{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T02:44:00Z","timestamp":1783824240738,"version":"3.55.0"},"reference-count":75,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T00:00:00Z","timestamp":1620691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R01ES032189"],"award-info":[{"award-number":["R01ES032189"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R35ES028373"],"award-info":[{"award-number":["R35ES028373"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["P42ES023716"],"award-info":[{"award-number":["P42ES023716"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["P30ES030283"],"award-info":[{"award-number":["P30ES030283"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R21ES031510"],"award-info":[{"award-number":["R21ES031510"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["T35ES14559"],"award-info":[{"award-number":["T35ES14559"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["T32ES011564"],"award-info":[{"award-number":["T32ES011564"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R21ES031531"],"award-info":[{"award-number":["R21ES031531"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["F32AA027950"],"award-info":[{"award-number":["F32AA027950"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["P50AA024337"],"award-info":[{"award-number":["P50AA024337"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM113226"],"award-info":[{"award-number":["P20GM113226"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: High-level occupational vinyl chloride (VC) exposures have been associated with hepatic hemangiosarcoma, which typically develops following a long latency period. Although VC is genotoxic, a more comprehensive mode of action has not been determined and diagnostic biomarkers have not been established. The purpose of this study is to address these knowledge gaps through plasma metabolomics. Methods: Plasma samples from polyvinyl chloride polymerization workers who developed hemangiosarcoma (cases, n = 15) and VC exposure-matched controls (n = 17) underwent metabolomic analysis. Random forest and bioinformatic analyses were performed. Results: Cases and controls had similar demographics and routine liver biochemistries. Mass spectroscopy identified 606 known metabolites. Random forest analysis had an 82% predictive accuracy for group classification. 60 metabolites were significantly increased and 44 were decreased vs. controls. Taurocholate, bradykinin and fibrin degradation product 2 were up-regulated by greater than 80-fold. The naturally occurring anti-angiogenic phenol, 4-hydroxybenzyl alcohol, was down-regulated 5-fold. Top affected ontologies involved: (i) metabolism of bile acids, taurine, cholesterol, fatty acids and amino acids; (ii) inflammation and oxidative stress; and (iii) nicotinic cholinergic signaling. Conclusions: The plasma metabolome was differentially regulated in polyvinyl chloride workers who developed hepatic hemangiosarcoma. Ontologies potentially involved in hemangiosarcoma pathogenesis and candidate biomarkers were identified.<\/jats:p>","DOI":"10.3390\/ijms22105093","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T22:53:40Z","timestamp":1620773620000},"page":"5093","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Plasma Metabolomics Analysis of Polyvinyl Chloride Workers Identifies Altered Processes and Candidate Biomarkers for Hepatic Hemangiosarcoma and Its Development"],"prefix":"10.3390","volume":"22","author":[{"given":"John J.","family":"Guardiola","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josiah E.","family":"Hardesty","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Hepatology and Nutrition, University of Louisville Division of Gastroenterology, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane I.","family":"Beier","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"University of Pittsburgh Liver Research Center (PLRC), Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell A.","family":"Prough","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7219-8939","authenticated-orcid":false,"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Hepatology and Nutrition, University of Louisville Division of Gastroenterology, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA"},{"name":"The UofL Health\u2014Jewish Hospital Trager Transplant Center, Louisville, KY 40202, USA"},{"name":"The University of Louisville Superfund Research Center, Department of Medicine, University of Louisville, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew C.","family":"Cave","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Louisville, Louisville, KY 40202, USA"},{"name":"Hepatology and Nutrition, University of Louisville Division of Gastroenterology, Louisville, KY 40202, USA"},{"name":"University of Pittsburgh Liver Research Center (PLRC), Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40202, USA"},{"name":"Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA"},{"name":"The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206, USA"},{"name":"The UofL Health\u2014Jewish Hospital Trager Transplant Center, Louisville, KY 40202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/toxsci\/kfp131","article-title":"Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance","volume":"111","author":"Cohen","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1093\/toxsci\/kfq371","article-title":"Endogenous versus exogenous DNA adducts: Their role in carcinogenesis, epidemiology, and risk assessment","volume":"120","author":"Swenberg","year":"2011","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_3","first-page":"150","article-title":"Angiosarcoma of liver in the manufacture of polyvinyl chloride","volume":"16","author":"Creech","year":"1974","journal-title":"J. Occup. Med. Off. Publ. Ind. Med. Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1001\/jama.1974.03240010027023","article-title":"Hepatic disease among workers at a vinyl chloride polymerization plant","volume":"230","author":"Falk","year":"1974","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1136\/oemed-2016-104051","article-title":"Quantitative estimated exposure to vinyl chloride and risk of angiosarcoma of the liver and hepatocellular cancer in the US industry-wide vinyl chloride cohort: Mortality update through 2013","volume":"74","author":"Mundt","year":"2017","journal-title":"Occup. Environ. Med."},{"key":"ref_6","first-page":"459","article-title":"Liver angiosarcoma from past exposure to vinyl chloride: A case report","volume":"103","author":"Corfiati","year":"2012","journal-title":"La Med. Del Lav."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4885","DOI":"10.3748\/wjg.v25.i33.4885","article-title":"Occupational exposure to vinyl chloride and liver diseases","volume":"25","author":"Fedeli","year":"2019","journal-title":"World J. Gastroenterol"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"(2019). EASL Clinical Practice Guideline: Occupational liver diseases. J. Hepatol., 71, 1022\u20131037.","DOI":"10.1016\/j.jhep.2019.08.008"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1111\/jgh.12506","article-title":"Primary hepatic angiosarcoma and potential treatment options","volume":"29","author":"Zheng","year":"2014","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_10","first-page":"133","article-title":"Vinyl Chloride Induced Hepatic Angiosarcoma: An Update of the Louisville Experience [abstract]","volume":"132","author":"Cave","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/hep.23321","article-title":"Toxicant-associated steatohepatitis in vinyl chloride workers","volume":"51","author":"Cave","year":"2010","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.taap.2016.10.001","article-title":"Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome","volume":"313","author":"Guardiola","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_13","first-page":"124","article-title":"The kinin system--bradykinin: Biological effects and clinical implications. Multiple role of the kinin system\u2014bradykinin","volume":"11","author":"Golias","year":"2007","journal-title":"Hippokratia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"23279","DOI":"10.1038\/srep23279","article-title":"Serum complement C3 levels are associated with nonalcoholic fatty liver disease independently of metabolic features in Chinese population","volume":"6","author":"Xu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_15","first-page":"71","article-title":"Resolution of Cancer-Promoting Inflammation: A New Approach for Anticancer Therapy","volume":"8","author":"Zhang","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nrgastro.2017.119","article-title":"Bile acid\u2013microbiota crosstalk in gastrointestinal inflammation and carcinogenesis","volume":"15","author":"Jia","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_17","first-page":"1169","article-title":"Gamma-glutamyltransferase of cancer cells at the crossroads of tumor progression, drug resistance and drug targeting","volume":"30","author":"Corti","year":"2010","journal-title":"Anticancer. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/j.1478-3231.2010.02375.x","article-title":"Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease","volume":"31","author":"Kotronen","year":"2011","journal-title":"Liver Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1210\/me.2009-0212","article-title":"Minireview: Nuclear Receptor-Controlled Steroid Hormone Synthesis and Metabolism","volume":"24","author":"He","year":"2010","journal-title":"Mol. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1002\/pmic.201500514","article-title":"High-grade sarcoma diagnosis and prognosis: Biomarker discovery by mass spectrometry imaging","volume":"16","author":"Lou","year":"2016","journal-title":"Proteomics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s13361-016-1544-4","article-title":"Prognostic Metabolite Biomarkers for Soft Tissue Sarcomas Discovered by Mass Spectrometry Imaging","volume":"28","author":"Lou","year":"2017","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1152\/physrev.00024.2009","article-title":"Peptide hormone regulation of angiogenesis","volume":"89","author":"Clapp","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/S1567-5769(01)00193-X","article-title":"Roles of bradykinin in vascular permeability and angiogenesis in solid tumor","volume":"2","author":"Ishihara","year":"2002","journal-title":"Int. Immunopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.bcp.2013.10.016","article-title":"Bradykinin promotes vascular endothelial growth factor expression and increases angiogenesis in human prostate cancer cells","volume":"87","author":"Yu","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1093\/toxsci\/kfw045","article-title":"Vinyl Chloride Metabolites Potentiate Inflammatory Liver Injury Caused by LPS in Mice","volume":"151","author":"Anders","year":"2016","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1038\/nrd2694","article-title":"Icatibant","volume":"7","author":"Bork","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7175","DOI":"10.1158\/0008-5472.CAN-09-2068","article-title":"KDR activating mutations in human angiosarcomas are sensitive to specific kinase inhibitors","volume":"69","author":"Antonescu","year":"2009","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1097\/PAS.0000000000000582","article-title":"Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases With Concurrent Investigation of PLCG1, KDR, MYC, and FLT4 Gene Alterations","volume":"40","author":"Huang","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.canlet.2013.12.009","article-title":"The role of kinin receptors in cancer and therapeutic opportunities","volume":"345","author":"Sirois","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16051","DOI":"10.1016\/S0021-9258(18)37555-0","article-title":"Purification, and identification of [hydroxyprolyl3] bradykinin in ascitic fluid from a patient with gastric cancer","volume":"263","author":"Maeda","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"499","DOI":"10.6004\/jnccn.2016.0058","article-title":"Antitumor Response of VEGFR2- and VEGFR3-Amplified Angiosarcoma to Pazopanib","volume":"14","author":"Ravi","year":"2016","journal-title":"J. Natl. Compr. Canc. Netw."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.2147\/CMAR.S159641","article-title":"A review of soft-tissue sarcomas: Translation of biological advances into treatment measures","volume":"10","author":"Hoang","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/978-3-0348-0837-8_11","article-title":"The Role of Inflammation in Sarcoma","volume":"816","author":"Radons","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1055\/s-2007-1002674","article-title":"Fibrinolysis and Cancer","volume":"16","author":"Kwaan","year":"1990","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1042\/bst0300173","article-title":"Mechanism of thrombin-induced angiogenesis","volume":"30","author":"Maragoudakis","year":"2002","journal-title":"Biochem. Soc. Trans."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.biopha.2012.10.003","article-title":"The urokinase plasminogen activator system in breast cancer invasion and metastasis","volume":"67","author":"Tang","year":"2013","journal-title":"Biomed. Pharmacother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1002\/path.1711680109","article-title":"Angiogenic activity of fibrin degradation products is located in fibrin fragment E","volume":"168","author":"Thompson","year":"1992","journal-title":"J. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1136\/bmj.4.5785.458","article-title":"Fibrin degradation products and ovarian tumours","volume":"4","author":"Astedt","year":"1971","journal-title":"Br. Med. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1111\/j.1365-2036.2004.02212.x","article-title":"The new DR-70 immunoassay detects cancer of the gastrointestinal tract: A validation study","volume":"20","author":"Kerber","year":"2004","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1111\/j.1440-1746.2011.06896.x","article-title":"DR-70 immunoassay for the surveillance of hepatocellular carcinoma","volume":"27","author":"Lin","year":"2012","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"737","DOI":"10.3892\/br.2014.315","article-title":"Comparison of the serum fibrin-fibrinogen degradation products with cytokeratin 19 fragment as biomarkers in patients with lung cancer","volume":"2","author":"So","year":"2014","journal-title":"Biomed. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/hep4.1151","article-title":"Vinyl chloride dysregulates metabolic homeostasis and enhances diet-induced liver injury in mice","volume":"2","author":"Lang","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1939-1676.1991.tb00923.x","article-title":"Hemostatic abnormalities in dogs with hemangiosarcoma","volume":"5","author":"Hammer","year":"1991","journal-title":"J. Vet. Intern. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/0002-9343(85)90464-4","article-title":"Use of serum bile acids in the identification of vinyl chloride hepatotoxicity","volume":"78","author":"Liss","year":"1985","journal-title":"Am. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1039\/b820224a","article-title":"A metabonomic study of hepatitis B-induced liver cirrhosis and hepatocellular carcinoma by using RP-LC and HILIC coupled with mass spectrometry","volume":"5","author":"Yin","year":"2009","journal-title":"Mol. Biosyst."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"M110.004945","DOI":"10.1074\/mcp.M110.004945","article-title":"Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma","volume":"10","author":"Chen","year":"2011","journal-title":"Mol. Cell. Proteom."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1002\/hep.27085","article-title":"Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2","volume":"60","author":"Liu","year":"2014","journal-title":"Hepatology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1002\/hep.510230616","article-title":"Biochemical epidemiology of gallbladder cancer","volume":"23","author":"Strom","year":"1996","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0304-3835(84)90168-X","article-title":"Effect of taurocholic acid feeding on methyl-nitro-N-nitroso-guanidine induced gastric tumors","volume":"22","author":"Salmon","year":"1984","journal-title":"Cancer Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1002\/hep.20942","article-title":"Conjugated bile acids promote ERK1\/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes","volume":"42","author":"Dent","year":"2005","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/nature06778","article-title":"Tumour maintenance is mediated by eNOS","volume":"452","author":"Lim","year":"2008","journal-title":"Nature"},{"key":"ref_52","first-page":"949","article-title":"Nitric oxide synthases in Kaposi\u2019s sarcoma are expressed predominantly by vessels and tissue macrophages","volume":"78","author":"Weninger","year":"1998","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00726-006-0416-9","article-title":"g-Glutamyl compounds and their enzymatic production using bacterial g-glutamyltranspeptidase","volume":"32","author":"Suzuki","year":"2007","journal-title":"Amino Acids"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7109","DOI":"10.3748\/wjg.v11.i45.7109","article-title":"Associations between gamma-glutamyl transferase, metabolic abnormalities and inflammation in healthy subjects from a population-based cohort: A possible implication for oxidative stress","volume":"11","author":"Bo","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/j.jhep.2011.01.031","article-title":"Serum metabolomics reveals \u03b3-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease","volume":"55","author":"Soga","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Cheng, J., Joyce, A., Yates, K., Aouizerat, B., and Sanyal, A.J. (2012). Metabolomic Profiling to Identify Predictors of Response to Vitamin E for Non-Alcoholic Steatohepatitis (NASH). PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044106"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1038\/bjc.2016.305","article-title":"Serum metabolomic profiling of prostate cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial","volume":"115","author":"Huang","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1186\/s13058-014-0415-9","article-title":"A joint analysis of metabolomics and genetics of breast cancer","volume":"16","author":"Tang","year":"2014","journal-title":"Breast Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/1097-0142(197601)37:1<149::AID-CNCR2820370122>3.0.CO;2-7","article-title":"Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers","volume":"37","author":"Mark","year":"1976","journal-title":"Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"750","DOI":"10.20344\/amp.8593","article-title":"Hepatic Angiosarcoma Masquerading as Hemangioma: A Challenging Differential Diagnosis","volume":"30","author":"Garcia","year":"2017","journal-title":"Acta M\u00e9dica Port."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0304-4165(79)90309-X","article-title":"4-Hydroxybenzyl alcohol. A metabolite produced during the biosynthesis of thiamine in Escherichia coli","volume":"583","author":"White","year":"1979","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1211\/jpp.59.9.0007","article-title":"Anti-angiogenic, anti-inflammatory and anti-nociceptive activity of 4-hydroxybenzyl alcohol","volume":"59","author":"Lim","year":"2007","journal-title":"J. Pharm. Pharm."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Luo, L., Kim, S.-W., Lee, H.-K., Kim, I.-D., Lee, H., and Lee, J.-K. (2017). Anti-oxidative effects of 4-hydroxybenzyl alcohol in astrocytes confer protective effects in autocrine and paracrine manners. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177322"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1007\/s12031-018-1027-0","article-title":"Evaluation of the Mitochondria-Related Redox and Bioenergetics Effects of Gastrodin in SH-SY5Y Cells Exposed to Hydrogen Peroxide","volume":"64","year":"2018","journal-title":"J. Mol. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1111\/j.1476-5381.2011.01292.x","article-title":"In vitro and in vivo evaluation of the anti-angiogenic actions of 4-hydroxybenzyl alcohol","volume":"163","author":"Laschke","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"D\u2019Eliseo, D., and Velotti, F. (2016). Omega-3 Fatty Acids and Cancer Cell Cytotoxicity: Implications for Multi-Targeted Cancer Therapy. J. Clin. Med., 5.","DOI":"10.3390\/jcm5020015"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18441","DOI":"10.1074\/jbc.M802107200","article-title":"In Vivo and in Vitro Regulation of Syndecan 1 in Prostate Cells by n -3 Polyunsaturated Fatty Acids","volume":"283","author":"Edwards","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1158\/0008-5472.CAN-07-2305","article-title":"Peroxisome proliferator-activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells","volume":"68","author":"Sun","year":"2008","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1593\/neo.04457","article-title":"Inverse relationship between 15-lipoxygenase-2 and PPAR-gamma gene expression in normal epithelia compared with tumor epithelia","volume":"7","author":"Subbarayan","year":"2005","journal-title":"Neoplasia"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1136\/thx.2009.122747","article-title":"5-Lipoxygenases and its metabolites 15(S)-HETE and 13(S)-HODE in the development of non-small cell lung cancer","volume":"65","author":"Yuan","year":"2010","journal-title":"Thorax"},{"key":"ref_71","first-page":"497","article-title":"15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells","volume":"61","author":"Shappell","year":"2001","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1002\/ijc.11447","article-title":"15-hydroxy-eicosatetraenoic acid arrests growth of colorectal cancer cellsvia a peroxisome proliferator-activated receptor gamma-dependent pathway","volume":"107","author":"Chen","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"9716","DOI":"10.3748\/wjg.v20.i29.9716","article-title":"Inflammatory pathways in the early steps of colorectal cancer development","volume":"20","author":"Mariani","year":"2014","journal-title":"World J. Gastrenterol."},{"key":"ref_74","first-page":"353","article-title":"Exposure indices for epidemiological surveillance of carcinogenic agents in an industrial chemical environment","volume":"23","author":"Greenberg","year":"1981","journal-title":"J. Occup. Med. Off. Publ. Ind. Med. Assoc."},{"key":"ref_75","first-page":"18","article-title":"Classification and Regression by randomForest","volume":"2","author":"Liaw","year":"2002","journal-title":"R News"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5093\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:59:27Z","timestamp":1760162367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5093"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,11]]},"references-count":75,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22105093"],"URL":"https:\/\/doi.org\/10.3390\/ijms22105093","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,11]]}}}