Relationships between T-lymphocytes and physical function in adults with chronic lymphocytic leukemia: Results from the HEALTH4CLL pilot study.

OBJECTIVE: Examine physical function and T-cell phenotype in patients with chronic lymphocytic leukemia (CLL) before and after a physical activity (PA) intervention. METHODS: Physical function measures and blood samples were collected from CLL patients (Rai stage 0-4, 50% receiving targeted therapy, N = 24) enrolled in a 16-week intervention of at-home aerobic and/or resistance exercise. Flow cytometry characterized T-cells in cryopreserved peripheral blood cells. Wilcoxon signed-rank test compared physical function and T-cell phenotype at baseline and 16-weeks; Kendall's Tau assessed associations between variables. RESULTS: Godin leisure-time PA score increased from baseline to 16-weeks (mean difference: 14.61, p < .01) and fatigue decreased (mean difference: 6.71, p < .001). At baseline, lower fatigue correlated with a lower proportion of CD8+ T-cells (τ = 0.32, p = .03) and cardiorespiratory fitness (CRF) inversely correlated with the percentage of PD-1+CD8+ T-cells (τ -0.31, p = .03). At 16-weeks, CRF inversely correlated with the proportion of PD-1+CD4+ T-cells (τ -0.34, p = .02). Reduced fatigue at 16-weeks correlated with an increased CD4:CD8 ratio (τ = 0.36, p = .02) and lower percentage of HLA-DR+PD-1+CD4+ T-cells (τ = -0.37, p = .01). CONCLUSIONS: This intervention increased leisure-time PA and decreased fatigue in CLL patients. These changes correlated with an increased CD4:CD8 T-cell ratio and reduced proportion of T-cells subsets previously associated with poor outcomes in CLL patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02194387.

A Scoping Review on the Effects of Physical Exercise and Fitness on Peripheral Leukocyte Energy Metabolism in Humans.

Background: Both acute and chronic exercise have profound effects on systemic metabolism and the immune system. While acute exercise transiently disturbs energy homeostasis and elicits acute inflammation, exercise training improves systemic metabolic capacity, lowers basal inflammation, and reduces infection risk. Accordingly, accumulating evidence indicates links between systemic and immune cell metabolism and suggests that cellular metabolism may be an important way exercise influences immune function. Yet, no reviews have systematically surveyed the literature in this area. Aims: The aims of this scoping review were to collect, summarize, and provide descriptive analysis of literature on the effects of acute exercise, chronic exercise, and physical fitness on peripheral leukocyte energy metabolism of human adults. Methods: Reports were retrieved from the databases Pubmed, Scopus, and Embase and hierarchically filtered for eligibility. Eligible reports were those that implemented acute or chronic exercise interventions, or assessed physical fitness, in relation to the regulation or function of leukocyte energy metabolism in human adults. Data were charted from eligible reports by two independent reviewers, confirmed by conference, and organized for reporting. Results & Conclusion: Results suggest acute exercise can influence the regulation and function of leukocyte metabolism, with some similarities to what has been previously documented in skeletal muscle. Data also evidence that exercise training and/ or physical fitness alters cellular metabolic regulation and function. Improvements in markers of cell respiratory function or mitochondrial regulation were frequently observed following training or with greater fitness. However, notable gaps in the literature remain. These gaps include: the effects of acute exercise and exercise training on leukocyte glycolysis, the effects of resistance and concurrent exercise, and potential differences in the effects of exercise between immune cell types and subsets. Future research is encouraged to fill the latter gaps and further delineate how exercise influences the immune system and can be used to support overall health.

Effect of exercise on pancreatic cancer patients during treatment: a scoping review of the literature.

INTRODUCTION: Exercise can lower the risk of developing pancreatic cancer and has the potential to improve physical fitness and quality of life in patients with the disease. Yet, the effects of exercise training during pancreatic cancer treatment remain poorly characterized. This hampers the development of evidence-based disease-specific exercise recommendations. PURPOSE: The purpose of this review was to describe and interpret the effect of exercise on physiological, QoL, and cancer-specific outcomes reported in clinical trials among pancreatic cancer patients during treatment. METHODS: We conducted a scoping review of the literature according to the framework proposed by Arksey and O'Malley. Articles published prior to December 2021 were retrieved from PubMed, EMBASE, and Scopus. We only included studies that prescribed structured cardiorespiratory and/or resistance exercise in pancreatic cancer patients undergoing treatment. RESULTS: A total of 662 references were retrieved, of which 24 are included in the review. Twelve articles were randomized controlled trials and 12 were single-arm trials. Overlap in the trials from which data were reported occurred in 16 articles. Moderate intensity exercise was most commonly prescribed, reported feasible for most patients, with potential to enhance physical fitness and QoL. However, exercise adherence and beneficial effects may diminish with disease progression. Limited evidence suggests exercise may benefit cancer-specific outcomes. CONCLUSION: The results of this review indicate that exercise is feasible during pancreatic cancer treatment. Exercise can also improve physical fitness and QoL. However, its beneficial effects may fall with advanced disease and more rigorous research is needed to develop precise exercise protocols for this population.

Autologous serum collected 1 h post-exercise enhances natural killer cell cytotoxicity.

Natural Killer cells are cytotoxic lymphocytes that recognize and eliminate tumor cells. Exercise enhances NK cell cytotoxic activity (NKCA), yet the underlying mechanisms are not fully understood. Exercise-induced shifts in NK-cell subsets has been proposed as one mechanism. Alternatively, exercise alters stress hormone and cytokine levels, which are also known to affect NKCA. AIM: Determine the role(s) of exercise-induced shifts in the proportions of NK-cell subsets found in the blood, and changes in serum IL-2, IL-6, IL-12, IFN-γ, TNF-α and cortisol, on exercise-induced changes in NKCA. METHODS: Twelve adults cycled 30 min at 115% of their lactate threshold power. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from blood collected pre-, post-, and 1 h post-exercise. To investigate the effect of shifts in NK-cell subsets, pre-, post- and 1 h post-exercise NK cells were incubated with target cells (K562 and U266) in the presence of autologous pre-exercise serum. The effects of hormones and cytokines released during exercise were determined by incubating pre-exercise PBMCs with tumor target cells (K562 and U266) in the presence of pre-, post-, and 1 h post-exercise serum. NKCA and phenotypes were assessed by flow cytometry. RESULTS: Although exercise mobilized high-differentiated NK cell subsets (NKG2A-/KIR+), NKCA per cell was not altered post-exercise in the presence of pre-exercise serum. Conversely, 1 h post-exercise serum significantly increased the cytotoxicity of pre-exercise NK cells against HLA-expressing target cells (U266). This increase associated with lower levels of cortisol, and occurred when serum contained higher levels of IFN-γ. CONCLUSIONS: Exercise-induced shifts in NK-cell subsets did not fully explain changes in NKCA. Rather, factors present in serum during exercise recovery enhanced NKCA against target cells. Our results suggest lower cortisol and higher IFN-γ levels may explain exercise-induced changes in NKCA.

ß2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans.

Acute exercise preferentially mobilizes cytotoxic T-cells, NK-cells and non-classical monocytes to the bloodstream under the influence of hemodynamic forces and/or ß2-adrenergic receptor (ß2-AR) signaling. However, the relative contribution of these mechanisms to the redeployment of the most exercise-responsive cell types is largely unknown. We determined the lymphocyte and monocyte subtypes mobilized to blood during exercise via ß2-AR signaling whilst controlling for ß1-AR mediated reductions in hemodynamic forces. In a randomized, double blind, complete cross-over design, 14 healthy cyclists exercised for 30-minutes at +10% of blood lactate threshold after ingesting: (1) a placebo, (2) a ß1-preferential antagonist (10 mg bisoprolol), or (2) a non-preferential ß1 + ß2-antagonist (80 mg nadolol) across three trials separated by >7-days. Bisoprolol was administered to reduce hemodynamic forces (heart rate and blood pressure) during exercise to levels comparable with nadolol but without blocking ß2-ARs. The mobilization of total NK-cells, terminally differentiated (CD57+) NK-cells, central memory, effector memory and CD45RA+ effector memory CD8+ T-cells; non-classical monocytes; and γδ T-cells were significantly blunted or abrogated under nadolol compared to both bisoprolol and placebo, indicating that the exercise-induced mobilization of these cell types to the blood is largely influenced by ß2-AR signaling. Nadolol failed to inhibit the mobilization of classical monocytes, CD4+ T-cells (and their subsets) or naïve CD8+ T-cells, indicating that these cell types are mobilized with exercise independently of the ß2-AR. We conclude that the preferential mobilization of NK-cells, non-classical monocytes and differentiated subsets of CD8+ T-cells with exercise is largely dependent on catecholamine signaling through the ß2-AR. These findings provide mechanistic insights by which distinct lymphocyte and monocyte subtypes are preferentially mobilized to protect the host from anticipated injury or infection in response to an acute stress response.

Exercise, inflammation, and fatigue in cancer survivors.

Cancer-related fatigue significantly disrupts normal functioning and quality of life for a substantial portion of cancer survivors, and may persist for years following cancer treatment. While the causes of persistent fatigue among cancer survivors are not yet fully understood, accumulating evidence suggests that several pathways, including chronic inflammation, autonomic imbalance, HPA-axis dysfunction, and/or mitochondrial damage, could contribute towards the disruption of normal neuronal function and result in the symptom of cancer-related fatigue. Exercise training interventions have been shown to be some of the more successful treatment options to address cancer-related fatigue. In this review, we discuss the literature regarding the causes of persistent fatigue in cancer survivors and the mechanisms by which exercise may relieve this symptom. There is still much work to be done until the prescription of exercise becomes standard practice for cancer survivors. With improvements in the quality of studies, evidenced-based exercise interventions will allow exercise scientists and oncologists to work together to treat cancer-related fatigue.

Human cytomegalovirus infection and the immune response to exercise.

Human cytomegalovirus (HCMV) is a ubiquitous -herpes virus that has co-evolved with its host since the very beginning of human life. The vast majority of adults worldwide carry the virus in a latent state, which is known to have striking effects on the composition and function of both T-cells and NK-cells. While there is evidence to suggest that prior exposure to HCMV can have beneficial effects in the immune competent host, poor control of the virus may contribute to T-cell exhaustion and the early onset of immunosenescence. The interaction between HCMV and exercise has garnered a lot of recent research attention. This stemmed from observations that people with HCMV redeploy greater numbers of CD8+ T-cells in response to a single exercise bout, while NK-cell mobilization is, conversely, impaired. Moreover, athletes with latent HCMV infection may be better protected against symptoms of upper respiratory illness (URI), and it has been suggested that the host's ability to control HCMV (i.e. keeping CMV in a latent state) may connect apparent bidirectional effects of exercise volume on host immunity and infection risk. This work has set a new paradigm that immune responses to both acute and chronic exercise might be governed by the infection history of the host. In this review, we summarize current knowledge on the effects of HCMV infection on T-cells and NK-cells and synthesize the literature on HCMV and the immune response to both single exercise bouts and prolonged periods of exercise training. We also discuss potential clinical and practical applications of this work including the use of HCMV reactivation as a biomarker of immune depression in athletes, its relevance in immunosenescence and the associated immune risk profile, and the potential for exercise to augment vaccine responses and the man ufacture of immune cells for adoptive transfer immunotherapy. Although research in this area is still in its infancy, we conclude that host infection history and the ability to regulate dormant pathogens is likely to play a key role in our understanding of how the immune system responds to both acute and chronic exercise across the entire exercise volume continuum.

A single bout of dynamic exercise by healthy adults enhances the generation of monocyte-derived-dendritic cells.

The ex vivo generation of monocyte-derived-dendritic cells (mo-DCs) has facilitated the use of DCs in immunotherapy research. However, low blood monocyte numbers frequently limit the manufacture of sufficient numbers of mo-DCs for subsequent experimental and clinical procedures. Because exercise mobilizes monocytes to the blood, we tested if acute dynamic exercise by healthy adults would augment the generation of mo-DCs without compromising their differentiation or function. We compared mo-DC generation from before- and after-exercise blood over 8-days of culture. Function was assessed by FITC-dextran uptake and the stimulation of autologous cytomegalovirus (pp65)-specific-T-cells. Supporting the hypothesis, we found a near fourfold increase in number of mo-DCs generated after-exercise. Furthermore, relative FITC-dextran uptake, differentiation rate, and stimulation of pp65-specific-T-cells did not differ between before- and after-exercise mo-DCs. We conclude that exercise enhances the ex vivo generation of mo-DCs without compromising their function, and so may overcome some limitations associated with manufacturing these cells for immunotherapy.

A single bout of dynamic exercise enhances the expansion of MAGE-A4 and PRAME-specific cytotoxic T-cells from healthy adults.

The ex vivo expansion of tumor-associated-antigen (TAA)- specific cytotoxic T-cells (CTLs) from healthy donors for adoptive transfer to cancer patients is now providing additional treatment options for patients. Many studies have shown that adoptive transfer of expanded CTLs can reduce the risk of relapse in cancer patients following hematopoietic stem cell transplantation (HSCT). However, the procedure can be limited by difficulties in priming and expanding sufficient numbers of TAA-specific-CTLs. Because acute dynamic exercise mobilizes large numbers of T-cells to peripheral blood, we hypothesized that a single bout of exercise would augment the ex vivo expansion of TAA-specific-CTLs.We therefore collected lymphocytes from blood donated by healthy adults at rest and after brief maximal dynamic exercise. TAA-specific CTLs were expanded using autologous monocyte-derived-dendritic cells pulsed with melanoma-associated antigen 4 (MAGE-A4), with preferentially expressed antigen in melanoma (PRAME), and with Wilms' tumor protein (WT-1). Post exercise, 84% of the participants had a greater number of CTLs specific for at least one of the three TAA.Cells expanded from post exercise blood yielded a greater number of MAGE-A4 and PRAME-specific-cells in 70% and 61% of participants, respectively. In the 'exercise-responsive' participants (defined as participants with at least a 10% increase in TAA-specific-CTLs post-exercise), MAGEA4- and PRAME-specific-CTLs increased 3.4-fold and 6.2- fold respectively. Moreover, expanded TAA-specific CTLs retained their antigen-specific cytotoxic activity. No phenotype differences were observed between expanded cells donated at rest and postexercise. We conclude that exercise can enhance the ex vivo expansion of TAA-specific-CTLs from healthy adults without compromising cytotoxic function. Hence, this study has implications for immunotherapy using adoptive T-cell transfer of donor-derived T-cells after allogeneic HSCT.

The effects of age and latent cytomegalovirus infection on the redeployment of CD8+ T cell subsets in response to acute exercise in humans.

Dynamic exercise evokes a rapid redeployment of cytotoxic T cell subsets with high expression of ß2 adrenergic receptors, presumably to enhance immunosurveillance during acute stress. As this response is affected by age and infection history, this study examined latent CMV infection as a potential confounder to age-related differences in blood CD8+ T-cell responses to exercise. Healthy young (n=16) and older (n=16) humans counterbalanced by CMV IgG serostatus (positive or negative) exercised for 30-min at ∼80% peak cycling power. Those with CMV redeployed ∼2-times more CD8+ T-cells and ∼6-times more KLRG1+/CD28- and CD45RA+/CCR7- CD8+ subsets than non-infected exercisers. Seronegative older exercisers had an impaired redeployment of total CD8+ T-cells, CD45RA+/CCR7+ and KLRG1-/CD28+ CD8+ subsets compared to young. Redeployed CD8+ T-cell numbers were similar between infected young and old. CMVpp65 specific CD8+ cells in HLA/A2(∗) subjects increased ∼2.7-fold after exercise, a response that was driven by the KLRG1+/CD28-/CD8+ subset. Stimulating PBMCs before and after exercise with CMVpp65 and CMV IE-1 antigens and overlapping peptide pools revealed a 2.1 and 4.4-fold increases in CMVpp65 and CMV IE-1 IFN-γ secreting cells respectively. The breadth of the T cell response was maintained after exercise with the magnitude of the response being amplified across the entire epitope repertoire. To conclude, latent CMV infection overrides age-related impairments in CD8+ T-cell redeployment with exercise. We also show for the first time that many T-cells redeployed with exercise are specific to CMVpp65 and CMV IE-1 antigens, have broad epitope specificity, and are mostly of a high-differentiated effector memory phenotype.

Optimization of mHealth behavioral interventions for patients with chronic lymphocytic leukemia: the HEALTH4CLL study.

PURPOSE: This pilot study of a diet and physical activity intervention (HEALTH4CLL) was conducted to reduce fatigue and improve physical function (PF) in patients with chronic lymphocytic leukemia (CLL). METHODS: The HEALTH4CLL study used a randomized factorial design based on the multiphase optimization strategy (MOST). Patients received diet, exercise, and body weight management instructional materials plus a Fitbit and were randomized to undergo one of 16 combinations of 4 evidence-based mHealth intervention strategies over 16 weeks. Patients' fatigue, PF, health-related quality of life, behavior changes, and program satisfaction and retention were assessed. Paired t-tests were used to examine changes in outcomes from baseline to follow-up among patients. Factorial analysis of variance examined effective intervention components and their combinations regarding improvement in fatigue and PF scores. RESULTS: Among 31 patients, we observed significant improvements in fatigue (+ 11.8; t = 4.08, p = 0.001) and PF (+ 2.6; t = 2.75, p = 0.01) scores. The combination of resistance and aerobic exercise with daily self-monitoring was associated with improved fatigue scores (ß = 3.857, SE = 1.617, p = 0.027). Analysis of the individual components of the MOST design demonstrated greater improvement in the PF score with resistance plus aerobic exercise than with aerobic exercise alone (ß = 2.257, SE = 1.071, p = 0.048). CONCLUSIONS: Combined aerobic and resistance exercise and daily self-monitoring improved PF and reduced fatigue in patients with CLL. IMPLICATIONS FOR CANCER SURVIVORS: This pilot study supported the feasibility of a low-touch mHealth intervention for survivors of CLL and provided preliminary evidence that exercising, particularly resistance exercise, can improve their symptoms and quality of life.

The effects of age and viral serology on γδ T-cell numbers and exercise responsiveness in humans.

γδ T-cells are cytotoxic effector cells that preferentially migrate to peripheral tissues and recognize many types of antigen. We examined the effects of age and viral serology on the exercise responsiveness of γδ T-cells. Blood was collected from 17 younger (age: 23-35yrs) and 17 older (50-64yrs) healthy males matched for cytomegalovirus (CMV), Epstein-Barr virus, herpes simplex virus-1 and Parvovirus B19 serologic status before and after a single bout of cycling exercise. Older had lower numbers and proportions of γδ T-cells than younger, while CMV was associated with increased numbers and proportions of γδ T-cells in younger but not older. Exercise evoked a ∼2-fold increase in circulating γδ T-cell numbers. The magnitude of this response was 3-times greater in younger compared to older, and 1.6-times greater in younger CMV-infected compared to younger non CMV-infected. To conclude, γδ T-cell numbers and exercise responsiveness decreases with age and may contribute to impaired immunosurveillance after acute acute physical stress.

Acute aerobic exercise in humans increases cytokine expression in CD27(-) but not CD27(+) CD8(+) T-cells.

Exercise alters the percentage of CD8(+) T-cells in the bloodstream expressing type I and type II cytokines. It is unknown if this reflects a change in cytokine expression within individual cells, or whether these observations result from the exercise-induced shift in the proportions of early/intermediate (CD27(+)) and late (CD27(-)) differentiated cells, which have vastly different cytokine profiles. 16 males cycled for 60 min at 95% maximal steady state. Mononuclear cells isolated from blood collected before, immediately after, and 1 h after exercise were cultured overnight with and without phytohaemagglutinin stimulation. CD8(+) T-cells were assessed for differentiation markers and intracellular cytokine expression by flow cytometry. The numbers and percentage of CD27(-)CD8(+) T-cells increased immediately after exercise and fell below pre-exercise values 1 h later. At 1 h after exercise, an increased number and percentage of CD8(+) T-cells expressing IL-2, IFN-γ, TNF-α, IL-6, IL-4, and IL-10 was observed in both stimulated and unstimulated cells. The cytokine response to exercise was confined to CD27(-)CD8(+) T-cells, although cytokine expression among CD8(+) T-cells was highest when the proportion of CD27(-)CD8(+) T-cells was lowest. Moreover, the cytokine response to exercise could be predicted by the number of late cells in resting blood: cytokine expression was highest among those with low resting proportions of late cells. We conclude that exercise-induced changes in the percentage of CD8(+) T-cells expressing cytokines are not due to proportional shifts in early/intermediate and late differentiated T-cells. Exercise may prime late-differentiated blood CD8(+) T-cells to initiate effector functions in preparation for their extravasation into the tissues.

Latent cytomegalovirus infection and innate immune function following a 75 km cycling time trial.

PURPOSE: This study compared the acute immune response, inflammation, and lipid peroxidation to a 75 km cycling time trial in male athletes testing positive or negative for latent cytomegalovirus (CMV) infection. DESIGN: Trained cyclists (N = 20) were tested for CMV serostatus, and cycled 75 km on a mountainous course using indoor trainers with continuous workload monitoring. Pre-, post-, and 1 h post-exercise blood samples were analyzed for total blood leukocyte counts, blood granulocyte (GR) and monocyte (MO) phagocytosis (PHAG) and oxidative burst activity (OBA), four plasma cytokines, and plasma F2-isoprostanes. RESULTS: Forty percent of the subjects tested positive for CMV. No differences in subject characteristics were found between CMVpos and CMVneg groups. Mean power (57.3 ± 1.6, 59.4 ± 1.8 % maximal Watts, p = 0.803), heart rate (87.0 ± 1.0, 86.5 ± 1.3 % maximal heart rate, p = 0.376), and total time (2.56 ± 0.08, 2.60 ± 0.08 h, p = 0.744) to complete the 75 km cycling time trial did not differ between CMVpos and CMVneg groups. Whereas exercise induced significant changes in total blood leukocyte counts, GR and MO-PHAG, four plasma cytokines, and plasma F2-isoprostanes (p < 0.05, ω(2) > 0.03), these exercise-induced changes did not differ between CMVpos and CMVneg groups (p > 0.05, ω(2) < 0.01). CONCLUSIONS: CMV serostatus does not appear to influence these innate immune responses or markers of inflammation and lipid peroxidation in response to a single bout of heavy exertion.

Exercise Training Improves Brachial Artery Endothelial Function, but Does Not Alter Inflammatory Biomarkers in Patients with Peripheral Artery Disease: a Systematic Review and Meta-analysis.

The study aimed to systematically review the effects of exercise training (EX) on brachial artery flow-mediated dilation (FMD) and inflammatory biomarkers in patients with peripheral artery disease (PAD). Five electronic databases were searched: (i) patients with PAD aged ≥ 18; (ii) structured EX ≥ 2 weeks; (iii) measured brachial artery FMD; and (iv) measured blood inflammatory biomarkers. Eighteen studies met the inclusion criteria. EX increased FMD but had no effect on C-reactive protein, interleukin-6, and tumor necrosis factor-α. Subgroups with moderate intensity had a greater increase in FMD than subgroups with vigorous intensity. There was no difference in effect on FMD and three inflammatory biomarkers between subgroups training for ≤ 12 weeks and > 12 weeks of EX, < 50 min and ≥ 50 min of session duration, and < 150 min and ≥ 150 min of weekly volume, respectively. These results suggest that EX-induced improvement in vascular function can be independent of the improvement of systemic inflammation.

Objective and subjective sleep patterns and biomarkers of stress among women with a history of sexual abuse in childhood.

OBJECTIVE: Childhood sexual abuse (CSA) is associated with posttraumatic stress symptoms (PTSSs) and sleep disturbance into adulthood. The latter is thought to emerge from dysregulation in biobehavioral systems, including nighttime hyperarousal; however, studies investigating specific mechanisms to explain these long-term sleep problems are limited. The present study examined presleep arousal, fear of sleep, and the cortisol awakening response (CAR) as putative mediators between PTSS and sleep disturbance in women with a history of CSA. METHOD: N = 64 cis-gendered women with a self-reported history of CSA completed a baseline diagnostic interview, self-reported mental health and sleep measures, 7 days of actigraphy monitoring with concurrent sleep diary, and 2 days of saliva sampling. RESULTS: PTSSs were not significantly associated with actigraphy-estimated sleep variables but were positively associated with self-reported sleep onset latency (SOL) and negatively associated with self-reported sleep quality. Similarly, PTSSs were not significantly associated with CAR but were associated with higher presleep arousal and fear of sleep ratings. Mediational models identified greater presleep cognitive arousal to partially explain the PTSS-SOL relationship. Specific features of CSA (i.e., age at time of abuse, location of abuse, relationship to the perpetrator) did not moderate this association. CONCLUSION: Findings suggest that targeting maladaptive cognitions (e.g., worries, rumination) that occur during the presleep period may be a potential intervention target in mitigating sleep disturbance and PTSSs in this population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Characterization of transitional memory CD4+ and CD8+ T-cell mobilization during and after an acute bout of exercise.

T-cell subsets, including naïve (NA), central memory (CM), transitional memory (TM), effector memory (EM), and RA + effector memory (EMRA), differ in phenotype and function. T-cells are mobilized by exercise, with differences in the magnitude of mobilization between subsets. However, the response of TM T-cells to exercise has not yet been described. Further, T-cells expressing the late differentiation marker CD57 are known to be highly responsive to exercise, but the relative response of CD57 + and CD57- within T-cell subsets is unknown. We therefore aimed to characterize the exercise-induced mobilization of TM T-cells, as well as to compare the exercise response of CD57 + and CD57- cells within T-cell subsets. Methods: Seventeen participants (7 female; aged 18-40 years) cycled 30 min at 80% of their estimated maximum heart rate. Venous blood obtained pre, post, and 1H post-exercise was analyzed by flow cytometry. CD45RA, CCR7, and CD28 expression within CD4 + and CD8+ T-cells identified NA, CM, TM, EM, and EMRA subsets. CD57 expression within EM, EMRA, and CD28+ T-cells was also quantified. The relative mobilization of each subset was compared by calculating fold change in cell concentration during (ingress, post/pre) and after exercise (egress,1H post/post). Cytomegalovirus (CMV) serostatus was determined by ELISA and was considered in models. Results: TM CD8+ T-cell concentration was greater post-exercise than pre-exercise (138.59 ± 56.42 cells/µl vs. 98.51 ± 39.68 cells/µl, p < 0.05), and the proportion of CD8 + with a TM phenotype was elevated 1H post-exercise (1H: 32.44 ± 10.38% vs. Pre: 30.15 ± 8.77%, p < 0.05). The relative mobilization during and after exercise of TM T-cells did not differ from NA and CM but was less than EM and EMRA subsets. Similar results were observed within CD4+ T-cells. CD57 + subsets of CD28+ T-cells and of EM and EMRA CD8+ T-cells exhibited a greater relative mobilization than CD57- subsets (all p < 0.05). Conclusion: These results indicate TM CD4 + and CD8+ T-cells are transiently mobilized into the blood with exercise, but not to as great of an extent as later differentiated EM and EMRA T-cells. Results also indicate CD57 identifies highly exercise responsive cells within CD8+ T-cell subsets.

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

Background: Every 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. Methods: Peripheral 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. Results: Exercise 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. Conclusion: Exercise 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.

Aerobic Exercise Alters the Melanoma Microenvironment and Modulates ERK5 S496 Phosphorylation.

Exercise changes the tumor microenvironment by remodeling blood vessels and increasing infiltration by cytotoxic immune cells. The mechanisms driving these changes remain unclear. Herein, we demonstrate that exercise normalizes tumor vasculature and upregulates endothelial expression of VCAM1 in YUMMER 1.7 and B16F10 murine models of melanoma but differentially regulates tumor growth, hypoxia, and the immune response. We found that exercise suppressed tumor growth and increased CD8+ T-cell infiltration in YUMMER but not in B16F10 tumors. Single-cell RNA sequencing and flow cytometry revealed exercise modulated the number and phenotype of tumor-infiltrating CD8+ T cells and myeloid cells. Specifically, exercise caused a phenotypic shift in the tumor-associated macrophage population and increased the expression of MHC class II transcripts. We further demonstrated that ERK5 S496A knock-in mice, which are phosphorylation deficient at the S496 residue, "mimicked" the exercise effect when unexercised, yet when exercised, these mice displayed a reversal in the effect of exercise on tumor growth and macrophage polarization compared with wild-type mice. Taken together, our results reveal tumor-specific differences in the immune response to exercise and show that ERK5 signaling via the S496 residue plays a crucial role in exercise-induced tumor microenvironment changes. See related Spotlight by Betof Warner, p. 1158.