{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:28:56Z","timestamp":1777480136209,"version":"3.51.4"},"reference-count":66,"publisher":"Portland Press Ltd.","issue":"5","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":275,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,10,31]]},"abstract":"<jats:p>Brain metastases are the most common intracranial tumors in adults. They usually originate from: lung, breast, renal cell and gastrointestinal cancers, as well as melanoma. Prognosis for brain metastases is still poor and classical treatment combining surgery and radiation therapy should be strongly supported with molecular approaches. However, their successful application depends on a deep understanding of not only genetic, but also epigenetic background of the disease. That will result in an earlier and more precise diagnosis, successful treatment, as well as individualized estimation of clinical outcomes and prognosis. It has already been shown that the epigenetic machinery plays a crucial role in cancer biology, development, and progression. Therefore, we decided to look for metastasis through changes in the most studied epigenetic mark, 5-methylcytosine (m5C) in DNA. We performed global analysis of the m5C contents in DNA isolated from the brain metastatic tumor tissue and peripheral blood samples of the same patients, using thin layer chromatography separation of radioactively labeled nucleotides. We found that the m5C level in DNA from brain metastases: changes in the broad range, overlaps with that of blood, and negatively correlates with the increasing tumor grade. Because the amount of m5C in tumor tissue and blood is almost identical, the genomic DNA methylation can be a useful marker for brain metastases detection and differentiation. Our research creates a scope for future studies on epigenetic mechanisms in neuro-oncology and can lead to development of new diagnostic methods in clinical practice.<\/jats:p>","DOI":"10.1042\/bsr20180731","type":"journal-article","created":{"date-parts":[[2018,9,25]],"date-time":"2018-09-25T09:15:41Z","timestamp":1537866941000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Global DNA demethylation as an epigenetic marker of human brain metastases"],"prefix":"10.1042","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7179-1474","authenticated-orcid":false,"given":"Anna-Maria","family":"Barciszewska","sequence":"first","affiliation":[{"name":"Intraoperative Imaging Unit, Chair and Clinic of Neurosurgery and Neurotraumatology, Karol Marcinkowski University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland"},{"name":"Department of Neurosurgery and Neurotraumatology, Heliodor Swiecicki Clinical Hospital, Przybyszewskiego 49, 60-355 Poznan, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2018,10,23]]},"reference":[{"key":"2021111619111605000_B1","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1093\/neuonc\/now127","article-title":"Updates in the management of brain metastases","volume":"18","author":"Arvold","year":"2016","journal-title":"Neuro Oncol."},{"key":"2021111619111605000_B2","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.ijrobp.2009.08.025","article-title":"Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients","volume":"77","author":"Sperduto","year":"2010","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"2021111619111605000_B3","doi-asserted-by":"publisher","first-page":"6404","DOI":"10.1158\/1078-0432.CCR-13-0790","article-title":"CNS metastases in breast cancer: old challenge, new frontiers","volume":"19","author":"Lin","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"2021111619111605000_B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10014-015-0235-3","article-title":"Brain metastasis: clinical characteristics, pathological findings and molecular subtyping for therapeutic implications","volume":"33","author":"Takei","year":"2016","journal-title":"Brain Tumor Pathol."},{"key":"2021111619111605000_B5","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1200\/JCO.2011.38.0527","article-title":"Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases","volume":"30","author":"Sperduto","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"2021111619111605000_B6","first-page":"4655","article-title":"Recent trends in epidemiology of brain metastases: an overview","volume":"32","author":"Tabouret","year":"2012","journal-title":"Anticancer Res."},{"key":"2021111619111605000_B7","doi-asserted-by":"publisher","first-page":"S192","DOI":"10.4103\/2152-7806.111296","article-title":"Epidemiology and prognosis of brain metastases","volume":"4","author":"Stelzer","year":"2013","journal-title":"Surg. Neurol. Int."},{"key":"2021111619111605000_B8","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s11912-016-0555-4","article-title":"The treatment of melanoma brain metastases","volume":"18","author":"Kibbi","year":"2016","journal-title":"Curr. Oncol. Rep."},{"key":"2021111619111605000_B9","first-page":"e551","article-title":"Brain metastases as presenting feature in \u2018burned out\u2019 testicular germ cell tumor","volume":"8","author":"Johnson","year":"2016","journal-title":"Cureus"},{"key":"2021111619111605000_B10","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1159\/000331190","article-title":"Brain metastasis from renal cell carcinoma","volume":"25","author":"Kim","year":"2012","journal-title":"Prog. Neurol. Surg."},{"key":"2021111619111605000_B11","doi-asserted-by":"publisher","first-page":"9519","DOI":"10.3390\/ijms15069519","article-title":"Molecular biology of brain metastasis","volume":"15","author":"Svokos","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"2021111619111605000_B12","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.2217\/epi.15.77","article-title":"Epigenomic landscape of melanoma progression to brain metastasis: unexplored therapeutic alternatives","volume":"7","author":"Marzese","year":"2015","journal-title":"Epigenomics"},{"key":"2021111619111605000_B13","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/ijc.29347","article-title":"The increasing roles of epigenetics in breast cancer: implications for pathogenicity, biomarkers, prevention and treatment","volume":"137","author":"Basse","year":"2015","journal-title":"Int. J. Cancer"},{"key":"2021111619111605000_B14","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.dnarep.2016.05.013","article-title":"Active DNA demethylation by DNA repair: facts and uncertainties","volume":"44","author":"Schuermann","year":"2016","journal-title":"DNA Repair (Amst.)"},{"key":"2021111619111605000_B15","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1038\/nsmb.2518","article-title":"DNA methylation dynamics in health and disease","volume":"20","author":"Bergman","year":"2013","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021111619111605000_B16","doi-asserted-by":"publisher","first-page":"5629","DOI":"10.18632\/oncotarget.13562","article-title":"Whole genome DNA methylation: beyond genes silencing","volume":"8","author":"Tirado-Magallanes","year":"2017","journal-title":"Oncotarget"},{"key":"2021111619111605000_B17","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1101\/gr.083451.108","article-title":"Finding the fifth base: genome-wide sequencing of cytosine methylation","volume":"19","author":"Lister","year":"2009","journal-title":"Genome Res."},{"key":"2021111619111605000_B18","doi-asserted-by":"publisher","first-page":"18347","DOI":"10.1074\/jbc.R110.205286","article-title":"DNA methylation and demethylation in mammals","volume":"286","author":"Chen","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2021111619111605000_B19","doi-asserted-by":"publisher","first-page":"a019133","DOI":"10.1101\/cshperspect.a019133","article-title":"DNA methylation in mammals","volume":"6","author":"Li","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2021111619111605000_B20","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.tins.2013.05.001","article-title":"Epigenetic layers and players underlying neurodevelopment","volume":"36","author":"LaSalle","year":"2013","journal-title":"Trends Neurosci."},{"key":"2021111619111605000_B21","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.coph.2010.05.003","article-title":"Redox metabolism and malignancy","volume":"10","author":"Grek","year":"2010","journal-title":"Curr. Opin. Pharmacol."},{"key":"2021111619111605000_B22","doi-asserted-by":"publisher","first-page":"168","DOI":"10.4161\/oxim.3.3.12106","article-title":"Oxidative stress and autophagy in cardiac disease, neurological disorders, aging and cancer","volume":"3","author":"Essick","year":"2010","journal-title":"Oxid. Med. Cell. Longev."},{"key":"2021111619111605000_B23","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1038\/nrg2881","article-title":"Stress and the epigenetic landscape: a link to the pathobiology of human diseases?","volume":"11","author":"Johnstone","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"2021111619111605000_B24","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.tox.2011.03.001","article-title":"Advances in metal-induced oxidative stress and human disease","volume":"283","author":"Jomova","year":"2011","journal-title":"Toxicology"},{"key":"2021111619111605000_B25","doi-asserted-by":"publisher","first-page":"1994","DOI":"10.1016\/j.febslet.2010.10.061","article-title":"The DNA methylome","volume":"585","author":"Pelizzola","year":"2011","journal-title":"FEBS Lett."},{"key":"2021111619111605000_B26","doi-asserted-by":"publisher","first-page":"479","DOI":"10.3109\/10715761003667554","article-title":"Reactive oxygen species in cancer","volume":"44","author":"Liou","year":"2010","journal-title":"Free Radic. Res."},{"key":"2021111619111605000_B27","doi-asserted-by":"publisher","first-page":"13","DOI":"10.2174\/1389450116666150113121054","article-title":"ROS-mediated DNA methylation pattern alterations in carcinogenesis","volume":"16","author":"Wu","year":"2015","journal-title":"Curr. Drug Targets"},{"key":"2021111619111605000_B28","doi-asserted-by":"publisher","first-page":"301","DOI":"10.2217\/epi.13.26","article-title":"DNA methylation data analysis and its application to cancer research","volume":"5","author":"Ma","year":"2013","journal-title":"Epigenomics"},{"key":"2021111619111605000_B29","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.forsciint.2015.01.037","article-title":"DNA methylation and application in forensic sciences","volume":"249","author":"Kader","year":"2015","journal-title":"Forensic Sci. Int."},{"key":"2021111619111605000_B30","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1158\/1541-7786.196.2.3","article-title":"A simple epigenetic method for the diagnosis and classification of brain tumors","volume":"2","author":"Zukiel","year":"2004","journal-title":"Mol. Cancer Res."},{"key":"2021111619111605000_B31","doi-asserted-by":"publisher","first-page":"e92599","DOI":"10.1371\/journal.pone.0092599","article-title":"The degree of global DNA hypomethylation in peripheral blood correlates with that in matched tumor tissues in several neoplasia","volume":"9","author":"Barciszewska","year":"2014","journal-title":"PLoS ONE"},{"key":"2021111619111605000_B32","doi-asserted-by":"publisher","first-page":"7450","DOI":"10.1093\/nar\/gku334","article-title":"Hydroxyl-radical-induced oxidation of 5-methylcytosine in isolated and cellular DNA","volume":"42","author":"Madugundu","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2021111619111605000_B33","first-page":"138","article-title":"DNA hypomethylation and human diseases","author":"Wilson","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"2021111619111605000_B34","doi-asserted-by":"publisher","first-page":"D1030","DOI":"10.1093\/nar\/gkr1169","article-title":"DiseaseMeth: a human disease methylation database","volume":"40","author":"Lv","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2021111619111605000_B35","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/978-94-007-4525-4_26","article-title":"DNA methylation and cancer","volume":"61","author":"Gokul","year":"2013","journal-title":"Subcell. Biochem."},{"key":"2021111619111605000_B36","doi-asserted-by":"publisher","first-page":"e98464","DOI":"10.1371\/journal.pone.0098464","article-title":"Allele-specific methylation occurs at genetic variants associated with complex disease","volume":"9","author":"Hutchinson","year":"2014","journal-title":"PLoS ONE"},{"key":"2021111619111605000_B37","doi-asserted-by":"publisher","first-page":"e1007362","DOI":"10.1371\/journal.pgen.1007362","article-title":"Cancer epigenetics: moving forward","volume":"14","author":"Nebbioso","year":"2018","journal-title":"PLoS Genet."},{"key":"2021111619111605000_B38","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyw058","article-title":"Making sense of epigenetics","volume":"19","author":"Schuebel","year":"2016","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"2021111619111605000_B39","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1186\/1471-2407-8-222","article-title":"A high-throughput and sensitive method to measure global DNA methylation: application in lung cancer","volume":"8","author":"Anisowicz","year":"2008","journal-title":"BMC Cancer"},{"key":"2021111619111605000_B40","doi-asserted-by":"publisher","first-page":"2249","DOI":"10.1007\/s00018-009-0015-5","article-title":"DNA hypomethylation in the origin and pathogenesis of human diseases","volume":"66","author":"Pogribny","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"2021111619111605000_B41","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s13148-010-0010-6","article-title":"Cancer: evolutionary, genetic and epigenetic aspects","volume":"1","author":"Lichtenstein","year":"2010","journal-title":"Clin. Epigenetics"},{"key":"2021111619111605000_B42","doi-asserted-by":"publisher","first-page":"545","DOI":"10.3390\/cells2030545","article-title":"DNA methylation and apoptosis resistance in cancer cells","volume":"2","author":"Hervouet","year":"2013","journal-title":"Cells"},{"key":"2021111619111605000_B43","first-page":"S463","article-title":"The pivotal role of pathology in the management of lung cancer","volume":"5","author":"Davidson","year":"2013","journal-title":"J. Thorac. Dis."},{"key":"2021111619111605000_B44","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.trsl.2014.03.001","article-title":"Epigenetics of lung cancer","volume":"165","author":"Langevin","year":"2015","journal-title":"Transl. Res."},{"key":"2021111619111605000_B45","doi-asserted-by":"publisher","first-page":"401","DOI":"10.21037\/tlcr.2016.07.10","article-title":"Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors","volume":"5","author":"Dorantes-Heredia","year":"2016","journal-title":"Transl. Lung Cancer Res."},{"key":"2021111619111605000_B46","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1684\/ejd.2014.2292","article-title":"Clinical implications of distinct metastasizing preferences of different melanoma subtypes","volume":"24","author":"Schoenewolf","year":"2014","journal-title":"Eur. J. Dermatol."},{"key":"2021111619111605000_B47","doi-asserted-by":"publisher","first-page":"i1","DOI":"10.1093\/neuonc\/now197","article-title":"Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma","volume":"19","author":"Chamberlain","year":"2017","journal-title":"Neuro Oncol."},{"key":"2021111619111605000_B48","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.biocel.2016.07.025","article-title":"Brain metastasis in lung cancer: building a molecular and systems-level understanding to improve outcomes","volume":"78","author":"Ebben","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2021111619111605000_B49","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ygyno.2016.04.013","article-title":"Primary brain metastases of endometrial cancer: a report of 18 cases and review of the literature","volume":"142","author":"Uccella","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"2021111619111605000_B50","doi-asserted-by":"publisher","first-page":"S488","DOI":"10.4103\/2152-7806.185784","article-title":"Metastatic brain tumor from urothelial carcinoma of the prostatic urethra","volume":"7","author":"Morita","year":"2016","journal-title":"Surg. Neurol. Int."},{"key":"2021111619111605000_B51","doi-asserted-by":"publisher","first-page":"2419","DOI":"10.1016\/S0022-5347(05)64996-8","article-title":"Brain metastases from bladder carcinoma: presentation, treatment and survival","volume":"167","author":"Mahmoud-Ahmed","year":"2002","journal-title":"J. Urol."},{"key":"2021111619111605000_B52","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.2353\/ajpath.2010.100105","article-title":"Ovarian cancer development and metastasis","volume":"177","author":"Lengyel","year":"2010","journal-title":"Am. J. Pathol."},{"key":"2021111619111605000_B53","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/j.ygyno.2016.09.025","article-title":"Brain metastases in patients with EOC: clinico-pathological and prognostic factors. A multicentric retrospective analysis from the MITO group (MITO 19)","volume":"143","author":"Marchetti","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"2021111619111605000_B54","doi-asserted-by":"publisher","first-page":"32","DOI":"10.2119\/molmed.2015.00207","article-title":"Blood-brain barrier remodeling during brain metastasis formation","volume":"22","author":"Wrobel","year":"2016","journal-title":"Mol. Med."},{"key":"2021111619111605000_B55","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.mcn.2012.10.004","article-title":"Role of the systemic immune system in brain metastasis","volume":"53","author":"Hamilton","year":"2013","journal-title":"Mol. Cell. Neurosci."},{"key":"2021111619111605000_B56","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13058-015-0665-1","article-title":"Breast cancer brain metastases: biology and new clinical perspectives","volume":"18","author":"Witzel","year":"2016","journal-title":"Breast Cancer Res."},{"key":"2021111619111605000_B57","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/bjc.2016.103","article-title":"Metastasis-inducing proteins are widely expressed in human brain metastases and associated with intracranial progression and radiation response","volume":"114","author":"Zakaria","year":"2016","journal-title":"Br. J. Cancer"},{"key":"2021111619111605000_B58","doi-asserted-by":"publisher","first-page":"82","DOI":"10.18632\/oncoscience.11","article-title":"Melanoma brain colonization involves the emergence of a brain-adaptive phenotype","volume":"1","author":"Nygaard","year":"2014","journal-title":"Oncoscience"},{"key":"2021111619111605000_B59","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1038\/sj.onc.1209331","article-title":"Genome-wide profiling of promoter methylation in human","volume":"25","author":"Hatada","year":"2006","journal-title":"Oncogene"},{"key":"2021111619111605000_B60","doi-asserted-by":"publisher","first-page":"384","DOI":"10.2188\/jea.JE20120003","article-title":"DNA methylation in peripheral blood: a potential biomarker for cancer molecular epidemiology","volume":"22","author":"Li","year":"2012","journal-title":"J. Epidemiol."},{"key":"2021111619111605000_B61","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s13148-017-0322-x","article-title":"Epigenome-wide discovery and evaluation of leukocyte DNA methylation markers for the detection of colorectal cancer in a screening setting","volume":"9","author":"Heiss","year":"2017","journal-title":"Clin. Epigenetics"},{"key":"2021111619111605000_B62","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.lfs.2016.02.002","article-title":"Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies","volume":"148","author":"Rani","year":"2016","journal-title":"Life Sci."},{"key":"2021111619111605000_B63","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1186\/1471-2407-14-830","article-title":"The molecular significance of methylated BRCA1 promoter in white blood cells of cancer-free females","volume":"14","author":"Al-Moghrabi","year":"2014","journal-title":"BMC Cancer"},{"key":"2021111619111605000_B64","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.18632\/oncotarget.12883","article-title":"Detection of circulating tumor DNA in patients with advanced non-small cell lung cancer","volume":"8","author":"Yao","year":"2017","journal-title":"Oncotarget"},{"key":"2021111619111605000_B65","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1158\/1078-0432.CCR-16-0825","article-title":"Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high circulating tumor cell counts","volume":"23","author":"Shaw","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"2021111619111605000_B66","first-page":"3573","article-title":"Accelerated age-related CpG island methylation in ulcerative colitis","volume":"61","author":"Issa","year":"2001","journal-title":"Cancer Res."}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20180731\/808946\/bsr-2018-0731-t.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/doi\/10.1042\/BSR20180731\/808946\/bsr-2018-0731-t.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T13:52:27Z","timestamp":1662126747000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/38\/5\/BSR20180731\/87489\/Global-DNA-demethylation-as-an-epigenetic-marker"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,23]]},"references-count":66,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2018,10,31]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20180731","relation":{"is-referenced-by":[{"id-type":"doi","id":"10.1007\/s00401-025-02880-9","asserted-by":"object"}]},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"value":"0144-8463","type":"print"},{"value":"1573-4935","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,23]]},"article-number":"BSR20180731"}}