tbuckley/cabot-search huggingface dataset:
Do Anionic Phospholipids Serve as Cofactors or Second Messengers for the Regulation of Activity of Cloned ATP-Sensitive K <sup>+</sup> Channels?
Authors: Kathryn V. Quinn, Yi Cui, Jonathan P. Giblin, Lucie H. Clapp, Andrew Tinker
Journal: Circulation Research (2003)

The regulation of ion channels by anionic phospholipids is currently very topical. An outstanding issue is whether phosphatidylinositol 4,5-diphosphate and related species act as true second messengers in signaling or behave in a manner analogous to an enzymatic cofactor. This question is especially pertinent regarding ATP-sensitive K+ channels in smooth muscle, for which there is substantial literature supporting inhibitory regulation by hormones. In this study, we have examined regulation of the potential cloned equivalents of the smooth muscle ATP-sensitive K+ channel (SUR2B/Kir6.1 and SUR2B/Kir6.2). We find that both can be inhibited via the Gq/11-coupled muscarinic M3 receptor but that the pathways by which this occurs are different. Our data show that SUR2B/Kir6.1 is inhibited by protein kinase C and binds anionic phospholipids with high affinity, such that potential physiological fluctuations in their levels do not influence channel activity. In contrast, Kir6.2 is not regulated by protein kinase C but binds anionic phospholipids with low affinity. In this case, phosphatidylinositol 4,5-diphosphate and related species have the potential to act as second messengers in signaling. Thus, Kir6.1 and Kir6.2 are regulated by distinct inhibitory mechanisms.
Hospital compromised safety of its patients, report says
Authors: Adrian O'Dowd
Journal: BMJ (2006)

A medical directorate at an NHS trust that failed to protect the safety of its patients is being completely overhauled, after a highly critical investigation was published this week.

The report into the Mid Cheshire Hospitals NHS Trust by England's health regulator, the Healthcare Commission, made 21 recommendations and insisted on four urgent actions.

The investigation followed the conviction in 2004 of a former ward sister, Barbara Salisbury, on two counts of attempted murder. Ms Salisbury, who was given a five year jail sentence, was convicted in relation to incidents at Leighton …
Sports medicine clinical trial research publications in academic medical journals between 1996 and 2005: an audit of the PubMed MEDLINE database
Authors: A W Nichols
Journal: British Journal of Sports Medicine (2007)

Objective: To identify sports medicine-related clinical trial research articles in the PubMed MEDLINE database published between 1996 and 2005 and conduct a review and analysis of topics of research, experimental designs, journals of publication and the internationality of authorships. Hypothesis: Sports medicine research is international in scope with improving study methodology and an evolution of topics. Design: Structured review of articles identified in a search of a large electronic medical database. Setting: PubMed MEDLINE database. Participants: Sports medicine-related clinical research trials published between 1996 and 2005. Interventions: Review and analysis of articles that meet inclusion criteria. Main outcome measurements: Articles were examined for study topics, research methods, experimental subject characteristics, journal of publication, lead authors and journal countries of origin and language of publication. Results: The search retrieved 414 articles, of which 379 (345 English language and 34 non-English language) met the inclusion criteria. The number of publications increased steadily during the study period. Randomised clinical trials were the most common study type and the “diagnosis, management and treatment of sports-related injuries and conditions” was the most popular study topic. The knee, ankle/foot and shoulder were the most frequent anatomical sites of study. Soccer players and runners were the favourite study subjects. The American Journal of Sports Medicine had the highest number of publications and shared the greatest international diversity of authorships with the British Journal of Sports Medicine . The USA, Australia, Germany and the UK produced a good number of the lead authorships. In all, 91% of articles and 88% of journals were published in English. Conclusions: Sports medicine-related research is internationally diverse, clinical trial publications are increasing and the sophistication of research design may be improving.
Proliferation Imaging to Measure Early Cancer Response to Targeted Therapy
Authors: David A. Mankoff, Janet F. Eary
Journal: Clinical Cancer Research (2008)

Abstract Positron emission tomography imaging using thymidine and analogues labeled with positron emitters provides noninvasive and quantitative estimates of regional cellular proliferation. This CCR Translations summary reviews the biological basis for proliferation imaging and discusses recent results using 18F-fluorothymidine-positron emission tomography to measure response to targeted therapy in the context of prior studies and potential future applications.
Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models
Authors: Maria Armakola, Matthew J Higgins, Matthew D Figley, Sami J Barmada, Emily A Scarborough, Zamia Diaz, Xiaodong Fang, James Shorter, Nevan J Krogan, Steven Finkbeiner, Robert V Farese, Aaron D Gitler
Journal: Nature Genetics (2012)
Complement Activation in Nasal Tissue of Patients with Chronic Rhinosinusitis
Authors: Griet A. Van Roey, Christopher C. Vanison, He Huang, Robert C. Kern, Rakesh K. Chandra, Stephanie Shintani Smith, David B. Conley, Kathryn E. Hulse, Atsushi Kato, Lydia Suh, Roderick G. Carter, Robert P. Schleimer, Bruce Tan
Journal: Journal of Allergy and Clinical Immunology (2015)
Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension
Authors: S. Provencher, D. Chemla, P. Hervé, O. Sitbon, M. Humbert, G. Simonneau
Journal: European Respiratory Journal (2005)

Patients with pulmonary arterial hypertension (PAH) exhibit a limited increase in stroke volume on exercise, and the heart rate (HR) increases may reflect the main mechanism that allows cardiac output to increase. The current prospective study documented the contribution of HR to the 6-min walking distance (6MWD) in idiopathic (IPAH) and nonidiopathic PAH. Eighty-three patients (46 IPAH and 37 nonidiopathic PAH) underwent haemodynamic evaluation and a 6MWD test. Chronotropic response (peak walking HR minus resting HR) and peripheral oxygen saturation were monitored. Fifty-seven patients were also assessed after 5±2 months of treatment (bosentan n = 38, epoprostenol n = 14, bosentan-epoprostenol n = 3, iloprost n = 2). Before treatment, the 6MWD was related to numerous demographic, haemodynamic and walking test characteristics. Stepwise regression analysis indicated that the only factors significantly associated with the 6MWD were stroke volume and chronotropic response in both IPAH and nonidiopathic PAH patients. Following treatment, changes in 6MWD were significantly related to changes in chronotropic response in both IPAH and nonidiopathic PAH. In conclusion, baseline stroke volume and chronotropic response were independently associated with the 6-min walking distance in pulmonary arterial hypertension. The lack of chronotropic response may reflect the loss in normal physiological reserve in more unwell patients.
Regulation of lipoprotein lipase in the diabetic rat.
Authors: K Tavangar, Y Murata, M E Pedersen, J F Goers, A R Hoffman, F B Kraemer
Journal: Journal of Clinical Investigation (1992)

Diabetes mellitus is associated with a reduction of lipoprotein lipase (LPL) activity and development of hypertriglyceridemia. In the current experiments the mechanisms involved in the regulation of LPL have been examined in control rats, streptozocin-induced diabetic rats, and diabetic rats treated chronically or with a single injection of insulin. Diabetes decreased adipose tissue LPL activity partially by decreasing immunoreactive LPL protein and the steady-state levels of LPL mRNA, but primarily by reducing the catalytic activity of LPL. Both chronic and acute insulin increased adipose tissue LPL activity by correcting the defect in the catalytic activity of LPL and increasing immunoreactive LPL protein; however, only chronic insulin restored LPL mRNA levels to normal. In the heart, LPL activity tended to be elevated with diabetes in parallel to an increase in immunoreactive LPL protein even though levels of LPL mRNA declined. Both chronic and acute insulin normalized LPL activity and immunoreactive LPL protein, while only chronic insulin corrected the levels of LPL mRNA. No changes in the catalytic activity of LPL in heart were detected among the groups. Thus, diabetes and insulin treatment regulate LPL expression pretranslationally, translationally, and post-translationally, with tissue-specific differences apparent in the mechanisms involved.
The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon γ production
Authors: Duncan Howie, Susumo Okamoto, Svend Rietdijk, Kareem Clarke, Ninghai Wang, Charles Gullo, Joost P. Bruggeman, Stephen Manning, Anthony J. Coyle, Edward Greenfield, Vijay Kuchroo, Cox Terhorst
Journal: Blood (2002)
Immunological and histological study of temporal arteries.
Authors: J R Park, B L Hazleman
Journal: Annals of the Rheumatic Diseases (1978)

Sixty-four temporal arteries were studied. 36 were from patients with clinically active temporal arteritis or polymyalgia rheumatica; 22 showed histological changes of temporal arteritis, 12 of which were in an active stage. 28 arteries, none of which showed histological changes, were taken at necropsy or from patients with unrelated disease. Extracellular immunoglobulin and complement deposition was seen in the artery biopsies showing active arteries and in 1 of the 10 biopsies with inactive arteritis. There was no immunoglobulin or complement deposition in the 14 patients with clinically active temporal arteritis and/or polymyalgia rheumatica, but with a normal artery biopsy. Patients with clinically active temporal arteritis were more likely to have a positive biopsy. Our results support the suggestion that the immune deposition is concurrent with an active histologically proven arteritis. Immunofluorescent examination does not appear to be a better diagnostic test than histological examination.
Mouse Models for the p53 R72P Polymorphism Mimic Human Phenotypes
Authors: Feng Zhu, Martijn E.T. Dollé, Thomas R. Berton, Raoul V. Kuiper, Carrie Capps, Alexsandra Espejo, Mark J. McArthur, Mark T. Bedford, Harry van Steeg, Annemieke de Vries, David G. Johnson
Journal: Cancer Research (2010)

The p53 tumor suppressor gene contains a common single nucleotide polymorphism (SNP) that results in either an arginine or proline at position 72 of the p53 protein. This polymorphism affects the apoptotic activity of p53 but the mechanistic basis and physiologic relevance of this phenotypic difference remain unclear. Here, we describe the development of mouse models for the p53 R72P SNP using two different approaches. In both sets of models, the human or humanized p53 proteins are functional as evidenced by the transcriptional induction of p53 target genes in response to DNA damage and the suppression of early lymphomagenesis. Consistent with in vitro studies, mice expressing the 72R variant protein (p53R) have a greater apoptotic response to several stimuli compared with mice expressing the p53P variant. Molecular studies suggest that both transcriptional and nontranscriptional mechanisms may contribute to the differential abilities of the p53 variants to induce apoptosis. Despite a difference in the acute response to UV radiation, no difference in the tumorigenic response to chronic UV exposure was observed between the polymorphic mouse models. These findings suggest that under at least some conditions, the modulation of apoptosis by the R72P polymorphism does not affect the process of carcinogenesis.
Pulmonary Artery Catheterization and Clinical Outcomes
Authors: G R Bernard, G Sopko, F Cerra, R Demling, H Edmunds, S Kaplan, L Kessler, H Masur, P Parsons, D Shure, C Webb, H Weidemann, G Weinmann, D Williams
Journal: JAMA (2000)

The efficacy and safety of the pulmonary artery catheter are under scrutiny because of its association with increased morbidity and mortality in observational studies. In response, the National Heart, Lung, and Blood Institute (NHLBI) and the US Food and Drug Administration (FDA) conducted the Pulmonary Artery Catheterization and Clinical Outcomes workshop in Alexandria, Va, on August 25 and 26, 1997, to develop recommendations regarding actions to improve pulmonary artery catheter utility and safety.The NHLBI and FDA planning task force selected a workshop chairperson, subcommittee chairs, and participants. Approximately 85 participants were selected for their collective expertise in critical care, pulmonary medicine, cardiovascular medicine and surgery, pediatrics, nursing, biostatistics, and medical economics. The meeting was open to industry representatives and other government and lay observers. This workshop was funded by the NHLBI and the FDA's Division of Devices.Published reports relating to the efficacy and safety of the pulmonary artery catheter, especially consensus documents developed by professional societies.The planning task force disseminated materials, held teleconferences, and developed draft position papers prior to the workshop. These were modified during the workshop and thereafter in the course of several teleconferences, and presented to the entire group for final modifications and approval.A need exists for collaborative education of physicians and nurses in performing, obtaining, and interpreting information from the use of pulmonary artery catheters. This effort should be led by professional societies, in collaboration with federal agencies, with the purpose of developing and disseminating standardized educational programs. Areas given high priority for clinical trials were pulmonary artery catheter use in persistent/refractory congestive heart failure, acute respiratory distress syndrome, severe sepsis and septic shock, and low-risk coronary artery bypass graft surgery. JAMA. 2000;283:2568-2572
Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism
Authors: Sarah-Maria Fendt, Eric L. Bell, Mark A. Keibler, Shawn M. Davidson, Gregory J. Wirth, Brian Fiske, Jared R. Mayers, Matthias Schwab, Gary Bellinger, Alfredo Csibi, Akash Patnaik, Marie Jose Blouin, Lewis C. Cantley, Leonard Guarente, John Blenis, Michael N. Pollak, Aria F. Olumi, Matthew G. Vander Heiden, Gregory Stephanopoulos
Journal: Cancer Research (2013)

Abstract Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer taking metformin; however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation, whereas increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer. Cancer Res; 73(14); 4429–38. ©2013 AACR.
Prediction of the Onset of Disturbed Eating Behavior in Adolescent Girls With Type 1 Diabetes
Authors: Marion P. Olmsted, Patricia A. Colton, Denis Daneman, Anne C. Rydall, Gary M. Rodin
Journal: Diabetes Care (2008)

The purpose of this study was to identify predictors of the onset of disturbed eating behavior (DEB) in adolescent girls with type 1 diabetes.In this prospective study, participants completed the Children's Eating Disorder Examination interview and self-report measures at baseline and at four follow-up assessments over 5 years. Participants were 126 girls with type 1 diabetes, aged 9-13 years at baseline. Of the 101 girls who did not have DEB at baseline, 45 developed DEB during the follow-up period; the 38 for whom data were available for the assessment before onset of DEB were compared with 38 age-matched girls who did not develop DEB. DEB was defined as dieting for weight control, binge eating, self-induced vomiting, or the use of diuretics, laxatives, insulin omission, or intense exercise for weight control.Logistic regression indicated that a model including BMI percentile, weight and shape concern, global and physical appearance-based self-worth, and depression was significantly associated with DEB onset (chi(2) = 46.0, 5 d.f., P < 0.0001) and accounted for 48.2% of the variance.Even though scores on the measures were within the published normal range, the onset of DEB was predicted by higher depression and weight and shape concerns and lower global and physical appearance-based self-worth as well as higher BMI percentile 1-2 years earlier compared with those not developing DEB. Early interventions focused on helping girls with diabetes develop positive feelings about themselves, their weight and shape, and their physical appearance may have protective value.
Relationship of Epidermal Growth Factor Receptor Expression to ErbB-2 Signaling Activity and Prognosis in Breast Cancer Patients
Authors: Michael P. DiGiovanna, David F. Stern, Susan M. Edgerton, Steve G. Whalen, Dan Moore, Ann D. Thor
Journal: Journal of Clinical Oncology (2005)

Purpose To examine the relationship of epidermal growth factor receptor (EGFR) expression to ErbB-2 signaling activity in breast cancer and the impact that this interaction has on the prognosis of patients with early-stage breast cancer. Patients and Methods Paraffin tumor sections were collected retrospectively from 807 breast cancer patients diagnosed between 1976 and 1983. Immunohistochemical assays for ErbB-2, phosphorylated (activated) ErbB-2, and EGFR were performed, and the results were correlated with clinicopathologic variables and outcome. Results EGFR expression was detectable in 15% of 807 invasive breast cancers, including 35% of the 306 ErbB-2–positive patients. Conversely, the majority (87%) of EGFR-positive tumors co-overexpressed ErbB-2. Ninety-seven percent of tumors with phosphorylated ErbB-2 co-overexpressed EGFR. Patients whose cancers demonstrated ErbB-2 phosphorylation or co-overexpression of ErbB-2 and EGFR had the shortest survival. In contrast, patients whose tumors were negative for all three markers and those tumors that expressed only EGFR or only nonphosphorylated ErbB-2 had a relatively favorable outcome. Conclusion These data provide the first clinical evidence that EGFR expression is linked to activation of ErbB-2 in human breast cancers. We have further shown that the adverse prognostic value of ErbB-2 overexpression is observed only when ErbB-2 is in the phosphorylated (activated) state or coexpressed with EGFR. These data suggest that ligand-dependent mechanisms of ErbB-2 activation are important in human breast cancer. These results also suggest that agents targeting EGFR may be useful in the treatment of tumors with activated ErbB-2.
High glucose level unmasks a genetic predisposition to enhanced extracellular matrix production in mesangial cells from the Milan normotensive strain.
Authors: G Pugliese, F Pricci, P Menè, G Romeo, I Nofroni, S Giannini, B Cresci, G Galli, C M Rotella, U Di Mario, F Pugliese
Journal: Journal of the American Society of Nephrology (1997)

A growing body of evidence indicates that the individual genetic background plays a role in the pathogenesis of diabetic glomerular disease by either favoring or protecting against injury produced by hyperglycemia. Two genetically related rat strains, the Milan normotensive strain (MNS) and the Milan hypertensive strain (MHS) display different susceptibilities to develop glomerulosclerosis with age. Glomerular sclerosing lesions occur in the MNS rats, which remain normotensive throughout their entire life-span, but not in the MHS rats, despite the presence of arterial hypertension. Previous studies have reported that extracellular matrix production and cell proliferation increased with donor-aging in mesangial cells isolated from MNS rats, but not in those from MHS rats, thus suggesting the existence of an inherited defect in the regulation of cell and matrix turnover, which translates into an abnormal response to growth-promoting stimuli favoring the development of glomerulosclerosis. In the study presented here, it was hypothesized that, in addition to donor-aging, other independent risk factors for the development of glomerular disease, such as metabolic injury by hyperglycemia, would be able to trigger and/or precipitate the occurrence of these changes in mesangial cells from the susceptible normotensive strain, but not in those from the protected hypertensive strain. To test this hypothesis, mesangial cells obtained from these rat strains (before the onset of either glomerulosclerosis or hypertension) were used to assess the effects of prolonged (4 wk) exposure to high (30 mmol/L) versus normal (5.5 mmol/L) glucose concentrations on extracellular matrix and cytokine production and cell proliferation. The accumulation and/or gene expression of the matrix components fibronectin, laminin, and collagen IV, and of the cytokines insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) did not change under normal glucose and increased progressively in response to high glucose in both MNS and MHS cells. These increases, with the exception of the increment in TGF-beta gene expression, were significantly more pronounced in MNS cells than in MHS cells. In contrast, the proliferative response to serum was not affected by high glucose, but increased in MNS cells, and decreased, although not significantly, in MHS cells during the 4-wk period, thus mimicking the changes previously observed in these rat strains as a function of age. These results indicate that high glucose unmasks a genetic tendency to produce increasing amounts of extracellular matrix, not yet evident under normal glucose conditions, and suggest that a genetically determined propensity of mesangial cells to hyperrespond to chronic hyperglycemia may be implicated in the pathogenesis of diabetic glomerular disease.
A phase II study of cisplatin and docetaxel administered as three consecutive weekly infusions for advanced non-small-cell lung cancer in elderly patients
Authors: Y. Ohe, S. Niho, R. Kakinuma, K. Kubota, H. Ohmatsu, K. Goto, H. Nokihara, H. Kunitoh, N. Saijo, H. Aono, K. Watanabe, M. Tango, A. Yokoyama, Y. Nishiwaki
Journal: Annals of Oncology (2003)
Molecular biology and respiratory disease. 5. Molecular biology of receptors: implications for lung disease.
Authors: P J Barnes
Journal: Thorax (1990)

Receptors have a critical role in regulating lung function in health and disease.'Several such receptors have recently been sequenced, cloned, and genetically expressed.This opens up new vistas for investigating receptor regu- lation in pulmonary cells, for identifying receptor subtypes, and for understanding how disease may affect these regulatory processes.In the future it may also lead to new and more specific therapeutic approaches.This article attempts to discuss some of the areas in which molecular approaches have been used to study receptor structure and regulation.At present, these novel techniques have hardly been applied to pulmonary tissues and lung disease, but it is clear that these are extraordinarily powerful tools that may now address previously unanswerable questions.