Dubé JJ, Coen PM, DiStefano G, Chacon AC, Helbling NL, Desimone ME, Stafanovic-Racic M, Hames KC, Despines AA, Toledo FG, Goodpaster BH. Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance. Am J Physiol Endocrinol Metab 307: E1117-E1124, 2014. First published October 28, 2014; doi:10.1152/ajpendo.00257.2014.-We hypothesized that acute lipid-induced insulin resistance would be attenuated in highoxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload. lipids; mitochondria; skeletal muscle CHRONIC SUBSTRATE OVERLOAD, coupled with physical inactivity, is a key mediator of the development of obesity and insulin resistance (49). It has been suggested that mitochondrial dysfunction (1, 17), perhaps a result of nutrient oversupply, particularly saturated fatty acids and/or physical inactivity, plays a key role in decreased insulin action observed in the obese state. However, there is evidence to suggest that mitochondrial content and performance are normal in insulinresistant obese subjects (14). Although there is controversy regarding the influence of mitochondrial performance on the development of insulin resistance (17,22), there is little debate that increased physical activity (i.e., aerobic exercise) provides a necessary stimulus for increased mitochondrial content (24), capacity for fat oxidation (6), and improved insulin sensitivity (13). Yet few studies have directly assessed the effects of lipid oversupply on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance in high-vs. lowoxidative muscle (9, 40).Using the exogenous lipid infusion model of insulin resistance (7, 26), we hypothesized that excess fatty acids would be preferentially oxidized in enduranc...

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Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of genetic instability associated with tumorigenesis. As the epitome of personalized medicine, TIL-ACT bypasses the issue of intertumoral heterogeneity by utilizing the patient’s existing antitumor immune response. Despite being one of the few therapies capable of inducing durable, complete tumor regression, many patients fail to respond. Recent research has focused on increasing therapeutic efficacy by refining various aspects of the TIL protocol, which includes the isolation, ex vivo expansion, and subsequent infusion of tumor specific lymphocytes. This review will explore how the therapy has evolved with time by highlighting various resistance mechanisms to TIL therapy and the novel strategies to overcome them.

Restoration of joint stability during total shoulder arthroplasty can be challenging in the face of severe glenoid retroversion. A novel technique of humeral head component anterior-offsetting has been proposed to address posterior instability. We evaluated the biomechanical benefits of this technique in cadaveric specimens. Total shoulder arthroplasty was performed in 14 cadaveric shoulders from 7 donors. Complementary shoulders were assigned to either 10˚or 20˚glenoid retroversion, with retroversion created by eccentric reaming. Two humeral head component offset positions were tested in each specimen: The anatomic (posterior) and anterior (reverse). With loads applied to the rotator cuff and deltoid, joint contact pressures and the force and energy required for posterior humeral head translation were measured. The force and energy required to displace the humeral head posteriorly increased significantly with the anterior offset position compared to the anatomic offset position. The joint contact pressures were significantly shifted anteriorly, and the joint contact area significantly increased with the anterior offset position. Anterior offsetting of the humeral head component increased the resistance to posterior humeral head translation, shifted joint contact pressures anteriorly, and increased joint contact area, thus, potentially increasing the joint stability in total shoulder arthroplasty with simulated glenoid retroversion. ß

Background Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of unknown etiology and unpredictable natural history. To date, no large‐scale studies have been published evaluating this disease due to its rare occurrence. Methods The National Cancer Database was reviewed between 2004 and 2016 to identify patients with HEH. Univariate analysis with overall survival (OS) was performed by Cox proportional hazards model. Kaplan–Meier method was used to create OS curves and compared using the log‐rank test. Results We identified 229 patients with HEH. The majority of patients were female (61.1%), white (84.3%), and had a Charlson–Deyo score of 0 (75%). Chemotherapeutic intervention was seen in 26% of the patients while 33% received surgical intervention in the form of wedge/segmental liver resection (n = 27), hepatectomy lobectomy/extended lobectomy (n = 18), and liver transplant (n = 22). Five‐year survival in surgical patients was 90.5%, 66.5% and 81%, respectively (p = 0.485). Age greater than 55 years (hazard ratio [HR], 2.78; p < 0.001), Asian ethnicity compared to white (HR, 2.84; p = 0.012), and a higher Charlson–Deyo score (score 1: HR, 2.28; p < 0.001 and score ≥2: HR, 2.76; p = 0.011) were associated with worse OS. Conclusion Treatment for HEH remains variable with only a third of the patients undergoing surgery. International collaboration is necessary to determine the optimal treatment for this rare disease.