tbuckley/cabot-search huggingface dataset:
Hypoxic Induction of the Hypoxia-Inducible Factor Is Mediated via the Adaptor Protein Shc in Endothelial Cells
Authors: Frank Jung, Judith Haendeler, Jörg Hoffmann, Agnes Reissner, Elisabeth Dernbach, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation Research (2002)

Tyrosine kinase cascades may play a role in the hypoxic regulation of hypoxia-inducible factor (HIF)-1. We investigated the role of tyrosine kinase phosphorylation and of the Shc/Ras cascade on hypoxic HIF-1 stabilization. Exposure of human umbilical vein endothelial cells to hypoxia results in HIF protein stabilization as early as 10 minutes, with a maximum at 3 hours, and also in Shc tyrosine phosphorylation, with a maximum at 10 minutes. To test whether Shc directly mediates hypoxia-induced HIF stabilization, human umbilical vein endothelial cells were transfected with a dominant-negative Shc mutant (dnShc), resulting in significantly reduced HIF protein levels compared with control. Similar results were obtained with cells transfected with dominant-negative Ras, a known downstream effector of Shc. Hypoxia-induced Ras activity was significantly reduced in cells transfected with dnShc compared with control levels, indicating that Ras indeed acts downstream from Shc. Moreover, cells pretreated with a specific Raf-1 kinase inhibitor, a known downstream effector of Ras, exhibited reduced HIF protein levels. To examine the functional consequences of Shc in hypoxic signaling, HIF-1 ubiquitination, protein stabilization, and endothelial cell migration were assessed. Overexpression of dnShc increased ubiquitination of HIF-1 and reduced the half-life of the protein. Moreover, dnShc, dominant-negative Ras, or the Raf-1 kinase inhibitor significantly inhibited migration under hypoxia. Thus, Shc in concert with Ras and Raf-1 contributes to hypoxia-induced HIF-1α protein stabilization and endothelial cell migration.
SMBE Proposal to the Government of Japan
Authors: K. Wolfe, M. L. Wayne, K. Makova, T. Y. Steen, M. Uyenoyama, N. Takahata
Journal: Molecular Biology and Evolution (2011)

Ken Wolfe, Marta L. Wayne, Kateryna Makova, Tomoko Y. Steen, Marcy Uyenoyama, and Naoyuki Takahata Smurfit Institute of Genetics, Trinity College, University of Dublin, Ireland Department of Biology, University of Florida, USA Department of Biology, Pennsylvania State University, USA Department of History, Johns Hopkins University, USA Department of Biology, Duke University, USA The Graduate University for Advanced Studies, Japan
Do we understand why regression of left ventricular hypertrophy is beneficial?
Authors: E Kaplinsky
Journal: Cardiovascular Research (2003)

See article by Botchway et al. [12] (pages 510–517) in this issue .

Hypertrophy is the mechanism by which muscle, any muscle, copes with persistent and repetitive overloads. Any increase in cardiac chamber radius ( r ) and/or pressure ( p ) will result in a proportional increase in total wall tension ( T ) according to the ideal Laplace formula, T = pr . The true load on the individual myocardial fibers can be appreciated by dividing the tension by the width of the chamber wall ( h ): T s=( pr )/ h . The result is the tensile stress (here, T s), which is the force exerted across an area. With an increase in afterload (e.g. essential hypertension, aortic stenosis), the increase in the resultant wall tension and stress triggers almost immediately the synthesis of new contractile elements. The increase in wall thickness will then reduce wall stress towards normal while maintaining the increase in wall tension, although not without a price. The negative side is the associated increase in extracellular matrix and fibroblasts, the reduced coronary flow reserve, and increased chamber stiffness. Until 1960, the major complications of the disease processes causing left ventricular hypertrophy …
Electrical behavior of T-Wave polarity alternans in patients with congenital long QT syndrome
Authors: Fernando E.S Cruz Filho, Ivan G Maia, Márcio L.A Fagundes, Rosa Celia P Barbosa, Paulo A.G Alves, Roberto M.S Sá, Silvia H Boghossian, Jose Carlos Ribeiro
Journal: Journal of the American College of Cardiology (2000)
The Effect of Exogenous Glucose-Dependent Insulinotropic Polypeptide in Combination With Glucagon-Like Peptide-1 on Glycemia in the Critically Ill
Authors: Michael Y. Lee, Jonathan D. Fraser, Marianne J. Chapman, Krishnaswamy Sundararajan, Mahesh M. Umapathysivam, Matthew J. Summers, Antony V. Zaknic, Christopher K. Rayner, Juris J. Meier, Michael Horowitz, Adam M. Deane
Journal: Diabetes Care (2013)

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have additive insulinotropic effects when coadministered in health. We aimed to determine whether GIP confers additional glucose lowering to that of GLP-1 in the critically ill.Twenty mechanically ventilated critically ill patients without known diabetes were studied in a prospective, randomized, double-blind, crossover fashion on 2 consecutive days. Between T0 and T420 minutes, GLP-1 (1.2 pmol/kg·min(-1)) was infused intravenously with either GIP (2 pmol/kg·min(-1)) or 0.9% saline. Between T60 and T420 minutes, nutrient liquid was infused into the small intestine at 1.5 kcal/min.Adding GIP did not alter blood glucose or insulin responses to small intestinal nutrient. GIP increased glucagon concentrations slightly before nutrient delivery (P=0.03), but not thereafter.The addition of GIP to GLP-1 does not result in additional glucose-lowering or insulinotropic effects in critically ill patients with acute-onset hyperglycemia.
Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death
Authors: Dipanjan Chowdhury, Judy Lieberman
Journal: Annual Review of Immunology (2008)

The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.
Association between Large-scale Genomic Homozygosity without Chromosomal Loss and Nonseminomatous Germ Cell Tumor Development
Authors: Yong-Jie Lu, Jinshu Yang, Elodie Noel, Spyros Skoulakis, Tracy Chaplin, Manoj Raghavan, Trisha Purkis, Alan Mcintyre, Sakunthala C. Kudahetti, Mahmoud Naase, Dan Berney, Janet Shipley, R. Timothy D. Oliver, Bryan D. Young
Journal: Cancer Research (2005)

Abstract The genotype of a tumor determines its biology and clinical behavior. The genetic alterations associated with the unique embryonal morphology of nonseminomatous subtypes of testicular germ cell tumors remain to be established. Using single nucleotide polymorphism microarray analysis, we found in all of the 15 nonseminomas analyzed, large-scale chromosomal homozygosities, most of which were not associated with relative chromosome loss. This unusual genotype, distinguishing nonseminoma from seminomas and other human tumors, may be associated with the special embryonal development morphologic transition of this malignancy. Based on these genetic data, we hypothesized a new potential origin of nonseminomas through sperm fusion. Nonrandom involvement of certain chromosomes also suggests that genes on these chromosome regions may play an important role in nonseminoma development.
Accelerated neutrophil apoptosis in the acquired immunodeficiency syndrome.
Authors: D L Pitrak, H C Tsai, K M Mullane, S H Sutton, P Stevens
Journal: Journal of Clinical Investigation (1996)

Neutrophil (PMNL) function defects occur as a consequence of HIV infection. This study examined PMNL apoptosis in patients with the acquired immunodeficiency syndrome (AIDS) to determine if accelerated apoptosis contributes to impaired function. PMNL were isolated from 10 HIV-infected patients with CD4+ lymphocyte counts < 200/mm3 without signs of active infection and 7 healthy volunteers. PMNL were stained with acridine orange and ethidium bromide after 0, 3, 6, and 18 h in culture, and examined for the morphologic changes of apoptosis and viability by fluorescent microscopy. Apoptosis was also demonstrated by electron microscopy, flow cytometry, and DNA gel electrophoresis. Apoptosis was minimal at 0 h, but PMNL from AIDS patients exhibited significantly greater apoptosis than controls at 3 h (22.5+/-11.5 vs. 8.9+/-6.9%, P = 0.015), 6 h (38.1+/-14.2 vs. 18.1+/-4.5%, P = 0.003), and 18 h (71.3+/-19.0 vs. 38.8+/-16.7%, P = 0.002). Viabilities were > or = 88.0% for both groups from 0-6 h, but by 18 h viability was significantly decreased for the HIV group (58.8+/-12.4 vs. 83.5+/-10.4%, P = 0.001) due to an increase in non-viable apoptotic cells. Incubation with serum from AIDS patients had no effect on control PMNL, and incubation with control serum did not reduce the rate of apoptosis of PMNL from AIDS patients. Incubation with granulocyte colony-stimulating factor (G-CSF) in vitro significantly decreased apoptosis for PMNL from AIDS patients. PMNL from patients with AIDS exhibit markedly accelerated apoptosis ex vivo. In vivo, apoptosis and functional impairment of PMNL may contribute to the risk of secondary infections, and cytokine therapy may be of potential clinical benefit in this circumstance.
Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin
Authors: Jianmin Ding, Hirokazu Komatsu, Atsushi Wakita, Miyuki Kato-Uranishi, Masato Ito, Atsushi Satoh, Kazuya Tsuboi, Masakazu Nitta, Hiroshi Miyazaki, Shinsuke Iida, Ryuzo Ueda
Journal: Blood (2004)
Enhancing Incretin Action for the Treatment of Type 2 Diabetes
Authors: Daniel J. Drucker
Journal: Diabetes Care (2003)

OBJECTIVE—To examine the mechanisms of action, therapeutic potential, and challenges inherent in the use of incretin peptides and dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment of type 2 diabetes. RESEARCH DESIGN AND METHODS—The scientific literature describing the biological importance of incretin peptides and DPP-IV inhibitors in the control of glucose homeostasis has been reviewed, with an emphasis on mechanisms of action, experimental diabetes, human physiological experiments, and short-term clinical studies in normal and diabetic human subjects. RESULTS—Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) exert important effects on β-cells to stimulate glucose-dependent insulin secretion. Both peptides also regulate β-cell proliferation and cytoprotection. GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of GLP-1, but not GIP, are preserved in subjects with type 2 diabetes. However, native GLP-1 is rapidly degraded by DPP-IV after parenteral administration; hence, degradation-resistant, long-acting GLP-1 receptor (GLP-1R) agonists are preferable agents for the chronic treatment of human diabetes. Alternatively, inhibition of DPP-IV–mediated incretin degradation represents a complementary therapeutic approach, as orally available DPP-IV inhibitors have been shown to lower glucose in experimental diabetic models and human subjects with type 2 diabetes. CONCLUSIONS—GLP-1R agonists and DPP-IV inhibitors have shown promising results in clinical trials for the treatment of type 2 diabetes. The need for daily injections of potentially immunogenic GLP-1–derived peptides and the potential for unanticipated side effects with chronic use of DPP-IV inhibitors will require ongoing scrutiny of the risk-benefit ratio for these new therapies as they are evaluated in the clinic.
Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study
Authors: Kirsten K. Ness, Kevin R. Krull, Kendra E. Jones, Daniel A. Mulrooney, Gregory T. Armstrong, Daniel M. Green, Wassim Chemaitilly, Webb A. Smith, Carmen L. Wilson, Charles A. Sklar, Kyla Shelton, Deo Kumar Srivastava, Sabeen Ali, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2013)

Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Prevention of Recurrent Lone Atrial Fibrillation by the Angiotensin-II Converting Enzyme Inhibitor Ramipril in Normotensive Patients
Authors: Fabio Belluzzi, Laura Sernesi, Paola Preti, Francesco Salinaro, Maria Luisa Fonte, Stefano Perlini
Journal: Journal of the American College of Cardiology (2008)
Effects of 3-nitro-l-tyrosine on thyroid function in the rat: an experimental model for the dehalogenase defect
Authors: William L. Green
Journal: Journal of Clinical Investigation (1971)

The effects on thyroid function of an inhibitor of tyrosine dehalogenase, 3-nitro-L-tyrosine (MNT) have been investigated in rats. In preliminary studies, marked inhibition of iodotyrosine deiodination was demonstrated in rats drinking 8 mM MNT. A series of experiments was then performed in which rats received Remington low iodine diet and 8 mM MNT as drinking fluid. This regimen had the following effects, compared to the effects of a low iodine diet alone: (a) a decrease in serum protein-bound iodine, elevation of serum thyrotropin level, goiter, and growth inhibition all prevented or reversed by iodine supplements: (b) on initiation of MNT, a 2- to 3-fold increase in the rate of release of radioiodine from the thyroid and concomitant urinary excretion of large amounts of organic iodine: and (c) after 2 wk of MNT, a greatly increased rate of thyroidal uptake and release of (131)I, an increase in the ratio of monoiodotyrosine-(131)I to diiodotyrosine-(131)I in thyroid proteolysates and the appearance of labeled iodotyrosines in serum. Acute administration of MNT intraperitoneally to rats on either an iodine-deficient or iodine-sufficient diet did not inhibit thyroidal uptake of (131)I or alter the distribution of (131)I among thyroidal iodoamino acids. It is concluded that MNT is an effective inhibitor of iodotyrosine deiodination in vivo, without other important actions on thyroid function. Thus, MNT treatment affords a model for the human dehalogenase defect. By provoking iodotyrosine secretion and consequent urinary loss of iodine, MNT can exaggerate the effects of a low iodine intake, producing goitrous hypothyroidism despite a rapid rate of iodine turnover in the thyroid.
NITROXYL (HNO): Chemistry, Biochemistry, and Pharmacology
Authors: Jon M. Fukuto, Christopher H. Switzer, Katrina M. Miranda, David A. Wink
Journal: The Annual Review of Pharmacology and Toxicology (2005)

▪ Abstract Recent discoveries of novel and potentially important biological activity have spurred interest in the chemistry and biochemistry of nitroxyl (HNO). It has become clear that, among all the nitrogen oxides, HNO is unique in its chemistry and biology. Currently, the intimate chemical details of the biological actions of HNO are not well understood. Moreover, many of the previously accepted chemical properties of HNO have been recently revised, thus requiring reevaluation of possible mechanisms of biological action. Herein, we review these developments in HNO chemistry and biology.
Cetuximab Plus Mfolfox-6 As First-Line Therapy for Patients with Kras Wild-Type Unresectable Colorectal Liver-Limited Metastases: an Open, Non-Randomized, Multicenter Phase Ii Clinical Trial (Clime Study)
Authors: S. Cai, W. Zhang, W. Li, Y. Xu, W. Gu, Z. Guan, J. Cai, C. Song, J. Xu, P. Chi, J. Lin, K. Zhang, D. Li, X. Wang, H. Pei, X. Zhang, D. Wan, J. Wang, C. Dang, X. Yuan
Journal: Annals of Oncology (2014)
Susceptibility of Cholangiocarcinoma Cells to Parthenolide-Induced Apoptosis
Authors: Jong-Hyun Kim, Lan Liu, Seung-Ok Lee, Yong-Tae Kim, Kyung-Ran You, Dae-Ghon Kim
Journal: Cancer Research (2005)

Abstract Cholangiocarcinomas are intrahepatic bile duct carcinomas that are known to have a poor prognosis. Sesquiterpene lactone parthenolide, which is the principal active component in medicinal plants, has been used to treat tumors. Parthenolide effectively induced apoptosis in all four cholangiocarcinoma cell lines in a dose-dependent manner. However, the sarcomatous SCK cells were more sensitive to parthenolide than the other adenomatous cholangiocarcinoma cells. Therefore, this study investigated whether or not the expression of p53, the Fas/Fas ligand (FasL), Bcl-2/Bcl-XL determines the enhanced drug susceptibility of SCK cells. The results showed that Bcl-2 family molecules, such as Bid, Bak, and Bax, are involved in the parthenolide-induced apoptosis and that the defective expression of Bcl-XL might contribute to the higher parthenolide sensitivity in the SCK cells than in the other adenomatous cholangiocarcinoma cells. SCK cells, which stably express Bcl-XL, were resistant to parthenolide, whereas Bcl-XL-positive Choi-CK cells transfected with the antisense Bcl-XL showed a higher parthenolide sensitivity than the vector control cells. Molecular dissection revealed that Bcl-XL inhibited the translocation of Bax to the mitochondria, decreased the generation of intracellular reactive oxygen species, reduced the mitochondrial transmembrane potential (ΔΨm), decreased the release of cytochrome c, decreased the cleavage of poly(ADP-ribose) polymerase, and eventually inhibited apoptotic cell death. These results suggest that parthenolide effectively induces oxidative stress-mediated apoptosis, and that the susceptibility to parthenolide in cholangiocarcinoma cells might be modulated by Bcl-XL expression in association with Bax translocation to the mitochondria.
Adaptation to Stimulus Statistics in the Perception and Neural Representation of Auditory Space
Authors: Johannes C. Dahmen, Peter Keating, Fernando R. Nodal, Andreas L. Schulz, Andrew J. King
Journal: Neuron (2010)

Sensory systems are known to adapt their coding strategies to the statistics of their environment, but little is still known about the perceptual implications of such adjustments. We investigated how auditory spatial processing adapts to stimulus statistics by presenting human listeners and anesthetized ferrets with noise sequences in which interaural level differences (ILD) rapidly fluctuated according to a Gaussian distribution. The mean of the distribution biased the perceived laterality of a subsequent stimulus, whereas the distribution's variance changed the listeners' spatial sensitivity. The responses of neurons in the inferior colliculus changed in line with these perceptual phenomena. Their ILD preference adjusted to match the stimulus distribution mean, resulting in large shifts in rate-ILD functions, while their gain adapted to the stimulus variance, producing pronounced changes in neural sensitivity. Our findings suggest that processing of auditory space is geared toward emphasizing relative spatial differences rather than the accurate representation of absolute position.
Systemic and microcirculatory responses to progressive hemorrhage
Authors: Arnaldo Dubin, Mario Omar Pozo, Gonzalo Ferrara, Gastón Murias, Enrique Martins, Carlos Canullán, Héctor Saul Canales, Vanina Siham Kanoore Edul, Elisa Estenssoro, Can Ince
Journal: Intensive Care Medicine (2009)
A critical study of sports talent selection and promotion of sports participation, at young age
Authors: Devinder K Kansal
Journal: British Journal of Sports Medicine (2010)

It has been a long drawn effort of the author to draw attention of the authorities to the importance and emphasis needed to be given to the question of most appropriate talent selection at young age for prospective excellence in sports. Unfortunately non-existence of graduation degree in sports coaching in India and wide spread unawareness, among departments and institutions of higher education in physical education and sports to the fields of physical growth, development, physique and physiological variations prevalent in India, children are left to select mostly sports unsuitable to their adult body potentials. The present study has been based on survey and critical analysis and new interpretations of existing research data on Olympic Champions (Carter 1984; Hirata 1979; Tanner 1964). In general, coaches and sports federations in India have been found to lack not only in the application of existing scientific principles but also in developing or maintaining any library or any literature on talent selection, or on measurement and evaluation even at any offices of national and state level sports associations/federations. The study has presented the scientific results on talent selection in a suitable form to make it easy to be used by the sports trainers and sports counsellors. Critical points of failure in the talent selection at young age have been dealt with scientifically along with a mapping of the long term plans and easy solutions for removing many hurdles currently in implementation of scientific preparation of Indian teams for national and international participation. Findings have also been reported to improve the number of sports participants in the country through proper talent selection at young age. The present population of sportspersons in India is extremely less, being less than 1% of the students up to middle schools and less than 10% of the students in colleges and universities. It has been proposed for better sports talent grooming that all high schools should be given sports infrastructure for training and participation in atleast one outdoor sport and one indoor sport/fitness activity. Each school must be accordingly required to participate in inter scholastic competitions in atleast these two sports or one sports and one fitness event. Prediction of adult physique at young age and scientific selection of most suitable sports has been presented in the present paper, to be presented in the Commonwealth Games 2010 Conference. It has also been explained that there is an urgent need to start an international CAKE (ie, Centre of Application of Knowledge Existing in the field of Sports research literature for preparing key guidelines for talent selection at young age). Sports participation will be increased many fold if children are guided properly to select a right sport as per their adult physiques and sports potentials.