The Warburg Effect Is Genetically Determined in Inherited Pheochromocytomas

The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Community-based interventions for enhancing access to or consumption of fruit and vegetables among five to 18-year olds: a scoping review

<p>Abstract</p> <p>Background</p> <p>Low fruit and vegetable ( FV) consumption is a key risk factor for morbidity and mortality. Consumption of FV is limited by a lack of access to FV. Enhanced understanding of interventions and their impact on both access to and consumption of FV can provide guidance to public health decision-makers. The purpose of this scoping review is to identify and map literature that has evaluated effects of community-based interventions designed to increase FV access or consumption among five to 18-year olds.</p> <p>Methods</p> <p>The search included 21 electronic bibliographic databases, grey literature, targeted organization websites, and 15 key journals for relevant studies published up to May 2011. Retrieved citations were screened in duplicate for relevance. Data extracted from included studies covered: year, country, study design, target audience, intervention setting, intervention strategies, interventionists, and reported outcomes.</p> <p>Results</p> <p>The search located 19,607 unique citations. Full text relevance screening was conducted on 1,908 studies. The final 289 unique studies included 30 knowledge syntheses, 27 randomized controlled trials, 55 quasi-experimental studies, 113 cluster controlled studies, 60 before-after studies, one mixed method study, and three controlled time series studies. Of these studies, 46 included access outcomes and 278 included consumption outcomes. In terms of target population, 110 studies focused on five to seven year olds, 175 targeted eight to 10 year olds, 192 targeted 11 to 14 year olds, 73 targeted 15 to 18 year olds, 55 targeted parents, and 30 targeted teachers, other service providers, or the general public. The most common intervention locations included schools, communities or community centres, and homes. Most studies implemented multi-faceted intervention strategies to increase FV access or consumption.</p> <p>Conclusions</p> <p>While consumption measures were commonly reported, this review identified a small yet important subset of literature examining access to FV. This is a critically important issue since consumption is contingent upon access. Future research should examine the impact of interventions on direct outcome measures of FV access and a focused systematic review that examines these interventions is also needed. In addition, research on interventions in low- and middle-income countries is warranted based on a limited existing knowledge base.</p

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien–Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4–7) and 7 (6–8) days respectively (P &lt; 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent; P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46; P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent; major 3·3 versus 3·4 per cent; P = 0·110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients