Radiation research最新文献

{"title":"The FLASH Effect in 3D and 2D Models: Preserving Tumor Control while Reducing Apoptosis in Normal Cells.","authors":"Andrea Scarmelotto, Emma Lambert, Victor Delprat, Charbel Koumeir, Carine Michiels, Stéphane Lucas, Anne-Catherine Heuskin","doi":"10.1667/RADE-25-00051.1","DOIUrl":"https://doi.org/10.1667/RADE-25-00051.1","url":null,"abstract":"<p><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.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147532446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TSPAN8-mediated Epithelial-mesenchymal Transition Drives Acquired Radioresistance in Cervical Cancer.","authors":"Jing-Nan Wang, Ling-Li Liao, Fan Yang, Ru Wang, Lei Zhang, Ao-Xue Li, Peng-Jie Yu, Ruo-Tong Wu, Nuo Chen, Yu-Qiao Xu, Yong-Chun Zhou","doi":"10.1667/RADE-25-00233.1","DOIUrl":"10.1667/RADE-25-00233.1","url":null,"abstract":"<p><p>Acquired radioresistance remains a major obstacle to effective radiotherapy for cervical cancer, often driven by epithelial-mesenchymal transition (EMT). This study reveals TSPAN8 as a novel regulator of EMT-mediated radioresistance, offering new insights for overcoming treatment failure. Radioresistant subclones of HeLa-R25 and SiHa-R25 cells were established by repeated 2 Gy fractions. Radioresistance, apoptosis, EMT, and stemness were assessed by clonogenic survival, flow cytometry, immunoblotting, and immunofluorescence. Differentially expressed genes were identified by microarray, validated by protein-protein interaction analysis and co-immunoprecipitation, and functionally examined via TSPAN8 overexpression/knockdown, xenograft models, and immunohistochemistry of primary, metastatic, and recurrent post-radiotherapy specimens. Prognostic relevance was analyzed in the TCGA-CESC cohort. Fractionated irradiation induced EMT and radioresistance, with significantly higher clonogenic survival in R25 cells (P < 0.05), characterized by E-cadherin loss, N-cadherin/Vimentin upregulation, and increased CD44/Oct4. TSPAN8 was the most upregulated gene and directly interacted with E-cadherin. Overexpression enhanced EMT, invasion, and resistance to apoptosis, while knockdown reversed these effects and restored radiosensitivity in vivo. TSPAN8 knockdown in radioresistant xenografts significantly suppressed tumor growth (P < 0.05), and combined knockdown with irradiation further reduced tumor volume (P < 0.05). In patient samples, post-radiotherapy recurrences and metastases exhibited high TSPAN8 and vimentin with reduced E-cadherin. TCGA data confirmed that elevated TSPAN8 was associated with worse outcomes, including shorter disease-specific survival (HR = 2.02, 95% CI 1.01-3.71, P = 0.02) and progression-free survival (HR = 3.09, 95% CI 1.80-5.30, P < 0.001). These data suggest that TSPAN8 drives EMT-mediated radioresistance in cervical cancer, is associated with recurrence and poor survival, and represents a potential biomarker and therapeutic target. Targeting TSPAN8 may enhance radiosensitivity and improve personalized radiotherapy outcomes.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":"205 5","pages":"513-527"},"PeriodicalIF":2.4,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The FLASH Effect in 3D and 2D Models: Preserving Tumor Control while Reducing Apoptosis in Normal Cells.","authors":"Andrea Scarmelotto, Emma Lambert, Victor Delprat, Charbel Koumeir, Carine Michiels, Stéphane Lucas, Anne-Catherine Heuskin","doi":"10.1667/RADE-25-00051","DOIUrl":"10.1667/RADE-25-00051","url":null,"abstract":"<p><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.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":"206 1","pages":"32-42"},"PeriodicalIF":2.4,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Radiosensitivity in T-Cell Subsets: Metabolic and Antioxidative Mechanisms Underlying Naïve T-Cell Vulnerability.","authors":"Lorreta Yun-Tien Lin, Anika Kot, Albert J Fornace, Heng-Hong Li","doi":"10.1667/RADE-25-00083","DOIUrl":"10.1667/RADE-25-00083","url":null,"abstract":"<p><p>T cells, which are generally highly sensitive to DNA damage-induced cell death, exhibit distinct responses to ionizing radiation (IR) depending on their differentiation state. In this study, we investigated the heightened radiosensitivity of naïve T cells (Tn) compared to memory T cells (Tm) through in vivo and in vitro models. Following whole-body irradiation (WBI), naïve T cells, particularly naïve CD8+ T cells, displayed significant depletion and delayed recovery, compared to their Tm counterparts. Transcriptomic analyses revealed similar p53 pathway activation in both Tn and Tm postirradiation but highlighted key differences in cytokine signaling and metabolic profiles between these two cell states. Tm cells showed elevated expression of survival-promoting cytokine receptors, anti-apoptotic genes, and mitochondrial respiratory activity, coupled with robust antioxidative defense systems, including increased glutathione synthesis and thioredoxin reductase activity. Supplementation with N-acetylcysteine, a reactive oxygen species (ROS) scavenger, partially mitigated Tn depletion after WBI, underscoring the role of oxidative stress in Tn radiosensitivity. These findings suggest that the metabolic and antioxidative adaptations of Tm confer greater intrinsic resilience against radiation-induced damage than those of Tn. This disparity underscores the importance of targeted interventions to preserve naïve T cell populations and maintain immune balance after radiation exposure.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"20-31"},"PeriodicalIF":2.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13391234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced Response to Radiopharmaceutical Therapy in Preclinical Tumor Models with XRD-0394, a Dual Inhibitor of ATM Kinase and DNA-PKcs.","authors":"Caroline P Kerr, Won Jong Jin, Alejandro J Oñate, Ohyun Kwon, Hansel Comas Rojas, Paul A Clark, Meredith Hyun, Carolina A Ferreira, Malick Bio Idrissou, Md Mahfuzur Rahman, Yujuan Wang, Julia Sheehan-Klenk, Tessa Chen, Justin C Jagodinsky, Erin Nystuen, Luke M Zangl, Anatoly N Pinchuk, KyungMann Kim, Reinier Hernandez, Bryan P Bednarz, Jamey P Weichert, Michael B Kastan, Tona M Gilmer, Zachary S Morris","doi":"10.1667/RADE-25-00203.1","DOIUrl":"10.1667/RADE-25-00203.1","url":null,"abstract":"<p><p>Enhanced DNA repair is a common mechanism of radiation resistance. XRD-0394, a novel small molecule dual inhibitor of ataxia telangiectasia mutated (ATM) kinase and deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs), may sensitize tumor cells to killing by external beam radiation therapy (EBRT) or radiopharmaceutical therapy (RPT). DNA damage response inhibition and increased cytotoxicity were observed in Myc-CaP prostate cancer tumor cells after irradiation + XRD-0394 as indicated by the inhibition of radiation- induced phosphorylation of KAP1, p53, and H2A.X and decreased clonogenic potential. In mice bearing the FaDu head and neck squamous cell carcinoma (HNSCC) xenograft tumor model, the combination of irradiation or 177Lu-NM600 + XRD-0394 improved tumor response and overall survival compared to monotherapy controls. Increased expression of type I interferon response genes was observed after irradiation + XRD-0394 compared to irradiation alone, suggesting that XRD-0394 may also accentuate the immunogenic effects of radiation on tumor cells. Further investigation is warranted into treatment approaches that combine radiopharmaceutical therapies, DNA repair inhibitors, and immunotherapies.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"459-471"},"PeriodicalIF":2.4,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13680051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient Oxygen Depletion and FLASH: Are We Ruling It Out Too Soon?","authors":"George D D Jones, Jan Schuemann, Bethany Rothwell","doi":"10.1667/RADE-25-00254","DOIUrl":"10.1667/RADE-25-00254","url":null,"abstract":"<p><p>The contribution of transient oxygen depletion (TOD) to the FLASH effect has been challenged, primarily because measurements indicate both insufficient depletion rates and normal tissue oxygenation levels that are too high. We argue that these parameters have been overly constrained, and that realistic ranges of tissue oxygen heterogeneity and reported ranges of oxygen consumption rates still enable meaningful depletion in regions of healthy tissue during ultra-high dose rate irradiation. Further evaluation of these measures is essential; TOD is a recognized protective phenomenon which, together with other mechanisms, can contribute towards a unified understanding of the FLASH effect.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"91-93"},"PeriodicalIF":2.4,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Underscoring the Effects of Proton Radiation on Neuronal Function in 2D and 3D In Vitro Cortical Tissue Models.","authors":"Neal M Lojek, Nazli Bostanci, Paulo H Borges, Andrew M Rogers, Erno Sajo, Isaac Meyer, Jan Schuemann, Egle Cekanaviciute, Bryan J Black, Chiara E Ghezzi","doi":"10.1667/RADE-25-00217","DOIUrl":"10.1667/RADE-25-00217","url":null,"abstract":"<p><p>Proton radiation is known to have detrimental neurological effects, but there is limited scientific understanding of these effects at the cellular and tissue levels. We leveraged our 3D in vitro cortical tissue model alongside 2D cortical cultures to study the effects of proton radiation on neuronal tissue. This platform is based on an established biofabrication method that produces tissue-like constructs seeded with human induced pluripotent stem cell-derived neurons and astrocytes or mouse embryonic cortical neurons and glia. Both 2D and 3D cultures were exposed to 3.0 MeV protons (10 Gy cumulative dose), and additional 2D samples were treated with the known radioprotectant drug amifostine. Biological readouts included DNA damage quantification, cytomorphology assessed by quantitative immunocytochemistry, inflammatory cytokine secretion, and electrophysiology using microelectrode array. We found a significant increase in DNA damage in irradiated 3D samples at 30 min post-proton irradiation, as expected. There was a significant decrease in GFAP and Iba1 expression, no significant changes in cytokine secretion due to proton radiation or amifostine treatment alone, and no significant changes in electrophysiological activity in 2D cultures over time. This work represents a functional analysis of a novel 3D multicellular cortical model and highlights neuronal resilience to acute proton-radiation exposure.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"1-19"},"PeriodicalIF":2.4,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Sequence of Cytopenia after Total-body Irradiation using Unsupervised Machine Learning.","authors":"Rahul K Goyal, John L McManus, Mathangi Gopalakrishnan","doi":"10.1667/RADE-25-00073.1","DOIUrl":"10.1667/RADE-25-00073.1","url":null,"abstract":"<p><p>Hematopoietic acute radiation syndrome (H-ARS) elicits multidimensional effects, as total-body irradiation (TBI) induced myelosuppression results in distinct patterns of loss and recovery across blood cell lineages. This study aimed to characterize the sequence of pancytopenia after TBI in male and female non-human primates (NHPs) with and without sargramostim treatment using unsupervised machine learning (ML). Longitudinal blood cell measures from three 60-day randomized, controlled trials of NHPs (N = 501) exposed to TBI and administered either vehicle (n = 173) or sargramostim (n = 328) were pooled for analysis. Hierarchical clustering of blood cells was performed using dynamic time warping (DTW) distances. Summary metrics of longitudinal trends were compared across treatment groups and sex. All analyses were performed in Pumas 2.0. Trends in each cluster showed that lymphocytes and reticulocytes are the first two cell populations to deplete rapidly, almost immediately after TBI, followed by white blood cell (WBC) related cells, platelets, and red blood cell (RBC) related cells. Reticulocytes reach nadir at day 8, followed by WBC-related cells at day 12, platelets at day 13, and RBC-related cells at day 17. The characterized pancytopenia sequence aligns with the typical lifespan of impaired blood cells, except for RBCs. Comparison across clusters between treated and untreated NHPs showed that sargramostim-treated animals started to recover earlier or at the same time as untreated animals. Female NHPs generally experienced deeper nadirs than males. In summary, characterizing pancytopenia using unsupervised machine learning improves understanding of the pathogenesis of H-ARS, which can enable improved therapeutic care, countermeasure development, and efficient medical triage.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":"205 6","pages":"563-571"},"PeriodicalIF":2.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148199847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the Sequence of Cytopenia after Total-body Irradiation using Unsupervised Machine Learning.","authors":"Rahul K Goyal, John L McManus, Matangi Gopalakrishnan","doi":"10.1667/RADE-25-00073","DOIUrl":"https://doi.org/10.1667/RADE-25-00073","url":null,"abstract":"<p><p>Hematopoietic acute radiation syndrome (H-ARS) elicits multidimensional effects, as total-body irradiation (TBI) induced myelosuppression results in distinct patterns of loss and recovery across blood cell lineages. This study aimed to characterize the sequence of pancytopenia after TBI in male and female non-human primates (NHPs) with and without sargramostim treatment using unsupervised machine learning (ML). Longitudinal blood cell measures from three 60-day randomized, controlled trials of NHPs (N = 501) exposed to TBI and administered either vehicle (n = 173) or sargramostim (n = 328) were pooled for analysis. Hierarchical clustering of blood cells was performed using dynamic time warping (DTW) distances. Summary metrics of longitudinal trends were compared across treatment groups and sex. All analyses were performed in Pumas 2.0. Trends in each cluster showed that lymphocytes and reticulocytes are the first two cell populations to deplete rapidly, almost immediately after TBI, followed by white blood cell (WBC) related cells, platelets, and red blood cell (RBC) related cells. Reticulocytes reach nadir at day 8, followed by WBC-related cells at day 12, platelets at day 13, and RBC-related cells at day 17. The characterized pancytopenia sequence aligns with the typical lifespan of impaired blood cells, except for RBCs. Comparison across clusters between treated and untreated NHPs showed that sargramostim-treated animals started to recover earlier or at the same time as untreated animals. Female NHPs generally experienced deeper nadirs than males. In summary, characterizing pancytopenia using unsupervised machine learning improves understanding of the pathogenesis of H-ARS, which can enable improved therapeutic care, countermeasure development, and efficient medical triage.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Toxicity and Biodistribution of Boron-loaded Liposomes in Canine and Feline Models.","authors":"M Heidari-Kharaji, Peter J Orto, T A Everett, S S Jalisatgi, J N Bryan, C A Maitz","doi":"10.1667/RADE-25-00102.1","DOIUrl":"10.1667/RADE-25-00102.1","url":null,"abstract":"<p><p>Boron neutron capture therapy (BNCT) is a targeted cancer treatment that relies on the selective accumulation of boron-containing agents in tumor cells, followed by irradiation with low-energy neutrons to produce a cytotoxic reaction. Liposome-mediated delivery systems have shown promise in improving the biodistribution and tumor specificity of boron agents in mice. This study aimed to evaluate the toxicity of boron-loaded liposomes (MAC/TAC formulations) in canine and feline models and to measure biodistribution in dogs with naturally occurring tumors. Boron-loaded liposomes were prepared using a thin-film hydration method and characterized for size, stability, and boron content. Toxicity was assessed by clinical signs, complete blood count (CBC), serum chemistry, and histopathological analysis. Biodistribution was analyzed using inductively coupled plasma optical emission spectroscopy (ICP-OES) to quantify boron levels in blood, tumors, and vital organs. Adverse reactions were observed in both species, with mild nausea and transient fever being the most common. Higher doses resulted in hematological changes, including leukocytosis and thrombocytopenia, particularly in feline subjects. Biodistribution studies showed a tumor-to-blood boron ratio <1:1 in most cases, which is insufficient for effective BNCT. Findings indicated that cancer-bearing dogs receiving boron-containing liposomes experienced significant toxicity responses, including lethargy, nausea, and inflammatory reactions, which were dose- and dose rate-dependent, consistent with the previously described C activation-related pseudoallergy (CARPA) syndrome. The role of this response on boron biodistribution warrants further investigation.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"528-536"},"PeriodicalIF":2.4,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}