tbuckley/cabot-search huggingface dataset:
Effect of High Glucose on Vasculature
Authors: Raffaele Marfella, Katherine Esposito, Dario Giugliano
Journal: Circulation (2003)

Cosentino et al 1 report that high glucose causes PKCdependent upregulation of inducible cyclooxygenase and endothelial NO synthase (eNOS) expression in human aortic endothelial cells associated with a selective increase of thromboxane production and reduced NO release.As stated by the authors, these data are in contrast with recent observations that eNOS activity was reduced to 43% in hyperglycemic and/or diabetic aortic cell culture compared with controls. 2High production of NO resulting from increased inducible NO synthase (iNOS) expression may be linked to increased cardiovascular disease in nondiabetic patients. 3 Recently, we reported that high glucose 4 increased iNOS expression and NO release in working rat hearts.Upregulation of iNOS and raised NO generation were accompanied by a marked concomitant increase of superoxide production.The interaction of superoxide with NO is very rapid and leads to inactivation of NO and production of the potent oxidant peroxynitrite. 5 As nitrotyrosine is considered a good marker of peroxynitrite formation, 5 detection of nitrotyrosine in hearts perfused with high glucose is strongly suggestive for increased generation of peroxynitrite, which can mediate the toxic effects of high glucose on the heart, as suggested by the detection of cell apoptosis. 4 On the other hand, we failed to observe modification of the intensity of eNOS expression in the presence of high glucose. 4 Further studies are needed to evaluate whether upregulation of iNOS by high glucose plays a role in the mediation of its toxic effect on the vasculature.
A systematic review of concussion in rugby league
Authors: Andrew Gardner, Grant L Iverson, Christopher R Levi, Peter W Schofield, Frances Kay-Lambkin, Ryan M N Kohler, Peter Stanwell
Journal: British Journal of Sports Medicine (2014)

Objectives Concussion remains one of the inherent risks of participation in rugby league. While other injuries incurred by rugby league players have been well studied, less focus and attention has been directed towards concussion. Review method The current review examined all articles published in English from 1900 up to June 2013 pertaining to concussion in rugby league players. Data sources Publications were retrieved via six databases using the key search terms: rugby league, league, football; in combination with injury terms: athletic injuries, concussion, sports concussion, sports-related concussion, brain concussion, brain injury, brain injuries, mild traumatic brain injury, mTBI, traumatic brain injury, TBI, craniocerebral trauma, head injury and brain damage. Observational, cohort, correlational, cross-sectional and longitudinal studies were all included. Results 199 rugby league injury publications were identified. 39 (20%) were related in some way to concussion. Of the 39 identified articles, 6 (15%) had the main aim of evaluating concussion, while the other 33 reported on concussion incidence as part of overall injury data analyses. Rugby league concussion incidence rates vary widely from 0.0 to 40.0/1000 playing hours, depending on the definition of injury (time loss vs no time loss). The incidence rates vary across match play versus training session, seasons (winter vs summer) and playing position (forwards vs backs). The ball carrier has been found to be at greater risk for injury than tacklers. Concussion accounts for 29% of all injuries associated with illegal play, but only 9% of injuries sustained in legal play. Conclusions In comparison with other collision sports, research evaluating concussion in rugby league is limited. With such limited published rugby league data, there are many aspects of concussion that require attention, and future research may be directed towards these unanswered questions.
Mental Disorders and Disability Among Patients in a Primary Care Group Practice
Authors: Mark Olfson, Bruce Fireman, Myrna M. Weissman, Andrew C. Leon, David V. Sheehan, Roger G. Kathol, Christina Hoven, Leslie Farber
Journal: American Journal of Psychiatry (1997)

This article examines social and occupational disability associated with several DSM-IV mental disorders in a group of adult primary care outpatients.The subjects were 1,001 primary care patients (aged 18-70 years) in a large health maintenance organization. Data on each patient's sociodemographic characteristics and functional disability, including scores on the Sheehan Disability Scale, were collected at the time of a medical visit. A structured diagnostic interview for current DSM-IV disorders was then completed by a mental health professional over the telephone within 4 days of the visit.The most prevalent disorders were phobias (7.7%), major depressive disorder (7.3%), alcohol use disorders (5.2%), generalized anxiety disorder (3.7%), and panic disorder (3.0%). A total of 8.3% of the patients met the criteria for more than one mental disorder. The proportion of patients with co-occurring mental disorders varied by index disorder from 50.0% (alcohol use disorder) to 89.2% (generalized anxiety disorder). Compared with patients who had a single mental disorder, patients with co-occurring disorders reported significantly more disability in social and occupational functioning. After adjustment for other mental disorders and demographic and general health factors, compared with patients with no mental disorder, only patients with major depressive disorder, bipolar disorder, phobias, and substance use disorders had significantly increased disability, as measured by the Sheehan Disability Scale.Primary care patients with more than one mental disorder are common and highly disabled. Individual mental disorders have distinct patterns of psychiatric comorbidity and disability.
MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease
Authors: Seung-Ok Lee, Tatyana Masyuk, Patrick Splinter, Jesús M. Banales, Anatoliy Masyuk, Angela Stroope, Nicholas LaRusso
Journal: Journal of Clinical Investigation (2008)

Hyperproliferation of bile duct epithelial cells due to cell-cycle dysregulation is a key feature of cystogenesis in polycystic liver diseases (PCLDs). Recent evidence suggests a regulatory role for microRNAs (miRNAs) in a variety of biological processes, including cell proliferation. We therefore hypothesized that miRNAs may be involved in the regulation of selected components of the cell cycle and might contribute to hepatic cystogenesis. We found that the cholangiocyte cell line PCK-CCL, which is derived from the PCK rat, a model of autosomal recessive polycystic kidney disease (ARPKD), displayed global changes in miRNA expression compared with normal rat cholangiocytes (NRCs). More specific analysis revealed decreased levels of 1 miRNA, miR15a, both in PCK-CCL cells and in liver tissue from PCK rats and patients with a PCLD. The decrease in miR15a expression was associated with upregulation of its target, the cell-cycle regulator cell division cycle 25A (Cdc25A). Overexpression of miR15a in PCK-CCL cells decreased Cdc25A levels, inhibited cell proliferation, and reduced cyst growth. In contrast, suppression of miR15a in NRCs accelerated cell proliferation, increased Cdc25A expression, and promoted cyst growth. Taken together, these results suggest that suppression of miR15a contributes to hepatic cystogenesis through dysregulation of Cdc25A.
Quantitative protein expression profiling reveals extensive post-transcriptional regulation and post-translational modifications in schizont-stage malaria parasites
Authors: Bernardo J Foth, Neng Zhang, Sachel Mok, Peter R Preiser, Zbynek Bozdech
Journal: Genome biology (2008)

Abstract Background Malaria is a one of the most important infectious diseases and is caused by parasitic protozoa of the genus Plasmodium . Previously, quantitative characterization of the P. falciparum transcriptome demonstrated that the strictly controlled progression of these parasites through their intra-erythrocytic developmental cycle is accompanied by a continuous cascade of gene expression. Although such analyses have proven immensely useful, the correlations between abundance of transcripts and their cognate proteins remain poorly characterized. Results Here, we present a quantitative time-course analysis of relative protein abundance for schizont-stage parasites (34 to 46 hours after invasion) based on two-dimensional differential gel electrophoresis of protein samples labeled with fluorescent dyes. For this purpose we analyzed parasite samples taken at 4-hour intervals from a tightly synchronized culture and established more than 500 individual protein abundance profiles with high temporal resolution and quantitative reproducibility. Approximately half of all profiles exhibit a significant change in abundance and 12% display an expression peak during the observed 12-hour time interval. Intriguingly, identification of 54 protein spots by mass spectrometry revealed that 58% of the corresponding proteins - including actin-I, enolase, eukaryotic initiation factor (eIF)4A, eIF5A, and several heat shock proteins - are represented by more than one isoform, presumably caused by post-translational modifications, with the various isoforms of a given protein frequently showing different expression patterns. Furthermore, comparisons with transcriptome data generated from the same parasite samples reveal evidence of significant post-transcriptional gene expression regulation. Conclusions Together, our data indicate that both post-transcriptional and post-translational events are widespread and of presumably great biological significance during the intra-erythrocytic development of P. falciparum .
Why do animal models of post-angioplasty restenosis sometimes poorly predict the outcome of clinical trials?
Authors: A Lafont
Journal: Cardiovascular Research (1998)

Time for primary review 22 days. 

The 20th anniversary of percutaneous transluminal coronary angioplasty (PTCA), first introduced by Andreas Gruentzig MD, was recently celebrated. Since its introduction, millions of people have been successfully treated by PTCA. Despite its overwhelming success, 30 to 50% of patients develop restenosis, a rate that has changed little since the introduction of the technique. After 20 years of dramatic technical refinement and intensive research, we still do not know why a dilated artery will maintain patency and not develop restenosis or will develop restenosis. The lack of understanding about restenosis has often been attributed to inappropriate experimental models, incomplete or incorrect analysis of the models that has led to a focus on the wrong pathophysiologic target [1–4]. In the review, we will describe the various animal models used to study restenosis, and clarify the limitations and advantages of each in order to better delineate the ideal model of experimental angioplasty and restenosis. While outstanding reviews have already been written on this subject within the last five years [5–8], this review will be different from the former ones because it will take into account the following major changes: Stent-related restenosis, which is different from balloon-related restenosis, and arterial remodeling [9–12]. Arterial remodeling has transformed our understanding of restenosis and is of great clinical relevance, as shown by the good concordance between experimental data and human data obtained by intravascular ultrasound [13–19].

Before angioplasty started, balloon abrasion with endothelial denudation represented the gold standard for studying the response to vascular injury and smooth muscle cell proliferation and migration [20–25]. The idea of balloon angioplasty seemed to be a questionable method, and the occurrence of restenosis was not a surprise. Thus, experimental models of restenosis preexisted the clinical recognition of restenosis after angioplasty. … 

* Corresponding author. Tel.: 33609664209; E-mail: antoine.lafont@bcc.ap-hop-paris.fr
Gadd45a sensitizes medulloblastoma cells to irradiation and suppresses MMP-9–mediated EMT
Authors: Swapna Asuthkar, Arun Kumar Nalla, Christopher S. Gondi, Dzung H. Dinh, Meena Gujrati, Sanjeeva Mohanam, Jasti S. Rao
Journal: Neuro-Oncology (2011)

Medulloblastomas are the most common malignant tumors of the central nervous system during childhood. Radiation-induced medulloblastoma tumor recurrences are aggressive and metastatic in nature. In the present study, we demonstrate that Gadd45a expression can sensitize medulloblastoma cells to radiotherapy. We have elucidated the role of Gadd45a in ionizing radiation (IR)–induced G2-M arrest and invasion and metastatic potential of the medulloblastoma cancer cell lines DAOY and D283. We demonstrate that Gadd45a is induced by IR and results in p53 phosphorylation. The role of IR-induced Gadd45a in G2-M arrest is demonstrated by fluorescence-activated cell sorting analysis in the cells treated with siRNA Gadd45a and Ov-exp Gadd45a. We show that Ov-exp Gadd45a aggravates G2-M blockage and also increases binding of Gadd45a to Cdc2 by immunocytochemistry analysis. Furthermore, we show the anti-tumorigenic role of Gadd45a to be mediated by the negative regulation of IR-induced cancer cell invasion and migration-associated proteins, such as matrix metallopeptidase (MMP)–9 and β-catenin. When compared with IR treatment alone, Ov-exp Gadd45a plus IR treatment resulted in decreased nuclear localization and increased membrane localization of β-catenin, and this was further confirmed by membrane distribution. We also show that Ov-exp Gadd45a resulted in downregulation of MMP-9 and suppression of epithelial-mesenchymal transition (EMT). Alternatively, inhibition of MMP-9 (pM) resulted in upregulation of Gadd45a and suppression of EMT. The anti-tumor effect of pM was correlated with increased expression of Gadd45a protein in nude mice intracranial tumors. Taken together, our studies demonstrate that upregulation of Gadd45a or suppression of MMP-9 (pM) with IR retards medulloblastoma tumor metastatic potential.
Prostaglandin E <sub>2</sub> Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP <sub>4</sub>
Authors: Chun-Yang Xiao, Koh-ichi Yuhki, Akiyoshi Hara, Takayuki Fujino, Shuhko Kuriyama, Takehiro Yamada, Koji Takayama, Osamu Takahata, Hideji Karibe, Takanobu Taniguchi, Shuh Narumiya, Fumitaka Ushikubi
Journal: Circulation (2004)

In the heart with acute myocardial infarction, production of prostaglandin (PG) E2 increases significantly. In addition, several subtypes of PGE2 receptors (EPs) have been reported to be expressed in the heart. The role of PGE2 in cardiac ischemia-reperfusion (I/R) injury, however, remains unknown. We intended to clarify the role of PGE2 via EP4, an EP subtype, in I/R injury using mice lacking EP4 (EP4-/- mice).In murine cardiac ventricle, competitive reverse transcription-polymerase chain reaction revealed the highest expression level of EP4 mRNA among EP mRNAs. EP4-/- mice had larger infarct size than wild-type mice in a model of I/R; the left anterior descending coronary artery was occluded for 1 hour, followed by 24 hours of reperfusion. In addition, isolated EP4-/- hearts perfused according to the Langendorff technique had greater functional and biochemical derangements in response to I/R than wild-type hearts. In vitro, AE1-329, an EP4 agonist, raised cAMP concentration remarkably in noncardiomyocytes, whereas the action was weak in cardiomyocytes. When 4819-CD, another EP4 agonist, was administered 1 hour before coronary occlusion, it reduced infarct size significantly in wild-type mice. Notably, a similar cardioprotective effect was observed even when it was administered 50 minutes after coronary occlusion.Both endogenous PGE2 and an exogenous EP4 agonist protect the heart from I/R injury via EP4. The potent cardioprotective effects of 4819-CD suggest that the compound would be useful for treatment of acute myocardial infarction.
Clinical, Autoimmune, and Genetic Characteristics of Adult-Onset Diabetic Patients With GAD Autoantibodies in Japan (Ehime Study)
Authors: Haruyo Takeda, Eiji Kawasaki, Ikki Shimizu, Etsushi Konoue, Masao Fujiyama, Satoshi Murao, Kiyonobu Tanaka, Kennichi Mori, Yoshinao Tarumi, Isamu Seto, Yasuhisa Fujii, Kenichi Kato, Shiori Kondo, Yasuharu Takada, Nobuaki Kitsuki, Yukikazu Kaino, Kaichi Kida, Naotake Hashimoto, Yukio Yamane, Takashi Yamawaki, Hiroshi Onuma, Tatsuya Nishimiya, Haruhiko Osawa, Yasushi Saito, Hideichi Makino
Journal: Diabetes Care (2002)

To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies.GAD autoantibodies (GADab) were screened in 4,980 diabetic patients with age of onset >20 years in the hospital-based Ehime Study, and the GADab-positive (GADab(+)) patients were then divided into two groups according to their insulin secretion and compared with nondiabetic subjects. The insulin-deficient state was defined as <0.33 nmol/l serum C-peptide (CPR) at 2 h postprandial or 6 min after a 1-mg glucagon load.GADab was detected in 188 (3.8%) of the 4,980 diabetic patients tested. Of these patients, 72 (38.3%) were classified as insulin deficient, 97 (51.6%) were classified as non-insulin deficient, and 19 (10.1%) were unclassified. The GADab(+) insulin-deficient patients were characterized by young age at onset of diabetes, low BMI, low maximum BMI, and high levels of HbA(1c). The prevalence of IA-2 autoantibodies and thyrogastric autoantibodies in the GADab(+) insulin-deficient patients were significantly higher than those in the GADab(+) non-insulin-deficient patients (P < 0.05). GADab(+) patients with insulin deficiency had increased frequencies of HLA DRB1*0405-DQB1*0401, *0802-*0302, and *0901-*0303 haplotypes, whereas the frequency of only HLA DRB1*0405-DQB1*0401 was increased in the case of GADab(+) non-insulin-deficient patients. Of note is the fact that the GADab(+) non-insulin-deficient group did not differ from healthy control subjects with respect to type 1 diabetes protective haplotype HLA DRB1*1502-DQB1*0601. A total of 13% of the GADab(+) patients with diabetes had genotypes comprising the DRB1*1501-DQB1*0602 or *1502-*0601 and were characterized by old age at onset of diabetes, high BMI, resistance to the insulin-deficient state, low titer of GADab, and low frequency of other organ-specific autoantibodies.We conclude that GADab(+) non-insulin-deficient patients differ from GADab(+) patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.
ATP Citrate Lyase: Activation and Therapeutic Implications in Non–Small Cell Lung Cancer
Authors: Toshiro Migita, Tadahito Narita, Kimie Nomura, Erika Miyagi, Fumika Inazuka, Masaaki Matsuura, Masaru Ushijima, Tetsuo Mashima, Hiroyuki Seimiya, Yukitoshi Satoh, Sakae Okumura, Ken Nakagawa, Yuichi Ishikawa
Journal: Cancer Research (2008)

Abstract Enhanced glucose and lipid metabolism is one of the most common properties of malignant cells. ATP citrate lyase (ACLY) is a key enzyme of de novo fatty acid synthesis responsible for generating cytosolic acetyl-CoA and oxaloacetate. To evaluate its role in lung cancer progression, we here analyzed ACLY expression in a subset of human lung adenocarcinoma cell lines and showed a relationship with the phosphatidyl-inositol-3 kinase–Akt pathway. The introduction of constitutively active Akt into cells enhanced the phosphorylation of ACLY, whereas dominant-negative Akt caused attenuation. In human lung adenocarcinoma samples, ACLY activity was found to be significantly higher than in normal lung tissue. Immunohistochemical analysis further showed phosphorylated ACLY overexpression in 162 tumors, well-correlating with stage, differentiation grade, and a poorer prognosis. Finally, to show the therapeutic potential and mechanism of ACLY inhibition for lung cancer treatment, we assessed the effect of RNA interference targeting ACLY on lipogenesis and cell proliferation in A549 cells. ACLY inhibition resulted in growth arrest in vitro and in vivo. Interestingly, increased intracellular lipids were found in ACLY knockdown cells, whereas de novo lipogenesis was inhibited. Supplementation of insulin could rescue the proliferative arrest elicited by ACLY inhibition; however, in contrast, fatty acid palmitate induced cell death. Taken together, these findings suggest that ACLY is involved in lung cancer pathogenesis associated with metabolic abnormality and might offer a novel therapeutic target. [Cancer Res 2008;68(20):8547–54]
Immunomodulatory Monoclonal Antibodies Combined with Peptide Vaccination Provide Potent Immunotherapy in an Aggressive Murine Neuroblastoma Model
Authors: Emily L. Williams, Stuart N. Dunn, Sonya James, Peter W. Johnson, Mark S. Cragg, Martin J. Glennie, Juliet C. Gray
Journal: Clinical Cancer Research (2013)

Neuroblastoma is one of the commonest extracranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here, we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models.Neuroblastoma-bearing mice were treated with mAb targeting 4-1BB, CD40, and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy were assessed.In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single-agent mAb therapy provides ineffective therapy. However, if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination, then 60% long-term survival is achieved. This is associated with the generation of survivin-specific T-cell immunity, which again is only shown in the presence of tumor antigen.These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting.
Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia
Authors: Marc S. Sabatine, David A. Morrow, James A. de Lemos, Torbjorn Omland, Milind Y. Desai, Milenko Tanasijevic, Christian Hall, Carolyn H. McCabe, Eugene Braunwald
Journal: Journal of the American College of Cardiology (2004)