{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:33Z","timestamp":1789448553833,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003193","name":"Ministry of Education, Science, Research and Sport of the Slovak Republic","doi-asserted-by":"publisher","award":["VEGA 1\/0090\/22"],"award-info":[{"award-number":["VEGA 1\/0090\/22"]}],"id":[{"id":"10.13039\/501100003193","id-type":"DOI","asserted-by":"publisher"}]},{"award":["VEGA 1\/0090\/22"],"award-info":[{"award-number":["VEGA 1\/0090\/22"]}],"id":[{"id":"https:\/\/ror.org\/044gwpv05","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"crossref","award":["APVV-22-0231"],"award-info":[{"award-number":["APVV-22-0231"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"crossref","award":["APVV-22-0554"],"award-info":[{"award-number":["APVV-22-0554"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"crossref"}]},{"award":["APVV-22-0231"],"award-info":[{"award-number":["APVV-22-0231"]}],"id":[{"id":"https:\/\/ror.org\/037nx0e70","id-type":"ROR","asserted-by":"publisher"}]},{"award":["APVV-22-0554"],"award-info":[{"award-number":["APVV-22-0554"]}],"id":[{"id":"https:\/\/ror.org\/037nx0e70","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007594","name":"Comenius University","doi-asserted-by":"crossref","award":["UK\/1364\/2025"],"award-info":[{"award-number":["UK\/1364\/2025"]}],"id":[{"id":"10.13039\/100007594","id-type":"DOI","asserted-by":"crossref"}]},{"name":"OncoReSearch","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Extracellular DNA (extracellular DNA) is a promising biomarker for tumor burden and systemic inflammation. However, its clinical significance in urothelial carcinoma remains unclear. This study evaluated plasma extracellular DNA (nuclear and mitochondrial fractions) and DNase activity in patients with bladder cancer (BC) in comparison to healthy controls, and explored their associations with tumor stage, survival, and heart rate variability (HRV) as a non-invasive marker of autonomic regulation. Methods: We prospectively analyzed 84 subjects: 63 patients with urothelial carcinoma (52 non-muscle-invasive [NMIBC]; 11 muscle-invasive [MIBC]) and 21 healthy controls. Plasma extracellular DNA was quantified fluorometrically, while ncDNA and mtDNA fractions were assessed via quantitative real-time PCR. DNase activity was determined using the single radial enzyme diffusion assay. Clinical associations were evaluated through group comparisons, multivariable logistic regression, survival analysis, and correlation with HRV parameters. Results: Patients with BC exhibited slightly but significantly higher extracellular DNA compared to healthy controls (by 9%); ncDNA showed a similar trend. Regarding disease progression, ncDNA demonstrated a stronger association with tumor stage than total extracellular DNA, with the highest concentrations observed in patients with MIBC. In multivariable logistic regression models adjusted for age, BMI, sex, smoking, and alcohol consumption, extracellular DNA remained independently associated with BC status (OR 5.99, 95% CI 1.43\u201325.12, p = 0.015). Log-transformed ncDNA was also associated with BC status, although the model was constrained by missing data. No significant differences in overall survival were observed when stratified by cutoff values of extracellular DNA, ncDNA, mtDNA, or DNase activity. Notably, while extracellular DNA correlated significantly with several HRV parameters in healthy individuals (after FDR correction), this physiological coupling was absent in patients with BC. Conclusions: Circulating extracellular DNA and ncDNA are independently associated with BC, with ncDNA showing a stronger correlation with tumor stage. While prognostic value regarding survival was not confirmed in this cohort, the absence of extracellular DNA\u2013HRV correlations in patients, despite significant associations in healthy controls, suggests the loss of physiological coupling between circulating DNA and autonomic regulation. Further longitudinal studies are needed to validate the clinical utility and biological interpretation of these markers.<\/jats:p>","DOI":"10.3390\/cancers18182952","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:34:01Z","timestamp":1789378441000},"page":"2952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Role of Circulating Extracellular DNA in Patients with Bladder Cancer: Clinical Associations and Exploratory Links with Heart Rate Variability"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4505-0952","authenticated-orcid":false,"given":"Patrik","family":"Palacka","sequence":"first","affiliation":[{"name":"2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenov\u00e1 1, 833 10 Bratislava, Slovakia"},{"name":"Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Hana","family":"Kov\u00e1\u010dov\u00e1 Ilijew","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University, Odbor\u00e1rske N\u00e1mestie 14, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4443-9069","authenticated-orcid":false,"given":"Iveta","family":"Mikol\u00e1\u0161kov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University, Odbor\u00e1rske N\u00e1mestie 14, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Such\u00e1nkov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University, Odbor\u00e1rske N\u00e1mestie 14, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1ria","family":"Paulovi\u010dov\u00e1","sequence":"additional","affiliation":[{"name":"2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenov\u00e1 1, 833 10 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Be\u00e1ta","family":"Rondzikov\u00e1","sequence":"additional","affiliation":[{"name":"2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenov\u00e1 1, 833 10 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Boris","family":"Koll\u00e1rik","sequence":"additional","affiliation":[{"name":"2nd Department of Urology, Faculty of Medicine and Bory Hospital, Comenius University, Ivana Kadle\u010d\u00edka 2, 841 03 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Peter","family":"Celec","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia"},{"name":"Institute of Pathophysiology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"\u013duba","family":"Hun\u00e1kov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University, Odbor\u00e1rske N\u00e1mestie 14, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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