Beyond muscles: Investigating immunoregulatory myokines in acute resistance exercise - A systematic review and meta-analysis.

Myokines, released from the muscle, enable communication between the working muscles and other tissues. Their release during physical exercise is assumed to depend on immune-hormonal-metabolic interactions concerning mode (endurance or resistance exercise), duration, and intensity. This meta-analysis aims to examine the acute changes of circulating myokines inducing immunoregulatory effects caused by a bout of resistance exercise and to consider potential moderators of the results. Based on this selection strategy, a systematic literature search was conducted for resistance exercise intervention studies measuring interleukin (IL-) 6, IL-10, IL-1ra, tumor necrosis factor (TNF-) α, IL-15, IL-7, transforming growth factor (TGF-) ß1, and fractalkines (FKN) before and immediately after resistance exercise in healthy individuals. Random-effects meta-analysis was performed for each myokine. We identified a moderate positive effect of resistance exercise for IL-6 and IL-1ra. Regarding IL-15 and TNF-α, small to moderate effects were found. For IL-10, no significant effect was observed. Due to no data, meta-analyses for IL-7, TGF-ß1, and FKN could not be performed. No moderators (training status, type of exercise, risk of bias, age, sex, time of day, exercise volume, exercise intensity, exercise dose) of the results were detected for all tested myokines. Taken together, this systematic review and meta-analysis showed immediate positive effects of an acute resistance exercise session on IL-6, IL-1ra, TNF-α, and IL-15 levels.

Acute exercise activates the AHR in peripheral blood mononuclear cells in an intensity-dependent manner.

The kynurenine pathway of tryptophan degradation generates several metabolites such as kynurenine or kynurenic acid that serve as endogenous ligands of the aryl hydrocarbon receptor (AHR). Due to its distinct biological roles particularly modulating the immune system, the AHR is a current therapeutic target across different inflammation-related diseases. Here, we show an acute exercise-induced increase in AHR ligand availability on a systemic level and a kynurenine pathway activation in peripheral blood mononuclear cells (PBMCs). Concurrently, the AHR is activated in PBMCs following acute exercise. Exercise effects on both, kynurenic acid and AHR activation in PBMCs were greater in response to high-intensity interval exercise (50 min., six three-minute intervals á 90% V̇O2peak, and three-minute intervals at 50% V̇O2peak in between) compared to workload-matched moderate intensity continuous exercise (50 min.). In conclusion, these data indicate a novel mechanistic link how exercise modulates the immune system through the kynurenine pathway-AHR axis, potentially underlying exercise-induced benefits in various chronic diseases.

Efficacy and safety of everolimus plus exemestane in patients with hormone receptor-positive, HER-2-negative advanced breast cancer: Results from the open-label, multicentre, non-interventional BRAWO study.

BRAWO, a real-world study, assessed the efficacy, quality of life (QoL) and safety of EVE + EXE in postmenopausal women with HR+/HER2- advanced breast cancer (ABC) in routine clinical practice. Postmenopausal women with HR+/HER2-ABC with recurrence or progression after a NSAI were included. Primary Observation parameters included the evaluation of the effectiveness of EVE + EXE. A multivariate-analysis using Cox proportional hazard model was built to identify predictors of progression. Overall, 2100 patients were enrolled (August 2012-December 2017); 2074 were evaluable for efficacy and safety analyses. Majority of patients (60.6%) received EVE + EXE as first (28.7%) or second-line (31.9%) therapy. Visceral metastases were present in 54.1% patients. Median progression-free survival (mPFS) reported as 6.6 months (95%CI: 6.3-7.0). Multivariate-analysis in a subset of patients (n = 1837) found higher body mass index (BMI) and non-visceral metastases to be independent predictors of favorable PFS. Patients with a BMI of 20 to <25 had a mPFS of 6.0 (95%CI: 5.4-6.4) and those with a BMI ≥30 had mPFS of 8.5 (95%CI: 6.9-9.9). 41.2% patients achieved stable disease and 7.3% partial response. No major changes were observed QoL; 86.4% patients received stomatitis prophylaxis and 41.4% experienced EVE related AEs of stomatitis, mainly low grade. AEs occurred in 91.2% of patients, of which stomatitis (42.6%) and fatigue (19.8%) were most frequent. The BRAWO study provides real-world evidence of efficacy and safety of EVE + EXE in patients with HR+, HER2- ABC. A high BMI and the absence of visceral metastases were independent predictors of PFS in this cohort of patients.

Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair.

Activation of the immune response during injury is a critical early event that determines whether the outcome of tissue restoration is regeneration or replacement of the damaged tissue with a scar. The mechanisms by which immune signals control these fundamentally different regenerative pathways are largely unknown. We have demonstrated that, during skin repair in mice, interleukin-4 receptor α (IL-4Rα)-dependent macrophage activation controlled collagen fibril assembly and that this process was important for effective repair while having adverse pro-fibrotic effects. We identified Relm-α as one important player in the pathway from IL-4Rα signaling in macrophages to the induction of lysyl hydroxylase 2 (LH2), an enzyme that directs persistent pro-fibrotic collagen cross-links, in fibroblasts. Notably, Relm-ß induced LH2 in human fibroblasts, and expression of both factors was increased in lipodermatosclerosis, a condition of excessive human skin fibrosis. Collectively, our findings provide mechanistic insights into the link between type 2 immunity and initiation of pro-fibrotic pathways.

Comparison of the cytokine responses to acute strength exercise between oral contraceptive users and naturally cycling women.

PURPOSE: Cytokines are released as part of an inflammatory reaction in response to strength exercise to initiate muscle repair and morphological adaptations. Whether hormonal fluctuations induced by the menstrual cycle or oral contraceptives affect inflammatory responses to strength exercise remains unknown. Therefore, we aimed to compare the response of cytokines after acute strength exercise in naturally menstruating women and oral contraceptive users. METHODS: Naturally menstruating women (MC, n = 13, 24 ± 4 years, weekly strength training: 4.3 ± 1.7 h) and women using a monophasic combined pill (> 9 months) (OC, n = 8, 22 ± 3 years, weekly strength training: 4.5 ± 1.9 h) were recruited. A one-repetition-maximum (1RM) test and strength exercise in the squat (4 × 10 repetitions, 70%1RM) was performed in the early follicular phase or pill free interval. Concentrations of oestradiol, IL-1ß, IL-1ra, IL-6, IL-8, and IL-10 were assessed before (pre), directly after (post) and 24 h after (post24) strength exercise. RESULTS: IL-1ra increased from pre to post (+ 51.1 ± 59.4%, p = 0.189) and statistically decreased from post to post24 (- 20.5 ± 13.5%, p = 0.011) only in OC. Additionally, IL-1ß statistically decreased from post to post24 (- 39.6 ± 23.0%, p = 0.044) only in OC. There was an interaction effect for IL-1ß (p = 0.038) and concentrations were statistically decreased at post24 in OC compared to MC (p = 0.05). IL-8 increased across both groups from post to post24 (+ 66.6 ± 96.3%, p = 0.004). CONCLUSION: We showed a differential regulation of IL-1ß and IL-1ra between OC users in the pill-free interval and naturally cycling women 24 h after strength exercise, while there was no effect on other cytokines. Whether this is associated with previously shown compromised morphological adaptations remains to be investigated.

Balance training during acute medical treatment for pediatric cancer - subjective benefits and preliminary effects on selected physical abilities.

BACKGROUND: As balance training seems to be a promising training method to improve physical limitations of the lower limbs, this study aims to evaluate feasibility, subjective benefits and preliminary effects on physical abilities of balance training in pediatric cancer patients. PATIENTS: 11 pediatric cancer patients (5-21 years) undergoing acute medical treatment were included in the study. METHOD: Participants took part in a 4-week balance training intervention. 3 trainings/week were conducted either supervised or self-administered. Subjective benefits were evaluated using a questionnaire, effects on selected physical abilities were assessed using functional-motor assessments. RESULTS: Participants completed 71.21+37.34% of balance training sessions, no adverse events occurred. Participants were satisfied with the intervention and described various subjective benefits. Significant improvements were found in functional strength of the lower limbs as well as positive trends in balance. DISCUSSION: Balance training seems feasible with pediatric cancer patients undergoing acute medical treatment potentially improving functions of the lower limbs relevant for daily physical activity. CONCLUSION: Balance training can be a valuable conjunct to general exercise programs in pediatric oncology. HINTERGRUND: Da ein Gleichgewichtstraining eine vielversprechende Trainingsmethode zur Verbesserung körperlicher Beeinträchtigungen der unteren Extremitäten darstellt, untersucht die vorliegende Studie die Machbarkeit, subjektive und erste objektive Effekte eines Gleichgewichtstrainings auf körperliche Fähigkeiten bei onkologisch erkrankten Kindern. PATIENTEN: 11 Kinder und Jugendliche (5-21 Jahre) während der akutmedizinischen Behandlung einer onkologischen Erkrankung wurden in die Studie eingeschlossen. METHODIK: Die Patient*innen nahmen an einem 4-wöchigen Gleichgewichtstraining teil. 3 Trainingseinheiten/Woche wurden entweder supervidiert oder selbstständig umgesetzt. Subjektive Effekte wurden mit einem Fragebogen und die Effekte auf ausgewählte körperliche Fähigkeiten mittels funktionell-motorischer Testungen evaluiert. ERGEBNISSE: Die Teilnehmer*innen absolvierten 71.21+37.34% der Trainingseinheiten und es traten keine trainingsbedingten Zwischenfälle auf. Die Kinder waren zufrieden mit der Intervention und beschrieben verschiedene subjektive Effekte. Positive Veränderungen zeigten sich im Bereich der funktionellen Kraft der unteren Extremitäten und des Gleichgewichts. DISKUSSION: Ein Gleichgewichtstraining während der akutmedizinischen Behandlung in der Kinderonkologie scheint machbar und zeigt potenziell positive Effekte auf relevante Funktionen der unteren Extremitäten. SCHLUSSFOLGERUNG: Ein Gleichgewichtstraining kann eine wertvolle Ergänzung allgemeiner Bewegungsprogramme in der pädiatrischen Onkologie darstellen.

Skeletal muscle fiber type-specific expressions of mechanosensors integrin-linked kinase, talin, and vinculin and their modulation by loading and environmental conditions in humans.

Mechanosensors control muscle integrity as demonstrated in mice. However, no information is available in human muscle about the distribution of mechanosensors and their adaptations to mechanical loading and environmental conditions (hypoxia). Here, we hypothesized that mechanosensors show fiber-type-specific distributions and that loading and environmental conditions specifically regulate mechanosensors. We randomly subjected 28 healthy males to one of the following groups (n = 7 each) consisting of nine loading sessions within 3 weeks: normoxia moderate (NM), normoxia intensive (NI), hypoxia moderate (HM), and hypoxia intensive (HI). We took six biopsies: pre (T0), 4 h (T1), and 24 h (T2) after the third as well as 4 h (T3), 24 h (T4), and 72 h (T5) after the ninth training session. We analyzed subjects' maximal oxygen consumption (V̇O2 max), maximal power output (Pmax), muscle fiber types and cross-sectional areas (CSA), fiber-type-specific integrin-linked kinase (ILK) localizations as well as ILK, vinculin and talin protein and gene expressions in dependence on loading and environmental conditions. V̇O2 max increased upon NM and HM, Pmax upon all interventions. Fiber types did not change, whereas CSA increased upon NI and HI, but decreased upon HM. ILK showed a type 2-specific fiber type localization. ILK, vinculin, and talin protein and gene expressions differed depending on loading and environmental conditions. Our data demonstrate that mechanosensors show fiber type-specific distributions and that exercise intensities rather than environmental variables influence their profiles in human muscles. These data are the first of their kind in human muscle and indicate that mechanosensors manage the mechanosensing at a fiber-type-specific resolution and that the intensity of mechanical stimulation has a major impact.

Maintaining proteostasis under mechanical stress.

Cell survival, tissue integrity and organismal health depend on the ability to maintain functional protein networks even under conditions that threaten protein integrity. Protection against such stress conditions involves the adaptation of folding and degradation machineries, which help to preserve the protein network by facilitating the refolding or disposal of damaged proteins. In multicellular organisms, cells are permanently exposed to stress resulting from mechanical forces. Yet, for long time mechanical stress was not recognized as a primary stressor that perturbs protein structure and threatens proteome integrity. The identification and characterization of protein folding and degradation systems, which handle force-unfolded proteins, marks a turning point in this regard. It has become apparent that mechanical stress protection operates during cell differentiation, adhesion and migration and is essential for maintaining tissues such as skeletal muscle, heart and kidney as well as the immune system. Here, we provide an overview of recent advances in our understanding of mechanical stress protection.

Safety and feasibility of exercise interventions in patients with hematological cancer undergoing chemotherapy: a systematic review.

OBJECTIVE: Exercise during and after cancer treatment has established quality of life and health benefits. However, particularly for patients with hematological cancer clear recommendations regarding the safety and feasibility of exercise are under-investigated. The aim of our systematic review was to summarize the literature regarding the feasibility and safety of exercise interventions in patients diagnosed with hematological cancer undergoing chemotherapy. METHOD: A systematic literature review was conducted using PubMed, SPORTDiscus, MEDLINE, Science Direct, and Web of Science electronic databases. Eligible studies were scientific publications reporting the feasibility and/or safety of an exercise intervention program carried out in inpatient patients diagnosed with hematological cancer undergoing chemotherapy. RESULT: Out of 12 studies (six RCTs) included in this review, six investigations reported results with regard to safety and 10 with regard to feasibility. While all studies claim that their exercise interventions were safe and/or feasible, it is noteworthy that this claim often remains unsupported as detailed information on how the feasibility of the intervention was asserted is missing. CONCLUSION: Exercise appears to be safe and feasible in hematological cancer patients. However, due to a striking lack of information on how the feasibility of the intervention was asserted, contextualizing the results and deducing recommendations for further studies remains challenging. Further research should therefore incorporate information on the execution of the exercise intervention in more detail.

Cellular Integrative Immune Markers in Elite Athletes.

The integrative immune markers neutrophil-lymphocyte-ratio (NLR), platelet-lymphocyte-ratio (PLR) and systemic immune inflammation index (SII) are established markers in clinical patient care. Adoption of these markers in elite athletics might prove beneficial for monitoring training and health. Blood samples of 195 healthy national Olympic squad athletes were collected before a graded bicycle-ergometric exercise test until complete exhaustion. Measurements included white blood cells, lymphocytes and platelets, allowing for the calculation of the integrative immune markers. Correlations between athlete characteristics (sex, age, sporting discipline, training experience, training volume) and integrative immune marker-values were assessed. In a subgroup analysis a second blood sample was collected from 25 athletes at 1 minute after exercise test to assess its effect on the immune marker levels.An inverse correlation between peak power output and SII-level (Pearson correlation coefficient=-.270, p<.001) and NLR-level (Pearson correlation coefficient=-.249, p<.001) was found. Athletes with higher aerobic fitness had significantly lower values of SII and PLR compared to athletes with lower aerobic fitness. An elevated SII (p=.003) and a reduced PLR (p=.001) was documented as acute response to the exercise test. The integrative immune markers might be a promising tool for monitoring training and health in elite athletes.

Dental Pulp Inflammation Initiates the Occurrence of Mast Cells Expressing the α1 and ß1 Subunits of Soluble Guanylyl Cyclase.

The binding of nitric oxide (NO) to heme in the ß1 subunit of soluble guanylyl cyclase (sGC) activates both the heterodimeric α1ß1 and α2ß1 isoforms of the enzyme, leading to the increased production of cGMP from GTP. In cultured human mast cells, exogenous NO is able to inhibit mast cell degranulation via NO-cGMP signaling. However, under inflammatory oxidative or nitrosative stress, sGC becomes insensitive to NO. The occurrence of mast cells in healthy and inflamed human tissues and the in vivo expression of the α1 and ß1 subunits of sGC in human mast cells during inflammation remain largely unresolved and were investigated here. Using peroxidase and double immunohistochemical incubations, no mast cells were found in healthy dental pulp, whereas the inflammation of dental pulp initiated the occurrence of several mast cells expressing the α1 and ß1 subunits of sGC. Since inflammation-induced oxidative and nitrosative stress oxidizes Fe2+ to Fe3+ in the ß1 subunit of sGC, leading to the desensitization of sGC to NO, we hypothesize that the NO- and heme-independent pharmacological activation of sGC in mast cells may be considered as a regulatory strategy for mast cell functions in inflamed human dental pulp.

Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti-oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune-responsive tumor entities.

Even patients with mild COVID-19 symptoms after SARS-CoV-2 infection show prolonged altered red blood cell morphology and rheological parameters.

Infection with the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the associated coronavirus disease-19 (COVID-19) might affect red blood cells (RBC); possibly altering oxygen supply. However, investigations of cell morphology and RBC rheological parameters during a mild disease course are lacking and thus, the aim of the study. Fifty individuals with mild COVID-19 disease process were tested after the acute phase of SARS-CoV-2 infection (37males/13 females), and the data were compared to n = 42 healthy controls (30 males/12 females). Analysis of venous blood samples, taken at rest, revealed a higher percentage of permanently elongated RBC and membrane extensions in COVID-19 patients. Haematological parameters and haemoglobin concentration, MCH and MCV in particular, were highly altered in COVID-19. RBC deformability and deformability under an osmotic gradient were significantly reduced in COVID-19 patients. Higher RBC-NOS activation was not capable to at least in part counteract these reductions. Impaired RBC deformability might also be related to morphological changes and/or increased oxidative state. RBC aggregation index remained unaffected. However, higher shear rates were necessary to balance the aggregation-disaggregation in COVID-19 patients which might be, among others, related to morphological changes. The data suggest prolonged modifications of the RBC system even during a mild COVID-19 disease course.

The Kunitz-type serine protease inhibitor Spint2 is required for cellular cohesion, coordinated cell migration and cell survival during zebrafish hatching gland development.

We have previously shown that the Kunitz-type serine protease inhibitor Spint1a, also named Hai1a, is required in the zebrafish embryonic epidermis to restrict the activity of the type II transmembrane serine protease (TTSP) Matriptase1a/St14a, thereby ensuring epidermal homeostasis. A closely related Kunitz-type inhibitor is Spint2/Hai2, which in mammals plays multiple developmental roles that are either redundant or non-redundant with those of Spint1. However, the molecular bases for these non-redundancies are not fully understood. Here, we study spint2 during zebrafish development. It is co-expressed with spint1a in multiple embryonic epithelia, including the outer/peridermal layer of the epidermis. However, unlike spint1a, spint2 expression is absent from the basal epidermal layer but present in hatching gland cells. Hatching gland cells derive from the mesendodermal prechordal plate, from where they undergo a thus far undescribed transit into, and coordinated sheet migration within, the interspace between the outer and basal layer of the epidermis to reach their final destination on the yolk sac. Hatching gland cells usually survive their degranulation that drives embryo hatching but die several days later. In spint2 mutants, cohesion among hatching gland cells and their collective intra-epidermal migration are disturbed, leading to a discontinuous organization of the gland. In addition, cells undergo precocious cell death before degranulation, so that embryos fail to hatch. Chimera analyses show that Spint2 is required in hatching gland cells, but not in the overlying periderm, their potential migration and adhesion substrate. Spint2 acts independently of all tested Matriptases, Prostasins and other described Spint1 and Spint2 mediators. However, it displays a tight genetic interaction with and acts at least partly via the cell-cell adhesion protein E-cadherin, promoting both hatching gland cell cohesiveness and survival, in line with formerly reported effects of E-cadherin during morphogenesis and cell death suppression. In contrast, no such genetic interaction was observed between Spint2 and the cell-cell adhesion molecule EpCAM, which instead interacts with Spint1a. Our data shed new light onto the mechanisms of hatching gland morphogenesis and hatching gland cell survival. In addition, they reveal developmental roles of Spint2 that are strikingly different from those of Spint1, most likely due to differences in the expression patterns and relevant target proteins.

Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical protein kinase C/Par6 in podocytes to maintain the kidney filtration barrier.

Glomerular diseases are a major cause for chronic kidney disorders. In most cases podocyte injury is causative for disease development. Cytoskeletal rearrangements and morphological changes are hallmark features of podocyte injury and result in dedifferentiation and loss of podocytes. Here, we establish a link between the Par3 polarity complex and actin regulators necessary to establish and maintain podocyte architecture by utilizing mouse and Drosophila models to characterize the functional role of Par3A and Par3B and its fly homologue Bazooka in vivo. Only simultaneous inactivation of both Par3 proteins caused a severe disease phenotype. Rescue experiments in Drosophila nephrocytes revealed atypical protein kinase C (aPKC)-Par6 dependent and independent effects. While Par3A primarily acts via aPKC-Par6, Par3B function was independent of Par6. Actin-associated synaptopodin protein levels were found to be significantly upregulated upon loss of Par3A/B in mouse podocytes. Tropomyosin2, which shares functional similarities with synaptopodin, was also elevated in Bazooka depleted nephrocytes. The simultaneous depletion of Bazooka and Tropomyosin2 resulted in a partial rescue of the Bazooka knockdown phenotype and prevented increased Rho1-GTP, a member of a GTPase protein family regulating the cytoskeleton. The latter contribute to the nephrocyte phenotype observed upon loss of Bazooka. Thus, we demonstrate that Par3 proteins share a high functional redundancy but also have specific functions. Par3A acts in an aPKC-Par6 dependent way and regulates RhoA-GTP levels, while Par3B exploits Par6 independent functions influencing synaptopodin localization. Hence, Par3A and Par3B link elements of polarity signaling and actin regulators to maintain podocyte architecture.

Basement membrane stiffness determines metastases formation.

The basement membrane (BM) is a special type of extracellular matrix and presents the major barrier cancer cells have to overcome multiple times to form metastases. Here we show that BM stiffness is a major determinant of metastases formation in several tissues and identify netrin-4 (Net4) as a key regulator of BM stiffness. Mechanistically, our biophysical and functional analyses in combination with mathematical simulations show that Net4 softens the mechanical properties of native BMs by opening laminin node complexes, decreasing cancer cell potential to transmigrate this barrier despite creating bigger pores. Our results therefore reveal that BM stiffness is dominant over pore size, and that the mechanical properties of 'normal' BMs determine metastases formation and patient survival independent of cancer-mediated alterations. Thus, identifying individual Net4 protein levels within native BMs in major metastatic organs may have the potential to define patient survival even before tumour formation. The ratio of Net4 to laminin molecules determines BM stiffness, such that the more Net4, the softer the BM, thereby decreasing cancer cell invasion activity.

Acute effects of heavy resistance exercise on biomarkers of neuroendocrine-immune regulation in healthy adults: a systematic review.

BACKGROUND: The nervous system integrates the immune system in the systemic effort to maintain or restore the organism's homeostasis. Acute bouts of exercise may alter the activity of specific pathways associated with neuroendocrine regulation of the immune system. OBJECTIVE: To examine the acute effects of heavy resistance exercise on biomarkers of neuroendocrine-immune regulation in healthy adults. METHODS: A systematic literature search was conducted using PubMed, Cochrane Controlled Trials Register, Web of Science and SportDiscus with no date restrictions up to March 2021. Clinical trials in English or German were included if they measured the blood plasma or serum concentrations of specific biomarkers of neuroendocrine-immune regulation (adrenaline, noradrenaline, acetylcholine, vasoactive intestinal peptide (VIP), cortisol, growth hormone, calcitonin gene-related peptide (CGRP), substance p, serotonin, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) or glia-derived neurotrophic factor (GDNF)) in a resting state prior to and no later than 60 minutes after an acute bout of heavy resistance exercise in healthy adults. RESULTS: 7801 records were identified through literature search, of which 36 studies, with a total of 58 intervention groups, met the inclusion criteria. Evidence was found that an acute bout of heavy resistance exercise increased the levels of adrenaline (median: 185%), noradrenaline (median: 113%) and GH (median: 265%) immediately after the exercise. Mixed results were found for cortisol (median: 0%), suggesting that its response might be more sensitive to the configuration of the exercise scheme. The limited evidence regarding the effects on BDNF and ACTH allows no firm conclusions to be drawn about their response to heavy resistance exercise. The vast majority of the included studies reported a return of the biomarker concentrations to their baseline value within one hour after the termination of the exercise bout. No studies were identified that investigated the response of acetylcholine, VIP, CGRP, substance p, serotonin, NGF or GDNF to heavy resistance exercise. CONCLUSIONS: A bout of heavy resistance exercise alters the circulating concentrations of selected biomarkers of neuroendocrine-immune regulation. Both subject characteristics, such as sex as well as exercise parameters, such as rest intervals appear to have the potential to influence these effects.

Exercise reduces systemic immune inflammation index (SII) in childhood cancer patients.

While exercise and physical activity have been suggested to reduce mortality and symptoms in cancer, knowledge on these associations in patients with childhood cancer (CCPs) is sparse. Anti-inflammatory properties of exercise might mediate these beneficial effects. We investigated the influence of exercise on the inflammation markers neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic-immune-inflammation index (SII) and associations to patient-reported-outcomes in CCPs in a randomized-controlled trial. Results show associations between inflammation markers and patient-reported outcomes. Compared to the control group, SII was significantly reduced following exercise (p=0.036). Anti-inflammatory effects of exercise are also present in CCPs and may underlie exercise-induced benefits on symptoms. Clinical Trial Registration Number: NCT02612025.

Sleep problems and their interaction with physical activity and fatigue in hematological cancer patients during onset of high dose chemotherapy.

PURPOSE: Sleep problems reported by hematological cancer patients are usually linked to higher levels of cancer-related fatigue. Although the awareness of sleep problems in solid cancer patients is rising, there has been less attention to the issue in hematological cancer patients. The present study assesses the differences in sleep by comparing physical activity and fatigue levels among hematological cancer patients during the onset of chemotherapy. Furthermore, it investigates the relationship between sleep, physical activity, and fatigue through mediation analysis. METHODS: The recruited sample consists of 58 newly diagnosed hematological cancer patients (47.1 ± 15.4 yrs; 51.7% males). Subjects completed questionnaires assessing sleep (PSQI), physical activity (visual analogue scale), fatigue (MFI-20), anxiety, depression (HADS), and quality of life (EORTC QLQ-C30) within two weeks from starting treatment. RESULTS: The sample reported more sleep problems in comparison to the German population norm. The classification as good (ca 25%) or bad sleepers (ca 75%) showed less frequent physical activity (p = .04), higher fatigue (p = .032), anxiety (p = .003), depression (p = .011) and pain (p = .011) in bad sleepers. The mediation analysis revealed significant indirect effects of sleep on fatigue through physical activity habits. CONCLUSIONS: This study highlights the combined action of sleep problems and physical activity on fatigue during the onset of induction chemotherapy. These two parameters could represent meaningful intervention targets to improve a patient's status during chemotherapy. TRIAL REGISTRATION: The study was registered on the WHO trial register (DRKS00007824).

Effects of supervised aerobic exercise on cardiorespiratory fitness and patient-reported health outcomes in colorectal cancer patients undergoing adjuvant chemotherapy-a pilot study.

PURPOSE: Colorectal cancer and its treatment are associated with debilitating side effects. Exercise may improve the physical and psychological wellbeing of cancer patients; however, evidence in colorectal cancer patients undergoing adjuvant chemotherapy is limited. This pilot study aimed to explore the effects of supervised aerobic exercise on cardiorespiratory fitness and patient-reported health outcomes in colorectal cancer patients undergoing adjuvant chemotherapy. METHODS: Patients who had undergone curative resection for colorectal cancer (stages II-III) and were scheduled to receive adjuvant chemotherapy were enrolled into this non-randomized controlled trial. Patients in the intervention group (IG) took part in a 6-month supervised aerobic exercise program, while the control group (CG) received usual care. Cardiorespiratory fitness (measured by peak oxygen consumption) was assessed at baseline and 6 months. Fatigue, quality of life, and physical activity levels were additionally assessed at 3 months. RESULTS: In total, 59 patients (33 in IG vs. 26 in CG) were enrolled into this study. Eighteen patients (9 in IG vs. 9 in CG) dropped out of the study prior to the 6-month follow-up. Significant improvements in cardiorespiratory fitness (p = .002) and selected patient-reported health outcomes, such as reduced motivation (p = .015) and mental fatigue (p = .018), were observed in the IG when compared to the CG. CONCLUSION: To our knowledge, this is the first study to investigate the effects of a supervised aerobic exercise program in colorectal cancer patients undergoing adjuvant chemotherapy. The significant and clinically meaningful improvements in CRF warrant further randomized controlled trials to confirm these findings. TRIALS REGISTRATION: German Clinical Trials Register Identifier: DRKS00005793, 11/03/2014, retrospectively registered.