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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.
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-19 DOI: 10.1667/RADE-24-00050.1
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}
引用次数: 0
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.
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-12 DOI: 10.1667/RADE-23-00253.1
Megumi Ueno, Shuichi Setoguchi, Kazuhisa Matsunaga, Ken-Ichiro Matsumoto, Jiro Takata, Kazunori Anzai

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}
引用次数: 0
Timosaponin AIII Enhances Radiosensitivity in Breast Cancer through Induction of ROS-Mediated DNA Damage and Apoptosis.
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-12 DOI: 10.1667/RADE-24-00087.1
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}
引用次数: 0
The Role of Glutamine Synthetase on the Sensitivity to Radiotherapy of Hepatocellular Carcinoma.
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-04 DOI: 10.1667/RADE-22-00181.1
Yuan He, Huihan Yu, Yijun Lu, Chen Zhou, Yu Tian, Tianwei Song, Dandan Wang, Zhiyou Fang, Zhi Zhang, Hongzhi Wang, Junchao Qian

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.

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引用次数: 0
Pharmacokinetic and Metabolomic Studies with BBT-059 in Nonhuman Primates Exposed to Total-Body Gamma Radiation. 受全身伽玛辐射的非人灵长类动物体内BBT-059的药代动力学和代谢组学研究。
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-01 DOI: 10.1667/RADE-24-00219.1
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.

BBT-059是一种长效聚乙二醇化的白介素-11类似物,已被证明具有促进造血和抗凋亡的特性,目前正在研究作为一种治疗造血急性辐射综合征(H-ARS)的辐射对策。这种潜在的对策已被证明可以提高辐照小鼠的存活率。为了研究该制剂的毒性和安全性,14只非人灵长类动物(NHPs,恒河猴)在接受4 Gy全身照射24小时后皮下注射两种不同剂量的BBT-059,并在照射后的60天内进行监测。研究了血液样本的药代动力学和药效学及其对全血细胞计数、细胞因子、生命体征和代谢组学研究的影响。两组均未见不良反应。在两个治疗组中都观察到辐射引起的代谢组失调,BBT-059具有一定的短期辐射缓解作用。一些途径通常被辐射照射失调,包括类固醇激素生物合成途径、脂肪酸激活和甘油磷脂代谢。值得注意的是,两种剂量的BBT-059均可显著减轻辐射引起的亚油酸代谢途径失调。总之,本研究表明,BBT-059在辐照NHPs中具有良好的安全性,应继续发展其作为美国食品和药物管理局批准人类使用的医疗对策。
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引用次数: 0
Contribution of Nuclear Fragmentation to Dose and RBE in Carbon-Ion Radiotherapy.
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-01 DOI: 10.1667/RADE-24-00164.1
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}
引用次数: 0
Comparison of Acute and Protracted Gamma Irradiation Effects During Perinatal Development in Beagle Dogs.
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-01 DOI: 10.1667/RADE-24-00080.1
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.

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引用次数: 0
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. 日本原子弹爆炸幸存者实体癌死亡率和发病率数据的剂量反应偏离线性分析及低剂量外推因素的评估。
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-01 DOI: 10.1667/RADE-24-00202.1
Mark P Little, Nobuyuki Hamada, Harry M Cullings
<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
虽然日本原子弹爆炸幸存者的白血病数据长期以来一直呈上升趋势,但直到最近,实体癌的情况似乎并非如此。有人认为,最近在日本原子弹爆炸幸存者实体癌死亡率数据中观察到的剂量反应上升曲线可能是由于在中等剂量范围内(0.3-0.7戈瑞)剂量反应趋于平缓所致。为了调查这一点,使用了原子弹幸存者寿命研究队列的实体癌死亡率和发病率的最新版本数据集(分别在1950-2003年和1958-2009年进行了随访),以评估中等剂量范围内可能偏离线性的情况。拟合了线性样条模型,在剂量上也拟合到6阶多项式模型(高阶多项式往往不收敛)。用于所有实体癌的器官剂量都是结肠加权剂量。无论使用多项式模型还是线性样条模型,死亡率数据都有偏离线性的适度迹象。赤池信息准则(AIC)的应用表明,死亡率数据的最优模型是剂量的5阶多项式。在死亡率数据中,线性样条模型提供了临界显著(P = 0.071)的改善迹象。低剂量外推系数(LDEF)衡量的是在某一特定剂量范围内拟合的线性斜率对低剂量线性斜率的高估程度,根据剂量范围的不同,低剂量外推系数一般在1.1-2.0之间,置信上限有时超过10;尽管线性样条模型提供的最低剂量范围(0.2)的改善LDEF < 1。然而,AIC的使用表明,发生率数据的最佳模型是由一个三阶多项式给出的。在不同剂量范围内评估的LDEF一般在1.2-1.4之间,置信上限一般超过1.6;虽然LDEF < 1在最低剂量范围(2 Gy)。线性二次模型被广泛用于剂量反应的建模,并作为治疗计划的一部分被广泛应用于放射肿瘤学应用。这个基于双靶点模型的模型有一定的理论基础,尽管用于验证这一模型的数据主要是在体外进行的;可能存在比双靶模型所暗示的更复杂的相互作用,但是这些相互作用所产生的高次(比二次)剂量幂的作用,在中等剂量范围内可能不是很明显。
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引用次数: 0
Individual Sensitivity for Radiotherapy-related Adverse Tissue Reactions in Patients Treated Twice for Metachronous Cancers. 两次接受治疗的晚期癌症患者放疗相关组织不良反应的个体敏感性
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-01 DOI: 10.1667/RADE-24-00226.1
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。
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引用次数: 0
Super-competition as a Novel Mechanism of the Dose-rate Effect in Radiation Carcinogenesis: A Mathematical Model Study. 超级竞争作为辐射致癌剂量率效应的新机制:一个数学模型研究。
IF 2.5 3区 医学 Q2 BIOLOGY Pub Date : 2025-02-01 DOI: 10.1667/RADE-24-00191.1
Yuya Hattori, Kento Nagata, Ritsuko Watanabe, Akinari Yokoya, Tatsuhiko Imaoka

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.

来自动物实验的数据表明,如果剂量率降低,即使累积剂量不变(即剂量率效应),与辐射有关的癌症风险也会降低;然而,其潜在机制尚不清楚。为了探索实验大鼠乳腺癌发生过程中观察到的剂量率效应的潜在因素,我们建立了一个数学模型来解释癌变过程中的细胞动力学,然后检验该模型是否能预测癌症发病率。利用微分方程建立了辐射诱导细胞死亡和突变的多阶段癌变数学模型。突变率随剂量率而变化。该模型还考虑了不同突变水平的细胞之间的竞争。模型的主要参数是根据之前的实验数据确定的。模型参数与实验观测值基本一致。当剂量率与突变率呈线性二次或二次关系时,致癌作用的剂量率效应就变得明显。当突变较多的细胞优先补偿突变较少的细胞因辐射引起的死亡时,剂量率效应变得突出。突变细胞比正常细胞获得竞争优势的现象被称为超级竞争。在这里,我们发现超级竞争是一种潜在的致癌剂量率效应的新机制。数据还证实了剂量率和突变率之间关系的形状的相关性。因此,本研究为剂量率效应的机制提供了新的证据,对预测低剂量率辐照的癌症相关风险具有重要意义。
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