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Extracellular vesicles (EVs) transport biomolecules that mediate intercellular communication. We previously showed that EVs contain DNA (EV-DNA) representing the entire genome. However, the mechanism of genomic EV-DNA packaging and its role in cancer remain elusive. We now demonstrate that EV-DNA is predominantly localized on the vesicle surface and associated with uniquely modified and cleaved histones. Moreover, a genome-wide clustered regularly interspaced short palindromic repeats knockout screen revealed that immune developmental pathways and genes, including apoptotic peptidase activating factor 1 (APAF1) and neutrophil cytosolic factor 1 (NCF1), regulate EV-DNA packaging. Furthermore, in colorectal cancer models, uptake of EV-DNA by pre-metastatic liver Kupffer cells (KCs) activated DNA damage responses. This activation rewired KC cytokine production and promoted the formation of tertiary lymphoid structures, thereby suppressing liver metastasis. Conversely, loss of APAF1 decreased EV-DNA packaging and promoted liver metastasis. Importantly, colorectal cancer biopsy EV-DNA secretion could serve as a predictive biomarker for postoperative metastasis. Taken together, our findings indicate that uniquely chromatinized EV-DNA induces antitumor immunity., Competing Interests: Competing interests: D.L. is on the scientific advisory board of Aufbau Holdings. R.E.S. is on the scientific advisory board of Miromatrix and is a speaker and consultant for Alnylam. The remaining authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Aerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality, however, the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function, which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function, thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia, TIL infiltration and effector function, and mitochondrial content, morphology and function were evaluated. AET reduced tumor growth, improved survival, and decreased tumor hypoxia. An increased CD8 + TIL infiltration, IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively, AET decreases tumor growth partially by increasing CD8 + TIL effector function through an improvement in their mitochondrial content and function., Competing Interests: The authors declare no competing interest., (© 2024 The Authors.)

Exercise training reduces the incidence of several cancers, but the mechanisms underlying these effects are not fully understood. Exercise training can affect the spleen function, which controls the hematopoiesis and immune response. Analyzing different cancer models, we identified that 4T1, LLC, and CT26 tumor-bearing mice displayed enlarged spleen (splenomegaly), and exercise training reduced spleen mass toward control levels in two of these models (LLC and CT26). Exercise training also slowed tumor growth in melanoma B16F10, colon tumor 26 (CT26), and Lewis lung carcinoma (LLC) tumor-bearing mice, with minor effects in mammary carcinoma 4T1, MDA-MB-231, and MMTV-PyMT mice. In silico analyses using transcriptome profiles derived from these models revealed that platelet factor 4 (Pf4) is one of the main upregulated genes associated with splenomegaly during cancer progression. To understand whether exercise training would modulate the expression of these genes in the tumor and spleen, we investigated particularly the CT26 model, which displayed splenomegaly and had a clear response to the exercise training effects. RT-qPCR analysis confirmed that trained CT26 tumor-bearing mice had decreased Pf4 mRNA levels in both the tumor and spleen when compared to untrained CT26 tumor-bearing mice. Furthermore, exercise training specifically decreased Pf4 mRNA levels in the CT26 tumor cells. Aspirin treatment did not change tumor growth, splenomegaly, and tumor Pf4 mRNA levels, confirming that exercise decreased non-platelet Pf4 mRNA levels. Finally, tumor Pf4 mRNA levels are deregulated in The Cancer Genome Atlas Program (TCGA) samples and predict survival in multiple cancer types. This highlights the potential therapeutic value of exercise as a complementary approach to cancer treatment and underscores the importance of understanding the exercise-induced transcriptional changes in the spleen for the development of novel cancer therapies., (© 2023. The Author(s).)

Over the past decade, extracellular vesicles and particles (EVPs) have emerged as critical mediators of intercellular communication, participating in numerous physiological and pathological processes. In the context of cancer, EVPs exert local effects, such as increased invasiveness, motility, and reprogramming of tumor stroma, as well as systemic effects, including pre-metastatic niche formation, determining organotropism, promoting metastasis and altering the homeostasis of various organs and systems, such as the liver, muscle, and circulatory system. This review provides an overview of the critical advances in EVP research during the past decade, highlighting the heterogeneity of EVPs, their roles in intercellular communication, cancer progression, and metastasis. Moreover, the clinical potential of systemic EVPs as useful cancer biomarkers and therapeutic agents is explored. Last but not least, the progress in EVP analysis technologies that have facilitated these discoveries is discussed, which may further propel EVP research in the future., Competing Interests: Conflicts of interest David Lyden is an advisor of Aufbau Inc. and receives research support from Atossa Inc.

Cancer alters the function of multiple organs beyond those targeted by metastasis 1,2 . Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-α. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2α activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia.

We investigated the effects of AET on myomiRs expression in the skeletal muscle and serum of colon cachectic (CT26) and breast non-cachectic (MMTV-PyMT) cancer mice models. Colon cancer decreased microRNA-486 expression, increasing PTEN in tibialis anterior muscle (TA), decreasing the PI3K/mTOR protein pathway, body and muscle wasting, fibers' cross-sectional area and muscle dysfunction, that were not preserved by AET. In contrast, breast cancer decreased those muscle functions, but were preserved by AET. In circulation, the downregulation of microRNA-486 and -206 in colon cancer, and the downregulation of microRNA-486 and upregulation of microRNA-206 expression in breast cancer might be good cancer serum biomarkers. Since the microRNA-206 is skeletal muscle specific, their expression was increased in the TA, serum and tumor in MMTV, suggesting a communication among these three compartments. The AET prevents these effects on microRNA-206, but not on microRNA-486 in MMTV. In conclusion, cancer induced a downregulation of microRNA-486 expression in TA and serum of CT26 and MMTV mice and these effects were not prevented by AET; however, to MMTV, the trained muscle function was preserved, probably sustained by the downregulation of microRNA-206 expression. Serum microRNA-206 is a potential biomarker for colon (decreased) and breast (increased) cancer to monitor the disease evolution and the effects promoted by the AET.

Objective: To estimate the prevalence and analyze the association between sociodemographic and behavioral variables with the use of prehospital care, hospitalization and sequelae and/or disability in victims of road traffic accidents victims in Brazil., Methods: Data from the National Health Survey conducted in 2013 in Brazil were used. Data were collected through a direct household survey. The research sample consisted of 1,840 individuals who reported road traffic accidents in the previous 12 months. Poisson regression analysis was used to evaluate the factors associated with the use of prehospital care services, hospitalization, and the presence of sequelae and/or disability., Results: The prevalence of road traffic accidents victims who received prehospital care was 13.0% (95% Confidence Interval [95% CI]: 10.3-16.3) and the factors associated with this outcome were: residing in the Northeast or North region of Brazil; residing in rural areas; and being a motorcycle occupant at the moment of the road traffic accident. The frequency of hospitalization was 7.7% (95% CI: 6.0-10.0) and the associated factors were: age between 40 and 59 years; being a motorcycle occupant or pedestrian and having received on-site care at the moment of the road traffic accident. The prevalence of sequelae and/or disability was 15.1% (95% CI: 12.5-18.2) and the associated factors were: age range between 30 and 39 years or 40 and 59 years; being a motorcycle occupant, being a pedestrian or belonging to other category of modes of transport and having received on-site care at the moment of the road traffic accident., Conclusion: The study allowed to evaluate the factors associated with prehospital care, hospitalization and presence of sequelae and/or disability in the victims of road traffic accident and the results can guide the implementation of interventions that prioritize the population exposed to the highest risk of road traffic accident injuries and with less access to prehospital and hospital care services in Brazil., Competing Interests: The authors have declared that no competing interests exist.

We developed a modified protocol, based on differential ultracentrifugation (dUC), to isolate extracellular vesicles and particles (specifically exomeres) (EVPs) from various human and murine sources, including cell lines, surgically resected tumors and adjacent tissues, and bodily fluids, such as blood, lymphatic fluid, and bile. The diversity of these samples requires robust and highly reproducible protocols and refined isolation technology, such as asymmetric-flow field-flow fractionation (AF4). Our isolation protocol allows for preparation of EVPs for various downstream applications, including proteomic profiling. For complete details on the use and execution of this protocol, please refer to Hoshino et al. (2020)., Competing Interests: D.L., A.H., H.S.K., and L.B. have filed a US patent application related to this work., (© 2020 The Author(s).)

Aims: We aimed to investigate the impact of cancer cachexia and previous aerobic exercise training (AET) on cardiac function and structure in tumor bearing mice., Main Methods: Colon adenocarcinoma cells 26 (CT26) were subcutaneously injected in BALB/c mice to establish robust cancer cachexia model. AET was performed on a treadmill during 45 days, 60 min/5 days per week. Cardiac function was evaluated by echocardiography and cardiac morphology was assessed by light microscopy. The protein expression levels of mitochondrial complex were analyzed by Western blotting. The mRNA levels of genes related to cardiac remodeling and autophagy were analyzed by quantitative Real-Time PCR., Key Findings: Our data confirms CT26 tumor bearing mice as a well-characterized and robust model of cancer cachexia. CT26 mice exhibited cardiac remodeling and dysfunction characterized by cardiac atrophy and impaired left ventricle ejection fraction paralleled by cardiac necrosis, inflammation and fibrosis. AET partially reversed the left ventricle ejection fraction and led to significant anti-cardiac remodeling effect associated reduced necrosis, inflammation and cardiac collagen deposition in CT26 mice. Reduced TGF-β1 mRNA levels, increased mitochondrial complex IV protein levels and partial recovery of BNIP3 mRNA levels in cardiac tissue were associated with the cardiac effects of AET in CT26 mice. Thus, we suggest AET as a powerful regulator of key pathways involved in cardiac tissue homeostasis in cancer cachexia., Significance: Our study provides a robust model of cancer cachexia, as well as highlights the potential and integrative effects of AET as a preventive strategy for reducing cardiac damage in cancer cachexia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia., Methods: We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats., Results: Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity., Conclusions: These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: to identify the magnitude and factors associated with death and serious injuries among victims of traffic accidents in the urban area of Goiânia, Brazil., Methods: cross-sectional study with linkage between records of the Mortality Information System (SIM) Hospital Information System of the Brazilian National Health System (SIH/SUS) and occurrences of traffic accidents, from January to June 2013; Poisson regression was used., Results: among 9,795 identified victims, there were 155 deaths and 1,225 serious injuries; cyclists (Incidence ratio [IR]=2.26; 95%CI 1.19;4.30) and pedestrians (IR=2.12; 95%CI 1.26;3.58) had an increased risk of death, while the risk of serious injuries was higher among motorcyclists (IR=2.38; 95%CI 2.01;2.83), cyclists (IR=2.35; 95%CI 1.76;3.13) and pedestrians (IR=2.83; 95%CI 2.27;3.53)., Conclusion: the study revealed a number of deaths and serious injuries, closer to the real and identified vulnerable groups to plan traffic safety actions.

Background: In recent decades middle-income countries have experienced a rapid increase in the number of cars and motorcycles. Increased deaths and hospitalizations due to road traffic injuries (RTI) has been observed in several countries as a result. In this study we assessed the determinants of RTIs in Brazil by mode of transportation and compared differences in RTI rates among macro-regions., Methods: We used data from the National Health Survey (NHS) conducted in 2013 by the Brazilian Institute of Geography and Statistics and the Ministry of Health. NHS is a comprehensive household survey which includes a representative sample (N = 60,198) of individuals aged 18 years or older. The prevalence and determinants of RTI were estimated according to different modes of transport (car/van, motorcycle, and other) and regions of the country. Bivariate and multivariable logistic regression models were applied to assess crude and adjusted odds ratios, respectively, and their 95 % CI for RTI determinants., Results: The prevalence of RTI for the Southeast, South, Central-West, Northeast and North regions of Brazil was 2.4 %, 2.9 %, 4.4 %, 3.4 % and 4.8 %, respectively, pointing to important differences among regions. High percentages of motorcyclists were observed in the Northeast and North regions. For motorcyclists, factors associated with RTIs were being male (OR = 2.6;95 % CI:2.3;3.0), aged 18-29 (OR = 3.2; 95 % CI:2.7;3.8) and 30-39 years (OR = 2.0;95 % CI:1.7;2.5), black (OR = 1.4;95 % CI:1.1;1.7), having elementary educational (OR = 1.5;95 % CI:1.1;1.9), reporting binge drinking behavior (OR = 1.3;95 % CI:1.1;1.5), and living in the Central-West (OR = 2.0;95 % CI:1.6;2.5), Northeast (OR = 1.8;95 % CI:1.5;2.1) and North (OR = 2.0;95 % CI:1.6; 2.5) regions of the country. The independent variables associated with RTI for car/van occupants were being male (OR = 1.7;95 % CI:1.4;2.1), aged 18-29 (OR = 1.5;95 % CI:1.1;2.0) and 30-39 years (OR = 2.5;95 % CI:1.9;3.2), reporting binge drinking behavior (OR = 2.0;95 % CI:1.6;2.5) and living in the South region (OR = 1.6;95 % CI:1.3;2.1)., Conclusions: There were considerable regional disparities in RTI rates across Brazil's regions. Motorcyclists contributed to the high RTI rates in these regions as did demographic factors and behaviors such as alcohol use. These findings can help guide interventions to reduce the burden of RTIs in Brazil.

Objective: to analyze the support for learning, in the perspective of patient safety, offered in the work environment, according to health professionals working in primary care., Method: a transversal study, held with 86 health professionals working in primary care. A validated instrument was used, applied via the Internet. Descriptive statistical analysis was undertaken with a presentation of median, mean, standard deviation and coefficient of variation., Results: points which are favorable to supporting learning were evidenced, such as mutual respect, autonomy for organizing the work and valorization of new ideas, which obtained means above 7.0. The variables which hinder the process of learning in the work environment, perceived by the professionals, were: resistance to changes, and excess of work impeding reflection on how to improve the work, with means above 6.0., Conclusion: the study found evidence of indicators related to the process of staff development in the area of health and indicates the influence of support for learning for the improvement of the work processes and of patient safety. It is necessary that a culture involving the systematic assessment of educational interventions in health should be established, the aim being to diagnose actions which are more incisive for changing health professionals' attitude and, therefore, clinical practice.