exposure to Ionizing Radiation
Authors: Tom Stiff, Mark O’Driscoll, Nicole Rief, Kuniyoshi Iwabuchi, Markus Löbrich, Penny A. Jeggo
Journal: Cancer Research (2004)

H2AX phosphorylation is an early step in the response to DNA damage. It is widely accepted that ATM (ataxia telangiectasia mutated protein) phosphorylates H2AX in response to DNA double-strand breaks (DSBs). Whether DNA-dependent protein kinase (DNA-PK) plays any role in this response is unclear. Here, we show that H2AX phosphorylation after exposure to ionizing radiation (IR) occurs to similar extents in human fibroblasts and in mouse embryo fibroblasts lacking either DNA-PK or ATM but is ablated in ATM-deficient cells treated with LY294002, a drug that specifically inhibits DNA-PK. Additionally, we show that inactivation of both DNA-PK and ATM is required to ablate IR-induced H2AX phosphorylation in chicken cells. We confirm that H2AX phosphorylation induced by DSBs in nonreplicating cells is ATR (ataxia telangiectasia and Rad3-related protein) independent. Taken together, we conclude that under most normal growth conditions, IR-induced H2AX phosphorylation can be carried out by ATM and DNA-PK in a redundant, overlapping manner. In contrast, DNA-PK cannot phosphorylate other proteins involved in the checkpoint response, including chromatin-associated Rad17. However, by phosphorylating H2AX, DNA-PK can contribute to the presence of the damage response proteins MDC1 and 53BP1 at the site of the DSB.
DISTINCT AND SEPARABLE ROLES FOR HISTONE METHYLTRANSFERASE EZH2 IN NEUROGENIC ASTROCYTES
Authors: D. A. Lim, W. W. Hwang, R. D. Salinas, J. J. Siu, K. W. Kelley, R. N. Delgado, M. F. Paredes, A. Alvarez-Buylla, M. C. Oldham, D. A. Lim
Journal: Neuro-Oncology (2014)

BACKGROUND: The histone methyltransferase EZH2 is overexpressed in many tumors including gliomas. EZH2 catalyzes H3K27me3, which underlies Polycomb-mediated gene repression, and EZH2-inhibitors have been identified as potential therapeutic agents. In the adult brain subventricular zone (SVZ), a specialized population of astrocytes serves as neural stem cells (NSCs), generating new neurons throughout life. Understanding the epigenetic mechanisms that enable lifelong neurogenesis from SVZ NSCs may help inform therapeutic strategies for gliomas. METHODS: We studied the expression and function of EZH2 in postnatal mouse brain with genetic strategies, gene expression, and chromatin analysis. The expression of EZH2 in the human brain SVZ was also analyzed. RESULTS: In SVZ astroglia, EZH2 was distinctly required for both NSC self-renewal and neuronal lineage specification. By deleting the EZH2 target Ink4a/Arf, we were able to rescue NSC proliferation, but not neuronal differentiation. During adult neurogenesis from mouse SVZ astroglia, EZH2 directly targets Olig2, and repression of this bHLH transcription factor is required for neuronal differentiation. Genome-wide transcript and chromatin analyses also indicate that EZH2 prevents the inappropriate expression of transcription factors involved in non-SVZ neurogenesis. Analysis of human brain specimens indicated EZH2 expression in SVZ astrocytes as well as young migratory neurons. The cell-type expression and correlation with neurogenesis in the human SVZ was remarkably similar to that of the mouse, suggesting a conserved epigenetic mechanism for neurogenesis from this specialized population of astrocytes. CONCLUSIONS: Our finding that EZH2 plays distinct and separable roles in this astroglial population provides novel insights into the complex role of Polycomb gene repression in both normal brain development and brain tumors. Our results, while counterintuitive, indicate that EZH2 is critical for both self-renewal proliferation via Ink4a/Arf repression and differentiation by repressing key developmental regulators, including Olig2, which is required for glioma cell proliferation. The development of EZH2 inhibitors for cancer chemotherapy may benefit from this new understanding of the multiple, distinct roles that EZH2 plays in neural cell differentiation. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
The Effects of Hypertension and Body Mass Index on Cognition in Schizophrenia
Authors: Joseph I. Friedman, Sylvan Wallenstein, Erin Moshier, Michael Parrella, Leonard White, Stephanie Bowler, Stephanie Gottlieb, Philip D. Harvey, Thomas G. McGinn, Lauren Flanagan, Kenneth L. Davis
Journal: American Journal of Psychiatry (2010)

Objective: In recent years there has been a greater appreciation of the elevated prevalence of cardiovascular risk factors in the schizophrenia population and the liability some treatments have for their development. These vascular risk factors are in turn important risk factors in the development of dementia and more subtle cognitive impairments. However, their impact on the cognitive functions of patients with schizophrenia remains underexplored. The authors investigated whether vascular risk factors influence the cognitive impairments of schizophrenia and whether their effects on cognition in schizophrenia are different from those observed in nonpsychiatric comparison subjects. Method: The authors compared 100 patients with schizophrenia and 53 comparison subjects on cognitive test performance in 2×2 matrices composed of individual vascular risk factors and group (schizophrenia patients and comparison subjects). Results: Hypertension exerted a significant negative effect on immediate delayed and recognition memory in both groups. Patients with schizophrenia and hypertension were adversely affected in recognition memory, whereas comparison subjects were not. A body mass index above 25 was associated with negative effects on delayed memory in both groups, although the association fell short of statistical significance. Conclusions: Given that patients with schizophrenia have a higher prevalence of vascular risk factors than the general population and are undertreated for them, treatment of these risk factors may significantly improve cognitive outcome in schizophrenia.
Smooth Muscle Progenitor Cells in Human Blood
Authors: David Simper, Paul G. Stalboerger, Carmelo J. Panetta, Shaohua Wang, Noel M. Caplice
Journal: Circulation (2002)

Background— Recent animal data suggest that vascular smooth muscle cells within the neointima of the vessel wall may originate from bone marrow, providing indirect evidence for circulating smooth muscle progenitor cells (SPCs). Evidence for circulating SPCs in human subjects does not exist, and the mechanism whereby such putative SPCs may home to sites of plaque formation is presently not understood but is likely to involve expression of specific surface adhesion molecules, such as integrins. In this study, we aimed to culture smooth muscle outgrowth cells (SOCs) from SPCs in human peripheral blood and characterize surface integrin expression on these cells. Methods and Results— Human mononuclear cells isolated from buffy coat were seeded on collagen type 1 matrix and outgrowth cells selected in endothelial growth medium (EGM-2) or EGM-2 and platelet-derived growth factor BB. Selection in platelet-derived growth factor BB–enriched medium caused rapid outgrowth and expansion of SOC to &gt;40 population doublings in a 4-month period. These SOCs were positive for smooth muscle cell–specific α actin (αSMA), myosin heavy chain, and calponin on immunofluorescence and Western blotting and were also positive for CD34, Flt1, and Flk1 receptor but negative for Tie-2 receptor expression, suggesting a potential bone marrow angioblastic origin. In contrast, endothelial outgrowth cells (EOCs) grown in EGM-2 alone and the initial MNC population were negative for these smooth muscle–specific markers. Integrin α 5 β 1 expression by FACS and Western blotting was significantly increased in SOCs compared with EOCs, and this was confirmed by 8-fold greater adhesion of SOC to fibronectin ( P &lt;0.001), an effect that could be decreased using an α 5 β 1 antibody. Finally, SOC showed a significantly greater in vitro proliferative potential compared with EOCs of similar passage ( P &lt;0.001). Conclusions— This study demonstrates for the first time outgrowth of smooth muscle cells with a specific growth, adhesion, and integrin profile from putative SPC in human blood. These data have implications for our understanding of adult vascular smooth muscle cell differentiation, proliferation, and homing. (Circulation. 2002;106:1199–1204.)
Children With Obesity
Authors: Matthew W. Gillman, Jason P. Block
Journal: JAMA Pediatrics (2015)

One-sixth of US children and adolescents aged 2 to 19 years are obese, and about the same proportion are overweight.1 Compared with their normal-weight peers, children with obesity are at higher risk for developing health conditions, such as asthma, orthopedic problems, and depression, as well as adult obesity, diabetes mellitus, and cardiovascular disease.2 Children and adolescents with obesity are also at higher risk for adverse psychosocial consequences, including teasing, bullying, and depression,3 as well as a lower socioeconomic position in adulthood.4 A responsibility of society, including medical care, is to reduce these excess burdens by treating children with obesity equitably as well as effectively. Here, treating means not only therapy for excess weight but also how we address other attributes that accompany obesity. Sometimes it is better to single out children with obesity for special treatment and sometimes it means treating them the same way as all children. In many circumstances, the answer is somewhere in between.
Bacterial-induced protection against allergic inflammation through a multicomponent immunoregulatory mechanism
Authors: C. Nembrini, A. Sichelstiel, J. Kisielow, M. Kurrer, M. Kopf, B. J. Marsland
Journal: Thorax (2011)

<h3>Background</h3> Airborne microbial products have been reported to promote immune responses that suppress asthma, yet how these beneficial effects take place remains controversial and poorly understood. <h3>Methods</h3> We exposed mice to the bacterium Escherichia coli and subsequently induced allergic airway inflammation through sensitization and intranasal challenge with ovalbumin. <h3>Results</h3> Pulmonary exposure to the bacterium Escherichia coli leads to a suppression of allergic airway inflammation. This immune modulation was neither mediated by the induction of a T helper 1 (Th1) response nor regulatory T cells; however, it was dependent on Toll-like receptor 4 (TLR4) but did not involve TLR desensitisation. Dendritic cell migration to the draining lymph nodes and activation of T cells was unaffected by prior exposure to <i>E.coli</i>, while dendritic cells in the lung displayed a less activated phenotype and had impaired antigen presentation capacity. Consequently, in situ Th2 cytokine production was abrogated. The suppression of airway hyper-responsiveness was mediated through the recruitment of gd T cells; however, the suppression of dendritic cells and T cells was mediated through a distinct mechanism that could not be overcome by the local administration of activated dendritic cells, or by the in vivo administration of tumour necrosis factor a. <h3>Conclusion</h3> Our data reveal a localized immunoregulatory pathway that acts to protect the airways from allergic inflammation.
Gene Profiling of Clinical Routine Biopsies and Prediction of Survival in Non–Small Cell Lung Cancer
Authors: Florent Baty, Michaël Facompré, Sergio Kaiser, Martin Schumacher, Miklos Pless, Lukas Bubendorf, Spasenija Savic, Estelle Marrer, Wolfgang Budach, Martin Buess, Jeanne Kehren, Michael Tamm, Martin H. Brutsche
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Global gene expression analysis provides a comprehensive molecular characterization of non-small cell lung cancer (NSCLC).To evaluate the feasibility of integrating expression profiling into routine clinical work-up by including both surgical and minute bronchoscopic biopsies and to develop a robust prognostic gene expression signature.Tissue samples from 41 chemotherapy-naive patients with NSCLC and 15 control patients with inflammatory lung diseases were obtained during routine clinical work-up and gene expression profiles were gained using an oligonucleotide array platform (NovaChip; 34'207 transcripts). Gene expression signatures were analyzed for correlation with histological and clinical parameters and validated on independent published data sets and immunohistochemistry.Diagnostic signatures for adenocarcinoma and squamous cell carcinoma reached a sensitivity of 80%/80% and a specificity of 83%/94%, respectively, dependent on the proportion of tumor cells. Sixty-seven of the 100 most discriminating genes were validated with independent observations from the literature. A 13-gene metagene refined on four external data sets was built and validated on an independent data set. The metagene was a strong predictor of survival in our data set (hazard ratio = 7.7, 95% CI [2.8-21.2]) and in the independent data set (hazard ratio = 1.6, 95% CI [1.2-2.2]) and in both cases independent of the International Union against Cancer staging. Vascular endothelial growth factor-beta, one of the key prognostic genes, was further validated by immunohistochemistry on 508 independent tumor samples.Integration of functional genomics from small bronchoscopic biopsies allows molecular tumor classification and prediction of survival in NSCLC and might become a powerful adjunct for the daily clinical practice.
Grading the severity of airways obstruction: new wine in new bottles
Authors: Philip H. Quanjer, Jeffrey J. Pretto, Danny J. Brazzale, Piotr W. Boros
Journal: European Respiratory Journal (2013)

The objective of this study was to redesign the current grading of obstructive lung disease so that it is clinically relevant and free of biases related to age, height, sex and ethnic group. Spirometric records from 17 880 subjects (50.4% female) from hospitals in Australia and Poland, and 21 191 records (53.0% female) from two epidemiological studies (age range 18–95 years) were analysed. We adopted the American Thoracic Society(ATS)/European Respiratory Society (ERS) criteria for airways obstruction based on an forced expiratory volume in 1 s (FEV 1 )/(forced) vital capacity ((F)VC) ratio below the fifth percentile and graded the severity of pulmonary function impairment using z-scores for FEV 1 , which signify how many standard deviations a result is from the mean predicted value. Using the lower limit of normal for FEV 1 /(F)VC and z-scores for FEV 1 of -2, -2.5, -3 and -4 to delineate severity grades of airflow limitation leads to close agreement with ATS/ERS severity classifications and removes age, sex and height related bias. The new classification system is simple, easily memorised and clinically valid. It retains previously established associations with clinical outcomes and avoids biases due to the use of per cent predicted FEV 1 . Combined with the Global Lung Function prediction equations it provides a worldwide diagnostic standard, free of bias due to age, height, sex and ethnic group.
De-Nol stimulates gastric and duodenal alkaline secretion through prostaglandin dependent mechanism.
Authors: S J Konturek, J Bilski, N Kwiecien, W Obtulowicz, B Kopp, J Oleksy
Journal: Gut (1987)

This study was designed to determine the effects of colloidal bismuth subcitrate De-Nol on gastric HCO3- secretion in 24 healthy subjects and on gastric and duodenal HCO3- secretion in dogs with gastric and duodenal fistulae. Alkaline secretion was measured after pretreatment with ranitidine to abolish the H+ secretion using a constant perfusion aspiration system and back titration of the perfusates to the original pH 6.0. Luminal release of PGE2 was also measured in the gastric and duodenal perfusates. Addition of De-Nol in gradually increasing concentrations resulted in step wise increments in gastric HCO3- secretion in man and in dogs reaching, respectively, about 80% and 55% of the maximal HCO3- response to 16, 16dimethyl-PGE2 (dmPGE2). The duodenal HCO3- response to De-Nol in dogs reached 72% of the dmPGE2 maximum. These effects were accompanied by a significant increase in luminal release of PGE2. Pretreatment with atropine reduced basal and in part De-Nol induced alkaline secretion, whereas pirenzepine did not affect this secretion in man and dogs. Aspirin (in man) and indomethacin (in dogs) reduced the release of PGE2 by about 80% and suppressed almost completely the gastric and duodenal HCO3- response to De-Nol in these species. This study provides evidence that De-Nol stimulates gastroduodenal alkaline secretion through a prostaglandin dependent mechanism.
Francis William O’Grady
Authors: Richard Slack
Journal: BMJ (2015)

Francis William O’Grady had a distinguished career as a medical microbiologist and later as chief scientist at the Department of Health. He was an international authority on antimicrobial chemotherapy and urinary and airborne infections. After pathology training at the Bland Sutton Institute, Middlesex Hospital, he did national service in the Royal Army Medical Corps and then joined the Territorial Army, which started a long affiliation to the army and the award of the …
Tilescope: online analysis pipeline for high-density tiling microarray data
Authors: Zhengdong D Zhang, Joel Rozowsky, Hugo YK Lam, Jiang Du, Michael Snyder, Mark Gerstein
Journal: Genome biology (2007)

Abstract We developed Tilescope, a fully integrated data processing pipeline for analyzing high-density tiling-array data http://tilescope.gersteinlab.org . In a completely automated fashion, Tilescope will normalize signals between channels and across arrays, combine replicate experiments, score each array element, and identify genomic features. The program is designed with a modular, three-tiered architecture, facilitating parallelism, and a graphic user-friendly interface, presenting results in an organized web page, downloadable for further analysis.
Quality of life in cystic fibrosis
Authors: D J FRENCH
Journal: Thorax (1998)

In recent years the role of behavioural and psychological variables in the management of patients with cystic fibrosis has been noted.1-3 This interest has grown from the observation that improved diagnosis and treatment mean that many patients can now anticipate burdensome daily management routines continuing for some decades. Recent studies in this and other publications have included demonstrations that the health related quality of life (HRQOL) of adults with cystic fibrosis is in some respects impaired,1 3 and that HRQOL is a valuable outcome measure in clinical trials.4 5 Such findings are in contrast with earlier literature which tended to shown little evidence of psychosocial impact in children6 and adolescents7 with cystic fibrosis. There is, however, an important distinction between the psychosocial outcomes identified in the 1980s, often using instruments intended to detect psychopathology, and more recent conceptualisations of HRQOL.

HRQOL is a multidimensional construct encompassing a range of impacts including physical, functional, social, and emotional components. Definitions frequently emphasise not only this breadth of impact but the subjectivity of reports8—that is, HRQOL differs from reports of psychological adjustment or functional status in targeting the importance of the impairment to patients, assessed through their own reports where possible. This reliance upon self reporting is one reason for the dearth of paediatric studies since clinicians and researchers have doubted the capacity of children to self report.9 Even supposing the …
A Phase I Clinical Trial of the hu14.18-IL2 (EMD 273063) as a Treatment for Children with Refractory or Recurrent Neuroblastoma and Melanoma: a Study of the Children's Oncology Group
Authors: Kaci L. Osenga, Jacquelyn A. Hank, Mark R. Albertini, Jacek Gan, Adam G. Sternberg, Jens Eickhoff, Robert C. Seeger, Katherine K. Matthay, C. Patrick Reynolds, Clare Twist, Mark Krailo, Peter C. Adamson, Ralph A. Reisfeld, Stephen D. Gillies, Paul M. Sondel
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Evaluate the clinical safety, toxicity, immune activation/modulation, and maximal tolerated dose of hu14.18-IL2 (EMD 273063) in pediatric patients with recurrent/refractory neuroblastoma and other GD2-positive solid tumors. Experimental Design: Twenty-seven pediatric patients with recurrent/refractory neuroblastoma and one with melanoma were treated with a humanized anti-GD2 monoclonal antibody linked to human interleukin 2 (IL-2). Cohorts of patients received hu14.18-IL2, administered i.v. over 4 hours for three consecutive days, at varying doses. Patients with stable disease, partial, or complete responses were eligible to receive up to three additional courses of therapy. Results: Most of the clinical toxicities were anticipated and similar to those reported with IL-2 and anti-GD2 monoclonal antibody therapy and to those noted in the initial phase I study of hu14.18-IL2 in adults with metastatic melanoma. The maximal tolerated dose was determined to be 12 mg/m2/d, with agent-related dose-limiting toxicities of hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia. Three patients developed dose-limiting toxicity during course 1; seven patients in courses 2 to 4. Two patients required dopamine for hypotension. There were no treatment-related deaths, and all toxicity was reversible. Treatment with hu14.18-IL2 led to immune activation/modulation as evidenced by elevated serum levels of soluble IL-2 receptor α (sIL2Rα) and lymphocytosis. The median half-life of hu14.18-IL2 was 3.1 hours. There were no measurable complete or partial responses to hu14.18-IL2 in this study; however, three patients did show evidence of antitumor activity. Conclusion: Hu14.18-IL2 (EMD 273063) can be administered safely with reversible toxicities in pediatric patients at doses that induce immune activation. A phase II clinical trial of hu14.18-IL2, administered at a dose of 12 mg/m2/d × 3 days repeated every 28 days, will be done in pediatric patients with recurrent/refractory neuroblastoma.
Reply to: Very early rheumatoid arthritis as a predictor of remission: a multicentre real life prospective study
Authors: Henning Zeidler
Journal: Annals of the Rheumatic Diseases (2012)

Gremese et al conclude from the real-life prospective study performed in three early arthritis clinics, that 12 weeks disease duration, and an early intervention with disease-modifying antirheumatic drugs (DMARD), represent the most significant opportunities to reach remission of rheumatoid arthritis (RA). Moreover, it is supposed that vera early RA (VERA) represents a window of opportunity in terms of cost saving.1

A high level of confidence in the diagnosis of RA early in its course is mandatory for the validity of any study. Nevertheless, experts often disagree about diagnoses, and discrepancies may …