TY - JOUR AB - PURPOSE: Risk analyses, based on relative biological effectiveness (RBE) estimates for neutrons relative to gammas, were performed; and the change in the curvature of the risk to dose response with increasing neutron RBE was analyzed using all solid cancer mortality data from the Radiation Effect Research Foundation (RERF). Results were compared to those based on incidence data. MATERIALS AND METHODS: This analysis is based on RERF mortality data with separate neutron and gamma doses for colon doses, from which organ averaged doses could be calculated. A model for risk ratio variation with RBE was developed. RESULTS: The best estimate of the neutron RBE considering mortality data was 200 (95% confidence interval (CI): 50-1010) for colon dose using the weighted-dose approach and for organ averaged dose 110 (95% CI: 30-350). The ERR risk ratios for all solid cancers combined, for the best fitting neutron RBE estimate and the neutron RBE of 10 result in a ratio of 0.54 (95% CI: 0.17-0.85) for colon dose and 0.55 (95% CI: 0.18-0.87) for organ averaged dose. The risk to dose response curvature became significantly negative (concave down) with increasing RBE, at a neutron RBE of 170 using colon dose and at an RBE of 90 using organ averaged dose for males when fitting a linear-quadratic dose response. For females, the curvature decreased toward linearity with increasing neutron RBE and remained significantly positive until RBE of 80 and 40 using colon and organ averaged dose, respectively. For higher neutron RBEs, no significant conclusion could be drawn about the shape of the dose-response curve. CONCLUSIONS: Application of neutron RBE values higher than 10 results in substantially reduced cancer mortality risk estimates and a significant reduction in curvature of the risk to dose responses for males. Using mortality data, the best fitting neutron RBE is much higher than when incidence data is used. The neutron RBE ranges covered by the overlap in the CIs from both the mortality and incidence analyses are 50-190 using colon dose and in all cases, the best fitting neutron RBE and lower 95% CI are higher than the value of 10 traditionally applied by the RERF. Therefore, it is recommended to consider uncertainties in neutron RBE values when calculating radiation risks and discussing the shape of dose responses using Japanese A-bomb survivors data. AU - Hafner, L.* AU - Walsh, L.* AU - Rühm, W. C1 - 68636 C2 - 54823 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 61-71 TI - Assessing the impact of neutron relative biological effectiveness on all solid cancer mortality risks in the Japanese atomic bomb survivors. JO - Int. J. Radiat. Biol. VL - 100 IS - 1 PB - Taylor & Francis Ltd PY - 2023 SN - 0955-3002 ER - TY - JOUR AB - BACKGROUND: Epidemiological studies have indicated that exposure of the heart to doses of ionizing radiation as low as 0.5 Gy increases the risk of cardiac morbidity and mortality with a latency period of decades. The damaging effects of radiation to myocardial and endothelial structures and functions have been confirmed radiobiologically at high dose, but much less are known at low dose. Integration of radiation biology and epidemiology data is a recommended approach to improve the radiation risk assessment process. The adverse outcome pathway (AOP) framework offers a comprehensive tool to compile and translate mechanistic information into pathological endpoints which may be relevant for risk assessment at the different levels of a biological system. Omics technologies enable the generation of large volumes of biological data at various levels of complexity, from molecular pathways to functional organisms. Given the quality and quantity of available data across levels of biology, omics data can be attractive sources of information for use within the AOP framework. It is anticipated that radiation omics studies could improve our understanding of the molecular mechanisms behind the adverse effects of radiation on the cardiovascular system. In this review, we explored the available omics studies on radiation-induced cardiovascular disease (CVD) and their applicability to the proposed AOP for CVD. RESULTS: The results of 80 omics studies published on radiation-induced CVD over the past 20 years have been discussed in the context of the AOP of CVD proposed by Chauhan et al. Most of the available omics data on radiation-induced CVD are from proteomics, transcriptomics, and metabolomics, whereas few datasets were available from epigenomics and multi-omics. The omics data presented here show great promise in providing information for several key events (KEs) of the proposed AOP of CVD, particularly oxidative stress, alterations of energy metabolism, extracellular matrix (ECM), and vascular remodeling. CONCLUSIONS: The omics data presented here shows promise to inform the various levels of the proposed AOP of CVD. However, the data highlight the urgent need of designing omics studies to address the knowledge gap concerning different radiation scenarios, time after exposure, and experimental models. This review presents the evidence to build a qualitative omics-informed AOP and provides views on the potential benefits and challenges in using omics data to assess risk-related outcomes. AU - Azimzadeh, O.* AU - Moertl, S.* AU - Ramadan, R.* AU - Baselet, B.* AU - Laiakis, E.C.* AU - Sebastian, S.* AU - Beaton, D.* AU - Hartikainen, J.M.* AU - Kaiser, J.C. AU - Beheshti, A.* AU - Salomaa, S.* AU - Chauhan, V.P.* AU - Hamada, N.* C1 - 66010 C2 - 53052 SP - 1722-1751 TI - Application of radiation omics in the development of adverse outcome pathway networks: An example of radiation-induced cardiovascular disease. JO - Int. J. Radiat. Biol. VL - 98 IS - 12 PY - 2022 SN - 0955-3002 ER - TY - JOUR AB - Purpose: The Adverse Outcome Pathway (AOP) framework, a systematic tool that can link available mechanistic data with phenotypic outcomes of relevance to regulatory decision-making, is being explored in areas related to radiation risk assessment. To examine the challenges including the use of AOPs to support the radiation protection community, an international horizon-style exercise (HSE) was initiated through the Organisation for Economic Co-operation and Development Nuclear Energy Agency High-Level Group on Low Dose Research Radiation/Chemical AOP Joint Topical Group (JTG). The objective of the HSE was to facilitate the collection of ideas from a range of experts, to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose/dose-rate exposures, as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures.Materials and methods: The HSE was guided by an international steering committee (SC) of radiation risk experts. In the first phase, research questions were solicited on areas that can be supported by the AOP framework, or challenges on the use of AOPs in radiation risk assessment. In the second phase, questions received were refined and sorted by the SC using a best-worst scaling (BWS) method. During a virtual 3-day workshop, the list of questions was further narrowed. In the third phase, an international survey of the broader radiation protection community led to an orderly ranking of the top questions.Results: Of the 271 questions solicited, 254 were accepted and categorized into 9 themes. These were further refined to the top 25 prioritized questions. Among these, the higher ranked questions will be considered as 'important' to drive future initiatives in the low dose radiation protection community. These included questions on the ability of AOPs to delineate responses across different levels of biological organization, and how AOPs could be applied to address research questions on radiation quality, doses or dose-rates, exposure time patterns and deliveries, and uncertainties in low dose/dose-rate effects. A better understanding of these concepts is required to support the use of the AOP framework in radiation risk assessment.Conclusion: Through dissemination of these results and considerations on next steps, the JTG will address select priority questions to advance the development and use of AOPs in the radiation protection community. The major themes observed will be discussed in the context of their relevance to areas of research that support the system of radiation protection. AU - Burtt, J.J.* AU - Leblanc, J.* AU - Randhawa, K.* AU - Ivanova, A.* AU - Rudd, M.A.* AU - Wilkins, R.* AU - Azzam, E.I.* AU - Hecker, M.* AU - Horemans, N.* AU - Vandenhove, H.* AU - Adam-Guillermin, C.* AU - Armant, O.* AU - Klokov, D.* AU - Audouze, K.* AU - Kaiser, J.C. AU - Moertl, S.* AU - Lumniczky, K.* AU - Tanaka, I.B.* AU - Yamada, Y.* AU - Hamada, N.* AU - Al-Nabulsi, I.* AU - Preston, J.D.* AU - Bouffler, S.* AU - Applegate, K.E.* AU - Cool, D.* AU - Beaton, D.* AU - Tollefsen, K.E.* AU - Garnier-Laplace, J.* AU - Laurier, D.* AU - Chauhan, V.P.* C1 - 66173 C2 - 53111 SP - 1763-1776 TI - Radiation adverse outcome pathways (AOPs) are on the horizon: Advancing radiation protection through an international horizon-style exercisewe. JO - Int. J. Radiat. Biol. VL - 98 IS - 12 PY - 2022 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Development of a model characterizing risk variation with RBE to investigate how the incidence risk for all solid cancers combined varies with higher neutron RBEs and different organ dose types. MATERIAL AND METHODS: The model is based on RERF data with separate neutron and gamma dose information. RESULTS: For both additive and multiplicative linear excess risks per unit organ averaged dose, a reduction of 50% in the risk coefficient per weighted dose arises when a neutron RBE of 110 is used instead of 10. Considering risk per unit liver dose, this reduction occurs for an RBE of 130 and for risks per unit colon dose for an RBE of 190. The change in the shape of the dose response curve when using higher neutron RBEs is evaluated. The curvature changed and became significantly negative for males at an RBE of 140 for colon dose, 100 for liver dose and 80 for organ averaged dose. For females this is the case at an RBE of 110, 80 and 60, respectively. CONCLUSIONS: Uncertainties in neutron RBE values should be considered when radiation risks and the shape of dose responses are deduced from cancer risk data from the atomic bomb survivors. AU - Hafner, L.* AU - Walsh, L.* AU - Rühm, W. C1 - 66309 C2 - 52812 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 629-643 TI - Assessing the impact of different neutron RBEs on the all solid cancer radiation risks obtained from the Japanese A-bomb survivors data. JO - Int. J. Radiat. Biol. VL - 99 IS - 4 PB - Taylor & Francis Ltd PY - 2022 SN - 0955-3002 ER - TY - JOUR AB - Purpose: FLASH (ultra-high dose rate) radiotherapy spares normal tissue while keeping tumor control. However, the mechanism of the FLASH effect remains unclear and may have consequences beyond the irradiated area. Materials and methods: We reanalyze the available results of ultra-high-dose-rate-related experiments to find out the key points of the mechanism of the FLASH effect. Then, we present a hypothesis on the mechanism of the FLASH effect: FLASH beams generate a high transient concentration of peroxyl radicals leading to a high fraction of radical recombination, which results in less oxidation damage to normal tissue. For the cells containing higher concentrations of antioxidants, the fractions of radical recombination are smaller because the antioxidants compete to react with peroxyl radicals. Therefore the damages by different dose rate beams differ slightly in this condition. Since some tumors contain a higher level of antioxidants, this may be the reason for the loss of the protective effect in tumors irradiated by FLASH beams. The high concentration of antioxidants in tumors results in slight radiolytic oxygen consumption, and consequently the protective effect observed in in vitro experiment cannot be observed in in vivo experiment. To quantitatively elaborate our hypothesis, a kinetic model is implemented to simulate the reactions induced by irradiation. Two parameters are defined to abstractly study the factors affecting the reaction, such as dose rate, antioxidants, total dose and reaction rate constants. Results and conclusions: We find that the explanation of the difference between in vivo and in vitro experiments is crucial to understanding the mechanism of the FLASH effect. Our hypothesis agrees with the results of related experiments. Based on the kinetic model, the effects of these factors on the FLASH effect are quantitatively investigated. AU - Hu, A.* AU - Qiu, R.* AU - Li, W.B. AU - Zhou, W.* AU - Wu, Z.* AU - Zhang, H.* AU - Li, J.* C1 - 65905 C2 - 52540 TI - Radical recombination and antioxidants: A hypothesis on the FLASH effect mechanism. JO - Int. J. Radiat. Biol. PY - 2022 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: This article summarizes a number of presentations from a session on "Radiation and Circulatory Effects" held during the Radiation Research Society Online 67th Annual Meeting, October 3-6 2021. MATERIALS AND METHODS: Different epidemiological cohorts were analyzed with various statistical means common in epidemiology. The cohorts included the one from the U.S. Million Person Study and the Canadian Fluoroscopy Cohort Study. In addition, one of the contributions in our article relies on results from analyses of the Japanese atomic bomb survivors, Russian emergency and recovery workers and cohorts of nuclear workers. The Canadian Fluoroscopy Cohort Study data were analyzed with a larger series of linear and nonlinear dose-response models in addition to the linear no-threshold (LNT) model. RESULTS AND CONCLUSIONS: The talks in this symposium showed that low/moderate acute doses at low/moderate dose rates can be associated with an increased risk of CVD, although some of the epidemiological results for occupational cohorts are equivocal. The usually only limited availability of information on well-known risk factors for circulatory disease (e.g. smoking, obesity, hypertension, diabetes, physical activity) is an important limiting factor that may bias any observed association between radiation exposure and detrimental health outcome, especially at low doses. Additional follow-up and careful dosimetric and outcome assessment are necessary and more epidemiological and experimental research is required. Obtaining reliable information on other risk factors is especially important. AU - Schöllnberger, H.* AU - Dauer, L.T.* AU - Wakeford, R.* AU - Constanzo, J.* AU - Golden, A.* C1 - 66024 C2 - 53057 TI - Summary of radiation research society online 67th annual meeting, symposium on "Radiation and circulatory effects". JO - Int. J. Radiat. Biol. PY - 2022 SN - 0955-3002 ER - TY - JOUR AB - BACKGROUND: The circulatory system distributes nutrients, signaling molecules, and immune cells to vital organs and soft tissues. Epidemiological, animal, and in vitro cellular mechanistic studies have highlighted that exposure to ionizing radiation (IR) can induce molecular changes in cellular and subcellular milieus leading to long-term health impacts, particularly on the circulatory system. Although the mechanisms for the pathologies are not fully elucidated, endothelial dysfunction is proven to be a critical event via radiation-induced oxidative stress mediators. To delineate connectivities of events specifically to cardiovascular disease (CVD) initiation and progression, the adverse outcome pathway (AOP) approach was used with consultation from field experts. AOPs are a means to organize information around a disease of interest to a regulatory question. An AOP begins with a molecular initiating event and ends in an adverse outcome via sequential linkages of key event relationships that are supported by evidence in the form of the modified Bradford-Hill criteria. Detailed guidelines on building AOPs are provided by the Organisation for Economic Cooperation and Development (OECD) AOP program. Here, we report on the questions and discussions needed to develop an AOP for CVD resulting from IR exposure. A recent workshop jointly organized by the MELODI (Multidisciplinary European Low Dose Initiative) and the ALLIANCE (European Radioecology Alliance) associations brought together experts from the OECD to present the AOP approach and tools with examples from the toxicology field. As part of this workshop, four working groups were formed to discuss the identification of adverse outcomes relevant to radiation exposures and development of potential AOPs, one of which was focused on IR-induced cardiovascular effects. Each working group comprised subject matter experts and radiation researchers interested in the specific disease area and included an AOP coach. Conclusion: The working group identified the critical questions of interest for AOP development, including the exposure scenario that would inform the evidence, the mechanisms of toxicity, the initiating event, intermediate key events/relationships, and the type of data currently available. This commentary describes the four-day discussion of the CVD working group, its outcomes, and demonstrates how collaboration and expert consultation is vital to informing AOP construction. AU - Chauhan, V.P.* AU - Hamada, N.* AU - Monceau, V.* AU - Ebrahimian, T.G.* AU - Adam, N.* AU - Wilkins, R.C.* AU - Sebastian, S.* AU - Patel, Z.S.* AU - Huff, J.L.* AU - Simonetto, C. AU - Iwasaki, T.* AU - Kaiser, J.C. AU - Salomaa, S.* AU - Moertl, S.* AU - Azimzadeh, O.* C1 - 62897 C2 - 51151 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England TI - Expert consultation is vital for adverse outcome pathway development: A case example of cardiovascular effects of ionizing radiation. JO - Int. J. Radiat. Biol. PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Depending on the exposure scenario, different biological and/or physical assays will be required to recover the exposure situation and to obtain reliable dose estimates to aid medical decision making. Inter-laboratory comparisons (ILCs) are a central tool to validate and improve the performance of methods and laboratories. In most cases such ILCs are performed under laboratory conditions where the influence of parameters contributing to uncertainties can be minimized. In a real-life scenario, the situation is much more complicated, and it is therefore crucial to validate methods and laboratories' abilities to carry out these methods under more realistic conditions. In 2019, EURADOS (The European Radiation Dosimetry Group) Working Group 10 (Retrospective Dosimetry) and RENEB (Running the European Network of Biological and retrospective Physical dosimetry) organized a field exercise in Lund, Sweden, to validate different methods for biological and physical retrospective dosimetry in parallel by simulating real-life exposure scenarios. MATERIALS AND METHODS: For the dicentric chromosome assay (DCA), 18 blood tubes were distributed across 8 thermos flasks filled with heated water and positioned at the hips and shoulders of anthropomorphic phantoms in different geometries. Two irradiations were performed with a 1.36 TBq 192Ir-source, each with two phantoms, to simulate close, distant, lateral or partially shielded exposures. For each of the blood tubes DCA dose estimates were provided by at least one laboratory and for tubes from four thermos flasks by 17 participating RENEB laboratories. In addition, blood from the different thermos flasks on each phantom was mixed to simulate heterogeneous exposures. Three radio-photoluminescence (RPL) glass dosimeters (GD) were placed at each tube to assess reference doses and the inter- and intra-tube variability. RESULTS: The results from the DCA were homogeneous between participants and matched well with RPL GD reference doses (≥95% of estimates within ±0.5 Gy of the reference). For samples close to the source, exposed to doses >1 Gy, systematic underestimation could be corrected by accounting for exposure time. Heterogeneity within and between tubes was detected for RPL GD reference doses as well as for doses estimates from the DCA. The sample simulating a heterogeneous exposure with two different doses was detected by ∼50% of the participants. CONCLUSIONS: The participants were able to successfully estimate the doses and to provide important information on the exposure scenarios under conditions closely resembling a real-life situation. The reliability of the results emphasizes the value of the DCA for retrospective dosimetry under field conditions. AU - Endesfelder, D.* AU - Oestreicher, U.* AU - Kulka, U.* AU - Ainsbury, E.A.* AU - Moquet, J.* AU - Barnard, S.* AU - Gregoire, E.* AU - Martinez, J.S.* AU - Trompier, F.* AU - Ristic, Y.* AU - Woda, C. AU - Waldner, L.* AU - Beinke, C.* AU - Vral, A.* AU - Barquinero, J.F.* AU - Hernandez, A.* AU - Sommer, S.* AU - Lumniczky, K.* AU - Hargitai, R.* AU - Montoro, A.* AU - Milić, M.* AU - Monteiro Gil, O.* AU - Valente, M.* AU - Bobyk, L.* AU - Sevriukova, O.* AU - Sabatier, L.* AU - Prieto, M.J.* AU - Moreno Domene, M.* AU - Testa, A.* AU - Patrono, C.* AU - Terzoudi, G.* AU - Triantopoulou, S.* AU - Histova, R.* AU - Wojcik, A.* C1 - 62331 C2 - 50786 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 1181-1198 TI - RENEB/EURADOS field exercise 2019: Robust dose estimation under outdoor conditions based on the dicentric chromosome assay. JO - Int. J. Radiat. Biol. VL - 97 IS - 9 PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - Purpose:Thyroid cancer of papillary histology (PTC) is the dominant type in radio-epidemiological cohorts established after nuclear accidents or warfare. Studies on post-Chernobyl PTC and on thyroid cancer in the life span study (LSS) of Japanese a-bomb survivors consistently revealed high radiation risk after exposure during childhood and adolescence. For post-Chernobyl risk assessment overexpression of the CLIP2 gene was proposed as molecular biomarker to separate radiogenic from sporadic PTC. Based on such binary marker a biologically-based risk model of PTC carcinogenesis has been developed for observational Chernobyl data. The model featured two independent molecular pathways of disease development, of which one was associated with radiation exposure. To gain credibility the concept for a mechanistic risk model must be based on general biological features which transcend findings in a single cohort. The purpose of the present study is therefore to demonstrate portability of the model concept by application to PTC incidence data in the LSS. By exploiting the molecular two-path concept we improve the determination of the probability of radiation causing cancer (POC). Materials and methods:The current analysis uses thyroid cancer incidence data of the LSS with thyroid cancer diagnoses and papillary histology (n = 292) from the follow-up period between 1958 and 2005. Risk analysis was performed with both descriptive and biologically-based models. Results:Judged by goodness-of-fit all applied models described the data almost equally well. They yielded similar risk estimates in cohorts post-Chernobyl and LSS. The preferred mechanistic model was selected by biological plausibility. It reflected important features of an imperfect radiation marker which are not easily addressed by descriptive models. Precise model predictions of marker prevalence in strata of epidemiological covariables can be tested by molecular measurements. Application of the radiation-related molecular pathway from our preferred model in retrospective risk assessment decreases the threshold dose for 50% POC from 0.33 (95% confidence interval (CI) 0.18; 0.64) Gy to 0.04 (95% CI 0.01; 0.19) Gy for females and from 0.43 (95% CI 0.17; 1.84) Gy to 0.19 (95% CI 0.05; 1.00) Gy for males. These improvements are still not sufficient to separate radiation-induced from sporadic PTC cases at very low doses Conclusions:Successful application of our preferred mechanistic model to LSS incidence data confirms and improves the biological two-path concept of radiation-induced PTC. Model predictions suggest further molecular validation studies to consolidate the basis of biologically-based risk estimation. AU - Kaiser, J.C. AU - Misumi, M.* AU - Furukawa, K.* C1 - 59551 C2 - 48901 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 19-30 TI - Biologically-based modeling of radiation risk and biomarker prevalence for papillary thyroid cancer in Japanese a-bomb survivors 1958-2005. JO - Int. J. Radiat. Biol. VL - 97 IS - 1 PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: In radiation risk analysis the state-of-the-art approach is based on descriptive models which link excess rates of cancer incidence and mortality to radiation exposure by statistical association. To estimate the number of sporadic and radiation-induced cases descriptive models apply parametric dose response function which directly determine the radiation risk. In biologically-based models of cancer risk (BBCR models) dose responses are implemented for key events on the biological level such as early mutations or clonal expansion of initiated cells. Influenced by radiation these events then shape the risk response on the epidemiological level. Although BBCR models facilitate a more comprehensive consideration of biological processes for risk assessment, their range of application in radiation research remains limited. Therefore, we emphasize their ability to improve understanding of radiation-related carcinogenesis by integrating molecular biology with epidemiology. We highlight the potential of BBCR models to harness information from adverse outcome pathways (AOPs) for risk estimation with closer links to radiobiology. The AOP concept originates from toxicology and may be applied profitably in radiation research. CONCLUSION: The conceptual design of BBCR models can be guided by the high-dimensional data environment provided by AOPs. Risk estimates from BBCR models pertain not only to classical radioepidemiological covariables such as radiation dose or attained age but also to well characterized molecular pathways. By additionally deploying biological information BBCR models facilitate finer risk stratification for a more personalized risk assessment. They leave behind the one-size-fits-all approach of descriptive modeling with the downside of more involved model development. Importantly, predictions from BBCR models can be validated against molecular measurements. Validated predictions would confirm the model design and strengthen the link between molecular biology and epidemiology. But the availability of cancer tissue in good quality from patients with known radiation exposure constitutes a major bottleneck. More ambitious initiative is needed to recover stored tissue samples and make them available for molecular investigations. To conclude, risk estimation will not only on rely on statistical association but will be quantitatively informed with radiobiological insight. Combined with the AOP framework BBCR models could improve accuracy and reduce uncertainty of radiation risk estimates in future research. AU - Kaiser, J.C. AU - Blettner, M.* AU - Stathopoulos, G.T. C1 - 59552 C2 - 48921 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England TI - Biologically based models of cancer risk in radiation research. JO - Int. J. Radiat. Biol. PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: The long-term effect of low and moderate doses of ionizing radiation on the lens is still a matter of debate and needs to be evaluated in more detail. MATERIAL AND METHODS: We conducted a detailed histological analysis of eyes from B6C3F1 mice cohorts after acute gamma irradiation (60Co source; 0.063 Gy/min) at young adult age of 10 weeks with doses of 0.063, 0.125 and 0.5 Gy. Sham irradiated (0 Gy) mice were used as controls. To test for genetic susceptibility heterozygous Ercc2 mutant mice were used and compared to wild type mice of the same strain background. Mice of both sexes were included in all cohorts. Eyes were collected 4 hours, 12, 18 and 24 months after irradiation. For a better understanding of the underlying mechanisms, metabolomics analyses were performed in lenses and plasma samples of the same mouse cohorts at 4 and 12 hours as well as 12, 18 and 24 months after irradiation. For this purpose, a targeted analysis was chosen. RESULTS: This analysis revealed histological changes particularly in the posterior part of the lens that rarely can be observed by using Scheimpflug imaging, as we reported previously. We detected a significant increase of posterior subcapsular cataracts 18 and 24 months after irradiation with 0.5 Gy (odds ratio 9.3; 95%-confidence interval 2.1 - 41.3) independent of sex and genotype. Doses below 0.5 Gy (i.e. 0.063 and 0.125 Gy) did not significantly increase the frequency of posterior subcapsular cataracts at any time point. In lenses, we observed a clear effect of sex and aging but not of irradiation or genotype. While metabolomics analyses of plasma from the same mice showed only a sex effect. CONCLUSIONS: This paper demonstrates a significant radiation-induced increase in the incidence of posterior subcapsular cataracts, which could not be identified using Scheimpflug imaging as the only diagnostic tool. AU - Kunze, S. AU - Cecil, A. AU - Prehn, C. AU - Möller, G. AU - Ohlmann, A.* AU - Wildner, G.* AU - Thurau, S.* AU - Unger, K. AU - Rößler, U.* AU - Hölter, S.M. AU - Tapio, S. AU - Wagner, F. AU - Beyerlein, A. AU - Theis, F.J. AU - Zitzelsberger, H. AU - Kulka, U.* AU - Adamski, J. AU - Graw, J. AU - Dalke, C. C1 - 61089 C2 - 49245 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 529-540 TI - Posterior subcapsular cataracts are a late effect after acute exposure to 0.5 Gy ionizing radiation in mice. JO - Int. J. Radiat. Biol. VL - 97 IS - 4 PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AU - Milder, C.M.* AU - Kendall, G.M.* AU - Arsham, A.* AU - Schöllnberger, H. AU - Wakeford, R.* AU - Cullings, H.M.* AU - Little, M.P.* C1 - 61363 C2 - 50115 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 866-873 TI - Summary of Radiation Research Society Online 66th Annual Meeting, Symposium on “Epidemiology: Updates on epidemiological low dose studies,” including discussion. JO - Int. J. Radiat. Biol. VL - 97 IS - 6 PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: In a nuclear or radiological event, an early diagnostic or prognostic tool is needed to distinguish the worried well from low-exposed and those individuals who may later develop life-threatening hematologic acute radiation syndrome (H-ARS). In previous studies, we identified and validated genes in peripheral blood for this purpose. To gain a deeper understanding and to make methodological improvements, we examined the contribution of the peripheral blood´s cell populations on radiation-induced gene expression changes. MATERIALS AND METHODS: EDTA whole blood from six healthy donors was X-irradiated with 0 and 4 Gy, cultured in vitro for 24 h and cell populations of T-lymphocytes (CD3), B-lymphocytes (CD19), NK-cells (CD56) and granulocytes (CD15) were separated using immunomagnetic methods. Whole blood was used as a positive control to ensure the expected radiation-induced gene expression response based on previous examinations. Purity of cell separation and cell counts was validated using immunofluorescence imaging flow cytometry. After RNA isolation, gene expressions of FDXR, DDB2, POU2AF1 and WNT3 were examined in the cell populations and whole blood. RESULTS: The cell populations, on average, contributed to the total RNA amount with a ratio of 11.6 for T-lymphocytes: 1.2 for B-cells: 1.2 for NK-cells: 1.0 for granulocytes. In order to estimate the contribution of gene expression per cell population, the baseline (0 Gy) as well as the radiation-induced fold-change in gene expression relative to unexposed was considered for each gene. After considering all three parameters, the T-lymphocytes (74.8%/80.5%) contributed predominantly to the radiation-induced up-regulation observed for FDXR/DDB2 and the B-lymphocytes (97.1%/83.8%) for down-regulated POU2AF1/WNT3 with a similar effect on whole blood gene expression measurements reflecting a corresponding order of magnitude. CONCLUSIONS: T-lymphocytes and B-lymphocytes contributed predominantly to the radiation-induced up-regulation of FDXR/DDB2 and down-regulation of POU2AF1/WNT3. Further separation of cell populations will not increase the diagnostic sensitivity, but complicate an efficient workflow. Also, this study identifies undesired limitations of widely used whole blood in vitro models, but it still underlines the use of FDXR and DDB2 for biodosimetry purposes and POU2AF1 and WNT3 for effect prediction of acute health effects. AU - Ostheim, P.* AU - Don Mallawaratchy, A.* AU - Müller, T.* AU - Schüle, S.* AU - Hermann, C.* AU - Popp, T.* AU - Eder, S.* AU - Combs, S.E. AU - Port, M.* AU - Abend, M.* C1 - 61073 C2 - 50033 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 474-484 TI - Acute Radiation Syndrome-related gene expression in irradiated peripheral blood cell populations. JO - Int. J. Radiat. Biol. VL - 97 IS - 4 PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: The aim of this article is to describe the technical development in proteomics during the last two decades with the focus on its use in radiation biology. It is written from a subjective point of view and aims not to be a scientific review of the subject. CONCLUSION: Proteomics is a fast developing technique and it has already contributed greatly to our understanding of biological mechanisms following radiation exposure. Novel proteomics approaches can be used in adequately designed cellular and animal experiments and above all in big clinical trials to investigate effects of ionizing radiation in the future. AU - Tapio, S. C1 - 62449 C2 - 50874 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 341-345 TI - Twenty years of proteomics in radiation biology - a look back. JO - Int. J. Radiat. Biol. VL - 98 IS - 3 PB - Taylor & Francis Ltd PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - Purpose: The increasing use of low-dose ionizing radiation in medicine requires a systematic study of its long-term effects on the brain, behaviour and its possible association with neurodegenerative disease vulnerability. Therefore, we analysed the long-term effects of a single low-dose irradiation exposure at 10 weeks of age compared to medium and higher doses on locomotor, emotion-related and sensorimotor behaviour in mice as well as on hippocampal glial cell populations. Materials and methods: We determined the influence of radiation dose (0, 0.063, 0.125 or 0.5 Gy), time post-irradiation (4, 12 and 18 months p.i.), sex and genotype (wild type versus mice with Ercc2 DNA repair gene point mutation) on behaviour. Results: The high dose (0.5 Gy) had early-onset adverse effects at 4 months p.i. on sensorimotor recruitment and late-onset negative locomotor effects at 12 and 18 months p.i. Notably, the low dose (0.063 Gy) produced no early effects but subtle late-onset (18 months) protective effects on sensorimotor recruitment and exploratory behaviour. Quantification and morphological characterization of the microglial and the astrocytic cells of the dentate gyrus 24 months p.i. indicated heightened immune activity after high dose irradiation (0.125 and 0.5 Gy) while conversely, low dose (0.063 Gy) induced more neuroprotective features. Conclusion: This is one of the first studies demonstrating such long-term and late-onset effects on brain and behaviour after a single radiation event in adulthood. AU - Ung, M.-C. AU - Garrett, L. AU - Dalke, C. AU - Leitner, V.* AU - Dragosa, D.* AU - Hladik, D* AU - Neff, F. AU - Wagner, F. AU - Zitzelsberger, H. AU - Miller, G. AU - Hrabě de Angelis, M. AU - Rößler, U.* AU - Vogt Weisenhorn, D.M. AU - Wurst, W. AU - Graw, J. AU - Hölter, S.M. C1 - 60694 C2 - 49490 SP - 156-169 TI - Dose-dependent long-term effects of a single radiation event on behaviour and glial cells. JO - Int. J. Radiat. Biol. VL - 97 IS - 2 PY - 2021 SN - 0955-3002 ER - TY - JOUR AB - Purpose: We herein report on changes in gene expression after radiation exposure to iodine-131 from the Chernobyl accident in the Ukrainian-American thyroid cohort and to external gamma ray or internal plutonium exposure in the Mayak Production Association radiation workers. Materials and methods: Taking advantage of access to tissue samples from the thyroid cancer cases in the Ukrainian-American cohort, our group tried to identify candidate genes to discriminate spontaneously occurring thyroid cancers from thyroid cancers caused by radiation exposure. We also examined gene expression changes in normal and cancerous thyroid tissue in relation to iodine-131 dose separately. Gene expression changes in the peripheral blood of radiation exposed Mayak workers were examined to elucidate the dose-to-gene and gene-to-health (e.g. cardiovascular disease) relationships. Conclusions: Results of both projects are discussed under the aspect of dose-response relationships (dose-to-gene) and clinical outcome relationships (gene-to-effect) in light of how mechanistic data can be translated into actionable knowledge for radiation protection or clinical purposes. AU - Abend, M.* AU - Pfeiffer, R.M.* AU - Port, M.* AU - Hatch, M.* AU - Bogdanova, T.* AU - Tronko, M.D.* AU - Mabuchi, K.* AU - Azizova, T.* AU - Unger, K. AU - Braselmann, H. AU - Ostheim, P.* AU - Brenner, A.V.* C1 - 58980 C2 - 48500 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 12-18 TI - Utility of gene expression studies in relation to radiation exposure and clinical outcomes: Thyroid cancer in the Ukrainian-American cohort and late health effects in a MAYAK worker cohort. JO - Int. J. Radiat. Biol. VL - 97 IS - 1 PB - Taylor & Francis Ltd PY - 2020 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: The MSc Radiation Biology course is a highly interdisciplinary degree program placing radiation biology at the interface between biology, medicine, and physics, as well as their associated technologies. The goal was to establish an internationally acknowledged program with diverse and heterogeneous student cohorts, who benefit from each other academically as well as culturally. We have completed a Five-Year evaluation of the program to assess our qualification profile and the further direction we want to take. MATERIALS AND METHODS: We evaluated the student cohort's data from the last 5 years regarding gender, age, and nationality as well as the highest degree before applying and career path after graduation. RESULTS: Data shows a great diversity regarding nationalty as well as undergraduate background. Cohort sizes could be increased and future prospects mainly aimed to a PhD. Measures after regular quality meetings and students' feedback led to improving the curriculum and workload, teacher's training, and changes to examination regulations. CONCLUSIONS: After 5 years, statistics show that our expectations have been met exceedingly. All graduates had excellent career opportunities reflecting the necessity of this MSc and its topics. We are continuously working on improving the program and adapting the curriculum to the requirements in radiation sciences. The future vision includes an expansion of the program as well as undergraduate education opportunities in this field. AU - Kessel, C. AU - Atkinson, M.J. AU - Schmid, T.E. AU - Trott, K.* AU - Wilkens, J.J.* AU - Anastasov, N. AU - Rosemann, M. AU - Azimzadeh, O. AU - Tapio, S. AU - Moertl, S.* AU - Kulka, U.M.* AU - Abend, M.* AU - Port, M.* AU - Beinke, C.* AU - Mustafa, M.* AU - Neff, F.* AU - Pfeiffer, D.* AU - Berberat, P.* AU - Combs, S.E. C1 - 60643 C2 - 49556 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 256-264 TI - A five-year report on the conception and establishment of the MSc radiation biology at the Technical University of Munich. JO - Int. J. Radiat. Biol. VL - 97 IS - 2 PB - Taylor & Francis Ltd PY - 2020 SN - 0955-3002 ER - TY - JOUR AB - Purpose: Pulmonary inflammation is an adverse consequence of radiation therapy in breast cancer. The aim of this study was to elucidate biological pathways leading to this pathology. Materials and methods: Lung endothelial cells were isolated 24 h after thorax-irradiation (sham or 10 Gy X-ray) from female C57Bl/6 mice and cultivated for 6 days. Results: Quantitative proteomic analysis of lung endothelial cells was done using data independent acquisition (DIA) mass spectrometry. The data were analyzed using Ingenuity Pathway Analysis and STRINGdb. In total, 4220 proteins were identified using DIA of which 60 were dysregulated in the irradiated samples (fold change >= 2.00 or <= 0.50; q-value <0.05). Several (12/40) upregulated proteins formed a cluster of inflammatory proteins with STAT1 and IRF3 as predicted upstream regulators. The several-fold increased expression of STAT1 and STAT-associated ISG15 was confirmed by immunoblotting. The expression of antioxidant proteins SOD1 and PRXD5 was downregulated suggesting radiation-induced oxidative stress. Similarly, the phosphorylated (active) forms of STING and IRF3, both members of the cGAS/STING pathway, were downregulated. Conclusions: These data suggest the involvement of JAK/STAT and cGas/STING pathways in the genesis of radiation-induced lung inflammation. These pathways may be used as novel targets for the prevention of radiation-induced lung damage. AU - Philipp, J. AU - Sievert, W.* AU - Azimzadeh, O. AU - von Toerne, C. AU - Metzger, F. AU - Posch, A. AU - Hladik, D. AU - Subedi, P. AU - Multhoff, G.* AU - Atkinson, M.J. AU - Tapio, S. C1 - 57996 C2 - 48204 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 642-650 TI - Data independent acquisition mass spectrometry of irradiated mouse lung endothelial cells reveals a STAT-associated inflammatory response. JO - Int. J. Radiat. Biol. VL - 96 IS - 5 PB - Taylor & Francis Ltd PY - 2020 SN - 0955-3002 ER - TY - JOUR AB - The overall aim of this contribution to the 'Second Bill Morgan Memorial Special Issue' is to provide a high-level review of a recent report developed by a Committee for the National Council on Radiation Protection and Measurements (NCRP) titled 'Approaches for Integrating Information from Radiation Biology and Epidemiology to Enhance Low-Dose Health Risk Assessment'. It derives from previous NCRP Reports and Commentaries that provide the case for integrating data from radiation biology studies (available and proposed) with epidemiological studies (also available and proposed) to develop Biologically-Based Dose-Response (BBDR) models. In this review, it is proposed for such models to leverage the adverse outcome pathways (AOP) and key events (KE) approach for better characterizing radiation-induced cancers and circulatory disease (as the example for a noncancer outcome). The review discusses the current state of knowledge of mechanisms of carcinogenesis, with an emphasis on radiation-induced cancers, and a similar discussion for circulatory disease. The types of the various informative BBDR models are presented along with a proposed generalized BBDR model for cancer and a more speculative one for circulatory disease. The way forward is presented in a comprehensive discussion of the research needs to address the goal of enhancing health risk assessment of exposures to low doses of radiation. The use of an AOP/KE approach for developing a mechanistic framework for BBDR models of radiation-induced cancer and circulatory disease is considered to be a viable one based upon current knowledge of the mechanisms of formation of these adverse health outcomes and the available technical capabilities and computational advances. The way forward for enhancing low-dose radiation risk estimates will require there to be a tight integration of epidemiology data and radiation biology information to meet the goals of relevance and sensitivity of the adverse AU - Preston, R.J.* AU - Rühm, W. AU - Azzam, E.I.* AU - Boice, J.D.* AU - Bouffler, S.* AU - Held, K.D.* AU - Little, M.P.* AU - Shore, R.E.* AU - Shuryak, I.* AU - Weil, M.M.* C1 - 60788 C2 - 49549 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England TI - Adverse outcome pathways, key events, and radiation risk assessment. JO - Int. J. Radiat. Biol. PB - Taylor & Francis Ltd PY - 2020 SN - 0955-3002 ER - TY - JOUR AU - Salomaa, S.* AU - Cardis, E.* AU - Bouffler, S.D.* AU - Atkinson, M.J. AU - Hamada, N.* C1 - 59032 C2 - 48488 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England TI - Low dose radiation therapy for COVID-19 pneumonia: Is there any supportive evidence? JO - Int. J. Radiat. Biol. PB - Taylor & Francis Ltd PY - 2020 SN - 0955-3002 ER - TY - JOUR AB - Since early April 2020, there has been intense debate over proposed clinical use of ionizing radiation to treat life-threatening pneumonia in Coronavirus Disease 2019 (COVID-19) patients. At least twelve relevant papers appeared by 20 May 2020. The radiation dose proposed for clinical trials are a single dose (0.1-1 Gy) or two doses (a few mGy followed by 0.1-0.25 Gy involving a putative adaptive response, or 1-1.5 Gy in two fractions 2-3 days apart). The scientific rationale for such proposed so-called low dose radiotherapy (LDRT) is twofold (note that only doses below 0.1 Gy are considered as low doses in the field of radiation protection, but here we follow the term as conventionally used in the field of radiation oncology). Firstly, the potentially positive observations in human case series and biological studies in rodent models on viral or bacterial pneumonia that were conducted in the pre-antibiotic era. Secondly, the potential anti-inflammatory properties of LDRT, which have been seen when LDRT is applied locally to subacute degenerative joint diseases, mainly in Germany. However, the human and animal studies cited as supportive evidence have significant limitations, and whether LDRT produces anti-inflammatory effects in the inflamed lung or exacerbates ongoing COVID-19 damage remains unclear. Therefore, we conclude that the available scientific evidence does not justify clinical trials of LDRT for COVID-19 pneumonia, with unknown benefit and known mortality risks from radiogenic cancer and circulatory disease. Despite the significant uncertainties in these proposals, some clinical trials are ongoing and planned. This paper gives an overview of current situations surrounding LDRT for COVID-19 pneumonia. AU - Salomaa, S.* AU - Bouffler, S.D.* AU - Atkinson, M.J. AU - Cardis, E.* AU - Hamada, N.* C1 - 59575 C2 - 48924 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 1228-1235 TI - Is there any supportive evidence for low dose radiotherapy for COVID-19 pneumonia? JO - Int. J. Radiat. Biol. VL - 96 IS - 10 PB - Taylor & Francis Ltd PY - 2020 SN - 0955-3002 ER - TY - JOUR AB - Purpose: Mitochondria have been implicated in initiating and/or amplifying the biological effects of ionizing radiation not mediated via damage to nuclear DNA. To help elucidate the underlying mechanisms, energy deposition patterns to mitochondria and radiation damage to their DNA have been modelled. Methods: Track-structure simulations have been performed with PARTRAC biophysical tool for Co-60 gamma-rays and 5 MeV alpha-particles. Energy deposition to the cell's mitochondria has been analyzed. A model of mitochondrial DNA reflecting experimental information on its structure has been developed and used to assess its radiation-induced damage. Results: Energy deposition to mitochondria is highly inhomogeneous, especially at low doses. Although a dose-dependent fraction of mitochondria sees no energy deposition at all, the hit ones receive rather high amounts of energy. Nevertheless, only little damage to mitochondrial DNA occurs, even at large doses. Conclusion: Mitochondrial DNA does not represent a critical target for radiation effects. Likely, the key role of mitochondria in radiation-induced biological effects arises from the communication between mitochondria and/or with the nucleus. Through this signaling, initial modifications in a few heavily hit mitochondria seem to be amplified to a massive long-term effect manifested in the whole cell or even tissue. AU - Friedland, W. AU - Schmitt, E. AU - Kundrat, P. AU - Baiocco, G.* AU - Ottolenghi, A.* C1 - 53324 C2 - 44662 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 3-11 TI - Track-structure simulations of energy deposition patterns to mitochondria and damage to their DNA. JO - Int. J. Radiat. Biol. VL - 95 IS - 1 PB - Taylor & Francis Ltd PY - 2019 SN - 0955-3002 ER - TY - JOUR AB - Over the past 60 years a great number of very large datasets have been generated from the experimental exposure of animals to external radiation and internal contamination. This accumulation of 'big data' has been matched by increasingly large epidemiological studies from accidental and occupational radiation exposure, and from plants, humans and other animals affected by environmental contamination. We review the creation, sustainability and reuse of this legacy data, and discuss the importance of Open data and biomaterial archives for contemporary radiobiological sciences, radioecology and epidemiology. We find evidence for the ongoing utility of legacy datasets and biological materials, but that the availability of these resources depends on uncoordinated, often institutional, initiatives to curate and archive them. The importance of open data from contemporary experiments and studies is also very clear, and yet there are few stable platforms for their preservation, sharing, and reuse. We discuss the development of the ERA and STORE data sharing platforms for the scientific community, and their contribution to FAIR sharing of data. The contribution of funding agency and journal policies to the support of data sharing is critical for the maximum utilisation and reproducibility of publicly funded research, but this needs to be matched by training in data management and cultural changes in the attitudes of investigators to ensure the sustainability of the data and biomaterial commons. AU - Schofield, P.N.* AU - Kulka, U.* AU - Tapio, S. AU - Grosche, B.* C1 - 55712 C2 - 46521 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 861-878 TI - Big data in radiation biology and epidemiology; an overview of the historical and contemporary landscape of data and biomaterial archives. JO - Int. J. Radiat. Biol. VL - 95 IS - 7 PB - Taylor & Francis Ltd PY - 2019 SN - 0955-3002 ER - TY - JOUR AB - Purpose: Widespread medical use of radiation in diagnosis, imaging and treatment of different central nervous system malignancies lead to various consequences. Aim of this study was to further elucidate mechanism of cell response to radiation and possible consequence on neural differentiation. Materials and methods: NT2/D1 cells that resemble neural progenitors were used as a model system. Undifferentiated NT2/D1 cells and NT2/D1 cells in the early phase of neural differentiation were irradiated with low (0.2 Gy) and moderate (2 Gy) doses of γ radiation. The effect was analyzed on apoptosis, cell cycle, senescence, spheroid formation and the expression of genes and miRNAs involved in the regulation of pluripotency or neural differentiation. Results: Two grays of irradiation induced apoptosis, senescence and cell cycle arrest of NT2/D1 cells, accompanied with altered expression of several genes (SOX2, OCT4, SOX3, PAX6) and miRNAs (miR-219, miR-21, miR124-a). Presented results show that 2 Gy of radiation significantly affected early phase of neural differentiation in vitro. Conclusions: These results suggest that 2 Gy of radiation significantly affected early phase of neural differentiation and affect the population of neural progenitors. These findings might help in better understanding of side effects of radiotherapy in treatments of central nervous system malignancies. AU - Stanisavljevic, D.* AU - Popovic, J.* AU - Petrovic, I.* AU - Davidovic, S.* AU - Atkinson, M.J. AU - Anastasov, N. AU - Stevanovic, M.* C1 - 56864 C2 - 47350 SP - 1627-1639 TI - Radiation effects on early phase of NT2/D1 neural differentiation in vitro. JO - Int. J. Radiat. Biol. VL - 95 IS - 12 PY - 2019 SN - 0955-3002 ER - TY - JOUR AB - Purpose: Previous investigations revealed influences of irradiation up to 2Gy on the cytokine secretion profile of inflammatory and peritoneal mouse macrophages (pMCYRILLIC CAPITAL LETTER EF). This raised the question if those alterations impact on dendritic cells and consecutive T-cell responses. Further, the impact of irradiation directly on pMCYRILLIC CAPITAL LETTER EF capacity to induce T-cell responses was analyzed. Materials and methods: pMCYRILLIC CAPITAL LETTER EF were LPS-activated, irradiated and the expression of activation markers was assessed. Treated pMCYRILLIC CAPITAL LETTER EF were co-incubated with T-cells to investigate proliferation. To verify modulating properties of pMCYRILLIC CAPITAL LETTER EF supernatants isolated 24 h after irradiation, bone marrow-derived dendritic cells (BMDC) were co-incubated with supernatants and activation markers as well as the BMDC-induced proliferation of T-cells were measured. Results: pMCYRILLIC CAPITAL LETTER EF showed a highly significantly decreased major histocompatibility complexII (MHCII) expression within a dose range from 0.7-2Gy. Further, the proliferation rate of cluster of differentiation 4(+) (CD4(+)) T-cells was decreased after co-incubation particularly with 2 Gy irradiated pMCYRILLIC CAPITAL LETTER EF. The co-incubation of BMDC with supernatants of activated, irradiated pMCYRILLIC CAPITAL LETTER EF significantly reduced the CD40 expression, but did not impact on the BMDC-derived induction of T-cell proliferation. Conclusions: Inflammatory macrophages being exposed to irradiation have the potential to modulate consecutive adaptive immune reactions. But supernatants of irradiated macrophages do not influence the dendritic cells (DC)-mediated induction of T cell proliferation. AU - Wunderlich, R. AU - Rühle, P.F.* AU - Deloch, L.* AU - Rödel, F.* AU - Fietkau, R.* AU - Gaipl, U.S.* AU - Frey, B.* C1 - 54210 C2 - 45440 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 33-43 TI - Ionizing radiation reduces the capacity of activated macrophages to induce T-cell proliferation, but does not trigger dendritic cell-mediated non-targeted effects. JO - Int. J. Radiat. Biol. VL - 95 IS - 1 PB - Taylor & Francis Ltd PY - 2019 SN - 0955-3002 ER - TY - JOUR AB - Purpose: We assessed students' expectations to a full two-year Master of Science course regarding workload, extracurricular activities, learning methods, and career plans. Materials and methods: A questionnaire was handed out to all students in the MSc radiation biology course. Questions evaluated the time for study and lectures expected a desire for specific teaching and testing formats, expectations from extracurricular activities as well as the motivation to study the subject and the future career plans. All students (100%) enrolled in the first semester were handed out and completed the questionnaire. Results: Most students had learned about the course from the internet (68.75%) or received information from teachers or professors (25%). Two students stated that all disciplines were equally relevant (25%). Others students made clear preferences: fourteen voted molecular biology (87.5%) as relevant, radiation protection in 93.75%, 81.25% consider physics the most important topic, followed by immunology (62.5%). Tutorials and lectures were preferred teaching formats. Generally, a workload of 20 hours per week is preferred. Conclusions: An ongoing feedback loop is important in designing a modern Master of Science course in the context of the Bologna process. Valuable information is given by students and should be integrated continuously in the design and continuation process. AU - Combs, S.E. AU - Kessel, C. AU - Berberat, P.O.* AU - Atkinson, M.J. C1 - 54599 C2 - 45704 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 233-237 TI - Students' expectations in an international Master of Science course in radiation biology. JO - Int. J. Radiat. Biol. VL - 95 IS - 2 PB - Taylor & Francis Ltd PY - 2018 SN - 0955-3002 ER - TY - JOUR AB - Purpose: Automated detection of dicentric chromosomes from a large number of cells was applied to study age-dependent radiosensitivity after in vitro CT exposure of blood from healthy donors. Materials and methods: Blood samples from newborns, children (2-5 years) and adults (20-50 years) were exposed in vitro to 0 mGy, 41 mGy and 978 mGy using a CT equipment. In this study, automated scoring based on 13,000-31,000 cells/dose point/age group was performed. Results for control and low dose points were validated by manually counting about 26,000 cells/dose point/age group. Results: For all age groups, the high number of analyzed cells enabled the detection of a significant increase in the frequency of radiation induced dicentric chromosomes in cells exposed to 41 mGy as compared to control cells. Moreover, differences between the age groups could be resolved for the low dose: young donors showed significantly increased risk for induced dicentrics at 41 mGy compared to adults. Conclusions: The results very clearly demonstrate that the automated dicentric scoring method is capable of discerning radiation induced biomarkers in the low dose range (<100 mGy) and thus may open possibilities for large-scale molecular epidemiology studies in radiation protection. AU - Oestreicher, U.* AU - Endesfelder, D.* AU - Gomolka, M.* AU - Kesminiene, A.* AU - Lang, P.* AU - Lindholm, C.* AU - Röβler, U.* AU - Samaga, D. AU - Kulka, U.* C1 - 54441 C2 - 45608 CY - 2-4 Park Square, Milton Park, Abingdon Or14 4rn, Oxon, England SP - 1017-1026 TI - Automated scoring of dicentric chromosomes differentiates increased radiation sensitivity of young children after low dose CT exposure in vitro. JO - Int. J. Radiat. Biol. VL - 94 IS - 11 PB - Taylor & Francis Ltd PY - 2018 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: RENEB, 'Realising the European Network of Biodosimetry and Physical Retrospective Dosimetry,' is a network for research and emergency response mutual assistance in biodosimetry within the EU. Within this extremely active network, a number of new dosimetry methods have recently been proposed or developed. There is a requirement to test and/or validate these candidate techniques and inter-comparison exercises are a well-established method for such validation. MATERIALS AND METHODS: The authors present details of inter-comparisons of four such new methods: dicentric chromosome analysis including telomere and centromere staining; the gene expression assay carried out in whole blood; Raman spectroscopy on blood lymphocytes, and detection of radiation-induced thermoluminescent signals in glass screens taken from mobile phones. RESULTS: In general the results show good agreement between the laboratories and methods within the expected levels of uncertainty, and thus demonstrate that there is a lot of potential for each of the candidate techniques. CONCLUSIONS: Further work is required before the new methods can be included within the suite of reliable dosimetry methods for use by RENEB partners and others in routine and emergency response scenarios. AU - Ainsbury, E.* AU - Badie, C.* AU - Barnard, S.* AU - Manning, G.* AU - Moquet, J.* AU - Abend, M.* AU - Bassinet, C.* AU - Bortolin, E.* AU - Bossin, L.* AU - Bricknell, C.* AU - Brzoska, K.* AU - Čemusová, Z.* AU - Christiansson, M.* AU - Cosler, G.* AU - Della Monaca, S.* AU - Desangles, F.* AU - Discher, M.* AU - Doucha-Senf, S.* AU - Eakins, J.* AU - Fattibene, P.* AU - Gregoire, E.* AU - Guogyte, K.* AU - Kriehuber, R.* AU - Lee, J.* AU - Lloyd, D.* AU - Lyng, F.* AU - Macaeva, E.* AU - Majewski, M.* AU - McKeever, S.W.S.* AU - Meade, A.* AU - M'kacher, R.* AU - Medipally, D.* AU - Oestreicher, U.* AU - Oskamp, D.* AU - Pateux, J.* AU - Port, M.* AU - Quattrini, M.C.* AU - Quintens, R.* AU - Ricoul, M.* AU - Roy, L.* AU - Sabatier, L.* AU - Sholom, S.* AU - Strunz, S.* AU - Trompier, F.* AU - Valente, M.* AU - van Hoey, O.* AU - Veronese, I.* AU - Wojcik, A.* AU - Woda, C. C1 - 49131 C2 - 41628 CY - Abingdon SP - 99-109 TI - Integration of new biological and physical retrospective dosimetry methods into EU emergency response plans - joint RENEB and EURADOS inter-laboratory comparisons. JO - Int. J. Radiat. Biol. VL - 93 IS - 1 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - Purpose Reliable dose estimation is an important factor in appropriate dosimetric triage categorization of exposed individuals to support radiation emergency response. Materials and Methods Following work done under the EU FP7 MULTIBIODOSE and RENEB projects, formal methods for defining uncertainties on biological dose estimates are compared using simulated and real data from recent exercises. Results The results demonstrate that a Bayesian method of uncertainty assessment is the most appropriate, even in the absence of detailed prior information. The relative accuracy and relevance of techniques for calculating uncertainty and combining assay results to produce single dose and uncertainty estimates is further discussed. Conclusions Finally, it is demonstrated that whatever uncertainty estimation method is employed, ignoring the uncertainty on fast dose assessments can have an important impact on rapid biodosimetric categorization. AU - Ainsbury, E.A.* AU - Higueras, M.* AU - Puig, P.* AU - Einbeck, J.* AU - Samaga, D.* AU - Barquinero, J.F.* AU - Barrios, L.* AU - Brzozowska, B.* AU - Fattibene, P.* AU - Gregoire, E.* AU - Jaworska, A.* AU - Lloyd, D.* AU - Oestreicher, U.* AU - Romm, H.* AU - Rothkamm, K.* AU - Roy, L.* AU - Sommer, S.* AU - Terzoudi, G.* AU - Thierens, H.* AU - Trompier, F.* AU - Vral, A.* AU - Woda, C. C1 - 49347 C2 - 41757 CY - Abingdon SP - 127-135 TI - Uncertainty of fast biological radiation dose assessment for emergency response scenarios. JO - Int. J. Radiat. Biol. VL - 93 IS - 1 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Epidemiological studies indicate that radiation doses as low as 0.5 Gy increase the risk of cardiovascular disease decades after the exposure. The aim of the present study was to investigate whether this radiation dose causes late molecular alterations in endothelial cells that could support the population-based data. MATERIALS AND METHODS: Human coronary artery endothelial cells were irradiated at 0.5 Gy (X-ray) and radiation-induced changes in the proteome were investigated after different time intervals (1, 7 and 14 d) using ICPL technology. Key changes identified by proteomics and bioinformatics were validated by immunoblotting and ELISA. RESULTS: The radiation-induced alteration of the endothelial proteome was characterized by sustained perturbation of Rho GDP-dissociation inhibitor (RhoGDI) and nitric oxide (NO) signalling pathways. At later time-points, this was accompanied by reduced proteasome activity, enhanced protein carbonylation indicating augmented oxidative stress, and senescence. CONCLUSIONS: These molecular changes are indicative of long-term premature endothelial dysfunction and provide a mechanistic framework to the epidemiological data showing increased risk of cardiovascular disease at 0.5 Gy. AU - Azimzadeh, O. AU - Subramanian, V. AU - Ständer, S. AU - Merl-Pham, J. AU - Lowe, D.* AU - Barjaktarovic, Z. AU - Mörtl, S. AU - Raj, K.* AU - Atkinson, M.J. AU - Tapio, S. C1 - 51504 C2 - 43290 CY - Abingdon SP - 920-928 TI - Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways. JO - Int. J. Radiat. Biol. VL - 93 IS - 9 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Ionizing radiation induces cardiovascular disease, the endothelium being the main target. The exact mechanism of the damage is unclear but the involvement of multiple signaling pathways is probable. Reversible lysine acetylation is a posttranslational protein modification that regulates activity across a broad range of signaling pathways. The goal of this study was to determine if a low radiation dose results in acetylome alteration in endothelial cells. MATERIALS AND METHODS: Human coronary artery endothelial cell line was irradiated with Cs-137 gamma-rays (0.5 Gy) and proteomics analysis was performed using enriched acetylated peptides and all peptides. Data were validated using immunoblotting, deacetylase activity assay, and RhoA activity assay. RESULTS: Nearly a hundred proteins were found to have an altered acetylation status 24 h after irradiation, primarily due to an overall decrease in acetylation. The expression of specific deacetylases was significantly increased, coinciding with an enhancement in global deacetylase activity. Proteins changed in their acetylation status belonged to several pathways including protein synthesis, cytoskeleton-related processes, protein folding and calcium signaling. The predicted changes in the RhoA/actin cytoskeleton pathway were validated by immunoassay. CONCLUSIONS: This study shows that protein acetylation is an important mediator of radiation responses in human cardiac coronary endothelial cells. Increased knowledge of the endothelial response to radiation is crucial for the development of normal tissue sparing modalities during radiation therapy. AU - Barjaktarovic, Z. AU - Merl-Pham, J. AU - Azimzadeh, O. AU - Kempf, S.J. AU - Raj, K.* AU - Atkinson, M.J. AU - Tapio, S. C1 - 49542 C2 - 40766 CY - Abingdon SP - 156-164 TI - Low-dose radiation differentially regulates protein acetylation and histone deacetylase expression in human coronary artery endothelial cells. JO - Int. J. Radiat. Biol. VL - 93 IS - 2 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: The RENEB accident exercise was carried out in order to train the RENEB participants in coordinating and managing potentially large data sets that would be generated in case of a major radiological event. MATERIALS AND METHODS: Each participant was offered the possibility to activate the network by sending an alerting email about a simulated radiation emergency. The same participant had to collect, compile and report capacity, triage categorization and exposure scenario results obtained from all other participants. The exercise was performed over 27 weeks and involved the network consisting of 28 institutes: 21 RENEB members, four candidates and three non-RENEB partners. RESULTS: The duration of a single exercise never exceeded 10 days, while the response from the assisting laboratories never came later than within half a day. During each week of the exercise, around 4500 samples were reported by all service laboratories (SL) to be examined and 54 scenarios were coherently estimated by all laboratories (the standard deviation from the mean of all SL answers for a given scenario category and a set of data was not larger than 3 patient codes). CONCLUSIONS: Each participant received training in both the role of a reference laboratory (activating the network) and of a service laboratory (responding to an activation request). The procedures in the case of radiological event were successfully established and tested. AU - Brzozowska, B.* AU - Ainsbury, E.* AU - Baert, A.E.* AU - Beaton-Green, L.* AU - Barrios, L.* AU - Barquinero, J.F.* AU - Bassinet, C.* AU - Beinke, C.* AU - Benedek, A.* AU - Beukes, P.* AU - Bortolin, E.* AU - Buraczewska, I.* AU - Burbidge, C.I.* AU - de Amicis, A.* AU - de Angelis, C.* AU - Della Monaca, S.* AU - Depuydt, J.* AU - de Sanctis, S.* AU - Dobos, K.* AU - Domene, M.M.* AU - Domínguez, I.* AU - Facco, E.* AU - Fattibene, P.* AU - Frenzel, M.* AU - Monteiro Gil, O.* AU - Gonon, G.* AU - Gregoire, E.* AU - Gruel, G.* AU - Hadjidekova, V.* AU - Hatzi, V.I.* AU - Hristova, R.* AU - Jaworska, A.* AU - Kis, E.* AU - Kowalski, M.* AU - Kulka, U.* AU - Lista, F.* AU - Lumniczky, K.* AU - Martínez-López, W.* AU - Meschini, R.* AU - Mörtl, S. AU - Moquet, J.* AU - Noditi, M.* AU - Oestreicher, U.* AU - Orta Vázquez, M.L.* AU - Palma, V.* AU - Pantelias, G.* AU - Montoro Pastor, A.* AU - Patrono, C.* AU - Piqueret-Stephan, L.* AU - Quattrini, M.C.* AU - Regalbuto, E.* AU - Ricoul, M.* AU - Roch-Lefevre, S.* AU - Roy, L.* AU - Sabatier, L.* AU - Sarchiapone, L.* AU - Sebastià, N.* AU - Sommer, S.* AU - Sun, M.* AU - Suto, Y.* AU - Terzoudi, G.* AU - Trompier, F.* AU - Vral, A.* AU - Wilkins, R.* AU - Zafiropoulos, D.* AU - Wieser, A. AU - Woda, C. AU - Wojcik, A.* C1 - 49326 C2 - 41761 CY - Abingdon SP - 75-80 TI - RENEB accident simulation exercise. JO - Int. J. Radiat. Biol. VL - 93 IS - 1 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - Purpose: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios. Results: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015. Conclusions: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects. AU - Kulka, U.* AU - Abend, M.* AU - Ainsbury, E.* AU - Badie, C.* AU - Barquinero, J.F.* AU - Barrios, L.* AU - Beinke, C.* AU - Bortolin, E.* AU - Cucu, A.* AU - de Amicis, A.* AU - Domínguez, I.* AU - Fattibene, P.* AU - Frøvig,, A.M.* AU - Gregoire, E.* AU - Guogyte, K.* AU - Hadjidekova, V.* AU - Jaworska, A.* AU - Kriehuber, R.* AU - Lindholm, C.* AU - Lloyd, D.* AU - Lumniczky, K.* AU - Lyng, F.* AU - Meschini, R.* AU - Mörtl, S. AU - Della Monaca, S.* AU - Monteiro Gil, O.* AU - Montoro, A.* AU - Moquet, J.* AU - Moreno, M.* AU - Oestreicher, U.* AU - Palitti, F.* AU - Pantelias, G.* AU - Patrono, C.* AU - Piqueret-Stephan, L.* AU - Port, M.* AU - Prieto, M.J.* AU - Quintens, R.* AU - Ricoul, M.* AU - Romm, H.* AU - Roy, L.* AU - Sáfrány, G.* AU - Sabatier, L.* AU - Sebastià, N.* AU - Sommer, S.* AU - Terzoudi, G.* AU - Testa, A.* AU - Thierens, H.* AU - Turai, I.* AU - Trompier, F.* AU - Valente, M.* AU - Vaz, P.* AU - Vral, A.* AU - Woda, C. AU - Zafiropoulos, D.* AU - Wojcik, A.* C1 - 49739 C2 - 40901 CY - Abingdon SP - 2-14 TI - RENEB – Running the European Network of biological dosimetry and physical retrospective dosimetry. JO - Int. J. Radiat. Biol. VL - 93 IS - 1 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Two quality controlled inter-laboratory exercises were organized within the EU project 'Realizing the European Network of Biodosimetry (RENEB)' to further optimize the dicentric chromosome assay (DCA) and to identify needs for training and harmonization activities within the RENEB network. MATERIALS AND METHODS: The general study design included blood shipment, sample processing, analysis of chromosome aberrations and radiation dose assessment. After manual scoring of dicentric chromosomes in different cell numbers dose estimations and corresponding 95% confidence intervals were submitted by the participants. RESULTS: The shipment of blood samples to the partners in the European Community (EU) were performed successfully. Outside the EU unacceptable delays occurred. The results of the dose estimation demonstrate a very successful classification of the blood samples in medically relevant groups. In comparison to the 1st exercise the 2nd intercomparison showed an improvement in the accuracy of dose estimations especially for the high dose point. CONCLUSIONS: In case of a large-scale radiological incident, the pooling of ressources by networks can enhance the rapid classification of individuals in medically relevant treatment groups based on the DCA. The performance of the RENEB network as a whole has clearly benefited from harmonization processes and specific training activities for the network partners. AU - Oestreicher, U.* AU - Samaga, D.* AU - Ainsbury, E.* AU - Antunes, A.C.* AU - Baeyens, A.* AU - Barrios, L.* AU - Beinke, C.* AU - Beukes, P.* AU - Blakely, W.F.* AU - Cucu, A.* AU - de Amicis, A.* AU - Depuydt, J.* AU - de Sanctis, S.* AU - Di Giorgio, M.* AU - Dobos, K.* AU - Domínguez, I.* AU - Duy, P.N.* AU - Espinoza, M.E.* AU - Flegal, F.N.* AU - Figel, M. AU - Garcia, O.* AU - Monteiro Gil, O.* AU - Gregoire, E.* AU - Guerrero-Carbajal, C.* AU - Guclu, I.* AU - Hadjidekova, V.* AU - Hande, P.* AU - Kulka, U.* AU - Lemon, J.* AU - Lindholm, C.* AU - Lista, F.* AU - Lumniczky, K.* AU - Martínez-López, W.* AU - Maznyk, N.* AU - Meschini, R.* AU - M'kacher, R.* AU - Montoro, A.* AU - Moquet, J.* AU - Moreno, M.* AU - Noditi, M.* AU - Pajic, J.* AU - Radl, A.* AU - Ricoul, M.* AU - Romm, H.* AU - Roy, L.* AU - Sabatier, L.* AU - Sebastià, N.* AU - Slabbert, J.* AU - Sommer, S.* AU - Stuck Oliveira, M.* AU - Subramanian, U.* AU - Suto, Y.* AU - Que, T.* AU - Testa, A.* AU - Terzoudi, G.* AU - Vral, A.* AU - Wilkins, R.* AU - Yanti, L.* AU - Zafiropoulos, D.* AU - Wojcik, A.* C1 - 49799 C2 - 40955 CY - Abingdon SP - 20-29 TI - RENEB intercomparisons applying the conventional Dicentric Chromosome Assay (DCA). JO - Int. J. Radiat. Biol. VL - 93 IS - 1 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - Purpose: MicroRNA miR-21 has emerged as a therapeutic target in the treatment of breast cancer. This study was designed to compare the responses of breast cancer cells and non-transformed breast epithelial cells to a combined regimen of miR-21 inhibition and radiation. Materials and methods: The MDA-MB-361 (breast cancer) and MCF-10A (non-transformed mammary epithelial) cell lines were used for the comparison in this in vitro study. The stable knockdown of miR-21 was performed by using lentiviral approach. The response of the cells was monitored 4, 24 and 48 h after the irradiation with 0.25 and 2.5 Gy, using sham-irradiated cells as controls. The response of the cells was established by performing various functional assays – cell viability and cell attachment, clonogenic survival, cell cycle analysis and 3D microtissue formation. Results: The knockdown of miR-21 induced significant increase in apoptosis and growth delay in MDA-MB-361 cancer cells compared to non-transformed MCF-10A cells. After combined radiation and anti-miR-21 treatment, MDA-MB-361 cells show reduced cell growth and viability what is presented in their inability to form colonies. MCF-10A cells were not as sensitive to the combined treatment and that has also been confirmed with colony forming assay. Conclusions: Cellular response to a combined treatment of anti-miR-21 and radiation is different between cancer and non-cancer cells which highly support the idea of linking miR-21 inhibitor and radiation treatment in the future therapeutic approaches for breast cancer. AU - Radulovic, V. AU - Heider, T. AU - Richter, S. AU - Mörtl, S. AU - Atkinson, M.J. AU - Anastasov, N. C1 - 50328 C2 - 42394 CY - Abingdon SP - 361-372 TI - Differential response of normal and transformed mammary epithelial cells to combined treatment of anti-miR-21 and radiation. JO - Int. J. Radiat. Biol. VL - 93 IS - 4 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - Purpose: Biologically-based mechanistic models that are used in combining current understanding of human carcinogenesis with epidemiological studies were reviewed. Assessment was made of how well they fit the data, whether they account for non-linear radiobiological low-dose effects, and whether they suggest any implications for the dose response at low doses and dose rates. However, the present paper does not make an attempt to provide a complete review of the existing literature on biologically-based models and their application to epidemiological data. Conclusion: In most studies the two-stage clonal expansion (TSCE) model of carcinogenesis was used. The model provided robust estimates of identifiable parameters and radiation risk. While relatively simple, it is flexible, so that more stages can easily be added, and tests made of various types of radiation action. In general, the model performed similarly or better than descriptive excess absolute and excess relative risk models, in terms of quality of fit and number of parameters. Only very rarely the shape of dose-response predicted by the models was investigated. For some tumors, when more detailed biological information was known, additional pathways were included in the model. The future development of these models will benefit from growing knowledge on carcinogenesis processes, and in particular from use of biobank tissue samples and advances in omics technologies. Their use appears a promising approach to investigate the radiation risk at low doses and low dose rates. However, the uncertainties involved are still considerable, and the models provide only a simplified description of the underlying complexity of carcinogenesis. Current assumptions in radiation protection including the linear-non-threshold (LNT) model are not in contradiction to what is presently known on the process of cancer development. AU - Rühm, W. AU - Eidemüller, M. AU - Kaiser, J.C. C1 - 51154 C2 - 42658 CY - Abingdon SP - 1093-1117 TI - Biologically-based mechanistic models of radiation-related carcinogenesis applied to epidemiological data. JO - Int. J. Radiat. Biol. VL - 93 IS - 5 PB - Informa Healthcare, Taylor & Francis Group PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Estimated radiation risks used for radiation protection purposes have been based primarily on the Life Span Study (LSS) of atomic bomb survivors who received brief exposures at high dose rates, many with high doses. Information is needed regarding radiation risks from low dose-rate (LDR) exposures to low linear-energy-transfer (low-LET) radiation. We conducted a meta-analysis of LDR epidemiologic studies that provide dose-response estimates of total solid cancer risk in adulthood in comparison to corresponding LSS risks, in order to estimate a dose rate effectiveness factor (DREF). MATERIALS AND METHODS: We identified 22 LDR studies with dose-response risk estimates for solid cancer after minimizing information overlap. For each study, a parallel risk estimate was derived from the LSS risk model using matching values for sex, mean ages at first exposure and attained age, targeted cancer types, and accounting for type of dosimetric assessment. For each LDR study a ratio of the excess relative risk per Gy (ERR Gy(-1)) to the matching LSS ERR risk estimate (LDR/LSS) was calculated, and a meta-analysis of the risk ratios was conducted. The reciprocal of the resultant risk ratio provided an estimate of the DREF. RESULTS: The meta-analysis showed a LDR/LSS risk ratio of 0.36 (95% confidence interval (CI) 0.14, 0.57) for the 19 studies of solid cancer mortality and 0.33 (95% CI 0.13, 0.54) when three cohorts with only incidence data also were added, implying a DREF with values around 3, but statistically compatible with 2. However, the analyses were highly dominated by the Mayak worker study. When the Mayak study was excluded the LDR/LSS risk ratios increased: 1.12 (95% CI 0.40, 1.84) for mortality and 0.54 (95% CI 0.09, 0.99) for mortality+incidence, implying a lower DREF in the range of 1 to 2. Meta-analyses that included only cohorts in which the mean dose was <100 mGy yielded a risk ratio of 1.06 (95% CI 0.30, 1.83) for solid cancer mortality and 0.58 (95% CI 0.10, 1.06) for mortality+incidence data. CONCLUSIONS: The interpretation of a best estimate for a value of the DREF depends on the appropriateness of including the Mayak study. This study indicates a range of uncertainty in the value of DREF between 1 and about 2 after protracted radiation exposure. The LDR data provide direct evidence regarding risk from exposures at low dose rates as an important complement to the LSS risk estimates used for radiation protection purposes. AU - Shore, R.* AU - Walsh, L.* AU - Azizov, A.* AU - Rühm, W. C1 - 50965 C2 - 42613 CY - Abingdon SP - 1064-1078 TI - Risk of solid cancer in low dose-rate radiation epidemiological studies and the dose-rate effectiveness factor. JO - Int. J. Radiat. Biol. VL - 93 IS - 10 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - Purpose In the EC funded project RENEB (Realizing the European Network in Biodosimetry), physical methods applied to fortuitous dosimetric materials are used to complement biological dosimetry, to increase dose assessment capacity for large-scale radiation/nuclear accidents. This paper describes the work performed to implement Optically Stimulated Luminescence (OSL) and Electron Paramagnetic Resonance (EPR) dosimetry techniques. Materials and Methods OSL is applied to electronic components and EPR to touch-screen glass from mobile phones. To implement these new approaches, several blind tests and inter-laboratory comparisons (ILCs) were organized for each assay. Results OSL systems have shown good performances. EPR systems also show good performance in controlled conditions, but ILCs have also demonstrated that post-irradiation exposure to sunlight increases the complexity of the EPR signal analysis. Conclusions Physically based dosimetry techniques present high capacity, new possibilities for accident dosimetry, especially in the case of large-scale events. Some of the techniques applied can be considered as operational (e.g. OSL on Surface Mounting Devices (SMD)) and provide a large increase of measurement capacity for existing networks. Other techniques and devices currently undergoing validation or development in Europe could lead to considerable increases in the capacity of the RENEB accident dosimetry network. AU - Trompier, F.* AU - Burbidge, C.I.* AU - Bassinet, C.* AU - Baumann, M.* AU - Bortolin, E.* AU - de Angelis, C.* AU - Eakins, J.* AU - Della Monaca, S.* AU - Fattibene, P.* AU - Quattrini, M.C.* AU - Tanner, R.* AU - Wieser, A. AU - Woda, C. C1 - 49358 C2 - 41778 CY - Abingdon SP - 65-74 TI - Overview of physical dosimetry methods for triage application integrated in the new European network RENEB. JO - Int. J. Radiat. Biol. VL - 93 IS - 1 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Multiple cell types secrete exosome-like extracellular vesicles (ELVs) to the extracellular environment. Pathological conditions can produce characteristic changes to the vesicle cargo. We investigated if ionizing radiation is capable of inducing changes in the protein and microRNA (miRNA) cargo of ELVs. MATERIALS AND METHODS: Whole blood samples from healthy donors were irradiated with 2 Gy gamma rays and then peripheral blood mononuclear cells and plasma were separated from residual blood and co-cultivated for 24 h. The released ELVs were collected by differential ultracentrifugation from irradiated and non-irradiated samples. microRNAs and proteins were quantified by qPCR and label-free proteomics. RESULTS: Here we report a first characterization of radiation-induced changes in the protein and miRNA cargo of ELVs isolated from plasma. Proteome analysis of ELVs identified 214 proteins, of which nine significantly changed their abundance after irradiation. The radiation-induced down-regulation of afamin and serpine peptidase F1 was confirmed by immunoblotting. miRNA expression profiling identified 58 different exosomal miRNAs, the expression of miR-204-5p, miR-92a-3p and miR-31-5p was significantly increased in ELVs from irradiated samples. CONCLUSIONS: This study provides evidence that radiation-induced changes occur in the protein and miRNA cargo of plasma ELVs. These data imply a novel systemic communication pathway between irradiated and non-irradiated cells and tissues. AU - Yentrapalli, R. AU - Merl-Pham, J. AU - Azimzadeh, O. AU - Mutschelknaus, L. AU - Peters, C.* AU - Hauck, S.M. AU - Atkinson, M.J. AU - Tapio, S. AU - Mörtl, S. C1 - 50613 C2 - 42624 CY - Abingdon SP - 1-12 TI - Quantitative changes in the protein and miRNA cargo of plasma exosome-like vesicles after exposure to ionizing radiation. JO - Int. J. Radiat. Biol. VL - 7 IS - 6 PB - Taylor & Francis Ltd PY - 2017 SN - 0955-3002 ER - TY - JOUR AB - Abstract Purpose: To develop a physiologically based compartmental approach for modeling plutonium decorporation therapy with the chelating agent Diethylenetriaminepentaacetic acid (Ca-DTPA/Zn-DTPA). Materials and methods: Model calculations were performed using the software package SAAM II (©The Epsilon Group, Charlottesville, Virginia, USA). The Luciani/Polig compartmental model with age-dependent description of the bone recycling processes was used for the biokinetics of plutonium. Results: The Luciani/Polig model was slightly modified in order to account for the speciation of plutonium in blood and for the different affinities for DTPA of the present chemical species. The introduction of two separate blood compartments, describing low-molecular-weight complexes of plutonium (Pu-LW) and transferrin-bound plutonium (Pu-Tf) respectively, and one additional compartment describing plutonium in the interstitial fluids was performed successfully. Conclusions: The next step of the work is the modeling of the chelation process, coupling the physiologically modified structure with the biokinetic model for DTPA. Results of animal studies performed under controlled conditions will enable to better understand the principles of the involved mechanisms. AU - Kastl, M. AU - Giussani, A.* AU - Blanchardon, E.* AU - Breustedt, B.* AU - Fritsch, P.* AU - Hoeschen, C. AU - López, M.A.* C1 - 31573 C2 - 34557 SP - 1062-1067 TI - Developing a physiologically based approach for modeling plutonium decorporation therapy with DTPA. JO - Int. J. Radiat. Biol. VL - 90 IS - 11 PY - 2014 SN - 0955-3002 ER - TY - JOUR AB - Purpose: Ionizing radiation has been recognized to increase the risk of cardiovascular diseases (CVD). However, there is no consensus concerning the dose-risk relationship for low radiation doses and a mechanistic understanding of low dose effects is needed. Material and methods: Previously, human umbilical vein endothelial cells (HUVEC) were exposed to chronic low dose rate radiation (1.4 and 4.1 mGy/h) during one, three and six weeks which resulted in premature senescence in cells exposed to 4.1 mGy/h. To gain more insight into the underlying signaling pathways, we analyzed gene expression changes in these cells using microarray technology. The obtained data were analyzed in a dual approach, combining single gene expression analysis and Gene Set Enrichment Analysis. Results: An early stress response was observed after one week of exposure to 4.1 mGy/h which was replaced by a more inflammation-related expression profile after three weeks and onwards. This early stress response may trigger the radiation-induced premature senescence previously observed in HUVEC irradiated with 4.1 mGy/h. A dedicated analysis pointed to the involvement of insulin-like growth factor binding protein 5 (IGFBP5) signaling in radiation-induced premature senescence. Conclusion: Our findings motivate further research on the shape of the dose-response and the dose rate effect for radiation-induced vascular senescence. AU - Rombouts, C.* AU - Aerts, A.L.* AU - Quintens, R.* AU - Baselet, B.* AU - El-Saghire, H.* AU - Harms-Ringdahl, M.* AU - Haghdoost, S.* AU - Janssen, A.* AU - Michaux, A.* AU - Yentrapalli, R. AU - Benotmane, M.A.* AU - van Oostveldt, P.M.* AU - Baatout, S.* C1 - 31770 C2 - 34744 CY - London SP - 560-574 TI - Transcriptomic profiling suggests a role for IGFBP5 in premature senescence of endothelial cells after chronic low dose rate irradiation. JO - Int. J. Radiat. Biol. VL - 90 IS - 7 PB - Informa Healthcare PY - 2014 SN - 0955-3002 ER - TY - JOUR AB - Abstract Purpose: The 2012 Conference on Radiation and Health in Kennebunkport, Maine, USA, brought together epidemiologists, statisticians, basic scientists, and clinical scientists interested in the health effects of radiation exposure due to medical, diagnostic, occupational, and non-medical sources, to review the current status of epidemiologic and clinical research on radiation exposure in relation to risk of breast, thyroid cancer, and leukemia, cardiopulmonary events, and other late effects. Topics discussed included synergy between radiation exposure and genetic background; late effects of radiation therapy in childhood cancer survivors and several other medically exposed cohorts; leukemia risk seen in Russian and Chernobyl studies, and leukemia risk from computed tomography scans in childhood. Results and conclusions: This report summarizes the presentations at the meeting and discusses their significance in light of earlier studies and of other ongoing research. AU - Jacob, P. AU - Stram, D.O.* C1 - 26743 C2 - 32364 SP - 673-683 TI - Late health effects of radiation exposure: New statistical, epidemiological, and biological approaches. JO - Int. J. Radiat. Biol. VL - 89 IS - 8 PB - Informa Healthcare PY - 2013 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: The role of track structures for understanding the biological effects of radiation has been the subject of research activities for decades. The physics that describes such processes is the core Monte Carlo codes, such as the biophysical PARTRAC (PARticle TRACks) code described in this review, which follow the mechanisms of radiation-matter interaction from the early stage. In this paper a review of the track structure theory (and of its possible extension concerning non-DNA targets) is presented MATERIALS AND METHODS: The role of radiation quality and track structure is analyzed starting from the heavy ions results obtained with the biophysical Monte Carlo code PARTRAC (PARticles TRACks). PARTRAC calculates DNA damage in human cells based on the superposition of simulated track structures in liquid water to an 'atom-by-atom' model of human DNA. RESULTS: Calculations for DNA fragmentation compared with experimental data for different radiation qualities are illustrated. As an example, the strong dependence of the complexity of DNA damage on radiation track structure, and the very large production of very small DNA fragments (lower than 1 kbp (kilo base pairs) usually not detected experimentally) after high LET (high-Linear Energy Transfer) irradiation is shown. Furthermore the possible importance of non-nuclear/non-DNA targets is discussed in the particular case of cellular membrane and mitochondria. CONCLUSIONS: The importance of the track structure is underlined, in particular the dependence of a given late cellular effect on the spatial distribution of DNA double-strand breaks (DSB) along the radiation track. These results show that the relative biological effectiveness (RBE) for DSB production can be significantly larger than 1. Moreover the cluster properties of high LET radiation may determine specific initial targets and damage evolution. AU - Alloni, D.* AU - Campa, A.* AU - Friedland, W. AU - Mariotti, L.* AU - Ottolenghi, A.* C1 - 7165 C2 - 29505 SP - 77-86 TI - Track structure, radiation quality and initial radiobiological events: Considerations based on the PARTRAC code experience. JO - Int. J. Radiat. Biol. VL - 88 IS - 1-2 PB - Informa Healthcare PY - 2012 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: To test the stochastic model for DNA double-strand break (DSB) repair via non-homologous end joining (NHEJ) implemented in the Monte Carlo code PARTRAC (PARticle TRACks) against measured repair kinetics after nitrogen ion and (60)Co γ reference irradiation. MATERIAL AND METHODS: By combining Monte Carlo track structure calculations with multi-scale models of cellular DNA, yields of DSB are calculated for N ion and (60)Co γ-irradiation. The NHEJ model in PARTRAC is used to determine rejoining kinetics of the DNA ends and DNA fragment distributions after certain repair times. Model parameters are adapted to the measured rejoining kinetics for the different radiation types. RESULTS: DSB rejoining kinetics after low- and high-linear energy transfer (LET) irradiation have been reproduced after refinements of the DNA repair model, in particular by considering an ongoing production of detectable DSB in the initial phase, e.g., by enzymatic processing of labile sites, and by assuming a limited availability of repair enzymes needed for processing complex lesions during the slow repair phase. CONCLUSIONS: The need for certain model refinements suggests mechanisms that may significantly contribute to the DSB rejoining kinetics during both initial and later phases of NHEJ. AU - Friedland, W. AU - Kundrát, P. AU - Jacob, P. C1 - 7164 C2 - 29504 SP - 129-136 TI - Stochastic modelling of DSB repair after photon and ion irradiation. JO - Int. J. Radiat. Biol. VL - 88 IS - 1-2 PB - Informa Healthcare PY - 2012 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: To investigate alternative scenarios for the dose-dependent emission of bystander signals by irradiated cells in medium transfer experiments. METHODS: Energy deposition patterns to hypothetical intracellular targets whose hit by radiation initiates the emission of bystander signals have been simulated by Monte Carlo code PARTRAC, evaluating the effects of target size, multiplicity and threshold energy for activation. Scenarios in which individual irradiated cells release signals independently as well as those with signal amplification by neighbour cells have been analyzed. The non-linear response of unirradiated cells to signals in the transferred medium has been considered. RESULTS: The experimentally observed dose dependence of bystander effects is consistent with cell-autonomous signal release with a wide distribution of characteristic doses, covering the range of 3 mGy to 3 Gy. Alternatively, the data can be explained by assuming that only cells receiving a high specific energy (3 Gy to 0.5 μm targets) release primary signals, which are then amplified by secondary signalling by neighbour cells within about a millimetre distance. -CONCLUSION: Alternative signal emission scenarios are consistent with the observed dose dependence of bystander effects in medium transfer experiments. Thus, further experimental research is needed to identify the actual mechanism of bystander signal emission. AU - Kundrát, P. AU - Friedland, W. C1 - 7163 C2 - 29503 SP - 98-102 TI - Track structure calculations on intracellular targets responsible for signal release in bystander experiments with transfer of irradiated cell-conditioned medium. JO - Int. J. Radiat. Biol. VL - 88 IS - 1-2 PB - Informa Healthcare PY - 2012 SN - 0955-3002 ER - TY - JOUR AB - Purpose: To analyze the response of naive cells to bystander signals, thus complementing previous studies on signal emission by irradiated cells and improving quantitative understanding of bystander effects. Materials and methods: Published data on reduced clonogenic survival and mutation induction in bystander experiments with undiluted and diluted irradiated cell-conditioned medium were analyzed using linear and non-linear response functions. Results: The data indicated a highly non-linear response of cells to bystander signals. It can be described with sigmoid response functions, involving only a single additional parameter compared to the linear response assumed in existing models. Accounting for this non-linearity significantly modifies bystander characteristics inferred from the modelling, such as signal lifetime or dose dependence of signal release. Some signal release models are even ruled out. Conclusions: The sigmoid response to signals reflects complex intracellular pathways triggered and, together with the non-linear release of signals, supports the involvement of cytokines and/or reactive oxygen species in bystander effects. Further research combining experimental and modelling approaches is needed to elucidate the mechanisms of intercellular communication and their modifications by radiation, in particular to determine the nature of bystander signals, dynamics of their release after irradiation, and cellular responses to these signals. AU - Kundrát, P. AU - Friedland, W. C1 - 10708 C2 - 30365 SP - 743-750 TI - Non-linear response of cells to signals leads to revised characteristics of bystander effects inferred from their modelling. JO - Int. J. Radiat. Biol. VL - 88 IS - 10 PB - Informa Healthcare PY - 2012 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: To date, simultaneously performed investigations on the differential radiosensitivity of an Epstein-Barr virus (EBV)-transformed B cell line as well as B and T lymphocytes of human peripheral blood are not available. Thus the aim of the present study was to fill this gap by directly comparing the corresponding dose-response relationships of dicentrics obtained in blood samples from the same donor. MATERIAL AND METHODS: Cell samples of whole blood or low passage cells of an EBV-transformed B cell line were irradiated by 120 kV X-rays in chambers tightly embedded in a polymethylmethacrylate phantom. Chromosome analysis was performed in phytohemagglutinin-stimulated T lymphocytes, in pokeweed mitogen-stimulated B lymphocytes and in the EBV-transformed B cell line. RESULTS: Based on dose-response relationships of dicentrics, different radiosensitivity values relative to T lymphocytes were found from 1.53-1.46 for the EBV-transformed cell line, from 0.76-0.80 for resting B lymphocytes and from 2.36-2.20 for cycling B lymphocytes within the dose range from 0.25-4 Gy. CONCLUSIONS: Owing to these different radiosensitivity values, care has to be taken when dose-response relationships of dicentrics determined in B cell lines are used in biological dosimetry to estimate any dose levels for radiation protection purposes. AU - Schmid, E.* AU - Roos, H.* AU - Sauter, W. AU - Rickinger, A. AU - Jaehnert, I. AU - Eckardt-Schupp, F. C1 - 275 C2 - 27119 SP - 47-55 TI - Chromosome analysis of the differential radiosensitivity of an Epstein-Barr virus (EBV)-transformed B cell line and B and T lymphocytes from the same blood donor. JO - Int. J. Radiat. Biol. VL - 86 IS - 1 PB - Taylor&Francis Ltd. PY - 2010 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: In order to obtain more insight into heavy ion tumour therapy, some features of the underlying molecular mechanisms controlling the cellular response to high linear energy transfer (LET) radiation are currently analysed. MATERIALS AND METHODS: We analysed the decay of the integrated fluorescence intensity of gamma-H2AX (phosphorylated histone H2AX) which is thought to reflect the repair kinetics of radiation-induced DNA double-strand breaks (DSB) using Laser-Scanning-Cytometry. Asynchronous human HeLa cells were irradiated with a single dose of either 1.89 Gy of 55 MeV carbon ions or 5 Gy of 70 kV X-rays. RESULTS: Measurements of the gamma-H2AX-intensities from 15-60 min resulted in a 16 % decrease for carbon ions and in a 43 % decrease for X-rays. After 21 h, the decrease was 77 % for carbon ions and 85 % for X-rays. The corresponding time-effect relationship was fitted by a bi-exponential function showing a fast and a slow component with identical half-life values for both radiation qualities being 24 +/- 4 min and 13.9 +/- 0.7 h, respectively. Apparent differences in the kinetics following high and low LET irradiation could completely be attributed to quantitative differences in their contributions, with the slow component being responsible for 47 % of the repair after exposure to X-rays as compared to 80 % after carbon ion irradiation. CONCLUSION: gamma-H2AX loss kinetics follows a bi-exponential decline with two definite decay times independent of LET. The higher contribution of the slow component determined for carbon ion exposure is thought to reflect the increased amount of complex DSB induced by high LET radiation. AU - Schmid, T.E.* AU - Dollinger, G.* AU - Beisker, W. AU - Hable, V.* AU - Greubel, C.* AU - Auer, S.* AU - Mittag, A.* AU - Tarnok, A.* AU - Friedl, A.A.* AU - Molls, M.* AU - Röper, B.* C1 - 2766 C2 - 27522 SP - 682-691 TI - Differences in the kinetics of γ-H2AX fluorescence decay after exposure to low and high LET radiation. JO - Int. J. Radiat. Biol. VL - 86 IS - 8 PB - Taylor&Francis Ltd. PY - 2010 SN - 0955-3002 ER - TY - JOUR AB - Purpose: The European Radiobiology Archives (ERA), together with corresponding Japanese and American databases, hold data from nearly all experimental animal radiation biology studies carried out between 1960 and 1998, involving more than 300,000 animals. The Federal Office for Radiation Protection, together with the University of Cambridge have undertaken to transfer the existing ERA archive to a web-based database to maximize its usefulness to the scientific community and bring data coding and structure of this legacy database into congruence with currently accepted semantic standards for anatomy and pathology. Methods: The accuracy of the primary data input was assessed and improved. The original rodent pathology nomenclature was recoded to replace the local 'DIS-ROD' (Disease Rodent) formalism with Mouse Pathology (MPATH) and Mouse Anatomy (MA) ontology terms. A pathology panel sampled histopathological slide material and compared the original diagnoses with currently accepted diagnostic criteria. Results: The overall non-systematic error rate varied among the studies between 0.26% and 4.41%, the mean error being 1.71%. The errors found have been corrected and the studies thus controlled have been annotated. The majority of the original pathology terms have been successfully translated into a combination of MPATH and MA ontology terms. Conclusions: ERA has the potential of becoming a world-wide radiobiological research tool for numerous applications, such as the re-analysis of existing data with new approaches in the light of new hypotheses and techniques, and using the database as an information resource for planning future animal studies. When the database is opened for new data it may be possible to offer long-term storage of data from recent and future animal studies. AU - Tapio, S. AU - Schofield, P.N.* AU - Adelmann, C. AU - Atkinson, M.J.* AU - Bard, J.L.* AU - Bijwaard, H.* AU - Birschwilks, M. AU - Dubus, P.* AU - Fiette, L.* AU - Gerber, G.* AU - Gruenberger, M.* AU - Quintanilla-Martinez, L. AU - Rozell, B.* AU - Saigusa, S.* AU - Warren, M.* AU - Watson, C.R.* AU - Grosche, B.* C1 - 2298 C2 - 25989 SP - 930-936 TI - Progress in updating the European Radiobiology Archives. JO - Int. J. Radiat. Biol. VL - 84 IS - 11 PB - Taylor & Francis Ltd. PY - 2008 SN - 0955-3002 ER - TY - JOUR AB - To evaluate whether immunotherapy based on adoptively transferred cytotoxic T-cells (CTL) can improve the antitumour efficacy of irradiation. Material and methods: The experiments were performed using the human squamous cell carcinoma line UT-SCC-15, which expresses human leukocyte antigen (HLA)-A2. The UT-SCC-15 cell-mediated activation of JB4 CTL in terms of interferon (IFN)-gamma secretion and cytotoxic potential was determined by enzyme-linked immunosorbent assay and chromium release assay, the perforin content of JB4 cells by flow cytometry. In vivo, tumours were irradiated with 14 Gy. Subsequently, JB4 CTL were injected intra- and peritumourally. Volume doubling times were calculated as a marker of tumour growth delay. Results: UT-SCC-15 tumour cells were well recognized by JB4 CTL in vitro, as indicated by profound IFN-gamma secretion and tumour cell lysis. This response was completely abrogated in the presence of an anti-HLA-A2 antibody. In vivo, adoptive transfer of JB4 CTL after irradiation did not delay tumour growth in comparison to irradiation alone. As a possible underlying mechanism, a loss of perforin content and cytolytic function of the CTL in the absence of interleukin (IL)- 2 or IL-15 was found in vitro. Conclusion: HLA-A2-alloreactive JB4 cells efficiently recognize and destroy UT-SCC-15 tumour cells in vitro. However, the intratumoural application of JB4 cells after irradiation does not enhance the in vivo effect of radiotherapy alone, which might be caused by the reduced cytotoxic potential of JB4 cells in the absence of IL-2 or IL-15. Thus, co-administration of these cytokines might improve the efficacy of combined irradiation and CTL treatment. AU - Krause, M.* AU - Schmitz, M.* AU - Nößner, E. AU - Skrablin, P.S. AU - Wehner, R.* AU - Rieber, E.P.* AU - Baumann, M.* C1 - 3462 C2 - 25073 SP - 827 - 836 TI - Adoptive transfer of cytotoxic T-cells for treatment of residual disease after irradiation. JO - Int. J. Radiat. Biol. VL - 83 IS - 11-12 PB - Informa Healthcare PY - 2007 SN - 0955-3002 ER - TY - JOUR AB - To determine whether computed tomography (CT) could enhance the chromosome aberration yields in paediatric patients.Material and methods: Blood samples were taken before and after CT scans from 10 children for whom the medical justifications for CT examinations were accidental injuries and not diseases as investigated in earlier studies. Chromosome analysis was carried out in lymphocytes by fluorescence plus Giemsa (FPG) staining exclusively in metaphases of the first cell cycle in vitro.The mean blood dose of the 10 children was about 12.9 mGy which was determined by a newly developed dose estimation. Based on more than 20,000 analyzed cells it was found that after CT examination the frequencies of dicentrics (dic) and excess acentric fragments (ace) in lymphocytes were significantly increased. By subdividing the children into two age groups, those with an age from 0.4 years to 9 years and from 10 - 15 years, it became obvious that the observed increase in chromosome aberrations was mainly contributed by the younger age group. In this group the frequency of dicentrics was significantly increased whereas in the older group the observed increase was not significant.Our results demonstrate that CT examinations enhance the dicentrics yields in peripheral lymphocytes of children aged up to 15 years. Since in particular significantly increased dicentric yields could be observed in children with an age from 0.4 - 9 years, it can be assumed that children younger than 10 years may be more radiation sensitive than older subjects. AU - Stephan, G.* AU - Schneider, K.* AU - Panzer, W. AU - Walsh, L. AU - Oestreicher, U.* C1 - 4793 C2 - 24458 SP - 281-287 TI - Enhanced yield of chromosome aberrations after CT examinations in paediatric patients. JO - Int. J. Radiat. Biol. VL - 83 PB - Taylor & Francis PY - 2007 SN - 0955-3002 ER - TY - JOUR AB - Purpose: To quantify the role played by radiation track structure and background fragments in modulating DNA fragmentation in human cells exposed to γrays and light ions. Materials and methods: Human fibroblasts were exposed in vitro to different doses (in the range from 40-200 Gy) of 60Co γ-rays and 0.84 MeV protons (Linear Energy Transfer, LET, in tissue 28.5 keV/μm). The resulting DNA fragments were scored under two electrophoretic conditions, in order to optimize separation in the size ranges 0.023-1.0 Mbp and 1.0-5.7 Mbp. In parallel, DNA fragmentation was simulated both with a phenomenological approach based on the "generalized broken-stick" model, and with a mechanistic approach based on the PARTRAC (acronym of PARticle TRACk) Monte Carlo code (1.32 MeV photons were used for the simulation of 60Co γ-rays). Results: For both γ-rays and protons, the experimental dose response in the range 0.023-5.7 Mbp could be approximated as a straight line, the slope of which provided a yield of (5.3 ± 0.4)·10-9 Gy-1 bp-1 for γ-rays and (7.1 ± 0.6)·10-9 Gy-1 bp-1 for protons, leading to a Relative Biological Effectiveness (RBE) of 1.3 ± 0.2. From both theoretical analyses it appeared that, while γ-ray data were consistent with double-strand breaks (DSB) random induction, protons at low doses showed significant deviation from randomness, implying enhanced production of small fragments in the low molecular weight part of the experimental range. The theoretical analysis of fragment production was then extended to ranges where data were not available, i.e. to fragments larger than 5.7 Mbp and smaller than 23 kbp. The main outcome was that small fragments (< 23 kbp) are produced almost exclusively via non-random processes, since their number is considerably higher than that produced by a random insertion of DSB. Furthermore, for protons the number of these small fragments is a significant fraction (about 20%) of the total number of fragments; these fragments remain undetected in these experiments. Calculations for 3.3 MeV alpha particle irradiation (for which no experimental data were available) were performed to further investigate the role of fragments smaller than 23 kbp; in this case, besides the non-random character of their production, their number resulted to be at least as much as half of the total number of fragments. Conclusion: Comparison between experimental data and two different theoretical approaches provided further support to the hypothesis of an important role of track structure in modulating DNA damage. According to the theoretical approaches, non-randomness of fragment production was found for proton irradiation for the smaller fragments in the experimental size range and, in a significantly larger extent, for fragments of size less than 23 kbp, both for protons and alpha particles. © 2005 Taylor & Francis. AU - Campa, A.* AU - Ballarini, F.* AU - Belli, M.* AU - Cherubini, R.* AU - Dini, V.* AU - Esposito, G.* AU - Friedland, W. AU - Gerardi, S.* AU - Molinelli, S.* AU - Ottolenghi, A.* AU - Paretzke, H.G. AU - Simone, G.* AU - Tabocchini, M.A.* C1 - 2007 C2 - 23459 SP - 841-854 TI - DNA DSB induced in human cells by charged particles and gamma rays: Experimental results and theoretical approach. JO - Int. J. Radiat. Biol. VL - 81 IS - 11 PY - 2005 SN - 0955-3002 ER - TY - JOUR AU - Barquinero, J.F.* AU - Stephan, G.* AU - Schmid, E. C1 - 4109 C2 - 21883 SP - 155-164 TI - Effect of americium-241 alpha-particles on the dose-response of chromosome aberrations in human lymphocytes analysed by fluorescence in situ hybridization. JO - Int. J. Radiat. Biol. VL - 80 PY - 2004 SN - 0955-3002 ER - TY - JOUR AU - Mestres, M.* AU - Caballin, M.R.* AU - Schmid, E. AU - Stephan, G.* AU - Sachs, R.* AU - Barrios, L.* AU - Barquinero, J.F.* C1 - 4705 C2 - 22091 SP - 1-8 TI - Analysis of alpha-particle induced chromosome aberrations in human lymphocytes, using pan-centromeric and pan-telomeric probes. JO - Int. J. Radiat. Biol. VL - 80 PY - 2004 SN - 0955-3002 ER - TY - JOUR AU - Braselmann, H. AU - Kulka, U.* AU - Huber, R. AU - Figel, A.-M. AU - Zitzelsberger, H. C1 - 9724 C2 - 21154 SP - 393-403 TI - Distribution of radiation-induced exchange aberrations in all human chromosomes. JO - Int. J. Radiat. Biol. VL - 79 PY - 2003 SN - 0955-3002 ER - TY - JOUR AU - Valota, A.* AU - Ballarini, F.* AU - Friedland, W. AU - Jacob, P. AU - Ottolenghi, A.* AU - Paretzke, H.G. C1 - 9725 C2 - 21264 SP - 643-653 TI - Modelling study on the protective role of OH radical scavengers and DNA higher-order structures in induction of single- and double-strand break by gamma-radiation. JO - Int. J. Radiat. Biol. VL - 79 PY - 2003 SN - 0955-3002 ER - TY - JOUR AB - Purpose: To perform an interlaboratory comparison of FISH chromosome painting and to study the time-course of translocations and dicentrics in three accident victims exposed to radiation. Also, to use the data in the validation of the FISH technique as a retrospective dosimeter.Materials and methods: Twelve blood samples were collected during 4 years from three subjects exposed to radiation in an accident in Estonia in 1994 involving gamma-radiation from a Cs-137 source. Two of the subjects were exposed during approximately 7 h, both receiving a protracted dose of about 1 Gy and also localized exposure. The third subject received a protracted whole-body dose of 2.7 Gy during 4 weeks as well as a short-term partial-body dose. Preparations from 48-h metaphase cultures were painted by the FISH technique using routine methods and probe cocktails in four laboratories. Samples from each subject were analysed in two different laboratories that used different combinations of whole chromosome probes. The PAINT nomenclature was applied when recording chromosome aberrations.Results: The intercomparison of FISH analysis data showed reasonable similarities between laboratories, the largest discrepancy being 21% in the frequency of two-way translocations in subject 3. Half-time calculations, based on combined data sets from two laboratories, showed that dicentrics decreased rapidly with half-times of approximately 2 years. In all cases, the initial dicentric yields were lower than the initial translocation yields. During the 4-year follow-up, the frequencies of all translocations in cells containing only simple rearrangements fell on average to about 65% of their initial value. Two-way translocations were slightly more persistent than all translocations. The average half-time was about 8 years for two-way translocations and around 6 years for all translocations. Cells containing complex rearrangements were few in number and they disappeared with time. In general, the inclusion of complex cells caused a more rapid fall in aberration yield.Conclusions: In general, the results imply that relatively consistent scoring data were obtained with different chromosome painting protocols. They also support the idea that the reduction of translocations with time is associated with partial-body irradiation. AU - Lindholm, C.* AU - Romm, H.* AU - Stephan, G.* AU - Schmid, E. AU - Moquet, J.* AU - Edwards, A.* C1 - 9723 C2 - 20358 SP - 883-890 TI - Intercomparison of translocation and dicentric frequencies between laboratories in a follow-up of the radiological accident in Estonia. JO - Int. J. Radiat. Biol. VL - 78 PB - Informa Healthcare PY - 2002 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: To assess the persistence of exchange aberrations measured by FISH chromosome painting after accidental radiation exposure. MATERIALS AND METHODS: Chromosome analyses were carried out in peripheral lymphocytes of a 13-year-old boy exposed to protracted low dose-rate whole-body and short-time partial-body irradiation from a radiation accident in Estonia in 1994. Up to November 1998, the frequencies of translocations and dicentrics were periodically measured using FISH chromosome painting of the target chromosomes 1, 4 and 12, with a simultaneous pancentromeric probe. RESULTS: For the yields of dicentrics, an expected rapid temporal decline was found with a half-time of 14.2+/-1.9 months. The yields of reciprocal translocations also revealed a gradual but significant reduction with a half-time of 51.7+/-12.7 months. CONCLUSION: An unchanged temporal persistence of so-called stable translocations cannot be assumed. Any significant reduction of this aberration type with time obviously limits the application of FISH-based translocation measurements for reliable long-term biodosimetry after combined protracted whole-body and partial-body radiation exposure. AU - Bauchinger, M. AU - Schmid, E. AU - Braselmann, H. C1 - 23348 C2 - 31097 SP - 553-557 TI - Time-course of translocation and dicentric frequencies in a radiation accident case. JO - Int. J. Radiat. Biol. VL - 77 IS - 5 PB - Informa Healthcare PY - 2001 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: To investigate within the framework of a multilaboratory study the suitability of FISH chromosome painting to measure so-called stable translocations in peripheral lymphocytes of Mayak nuclear-industrial workers (from the Southern Urals) and their use for retrospective biodosimetry. MATERIALS AND METHODS: Chromosime analyses were carried out from 69 workers who had received protracted occupational radiation exposures (0.012-6.065 Gy) up to approximately 40 years before blood sampling. Twenty-one unexposed people living in the same area were controls. A multicolour FISH-painting protocol with the target chromosomes 1, 4 and 8 simultaneously with a pancentromeric probe was used to score potentially transmissible chromosome-type aberrations (reciprocal translocations 2B and related 'one-way' patterns I-III according to the S&S classification). RESULTS: Individual biodosimetry estimates were obtained in terms of these potentially long-term surviving aberration types based on the linear component of a low dose-rate gamma-ray calibration curve produced using identical staining and scoring protocols. For comparison, the workers personal and total background doses were converted to red bone marrow doses. The estimated doses were mainly lower than would be predicted by the calibration curve, particularly at accumulated higher dose levels. CONCLUSIONS: Owing to the limited life-time of circulating T-lymphocytes, the long-term persistence of translocations in vivo requires the assumption of a clonal repopulation of these naturally senescing cells from the haemopoietic stem cell compartments. Obviously such a replacement cannot be fully achieved, leading to a temporal decline even of the yield of transmissible aberrations types. Assuming further a highly selective capacity of stem cells against any type of chromosomal damage and the fact that one must rely on partial genome findings, the potential of FISH chromosome painting for retrospective dose reconstruction is probably limited to a decade or so after high-level protracted radiation exposure. AU - Bauchinger, M. AU - Braselmann, H. AU - Savage, J.R.* AU - Natarajan, A.T.* AU - Terzoudi, G.I.* AU - Pantelias, G.E.* AU - Darroudi, F.* AU - Figgitt, M.* AU - Griffin, C.S.* AU - Knehr, S. AU - Okladnikova, N.D.* AU - Santos, S.* AU - Snigiryova, G.* C1 - 23350 C2 - 31096 SP - 259-267 TI - Collaborative exercise on the use of FISH chromosome painting for retrospective biodosimetry of Mayak nuclear-industrial personnel. JO - Int. J. Radiat. Biol. VL - 77 IS - 3 PB - Informa Healthcare PY - 2001 SN - 0955-3002 ER - TY - JOUR AB - PURPOSE: Between 1990 and 1991 a leukaemia cluster was observed in children living close to the combined site of a nuclear power plant and a nuclear research facility in Elbmarsch, a region in Lower Saxony (Germany). We aim to investigate the prevalence of presumably radiation-induced chromosomal aberrations in peripheral blood lymphocytes of children in Elbmarsch and children of a control region in order to find out whether there was an uncontrolled release of radioactive material which resulted in a substantial exposure. MATERIALS AND METHODS: The frequency of dicentric and ring chromosomes in lymphocytes of the peripheral blood in 42 children in Elbmarsch and 30 children in Plön was investigated. Children in both groups had been permanent residents of the study area. RESULTS: The mean frequency of dicentric and ring chromosomes in Elbmarsch was 14/32580 cells (=0.430 x 10(-3); 95% CI 0.24-0.70 x 10(-3) cells), and in Plön it was 17/24065 cells (=0.706 x 10(-3); 95% CI 0.42-1.10 x 10(-3) cells). CONCLUSIONS: No difference in the frequency of dicentric and ring chromosomes was observed between children in Elbmarsch living close to a combined site of a nuclear power plant and a nuclear research facility and children living in the control area Plön. The power of the study to detect a threefold or higher increase in the aberration frequency was at least 0.86. AU - Brüske, I. AU - Scherb, H. AU - Bauchinger, M. AU - Schmid, E. AU - Fender, H.* AU - Wolf, G.* AU - Obe, G.* AU - Schmitz-Feuerhake, I.* AU - Schröder, H.* AU - Stephan, G.* AU - Csicsaky, M.* AU - Wichmann, H.-E. C1 - 9722 C2 - 19878 SP - 111-116 TI - A cluster of childhood leukaemias near two neighbouring nuclear installations in Northern Germany : Prevalence of chromosomal aberrations in peripheral blood lymphocytes. JO - Int. J. Radiat. Biol. VL - 77 IS - 1 PB - Taylor & Francis Ltd. PY - 2001 SN - 0955-3002 ER - TY - JOUR AU - Lohrer, H.D.* AU - Braselmann, H. AU - Richter, H. AU - Jackl, G. AU - Herbeck, J.* AU - Hieber, L. AU - Kellerer, A.M. AU - Bauchinger, M. C1 - 22023 C2 - 20585 SP - 891-899 TI - Instability of microsatellites in radiation-associated thyroid tumours with short latency periods. JO - Int. J. Radiat. Biol. VL - 77 PY - 2001 SN - 0955-3002 ER - TY - JOUR AU - Volf, V.* AU - Luz, A. AU - Schäffer, E.H. AU - Müller, W.A. AU - Rencova, J.* C1 - 21147 C2 - 19188 SP - 929-941 TI - Effect of oral ZnDTPA on late effects of enjected plutonium in rat. JO - Int. J. Radiat. Biol. VL - 75 PY - 1999 SN - 0955-3002 ER - TY - JOUR AU - Bauchinger, M. AU - Braselmann, H. AU - Kulka, U. AU - Huber, R. AU - Georgiadou-Schumacher, V. C1 - 20756 C2 - 17447 SP - 657-663 TI - Quantification of FISH-painted chromosome aberrations after domestic radon exposure. JO - Int. J. Radiat. Biol. VL - 70 PY - 1996 SN - 0955-3002 ER - TY - JOUR AB - The proliferation response and changes in cellularity of mouse tongue epithelium were studied after single doses of X-rays and during 3 weeks of daily irradiation. A single dose of 13 Gy resulted in minimum cellularity (70% of control values) on days 3-5 and complete restoration on day 7. Mitotic activity ceased for 1 day followed by normal-to-supranormal values until day 15. A wave of abnormal mitoses was observed with a peak at days 4-7. Daily irradiation with 3 or 4 Gy induced neither major structural nor visible cellular damage. Cellularity decreased to ∼ 60% during week 1 and subsequently remained at 60-70%. The proliferation activity was reduced to ∼ 8% by day 2. Mitotic activity during weeks 2 and 3 was subnormal-to-normal, with a dose-dependent increase to normal counts during the first weekend and a distinct overshoot over the second weekend respectively. A proliferation model is presented to explain the present findings and previous functional measurements of changes in tissue tolerance. Its major features are accelerated symmetrical stem cell divisions and abortive divisions of sterilized cells. AU - Dörr, W. AU - Emmendörfer, H. AU - Haide, E. AU - Kummermehr, J.C. C1 - 33754 C2 - 37974 SP - 157-167 TI - Proliferation equivalent of accelerated repopulation in mouse oral mucosa. JO - Int. J. Radiat. Biol. VL - 66 IS - 2 PY - 1994 SN - 0955-3002 ER - TY - JOUR AB - Fluorescence in situ hybridization (FISH) with five cocktails of composite whole chromosome-specific DNA probes 1, 4, 12; 2, 7, 9; 2, 7, 9dig; 3, 6, 10dig and 8, 14 Xdig and a degenerate αsatellite pancentromeric DNA probe was used to examine in vitro radiation-induced symmetrical translocations and dicentrics in peripheral lymphocytes for a DNA-proportional distribution. For a discrimination between morphologically similar target chromosomes, chromosomes 9, 10 and X were labelled with digoxigenin (dig). Among the five combinations, significantly higher translocation frequencies than expected from the DNA content were found in 8, 14, Xdig, whereas for this combination no deviation became apparent for dicentrics. The chromosome-specific analysis showed that chromosome 2 was involved in fewer symmetrical translocations, whereas chromosomes 9, 10 and 12 were more frequently involved in dicentrics than predicted. Comparing the ratios of symmetrical translocations to dicentrics, an excess of symmetrical translocations was found for the combinations 1, 4, 12; 2, 7, 9dig and 8, 14, Xdig and for the chromosomes 1, 4, 6, 7, 8 and X. Provided the present data can be confirmed in further experiments, the formula Ŷi = 2.05fi(1 - fi)FG, relating the translocation or dicentric frequency measured by FISH to the respective genomic FG (fi is the labelled genomic fraction) cannot be used to scale up to equal the full genome unless appropriate weighting factors are included. AU - Knehr, S. AU - Zitzelsberger, H. AU - Braselmann, H. AU - Bauchinger, M. C1 - 40043 C2 - 37855 SP - 683-690 TI - Analysis for DNA-proportional distribution of radiation-induced chromosome aberrations in various triple combinations of human chromosomes using fluorescence in situ hybridization. JO - Int. J. Radiat. Biol. VL - 65 IS - 6 PY - 1994 SN - 0955-3002 ER - TY - JOUR AU - Bauchinger, M. AU - Schmid, E. AU - Zitzelsberger, H. AU - Braselmann, H. AU - Nahrstedt, U. C1 - 20503 C2 - 13712 SP - 179-184 TI - Radiation-induced Chromosome Aberrations Analysed by two-colour Fluorescence in situ Hybridization with Composite whole Chromosome-Specific DNA Probes and a Pancentromeric DNA Probe. JO - Int. J. Radiat. Biol. VL - 64 PY - 1993 SN - 0955-3002 ER - TY - JOUR AB - Fluorescence in situ hybridization with composite whole chromosome-specific DNA probes for human chromosomes 1, 4 and 12 and a degenerate αsatellite pancentromeric DNA probe labelled with digoxigenin was used to measure symmetrical translocations and dicentrics induced in vitro by 137Cs γrays (0-6.0 Gy) in peripheral lymphocytes. Despite subtracting our mean background translocation frequency of 0.0016 per cell (11 411 cells scored from 11 individuals) from induced frequencies, about 1.3-1.8-fold more translocations were found than dicentrics at a given dose. Translocation frequencies determined only in stable cells agree well with total translocation frequencies determined also in cells containing additional unstable chromosomal changes. The linear quadratic calibration curve generated for total stable translocations is based on approx. 17 000 cells. The suitability of this curve for biological dosimetry of human radiation exposure can now be evaluated in comparison with dose estimates based on a conventional dicentric dose-response curve. AU - Bauchinger, M. AU - Schmid, E. AU - Zitzelsberger, H. AU - Braselmann, H. AU - Nahrstedt, U. C1 - 40293 C2 - 38966 SP - 179-184 TI - Radiation-induced chromosome aberrations analysed by two-colour fluorescence in situ hybridization with composite whole chromosome-specific DNA probes and a pancentromeric DNA probe. JO - Int. J. Radiat. Biol. VL - 64 IS - 2 PY - 1993 SN - 0955-3002 ER - TY - JOUR AB - The relative contributions of the OH-mediated and direct radiation effect on the induction of DNA double-strand breaks (dsbs) were evaluated in two haploid yeast cell lines (GSH+ and gsh-) irradiated under oxic or hypoxic conditions in the absence or presence of 6 m glycerol as an OH radical scavenger. Gsh- cells are deficient in glutathione (GSH) biosynthesis, their GSH content is only 2% compared with GSH+ cells. Similar relative contributions are observed for both cell lines. Under oxic irradiation conditions about 64% of the response can be attributed to the OH-mediated (or indirect) radiation effect, whereas in hypoxic cells the indirect effect is only about 45%. High oxygen enhancement ratios (OERs) are observed for the OH-mediated radiation effect (4.24 for GSH+, 2.70 for gsh- cells) and low OERs for the direct effect (1.66 for GSH+, 1.44 for gsh- cells). The weighted total (i.e. direct and indirect) OER is 2.74 (GSH+) and 2.03 (gsh-). The dependence of radiosensitization for double-strand breakage on oxygen concentration is characterized by three components whose K-values are 0.5, 4 and 20% oxygen for GSH+ cells and 0.45, 5 and 60% oxygen for gsh- cells. Evidence is presented that the first two components represent the radiosensitization by oxygen of the OH-mediated effect, whereas the third component, requiring the highest oxygen concentration for sensitization, represents the radiosensitization by the direct effect. GSH+ and gsh- cells show virtually the same K-values for the OH-mediated effect, but different K-values for the direct effect. AU - Frankenberg, D.* AU - Frankenberg-Schwager, M. AU - Harbich, R.* C1 - 40284 C2 - 38989 SP - 511-521 TI - Mechanisms of oxygen radiosensitization in irradiated yeast: I. DNA double-Strand breakage. JO - Int. J. Radiat. Biol. VL - 64 IS - 5 PY - 1993 SN - 0955-3002 ER - TY - JOUR AU - Friedl, A.A. AU - Beisker, W. AU - Eckardt-Schupp, F. C1 - 19450 C2 - 12544 SP - 173-181 TI - Application of Pulsed-Field Gel Electrophoresis to Determine of ..-ray-induced Double-Strand breaks in Yeast Chromosomal Molecules. JO - Int. J. Radiat. Biol. VL - 63 PY - 1993 SN - 0955-3002 ER - TY - JOUR AB - The frequency of DNA double-strand breaks (dsb) was determined in yeast cells exposed to γrays under anoxic conditions. Genomic DNA of treated cells was separated by pulsed field gel electrophoresis, and two different approaches for the evaluation of the gels were employed: (1) The DNA mass distribution profile obtained by electrophoresis was compared to computed profiles, and the number of DSB per unit length was then derived in terms of a fitting procedure; (2) hybridization of selected chromosomes was performed, and a comparison of the hybridization signals in treated and untreated samples was then used to derive the frequency of dsb. The two assays gave similar results for the frequency of dsb ((1.07 ± 0.06) × 10-9 Gy-1 bp-1 and (0.93 ± 0.09) × 10-9 Gy-1 bp-1, respectively). The dsb frequency was found to be linearly dependent on dose. AU - Friedl, A.A. AU - Beisker, W. AU - Hahn, K.R. AU - Eckardt-Schupp, F. AU - Kellerer, A.M. C1 - 40336 C2 - 0 SP - 173-181 TI - Application of pulsed Field gel electrophoresis to determine γray-induced double-strand breaks in yeast chromosomal molecules. JO - Int. J. Radiat. Biol. VL - 63 IS - 2 PY - 1993 SN - 0955-3002 ER - TY - JOUR AU - Saran, M. AU - Bertram, H. AU - Bors, W. AU - Czapski, G. C1 - 20654 C2 - 13869 SP - 311-318 TI - On the Cytotoxicity of Irradiated Media. To what extent are stable products of radical chain reactions in physiological saline responsible for cell death?. JO - Int. J. Radiat. Biol. VL - 64 PY - 1993 SN - 0955-3002 ER - TY - JOUR AB - In a previous publication (Czapski et al. 1992) we reported that HOCl accounts for the toxicity of irradiated phosphate-buffered saline towards Escherichia coli bacterial cells. We have now investigated the respective toxicities towards λ phage and mammalian cells. For phage, as with bacteria, cytotoxicity of the irradiated media seems to derive from HOCl without detectable contribution of H2O2. Mammalian cells (V79 CHO), in contrast, are more sensitive to H2O2 than to HOCl. Both agents, however, are not able to account quantitatively for the toxicity of irradiated solutions towards V79 cells; a hitherto unidentified chlorine/oxygen derivative-being formed in the sub-micromolar concentration range-is suggested to be responsible for toxicity in the case of eukaryotes. AU - Saran, M. AU - Bertram, H.* AU - Bors, W. AU - Czapski, G. C1 - 40325 C2 - 0 SP - 311-318 TI - On the cytotoxicity of irradiated media. To what extent are stable products of radical chain reactions in physiological saline responsible for cell death?. JO - Int. J. Radiat. Biol. VL - 64 IS - 3 PY - 1993 SN - 0955-3002 ER - TY - JOUR AU - Schreiber, G.A. AU - Beisker, W. AU - Braselmann, H. AU - Bauchinger, M. AU - Bögl, K.W. AU - Nüsse, M. C1 - 20316 C2 - 13506 SP - 695-709 TI - Technical Report : An automated Flow Cytometric Micronucleus Assay for Human Lymphocytes. JO - Int. J. Radiat. Biol. VL - 62 PY - 1993 SN - 0955-3002 ER - TY - JOUR AB - The degradation of sensitizers used in photodynamic therapy (PDT) involves photooxidation either by molecular oxygen or by oxygen intermediates which leads to hydroxyaldehyde and formyl products or to ring opening. Our investigations focused on the spectroscopic changes which protoporphyrin-dimethylester (PP) exhibits upon irradiation. As the microenvironment strongly influences the effects, we used an aprotic organic solvent, l-αphosphatidylcholine dioleoyl (DOPC) liposomes and isogenic fibrosarcoma cells (SSKII) as carriers for PP. Hydroxyaldehyde product isomers develop a new absorption band centred around 670 nm and a new emission band at 676 nm. These characteristics can be used to discriminate them from formyl products and intact PP. In organic solvents, the formation of the hydroxyaldehyde products dominates. In DOPC liposomes and cells, the hydroxyaldchyde yield drops and photooxidation results in attack of the macrocycle. Time-resolved fluorescence spectroscopy of monomeric PP in an organic solvent gives a monoexponential decay time τ of 10.1 ± 1.3 ns. Upon irradiation a second component with a decay time of 4.9 ± 0.6 ns, resulting from the hydroxyaldchyde product, was detected. In liposomes and cells the monomeric decay time was significantly longer (15 ns) due to the altered microenvironment. Additionally, we observed in liposomes and in cells a small contribution of a short component (1 ns) which is attributed to an aggregated sensitizer species. In irradiated cells the aggregated fraction doubles, indicating a change in the microenvironment caused by the photodynamic action of the sensitizer. AU - Wessels, J.M. AU - Sroka, R.C.* AU - Heil, P.* AU - Seidlitz, H.K. C1 - 40352 C2 - 40026 SP - 475-484 TI - Photodegradation of protoporphyrin-dimethylester in solution and in organized environments. JO - Int. J. Radiat. Biol. VL - 64 IS - 5 PY - 1993 SN - 0955-3002 ER - TY - JOUR AB - Mutations in the lambda repressor gene cI (710 bp) were induced by 60Co-gamma radiation in dissolved lambda phage DNA. After in vitro DNA packaging to lambda phage particles (pack phage) and phenotypic expression of the mutants, DNA was sequenced directly. Two-thirds of mutations were located in the amino terminus region of the gene without any signs of hotspots. Changes consisted of (+1) insertions (25%) and base substitutions (75%). Transitions were exclusively G/C to A/T. Transversions were mostly G/C to C/G and few G/C to T/A. We did not find A/T to T/A transversions, A/T to G/C transitions, deletions and gross rearrangements. In most of the base substitutions a pre-existing base pair had been replaced by an A/T pair; this might come from non-instructional sites like abasic sites. Several mechanisms for base substitutions are considered. AU - Bertram, H. AU - Hagen, U. C1 - 40645 C2 - 38912 SP - 3-8 TI - Radical effects on mutation spectra in lambda phage. JO - Int. J. Radiat. Biol. VL - 62 IS - 1 PY - 1992 SN - 0955-3002 ER - TY - JOUR AB - Effects of 2-deoxy-d-glucose (2-DG) on radiation-induced DNA double-strand breaks (dsb) have been studied under non-growth conditions in a respiratory-deficient strain of the yeast Saccharomyces cerevisiae. Velocity sedimentation in neutral sucrose gradients was used to measure DNA dsb. Addition of 2-DG to the liquid-holding medium (67 mm phosphate buffer, pH 5, 30°C) at an equimolar concentration with glucose (50 mm) reduced the rate and extent of dsb rejoining. The inhibition of rejoining mediated by 2-DG is reversible for the majority-but not all-of the radiation-induced dsb. AU - Frankenberg-Schwager, M. AU - Harbich, R.* AU - Frankenberg, D. AU - Jain, V.K. C1 - 40595 C2 - 12037 SP - 185-190 TI - 2-deoxy-d-glucose inhibits rejoining of radiation-induced DNA double-Strand breaks in yeast. JO - Int. J. Radiat. Biol. VL - 61 IS - 2 PY - 1992 SN - 0955-3002 ER - TY - JOUR AB - Serial blood samples were taken from four healthy individuals (three males, one female, aged between 26 and 51 years) in 3-monthly intervals during 1 year. Leucocyte suspensions were prepared and exposed to 3 Gy of 137Cs γrays or left unirradiated as controls. In a cytokinesis-blocked (CB) micronucleus (MN) assay significant inter- and intra-donor variations of background and radiation-induced MN incidences became apparent. The two sources of variation lead to an extra variance σ2 I, in addition to the sample variance σ2 e of MN incidences. The contributions of the different components to the total variance were estimated by means of a variance component model. The deviation σI for the mean background MN level of 1.53 × 10-2 MN/CB cell was +- 0.67 × 10-2 and for the mean radiation-induced MN level of 0.53 MN/CB cell it was ± 0.10. The contribution of the intra-individual variance to σ2 I was about 50% for background MN levels and 75% for radiation-induced MN frequencies. With respect to the application of the CB-MN assay as a biological dosimetry system, the consequences of the present findings for calibration purposes and low-dose estimation are discussed. The calculation of the variance components is explained in an appendix, which serves also as an example for the adaptation of analysis of variance techniques to the evaluation of data derived from scoring of MN, as well as from scoring of metaphase chromosomal aberrations. AU - Huber, R.D. AU - Braselmann, H. AU - Bauchinger, M. C1 - 40529 C2 - 38014 SP - 655-661 TI - Intra- and inter-individual variation of background and radiation-induced micronucleus frequencies in human lymphocytes. JO - Int. J. Radiat. Biol. VL - 61 IS - 5 PY - 1992 SN - 0955-3002 ER - TY - JOUR AB - The distribution of the DNA content of radiation-induced micronuclei was analysed in several cell lines (Chinese hamster, Syrian hamster and mouse NIH-3T3 cells) by flow cytometry. Frequency and DNA content of micronuclei were measured simultaneously using fluorescence and forward scatter signals of micronuclei and nuclei in suspension stained with ethidium bromide. Computerized random breakage of chromosomes and random combination of fragments was performed to compare the measured micronucleus distributions in synchronized cells irradiated during G1-phase with calculated distributions. The measured DNA distribution of radiation-induced micronuclei was found to be influenced by several factors: (1) the DNA distribution and the centromeric index of the chromosomes in the various cell lines; (2) the cell cycle phase at time of micronucleus measurement due to DNA synthesis in micronuclei; (3) the presence of chromosome fragments in micronuclei; and (4) the presence of whole chromosomes in micronuclei. These factors were shown to be responsible for the previously found large radiation-induced micronuclei which could not be explained by the classic assumption only that radiation-induced micronuclei are mainly produced by single acentric fragments. AU - Nüsse, M. AU - Kramer, J. AU - Miller, B.M. C1 - 20319 C2 - 13509 SP - 587-602 TI - Factors Influencing the DNA Content of Radiation-induced Micronuclei. JO - Int. J. Radiat. Biol. VL - 62 IS - 5 PY - 1992 SN - 0955-3002 ER - TY - JOUR AB - Fluorescence in situ hybridization (FISH) with a combination of three composite whole chromosome-specific DNA probes for human chromosomes 1, 4 and 12 was used to analyse in vitro radiation-induced dicentrics and symmetrical translocations in peripheral lymphocytes. Translocations could be rapidly and efficiently detected by FISH. Their frequencies were 1.8-fold higher than the frequencies for dicentrics at a given dose. The dose-response curves for translocations and dicentrics were linear quadratic with a significant higher quadratic component for translocations. The application of FISH for scoring stable translocations for biological dosimetry of radiation exposures is discussed. AU - Schmid, E. AU - Zitzelsberger, H.* AU - Braselmann, H. AU - Gray, J.W. AU - Bauchinger, M. C1 - 40651 C2 - 38908 SP - 673-678 TI - Radiation-induced chromosome aberrations analysed by fluorescence in situ hybridization with a triple combination of composite whole chromosome-specific DNA probes. JO - Int. J. Radiat. Biol. VL - 62 IS - 6 PY - 1992 SN - 0955-3002 ER - TY - JOUR AB - Clinical and experimental heart irradiation can cause a variety of sequelae. A single dose of ≥15 Gy leads to a reversible exudative pericarditis, occurring in dogs, rabbits or rats at around 100 days. Its time-course is very similar in all species investigated, but there are considerable species and strain differences in severity and incidence. After longer, dose-dependent latency times chronic congestive myocardial failure develops. At histological examination myocardial degeneration and necrosis is observed, which in some species is accompanied by a variable degree of interstitial fibrosis. In rabbits and rats, myocardial degeneration becomes apparent at around 70 days after 20 Gy and is preceded by a marked reduction in capillary density as well as ultrastructural endothelial cell degeneration. Simultaneously to structural capillary damage, a focal loss of the endothelial marker enzyme alkaline phosphatase was observed in rats in areas with subsequent myocardial degeneration. Cell kinetic studies in rabbits and rats revealed a radiation-induced wave of increased endothelial cell proliferation at 30-100 days postirradiation. In the rat it is exclusively seen in conjunction with alteration of endothelial cell marker enzymes. The temporal and spatial pattern of proliferative response exludes endothelial cell death in mitosis as the sole pathogenetic mechanism causing capillary loss and myocardial degeneration. Parallel to development of morphological damage, haemodynamic studies in various rats strains revealed a drop in cardiac output and left ventricular ejection fraction to about 64% of normal values after 20 Gy. In vivo, this slightly reduced cardiac function was then maintained in a steady state for many weeks, probably due to a compensatory up-regulation of cardiac βadrenergic receptors. In denervated working heart preparations in vitro, however, these compensatory mechanisms are not effective and stroke volume as well as cardiac contractility show a rapid and steady deterioration. In many respects radiation-induced heart disease conforms to radiobiological concepts of late-responding tissues, showing a chronic progressive time-course and a very pronounced fractionation effect. However, pathogenesis cannot be understood in terms of target cell depletion alone, and experimental evidence indicates the importance of alterations of regulatory mechanisms. AU - Schultz-Hector, S. C1 - 40626 C2 - 38017 SP - 149-160 TI - Radiation-induced heart disease: Review of experimental data on dose reponse and pathogenesis. JO - Int. J. Radiat. Biol. VL - 61 IS - 2 PY - 1992 SN - 0955-3002 ER - TY - JOUR AU - Ahne, F. AU - Wendel, S. AU - Niederfellner, G. AU - Kurtkaya, E. AU - Obermaier, S. AU - Eckardt-Schupp, F. C1 - 18985 C2 - 12023 SP - S. 575 TI - Molecular Structure of the REV2 Gene in Yeast. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Akpa, T.C. AU - Weber, K.J. AU - Kiefer, J. AU - Frankenberg-Schwager, M. AU - Harbich, R. AU - Frankenberg, D. C1 - 18986 C2 - 12024 SP - S. 572 TI - DNA Double-Strand Break Induction in Yeast by Heavy Ion Irradiation. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Baur, M. AU - Friedl, A.A. AU - Geigl, E.-M. AU - Wendel, S. AU - Eckardt-Schupp, F. C1 - 18991 C2 - 12029 SP - S. 571 TI - Quantification of Double-strand Breaks by Pulse Field Gel Electrophoresis. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Baur, M. AU - Eckardt-Schupp, F. C1 - 18995 C2 - 12033 SP - S. 564 TI - The Role of Glutathione in the Induction of Repair of Gamma-ray-induced DNA Double-strand Breaks as Measured by Pulsed Field Gel Electrophoresis. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Bors, W. C1 - 18989 C2 - 12027 SP - S. 586 TI - Antioxidants and anticarcinogens: similarities and differences. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AB - Multifractionation isoeffect data are commonly analysed under the assumption that cell survival determines the observed tissue or tumour response, and that it follows a linear-quadratic dose dependence. The analysis is employed to derive the αbeta; ratios of the linear-quadratic dose dependence, and different methods have been developed for this purpose. A common method uses the so-called Fe plot. A more complex but also more rigorous method has been introduced by Lam et al. (1979). Their method, which is based on numerical optimization procedures, is generalized and somewhat simplified in the present study. Tumour-regrowth data are used to explain the nonparametric procedure which provides αbeta; ratios without the need to postulate analytical expressions for the relationship between cell survival and regrowth delay. AU - Chmelevsky, D. AU - Guttenberger, R. AU - Kummermehr, J.C.* AU - Kellerer, A.M. C1 - 34080 C2 - 40219 SP - 1253-1268 TI - A nonparametric method for the derivation of αbeta; ratios from the effect of fractionated irradiations. JO - Int. J. Radiat. Biol. VL - 59 IS - 5 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Eichholtz-Wirth, H. C1 - 18982 C2 - 12020 SP - S. 587 TI - Cisplatin-resistant Fibrosarcoma Cells Characterized by Elevated Metallothionein Content. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Frankenberg, D. AU - Frankenberg-Schwager, M. AU - Harbich, R. C1 - 18994 C2 - 12032 SP - 563-564 TI - The Influence of Ionization Density, Dose and Anoxia During Irradiation on the Rejoining of DNA Double-strand Breaks in Yeast. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Frankenberg-Schwager, M. C1 - 18993 C2 - 12031 SP - 559-560 TI - Induction, Repair and Biological Relevance of Radiation-induced Lesions in the DNA of Eukaryotic Cells. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Hagen, U. C1 - 18987 C2 - 12025 SP - S. 588 TI - Molecular Radiation Biology - Future Aspects. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Hietkamp, J. AU - Eckardt-Schupp, F. C1 - 18990 C2 - 12028 SP - S. 575 TI - Molecular Cloning of the GSH1 Gene of the Yeast Saccharomyces Cerevisiae. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Nikjoo, H. AU - Goodhead, D.T. AU - Charlton, D.E. AU - Paretzke, H.G. C1 - 19899 C2 - 13053 SP - 739-756 TI - Energy Deposition in Small Cylindrical Targets by Monoenergetic Electrons. JO - Int. J. Radiat. Biol. VL - 60 PY - 1991 SN - 0955-3002 ER - TY - JOUR AB - Calculations of energy deposition in cylindrical target volumes of diameter and height 1-100 nm, including those similar to the dimensions of biological molecules and structures such as DNA, nucleosomes and chromatin fibre, have been made. The calculations used the Monte Carlo track structure program MOCA8B for electrons of initial energy 0.1-100 keV. Details of the calculation are presented, as well as a selection of results. The frequency distributions of energy deposition events per gray per target, placed at random in a homogeneous aqueous medium, are given for uniform irradiation with monoenergetic electrons of various energies. The frequency distributions have been used to predict the initial biophysical parameters such as relative effectiveness for initial damage. These suggest that the final biological effects which depend on complex local damage may show substantial variations in biological effectiveness for different low linear energy transfer radiations, whereas those that depend on simple local damage may not. AU - Nikjoo, H.* AU - Goodhead, D.T.* AU - Charlton, D.E. AU - Paretzke, H.G.* C1 - 33985 C2 - 40222 SP - 739-756 TI - Energy deposition in small cylindrical targets by monoenergetic electrons. JO - Int. J. Radiat. Biol. VL - 60 IS - 5 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Nüsse, M. AU - Kramer, J. AU - Schreiber, G.A. AU - Beisker, W. C1 - 18984 C2 - 12022 SP - 567-568 TI - Analysis of Radiation-induced Micronuclei in Mammalian Cells Using Flow Cytometry and Immunofluorescence Techniques. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Saran, M. C1 - 18988 C2 - 12026 SP - S. 584 TI - Radical Reactions in Vivo - an Overview. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Schultz-Hector, S. AU - Kummermehr, J.C.* AU - Suit, H.D. C1 - 34138 C2 - 40168 SP - 101-107 TI - Vascular architecture of experimental tumours-influence of tumour volume and transplantation site. JO - Int. J. Radiat. Biol. VL - 60 IS - 1-2 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Strauss, P.G. AU - Tölg, C. AU - Sturm, S.A. AU - Erfle, V. C1 - 18983 C2 - 12021 SP - 577-578 TI - Activation of Oncogenes and Endogenous Proviruses in Radiation-induced Osteosarcomas. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AU - Wendel, S. AU - Ahne, F. AU - Eckardt-Schupp, F. C1 - 18992 C2 - 12030 SP - 579-580 TI - Quantitative Studies of the Rev2 Transcript in Saccharomyces Cerevisiae. JO - Int. J. Radiat. Biol. VL - 59 PY - 1991 SN - 0955-3002 ER - TY - JOUR AB - Lifetimes of oxygen-dependent precursors of DNA double-strand breaks (dsb), as determined by applying the gas explosion technique, were found to be dose-dependent. The analysis of data for dsb induction obtained in diploid 211*B cells by the neutral sucrose sedimentation technique exhibits a half-life of 2.18 ms at a pulse dose of 500 Gy. Lifetimes are also obtained indirectly by analysing the inactivation of diploid rad54-3 cells, which are defective in the rejoining of dsb when incubated at 36°C. The half-life at a pulse dose of 40 Gy is only 0·25 ms. Since the cell size of both strains is very similar, the nine-fold longer lifetime determined in cells of strain 211*B may be caused by radiolytic depletion of glutathione due to the 12-fold higher dose applied to these cells. Therefore, the lifetime measured by the inactivation of rad54-3 cells (36°C) is considered to be more relevant than that obtained by direct measurements of dsb. The influence of dsb rejoining on the fast kinetics of the oxygen effect was studied using rad54-3 cells, which are capable of rejoining dsb when incubated at 23°C. When allowance for dsb rejoining was made, two components become detectable with half-lives of 0·75 and 29 ms. Haploid yeast cells in stationary phase are not capable of rejoining dsb. Using such cells proficient or deficient in the synthesis of glutathione (GSH), the lifetimes were found to be 0·37 or 0·49 ms for GSH-proficient (100 per cent GSH) and -deficient (2·1 per cent GSH) cells, which is in agreement with the view that chemical restitution of oxygen-dependent precursors is impaired in gsh- cells. AU - Frankenberg, D. AU - Michael, B.D.* AU - Frankenberg-Schwager, M. AU - Harbich, R. C1 - 41992 C2 - 40144 SP - 485-501 TI - Fast kinetics of the oxygen effect for DNA double-Strand breakage and cell killing in irradiated yeast. JO - Int. J. Radiat. Biol. VL - 57 IS - 3 PY - 1990 SN - 0955-3002 ER - TY - JOUR AB - Yeast is a suitable eukaryotic organism in which to study DNA double-strand breakage measured by the neutral sucrose gradient sedimentation technique and cell killing in the same range dose of sparsely ionizing radiations. Radiosensitive mutants (including temperature conditional ones) exist in which rejoining of double-strand breaks (dsb) is not detectable. In such mutants approximately one dsb per cell corresponds to a lethal event, suggesting that a dsb is a potentially lethal lesion. There are two modes by which dsb may confer cell lethality: firstly, an unrepaired dsb may be lethal on its own and secondly, two dsb may interact to form a lethal lesion (binary misrepair). The operationally defined cellular phenomena of potentially lethal damage (PLD) repair and sublethal damage (SLD) repair are both based on the repair of dsb. Induced dsb show a linear and unrejoined dsb a linear-quadratic relationship with dose. At low dose rate the quadratic component is abolished in accordance with the exponential survival curve observed. The dose-rate effect is based on dsb repair during irradiation; it is absent in dsb repair-deficient mutants. AU - Frankenberg-Schwager, M. AU - Frankenberg, D. C1 - 42265 C2 - 11653 SP - 569-575 TI - DNA double-Strand breaks: Their repair and relationship to cell killing in yeast. JO - Int. J. Radiat. Biol. VL - 58 IS - 4 PY - 1990 SN - 0955-3002 ER - TY - JOUR AB - Yeast cells were irradiated with 3·5 MeV αparticles and 30 MeV electrons, as reference radiation. The kinetics of DNA double-strand break (dsb) rejoining during incubation of cells under non-growth conditions (PLDR conditions) were measured using the neutral sedimentation technique. A monophasic kinetic was found after irradiation of cells with αparticles, with a dose-independent t1/2 value of about 13 h. The kinetics of rejoining of dsb induced by 30 MeV electrons was found to be biphasic, with dose-independent t1/2 values of 3·8 h for the initial and of about 11 h for the slow component. The fraction of the slow component was, however, dose-dependent. These kinetics were measured for both types of radiation at doses yielding high surviving fractions (5% up to 100%). Dsb are induced linearly with dose of both radiations. The RBE value of αparticles was found to be 2·5 for initial dsb. The RBE of αparticles increased as a consequence of dsb rejoining. This increase in RBE value suggests that DSB may be primary lesions for chromosome aberrations, cellular inactivation and oncogenic transformation of mammalian cells which all exhibit high RBE values of αparticles. AU - Frankenberg-Schwager, M. AU - Frankenberg, D. AU - Harbich, R. AU - Adamczyk, C. C1 - 42543 C2 - 40193 SP - 1151-1168 TI - A comparative study of rejoining of DNA double-Strand breaks in yeast irradiated with 3·5 mev αparticles or with 30 mev electrons. JO - Int. J. Radiat. Biol. VL - 57 IS - 6 PY - 1990 SN - 0955-3002 ER - TY - JOUR AB - In mice, external X- or γirradiation may induce thymic lymphomas or myeloid leukaemias, while bone-seeking αemitters may induce osteosarcomas and, to a lesser extent, acute myeloid leukaemia. The present paper aims to review briefly some of the experimental data with respect to the molecular mechanisms underlying these radiation-induced carcinogenic processes. Thymic lymphomagenesis proceeds through an indirect mechanism. Recombinant proviruses often occur in the tumour cell DNA, favouring the idea that they might be involved. However, there are indications that they might mediate tumour growth rather than induction. It is plausible that activation of ras oncogenes by somatic point mutations might play a role in the carcinogenic process, although at a yet undetermined stage. Myeloid leukaemogenesis is characterized by a very early, putative initiating event, consisting of non-random rearrangements and/or deletions of chromosome 2. These may be related to deletions in the developmentally important homeobox gene clusters and to rearrangements of the sequences flanking the IL-1β gene. Either a gene of the homeobox family or IL-1β might be considered as potentially involved in the induction process. Osteosarcomagenesis in mice is often associated with the expression of proviruses, and the tumours often contain somatically acquired proviruses. These viruses may contribute to tumour development by affecting various growth-suppressor genes. Viruses isolated from bone tumours, although non-sarcomagenic, induce osteopetrosis, osteomas and lymphomas upon infection of newborn mice. Osteogenic tumours frequently display amplification of a region on mouse chromosome 15, which encompasses c-myc and Mlvi-1 sequences. Enhanced transcription of various oncogenes is found in individual tumours, but no specificity for osteosarcomas has been identified. In vitro systems of skeletoblast differentiation are being developed to study tumour induction in vitro. AU - Janowski, M.* AU - Cox, R.D.* AU - Strauß, P.G. C1 - 42545 C2 - 40194 SP - 677-691 TI - The molecular biology of radiation-induced carcinogenesis: Thymic lymphoma, myeloid leukaemia and osteosarcoma. JO - Int. J. Radiat. Biol. VL - 57 IS - 4 PY - 1990 SN - 0955-3002 ER - TY - JOUR AB - Radiation-induced myocardial degeneration in the rat is preceded by changes in capillary structure and function, which may be a major factor in the pathogenesis of radiation-induced heart disease. In order to investigate the mechanism of capillary damage we studied endothelial cell proliferation in untreated control rats and in rats at different times following local heart irradiation with 20 Gy using [3H]thymidine autoradiography. Since the latency times of myocardial degeneration as well as capillary damage are about twice as long in Sprague-Dawley rats as in Wistar rats, endothelial cell proliferation was studied in both strains. The percentage of labelled nuclei (LI) after repeated labelling over a period of 12 h was 0·32 ± 0·06 in control animals of both strains. Therefore the turnover time of endothelial cells was estimated to be between 115 and 400 days. Following irradiation the LI increased above control levels. In both strains this was concurrent with the time of onset of capillary depletion and alkaline phosphatase loss, which occurred at around 23 days post-irradiation in Wistar rats and 58-74 days in Sprague-Dawley rats. In both strains the increase in LI was confined to alkaline-phosphatase-negative areas. In phosphatase-positive areas endothelial cell proliferation was unchanged in spite of the reduction in capillary density. Since, in general, the latency to post-irradiation death of a cell is closely related to its normal turnover time, the decrease in capillary density is not due to mitotic death of proliferating cells as is commonly seen in other tissues. AU - Lauk, S. AU - Trott, K.R.* C1 - 42051 C2 - 40279 SP - 1017-1030 TI - Endothelial cell proliferation in the rat heart following local heart irradiation. JO - Int. J. Radiat. Biol. VL - 57 IS - 5 PY - 1990 SN - 0955-3002 ER - TY - JOUR AU - Rimpl, G.R. AU - Schmid, E. AU - Braselmann, H. AU - Bauchinger, M. C1 - 18768 C2 - 11350 SP - 999-1007 TI - Chromosome Aberrations induced in Human Lymphocytes by 16.5 MeV Protons. JO - Int. J. Radiat. Biol. VL - 58 PY - 1990 SN - 0955-3002 ER - TY - JOUR AU - Schultz-Hector, S. AU - Kummermehr, J. AU - Suit, H.D. C1 - 18519 C2 - 11673 TI - Vascular Architecture of Experimental Tumours - Influence of Tumour Volume and Transplantation Site. JO - Int. J. Radiat. Biol. PY - 1990 SN - 0955-3002 ER - TY - JOUR AB - Exposure of the mouse fetus (NMRI-strain) to 1.0 Gy X-irradiation has a marked effect on postnatally xenotransplanted glioma cells. In comparison to non-irradiated animals, irradiation on gestation day 14 resulted in: (a) a significantly higher rate of animals which failed to develop visible tumours growing from the inoculum; (b) a significant inhibition of the growth rate of solid gliomas; (c) a pronounced granulocytic and mast cell infiltration, and tissue necrosis, in the invading gliomas. The results suggest that irradiation in prenatal life exerts an amplifying effect on the antitumour response in postnatal life. AU - Plendl, J. AU - Schmahl, W. AU - Heinzmann, U. C1 - 17877 C2 - 10795 SP - 821-827 TI - The Effect of Fetal Irradiation on the Growth of Postnatally Xenotransplanted Tumour Cells. JO - Int. J. Radiat. Biol. VL - 55 PY - 1989 SN - 0955-3002 ER - TY - JOUR AB - Three hours following X-irradiation of chick embryos with doses of 4 and 8 Gy the in vitro incorporation of tritiated thymidine ([3H]dT) into DNA (scheduled DNA synthesis, ss) of hepatocytes was reduced to about one-third. Within 24 h after the exposure, ss returned to control values. The return of ss to a normal rate could be strongly inhibited by 2'3'dideoxythymidine (ddT), and to a lesser extent by 1-βd-arabinofuranosylcytosine (araC). In strong contrast to ss, the hydroxyurea (hu)-resistant [3H]dT incorporation (unscheduled DNA synthesis, us) showed a highly significant increase 24 h after treatment of the embryos with araC and/or X-irradiation. Autoradiographic studies revealed no change of total [3H]dT labelling frequency in the whole chick embryo liver 24 h after treatment with araC and/or X-irradiation, but a persistent depression of ss and a simultaneous increase of us. The histological discrimination between affected and non-affected areas argue for a stimulation of DNA synthesis as an antecedent of subsequent mitosis and reparative proliferation adjacent to cell necrosis. It is suggested that the fast recovery of ss in the 12-15-day-old chick embryo is due to an efficient DNA repair system for which DNA polymerase β is important. The increase of hu-resistance may be an expression of an aberrant DNA synthesis. AU - Stammberger, I.* AU - Schmahl, W.G. AU - Tempel, K.H.* C1 - 41147 C2 - 36522 SP - 325-333 TI - Scheduled and unscheduled DNA synthesis in chick embryo liver following x-irradiation and treatment with DNA repair inhibitors in vivo. JO - Int. J. Radiat. Biol. VL - 56 IS - 3 PY - 1989 SN - 0955-3002 ER - TY - JOUR AB - The clonogenic potential of the progeny of irradiated cells was tested in vitro by replating irradiated cultures after various times, allowing between five and over 25 subsequent divisions to take place after irradiation. Whereas the plating efficiency of surviving Chinese hamster cells was not decreased, in C3H10T1/2 cells a dose-dependent but slight decrease in plating efficiency was observed even after the longest follow-up period. These data do not contradict the prevalent hypothesis in radiobiology that the proliferation potential of a colonogenic cell surviving after irradiation is not significantly different from that of a non-irradiated cell. AU - Born, R. AU - Trott, K.R.* C1 - 42612 C2 - 36444 SP - 319-330 TI - Clonogenicity of the progeny of surviving cells after irradiation. JO - Int. J. Radiat. Biol. VL - 53 IS - 2 PY - 1988 SN - 0955-3002 ER - TY - JOUR AU - Wenisch, T. AU - Pohlit, W. C1 - 17317 C2 - 10103 TI - Does the level of induced DNA double-strand breakage correlate with cell killing after irradiation? JO - Int. J. Radiat. Biol. PY - 1988 SN - 0955-3002 ER - TY - JOUR AU - Wenisch, T. AU - Pohlit, W. C1 - 17318 C2 - 10102 TI - Non-Linear-Dose-Effect Relationship for DNA Double-Strand Breaks. JO - Int. J. Radiat. Biol. PY - 1988 SN - 0955-3002 ER - TY - JOUR AB - The effect of endogenous glutathione (GSH) on the induction of DNA double strand breaks (dsb) by 25 MeV electrons was investigated using stationary haploid yeast cells defective in γglutamyl-cysteine-synthetase (gsh 1) containing less than 5 per cent of the normal GSH content. In gsh 1 cells the induction of dsb is increased by a factor of 1·5 under oxic and 1·8 under anoxic irradiation conditions: whereas the oxygen enhancement ratio was only slightly decreased (1·9) compared to wild-type cells (2·4). AU - Frankenberg, D. AU - Kistler, M. AU - Eckardt-Schupp, F. C1 - 42274 C2 - 36220 SP - 185-190 TI - Effect of cellular glutathione content on the induction of DNA double Strand breaks by 25 mev electrons. JO - Int. J. Radiat. Biol. VL - 52 IS - 2 PY - 1987 SN - 0955-3002 ER - TY - JOUR AB - The yeast mutant rad54-3, which is temperature conditional for dsb rejoining, is sensitive to u.v. light when held at the restrictive temperature following exposure. We propose that this is attributable to the enzymatic formation of dsb in DNA containing u.v. lesions and a subsequent lack of dsb repair in this mutant. AU - Frankenberg-Schwager, M. AU - Frankenberg, D. AU - Harbich, R. C1 - 41929 C2 - 36236 SP - 107-113 TI - Possible occurrence of DNA double-strand breaks during repair of u.v.-induced damage in yeast. JO - Int. J. Radiat. Biol. VL - 52 IS - 1 PY - 1987 SN - 0955-3002 ER - TY - JOUR AB - Jejunal crypt survival after fractionated total body irradiation of C3H mice given at dose rates between 1·2 and 0·08 Gy/min was studied and the results analysed according to the linear quadratic model. Whereas α was independent of dose rate β decreased with dose rate to approach zero at about 0·01 Gy/min. During the period of recovery, sublethal damage from doses given at high dose rate interact with low dose rate irradiation given immediately after, and increases its effectiveness. AU - Huczkowski, J. AU - Trott, K.R. C1 - 41588 C2 - 36243 SP - 131-137 TI - Jejunal crypt stem-cell survival after fractionated γ-irradiation performed at different dose rates. JO - Int. J. Radiat. Biol. VL - 51 IS - 1 PY - 1987 SN - 0955-3002 ER - TY - JOUR AB - Mice were X-irradiated on day 14, 15 or 16 of gestation with 1·0 Gy. This did not result in an increased tumour frequency in the offspring until 12 months. Mice treated with ethylnitrosourea (ENU) (45 mg/kg) on these gestation days developed a significantly increased tumour frequency in the lungs and liver, and in the ovaries after treatment on day 15 of gestation. Additionally this experiment was the first to show that ENU treatment on gestation day 14, 15 or 16 results in haemangiosarcomas of the subcutis at a low incidence (2·0, 2·4, 2·6 per cent). After combined treatment with these two agents in the sequence X + ENU and an interval of 4 h, a significantly increased incidence rate of animals with tumours was observed in the offspring treated on gestation day 14 or 16. Moreover, the treatment on gestation day 16 exhibited the highest tumour frequency per examined animal (5·7) of all treatment groups. This result is due to a relatively uniform increase of all tumor types. Within this pattern, the frequency of liver tumours was most marked. The diagnosed liver tumours were significantly augmented after X + ENU treatment on day 16. In the reverse sequence (ENU + X), the total tumour outcome was not significantly altered compared with the effects of ENU alone. However, detailed analysis also showed a significant augmentation of the liver tumour frequency with treatment on day 15. AU - Wiggenhauser, A.* AU - Schmahl, W. C1 - 41583 C2 - 36241 SP - 1021-1029 TI - Postnatal development and neoplastic disease pattern in NMRI mice after combined treatment with ethylnitrosourea and X-irradiation on different days of the fetal period. JO - Int. J. Radiat. Biol. VL - 51 IS - 6 PY - 1987 SN - 0955-3002 ER - TY - JOUR AB - Late damage in the rectum of rats was studied after local irradiation with 2 MeV fast fission neutrons and the results were compared with those for 300 kV X-rays. A similarity between latency times, and between clinical, gross pathological and histological appearances of the rectal obstruction after the two types of radiation was observed. The r.b.e. evaluated from ED 50 200 days values was 1·8 for single doses, 2·1 for two fractions and 3 for five fractions and these are similar to r.b.e.s from other investigations of chronic intestinal radiation damage. Using linear quadratic analysis, a limiting r.b.e. of 5 was obtained. The βvalues are similar for both radiation qualities. Because of the high γcontamination (25 per cent) in the RENT I beam a possible correction of the r.b.e. for neutrons only, assuming interaction, is discussed. AU - Breiter, N.* AU - Kneschaurek, P.* AU - Burger, G. AU - Huczkowski, J.* AU - Trott, K.R.* C1 - 41003 C2 - 36106 SP - 1031-1038 TI - The R.B.E. Of fast fission neutrons (2 mev) for chronic radiation damage of the large bowel of rats after single dose and fractionated irradiation. JO - Int. J. Radiat. Biol. VL - 49 IS - 6 PY - 1986 SN - 0955-3002 ER - TY - JOUR AB - Induction of DNA double-strand breaks in diploid wild-type yeast cells, and inactivation of diploid mutant cells (rad54-3) unable to repair DNA double-strand breaks, were studied with aluminium K (1·5 keV) and carbon K (0·278 keV) characteristic X-rays. The induction of DNA double-strand breaks was found to increase linearly with absorbed dose for both characteristic X-rays. Carbon K X-rays were more effective than aluminium K X-rays. Relative to 60Co γrays the r.b.e-values for the induction of DNA double-strand breaks were found to be 3·8 and 2·2 for carbon K and aluminium K X-rays respectively. The survival curves of the rad54-3 mutant cells were exponential for both ultrasoft X-rays. For inactivation of rad54-3 mutant cells, the r.b.e.-values relative to 60Co γrays were 2·6 and 2·4 for carbon K and aluminium K X-rays, respectively. The DNA double-strand break data obtained with aluminium K and carbon K X-rays are in agreement with the data obtained for gene mutation, chromosome aberrations and inactivation of mammalian cells, suggesting that DNA double-strand breaks are the possible molecular lesions leading to these effects. AU - Frankenberg, D. AU - Goodhead, D.T.* AU - Frankenberg-Schwager, M. AU - Harbich, R. AU - Bance, D.A. AU - Wilkinson, R.E. C1 - 41780 C2 - 38264 SP - 727-741 TI - Effectiveness of 1·5 kev aluminium k and 0·3 kev carbon k characteristic x-rays at inducing DNA double-Strand breaks in yeast cells. JO - Int. J. Radiat. Biol. VL - 50 IS - 4 PY - 1986 SN - 0955-3002 ER - TY - JOUR AB - DNA has been isolated from γirradiated yeast cells and then treated with the enzyme S1 nuclease. This enzyme cleaves DNA specifically at sites where localized denaturation has occurred and can therefore be used as a lesion probe to identify regions in the DNA where base-pairing has been disrupted. By analysing the number of single strand breaks, double strand breaks and alkali-labile sites in the DNA before and after treatment with S1 nuclease, it has been possible to calculate the number of S1 nuclease-sensitive sites induced as a result of exposure to ionizing radiation. These sites were found to occur with a frequency about twice that of the double strand break and are thought to result from a primary ionization event in the DNA. AU - Andrews, J.F. AU - Martin-Bertram, H.* AU - Hagen, U. C1 - 41297 C2 - 38652 SP - 497-504 TI - S1 nuclease-sensitive sites in yeast DNA: An assay for radiation-induced base damage. JO - Int. J. Radiat. Biol. VL - 45 IS - 5 PY - 1984 SN - 0955-3002 ER - TY - JOUR AB - The dose-response relationships of dicentrics and excess acentrics were analysed after exposure of human lymphocytes to a mixed fission neutron-γray beam. From the analysis of exclusively first division cells a linear-quadratic relation was obtained for dicentrics with the ratio of linear and quadratic components, ζ equal to 2·76 Gy. Over the range of doses studied (0·04-1·97 Gy) intratrack events therefore predominated. This also applied to acentrics which were linearly related to dose. At the lowest level of observed effect and dose, r.b.e. values with respect to 60Co γrays of up to about 11 were derived for dicentrics and acentrics. With increasing neutron dose the r.b.e. decreased. AU - Bauchinger, M. AU - Koester, L.* AU - Schmid, E. AU - Dresp, J.H. AU - Streng, S. C1 - 42306 C2 - 38339 SP - 449-457 TI - Chromosome aberrations in human lymphocytes induced by fission neutrons. JO - Int. J. Radiat. Biol. VL - 45 IS - 5 PY - 1984 SN - 0955-3002 ER - TY - JOUR AB - DNA double-strand breaks are the molecular lesions the repair of which leads to the reappearance of the shoulder observed in split-dose experiments. This conclusion is based on results obtained with the help of a diploid yeast mutant rad54-3 which is temperature-conditional for the repair of DNA double-strand breaks. Two repair steps must be met to yield the reappearance of the shoulder on a split-dose survival curve: the repair of double-strand breaks during the interval between two doses and on the nutrient agar plate after the second dose. In yeast lethality may be attributable to either an unrepaired double-strand break (i.e. a double-strand break is a potentially lethal lesion) or to the interaction of two double-strand breaks (misrepair of double-strand breaks). Evidence is presented that the two cellular phenomena of liquid holding recovery (repair of potentially lethal damage) and of split-dose recovery (repair of sublethal damage) are based on the repair of the same molecular lesion, the DNA double-strand break. AU - Frankenberg, D. AU - Frankenberg-Schwager, M. AU - Harbich, R. C1 - 33137 C2 - 35555 SP - 541-553 TI - Split-dose recovery is due to the repair of DNA double-strand breaks. JO - Int. J. Radiat. Biol. VL - 46 IS - 5 PY - 1984 SN - 0955-3002 ER - TY - JOUR AB - Jejunal crypt survival after fractionated total body irradiation of C3H mice given at dose rates of 1·2 or 0·08 Gy/min was studied. The fractionation effect was more pronounced at the high dose rate than at the low dose rate. Analysis of the data according to the linear-quadratic survival curve model yielded an αbeta; value at 1·2 Gy/min of 13·3 Gy and at 0·08 Gy/min of 96 Gy. AU - Huczkowski, J. AU - Trott, K.R.* C1 - 41436 C2 - 38655 SP - 293-298 TI - Dose fractionation effects in low dose rate irradiation of jejunal crypt stem cells. JO - Int. J. Radiat. Biol. VL - 46 IS - 3 PY - 1984 SN - 0955-3002 ER - TY - JOUR AB - Double-strand breaks and regions with unpaired bases (S1-nuclease sensitive sites) are formed in the DNA of γirradiated λphages. The frequency of both events was determined in the various fragments produced after digestion with a restriction enzyme (Eco RI). The results show that both types of radiation damage are randomly distributed in the DNA molecule. There is no hint that the S1 sites are formed in preferred regions of the λgenome. AU - Junker, B. AU - Martin-Bertram, H. AU - Hagen, U. C1 - 33138 C2 - 35554 SP - 675-679 TI - Distribution of s1-nuclease sensitive sites and double-Strand breaks in γ-irradiated λ-DNA. JO - Int. J. Radiat. Biol. VL - 46 IS - 6 PY - 1984 SN - 0955-3002 ER - TY - JOUR AB - Human lymphocytes were irradiated with 14.5 MeV (d + T) neutrons at the positions sternal, retrosternal, liver and gonads of a waterfilled Plexiglas man phantom of 37 degrees C. After BUdR treatment of lymphocyte cultures and FPG-staining of metaphases, exclusively first post-irradiation divisions (M1-cells) were analysed. A regression analysis was carried out by means of a weighted least-squares method. Dose-effect relations of dicentrics and acentrics could be fitted by the linear-quadratic model. A comparison of the dose-effect curves established with either conventional or FPG-staining technique revealed statistically significant differences. The M1-evaluation yielded about 46 per cent more dicentrics and about 37 per cent more acentrics. The consequences of these results are discussed in relation to the application of chromosome analysis in 'biological dosimetry'. AU - Bauchinger, M. AU - Kühn, H. AU - Dresp, J.H. AU - Schmid, E. AU - Streng, S. C1 - 41843 C2 - 38482 SP - 571-578 TI - Dose-effect relationship for 14·5 mev (d + t) neutron-induced chromosome aberrations in human lymphocytes irradiated in a man phantom. JO - Int. J. Radiat. Biol. VL - 43 IS - 5 PY - 1983 SN - 0955-3002 ER - TY - JOUR AU - Blöcher, D. AU - Nüsse, M.* AU - Bryant, P.E. C1 - 33273 C2 - 38602 SP - 579-584 TI - Kinetics of double Strand break repair in the DNA of x-irradiated synchronized mammalian cells. JO - Int. J. Radiat. Biol. VL - 43 IS - 5 PY - 1983 SN - 0955-3002 ER - TY - JOUR AB - Treatment of X-irradiated stationary Ehrlich ascites tumour cells with the DNA synthesis inhibitor beta-ara A (120 mumol/l, 30 min before and for 7 hours after irradiation) is shown to lead to a large increase in the incidence of anaphase chromosome abnormalities (anaphase bridges and fragments) at the first mitosis following irradiation. This increase is similar to the increase in cell killing observed for this cell line when treated with beta-ara A under the same conditions (Iliakis 1980). The results suggest that the increased frequency of chromosome abnormalities caused by beta-ara A may result not only from the inhibition of DNA double strand break repair, leading to additional unrepaired d.s.b. (Bryant and Blocher 1982) and chromosome deletions, but also from an increase in the frequency of misrepair of d.s.b. leading to exchange aberrations. AU - Bryant, P.E. C1 - 41797 C2 - 38399 SP - 459-464 TI - 9-βd-arabinofuranosyladenine increases the frequency of x-ray induced chromosome abnormalities in mammalian cells. JO - Int. J. Radiat. Biol. VL - 43 IS - 4 PY - 1983 SN - 0955-3002 ER - TY - JOUR AB - At the present time no unequivocal evidence exists which shows that a reduction in the body-burden of a radionuclide by decorporative treatment results in a proportional decrease in the risk of long-term radiation effects. We have investigated the effectiveness of the daily administration of Na-alginate via the diet in removing 226Ra from the skeleton and in reducing the number of late effects such as osteosarcomas. The animals used were male C57Bl mice which had been injected with one of three different amounts of 226Ra (4·4, 10·7 or 24·8 kBq) four days prior to the onset of the decorporative treatment. The results showed that although this treatment was able to produce a substantial reduction in the 226Ra content of the mice it did not reduce the incidence of osteosarcoma. These results question the effectiveness of decorporation procedures initiated at longer times after contamination. AU - Schoeters, G.E.R.* AU - Luz, A. AU - Vanderborght, O.L.J.* C1 - 41617 C2 - 38489 SP - 231-247 TI - 226Ra induced bone-cancers: The effects of a delayed na-alginate treatment. JO - Int. J. Radiat. Biol. VL - 43 IS - 3 PY - 1983 SN - 0955-3002 ER - TY - JOUR AB - The participation of the primary radicals in the bleaching of aqueous solutions of the carotenoid crocin by ionizing radiation was investigated, employing both X-radiolysis and pulse radiolysis. The pulse-radiolytic data demonstrated a very rapid diffusion-controlled attack by both hydroxyl radicals (·OH) and hydrated electrons (e- aq), while superoxide anions (O- 2) did not react at all. The site of the initial reaction of these radicals was not limited to the polyene chromophore. Slower secondary reactions involving crocin alkyl or peroxy radicals contribute mainly to the overall bleaching, in particular during steady-state irradiation. AU - Bors, W. AU - Saran, M. AU - Michel, C. C1 - 41818 C2 - 38578 SP - 493-501 TI - Radical intermediates involved in the bleaching of the carotenoid crocin. Hydroxyl radicals, superoxide anions and hydrated electrons. JO - Int. J. Radiat. Biol. VL - 41 IS - 5 PY - 1982 SN - 0955-3002 ER - TY - JOUR AB - T1-prospermatogonia pass through a quiescent stage which lasts from before birth until day 4 after birth (p.n.). They progress into DNA synthesis and mitosis in two synchronous waves which are separated by 24 hours in the evenings of day 4 and 5. The first wave contains about 25 per cent of the total population, the second 75 per cent. The mean duration of S-phase is 10 hours, the mean duration of G2-phase is 4 hours. After irradiation, the capacity of T1-prospermatogonia to produce the normal number of proliferating and differentiating cells in the testes is reduced. During maturation, between day 21 post-conception (p.c.) and day 5 p.n. the radiosensitivity of T1-prospermatogonia decreases by a factor of over 5. AU - Hilscher, W.M.* AU - Trott, K.R. C1 - 42420 C2 - 36265 SP - 517-524 TI - Cell progression and radiosensitivity of T1-prospermatogonia in wistar rats. JO - Int. J. Radiat. Biol. VL - 41 IS - 5 PY - 1982 SN - 0955-3002 ER - TY - JOUR AB - The ability of Ehrlich ascites tumour cells (EAT-cells) to perform split-dose recovery after U.V. exposure was studied with unfed plateau phase as well as with synchronized cells selected from exponentially growing cultures. The cells were kept in balanced salt solution which inhibited the progression of the cells through the cell cycle. The results indicated that split-dose recovery occurred in EAT-cells in all phases of the cell cycle and that progression of the cells into S-phase was not a prerequisite for this type of repair. The second-dose survival curves of G1- and S-phase cells showed, 24 hours after the first U.V. exposure, a shoulder width comparable to that of singly irradiated cells. Second-dose survival curves for G2-cells showed, after the same time interval, a shoulder width smaller than that for singly exposed cells, presumably due to some cell division. The recovery time constant (50 between 4 and 8 hours) increased with increasing U.V. exposure. AU - Iliakis, G.E. AU - Nüsse, M. C1 - 41286 C2 - 38428 SP - 503-515 TI - Evidence that progression of cells into s-phase is not a prerequisite for recovery between Split doses of u.v.-light in synchronized and plateau phase cultures of ehrlich ascites tumour cells. JO - Int. J. Radiat. Biol. VL - 41 IS - 5 PY - 1982 SN - 0955-3002 ER - TY - JOUR AB - It is shown theoretically that a shouldered dose-response curve may be obtained when repair of Poisson-distributed potentially lethal lesions occurs during a restricted time period between plating irradiated cells on nutrient agar and fixation of potentially lethal lesions. This interpretation is supported by experiments showing that an increased shoulder width of the dose-response curve is observed when irradiated cells are given more time for repair of potentially lethal lesions. AU - Frankenberg, D. AU - Frankenberg-Schwager, M. C1 - 41669 C2 - 38565 SP - 617-631 TI - Interpretation of the shoulder of dose-response curves with immediate plating in terms of repair of potentially lethal lesions during a restricted time period. JO - Int. J. Radiat. Biol. VL - 39 IS - 6 PY - 1981 SN - 0955-3002 ER - TY - JOUR AU - Bauchinger, M. AU - Kolin-Gerresheim, J. AU - Schmid, E. AU - Dresp, J.H. C1 - 41858 C2 - 38845 SP - 577-581 TI - Chromosome analyses of nuclear-power plant workers. JO - Int. J. Radiat. Biol. VL - 38 IS - 5 PY - 1980 SN - 0955-3002 ER - TY - JOUR AB - Two main components of DNA strand break repair have been found using the unwinding method. The first has a time constant (t37) of some minutes and the second, much slower component, a time constant of several hours. The time constant for the slower component of repair was found to vary with the conditions of incubation and to depend on the quality of the radiation. The t37 values obtained for slow repair under various conditions after X-irradiation and after alpha-irradiation were found to be close to those for repair of double strand breaks as measured by velocity sedimentation. Values for initial breaks, obtained by extrapolation of slow repair data back to time zero, were also close to those obtained for double strand breaks. We therefore propose that the unwinding method can be a useful technique for monitoring the repair of double strand breaks. AU - Bryant, P.E. AU - Blöcher, D. C1 - 40937 C2 - 38310 SP - 335-347 TI - Measurement of the kinetics of DNA double Strand break repair in ehrlich ascites tumour cells using the unwinding method. JO - Int. J. Radiat. Biol. VL - 38 IS - 3 PY - 1980 SN - 0955-3002 ER - TY - JOUR AU - Frankenberg-Schwager, M. AU - Frankenberg, D. AU - Blöcher, D. AU - Adamczyk, C. C1 - 41499 C2 - 38834 SP - 207-212 TI - The linear relationship between DNA double-Strand breaks and radiation dose (30 mev electrons) is converted into a quadratic function by cellular repair. JO - Int. J. Radiat. Biol. VL - 37 IS - 2 PY - 1980 SN - 0955-3002 ER - TY - JOUR AB - Monolayer cultures of EAT cells when plated immediately after irradiation show a decrease in survival as they age in the plateau phase of growth. This decrease, which is manifest as a diminution of the shoulder width of the survival curve down to values approaching zero, is reversible if the cells are kept in their growth medium for some hours after irradiation before trypsinization and plating. Survival curves obtained by this holding procedure are similar in shape to those shown by exponentially growing or early plateau phase cells. We interpret this effect in terms of repair of potentially lethal damage which occurs after immediate plating in young cultures but only declared during plating in cultures which have aged in the plateau phase. The kinetics of this repair and the effects caused by the addition of serum after irradiation in the cultures have been studied. AU - Iliakis, G.E. C1 - 41054 C2 - 38811 SP - 591-600 TI - Repair of potentially lethal damage in unfed plateau phase cultures of ehrlich ascites tumour cells: II. Monolayer cultures. JO - Int. J. Radiat. Biol. VL - 37 IS - 5 PY - 1980 SN - 0955-3002 ER - TY - JOUR AB - Structural damage to isolated erythrocyte membranes (ghosts has been studied following gamma-irradiation under a variety of conditions. For this two fluorescent probes were used; one 1-anilino-8-naphthalene sulphonate probes the lipid-aqueous interface, the other, diphenylhexatriene, was used to probe the membrane fluidity. Irradiation of the membranes caused a decrease in fluorescent intensity of the added probes, and changes in polarization of fluorescence. Oxygen was found to enhance the radiation damage, and scavenger experiments showed the hydroxyl radical was the major radical species involved. The structural modifications are therefore interpreted in terms of preliminary chemical damage involving peroxidation of unsaturated lipids. In addition sensitization and protection was observed in the presence of known dose-modifying chemicals. AU - Purohit, S.C.* AU - Bisby, R.H. AU - Cundall, R.B.* C1 - 41082 C2 - 38807 SP - 147-158 TI - Structural modification of human erythrocyte membranes following gamma-irradiation. JO - Int. J. Radiat. Biol. VL - 38 IS - 2 PY - 1980 SN - 0955-3002 ER - TY - JOUR AB - In air saturated suspensions of erythrocyte ghost membranes γirradiation causes formation of lipid peroxides, measured as malonaldehyde, and a loss of membrane protein sulphydryl groups. Addition of N-(p-amino-benzoyl)-1-glutamate prevented peroxidation up to doses of 2 × 103 Gy, due to scavenging of hydroxyl radicals. Another hydroxyl scavenger sodium formate, also prevented peroxidation at low doses, but lost its protective effect at higher doses probably because of secondary reactions of the resulting superoxide radical anion. Two sulphur containing radioprotectants also were able to reduce the extent of lipid peroxidation. The enzymes catalase and superoxide dismutase were added to the irradiated suspensions in order to determine the contribution from hydrogen peroxide and superoxide to peroxidation. The extents of peroxidation are compared with structural modification of the membrane under the same conditions of irradiation. AU - Purohit, S.C.* AU - Bisby, R.H. AU - Cundall, R.B.* C1 - 42511 C2 - 38143 SP - 159-166 TI - Chemical damage in gamma-irradiated human erythrocyte membranes. JO - Int. J. Radiat. Biol. VL - 38 IS - 2 PY - 1980 SN - 0955-3002 ER - TY - JOUR AB - Ethylene was determined by gas chromatography after reaction of radiolytically produced ·OH and O- 2 radicals with methionine, methionine + pyridoxal phosphate and S-adenosyl-methionine (SAM). Both oxygen radicals, alone or in combination, liberate ethylene from methionine and methionine/pyridoxal phosphate. From SAM ethylene was primarily produced by the combined attack of ·OH and H2O2 or O- 2. AU - Saran, M. AU - Bors, W.* AU - Michel, C. AU - Elstner, E.F. C1 - 41089 C2 - 38828 SP - 521-527 TI - Formation of ethylene from methionine. Reactivity of radiolytically produced oxygen radicals and effect of substrate activation. JO - Int. J. Radiat. Biol. VL - 37 IS - 5 PY - 1980 SN - 0955-3002 ER - TY - JOUR AU - Schmid, E. AU - Dresp, J.H.* AU - Bauchinger, M. AU - Franke, H.D. AU - Langendorff, G. AU - Hess, A. C1 - 42179 C2 - 38849 SP - 691-695 TI - Radiation-induced chromosome damage in patients after tumour therapy with 14 mev, DT neutrons. JO - Int. J. Radiat. Biol. VL - 38 IS - 6 PY - 1980 SN - 0955-3002 ER - TY - JOUR AB - The dose relation for dicentrics after in vitro Co γirradiation of human lymphocytes with dose rates of 50 and 1·7 rad/min fit the linear-quadratic function y = αD + βD2. Compared with 50 rad/min, after 1·7 rad/min αD was unchanged, whereas βD2 was decreased by 36 per cent. By applying the mean interaction time t̃ ≈ 110 min for primary breaks, determined in an earlier experiment, and Lea's G-function, a theoretical dose relation for 1·7 rad/min can be calculated from the dose relation of the higher dose rate. This theoretical function is not significantly different from the corresponding experimental curve. Thus, from calibration curves with conventional dose rates dose-effect curves for low dose rates can be derived without the need for time-consuming chromosome analyses. AU - Bauchinger, M. AU - Schmid, E. AU - Dresp, J.H. C1 - 41603 C2 - 35494 SP - 229-233 TI - Calculation of the dose-rate dependence of the dicentric yield after co γ-irradiation of human lymphocytes. JO - Int. J. Radiat. Biol. VL - 35 IS - 3 PY - 1979 SN - 0955-3002 ER - TY - JOUR AB - It is shown that in diploid yeast there are significant differences in the extent of irreparable damage after irradiation with X-rays, 60Co-gamma-rays and 30 MeV electrons. At extremely low dose rates, 60Co-gamma-rays were found to produce almost no irreparable damage at least up to 1200 Gy. X-rays, however, at the same low dose rate caused irreparable damage in the same dose range yielding a surviving fraction of 0·25 at 1200 Gy. For irradiations at high dose rate followed by liquid holding recovery the relative biological effectiveness of X-rays amounted to at least 4 for absorbed doses of up to 1000 Gy. With 30 MeV electrons at high dose rates an accumulation of sublethal and potentially lethal damage resulting in irreparable damage occurred above 1000 Gy. It is suggested that irreparable damage in yeast is due to a cooperative effect of neighbouring track ends. AU - Frankenberg, D. C1 - 41455 C2 - 38172 SP - 317-324 TI - Reparable and irreparable damage in yeast cells induced by sparsely ionizing radiation. JO - Int. J. Radiat. Biol. VL - 36 IS - 4 PY - 1979 SN - 0955-3002 ER - TY - JOUR AB - Survival and induction of DNA double-strand breaks were studied in cells of Saccharomyces cerevisiae irradiated under oxic or anoxic conditions with 30 MeV electrons. A linear relationship between DNA double-strand breakage and dose was found in both cases. The o.e.r.-value for colony forming ability was found to be 1·9 ± 0·2, whereas the o.e.r.-value for DNA double-strand breakage was 3·0 ± 0·1. These results are not inconsistent with the idea that DNA double-strand breaks are involved in killing of yeast cells. The frequency of induction of DNA double-strand breaks was found to be 0·74 × 10-11 double-strand breaks per g/mol per Gy when cells were irradiated under oxygen and 0·24 × 10-11 double-strand breaks per g/mol per Gy under nitrogen. AU - Frankenberg-Schwager, M. AU - Frankenberg, D.* AU - Blöcher, D. AU - Adamczyk, C. C1 - 33716 C2 - 38616 SP - 261-270 TI - The influence of oxygen on the survival and yield of DNA double-Strand breaks in irradiated yeast cells. JO - Int. J. Radiat. Biol. VL - 36 IS - 3 PY - 1979 SN - 0955-3002 ER - TY - JOUR AB - The uptake of radioactive 5'dTMP into the DNA of diploid yeast cells was measured in the G1 and S-phase of the cell-cycle. In control cells, the uptake is zero in G1 and increases with time in the S-phase. Cells irradiated in early G1 show an uptake (unscheduled DNA synthesis) which is higher than if irradiation is performed later in G1. An analysis which takes into consideration the incomplete synchronization of the cell population shows that, at the end of G1, no uptake would be present in an ideally-synchronous population. At the end of G1 the shoulder in the dose - effect curve for cell survival also disappears. This provides additional evidence that the shoulder in a dose - effect curve might be due to repair reactions in living cells. AU - Höltz, G.W. AU - Pohlit, W. C1 - 42374 C2 - 35664 SP - 121-129 TI - Unscheduled DNA synthesis in diploid yeast after x-irradiation in different phases of the cell-cycle. JO - Int. J. Radiat. Biol. VL - 31 IS - 2 PY - 1977 SN - 0955-3002 ER - TY - JOUR AB - The effects of the glucose antimetabolite, 2-deoxy-D-glucose (2-DG), on DNA repair (assayed by unscheduled DNA synthesis) and on the repair of potentially-lethal damage (assayed by cell viability after irradiation) have been studied in X-irradiated respiratory-deficient yeast cells (auxotroph for 5'thymidine-monophosphate). Experimental results show that: (a) both these phenomena can be inhibited by 2-DG; (b) the repair of potentially-lethal damage occurs after the unscheduled DNA synthesis is almost complete; and (c) the repair of potentially-lethal damage can be inhibited by 2-DG even after the completion of the unscheduled DNA synthesis. AU - Jain, V.K.* AU - Höltz, G.W. AU - Pohlit, W.* AU - Purohit, S.C.* C1 - 42369 C2 - 35669 SP - 175-180 TI - Inhibition of unscheduled DNA synthesis and repair of potentially lethal X-ray damage by 2-deoxy-D-glucose in yeast. JO - Int. J. Radiat. Biol. VL - 32 IS - 2 PY - 1977 SN - 0955-3002 ER - TY - JOUR AB - A model for radiation reactions in living cells is described. It assumes three different states of the cell. State A is a cell which can grow up to a macrocolony; in state B and C the cell is not able to do so. In state B an 'essential molecule' of the cell has been damaged reparably, in state C irreparably. The sensitivity of the cell is assumed to increase with absorbed dose and to be reduced by recovery reactions in the cell. This can be explained, for example, by indirect radiation reactions with molecules competing with the essential molecule. These competing molecules can be replenished by the cell using an internal energy reservoir. Methods for the experimental determination of all parameters appearing in this model are described. Experiments with stationary diploid yeast cells, irradiated with x-rays, show that the time-constants of recovery and repair are of the same order of magnitude but are dependent on the time interval between or after irradiations, and are dependent on absorbed dose. We expect that this model can be applied also to radiation reactions in other types of cells, and to other ionizing radiations. AU - Kappos, A. AU - Pohlit, W. C1 - 41711 C2 - 38195 SP - 51-65 TI - A cybernetic model for radiation reactions in living cells: I. Sparsely-ionizing radiations; stationary cells. JO - Int. J. Radiat. Biol. VL - 22 IS - 1 PY - 1972 SN - 0955-3002 ER - TY - JOUR AU - Kollmer, W.E. C1 - 42590 C2 - 35843 SP - 183-186 TI - Ausscheidungsintensivierung von Radiostrontium während der Laktation in Abhängigkeit vom Alter der Tiere. JO - Int. J. Radiat. Biol. VL - 19 IS - 2 PY - 1971 SN - 0955-3002 ER - TY - JOUR AB - The distribution of intraperitonally-injected 224Ra was studied in NMRI mice and WISTAR rats. The highest activity concentrations were found in the skeleton. High radium concentrations were also obtained in the spleen (in mice higher than in rats, increasing with age). The calculated values were 12 rads/day for initial skeletal dose-rate and 30 rads for total averaged skeletal dose by supporting 1 μCi/kg 224Ra. The dose relationships of the short-lived 224Ra were contrasted to those of the long-lived 226Ra. Osteosarcoma-induction related to skeletal dose is discussed and compared with results of 226Ra known from the literature. AU - Müller, W.A. C1 - 41728 C2 - 37944 SP - 27-38 TI - Studies on short-lived internal αemitters in mice and rats: Part i. 224ra. JO - Int. J. Radiat. Biol. VL - 20 IS - 1 PY - 1971 SN - 0955-3002 ER - TY - JOUR AB - 227Th is an interesting model for a short-lived bone 'surface-seeker' with αemission. The distribution after intraperitoneal injection of 227Th-citrate in the different organs is described. About 70 per cent of the injected Th was retained in the skeleton. The total dose burden depends to a high degree on distribution of decay products, especially 223Ra. Calculations were done for the skeletal dose burden in mice. They yielded 200 rads per 1 μCi of 227Th injected. The highest skeletal dose-rate (7 rads/day per 1 μCi/kg) was reached at the third day after injection. The possibility of bone sarcoma induction is discussed by comparison with dose relationships after incorporation of 228Th. A provisional mechanical technique is described for estimation - to a certain extent - of the activity at bone surface and volume separately. AU - Müller, W.A. C1 - 42600 C2 - 35434 SP - 233-243 TI - Studies on short-lived internal αemitters in mice and rats: Part II. 227th. JO - Int. J. Radiat. Biol. VL - 20 IS - 3 PY - 1971 SN - 0955-3002 ER -