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Receptor downregulation is instrumental for many therapeutic interventions. Receptor knockout through gene-editing technologies is efficient but can introduce off-target mutations and chromothripsis. Regulation of gene expression at the protein level is a promising alternative. Here, we present results showing the targeted T cell antigen receptor (TCR) degradation using chimeric E3 fusion proteins that we call Receptor Targeting Chimeras (ReceptorTAC). We show that TCR degradation is dependent on enzymatically active, membrane-anchored E3 ligase variants. TCR specificity was achieved by direct fusion of an E3 domain to the CD3ζ transmembrane sequence. Jurkat and primary T cells stably expressing the ReceptorTAC constructs showed significantly reduced responses to TCR stimulation. We also used our ReceptorTAC technology to generate TCR-deficient, claudin18.2-specific CAR T cells, where the activity of the CAR was unaffected by the expression of the ReceptorTAC. These data indicate that our ReceptorTAC molecule can be used to generate allogeneic CAR T cells.

PURPOSE Epidemiological studies suggest that sedentary behavior is an independent risk factor for cardiovascular mortality independent of meeting physical activity guidelines. However, limited evidence of this relationship is available from prospective interventions. The purpose of the present study is to evaluate the combined effect of aerobic training and increasing nonexercise physical activity on body composition and cardiometabolic risk factors. METHODS Obese adults (N = 45) were randomized to 6 months of aerobic training (AERO), aerobic training and increasing nonexercise physical activity (~3000 steps above baseline levels; AERO-PA), or a control (CON) group. The AERO and AERO-PA groups performed supervised aerobic training (3-4 times per week). The AERO-PA group wore Fitbit One accelerometers and received behavioral coaching to increase nonexercise physical activity. RESULTS There was a larger increase in fitness in the AERO-PA group (0.27 L·min-1; confidence interval (CI), 0.16 to 0.40 L·min-1) compared with the AERO group (0.09 L·min-1; CI, -0.04 to 0.22 L·min-1) and the CON group (0.01; CI, -0.11 to 0.12 L·min-1). Although significant findings were not observed in the entire study sample, when the analysis was restricted to participants compliant to the intervention (n = 33), we observed significant reductions in waist circumference, percent weight loss, body fat, 2-h glucose, and 2-h insulin in comparison to the CON group (P < 0.05), but not the AERO group. Furthermore, linear regression models showed that change in steps was associated with 21% and 26% of the variation in percent weight loss and percent fat loss, respectively. CONCLUSIONS Increasing nonexercise physical activity with aerobic training may represent a viable strategy to augment the fitness response in comparison to aerobic training alone and has promise for other health indicators.

There is limited evidence on the impact of weight loss via caloric restriction and aerobic exercise on Life’s Simple 7 (LS7), a health assessment tool used by the American Heart Association to promote and track cardiovascular health (CVH) via modifiable risk factors and health behaviors. Individuals with obesity have a greater prevalence of traditional and non-traditional cardiometabolic risk factors than lean individuals. Objective: Examine the effect of a weight loss intervention on LS7 and assess predictors of change in adults with obesity. Methods: Twenty-six adults (44.9 ± 9.7 years; weight: 93.9 ± 11.1 kg; body mass index: 34.1 ± 3.4 kg/m 2 ) participated in a 10-week medical weight loss program (OPTIFAST) and supervised exercise training program (50-75% VO 2 max) to achieve clinically significant weight loss (≥7% body weight). Poor, intermediate, and ideal CVH categories were defined as scores 0 to 4, 5 to 9, and 10 to 14, respectively. Baseline and post-weight loss LS7 scores were calculated via participant demographics, smoking status, anthropometry, physical activity level, diet intake, and blood lab reports. Paired samples t-test and Pearson’s correlations were used. Results: Mean weight loss was significant (-9.2 ± 3.6 kg, p < 0.001). Mean LS7 score significantly increased from baseline to weight loss (7.3 ± 1.5 vs. 9.6 ± 1.2, respectively, p < 0.001) and 57.7% of participants (15 of 26) improved to ideal CVH following weight loss. A significant inverse association was observed between change in LS7 and systolic blood pressure ( r = -0.41, p < 0.05), total cholesterol ( r = -0.45, p < 0.05), and glucose ( r = -0.41, p < 0.05). There were no further significant relationships with LS7 (i.e. change in weight, body mass index, physical activity, diastolic blood pressure). Discussion: A combined caloric restriction and aerobic exercise training intervention improved a multitude of cardiovascular disease risk factors. Previous epidemiological studies indicate meeting the ideal LS7 metrics is associated with 78% and 49% reduced risk of cardiovascular disease morbidity and mortality, respectively. Thus, the long-term modification of health behaviors and cardiometabolic risk factors to achieve ideal cardiovascular health may reduce risks of cardiovascular morbidity and mortality in individuals with obesity.

Clinically significant weight loss is associated with health benefits for overweight and obese adults. Participation in adequate amounts of physical activity is critical for weight maintenance. However, the recommended amount of physical activity needed to promote weight maintenance is based primarily on retrospective studies that quantified physical activity levels through questionnaires which tend to overestimate physical activity levels. In addition, the present literature has provided little data on the impact of these physical activity levels on cardiovascular and diabetes risk factors, which may have equal or more clinical importance than weight changes. The Prescribed Exercise to Reduce Recidivism After Weight Loss-Pilot (PREVAIL-P) study will evaluate the effect of aerobic exercise training amount on weight maintenance following clinically significant weight loss in overweight and obese adults (BMI 25–40 kg/m2) age 30–65 years. Participants (N = 39) will complete a 10-week OPTIFAST® weight loss program with supervised aerobic exercise training. Individuals who achieve ≥7% weight loss from baseline will be subsequently randomized to levels of aerobic training consistent with physical activity recommendations (PA-REC) or weight maintenance recommendations (WM-REC) for 18 additional weeks. The primary outcome of the PREVAIL-P study will be change in weight from the completion of OPTIFAST® program to the end of the study. Notable secondary measures include changes in clinically relevant cardiometabolic risk factors between study groups (e.g. blood lipids concentrations, oral glucose tolerance, arterial stiffness). This pilot study will be used to estimate the effect sizes needed for a randomized controlled trial on this topic.

Objective: The OPTIFAST diet has known effects for weight loss, but little data exists on the effects of the diet on arterial stiffness. Methods: Overweight and obese (BMI: 34.5 + 4.0) adults (N=17) participated in a 10-week OPTIFAST™ weight loss program and supervised aerobic exercise training (50%-75% VO 2 max). The diet consisted of OPTIFAST meal replacement products with a goal of reducing total caloric intake to 800 kcals/day and attending a weekly weight management class. Aerobic exercise was performed 3 times per week and the exercise volume was progressed from 300 to 700 MET mins. per week at an intensity of 50%-75% VO2 max. The goal of study participants was to achieve a 7% weight loss. Carotid-to-femoral pulse wave velocity, blood pressure (aortic and brachial), vascular age, augmentation index and blood samples were measured in the morning after an overnight fast at baseline and follow-up. A paired t-test was performed to evaluate the change in outcomes variables. Results: The mean percent weight loss in the sample was 9.0% (-8.5 kg), with 83.3% of participants achieving 7% weight loss (94.1% achieving ≥5%). The adherence to the exercise program was 94.9% and attendance in the weight loss classes was 81.8%. There was a reduction in pulse wave velocity (-0.44 m/s, p=0.030), aortic systolic blood pressure (-10.5 mmHg, p0.05). Discussion: A hypo-caloric dietary program in combination with aerobic exercise training improves arterial stiffness, aortic blood pressure, and brachial blood pressure in overweight and obese adults An important limitation of the present study is that we cannot separate the health benefits of the diet from the exercise.

Obesity represents a major health problem in the United States and is associated with increased prevalence of cardiovascular (CV) disease risk factors. Physical activity (PA) and exercise training (ET) are associated with reduced CV risk, improved cardiometabolic risk factors, and facilitated weight loss through creating a negative energy balance. Clinicians need to counsel overweight and obese patients on how much PA/ET is needed to promote weight loss and weight loss maintenance. This will help establish realistic expectations and maximize improvements in CV risk factors. Although the minimum guidelines for aerobic PA (150 min of moderate or 75 min of vigorous physical activity per week) can improve CV health, these levels are generally inadequate for clinically significant weight loss or weight maintenance without caloric restriction. The purpose of this review is to evaluate the role of ET to promote clinically significant weight loss and promote weight maintenance. In particular, we will evaluate the likelihood of weight loss from ET programs composed of aerobic training only, resistance training only and programs that combine diet and ET. We will also explore the role of PA in promoting short-term and long-term weight maintenance.

African Americans (AAs) have a higher risk for cardiovascular disease (CVD) compared to their Caucasian American (CA) counterparts, which represents a major health disparity. Low cardiorespiratory fitness (CRF) is a well-established independent risk factor for all-cause and CVD mortality, which has been shown across many epidemiological and clinical trials to be lower in AAs compared to CAs. While much attention has been given to traditional health disparity risk factors (e.g. blood pressure, obesity, insulin resistance), the impact of racial differences in CRF on CVD mortality has not been widely considered. Thus, the purpose of this paper is to review the literature on: 1) the magnitude of racial differences in CRF and the potential clinical significance, 2) examine the relationships between CRF and mortality in AAs and CAs, 3) Potential physiological and behavioral etiologies for racial difference in CRF, and 4) the impact of exercise training on CRF and other cardiometabolic risk factors in AAs compared to CAs. Given that both CRF and change in CRF are associated with reduced CVD mortality, advocating aerobic exercise training or moderate to vigorous activities in AAs has the potential to reduce racial cardiovascular health disparities.

Background African Americans have a disproportionate prevalence and incidence of type 2 diabetes compared with Caucasians. Recent evidence indicates that low cardiorespiratory fitness (CRF) level, an independent risk factor for type 2 diabetes, is also more prevalent in African Americans than Caucasians. Numerous studies in Caucasian populations suggest that vigorous exercise intensity may promote greater improvements in CRF and other type 2 diabetes risk factors (e.g., reduction of glucose/insulin levels, pulse wave velocity, and body fat) than moderate intensity. However, current evidence comparing health benefits of different aerobic exercise intensities on type 2 diabetes risk factors in African Americans is negligible. This is clinically important as African Americans have a greater risk for type 2 diabetes and are less likely to meet public health recommendations for physical activity than Caucasians. The purpose of the HI-PACE (High-Intensity exercise to Promote Accelerated improvements in CardiorEspiratory fitness) study is to evaluate whether high-intensity aerobic exercise elicits greater improvements in CRF, insulin action, and arterial stiffness than moderate-intensity exercise in African Americans. Methods/Design A randomized controlled trial will be performed on overweight and obese (body mass index of 25–45 kg/m2) African Americans (35–65 years) (n = 60). Participants will be randomly assigned to moderate-intensity (MOD-INT) or high-intensity (HIGH-INT) aerobic exercise training or a non-exercise control group (CON) for 24 weeks. Supervised exercise will be performed at a heart rate associated with 45–55% and 70–80% of VO2 max in the MOD-INT and HIGH-INT groups, respectively, for an exercise dose of 600 metabolic equivalents of task (MET)-minutes per week (consistent with public health recommendations). The primary outcome is change in CRF. Secondary outcomes include change in insulin sensitivity (measured via an intravenous glucose tolerance test), skeletal muscle mitochondrial oxidative capacity (via near-infrared spectroscopy), skeletal muscle measurements (i.e., citrate synthase, COX IV, GLUT-4, CPT-1, and PGC1-α), arterial stiffness (via carotid-femoral pulse wave velocity), body fat, C-reactive protein, and psychological outcomes (quality of life/exercise enjoyment). Discussion The anticipated results of the HI-PACE study will provide vital information on the health effects of high-intensity exercise in African Americans. This study will advance health disparity research and has the potential to influence future public health guidelines for physical activity. Trial registration ClinicalTrials.gov identifier: NCT02892331. Registered on September 8, 2016. Electronic supplementary material The online version of this article (10.1186/s13063-019-3611-1) contains supplementary material, which is available to authorized users.

Introduction: Previous studies have shown that lipoprotein particle size and lipoprotein subclasses are associated with cardiovascular and type 2 diabetes risk, and have independent prognostic value above traditional lipid concentrations. The impact of exercise training and increasing non-exercise physical activity on lipoprotein subclasses and size has not been previously investigated. Methods: In this pilot study, 35 obese adults were randomized to aerobic exercise training (50-75% of VO 2 max) (AERO, n=11), aerobic training and increasing non-exercise physical activity (AERO-PA, n=10, ~3,000 steps above baseline levels), or a non-exercise control group (n=14) for 6 months. Baseline and follow-up blood samples were analyzed for lipoprotein subclass, size, and lipoprotein insulin resistance score (LP-IR) using nuclear magnetic resonance spectroscopy (Liposcience, NC). Analysis of covariance was used to evaluate the change in outcome variables following the intervention across groups with adjustment for baseline value and age. Participants who changed lipid medications during the intervention (n=2) or who were non-adherent to exercise training (n=2) were excluded from the analysis. Results: Significant reductions were observed for mean VLDL size in the AERO-PA group (-4.7 nm, CI: -8.7 to -0.8) compared to control group (0.7 nm, CI: -2.7 to 4.4) and the AERO group (1.1 nm, CI: -2.9 to 5.0). Reductions in triglyceride concentrations were observed in the AERO-PA group (-28.3 mg/dL, CI: -50.3 to -6.4) compared to control (4.1 mg/dL, CI: -14.6 to 22.8). Additionally, we observed a trend for LP-IR index (p=0.055) and the concentration of small HDL particles (p=0.093) to decrease in the AERO-PA group compared to controls, with no differences compared to the AERO group (p>0.10). No significant changes were observed for other notable lipoprotein measures, such as LDL size, HDL size, concentration of small LDL particles, or chylomicron measures (p>0.05). In the AERO-PA group, the change in steps was associated with the change in LP-IR index (r= -0.71, p=0.013), but not with change in VLDL size (r= -0.24, p=0.463) or triglyceride concentrations (r=-0.28, p=0.388). Conclusions: Aerobic training combined with increasing non-exercise physical activity leads to favorable changes in the lipoprotein profile, specifically reductions in VLDL size and triglycerides, and may have promise for other lipoprotein traits (reductions in LP-IR and small HDL particles) that were not observed with aerobic training alone.