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Hence, the purpose of this salivary biomarker discovery study is to set the fundamentals for the realization of POC diagnostics for HFMD. Whole salivary proteome profiling was performed on the saliva obtained from children with HFMD and healthy children, using a reductive dimethylation chemical labeling method coupled with high\u2010resolution mass spectrometry\u2010based quantitative proteomics technology. We identified 19 upregulated (fold change\u2009=\u20091.5\u20135.8) and 51 downregulated proteins (fold change\u2009=\u20090.1\u20130.6) in the saliva samples of HFMD patients in comparison to that of healthy volunteers. Four upregulated protein candidates were selected for dot blot\u2010based validation assay, based on novelty as biomarkers and exclusions in oral diseases and cancers. Salivary legumain was validated in the Singapore (<jats:italic>n<\/jats:italic>\u2009=\u200943 healthy, 28 HFMD cases) and Taiwan (<jats:italic>n<\/jats:italic>\u2009=\u200960 healthy, 47 HFMD cases) cohorts with an area under the receiver operating characteristic curve of 0.7583 and 0.8028, respectively. This study demonstrates the feasibility of a broad\u2010spectrum HFMD POC diagnostic test based on legumain, a virus\u2010specific host systemic signature, in saliva.<\/jats:p>","DOI":"10.1002\/jmv.29243","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T22:38:18Z","timestamp":1701124698000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Potential relevance of salivary legumain for the clinical diagnostic of hand, foot, and mouth disease"],"prefix":"10.1002","volume":"95","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8034-2291","authenticated-orcid":false,"given":"Yong Wah","family":"Tan","sequence":"first","affiliation":[{"name":"Collaborative and Translation Unit for Hand, Foot and Mouth Disease (HFMD) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona Mei Shan","family":"Teo","sequence":"additional","affiliation":[{"name":"Collaborative and Translation Unit for Hand, Foot and Mouth Disease (HFMD) Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siok Ghee","family":"Ler","sequence":"additional","affiliation":[{"name":"Translational Biomedical Proteomics Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7477-0495","authenticated-orcid":false,"given":"Asfa","family":"Alli\u2010Shaik","sequence":"additional","affiliation":[{"name":"Translational Biomedical Proteomics Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR) Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5936-6969","authenticated-orcid":false,"given":"Min","family":"Nyo","sequence":"additional","affiliation":[{"name":"Infectious Disease Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine National University of Singapore  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3919-3324","authenticated-orcid":false,"given":"Chia Yin","family":"Chong","sequence":"additional","affiliation":[{"name":"Infectious Disease Service, Department of Paediatrics KK Women's and Children's Hospital  Singapore Singapore"},{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine National University of Singapore"},{"name":"Duke\u2010NUS Medical School Singapore Singapore"},{"name":"Lee Kong Chian School of Medicine Nanyang Technological University  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7380-5008","authenticated-orcid":false,"given":"Natalie Woon Hui","family":"Tan","sequence":"additional","affiliation":[{"name":"Infectious Disease Service, Department of Paediatrics KK Women's and Children's Hospital  Singapore Singapore"},{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine National University of Singapore"},{"name":"Duke\u2010NUS Medical School Singapore Singapore"},{"name":"Lee Kong Chian School of Medicine Nanyang Technological University  Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1322-3890","authenticated-orcid":false,"given":"Robert Y. 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