tbuckley/cabot-search huggingface dataset:
Pharmacological and physiological stimuli do not promote Ca<sup>2+</sup>-sensitive K<sup>+</sup>channel activity in isolated heart mitochondria
Authors: Douglas V. Cancherini, Bruno B. Queliconi, Alicia J. Kowaltowski
Journal: Cardiovascular Research (2006)

Objective: Mitochondrial calcium-activated K+ (mitoKCa) channels have been described as channels that are activated by Ca2+, inner mitochondrial membrane depolarization and drugs such as NS-1619. NS-1619 is cardioprotective, leading to the assumption that this effect is related to the opening of mitoKCa channels. Here, we show several weaknesses in this hypothesis.
Biologic Monitoring to Characterize Organophosphorus Pesticide Exposure among Children and Workers: An Analysis of Recent Studies in Washington State
Authors: Richard A. Fenske, Chensheng Lu, Cynthia L. Curl, Jeffry H. Shirai, John C. Kissel
Journal: Environmental Health Perspectives (2005)

We examined findings from five organophosphorus pesticide biomonitoring studies conducted in Washington State between 1994 and 1999. We compared urinary dimethylthiophosphate (DMTP) concentrations for all study groups and composite dimethyl alkylphosphate (DMAP) concentrations for selected groups. Children of pesticide applicators had substantially higher metabolite levels than did Seattle children and farmworker children (median DMTP, 25 μg/L; p < 0.0001). Metabolite levels of children living in agricultural communities were elevated during periods of crop spraying. Median DMTP concentrations for Seattle children and farmworker children did not differ significantly (6.1 and 5.8 μg/L DMTP, respectively; p = 0.73); however, the DMAP concentrations were higher for Seattle children than for farmworker children (117 and 87 nmol/L DMAP, respectively; p = 0.007). DMTP concentrations of U.S. children 6–11 years of age (1999–2000 National Health and Nutrition Examination Survey population) were higher than those of Seattle children and farmworker children at the 75th, 90th, and 95th percentiles. DMTP concentrations for workers actively engaged in apple thinning were 50 times higher than DMTP concentrations for farmworkers sampled outside of peak exposure periods. We conclude that workers who have direct contact with pesticides should continue to be the focus of public health interventions and that elevated child exposures in agricultural communities may occur during active crop-spraying periods and from living with a pesticide applicator. Timing of sample collection is critical for the proper interpretation of pesticide biomarkers excreted relatively soon after exposure. We surmise that differences in dietary exposure can explain the similar exposures observed among farmworker children, children living in the Seattle metropolitan area, and children sampled nationally.
Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model
Authors: Nobuyasu Shindo, Tomomi Fujisawa, Ken Sugimoto, Koji Nojima, Aya Oze-Fukai, Yuki Yoshikawa, Xiang Wang, Osamu Yasuda, Hiroshi Ikegami, Hiromi Rakugi
Journal: Journal of Hepatology (2010)
Antibiotic treatment for 6 weeks versus 12 weeks in patients with pyogenic vertebral osteomyelitis: an open-label, non-inferiority, randomised, controlled trial
Authors: Louis Bernard, Aurélien Dinh, Idir Ghout, David Simo, Valerie Zeller, Bertrand Issartel, Vincent Le Moing, Nadia Belmatoug, Philippe Lesprit, Jean-Pierre Bru, Audrey Therby, Damien Bouhour, Eric Dénes, Alexa Debard, Catherine Chirouze, Karine Fèvre, Michel Dupon, Philippe Aegerter, Denis Mulleman
Journal: The Lancet (2014)
The association of environmental heat stress with performance: analysis of the 2014 FIFA World Cup Brazil
Authors: George P Nassis, Joao Brito, Jiri Dvorak, Hakim Chalabi, Sebastien Racinais
Journal: British Journal of Sports Medicine (2015)

The 2014 FIFA World Cup Brazil included 64 matches in temperate to tropical environmental conditions. We analysed performance data in relation to the environmental conditions to identify potential association.Wet-bulb globe temperature (WBGT) parameters were obtained at the centre of the field 1 h before the start of play. Environmental stress was estimated (low, moderate and high) for each match using WBGT and relative humidity. Various physical and technical performance indices were recorded during each match (average of both teams).Over the 64 matches, 28 were played under low, 20 under moderate and 16 under high environmental stress. There was no difference in actual playing time (p=0.517), total distance covered (p=0.491), number of goals scored (p=0.485) and number of cards (p=0.618) between the matches played under different environmental stress categories. The number of sprints was lower in high than in moderate or low environmental stress (-10%, p<0.05) but peak speed was unaffected. The distance covered at high intensity was also lower under high (24.8±2.8 m/min/player) than low environmental stress (26.9±2.3 m/min/player, p=0.02). Number of passes was not different but the rate of successful passes was higher under high (76.8±4.4%) than low (73.6±10.8%) environmental stress (p=0.031).Top-level players seem to modulate their activity pattern during matches in a hot and humid environment (ie, less high-intensity but more low-intensity running and successful passes) to preserve the global match characteristics (ie, similar actual playing time, total distance covered, peak running speed and goals scored).
Non-contact ACL injuries in female athletes: an International Olympic Committee current concepts statement
Authors: P Renstrom, A Ljungqvist, E Arendt, B Beynnon, T Fukubayashi, W Garrett, T Georgoulis, T E Hewett, R Johnson, T Krosshaug, B Mandelbaum, L Micheli, G Myklebust, E Roos, H Roos, P Schamasch, S Shultz, S Werner, E Wojtys, L Engebretsen
Journal: British Journal of Sports Medicine (2008)

The incidence of anterior cruciate ligament (ACL) injury remains high in young athletes. Because female athletes have a much higher incidence of ACL injuries in sports such as basketball and team handball than male athletes, the IOC Medical Commission invited a multidisciplinary group of ACL expert clinicians and scientists to (1) review current evidence including data from the new Scandinavian ACL registries; (2) critically evaluate high-quality studies of injury mechanics; (3) consider the key elements of successful prevention programmes; (4) summarise clinical management including surgery and conservative management; and (5) identify areas for further research. Risk factors for female athletes suffering ACL injury include: (1) being in the preovulatory phase of the menstrual cycle compared with the postovulatory phase; (2) having decreased intercondylar notch width on plain radiography; and (3) developing increased knee abduction moment (a valgus intersegmental torque) during impact on landing. Well-designed injury prevention programmes reduce the risk of ACL for athletes, particularly women. These programmes attempt to alter dynamic loading of the tibiofemoral joint through neuromuscular and proprioceptive training. They emphasise proper landing and cutting techniques. This includes landing softly on the forefoot and rolling back to the rearfoot, engaging knee and hip flexion and, where possible, landing on two feet. Players are trained to avoid excessive dynamic valgus of the knee and to focus on the “knee over toe position” when cutting.
Comparative analysis indicates regulatory neofunctionalization of yeast duplicates
Authors: Itay Tirosh, Naama Barkai
Journal: Genome biology (2007)

Gene duplication provides raw material for the generation of new functions, but most duplicates are rapidly lost due to the initial redundancy in gene function. How gene function diversifies following duplication is largely unclear. Previous studies analyzed the diversification of duplicates by characterizing their coding sequence divergence. However, functional divergence can also be attributed to changes in regulatory properties, such as protein localization or expression, which require only minor changes in gene sequence.We developed a novel method to compare expression profiles from different organisms and applied it to analyze the expression divergence of yeast duplicated genes. The expression profiles of Saccharomyces cerevisiae duplicate pairs were compared with those of their pre-duplication orthologs in Candida albicans. Duplicate pairs were classified into two classes, corresponding to symmetric versus asymmetric rates of expression divergence. The latter class includes 43 duplicate pairs in which only one copy has a significant expression similarity to the C. albicans ortholog. These may present cases of regulatory neofunctionalization, as supported also by their dispensability and variability.Duplicated genes may diversify through regulatory neofunctionalization. Notably, the asymmetry of gene sequence evolution and the asymmetry of gene expression evolution are only weakly correlated, underscoring the importance of expression analysis to elucidate the evolution of novel functions.
Neurohormonal Regulation of Cardiac Histone Deacetylase 5 Nuclear Localization by Phosphorylation-Dependent and Phosphorylation-Independent Mechanisms
Authors: Robert S. Haworth, Konstantina Stathopoulou, Alexandra J. Candasamy, Metin Avkiran
Journal: Circulation Research (2012)

Myocyte enhancer factor 2 (MEF2) transcription factors drive the genetic reprogramming that precipitates pathological cardiac hypertrophy and remodeling. Class II histone deacetylase (HDAC) isoforms, such as HDAC5, act as signal-responsive repressors of MEF2 activity in cardiac myocytes and their nuclear export provides a key mechanism for the neurohormonal induction of such activity.To delineate the mechanism(s) through which 2 clinically relevant neurohormonal stimuli, endothelin-1 (ET1) and the β-adrenergic receptor (β-AR) agonist isoproterenol (ISO), may regulate HDAC5 nuclear localization in adult cardiac myocytes.ET1 induced HDAC5 phosphorylation and nuclear export in ventricular myocytes from the adult rat heart. Use of a novel, highly selective protein kinase D (PKD) inhibitor and a nonphosphorylatable HDAC5 mutant revealed that PKD-mediated phosphorylation was necessary for ET1-induced HDAC5 nuclear export. In contrast, ISO reduced HDAC5 phosphorylation in the presence or absence of ET1 but still induced HDAC5 nuclear export. ISO-induced HDAC5 nuclear export occurred through a β(1)-AR-mediated oxidative process that was independent of PKD, protein kinase A, and Ca(2+)/calmodulin-dependent kinase II activities. Although ET1 and ISO shared a similar ability to induce HDAC5 nuclear export, albeit through distinct phosphorylation-dependent versus phosphorylation-independent mechanisms, ISO induced a significantly greater increase in MEF2 activity.PKD-mediated HDAC5 phosphorylation and nuclear export are unlikely to be of major importance in regulating MEF2-driven cardiac remodeling in the presence of sympathetic activity with intact β(1)-AR signaling, which would not only counteract HDAC5 phosphorylation but also induce HDAC5 nuclear export through a novel phosphorylation-independent, oxidation-mediated mechanism. Inhibition of this mechanism may contribute to the therapeutic efficacy of β(1)-AR antagonists in heart failure.
Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling
Authors: Tai W. Wong, Francis Y. Lee, Chiang Yu, Feng R. Luo, Simone Oppenheimer, Hongjian Zhang, Richard A. Smykla, Harold Mastalerz, Brian E. Fink, John T. Hunt, Ashvinikumar V. Gavai, Gregory D. Vite
Journal: Clinical Cancer Research (2006)

The studies described here are intended to characterize the ability of BMS-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2.The potency and selectivity of BMS-599626 were assessed in biochemical assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was determined in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunoprecipitation. Antitumor activity of BMS-599626 was evaluated using a number of different xenograft models that represent a spectrum of human tumors with HER1 or HER2 overexpression.BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity.BMS-599626 is a highly selective and potent inhibitor of HER1 and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an additional mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth. The preclinical data support the advancement of BMS-599626 into clinical development for the treatment of cancer.
Second Malignant Neoplasms in Five-Year Survivors of Childhood Cancer: Childhood Cancer Survivor Study
Authors: J. P. Neglia, D. L. Friedman, Y. Yasui, A. C. Mertens, S. Hammond, M. Stovall, S. S. Donaldson, A. T. Meadows, L. L. Robison
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Because survival rates among childhood cancer patients are increasing, assessing the risk of second and subsequent malignant neoplasms (SMNs) is ever more important. Using the Childhood Cancer Survivor Study cohort, we identified the risk of SMNs. Methods: A retrospective cohort of 13 581 children diagnosed with common cancers before age 21 years and surviving at least 5 years was constructed with the use of data from patients treated at 25 U.S. and Canadian institutions. SMNs were ascertained through self-administered questionnaires and verified by pathology reports. Information on therapeutic exposures was abstracted from medical records. The risk of SMN was evaluated by standardized incidence ratios (SIRs) and excess absolute risk. Poisson multiple regression models were used to assess the impact of host and therapy factors on the risk of developing SMNs. All statistical tests were two-sided. Results: In 298 individuals, 314 SMNs were identified (SIR = 6.38; 95% confidence interval [CI] = 5.69 to 7.13). The largest observed excess SMNs were bone and breast cancers (SIR = 19.14 [95% CI = 12.72 to 27.67] and SIR = 16.18 [95% CI = 12.35 to 20.83], respectively). A statistically significant excess of SMNs followed all childhood cancers. In multivariate regression models adjusted for therapeutic radiation exposure, SMNs of any type were independently associated with female sex (P<.001), childhood cancer at a younger age (P for trend <.001), childhood Hodgkin's disease or soft-tissue sarcoma (P<.001 and P = .01, respectively), and exposure to alkylating agents (P for trend = .02). Twenty years after the childhood cancer diagnosis, the cumulative estimated SMN incidence was 3.2%. However, only 1.88 excess malignancies occurred per 1000 years of patient follow-up. Conclusions: Success in treating children with cancer should not be overshadowed by the incidence of SMNs. However, patients and health-care providers must be aware of risk factors for SMNs so that surveillance is focused and early prevention strategies are implemented.
CD20+ Tumor-Infiltrating Lymphocytes Have an Atypical CD27− Memory Phenotype and Together with CD8+ T Cells Promote Favorable Prognosis in Ovarian Cancer
Authors: Julie S. Nielsen, Rob A. Sahota, Katy Milne, Sara E. Kost, Nancy J. Nesslinger, Peter H. Watson, Brad H. Nelson
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Tumor-infiltrating lymphocytes (TIL), in particular CD8+ T cells and CD20+ B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8+ TIL can mediate direct cytolytic activity against tumors, the role of CD20+ TIL is poorly understood. Here, we investigate the possible contributions of CD20+ TIL to humoral and cellular tumor immunity. Experimental Design: Tumor and serum specimens were obtained from patients with high-grade serous ovarian cancer. CD8+ and CD20+ TIL were analyzed by immunohistochemistry and flow cytometry. Immunoglobulin molecules were evaluated by DNA sequencing. Serum autoantibody responses to the tumor antigens p53 and NY-ESO-1 were measured by ELISA. Results: The vast majority of CD20+ TIL were antigen experienced, as evidenced by class-switching, somatic hypermutation, and oligoclonality, yet they failed to express the canonical memory marker CD27. CD20+ TIL showed no correlation with serum autoantibodies to p53 or NY-ESO-1. Instead, they colocalized with activated CD8+ TIL and expressed markers of antigen presentation, including MHC class I, MHC class II, CD40, CD80, and CD86. The presence of both CD20+ and CD8+ TIL correlated with increased patient survival compared with CD8+ TIL alone. Conclusions: In high-grade serous ovarian tumors, CD20+ TIL have an antigen–experienced but atypical CD27− memory B-cell phenotype. They are uncoupled from serum autoantibodies, express markers of antigen-presenting cells, and colocalize with CD8+ T cells. We propose that the association between CD20+ TIL and patient survival may reflect a supportive role in cytolytic immune responses. Clin Cancer Res; 18(12); 3281–92. ©2012 AACR.
University of Wisconsin Solution Preserves Myocardial Calcium Current Response to Isoproterenol in Isolated Canine Ventricular Myocytes
Authors: Katsushige Ono, Naoki Gondo, Makoto Arita, Harry A. Fozzard, Tetsuo Hadama, Yuzo Uchida
Journal: Circulation (1995)

Background University of Wisconsin (UW) solution has been shown to be an effective solution for cold storage of various organs. This study was designed to evaluate the subcellular protective mechanism of UW solution during cardiac myocyte storage using patch-clamp techniques for the first time as a tool for the detection of myocyte viability. Methods and Results The protective effects of UW solution on the preservation of dihydropyridine-sensitive Ca 2+ channel current response to catecholamine were evaluated in canine cardiac ventricular cells by measurement of single channel open probability. Single ventricular myocytes were isolated and stored in UW solution, in Stanford (SF) solution, or in St Thomas’ (ST) solution at 4°C for 2, 6, 12, and 24 hours, and after each storage period, recordings were made of cell-attached single Ca 2+ channel currents. When 0.1 μmol/L isoproterenol was applied, percent mean open probability of the Ca 2+ channel tested in freshly isolated cells was 167±4% (n=24) of controls (100%). The response was decrescent with increased duration of the hypothermic storage and was only 130±12% (n=4) after 24 hours of storage in SF solution and 135±9% (n=7) in ST solution. However, it was significantly highly preserved as much as 165±9% (n=6) in UW solution. Ca 2+ channel kinetics and channel conductance were not changed after up to 24 hours of hypothermic storage. Conclusions Hypothermic storage of canine cardiac myocytes in UW solution preserved β-adrenergic response, which suggests that UW solution during cold storage preserved high-energy phosphates in myocytes that are responsible for Ca 2+ channel phosphorylations.
High cardiovascular disease mortality in subjects with visual impairment caused by diabetic retinopathy.
Authors: U Rajala, H Pajunpää, P Koskela, S Keinänen-Kiukaanniemi
Journal: Diabetes Care (2000)

OBJECTIVE: The aim of this study was to assess mortality and causes of death in subjects with visual impairment caused by diabetic retinopathy (DR). Only limited data are available concerning the mortality of subjects with DR, and to our knowledge, no data so far have been published on the mortality of subjects with visual impairment caused by DR. RESEARCH DESIGN AND METHODS: We identified 34 men and 73 women living in northern Finland with visual impairment caused by DR on 31 December 1993. The median age of the subjects was 71 years (range 27-88). The mortality of these 107 diabetic subjects was followed up for 4 years, until 31 December 1997, and compared with the mortality rates of 3 age- and sex-matched control groups. The first control group consisted of subjects treated for DR by laser coagulation from 1990 to 1993. The second control group consisted of diabetic subjects who had had fundus photographs taken from 1991 to 1992. The third control group comprised nondiabetic subjects selected from the population register. Information on deaths was obtained from official death certificates. RESULTS: A total of 91 diabetic and 10 nondiabetic subjects died during the follow-up. Of the deaths, 51 occurred in the subjects with visual impairment caused by DR, with a 4-year mortality rate of 477/1,000 (95% CI 382-571/1,000). Mortality rates were 224/1,000 (145-303/1,000) for the diabetic subjects with retinopathy treated by laser coagulation; 150/1,000 (82-217/1,000) for the diabetic subjects who had undergone fundus photography; and 94/1,000 (46-165/1,000) for the nondiabetic subjects. Cardiovascular diseases were the underlying cause of death in 55% of the subjects with visual impairment. Nephropathy was mentioned as the immediate cause of death for only 10% of the subjects. Compared with the nondiabetic control subjects, the odds ratios (ORs) for all-cause mortality were 5.1 (2.6-11) in the diabetic subjects with visual impairment caused by DR, and 5.6 (2.1-19) for mortality caused by diseases of the circulatory system. The ORs for all-cause mortality were 2.4 (1.1-5.6) in the diabetic subjects with retinopathy treated by laser coagulation and 1.6 (0.68-4.0) in the diabetic subjects with fundus photographs taken. CONCLUSIONS: The survival of diabetic subjects with visual impairment caused by DR was poor. The high mortality rate was attributed mainly to cardiovascular diseases. Therefore, severe retinopathy proves to be a risk marker of cardiovascular death in diabetic patients.