The effect of combined ß-lactoglobulin supplementation and resistance exercise training prior to limb immobilisation on muscle protein synthesis rates in healthy young adults: study protocol for a randomised controlled trial.

BACKGROUND: The decline in skeletal muscle mass experienced following a short-term period (days to weeks) of muscle disuse is mediated by impaired rates of muscle protein synthesis (MPS). Previous RCTs of exercise or nutrition prehabilitation interventions designed to mitigate disuse-induced muscle atrophy have reported limited efficacy. Hence, the aim of this study is to investigate the impact of a complex prehabilitation intervention that combines ß-lactoglobulin (a novel milk protein with a high leucine content) supplementation with resistance exercise training on disuse-induced changes in free-living integrated rates of MPS in healthy, young adults. METHODS/DESIGN: To address this aim, we will recruit 24 healthy young (18-45 years) males and females to conduct a parallel, double-blind, 2-arm, randomised placebo-controlled trial. The intervention group will combine a 7-day structured resistance exercise training programme with thrice daily dietary supplementation with 23 g of ß-lactoglobulin. The placebo group will combine the same training programme with an energy-matched carbohydrate (dextrose) control. The study protocol will last 16 days for each participant. Day 1 will be a familiarisation session and days 2-4 will be the baseline period. Days 5-11 represent the 'prehabilitation period' whereby participants will combine resistance training with their assigned dietary supplementation regimen. Days 12-16 represent the muscle disuse-induced 'immobilisation period' whereby participants will have a single leg immobilised in a brace and continue their assigned dietary supplementation regimen only (i.e. no resistance training). The primary endpoint of this study is the measurement of free-living integrated rates of MPS using deuterium oxide tracer methodology. Measurements of MPS will be calculated at baseline, over the 7-day prehabilitation period and over the 5-day immobilisation period separately. Secondary endpoints include measurements of muscle mass and strength that will be collected on days 4 (baseline), 11 (end of prehabilitation) and 16 (end of immobilisation). DISCUSSION: This novel study will establish the impact of a bimodal prehabilitation strategy that combines ß-lactoglobulin supplementation and resistance exercise training in modulating MPS following a short-term period of muscle disuse. If successful, this complex intervention may be translated to clinical practice with application to patients scheduled to undergo, for example, hip or knee replacement surgery. TRIAL REGISTRATION: NCT05496452. Registered on August 10, 2022. PROTOCOL VERSION: 16-12-2022/1.

Valproic acid disables the Nrf2 anti-oxidant response in acute myeloid leukaemia cells enhancing reactive oxygen species-mediated killing.

BACKGROUND: We previously demonstrated the in vitro killing of AML cells by the combination of the lipid-lowering agent bezafibrate (BEZ) and the contraceptive hormone medroxyprogesterone acetate (MPA). A phase II trial demonstrated in vivo safety and efficacy of BEZ and MPA (BaP) in elderly, relapsed/refractory AML and high-risk myelodysplastic syndrome (MDS) patients. However, we observed dose-limiting toxicities in a second trial that attempted to improve outcomes via escalation of BaP doses. Thus we sought to identify a third repurposed drug that potentiates activity of low dose BaP (BaP 0.1 mM). METHODS AND RESULTS: We demonstrate that addition of a commonly used anti-epileptic, valproic acid (VAL) to low dose BaP (BaP 0.1 mM)(VBaP) enhanced killing of AML cell lines/primary AML cells to levels similar to high dose BaP (BaP 0.5 mM). Similarly, addition of VAL to BaP 0.1 mM enhanced reactive oxygen species (ROS), lipid peroxidation and inhibition of de novo fatty acid synthesis. Overexpression of Nrf2 in K562 and KG1a completely inhibited ROS production and rescued cells from VAL/BaP 0.1 mM/VBaP killing. CONCLUSIONS: Given the good safety data of low-dose BaP in elderly/relapsed/refractory AML patients, and that VAL alone is well-tolerated, we propose VBaP as a novel therapeutic combination for AML.

The association between oral health and general health and quality of life in older male cancer patients.

OBJECTIVES: To describe the long-term effects of oral health problems on quality of life (QoL), functional status, pain, and general health in older male cancer patients. DESIGN: Secondary analysis of a prospective observational study. SETTING: Community dwelling cancer patients served by a Department of Veterans Affairs hospital. PARTICIPANTS: One hundred fifty male cancer patients responded to the question "Do you have tooth or mouth problems making it hard to eat?" The relationship between patients answering "yes" and the following parameters was assessed: demographics, comorbid conditions, habits, activities of daily living, pain, anxiety, depression, social support, spirituality, QoL, and overall health ratings. MEASUREMENTS: Chi-square contingency tables for dichotomous variables, Cochran-Mantel-Haenszel for ordered categorical variables, and t tests for associations with continuous variables. RESULTS: The median age of respondents was 67. Those reporting tooth or mouth problems had had their cancer diagnosed on average 2.9 years before, and 83.3% were found clinically to be cancer free. Patients with these problems had significantly lower global (P=.003) and subscale scores on QoL analysis and higher levels of anxiety (P<.001) and depression (P=.01) than those without tooth or mouth problems; they also had significantly more pain (P<.001) and lower physical functioning (P<.001) and were more impaired in activities of daily living (P<.001). Those with tooth or mouth problems were more likely to describe their overall health as fair or poor (P=.01). Having cancer located in the head and neck region related significantly to having mouth or tooth problems (P=.005), but these problems were not associated with race, education, income, insurance coverage, age, comorbid conditions, alcohol consumption, tobacco or medication usage, type of cancer treatment, tumor stage at diagnosis or follow-up, perceived social support, or spirituality. CONCLUSION: Older male cancer patients with mouth or tooth problems making it hard to eat are more likely to have a lower QoL, poorer emotional health, lower levels of physical functioning, and greater pain than patients without these problems.