Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice

BackgroundEvery bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from healthy volunteers at rest and at the end of an acute bout of cycling exercise. Flow cytometry and single-cell RNA sequencing was performed to identify phenotypic and transcriptomic differences between resting and exercise-mobilized cells using a targeted gene expression panel curated for human immunology. PBMCs were injected into the tail vein of xenogeneic NSG-IL-15 mice and subsequently challenged with a luciferase tagged chronic myelogenous leukemia cell line (K562). Tumor growth (bioluminescence) and xenogeneic graft-versus-host disease (GvHD) were monitored bi-weekly for 40-days.ResultsExercise preferentially mobilized NK-cell, CD8+ T-cell and monocyte subtypes with a differentiated and effector phenotype, without significantly mobilizing CD4+ regulatory T-cells. Mobilized effector lymphocytes, particularly effector-memory CD8+ T-cells and NK-cells, displayed differentially expressed genes and enriched gene sets associated with anti-tumor activity, including cytotoxicity, migration/chemotaxis, antigen binding, cytokine responsiveness and alloreactivity (e.g. graft-versus-host/leukemia). Mice receiving exercise-mobilized PBMCs had lower tumor burden and higher overall survival (4.14E+08 photons/s and 47%, respectively) at day 40 compared to mice receiving resting PBMCs (12.1E+08 photons/s and 22%, respectively) from the same donors (p<0.05). Human immune cell engraftment was similar for resting and exercise-mobilized DLI. However, when compared to non-tumor bearing mice, K562 increased the expansion of NK-cell and CD3+/CD4-/CD8- T-cells in mice receiving exercise-mobilized but not resting lymphocytes, 1-2 weeks after DLI. No differences in GvHD or GvHD-free survival was observed between groups either with or without K562 challenge.ConclusionExercise in humans mobilizes effector lymphocytes with an anti-tumor transcriptomic profile and their use as DLI extends survival and enhances the graft-versus-leukemia (GvL) effect without exacerbating GvHD in human leukemia bearing xenogeneic mice. Exercise may serve as an effective and economical adjuvant to increase the GvL effects of allogeneic cell therapies without intensifying GvHD

A new method for identifying outlying subsets of data

In various branches of science, e.g. medicine, economics, sociology, it is necessary to identify or detect outlying subsets of data. Suppose that the set of data is partitioned into many relatively small subsets and we have some reason to suspect that one or several of these subsets may be atypical or aberrant. We propose applying a new measure of separability, based on the ideas borrowed from the discriminant analysis. In our paper we define two versions of this measure, both using a jacknife, leave-one-out, estimator of classification error. If a suspected subset is significantly well separated from the main bulk of data, then we regard it as outlying. The usefulness of our algorithm is illustrated on a set of medical data collected in a large survey "Epidemiology of Allergic Diseases in Poland" (ECAP). We also tested our method on artificial data sets and on the classical IRIS data set. For a comparison, we report the results of a homogeneity test of Bartoszyński, Pearl and Lawrence, applied to the same data sets

Rank correlation estimators and their limiting distributions

Ranking, Linear ranking rule, Discontinuous criterion function, Support vector machines, Convex minimization, U-statistics,

A Carbohydrate Beverage Reduces Monocytes Expressing TLR4 in Children with Overweight or Obesity

Background: Childhood obesity is increasing, with about one-third of children overweight or obese. Obesity is characterized by a state of chronic low-grade inflammation that is related to cardiometabolic comorbidities. Inflammatory monocytes, which are classified into 3 different groups-classical, intermediate, and nonclassical monocytes, with Toll-like receptor 4 (TLR4(+)) expression indicating a proinflammatory state-underlie several obesity-associated morbidities. Objectives: This study aimed to assess the responses of monocyte populations to beverages of differing macronutrient composition in children with healthy weight (HW) or overweight/obesity (OW/OB). Methods: Ten HW children (5th to 84.9th percentile; mean age 12.29 +/- 2.5 y) and 7 children with OW/OB (85th to 99.99th percentile; mean age 11.96 +/- 3.8 y) completed the study. Adiposity was determined via DXA. Using a doubleblinded, randomized, crossover design, participants consumed either a high-carbohydrate (CHO; 210 kcal; 0 g fat/56 g carbohydrates/0 g protein) or a whole-egg-based high-protein/fat (EGG; 210 kcal; 15 g fat/0 g carbohydrates/18 g protein) beverage. Venous blood was collected at baseline and 2 h postprandially for evaluation of metabolic and inflammatory responses. Repeated measures ANOVA and Pearson correlations were conducted. Results: Consuming the CHO beverage significantly reduced the primary outcome: TLR4(+) expression on classical monocytes in children with OW/OB only (25.60% decrease from baseline in OW/OB compared with 1.61% increase in HW). Children with OW/OB had significantly less percentages of TLR4(+) nonclassical monocytes than HW (4766% lower after CHO). Insulin and glucose (secondary outcomes), were significantly higher after the CHO condition compared with baseline (230.61% and 9.93% increase, respectively). Changes in glucose were significantly and negatively related to changes in monocyte populations in the CHO condition. Conclusions: These data suggest that high-carbohydrate beverages alter monocyte populations in the blood in children with OW/OB, which is related to glucose metabolism. These findings have implications for nutritional recommendations in children with overweight/obesity.12 month embargo; published online: 11 December 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

A study of the leakage of surface electromagnetic fields through holes and cracks in metal plates

A study of the leakage of surface electromagnetic fields through holes and cracks in metal plate