{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:06:42Z","timestamp":1793210802026,"version":"4.5.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Aim of study<\/jats:title>\n                    <jats:p>\n                      Fast neutron data from Hammersmith (UK) showed that the inverse relationship between dose and RBE (Relative Biological Effectiveness) is not maintained in many\n                      <jats:italic>in vivo<\/jats:italic>\n                      situations, originally attributed to hypoxic effects. The present study aims to simulate these RBE patterns in two cancers and one normal tissue for neutrons as well as protons.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A new model uses LQ formulism with radiosensitivity changes increasing with LET and with LET-related reductions in hypoxia. Inequalities are defined for the parameter ratios used to estimate RBEs in oxic and hypoxic compartments, with the overall RBE being also determined by the initial hypoxic fraction and the compartmental surviving fractions with increasing dose. Extrapolation from neutrons to protons is assumed by using a 90% RBE reduction for the excess of RBE beyond unity. Also, the separate influence of the dose rate effect on RBE at higher doses is investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>For normal skin, the C3H mouse mammary carcinoma and the Ehrlich ascites cancer, three quite different RBE responses are fitted by the model within practical statistical bounds. The overall RBE initially follows the oxic curve but shifts with increasing dose to the higher hypoxic RBE curve, the response depending mostly on the pretreatment hypoxic fraction and other hypoxia parameters. Such patterns of RBE changes are also obtained for protons, but cannot be obtained from the dose rate effect at higher dose, although the DNA repair rate will increase RBE with dose.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This tentative but complex radiobiological modelling study shows that the Hammersmith neutron RBE results can be simulated by the presence of two physiological compartments and that similar RBE changes may occur for protons. Further experimental research is suggested for determining if protons do show effects at similar dose ranges, which could be relevant for hypo-fractionated or single fraction schedules.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1792868","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:48:46Z","timestamp":1778129326000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Deviations from the inverse relationship between tumor and normal tissue dose and RBE in fast neutron data are compatible with the presence of hypoxia, with possible applications to hypo-fractionated proton therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Bleddyn","family":"Jones","sequence":"first","affiliation":[{"name":"Gray Laboratory, Oxford Institute for Radiation Oncology and Biology","place":["Oxford, United Kingdom"]},{"name":"Green Templeton College","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.01537","article-title":"Clinical Radiobiology of Fast Neutron Therapy: what was learnt","volume":"10","author":"Jones","year":"2020","journal-title":"Front Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1148\/97.3.649","article-title":"The relative biological effectiveness of fast neutrons for intestinal damage","volume":"97","author":"Hornsey","year":"1970","journal-title":"Radiology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1177\/003591577206501010","article-title":"An historical survey of radiobiology and radiotherapy with fast neutrons","volume":"11","author":"Field","year":"1976","journal-title":"Curr Top. Radiat Res Q"},{"key":"B4","doi-asserted-by":"publisher","first-page":"20180097","DOI":"10.1259\/bjr.20180097","article-title":"The evolution of practical radiobiological modelling","volume":"92","author":"Jones","year":"2018","journal-title":"Br J Radiol"},{"key":"B5","article-title":"High LET radiobiology and radiotherapy","volume-title":"Textbook: The Radiobiology of Human Cancer Radiotherapy","author":"Andrews","year":"1978"},{"key":"B6","article-title":"Radiobiological principles","volume-title":"Nuclear Particles in Cancer Treatment, Medical Physics Handbooks (8)","author":"Fowler","year":"1981"},{"key":"B7","volume":"10","author":"Barendsen","year":"1966","journal-title":"Int J Radiat Biol Relat Stud Phys Chem Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1259\/0007-1285-46-551-996","article-title":"Survival of murine leukaemia cells in vivo after irradiation in vitro under aerobic and hypoxic conditions with monoenergetic accelerated charged particles","volume":"44","author":"Berry","year":"1970","journal-title":"Radiat Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2307\/3574026","article-title":"RBE and OER variations of mixtures of plutonimum alpha particles and x-rays for damage to human kidney cells (T1)","volume":"60","author":"Raju","year":"1974","journal-title":"Radiat Res"},{"key":"B10","first-page":"1","article-title":"Radiobiology with heavy charged particles: a historical review","volume":"14","author":"Skarsgard","year":"1998","journal-title":"Phys Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1667\/0033-7587","article-title":"Inactivation of aerobic and hypoxic cells from three different cell lines by accelerated (3)He-, (12)C- and (20)Ne-ion beams","volume":"154","author":"Furusawa","year":"2000","journal-title":"Radiat Res"},{"key":"B12","doi-asserted-by":"publisher","first-page":"045028","DOI":"10.1088\/1361-6560\/abddd0","article-title":"Fast neutron energy-based modelling of biological effectiveness with implications for proton and ion beams","volume":"66","author":"Jones","year":"2021","journal-title":"Phys Med Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1080\/0955300021000038653","article-title":"Single-hit mechanism of tumor cell killing by radiation","volume":"79","author":"Chapman","year":"2003","journal-title":"Int J Radiat Biol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/s0360-3016(03)00534-0","article-title":"Incorporating clinical measurements of hypoxia into tumor local control modeling of prostate cancer: implications for the alpha\/beta ratio","volume":"57","author":"Nahum","year":"2003","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.2307\/3577937","article-title":"Dose dependence of the oxygen enhancement ratio (OER) in radiation inactivation of Chinese hamster V79\u2013171 cells","volume":"127","author":"Skarsgard","year":"1991","journal-title":"Radiat Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1259\/bjr.20180070","article-title":"Radiation repair models for clinical application","volume":"92","author":"Dale","year":"2019","journal-title":"Br J Radiol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3109\/00016926009171671","article-title":"Quantitative measurements of oxygen tension in normal tissues and in the tumors of patients before and after radiotherapy","volume":"53","author":"Cater","year":"1960","journal-title":"Acta Radiol (Stockh)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054430","article-title":"Hypoxia in skin cancer: molecular basis and clinical implications","volume":"24","author":"Jeon","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3109\/02841869509093983","article-title":"Reoxygenation in a C3H mouse mammary carcinoma. The importance of chronic rather than acute hypoxia","volume":"34","author":"Horsman","year":"1995","journal-title":"Acta Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1997.448","article-title":"Detection of hypoxic cells in a C3H mouse mammary carcinoma using the comet assay","volume":"76","author":"Olive","year":"1997","journal-title":"Br J Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2014.02.010","article-title":"(18)F-fluorodeoxyglucose uptake and tumor hypoxia: revisit (18)f-fluorodeoxyglucose in oncology application","volume":"7","author":"Li","year":"2014","journal-title":"Transl Oncol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/0167-8140(90)90166-t","article-title":"The RBE of euoxic and hypoxic Ehrlich ascites tumor cells irradiated with negative pions in vitro and in vivo","volume":"19","author":"J\u00fcling-Pohlit","year":"1990","journal-title":"Radiother. Oncol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.radonc.2003.11.010","article-title":"Compensation for changes in dose-rate in radical low-dose-rate brachytherapy: a radiobiological analysis of a randomised clinical trial","volume":"70","author":"Roberts","year":"2004","journal-title":"Radiother. Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3109\/02841869409098414","article-title":"In vitro studies of intrinsic cellular radiosensitivity following 4 MeV photons or 62.5 MeV (p-->Be+) neutrons. Potential implications for high LET therapy","volume":"33","author":"Warenius","year":"1994","journal-title":"Acta Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1667\/rr2737.1","article-title":"Variations in the RBE for cell killing along the depth-dose profile of a modulated proton therapy beam","volume":"179","author":"Britten","year":"2013","journal-title":"Radiat Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2010.09.003","article-title":"Radiobiological characterization of two therapeutic proton beams with different initial energy spectra used at the Institut Curie Proton Therapy Center in Orsay","volume":"81","author":"Calugaru","year":"2011","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2014-305313","article-title":"Transpalpebral proton beam radiotherapy of choroidal melanoma","volume":"99","author":"Konstantinidis","year":"2015","journal-title":"Br J Ophthalmol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1088\/1361-6560\/ac6ebb","article-title":"The influence of hypoxia on LET and RBE relationships with implications for ultra-high dose rates and FLASH modelling","volume":"67","author":"Jones","year":"2022","journal-title":"Phys Med Biol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1792868\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:48:58Z","timestamp":1778129338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1792868\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":28,"alternative-id":["10.3389\/fonc.2026.1792868"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1792868","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"article-number":"1792868"}}