{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T12:35:24Z","timestamp":1793018124778,"version":"4.5.0"},"reference-count":60,"publisher":"IOP Publishing","issue":"20","license":[{"start":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T00:00:00Z","timestamp":1792972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/iop-standard\/v1"},{"start":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T00:00:00Z","timestamp":1792972800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/iopscience.iop.org\/info\/page\/text-and-data-mining"},{"start":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T00:00:00Z","timestamp":1792972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/questions\/alternative-author-rights-policies\/"},{"start":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T00:00:00Z","timestamp":1792972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/questions\/alternative-author-rights-policies\/"}],"funder":[{"name":"Duke-NUS Medical School","award":["08\/FY2022\/P2\/02-A68"],"award-info":[{"award-number":["08\/FY2022\/P2\/02-A68"]}],"id":[{"id":"https:\/\/ror.org\/02j1m6098","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Japan Society for the Promotion of Science","award":["22K07695"],"award-info":[{"award-number":["22K07695"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["iopscience.iop.org"],"crossmark-restriction":false},"short-container-title":["Phys. Med. Biol."],"published-print":{"date-parts":[[2026,10,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Objective.<\/jats:italic>\n                    Ultra-high dose rate (uHDR: FLASH) radiotherapy reduces normal tissue toxicity while preserving tumor control. The oxygen depletion hypothesis posits that rapid oxygen consumption during FLASH irradiation transiently reduces radiosensitivity. However, experimental measurements suggest oxygen depletion may be limited, particularly under normoxia. This study quantitatively assesses the adequacy of this hypothesis in reproducing experimentally observed sparing effects by comparing mechanistic simulations with\n                    <jats:italic>in vitro<\/jats:italic>\n                    cell survival data across a wide range of irradiation conditions.\n                    <jats:italic>Approach.<\/jats:italic>\n                    We developed a phenomenological framework for radiolytic oxygen depletion incorporating temporal dose delivery, dose rate, and linear energy transfer (LET). LET dependence was included through oxygen consumption efficiency and the maximum oxygen enhancement ratio. For direct comparison, simulation results were linked to clonogenic cell survival using a damage reduction factor (DRF) derived from the linear-quadratic model. Simulated DRFs were compared with experimental DRFs from six independent\n                    <jats:italic>in vitro<\/jats:italic>\n                    studies involving electrons, protons, helium ions, and carbon ions over broad ranges of LET, oxygenation, and dose rates using parity plots, residual analyses, stratified weighted statistics, and correlation analyses.\n                    <jats:italic>Main results.<\/jats:italic>\n                    Under most irradiation conditions, simulated DRFs remained close to unity (minimum values approximately 0.96), indicating limited predicted protection from oxygen depletion. Conversely, experimental DRFs exhibited substantially larger deviations. Stratified analyses revealed systematic discrepancies between simulated and experimental DRFs across oxygenation, LET, and dose rate, with pronounced disagreement under normoxia, high LET, and uHDRs. Residual analyses demonstrated underestimation of the sparing effect by the model. Correlation analyses showed statistically insignificant associations between simulated and experimental metrics.\n                    <jats:italic>Significance.<\/jats:italic>\n                    The oxygen depletion model considered in this work insufficiently reproduces the observed sparing effect under the\n                    <jats:italic>in vitro<\/jats:italic>\n                    conditions considered. Additional biological and physicochemical mechanisms likely play a significant role. This framework provides a quantitative basis for evaluating alternative mechanisms and integrating future experimental data toward a more complete understanding of FLASH radiotherapy.\n                  <\/jats:p>","DOI":"10.1088\/1361-6560\/aeb05e","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:51:33Z","timestamp":1791240693000},"page":"205031","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A generalized phenomenological model of oxygen depletion for FLASH particle radiotherapy: evidence from\n                    <i>in vitro<\/i>\n                    data"],"prefix":"10.1088","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8390-2425","authenticated-orcid":true,"given":"Kailin","family":"Fu","sequence":"first","affiliation":[{"name":"School of Physical and Mathematical Sciences, Nanyang Technological University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5695-1540","authenticated-orcid":true,"given":"Jun Ken","family":"Gan","sequence":"additional","affiliation":[{"name":"School of Physical and Mathematical Sciences, Nanyang Technological University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Yagi","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore"},{"name":"The University of Osaka Graduate School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford Ghee Ann","family":"Chua","sequence":"additional","affiliation":[{"name":"School of Physical and Mathematical Sciences, Nanyang Technological University"},{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1824-2724","authenticated-orcid":true,"given":"Kang Hao","family":"Lee","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kah Seng","family":"Lew","sequence":"additional","affiliation":[{"name":"School of Physical and Mathematical Sciences, Nanyang Technological University"},{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin Wei Yang","family":"Koh","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumasa","family":"Minami","sequence":"additional","affiliation":[{"name":"The University of Osaka Graduate School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeap Ping","family":"Lin","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Wibawa","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zubin","family":"Master","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Siang","family":"Lew","sequence":"additional","affiliation":[{"name":"School of Physical and Mathematical Sciences, Nanyang Technological University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James Cheow Lei","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Physical and Mathematical Sciences, Nanyang Technological University"},{"name":"National Cancer Centre Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"The University of Osaka Graduate School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7961-2119","authenticated-orcid":true,"given":"Sung Yong","family":"Park","sequence":"additional","affiliation":[{"name":"National Cancer Centre Singapore"},{"name":"Oncology Academic Clinical Programme, Duke-NUS Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7878-4544","authenticated-orcid":true,"given":"Hong Qi","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Physical and Mathematical Sciences, Nanyang Technological University"},{"name":"National Cancer Centre Singapore"},{"name":"Oncology Academic Clinical Programme, Duke-NUS Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2026,10,26]]},"reference":[{"key":"pmbaeb05ebib1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.686142","type":"journal-article","article-title":"Cancer cells can exhibit a sparing FLASH effect at low doses under normoxic in vitro-conditions","volume":"11","author":"Adrian","year":"2021","journal-title":"Front. 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