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The scientific literature concerning cytogenetic biodosimetry has been reviewed to identify the range of scenarios of radiation exposure where biodosimetry has been carried out. Limitations in the existing standardized statistical methodology have been identified and categorized, and the reasons for these limitations have been explored. Statistical problems generally occur due to either low numbers of aberrations leading to large uncertainties or deviations in aberration-per-cell distributions leading to over- or under-dispersion with respect to the Poisson model. A number of difficulties also stem from limitations of the classical statistical methodology, which requires that chromosome aberration yields be considered as something “fixed” and thus provides a deterministic estimate of radiation dose and associated confidence limits (because an assignment of a probability to an event is based solely on the observed frequency of occurrence of the event). Therefore, it is suggested that solutions to the listed problems should be based in the Bayesian framework. This will allow the investigator to take a probabilistic approach to analysis of cytogenetic data, which can be considered highly appropriate for biological dose estimation.
The ATM-dependent DNA damage checkpoint plays a pivotal role in cellular response to ionizing radiation. Although amplification of the DNA damage signal through multifactorial protein complex formation of DNA damage checkpoint factors is crucial for proper DNA damage response in two-dimensionally cultured cells, the dynamics of the DNA damage response in three-dimensional tissues or organs remained to be determined. Here we used a model of reconstituted human skin and investigated the spatiotemporal dynamics of focus formation of DNA damage checkpoint factors after X irradiation. We found that DNA damage-induced foci were differentially formed in different layers. All cells in basal layers and approximately 40% of cells in spinous layers displayed foci. In basal cells, the foci showed linear dose relationships, and the number of foci decreased with increasing time after irradiation. We found that the initial foci grew within a few hours after irradiation, and persistent signals developed large foci. Colocalization of phosphorylated ATM, phosphorylated histone H2AX, MDC1 and 53BP1 foci was detected, and all of them showed simultaneous focus growth, indicating amplification of DNA damage signals. These results confirmed a dynamic DNA damage response in three-dimensional tissue, which provides a practical model for studying DNA damage response in vivo.
In higher eukaryotes, DNA double-strand breaks (DSBs) induced by ionizing radiation activate checkpoints that delay progression through the cell cycle. Compared to delays in other phases of the cell cycle, delays induced in G2 are longer and frequently correlate with resistance to killing by radiation. Therefore, modulation of the G2 checkpoint offers a means to modulate cellular radiosensitivity. Although compounds are known that reduce the G2 checkpoint and act as radiosensitizers, compounds enhancing this checkpoint have not been reported. Here we summarize evidence for a factor with such properties. We show that a highly radioresistant rat embryo fibroblast (REF) cell line displays a strong G2 checkpoint partly as a result of a factor excreted into the growth medium by nonirradiated cells. Various tests indicate that this G2-arrest modulating activity (GAMA) is a small molecule showing detectable retention only after passing through filters with a molecular weight cutoff limit of less than 1,000 Da. GAMA is heat stable and resistant to treatment with proteases or nucleases. Electroelution tests show that GAMA is uncharged at neutral pH, a result that is in agreement with the observed failure to bind S- or Q-Sepharose. Investigations on the mechanism of GAMA function indicate ligand-receptor interactions and allow the classification of cells as producers, responders or both. Compounds with properties such as those of GAMA bridge intercellular communication with the DNA damage response and may function as radioprotectors.
The usefulness of laser plasma X-ray pulses for medical and radiation biological studies was investigated, and the effects of laser plasma X rays were compared with those of conventional sources such as a linear accelerator. A cell irradiation system was developed that used copper-Kα (8 keV) lines from an ultrashort high-intensity laser to produce plasma. The absorbed dose of the 8 keV laser plasma X-ray pulse was estimated accurately with Gafchromic® EBT film. When the cells were irradiated with approximately 2 Gy of laser plasma X rays, the circular regions on γ-H2AX-positive cells could be clearly identified. Moreover, the numbers of γ-H2AX and phosphorylated ataxia telangiectasia mutated (ATM) foci induced by 8 keV laser plasma X rays were comparable to those induced by 4 MV X rays. These results indicate that the laser plasma X ray source may be useful for radiation biology studies.
To examine the possibility of using fractionated radiation in a unique way with molecular targeted therapy, gene expression profiles of prostate carcinoma cells treated with 10 Gy radiation administered either as a single dose or as fractions of 2 Gy × 5 and 1 Gy × 10 were examined by microarray analysis. Compared to the single dose, the fractionated irradiation resulted in significant increases in differentially expressed genes in both cell lines, with more robust changes in PC3 cells than in DU145 cells. The differentially expressed genes (>twofold change; P < 0.05) were clustered and their ontological annotations evaluated. In PC3 cells genes regulating immune and stress response, cell cycle and apoptosis were significantly up-regulated by multifractionated radiation compared to single-dose radiation. Ingenuity Pathway Analysis (IPA) of the differentially expressed genes revealed that immune response and cardiovascular genes were in the top functional category in PC3 cells and cell-to-cell signaling in DU145 cells. RT-PCR analysis showed that a flexure point for gene expression occurred at the 6th–8th fraction and AKT inhibitor perifosine produced enhanced cell killing after 1 Gy × 8 fractionated radiation in PC3 and DU145 cells compared to single dose. This study suggests that fractionated radiation may be a uniquely exploitable, non-oncogene-addiction stress pathway for molecular therapeutic targeting.
Labeling of all proliferating cells in C57BL/6J mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2′-deoxyuridine (BrdU). Tumors were irradiated with γ rays at a high dose rate or a reduced dose rate at 1 h after the administration of pimonidazole. Assessment of the responses of quiescent and total ( = proliferating quiescent) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The total cell fraction that was not labeled with pimonidazole showed significantly enhanced radiosensitivity. However, a significantly greater decrease in radiosensitivity, evaluated using a delayed assay or a decrease in radiation dose rate, was observed in the quiescent cell compared with the total cell population. Overall, the quiescent cell population showed significantly greater radioresistance and capacity to recover from radiation-induced damage than the total tumor cell population. Thus we believe that the subfraction of the quiescent tumor cell population that was not labeled with pimonidazole and that was probably oxygenated is a critical target in the control of solid tumors.
In this study we investigated the effect of repeated low-dose radiation exposure (75 mGy X ray) on skin wound healing in a rat model of diabetes. A skin wound was made on the backs of diabetic and age-matched control rats 60 days after diabetes was induced by a single injection of streptozotocin. Rats with skin wounds were immediately treated with whole-body radiation daily for 5, 10 or 15 days with a 2-day break every 5 days. Wound size was estimated 5, 10 and 15 days after wound formation. Repeated exposure of diabetic rats to low-dose radiation significantly accelerated skin wound healing compared to the nonirradiated diabetic group. Furthermore, low-dose radiation-induced improvement in healing was associated with increases in bone marrow and circulating CD31/CD34 stem cells, vessel regeneration and cell proliferation in the wound tissue, and matrix metalloproteinase 2 and 9 expression. Therefore, we conclude that the acceleration of wound healing in diabetic rats by repeated exposure to low-dose radiation is associated with stimulation of bone marrow stem cell proliferation and peripheral mobilization.
The effects of acute exposure to low- and high-dose radiation on the quantitative and functional parameters of the immune system were analyzed. C57BL/6 mice were irradiated with different doses of γ radiation (0.01, 0.05, 0.1, 0.5 and 2 Gy) and splenocytes were isolated at various times. Alterations in the distribution and surviving fraction of splenocyte subsets such as CD4 and CD8 T lymphocytes, regulatory T cells (Treg), natural killer (NK) cells, dendritic cells (DCs) and B lymphocytes were analyzed by flow cytometry. Apoptosis frequency was quantified by the TdT-mediated dUTP-biotin nick end labeling (TUNEL) method 4 h after irradiation. Cytokine expression was investigated by real-time reverse transcription-polymerase chain reaction (RT-PCR). Low doses decreased apoptosis in the splenocyte subpopulations studied most prominently in NK cells and DCs. Exposure to 2 Gy increased apoptosis in all splenocyte subpopulations; B cells were the most sensitive and NK cells and DCs the least sensitive. The lowest cell numbers were measured 3 days after irradiation, with minor changes by day 7. CD8 and B cells were rather resistant to low doses but were very sensitive to 2 Gy, while NK cells, DCs and Treg cells were much more resistant to high doses. Expression of the T-helper 1 (Th1)- and helper 2 (Th2)-type cytokines decreased after low doses and increased after high doses. Interleukin 6 (IL-6) reacted at early times and IL-10 at later times. IL-5 levels were consistently elevated. These data highlight the differences in the responses of different splenocyte subpopulations to low- and high-dose radiation.
The lens of the eye is one of the most radiosensitive tissues in the body, and exposure of the lens to ionizing radiation can cause cataract. Cumulative X-ray doses to the lenses of interventional cardiologists and associated staff can be high. The International Commission on Radiological Protection recently noted considerable uncertainty concerning radiation risk to the lens. This study evaluated risk of radiation cataract after occupational exposure in interventional cardiology personnel. Comprehensive dilated slit-lamp examinations were performed in interventional cardiologists, associated workers and controls. Radiation exposures were estimated using experimental data from catheterization laboratories and answers to detailed questionnaires. A total of 116 exposed and 93 similarly aged nonexposed individuals were examined. The relative risk of posterior subcapsular opacities in interventional cardiologists compared to unexposed controls was 3.2 (38% compared to 12%; P < 0.005). A total of 21% of nurses and technicians had radiation-associated posterior lens changes typically associated with ionizing radiation exposure. Cumulative median values of lens doses were estimated at 6.0 Sv for cardiologists and 1.5 Sv for associated medical personnel. A significantly elevated incidence of radiation-associated lens changes in interventional cardiology workers indicates there is an urgent need to educate these professionals in radiation protection to reduce the likelihood of cataract.
This paper summarizes the biokinetic database for iodine in the human body and proposes a biokinetic model for systemic iodine for use in dose assessments for internally deposited radioiodine. The model consolidates and extends existing physiological systems models describing three subsystems of the iodine cycle in the body: circulating inorganic iodide, thyroidal iodine (trapping and organic binding of iodide and synthesis, storage and secretion of thyroid hormones), and extrathyroidal organic iodine. Thyroidal uptake of inorganic iodide is described as a function of stable iodine intake (Y, µg day−1) and thyroidal secretion of hormonal iodine (S, µg day−1). Baseline parameter values are developed for reference adults with typical iodine intake. Compared with the current systemic biokinetic model of the International Commission on Radiological Protection (ICRP) for occupational intake of radioiodine, the proposed model predicts higher absorbed doses to the thyroid per unit uptake to blood for very short-lived iodine isotopes, similar absorbed doses to thyroid for iodine isotopes with half-life of at least a few hours, and substantially higher estimates of absorbed dose to stomach wall, salivary gland and kidneys for most iodine isotopes. Absorbed dose estimates for intravenous administration of radioiodine-labeled thyroid hormones based on the proposed model differ substantially in some cases from current ICRP values.
In light-ion radiation therapy, both the dose and the local energy spectrum, which is often characterized with the linear energy transfer (LET), must be considered. In treatment optimization, it is advantageous to use a radiobiological model that analytically accounts for both dose and LET for the ion type of interest. With such a model the biological effect can also be estimated for dose and LET combinations for which there are no observations in the underlying experimental data. In this study, the repairable-conditionally repairable (RCR) damage model was extended by expressing its parameters as functions of LET to provide a radiobiological model that accounts for both the dose and the LET for a given ion type and cell line. This LET-parameterized RCR model was fitted to published cell survival data for HSG and V79 cells irradiated with carbon ions and for T1 cells irradiated with helium ions. To test the robustness of the model, fittings to only a subset of the data were performed. Good agreement with the cell survival data was obtained, including survival data for LET values not used for model fitting, opening up the possibility of using the model in treatment planning for light ions.
A novel spleen tyrosine kinase (SYK) P-site inhibitor, 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C-61), (but not vehicle) markedly enhanced H2O2-induced apoptosis of primary leukemia cells from each of five relapsed B-lineage acute lymphoblastic leukemia (ALL) patients, as measured by in vitro TUNEL assays. A highly radiation-resistant subclone of the murine B-lineage leukemia cell line BCL-1 was next used to investigate the in vivo radiosensitizing effects of C-61. C-61 enhanced the antileukemia potency of 7 Gy total-body irradiation (TBI) in the context of syngeneic bone marrow transplantation (BMT) at 20% of its nonobservable adverse effect level (NOAEL) that does not exhibit detectable single-agent activity against BCL-1 leukemia in vivo. Based on this preclinical proof-of-principle study, we hypothesize that the incorporation of C-61 into the pretransplant TBI regimens of patients with recurrent or high-risk B-lineage acute lymphoblastic leukemia (ALL) will help overcome the radiochemotherapy resistance of their leukemia cells and thereby improve their treatment response and survival outcome after BMT.
Induction of an adaptive response by priming X rays in combination with challenge irradiations from high-LET accelerated heavy ions was attempted in young adult female C57BL/6J Jms mice using 30-day survival after the challenge irradiations as an index. Three kinds of accelerated heavy ions from monoenergetic beams of carbon, silicon and iron ions with LETs of about 15, 55 and 200 keV/μm, respectively, were examined. A priming low dose of 0.50 Gy X rays in combination with a challenging dose of 7.50 Gy was used in the animals serving as a positive control group to confirm the successful induction of an adaptive response. The priming low dose of 0.50 Gy X rays was also used in combination with accelerated heavy ions. The priming low dose of X rays significantly reduced the mortality from the high challenge doses of carbon or silicon particles but not from iron particles. These results indicate that an adaptive response could be induced by priming low-LET X rays in combination with subsequent challenge high-LET irradiations from certain kinds of accelerated heavy ions, and successful induction of an adaptive response would possibly be an event related to the LET and/or the type of heavy ions. This is the first time that the existence of an adaptive response induced by low-LET X rays against high-LET whole-body irradiation in mice has been demonstrated. These findings would provide new insight into the radiation-induced adaptive response in vivo.