{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:55:32Z","timestamp":1791237332394,"version":"4.1.0"},"reference-count":56,"publisher":"Radiation Research Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Radiation Research"],"published-print":{"date-parts":[[2026,3,27]]},"abstract":"<jats:p>Irradiation at ultra-high dose rates is gaining increased attention due to its ability to limit damage to surrounding healthy tissues, thereby preventing radiation-induced side effects. Although there are some exceptions, this protective effect (the FLASH effect) has been demonstrated in many preclinical models, primarily after low-LET irradiation and high-dose irradiation. Here, we report that both ultra-high dose rate (UHDR) and conventional dose rate (CONV) irradiations produce similar growth delays in 3D tumor spheroids (composed of HCT116 and T98G, colorectal carcinoma or glioblastoma cell lines), indicating comparable efficacy in tumor control. In normal cells (HIEC-6, a non-malignant epithelial cell line from the small intestine), UHDR and CONV irradiation induced comparable senescence, while a lower induction of apoptosis was observed after UHDR irradiation at clinically relevant doses and early time points postirradiation. Collectively, these findings highlight the potential of UHDR irradiation to modulate normal tissue responses while achieving comparable tumor control.<\/jats:p>","DOI":"10.1667\/rade-25-00051","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:07:49Z","timestamp":1791234469000},"page":"32-42","source":"Crossref","is-referenced-by-count":0,"title":["The FLASH Effect in 3D and 2D Models: Preserving Tumor Control while Reducing Apoptosis in Normal Cells"],"prefix":"10.1667","volume":"206","author":[{"given":"Andrea","family":"Scarmelotto","sequence":"first","affiliation":[{"name":"Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Lambert","sequence":"additional","affiliation":[{"name":"Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Delprat","sequence":"additional","affiliation":[{"name":"Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charbel","family":"Koumeir","sequence":"additional","affiliation":[{"name":"GIP ARRONAX, Saint-Herblain, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine","family":"Michiels","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche en Biologie Cellulaire (URBC), Namur Research Institute For Life Sciences (NARILIS), University of Namur, Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Lucas","sequence":"additional","affiliation":[{"name":"Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Catherine","family":"Heuskin","sequence":"additional","affiliation":[{"name":"Laboratory for Analysis by Nuclear Reaction (LARN), Namur Research Institute for Life Sciences (NARILIS), University of Namur, Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1243","reference":[{"key":"39","doi-asserted-by":"crossref","unstructured":"P Montay-Gruel, MM Acharya, P Gon\u00e7alves Jorge, et al.  \"Clin Cancer Res.\"  27, \"Hypofractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side effects in mice.\" 775 (2021)","DOI":"10.1158\/1078-0432.CCR-20-0894"},{"key":"32","doi-asserted-by":"crossref","unstructured":"CL Limoli  and MC Vozenin  \"Annu Rev Cancer Biol.\"  7, \"Reinventing radiobiology in the light of FLASH radiotherapy.\" 1 (2023)","DOI":"10.1146\/annurev-cancerbio-061421-022217"},{"key":"30","doi-asserted-by":"crossref","unstructured":"B Lin, D Huang, F Gao, et al.  \"Front Oncol.\"  12, \"Mechanisms of FLASH effect.\" 995612 (2022)","DOI":"10.3389\/fonc.2022.995612"},{"key":"31","doi-asserted-by":"crossref","unstructured":"AA Friedl, KM Prise, KT Butterworth, et al.  \"Med Phys.\"  49, \"Radiobiology of the FLASH effect.\" 1993 (2022)","DOI":"10.1002\/mp.15184"},{"key":"33","doi-asserted-by":"crossref","unstructured":"A Scarmelotto, V Delprat, C Michiels, et al.  \"Clin Transl Radiat Oncol.\"  49, \"The oxygen puzzle in FLASH radiotherapy: A comprehensive review and experimental outlook.\" 100860 (2024)","DOI":"10.1016\/j.ctro.2024.100860"},{"key":"44","doi-asserted-by":"crossref","unstructured":"J Giroud, I Bouriez, H Paulus, et al.  \"Int J Mol Sci.\"  24, \"Exploring the communication of the SASP: Dynamic, interactive, and adaptive effects on the microenvironment.\" 10788 (2023)","DOI":"10.3390\/ijms241310788"},{"key":"27","doi-asserted-by":"crossref","unstructured":"H Riquier, D Abel, AC Wera, et al.  \"Cancers.\"  7, \"Effects of alpha particle and proton beam irradiation as putative cross-talk between A549 cancer cells and the endothelial cells in a co-culture system.\" 481 (2015)","DOI":"10.3390\/cancers7010481"},{"key":"24","doi-asserted-by":"crossref","unstructured":"JD Thomas, GS Hodges, DG Seely, et al.  \"Nucl Instrum Methods Phys Res Sect Accel Spectrometers Detect Assoc Equip.\"  536, \"Performance enhancement study of an electrostatic Faraday cup detector.\" 11 (2005)","DOI":"10.1016\/j.nima.2004.07.211"},{"key":"25","doi-asserted-by":"crossref","unstructured":"L Schoenauen, R Coos, JL Colaux, et al.  \"Nucl Instrum Methods Phys Res Sect Accel Spectrometers Detect Assoc Equip.\"  1064, \"Design and optimization of a dedicated Faraday cup for UHDR proton dosimetry: Implementation in a UHDR irradiation station.\" 169411 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(2021)","DOI":"10.1016\/j.radonc.2021.02.003"},{"key":"7","doi-asserted-by":"crossref","unstructured":"MC Vozenin, JH Hendry, CL Limoli,  \"Clin Oncol.\"  31, \"Biological nenefits of ultra-high dose rate FLASH radiotherapy: Sleeping Beauty Awoken.\" 407 (2019)","DOI":"10.1016\/j.clon.2019.04.001"},{"key":"8","doi-asserted-by":"crossref","unstructured":"L Schoenauen, FX Stubbe, D Van Gestel, et al.  \"Clin Transl Radiat Oncol.\"  45, \"C. elegans: A potent model for high-throughput screening experiments investigating the FLASH effect.\" 100712 (2024)","DOI":"10.1016\/j.ctro.2023.100712"},{"key":"12","doi-asserted-by":"crossref","unstructured":"J Bourhis, WJ Sozzi, PG Jorge, et al.  \"Radiother Oncol J Eur Soc Ther Radiol Oncol.\"  139, \"Treatment of a first patient with FLASH-radiotherapy.\" 18 (2019)","DOI":"10.1016\/j.radonc.2019.06.019"},{"key":"13","doi-asserted-by":"crossref","unstructured":"K Liu, T Waldrop, E Aguilar, et al.  \"Int J Radiat Oncol Biol Phys.\"  121, \"Redefining FLASH RT: the impact of mean dose rate and dose per pulse in the gastrointestinal tract.\" 1063 (2025)","DOI":"10.1016\/j.ijrobp.2024.10.009"},{"key":"14","doi-asserted-by":"crossref","unstructured":"F Banaz-Ya\u015far, R Tischka, G Iliakis, et al.  \"Cell Commun Adhes.\"  12, \"Cell line specific modulation of connexin43 expression after exposure to ionizing radiation.\" 249 (2005)","DOI":"10.1080\/15419060500514101"},{"key":"15","doi-asserted-by":"crossref","unstructured":"K Liu, M Kasper, A Bierhaus, et al.  \"Radiat Res.\"  147, \"Connexin 43 expression in normal and irradiated mouse skin.\" 437 (1997)","DOI":"10.2307\/3579500"},{"key":"16","doi-asserted-by":"crossref","unstructured":"D Glover, JB Little, MF Lavin, et al.  \"Int J Radiat Biol.\"  79, \"Low dose ionizing radiation-induced activation of connexin 43 expression.\" 955 (2003)","DOI":"10.1080\/09553000310001632895"},{"key":"17","doi-asserted-by":"crossref","unstructured":"M Amino, K Yoshioka, D Fujibayashi, et al.  \"Am J Physiol.\"  298, \"Year-long upregulation of connexin43 in rabbit hearts by heavy ion irradiation.\" H1014 (2010)","DOI":"10.1152\/ajpheart.00160.2009"},{"key":"19","doi-asserted-by":"crossref","unstructured":"M Chanson,  DerouetteJ-P, I Roth, et al.  \"Biochim Biophys Acta.\"  1711, \"Gap junctional communication in tissue inflammation and repair.\" 197 (2005)","DOI":"10.1016\/j.bbamem.2004.10.005"},{"key":"20","doi-asserted-by":"crossref","unstructured":"T Delvaeye, P Vandenbeele, G Bultynck, et al.  \"Trends Mol Med.\"  24, \"Therapeutic targeting of connexin channels: New views and challenges.\" 1036 (2018)","DOI":"10.1016\/j.molmed.2018.10.005"},{"key":"21","doi-asserted-by":"crossref","unstructured":"M Vinken, T Vanhaecke, P Papeleu, et al.  \"Cell Signal.\"  18, \"Connexins and their channels in cell growth and cell death.\" 592 (2006)","DOI":"10.1016\/j.cellsig.2005.08.012"},{"key":"22","doi-asserted-by":"crossref","unstructured":"M Kibschull, TM Magin, O Traub, et al.  \"Dev Dyn.\"  233, \"Cx31 and Cx43 double-deficient mice reveal independent functions in murine placental and skin development.\" 853 (2005)","DOI":"10.1002\/dvdy.20424"},{"key":"23","doi-asserted-by":"crossref","unstructured":"A Edelstein, N Amodaj, K Hoover, et al.  \"Curr Protoc Mol Biol.\"  92, \"Computer control of microscopes using \u00b5Manager.\" 14.20.1 (2010)","DOI":"10.1002\/0471142727.mb1420s92"},{"key":"26","doi-asserted-by":"crossref","unstructured":"A-C Wera, H Riquier, A-C Heuskin, et al.  \"Nucl Instrum Methods Phys Res Sect B.\"  269, \"In vitro irradiation station for broad beam radiobiological experiments.\" 3120 (2011)","DOI":"10.1016\/j.nimb.2011.04.104"},{"key":"28","doi-asserted-by":"crossref","unstructured":"C Koumeir, V De Nadal, R Cherubini, et al.  \"Radiat Prot Dosimetry.\"  183, \"The radiobiological platform at Arronax.\" 270 (2019)","DOI":"10.1093\/rpd\/ncy301"},{"key":"29","unstructured":"F Poirier, G Blain, F Bulteau-Harel, et al.  \"22nd International Conference on Cyclotrons and their applications. Cyclotrons.\"  \"The Injection and Chopper-Based System at Arronax C70XP Cyclotron.\" 159 (2019)"},{"key":"34","doi-asserted-by":"crossref","unstructured":"N Vilaplana-Lopera, A Abu-Halawa, E Walker, et al.  \"Br J Radiol.\"  95, \"Ferroptosis, a key to unravel the enigma of the FLASH effect?\" 20220825 (2022)","DOI":"10.1259\/bjr.20220825"},{"key":"35","doi-asserted-by":"crossref","unstructured":"A Kyle, T Karan, HEJ Baker, et al.  \"Radiother Oncol.\"  196, \"Detection of FLASH-radiotherapy tissue sparing in a 3D-spheroid model using DNA damage response markers.\" 110326 (2024)","DOI":"10.1016\/j.radonc.2024.110326"},{"key":"36","doi-asserted-by":"crossref","unstructured":"H Iwata, T Toshito, C Omachi, et al.  \"Int J Radiat Oncol Biol Phys.\"  121, \"Proton FLASH irradiation using a synchrotron accelerator: Differences by irradiation positions.\" 1293 (2025)","DOI":"10.1016\/j.ijrobp.2024.11.066"},{"key":"37","doi-asserted-by":"crossref","unstructured":"S Khan, M Bassenne, J Wang, et al.  \"Int J Radiat Oncol Biol Phys.\"  110, \"Multicellular spheroids as in vitro models of oxygen depletion during FLASH irradiation.\" 833 (2021)","DOI":"10.1016\/j.ijrobp.2021.01.050"},{"key":"40","doi-asserted-by":"crossref","unstructured":"MM Kim, II Verginadis, D Goia, et al.  \"Cancers.\"  13, \"Comparison of FLASH proton entrance and the spread-out Bragg peak dose regions in the sparing of mouse intestinal crypts and in a pancreatic tumor model.\" 4244 (2021)","DOI":"10.3390\/cancers13164244"},{"key":"41","doi-asserted-by":"publisher","unstructured":"K Levy, S Natarajan, J Wang, et al.  \"FLASH irradiation enhances the therapeutic index of abdominal radiotherapy for the treatment of ovarian cancer\"","DOI":"10.1101\/2019.12.12.873414"},{"key":"42","doi-asserted-by":"crossref","unstructured":"R Dela, L Lemos Da Silva, S Beyer, et al.  \"Br J Radiol.\"  99, \"Not all tumors are alike: varying efficacy of FLASH across tumor types and oxygenation status in spheroid models.\" 65 (2026)","DOI":"10.1093\/bjr\/tqaf219"},{"key":"43","doi-asserted-by":"crossref","unstructured":"D De Ruysscher, E Sterpin, K Haustermans, et al.  \"Cancers.\"  7, \"Tumour movement in proton therapy: Solutions and remaining questions: A review.\" 1143 (2015)","DOI":"10.3390\/cancers7030829"},{"key":"48","doi-asserted-by":"crossref","unstructured":"R Ramadan, E Vromans, DC Anang, et al.  \"Sci Rep.\"  9, \"Single and fractionated ionizing radiation induce alterations in endothelial connexin expression and channel function.\" 4643 (2019)","DOI":"10.1038\/s41598-019-39317-9"},{"key":"49","doi-asserted-by":"crossref","unstructured":"H Liu, DC Radisky, MJ Bissell,  \"Cell Cycle.\"  4, \"Proliferation and polarity in breast vancer: Untying the Gordian Knot.\" 646 (2005)","DOI":"10.4161\/cc.4.5.1674"},{"key":"50","doi-asserted-by":"crossref","unstructured":"T Martins-Marques, T Ribeiro-Rodrigues, D Batista-Almeida, et al.  \"Trends Cell Biol.\"  29, \"Biological functions of connexin43 beyond intercellular communication.\" 835 (2019)","DOI":"10.1016\/j.tcb.2019.07.001"},{"key":"51","doi-asserted-by":"crossref","unstructured":"J Han, Z Mei, C Lu, et al.  \"Front Cell Dev Biol.\"  9, \"Ultra-high dose rate FLASH irradiation induced radio-resistance of normal fibroblast cells can be enhanced by hypoxia and mitochondrial Dysfunction Resulting From loss of Cytochrome C.\" 67292 (2021)","DOI":"10.3389\/fcell.2021.672929"},{"key":"53","unstructured":"J Lv, J Sun, Y Luo, et al.  \"FLASH irradiation regulates IFN-\u03b2 induction by mtDNA via cytochrome c leakage\""},{"key":"54","doi-asserted-by":"crossref","unstructured":"A Sesink, R Geyer, P Devanand, et al.  \"Radiother Oncol.\"  214, \"Decrease in dose per fraction impairs the FLASH sparing effect in murine intestine model.\" 111262 (2026)","DOI":"10.1016\/j.radonc.2025.111262"},{"key":"55","doi-asserted-by":"crossref","unstructured":"S Paillas, ERJF Taylor, N L\u00f6vgren, et al.  \"Clin Transl Radiat Oncol.\"  56, \"Quantifying the flash effect and its dependence on average dose rate in vivo for 6 MeV electron and 6 MV photon beams.\" 101052 (2026)","DOI":"10.1016\/j.ctro.2025.101052"},{"key":"56","doi-asserted-by":"crossref","unstructured":"V Grilj, AV Zayas, A Sesink, et al.  \"Int J Radiat Oncol.\"  123, \"Average dose rate is the major temporal beam structure parameter for preserving murine intestines with pulsed electron FLASH radiation therapy.\" 593 (2025)","DOI":"10.1016\/j.ijrobp.2025.04.021"},{"key":"38","doi-asserted-by":"crossref","unstructured":"K Levy, S Natarajan, J Wang, et al.  \"Sci Rep.\"  10, \"Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice.\" 21600 (2020)","DOI":"10.1038\/s41598-020-78017-7"},{"key":"2","doi-asserted-by":"crossref","unstructured":"MB Barton, S Jacob, J Shafiq, et al.  \"Radiother Oncol.\"  112, \"Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012.\" 140 (2014)","DOI":"10.1016\/j.radonc.2014.03.024"},{"key":"3","doi-asserted-by":"crossref","unstructured":"V Favaudon, L Caplier, V Monceau, et al.  \"Sci Transl Med.\"  6, \"Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.\" 245ra93 (2014)","DOI":"10.1126\/scitranslmed.3008973"},{"key":"4","doi-asserted-by":"crossref","unstructured":"P Montay-Gruel, MM Acharya, K Petersson, et al.  \"Proc Natl Acad Sci U S A.\"  116, \"Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species.\" 10943 (2019)","DOI":"10.1073\/pnas.1901777116"},{"key":"5","doi-asserted-by":"crossref","unstructured":"P Montay-Gruel, K Petersson, M Jaccard, et al.  \"Radiother Oncol.\"  124, \"Irradiation in a flash: Unique sparing of memory in mice after whole brain irradiation with dose rates above 100Gy\/s.\" 365 (2017)","DOI":"10.1016\/j.radonc.2017.05.003"},{"key":"46","doi-asserted-by":"crossref","unstructured":"C Fouillade, S Curras-Alonso, L Giuranno, et al.  \"Clin Cancer Res.\"  26, \"FLASH irradiation spares lung progenitor cells and limits the incidence of radio-induced senescence.\" 1497 (2020)","DOI":"10.1158\/1078-0432.CCR-19-1440"},{"key":"47","doi-asserted-by":"crossref","unstructured":"M Buonanno, V Grilj, DJ Brenner,  \"Radiother Oncol.\"  139, \"Biological effects in normal cells exposed to FLASH dose rate protons.\" 51 (2019)","DOI":"10.1016\/j.radonc.2019.02.009"},{"key":"9","doi-asserted-by":"crossref","unstructured":"MC Vozenin, P De Fornel, K Petersson, et al.  \"Clin Cancer Res.\"  25, \"The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients.\" 35 (2019)","DOI":"10.1158\/1078-0432.CCR-17-3375"},{"key":"11","doi-asserted-by":"crossref","unstructured":"B B\u00f8rresen, ML Arendt, E Konradsson, et al.  \"Front Oncol.\"  13, \"Evaluation of single-fraction high dose FLASH radiotherapy in a cohort of canine oral cancer patients.\" 1256760 (2023)","DOI":"10.3389\/fonc.2023.1256760"},{"key":"10","doi-asserted-by":"crossref","unstructured":"E Konradsson, ML Arendt, K Bastholm Jensen, et al.  \"Front Oncol.\"  11, \"Establishment and initial experience of clinical FLASH radiotherapy in canine cancer patients.\" 658004 (2021)","DOI":"10.3389\/fonc.2021.658004"},{"key":"18","doi-asserted-by":"crossref","unstructured":"M Amino, K Yoshioka, T Tanabe, et al.  \"Cardiovasc Res.\"  72, \"Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction.\" 412 (2006)","DOI":"10.1016\/j.cardiores.2006.09.010"}],"container-title":["Radiation Research"],"original-title":[],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:07:57Z","timestamp":1791234477000},"score":1,"resource":{"primary":{"URL":"https:\/\/bioone.org\/journals\/radiation-research\/volume-206\/issue-1\/RADE-25-00051\/The-FLASH-Effect-in-3D-and-2D-Models--Preserving\/10.1667\/RADE-25-00051.full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1667\/rade-25-00051","relation":{},"ISSN":["0033-7587","1938-5404"],"issn-type":[{"value":"0033-7587","type":"print"},{"value":"1938-5404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]}}}