Restoring Skeletal Muscle Health through Exercise in Breast Cancer Patients and after Receiving Chemotherapy.

Breast cancer (BC) stands out as the most commonly type of cancer diagnosed in women worldwide, and chemotherapy, a key component of treatment, exacerbates cancer-induced skeletal muscle wasting, contributing to adverse health outcomes. Notably, the impact of chemotherapy on skeletal muscle seems to surpass that of the cancer itself, with inflammation identified as a common trigger for muscle wasting in both contexts. In skeletal muscle, pro-inflammatory cytokines modulate pathways crucial for the delicate balance between protein synthesis and breakdown, as well as satellite cell activation and myonuclear accretion. Physical exercise consistently emerges as a crucial therapeutic strategy to counteract cancer and chemotherapy-induced muscle wasting, ultimately enhancing patients' quality of life. However, a "one size fits all" approach does not apply to the prescription of exercise for BC patients, with factors such as age, menopause and comorbidities influencing the response to exercise. Hence, tailored exercise regimens, considering factors such as duration, frequency, intensity, and type, are essential to maximize efficacy in mitigating muscle wasting and improving disease outcomes. Despite the well-established anti-inflammatory role of aerobic exercise, resistance exercise proves equally or more beneficial in terms of mass and strength gain, as well as enhancing quality of life. This review comprehensively explores the molecular pathways affected by distinct exercise regimens in the skeletal muscle of cancer patients during chemotherapy, providing critical insights for precise exercise implementation to prevent skeletal muscle wasting.

The effect of high-voltage monophasic pulsed current on diabetic ulcers and their potential pathophysiologic factors: A systematic review and meta-analysis.

The present review was conducted to determine the efficacy of high-voltage monophasic pulsed current (HVMPC) in treating diabetic ulcers, assess its effect on skin lesions with each of the pathophysiologic factors potentially contributing to diabetic ulcers, evaluate its safety, and identify treatment parameters. Electronic search of PubMed, Scopus, PEDro and Google Scholar databases was conducted. The revised tool for assessing risk of bias in randomised trials (RoB 2), the risk of bias in non-randomised studies-of interventions (ROBINS-I) and the Joanna Briggs Institute (JBI) critical appraisal tool were used to assess risk of bias and methodological quality. Overall quality of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principles. Thirty-two studies matched the eligibility criteria, and included 1061 patients with 1103 skin lesions of selected aetiologies; 12 randomised controlled trials were included in quantitative synthesis. HVMPC plus standard wound care (SWC) likely increased the probability of complete wound healing of pressure ulcers (PrUs) compared with sham/no stimulation plus SWC; relative risk (RR) 2.08; 95% CI: [1.42, 3.04], p = 0.0002; I2  = 0%, p = 0.61; eight studies, 358 ulcers. Although conclusive evidence regarding the effect of HVMPC on diabetic ulcers was not found, collateral evidence might suggest a potential benefit. Direct evidence, with moderate certainty, may support its efficacy in treating PrUs, albeit few adverse reactions were reported. Other observations, moreover, might indicate that this efficacy may not be limited to PrUs. Nonetheless, several aspects remain to be clarified for safe and effective application of electrical stimulation for wound healing.

The role of inflammation and antioxidant defenses in the cardiotoxicity of doxorubicin in elderly CD-1 male mice.

Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18-20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug's short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1ß, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring.

Protein Turnover in Skeletal Muscle: Looking at Molecular Regulation towards an Active Lifestyle.

Skeletal muscle is a highly plastic tissue, able to change its mass and functional properties in response to several stimuli. Skeletal muscle mass is influenced by the balance between protein synthesis and breakdown, which is regulated by several signaling pathways. The relative contribution of Akt/mTOR signaling, ubiquitin-proteasome pathway, autophagy among other signaling pathways to protein turnover and, therefore, to skeletal muscle mass, differs depending on the wasting or loading condition and muscle type. By modulating mitochondria biogenesis, PGC-1α has a major role in the cell's bioenergetic status and, thus, on protein turnover. In fact, rates of protein turnover regulate differently the levels of distinct protein classes in response to atrophic or hypertrophic stimuli. Mitochondrial protein turnover rates may be enhanced in wasting conditions, whereas the increased turnover of myofibrillar proteins triggers muscle mass gain. The present review aims to update the knowledge on the molecular pathways implicated in the regulation of protein turnover in skeletal muscle, focusing on how distinct muscle proteins may be modulated by lifestyle interventions with emphasis on exercise training. The comprehensive analysis of the anabolic effects of exercise programs will pave the way to the tailored management of muscle wasting conditions.

Regular Voluntary Running is Associated with Increased Tumor Vascularization and Immune Cell Infiltration and Decreased Tumor Growth in Mice.

Tumors present dysfunctional vasculature that limits blood perfusion and hinders immune cells delivery. We aimed to investigate if regular voluntary running promotes tumor vascular remodelling, improves intratumoral immune cells infiltration and inhibits tumor growth. Tumors were induced in C57BL/6 male mice (n=28) by subcutaneous inoculation in the dorsal region with a suspension of RM1 cells (1.5×105 cells/500 µL PBS) and randomly allocated into two groups: sedentary (n=14) and voluntarily exercised on a wheel (n=14). Seven mice from each group were sacrificed 14 and 28 days after cells' inoculation to evaluate tumor weight, microvessel density, vessels' lumen regularity and the intratumoral quantity of NKG2D receptors, CD4+and CD8+T cells, by immunohistochemistry. The statistical inference was done through a two-way ANOVA. Exercised mice developed smaller tumors at 14 (0.17±0.1 g vs. 0.48±0.2 g, p<0.05) and 28 (0.92±0.7 g vs. 2.09±1.3 g, p<0.05) days, with higher microvessel density (21.20±3.2 vs. 15.86±4.0 vessels/field, p<0.05), more regular vessels' lumen (1.06±0.2 vs. 1.43±0.2, p<0.05), and higher CD8+T cells (464.95±48.0 vs. 364.70±49.4 cells/mm2, p<0.01), after 28 days. NKG2D expression was higher in exercised mice at 14 (263.27±25.8 cells/mm2, p<0.05) and 28 (295.06±56.2 cells/mm2, p<0.001) days. Regular voluntary running modulates tumor vasculature, increases immune cells infiltration and attenuates tumor growth, in mice.

Long-Term Exposure to Supraphysiological Levels of Testosterone Impacts Rat Submandibular Gland Proteome.

The salivary glands play a central role in the secretion of saliva, whose composition and volume affect oral and overall health. A lesser-explored dimension encompasses the possible changes in salivary gland proteomes in response to fluctuations in sex hormone levels. This study aimed to examine the effects of chronic exposure to testosterone on salivary gland remodeling, particularly focusing on proteomic adaptations. Therefore, male Wistar rats were implanted with subcutaneous testosterone-releasing devices at 14 weeks of age. Their submandibular glands were histologically and molecularly analyzed 47 weeks later. The results underscored a significant increase in gland mass after testosterone exposure, further supported by histologic evidence of granular duct enlargement. Despite increased circulating sex hormones, there was no detectable shift in the tissue levels of estrogen alpha and androgen receptors. GeLC-MS/MS and subsequent bioinformatics identified 308 proteins in the submandibular glands, 12 of which were modulated by testosterone. Of note was the pronounced upregulation of Klk3 and the downregulation of Klk6 and Klk7 after testosterone exposure. Protein-protein interaction analysis with the androgen receptor suggests that Klk3 is a potential target of androgenic signaling, paralleling previous findings in the prostate. This exploratory analysis sheds light on the response of salivary glands to testosterone exposure, providing proteome-level insights into the associated weight and histological changes.

Reply to the Letter to the Editor from Dr. Seet-Lee and Colleagues.

The authors would like to thank Dr. Seet-Lee and colleagues for their comments on our recently-published manuscript in the International Journal of Sports Medicine 1. Dr. Seet-Lee and colleagues highlighted some inadequacies, specifically when using mean difference or raw mean difference as effect measure. However, when evaluating blood vessel density by different reliable and validated histological procedures, would it be wrong to assume, as we did, that all the obtained measurements from different staining always vary equally, directly and linearly, with the actual parameter under study? Are Dr. Seet-Lee and colleagues assuming that the results of histological observations of blood vessels, marked with different techniques and stains, are neither compatible nor governed by the same measurement scales? We regret, but we are firmly convinced that we proceeded properly. Moreover, we should not assume that standardized effect sizes will make comparisons meaningful 2. Particularly, as the standardized mean difference indicates the difference before and after the intervention in terms of standard deviations instead of actual scores, it assumes that different outcome scales are linear transformation of each other and the standard deviation (SD) is equal across all studies 3.

Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach.

Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer.

In vivo toxicometabolomics reveals multi-organ and urine metabolic changes in mice upon acute exposure to human-relevant doses of 3,4-methylenedioxypyrovalerone (MDPV).

3,4-Methylenedioxypyrovalerone (MDPV) is consumed worldwide, despite its potential to cause toxicity in several organs and even death. There is a recognized need to clarify the biological pathways through which MDPV elicits general and target-organ toxicity. In this work, a comprehensive untargeted GC-MS-based metabolomics analysis was performed, aiming to detect metabolic changes in putative target organs (brain, heart, kidneys and liver) but also in urine of mice after acute exposure to human-relevant doses of MDPV. Male CD-1 mice received binge intraperitoneal administrations of saline or MDPV (2.5 mg/kg or 5 mg/kg) every 2 h, for a total of three injections. Twenty-four hours after the first administration, target organs, urine and blood samples were collected for metabolomics, biochemical and histological analysis. Hepatic and renal tissues of MDPV-treated mice showed moderate histopathological changes but no significant differences were found in plasma and tissue biochemical markers of organ injury. In contrast, the multivariate analysis significantly discriminated the organs and urine of MDPV-treated mice from the control (except for the lowest dose in the brain), allowing the identification of a panoply of metabolites. Those levels were significantly deviated in relation to physiological conditions and showed an organ specific response towards the drug. Kidneys and liver showed the greatest metabolic changes. Metabolites related with energetic metabolism, antioxidant defenses and inflammatory response were significantly changed in the liver of MDPV-dosed animals, while the kidneys seem to have developed an adaptive response against oxidative stress caused by MDPV. On the other hand, the dysregulation of metabolites that contribute to metabolic acidosis was also observed in this organ. The heart showed an increase of fatty acid biosynthesis, possibly as an adaptation to maintain the cardiac energy homeostasis. In the brain, changes in 3-hydroxybutyric acid levels may reflect the activation of a neurotoxic pathway. However, the increase in metabolites with neuroprotective properties seems to counteract this change. Metabolic profiling of urine from MDPV-treated mice suggested that glutathione-dependent antioxidant pathways may be particularly involved in the compensatory mechanism to counteract oxidative stress induced by MDPV. Overall, this study reports, for the first time, the metabolic profile of liver, kidneys, heart, brain, and urine of MDPV-dosed mice, providing unique insights into the biological pathways of toxicity. Our findings also underline the value of toxicometabolomics as a robust and sensitive tool for detecting adaptive/toxic cellular responses upon exposure to a physiologically relevant dose of a toxic agent, earlier than conventional toxicity tests.

The Effects of Physical Exercise on Tumor Vasculature: Systematic Review and Meta-analysis.

A wealth of evidence supports an association between physical exercise, decreased tumor growth rate, and reduced risk of cancer mortality. In this context, the tumor vascular microenvironment may play a key role in modulating tumor biologic behavior. The present systematic review and meta-analysis aimed to summarize the evidence regarding the effects of physical exercise on tumor vasculature in pre-clinical studies. We performed a computerized research on the PubMed, Scopus, and EBSCO databases to identify pre-clinical studies that evaluated the effect of physical exercise on tumor vascular outcomes. Mean differences were calculated through a random effects model. The present systematic review included 13 studies involving 373 animals. From these, 11 studies evaluated chronic intratumoral vascular adaptations and 2 studies assessed the acute intratumoral vascular adaptations to physical exercise. The chronic intratumoral vascular adaptations resulted in higher tumor microvessel density in 4 studies, increased tumor perfusion in 2 studies, and reduced intratumoral hypoxia in 3 studies. Quantitatively, regular physical exercise induced an increased tumor vascularization of 2.13 [1.07, 3.20] (p<0.0001). The acute intratumoral vascular adaptations included increased vascular conductance and reduced vascular resistance, which improved tumor perfusion and attenuated intratumoral hypoxia. In pre-clinical studies, physical exercise seems to improve tumor vascularization.

Role of Regular Physical Exercise in Tumor Vasculature: Favorable Modulator of Tumor Milieu.

The tumor vessel network has been investigated as a precursor of an inhospitable tumor microenvironment, including its repercussions in tumor perfusion, oxygenation, interstitial fluid pressure, pH, and immune response. Dysfunctional tumor vasculature leads to the extravasation of blood to the interstitial space, hindering proper perfusion and causing interstitial hypertension. Consequently, the inadequate delivery of oxygen and clearance of by-products of metabolism promote the development of intratumoral hypoxia and acidification, hampering the action of immune cells and resulting in more aggressive tumors. Thus, pharmacological strategies targeting tumor vasculature were developed, but the overall outcome was not satisfactory due to its transient nature and the higher risk of hypoxia and metastasis. Therefore, physical exercise emerged as a potential favorable modulator of tumor vasculature, improving intratumoral vascularization and perfusion. Indeed, it seems that regular exercise practice is associated with lasting tumor vascular maturity, reduced vascular resistance, and increased vascular conductance. Higher vascular conductance reduces intratumoral hypoxia and increases the accessibility of circulating immune cells to the tumor milieu, inhibiting tumor development and improving cancer treatment. The present paper describes the implications of abnormal vasculature on the tumor microenvironment and the underlying mechanisms promoted by regular physical exercise for the re-establishment of more physiological tumor vasculature.

Metabolic Syndrome Pathophysiology and Predisposing Factors.

Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors with high prevalence among adult populations and elevated costs for public health systems worldwide. Despite the lack of consensus regarding the syndrome definition and diagnosis criteria, it is characterized by the coexistence of risk factors such as abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, a prothrombotic and pro-inflammatory state, insulin resistance (IR), and higher glucose levels, factors indubitably linked to an increased risk of developing chronic conditions, such as type 2 diabetes (T2D) and cardiovascular disease (CVD). The syndrome has a complex and multifaceted origin not fully understood; however, it has been strongly suggested that sedentarism and unbalanced dietary patterns might play a fundamental role in its development. The purpose of this review is to provide an overview from the syndrome epidemiology, costs, and main etiological traits from its relationship with unhealthy diet patterns and sedentary lifestyles.

Mitoxantrone impairs proteasome activity and prompts early energetic and proteomic changes in HL-1 cardiomyocytes at clinically relevant concentrations.

Mitoxantrone (MTX) is used to treat several types of cancers and to improve neurological disability in multiple sclerosis. Unfortunately, cardiotoxicity is a severe and common adverse effect in MTX-treated patients. Herein, we aimed to study early and late mechanisms of MTX-induced cardiotoxicity using murine HL-1 cardiomyocytes. Cells were exposed to MTX (0.1, 1 or 10 µM) during short (2, 4, 6, or 12 h) or longer incubation periods (24 or 48 h). At earlier time points, (6 and 12 h) cytotoxicity was already observed for 1 and 10 µM MTX. Proteomic analysis of total protein extracts found 14 proteins with higher expression and 26 with lower expression in the cells exposed for 12 h to MTX (pH gradients 4-7 and 6-11). Of note, the expression of the regulatory protein 14-3-3 protein epsilon was increased by a factor of two and three, after exposure to 1 and 10 µM MTX, respectively. At earlier time-points, 10 µM MTX increased intracellular ATP levels, while decreasing media lactate levels. At later stages (24 and 48 h), MTX-induced cytotoxicity was concentration and time-dependent, according to the MTT reduction and lactate dehydrogenase leakage assays, while caspase-9, -8 and -3 activities increased at 24 h. Regarding cellular redox status, total glutathione increased in 1 µM MTX (24 h), and that increase was dependent on gamma-glutamylcysteine synthetase activity. Meanwhile, for both 1 and 10 µM MTX, oxidized glutathione was significantly higher than control at 48 h. Moreover, MTX was able to significantly decrease proteasomal chymotrypsin-like activity in a concentration and time-independent manner. In summary, MTX significantly altered proteomic, energetic and oxidative stress homeostasis in cardiomyocytes at clinically relevant concentrations and our data clearly demonstrate that MTX causes early cardiotoxicity that needs further study.

Deep Friction Massage in the Management of Patellar Tendinopathy in Athletes: Short-Term Clinical Outcomes.

CONTEXT: Deep friction massage (DFM) is often used in the treatment of tendinopathies; however, the pressure applied may vary and interfere with the obtained results. OBJECTIVE: To assess whether the immediate effects of DFM on pain (pain intensity and time to onset of analgesia) and muscle strength are dependent on the pressure applied during the DFM application in athletes with patellar tendinopathy. DESIGN: Randomized, controlled, cross-over trial. SETTING: University research laboratory (institutional). PARTICIPANTS: Ten athletes with diagnosis of unilateral patellar tendinopathy (age 27.90 [5.24] y). INTERVENTIONS: All participants attended 4 sessions, 3 treatment sessions with DFM applied with different pressures (the mean pressure-previously determined for each participant-and the mean pressure ± 25%) and a control session, each of which was separated by 48 hours. MAIN OUTCOME MEASURES: Pain (intensity upon palpation and time to onset of analgesia), and muscle strength of knee extensors were assessed before and immediately after each session. RESULTS: Pain intensity changed significantly over time (F1,9 = 52.364; P < .001; ηp2=.853) and among sessions (F3,27 = 82.588; P < .001; ηp2=.902), with a significant interaction for group × time (F3,27 = 19.841; P < .001; ηp2=.688). The knee extensors strength did not change significantly over time (F1,9 = 2.240; P = .17; ηp2=.199), nor a significant interaction for session × time was observed (F3,27 = 3.276; P = .07; ηp2=.267). Regardless of the pressure applied, the time to onset of analgesia was not significantly different (F2,18 = 1.026; P > .05; ηp2=.102). CONCLUSION: It was shown that DFM induces an immediate reduction in pain intensity upon palpation, regardless of the pressure performed. Notwithstanding, the reader should take into account the small sample size and the caution needed in the results' interpretation.

An effective antidotal combination of polymyxin B and methylprednisolone for α-amanitin intoxication.

Amanita phalloides is one of the most toxic mushrooms worldwide, and it is involved in the majority of human fatal cases of mushroom poisoning. α-Amanitin, the most deleterious toxin of A. phalloides to humans, inhibits RNA polymerase II (RNAPII), causing hepatic and renal failure. Previously, we have shown that polymyxin B (polB) reverts α-amanitin inhibition of RNAPII, although it was not able to guarantee the full survival of α-amanitin-intoxicated mice or prevent α-amanitin pro-inflammatory effects. α-Amanitin is also a substrate of the organic-anion-transporting polypeptide 1B3 (OATP1B3) and Na(+)-taurocholate cotransporter polypeptide (NTCP) transporters. Therefore, in the present work, we used a combination of polB [(2.5 mg/kg intraperitoneal (i.p.)] with the anti-inflammatory and NTCP inhibitor drug, methylprednisolone (MP) (10 mg/kg i.p.), as an attempt to fully revert α-amanitin-induced toxicity (0.33 mg/kg i.p.) in CD-1 mice. Results showed that the administration of the polB + MP combination, 4 h after α-amanitin, led to the full survival of the intoxicated animals, with a significant attenuation of α-amanitin-induced renal and hepatic necrosis. Also, the combination polB + MP led to a decrease of aminotransferase plasma levels, of the renal myeloperoxidase activity and of renal inflammatory cell infiltrate promoted by α-amanitin, although not preventing any of the hepatic pro-inflammatory effect of the toxin. The obtained results indicate that this combination may represent an important and valuable therapeutic approach to be used against α-amanitin intoxication.

Regular voluntary running has favorable histological effects on doxorubicin-induced kidney toxicity in Wistar rats.

Knowing the therapeutic effects of regular physical exercise on kidney toxicity induced by a single dose of doxorubicin (DOX) in animal models, the aim of this study is to verify the effectiveness of regular voluntary running on kidney histology after a prolonged DOX administration, mimicking a chemotherapy protocol. Thirty-four male Wistar rats were randomly divided into two clusters: DOX (n = 17) and SSS (sterile saline solution, n = 17), receiving a weekly intraperitoneal injection of DOX (2 mg/kg) or vehicle for 7 weeks, respectively. Two weeks after the last injection, five animals from each cluster (SSSG, n = 5; DOXG, n = 5) were euthanized, while the remaining ones were divided into sedentary (DOXsed, n = 6; SSSsed, n = 6) and active subgroups (DOXact, n = 6; SSSact, n = 6). Active animals were placed individually in cages with a running wheel for regular voluntary activity. After 2 months, the animals were euthanized and kidneys were histologically examined. Compared to SSSG, kidneys from DOXG revealed higher levels of damage, more collagen content and thickening of Bowman's capsule (p < .05). The levels of damage and thickness of Bowman's capsule increased in DOXsed as compared to DOXG (p < .05). Compared to DOXsed, the DOXact presented an overall improvement in kidney structure (p < .05), with a decrease in collagen content and of the thickness of Bowman's capsule. The results allow concluding that regular voluntary running attenuate the long-term harmful effects on kidney structure induced by a prolonged DOX treatment. These results, supporting the potential benefit of physical activity in patients under DOX treatment, need to be tested in humans.

Exercise training protects against cancer-induced cardiac remodeling in an animal model of urothelial carcinoma.

Limiting cancer-induced cardiac damage has become an increasingly important issue to improve survival rates and quality of life. Exercise training has been shown to reduce cardiovascular complications in several diseases; however, its therapeutic role against cardiovascular consequences of cancer is in its infancy. In order to add new insights on the potential therapeutic effect of exercise training on cancer-related cardiac dysfunction, we used an animal model of urothelial carcinoma submitted to 13 weeks of treadmill exercise after 20 weeks of exposure to the carcinogenic N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Data showed that 13 weeks of treadmill exercise reverted cancer-induced cardiomyocytes atrophy and fibrosis, improved cardiac oxidative capacity given by citrate synthase activity and MnSOD content, and increased the levels of the mitochondrial biogenesis markers PGC-1α and mtTFA. Moreover, exercise training reverted cancer-induced decrease of cardiac c-kit levels suggesting enhanced regenerative ability of heart. These cardiac adaptations to exercise were related to a lower incidence of malignant urothelial lesions and less signs of inflammation. Taken together, data from the present study support the beneficial effect of exercise training when started after cancer diagnosis, envisioning the improvement of the cardiovascular function.

Changes to the Editorial Team of the IJSM.

There have been some changes to the Board of Editors of the IJSM. Already this year, Prof. Donald Dengel of the University of Minnesota, USA, replaced editor Prof. Joseph Houmard, who had been with the journal since 2006 and chose to leave the team for professional reasons.Unfortunately, our Editor-in-Chief Prof. Appell Coriolano is fast approaching his retirement from academia and will also be leaving the IJSM editorial team. Hans-Joachim Appell Coriolano joined the Editorial Board of the IJSM in 1987 and accepted the position of Assistant Editor in 1989. Over the years, he gradually assumed even greater responsibility for manuscript organization and editing. He has served as Editor-in-Chief since 2006 and is regarded as a true "primus inter pares" within the editors' team. For his tremendous commitment and unwavering dedication to the IJSM for nearly 30 years, Prof. Appell Coriolano is acknowledged by his peers and Thieme Publishers as the "heart and soul" of the IJSM as it exists today. The level of scientific quality and international recognition attained by the IJSM is in large part due to his valuable contributions and scientific rigor. It is therefore with great regret that we bid him farewell, but we are sure that his guidance and spirit will continue to shape the future of this publication.

Efficacy of Exercise on Breast Cancer Outcomes: A Systematic Review and Meta-analysis of Preclinical Data.

The use of preclinical models to investigate antitumor effects of exercise on breast tumor (BT) development and progression are critical. However, published results have not been quantitatively summarized or examined for potential exercise-moderating variables. We conducted this review to summarize and quantify the effect-size of exercise on BT outcomes in preclinical studies. A literature search was performed in MEDLINE, PubMed, Web of Science and System for Information on Grey Literature in Europe (SIGLE) databases. Risk of bias was assessed using SYRCLE's RoB tool. A total of 116 correlations were performed to analyze 28 preclinical studies published through December 2016, which included 2,085 animals and 51 exercise programs. Positive effects of small, medium and large magnitude were observed in tumor incidence, growth and multiplicity, respectively. In the tumor microenvironment, positive effects of large magnitude were also observed in proliferation and apoptosis but not in angiogenesis. Moderator variables correlated with higher intervention effects were identified along with a considerable heterogeneity in exercise protocols that precluded us from clearly perceiving the benefits of exercise exposure. In conclusion, exercise performed under specific conditions benefits BT outcomes. Preclinical studies with exercise designs mimicking exercise exposure that can be used in clinical contexts are needed.

Exercise Training-induced Modulation in Microenvironment of Rat Mammary Neoplasms.

Despite the importance attributed to exercise training in the breast cancer (BC) continuum, the underlying mechanisms modulating tumor behavior are unknown. We evaluated the effects of long-term moderate-exercise in the development of mammary tumors, and studied the microenvironment of infiltrative lesions, the amount of connective tissue, and balance between cellular proliferation/death.Fifty Sprague-Dawley rats, randomly assigned into four groups: two control groups (sedentary and exercised) and two models of BC groups (sedentary and exercised) induced by N-methyl-N-nitrosoureia (MNU), were sacrificed after 35 weeks of moderate-exercise, and all perceptible tumors were removed for histological and immunohistochemistry analysis.The median number of infiltrative-lesions per animal was lower in the MNU exercised animals (p=0.02). More than one histological pattern was identified, and papillary carcinoma was the most frequent in both groups. Within infiltrative-lesions, the number of immunopositive cells per µm2 of Ki67 was lower in exercised animals (p=0.002). This presents increased cell death per µm2 (p=0.019). Tumors from sedentary animals had a higher expression of collagen deposition (p=0.027).Long-term moderate-exercise has beneficial effects in tumor development with a diminished prevalence of malignancy. Within infiltrative-lesions, moderate-exercise improves the balance between cell-proliferation and cell-death with decreased connective tissue that suggests lower tumor aggressiveness.