tbuckley/cabot-search huggingface dataset:
Human IAPP–induced pancreatic β cell toxicity and its regulation by autophagy
Authors: Nayumi Shigihara, Ayako Fukunaka, Akemi Hara, Koji Komiya, Akira Honda, Toyoyoshi Uchida, Hiroko Abe, Yukiko Toyofuku, Motoyuki Tamaki, Takeshi Ogihara, Takeshi Miyatsuka, Henry J. Hiddinga, Setsuya Sakagashira, Masato Koike, Yasuo Uchiyama, Tamotsu Yoshimori, Norman L. Eberhardt, Yoshio Fujitani, Hirotaka Watada
Journal: Journal of Clinical Investigation (2014)

Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of β cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on β cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet–induced compensatory increase in β cell mass, which was due to limited β cell proliferation and enhanced β cell apoptosis. Importantly, expression of hIAPP in mice with a β cell–specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance β cell dysfunction and progression of T2DM.
Energy Metabolism in Diabetic and Nondiabetic Heart Transplant Recipients
Authors: Stefano Benedini, Roberto Fiocchi, Alberto Battezzati, Paola Scifo, Lucia Piceni Sereni, Amando Gamba, Carmelo Mammana, Alessandro Del Maschio, Gianluca Perseghin, Livio Luzi
Journal: Diabetes Care (2002)

OBJECTIVE—This study examined the metabolic effects of heart transplantation in patients in end-stage cardiac failure. RESEARCH DESIGN AND METHODS—A total of 18 patients after heart transplantation for end-stage heart disease (age 47± 3 years; transplant age 5.5± 1.5 years; BMI 25.8± 0.8 kg/m2; cyclosporin A 4.2 ±0.6 mg/[kg·day]; azathioprine 0.87± 0.31 mg/[kg·day]), 12 patients with type 2 diabetes (D-Tx), and 6 patients without type 2 diabetes (Tx) were studied by means of 1) an oral glucose tolerance test (OGTT) to assess the β-cell secretory response, 2) a euglycemic-hyperinsulinemic (1 mU/[kg·min]) clamp combined with indirect calorimetry and a primed continuous infusion of [6,6-2H2]glucose and [1-13C]leucine to measure postabsorptive and insulin-stimulated carbohydrate and protein metabolism, and 3) 1H-NMR spectroscopy of the calf muscles to measure intramyocellular triglyceride (IMCL) content. The patients were selected from 480 transplant patients in whom there was a 6% prevalence of type 2 diabetes. Five healthy subjects matched for anthropometric parameters served as control subjects (CON). RESULTS—Tx had postabsorptive and insulin-stimulated glucose, leucine, and free fatty acid metabolism, as well as IMCL content, similar to that of CON. D-Tx were characterized by a reduced secretory response during the OGTT and peripheral insulin resistance with respect to glucose metabolism, which was paralleled by increased plasma free fatty acid concentrations and IMCL content. A defective insulin-dependent suppression of the endogenous leucine flux (index of proteolysis) was also evident during the clamp in D-Tx. CONCLUSIONS—Heart transplantation, notwithstanding the immunosuppressive therapy, was characterized by a normal postabsorptive and insulin-stimulated glucose, leucine, and free fatty acid metabolism in Tx. In contrast, insulin resistance with respect to glucose, free fatty acids, and protein metabolism was present in D-Tx regardless of whether diabetes was preexisting or consequent to heart transplantation.
Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemic cells
Authors: L Tentori, P Vernole, PM Lacal, R Madaio, I Portarena, L Levati, A Balduzzi, M Turriziani, P Dande, B Gold, E Bonmassar, G Graziani
Journal: Leukemia (2000)
Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non–Small-Cell Lung Cancer
Authors: Giorgio V. Scagliotti, Ugo Pastorino, Johan F. Vansteenkiste, Lorenzo Spaggiari, Francesco Facciolo, Tadeusz M. Orlowski, Luigi Maiorino, Martin Hetzel, Monika Leschinger, Carla Visseren-Grul, Valter Torri
Journal: Journal of Clinical Oncology (2011)

This study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non-small-cell lung cancer (NSCLC).Patients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m(2) days 1 and 8 every 3 weeks plus cisplatin 75 mg/m(2) day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS). Results The study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P = .003) and 0.63 (95% CI, 0.43 to 0.92; P = .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P = .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent.Although the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC.
A single amino acid mutation in a protein antigen abrogates presentation of certain T cell determinants.
Authors: A Finnegan, C F Amburgey
Journal: The Journal of Experimental Medicine (1989)

Nase-specific T cell recognize the 86-100 peptide in association with B10.A APC. Clone N40 recognizes the 86-100 peptide in association with B10.A (Ek alpha Ek beta) and B10.A (5R) (Ek alpha Eb beta) APCs. We demonstrate here that a single amino acid substitution in the staphylococcal nuclease protein alters the structure of the processed peptide such that the T cell epitope recognized by clone N40 was only available for recognition in conjunction with B10.A (5R) but not the B10.A APCs. Other Nase-specific T cells recognize the mutant nuclease, and a synthetic peptide corresponding to the immunodominant region of the mutant protein was stimulatory for all the Nase-specific T cells. These results suggest that the mutation either affects the processing of the protein into antigenic peptides or affects the conformation of the processed fragment differently from that of the peptide.
Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery
Authors: Jaya Mishra, Catherine Dent, Ridwan Tarabishi, Mark M Mitsnefes, Qing Ma, Caitlin Kelly, Stacey M Ruff, Kamyar Zahedi, Mingyuan Shao, Judy Bean, Kiyoshi Mori, Jonathan Barasch, Prasad Devarajan
Journal: The Lancet (2005)
Results From a Prospective, Open-Label, Phase II Trial of Bendamustine in Refractory or Relapsed T-Cell Lymphomas: The BENTLY Trial
Authors: Gandhi Damaj, Rémy Gressin, Krimo Bouabdallah, Guillaume Cartron, Bachra Choufi, Emmanuel Gyan, Anne Banos, Arnaud Jaccard, Sophie Park, Olivier Tournilhac, Jean-Marc Schiano-de Collela, Laurent Voillat, Bertrand Joly, Steven Le Gouill, Alain Saad, Pascale Cony-Makhoul, Jean-Pierre Vilque, Laurence Sanhes, Aline Schmidt-Tanguy, Michael Bubenheim, Roch Houot, Momar Diouf, Jean-Pierre Marolleau, Marie-Christine Béné, Antoine Martin, Thierry Lamy
Journal: Journal of Clinical Oncology (2012)

To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas.Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m(2) per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS).Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%).Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.
Association of Insulin Resistance, Hyperleptinemia, and Impaired Nitric Oxide Release With In-Stent Restenosis in Patients Undergoing Coronary Stenting
Authors: PierMarco Piatti, Carlo Di Mario, Lucilla D. Monti, Gabriele Fragasso, Fabio Sgura, Andrea Caumo, Emanuela Setola, Pietro Lucotti, Elena Galluccio, Cristina Ronchi, Anna Origgi, Ivana Zavaroni, Alberto Margonato, Antonio Colombo
Journal: Circulation (2003)

Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting.Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only DeltaAUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up.We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.
Retinoids Inhibit the Actions of Angiotensin II on Vascular Smooth Muscle Cells
Authors: Volker Haxsen, Sylvie Adam-Stitah, Eberhard Ritz, Jürgen Wagner
Journal: Circulation Research (2001)

Abstract — Retinoids are derivatives of vitamin A and powerful inhibitors of cell proliferation and inflammation. Angiotensin II (Ang II) contributes to vascular lesions by promoting cell growth of vascular smooth muscle cells (VSMCs). Therefore, we examined whether retinoids interfere with the proproliferative actions of Ang II in VSMCs via AT 1 receptor–dependent or activator protein-1 (AP-1)–dependent mechanisms. VSMCs express retinoid receptor proteins, ie, retinoic acid receptor (RAR) α and retinoid X receptor (RXR) α. Long-term exposure to 1 μmol/L all- trans retinoic acid (RA) dose-dependently inhibited Ang II–induced cell proliferation ( P &lt;0.005) as well as DNA and protein synthesis ( P &lt;0.001). All- trans RA blocked Ang II stimulation of transforming growth factor-β 1 mRNA ( P &lt;0.005). All- trans RA inhibition of vascular VSMC growth was mediated both via RAR- and RXR-dependent pathways, as shown by receptor-specific synthetic retinoids. Transfection experiments revealed that inhibition of AP-1–dependent gene transcription is one mechanism by which all- trans RA inhibits Ang II action. RARα cotransfection enhanced the anti–AP-1 effects of all- trans RA dose-dependently. AP-1 activity was similarly inhibited by cotransfection with either RARα or RXRα. Ang II–induced gene expression of c-fos was abrogated by all- trans RA treatment ( P &lt;0.005). In VSMCs, all- trans RA downregulated AT 1 receptor mRNA ( P &lt;0.01) and reduced B max ( P &lt;0.001). All- trans RA repressed Ang II–stimulated AT 1 receptor promoter activity. The all- trans RA inhibitory effect was abolished when the AP-1 consensus site on the AT 1 receptor promoter was deleted. Our findings demonstrate that retinoids are potent inhibitors of the actions of Ang II on VSMCs. The findings support the notion that retinoids may interfere with proliferative vascular disease.
Infectious Agents Are Not Necessary for Murine Atherogenesis
Authors: Samuel D. Wright, Charlotte Burton, Melba Hernandez, Heide Hassing, Judy Montenegro, Steve Mundt, Sushma Patel, Deborah J. Card, Anne Hermanowski-Vosatka, James D. Bergstrom, Carl P. Sparrow, Patricia A. Detmers, Yu-Sheng Chao
Journal: The Journal of Experimental Medicine (2000)

Recent work has revealed correlations between bacterial or viral infections and atherosclerotic disease. One particular bacterium, Chlamydia pneumoniae, has been observed at high frequency in human atherosclerotic lesions, prompting the hypothesis that infectious agents may be necessary for the initiation or progression of atherosclerosis. To determine if responses to gram-negative bacteria are necessary for atherogenesis, we first bred atherosclerosis-prone apolipoprotein (apo) E(-/)- (deficient) mice with animals incapable of responding to bacterial lipopolysaccharide. Atherogenesis was unaffected in doubly deficient animals. We further tested the role of infectious agents by creating a colony of germ-free apo E(-/)- mice. These animals are free of all microbial agents (bacterial, viral, and fungal). Atherosclerosis in germ-free animals was not measurably different from that in animals raised with ambient levels of microbial challenge. These studies show that infection is not necessary for murine atherosclerosis and that, unlike peptic ulcer, Koch's postulates cannot be fulfilled for any infectious agent in atherosclerosis.
From clot to collagen: coagulation peptides in interstitial lung disease
Authors: K Dabbagh, RC Chambers, GJ Laurent
Journal: European Respiratory Journal (1998)

The fragile architecture of the lung is constantly threatened by a barrage of insults originating from both air and blood interfaces. The necessity to protect our lungs has lead to the evolution of exquisite defence systems. These comprise a complex screen of antioxidants, a mucocilliary escalator which is constantly clearing the respiratory tract and sophisticated immune defence mechanisms. When the insult involves vascular damage, the coagulation cascade is activated and is responsible for preventing blood loss at sites of injury by promoting the generation of a fibrin clot. This is vital for haemostasis, but chronic activation of this cascade with persistent fibrin deposition is frequently observed in respiratory diseases involving both the airways (e.g. asthma, chronic obstructive pulmonary disease) and the lung parenchyma (e.g. interstitial lung disease). It is often speculated that these events might be important in the pathogenesis of these diseases, but solid evidence for this has been scarce and, until quite recently, researchers have failed to provide data which could link the features of these diseases (i.e. chronic inflammation and tissue repair) to any known actions of coagulation cascade proteins. In this article, we will review research developments which suggest an ever increasing range of cellular functions for elements of the coagulation cascade. These functions are such that many of the pro-inflammatory and fibroproliferative events which are commonly observed in respiratory diseases, and are most commonly ascribed to elements of a cytokine network, could in fact be orchestrated by proteins of the coagulation cascade. This article will focus on the relevance of these proteins in interstitial lung diseases in which tissue repair and fibrosis are commonly observed.
A Breast Cancer Risk Haplotype in the Caspase-8 Gene
Authors: Neil Duncan Shephard, Ryan Abo, Sushila Harkisandas Rigas, Bernd Frank, Wei-Yu Lin, Ian Wallace Brock, Adam Shippen, Sabapathy Prakash Balasubramanian, Malcolm Walter Ronald Reed, Claus Rainer Bartram, Alfons Meindl, Rita Katharina Schmutzler, Christoph Engel, Barbara Burwinkel, Lisa Anne Cannon-Albright, Kristina Allen-Brady, Nicola Jane Camp, Angela Cox
Journal: Cancer Research (2009)

Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P=8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q=0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.
Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system
Authors: Steven D. Crowley, Susan B. Gurley, Michael I. Oliverio, A. Kathy Pazmino, Robert Griffiths, Patrick J. Flannery, Robert F. Spurney, Hyung-Suk Kim, Oliver Smithies, Thu H. Le, Thomas M. Coffman
Journal: Journal of Clinical Investigation (2005)

Angiotensin II, acting through type 1 angiotensin (AT1) receptors, has potent effects that alter renal excretory mechanisms. Control of sodium excretion by the kidney has been suggested to be the critical mechanism for blood pressure regulation by the renin-angiotensin system (RAS). However, since AT1 receptors are ubiquitously expressed, precisely dissecting their physiological actions in individual tissue compartments including the kidney with conventional pharmacological or gene targeting experiments has been difficult. Here, we used a cross-transplantation strategy and AT1A receptor–deficient mice to demonstrate distinct and virtually equivalent contributions of AT1 receptor actions in the kidney and in extrarenal tissues to determining the level of blood pressure. We demonstrate that regulation of blood pressure by extrarenal AT1A receptors cannot be explained by altered aldosterone generation, which suggests that AT1 receptor actions in systemic tissues such as the vascular and/or the central nervous systems make nonredundant contributions to blood pressure regulation. We also show that interruption of the AT1 receptor–mediated short-loop feedback in the kidney is not sufficient to explain the marked stimulation of renin production induced by global AT1 receptor deficiency or by receptor blockade. Instead, the renin response seems to be primarily determined by renal baroreceptor mechanisms triggered by reduced blood pressure. Thus, the regulation of blood pressure by the RAS is mediated by AT1 receptors both within and outside the kidney.
Effect of yoga training on handgrip, respiratory pressures and pulmonary function
Authors: T Prabhakar Reddy
Journal: British Journal of Sports Medicine (2010)

Although there are a number of reports on the effect of yoga training on pulmonary functions, very few studies have been undertaken on the effect of yoga training on respiratory pressures and handgrip endurance. Hence the present work was planned to study the effect of yoga training on hand grip strength (HGS), hand grip endurance, forced expiratory volume (FEV), forced expiratory volume in 1 s (FEV 1 ) and peak expiratory flow rate (PEFR), 20 school children in the age group of 12–15 years were given yoga training (asanas and pranayama) for 6 months, 20 age and gender matched students formed the control group. Yoga training produced statistically significant (p &lt; 0.05) increase in HGS and HE, MEP, MIP, FEV, FEV 1 , PEFR also increased significantly (p &lt;0.01) after the yoga training. In contrast, the increase in these parameters in the control group was statistically insignificant. One study shows that yoga training for 6 months improves lung function, strength of inspiratory and expiratory muscles as well as skeletal muscle strength and endurance. It is suggested that yoga be introduced at school level in order to improve physiological functions, overall health and performance of students.