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Haynes B.P.,Royal Marsden Hospital | Straume A.H.,University of Bergen | Geisler J.,University of Oslo | A'Hern R.,Cancer Research UK Research Institute | And 4 more authors.
Clinical Cancer Research | Year: 2010

Purpose: The concentration of estradiol (E2) in breast tumors is significantly higher than that in plasma, particularly in postmenopausal women. The contribution of local E2 synthesis versus uptake of E 2 from the circulation is controversial. Our aim was to identify possible determinants of intratumoral E2 levels in breast cancer patients. Experimental Design: The expression of genes involved in estrogen synthesis, metabolism, and signaling was measured in 34 matched samples of breast tumor and normal breast tissue, and their correlation with estrogen concentrations assessed. Results: ESR1 (9.1-fold; P < 0.001) and HSD17B7 (3.5-fold; P < 0.001) were upregulated in ER+ tumors compared with normal tissues, whereas STS (0.34-fold; P < 0.001) and HSD17B5 (0.23-fold; P < 0.001) were downregulated. Intratumoral E2 levels showed a strong positive correlation with ESR1 expression in all patients (Spearman r = 0.55, P < 0.001) and among the subgroups of postmenopausal (r = 0.76, P < 0.001; n = 23) and postmenopausal ER+ patients (r = 0.59, P = 0.013; n = 17). HSD17B7 expression showed a significant positive correlation (r = 0.59, P < 0.001) whereas HSD17B2 (r = -0.46, P = 0.0057) and HSD17B12 (r = -0.45, P = 0.0076) showed significant negative correlations with intratumoral E 2 in all patients. Intratumoral E2 revealed no correlation to CYP19, STS, and HSD17B1 expression. Multivariate models comprising ESR1 and plasma E2 predicted between 50% and 70% of intratumoral E2 variability. Conclusion: Uptake due to binding to the ER, rather than intratumoral estrogen synthesis by aromatase or sulfatase, is the single most important correlate and a probable determinant of intratumoral E2. An increased expression of HSD17B7 may explain the increased ratio of E 2 to estrone (E1) in breast tumors compared with normal tissue. ©2010 AACR.

Taylor A.E.,University of Bath | Kemp S.,Medicine | Trewartha G.,University of Bath | Stokes K.A.,University of Bath
British Journal of Sports Medicine | Year: 2014

Objective To assess and evaluate the injury risk associated with the scrum in English professional rugby union in the 2011-2012 season. Design Prospective, cohort. Participants Players at English Premiership rugby union clubs. Outcome measures Frequency of team scrum-events per match; incidence (injuries per 1000 player-hours; propensity (injuries/1000 events); risk (days absence per 1000 player-hours and days absence per 1000 events). Results 31% of scrums in competitive matches resulted in collapse. Injury incidence associated with collapsed scrum-events (incidence: 8.6 injuries/1000 scrum-events) was significantly higher than those scrums that did not collapse (incidence: 4.1/1000 scrum-events). Conclusions The injury risk associated with collapsed scrum supports the continued focus on reducing scrum collapse through changes in, and strict application of, the laws surrounding the scrum.

Singh T.P.,Boston Childrens Hospital | Singh T.P.,Harvard University | Almond C.S.,Boston Childrens Hospital | Almond C.S.,Harvard University | And 4 more authors.
Circulation | Year: 2012

Background-Racial differences in long-term survival after heart transplant (HT) are well known. We sought to assess racial/ethnic differences in wait-list outcomes among patients listed for HT in the United States in the current era. Methods and Results-We compared wait-list and posttransplant in-hospital mortality among white, black, and Hispanic patients ≥18 years of age listed for their primary HT in the United States between July 2006 and September 2010. Of 10 377 patients analyzed, 71% were white, 21% were black, and 8% were Hispanic. Black and Hispanic patients were more likely to be listed with higher urgency (listing status 1A/1B) in comparison with white patients (P<0.001). Overall, 10.5% of white, 11.6% of black, and 13.4% of Hispanic candidates died on the wait-list or became too sick for a transplant within 1 year of listing. After adjusting for baseline risk factors, Hispanic patients were at higher risk of wait-list mortality (hazard ratio 1.51, 95% CI 1.23, 1.85) in comparison with white patients, but not black patients (hazard ratio 1.13, 95% CI 0.97, 1.31). In comparison with white HT recipients, posttransplant in-hospital mortality was higher in black recipients (odds ratio 1.53, 95% CI 1.15, 2.03) but was not different in Hispanic recipients (odds ratio 0.78, 95% CI 0.48, 1.29). Conclusions-Hispanic patients listed for HT in the United States appear to be at higher risk of dying on the wait-list or becoming too sick for a transplant in comparison with white patients. Black patients are not at higher risk of wait-list mortality, but they have higher early posttransplant mortality. © 2012 American Heart Association, Inc.

Mitema D.,Mayo Medical School | Atta M.G.,Medicine
Current Drug Metabolism | Year: 2015

Highly active antiretroviral therapy (HAART) and direct acting antiviral agents (DAAs) are key elements in the effective pharmacotherapy of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) respectively. These two chronic illnesses affect millions of persons at any given time, though only a select proportion has been eligible for successful treatment. With the development of newer, safer and more effective antiviral therapies it is expected that a greater proportion of those infected will have access to these life-saving therapies. However, it is also important to appreciate that this very population will also be subject to increased toxicities from these agents. In this review we outline the published nephrotoxic effects of select new agents used in the management of HIV and HCV, specifically commenting, where possible, on the role of epithelial organic transporters in explaining the said renal toxicities. © 2015 Bentham Science Publishers.

Ren Z.,Renmin University of China | Liang W.,Renmin University of China | Chen C.,Renmin University of China | Yang H.,Renmin University of China | And 2 more authors.
Cellular Signalling | Year: 2012

Nephrin, an important structural and signal molecule of podocyte slit-diaphragm (SD), has been suggested to contribute to the angiotensin II (Ang II)-induced podocyte injury. Caveolin-1 has been demonstrated to play a crucial role in signaling transduction. In the present study, we evaluated the role of caveolin-1 in Ang II-induced nephrin phosphorylation in podocytes. Wistar rats-receiving either Ang II (400ng/kg/min) or normal saline (via subcutaneous osmotic mini-pumps, control) were administered either vehicle or telmisartan (3mg/kg/min) for 14 or 28days. Blood pressure, 24-hour urinary albumin and serum biochemical profile were measured at the end of the experimental period. Renal histomorphology was evaluated through light and electron microscopy. In vitro, cultured murine podocytes were exposed to Ang II (10 -6M) pretreated with or without losartan (10 -5M) for variable time periods. Nephrin and caveolin-1 expression and their phosphorylation were analyzed by Western-blotting and immunofluorescence. Caveolar membrane fractions were isolated by sucrose density gradient centrifugation, and then the distribution and interactions between Ang II type 1 receptor (AT1), nephrin, C-terminal Src kinase (Csk) and caveolin-1 were evaluated using Western-blotting and co-immunoprecipitation. Podocyte apoptosis was evaluated by cell nucleus staining with Hoechst-33342.Ang II-receiving rats displayed diminished phosphorylation of nephrin but enhanced glomerular/podocyte injury and proteinuria when compared to control rats. Under control conditions, podocyte displayed expression of caveolin-1 in abundance but only a low level of phospho moiety. Nonetheless, Ang II stimulated caveolin-1 phosphorylation without any change in total protein expression. Nephrin and caveolin-1 were co-localized in caveolae fractions. AT1 receptors and Csk were moved to caveolae fractions and had an interaction with caveolin-1 after the stimulation with Ang II. Transfection of caveolin-1 plasmid (pEGFPC3-cav-1) significantly increased Ang II-induced nephrin dephosphorylation and podocyte apoptosis. Furthermore, knockdown of caveolin-1 expression (using siRNA) inhibited nephrin dephosphorylation and prevented Ang II-induced podocyte apoptosis. These findings indicate that Ang II induces nephrin dephosphorylation and podocyte injury through a caveolin-1-dependent mechanism. © 2011 Elsevier Inc..

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