{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:42:16Z","timestamp":1790167336770,"version":"4.1.0"},"reference-count":54,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"837","funder":[{"DOI":"10.13039\/100008903","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["MOHW114-TDU-B-221-144005"],"award-info":[{"award-number":["MOHW114-TDU-B-221-144005"]}],"id":[{"id":"10.13039\/100008903","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008903","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["MOHW114-TDU-B-221-144005"],"award-info":[{"award-number":["MOHW114-TDU-B-221-144005"]}],"id":[{"id":"10.13039\/100008903","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Higher Education Sprout Project by the Ministry of Education, Taipei, Taiwan."},{"name":"The Higher Education Sprout Project by the Ministry of Education, Taipei, Taiwan."},{"name":"National Science and Technology Council","award":["NSTC 114-2640-B-006-004"],"award-info":[{"award-number":["NSTC 114-2640-B-006-004"]}]},{"name":"National Science and Technology Council","award":["NSTC 114-2640-B-006-004"],"award-info":[{"award-number":["NSTC 114-2640-B-006-004"]}]},{"name":"the Miin-Wu School of Computing at National Cheng Kung University","award":["FD109037-11402"],"award-info":[{"award-number":["FD109037-11402"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,2,18]]},"abstract":"<jats:p>\n                    Chemotherapy-induced peripheral neuropathy (CIPN) remains a major unmet challenge in oncology, affecting treatment adherence and patient quality of life. Despite its prevalence, reliable predictive biomarkers and targeted neuroprotective strategies remain elusive. This study integrates clinical data, whole-genome sequencing, and translational research to identify genetic determinants of CIPN susceptibility and validate therapeutic approaches. Through comprehensive analysis of patients with colorectal cancer, including neurophysiological evaluations and CIPN-specific quality-of-life assessments, we identified the\n                    <jats:italic toggle=\"yes\">BDNF<\/jats:italic>\n                    c.196G&gt;A polymorphism (Val\n                    <jats:sup>66<\/jats:sup>\n                    Met) as a critical factor in CIPN development. Using humanized transgenic mouse models, we demonstrated that the Met\n                    <jats:sup>66<\/jats:sup>\n                    allele of the functional Val\n                    <jats:sup>66<\/jats:sup>\n                    Met polymorphism in\n                    <jats:italic toggle=\"yes\">BDNF<\/jats:italic>\n                    confers protection against oxaliplatin-induced sensory deficits, whereas the Val\n                    <jats:sup>66<\/jats:sup>\n                    allele increases susceptibility to neuropathy. Mechanistic studies revealed that this protection operates through modulation of p75NTR-mediated signaling pathways and neuroinflammatory responses. On the basis of these findings, we evaluated two therapeutic strategies: the p75NTR modulator LM11A-31 and a compound we have developed, CN016. Both agents exhibited notable efficacy in alleviating oxaliplatin-induced neuropathy, particularly in genetically susceptible\n                    <jats:italic toggle=\"yes\">BDNF<\/jats:italic>\n                    Val\/Val carriers. LM11A-31 normalized neurotrophic signaling and preserved sensory structures, and CN016 effectively modulated neuroinflammatory pathways through macrophage inhibition at an optimal dose of 20 mg\/kg. The\n                    <jats:italic toggle=\"yes\">BDNF<\/jats:italic>\n                    Met\n                    <jats:sup>66<\/jats:sup>\n                    variant shows about 49% prevalence in East Asian populations and 1 to 20% in other ethnic groups, suggesting population-specific susceptibility to CIPN. These findings establish\n                    <jats:italic toggle=\"yes\">BDNF<\/jats:italic>\n                    genetic variation as a crucial determinant of CIPN risk and validate two promising therapeutic approaches, providing a foundation for personalized neuroprotective strategies in cancer treatment.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adx1436","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T18:58:48Z","timestamp":1771441128000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["<i>BDNF<\/i>\n                    Val\n                    <sup>66<\/sup>\n                    Met protects oxaliplatin-induced peripheral neuropathy in patients with colorectal cancer"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4321-1882","authenticated-orcid":true,"given":"Li-Hsien","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan."},{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan."},{"name":"University Center of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9424-1985","authenticated-orcid":true,"given":"Peng-Chan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan."},{"name":"Department of Genomic Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Min","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5581-9329","authenticated-orcid":true,"given":"Chung-I","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Statistics, College of Management, National Cheng Kung University, Tainan 70101, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7141-3301","authenticated-orcid":true,"given":"Lian-Yun","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6515-5930","authenticated-orcid":true,"given":"Jang-Yang","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan."},{"name":"TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0506-3505","authenticated-orcid":true,"given":"Meng-Ru","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan."},{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, 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