Mutations in the N-domain of aryl hydrocarbon receptor interacting protein affect interactions with heat shock protein 90ß and phosphodiesterase 4A5.

The aryl hydrocarbon receptor interacting protein (AIP) is a cytoplasmic molecular co-chaperone and tumour suppressor that assists in protein stability and complex formation involving the aryl hydrocarbon receptor. Germline mutations in the AIP gene predispose to pituitary tumourigenesis with patients exhibiting an aggressive clinical phenotype. Full length AIP harbouring N-domain mutations (R9Q, R16H, V49M and K103R) were purified from E.coli utilizing a methodology that maintained structural integrity and monomeric stability. Mutations did not significantly affect the thermal stability of the protein and caused no overall disruptive effect in the protein structure. The mutations studied lowered the binding affinity of AIP towards two of its binding partners; heat shock protein 90ß and phosphodiesterase 4A5 (PDE4A5). The inhibition of phosphodiesterase activity by AIP was also greatly reduced by all mutants. While previously published data has mainly concentrated on the tetratricopeptide repeats of the C-domain of AIP, we present clear evidence that AIP N-domain mutations play a significant role in two protein:protein interactions with partner proteins. The complex interactome of AIP suggests that any observable change in one or more of its binding partners cannot be disregarded as it may have repercussions on other biochemical pathways.

Role of Gut Microbe Composition in Psychosocial Symptom Response to Exercise Training in Breast Cancer Survivors (ROME) study: protocol for a randomised controlled trial.

INTRODUCTION: Breast cancer survivors have an increased risk for chronic fatigue and altered gut microbiota composition, both with negative health and quality of life affects. Exercise modestly improves fatigue and is linked to gut microbial diversity and production of beneficial metabolites. Studies suggest that gut microbiota composition is a potential mechanism underlying fatigue response to exercise. Randomised controlled trials testing the effects of exercise on the gut microbiome are limited and there is a scarcity of findings specific to breast cancer survivors. The objective of this study is to determine if fitness-related modifications to gut microbiota occur and, if so, mediate the effects of aerobic exercise on fatigue response. METHODS AND ANALYSIS: The research is a randomised controlled trial among breast cancer survivors aged 18-74 with fatigue. The primary aim is to determine the effects of aerobic exercise training compared with an attention control on gut microbiota composition. The secondary study aims are to test if exercise training (1) affects the gut microbiota composition directly and/or indirectly through inflammation (serum cytokines), autonomic nervous system (heart rate variability) or hypothalamic-pituitary-adrenal axis mediators (hair cortisol assays), and (2) effects on fatigue are direct and/or indirect through changes in the gut microbiota composition. All participants receive a standardised controlled diet. Assessments occur at baseline, 5 weeks, 10 weeks and 15 weeks (5 weeks post intervention completion). Faecal samples collect the gut microbiome and 16S gene sequencing will identify the microbiome. Fatigue is measured by a 13-item multidimensional fatigue scale. ETHICS AND DISSEMINATION: The University of Alabama at Birmingham Institutional Review Board (IRB) approved this study on 15 May 2019, UAB IRB#30000320. A Data and Safety Monitoring Board convenes annually or more often if indicated. Findings will be disseminated in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04088708.

Serum syndecan-4 correlates with blood pressure and cardiovascular parameters but not proinflammatory markers in healthy older women.

Aging is accompanied by a low-grade proinflammatory status that plays a role in age-related vascular alterations. Syndecan-4 (SDC4) is a key component of the endothelial glycocalyx, and its extracellular domain can be shed by matrix metalloproteinase-9 (MMP-9). In vitro studies demonstrated that MMP-9-mediated shedding of SDC4 is induced by tumor necrosis factor-α (TNF- α) in human endothelial cells. However, the relationship between circulating shed SDC4, systemic inflammation, and age-related vascular alterations remains unknown. Here, we used linear regression models to examine the associations of serum SDC4 levels with cardiovascular hemodynamic phenotypes, serum MMP-9, and serum TNF-α and inteleukin-6 in healthy older women (n = 74). Serum SDC4 was not associated with proinflammatory cytokines or arterial elasticity. Nevertheless, we found significant correlations of SDC4 with MMP-9, heart rate, left ventricular ejection time, systemic vascular resistance, and blood pressure. Our preliminary evidence suggests that systemic inflammation might not induce SDC4 shedding in healthy aging.

Vascular hemodynamics and blood pressure differences between young and older women.

BACKGROUND: Cardiovascular disease is one of the main causes of death in the United States, and hypertension is a primary risk factor. Therefore, the primary causes of hypertension need to be identified so they may be addressed for treatment. The purpose of this study was to compare blood pressure with hemodynamic values and identify factors that may explain blood pressure differences between a cohort of healthy normotensive younger and older women. METHODS: Participants were 49 young (age: 33.8 ± 5.9) and 103 old (age: 65.8 ± 4) who were non-hypertensive, had no previous history of heart disease or type 2 diabetes, body mass index less than 30 kg/m2, normal electrocardiography response at rest and during exercise, nonsmokers, and no use of medications known to affect cardiovascular or metabolic function. Body composition measured by dual-energy X-ray absorptiometry. Hemodynamic values measured by non-invasive pulse wave velocity through radial artery tonometry. Markers of inflammation measured through blood sample analysis. RESULTS: Significant differences exist between young and old groups in %fat (P < 0.001), systolic blood pressure (SBP) (P = 0.001), large artery elasticity (P = 0.005), small artery elasticity (P < 0.001), systemic vascular resistance (P = 0.004), total vascular impedance (P < 0.001), estimated cardiac output (P < 0.001), and tumor necrosis factor-⍺ (TNF-⍺) (P < 0.001). Using ANCOVA the difference in SBP between age groups was no longer significant after adjusting for small artery elasticity (P < 0.001) and TNF-⍺ (P = 0.041). CONCLUSIONS: These data demonstrate that blood pressure and vascular hemodynamic measures differ significantly between young and old women independent of body composition. Furthermore, these differences may be explained by the inflammation marker TNF-⍺ and/or small artery elasticity.

Substitution of histidine 30 by asparagine in manganese superoxide dismutase alters biophysical properties and supports proliferation in a K562 leukemia cell line.

We have generated a mutant of C. elegans manganese superoxide dismutase at histidine 30 by site-directed mutagenesis. The structure was solved at a resolution of 1.52 Å by X-ray crystallography (pdb: 6S0D). His30 was targeted, as it forms as a gateway residue at the top of the solvent access funnel to the active site, together with Tyr34. In the wild-type protein, these gateway residues are involved in the hydrogen-bonding network providing the protons necessary for the catalytic reaction at the metal center. However, biophysical characterization and cell viability experiments reveal that a mutation from histidine to asparagine in the H30N mutant modifies metal selectivity in the protein, favoring the uptake of iron over manganese in minimal media conditions, alters active-site coordination from the characteristic trigonal bipyramidal to octahedral geometry, and encourages cellular proliferation in K562 cells, when added exogenously to the cells.

Exercise plasma metabolomics and xenometabolomics in obese, sedentary, insulin-resistant women: impact of a fitness and weight loss intervention.

Insulin resistance has wide-ranging effects on metabolism, but there are knowledge gaps regarding the tissue origins of systemic metabolite patterns and how patterns are altered by fitness and metabolic health. To address these questions, plasma metabolite patterns were determined every 5 min during exercise (30 min, ∼45% of V̇o2peak, ∼63 W) and recovery in overnight-fasted sedentary, obese, insulin-resistant women under controlled conditions of diet and physical activity. We hypothesized that improved fitness and insulin sensitivity following a ∼14-wk training and weight loss intervention would lead to fixed workload plasma metabolomics signatures reflective of metabolic health and muscle metabolism. Pattern analysis over the first 15 min of exercise, regardless of pre- versus postintervention status, highlighted anticipated increases in fatty acid tissue uptake and oxidation (e.g., reduced long-chain fatty acids), diminution of nonoxidative fates of glucose [e.g., lowered sorbitol-pathway metabolites and glycerol-3-galactoside (possible glycerolipid synthesis metabolite)], and enhanced tissue amino acid use (e.g., drops in amino acids; modest increase in urea). A novel observation was that exercise significantly increased several xenometabolites ("non-self" molecules, from microbes or foods), including benzoic acid-salicylic acid-salicylaldehyde, hexadecanol-octadecanol-dodecanol, and chlorogenic acid. In addition, many nonannotated metabolites changed with exercise. Although exercise itself strongly impacted the global metabolome, there were surprisingly few intervention-associated differences despite marked improvements in insulin sensitivity, fitness, and adiposity. These results and previously reported plasma acylcarnitine profiles support the principle that most metabolic changes during submaximal aerobic exercise are closely tethered to absolute ATP turnover rate (workload), regardless of fitness or metabolic health status.

Inverse association between changes in energetic cost of walking and vertical accelerations in non-metastatic breast cancer survivors.

PURPOSE: With accelerometry, the utility to detect changes in physical activity are predicated on the assumption that walking energetics and gait mechanics do not change. The present work examined associations between changes (∆) in walking energetics, exercise self-efficacy, and several accelerometer-derived metrics. METHODS: Secondary analyses were performed among a sub-sample (n = 29) of breast cancer survivors participating in a larger randomized trial. During 4 min of treadmill walking (0.89 m s-1, 0% grade), indirect calorimetry quantified steady-state energy expenditure (EE), wherein, participants were fitted with a heart rate monitor and hip-worn triaxial accelerometer. Exercise self-efficacy was measured using a 9-item questionnaire, while vector magnitude (VM) and individual planes (e.g., mediolateral, vertical, and anteroposterior) of the movement were extracted for data analyses. Evaluations were made at baseline and after 3 months. RESULTS: From baseline to 3 months, the energetic cost of walking (kcals min-1) significantly decreased by an average of - 5.1% (p = 0.001; d = 0.46). Conversely, VM significantly increased (p = 0.007; d = 0.53), exclusively due to greater vertical accelerations (acc) (+ 5.7 ± 7.8 acc; p = 0.001; d = 0.69). Changes in vertical accelerations were inversely and positively associated with ∆walking EE (r = - 0.37; p = 0.047) and ∆exercise self-efficacy (r = 0.39; p = 0.034), respectively. CONCLUSION: Hip-worn accelerometers do not appear well-suited to correctly detect changes in ease of walking as evidenced by reduced energetic cost. Further research should determine if a divergence between measured EE and vertical accelerations could contribute to erroneous inferences in free-living physical activity.

Gut microbiota diversity is associated with cardiorespiratory fitness in post-primary treatment breast cancer survivors.

NEW FINDINGS: What is the central question of this study? Does the link between cardiorespiratory fitness and gut microbiota diversity persist after adjusting for the potential effects of percentage body fat and activity-related energy expenditure (AEE)? What is the main finding and its importance? This is the first study to examine the link between cardiorespiratory fitness and gut microbiota diversity while accounting for the underlying effects of percentage body fat and free-living AEE. Results from the present work suggest that cardiorespiratory fitness, not physical activity, is a superior correlate of gut microbiota diversity among post-primary treatment, non-metastatic breast cancer survivors. ABSTRACT: Cancer treatment uniquely triggers multiple physiological shifts detrimental to overall health. Although previous research indicates a link between the gut microbiota and cardiorespiratory fitness, it is unclear whether these findings are attributable to potential underlying effects of percentage body fat or free-living activity energy expenditure (AEE). The microbe composition of faecal specimens from 37 breast cancer survivors was determined using 16S microbiome analyses. Individual-sample microbiota diversity (α-diversity) and between-sample community differences (ß-diversity) were examined. Peak oxygen uptake ( V̇O2peak ) was estimated from a graded exercise test consistent with the modified Naughton protocol, in which exercise terminates at 85% of age-predicted maximal heart rate. The AEE was measured over 10 days using doubly labelled water, wherein the percentage body fat was calculated from total body water. Pearson correlations revealed α-diversity indices (Chao1, observed species, PD whole tree and Shannon) to be positively associated with V̇O2peak (r = 0.34-0.51; P < 0.05), whereas the percentage of maximal heart rate during stages 1-4 of the graded exercise test (r = -0.34 to -0.50; P < 0.05) and percentage body fat (r = -0.32 to -0.41; P < 0.05) were negatively associated with the same α-diversity indices. Multiple linear regression models showed that V̇O2peak accounted for 22 and 26% of the variance in taxonomic richness (observed species) and phylogenic diversity after adjustment for percentage body fat and menopausal status. Unweighted UniFrac (ß-diversity) was significant for several outcomes involving cardiorespiratory fitness, and significant taxa comparisons were found. Associations between gut microbiota and free-living AEE were not found. Results from the present work suggest that cardiorespiratory fitness, not physical activity, is a superior correlate of gut microbiota diversity.

Serum Tumor Necrosis Factor-alpha associates with Myocardial Oxygen Demand and Exercise Tolerance in Postmenopausal Women.

The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO2max). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest and during two submaximal workloads (i.e., ≈55% and ≈75% VO2max). RPP was calculated by dividing the product of heart rate and systolic blood pressure (via auscultation) by 100. Exercise tolerance corresponded with the cessation of the graded exercise test. During higher-intensity exertion, ≈75% VO2max, multiple linear regression revealed a positive association (r = 0.43; p = 0.015) between TNF-α and RPP while adjusting for maximal heart rate, VO2max, large artery compliance, and percent body fat. Path analyses revealed a significant indirect effect of large artery compliance on exercise tolerance through TNF-α, ß = 0.13, CI [0.03, 0.35], indicating greater levels of TNF-α associated with poorer exercise tolerance. These data suggest TNF-α independently associates with myocardial oxygen demand during physical exertion, thus highlighting the utility of higher-intensity efforts to expose important phenomena not apparent at rest. TNF-α also appears to be indirectly associated with the link between large artery compliance and exercise tolerance.

Ease of walking associates with greater free-living physical activity and reduced depressive symptomology in breast cancer survivors: pilot randomized trial.

PURPOSE: We hypothesized exercise training-induced improvements in ease of walking would associate with favorable changes in objectively measured physical activity (PA) and self-reported depressive symptoms following a PA behavior-change intervention in non-metastatic breast cancer survivors (BCS). METHODS: Twenty-seven BCS received random assignment to an intervention (INT) or control group (CON). INT included counseling/group discussions coupled with supervised exercise tapered to unsupervised exercise. PA, depressive symptoms, and ease of walking were evaluated pre-/post-intervention using 10-day accelerometry, HADS depression subscale, and indirect calorimetry during a standardized treadmill test, respectively. PA composite score was calculated by converting weekly minutes of moderate-to-vigorous PA and average steps/day to z-scores then dividing the sum by 2. Cardiac efficiency was determined by dividing steady-state oxygen uptake by heart rate to evaluate the volume of oxygen consumed per heartbeat. RESULTS: ANCOVA revealed a significant time by group interaction showing the INT group exhibited greater positive changes in the PA composite compared to the CON (INT, + 0.14 ± 0.66 au vs. CON, - 0.48 ± 0.49 au; p = 0.019; η p2 = 0.21). Changes occurring from baseline to follow-up, among all participants, revealed improved ease of walking (less oxygen uptake) associated with increased PA composite (r = - 0.52; p = 0.010) and lower depressive symptomology (r = 0.50; p = 0.012) adjusted for age, race, and months since cancer diagnosis. Increased cardiac efficiency during the standardized treadmill test also associated with less daily sedentary time (r = - 0.52; p = 0.021). CONCLUSIONS: These data support the assertion that reducing the physiological difficulty of walking may contribute to greater engagement in free-living PA, less sedentary time, and decreased psychosocial distress among BCS.

Dietary Changes Impact the Gut Microbe Composition in Overweight and Obese Men with Prostate Cancer Undergoing Radical Prostatectomy.

BACKGROUND: Diet and obesity influence prostate cancer risk and progression-effects that may be mediated through the gut microbiome. OBJECTIVE: Our aim was to explore relationships among diet, gut microbes, and Gleason sum in overweight and obese prostate cancer patients enrolled in a presurgical weight-loss trial. DESIGN: Randomized controlled trial (NCT01886677) secondary analysis. PARTICIPANTS/SETTING: In 2013-2014, 40 prostate cancer patients in the southeastern United States were randomized and allocated equally to weight-loss and wait-list control arms while they awaited prostatectomy; stool samples were collected on a subset of 22 patients. INTERVENTION: Registered dietitian nutritionists and exercise physiologists provided semi-weekly in-person and telephone-based guidance on calorie-restricted diets and exercise to promote an approximate weight loss of 0.91 kg/wk. MAIN OUTCOME MEASURES: Baseline and follow-up 24-hour dietary recalls were conducted and analyzed (using the Automated Self-Administered 24-hour dietary recall system; National Cancer Institute, Bethesda, MD) for macronutrients, micronutrients, and food groups. Microbiome analysis targeting the V4 region of the 16S ribosomal RNA gene was performed on fecal samples. Biopsy Gleason sum data were accessed from diagnostic pathology reports. STATISTICAL ANALYSES PERFORMED: Associations between dietary factors and operational taxonomic units were determined by ß-diversity analysis. Wilcoxon signed rank, and Mann-Whitney U testing assessed within- and between-arm differences. Associations between Gleason sum and operational taxonomic units, and diet and operational taxonomic units, were analyzed using Spearman correlations. RESULTS: At baseline, Proteobacteria (median 0.06, interquartile range 0.01 to 0.16) were abundant, with four orders positively associated with Gleason sum. Gleason sum was associated with Clostridium (ρ=.579; P=0.005) and Blautia (ρ=-0.425, P=0.049). Increased red meat consumption from baseline was associated with Prevotella (ρ=-.497; P=0.018) and Blautia (ρ=.422; P=0.039). Men who increased poultry intake had decreased Clostridiales abundance (P=0.009). CONCLUSIONS: This hypothesis-generating study provides a starting point for investigating the relationships between the fecal microbiome, diet, and prostate cancer. Adequately powered studies are required to further explore and validate these findings.

Why intensity is not a bad word: Optimizing health status at any age.

Age-related declines in health and function make locomotion increasingly difficult leading to reductions in non-exercise activity thermogenesis (NEAT), skeletal muscle size and strength, and increased adiposity. Exercise is an important strategy to attenuate loss of function through the life cycle. Despite claims to the contrary, high-intensity exercise is important for the prevention of obesity and sarcopenia with advancing age. Therefore, the purpose of this mini-review is to present literature supporting the contention that low volume, high-intensity aerobic and/or resistance training can slow sarcopenia, sustain ease of movement, stimulate NEAT, and attenuate the accretion of fat mass.

A Single Mutation is Sufficient to Modify the Metal Selectivity and Specificity of a Eukaryotic Manganese Superoxide Dismutase to Encompass Iron.

We have generated a site-directed mutant of the manganese superoxide dismutase SOD-3 of C.elegans (MnSOD-3) which modifies the metal specificity of the enzyme. While wild-type MnSOD-3 functions with manganese in the active site (3600 U mg-1 of protein) it has little or no activity when iron is incorporated. However, when histidine replaces glutamine 142 in the active site, the enzyme retains 50 % of its activity and becomes cambialistic for its metal cofactor exhibiting very similar specific activity with either manganese or iron.

Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer.

BACKGROUND: Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. METHODS: This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-of-life, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. RESULTS: The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: -4.7 (3.1) kg vs -2.2 (4.4) kg (P=0.0508); caloric intake: -500 (636) vs -159 (600) kcal per day (P=0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.l4) vs -1.8 (8.1) (P=0.0491); testosterone: +55.1 (86.0) vs -48.3 (203.7) ng dl-1 (P=0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l-1 (P=0.0023); and leptin: -2.16 (2.6) vs -0.03 (3.75) (P=0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P=0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. CONCLUSIONS: Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer.

Acylcarnitines as markers of exercise-associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons.

NEW FINDINGS: What is the central question of this study? Does improved metabolic health and insulin sensitivity following a weight-loss and fitness intervention in sedentary, obese women alter exercise-associated fuel metabolism and incomplete mitochondrial fatty acid oxidation (FAO), as tracked by blood acylcarnitine patterns? What is the main finding and its importance? Despite improved fitness and blood sugar control, indices of incomplete mitochondrial FAO increased in a similar manner in response to a fixed load acute exercise bout; this indicates that intramitochondrial muscle FAO is inherently inefficient and is tethered directly to ATP turnover. With insulin resistance or type 2 diabetes mellitus, mismatches between mitochondrial fatty acid fuel delivery and oxidative phosphorylation/tricarboxylic acid cycle activity may contribute to inordinate accumulation of short- or medium-chain acylcarnitine fatty acid derivatives [markers of incomplete long-chain fatty acid oxidation (FAO)]. We reasoned that incomplete FAO in muscle would be ameliorated concurrent with improved insulin sensitivity and fitness following a ∼14 week training and weight-loss intervention in obese, sedentary, insulin-resistant women. Contrary to this hypothesis, overnight-fasted and exercise-induced plasma C4-C14 acylcarnitines did not differ between pre- and postintervention phases. These metabolites all increased robustly with exercise (∼45% of pre-intervention peak oxygen consumption) and decreased during a 20 min cool-down. This supports the idea that, regardless of insulin sensitivity and fitness, intramitochondrial muscle ß-oxidation and attendant incomplete FAO are closely tethered to absolute ATP turnover rate. Acute exercise also led to branched-chain amino acid acylcarnitine derivative patterns suggestive of rapid and transient diminution of branched-chain amino acid flux through the mitochondrial branched-chain ketoacid dehydrogenase complex. We confirmed our prior novel observation that a weight-loss/fitness intervention alters plasma xenometabolites [i.e. cis-3,4-methylene-heptanoylcarnitine and γ-butyrobetaine (a co-metabolite possibly derived in part from gut bacteria)], suggesting that host metabolic health regulated gut microbe metabolism. Finally, we considered whether acylcarnitine metabolites signal to muscle-innervating afferents; palmitoylcarnitine at concentrations as low as 1-10 µm activated a subset (∼2.5-5%) of these neurons ex vivo. This supports the hypothesis that in addition to tracking exercise-associated shifts in fuel metabolism, muscle acylcarnitines act as signals of exertion to short-loop somatosensory-motor circuits or to the brain.

Physiological Effort in Submaximal Fitness Tests Predicts Weight Loss in Overweight and Obese Men with Prostate Cancer in a Weight Loss Trial.

BACKGROUND: Obesity and weight gain after the diagnosis of prostate cancer are associated with an increased risk of prostate cancer recurrence and mortality; individualized plans to help prostate cancer survivors maintain or lose weight may be beneficial for recurrence risk reduction. Herein, we explore whether gains in cardiovascular fitness predict successful weight loss in men participating in a weight loss trial (NCT01886677). METHODS: Forty men were randomized to receive twice-weekly in-person and telephone-based guidance on calorie-restricted diets and aerobic exercise to promote ~0.91 kg/week weight loss, or wait-list control. Thirty-two men completed submaximal VO2 Treadmill Tests (TT), anthropometric measures and two 24-hour dietary recalls at baseline and follow-up. For this secondary analysis, study arms were combined and associations between baseline and longitudinal changes in physiological effort (PE, measured by heart rate during TT), predicted VO2max, caloric intake and weight loss were analyzed. RESULTS: Men lost 3.4 kg in 50 ± 23 days on the study. Multivariate linear regression indicated weight change was associated with change in PE at stage 2TT (Partial R = 0.635, p < 0.001), days on study (Partial R = -0.589, p = 0.002) and change in caloric intake (Partial R = 0.457, p = 0.019). CONCLUSIONS: Untrained men experiencing elevated heart rates during stage 2TT at baseline were able to achieve greater weight loss over the study period; this association was strengthened by a decrease in PE at the same level from baseline to follow-up concomitant with reduced caloric intake. Therefore, for these middle-aged and older men with lower aerobic fitness, exercise appears to be a key factor in achieving higher degrees of weight loss.

Exercise following Mental Work Prevented Overeating.

UNLABELLED: Mental work may promote caloric intake, whereas exercise may offset positive energy balance by decreasing energy intake and increasing energy expenditure. PURPOSE: This study aimed to replicate previous findings that mental work increases caloric intake compared with a rest condition and assess whether exercise after mental work can offset this effect. METHODS: Thirty-eight male and female university students were randomly assigned to mental work + rest (MW + R) or mental work + exercise (MW + E). Participants also completed a baseline rest (BR) visit consisting of no mental work or exercise. Visit order was counterbalanced. During the MW + R or MW + E visit, participants completed a 20-min mental task and either a 15-min rest (MW + R) or a 15-min interval exercise (MW + E). Each visit ended with an ad libitum pizza lunch. A two-way repeated-measures ANOVA was used to compare eating behavior between groups. RESULTS: Participants in the MW + R condition consumed an average of 100 more kilocalories compared with BR (633.3 ± 72.9 and 533.9 ± 67.7, respectively, P = 0.02), and participants in MW + E consumed an average of 25 kcal less compared with BR (432.3 ± 69.2 and 456.5 ± 64.2, respectively, P > 0.05). When including the estimated energy expenditure of exercise in the MW + E conditions, participants were in negative energy balance by an average of 98.5 ± 41.5 kcal, resulting in a significant difference in energy balance between the two groups (P = 0.001). CONCLUSION: An acute bout of interval exercise after mental work resulted in significantly decreased food consumption compared with a nonexercise condition. These results suggest that an acute bout of exercise may be used to offset positive energy balance induced by mental tasks.

Lower rate-pressure product during submaximal walking: a link to fatigue improvement following a physical activity intervention among breast cancer survivors.

PURPOSE: Research showing a link between exercise-induced changes in aerobic fitness and reduced fatigue after a cancer diagnosis has been inconsistent. We evaluated associations of fatigue and rate-pressure product (RPP), a reliable index of myocardial oxygen demand, at rest and during submaximal walking following a physical activity intervention among post-primary treatment breast cancer survivors (BCS). METHODS: Secondary analyses of 152 BCS in a randomized controlled trial testing a physical activity intervention (INT) versus usual care (UC) were performed. The INT group completed counseling/group discussions along with supervised exercise sessions tapered to unsupervised exercise. Evaluations were made at baseline and immediately post-intervention (M3) on measures of physical activity (accelerometry), graded walk test, and average fatigue over the previous 7 days. RPP was calculated by dividing the product of heart rate and systolic blood pressure by 100. RESULTS: Resting and submaximal RPPs were significantly improved in both groups at M3; however, the magnitude of change (∆) was greater in the INT group from stage 1 (∆RPP1; INT -13 ± 17 vs. UC -7 ± 18; p = 0.03) through stage 4 (∆RPP4; INT -21 ± 26 vs. UC -9 ± 24; p < 0.01) of the walk test. The INT group reported significantly reduced fatigue (INT -0.7 ± 2.0 vs. UC +0.1 ± 2.0; p = 0.02) which was positively associated with ∆RPP during stages 2-4 of the walk test but not ∆aerobic fitness. CONCLUSIONS: Lower RPP during submaximal walking was significantly associated with reduced fatigue in BCS. IMPLICATIONS FOR CANCER SURVIVORS: Exercise/physical activity training programs that lower the physiological strain during submaximal walking may produce the largest improvements in reported fatigue.

Feasibility outcomes of a presurgical randomized controlled trial exploring the impact of caloric restriction and increased physical activity versus a wait-list control on tumor characteristics and circulating biomarkers in men electing prostatectomy for prostate cancer.

BACKGROUND: Obesity is associated with tumor aggressiveness and disease-specific mortality for more than 15 defined malignancies, including prostate cancer. Preclinical studies suggest that weight loss from caloric restriction and increased physical activity may suppress hormonal, energy-sensing, and inflammatory factors that drive neoplastic progression; however, exact mechanisms are yet to be determined, and experiments in humans are limited. METHODS: We conducted a randomized controlled trial among 40 overweight or obese, newly-diagnosed prostate cancer patients who elected prostatectomy to explore feasibility of a presurgical weight loss intervention that promoted a weight loss of roughly one kg. week(-1) via caloric restriction and physical activity, as well as to assess effects on tumor biology and circulating biomarkers. Measures of feasibility (accrual, retention, adherence, and safety) were primary endpoints. Exploratory aims were directed at the intervention's effect on tumor proliferation (Ki-67) and other tumor markers (activated caspase-3, insulin and androgen receptors, VEGF, TNFß, NFκB, and 4E-BP1), circulating biomarkers (PSA, insulin, glucose, VEGF, TNFß, leptin, SHBG, and testosterone), lymphocytic gene expression of corresponding factors and cellular bioenergetics in neutrophils, and effects on the gut microbiome. Consenting patients were randomized in a 1:1 ratio to either: 1) weight loss via a healthful, guidelines-based diet and exercise regimen; or 2) a wait-list control. While biological testing is currently ongoing, this paper details our methods and feasibility outcomes. RESULTS: The accrual target was met after screening 101 cases (enrollment rate: 39.6%). Other outcomes included a retention rate of 85%, excellent adherence (95%), and no serious reported adverse events. No significant differences by age, race, or weight status were noted between enrollees vs. non-enrollees. The most common reasons for non-participation were "too busy" (30%), medical exclusions (21%), and "distance" (16%). CONCLUSIONS: Presurgical trials offer a means to study the impact of diet and exercise interventions directly on tumor tissue, and other host factors that are feasible and safe, though modifications are needed to conduct trials within an abbreviated period of time and via distance medicine-based approaches. Pre-surgical trials are critical to elucidate the impact of lifestyle interventions on specific mechanisms that mediate carcinogenesis and which can be used subsequently as therapeutic targets. TRIAL REGISTRATION: NCT01886677.