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

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

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

Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis

Aim: To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Materials & methods: Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6- month confirmed disability progression (3mCDP and 6mCDP) were conducted. Results: For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. Conclusion: The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR)

Participant characteristics.

<p>Data are presented as means ± SEM.</p>A<p>Obese group data significantly different from lean group data, <i>P</i>≤0.01.</p>B<p>Obese group data significantly different from lean group data, <i>P</i>≤0.02.</p>C<p>Post-training significantly different from pre-training (main effect), <i>P</i>≤0.001.</p

Transmission electron microscopy assessment of intramyocellular lipid and mitochondrial content.

<p>Micrographs of a skeletal muscle cell illustrating subsarcolemmal (<b>A</b>) and intermyofibrillar (<b>B</b>) intramyocellular lipid (IMCL) and mitochondria prior to (<b>A</b>,<b>B</b>) and following 12-wk endurance training (<b>C</b>,<b>D</b>). Subsarcolemmal (SS) IMCL and mitochondria are located between the sarcolemma and the most superficial myofibrils. The intermyofibrillar (IMF) IMCL and mitochondria are located between parallel bundles of myofibrils. The micrographs (X6,500 magnification, scale bar: 1 µm) were obtained from a biopsy of the <i>vastus lateralis</i> muscle from an obese participant. L, intramyocellular lipid droplet; M, mitochondria, Z, Z-line. IMCL size (<b>E</b>), number (<b>F</b>), and density (<b>G</b>) in SS and IMF regions of skeletal muscle of lean (<i>n</i> = 9) and obese (<i>n</i> = 9) men prior to and following 12-wk endurance training. *<i>P</i>≤0.05 pre- <i>vs.</i> post-training (main effect). Mitochondria size (<b>H</b>), number (<b>I</b>), and density (<b>J</b>) in SS and IMF regions of skeletal muscle of lean (<i>n</i> = 9) and obese (<i>n</i> = 9) men prior to and following 12-wk endurance training. *<i>P</i>≤0.01 pre- <i>vs.</i> post-training (main effect).</p

Markers of mitochondrial function.

<p>(<b>A</b>) Mitochondrial protein content assessed by Western blot and (<b>B</b>) mitochondrial maximal enzyme activity in skeletal muscle of lean (<i>n</i> = 9) and obese (<i>n</i> = 9) men prior to and following 12-wk endurance training. (<b>A</b>) PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; CS, citrate synthase; COX, cytochrome <i>c</i> oxidase - subunits II and IV. Results were normalized to β-actin protein content. *<i>P</i>≤0.04 pre- <i>vs.</i> post-training (main effect). (<b>B</b>) CS, citrate synthase; COX, cytochrome <i>c</i> oxidase; SCHAD, short-chain β-hydroxyacyl-CoA dehydrogenase. *<i>P</i>≤0.03 pre- <i>vs.</i> post-training (main effect). (<b>C</b>) Mitochondrial DNA (mtDNA) copy number determined by real-time quantitative PCR using a TaqMan probe against NADH dehydrogenase 4 (ND4) and β-globin. mtDNA copy number was calculated as the ratio of ND4 to β-globin in skeletal muscle of lean (<i>n</i> = 3) and obese (<i>n</i> = 5) men prior to and following 12-wk endurance training. *<i>P</i> = 0.10 pre- <i>vs.</i> post-training (main effect).</p