The effect of endurance exercise on both skeletal muscle and systemic oxidative stress in previously sedentary obese men

Background: Obesity is associated with low-grade systemic inflammation, in part because of secretion of proinflammatory cytokines, resulting into peripheral insulin resistance (IR). Increased oxidative stress is proposed to link adiposity and chronic inflammation. The effects of endurance exercise in modulating these outcomes in insulin-resistant obese adults remain unclear. We investigated the effect of endurance exercise on markers of oxidative damage (4-hydroxy-2-nonenal (4-HNE), protein carbonyls (PCs)) and antioxidant enzymes (superoxide dismutase (SOD), catalase) in skeletal muscle; urinary markers of oxidative stress (8-hydroxy-2-deoxyguanosine (8-OHdG), 8-isoprostane); and plasma cytokines (C-reactive protein (CRP), interleukin-6 (IL-6), leptin, adiponectin). Methods: Age- and fitness-matched sedentary obese and lean men (n=9 per group) underwent 3 months of moderate-intensity endurance cycling training with a vastus lateralis biopsy, 24-h urine sample and venous blood samples taken before and after the intervention. Results: Obese subjects had increased levels of oxidative damage: 4-HNE (+37% P⩽0.03) and PC (+63% P⩽0.02); evidence of increased adaptive response to oxidative stress because of elevated levels of copper/zinc SOD (Cu/ZnSOD) protein content (+84% P⩽0.01); increased markers of inflammation: CRP (+737% P⩽0.0001) and IL-6 (+85% P⩽0.03), and these correlated with increased markers of obesity; and increased leptin (+262% P⩽0.0001) with lower adiponectin (−27% P⩽0.01) levels vs lean controls. Training reduced 4-HNE (−10% P⩽0.04), PC (−21% P⩽0.05), 8-isoprostane (−26% P⩽0.02) and leptin levels (−33% P⩽0.01); had a tendency to decrease IL-6 levels (−21% P=0.07) and IR (−17% P=0.10); and increased manganese SOD (MnSOD) levels (+47% P⩽0.01). Conclusion: Endurance exercise reduced skeletal muscle-specific and systemic oxidative damage while improving IR and cytokine profile associated with obesity, independent of weight loss. Hence, exercise is a useful therapeutic modality to reduce risk factors associated with the pathogenesis of IR in obesity

Efficacy and safety of crizotinib in the treatment of advanced non-small cell Lung cancer with ROS1 gene fusion: A systematic literature review and Meta-Analysis of real-world evidence

Background: Crizotinib was approved to treat patients with advanced non -small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify realworld evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta-analyses (MA) for objective response rate (ORR), real -world progression -free survival (PFS), and overall survival (OS). Methods: We searched MEDLINE (R), Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid (R) for published single -arm or comparative RWE studies evaluating patients (N >= 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real -world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan -Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first -line crizotinib. Results: Fourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I2 > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate). Conclusion: The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real -world setting

Markers of Skeletal Muscle Mitochondrial Function and Lipid Accumulation Are Moderately Associated with the Homeostasis Model Assessment Index of Insulin Resistance in Obese Men

Lower skeletal muscle mitochondrial oxidative phosphorylation capacity (OXPHOS) and intramyocellular lipid (IMCL) accumulation have been implicated in the etiology of insulin resistance (IR) in obesity. The purpose of this study was to examine the impact of endurance exercise on biochemical and morphological measures of IMCL and mitochondrial content, and their relationship to IR in obese individuals. We examined mitochondrial content (subunit protein abundance and maximal activity of electron transport chain enzymes), IMCL/mitochondrial morphology in both subsarcolemmal (SS) and intermyofibrillar (IMF) regions by transmission electron microscopy, and intracellular lipid metabolites (diacylglycerol and ceramide) in vastus lateralis biopsies, as well as, the homeostasis model assessment index of IR (HOMA-IR) prior to and following twelve weeks of an endurance exercise regimen in healthy age- and physical activity-matched lean and obese men. Obese men did not show evidence of mitochondrial OXPHOS dysfunction, disproportionate IMCL content in sub-cellular regions, or diacylglycerol/ceramide accretion despite marked IR vs. lean controls. Endurance exercise increased OXPHOS and mitochondrial size and density, but not number of individual mitochondrial fragments, with moderate improvements in HOMA-IR. Exercise reduced SS IMCL content (size, number and density), increased IMF IMCL content, while increasing IMCL/mitochondrial juxtaposition in both regions. HOMA-IR was inversely associated with SS (r = −0.34; P = 0.051) and IMF mitochondrial density (r = −0.29; P = 0.096), IMF IMCL/mitochondrial juxtaposition (r = −0.30; P = 0.086), and COXII (r = −0.32; P = 0.095) and COXIV protein abundance (r = −0.35; P = 0.052); while positively associated with SS IMCL size (r = 0.28; P = 0.119) and SS IMCL density (r = 0.25; P = 0.152). Our findings suggest that once physical activity and cardiorespiratory fitness have been controlled for, skeletal muscle mitochondrial and IMCL profile in obesity may only partially contribute to the development of IR

Meta-analysis of ciltacabtagene autoleucel versus physician’s choice therapy for the treatment of patients with relapsed or refractory multiple myeloma

[Objective]: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician’s choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM). [Methods]: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1. [Results]: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22–0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses. [Conclusions]: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.The CARTITUDE-1 study and these analyses were funded by Janssen Research & Development, LLC, and Legend Biotech, Inc. Medical writing support was provided by EVERSANA and funded by Janssen Global Services, LLC

Adverse Fetal and Neonatal Outcomes Associated with a Life-Long High Fat Diet: Role of Altered Development of the Placental Vasculature

Maternal obesity results in a number of obstetrical and fetal complications with both immediate and long-term consequences. The increased prevalence of obesity has resulted in increasing numbers of women of reproductive age in this high-risk group. Since many of these obese women have been subjected to hypercaloric diets from early childhood we have developed a rodent model of life-long maternal obesity to more clearly understand the mechanisms that contribute to adverse pregnancy outcomes in obese women. Female Sprague Dawley rats were fed a control diet (CON - 16% of calories from fat) or high fat diet (HF - 45% of calories from fat) from 3 to 19 weeks of age. Prior to pregnancy HF-fed dams exhibited significant increases in body fat, serum leptin and triglycerides. A subset of dams was sacrificed at gestational day 15 to evaluate fetal and placental development. The remaining animals were allowed to deliver normally. HF-fed dams exhibited a more than 3-fold increase in fetal death and decreased neonatal survival. These outcomes were associated with altered vascular development in the placenta, as well as increased hypoxia in the labyrinth. We propose that the altered placental vasculature may result in reduced oxygenation of the fetal tissues contributing to premature demise and poor neonatal survival

Aging Hallmarks: the benefits of physical exercise

World population has been continuously increasing and progressively aging. Aging is characterized by a complex and intraindividual process associated with nine major cellular and molecular hallmarks, namely, genomic instability, telomere attrition, epigenetic alterations, a loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. This review exposes the positive antiaging impact of physical exercise at the cellular level, highlighting its specific role in attenuating the aging effects of each hallmark. Exercise should be seen as a polypill, which improves the health-related quality of life and functional capabilities while mitigating physiological changes and comorbidities associated with aging. To achieve a framework of effective physical exercise interventions on aging, further research on its benefits and the most effective strategies is encouraged

Meta-analysis of ciltacabtagene autoleucel versus physician’s choice therapy for the treatment of patients with relapsed or refractory multiple myeloma [Dataset]

Figure A.1: Selection of Comparator Arms for ITC Analyses Figure A.2: Results of sensitivity analyses with OIs removed for OS at all (A) and first (B) index dates Figure A.3: Results of sensitivity analyses with LocoMMotion removed for OS at all (A) and first (B) index dates, and PF at first index dates (C) Table A.1: Characteristics of Data Sources for PCT arms in ITCs Table A.2: Published ITC Results and Augmented Results Included in Meta-analyses (All Index Dates) Table A.3: Published ITC Results and Augmented Results Included in Meta-analyses (First Index Dates) Table A.4: Baseline Covariates After Adjustment (mITT Populations; All Index Dates) Table A.5: Baseline Covariates After Adjustment (mITT Populations; First Index Dates) Table A.6: Outcome Definitions in ITC Analyses[Objective]: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician’s choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM). [Methods]: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1. [Results]: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22–0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses. [Conclusions]: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.Peer reviewe

Obesity-Related Oxidative Stress: the Impact of Physical Activity and Diet Manipulation

Obesity-related oxidative stress, the imbalance between pro-oxidants and antioxidants (e.g., nitric oxide), has been linked to metabolic and cardiovascular disease, including endothelial dysfunction and atherosclerosis. Reactive oxygen species (ROS) are essential for physiological functions including gene expression, cellular growth, infection defense, and modulating endothelial function. However, elevated ROS and/or diminished antioxidant capacity leading to oxidative stress can lead to dysfunction. Physical activity also results in an acute state of oxidative stress. However, it is likely that chronic physical activity provides a stimulus for favorable oxidative adaptations and enhanced physiological performance and physical health, although distinct responses between aerobic and anaerobic activities warrant further investigation. Studies support the benefits of dietary modification as well as exercise interventions in alleviating oxidative stress susceptibility. Since obese individuals tend to demonstrate elevated markers of oxidative stress, the implications for this population are significant. Therefore, in this review our aim is to discuss (i) the role of oxidative stress and inflammation as associated with obesity-related diseases, (ii) the potential concerns and benefits of exercise-mediated oxidative stress, and (iii) the advantageous role of dietary modification, including acute or chronic caloric restriction and vitamin D supplementation

Bitter gourd reduces elevated fasting plasma glucose levels in an intervention study among prediabetics in Tanzania

Ethnopharmacological relevance: Impaired glucose tolerance and diabetes mellitus have become major health issues even in non-industrialized countries. As access to clinical management is often poor, dietary interventions and alternative medicines are required. For bitter gourd, Momordica charantia L., antidiabetic properties have been claimed. Aim of the study: The main objective of the intervention study was to assess antidiabetic effects of daily bitter gourd consumption of 2.5 g powder over the course of eight weeks among prediabetic individuals. Materials and methods: In a randomized placebo-controlled single blinded clinical trial, 52 individuals with prediabetes were studied after consuming a bitter gourd or a cucumber juice. For reducing the impact of between subject differences in the study population, a crossover design was chosen with eight weeks for each study period and four weeks washout in between. Fasting plasma glucose was chosen as the primary outcome variable. Results: Comparing the different exposures, the CROS analysis (t=−2.23, p=0.031, r=0.326) revealed a significant difference in the change of FPG of 0.31 mmol/L (5.6 mg/dL) with a trend (R2=0,42387). The number of 44 finally complete data sets achieved a power of 0.82, with a medium-to-large effect size (Cohen's d 0.62). The effect was also proven by a general linear mixed model (estimate 0.31; SE: 0.12; p: 0.01; 95%CI: 0.08; 0.54). Not all participants responded, but the higher the initial blood glucose levels were, the more pronounced the effect was. No serious adverse effects were observed. Conclusions: Bitter gourd supplementation appeared to have benefits in lowering elevated fasting plasma glucose in prediabetes. The findings should be replicated in other intervention studies to further investigate glucose lowering effects and the opportunity to use bitter gourd for dietary self-management, especially in places where access to professional medical care is not easily assured