Paul J Villeneuve, Brianna Frangione, Robert Talarico, Tim Prendergast, Chenchung Yu, Gagan Gill, Lydia Zablotska
Ionizing radiation is a human carcinogen and has been shown to increase the risk of non-cancerous ocular disorders. Specifically, findings from epidemiological studies suggest that ionizing radiation leads to the development of cataracts and to a lesser extent glaucoma, however, there are uncertainties of these risks at lower exposures. We analyzed data from a cohort of 60,874 Ontario Nuclear Power Plant (NPP) workers within the Canadian National Dose Registry (NDR). These workers were monitored for whole-body exposure to ionizing radiation using dosimeters, with exposure estimates derived for each year of employment. Incident cases of surgically removed cataracts and glaucoma were identified through the record linkage of occupational histories to administrative health data for Ontario between 1991 and 2022. We compared the incidence of surgically removed cataracts and glaucoma in the cohort to Ontario's general population using indirect age- and sex-standardization with matching by place of residence. We evaluated exposure-response relationships with internal cohort comparisons using age-, sex-, and calendar-period-adjusted Poisson regression. The relative risks of cataract and glaucoma were estimated across categorical measures of whole-body dose [Hp(10)] from exposure to radiation (lagged 5 years). In total, 32,855 of the 60,874 workers (58%) had a positive cumulative dose exceeding the minimum reportable threshold. Among these workers, the mean cumulative whole-body lifetime dose at end of follow-up was 23.7 mSv (interquartile range: 1.1-26.4 mSv, maximum = 959.3 mSv). Overall, 4,401 (7.2%) of workers developed glaucoma, while 2,939 (4.8%) underwent cataract-removal surgery. There was no evidence of a dose-response relationship between cumulative whole-body dose ionizing radiation (lagged 5 years) and glaucoma, but some for surgically removed cataract. Specifically, among workers with a cumulative exposure of greater than 50 mSv relative to those with an exposure of less than 0.25 mSv, the relative risks of incident glaucoma and cataract removal surgery were 0.91 (95% CI: 0.81-1.05) and 1.13 (95% CI: 0.97-1.33), respectively. The linear excess risks per 100 mSv (lagged 5 years) for cataract removal surgery was 0.055 (95% CI: -0.042 to 0.163). Our findings provide some evidence that ionizing radiation increases the risk of cataracts but not glaucoma in an occupational cohort whose lifetime cumulative dose rarely exceeded 30 mSv.
{"title":"Occupational Exposure to Low Dose Ionizing Radiation and the Incidence of Surgically Removed Cataracts and Glaucoma in a Cohort of Ontario Nuclear Power Plant Workers.","authors":"Paul J Villeneuve, Brianna Frangione, Robert Talarico, Tim Prendergast, Chenchung Yu, Gagan Gill, Lydia Zablotska","doi":"10.1667/RADE-24-00050.1","DOIUrl":"https://doi.org/10.1667/RADE-24-00050.1","url":null,"abstract":"<p><p>Ionizing radiation is a human carcinogen and has been shown to increase the risk of non-cancerous ocular disorders. Specifically, findings from epidemiological studies suggest that ionizing radiation leads to the development of cataracts and to a lesser extent glaucoma, however, there are uncertainties of these risks at lower exposures. We analyzed data from a cohort of 60,874 Ontario Nuclear Power Plant (NPP) workers within the Canadian National Dose Registry (NDR). These workers were monitored for whole-body exposure to ionizing radiation using dosimeters, with exposure estimates derived for each year of employment. Incident cases of surgically removed cataracts and glaucoma were identified through the record linkage of occupational histories to administrative health data for Ontario between 1991 and 2022. We compared the incidence of surgically removed cataracts and glaucoma in the cohort to Ontario's general population using indirect age- and sex-standardization with matching by place of residence. We evaluated exposure-response relationships with internal cohort comparisons using age-, sex-, and calendar-period-adjusted Poisson regression. The relative risks of cataract and glaucoma were estimated across categorical measures of whole-body dose [Hp(10)] from exposure to radiation (lagged 5 years). In total, 32,855 of the 60,874 workers (58%) had a positive cumulative dose exceeding the minimum reportable threshold. Among these workers, the mean cumulative whole-body lifetime dose at end of follow-up was 23.7 mSv (interquartile range: 1.1-26.4 mSv, maximum = 959.3 mSv). Overall, 4,401 (7.2%) of workers developed glaucoma, while 2,939 (4.8%) underwent cataract-removal surgery. There was no evidence of a dose-response relationship between cumulative whole-body dose ionizing radiation (lagged 5 years) and glaucoma, but some for surgically removed cataract. Specifically, among workers with a cumulative exposure of greater than 50 mSv relative to those with an exposure of less than 0.25 mSv, the relative risks of incident glaucoma and cataract removal surgery were 0.91 (95% CI: 0.81-1.05) and 1.13 (95% CI: 0.97-1.33), respectively. The linear excess risks per 100 mSv (lagged 5 years) for cataract removal surgery was 0.055 (95% CI: -0.042 to 0.163). Our findings provide some evidence that ionizing radiation increases the risk of cataracts but not glaucoma in an occupational cohort whose lifetime cumulative dose rarely exceeded 30 mSv.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449665","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}
The present study examined the effects of whole-body carbon-ion-beam irradiation on bone marrow death in mice and investigated whether compounds/materials, which were identified as efficient radio-protectors or mitigators against X-ray-radiation-induced bone marrow death, were also effective against the carbon-ion-beam-induced death of mice. Amifostine and cysteamine were used as radio-protectors and zinc-containing heat-killed yeast (Zn-yeast) and γ-tocopherol-N,N-dimethylglycine ester (γTDMG) as radio-mitigators. Amifostine or cysteamine was intraperitoneally administered in a single injection of 1.95 mmol/kg body weight 30 min before whole-body carbon-ion-beam irradiation. Zn-yeast or γTDMG was administered in a single intraperitoneal injection of 100 mg/kg body weight immediately after whole-body carbon-ion-beam irradiation. The absorbed dose dependence of the 30-day survival rate after carbon-ion-beam irradiation was analyzed. The biological effectiveness of carbon-ion-beam irradiation (LD50/30 = 5.54 Gy) was estimated as 1.2 relative to X-ray irradiation (LD50/30 = 6.62 Gy). The dose reduction factors (DRF) of amifostine, cysteamine, Zn-yeast, and γTDMG estimated for carbon-ion-beam irradiation were 1.75, 1.53, 1.16, and 1.15, respectively. Radio-protectors and -mitigators that were effective against photon irradiation also exhibited efficacy against carbon-ion-beam irradiation; however, the DRF for carbon-ion-beam irradiation was slightly smaller than that for photon irradiation. Based on the radio-protective effects of amifostine and cysteamine, the contribution of ROS/free radicals to carbon-ion-beam-induced bone marrow death was 70-90% to that of photon irradiation. Since the suppression of tumor growth by carbon-ion-beam irradiation was not inhibited by the treatment with γTDMG or Zn-yeast, both mitigators have potential as normal tissue-selective protectors in carbon-ion irradiation.
{"title":"Effects of Whole-Body Carbon-Ion Beam Irradiation on Bone Marrow Death in Mice and an Examination of Candidates for Protectors or Mitigators against Carbon-Ion-Beam-Induced Bone Marrow Death.","authors":"Megumi Ueno, Shuichi Setoguchi, Kazuhisa Matsunaga, Ken-Ichiro Matsumoto, Jiro Takata, Kazunori Anzai","doi":"10.1667/RADE-23-00253.1","DOIUrl":"https://doi.org/10.1667/RADE-23-00253.1","url":null,"abstract":"<p><p>The present study examined the effects of whole-body carbon-ion-beam irradiation on bone marrow death in mice and investigated whether compounds/materials, which were identified as efficient radio-protectors or mitigators against X-ray-radiation-induced bone marrow death, were also effective against the carbon-ion-beam-induced death of mice. Amifostine and cysteamine were used as radio-protectors and zinc-containing heat-killed yeast (Zn-yeast) and γ-tocopherol-N,N-dimethylglycine ester (γTDMG) as radio-mitigators. Amifostine or cysteamine was intraperitoneally administered in a single injection of 1.95 mmol/kg body weight 30 min before whole-body carbon-ion-beam irradiation. Zn-yeast or γTDMG was administered in a single intraperitoneal injection of 100 mg/kg body weight immediately after whole-body carbon-ion-beam irradiation. The absorbed dose dependence of the 30-day survival rate after carbon-ion-beam irradiation was analyzed. The biological effectiveness of carbon-ion-beam irradiation (LD50/30 = 5.54 Gy) was estimated as 1.2 relative to X-ray irradiation (LD50/30 = 6.62 Gy). The dose reduction factors (DRF) of amifostine, cysteamine, Zn-yeast, and γTDMG estimated for carbon-ion-beam irradiation were 1.75, 1.53, 1.16, and 1.15, respectively. Radio-protectors and -mitigators that were effective against photon irradiation also exhibited efficacy against carbon-ion-beam irradiation; however, the DRF for carbon-ion-beam irradiation was slightly smaller than that for photon irradiation. Based on the radio-protective effects of amifostine and cysteamine, the contribution of ROS/free radicals to carbon-ion-beam-induced bone marrow death was 70-90% to that of photon irradiation. Since the suppression of tumor growth by carbon-ion-beam irradiation was not inhibited by the treatment with γTDMG or Zn-yeast, both mitigators have potential as normal tissue-selective protectors in carbon-ion irradiation.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399780","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}
Huiting Peng, Bingqing Cui, Jianming Wei, Min Yuan, Wenjuan Liu, Jing Shi, Yuguo Liu
Breast cancer is a commonly diagnosed cancer, while resistance to radiation therapy remains an important factor hindering the treatment of patients. Timosaponin AIII (Tim AIII) is a steroidal saponin from the Anemarrhena asphodeloides. Its pharmacologic effects and mechanisms for enhancing radiotherapy remain largely unknown. This study investigates Tim AIII ç and aims to unravel the underlying mechanisms. Experiments, including cell cloning, scratch assays, cell cycle, apoptosis assays, immunofluorescence staining, and reactive oxygen species (ROS) assessments, were conducted on breast cancer cell lines MDA-MB-231 and JIMT-1 to investigate the impact of Tim AIII combined with radiation. Western blot analyses were used to detect γ-H2AX expression, ROS-related pathways, ATM-CHK2, and AKT-MTOR pathways. Subcutaneous tumor experiments in nude mice confirmed in vivo radiation sensitization. When combined with radiation, Tim AIII significantly inhibited cell clone formation, impeded cancer cell migration, increased G2/M phase arrest and apoptosis. Immunofluorescence showed prolonged γ-H2AX signals. Molecular investigations indicated Tim AIII amplified radiation-induced ROS production, inducing ROS-mediated DNA damage and apoptosis. It activated ATM-CHK2 while inhibiting the AKT-MTOR pathway. Tim AIII enhances radiation sensitivity in breast cancer cells, both in vitro and in vivo. Through ROS-mediated DNA damage and apoptosis, activation of ATM/Chk2 and inhibition of the AKT-MTOR pathway induce G2/M phase arrest, ultimately boosting radiation sensitivity via the mitochondrial-mediated apoptotic pathway.
{"title":"Timosaponin AIII Enhances Radiosensitivity in Breast Cancer through Induction of ROS-Mediated DNA Damage and Apoptosis.","authors":"Huiting Peng, Bingqing Cui, Jianming Wei, Min Yuan, Wenjuan Liu, Jing Shi, Yuguo Liu","doi":"10.1667/RADE-24-00087.1","DOIUrl":"https://doi.org/10.1667/RADE-24-00087.1","url":null,"abstract":"<p><p>Breast cancer is a commonly diagnosed cancer, while resistance to radiation therapy remains an important factor hindering the treatment of patients. Timosaponin AIII (Tim AIII) is a steroidal saponin from the Anemarrhena asphodeloides. Its pharmacologic effects and mechanisms for enhancing radiotherapy remain largely unknown. This study investigates Tim AIII ç and aims to unravel the underlying mechanisms. Experiments, including cell cloning, scratch assays, cell cycle, apoptosis assays, immunofluorescence staining, and reactive oxygen species (ROS) assessments, were conducted on breast cancer cell lines MDA-MB-231 and JIMT-1 to investigate the impact of Tim AIII combined with radiation. Western blot analyses were used to detect γ-H2AX expression, ROS-related pathways, ATM-CHK2, and AKT-MTOR pathways. Subcutaneous tumor experiments in nude mice confirmed in vivo radiation sensitization. When combined with radiation, Tim AIII significantly inhibited cell clone formation, impeded cancer cell migration, increased G2/M phase arrest and apoptosis. Immunofluorescence showed prolonged γ-H2AX signals. Molecular investigations indicated Tim AIII amplified radiation-induced ROS production, inducing ROS-mediated DNA damage and apoptosis. It activated ATM-CHK2 while inhibiting the AKT-MTOR pathway. Tim AIII enhances radiation sensitivity in breast cancer cells, both in vitro and in vivo. Through ROS-mediated DNA damage and apoptosis, activation of ATM/Chk2 and inhibition of the AKT-MTOR pathway induce G2/M phase arrest, ultimately boosting radiation sensitivity via the mitochondrial-mediated apoptotic pathway.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399819","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}
The objective of this study was to investigate the relationship between radiotherapy sensitivity, glutamine synthetase (GS), and oxidative stress (OS) in human hepatocellular carcinoma (HCC) cells. HCC cells were X-ray irradiated, and the effect of glutamine synthetase inhibition on the proliferative capacity of HCC cells was examined using the CCK-8 colony formation assay. Real-time quantitative PCR assays were used to detect the effect of L-methionine sulfoximine (MSO) on cellular glutamine synthetase expression levels and the efficiency of glutamine synthetase knockdown in HepG2 cells. Glutamine synthetase activity assay kit was used to detect the viability of glutamine synthetase in cells and tissues. Oxidative stress production was assayed using an oxidative stress assay kit. Subcutaneous xenografts were used to detect the effects of L-methionine sulfoximine and radiation on tumor growth in vivo. The results showed that the apparent cell proliferation capacity of HCC cells after glutamine synthetase inhibition was significantly reduced after radiotherapy, which was closely related to the increased production of oxidative stress after radiotherapy. Furthermore, the results of animal experiments also showed that the combination of L-methionine sulfoximine and radiation induced a stronger tumor suppressive effect and that L-methionine sulfoximine could act as a radiosensitizer after radiotherapy.
{"title":"The Role of Glutamine Synthetase on the Sensitivity to Radiotherapy of Hepatocellular Carcinoma.","authors":"Yuan He, Huihan Yu, Yijun Lu, Chen Zhou, Yu Tian, Tianwei Song, Dandan Wang, Zhiyou Fang, Zhi Zhang, Hongzhi Wang, Junchao Qian","doi":"10.1667/RADE-22-00181.1","DOIUrl":"https://doi.org/10.1667/RADE-22-00181.1","url":null,"abstract":"<p><p>The objective of this study was to investigate the relationship between radiotherapy sensitivity, glutamine synthetase (GS), and oxidative stress (OS) in human hepatocellular carcinoma (HCC) cells. HCC cells were X-ray irradiated, and the effect of glutamine synthetase inhibition on the proliferative capacity of HCC cells was examined using the CCK-8 colony formation assay. Real-time quantitative PCR assays were used to detect the effect of L-methionine sulfoximine (MSO) on cellular glutamine synthetase expression levels and the efficiency of glutamine synthetase knockdown in HepG2 cells. Glutamine synthetase activity assay kit was used to detect the viability of glutamine synthetase in cells and tissues. Oxidative stress production was assayed using an oxidative stress assay kit. Subcutaneous xenografts were used to detect the effects of L-methionine sulfoximine and radiation on tumor growth in vivo. The results showed that the apparent cell proliferation capacity of HCC cells after glutamine synthetase inhibition was significantly reduced after radiotherapy, which was closely related to the increased production of oxidative stress after radiotherapy. Furthermore, the results of animal experiments also showed that the combination of L-methionine sulfoximine and radiation induced a stronger tumor suppressive effect and that L-methionine sulfoximine could act as a radiosensitizer after radiotherapy.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143123320","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}
Alana D Carpenter, Yaoxiang Li, Issa Melendez Miranda, Stephen Y Wise, Oluseyi O Fatanmi, Sarah A Petrus, Christine M Fam, Sharon J Carlson, George N Cox, Amrita K Cheema, Vijay K Singh
BBT-059 is a long-acting PEGylated interleukin-11 analog that has been shown to have hematopoiesis-promoting and anti-apoptotic attributes, and is being studied as a radiation countermeasure for the hematopoietic acute radiation syndrome (H-ARS). This potential countermeasure has been demonstrated to enhance survival in irradiated mice. To investigate the toxicity and safety profile of this agent, 14 nonhuman primates (NHPs, rhesus macaques) were administered two different doses of BBT-059 subcutaneously 24 h after 4 Gy total-body irradiation and were monitored for the next 60 days postirradiation. Blood samples were investigated for the pharmacokinetics and pharmacodynamics of this agent and its effects on complete blood counts, cytokines, vital signs, and metabolomics. No adverse health effects were observed in either treatment group. Radiation-induced metabolomic dysregulation was observed in both treatment groups, and BBT-059 afforded some short-term radiomitigation. A few pathways were commonly dysregulated by radiation exposure including steroid hormone biosynthesis pathways, fatty acid activation, and glycerophospholipid metabolism. Notably, radiation-induced dysregulation to the linoleate metabolism pathway was significantly mitigated by either dose of BBT-059. In brief, this study suggests that BBT-059 has a good safety profile in irradiated NHPs and that its development as a medical countermeasure for U.S. Food and Drug Administration approval for human use should be continued.
{"title":"Pharmacokinetic and Metabolomic Studies with BBT-059 in Nonhuman Primates Exposed to Total-Body Gamma Radiation.","authors":"Alana D Carpenter, Yaoxiang Li, Issa Melendez Miranda, Stephen Y Wise, Oluseyi O Fatanmi, Sarah A Petrus, Christine M Fam, Sharon J Carlson, George N Cox, Amrita K Cheema, Vijay K Singh","doi":"10.1667/RADE-24-00219.1","DOIUrl":"10.1667/RADE-24-00219.1","url":null,"abstract":"<p><p>BBT-059 is a long-acting PEGylated interleukin-11 analog that has been shown to have hematopoiesis-promoting and anti-apoptotic attributes, and is being studied as a radiation countermeasure for the hematopoietic acute radiation syndrome (H-ARS). This potential countermeasure has been demonstrated to enhance survival in irradiated mice. To investigate the toxicity and safety profile of this agent, 14 nonhuman primates (NHPs, rhesus macaques) were administered two different doses of BBT-059 subcutaneously 24 h after 4 Gy total-body irradiation and were monitored for the next 60 days postirradiation. Blood samples were investigated for the pharmacokinetics and pharmacodynamics of this agent and its effects on complete blood counts, cytokines, vital signs, and metabolomics. No adverse health effects were observed in either treatment group. Radiation-induced metabolomic dysregulation was observed in both treatment groups, and BBT-059 afforded some short-term radiomitigation. A few pathways were commonly dysregulated by radiation exposure including steroid hormone biosynthesis pathways, fatty acid activation, and glycerophospholipid metabolism. Notably, radiation-induced dysregulation to the linoleate metabolism pathway was significantly mitigated by either dose of BBT-059. In brief, this study suggests that BBT-059 has a good safety profile in irradiated NHPs and that its development as a medical countermeasure for U.S. Food and Drug Administration approval for human use should be continued.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"83-95"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142954075","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}
Shannon Hartzell, Fada Guan, Giuseppe Magro, Paige Taylor, Phillip J Taddei, Christine B Peterson, Stephen Kry
Variable relative biological effectiveness (RBE) of carbon radiotherapy may be calculated using several models, including the microdosimetric kinetic model (MKM), stochastic MKM (SMKM), repair-misrepair-fixation (RMF) model, and local effect model I (LEM), which have not been thoroughly compared. In this work, we compared how these four models handle carbon beam fragmentation, providing insight into where model differences arise. Monoenergetic and spread-out Bragg peak carbon beams incident on a water phantom were simulated using Monte Carlo. Using these beams, input parameters for each model (microdosimetric spectra, DNA double-strand break yield, kinetic energy spectra, physical dose fragment contributions) were calculated for each contributing carbon beam fragment (hydrogen, helium, lithium, beryllium, boron, secondary carbon, primary carbon, electrons, and "other"). Scored input parameters for each fragment were used to calculate linear (α) and quadratic (β) parameters according to each model, which were combined with reference α and β values and absorbed physical dose to calculate RBE. Contributions from secondary fragments were found to exceed 30% of the total physical dose. Using identical beam parameters, the four models produced not only different RBE values but also different RBE trends. In all models, RBE was highest for secondary carbon ions. Beyond secondary carbons, the RBE magnitude typically increased with the atomic number of the fragment, but RBE trends differed dramatically by model and beamline region (entrance, spread-out Bragg peak, and tail). Variations in fragment RBE were large enough to be apparent in biological dose predictions. This study demonstrated that fragmentation is a nonnegligible consideration in carbon radiotherapy. Our findings identified differences in RBE among specific fragments and the four models, contributing to variability in the total biological dose across models. Because these findings emphasize differences in how various models handle carbon beam fragments, greater care should be taken in characterization of secondary fragments in particle therapy.
{"title":"Contribution of Nuclear Fragmentation to Dose and RBE in Carbon-Ion Radiotherapy.","authors":"Shannon Hartzell, Fada Guan, Giuseppe Magro, Paige Taylor, Phillip J Taddei, Christine B Peterson, Stephen Kry","doi":"10.1667/RADE-24-00164.1","DOIUrl":"10.1667/RADE-24-00164.1","url":null,"abstract":"<p><p>Variable relative biological effectiveness (RBE) of carbon radiotherapy may be calculated using several models, including the microdosimetric kinetic model (MKM), stochastic MKM (SMKM), repair-misrepair-fixation (RMF) model, and local effect model I (LEM), which have not been thoroughly compared. In this work, we compared how these four models handle carbon beam fragmentation, providing insight into where model differences arise. Monoenergetic and spread-out Bragg peak carbon beams incident on a water phantom were simulated using Monte Carlo. Using these beams, input parameters for each model (microdosimetric spectra, DNA double-strand break yield, kinetic energy spectra, physical dose fragment contributions) were calculated for each contributing carbon beam fragment (hydrogen, helium, lithium, beryllium, boron, secondary carbon, primary carbon, electrons, and \"other\"). Scored input parameters for each fragment were used to calculate linear (α) and quadratic (β) parameters according to each model, which were combined with reference α and β values and absorbed physical dose to calculate RBE. Contributions from secondary fragments were found to exceed 30% of the total physical dose. Using identical beam parameters, the four models produced not only different RBE values but also different RBE trends. In all models, RBE was highest for secondary carbon ions. Beyond secondary carbons, the RBE magnitude typically increased with the atomic number of the fragment, but RBE trends differed dramatically by model and beamline region (entrance, spread-out Bragg peak, and tail). Variations in fragment RBE were large enough to be apparent in biological dose predictions. This study demonstrated that fragmentation is a nonnegligible consideration in carbon radiotherapy. Our findings identified differences in RBE among specific fragments and the four models, contributing to variability in the total biological dose across models. Because these findings emphasize differences in how various models handle carbon beam fragments, greater care should be taken in characterization of secondary fragments in particle therapy.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"96-106"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041526","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}
Shayenthiran Sreetharan, Stephanie Puukila, Christine Lalonde, Jake Pirkkanen, Gayle E Woloschak, Tatjana Paunesku, Antone L Brooks, Fiona E McNeill, Christopher Thome, Douglas R Boreham, Simon J Lees, Sujeenthar Tharmalingam, T C Tai
Ionizing radiation exposure during perinatal development can produce various biological effects on the developing offspring. These effects are dependent on a number of factors, including total dose, dose rate and the developmental processes occurring at the time of irradiation. The present study conducted an analysis of historical radiobiological archived data involving 60Co-gamma irradiation of beagle dogs at specific periods of prenatal or postnatal development. The original studies were performed at two sites where animals were exposed to a single, acute dose of 0.2 or 1.0 Gy at six different stages of perinatal development or with protracted exposures ranging from 0.004 to 0.35 Gy per day, over multiple days of gestation. A number of outcomes were investigated after perinatal irradiation including changes in sex ratio, survival probability, disease incidence and growth of animals, based on collected size and weight measurements of animals and different tissues. Protracted irradiations with doses up to 0.35 Gy per day did not significantly affect survival in animals when irradiated prenatally, although significant increases in the incidence of neoplasms and diseases related to the cardiovascular and urogenital system were observed at the time of death. Dogs irradiated at a dose rate of 0.10 Gy per day, with the irradiations continuing after birth and resulting in the accumulation of large total doses, were observed to have chronic radiation syndrome symptoms based on pathologies related to the hematopoietic system. Acute irradiation with 0.2 and 1.0 Gy resulted in changes of different body or tissue sizes measured in animals terminally, with changes detected after irradiation at all tested prenatal and postnatal time points, with the exception of irradiation at 365 days after birth. The present analysis provides new information regarding the biological effects of ionizing radiation during perinatal development in offspring in the unique mammalian study model of the beagle dog.
{"title":"Comparison of Acute and Protracted Gamma Irradiation Effects During Perinatal Development in Beagle Dogs.","authors":"Shayenthiran Sreetharan, Stephanie Puukila, Christine Lalonde, Jake Pirkkanen, Gayle E Woloschak, Tatjana Paunesku, Antone L Brooks, Fiona E McNeill, Christopher Thome, Douglas R Boreham, Simon J Lees, Sujeenthar Tharmalingam, T C Tai","doi":"10.1667/RADE-24-00080.1","DOIUrl":"10.1667/RADE-24-00080.1","url":null,"abstract":"<p><p>Ionizing radiation exposure during perinatal development can produce various biological effects on the developing offspring. These effects are dependent on a number of factors, including total dose, dose rate and the developmental processes occurring at the time of irradiation. The present study conducted an analysis of historical radiobiological archived data involving 60Co-gamma irradiation of beagle dogs at specific periods of prenatal or postnatal development. The original studies were performed at two sites where animals were exposed to a single, acute dose of 0.2 or 1.0 Gy at six different stages of perinatal development or with protracted exposures ranging from 0.004 to 0.35 Gy per day, over multiple days of gestation. A number of outcomes were investigated after perinatal irradiation including changes in sex ratio, survival probability, disease incidence and growth of animals, based on collected size and weight measurements of animals and different tissues. Protracted irradiations with doses up to 0.35 Gy per day did not significantly affect survival in animals when irradiated prenatally, although significant increases in the incidence of neoplasms and diseases related to the cardiovascular and urogenital system were observed at the time of death. Dogs irradiated at a dose rate of 0.10 Gy per day, with the irradiations continuing after birth and resulting in the accumulation of large total doses, were observed to have chronic radiation syndrome symptoms based on pathologies related to the hematopoietic system. Acute irradiation with 0.2 and 1.0 Gy resulted in changes of different body or tissue sizes measured in animals terminally, with changes detected after irradiation at all tested prenatal and postnatal time points, with the exception of irradiation at 365 days after birth. The present analysis provides new information regarding the biological effects of ionizing radiation during perinatal development in offspring in the unique mammalian study model of the beagle dog.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"73-82"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029456","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}
<p><p>Although leukemia in the Japanese atomic bomb survivor data has long exhibited upward curvature, until recently this appeared not to be the case for solid cancer. It has been suggested that the recently observed upward curvature in the dose response for the Japanese atomic bomb survivor solid cancer mortality data may be accounted for by flattening of the dose response in the moderate dose range (0.3-0.7 Gy). To investigate this, the latest version available of the solid cancer mortality and incidence datasets (with follow-up over the years 1950-2003 and 1958-2009 respectively) for the Life Span Study cohort of atomic bomb survivors was used to assess possible departures from linearity in the moderate dose range. Linear-spline models were fitted, also up to 6th order polynomial models in dose (higher order polynomials tended not to converge). The organ dose used for all solid cancers was weighted dose to the colon. There are modest indications of departures from linearity for the mortality data, whether using polynomial or linear-spline models. Use of the Akaike information criterion (AIC) suggests that the optimal model for the mortality data is given by a 5th order polynomial in dose. There is borderline significant (P = 0.071) indication of improvement provided by a linear-spline model in the mortality data. The low-dose extrapolation factor (LDEF), which measures the degree of overestimation of low-dose linear slope by the linear slope fitted over some specified dose range, is generally between 1.1-2.0 depending on the dose range, with upper confidence limits that sometimes exceed 10; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that exceeds 1.6. There are generally only modest indications of departures from linearity for the solid cancer incidence data, whether using polynomial or linear-spline models. In contrast to the mortality data, there are much weaker indications of improvement in fit provided by higher order polynomials, and only weak indications (P > 0.2) of improvement provided by linear-spline models. Nevertheless, use of AIC suggests that the optimal model for the incidence data is given by a 3rd order polynomial. LDEF evaluated over various dose ranges is generally between 1.2-1.4 with upper confidence limits that generally exceed 1.6; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that substantially exceeds 2.0. In summary, the evidence we have presented for higher order powers than the second in the dose response is not overwhelmingly strong, and is to some extent dependent on dose range. A feature of the dose response, which is reflected in the higher-order polynomials fitted to the data, is a leveling off or even a downturn in the response at doses >2 Gy. The linear-quadratic model is very widely used for modeling of dose response, and has been widely used in radiothe
{"title":"Analysis of Departures from Linearity in the Dose Response for Japanese Atomic Bomb Survivor Solid Cancer Mortality and Cancer Incidence Data and Assessment of Low-Dose Extrapolation Factors.","authors":"Mark P Little, Nobuyuki Hamada, Harry M Cullings","doi":"10.1667/RADE-24-00202.1","DOIUrl":"10.1667/RADE-24-00202.1","url":null,"abstract":"<p><p>Although leukemia in the Japanese atomic bomb survivor data has long exhibited upward curvature, until recently this appeared not to be the case for solid cancer. It has been suggested that the recently observed upward curvature in the dose response for the Japanese atomic bomb survivor solid cancer mortality data may be accounted for by flattening of the dose response in the moderate dose range (0.3-0.7 Gy). To investigate this, the latest version available of the solid cancer mortality and incidence datasets (with follow-up over the years 1950-2003 and 1958-2009 respectively) for the Life Span Study cohort of atomic bomb survivors was used to assess possible departures from linearity in the moderate dose range. Linear-spline models were fitted, also up to 6th order polynomial models in dose (higher order polynomials tended not to converge). The organ dose used for all solid cancers was weighted dose to the colon. There are modest indications of departures from linearity for the mortality data, whether using polynomial or linear-spline models. Use of the Akaike information criterion (AIC) suggests that the optimal model for the mortality data is given by a 5th order polynomial in dose. There is borderline significant (P = 0.071) indication of improvement provided by a linear-spline model in the mortality data. The low-dose extrapolation factor (LDEF), which measures the degree of overestimation of low-dose linear slope by the linear slope fitted over some specified dose range, is generally between 1.1-2.0 depending on the dose range, with upper confidence limits that sometimes exceed 10; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that exceeds 1.6. There are generally only modest indications of departures from linearity for the solid cancer incidence data, whether using polynomial or linear-spline models. In contrast to the mortality data, there are much weaker indications of improvement in fit provided by higher order polynomials, and only weak indications (P > 0.2) of improvement provided by linear-spline models. Nevertheless, use of AIC suggests that the optimal model for the incidence data is given by a 3rd order polynomial. LDEF evaluated over various dose ranges is generally between 1.2-1.4 with upper confidence limits that generally exceed 1.6; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that substantially exceeds 2.0. In summary, the evidence we have presented for higher order powers than the second in the dose response is not overwhelmingly strong, and is to some extent dependent on dose range. A feature of the dose response, which is reflected in the higher-order polynomials fitted to the data, is a leveling off or even a downturn in the response at doses >2 Gy. The linear-quadratic model is very widely used for modeling of dose response, and has been widely used in radiothe","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"115-127"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972104","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}
Luca Caramenti, Paweł Wołowiec, Piotr Kędzierawski, Stanisław Góźdź, André Buchali, Michael Hauptmann, Andrzej Wojcik
The role of genetics in susceptibility to radiotherapy-induced toxicities is unclear. A strong impact of genetics should cause correlated toxicities in patients with metachronous double radiotherapy. We ascertained information about demographics, lifestyle, radiotherapy and early toxicities in irradiated tissues for a retrospective cohort of 98 patients from 2 hospitals who underwent two metachronous radiotherapeutic treatments (2000-2022) of different anatomical regions. European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scores per organ system were combined to a single mean score. We considered as genetic component the variation of toxicity not explained by radiation dose to the tumor, age at radiotherapy, sex, smoking status, and surgery. Variance components of toxicity were evaluated by ordinal logistic regression with random intercept. Common site combinations were breast/contralateral breast (N = 16), breast/endometrium (N = 6), and cervix/breast (N = 5). Mean toxicity over exposed tissues was 0.70 (range, 0-3). Prescribed radiation dose was significantly associated with mean toxicity, with a 5% (95% CI 3-8) increase of the odds for a higher toxicity level per Gy. Sex, surgery, age and smoking were not. There was no genetic contribution to risk of toxicities after adjustment. Toxicity levels were not more similar within patients than between patients, suggesting a negligible impact of genotype on radiotherapy-related toxicities.
遗传学在放射治疗引起的毒性易感性中的作用尚不清楚。遗传学的强烈影响可能导致异时双重放疗患者的相关毒性。我们确定了来自2家医院的98名患者的人口统计学信息、生活方式、放射治疗和放射组织的早期毒性,这些患者接受了两次不同解剖区域的异时放射治疗(2007-2022)。欧洲癌症研究和治疗组织/放射治疗肿瘤组(EORTC/RTOG)每个器官系统的毒性评分合并为一个平均评分。我们认为遗传成分的毒性变异不能由肿瘤的辐射剂量、放疗年龄、性别、吸烟状况和手术来解释。采用随机截距的有序逻辑回归评估毒性的方差成分。常见的部位组合为乳房/对侧乳房(N = 16)、乳房/子宫内膜(N = 6)和宫颈/乳房(N = 5)。暴露组织的平均毒性为0.70(范围0-3)。规定的辐射剂量与平均毒性显著相关,每Gy较高毒性水平的几率增加5% (95% CI 3-8)。而性别、手术、年龄和吸烟则不在其中。调整后毒性风险无遗传影响。患者体内的毒性水平并不比患者之间更相似,这表明基因型对放疗相关毒性的影响可以忽略不计。
{"title":"Individual Sensitivity for Radiotherapy-related Adverse Tissue Reactions in Patients Treated Twice for Metachronous Cancers.","authors":"Luca Caramenti, Paweł Wołowiec, Piotr Kędzierawski, Stanisław Góźdź, André Buchali, Michael Hauptmann, Andrzej Wojcik","doi":"10.1667/RADE-24-00226.1","DOIUrl":"10.1667/RADE-24-00226.1","url":null,"abstract":"<p><p>The role of genetics in susceptibility to radiotherapy-induced toxicities is unclear. A strong impact of genetics should cause correlated toxicities in patients with metachronous double radiotherapy. We ascertained information about demographics, lifestyle, radiotherapy and early toxicities in irradiated tissues for a retrospective cohort of 98 patients from 2 hospitals who underwent two metachronous radiotherapeutic treatments (2000-2022) of different anatomical regions. European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scores per organ system were combined to a single mean score. We considered as genetic component the variation of toxicity not explained by radiation dose to the tumor, age at radiotherapy, sex, smoking status, and surgery. Variance components of toxicity were evaluated by ordinal logistic regression with random intercept. Common site combinations were breast/contralateral breast (N = 16), breast/endometrium (N = 6), and cervix/breast (N = 5). Mean toxicity over exposed tissues was 0.70 (range, 0-3). Prescribed radiation dose was significantly associated with mean toxicity, with a 5% (95% CI 3-8) increase of the odds for a higher toxicity level per Gy. Sex, surgery, age and smoking were not. There was no genetic contribution to risk of toxicities after adjustment. Toxicity levels were not more similar within patients than between patients, suggesting a negligible impact of genotype on radiotherapy-related toxicities.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"107-114"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142979789","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}
Data from animal experiments show that the radiation-related risk of cancer decreases if the dose rate is reduced, even though the cumulative dose is unchanged (i.e., a dose-rate effect); however, the underlying mechanism is not well understood. To explore factors underlying the dose-rate effect observed in experimental rat mammary carcinogenesis, we developed a mathematical model that accounts for cellular dynamics during carcinogenesis, and then examined whether the model predicts cancer incidence. A mathematical model of multistage carcinogenesis involving radiation-induced cell death and mutagenesis was constructed using differential equations. The mutation rate was changed depending on the dose rate. The model also considered competition among cells with various mutation levels. The main parameters of the model were determined using previous experimental data. The parameters of the model were consistent with experimental observations. A dose-rate effect on carcinogenesis became apparent when the relationship between dose rate and mutation rate was linear quadratic or quadratic. The dose-rate effect became prominent when cells with more mutations preferentially compensated for the radiation-induced death of cells with fewer mutations. The phenomenon by which mutated cells gain a competitive advantage over normal cells is known as super-competition. Here, we identified super-competition as a novel mechanism underlying the dose-rate effects on carcinogenesis. The data also confirmed the relevance of the shape of the relationship between dose rate and the mutation rate. Thus, this study provides new evidence for the mechanism underlying the dose-rate effect, which is important for predicting the cancer-related risks of low-dose-rate irradiation.
{"title":"Super-competition as a Novel Mechanism of the Dose-rate Effect in Radiation Carcinogenesis: A Mathematical Model Study.","authors":"Yuya Hattori, Kento Nagata, Ritsuko Watanabe, Akinari Yokoya, Tatsuhiko Imaoka","doi":"10.1667/RADE-24-00191.1","DOIUrl":"10.1667/RADE-24-00191.1","url":null,"abstract":"<p><p>Data from animal experiments show that the radiation-related risk of cancer decreases if the dose rate is reduced, even though the cumulative dose is unchanged (i.e., a dose-rate effect); however, the underlying mechanism is not well understood. To explore factors underlying the dose-rate effect observed in experimental rat mammary carcinogenesis, we developed a mathematical model that accounts for cellular dynamics during carcinogenesis, and then examined whether the model predicts cancer incidence. A mathematical model of multistage carcinogenesis involving radiation-induced cell death and mutagenesis was constructed using differential equations. The mutation rate was changed depending on the dose rate. The model also considered competition among cells with various mutation levels. The main parameters of the model were determined using previous experimental data. The parameters of the model were consistent with experimental observations. A dose-rate effect on carcinogenesis became apparent when the relationship between dose rate and mutation rate was linear quadratic or quadratic. The dose-rate effect became prominent when cells with more mutations preferentially compensated for the radiation-induced death of cells with fewer mutations. The phenomenon by which mutated cells gain a competitive advantage over normal cells is known as super-competition. Here, we identified super-competition as a novel mechanism underlying the dose-rate effects on carcinogenesis. The data also confirmed the relevance of the shape of the relationship between dose rate and the mutation rate. Thus, this study provides new evidence for the mechanism underlying the dose-rate effect, which is important for predicting the cancer-related risks of low-dose-rate irradiation.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"61-72"},"PeriodicalIF":2.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143010718","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}