{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T12:54:10Z","timestamp":1781528050812,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,12]]},"group-title":"Gastroenterology","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive molecular complexity, profound stromal remodeling, and limited responsiveness to systemic therapies. Although gemcitabine-based regimens remain widely utilized, the molecular pathways that influence treatment-associated biological variation are incompletely understood. The TGF\u03b2 and JAK\/STAT signaling networks are recognized regulators of tumor progression, immune modulation, and therapeutic resistance; however, their genomic architecture in clinically stratified PDAC populations remains poorly defined.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We employed a conversational artificial intelligence\u2013driven analytical framework to investigate TGF\u03b2 and JAK\/STAT pathway alterations in a cohort of 184 PDAC patients. Clinical and molecular data were integrated to generate age- and treatment-stratified cohorts, enabling pathway-level and gene-level analyses according to gemcitabine exposure. Findings generated through AI-assisted interrogation were subsequently evaluated using conventional statistical approaches.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>TGF\u03b2 pathway alterations were identified in approximately one-quarter to one-third of tumors across clinical subgroups and demonstrated relatively stable frequencies regardless of age at diagnosis or gemcitabine treatment status. Gene-level analyses revealed that pathway disruption was predominantly driven by recurrent alterations in SMAD4, with additional low-frequency events involving TGFBR1 and TGFBR2. Notably, TGFBR2 mutations were significantly more frequent among late-onset PDAC patients receiving gemcitabine compared with untreated late-onset patients (8.8% vs. 1.4%; p = 0.04), suggesting a potential treatment-associated enrichment. In contrast, JAK\/STAT pathway alterations were rare throughout the cohort, with only isolated mutations observed in pathway components including JAK1, JAK2, JAK3, STAT1, STAT3, and related regulatory genes. No significant differences in JAK\/STAT alteration frequencies were identified according to age or treatment exposure.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>TGF\u03b2 and JAK\/STAT pathways exhibit distinct genomic architectures in PDAC. TGF\u03b2 pathway disruption represents a recurrent feature of disease biology, largely driven by SMAD4 alterations, while TGFBR2 enrichment in gemcitabine-treated late-onset tumors suggests a potential context-specific association worthy of further investigation. Conversely, genomic alterations within the JAK\/STAT pathway are uncommon, indicating that pathway activity may be regulated predominantly through non-genomic mechanisms. These findings demonstrate the utility of conversational artificial intelligence agents for rapid, scalable, and clinically contextualized pathway interrogation and support future studies integrating multi-omic data to refine precision medicine strategies in PDAC.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.10.26355398","type":"posted-content","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T01:10:40Z","timestamp":1781313040000},"source":"Crossref","is-referenced-by-count":0,"title":["Conversational Artificial Intelligence-Enabled Precision Oncology Reveals Context-Specific TGF\u03b2 and JAK\/STAT Alterations in Pancreatic Cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2602-1526","authenticated-orcid":false,"given":"Fernando C.","family":"Diaz","sequence":"first","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7620-1451","authenticated-orcid":false,"given":"Brigette","family":"Waldrup","sequence":"additional","affiliation":[{"name":"City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA"}],"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":"City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0607-1784","authenticated-orcid":false,"given":"Sophia","family":"Manjarrez","sequence":"additional","affiliation":[{"name":"City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA"}],"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":"City of Hope, Beckman Research Institute, Department of Integrative Translational Sciences, Duarte, CA"},{"name":"City of Hope Comprehensive Cancer Center, Duarte, 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