A Multiomics Assessment of Preoperative Exercise in Pancreatic Cancer Survivors Receiving Neoadjuvant Therapy: A Case Series.

To molecularly characterize the impact of exercise on mitigating neoadjuvant treatment (NAT)-induced physical decline in pancreatic ductal adenocarcinoma (PDAC) patients, a multi-omics approach was employed for the analysis of plasma samples before and after a personalized exercise intervention. Consisting of personalized aerobic and resistance exercises, this intervention was associated with significant molecular changes that correlated with improvements in lean mass, appendicular skeletal muscle index (ASMI), and performance in the 400-m walk test (MWT) and sit-to-stand test. These alterations indicated exercise-induced modulation of inflammation and mitochondrial function markers. This case study provides proof-of-principal application for multiomics-based assessments of supervised exercise, thereby supporting this intervention as a feasible and beneficial intervention for PDAC patients to potentially enhance treatment response and patient quality of life. The molecular changes observed here underscore the importance of physical activity in cancer treatment protocols, advocating for the development of accessible multiomics-guided exercise programs for cancer patients.

Prospective assessment of fibrinolysis in morbid obesity: tissue plasminogen activator resistance improves after bariatric surgery.

BACKGROUND: Morbid obesity is associated with an increased risk of thrombotic events, which has been attributed to increased thrombotic activity. Multiple mechanisms have been proposed to explain this increased risk, including an inflammatory state with upregulation of procoagulant and antifibrinolytic proteins. We therefore hypothesize that patients with morbid obesity are hypercoagulable and will revert to normal after bariatric surgery. OBJECTIVES: To evaluate changes in the hypercoagulable state after bariatric surgery. SETTING: University Hospital, Bariatric Center of Excellence, United States. METHODS: Thromboelastography (TEG) data were collected on 72 subjects with morbid obesity, with 36 who had 6 months of follow-up after bariatric surgery. TEG data of 75 healthy subjects (HS) without obesity, recent trauma or surgery, acute infection, or chronic conditions (e.g., liver, cardiovascular, or kidney disease; cancer; diabetes; autoimmune or inflammatory disorders; and disorders of coagulation) were used for comparison. TEG was performed alone and with the addition of 75 and 150 ng/mL tissue plasminogen activator (tPA) to quantify fibrinolysis resistance (tPA-challenged TEG). RESULTS: The bariatric surgery cohort had a median age of 40.5 years, a median body mass index of 44.6 kg/m2, and 90% female patients. Median body mass index reduced significantly 6 months post surgery but remained elevated compared with the HS group (31.4 versus 25.4 kg/m2, P < .0001). At 6 months post surgery, subjects had longer reaction time (mean difference, 1.3; P = .02), lower maximum amplitude (-2.4, P = .01), and increased fibrinolysis with low-dose (3.1, P < .0001) and high-dose tPA-challenged TEG (9, P < .0001). Compared with HS, the postsurgery TEG values were still more likely to be abnormal (all P < .05). CONCLUSIONS: Patients with morbid obesity form stronger clots more rapidly and are more resistant to fibrinolysis than subjects without obesity. Bariatric surgery significantly improved the hypercoagulable profile and fibrinolysis resistance of morbid obesity.

Interleukin 37 reverses the metabolic cost of inflammation, increases oxidative respiration, and improves exercise tolerance.

IL-1 family member interleukin 37 (IL-37) has broad antiinflammatory properties and functions as a natural suppressor of innate inflammation. In this study, we demonstrate that treatment with recombinant human IL-37 reverses the decrease in exercise performance observed during systemic inflammation. This effect was associated with a decrease in the levels of plasma and muscle cytokines, comparable in extent to that obtained upon IL-1 receptor blockade. Exogenous administration of IL-37 to healthy mice, not subjected to an inflammatory challenge, also improved exercise performance by 82% compared with vehicle-treated mice (P = 0.01). Treatment with eight daily doses of IL-37 resulted in a further 326% increase in endurance running time compared with the performance level of mice receiving vehicle (P = 0.001). These properties required the engagement of the IL-1 decoy receptor 8 (IL-1R8) and the activation of AMP-activated protein kinase (AMPK), because both inhibition of AMPK and IL-1R8 deficiency abrogated the positive effects of IL-37 on exercise performance. Mechanistically, treatment with IL-37 induced marked metabolic changes with higher levels of muscle AMPK, greater rates of oxygen consumption, and increased oxidative phosphorylation. Metabolomic analyses of plasma and muscles of mice treated with IL-37 revealed an increase in AMP/ATP ratio, reduced levels of proinflammatory mediator succinate and oxidative stress-related metabolites, as well as changes in amino acid and purine metabolism. These effects of IL-37 to limit the metabolic costs of chronic inflammation and to foster exercise tolerance provide a rationale for therapeutic use of IL-37 in the treatment of inflammation-mediated fatigue.