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Carl N. Sprung, Yuqing Yang, Helen B. Forrester, Jason Li, Marina Zaitseva, Leonie Cann, Tina Restall, Robin L. Anderson, Jeffrey C. Crosbie, Peter A. W. Rogers
The majority of cancer patients achieve benefit from radiotherapy. A significant limitation of radiotherapy is its relatively low therapeutic index, defined as the maximum radiation dose that causes acceptable normal tissue damage to the minimum dose required to achieve tumor control. Recently, a new radiotherapy modality using synchrotron-generated X-ray microbeam radiotherapy has been demonstrated in animal models to ablate tumors with concurrent sparing of normal tissue. Very little work has been undertaken into the cellular and molecular mechanisms that differentiate microbeam radiotherapy from broad beam. The purpose of this study was to investigate and compare the whole genome transcriptional response of in vivo microbeam radiotherapy versus broad beam irradiated tumors. We hypothesized that gene expression changes after microbeam radiotherapy are different from those seen after broad beam. We found that in EMT6.5 tumors at 4–48 h postirradiation, microbeam radiotherapy differentially regulates a number of genes, including major histocompatibility complex (MHC) class II antigen gene family members, and other immunity-related genes including Ciita, Ifng, Cxcl1, Cxcl9, Indo and Ubd when compared to broad beam. Our findings demonstrate molecular differences in the tumor response to microbeam versus broad beam irradiation and these differences provide insight into the underlying mechanisms of microbeam radiotherapy and broad beam.
Age at the time of exposure to sparsely ionizing radiation has been established as a key determinant of radiation cataractogenesis. However, while some reports suggest that the lenses of the young are hypersensitive, data from older studies are often conflicting and somewhat difficult to interpret when the radioresponse of young lenses is compared to that of adult lenses. Moreover, the mechanism of the age-response function for radiation cataractogenesis has yet to be identified. Since steroid sex hormones, notably estradiol, appear to play a role in age-related cataractogenesis, we hypothesized that the age response for radiation cataractogenesis could be dictated by estradiol status. We recently showed that exposure to high-linear energy transfer (LET) radiation resulted in a reduced latent period for, and enhanced progression of cataracts in rats that were 1 year old at the time of exposure compared to those that were 56 days old. However, the enhanced sensitivity of older lenses compared to younger lenses was independent of estradiol status. In the current study, we found that for 1-year-old rats exposed to 10 Gy of low-LET 60Co γ rays, the rate of increase in the development of posterior and anterior subcapsular cataracts was higher in older ovary-intact rats compared to young rats. However, cataracts were detected much earlier in ovary-intact 56-day-old rats compared to 1-year-old rats, regardless of their treatment groups (ovary-intact, ovariectomized, or ovariectomized and implanted with capsules containing estradiol). Thus, despite a consistent estradiol response (potentiating effect of estrogen) within a given age group, the differences between the radiation response of old and young lenses cannot be accounted for solely by estradiol status.
Ritsu Sakata, Ruth A. Kleinerman, Kiyohiko Mabuchi, Marilyn Stovall, Susan A. Smith, Rita Weathers, Jean Wactawski-Wende, Diane L. Cookfair, John D. Boice, Peter D. Inskip
The purpose of this study is to quantify cancer mortality in relationship to organ-specific radiation dose among women irradiated for benign gynecologic disorders. Included in this study are 12,955 women treated for benign gynecologic disorders at hospitals in the Northeastern U.S. between 1925 and 1965; 9,770 women treated by radiation and 3,186 women treated by other methods. The average age at treatment was 45.9 years (range, 13–88 years), and the average follow-up period was 30.1 years (maximum, 69.9 years). Radiation doses to organs and active bone marrow were reconstructed by medical physicists using original radiotherapy records. The highest doses were received by the uterine cervix (median, 120 Gy) and uterine corpus (median, 34 Gy), followed by the bladder, rectum and colon (median, 1.7–7.2 Gy), with other abdominal organs receiving median doses ≤1 Gy and organs in the chest and head receiving doses <0.1 Gy. Standardized mortality rate ratios relative to the general U.S. population were calculated. Radiation-related risks were estimated in internal analyses using Poisson regression models. Mortality was significantly elevated among irradiated women for cancers of the uterine corpus, ovary, bladder, rectum, colon and brain, as well as for leukemia (exclusive of chronic lymphocytic leukemia) but not for cancer of the cervix, Hodgkin or non-Hodgkin lymphoma, multiple myeloma, or chronic lymphocytic leukemia. Evidence of a dose-response was seen for cancers of the ovary [excess relative risk (ERR) = 0.31/Gy, P < 0.001], bladder (ERR = 0.21/Gy, P = 0.02) and rectum (ERR = 0.23/Gy, P = 0.05) and suggested for colon (ERR = 0.09/Gy, P = 0.10), but not for cancers of the uterine corpus or brain nor for non-chronic lymphocytic leukemia. Relative risks of mortality due to cancers of the stomach, pancreas, liver and kidney were close to 1.0, with no evidence of dose-response over the range of 0–1.5 Gy. Breast cancer was not significantly associated with dose to the breast or ovary. Mortality due to cancers of heavily irradiated organs remained elevated up to 40 years after irradiation. Significantly elevated radiation-related risk was seen for cancers of organs proximal to the radiation source or fields (bladder, rectum and ovary), as well as for non-chronic lymphocytic leukemia. Our results corroborate those from previous studies that suggest that cells of the uterine cervix and lymphopoietic system are relatively resistant to the carcinogenic effects of radiation. Studies of women irradiated for benign gynecologic disorders, together with studies of women treated with higher doses of radiation for uterine cancers, provide quantitative information on cancer risks associated with a broad range of pelvic radiation exposures.
Dendritic cells play an essential role in the immune system. We have previously reported that X-irradiated monocytes, precursors of dendritic cells, can differentiate into dendritic cells and then mature in terms of surface antigen expression after tumor necrosis factor-α stimulation, but show reduced functionality. Dendritic cells can mature in response to various types of maturation stimuli. Therefore, this study investigated whether dendritic cells from monocytes exposed to ionizing radiation can adequately respond to pathogen-derived components and proinflammatory cytokines. Human monocytes separated from buffy coats were exposed to X rays, and were then differentiated into immature dendritic cells. Immature dendritic cells were stimulated by lipopolysaccharide (LPS) or proinflammatory cytokine mixture. The dendritic cells from nonirradiated and X-irradiated monocytes showed maturation after LPS and proinflammatory cytokine mixture stimulation as confirmed by findings of surface antigen expression. Upon LPS stimulation, however, the expression levels of CD80 and CD83 on dendritic cells from X-irradiated monocytes were lower than those of dendritic cells from nonirradiated monocytes. Such reductions were not observed upon proinflammatory cytokine mixture stimulation. Similarly, an impairment of matrix metalloproteinase-9 and cytokine production was observed in LPS-stimulated dendritic cells from X-irradiated monocytes, whereas these impairments were not observed upon proinflammatory cytokine mixture stimulation. The ability of dendritic cells to stimulate T cells was lower in the irradiated group compared with the nonirradiated group despite the type of maturation stimulus. Thus, the present study suggests that the influence of X irradiation on the maturation of dendritic cells depends on the type of maturation stimulus used and that X irradiation impairs the response of dendritic cells to LPS.
Exposure to galactic cosmic radiation is a potential health risk in long-term space travel and represents a significant risk to the central nervous system. The most harmful component of galactic cosmic radiation is the HZE [high mass, highly charged (Z), high energy] particles, e.g., 56Fe particle. In previous ground-based experiments, exposure to doses of HZE-particle radiation that an astronaut will receive on a deep space mission (i.e., ∼20 cGy) resulted in pronounced deficits in hippocampus-dependent learning and memory in rodents. Neurocognitive tasks that are dependent upon other regions of the brain, such as the striatum, are also impaired after exposure to low HZE-particle doses. These data raise the possibility that neurocognitive tasks regulated by the prefrontal cortex could also be impaired after exposure to mission relevant HZE-particle doses, which may prevent astronauts from performing complex executive functions. To assess the effects of mission relevant (20 cGy) doses of 1 GeV/u 56Fe particles on executive function, male Wistar rats received either sham treatment or were irradiated and tested 3 months later for their ability to perform attentional set shifting. Compared to the controls, rats that received 20 cGy of 1 GeV/u 56Fe particles showed significant impairments in their ability to complete the attentional set-shifting test, with only 17% of irradiated rats completing all stages as opposed to 78% of the control rats. The majority of failures (60%) occurred at the first reversal stage, and half of the remaining animals failed at the extra-dimensional shift phase of the studies. The irradiated rats that managed to complete the tasks did so with approximately the same ease as did the control rats. These observations suggest that exposure to mission relevant doses of 1 GeV/u 56Fe particles results in the loss of functionality in several regions of the cortex: medical prefrontal cortex, anterior cingulated cortex, posterior cingulated cortex and the basal forebrain. Our observation that 20 cGy of 1 GeV/u 56Fe particles is sufficient to impair the ability of rats to conduct attentional set-shifting raises the possibility that astronauts on prolonged deep space exploratory missions could subsequently develop deficits in executive function.
Skin toxicity is a ubiquitous side effect in radiotherapy and can be difficult to predict. Moist desquamation in cancer patients can decrease quality of life and occasionally demand unplanned treatment breaks thus worsening outcome. In breast cancer patients, moist desquamation occurs approximately one-third of the time, and while avenues such as intensity-modulated radiation therapy exist to decrease skin side effects, they may be prohibitively expensive to distribute widely. To selectively target patients who are at risk for high skin toxicity, toxicity prediction beyond heuristics is required. This study presents 3D thermal tomography, a translation technology that employs active thermal imaging to map the thermal effusivity of skin. Irradiated mice were imaged throughout reaction development to establish a correlation between effusivity changes and eventual toxicity severity. Female hairless mice (n = 11) were anesthetized and irradiated to 40 Gy in one fraction using a 1 cm Leipzig brachytherapy applicator with an Ir-192 source. After irradiation, thermal imaging was conducted daily with a flash lamp and infrared camera. Effusivity was calculated using custom software and tracked within irradiated and contralateral control regions. Mice were retrospectively grouped into high-grade (moist desquamation present, n = 6) and low-grade (n = 5). All mice showed an increase in the relative average effusivity difference among the treated and control regions between irradiation and peak reaction between 12 and 15 days after irradiation. The high-grade group showed an earlier increase in relative average effusivity difference (mean 1.7 days after irradiation versus 4.4 days after irradiation) than the low-grade group, and had a significantly greater relative average effusivity difference between 2–5 days after irradiation. We concluded that 3D thermal tomography is quick, non-invasive, non-ionizing and exhibited a correlative difference between mice that eventually developed moist desquamation and those that only presented dry desquamation. With further development, it may prove to be a useful tool in the clinic for differentiating patients who require preventative measures to reduce skin toxicity.
To overcome the limitations of existing biodosimetry methods, we examined dose- and time-dependent gene expression changes in human peripheral blood lymphocytes after exposure to low-, medium- and high-dose ionizing radiation and searched for genes suitable for predicting radiation doses in the low-dose range. Additionally, the experiments are intended to provide new insights into the biological effects of exposures to low-, medium- and high-dose radiation. Gene expression analysis using whole human genome DNA microarrays was performed in human blood from six healthy donors irradiated ex vivo with 0, 0.02, 0.1, 0.5, 1, 2 and 4 Gy (γ rays, 137Cs) at 6, 24 and 48 h after high-dose exposure (0.5–4 Gy), and at 24 and 48 h after low-dose exposures of 0.02 or 0.1 Gy. DNA microarray-based alterations in gene expression were found in a wide dose range in vitro and allowed us to identify nine genes with which low radiation doses could be accurately predicted with a sensitivity of 95.6%. In the low-, medium- and high-dose range, expression alterations increased with increasing dose and time after exposure, and were assigned to different biological processes such as nucleosome assembly, apoptosis and DNA repair response. We conclude from our results that gene expression profiles are suitable for predicting low-dose radiation exposure in a rapid and reliable manner and that acute low-dose exposure, as low as 20 mGy, leads to well-defined physiological responses in human peripheral blood lymphocytes.
The effect of radiation on the intestine has been studied for more than one hundred years. It remains unclear, however, whether this organ uses specific defensive mechanisms against ionizing radiation. The infection with Pseudomonas aeruginosa (PA14) in Caenorhabditis elegans induces up-regulation of innate immune response genes. Here, we found that exposure to ionizing radiation also induces certain innate immune response genes such as F49F1.6 (termed mul-1), clec-4, clec-67, lys-1 and lys-2 in the intestine. Moreover, pre-treatment with ionizing radiation before seeding on PA14 lawn plate significantly increased survival rate in the nematode. We also studied transcription pathway of the mul-1 in response to ionizing radiation. Induction of mul-1 gene was highly dependent on the ELT-2 transcription factor and p38 MAPK. Moreover, the insulin/IGF-1 signal pathway works to enhance induction of this gene. The mul-1 gene showed a different induction pattern from the DNA damage response gene, ced-13, which implies that the expression of this gene might be triggered as an indirect effect of radiation. Silencing of the mul-1 gene led to growth retardation after treatment with ionizing radiation. We describe the cross-tolerance between the response to radiation exposure and the innate immune system.
John D. Olson, Matthew C. Walb, Joseph E. Moore, Albert Attia, Heather L. Sawyer, Jennifer E. McBride, Kenneth T. Wheeler, Mark Steven Miller, Michael T. Munley
A gated-7T magnetic resonance imaging (MRI) application is described that can accurately and efficiently measure the size of in vivo mouse lung tumors from ∼0.1 mm3 to >4 mm3. This MRI approach fills a void in radiation research because the technique can be used to noninvasively measure the growth rate of lung tumors in large numbers of mice that have been irradiated with low doses (<50 mGy) without the additional radiation exposure associated with planar X ray, CT or PET imaging. High quality, high resolution, reproducible images of the mouse thorax were obtained in ∼20 min using: (1) a Bruker 7T micro-MRI scanner equipped with a 60 mm inner diameter gradient insert capable of generating a maximum gradient of 1000 mT/m; (2) a 35 mm inner diameter quadrature radiofrequency volume coil; and (3) an electrocardiogram and respiratory gated Fast Low Angle Shot (FLASH) pulse sequence. The images had an in-plane image resolution of 98 μm and a 0.5 mm slice thickness. Tumor diameter measured by MRI was highly correlated (R2 = 0.97) with the tumor diameter measured by electronic calipers. Data generated with an initiation/promotion mouse model of lung carcinogenesis and this MRI technique demonstrated that mice exposed to 4 weekly fractions of 10, 30 or 50 mGy of CT radiation had the same lung tumor growth rate as that measured in sham-irradiated mice. In summary, this high-field, double-gated MRI approach is an efficient way of quantitatively tracking lung tumor development and progression after exposure to low doses of ionizing radiation.
Caroline H. Johnson, Andrew D. Patterson, Kristopher W. Krausz, John F. Kalinich, John B. Tyburski, Dong Wook Kang, Hans Luecke, Frank J. Gonzalez, William F. Blakely, Jeffrey R. Idle
Mass spectrometry-based metabolomics has previously demonstrated utility for identifying biomarkers of ionizing radiation exposure in cellular, mouse and rat in vivo radiation models. To provide a valuable link from small laboratory rodents to humans, γ-radiation-induced urinary biomarkers were investigated using a nonhuman primate total-body-irradiation model. Mass spectrometry-based metabolomics approaches were applied to determine whether biomarkers could be identified, as well as the previously discovered rodent biomarkers of γ radiation. Ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry analysis was carried out on a time course of clean-catch urine samples collected from nonhuman primates (n = 6 per cohort) exposed to sham, 1.0, 3.5, 6.5 or 8.5 Gy doses of 60Co γ ray (∼0.55 Gy/min) ionizing radiation. By multivariate data analysis, 13 biomarkers of radiation were discovered: N-acetyltaurine, isethionic acid, taurine, xanthine, hypoxanthine, uric acid, creatine, creatinine, tyrosol sulfate, 3-hydroxytyrosol sulfate, tyramine sulfate, N-acetylserotonin sulfate, and adipic acid. N-Acetyltaurine, isethionic acid, and taurine had previously been identified in rats, and taurine and xanthine in mice after ionizing radiation exposure. Mass spectrometry-based metabolomics has thus successfully revealed and verified urinary biomarkers of ionizing radiation exposure in the nonhuman primate for the first time, which indicates possible mechanisms for ionizing radiation injury.
Estimation of the survival fractions of cells irradiated with various particles over a wide linear energy transfer (LET) range is of great importance in the treatment planning of charged-particle therapy. Two computational models were developed for estimating survival fractions based on the concept of the microdosimetric kinetic model. They were designated as the double-stochastic microdosimetric kinetic and stochastic microdosimetric kinetic models. The former model takes into account the stochastic natures of both domain and cell nucleus specific energies, whereas the latter model represents the stochastic nature of domain specific energy by its approximated mean value and variance to reduce the computational time. The probability densities of the domain and cell nucleus specific energies are the fundamental quantities for expressing survival fractions in these models. These densities are calculated using the microdosimetric and LET-estimator functions implemented in the Particle and Heavy Ion Transport code System (PHITS) in combination with the convolution or database method. Both the double-stochastic microdosimetric kinetic and stochastic microdosimetric kinetic models can reproduce the measured survival fractions for high-LET and high-dose irradiations, whereas a previously proposed microdosimetric kinetic model predicts lower values for these fractions, mainly due to intrinsic ignorance of the stochastic nature of cell nucleus specific energies in the calculation. The models we developed should contribute to a better understanding of the mechanism of cell inactivation, as well as improve the accuracy of treatment planning of charged-particle therapy.
In accidental exposure to ionizing radiation, it is essential to estimate the dose received by the victims. Currently dicentric scoring is the best biological indicator of exposure. The standard biological dosimetry procedure (500 metaphases scored manually) is suitable for a few dose estimations, but the time needed for analysis can be problematic in the case of a large-scale accident. Recently, a new methodology using automatic detection of dicentrics has greatly decreased the time needed for dose estimation and preserves the accuracy of the estimation. However, the capability to detect nonhomogeneous partial-body exposures is an important advantage of dicentric scoring-based biodosimetry, and this remains to be tested with automatic scoring. Thus we analyzed the results obtained with in vitro blood dilutions and in real cases of accidental exposure (partial- or whole-body exposure) using manual scoring and automatic detection of dicentrics. We confirmed that automatic detection allows threefold quicker dicentric scoring than the manual procedure with similar dose estimations and uncertainty intervals. The results concerning partial-body exposures were particularly promising, and homogeneously exposed samples were correctly distinguished from heterogeneously exposed samples containing 5% to 75% of blood irradiated with 2 Gy. In addition, the results obtained for real accident cases were similar whatever the methodology used. This study demonstrates that automatic detection of dicentrics is a credible alternative for recent and acute cases of whole- and partial-body accidental exposures to ionizing radiation.
Lene H. S. Veiga, Jay H. Lubin, Harald Anderson, Florent de Vathaire, Margaret Tucker, Parveen Bhatti, Arthur Schneider, Robert Johansson, Peter Inskip, Ruth Kleinerman, Roy Shore, Linda Pottern, Erik Holmberg, Michael M. Hawkins, M. Jacob Adams, Siegal Sadetzki, Marie Lundell, Ritsu Sakata, Lena Damber, Gila Neta, Elaine Ron
Childhood cancer five-year survival now exceeds 70–80%. Childhood exposure to radiation is a known thyroid carcinogen; however, data are limited for the evaluation of radiation dose-response at high doses, modifiers of the dose-response relationship and joint effects of radiotherapy and chemotherapy. To address these issues, we pooled two cohort and two nested case-control studies of childhood cancer survivors including 16,757 patients, with 187 developing primary thyroid cancer. Relative risks (RR) with 95% confidence intervals (CI) for thyroid cancer by treatment with alkylating agents, anthracyclines or bleomycin were 3.25 (0.9–14.9), 4.5 (1.4–17.8) and 3.2 (0.8–10.4), respectively, in patients without radiotherapy, and declined with greater radiation dose (RR trends, P = 0.02, 0.12 and 0.01, respectively). Radiation dose-related RRs increased approximately linearly for <10 Gy, leveled off at 10–15-fold for 10–30 Gy and then declined, but remained elevated for doses >50 Gy. The fitted RR at 10 Gy was 13.7 (95% CI: 8.0–24.0). Dose-related excess RRs increased with decreasing age at exposure (P < 0.01), but did not vary with attained age or time-since-exposure, remaining elevated 25 years after exposure. Gender and number of treatments did not modify radiation effects. Thyroid cancer risks remained elevated many decades following radiotherapy, highlighting the need for continued follow up of childhood cancer survivors.
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