{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:58Z","timestamp":1792787638036,"version":"4.5.0"},"reference-count":0,"publisher":"American Society for Clinical Investigation","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State of South Carolina","award":["Smart State Endowment"],"award-info":[{"award-number":["Smart State Endowment"]}]},{"name":"LeDucq Foundation","award":["LeDucq Foundation"],"award-info":[{"award-number":["LeDucq Foundation"]}],"id":[{"id":"https:\/\/ror.org\/01czwga19","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hollings Cancer Center, MUSC","award":["Biorepository & Tissue Analysis Shared Resource"],"award-info":[{"award-number":["Biorepository & Tissue Analysis Shared Resource"]}],"id":[{"id":"https:\/\/ror.org\/00w52vt71","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Hollings Cancer Center, MUSC","award":["Translational Science Laboratory"],"award-info":[{"award-number":["Translational Science Laboratory"]}],"id":[{"id":"https:\/\/ror.org\/00w52vt71","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Pittsburgh Liver Research Center","award":["Cells-Tissues and Models Core"],"award-info":[{"award-number":["Cells-Tissues and Models Core"]}]},{"name":"NIH","award":["R01CA285370"],"award-info":[{"award-number":["R01CA285370"]}]},{"name":"NIH","award":["R01CA289381"],"award-info":[{"award-number":["R01CA289381"]}]},{"name":"NIH","award":["R33CA267226"],"award-info":[{"award-number":["R33CA267226"]}]},{"name":"NIH","award":["R01CA282022"],"award-info":[{"award-number":["R01CA282022"]}]},{"name":"NIH","award":["R21CA263464"],"award-info":[{"award-number":["R21CA263464"]}]},{"name":"NIH","award":["R21CA286287"],"award-info":[{"award-number":["R21CA286287"]}]},{"name":"NIH","award":["R01CA253460"],"award-info":[{"award-number":["R01CA253460"]}]},{"name":"NIH","award":["R01AG078702"],"award-info":[{"award-number":["R01AG078702"]}]},{"name":"NIH","award":["R01CA251155"],"award-info":[{"award-number":["R01CA251155"]}]},{"name":"NIH","award":["R01CA250227"],"award-info":[{"award-number":["R01CA250227"]}]},{"name":"NIH","award":["U01CA271887"],"award-info":[{"award-number":["U01CA271887"]}]},{"name":"NIH","award":["P50CA295495"],"award-info":[{"award-number":["P50CA295495"]}]},{"name":"NIH","award":["S10OD030212"],"award-info":[{"award-number":["S10OD030212"]}]},{"name":"NIH","award":["P30CA138313"],"award-info":[{"award-number":["P30CA138313"]}]},{"name":"NIH","award":["P20GM130457"],"award-info":[{"award-number":["P20GM130457"]}]},{"name":"NIH","award":["P30DK123704"],"award-info":[{"award-number":["P30DK123704"]}]},{"name":"NIH","award":["P30DK120531"],"award-info":[{"award-number":["P30DK120531"]}]},{"name":"NIH","award":["R24DK139775"],"award-info":[{"award-number":["R24DK139775"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    <jats:bold>BACKGROUND.<\/jats:bold>\n                    Hepatocellular carcinoma (HCC) exhibits molecular heterogeneity that challenges histopathologic classification and biomarker discovery. We assessed whether spatially resolved N-glycan imaging with machine learning could classify tumor regions and infer glutamine synthetase (GS) status.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>METHODS.<\/jats:bold>\n                    In this retrospective study, MALDI mass spectrometry imaging of N-glycans was performed on formalin-fixed, paraffin-embedded sections from two independent cohorts (discovery, n = 88; validation, n = 60) with pathologist annotation. An XGBoost classifier was trained on 90 discriminative N-glycan features using patient-grouped cross-validation. Performance was assessed by AUC for pixel- and biopsy-level discrimination of tumor from adjacent non-tumor tissue, and for GS status classification.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>RESULTS.<\/jats:bold>\n                    Pixel-level AUCs were 0.95 (cross-validation) and 0.89 (external validation); biopsy-level AUCs were 1.0 and 0.97, correctly identifying 97% of tumor-containing biopsies. Probability maps recapitulated pathologist-defined boundaries; UMAP embeddings captured inter- and intratumoral heterogeneity. Discriminative species (\n                    <jats:italic>m\/z<\/jats:italic>\n                    2393.846, 1905.634, 1743.579, 1809.639) reflected complex, fucosylated, branched remodeling. N-glycans bearing six GlcNAc residues were enriched in GS+ (n = 45) versus GS\u2212 (n = 17) tumors (P = 0.001) and discriminated GS status (AUC = 0.75), consistent with\n                    <jats:italic>GLUL<\/jats:italic>\n                    and\n                    <jats:italic>MGAT5<\/jats:italic>\n                    upregulation in TCGA-LIHC.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>CONCLUSION<\/jats:bold>\n                    <jats:bold>.<\/jats:bold>\n                    MALDI N-glycan imaging with machine learning enables spatially resolved, objective classification of HCC and links glycan phenotypes to tumor-associated metabolic programs.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>TRIAL REGISTRATION.<\/jats:bold>\n                    Not applicable; retrospective analysis of archival, de-identified tissue.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>FUNDING.<\/jats:bold>\n                    NIH\/NCI R01CA285370, 1R01CA289381, R33CA267226, R01CA282022, R21CA263464, R21CA286287, R01CA253460, S10OD030212, R01CA251155, R01CA250227, U01CA271887, P50CA295495, P30CA138313, P20GM130457, P30DK123704, P30DK120531,R24DK139775; NIH\/NIA R01AG078702; Smart State Endowment, State of South Carolina; LeDucq Foundation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.209628","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:01:05Z","timestamp":1790697665000},"source":"Crossref","is-referenced-by-count":0,"title":["Spatial N-Glycan Imaging and Machine Learning Classify Hepatocellular Carcinoma and Predict Glutamine Synthetase Status"],"prefix":"10.1172","author":[{"given":"Muhammed F.","family":"Bayram","sequence":"first","affiliation":[{"name":"Medical University of South Carolina, Charleston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jade K.","family":"Macdonald","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina, Charleston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"DelaCourt","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina, Charleston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggi M.","family":"Angel","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina, Charleston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R.","family":"Drake","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina, Charleston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-7096","authenticated-orcid":true,"given":"Aatur","family":"Singhi","sequence":"additional","affiliation":[{"name":"Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Geller","sequence":"additional","affiliation":[{"name":"Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satdarshan P.","family":"Monga","sequence":"additional","affiliation":[{"name":"Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Singal","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Mehta","sequence":"additional","affiliation":[{"name":"Medical University of South Carolina, Charleston, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,9,29]]},"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/insight.jci.org\/articles\/view\/209628\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:01:07Z","timestamp":1790697667000},"score":1,"resource":{"primary":{"URL":"http:\/\/insight.jci.org\/articles\/view\/209628"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":0,"alternative-id":["10.1172\/jci.insight.209628"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.209628","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}