{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:45:36Z","timestamp":1781570736178,"version":"3.54.5"},"reference-count":34,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100017804","name":"Wall Fund for Pancreatic Cancer Research at City of Hope","doi-asserted-by":"publisher","award":["50393"],"award-info":[{"award-number":["50393"]}],"id":[{"id":"10.13039\/100017804","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Cancer Institute","award":["U2C CA252971"],"award-info":[{"award-number":["U2C CA252971"]}]},{"name":"NIH\/NCI","award":["P30 CA033572"],"award-info":[{"award-number":["P30 CA033572"]}]},{"name":"NIH\/NCI","award":["U54 CA285116"],"award-info":[{"award-number":["U54 CA285116"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite its marked molecular heterogeneity and variable response to gemcitabine-based therapies, pancreatic ductal adenocarcinoma (PDAC) remains poorly understood at the pathway level, particularly across age and treatment contexts. We applied a conversational artificial intelligence framework (AI-HOPE-TP53 and AI-HOPE-PI3K) to analyze clinical and genomic data from 184 PDAC tumors stratified by age and gemcitabine exposure. Pathway-centric analyses were performed and validated using conventional statistical methods. TP53 alterations were more frequent in early-onset compared to late-onset PDAC among gemcitabine-treated patients and showed a similar trend in early-onset untreated cases. In late-onset PDAC without gemcitabine exposure, absence of TP53 alterations was associated with improved overall survival. PI3K alterations were enriched in late-onset gemcitabine-treated tumors. Notably, late-onset patients without PI3K alterations who were not treated with gemcitabine demonstrated significantly improved survival. TP53 and PI3K pathway dependencies in PDAC are context-specific, varying by age and treatment exposure. These findings highlight the value of conversational AI for integrative precision oncology analyses and molecular stratification.<\/jats:p>","DOI":"10.3390\/ijms27114981","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:45:08Z","timestamp":1780404308000},"page":"4981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Age- and Treatment-Specific TP53 and PI3K Alterations in Pancreatic Ductal Adenocarcinoma (PDAC) Revealed by Conversational Artificial Intelligence"],"prefix":"10.3390","volume":"27","author":[{"given":"Fernando C.","family":"Diaz","sequence":"first","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5991-9779","authenticated-orcid":false,"given":"Brigette","family":"Waldrup","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-4197","authenticated-orcid":false,"given":"Francisco G.","family":"Carranza","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Manjarrez","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3603-6414","authenticated-orcid":false,"given":"Enrique","family":"Velazquez-Villarreal","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Duarte, CA 91010, USA"},{"name":"City of Hope, Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.2147\/DDDT.S60328","article-title":"Pancreatic cancer: Optimizing treatment options, new, and emerging targeted therapies","volume":"9","author":"Chiorean","year":"2015","journal-title":"Drug Des. 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