Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC

Altered mitochondrial function and energy metabolism is associated with a radioresistant phenotype in oesophageal adenocarcinoma

Neoadjuvant chemoradiation therapy (CRT) is increasingly the standard of care for locally advanced oesophageal cancer. A complete pathological response to CRT is associated with a favourable outcome. Radiation therapy is important for local tumour control, however, radioresistance remains a substantial clinical problem. We hypothesise that alterations in mitochondrial function and energy metabolism are involved in the radioresistance of oesophageal adenocarcinoma (OAC). To investigate this, we used an established isogenic cell line model of radioresistant OAC. Radioresistant cells (OE33 R) demonstrated significantly increased levels of random mitochondrial mutations, which were coupled with alterations in mitochondrial function, size, morphology and gene expression, supporting a role for mitochondrial dysfunction in the radioresistance of this model. OE33 R cells also demonstrated altered bioenergetics, demonstrating significantly increased intracellular ATP levels, which was attributed to enhanced mitochondrial respiration. Radioresistant cells also demonstrated metabolic plasticity, efficiently switching between the glycolysis and oxidative phosphorylation energy metabolism pathways, which were accompanied by enhanced clonogenic survival. This data was supported in vivo, in pre-treatment OAC tumour tissue. Tumour ATP5B expression, a marker of oxidative phosphorylation, was significantly increased in patients who subsequently had a poor pathological response to neoadjuvant CRT. This suggests for the first time, a role for specific mitochondrial alterations and metabolic remodelling in the radioresistance of OAC

Diet and Exercise for FRAILty (DEFRAIL): protocol for a study to examine the effect of a novel community-based group exercise and nutritional intervention, designed to reverse frailty in older adults

Introduction Frailty refers to a multifaceted age-related loss of physiological reserve. Aside from the immediate challenges it presents, it is also associated with various adverse health outcomes. Given our ageing population, the healthcare and societal costs resulting from frailty present a significant and growing public health challenge. Rapidly accumulating evidence suggests that resistance exercise combined with protein supplementation can reverse frailty in older adults. However, translation of these findings into practice has proven difficult, due to either a lack of clarity regarding the interventions used or the use of interventions not suitable for widespread implementation. There remains an absence of evidence-based programmes suitable for delivery to frail older adults in the community.Methods and analysis This paper outlines the protocol for a study to examine the effect of a novel programme of exercise and protein supplementation. This intervention has been developed by an expert consensus group, specifically for delivery to frail older adults in a group setting in the community. The study will take the form of a within-subjects non-randomised trial. Participants will be assessed at baseline, then following an 8-week period of regular activity, then following the 8-week intervention. Frailty (according to the Fried Frailty criteria) will be the primary outcome measure, along with a range of secondary outcome measures (including physical performance measures, body mass composition, psychosocial assessments and frailty-related biomarkers). If shown to be feasible to implement and effective at reversing frailty, the Diet and Exercise for FRAILty (DEFRAIL) intervention may facilitate more widespread participation in resistance exercise for frail older adults.Ethics and dissemination This study received ethical approval from the Research Ethics committees of both the Health Service Executive South-Eastern Area and Waterford Institute of Technology. Its findings will be disseminated through journal publications, conference presentations and other forms of public engagement.Trial registration number ISRCTN46458028; Pre-results

Changes in mitochondrial stability during the progression of the Barrett\u27s esophagus disease sequence

Background Barrett?s esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett?s esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett?s disease progression is under studied. Methods Using an in-vitro model representing the Barrett?s esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles. Results Barrett?s metaplastic cells demonstrated increased levels of ROS (p?<?0.005) and increased levels of random mitochondrial mutations (p?<?0.05) compared with all other stages of the Barrett?s disease sequence in-vitro. Using patient in-vivo samples, Barrett?s metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p?=?0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p?<?0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett?s metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p?=?0.003), SMAC/Diablo (p?=?0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett?s metaplastic tissue compared with matched normal squamous epithelium. Conclusions We have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett?s disease sequence

Obesity and Insulin Resistance Are the Main Determinants of Postprandial Lipoprotein Dysmetabolism in Polycystic Ovary Syndrome

Postprandial dyslipidaemia may be a plausible mechanism by which polycystic ovary syndrome (PCOS) increases cardiovascular risk. We sought to investigate whether the postprandial glucose and insulin and lipid and lipoprotein responses, including that of apolipoprotein B-48 (apoB-48) containing chylomicrons, to a mixed meal are different in obese PCOS women when compared to obese control subjects and whether differences, if any, are related to obesity, insulin resistance (IR), hyperandrogenaemia, or PCOS status. 26 women with PCOS (age 30.4±1.2 years (mean ± SEM), body mass index (BMI) 36.8±1.5 kg/m2) and 26 non-PCOS subjects (age 34.1±0.9 years, BMI 31.5±1.0 kg/m2) were studied before and up to 8 hours following a standard mixed meal. AUC-triglyceride (AUC-TG) was higher and AUC-high-density lipoprotein (AUC-HDL) lower in PCOS women. These differences were not apparent when BMI was accounted for. Insulin sensitivity (SI), AUC-apoB-48, and AUC-apolipoprotein B (AUC-apoB) were found to be independent predictors of AUC-TG, accounting for 55% of the variance. Only AUC-insulin remained significantly elevated following adjustment for BMI. Obesity related IR explains postprandial hypertriglyceridaemia and hyperinsulinaemic responses. Management of obesity in premenopausal women with PCOS is likely to reduce their cardiovascular risk burden

Diet and Exercise for FRAILty (DEFRAIL): protocol for a study to examine the effect of a novel community-based group exercise and nutritional intervention, designed to reverse frailty in older adults

Introduction: Frailty refers to a multifaceted age-related loss of physiological reserve. Aside from the immediate challenges it presents, it is also associated with various adverse health outcomes. Given our ageing population, the healthcare and societal costs resulting from frailty present a significant and growing public health challenge. Rapidly accumulating evidence suggests that resistance exercise combined with protein supplementation can reverse frailty in older adults. However, translation of these findings into practice has proven difficult, due to either a lack of clarity regarding the interventions used or the use of interventions not suitable for widespread implementation. There remains an absence of evidence-based programmes suitable for delivery to frail older adults in the community. Methods and analysis: This paper outlines the protocol for a study to examine the effect of a novel programme of exercise and protein supplementation. This intervention has been developed by an expert consensus group, specifically for delivery to frail older adults in a group setting in the community. The study will take the form of a within-subjects non-randomised trial. Participants will be assessed at baseline, then following an 8-week period of regular activity, then following the 8-week intervention. Frailty (according to the Fried Frailty criteria) will be the primary outcome measure, along with a range of secondary outcome measures (including physical performance measures, body mass composition, psychosocial assessments and frailty-related biomarkers). If shown to be feasible to implement and effective at reversing frailty, the Diet and Exercise for FRAILty (DEFRAIL) intervention may facilitate more widespread participation in resistance exercise for frail older adults. Ethics and dissemination: This study received ethical approval from the Research Ethics committees of both the Health Service Executive South-Eastern Area and Waterford Institute of Technology. Its findings will be disseminated through journal publications, conference presentations and other forms of public engagement. Trial registration number: ISRCTN46458028; Pre-results.</p

Sweet and umami taste perception differs with habitual exercise in males

Taste is influenced by several factors. However, whether habitual exercise level is associated with differences in taste perception has received little investigation. The aim of this study was to determine if habitual exercise is associated with differences in taste perception in men. Active (n = 16) and inactive (n = 14) males, between ages 18–55, underwent two days of sensory testing, using prototypical taste stimuli of high and low concentrations for sweet, salt, bitter, sour, umami, and carbohydrate (maltodextrin). Mean perceived intensity and hedonic ratings were recorded. Eating behaviour was assessed by the three factor eating questionnaire and food intake by EPIC food frequency questionnaire (FFQ). There were moderate to large differences between the two groups in perceived intensity for sweet taste at the high concentration and umami taste at both high and low concentrations, with active males recording a higher perceived intensity (p < 0.05 for all). The active group also recorded a greater dislike for umami low and carbohydrate low concentration (p < 0.01). Salt, bitter and sour perception did not significantly differ between the two groups. FFQ analysis showed no difference in % energy from macronutrients between the groups. Eating behaviour traits correlated with sweet taste intensity and umami taste liking, independent of activity status. Results indicated that sweet and umami taste perception differ in active compared to inactive males. Habitual exercise level should be considered in taste perception research and in product development. Whether differences in taste perception could be one factor influencing food intake and thus energy balance with habitual exercise warrants further investigation