{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T09:24:19Z","timestamp":1784366659789,"version":"3.55.0"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Primary sclerosing cholangitis (PSC) is a rare, progressive disease, characterized by inflammation and fibrosis of the bile ducts, lacking reliable prognostic biomarkers for disease activity. Machine learning applied to broad proteomic profiling of sera allowed for the discovery of markers of disease presence, severity, and cirrhosis and the exploration of the involvement of CCL24, a chemokine with fibro-inflammatory activity. Sera from 30 healthy controls and 45 PSC patients were profiled with proximity extension assay, quantifying the expression of 2870 proteins, and used to train an elastic net model. Proteins that contributed most to the model were tested for correlation to enhanced liver fibrosis (ELF) score and used to perform pathway analysis. Statistical modeling for the presence of cirrhosis was performed with principal component analysis (PCA), and receiver operating characteristics (ROC) curves were used to assess the useability of potential biomarkers. The model successfully predicted the presence of PSC, where the top-ranked proteins were associated with cell adhesion, immune response, and inflammation, and each had an area under receiver operator characteristic (AUROC) curve greater than 0.9 for disease presence and greater than 0.8 for ELF score. Pathway analysis showed enrichment for functions associated with PSC, overlapping with pathways enriched in patients with high levels of CCL24. Patients with cirrhosis showed higher levels of CCL24. This data-driven approach to characterize PSC and its severity highlights potential serum protein biomarkers and the importance of CCL24 in the disease, implying its therapeutic potential in PSC.<\/jats:p>","DOI":"10.3390\/ijms25116042","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T03:46:49Z","timestamp":1717127209000},"page":"6042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Machine Learning Identifies Key Proteins in Primary Sclerosing Cholangitis Progression and Links High CCL24 to Cirrhosis"],"prefix":"10.3390","volume":"25","author":[{"given":"Tom","family":"Snir","sequence":"first","affiliation":[{"name":"Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9634-4638","authenticated-orcid":false,"given":"Raanan","family":"Greenman","sequence":"additional","affiliation":[{"name":"Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Revital","family":"Aricha","sequence":"additional","affiliation":[{"name":"Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Frankel","sequence":"additional","affiliation":[{"name":"Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Lawler","sequence":"additional","affiliation":[{"name":"Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7635-9931","authenticated-orcid":false,"given":"Francesca","family":"Saffioti","sequence":"additional","affiliation":[{"name":"UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK"},{"name":"Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"},{"name":"Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Pinzani","sequence":"additional","affiliation":[{"name":"UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK"},{"name":"Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Thorburn","sequence":"additional","affiliation":[{"name":"UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK"},{"name":"Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Mor","sequence":"additional","affiliation":[{"name":"Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilan","family":"Vaknin","sequence":"additional","affiliation":[{"name":"Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.bpg.2011.10.009","article-title":"Pathogenesis of Primary Sclerosing Cholangitis","volume":"25","author":"Pollheimer","year":"2011","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1097\/MOG.0000000000000352","article-title":"Emerging Pharmacologic Therapies for Primary Sclerosing Cholangitis","volume":"33","author":"Cheung","year":"2017","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1111\/apt.16296","article-title":"Systematic Review: Non-Invasive Prognostic Tests for Primary Sclerosing Cholangitis","volume":"53","author":"Mazhar","year":"2021","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1111\/j.1365-2559.2011.03853.x","article-title":"Inflammatory Disease of the Bile Ducts\u2013Cholangiopathies: Liver Biopsy Challenge and Clinicopathological Correlation","volume":"60","author":"Portmann","year":"2012","journal-title":"Histopathology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1016\/j.bbadis.2017.08.002","article-title":"The Search for Novel Diagnostic and Prognostic Biomarkers in Cholangiocarcinoma","volume":"1864","author":"Macias","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"615978","DOI":"10.3389\/fmed.2021.615978","article-title":"Liver Fibrosis in Non-Alcoholic Fatty Liver Disease: From Liver Biopsy to Non-Invasive Biomarkers in Diagnosis and Treatment","volume":"8","author":"Heyens","year":"2021","journal-title":"Front. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100168","DOI":"10.1016\/j.mcpro.2021.100168","article-title":"Proximity Extension Assay in Combination with Next-Generation Sequencing for High-Throughput Proteome-Wide Analysis","volume":"20","author":"Wik","year":"2021","journal-title":"Mol. Cell Proteom."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Beltrami, A.P., De Martino, M., Dalla, E., Malfatti, M.C., Caponnetto, F., Codrich, M., Stefanizzi, D., Fabris, M., Sozio, E., and D\u2019Aurizio, F. (2022). Combining Deep Phenotyping of Serum Proteomics and Clinical Data via Machine Learning for COVID-19 Biomarker Discovery. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169161"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1027122","DOI":"10.3389\/fimmu.2022.1027122","article-title":"Targeted Proteomics Identifies Circulating Biomarkers Associated with Active COVID-19 and Post-COVID-19","volume":"13","author":"Zoodsma","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.ebiom.2019.05.044","article-title":"A Targeted Proteomics Approach Reveals a Serum Protein Signature as Diagnostic Biomarker for Resectable Gastric Cancer","volume":"44","author":"Shen","year":"2019","journal-title":"eBioMedicine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"162270","DOI":"10.1172\/jci.insight.162270","article-title":"CCL24 Regulates Biliary Inflammation and Fibrosis in Primary Sclerosing Cholangitis","volume":"8","author":"Greenman","year":"2023","journal-title":"JCI Insight"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Greenman, R., Snir, T., Katav, A., Aricha, R., Mishalian, I., Hay, O., Frankel, M., Lawler, J., Saffioti, F., and Pinzani, M. (2024). The Role of CCL24 in Primary Sclerosing Cholangitis: Bridging Patient Serum Proteomics to Preclinical Data. Cells, 13.","DOI":"10.3390\/cells13030209"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0016","DOI":"10.5041\/RMMJ.10504","article-title":"The Role of CCL24 in Systemic Sclerosis","volume":"14","author":"Levy","year":"2023","journal-title":"Rambam Maimonides Med. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1053\/j.gastro.2004.08.052","article-title":"Serum Markers Detect the Presence of Liver Fibrosis: A Cohort Study","volume":"127","author":"Rosenberg","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/hep.30237","article-title":"Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results with Insights on the Natural History of the Disease","volume":"69","author":"Muir","year":"2019","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/hep4.1797","article-title":"Transcriptomic Cross-Species Analysis of Chronic Liver Disease Reveals Consistent Regulation between Humans and Mice","volume":"6","author":"Holland","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e17216","DOI":"10.1097\/MD.0000000000017216","article-title":"Expression and Clinical Significance of Latent-Transforming Growth Factor Beta-Binding Protein 2 in Primary Hepatocellular Carcinoma","volume":"98","author":"Chen","year":"2019","journal-title":"Medicine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.matbio.2015.05.005","article-title":"Latent TGF-\u03b2-Binding Proteins","volume":"47","author":"Robertson","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5241","DOI":"10.1021\/acs.jproteome.1c00657","article-title":"Advances and Utility of the Human Plasma Proteome","volume":"20","author":"Deutsch","year":"2021","journal-title":"J. Proteome Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100574","DOI":"10.1016\/j.mcpro.2023.100574","article-title":"In-Depth Serum Proteomics Reveals the Trajectory of Hallmarks of Cancer in Hepatitis B Virus\u2013Related Liver Diseases","volume":"22","author":"Xu","year":"2023","journal-title":"Mol. Cell. Proteom."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bakhshi, H., Michelhaugh, S.A., Bruce, S.A., Seliger, S.L., Qian, X., Ambale Venkatesh, B., Varadarajan, V., Bagchi, P., Lima, J.A.C., and deFilippi, C. (2023). Association between Proteomic Biomarkers and Myocardial Fibrosis Measured by MRI: The Multi-Ethnic Study of Atherosclerosis. eBioMedicine, 90.","DOI":"10.1016\/j.ebiom.2023.104490"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"H\u00e9dou, J., Mari\u0107, I., Bellan, G., Einhaus, J., Gaudilli\u00e8re, D.K., Ladant, F.-X., Verdonk, F., Stelzer, I.A., Feyaerts, D., and Tsai, A.S. (Nat. Biotechnol., 2024). Discovery of Sparse, Reliable Omic Biomarkers with Stabl, Nat. Biotechnol., online ahead of print.","DOI":"10.1038\/s41587-023-02033-x"},{"key":"ref_23","unstructured":"R Core Team (2023). R: A Language and Environment for Statistical Computing 2023, R Foundation for Statistical Computing."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/hep.27825","article-title":"Enhanced Liver Fibrosis Score Predicts Transplant-Free Survival in Primary Sclerosing Cholangitis","volume":"62","author":"Vesterhus","year":"2015","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.21105\/joss.01686","article-title":"Welcome to the Tidyverse","volume":"4","author":"Wickham","year":"2019","journal-title":"J. Open Source Softw."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization Paths for Generalized Linear Models via Coordinate Descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v028.i05","article-title":"Building Predictive Models in R Using the Caret Package","volume":"28","author":"Kuhn","year":"2008","journal-title":"J. Stat. Softw."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Robin, X., Turck, N., Hainard, A., Tiberti, N., Lisacek, F., Sanchez, J.-C., and M\u00fcller, M. (2011). pROC: An Open-Source Package for R and S+ to Analyze and Compare ROC Curves. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-77"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING Database in 2023: Protein\u2013Protein Association Networks and Functional Enrichment Analyses for Any Sequenced Genome of Interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6042\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:51:24Z","timestamp":1760107884000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/6042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,30]]},"references-count":29,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25116042"],"URL":"https:\/\/doi.org\/10.3390\/ijms25116042","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,30]]}}}