HIF-2α downregulation in the absence of functional VHL is not sufficient for renal cell differentiation

<p>Abstract</p> <p>Background</p> <p>Mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary as well as sporadic clear cell renal carcinomas. The product of the VHL gene, pVHL, acts to target hypoxia-inducible factor alpha (HIF-α) subunits for ubiquitination and subsequent degradation. Using an RNA interference approach to lower levels of HIF-2α in two different renal cell lines that lack functional pVHL, we have tested the contribution of HIF-2α toward cellular pVHL activities.</p> <p>Results</p> <p>Knockdown of HIF-2α resulted in cell cycle arrest of renal cells that were grown on collagen I, indicating that this pVHL function is dependent on HIF-2α regulation. However, cellular morphological changes and downregulation of integrins α5 and β1, which were seen upon pVHL replacement, were not faithfully phenocopied by HIF-2α reduction. Moreover, fibronectin deposition and expression of renal cell differentiation markers were observed in cells containing replaced pVHL, but not in HIF-2α knockdown cells, indicating that these pVHL functions may occur independently of HIF-2α downregulation.</p> <p>Conclusion</p> <p>These results indicate that HIF-2α regulation is not sufficient for pVHL-induced renal cell differentiation. We hypothesize that in addition to HIF-2α dysregulation, abrogation of additional pVHL functions is required for the initiation of renal carcinogenesis.</p

International society of sports nutrition position stand: diets and body composition

Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature regarding the effects of diet types (macronutrient composition; eating styles) and their influence on body composition. The ISSN has concluded the following. 1) There is a multitude of diet types and eating styles, whereby numerous subtypes fall under each major dietary archetype. 2) All body composition assessment methods have strengths and limitations. 3) Diets primarily focused on fat loss are driven by a sustained caloric deficit. The higher the baseline body fat level, the more aggressively the caloric deficit may be imposed. Slower rates of weight loss can better preserve lean mass (LM) in leaner subjects. 4) Diets focused primarily on accruing LM are driven by a sustained caloric surplus to facilitate anabolic processes and support increasing resistance-training demands. The composition and magnitude of the surplus, as well as training status of the subjects can influence the nature of the gains. 5) A wide range of dietary approaches (low-fat to low-carbohydrate/ketogenic, and all points between) can be similarly effective for improving body composition. 6) Increasing dietary protein to levels significantly beyond current recommendations for athletic populations may result in improved body composition. Higher protein intakes (2.3–3.1 g/ kg FFM) may be required to maximize muscle retention in lean, resistance-trained subjects under hypocaloric conditions. Emerging research on very high protein intakes (\u3e3 g/kg) has demonstrated that the known thermic, satiating, and LM-preserving effects of dietary protein might be amplified in resistance-training subjects. 7) The collective body of intermittent caloric restriction research demonstrates no significant advantage over daily caloric restriction for improving body composition. 8) The long-term success of a diet depends upon compliance and suppression or circumvention of mitigating factors such as adaptive thermogenesis. 9) There is a paucity of research on women and older populations, as well as a wide range of untapped permutations of feeding frequency and macronutrient distribution at various energetic balances combined with training. Behavioral and lifestyle modification strategies are still poorly researched areas of weight management

A systematic review, meta-analysis and metaregression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults

Objective We performed a systematic review, metaanalysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength. Data sources A systematic search of Medline, Embase, CINAHL and SportDiscus. Eligibility criteria Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation. Design Random-effects meta-analyses and metaregressions with four a priori determined covariates. Twophase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM). ResultsData from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p Summary/conclusion Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM

Changes in body composition and performance with supplemental HMB-FA+ATP (Manuscript Clarification)

Additional co-authors: Matthew D. Vukovich, Colin Wilborn, and Darryn S. Willoughb

International society of sports nutrition position stand: diets and body composition

Abstract Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature regarding the effects of diet types (macronutrient composition; eating styles) and their influence on body composition. The ISSN has concluded the following. 1) There is a multitude of diet types and eating styles, whereby numerous subtypes fall under each major dietary archetype. 2) All body composition assessment methods have strengths and limitations. 3) Diets primarily focused on fat loss are driven by a sustained caloric deficit. The higher the baseline body fat level, the more aggressively the caloric deficit may be imposed. Slower rates of weight loss can better preserve lean mass (LM) in leaner subjects. 4) Diets focused primarily on accruing LM are driven by a sustained caloric surplus to facilitate anabolic processes and support increasing resistance-training demands. The composition and magnitude of the surplus, as well as training status of the subjects can influence the nature of the gains. 5) A wide range of dietary approaches (low-fat to low-carbohydrate/ketogenic, and all points between) can be similarly effective for improving body composition. 6) Increasing dietary protein to levels significantly beyond current recommendations for athletic populations may result in improved body composition. Higher protein intakes (2.3–3.1 g/kg FFM) may be required to maximize muscle retention in lean, resistance-trained subjects under hypocaloric conditions. Emerging research on very high protein intakes (>3 g/kg) has demonstrated that the known thermic, satiating, and LM-preserving effects of dietary protein might be amplified in resistance-training subjects. 7) The collective body of intermittent caloric restriction research demonstrates no significant advantage over daily caloric restriction for improving body composition. 8) The long-term success of a diet depends upon compliance and suppression or circumvention of mitigating factors such as adaptive thermogenesis. 9) There is a paucity of research on women and older populations, as well as a wide range of untapped permutations of feeding frequency and macronutrient distribution at various energetic balances combined with training. Behavioral and lifestyle modification strategies are still poorly researched areas of weight management

International Society of Sports Nutrition Position Stand: Diets and Body Composition

Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature regarding the effects of diet types (macronutrient composition; eating styles) and their influence on body composition. The ISSN has concluded the following. 1) There is a multitude of diet types and eating styles, whereby numerous subtypes fall under each major dietary archetype. 2) All body composition assessment methods have strengths and limitations. 3) Diets primarily focused on fat loss are driven by a sustained caloric deficit. The higher the baseline body fat level, the more aggressively the caloric deficit may be imposed. Slower rates of weight loss can better preserve lean mass (LM) in leaner subjects. 4) Diets focused primarily on accruing LM are driven by a sustained caloric surplus to facilitate anabolic processes and support increasing resistance-training demands. The composition and magnitude of the surplus, as well as training status of the subjects can influence the nature of the gains. 5) A wide range of dietary approaches (low-fat to low-carbohydrate/ketogenic, and all points between) can be similarly effective for improving body composition. 6) Increasing dietary protein to levels significantly beyond current recommendations for athletic populations may result in improved body composition. Higher protein intakes (2.3–3.1 g/kg FFM) may be required to maximize muscle retention in lean, resistance-trained subjects under hypocaloric conditions. Emerging research on very high protein intakes (\u3e3 g/kg) has demonstrated that the known thermic, satiating, and LM-preserving effects of dietary protein might be amplified in resistance-training subjects. 7) The collective body of intermittent caloric restriction research demonstrates no significant advantage over daily caloric restriction for improving body composition. 8) The long-term success of a diet depends upon compliance and suppression or circumvention of mitigating factors such as adaptive thermogenesis. 9) There is a paucity of research on women and older populations, as well as a wide range of untapped permutations of feeding frequency and macronutrient distribution at various energetic balances combined with training. Behavioral and lifestyle modification strategies are still poorly researched areas of weight management

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma