tbuckley/cabot-search huggingface dataset:
Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver-specific Gsα deficiency
Authors: Min Chen, Oksana Gavrilova, Wei-Qin Zhao, Annie Nguyen, Javier Lorenzo, Laura Shen, Lisa Nackers, Stephanie Pack, William Jou, Lee S. Weinstein
Journal: Journal of Clinical Investigation (2005)

The G protein Gsα is essential for hormone-stimulated cAMP generation and is an important metabolic regulator. We investigated the role of liver Gs-signaling pathways by developing mice with liver-specific Gsα deficiency (LGsKO mice). LGsKO mice had increased liver weight and glycogen content and reduced adiposity, whereas survival, body weight, food intake, and metabolic rates at ambient temperature were unaffected. LGsKO mice had increased glucose tolerance with both increased glucose-stimulated insulin secretion and increased insulin sensitivity in liver and muscle. Fed LGsKO mice were hypoglycemic and hypoinsulinemic, with low expression of hepatic gluconeogenic enzymes and PPARγ coactivator–1. However, LGsKO mice maintained normal fasting glucose and insulin levels, probably due to prolonged breakdown of glycogen stores and possibly increased extrahepatic gluconeogenesis. Lipid metabolism was unaffected in fed LGsKO mice, but fasted LGsKO mice had increased lipogenic and reduced lipid oxidation gene expression in liver and increased serum triglyceride and FFA levels. LGsKO mice had very high serum glucagon and glucagon-like peptide–1 levels and pancreatic α cell hyperplasia, probably secondary to hepatic glucagon resistance and/or chronic hypoglycemia. Our results define novel roles for hepatic Gs-signaling pathways in glucose and lipid regulation, which may prove useful in designing new therapeutic targets for diabetes and obesity.
Translation of Innovative Designs Into Phase I Trials
Authors: André Rogatko, David Schoeneck, William Jonas, Mourad Tighiouart, Fadlo R. Khuri, Alan Porter
Journal: Journal of Clinical Oncology (2007)

Purpose Phase I clinical trials of new anticancer therapies determine suitable doses for further testing. Optimization of their design is vital in that they enroll cancer patients whose well-being is distinctly at risk. This study examines the effectiveness of knowledge transfer about more effective statistical designs to clinical practice. Methods We examined abstract records of cancer phase I trials from the Science Citation Index database between 1991 and 2006 and classified them into clinical (dose-finding trials) and statistical trials (methodologic studies of dose-escalation designs). We then mapped these two sets by tracking which trials adopted new statistical designs. Results One thousand two hundred thirty-five clinical and 90 statistical studies were identified. Only 1.6% of the phase I cancer trials (20 of 1,235 trials) followed a design proposed in one of the statistical studies. These 20 clinical studies showed extensive lags between publication of the statistical paper and its translation into a clinical paper. These 20 clinical trials followed Bayesian adaptive designs. The remainder used variations of the standard up-and-down method. Conclusion A consequence of using less effective designs is that more patients are treated with doses outside the therapeutic window. Simulation studies have shown that up-and-down designs treated only 35% of patients at optimal dose levels versus 55% for Bayesian adaptive designs. This implies needless loss of treatment efficacy and, possibly, lives. We suggest that regulatory agencies (eg, US Food and Drug Administration) should proactively encourage the adoption of statistical designs that would allow more patients to be treated at near-optimal doses while controlling for excessive toxicity.
Increased Safety with Preserved Antitumoral Efficacy on Hepatocellular Carcinoma with Dual-Regulated Oncolytic Adenovirus
Authors: Qi Zhang, Guihua Chen, Linhui Peng, Xinghua Wang, Yang Yang, Chen Liu, Wenfang Shi, Changqing Su, Hongping Wu, Xinyuan Liu, Mengchao Wu, Qijun Qian
Journal: Clinical Cancer Research (2006)

Abstract Purpose: A dual-regulated adenovirus variant CNHK500, in which human telomerase reverse transcriptase promoter drove the adenovirus 5 (Ad5) E1a gene and hypoxia-response promoter controlled the E1b gene, was engineered. This virus has broad anticancer spectrum and higher specificity compared with mono-regulated adenovirus CNHK300. The objective of the current study is to show its antitumor selectivity and therapeutic potential. Experimental Design: The antitumor specificity of human telomerase reverse transcriptase and hypoxia response promoters was evaluated in a panel of tumor and normal cells. Under the control of these promoters, the tumor-selective expression of E1a and E1b genes was evaluated. Further in vitro antitumor specificity and potency of this virus were characterized by viral replication and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Subsequently, hepatocellular carcinoma xenografts were established to evaluate CNHK500 antitumor efficacy in vivo by different routes of virus administration and different dosages. Results: Human telomerase reverse transcriptase and hypoxia response promoters were activated in a tumor-selective manner or under hypoxia treatment in a broad panel of cells. Selective adenoviral early gene expression, efficient viral replication, and oncolysis were observed in all tested cancer cells with more attenuated replication capacity in normal cells. Significant regression of hepatocellular carcinoma xenografts and prolonged survival were observed by either i.t. or i.v. administration. Conclusions: CNHK500 greatly reduced side effects in normal cells via dual control of adenoviral essential genes while still preserving potent antitumor efficacy on broad-spectrum cancer cells in vitro and in vivo. It can be used as a powerful therapeutic agent not only for liver cancers but also for other solid tumors.
CYTOCHROME P450 ACTIVATION OF ARYLAMINES AND HETEROCYCLIC AMINES
Authors: Donghak Kim, F. Peter Guengerich
Journal: The Annual Review of Pharmacology and Toxicology (2004)

Arylamines and heterocyclic arylamines (HAAs) are of particular interest because of demonstrated carcinogenicity in animals and humans and the broad exposure to many of these compounds. The activation of these, and also some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 (P450). P450 1A2 plays a prominent role in these reactions. However, P450 1A1 and 1B1 and other P450s are also important in humans as well as experimental animals. Some arylamines (including drugs) are N-hydroxylated predominantly by P450s other than those in Family 1. Other oxygenases can also have roles. An important issue is extrapolation between species in predicting cancer risks, as shown by the low rates of HAA activation by rat P450 1A2 and low levels of P450 1A2 expression in some nonhuman primates.
Evidence for a Multiclonal Origin of Multicentric Advanced Lesions of Kaposi Sarcoma
Authors: R. Duprez, V. Lacoste, J. Briere, P. Couppie, C. Frances, D. Sainte-Marie, E. Kassa-Kelembho, M.-J. Lando, J.-L. Essame Oyono, B. Nkegoum, O. Hbid, A. Mahe, C. Lebbe, P. Tortevoye, M. Huerre, A. Gessain
Journal: JNCI Journal of the National Cancer Institute (2007)

Kaposi sarcoma (KS) is a complex tumor of uncertain clonality. Studying the viral clonality of the human herpesvirus 8 (HHV-8) in KS to determine clonality of the tumors, a strategy that has been used previously with Epstein–Barr virus and its associated tumors, may elucidate whether multicentric (disseminated) KS lesions correspond to metastatic lesions or to expansions of independent clones. A series of 139 KS biopsies (from skin, lymph node, or tonsil) was obtained from 98 patients, with 59 biopsies from 18 patients with disseminated multicentric KS skin lesions. The degree of spindle cell infiltration in biopsies was established by direct observation of hematoxylin-eosin–stained sections, and HHV-8 viral load was quantified by real-time polymerase chain reaction. To determine cellular clonality, the size heterogeneity of the HHV-8–fused terminal repeat (TR) region was determined by probing of electrophoresed restricted genomic DNA from KS biopsies for the HHV-8 TR sequence. HHV-8 clonality analysis was performed on the 62 samples for which sufficient DNA was obtained. Most samples corresponded to histologically nodular lesions with high spindle cell infiltration and high viral load. A clonal HHV-8 pattern was determined for 59 samples; 11 were found to be monoclonal and 48 to be oligoclonal. The informative samples that were from disseminated KS skin lesions (n = 26, from six patients) were either monoclonal or oligoclonal, and the size of HHV-8 episomes varied between these samples. Although some tumor KS lesions were monoclonal expansions of HHV-8–infected spindle cells, most advanced lesions were oligoclonal proliferations. Furthermore, individual KS disseminated tumor skin lesions were found to represent distinct expansions of HHV-8–infected spindle cells. Thus, our results suggest that KS lesions, especially in patients with advanced skin tumors, are reactive proliferations rather than true malignancies with metastatic dissemination.
TCT-573 Randomized comparison of Biolimus-eluting (Nobori) and Everolimus-eluting (Xience/Promus) stents in patients with multivessel coronary artery disease: 12-month follow-up data from COMPARE II study
Authors: Peter Smits, A.J. van Boven, Mariano Valdes, Antonio Serra, Jean-Jacques Goy, V. Voudris, Ramiro Trillo, J.M. Vazquez, Peter den Heijer, Ton Slagboom, A.G. Vuillomenet
Journal: Journal of the American College of Cardiology (2012)
Interventional study of high dose folic acid in gastric carcinogenesis in beagles
Authors: S D Xiao
Journal: Gut (2002)

Background: A decrease in folic acid and subsequent DNA hypomethylation may be involved in gastric carcinogenesis. Epidemiological and nutritional studies have indicated that folate status modulates the risk of developing cancers. Aims: To investigate whether folic acid plays an important role in the chemoprevention of gastric carcinogenesis induced by <i>N</i>-ethyl-<i>N</i>-nitrosoguanidine (ENNG) in beagles. Methods: Sixteen male beagles were randomly divided into two groups: folic acid treated group and control group. In both groups beagles were fed ENNG 75 mg per day for eight months and in the treated group 20 mg folic acid was given to beagles for 15 months. Gastroscopy and biopsies were performed before and every 2–3 months after administration of ENNG until the end of the experiment. Histopathological lesions were diagnosed with regard to the criteria for human gastric mucosal biopsies. Serum and gastric mucosal tissue folic acid concentrations were measured. Results: In the control group, all beagles developed gastric cancer (8/8) compared with only 3/8 in the folic acid treated group (p&lt;0.05). Moreover, serum and gastric mucosal tissue folic acid concentrations were markedly elevated 15 months after folic acid administration. The difference was statistically significant between the two groups (p&lt;0.05). Conclusions: Our results indicate that high dose folic acid plays an important role in the chemoprevention of gastric carcinogenesis induced by a chemical carcinogen ENNG in beagles.
American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control
Authors: Etie S. Moghissi, Mary T. Korytkowski, Monica DiNardo, Daniel Einhorn, Richard Hellman, Irl B. Hirsch, Silvio E. Inzucchi, Faramarz Ismail-Beigi, M. Sue Kirkman, Guillermo E. Umpierrez
Journal: Diabetes Care (2009)

4. Does inpatient management of hyperglycemia represent a safety concern? 5. What systems need to be in place to achieve these recommendations?6.Is treatment of inpatient hyperglycemia cost-effective?7. What are the optimal strategies for transition to outpatient care? 8. What are areas for future research? QUESTION 1: DOES IMPROVING GLYCEMIC CONTROL IMPROVE CLINICAL OUTCOMES FOR INPATIENTS WITHHYPERGLYCEMIA? -Hyperglycemia in hospitalized patients, irrespective of its cause, is unequivocally associated with adverse outcomes (5,6,18 -25).Hyperglycemia occurs in patients with known or undiagnosed diabetes, or it occurs during acute illness in those with previously normal glucose tolerance (termed "stress hyperglycemia") (8,26).Intervention directed at reducing blood glucose (BG) levels has resulted in improved outcomes in some, but not all, studies (5,18 -25).Several recent clinical trials in critically ill patients have reported no reduction in mortality from intensive treatment targeting near-euglycemia versus conventional management targeting BG Ͻ180 mg/dl (Ͻ10.0 mmol/l).Of considerable concern are reports of harm, with higher rates of severe hypoglycemia and even increased mortality (14) resulting from intensive glycemic control (12)(13)(14)16,27,28).This variability in results may be attributable to several factors, including differences in intravenous (IV) insulin treatment protocols and their implementation, glycemic targets, patient populations, methods for glucose monitoring, and insulin adjustment (12,29).The following section focuses primarily on results of recent studies with an RCT design that investigated patient outcomes with protocols targeting nearnormalization of BG levels.Readers are referred to a previous ACE position statement (9), an ACE/ADA consensus statement (11), and a technical review (8) for details related to earlier studies supporting inpatient glycemic management.
Hairdressing and the prevalence of scalp disease in African adults
Authors: N.P. Khumalo, S. Jessop, F. Gumedze, R. Ehrlich
Journal: British Journal of Dermatology (2007)

Journal Article Hairdressing and the prevalence of scalp disease in African adults Get access N.P. Khumalo, N.P. Khumalo Division of Dermatology Correspondence: N.P. Khumalo. E‐mail: nonhlanhla.khumalo@uct.ac.za; n_khumalo@hotmail.com Search for other works by this author on: Oxford Academic Google Scholar S. Jessop, S. Jessop Division of Dermatology Search for other works by this author on: Oxford Academic Google Scholar F. Gumedze, F. Gumedze Department of Statistical Sciences Search for other works by this author on: Oxford Academic Google Scholar R. Ehrlich R. Ehrlich School of Public Health and Family Medicine, Groote Schuur Hospital and the University of Cape Town, Observatory 7925, South Africa Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 157, Issue 5, 1 November 2007, Pages 981–988, https://doi.org/10.1111/j.1365-2133.2007.08146.x Published: 01 November 2007
Initial Safety Report of NSABP C-08: A Randomized Phase III Study of Modified FOLFOX6 With or Without Bevacizumab for the Adjuvant Treatment of Patients With Stage II or III Colon Cancer
Authors: Carmen J. Allegra, Greg Yothers, Michael J. O'Connell, Saima Sharif, Linda H. Colangelo, Samia H. Lopa, Nicholas J. Petrelli, Richard M. Goldberg, James N. Atkins, Thomas E. Seay, Louis Fehrenbacher, Seamus O'Reilly, Luis Chu, Catherine A. Azar, Norman Wolmark
Journal: Journal of Clinical Oncology (2009)

The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy.Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group).Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment.Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.
Diversity of the autochthonous colonic microbiota
Authors: Gerardo M. Nava, Thaddeus S. Stappenbeck
Journal: Gut Microbes (2011)

A longstanding hypothesis in intestinal microbial ecology is that autochthonous microbes (resident) play a role that is distinct from allochthonous microbes (transient microbes in the fecal stream). A challenge has been to identify this pool of microbes. We used laser capture microdissection to collect microbes from the mouse ascending colon. This area contains transverse folds that mimic human intestinal folds and contains a distinct population of intestinal microbes that is associated with the mucosa. Our analysis of bacterial 16S rRNA genes showed that this area was enriched for Lachnospiraceae and Ruminococcaceae. In this addendum, we further compare this community to studies of mucosa-associated microbes in humans. This analysis reveals common phylogenetic groups of bacteria that are present in both mouse and human. However, we found microorganisms at the genus and species levels including Faecalibacterium prausnitzii which appears to be specific for humans. We propose that that examination of the mucosa-associated microbes in wild type and genetically modified mice will be a valuable component to define host microbial interactions that are essential for homeostasis.
Protective role of nuclear factor of activated T cells 2 in CD8+ long-lived memory T cells in an allergy model
Authors: Roman Karwot, Joachim H. Maxeiner, Steffen Schmitt, Petra Scholtes, Michael Hausding, Hans A. Lehr, Laurie H. Glimcher, Susetta Finotto
Journal: Journal of Allergy and Clinical Immunology (2008)
Inflammatory Syndrome in Patients on Hemodialysis
Authors: Rosa Jofré, Patrocinio Rodriguez-Benitez, Juan M López-Gómez, Rafael Pérez-Garcia
Journal: Journal of the American Society of Nephrology (2006)

Mortality is markedly elevated in hemodialysis (HD) patients. Between 30 and 50% of prevalent patients have elevated serum levels of inflammatory markers such as C-reactive protein and IL-6. The presence of inflammation, chronic or episodic, has been found to be associated with increased mortality risk. The causes of inflammation are multifactorial and include patient-related factors, such as underlying disease, comorbidity, oxidative stress, infections, obesity, and genetic or immunologic factors, or on the other side, HD-related factors, mainly depending on the membrane biocompatibility and dialysate quality. The adequate knowledge of these causes and their prevention or treatment if possible may contribute to improving the inflammatory state of patients who are on HD and possibly their mortality.
A novel myelin P0–specific T cell receptor transgenic mouse develops a fulminant autoimmune peripheral neuropathy
Authors: Cédric Louvet, Beniwende G. Kabre, Dan W. Davini, Nicolas Martinier, Maureen A. Su, Jason J. DeVoss, Wendy L. Rosenthal, Mark S. Anderson, Hélène Bour-Jordan, Jeffrey A. Bluestone
Journal: The Journal of Experimental Medicine (2009)

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4+ T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4+ T cell hybridomas were generated from inflamed tissue–derived CD4+ T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0–specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3–5 wk of age. This abrupt disease was associated with the production of interferon γ by P0-specific T cells and a lack of CD4+ Foxp3+ regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy.
Outbreak of wound botulism in people who inject drugs, Norway, October to November 2013
Authors: E MacDonald, T M Arnesen, A  B Brantsaeter, P Gerlyng, M Grepp, B Å Hansen, K Jønsrud, B Lundgren, H Mellegård, J Møller-Stray, K Rønning, D F Vestrheim, L Vold
Journal: Eurosurveillance (2013)

Binary file ES_Abstracts_Final_ECDC.txt matches
High density lipoproteins and exercise.
Authors: D. R. Donaldson, R. C. Kester
Journal: British Journal of Sports Medicine (1980)

High density lipoprotein (HDL) and total cholesterol (TC) levels have been measured and their ratio compared in four groups of subjects - those with vascular disease, controls, middle-aged "keep-fit" enthusiasts and young physical education students. Each group has also been subjected to analysis of risk factors known for atherosclerosis. The HDL level was significantly raised in the Athletic and Exercise groups even though the latter were more overweight and had the highest total cholesterol level. This would appear to indicate that exercise may exert its protective effect against atherosclerosis, at least in part, by elevating the HDL level above a certain critical level. The HDL/TC ratio was significantly lower in the Vascular group and we would advocate that any ratio less than 20% is highly suspicious of atherosclerosis. We suggest that both the HDL level and HDL/TC ratio should be viewed together as reflecting the risk of atherosclerosis.
A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice.
Authors: H R Alexander, G M Doherty, C M Buresh, D J Venzon, J A Norton
Journal: The Journal of Experimental Medicine (1991)

Interleukin 1 (IL-1) is an endogenously produced cytokine that mediates a variety of physiological effects that may be beneficial or deleterious to the host. C57Bl/6 mice treated intravenously with a recently characterized human recombinant receptor antagonist protein to IL-1 (IL-1ra) had improved survival when treated after a lethal Escherichia coli endotoxin (lipopolysaccharide [LPS]) challenge. IL-1ra was effective when treatment was initiated after LPS, and intravenous administration every 4 h for 24 h was required. Serum levels of tumor necrosis factor (TNF) activity after LPS and in vitro TNF cytotoxicity were not altered by treatment with IL-1ra. These experiments provide direct evidence that the lethal effects of LPS may be mediated through the action of IL-1 and that the IL-1ra can provide a new treatment strategy for disease processes mediated via this cytokine.