{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:22:10Z","timestamp":1785424930194,"version":"3.56.0"},"reference-count":102,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic and Slovak Academy of Sciences","award":["VEGA 1\/0092\/22"],"award-info":[{"award-number":["VEGA 1\/0092\/22"]}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"publisher","award":["APVV-22-0231"],"award-info":[{"award-number":["APVV-22-0231"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"award":["APVV-22-0231"],"award-info":[{"award-number":["APVV-22-0231"]}],"id":[{"id":"https:\/\/ror.org\/037nx0e70","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic inflammation contributes to bladder cancer (BC) development and progression through dysregulated cytokine signaling and tumor\u2013immune interactions. This case\u2013control study investigated associations between IL6 rs1800795, TNF rs1800629, CCL2 rs1024611, and VEGFA rs699947 polymorphisms, circulating cytokine levels, clinicopathological characteristics, and autonomic nervous system balance assessed by heart rate variability (HRV) in 73 BC patients and 88 controls. Genotyping was performed using PCR\u2013RFLP, serum cytokine levels were measured by ELISA, and associations were evaluated using logistic, linear regression, and survival analyses. No significant associations with BC risk were observed for IL6, TNF, or VEGFA variants. However, the CCL2 rs1024611 GG genotype was associated with increased BC risk (recessive model: OR = 5.82, p = 0.026). Stratified analyses showed a lower frequency of the IL6 rs1800795 C allele and TNF rs1800629 GA genotype in high-grade and muscle-invasive tumors, suggesting potential associations with reduced tumor aggressiveness. No polymorphism was associated with serum cytokine levels or disease-free survival. In BC patients, the TNF rs1800629 A allele was associated with higher parasympathetic-related HRV indices and lower sympathetic parameters, whereas no such associations were observed in controls. These findings indicate that genetic variation within inflammatory pathways may contribute to BC susceptibility and tumor phenotype and may also modulate neuroimmune interactions.<\/jats:p>","DOI":"10.3390\/ijms27083361","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T07:48:07Z","timestamp":1775720887000},"page":"3361","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of IL6 rs1800795, TNF rs1800629, CCL2 rs1024611 and VEGFA rs699947 Polymorphisms with Bladder Cancer Risk, Tumor Aggressiveness, and HRV Parameters of Autonomic Nervous System Regulation"],"prefix":"10.3390","volume":"27","author":[{"given":"Vladimira","family":"Durmanova","sequence":"first","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4443-9069","authenticated-orcid":false,"given":"Iveta","family":"Mikolaskova","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7741-5779","authenticated-orcid":false,"given":"Juraj","family":"Javor","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4397-5310","authenticated-orcid":false,"given":"Agata","family":"Ocenasova","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Suchankova","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Kollarik","sequence":"additional","affiliation":[{"name":"Department of Urology, Bory Hospital, 841 03 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0165-6066","authenticated-orcid":false,"given":"Milan","family":"Zvarik","sequence":"additional","affiliation":[{"name":"Department of Nuclear Physics and Biophysics, Faculty of Mathematics, Physics and Computer Science, Comenius University in Bratislava, 842 48 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bucova","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luba","family":"Hunakova","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Faculty of Medicine, Comenius University in Bratislava, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,9]]},"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 A Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00428-015-1739-2","article-title":"Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old","volume":"466","author":"Roupret","year":"2015","journal-title":"Virchows Arch."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.eururo.2021.08.010","article-title":"European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ)","volume":"81","author":"Babjuk","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1038\/s41585-022-00578-1","article-title":"Recurrence mechanisms of non-muscle-invasive bladder cancer\u2014A clinical perspective","volume":"19","author":"Teoh","year":"2022","journal-title":"Nat. Rev. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.immuni.2019.06.025","article-title":"Inflammation and Cancer: Triggers, Mechanisms, and Consequences","volume":"51","author":"Greten","year":"2019","journal-title":"Immunity"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lu, L., Wang, F., Wang, Z., Guo, S., Jiang, M., and Ma, Z. (2025). Immune snapshots along the inflammation-to-cancer road in bladder urothelium. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1685237"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1001\/jama.2020.17598","article-title":"Bladder Cancer: A Review","volume":"324","author":"Lenis","year":"2020","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.urolonc.2010.12.001","article-title":"Expression of pigment epithelium-derived factor and tumor necrosis factor-\u03b1 is correlated in bladder tumor and is related to tumor angiogenesis","volume":"31","author":"Feng","year":"2013","journal-title":"Urol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.cyto.2012.04.017","article-title":"Autocrine CCL2 promotes cell migration and invasion via PKC activation and tyrosine phosphorylation of paxillin in bladder cancer cells","volume":"59","author":"Chiu","year":"2012","journal-title":"Cytokine"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vukovic, M., Chamlati, J.M., Hennenlotter, J., Todenh\u00f6fer, T., L\u00fctfrenk, T., Jersinovic, S., Tsaur, I., Stenzl, A., and Rausch, S. (2024). Interleukin-1\u03b2\/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer-An Exploratory Analysis of Clinical and Tumor Biological Significance. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202401.0776.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"102378","DOI":"10.1016\/j.clgc.2025.102378","article-title":"Prognostic Role of Serum IL-6 Levels in Bladder Cancer Patients and Hints of its Origin","volume":"23","author":"Engelmann","year":"2025","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ebner, B., Hirsch, J., Holz, A., Volz, Y., Eismann, L., Hermans, J., Pyrgidis, N., Kidess, M., Semmler, M., and Fouladgar, S.T. (2025). Association of interleukin-6 serum levels with local tumor stage and lymph node metastasis of urothelial carcinoma. Urol. Oncol., 43.","DOI":"10.1016\/j.urolonc.2025.08.026"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/intimm\/dxaa078","article-title":"IL-6 in inflammation, autoimmunity and cancer","volume":"33","author":"Hirano","year":"2021","journal-title":"Int. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Huang, B., Lang, X., and Li, X. (2022). The role of IL-6\/JAK2\/STAT3 signaling pathway in cancers. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1023177"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Chen, M.F., Lin, P.Y., Wu, C.F., Chen, W.C., and Wu, C.T. (2013). IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. PLoS ONE, 8, Correction in PLoS ONE 2016, 11, e0155774.","DOI":"10.1371\/journal.pone.0155774"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"365","DOI":"10.14740\/wjon1536","article-title":"Association Between Interleukin-6 Levels and Lymph Node Metastasis in Bladder Cancer Patients","volume":"13","author":"Warli","year":"2022","journal-title":"World. J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e19385","DOI":"10.7717\/peerj.19385","article-title":"Prognostic impact of serum interleukin-6 and 17 level in patients with bladder cancer: A systematic review and meta-analysis","volume":"13","author":"Liu","year":"2025","journal-title":"PeerJ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1172\/JCI2629","article-title":"The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis","volume":"102","author":"Fishman","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7869","DOI":"10.7314\/APJCP.2014.15.18.7869","article-title":"Interleukin-12 and interleukin-6 gene polymorphisms and risk of bladder cancer in the Iranian population","volume":"15","author":"Ebadi","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5746","DOI":"10.1200\/JCO.2005.01.598","article-title":"Polymorphisms in inflammation genes and bladder cancer: From initiation to recurrence, progression, and survival","volume":"23","author":"Leibovici","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cancergencyto.2008.02.015","article-title":"Anti- and proinflammatory cytokine gene polymorphism and genetic predisposition: Association with smoking, tumor stage and grade, and bacillus Calmette-Gu\u00e9rin immunotherapy in bladder cancer","volume":"184","author":"Ahirwar","year":"2008","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.cyto.2015.11.008","article-title":"Functional polymorphisms in the IL6 gene promoter and the risk of urinary bladder cancer in India","volume":"77","author":"Gautam","year":"2016","journal-title":"Cytokine"},{"key":"ref_23","first-page":"3598","article-title":"Association between the rs1800795G>C polymorphism in the promoter of interleukin-6 gene and bladder cancer","volume":"11","author":"Chiang","year":"2018","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nm.3085","article-title":"Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-\u03b1 in rheumatoid arthritis","volume":"19","author":"Nie","year":"2013","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1016\/j.celrep.2015.08.033","article-title":"TNF Counterbalances the Emergence of M2 Tumor Macrophages","volume":"12","author":"Kratochvill","year":"2015","journal-title":"Cell Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"155665","DOI":"10.1016\/j.prp.2024.155665","article-title":"TNF-\u03b1, and TNFRs in gastrointestinal cancers","volume":"263","author":"Mozooni","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/ijc.2910380120","article-title":"Quantification and characterization of high-affinity membrane receptors for tumor necrosis factor on human leukemic cell lines","volume":"38","author":"Scheurich","year":"1986","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/ijc.2910560603","article-title":"Expression of tumour necrosis factor (TNF alpha) and its receptors in benign and malignant breast tissue","volume":"56","author":"Miles","year":"1994","journal-title":"Int. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1158\/1535-7163.MCT-05-0303","article-title":"Expression and regulation of tumor necrosis factor alpha in normal and malignant ovarian epithelium","volume":"5","author":"Szlosarek","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.clnu.2007.08.014","article-title":"Serum concentrations of TNF-alpha as a surrogate marker for malnutrition and worse quality of life in patients with gastric cancer","volume":"26","author":"Correia","year":"2007","journal-title":"Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s13277-015-3829-9","article-title":"Clinical significance of serum interleukin-29, interleukin-32, and tumor necrosis factor alpha levels in patients with gastric cancer","volume":"37","author":"Erturk","year":"2016","journal-title":"Tumour Biol."},{"key":"ref_32","first-page":"1007","article-title":"Activation of matrix metalloproteinase-9 by TNF-alpha in human urinary bladder cancer HT1376 cells: The role of MAP kinase signaling pathways","volume":"19","author":"Lee","year":"2008","journal-title":"Oncol. Rep."},{"key":"ref_33","first-page":"75","article-title":"Gene polymorphism at position -308 of the tumor-necrosis-factor-alpha (TNF-alpha) in multiple sclerosis and it\u2019s influence on the regulation of TNF-alpha production","volume":"215","author":"Braun","year":"1996","journal-title":"Neurosci. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1073\/pnas.94.7.3195","article-title":"Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation","volume":"94","author":"Wilson","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1159\/000331882","article-title":"IL-4 and TNF-\u03b1 polymorphisms are associated with risk of multiple superficial tumors or carcinoma in situ development","volume":"87","author":"Lima","year":"2011","journal-title":"Urol. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.taap.2013.05.019","article-title":"Polymorphism of inflammatory genes and arsenic methylation capacity are associated with urothelial carcinoma","volume":"272","author":"Wu","year":"2013","journal-title":"Toxicol. Appl. Pharmocol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1159\/000341701","article-title":"Meta-analysis shows strong positive association of the TNF-\u03b1 gene with tumor stage in bladder cancer","volume":"89","author":"Yang","year":"2012","journal-title":"Urol. Int."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Jin, Y., Wang, Y., and Yang, R. (2025). Chemokine ligand 2: Beyond chemotaxis-a multifaceted role in tumor progression. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1685474"},{"key":"ref_39","first-page":"1010428317698383","article-title":"MiR-1-3p inhibits the proliferation and invasion of bladder cancer cells by suppressing CCL2 expression","volume":"39","author":"Wang","year":"2017","journal-title":"Tumour Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3826","DOI":"10.1038\/s41467-018-06152-x","article-title":"LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment","volume":"9","author":"Chen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1006\/bbrc.1999.0796","article-title":"A novel polymorphism in the MCP-1 gene regulatory region that influences MCP-1 expression","volume":"259","author":"Rovin","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/nrc909","article-title":"VEGF and the quest for tumour angiogenesis factors","volume":"2","author":"Ferrara","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.4049\/jimmunol.160.3.1224","article-title":"Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells","volume":"160","author":"Oyama","year":"1998","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1084\/jem.20140559","article-title":"VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors","volume":"212","author":"Voron","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1158\/0008-5472.CAN-12-2325","article-title":"VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer","volume":"73","author":"Terme","year":"2013","journal-title":"Cancer Res."},{"key":"ref_46","first-page":"2381","article-title":"Expression of VEGF and its receptors VEGFR1\/VEGFR2 is associated with invasiveness of bladder cancer","volume":"33","author":"Kopparapu","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"349","DOI":"10.3233\/CBM-150478","article-title":"Clinical significance of the VEGF level in urinary bladder carcinoma","volume":"15","author":"Sankhwar","year":"2015","journal-title":"Cancer Biomark."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1158\/1940-6207.CAPR-15-0345","article-title":"Prognostic Significance of VEGF after Twenty-Year Follow-up in a Randomized Trial of Fenretinide in Non-Muscle-Invasive Bladder Cancer","volume":"9","author":"Puntoni","year":"2016","journal-title":"Cancer Prev. Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"van der Fels, C.A.M., Leliveld, A., Buikema, H., van den Heuvel, M.C., and de Jong, I.J. (2022). VEGF, EGFR and PSMA as possible imaging targets of lymph node metastases of urothelial carcinoma of the bladder. BMC Urol., 22.","DOI":"10.1186\/s12894-022-01157-7"},{"key":"ref_50","first-page":"119","article-title":"Vascular endothelial growth factor production is regulated by gene polymorphisms","volume":"6","author":"Mohammadi","year":"2009","journal-title":"Iran. J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.ygyno.2009.11.011","article-title":"The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer","volume":"117","author":"Steffensen","year":"2010","journal-title":"Gynecol. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e22610","DOI":"10.1002\/jcla.22610","article-title":"Haplotype-based association of Vascular Endothelial Growth Factor gene polymorphisms with urothelial bladder cancer risk in Tunisian population","volume":"32","author":"Kallel","year":"2018","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.gene.2018.09.005","article-title":"Association between vascular endothelial growth factor rs699947 polymorphism and the risk of three major urologic neoplasms (bladder cancer, prostate cancer, and renal cell carcinoma): A meta-analysis involving 11,204 subjects","volume":"679","author":"Song","year":"2018","journal-title":"Gene"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.gene.2019.02.070","article-title":"Association between five polymorphisms in vascular endothelial growth factor gene and urinary bladder cancer risk: A systematic review and meta-analysis involving 6671 subjects","volume":"698","author":"Song","year":"2019","journal-title":"Gene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"155112","DOI":"10.1016\/j.cyto.2020.155112","article-title":"Association between VEGF gene promoter polymorphisms and bladder cancer: An updated meta-analysis","volume":"131","author":"Chen","year":"2020","journal-title":"Cytokine"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/j.1469-8986.1997.tb02140.x","article-title":"Heart rate variability: Origins, methods, and interpretive caveats","volume":"34","author":"Berntson","year":"1997","journal-title":"Psychophysiology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"R927","DOI":"10.1152\/ajpregu.00452.2003","article-title":"Heart rate variability","volume":"285","author":"Stauss","year":"2003","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1196\/annals.1366.014","article-title":"Beyond heart rate variability: Vagal regulation of allostatic systems","volume":"1088","author":"Thayer","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.psyneuen.2008.08.007","article-title":"The relationship between heart rate variability and inflammatory markers in cardiovascular diseases","volume":"33","author":"Haensel","year":"2008","journal-title":"Psychoneuroendocrinology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.bbi.2019.03.009","article-title":"Heart rate variability and inflammation: A meta-analysis of human studies","volume":"80","author":"Williams","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"104622","DOI":"10.1016\/j.neubiorev.2022.104622","article-title":"The cholinergic anti-inflammatory pathway in humans: State-of-the-art review and future directions","volume":"136","author":"Alen","year":"2022","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e003265","DOI":"10.1136\/rmdopen-2023-003265","article-title":"Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis","volume":"9","author":"Bellocchi","year":"2023","journal-title":"RMD Open"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/35013070","article-title":"Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin","volume":"405","author":"Borovikova","year":"2000","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.bbi.2005.03.015","article-title":"The cholinergic anti-inflammatory pathway","volume":"19","author":"Pavlov","year":"2005","journal-title":"Brain Behav. Immun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"178","DOI":"10.2119\/2006-00112.Sloan","article-title":"RR interval variability is inversely related to inflammatory markers: The CARDIA study","volume":"13","author":"Sloan","year":"2007","journal-title":"Mol. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00421-009-1341-x","article-title":"Low vagal tone is associated with impaired post stress recovery of cardiovascular, endocrine, and immune markers","volume":"109","author":"Weber","year":"2010","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.resp.2013.02.002","article-title":"Vagal function indexed by respiratory sinus arrhythmia and cholinergic anti-inflammatory pathway","volume":"187","author":"Tonhajzerova","year":"2013","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/5584_2014_10","article-title":"Alterations in vagal-immune pathway in long-lasting mental stress","volume":"832","author":"Visnovcova","year":"2015","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00392-010-0236-5","article-title":"Heart rate variability and biomarkers of systemic inflammation in patients with stable coronary heart disease: Findings from the Heart and Soul Study","volume":"100","author":"Carney","year":"2011","journal-title":"Clin. Res. Cardiol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Catalano, M., Roviello, G., Santi, R., Villari, D., Spatafora, P., Galli, I.C., Sessa, F., Conte, F.L., Mini, E., and Cai, T. (2023). Inflammation in Urological Malignancies: The Silent Killer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010866"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Mikolaskova, I., Zvarik, M., Szaboova, K., Tibenska, E., Durmanova, V., Suchankova, M., Kollarik, B., Hesko, P., Palacka, P., and Bucova, M. (2024). Association of Sympathovagal Imbalance with Increased Inflammation and Impaired Adaptive Immunity in Bladder Cancer Patients. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312765"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.urology.2004.06.018","article-title":"Association of bladder tumors and GA genotype of -308 nucleotide in tumor necrosis factor-alpha promoter with greater tumor necrosis factor-alpha expression","volume":"64","author":"Jeong","year":"2004","journal-title":"Urology"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Abd El-Raheem, T., Mahmoud, R.H., Hefzy, E.M., Masoud, M., Ismail, R., and Aboraia, N.M.M. (2020). Tumor necrosis factor (TNF)-\u03b1-308 G\/A gene polymorphism (rs1800629) in Egyptian patients with alopecia areata and vitiligo, a laboratory and in silico analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0240221"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"16102","DOI":"10.4238\/2015.December.7.22","article-title":"Association of tumor necrosis factor-\u03b1 308G\/A polymorphism with urogenital cancer risk: A systematic review and meta-analysis","volume":"14","author":"Cai","year":"2015","journal-title":"Genet. Mol. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"100848","DOI":"10.1016\/j.mgene.2020.100848","article-title":"TNF-\u03b1 gene polymorphisms and risk of urinary bladder cancer\u2014A case-control study and meta-analysis","volume":"27","author":"Tripathi","year":"2021","journal-title":"Meta Gene"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.urology.2009.04.016","article-title":"Genetic association of monocyte chemoattractant protein 1 (MCP-1)-2518 polymorphism in Mexican patients with transitional cell carcinoma of the bladder","volume":"74","author":"Lima","year":"2009","journal-title":"Urology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"685","DOI":"10.4238\/vol9-2gmr829","article-title":"CCR2-64I is a risk factor for development of bladder cancer","volume":"9","author":"Narter","year":"2010","journal-title":"Genet. Mol. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"9827","DOI":"10.1007\/s11033-012-1849-8","article-title":"Association of inflammatory chemokine gene CCL2I\/D with bladder cancer risk in North Indian population","volume":"39","author":"Singh","year":"2012","journal-title":"Mol. Biol. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.gene.2012.09.011","article-title":"The role of chemokine and chemokine receptor gene variants on the susceptibility and clinicopathological characteristics of bladder cancer","volume":"511","author":"Kucukgergin","year":"2012","journal-title":"Gene"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"23523735261417401","DOI":"10.1177\/23523735261417401","article-title":"Association of CCL2\/CCR2 gene polymorphisms and bladder cancer risk in a hispanic-rich US population","volume":"12","author":"Harmon","year":"2026","journal-title":"Bladder Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1080\/08820139.2020.1776726","article-title":"Relationship between the Monocyte Chemo-attractant Protein-1 gene rs1024611 A>G Polymorphism and Cancer Susceptibility: A Meta-analysis Involving 14,617 Subjects","volume":"50","author":"Chen","year":"2021","journal-title":"Immunol. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"El Azzouzi, M., El Ahanidi, H., Hafidi Alaoui, C., Chaoui, I., Benbacer, L., Tetou, M., Hassan, I., Bensaid, M., Oukabli, M., and Ameur, A. (2023). The Evaluation of Vascular Endothelial Growth Factor A (VEGFA) and VEGFR2 Receptor as Prognostic Biomarkers in Bladder Cancer. Diagnostics, 13.","DOI":"10.3390\/diagnostics13081471"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"443","DOI":"10.4149\/neo_2021_210805N1113","article-title":"Genetic contributions of MHC class I antigen processing and presentation pathway to bladder cancer risk and recurrence","volume":"69","author":"Wieczorek","year":"2022","journal-title":"Neoplasma"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Closas, M., Malats, N., Real, F.X., Yeager, M., Welch, R., Silverman, D., Kogevinas, M., Dosemeci, M., Figueroa, J., and Chatterjee, N. (2007). Large-scale evaluation of candidate genes identifies associations between VEGF polymorphisms and bladder cancer risk. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030029"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"10402","DOI":"10.1002\/jcb.28324","article-title":"VEGF gene rs3025039C\/T and rs833052C\/A variants are associated with bladder cancer risk in Asian descendants","volume":"120","author":"Zhang","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ruzzo, A., Catalano, V., Canestrari, E., Giacomini, E., Santini, D., Tonini, G., Vincenzi, B., Fiorentini, G., Magnani, M., and Graziano, F. (2014). Genetic modulation of the interleukin 6 (IL-6) system in patients with advanced gastric cancer: A background for an alternative target therapy. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-357"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Moreno-Guerrero, S.S., Ram\u00edrez-Pacheco, A., Rocha-Ram\u00edrez, L.M., Hern\u00e1ndez-Pliego, G., Egu\u00eda-Aguilar, P., Escobar-S\u00e1nchez, M.A., Reyes-L\u00f3pez, A., Ju\u00e1rez-Villegas, L.E., and Sienra-Monge, J.J.L. (2021). Association of Genetic Polymorphisms and Serum Levels of IL-6 and IL-8 with the Prognosis in Children with Neuroblastoma. Cancers, 13.","DOI":"10.3390\/cancers13030529"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"156024","DOI":"10.1016\/j.cyto.2022.156024","article-title":"Genotypic and haplotype analysis of Interleukin-6 and -18 gene polymorphisms in association with clinicopathological factors in breast cancer","volume":"160","author":"Padala","year":"2022","journal-title":"Cytokine"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Ram\u00edrez-Pacheco, A., Moreno-Guerrero, S.S., Rocha-Ram\u00edrez, L.M., Hern\u00e1ndez-Pliego, G., Escobar-S\u00e1nchez, M.A., Reyes-L\u00f3pez, A., Sienra-Monge, J.J.L., and Ju\u00e1rez-Villegas, L.E. (2024). Role of Genetic Polymorphisms -238 G>A and -308 G>A, and Serum TNF-\u03b1 Levels in a Cohort of Mexican Pediatric Neuroblastoma Patients: Preliminary Study. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910590"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"156193","DOI":"10.1016\/j.cyto.2023.156193","article-title":"Significant association of MCP1 rs1024611 and CCR2 rs1799864 polymorphisms with colorectal cancer and liver metastases susceptibility and aggressiveness: A case-control study","volume":"167","author":"Boughriba","year":"2023","journal-title":"Cytokine"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1007\/s00432-016-2137-0","article-title":"Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients","volume":"142","author":"Dornbusch","year":"2016","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1080\/15384047.2016.1190486","article-title":"Prognostic evaluation of VEGFA genotypes and haplotypes in a cohort of Brazilian women with non metastatic breast cancer","volume":"17","author":"Delou","year":"2016","journal-title":"Cancer Biol. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1038\/s41598-021-03952-y","article-title":"VEGF-A, VEGFR1 and VEGFR2 single nucleotide polymorphisms and outcomes from the AGITG MAX trial of capecitabine, bevacizumab and mitomycin C in metastatic colorectal cancer","volume":"12","author":"Chionh","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"235","DOI":"10.30773\/pi.2017.08.17","article-title":"Stress and Heart Rate Variability: A Meta-Analysis and Review of the Literature","volume":"15","author":"Kim","year":"2018","journal-title":"Psychiatry Investig."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1186\/s13075-014-0504-2","article-title":"The sympathetic nervous response in inflammation","volume":"16","author":"Pongratz","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3892\/br.2023.1662","article-title":"Linear and non-linear indices of vagal nerve in relation to sex and inflammation in patients with Covid-19","volume":"19","author":"Hunakova","year":"2023","journal-title":"Biomed. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.eururo.2022.07.002","article-title":"The 2022 World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs-Part B: Prostate and Urinary Tract Tumors","volume":"82","author":"Netto","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s11255-015-0922-3","article-title":"The protective effect of MCP-1-2518 A>G promoter polymorphism in Turkish chronic renal failure patients requiring long-term hemodialysis","volume":"47","author":"Bagci","year":"2015","journal-title":"Int. Urol. Nephrol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1111\/jog.14192","article-title":"Association of vascular endothelial growth factor A polymorphisms and aberrant expression of connexin 43 and VEGFA with idiopathic recurrent spontaneous miscarriage","volume":"46","author":"Sajjadi","year":"2020","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Durmanova, V., Mikolaskova, I., Zsemlye, E., Ocenasova, A., Bandzuchova, H., Suchankova, M., Kollarik, B., Palacka, P., Zvarik, M., and Bucova, M. (2024). Association of HLA-G Expression, Its Genetic Variants and Related Neuro-Immunomodulation with Characteristics of Bladder Carcinoma. Cancers, 16.","DOI":"10.3390\/cancers16223877"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1093\/bioinformatics\/btl268","article-title":"SNPStats: A web tool for the analysis of association studies","volume":"22","author":"Valls","year":"2006","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3361\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T07:52:11Z","timestamp":1775721131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3361"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":102,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083361"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083361","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]}}}