Low Dose Rate Irradiation Research Articles

MDM2-p53 mediate a miR-181c-3p/LIF axis to regulate low dose-rate radiation-induced DNA damage in human B lymphocytes

PurposeProlonged exposure to low dose-rate radiation (LDRR) is of growing concern to public health. Recent evidences indicates that LDRR causes deleterious health effects and is closely related to miRNAs. The aim of our study is to investigate the relationship between miRNAs and DNA damage caused by LDRR. Materials and methodsIn this study, we irradiated C57BL/6J mice with 12.5μGy/h dose of γ ray emitted from uranium ore for 8 h a day for 120 days at a total dose of 12 mGy, and identified differentially expressed miRNAs from the mice long-term exposed to LDRR through isolating serum RNAs, constructing small RNA library, Illumina sequencing. To further investigate the role of differential miRNA under LDRR，we first built DNA damage model in Immortal B cells irradiated with 12.5μGy/h dose of γ ray for 28 days at a total dose of 9.4 mGy. Then, we chose the highly conserved miR-181c-3p among 12 miRNA and its mechanism in alleviating DNA damage induced by LDRR was studied by transfection, quantitative PCR, luciferase assay, and Western blot. Results and conclusionsWe have found that 12 differentially expressed miRNAs including miR-181c-3p in serum isolated from irradiated mice. Analysis of GO and KEGG indicated that target genes of theses 12 miRNA enriched in pathways related to membrane, protein binding and cancer. Long-term exposure to LDRR induced upregulation of gamma-H2A histone family member X (γ-H2AX) expression, a classical biomarker for DNA damage in B cells. miR-181c-3p inhibited Leukemia inhibitory factor (LIF) expression via combining its 3‘UTR. LIF, MDM2, p53, and p-p53-s6 were upregulated after exposure to LDRR. In irradiated B cells, Transfection of miR-181c-3p reduced γ-H2AX expression and suppressed LIF and MDM2 protein levels, whereas p-p53-s6 expression was increased. As expected, the effect of LIF inhibition on irradiated B cells was similar to miR-181c-3p overexpression. Our results suggest that LDRR alters miRNA expression and induces DNA damage. Furthermore, miR-181c-3p can alleviate LDRR-induced DNA damage via the LIF/MDM2/p-p53-s6 pathway in human B lymphocytes. This could provide the basis for prevention and treatment of LDRR injury.

Optimization of Radiation Exposure when Examining Patients with Pathology of the Craniovertebral Region

The diagnostics are based on the principle of obtaining informative and high-quality images with minimal radiation exposure using radiation diagnostic methods: traditional radiography, multislice and cone-beam computed tomography.When conducting X-ray examinations, the main factors in reducing the risk of radiation exposure are the use of highly sensitive digital diagnostic image receivers, minimal exposure time, and a minimum number of images per examination. A lower current value and high anode voltage values, a minimum focal spot size, the placement of the tube as far as possible from the patient and the image receiver as close to the patient as possible, collimation of the radiation beam, and preference for a low radiation dose rate mode are also factors in reducing the risk of radiation exposure.Imaging of the craniovertebral region using cone beam computed tomography offers the opportunity to evaluate the bone structure of the region in detail, with an equal or less effective dose to the patient.

Low dose rate radiation impairs early follicles in young mice

Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly employed low-dose radiation delivered at a high dose rate on the ovary, the effect of low-dose radiation at a low dose rate on the ovary remains unknown. We investigated the effect of low-dose ionizing radiation delivered at a low dose rate on murine ovaries. Three- and ten-week-old mice were exposed to 0.1 and 0.5 Gy of radiation at a rate of 6 mGy/h and monitored after 3 and 30 days. While neither body weight nor ovarian area showed significant changes, ovarian cells were damaged, showing apoptosis and a decrease in cell proliferation after exposure to 0.1 and 0.5 Gy radiation. Follicle numbers decreased over time in both age groups proportionally to the radiation dose. Younger mice were more susceptible to radiation damage, as evidenced by decreased follicles in 3-week-old mice after 30 days of 0.1 Gy exposure, while 10-week-old mice showed reduced follicles only following 0.5 Gy exposure. Primordial or primary follicles were the most vulnerable to radiation. These findings suggest that even low-dose radiation, delivered at a low dose rate, can adversely affect ovarian function, particularly in the early follicles of younger mice.

Impacts of Combining Pulsed Low Dose Rate Radiotherapy (PLDR) and Anti-PD-1 Antibody on Tumor Growth and Its Mechanism for Lung Cancer in Mice

As an emerging anti-tumor strategy, Immunotherapies has been approved for the treatment of a variety of tumors. Recent data suggest that the efficacy of radiotherapy in various cancers can be augmented when combined with immune checkpoint blockade. Then, pulsed low dose rate radiotherapy (PLDR) is a new radiotherapy segmentation method. Therefore, this study investigated the inhibitory effect of PLDR combined with anti-PD-1 antibody on lung cancer in mice and its impact on tumor immune microenvironment. By transplanting murine LLC cells into the right leg of C57BL/6 mice with immune activity, a transplanted subcutaneous tumor model was established. The mice were randomly divided into five groups: control, conventional radiotherapy (RT)±anti-PD-1 antibody (mAb),PLDR±anti-PD-1 antibody (mAb). RT was delivered as a dose of 5 × 2 Gy whereas PLDR involved delivering a dose of 2 Gy as 10 pulses of 0.2 Gy, each 3 minutes apart and lasting for 5 days. Anti-PD-1 antibody and isotype control were administered intraperitoneally once every three days at a dose of 5mg/kg, three times in total. The tumor, blood and tumor-draining lymph nodes (TDLNs) were harvested after treatment, and a single cell suspension was prepared for flow cytometry to analyze the changes in the immune microenvironment of the tumor tissue, the expression of PD-L1. PD-1 and the activated systemic immune response; Finally, this study explored a mechanism able to explain the observed synergy of combined therapy. PLDR combined with anti-PD-1 antibody can better inhibit the growth of tumor than RT,PLDR and RT combined group. Survival analysis demonstrated a statistically significant advantage for PLDR+anti-PD-1 than other groups. Median survival with PLDR+anti-PD-1mAb was 63d compared with 54d with RT+anti-PD-1mAb,41d with RT and 40d with PLDR and 33 with control. Meanwhile both RT and PLDR induced up-regulation of PD-L1 expression on tumor surface and PD-1 expression on lymphocytes. Then, the frequency of CD4+,CD8+T cells were higher in the PLDR combined treatment group in tumor blood and draining lymph nodes, and synergistically reduce the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs) than others. Finally, the main reason for the better tumor inhibition effect of PLDR combined group is that it upgrades the number and activity of CD8+T cells in tumor. PLDR combined with anti-PD-1 antibody can result in better tumor growth inhibition and significantly delay the survival time of mice, which was mainly through the cytotoxic T cell-dependent mechanism, meanwhile increasing the infiltration of CD4 + and CD8 +T-cells in tissues.

Moon, Mars and Minds: Evaluating Parkinson’s disease mortality among U.S. radiation workers and veterans in the million person study of low-dose effects

BackgroundRadiation is one of the most important stressors related to missions in space beyond Earth’s orbit. Epidemiologic studies of exposed workers have reported elevated rates of Parkinson’s disease. The importance of cognitive dysfunction related to low-dose rate radiation in humans is not defined. A meta-analysis was conducted of six cohorts in the Million Person Study (MPS) of low-dose health effects to learn whether there is consistent evidence that Parkinson’s disease is associated with radiation dose to brain. Materials and methodsThe MPS evaluates all causes of death among U.S. radiation workers and veterans, including Parkinson’s disease. Systematic and consistent methods are applied to study all categories of workers including medical radiation workers, industrial radiographers, nuclear power plant workers, atomic veterans, and Manhattan Projects workers at the Los Alamos National Laboratory and at Rocky Flats. Consistent methods for all cohorts are used to estimate organ-specific doses and to obtain vital status and cause of death. ResultsThe meta-analysis include 6 cohorts within the MPS, consisting of 517,608 workers and 17,219,001 person-years of observation. The mean dose to brain ranged from 6.9 to 47.6 mGy and the maximum dose from 0.76 to 2.7 Gy. Five of the 6 cohorts revealed positive associations with Parkinson’s disease. The overall summary estimate from the meta-analysis was statistically significant based on 1573 deaths due to Parkinson’s disease. The summary excess relative risk at 100 mGy was 0.17 (95% CI: 0.05; 0.29). ConclusionsParkinson’s disease was positively associated with radiation in the MPS cohorts indicating the need for careful evaluation as to causality in other studies, delineation of possible mechanisms, and assessing possible implications for space travel as well as radiation protection guidance for terrestrial workers.

Measurements of radiation effects in an antifuse FPGA

This paper presents the irradiation and the measurement analysis for a commercial antifuse Field Programmable Gate Array (FPGA) from Microsemi’s Axcelerator family, part number AX250. Following proton and X-ray beam irradiation, at very high dose rate above 1krad/s, the total ionizing dose (TID) first effects were visible around 260 krad (SiO 2), and this threshold value increases at lower radiation dose rates. We expect for most space and accelerator applications that this value will be at least several Mrads, or even that the FPGA might never reach this threshold. At very high radiation dose rates, TID-induced leakage currents were observed in the device. FPGA data were recorded continuously for more than 100 h after each irradiation with a fully operating FPGA. Quantitatively, the room-temperature annealing of the radiation-induced defects leads to a fast decrease of the device leakage current by a factor of 7 in the first 100 h after irradiation. The last measurements done after three months place the currents to within 30% to 70 % relative to the before-irradiation values in case of two tested FPGA. Several firmware configurations were used to test different logic resources and to measure single event upsets (SEUs). An upper limit of SEU logic cross-section was found to be (2.56 ± 0.51) ⋅ 10−13 cm 2/FPGA for dose rates around 1krad/s. SEU cross-section values for RAM blocks have on average a value of (3.72 ± 0.8) ⋅ 10−14 cm 2/bit. The complete list of results is given and the effects are extrapolated to a high-energy physics experiment environment — LHCb RICH at CERN.

Modelled biological effectiveness comparisons of low, high and ultra-high (FLASH) radiation dose rates

This article considers quantitative comparisons of radiation effectiveness across a large range of dose rates, including low (LDR), medium, conventional or high (HDR) and ultra-high (or FLASH) dose rates.For comparisons of different continuous radiotherapy prescriptions, the linear quadratic model was used to derive ‘biological effective dose’ (BED) equations which included time-dependent enzymatic DNA repair in the low to high dose rate range for monophasic or biphasic repair kinetics. In a recent publication, much higher dose rates, associated with increasing overall radioresistance, was thought to be governed by a cube root (or similar) function of dose rate (which expresses the intensification of micro-volumetric linear energy transfer per unit volume and correlates with average inter-track distances) with resultant increases in the apparent α/β ratios. Explicit equations for assessments of BED* (defined as the excess BED beyond the threshold BED) are presented for dose rates ranging from around 0.1–5 × 106 Gy per hr. The method can also be adapted for tumour control comparisons.Graphical presentations are used to determine iso-effective doses of similar BED* values at different dose rates, for specified radiation doses. The threshold BEDs for radio-tolerance reduce in proportion to the change in the α radiosensitivity parameter. For dose rates above the HDR range, the intrinsic α/β ratio, which is independent of dose rate, continues to influence the magnitude of the changes in BED and dose required for a specified bio-effect, but in a modified form.For further research purposes, these tentative methods can provide isoeffective dose estimates to guide radiation use at different dose rates, but require further specific experimental validation. The methods may seem complex and contain many pitfalls. Further research is also required to identify residual enigmas, such as the exact dose rate and dose at which biological FLASH effects begin to operate and to validate these isoeffective dose predictions.

The Effects of Melatonin on the Bladder in the Application of Low and High Dose Rate Radiotherapy in the Abdominopelvic Region in Rats

The Effects of Melatonin on the Bladder in the Application of Low and High Dose Rate Radiotherapy in the Abdominopelvic Region in Rats

Analysis method of cellular stress caused by intermediate dose-rate irradiation using a cell lysate array technique.

Ionizing radiation damages DNA and may lead to the development of cancer. Irradiation also generates reactive oxygen species (ROS) which cause damage to various biological molecules. Relatively low dose-rate irradiation causes less damage. However, the damage and its effects on cell fate are difficult to evaluate. To develop a method to analyze the damage and accompanying changes in physiology in cells irradiated by γ-rays at a relatively low dose-rate, we used the protein array technique to quantify marker proteins involved in the stress response and the regulation of cell growth and death. This method enabled efficient analyses of many replicates of experimental data on cell lysate samples. We detected relatively small changes in the levels of these proteins in the irradiated cells. Changes in protein levels suggested ROS production and DNA damage as well as cell cycle retardation and the progression of cellular senescence. Thus, our approach shows promise for analyzing the biological effects of relatively low dose-rate irradiation.

Radiobiologie de la radiothérapie interne vectorisée

With several specialities approved by EMA in the last years, targeted radionuclide therapy (TRT) is undergoing a strong development and treat more and more patients. Compared to previously approved radiopharmaceuticals (e.g. Zevalin™), treatments are now fractionated (several injections) and spread over several months. The absorbed dose and absorbed dose rate, the genetic and/or epigenetic characteristics of the tumours, but also the intercellular communications such as those involving the immune system, are becoming the key parameters to be considered in order to improve the effectiveness of the treatment while protecting healthy tissue. Radiobiology, using both preclinical models and a growing number of available clinical data, should provide rational insight into both the efficacy and toxicity of this continuous low dose rate radiotherapy form for better patient management.

Transcriptomic Profiling and Pathway Analysis of Mesenchymal Stem Cells Following Low Dose-Rate Radiation Exposure.

Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic Radiation Syndrome (CRS), which can alter environmental sensitivity. Secondary effects of chronic low dose-rate radiation exposure include circulatory, digestive, cardiovascular, and neurological diseases, as well as cancer. Here, we investigated 1-2 Gy, 0.66 cGy/h, 60Co radiation effects on primary human mesenchymal stem cells (hMSC). There was no significant induction of apoptosis or DNA damage, and cells continued to proliferate. Gene ontology (GO) analysis of transcriptome changes revealed alterations in pathways related to cellular metabolism (cholesterol, fatty acid, and glucose metabolism), extracellular matrix modification and cell adhesion/migration, and regulation of vasoconstriction and inflammation. Interestingly, there was increased hypoxia signaling and increased activation of pathways regulated by iron deficiency, but Nrf2 and related genes were reduced. The data were validated in hMSC and human lung microvascular endothelial cells using targeted qPCR and Western blotting. Notably absent in the GO analysis were alteration pathways for DNA damage response, cell cycle inhibition, senescence, and pro-inflammatory response that we previously observed for high dose-rate radiation exposure. Our findings suggest that cellular gene transcription response to low dose-rate ionizing radiation is fundamentally different compared to high-dose-rate exposure. We hypothesize that cellular response to hypoxia and iron deficiency are driving processes, upstream of the other pathway regulation.

A pixelated liquid perovskite array for high-sensitivity and high-resolution X-ray imaging scintillation screens.

Scintillators with high spatial resolution at a low radiation dose rate are desirable for X-ray medical imaging. A low radiation dose rate can be achieved using a sufficiently thick scintillator layer to absorb the incident X-ray energy completely, however, often at the expense of low spatial resolution due to the issue of optical crosstalk of scintillation light. Therefore, to achieve high sensitivity combined with high-resolution imaging, a thick scintillator with perfect light guiding properties is in high demand. Herein, a new strategy is developed to address this issue by embedding liquid scintillators into lead-containing fiber-optical plates (FOPs, n = 1.5) via the siphon effect. The liquid scintillator is composed of perovskite quantum dots (QDs)/2,5-diphenyloxazole (PPO) and the non-polar high-refractive index (n = 1.66) solvent α-bremnaphthalene. Benefiting from the pixelated and thickness-adjustable scintillators, the proposed CsPbBr3 QDs/PPO liquid scintillator-based X-ray detector achieves a detection limit of 79.1 μGy s-1 and a spatial resolution of 4.6 lp mm-1. In addition, it displays excellent tolerance against radiation (>34 h) and shows outstanding stability under ambient conditions (>160 h). This strategy could also be applied to other liquid scintillators (such as CsPbCl3 QDs and Mn:CsPbCl3 QDs). The combination of high sensitivity, high spatial resolution and stability, easy fabrication and maintenance, and a reusable substrate matrix makes these liquid scintillators a promising candidate for practical X-ray medical imaging applications.

Mechanisms and Models for the Suppressed Defect Dynamics in SiO2–Si Structures under High‐To‐Low Switched Dose Rate Irradiations

Ionizing‐irradiation of Si electronic devices usually occurs under variable dose rate environments such as in the outer space. It is generally accepted that the defect dynamics in SiO2–Si structures under high‐to‐low switched dose rate (SDR) irradiation are independent, although they are different. Herein, it is clearly demonstrated that this is not true, especially for thick oxide layers. By studying the recombination rates on the oxygen vacancies of dimer and puckered configurations in SiO2, three new mechanisms under SDR irradiation are found: the low‐dose‐rate (LDR) irradiation induces a transformation of high‐dose‐rate (HDR) induced “old” centers to extra electric dipoles, which in turn significantly suppresses both the generation and conversion dynamics of “new” and P b centers under LDR irradiation. An analytic model is derived based on these new mechanisms and can consistently explain the data in the literature, which although displays remarkable nonlinearity and ripples as a function of the irradiation dose. The feasibility of the SDR technology is revisited based on these new findings, and the origin of the limitation for thick oxide layers is clarified.

Biological Effects of Low Dose and Low Dose Rate Radiation

Biological Effects of Low Dose and Low Dose Rate Radiation

LOW DOSE-RATE RADIATION-SPECIFIC ALTERATIONS FOUND IN A GENOME-WIDE GENE EXPRESSION ANALYSIS OF THE MOUSE LIVER.

Life span shortening and increased incidences of cancer and non-cancer diseases were observed in B6C3F1 mice irradiated with gamma-rays at a low dose-rate (LDR) of 20mGy/d for 400d. A genome-wide gene expression profiling of livers from mice irradiated at a LDR (20mGy/d, 100-400d) was performed. LDR radiation affected specific pathways such as those related to lipid metabolism, e.g. 'Cholesterol biosynthesis' and 'Adipogenesis' in females irradiated for 200 and 300d at 20mGy/d, with increased expression of genes encoding cholesterol biosynthesis enzymes (Cyp51, Sqle, Fdps) as age and radiation dose increased. No significant alterations in the expression of these genes were observed in male mice exposed similarly. However, the genes encoding adipogenesis regulators, Srebf1 and Pparg, increased with age and radiation dose in both sexes. Comparison between LDR-irradiated and medium dose-rate (400mGy/d) male mice revealed quite different gene expression profiles. These results seem to be consistent with the increased incidence of fatty liver and obesity in female mice exposed to LDR radiation and suggest that metabolism is an important target of LDR radiation.

COMPARISON OF THE PROLIFERATIVE RESPONSES OF HEMATOPOIETIC STEM CELLS EXPOSED TO LOW DOSE RATE RADIATION IN VIVO AND EX VIVO.

The hematopoietic stem cells (HSCs) are sensitive to radiation. Chronic exposure to low dose rate (LDR) radiation at 20mGy/day results in a decrease in the number of HSCs and an increase of leukemia. In this study, the proliferative capacities of ex vivo HSCs, exposed to 20mGy/day of gamma-rays for 20days, were compared with those of in vivo HSCs from similarly whole-body-irradiated mice. Radiation suppressed the growth of the ex vivo HSCs after Day 16 of irradiation and until Day 7 post-exposure. Almost all types of cells, particularly multipotent progenitors, common myeloid progenitors, granulocytes and macrophages, were significantly reduced in number at Day 20 of irradiation and Day 7 post-exposure in culture. HSCs and multipotent progenitors irradiated in vivo, however, decreased transiently and recovered by Day 7 post-exposure. These findings suggest that the microenvironment in vivo protects HSCs from the effects of LDR radiation.

ADAPTIVE RESPONSE IN MICE CONTINUOUSLY IRRADIATED WITH LOW DOSE-RATE RADIATION.

Previous reports showed a reduction in hematopoietic death in mice exposed to a high (challenge) radiation dose if exposed two weeks prior with a relatively small (priming) radiation dose (0.3-0.5Gy). This in vivo acquisition of radioresistance, known as "adaptive response" or the "Yonezawa effect," was shown in the experiments performed using high dose-rates (HDR) for priming. In the present study, we used low (LDR) and medium dose-rates (MDR) of radiation for priming in male C57BL mice. A total dose of 0.45-0.46Gy (LDR, 20mGy/day×23days or MDR, 18mGy/hour×25hours) was used for priming, and was followed by challenge exposure 12days later at an HDR (0.8Gy/min) to a total dose of 6.75Gy. Increased survival rates were observed in mice exposed to priming radiation delivered at LDR or MDR, suggesting that the adaptive responses induced are comparable with those induced at HDR.

COMBINED ANALYSIS OF CANCER INCIDENCE AND LIFESPAN IN MICE EXPOSED TO CHRONIC LOW DOSE RATE RADIATION.

The authors performed a combined analysis using the data obtained from continuous low dose rate irradiation experiments on mice conducted at the Institute for Environmental Sciences, namely, cancer incidence data and lifespan data. They estimated the length of cancer progression period, which is difficult to assess experimentally. The combined analysis showed that the mean cancer progression period is 173d in the control group and 103d in the irradiated group.

EXPERIMENTAL STUDIES AT THE IES ON THE BIOLOGICAL EFFECTS OF CHRONIC LOW DOSE-RATE RADIATION EXPOSURE IN MICE.

Research in the Department of Radiobiology at the Institute for Environmental Sciences (IES) has focused mainly on the biological effects of long-term low dose-rate radiation exposure on mice since its establishment 30y ago. The IES has exposed thousands of mice of various strains, to gamma-rays, mostly chronically, at low dose-rates of 0.05, 1, 20 or 100mGy/d, at medium dose-rates of 200 or 400mGy/d or at acute high dose-rates of 0.7-0.9Gy/min. The dose-rate 0.05mGy/d is comparable with the dose limit for radiation workers of 100mSv/5y. The results will be presented based on the parameters examined at various endpoints such as life span, neoplasm (cancer incidence), chromosome aberrations frequencies, alterations in mRNA levels, tumour transplantability and developmental abnormalities after in utero exposures. The results from research collaborations with universities and institutions both domestic (within Japan) and international will be presented. Lastly, an outline of experiments (e.g. juvenile exposure, low dose tritium exposures) and projects (e.g. radiobiology archives) currently in progress and future research perspectives will be described.

ON RADIATION-INDUCED AGING: ACCELERATED OR PREMATURE AGING.

The concept of radiation-induced aging is revisited from the viewpoint of a mathematical model. The effect of radiation on carcinogenesis is treated based on the Armitage-Doll multi-stage theory. The formula obtained for cancer incidence rate indicates that radiation dose can be explained in terms of time. Radiation-induced aging for acute and chronic exposures is described using age-specific cancer incidence rates as a measure of aging. It shows that accelerated aging is related to the dose rate, whereas premature aging is related to the cumulative dose, providing a simple and natural interpretation of radiation-induced aging. The usefulness of this approach is demonstrated by applying the formula to cancer prevalence data from mice chronically exposed to low dose-rate radiation.