{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T16:34:22Z","timestamp":1764174862754},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T00:00:00Z","timestamp":1608249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Kastner-Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Detection of asbestos-associated diseases like asbestosis or mesothelioma is still challenging. We sought to improve the diagnosis of benign asbestos-associated disease (BAAD) by detection of the protein cysteine-rich angiogenic inducer 61 (Cyr61) in human plasma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Plasma Cyr61 was quantified using an enzyme-linked immunosorbent assay. Plasma samples from males diagnosed with BAAD, but without a malignant disease (n\u2009=\u2009101), and malignant mesothelioma (n\u2009=\u200921; 15 males, 6 females), as well as nonasbestos-exposed healthy control participants (n\u2009=\u2009150; 58 males, 92 females) were analyzed. Clinical sensitivity and specificity of Cyr61 were determined by receiver operating characteristic analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The median plasma Cyr61 concentration for healthy control participants was 0.27\u2009ng\/mL. Cytoplasmic Cyr61 in peripheral blood mononuclear cells from healthy control participants was evenly distributed, as detected by immunofluorescent staining. The increase in plasma Cyr61 concentrations in the BAAD study group was statistically significant compared to the healthy control participants (P\u2009&amp;lt;\u20090.0001). For the detection of BAAD vs male healthy control participants, clinical sensitivity was 88% and clinical specificity 95% with an area under the curve of 0.924 at maximal Youden Index. For a predefined clinical specificity of 100%, the clinical sensitivity was 76%. For male mesothelioma patients vs male healthy control participants, the clinical sensitivity at maximal Youden Index was 95% with a clinical specificity of 100% (area under the curve, 0.997) and for a predefined clinical specificity of 100%, the clinical sensitivity was 93%.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In our study, plasma Cyr61 protein concentrations showed to be a new biomarker for asbestos-associated diseases like BAAD and mesothelioma in men, which deserves further investigation in large-scale cohort studies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/clinchem\/hvaa232","type":"journal-article","created":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T11:12:36Z","timestamp":1601032356000},"page":"363-373","source":"Crossref","is-referenced-by-count":3,"title":["Sensitive Blood-Based Detection of Asbestos-Associated Diseases Using Cysteine-Rich Angiogenic Inducer 61 as Circulating Protein Biomarker"],"prefix":"10.1093","volume":"67","author":[{"given":"Kai","family":"Bartkowiak","sequence":"first","affiliation":[{"name":"Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swaantje","family":"Casjens","sequence":"additional","affiliation":[{"name":"Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antje","family":"Andreas","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucija","family":"A\u010dkar","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon A","family":"Joosse","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irina","family":"Raiko","sequence":"additional","affiliation":[{"name":"Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Br\u00fcning","sequence":"additional","affiliation":[{"name":"Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Geffken","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven","family":"Peine","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Johnen","sequence":"additional","affiliation":[{"name":"Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel Gilbert","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Pantel","sequence":"additional","affiliation":[{"name":"Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,12,18]]},"reference":[{"key":"2021020107595536300_hvaa232-B1","first-page":"1","article-title":"IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: asbestos","volume":"14","year":"1977","journal-title":"IARC Monogr Eval Carcinog Risk Chem Man"},{"key":"2021020107595536300_hvaa232-B2","doi-asserted-by":"crossref","first-page":"58606","DOI":"10.18632\/oncotarget.9686","article-title":"Diagnostic value of microRNAs in asbestos exposure and malignant mesothelioma: systematic review and qualitative meta-analysis","volume":"7","author":"Micolucci","year":"2016","journal-title":"Oncotarget"},{"key":"2021020107595536300_hvaa232-B3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.aogh.2014.09.016","article-title":"The global spread of asbestos","volume":"80","author":"Frank","year":"2014","journal-title":"Ann Glob Health"},{"key":"2021020107595536300_hvaa232-B4","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1146\/annurev-publhealth-031811-124704","article-title":"The worldwide pandemic of asbestos-related diseases","volume":"34","author":"Stayner","year":"2013","journal-title":"Annu Rev Public Health"},{"key":"2021020107595536300_hvaa232-B5","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.3390\/ijerph15051000","article-title":"Global asbestos disaster","volume":"15","author":"Furuya","year":"2018","journal-title":"Int J Environ Res Public Health"},{"key":"2021020107595536300_hvaa232-B6","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ijheh.2009.09.001","article-title":"Cancer mortality in a surveillance cohort of German males formerly exposed to asbestos","volume":"213","author":"Pesch","year":"2010","journal-title":"Int J Hyg Environ Health"},{"key":"2021020107595536300_hvaa232-B7","first-page":"135","article-title":"Asbestos hazards in naval dockyards","volume":"11","author":"Harries","year":"1968","journal-title":"Ann Occup Hyg"},{"key":"2021020107595536300_hvaa232-B8","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/j.lungcan.2004.04.005","article-title":"Pathological anatomy and molecular pathology","volume":"45","author":"Krismann","year":"2004","journal-title":"Lung Cancer"},{"key":"2021020107595536300_hvaa232-B9","doi-asserted-by":"crossref","first-page":"170080","DOI":"10.1183\/16000617.0080-2017","article-title":"Current and new challenges in occupational lung diseases","volume":"26","author":"De Matteis","year":"2017","journal-title":"Eur Respir Rev"},{"key":"2021020107595536300_hvaa232-B10","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(17)32366-8","article-title":"Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016: a systematic analysis for the global burden of disease study 2016","volume":"390","year":"2017","journal-title":"Lancet"},{"key":"2021020107595536300_hvaa232-B11","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1038\/sj.bjc.6690105","article-title":"The European mesothelioma epidemic","volume":"79","author":"Peto","year":"1999","journal-title":"Br J Cancer"},{"key":"2021020107595536300_hvaa232-B12","doi-asserted-by":"crossref","first-page":"740","DOI":"10.3389\/fonc.2019.00740","article-title":"Liquid biopsy in malignant pleural mesothelioma: state of the art, pitfalls, and perspectives","volume":"9","author":"Cavallari","year":"2019","journal-title":"Front Oncol"},{"key":"2021020107595536300_hvaa232-B13","doi-asserted-by":"crossref","first-page":"14321","DOI":"10.1038\/s41598-018-32315-3","article-title":"Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin - a case-control comparison nested into a prospective cohort of asbestos-exposed workers","volume":"8","author":"Johnen","year":"2018","journal-title":"Sci Rep"},{"key":"2021020107595536300_hvaa232-B14","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/gcc.22695","article-title":"Liquid biopsies","volume":"58","author":"Lianidou","year":"2019","journal-title":"Genes Chromosomes Cancer"},{"key":"2021020107595536300_hvaa232-B15","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1007\/s00018-011-0778-3","article-title":"Ccn1\/cyr61: the very model of a modern matricellular protein","volume":"68","author":"Lau","year":"2011","journal-title":"Cell Mol Life Sci"},{"key":"2021020107595536300_hvaa232-B16","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1165\/rcmb.2013-0053OC","article-title":"Asbestos-induced alveolar epithelial cell apoptosis. The role of endoplasmic reticulum stress response","volume":"49","author":"Kamp","year":"2013","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2021020107595536300_hvaa232-B17","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1165\/rcmb.2009-0206TR","article-title":"Asbestos, lung cancers, and mesotheliomas: from molecular approaches to targeting tumor survival pathways","volume":"42","author":"Heintz","year":"2010","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2021020107595536300_hvaa232-B18","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1172\/JCI118246","article-title":"Vitronectin enhances internalization of crocidolite asbestos by rabbit pleural mesothelial cells via the integrin alpha v beta 5","volume":"96","author":"Boylan","year":"1995","journal-title":"J Clin Invest"},{"key":"2021020107595536300_hvaa232-B19","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1071\/RD10335","article-title":"Epidermal growth factor upregulates endometrial cyr61 expression via activation of the jak2\/stat3 pathway","volume":"24","author":"Klein","year":"2012","journal-title":"Reprod Fertil Dev"},{"key":"2021020107595536300_hvaa232-B20","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.cellsig.2018.07.005","article-title":"Portal myofibroblasts are sensitive to CCN-mediated endoplasmic reticulum stress-related apoptosis with potential to attenuate biliary fibrogenesis","volume":"51","author":"Borkham-Kamphorst","year":"2018","journal-title":"Cell Signal"},{"key":"2021020107595536300_hvaa232-B21","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1038\/sj.onc.1208452","article-title":"Alphavbeta3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer","volume":"24","author":"Vellon","year":"2005","journal-title":"Oncogene"},{"key":"2021020107595536300_hvaa232-B22","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.ccell.2017.01.002","article-title":"Liquid biopsies, what we do not know (yet)","volume":"31","author":"Bardelli","year":"2017","journal-title":"Cancer Cell"},{"key":"2021020107595536300_hvaa232-B23","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41571-019-0187-3","article-title":"Liquid biopsy and minimal residual disease - latest advances and implications for cure","volume":"16","author":"Pantel","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"2021020107595536300_hvaa232-B24","doi-asserted-by":"crossref","first-page":"eabb9601","DOI":"10.1126\/science.abb9601","article-title":"Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention","volume":"369","author":"Lennon","year":"2020","journal-title":"Science"},{"key":"2021020107595536300_hvaa232-B25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/5756102","article-title":"Serum hmgb1 as a potential biomarker for patients with asbestos-related diseases","volume":"2017","author":"Ying","year":"2017","journal-title":"Dis Markers"},{"key":"2021020107595536300_hvaa232-B26","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1093\/jnci\/djs513","article-title":"Pleural plaques and the risk of pleural mesothelioma","volume":"105","author":"Pairon","year":"2013","journal-title":"J Natl Cancer Inst"},{"key":"2021020107595536300_hvaa232-B27","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3109\/08958378.2015.1051640","article-title":"Are pleural plaques an appropriate endpoint for risk analyses?","volume":"27","author":"Maxim","year":"2015","journal-title":"Inhal Toxicol"},{"key":"2021020107595536300_hvaa232-B28","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1016\/j.ajpath.2012.12.028","article-title":"New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas","volume":"182","author":"Mossman","year":"2013","journal-title":"Am J Pathol"},{"key":"2021020107595536300_hvaa232-B29","doi-asserted-by":"crossref","first-page":"329","DOI":"10.2217\/bmm-2017-0390","article-title":"Evaluation of serum cysteine-rich protein 61 concentrations in patients with coronary artery disease","volume":"12","author":"Deng","year":"2018","journal-title":"Biomark Med"},{"key":"2021020107595536300_hvaa232-B30","doi-asserted-by":"crossref","first-page":"3493","DOI":"10.1093\/eurheartj\/ehx640","article-title":"Cysteine-rich angiogenic inducer 61 (cyr61): a novel soluble biomarker of acute myocardial injury improves risk stratification after acute coronary syndromes","volume":"38","author":"Klingenberg","year":"2017","journal-title":"Eur Heart J"},{"key":"2021020107595536300_hvaa232-B31","doi-asserted-by":"crossref","first-page":"e834","DOI":"10.1097\/MD.0000000000000834","article-title":"Serum cyr61 is associated with clinical disease activity and inflammation in patients with systemic lupus erythematosus","volume":"94","author":"Lin","year":"2015","journal-title":"Medicine (Baltimore)"},{"key":"2021020107595536300_hvaa232-B32","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1007\/s00018-012-0981-x","article-title":"Ccn1: A novel inflammation-regulated biphasic immune cell migration modulator","volume":"69","author":"Lobel","year":"2012","journal-title":"Cell Mol Life Sci"},{"key":"2021020107595536300_hvaa232-B33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s12199-017-0661-4","article-title":"Search for biomarkers of asbestos exposure and asbestos-induced cancers in investigations of the immunological effects of asbestos","volume":"22","author":"Matsuzaki","year":"2017","journal-title":"Environ Health Prev Med"},{"key":"2021020107595536300_hvaa232-B34","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/nrd3599","article-title":"Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets","volume":"10","author":"Jun","year":"2011","journal-title":"Nat Rev Drug Discov"},{"key":"2021020107595536300_hvaa232-B35","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s10552-016-0838-y","article-title":"Incidence of malignant mesothelioma in Germany 2009-2013","volume":"28","author":"Lehnert","year":"2017","journal-title":"Cancer Causes Control"},{"key":"2021020107595536300_hvaa232-B36","doi-asserted-by":"crossref","first-page":"S383","DOI":"10.21037\/jtd.2017.10.84","article-title":"Health surveillance for former asbestos exposed worker: a specific programme developed in an Italian region","volume":"10","author":"Chellini","year":"2018","journal-title":"J Thorac Dis"},{"key":"2021020107595536300_hvaa232-B37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.respe.2012.06.402","article-title":"compensation for occupational diseases after tomodensitometry screening for benign pleuro-pulmonary disease in a multiregional post-occupational medical surveillance program of asbestos-exposed retired workers","volume":"61","author":"Gislard","year":"2013","journal-title":"Rev Epidemiol Sante Publique"},{"key":"2021020107595536300_hvaa232-B38","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/j.1445-5994.2011.02451.x","article-title":"Asbestos-related disease","volume":"41","author":"Jamrozik","year":"2011","journal-title":"Intern Med J"},{"key":"2021020107595536300_hvaa232-B39","doi-asserted-by":"crossref","first-page":"249","DOI":"10.2486\/indhealth.2017-0125","article-title":"Asbestos exposure biomarkers in the follow-up of asbestos-exposed workers","volume":"56","author":"Paolucci","year":"2018","journal-title":"Ind Health"},{"key":"2021020107595536300_hvaa232-B40","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1111\/cas.12687","article-title":"Chemokine (c-c motif) ligand 3 detection in the serum of persons exposed to asbestos: a patient-based study","volume":"106","author":"Xu","year":"2015","journal-title":"Cancer Sci"}],"container-title":["Clinical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/clinchem\/advance-article-pdf\/doi\/10.1093\/clinchem\/hvaa232\/34948531\/hvaa232.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/67\/2\/363\/36156862\/hvaa232.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/clinchem\/article-pdf\/67\/2\/363\/36156862\/hvaa232.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T08:22:24Z","timestamp":1612167744000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/clinchem\/article\/67\/2\/363\/6041272"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,18]]},"references-count":40,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,12,18]]},"published-print":{"date-parts":[[2021,1,30]]}},"URL":"https:\/\/doi.org\/10.1093\/clinchem\/hvaa232","relation":{},"ISSN":["0009-9147","1530-8561"],"issn-type":[{"value":"0009-9147","type":"print"},{"value":"1530-8561","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,2,1]]},"published":{"date-parts":[[2020,12,18]]}}}