tbuckley/cabot-search huggingface dataset:
Manganese Superoxide Dismutase Is a <i>p53</i>-Regulated Gene That Switches Cancers between Early and Advanced Stages
Authors: Sanjit K. Dhar, Jitbanjong Tangpong, Luksana Chaiswing, Terry D. Oberley, Daret K. St. Clair
Journal: Cancer Research (2011)

Abstract Manganese superoxide dismutase (MnSOD) plays a critical role in the survival of aerobic life, and its aberrant expression has been implicated in carcinogenesis and tumor resistance to therapy. However, despite extensive studies in MnSOD regulation and its role in cancer, when and how the alteration of MnSOD expression occurs during the process of tumor development in vivo are unknown. Here, we generated transgenic mice expressing a luciferase reporter gene under the control of human MnSOD promoter-enhancer elements and investigated the changes of MnSOD transcription using the 7,12-dimethylbenz(α)anthracene (DMBA)/12-O-tetradecanoylphorbol-l3-acetate (TPA) multistage skin carcinogenesis model. The results show that MnSOD expression was suppressed at a very early stage but increased at late stages of skin carcinogenesis. The suppression and subsequent restoration of MnSOD expression were mediated by two transcription-factors, Sp1 and p53. Exposure to DMBA and TPA activated p53 and decreased MnSOD expression via p53-mediated suppression of Sp1 binding to the MnSOD promoter in normal-appearing skin and benign papillomas. In squamous cell carcinomas, Sp1 binding increased because of the loss of functional p53. We used chromatin immunoprecipitation, electrophoretic mobility shift assay, and both knockdown and overexpression of Sp1 and p53 to verify their roles in the expression of MnSOD at each stage of cancer development. The results identify MnSOD as a p53-regulated gene that switches between early and advanced stages of cancer. These findings also provide strong support for the development of means to reactivate p53 for the prevention of tumor progression. Cancer Res; 71(21); 6684–95. ©2011 AACR.
Machine perfusion in liver transplantation as a tool to prevent non-anastomotic biliary strictures: Rationale, current evidence and future directions
Authors: Pepijn D. Weeder, Rianne van Rijn, Robert J. Porte
Journal: Journal of Hepatology (2015)

The high incidence of non-anastomotic biliary strictures (NAS) after transplantation of livers from extended criteria donors is currently a major barrier to widespread use of these organs. This review provides an update on the most recent advances in the understanding of the etiology of NAS. These new insights give reason to believe that machine perfusion can reduce the incidence of NAS after transplantation by providing more protective effects on the biliary tree during preservation of the donor liver. An overview is presented regarding the different endpoints that have been used for assessment of biliary injury and function before and after transplantation, emphasizing on methods used during machine perfusion. The wide spectrum of different approaches to machine perfusion is discussed, including the many different combinations of techniques, temperatures and perfusates at varying time points. In addition, the current understanding of the effect of machine perfusion in relation to biliary injury is reviewed. Finally, we explore directions for future research such as the application of (pharmacological) strategies during machine perfusion to further improve preservation. We stress the great potential of machine perfusion to possibly expand the donor pool by reducing the incidence of NAS in extended criteria organs.
Prospective Study of C-Reactive Protein, Homocysteine, and Plasma Lipid Levels as Predictors of Sudden Cardiac Death
Authors: Christine M. Albert, Jing Ma, Nader Rifai, Meir J. Stampfer, Paul M. Ridker
Journal: Circulation (2002)

Background — Sudden cardiac death (SCD) is an important cause of mortality even among apparently healthy populations. However, our ability to identify those at risk for SCD in the general population is poor, and more specific markers are needed. Methods and Results — To compare and contrast the relative importance of C-reactive protein (CRP), homocysteine, and lipids as long-term predictors of SCD, we performed a prospective, nested, case-control analysis involving 97 cases of SCD among apparently healthy men enrolled in the Physician’s Health Study. Of these plasma markers measured, only baseline CRP levels were significantly associated with the risk of SCD over the ensuing 17 years of follow-up ( P for trend=0.001). The increase in risk associated with CRP levels was primarily seen among men in the highest quartile, who were at a 2.78-fold increased risk of SCD (95% CI 1.35 to 5.72) compared with men in the lowest quartile. These results were not significantly altered in analyses that (in addition to the matching variables of age and smoking status) controlled for lipid parameters, homocysteine, and multiple cardiac risk factors (relative risk for highest versus lowest quartile 2.65, 95% CI 0.79 to 8.83; P for trend=0.03). In contrast to the positive relationship observed for CRP, neither homocysteine nor lipid levels were significantly associated with risk of SCD. Conclusions — These prospective data suggest that CRP levels may be useful in identifying apparently healthy men who are at an increased long-term risk of SCD.
Genome‐wide association study follow‐up identifies cyclin A2 as a regulator of the transition through cytokinesis during terminal erythropoiesis
Authors: Leif S. Ludwig, Hyunjii Cho, Aoi Wakabayashi, Jennifer C. Eng, Jacob C. Ulirsch, Mark D. Fleming, Harvey F. Lodish, Vijay G. Sankaran
Journal: American Journal of Hematology (2015)

Genome‐wide association studies (GWAS) hold tremendous promise to improve our understanding of human biology. Recent GWAS have revealed over 75 loci associated with erythroid traits, including the 4q27 locus that is associated with red blood cell size (mean corpuscular volume). The close linkage disequilibrium block at this locus harbors the CCNA2 gene that encodes cyclin A2. CCNA2 mRNA is highly expressed in human and murine erythroid progenitor cells and regulated by the essential erythroid transcription factor GATA1. To understand the role of cyclin A2 in erythropoiesis, we have reduced expression of this gene using short hairpin RNAs in a primary murine erythroid culture system. We demonstrate that cyclin A2 levels affect erythroid cell size by regulating the passage through cytokinesis during the final cell division of terminal erythropoiesis. Our study provides new insight into cell cycle regulation during terminal erythropoiesis and more generally illustrates the value of functional GWAS follow‐up to gain mechanistic insight into hematopoiesis.Am. J. Hematol. 90:386–391, 2015. © 2015 Wiley Periodicals, Inc.
Proximal Tubular Secretion of Creatinine by Organic Cation Transporter OCT2 in Cancer Patients
Authors: Giuliano Ciarimboli, Cynthia S. Lancaster, Eberhard Schlatter, Ryan M. Franke, Jason A. Sprowl, Hermann Pavenstädt, Vivian Massmann, Denise Guckel, Ron H. J. Mathijssen, Wenjian Yang, Ching-Hon Pui, Mary V. Relling, Edwin Herrmann, Alex Sparreboom
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Knowledge of transporters responsible for the renal secretion of creatinine is key to a proper interpretation of serum creatinine and/or creatinine clearance as markers of renal function in cancer patients receiving chemotherapeutic agents. Experimental Design: Creatinine transport was studied in transfected HEK293 cells in vitro and in wild-type mice and age-matched organic cation transporter 1 and 2–deficient [Oct1/2(−/−)] mice ex vivo and in vivo. Clinical pharmacogenetic and transport inhibition studies were done in two separate cohorts of cancer patients. Results: Compared with wild-type mice, creatinine clearance was significantly impaired in Oct1/2(−/−) mice. Furthermore, creatinine inhibited organic cation transport in freshly isolated proximal tubules from wild-type mice and humans, but not in those from Oct1/2(−/−) mice. In a genetic association analysis (n = 590), several polymorphisms around the OCT2/SLC22A2 gene locus, including rs2504954 (P = 0.000873), were significantly associated with age-adjusted creatinine levels. Furthermore, in cancer patients (n = 68), the OCT2 substrate cisplatin caused an acute elevation of serum creatinine (P = 0.0083), consistent with inhibition of an elimination pathway. Conclusions: Collectively, this study shows that OCT2 plays a decisive role in the renal secretion of creatinine. This process can be inhibited by OCT2 substrates, which impair the usefulness of creatinine as a marker of renal function. Clin Cancer Res; 18(4); 1101–8. ©2012 AACR.
DAP kinase and DAP-3: novel positive mediators of apoptosis
Authors: A. Kimchi
Journal: Annals of the Rheumatic Diseases (1999)

Programmed cell death is a genetically controlled response for cells to commit suicide. The process, which displays distinctive morphological features, is highly conserved through evolution, and takes place in all nucleated animal cells. It is tightly controlled by environmental stimuli including extracellular diffusible factors, or membrane bound molecules that mediate cell-cell or cell-matrix interactions, and by non-physiological insults to cells such as genotoxic agents. This type of regulation allows the elimination of cells that were either produced in excess during development, have completed their role, are potentially deleterious to the organism, or have become seriously damaged. Programmed cell death is therefore a critical process during embryonic development, tissue remodelling, development of the immune system, and the control of tissue homeostasis.1-3 In addition, several disorders associated with the disruption of this fundamental process, have been characterised. While a decrease in the apoptotic rate is linked in some cases to abnormal expansion in cell number (for example, in cancer or autoimmune diseases), an abnormal increase in the apoptotic rate is associated with some cell loss disorders (for example, neurodegenerative diseases).4 5 The link to cancer has been extensively studied from different aspects one of which is the apoptotic checkpoint that safeguards cells against hyperproliferative oncogenic signals.6 

Several types of programmed cell death have been characterised according to different morphological characteristics. Altogether, the spectrum of morphological hallmarks that has been attributed to the process is very wide, and includes specific nuclear alterations (for example, chromatin condensation followed by its segmentation, internucleosomal DNA fragmentation), cytoplasmic condensation and/or vacuolisation, disruption of cytoskeletal elements, cell surface blebbing, and in some cases, generation of apoptotic bodies that are rapidly phagocytosed by neighbouring cells.7 The understanding of molecular mechanisms underlying these different cellular changes has became, in the past few years, an important research …
Randomised controlled trial of non-directive counselling, cognitive-behaviour therapy, and usual general practitioner care for patients with depression. II: Cost effectiveness
Authors: P. Bower, S. Byford, B. Sibbald, E. Ward, M. King, M. Lloyd, M. Gabbay
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objective:</b> To compare the cost effectiveness of general practitioner care and two general practice based psychological therapies for depressed patients. <b>Design:</b> Prospective, controlled trial with randomised and patient preference allocation arms. <b>Setting:</b> General practices in London and greater Manchester. <b>Participants:</b> 464 of 627 patients presenting with depression or mixed anxiety and depression were suitable for inclusion. <b>Interventions:</b> Usual general practitioner care or up to 12 sessions of non-directive counselling or cognitive-behaviour therapy provided by therapists. <b>Main outcome measures:</b> Beck depression inventory scores, EuroQol measure of health related quality of life, direct treatment and non-treatment costs, and cost of lost production. <b>Results:</b> 197 patients were randomly assigned to treatment, 137 chose their treatment, and 130 were randomised only between the two psychological therapies. At four months, both non-directive counselling and cognitive-behaviour therapy reduced depressive symptoms to a significantly greater extent than usual general practitioner care. There was no significant difference in outcome between treatments at 12 months. There were no significant differences in direct costs, production losses, or societal costs between the three treatments at either four or 12 months. Sensitivity analyses did not suggest that the results depended on particular assumptions in the statistical analysis. <b>Conclusions:</b> Within the constraints of available power, the data suggest that both brief psychological therapies may be significantly more cost effective than usual care in the short term, as benefit was gained with no significant difference in cost. There are no significant differences between treatments in either outcomes or costs at 12 months.
753 BASELINE HBsAg PREDICTS HBsAg LOSS AFTER 2 YEARS OF TREATMENT-FREE FOLLOW-UP IN CHRONIC HEPATITIS B PATIENTS TREATED WITH PEGINTERFERON alfa-2a AND ADEFOVIR
Authors: L. Jansen, R.B. Takkenberg, A. de Niet, H.L. Zaaijer, C.J. Weegink, V. Terpstra, M.G.W. Dijkgraaf, R. Molenkamp, P.L.M. Janssen, M. Koot, V. Rijckborst, H.L.A. Janssen, M.G.H.M. Beld, H.W. Reesink
Journal: Journal of Hepatology (2013)
A Case of Fulminant Type 1 Diabetes With Graves’ Disease
Authors: Yoshitaka Miura, Atsushi Suzuki, Ikuko Sato, Yoko Kato, Yutaka Oiso
Journal: Diabetes Care (2002)

Type 1 diabetes is now classified as classic autoimmune (type 1A) and idiopathic (type 1B) diabetes. Fulminant type 1 diabetes was recently characterized as a novel subtype of type 1B diabetes. This disease was characterized as rapid onset, having an absence of diabetes-related autoantibodies, and having the presence of lymphocyte infiltration in exocrine pancreatic tissue without insulitis (1–3). Although fulminant type 1 diabetes has been clinically recognized, its etiology still remains obscure. In this article, we report a case of fulminant …
Sketches of Colonial Practice
Authors: W. P. Nesbitt
Journal: BMJ (1876)

alppearance of the meneses.Thle -cllneral coniditionis were in this way, after a time, much improved ; but all attempts at walking or effort again displaced the uterus; so at last I adapted the combination of the instruiments Nos.i andI 4, as represented in Fig. 5.It was worn for about six months, and then the uterus had so far recovered its fixed normal position, that wearing the gutta-percha vaginal support, figured in the first illustration to this paper, was sufficient to effect a satisfac- tory cure.In concluding this paper, which I have enideavoured to coimpress into the smallest possible limits, let me say that I deprecate, in the strongest manner, the nimiZia dfilZo-enzlia in the mechanical treatment of uterine (lisease genierally.I am strongly of opinion that an endeavour to correct the local trotuble should always be made in the first place, by treatment directed to correct the general state of liealth, and only when this, unaided, has failed, should local treatment, involving manual or operative interference with the parts, be attempted.Generally speaking, the speculum shoulcd never be used, unless local medication, first by the patient herself, has failed to arrest the abnormal discharges ; the sound should never be introduced unless there be presumptive evidence of uterine displacement or subinvolution; and, finally, let me say, me- chanical treatment of every kind should certainly be withheld in all cases, until relief by rest, position, and local medication has failed to be afforded.The diagnosis in all cases should be strictly iniductive under no circumstances either speculative or experimental.
Targeting MYCN: A Good BET for Improving Neuroblastoma Therapy?
Authors: Robert W. Schnepp, John M. Maris
Journal: Cancer Discovery (2013)

Abstract Summary: Direct targeting of oncogenic MYC proteins has been an elusive goal of many cancer drug development efforts. In this issue of Cancer Discovery, Stegmaier and colleagues demonstrate that pharmacologically interfering with the bromodomain and extraterminal (BET) class of proteins potently depletes MYCN in neuroblastoma cells, resulting in cellular cytotoxicity and thus providing a novel approach with a potential impact on a previously undruggable major oncogene. Cancer Discov; 3(3); 255–7. ©2013 AACR. See related article by Puissant et al., p. 308
Pharmacogenetic study of 5,10-methylenetetrahydrofolate reductase C677T and thymidylate synthase 3R/2R gene polymorphisms and methotrexate-related toxicity in Chinese Han patients with inflammatory arthritis
Authors: Q-Y Zeng, Y-K Wang, Z-Y Xiao, S-B Chen
Journal: Annals of the Rheumatic Diseases (2008)

<h3>ABSTRACT</h3> Voltage-gated sodium channels initiate action potentials in prokaryotes and in many eukaryotic cells, including vertebrate nerve and muscle. Their activation is steeply voltage-dependent, but it is unclear how the voltage sensitivity is set or whether it can be broadly shifted to positive voltages. Here we show that the voltage dependence of activation (V<sub>A</sub>) of the ancestral bacterial sodium channel Na<sub>V</sub>Ab can be progressively shifted from −118 mV to +35 mV in chimeras with increasing numbers of amino acid residues from the extracellular half of the voltage sensor of human Na<sub>V</sub>1.7 channels. In a minimal chimera in which only 32 residues were transferred, we analyzed the effects of six additional mutations of conserved amino acid residues singly, in pairs, and as triple mutations. The resulting chimeric mutants exhibited a broad range of voltage sensitivity from V<sub>A</sub>=−118 mV to V<sub>A</sub>=+120 mV. Three mutations (N48K, L112A, and M119V) shifted V<sub>A</sub> to +61 mV when substituted in Na<sub>V</sub>Ab itself, and substitution of two additional Cys residues in the Cys-free background of Na<sub>V</sub>Ab further shifted V<sub>A</sub> to +105 mV. In these mutants, measurement of gating currents revealed that the voltage dependence of gating charge movement (V<sub>Q</sub>) shifted to positive membrane potentials as much or more than V<sub>A</sub>, confirming that the gating charges are trapped in their resting positions by these V<sub>A</sub>-shifting mutations. Our results demonstrate broadband shifting of V<sub>A</sub> and V<sub>Q</sub> of a sodium channel across a range of 240 mV and provide a toolbox of methods and constructs to analyze sodium channel structure and function in the resting state at 0 mV and in activated states at positive membrane potentials. <h3>GRAPHICAL ABSTRACT</h3> The complete range of broadband tuning of voltage-dependent activation of a sodium channel.
Prospects and Perspectives: Implications of Social Change for Psychiatry
Authors: WALTER E. BARTON
Journal: American Journal of Psychiatry (1968)

The author assumes that psychiatrists wish to participate in the social evolution and revolution that are today's reality. However, he cautions against over-enthusiasm for the new fashions in psychiatry and stresses the need for careful evaluation and for the continuing pursuit of excellence. He also cites a number of areas and issues needing thoughtful study by psychiatrists.
Acute and long-term management of food allergy: systematic review
Authors: D. de Silva, M. Geromi, S. S. Panesar, A. Muraro, T. Werfel, K. Hoffmann-Sommergruber, G. Roberts, V. Cardona, A. E. J. Dubois, S. Halken, A. Host, L. K. Poulsen, R. Van Ree, B. J. Vlieg-Boerstra, I. Agache, A. Sheikh
Journal: Allergy (2013)

Background Allergic reactions to food can have serious consequences. This systematic review summarizes evidence about the immediate management of reactions and longer-term approaches to minimize adverse impacts. Methods Seven bibliographic databases were searched from their inception to September 30, 2012, for systematic reviews, randomized controlled trials, quasi-randomized controlled trials, controlled clinical trials, controlled before-and-after and interrupted time series studies. Experts were consulted for additional studies. There was no language or geographic restrictions. Two reviewers critically appraised the studies using the appropriate tools. Data were not suitable for meta-analysis due to heterogeneity so were narratively synthesized. Results Eighty-four studies were included, but two-thirds were at high risk of potential bias. There was little evidence about acute management for non-life-threatening reactions. H1-antihistamines may be of benefit, but this evidence was in part derived from studies on those with cross-reactive birch pollen allergy. Regarding long-term management, avoiding the allergenic food or substituting an alternative was commonly recommended, but apart from for infants with cow's milk allergy, there was little high-quality research on this management approach. To reduce symptoms in children with cow's milk allergy, there was evidence to recommend alternatives such as extensively hydrolyzed formula. Supplements such as probiotics have not proved helpful, but allergen-specific immunotherapy may be disease modifying and therefore warrants further exploration. Conclusions Food allergy can be debilitating and affects a significant number of people. However, the evidence base about acute and longer-term management is weak and needs to be strengthened as a matter of priority.
Health Insurance Coverage Among People With and Without Diabetes in the U.S. Adult Population
Authors: Sarah Stark Casagrande, Catherine C. Cowie
Journal: Diabetes Care (2012)

To compare health insurance coverage and type of coverage for adults with and without diabetes.The data used were from 2,704 adults who self-reported diabetes and 25,008 adults without reported diabetes in the 2009 National Health Interview Survey. Participants reported on their current type of health insurance coverage, demographic information, diabetes-related factors, and comorbidities. If uninsured, participants reported reasons for not having health insurance.Among all adults with diabetes, 90% had some form of health insurance coverage, including 85% of people 18-64 years of age and ~100% of people ≥65 years of age; 81% of people without diabetes had some type of coverage (vs. diabetes, P < 0.0001), including 78% of people 18-64 years of age and 99% of people ≥65 years of age. More adults 18-64 years of age with diabetes had Medicare coverage (14% vs. no diabetes, 3%; P < 0.0001); fewer people with diabetes had private insurance (58% vs. no diabetes, 66%; P < 0.0001). People 18-64 years of age with diabetes more often had two health insurance sources compared with people without diabetes (13 vs. 5%, P < 0.0001). The most common private plan was a preferred provider organization (PPO) followed by a health maintenance organization/independent practice organization (HMO/IPA) plan regardless of diabetes status. For participants 18-64 years of age, high health insurance cost was the most common reason for not having coverage.Two million adults <65 years of age with diabetes had no health insurance coverage, which has considerable public health and economic impact. Health care reform should work toward ensuring that people with diabetes have coverage for routine care.