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The effects of childhood hematopoietic stem cell transplantation (HSCT) on key organs can impair cardiorespiratory fitness, muscle strength, and physical performance. We aimed to provide an overview of childhood HSCT survivors’ status on these parameters compared with healthy controls and discuss current insights into clinical risk factors. We performed a systematic search in six scientific databases, including studies published before April 2019 and performed a meta-analysis on cardiorespiratory fitness. Muscle strength and physical performance status were presented narratively. We included ten studies embodying 517 childhood HSCT survivors (mean 17.8 years at follow-up). The meta-analysis (n = 4 studies) showed that childhood HSCT survivors have lower cardiorespiratory fitness compared with healthy controls (Standard mean difference (SMD) −1.32 [95% CI −1–58 to −1.07]; I2 2%, p < 0.00001). Collectively, the studies indicated that childhood HSCT survivors have lower muscle strength (n = 4 studies) and physical performance (n = 3 studies) compared with healthy controls. Childhood HSCT survivors have impaired cardiorespiratory fitness years after ended treatment. Muscle strength and physical performance seem to be impaired, although these measures are insufficiently investigated. Associations between HSCT-specific clinical risk factors and cardiorespiratory fitness, muscle strength, and physical performance are required.

Abstract Context Patients with colorectal cancer have increased risk of metabolic diseases including diabetes. Exercise training may counteract metabolic dysregulation, but the impact of exercise training on glycemic control, including postprandial glycemia, has never been explored in patients with colorectal cancer. Objective To examine the effects of home-based interval walking on aerobic and metabolic fitness and quality of life in patients with colorectal cancer. Design Randomized controlled trial. Setting Clinical research center. Participants Thirty-nine sedentary (<150 minutes moderate-intensity exercise per week) patients with stage I to III colorectal cancer who had completed primary treatment. Intervention Home-based interval walking 150 min/wk or usual care for 12 weeks. Main Outcome Measures Changes from baseline to week 12 in maximum oxygen uptake (VO2peak) by cardiopulmonary exercise test, glycemic control by oral glucose tolerance test (OGTT), body composition by dual-energy x-ray absorptiometry scan, blood biochemistry, and quality of life. Results Compared with control, interval walking had no effect on VO2peak [mean between-group difference: −0.32 mL O2 · kg−1 · min−1 (−2.09 to 1.45); P = 0.721] but significantly improved postprandial glycemic control with lower glucose OGTT area under the curve [−126 mM · min (−219 to −33); P = 0.009], 2-hour glucose concentration [−1.1 mM (−2.2 to 0.0); P = 0.056], and improved Matsuda index [1.94 (0.34; 3.54); P = 0.01]. Also, interval walking counteracted an increase in fat mass in the control group [−1.47 kg (−2.74 to −0.19); P = 0.025]. Conclusion A home-based interval-walking program led to substantial improvements in postprandial glycemic control and counteracted fat gain in posttreatment patients with colorectal cancer, possibly providing an effective strategy for prevention of secondary metabolic diseases. We show that home-based interval walking may be a feasible and effective strategy for prevention or treatment of secondary metabolic diseases in patients with colorectal cancer post–primary treatment.

Postdiagnosis physical activity is associated with improved cancer outcomes, but biological mechanisms mediating anticancer effects remain unclear. Recent findings suggest that physiological adaptations to acute exercise comprise potential anticancer effects, but these remain poorly explored in clinical settings. The objective of this study was to explore the effects of a single exercise bout on tumor oxygenation and immune cell infiltration in patients with prostate cancer. Thirty patients with localized prostate cancer were randomized (2:1) to either one high‐intensity interval training bout or no exercise on the day before radical prostatectomy. Immunohistochemical analyses were performed on prostatic tissue from surgery and assessed for tumor hypoxia, natural killer (NK) cell infiltration, and microvessel density (MVD). Acute systemic response in blood lymphocytes, epinephrine, norepinephrine, IL‐6, tumor necrosis factor, cortisol, lactate, and glucose was also evaluated. We did not find between‐group differences in tumor hypoxia (Mann–Whitney U test, U = 83.5, p = 0.604) or NK cell infiltration (U = 77.0, p = 0.328). Also, no significant correlation was found between MVD and tumor hypoxia or NK cell infiltration. One exercise bout is likely insufficient to modulate tumor hypoxia or NK cell infiltration. Future studies may elucidate if an accumulation of several exercise bouts can impact these outcomes (NCT03675529, www.clinicaltrials.gov). Biological mechanisms mediating anti‐cancer effects of physical exercise in humans are unclear, but physiological adaptations to acute exercise have been shown to hold anti‐cancer potential in preclinical studies. We explored the effects of one exercise bout on tumor oxygenation and immune cell infiltration in patients with prostate cancer and report that one exercise bout is not enough to impact these outcomes in a human setting, and the accumulation of several exercise bouts may be required to impact tumor biology.

Harms are often assessed during exercise sessions in the exercise group leading to more frequent assessment of harms. Since frequency of harms assessment is associated with number of harms reported, this can lead to inflated risk estimates of harms with exercise. [...]it assumes that exercise-related AEs will solely manifest during exercise sessions. [...]any exercise modifications that subsequently occurred need to be reported along with reasons. [...]we call for an update of exercise-specific reporting guidelines, as a supplement to the Consolidated Standards of Reporting Trials extension statement for harms reporting.8 Finally, common terminology that can be used to describe exercise-related harms is required to improve the consistency of harms reporting within and between trials. [...]epidemiological and real-world data are important complementary sources for detecting rare AEs that are unlikely to occur in small trials.

Myositis is associated with reduced quality of life, which is accompanied by significant impairments in muscle endurance and strength, altogether representing cardinal traits in patients with myositis. This randomised controlled trial aimed to investigate the effect of high-intensity resistance training on quality of life in patients with myositis. Thirty-two patients with established, stable myositis were randomised to 16 weeks of high-intensity resistance training (intervention group) or 16 weeks of usual care (control group). Primary outcome was quality of life assessed as the change in the physical component summary score (PCS) of the Short Form-36 health questionnaire from baseline to post-intervention. Secondary outcomes included functional capacity measures, such as functional index 3, and International Myositis Assessment and Clinical Studies Group (IMACS) disease activity and damage core set measures, including manual muscle testing 8 (MMT8). The primary outcome PCS showed an improvement in favour of high-intensity resistance training with a between-group difference of 5.33 (95% CI 0.61; 10.05) (p = 0.03). Additionally, functional index 3 showed a between-group difference indicating greater gains with high-intensity resistance training 11.49 (95% CI 3.37; 19.60) (p = 0.04), along with a between-group improvement in MMT8 1.30 (95% CI 0.09; 2.51) (p = 0.04). High-intensity resistance training for 16 weeks effectively improved quality of life in patients with myositis. Clinical measures of muscle endurance and muscle strength were also found to improve with high-intensity resistance training, while patients stayed in disease remission. Consequently, progressively adjusted high-intensity resistance training is feasible and causes no aggravation of the disease, while benefitting patients with myositis.Clinical trial registration: Clinicaltrials.gov ID: NCT04486261—https://clinicaltrials.gov/study/NCT04486261.

Exercise training reduces tumour growth by increasing tumour‐infiltrating T‐cell density in preclinical models. However, it remains unknown whether exercise training can modify intratumoural T cells in humans.The aim of this study was to compare the effects of an exercise training intervention versus control on human prostate intratumoural T‐cell density.This study is a secondary analysis of a randomized controlled trial. We randomly allocated men (age > 18 years) with treatment‐naive localized prostate cancer scheduled for radical prostatectomy 2:1 to exercise training intervention or control. The exercise intervention consisted of supervised, high‐intensity interval bicycling four times per week from the time of randomization until prostatectomy. Intratumoural CD3 + and CD8 + T‐cell densities in diagnostic biopsies and postsurgical prostatectomy specimens were quantified using immunohistochemistry. Between‐group differences in changes from baseline to follow‐up were estimated using constrained baseline linear mixed‐effect models.A total of 30 participants were included (exercise intervention, n  = 20; control, n  = 10). We found no between‐group differences in changes in CD3 + T cells [mean difference (95% confidence interval): −17 (−185; 150) cells/mm 2 ] or CD8 + T cells [mean difference (95% confidence interval): −16 (−206; 172) cells/mm 2 ]. Additionally, we found no statistically significant correlations between changes in T‐cell density and the number of exercise training sessions attended or changes in maximal oxygen consumption.In this secondary analysis of a randomized controlled trial, we found no impact of the exercise regimen on tumour‐infiltrating CD3 + and CD8 + T‐cell density in human prostate cancer. What is the central question of this study? Does exercise training increase human prostate intratumoural T‐cell density? What is the main finding and its importance? In this randomized controlled trial, we found no impact of the exercise training regimen on CD3 + and CD8 + T‐cell density. Although this suggests that exercise training might not modify intratumoural T‐cell composition in prostate cancer, important methodological challenges might limit the interpretation of our data. More studies are needed to evaluate the capacity of exercise training to modify human intratumoural immune cell composition.

Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.

This study aimed to comprehensively compare the lung disease phenotypes between single‐dose and repetitive‐dose bleomycin (BLEO)‐induced mouse models of idiopathic pulmonary fibrosis (IPF). Male C57BL/6JRj mice were randomized and stratified to treatment according to body weight. Mice received either a single intratracheal instillation of BLEO (n = 14) or a repetitive regimen involving bi‐weekly BLEO instillations over 4 weeks (n = 30). Two weeks after the last BLEO dose, mice were assigned as baseline (n = 13) or repetitive BLEO‐IPF mice (terminated 8 weeks after baseline, n = 17). Saline‐treated mice served as healthy controls (n = 10 per model). The repetitive BLEO‐IPF mouse demonstrated sustained features of lung fibrosis, including persistent increases in lung hydroxyproline content, Ashcroft scores, and quantitative collagen levels 8 weeks after baseline. Histological analysis revealed ongoing pulmonary inflammation and accumulation of senescent myofibroblasts. Lung functional impairment was selective but persistent, with FEV0.1 being significantly reduced on study week 8. Lung transcriptome signatures in repetitive BLEO‐IPF mice were comparable to those reported in end‐stage IPF patients, albeit attenuated 8 weeks after baseline, suggesting initiation of reparative processes. The repetitive BLEO‐IPF mouse model recapitulates histological features of progressive lung fibrosis with an evolving cellular senescence phenotype, offering a relevant preclinical platform for studying IPF pathophysiology and evaluating long‐term effects of antifibrotic and senescence‐targeted therapies.

This study comprehensively validated the bleomycin (BLEO) induced mouse model of IPF for utility in preclinical drug discovery. To this end, the model was rigorously evaluated for reproducible phenotype and TGFβ‐directed treatment outcomes. Lung disease was profiled longitudinally in male C57BL6/JRJ mice receiving a single intratracheal instillation of BLEO (n = 10–12 per group). A TGFβR1/ALK5 inhibitor (ALK5i) was profiled in six independent studies in BLEO‐IPF mice, randomized/stratified to treatment according to baseline body weight and non‐invasive whole‐body plethysmography. ALK5i (60 mg/kg/day) or vehicle (n = 10–16 per study) was administered orally for 21 days, starting 7 days after intratracheal BLEO installation. BLEO‐IPF mice recapitulated functional, histological and biochemical hallmarks of IPF, including declining expiratory/inspiratory capacity and inflammatory and fibrotic lung injury accompanied by markedly elevated TGFβ levels in bronchoalveolar lavage fluid and lung tissue. Pulmonary transcriptome signatures of inflammation and fibrosis in BLEO‐IPF mice were comparable to reported data in IPF patients. ALK5i promoted reproducible and robust therapeutic outcomes on lung functional, biochemical and histological endpoints in BLEO‐IPF mice. The robust lung fibrotic disease phenotype, along with the consistent and reproducible lung protective effects of ALK5i treatment, makes the spirometry‐confirmed BLEO‐IPF mouse model highly applicable for profiling novel drug candidates for IPF.

When reasoning about tasks that involve large amounts of data, a common approach is to represent data items as objects in the Hamming space where operations can be done efficiently and effectively. Object similarity can then be computed by learning binary representations (hash codes) of the objects and computing their Hamming distance. While this is highly efficient, each bit dimension is equally weighted, which means that potentially discriminative information of the data is lost. A more expressive alternative is to use real-valued vector representations and compute their inner product; this allows varying the weight of each dimension but is many magnitudes slower. To fix this, we derive a new way of measuring the dissimilarity between two objects in the Hamming space with binary weighting of each dimension (i.e., disabling bits): we consider a field-agnostic dissimilarity that projects the vector of one object onto the vector of the other. When working in the Hamming space, this results in a novel projected Hamming dissimilarity, which by choice of projection, effectively allows a binary importance weighting of the hash code of one object through the hash code of the other. We propose a variational hashing model for learning hash codes optimized for this projected Hamming dissimilarity, and experimentally evaluate it in collaborative filtering experiments. The resultant hash codes lead to effectiveness gains of up to +7% in NDCG and +14% in MRR compared to state-of-the-art hashing-based collaborative filtering baselines, while requiring no additional storage and no computational overhead compared to using the Hamming distance.