{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T01:45:02Z","timestamp":1792287902919,"version":"4.4.0"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,8,19]],"date-time":"2020-08-19T00:00:00Z","timestamp":1597795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2017YFA0700403"],"award-info":[{"award-number":["2017YFA0700403"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31822030"],"award-info":[{"award-number":["31822030"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31801113"],"award-info":[{"award-number":["31801113"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31771458"],"award-info":[{"award-number":["31771458"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2019M652623"],"award-info":[{"award-number":["2019M652623"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2018M632830"],"award-info":[{"award-number":["2018M632830"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2019T120664"],"award-info":[{"award-number":["2019T120664"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Immune checkpoint genes (ICGs) play critical roles in circumventing self-reactivity and represent a novel target to develop treatments for cancers. However, a comprehensive analysis for the expression profile of ICGs at a pan-cancer level and their correlation with patient response to immune checkpoint blockade (ICB) based therapy is still lacking. In this study, we defined three expression patterns of ICGs using a comprehensive survey of RNA-seq data of tumor and immune cells from the functional annotation of the mammalian genome (FANTOM5) project. The correlation between the expression patterns of ICGs and patients survival and response to ICB therapy was investigated. The expression patterns of ICGs were robust across cancers, and upregulation of ICGs was positively correlated with high lymphocyte infiltration and good prognosis. Furthermore, we built a model (ICGe) to predict the response of patients to ICB therapy using five features of ICG expression. A validation scenario of six independent datasets containing data of 261 patients with CTLA-4 and PD-1 blockade immunotherapies demonstrated that ICGe achieved area under the curves of 0.64\u20130.82 and showed a robust performance and outperformed other mRNA-based predictors. In conclusion, this work revealed expression patterns of ICGs and underlying correlations between ICGs and response to ICB, which helps to understand the mechanisms of ICGs in ICB signal pathways and other anticancer treatments.<\/jats:p>","DOI":"10.1093\/bib\/bbaa176","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T11:14:14Z","timestamp":1594811654000},"source":"Crossref","is-referenced-by-count":325,"title":["Expression profile of immune checkpoint genes and their roles in predicting immunotherapy response"],"prefix":"10.1093","volume":"22","author":[{"given":"Fei-Fei","family":"Hu","sequence":"first","affiliation":[{"name":"Wuhan University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3008-3375","authenticated-orcid":false,"given":"Chun-Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan-Lan","family":"Liu","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5099-7465","authenticated-orcid":false,"given":"An-Yuan","family":"Guo","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,8,19]]},"reference":[{"key":"2021052110393554600_ref1","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"2021052110393554600_ref2","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1158\/1078-0432.CCR-14-1860","article-title":"Immune escape mechanisms as a guide for cancer immunotherapy","volume":"21","author":"Beatty","year":"2015","journal-title":"Clin Cancer Res"},{"key":"2021052110393554600_ref3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13045-018-0582-8","article-title":"Next generation of immune checkpoint therapy in cancer: new developments and challenges","volume":"11","author":"Marin-Acevedo","year":"2018","journal-title":"J Hematol Oncol"},{"key":"2021052110393554600_ref4","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/j.1600-065X.2010.00923.x","article-title":"The PD-1 pathway in tolerance and autoimmunity","volume":"236","author":"Francisco","year":"2010","journal-title":"Immunol Rev"},{"key":"2021052110393554600_ref5","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.autrev.2013.07.002","article-title":"CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance","volume":"12","author":"Romo-Tena","year":"2013","journal-title":"Autoimmun Rev"},{"key":"2021052110393554600_ref6","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with Ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N Engl J Med"},{"key":"2021052110393554600_ref7","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","article-title":"Safety, activity, and immune correlates of anti-PD-1 antibody in cancer","volume":"366","author":"Topalian","year":"2012","journal-title":"N Engl J Med"},{"key":"2021052110393554600_ref8","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1200694","article-title":"Safety and activity of anti-PD-L1 antibody in patients with advanced cancer","volume":"366","author":"Brahmer","year":"2012","journal-title":"N Engl J Med"},{"key":"2021052110393554600_ref9","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1104621","article-title":"Ipilimumab plus Dacarbazine for previously untreated metastatic melanoma","volume":"364","author":"Robert","year":"2011","journal-title":"N Engl J Med"},{"key":"2021052110393554600_ref10","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s12943-019-1091-2","article-title":"Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4","volume":"18","author":"Qin","year":"2019","journal-title":"Mol Cancer"},{"key":"2021052110393554600_ref11","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/imr.12519","article-title":"LAG3 (CD223) as a cancer immunotherapy target","volume":"276","author":"Andrews","year":"2017","journal-title":"Immunol Rev"},{"key":"2021052110393554600_ref12","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/415536a","article-title":"Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease","volume":"415","author":"Monney","year":"2002","journal-title":"Nature"},{"key":"2021052110393554600_ref13","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/ni.1674","article-title":"The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells","volume":"10","author":"Yu","year":"2009","journal-title":"Nat Immunol"},{"key":"2021052110393554600_ref14","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, adaptive and acquired resistance to cancer immunotherapy","volume":"168","author":"Sharma","year":"2017","journal-title":"Cell"},{"key":"2021052110393554600_ref15","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41568-019-0116-x","article-title":"The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy","volume":"19","author":"Havel","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"2021052110393554600_ref16","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1056\/NEJMc1713444","article-title":"Tumor mutational burden and response rate to PD-1 inhibition","volume":"377","author":"Yarchoan","year":"2017","journal-title":"N Engl J Med"},{"key":"2021052110393554600_ref17","doi-asserted-by":"crossref","first-page":"eaaf8399","DOI":"10.1126\/science.aaf8399","article-title":"Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy","volume":"355","author":"Davoli","year":"2017","journal-title":"Science"},{"key":"2021052110393554600_ref18","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1172\/JCI91190","article-title":"IFN-\u03b3\u2013related mRNA profile predicts clinical response to PD-1 blockade","volume":"127","author":"Ayers","year":"2019","journal-title":"J Clin Invest"},{"key":"2021052110393554600_ref19","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1038\/s41591-018-0157-9","article-title":"Robust prediction of response to immune checkpoint blockade therapy in metastatic melanoma","volume":"24","author":"Auslander","year":"2018","journal-title":"Nat Med"},{"key":"2021052110393554600_ref20","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41591-018-0136-1","article-title":"Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response","volume":"24","author":"Jiang","year":"2018","journal-title":"Nat Med"},{"key":"2021052110393554600_ref21","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41586-018-0392-8","article-title":"Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response","volume":"560","author":"Chen","year":"2018","journal-title":"Nature"},{"key":"2021052110393554600_ref22","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.cell.2014.12.033","article-title":"Molecular and genetic properties of tumors associated with local immune cytolytic activity","volume":"160","author":"Rooney","year":"2015","journal-title":"Cell"},{"key":"2021052110393554600_ref23","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The Cancer Genome Atlas Pan-Cancer analysis project","volume":"45","author":"Chang","year":"2013","journal-title":"Nat Genet"},{"key":"2021052110393554600_ref24","doi-asserted-by":"crossref","first-page":"D737","DOI":"10.1093\/nar\/gkw995","article-title":"Update of the FANTOM web resource: high resolution transcriptome of diverse cell types in mammals","volume":"45","author":"Lizio","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2021052110393554600_ref25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/j.1365-2567.2010.03398.x","article-title":"Structure\/function of human killer cell immunoglobulin-like receptors: lessons from polymorphisms, evolution, crystal structures and mutations","volume":"132","author":"Campbell","year":"2011","journal-title":"Immunology"},{"key":"2021052110393554600_ref26","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00251-012-0619-z","article-title":"The butyrophilin (BTN) gene family: from milk fat to the regulation of the immune response","volume":"64","author":"Afrache","year":"2012","journal-title":"Immunogenetics"},{"key":"2021052110393554600_ref27","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res"},{"key":"2021052110393554600_ref28","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-1028-7","article-title":"Comprehensive analyses of tumor immunity: implications for cancer immunotherapy","volume":"17","author":"Li","year":"2016","journal-title":"Genome Biol"},{"key":"2021052110393554600_ref29","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1038\/s41591-018-0101-z","article-title":"Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer","volume":"24","author":"Kim","year":"2018","journal-title":"Nat Med"},{"key":"2021052110393554600_ref30","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.cell.2017.09.028","article-title":"Tumor and microenvironment evolution during immunotherapy with Nivolumab","volume":"171","author":"Riaz","year":"2017","journal-title":"Cell"},{"key":"2021052110393554600_ref31","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.cell.2017.01.010","article-title":"Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma","volume":"168","author":"Hugo","year":"2017","journal-title":"Cell"},{"key":"2021052110393554600_ref32","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1126\/science.aad0095","article-title":"Genomic correlates of response to CTLA-4 blockade in metastatic melanoma","volume":"350","author":"Van Allen","year":"2015","journal-title":"Science"},{"key":"2021052110393554600_ref33","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1093\/bioinformatics\/btx330","article-title":"Flexbar 3.0\u2014SIMD and multicore parallelization","volume":"33","author":"Roehr","year":"2017","journal-title":"Bioinformatics"},{"key":"2021052110393554600_ref34","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1038\/nprot.2016.095","article-title":"Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown","volume":"11","author":"Pertea","year":"2016","journal-title":"Nat Protoc"},{"key":"2021052110393554600_ref35","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An integrated TCGA Pan-cancer clinical data resource to drive high-quality survival outcome analytics","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"2021052110393554600_ref36","doi-asserted-by":"crossref","first-page":"170107","DOI":"10.1038\/sdata.2017.107","article-title":"FANTOM5 CAGE profiles of human and mouse reprocessed for GRCh38 and GRCm38 genome assemblies","volume":"4","author":"Abugessaisa","year":"2017","journal-title":"Sci Data"},{"key":"2021052110393554600_ref37","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nature14011","article-title":"Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients","volume":"515","author":"Herbst","year":"2014","journal-title":"Nature"},{"key":"2021052110393554600_ref38","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1126\/science.aad0501","article-title":"Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq","volume":"352","author":"Tirosh","year":"2016","journal-title":"Science"},{"key":"2021052110393554600_ref39","doi-asserted-by":"crossref","first-page":"15081","DOI":"10.1038\/ncomms15081","article-title":"Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer","volume":"8","author":"Chung","year":"2017","journal-title":"Nat Commun"},{"key":"2021052110393554600_ref40","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1200\/JCO.2014.59.0703","article-title":"Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial","volume":"33","author":"Motzer","year":"2015","journal-title":"J Clin Oncol"},{"key":"2021052110393554600_ref41","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fimmu.2018.00070","article-title":"Tissue-dependent tumor microenvironments and their impact on immunotherapy responses","volume":"9","author":"Oliver","year":"2018","journal-title":"Front Immunol"},{"key":"2021052110393554600_ref42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.36967","article-title":"Topography of cancer-associated immune cells in human solid tumors","volume":"7","author":"Kather","year":"2018","journal-title":"Elife"},{"key":"2021052110393554600_ref43","doi-asserted-by":"crossref","first-page":"e542","DOI":"10.1016\/S1470-2045(16)30406-5","article-title":"Predictive biomarkers for checkpoint inhibitor-based immunotherapy","volume":"17","author":"Gibney","year":"2016","journal-title":"Lancet Oncol"},{"key":"2021052110393554600_ref44","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"2021052110393554600_ref45","first-page":"e1338239","article-title":"EP4 antagonism by E7046 diminishes myeloid immunosuppression and synergizes with Treg-reducing IL-2-diphtheria toxin fusion protein in restoring anti-tumor immunity","volume":"6","author":"Albu","year":"2017","journal-title":"Onco Targets Ther"},{"key":"2021052110393554600_ref46","first-page":"1432","article-title":"Breakthrough of the year 2013","volume":"342","author":"Couzin-Frankel","year":"2013","journal-title":"Cancer Immunother Sci"},{"key":"2021052110393554600_ref47","doi-asserted-by":"crossref","first-page":"13819","DOI":"10.1021\/acsami.7b02258","article-title":"Immunomodulatory magnetic microspheres for augmenting tumor-specific infiltration of natural killer (NK) cells","volume":"9","author":"Park","year":"2017","journal-title":"ACS Appl Mater Interfaces"},{"key":"2021052110393554600_ref48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1126\/science.aaa8172","article-title":"The future of immune checkpoint therapy","volume":"348","author":"Sharma","year":"2015","journal-title":"Science"},{"issue":"Suppl 1","key":"2021052110393554600_ref49","doi-asserted-by":"crossref","first-page":"S279","DOI":"10.1093\/bioinformatics\/17.suppl_1.S279","article-title":"Separation of samples into their constituents using gene expression data","volume":"17","author":"Venet","year":"2001","journal-title":"Bioinformatics"},{"key":"2021052110393554600_ref50","doi-asserted-by":"crossref","first-page":"1902880","DOI":"10.1002\/advs.201902880","article-title":"ImmuCellAI: a unique method for comprehensive T-cell subsets abundance prediction and its application in cancer immunotherapy","volume":"7","author":"Miao","year":"2020","journal-title":"Adv Sci (Weinh)"},{"key":"2021052110393554600_ref51","doi-asserted-by":"crossref","first-page":"e1094","DOI":"10.1002\/cti2.1094","article-title":"Tissue-specific tumor microenvironments influence responses to immunotherapies","volume":"8","author":"Oliver","year":"2019","journal-title":"Clin Transl Immunol"},{"key":"2021052110393554600_ref52","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1158\/2159-8290.CD-17-1320","article-title":"Tissue-specific Immunoregulation: a call for better understanding of the \u2018Immunostat\u2019 in the context of cancer","volume":"8","author":"Pao","year":"2018","journal-title":"Cancer Discov"},{"key":"2021052110393554600_ref53","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.1093\/bioinformatics\/bty411","article-title":"GSCALite: a web server for gene set cancer analysis","volume":"34","author":"Liu","year":"2018","journal-title":"Bioinformatics"},{"key":"2021052110393554600_ref54","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.ccell.2017.04.013","article-title":"A pan-cancer proteogenomic atlas of PI3K\/AKT\/mTOR pathway alterations","volume":"31","author":"Zhang","year":"2017","journal-title":"Cancer Cell"},{"key":"2021052110393554600_ref55","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.celrep.2018.03.047","article-title":"Integrated genomic analysis of the ubiquitin pathway across cancer types","volume":"23","author":"Ge","year":"2018","journal-title":"Cell Rep"},{"key":"2021052110393554600_ref56","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.cels.2018.01.013","article-title":"The genomic landscape and pharmacogenomic interactions of clock genes in cancer chronotherapy","volume":"6","author":"Ye","year":"2018","journal-title":"Cell Syst"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/3\/bbaa176\/37966295\/bbaa176.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/3\/bbaa176\/37966295\/bbaa176.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T10:40:30Z","timestamp":1621593630000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaa176\/5894466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,19]]},"references-count":56,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,5,20]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaa176","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,5]]},"published":{"date-parts":[[2020,8,19]]},"article-number":"bbaa176"}}