{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:41:15Z","timestamp":1792593675569,"version":"4.5.0"},"reference-count":29,"publisher":"IOP Publishing","issue":"20","license":[{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/iop-standard\/v1"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/iopscience.iop.org\/info\/page\/text-and-data-mining"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/questions\/alternative-author-rights-policies\/"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/questions\/alternative-author-rights-policies\/"}],"content-domain":{"domain":["iopscience.iop.org"],"crossmark-restriction":false},"short-container-title":["Phys. Med. Biol."],"published-print":{"date-parts":[[2026,10,28]]},"abstract":"Abstract<\/jats:title>\n \n Objective.<\/jats:italic>\n FLASH radiotherapy spares normal tissue at ultra-high dose rates, but the dependence of this protection on linear energy transfer (LET) and tissue oxygenation is not mechanistically understood. We developed a model coupling Geant4-DNA track-structure\n G<\/jats:italic>\n -values to the Labarbe peroxyl-radical (ROO\u2022) kinetic framework to predict FLASH normal-tissue sparing as a joint function of LET and oxygenation.\n Approach. G<\/jats:italic>\n -values for \u2022OH, e\n \u2212<\/jats:sup>\n aq, H\u2022 and H\n 2<\/jats:sub>\n O\n 2<\/jats:sub>\n were computed with Geant4-DNA chem6 for electrons (0.16\u20138.70 keV\n \u00b5<\/jats:italic>\n m\n \u22121<\/jats:sup>\n ) and protons (0.69\u20139.5 keV\n \u00b5<\/jats:italic>\n m\n \u22121<\/jats:sup>\n ), with 500 primary events per LET point, and taken from published Monte Carlo data for carbon ions (10\u2013200 keV\n \u00b5<\/jats:italic>\n m\n \u22121<\/jats:sup>\n ). These were supplied to the Labarbe ordinary differential equation system using the published rate constants without adjustment and integrated across dose rates of 0.03\u201310\n 5<\/jats:sup>\n Gy s\n \u22121<\/jats:sup>\n , doses of 5\u201330 Gy and oxygen concentrations of 2\u2013200\n \u00b5<\/jats:italic>\n M. FLASH sparing was quantified as the fractional reduction in time-integrated ROO\u2022 exposure. The mechanism was tested by removing individual reactions from the kinetic system, and predictions were compared with three independent preclinical datasets.\n Main results.<\/jats:italic>\n Using the NTCP parameters published by Labarbe\n et al<\/jats:italic>\n (2020\n Radiother. Oncol.<\/jats:italic>\n 153<\/jats:bold>\n 153303-10), with no quantity fitted in the present work, the model gives a dose-modifying factor of 1.42; with the parameters refitted here, it gives 1.44, against experimentally reported values of 1.30\u20131.40. Sparing decreases monotonically with LET, from 32.3% at 0.16 keV\n \u00b5<\/jats:italic>\n m\n \u22121<\/jats:sup>\n to 11.2% at 200 keV\n \u00b5<\/jats:italic>\n m\n \u22121<\/jats:sup>\n . At matched LET, proton and electron yields converge below 2 keV\n \u00b5<\/jats:italic>\n m\n \u22121<\/jats:sup>\n but diverge by up to 19% in G(e\n \u2212<\/jats:sup>\n aq) at 8.7 keV\n \u00b5<\/jats:italic>\n m\n \u22121<\/jats:sup>\n , setting a validity limit on LET-only parameterization. Removing the ROO\u2022\u2013ROO\u2022 recombination term collapses sparing from 32.3% to 2.4%, identifying second-order peroxyl recombination as the operative mechanism. The oxygen dependence is dose- and dose-rate-gated, with the sparing difference across 2\u2013200\n \u00b5<\/jats:italic>\n M ranging from below 1 to approximately 40 percentage points (pp); at 30 Gy and 100 Gy s\n \u22121<\/jats:sup>\n , the model predicts 8.2 pp less sparing in bone osteocytes (15\n \u00b5<\/jats:italic>\n M) than in normoxic tissue, consistent with the absence of FLASH bone sparing reported in canine mandible.\n Significance.<\/jats:italic>\n Peroxyl-radical bimolecular recombination, driven by LET-dependent track-structure yields, provides a parameter-free chemical basis for the modality dependence of the FLASH effect. The predicted dose-, dose-rate- and oxygen-gating of sparing gives testable criteria for where FLASH protection should and should not occur.\n <\/jats:p>","DOI":"10.1088\/1361-6560\/aeafa6","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T22:53:19Z","timestamp":1790981599000},"page":"205018","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Radiolytic yields and peroxyl-radical kinetics predict the LET and oxygenation dependence of FLASH radiotherapy normal-tissue sparing"],"prefix":"10.1088","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1492-6787","authenticated-orcid":true,"given":"Khaoula","family":"Younous","sequence":"first","affiliation":[{"name":"Mohammed V University"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Rajaa","family":"Sebihi","sequence":"additional","affiliation":[{"name":"Mohammed V University"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4177-4515","authenticated-orcid":true,"given":"Morad El","family":"Kafhali","sequence":"additional","affiliation":[{"name":"Moulay Ismail University"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1788-848X","authenticated-orcid":true,"given":"Amine Walia","family":"Allah","sequence":"additional","affiliation":[{"name":"Mohammed V University"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"}]}],"member":"266","published-online":{"date-parts":[[2026,10,21]]},"reference":[{"key":"pmbaeafa6bib1","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/S0168-9002(03)01368-8","type":"journal-article","article-title":"Geant4: a simulation toolkit","volume":"506","author":"Agostinelli","year":"2003","journal-title":"Nucl. 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All rights, including for text and data mining, AI training, and similar technologies, are reserved.","name":"copyright_information","label":"Copyright Information"},{"value":"2026-05-28","name":"date_received","label":"Date Received","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2026-10-02","name":"date_accepted","label":"Date Accepted","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2026-10-21","name":"date_epub","label":"Online publication date","group":{"name":"publication_dates","label":"Publication dates"}}]}}