{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T07:46:18Z","timestamp":1793951178715,"version":"4.8.0"},"reference-count":93,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T00:00:00Z","timestamp":1702252800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T00:00:00Z","timestamp":1702252800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2014\/25830-9"],"award-info":[{"award-number":["2014\/25830-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["15\/04788-7"],"award-info":[{"award-number":["15\/04788-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["16\/22835-5"],"award-info":[{"award-number":["16\/22835-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2016\/01478-0"],"award-info":[{"award-number":["2016\/01478-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2014\/03016-8"],"award-info":[{"award-number":["2014\/03016-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2012\/25240-1"],"award-info":[{"award-number":["2012\/25240-1"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2012\/02528-0"],"award-info":[{"award-number":["2012\/02528-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["13\/21065-3"],"award-info":[{"award-number":["13\/21065-3"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["14\/26797-5"],"award-info":[{"award-number":["14\/26797-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2015\/22814-5"],"award-info":[{"award-number":["2015\/22814-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["306261\/2016-2"],"award-info":[{"award-number":["306261\/2016-2"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CAPES-PROEX","award":["0001"],"award-info":[{"award-number":["0001"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.\u00a0In silico\u00a0analyses using transcriptome profiles derived from these models revealed that\u00a0platelet factor 4\u00a0(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.\u00a0This 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.<\/jats:p>","DOI":"10.1038\/s41598-023-47217-2","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T18:02:13Z","timestamp":1702317733000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Aerobic exercise training mitigates tumor growth and cancer-induced splenomegaly through modulation of non-platelet platelet factor 4 expression"],"prefix":"10.1038","volume":"13","author":[{"given":"Gabriel C.","family":"Tobias","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o L. P.","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa G.","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa A.","family":"Voltarelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ney R.","family":"de Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo R.","family":"Jannig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo W. Alves","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos E.","family":"Negr\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edilamar M.","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Chammas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiano R. R.","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia C.","family":"Brum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,11]]},"reference":[{"key":"47217_CR1","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.1016\/j.celrep.2016.10.031","volume":"17","author":"F Pucci","year":"2016","unstructured":"Pucci, F. et al. PF4 promotes platelet production and lung cancer growth. Cell Rep. 17, 1764\u20131772 (2016).","journal-title":"Cell Rep."},{"key":"47217_CR2","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.cell.2016.12.022","volume":"168","author":"MH Spitzer","year":"2017","unstructured":"Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487-502.e15 (2017).","journal-title":"Cell"},{"key":"47217_CR3","doi-asserted-by":"publisher","first-page":"35419","DOI":"10.18632\/oncotarget.6214","volume":"6","author":"A Beheshti","year":"2015","unstructured":"Beheshti, A. et al. Tumor-host signaling interaction reveals a systemic, age-dependent splenic immune influence on tumor development. Oncotarget 6, 35419\u201335432 (2015).","journal-title":"Oncotarget"},{"key":"47217_CR4","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1093\/carcin\/bgl057","volume":"27","author":"L Michna","year":"2006","unstructured":"Michna, L. et al. Inhibitory effects of voluntary running wheel exercise on UVB-induced skin carcinogenesis in SKH-1 mice. Carcinogenesis 27, 2108\u20132115 (2006).","journal-title":"Carcinogenesis"},{"key":"47217_CR5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080123","volume":"8","author":"J Goh","year":"2013","unstructured":"Goh, J. et al. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner. PLoS One 8, e80123 (2013).","journal-title":"PLoS One"},{"key":"47217_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0097033","volume":"9","author":"G Wolff","year":"2014","unstructured":"Wolff, G., Balke, J. E., Andras, I. E., Park, M. & Toborek, M. Exercise modulates redox-sensitive small GTPase activity in the brain microvasculature in a model of brain metastasis formation. PLoS One 9, 1\u20138 (2014).","journal-title":"PLoS One"},{"key":"47217_CR7","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1186\/1471-2407-8-316","volume":"8","author":"J Ju","year":"2008","unstructured":"Ju, J. et al. Voluntary exercise inhibits intestinal tumorigenesis in Apc(Min\/+) mice and azoxymethane\/dextran sulfate sodium-treated mice. BMC Cancer 8, 316 (2008).","journal-title":"BMC Cancer"},{"key":"47217_CR8","first-page":"6811","volume":"50","author":"BD Roebuck","year":"1990","unstructured":"Roebuck, B. D., McCaffrey, J. & Baumgartner, K. J. Protective effects of voluntary exercise during the postinitiation phase of pancreatic carcinogenesis in the rat. Cancer Res 50, 6811\u20136816 (1990).","journal-title":"Cancer Res"},{"key":"47217_CR9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0109030","volume":"9","author":"P Hojman","year":"2014","unstructured":"Hojman, P. et al. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice. PLoS One 9, e109030 (2014).","journal-title":"PLoS One"},{"key":"47217_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jnci\/djv040","volume":"107","author":"AS Betof","year":"2015","unstructured":"Betof, A. S. et al. Modulation of murine breast tumor vascularity, hypoxia, and chemotherapeutic response by exercise. J. Natl. Cancer Inst. 107, 1\u20135 (2015).","journal-title":"J. Natl. Cancer Inst."},{"key":"47217_CR11","doi-asserted-by":"publisher","first-page":"3302","DOI":"10.1002\/cncr.28878","volume":"120","author":"KA Higgins","year":"2014","unstructured":"Higgins, K. A., Park, D., Lee, G. Y., Curran, W. J. & Deng, X. Exercise-induced lung cancer regression: Mechanistic findings from a mouse model. Cancer 120, 3302\u20133310 (2014).","journal-title":"Cancer"},{"key":"47217_CR12","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1001\/jamainternmed.2016.1548","volume":"176","author":"SC Moore","year":"2016","unstructured":"Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816\u2013825 (2016).","journal-title":"JAMA Intern. Med."},{"key":"47217_CR13","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1002\/cphy.c120033","volume":"3","author":"BK Pedersen","year":"2013","unstructured":"Pedersen, B. K. Muscle as a secretory organ. Compr. Physiol. 3, 1337\u20131362 (2013).","journal-title":"Compr. Physiol."},{"key":"47217_CR14","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1016\/j.cell.2014.03.065","volume":"157","author":"RR Rao","year":"2014","unstructured":"Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279\u20131291 (2014).","journal-title":"Cell"},{"key":"47217_CR15","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1016\/j.cell.2012.10.050","volume":"151","author":"JL Ruas","year":"2012","unstructured":"Ruas, J. L. et al. A PGC-1\u03b1 isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151, 1319\u20131331 (2012).","journal-title":"Cell"},{"key":"47217_CR16","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1161\/CIRCRESAHA.118.314635","volume":"124","author":"Z Hou","year":"2019","unstructured":"Hou, Z. et al. Longterm exercise-derived exosomal miR-342-5p: A novel exerkine for cardioprotection. Circ. Res. 124, 1386\u20131400 (2019).","journal-title":"Circ. Res."},{"key":"47217_CR17","doi-asserted-by":"publisher","first-page":"H1162","DOI":"10.1152\/ajpheart.00500.2017","volume":"313","author":"R Shah","year":"2017","unstructured":"Shah, R. et al. Small RNA-seq during acute maximal exercise reveal RNAs involved in vascular inflammation and cardiometabolic health: Brief report. Am. J. Physiol. Heart Circ. Physiol. 313, H1162\u2013H1167 (2017).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"47217_CR18","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.cmet.2013.12.003","volume":"19","author":"LD Roberts","year":"2014","unstructured":"Roberts, L. D. et al. \u03b2-Aminoisobutyric acid induces browning of white fat and hepatic \u03b2-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96\u2013108 (2014).","journal-title":"Cell Metab."},{"key":"47217_CR19","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cell.2014.07.051","volume":"159","author":"LZ Agudelo","year":"2014","unstructured":"Agudelo, L. Z. et al. Skeletal muscle PGC-1a1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159, 33\u201345 (2014).","journal-title":"Cell"},{"key":"47217_CR20","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1080\/01926230600867743","volume":"34","author":"MF Cesta","year":"2006","unstructured":"Cesta, M. F. Normal structure, function, and histology of the spleen. Toxicol. Pathol. 34, 455\u2013465 (2006).","journal-title":"Toxicol. Pathol."},{"key":"47217_CR21","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/j.immuni.2013.10.010","volume":"39","author":"V Bronte","year":"2013","unstructured":"Bronte, V. & Pittet, M. J. The spleen in local and systemic regulation of immunity. Immunity 39, 806\u2013818 (2013).","journal-title":"Immunity"},{"key":"47217_CR22","first-page":"255","volume":"15","author":"J Lee","year":"2001","unstructured":"Lee, J. et al. Hematopoietic switch from lymphoid to granulocytic development in 3LL tumor-bearing mice. In Vivo (Brooklyn) 15, 255\u2013264 (2001).","journal-title":"In Vivo (Brooklyn)"},{"key":"47217_CR23","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.yexmp.2006.06.007","volume":"82","author":"SA DuPre","year":"2007","unstructured":"DuPre, S. A. & Hunter, K. W. Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: Association with tumor-derived growth factors. Exp. Mol. Pathol. 82, 12\u201324 (2007).","journal-title":"Exp. Mol. Pathol."},{"key":"47217_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/jnci\/dju147","volume":"106","author":"S Mabuchi","year":"2014","unstructured":"Mabuchi, S. et al. Uterine cervical cancer displaying tumor-related leukocytosis: A distinct clinical entity with radioresistant feature. J. Natl. Cancer Inst. 106, 1\u201311 (2014).","journal-title":"J. Natl. Cancer Inst."},{"key":"47217_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13058-018-1054-3","volume":"20","author":"S Ravindranathan","year":"2018","unstructured":"Ravindranathan, S. et al. Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines. Breast Cancer Res. 20, 1\u201317 (2018).","journal-title":"Breast Cancer Res."},{"key":"47217_CR26","first-page":"949","volume":"150","author":"S Safarians","year":"1997","unstructured":"Safarians, S., Rivera, S. P., Sternlicht, M. D., Naeim, F. & Barsky, S. H. Ectopic G-CSF expression in human melanoma lines marks a trans-dominant pathway of tumor progression. Am. J. Pathol. 150, 949\u2013962 (1997).","journal-title":"Am. J. Pathol."},{"key":"47217_CR27","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1002\/jcsm.12310","volume":"9","author":"TA Nissinen","year":"2018","unstructured":"Nissinen, T. A. et al. Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses. J. Cachexia Sarcopenia Muscle 9, 514\u2013529 (2018).","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"47217_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciadv.abi4852","volume":"7","author":"R Furrer","year":"2021","unstructured":"Furrer, R. et al. Remodeling of metabolism and inflammation by exercise ameliorates tumor-associated anemia. Sci. Adv. 7, 1\u201318 (2021).","journal-title":"Sci. Adv."},{"key":"47217_CR29","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.cell.2018.02.061","volume":"173","author":"Y Han","year":"2018","unstructured":"Han, Y. et al. Tumor-induced generation of splenic erythroblast-like ter-cells promotes tumor progression. Cell 173, 634-648.e12 (2018).","journal-title":"Cell"},{"key":"47217_CR30","volume":"4","author":"S Sun","year":"2023","unstructured":"Sun, S. et al. A single-cell transcriptomic atlas of exercise-induced anti-inflammatory and geroprotective effects across the body. Innovation 4, 100380 (2023).","journal-title":"Innovation"},{"key":"47217_CR31","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1016\/j.cmet.2016.01.011","volume":"23","author":"L Pedersen","year":"2016","unstructured":"Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 23, 554\u2013562 (2016).","journal-title":"Cell Metab."},{"key":"47217_CR32","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1158\/1940-6207.CAPR-17-0233","volume":"12","author":"WJ Turbitt","year":"2019","unstructured":"Turbitt, W. J. et al. Physical activity plus energy restriction prevents 4T1.2 mammary tumor progression, MDSC accumulation, and an immunosuppressive tumor microenvironment. Cancer Prevent. Res. 12, 493\u2013505 (2019).","journal-title":"Cancer Prevent. Res."},{"key":"47217_CR33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cancers13225728","volume":"13","author":"JLP Gomes","year":"2021","unstructured":"Gomes, J. L. P. et al. Effects of aerobic exercise training on myomirs expression in cachectic and non-cachectic cancer mice. Cancers (Basel) 13, 1\u201319 (2021).","journal-title":"Cancers (Basel)"},{"key":"47217_CR34","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.ygyno.2015.05.027","volume":"138","author":"AB Peel","year":"2015","unstructured":"Peel, A. B. et al. Cardiorespiratory fitness in survivors of cervical, endometrial, and ovarian cancers: The Cooper Center Longitudinal Study. Gynecol. Oncol. 138, 394\u2013397 (2015).","journal-title":"Gynecol. Oncol."},{"key":"47217_CR35","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1001\/jamaoncol.2015.0226","volume":"1","author":"SG Lakoski","year":"2015","unstructured":"Lakoski, S. G. et al. Midlife cardiorespiratory fitness, incident cancer, and survival after cancer in men: The Cooper Center Longitudinal Study. JAMA Oncol. 1, 231\u2013237 (2015).","journal-title":"JAMA Oncol."},{"key":"47217_CR36","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1161\/CIRCRESAHA.111.253807","volume":"109","author":"LG Koch","year":"2011","unstructured":"Koch, L. G. et al. Intrinsic aerobic capacity sets a divide for aging and longevity. Circ. Res. 109, 1162\u20131172 (2011).","journal-title":"Circ. Res."},{"key":"47217_CR37","first-page":"45","volume":"307","author":"EM Morris","year":"2014","unstructured":"Morris, E. M. et al. Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis. Am. J. Physiol. Endocrinol. Metab. 307, 45 (2014).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"47217_CR38","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1152\/ajpregu.00659.2010","volume":"300","author":"DA Rivas","year":"2011","unstructured":"Rivas, D. A. et al. Low intrinsic running capacity is associated with reduced skeletal muscle substrate oxidation and lower mitochondrial content in white skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, 33 (2011).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"47217_CR39","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1007\/s00395-010-0087-2","volume":"105","author":"M Schwarzer","year":"2010","unstructured":"Schwarzer, M., Britton, S. L., Koch, L. G., Wisloff, U. & Doenst, T. Low intrinsic aerobic exercise capacity and systemic insulin resistance are not associated with changes in myocardial substrate oxidation or insulin sensitivity. Basic Res. Cardiol. 105, 357\u2013364 (2010).","journal-title":"Basic Res. Cardiol."},{"key":"47217_CR40","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1038\/nri1669","volume":"5","author":"RE Mebius","year":"2005","unstructured":"Mebius, R. E. & Kraal, G. Structure and function of the spleen. Nat. Rev. Immunol. 5, 606\u2013616 (2005).","journal-title":"Nat. Rev. Immunol."},{"issue":"355","key":"47217_CR41","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1126\/science.aah4115","volume":"1979","author":"CP Martinez-Jimenez","year":"2017","unstructured":"Martinez-Jimenez, C. P. et al. Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 1979(355), 1433\u20131436 (2017).","journal-title":"Science"},{"key":"47217_CR42","doi-asserted-by":"publisher","first-page":"1775","DOI":"10.1080\/15384047.2015.1095404","volume":"16","author":"Y Zhang","year":"2015","unstructured":"Zhang, Y. et al. CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity. Cancer Biol. Ther. 16, 1775\u20131783 (2015).","journal-title":"Cancer Biol. Ther."},{"key":"47217_CR43","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.stemcr.2019.02.009","volume":"12","author":"O Leiter","year":"2019","unstructured":"Leiter, O. et al. Exercise-induced activated platelets increase adult hippocampal precursor proliferation and promote neuronal differentiation. Stem Cell Rep. 12, 667\u2013679 (2019).","journal-title":"Stem Cell Rep."},{"key":"47217_CR44","doi-asserted-by":"publisher","first-page":"4786","DOI":"10.1182\/blood-2006-07-038539","volume":"109","author":"JA Coppinger","year":"2007","unstructured":"Coppinger, J. A. et al. Moderation of the platelet releasate response by aspirin. Blood 109, 4786\u20134792 (2007).","journal-title":"Blood"},{"key":"47217_CR45","doi-asserted-by":"publisher","first-page":"1458","DOI":"10.1016\/j.celrep.2018.10.047","volume":"25","author":"MP Kumar","year":"2018","unstructured":"Kumar, M. P. et al. Analysis of single-cell RNA-seq identifies cell\u2013cell communication associated with tumor characteristics. Cell Rep. 25, 1458-1468.e4 (2018).","journal-title":"Cell Rep."},{"key":"47217_CR46","doi-asserted-by":"publisher","first-page":"452","DOI":"10.18632\/oncotarget.27464","volume":"11","author":"E Wennerberg","year":"2020","unstructured":"Wennerberg, E. et al. Exercise reduces immune suppression and breast cancer progression in a preclinical model. Oncotarget 11, 452\u2013461 (2020).","journal-title":"Oncotarget"},{"key":"47217_CR47","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1007\/s11332-021-00826-8","volume":"18","author":"H Shirvani","year":"2022","unstructured":"Shirvani, H. et al. Therapeutic and preventive effects of exercise training on metabolic regulators\/markers in mouse colorectal cancer cells. Sport Sci. Health 18, 463\u2013471 (2022).","journal-title":"Sport Sci. Health"},{"key":"47217_CR48","first-page":"1246","volume":"9","author":"L Melo","year":"2019","unstructured":"Melo, L. & Hagar, A. How to train a mouse-methodological issues in pre-clinical exercise oncology. Am. J. Cancer Res. 9, 1246\u20131253 (2019).","journal-title":"Am. J. Cancer Res."},{"key":"47217_CR49","doi-asserted-by":"publisher","first-page":"81","DOI":"10.3389\/fphys.2021.782695","volume":"12","author":"MP Massett","year":"2021","unstructured":"Massett, M. P., Matejka, C. & Kim, H. Systematic review and meta-analysis of endurance exercise training protocols for mice. Front. Physiol. 12, 81 (2021).","journal-title":"Front. Physiol."},{"key":"47217_CR50","doi-asserted-by":"publisher","first-page":"4122","DOI":"10.1038\/onc.2015.484","volume":"35","author":"QB Zhang","year":"2016","unstructured":"Zhang, Q. B. et al. Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: With reference to nervous system. Oncogene 35, 4122\u20134131 (2016).","journal-title":"Oncogene"},{"key":"47217_CR51","doi-asserted-by":"publisher","first-page":"26991","DOI":"10.1038\/srep26991","volume":"6","author":"E Pigna","year":"2016","unstructured":"Pigna, E. et al. Aerobic Exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer. Sci. Rep. 6, 26991 (2016).","journal-title":"Sci. Rep."},{"key":"47217_CR52","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0229290","volume":"15","author":"LA Buss","year":"2020","unstructured":"Buss, L. A. et al. Effect of post-implant exercise on tumour growth rate, perfusion and hypoxia in mice. PLoS One 15, 1\u201316 (2020).","journal-title":"PLoS One"},{"key":"47217_CR53","doi-asserted-by":"publisher","first-page":"43202","DOI":"10.18632\/oncotarget.6439","volume":"6","author":"F Pin","year":"2015","unstructured":"Pin, F. et al. Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations. Oncotarget 6, 43202\u201343215 (2015).","journal-title":"Oncotarget"},{"key":"47217_CR54","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1152\/japplphysiol.00975.2004","volume":"98","author":"KA Mehl","year":"2005","unstructured":"Mehl, K. A. Decreased intestinal polyp multiplicity is related to exercise mode and gender in ApcMin\/+ mice. J. Appl. Physiol. 98, 2219\u20132225 (2005).","journal-title":"J. Appl. Physiol."},{"key":"47217_CR55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cancers12082312","volume":"12","author":"G Aquila","year":"2020","unstructured":"Aquila, G. et al. Trabectedin and lurbinectedin extend survival of mice bearing c26 colon adenocarcinoma, without affecting tumor growth or cachexia. Cancers (Basel) 12, 1\u201324 (2020).","journal-title":"Cancers (Basel)"},{"key":"47217_CR56","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1139\/apnm-2019-0407","volume":"45","author":"ME Rosa-Caldwell","year":"2020","unstructured":"Rosa-Caldwell, M. E. et al. Hepatic alterations during the development and progression of cancer cachexia. Appl. Physiol. Nutr. Metab. 45, 500\u2013512 (2020).","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"47217_CR57","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1002\/bjs.1800800838","volume":"80","author":"SF Purkiss","year":"1993","unstructured":"Purkiss, S. F. & Williams, N. S. Growth rate and percentage hepatic replacement of colorectal liver metastases. Br. J. Surg. 80, 1036\u20131038 (1993).","journal-title":"Br. J. Surg."},{"key":"47217_CR58","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13550-021-00834-2","volume":"11","author":"J Han","year":"2021","unstructured":"Han, J. et al. Imaging modalities for diagnosis and monitoring of cancer cachexia. EJNMMI Res. 11, 34 (2021).","journal-title":"EJNMMI Res."},{"key":"47217_CR59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cytogfr.2010.10.011","volume":"22","author":"J Vandercappellen","year":"2011","unstructured":"Vandercappellen, J., Van Damme, J. & Struyf, S. The role of the CXC chemokines platelet factor-4 (CXCL4\/PF-4) and its variant (CXCL4L1\/PF-4var) in inflammation, angiogenesis and cancer. Cytokine Growth Factor Rev. 22, 1\u201318 (2011).","journal-title":"Cytokine Growth Factor Rev."},{"key":"47217_CR60","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1007\/s10456-012-9259-z","volume":"15","author":"JE Peterson","year":"2012","unstructured":"Peterson, J. E. et al. VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients. Angiogenesis 15, 265\u2013273 (2012).","journal-title":"Angiogenesis"},{"key":"47217_CR61","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1158\/1078-0432.CCR-08-2701","volume":"15","author":"GM Fiedler","year":"2009","unstructured":"Fiedler, G. M. et al. Serum peptidome profiling revealed platelet factor 4 as a potential discriminating peptide associated with pancreatic cancer. Clin. Cancer Res. 15, 3812\u20133819 (2009).","journal-title":"Clin. Cancer Res."},{"key":"47217_CR62","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1182\/blood-2007-04-084798","volume":"111","author":"D Cervi","year":"2008","unstructured":"Cervi, D. et al. Platelet-associated PF-4 as a biomarker of early tumor growth. Blood 111, 1201\u20131207 (2008).","journal-title":"Blood"},{"key":"47217_CR63","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1016\/j.cell.2015.08.015","volume":"162","author":"S Zelenay","year":"2015","unstructured":"Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257\u20131270 (2015).","journal-title":"Cell"},{"key":"47217_CR64","doi-asserted-by":"publisher","first-page":"3000","DOI":"10.7150\/ijbs.60866","volume":"17","author":"B Zeng","year":"2021","unstructured":"Zeng, B. et al. SEC23A inhibit melanoma metastatic through secretory PF4 cooperation with SPARC to inhibit MAPK signaling pathway. Int. J. Biol. Sci. 17, 3000\u20133012 (2021).","journal-title":"Int. J. Biol. Sci."},{"key":"47217_CR65","first-page":"829","volume":"18","author":"Y Li","year":"2003","unstructured":"Li, Y. et al. Suppression of tumor growth by viral vector-mediated gene transfer of N-terminal truncated platelet factor 4. Cancer Biother. Radiopharm. 18, 829\u2013840 (2003).","journal-title":"Cancer Biother. Radiopharm."},{"key":"47217_CR66","doi-asserted-by":"publisher","first-page":"5611","DOI":"10.1002\/cam4.1783","volume":"7","author":"Z Zhang","year":"2018","unstructured":"Zhang, Z. et al. GNA13 promotes tumor growth and angiogenesis by upregulating CXC chemokines via the NF-\u03baB signaling pathway in colorectal cancer cells. Cancer Med. 7, 5611\u20135620 (2018).","journal-title":"Cancer Med."},{"key":"47217_CR67","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1093\/rheumatology\/keab532","volume":"61","author":"A Ottria","year":"2022","unstructured":"Ottria, A. et al. Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2\u03b1. Rheumatol. (U.K.) 61, 2682\u20132693 (2022).","journal-title":"Rheumatol. (U.K.)"},{"key":"47217_CR68","first-page":"32","volume":"12","author":"E Fehri","year":"2023","unstructured":"Fehri, E., Ennaifer, E., Bel Haj Rhouma, R., Ardhaoui, M. & Boubaker, S. TLR9 and glioma: Friends or foes?. Cells 12, 32 (2023).","journal-title":"Cells"},{"key":"47217_CR69","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.jhep.2015.02.009","volume":"63","author":"Y Liu","year":"2015","unstructured":"Liu, Y. et al. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J. Hepatol. 63, 114\u2013121 (2015).","journal-title":"J. Hepatol."},{"key":"47217_CR70","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1002\/hep.29184","volume":"66","author":"S Tohme","year":"2017","unstructured":"Tohme, S. et al. Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction. Hepatology 66, 182\u2013197 (2017).","journal-title":"Hepatology"},{"key":"47217_CR71","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1093\/oxfordjournals.eurheartj.a062155","volume":"8","author":"U Berglund","year":"1987","unstructured":"Berglund, U., Lassvik, C. & Wallentin, L. Effects of the platelet inhibitor ticlopidine on exercise tolerance in stable angina pectoris. Eur. Heart J. 8, 25\u201330 (1987).","journal-title":"Eur. Heart J."},{"key":"47217_CR72","doi-asserted-by":"publisher","first-page":"2877","DOI":"10.1161\/01.CIR.90.6.2877","volume":"90","author":"JS Wang","year":"1994","unstructured":"Wang, J. S. et al. Different effects of strenuous exercise and moderate exercise on platelet function in men. Circulation 90, 2877\u20132885 (1994).","journal-title":"Circulation"},{"key":"47217_CR73","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/0002-8703(85)90147-4","volume":"110","author":"WE Strauss","year":"1985","unstructured":"Strauss, W. E., Cella, G., Parisi, A. F. & Sasahara, A. A. Serial studies of platelet factor 4 and beta thromboglobulin during exercise in patients with coronary artery disease. Am. Heart J. 110, 293\u2013299 (1985).","journal-title":"Am. Heart J."},{"key":"47217_CR74","first-page":"1333","volume":"57","author":"MJ Mant","year":"1984","unstructured":"Mant, M. J., Kappagoda, C. T. & Quinlan, J. Lack of effect of exercise on platelet activation and platelet reactivity. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 57, 1333\u20131337 (1984).","journal-title":"J. Appl. Physiol. Respir. Environ. Exerc. Physiol."},{"key":"47217_CR75","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1002\/ajh.2830170204","volume":"17","author":"SP Levine","year":"1984","unstructured":"Levine, S. P., Suarez, A. J., Sorenson, R. R., Raymond, N. M. & Knieriem, L. K. Platelet factor 4 release during exercise in patients with coronary artery disease. Am. J. Hematol. 17, 117\u2013127 (1984).","journal-title":"Am. J. Hematol."},{"key":"47217_CR76","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1007\/s00421-013-2645-4","volume":"113","author":"BC Creighton","year":"2013","unstructured":"Creighton, B. C. et al. Influence of training on markers of platelet activation in response to a bout of heavy resistance exercise. Eur. J. Appl. Physiol. 113, 2203\u20132209 (2013).","journal-title":"Eur. J. Appl. Physiol."},{"key":"47217_CR77","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1055\/s-0038-1661199","volume":"52","author":"P Douste-Blazy","year":"1984","unstructured":"Douste-Blazy, P., Sie, P. & Boneu, B. Exercise-induced platelet activation in myocardial infarction survivors with normal coronary arteriogram. Thromb. Haemost. 52, 297\u2013300 (1984).","journal-title":"Thromb. Haemost."},{"key":"47217_CR78","doi-asserted-by":"publisher","DOI":"10.1016\/j.joim.2023.01.002","author":"C Xiao","year":"2023","unstructured":"Xiao, C. et al. Physical exercise suppresses hepatocellular carcinoma progression by alleviating hypoxia and attenuating cancer stemness through the Akt\/GSK-3\u03b2\/\u03b2-catenin pathway. J. Integr. Med. https:\/\/doi.org\/10.1016\/j.joim.2023.01.002 (2023).","journal-title":"J. Integr. Med."},{"key":"47217_CR79","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00561.2022","author":"PB Elming","year":"2023","unstructured":"Elming, P. B. et al. The effect of single bout and prolonged aerobic exercise on tumour hypoxia in mice. J. Appl. Physiol. https:\/\/doi.org\/10.1152\/japplphysiol.00561.2022 (2023).","journal-title":"J. Appl. Physiol."},{"key":"47217_CR80","doi-asserted-by":"publisher","first-page":"2190","DOI":"10.3390\/cancers13092190","volume":"13","author":"I-J Tsai","year":"2021","unstructured":"Tsai, I.-J., Su, E.C.-Y., Tsai, I.-L. & Lin, C.-Y. Clinical assay for the early detection of colorectal cancer using mass spectrometric wheat germ agglutinin multiple reaction monitoring. Cancers (Basel) 13, 2190 (2021).","journal-title":"Cancers (Basel)"},{"key":"47217_CR81","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1158\/1055-9965.EPI-10-0178","volume":"19","author":"KE Poruk","year":"2010","unstructured":"Poruk, K. E. et al. Serum platelet factor 4 is an independent predictor of survival and venous thromboembolism in patients with pancreatic adenocarcinoma. Cancer Epidemiol. Biomark. Prevent. 19, 2605\u20132610 (2010).","journal-title":"Cancer Epidemiol. Biomark. Prevent."},{"key":"47217_CR82","doi-asserted-by":"publisher","first-page":"11117","DOI":"10.1038\/s41598-019-47308-z","volume":"9","author":"W Zhang","year":"2019","unstructured":"Zhang, W. et al. Comparative study of subcutaneous and orthotopic mouse models of prostate cancer: Vascular perfusion, vasculature density, hypoxic burden and BB2r-targeting efficacy. Sci. Rep. 9, 11117 (2019).","journal-title":"Sci. Rep."},{"key":"47217_CR83","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2022.1011943","volume":"13","author":"M Denis","year":"2023","unstructured":"Denis, M. et al. Impact of mouse model tumor implantation site on acquired resistance to anti-PD-1 immune checkpoint therapy. Front. Immunol. 13, 1\u201311 (2023).","journal-title":"Front. Immunol."},{"key":"47217_CR84","first-page":"1","volume":"22","author":"M Brand","year":"2021","unstructured":"Brand, M. et al. Characterization and differentiation of the tumor microenvironment (Tme) of orthotopic and subcutaneously grown head and neck squamous cell carcinoma (hnscc) in immunocompetent mice. Int. J. Mol. Sci. 22, 1\u201320 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"47217_CR85","first-page":"378","volume":"4","author":"J Goh","year":"2014","unstructured":"Goh, J., Endicott, E. & Ladiges, W. C. Pre-tumor exercise decreases breast cancer in old mice in a distance-dependent manner. Am. J. Cancer Res. 4, 378\u2013384 (2014).","journal-title":"Am. J. Cancer Res."},{"key":"47217_CR86","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s11248-006-9056-9","volume":"16","author":"SA Davie","year":"2007","unstructured":"Davie, S. A. et al. Effects of FVB\/NJ and C57Bl\/6J strain backgrounds on mammary tumor phenotype in inducible nitric oxide synthase deficient mice. Transgenic Res. 16, 193\u2013201 (2007).","journal-title":"Transgenic Res."},{"key":"47217_CR87","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1172\/JCI200317929","volume":"111","author":"G Bergers","year":"2003","unstructured":"Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E. & Hanahan, D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J. Clin. Invest. 111, 1287\u20131295 (2003).","journal-title":"J. Clin. Invest."},{"key":"47217_CR88","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.ccell.2017.10.003","volume":"32","author":"A Palazon","year":"2017","unstructured":"Palazon, A. et al. An HIF-1\u03b1\/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32, 669-683.e5 (2017).","journal-title":"Cancer Cell"},{"key":"47217_CR89","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1111\/j.1440-1681.2007.04635.x","volume":"34","author":"JCB Ferreira","year":"2007","unstructured":"Ferreira, J. C. B. et al. Maximal lactate steady state in running mice: Effect of exercise training. Clin. Exp. Pharmacol. Physiol. 34, 760\u2013765 (2007).","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"47217_CR90","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1158\/2326-6066.CIR-16-0114","volume":"5","author":"SIS Mosely","year":"2017","unstructured":"Mosely, S. I. S. et al. Rational selection of syngeneic preclinical tumor models for immunotherapeutic drug discovery. Cancer Immunol. Res. 5, 29\u201341 (2017).","journal-title":"Cancer Immunol. Res."},{"key":"47217_CR91","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2014","unstructured":"Subramanian, A., Tamayo, P. & Mootha, V. GSEA\u202f: Gene set enrichment analysis gene set enrichment analysis\u202f: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545\u201315550 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"47217_CR92","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12859-015-0611-3","volume":"16","author":"H Heberle","year":"2015","unstructured":"Heberle, H., Meirelles, V. G., da Silva, F. R., Telles, G. P. & Minghim, R. InteractiVenn: A web-based tool for the analysis of sets through Venn diagrams. BMC Bioinform. 16, 1\u20137 (2015).","journal-title":"BMC Bioinform."},{"key":"47217_CR93","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1007\/s10549-009-0674-9","volume":"123","author":"B Gy\u00f6rffy","year":"2010","unstructured":"Gy\u00f6rffy, B. et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res. Treat. 123, 725\u2013731 (2010).","journal-title":"Breast Cancer Res. Treat."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-47217-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-47217-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-47217-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T18:06:23Z","timestamp":1702317983000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-47217-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,11]]},"references-count":93,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["47217"],"URL":"https:\/\/doi.org\/10.1038\/s41598-023-47217-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,11]]},"assertion":[{"value":"30 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"21970"}}