The mechanism underlying the carcinogenic potential of α radiation is not fully understood, considering that cell inactivation (e.g., mitotic cell death) as a main consequence of exposure efficiently counteracts the spreading of heritable DNA damage. The aim of this study is to improve our understanding of the effectiveness of α particles in inducing different types of chromosomal aberrations, to determine the respective values of the relative biological effectiveness (RBE) and to interpret the results with respect to exposure risk. Human peripheral blood lymphocytes (PBLs) from a single donor were exposed ex vivo to doses of 0–6 Gy X rays or 0–2 Gy α particles. Cells were harvested at two different times after irradiation to account for the mitotic delay of heavily damaged cells, which is known to occur after exposure to high-LET radiation (including α particles). Analysis of the kinetics of cells reaching first or second (and higher) mitosis after irradiation and aberration data obtained by the multiplex fluorescence in situ hybridization (mFISH) technique are used to determine of the cytogenetic risk, i.e., the probability for transmissible aberrations in surviving lymphocytes. The analysis shows that the cytogenetic risk after α exposure is lower than after X rays. This indicates that the actually observed higher carcinogenic effect of α radiation is likely to stem from small scale mutations that are induced effectively by high-LET radiation but cannot be resolved by mFISH analysis.

The scientific question of whether protracted low-dose or low-dose-rate exposure to external radiation is causally related to the risk of circulatory disease continues to be an important issue for radiation protection. Previous analyses of a matched case-control dataset nested in a large cohort of UK nuclear fuel cycle workers indicated that there was little evidence that observed associations between external radiation dose and ischemic heart disease (IHD) mortality risk [OR = 1.35 (95% CI: 0.99–1.84) for 15-year-lagged exposure] could alternatively be explained by confounding from pre-employment tobacco smoking, BMI or blood pressure, or from socioeconomic status or occupational exposure to excessive noise or shiftwork. To improve causal inference about the observed external radiation dose and IHD mortality association, we estimated the potential magnitude and direction of non-random errors, incorporated sensitivity analyses and simulated bias effects under plausible scenarios. We conducted quantitative bias analyses of plausible scenarios based on 1,000 Monte Carlo samples to explore the impact of exposure measurement error, missing information on tobacco smoking, and unmeasured confounding, and assessed whether observed associations were reliant on the inclusion of specific matched pairs using bootstrapping with 10% of matched pairs randomly excluded in 1,000 samples. We further explored the plausibility that having been monitored for internal exposure, which was an important confounding factor in the case-control analysis for which models were adjusted, was indeed a confounding factor or whether it might have been the result of some form of selection bias. Consistent with the broader epidemiological evidence-base, these analyses provide further evidence that the dose-response association between cumulative external radiation exposure and IHD mortality is non-linear in that it has a linear shape plateauing at an excess risk of 43% (95% CI: 7–92%) on reaching 390 mSv. Analyses of plausible scenarios of patterns of missing data for tobacco smoking at start of employment indicated that this resulted in relatively little bias towards the null in the original analysis. An unmeasured confounder would have had to have been highly correlated (r_p > 0.60) with cumulative external radiation dose to importantly bias observed associations. The confounding effect of “having been monitored for internal dose” was unlikely to have been a true confounder in a biological sense, but instead may have been some unknown factor related to differences over time and between sites in selection criteria for internal monitoring, possibly resulting in collider bias. Plausible patterns of exposure measurement error negatively biased associations regardless of the modeled scenario, but did not importantly change the shape of the observed dose-response associations. These analyses provide additional support for the hypothesis that the observed association between external radiation exposure and IHD mortality may be causal.

Canine soft tissue sarcoma (STS) has served as a preclinical model for radiation, hyperthermia, experimental therapeutics, and tumor microenvironmental research for decades. Stereotactic body radiotherapy (SBRT) demonstrates promising results for the control of various tumors in human and veterinary medicine; however, there is limited clinical data for the management of STS with SBRT. In this retrospective study, we aimed to define overall efficacy and toxicity of SBRT for the treatment of macroscopic canine STS to establish this preclinical model for comparative oncology research. Fifty-two canine patients met inclusion criteria. Total radiation dose prescribed ranged from 20–50 Gy delivered in 1–5 fractions. Median progression-free survival time (PFST) was 173 days and overall survival time (OST) 228 days. Best overall response was evaluable in 46 patients, with 30.4% responding to treatment (complete response n = 3; partial response n = 11). For responders, OST significantly increased to 475 days vs. 201 days (P = 0.009). Prognostic factors identified by multivariable Cox regressions included size of tumor and metastasis at presentation. Dogs were 3× more likely to progress (P = 0.009) or 3.5× more likely to experience death (P = 0.003) at all times of follow up if they presented with metastatic disease. Similarly, every 100-cc increase in tumor volume resulted in a 5% increase in the risk of progression (P = 0.002) and death (P = 0.001) at all times of follow up. Overall, 30.8% of patients developed acute toxicities, 7.7% grade 3; 28.8% of patients developed late toxicities, 11.5% grade 3. Increased dose administered to the skin significantly affected toxicity development. SBRT serves as a viable treatment option to provide local tumor control for canine macroscopic STS, particularly those with early-stage disease and smaller tumors. The results of this study will help to define patient inclusion criteria and to set dose limits for preclinical canine STS trials involving SBRT.

To elucidate the mechanism underlying the failure of root formation after irradiation, we established a method of local irradiation of the molar tooth germ and demonstrated that radiation directly affected dental root development. In the current study, to locally irradiate the lower first molars of 5-day-old C57BL/6J mice, we used lead glass containing a hole as a collimator. We confirmed that our local irradiation method targeted only the tooth germ. The irradiated root was immature in terms of apical growth, and dentin formation was irregular along the outside of the root apices. Moreover, calcified tissue apically surrounded Hertwig's epithelial root sheath, which disappeared abnormally early. This method using a local irradiation experimental model will facilitate research into radiation-induced disorders of dental root formation.

The mechanism(s) of vascular regression in adult organs remains an unexplored gap. Irradiation to the kidney results in vascular regression and renal failure. The goal of this work was to determine molecular mechanism(s) of radiation-induced vascular regression and its mitigation by the drug lisinopril. Female WAG/RijCmcr rats received either 13 Gy X-ray irradiation, sparing one leg, or no irradiation, the latter serving as age-matched controls. Some irradiated animals received lisinopril. Kidney miRNA-seq was performed 35 days postirradiation, before symptoms of nephropathy. MicroRNA expression profiles were compared with data from humans. MicroRNA targets were predicted using TargetScan and confirmed by qRT-PCR and Western blot. Renal vascular endothelial cell density was evaluated at 100 days to confirm vascular regression. The normal rat kidney microRNA profile resembled that of humans. MiR-34a was increased >7-fold and emerged as the predominant rat microRNA altered by radiation. Expression of Jagged1, a ligand in the Notch pathway of vascular development and a target of miR-34a-5p was decreased by radiation but not in irradiated rats receiving lisinopril. Radiation decreased endothelial cells in the kidneys at 100 days, confirming vascular regression. In conclusion, the results of this study showed that radiation greatly increased miRNA34-a in rat kidneys, while lisinopril mitigated radiation-induced decrease of the Notch ligand, Jagged1, a molecular target of miRNA34-a.

Development of a new methodology to induce immunological chimerism after allogeneic hematopoietic cell (HC) transplantation in a rhesus macaque model is described. The chimeric state was achieved using a non-myeloablative, helical tomotherapy-based total lymphoid irradiation (TomoTLI) conditioning regimen followed by donor HC infusions between 1-haplotype matched donor/recipient pairs. The technique was tested as a feasibility study in an experimental group of seven rhesus macaques that received the novel TomoTLI tolerance protocol and HC allo-transplants. Two tomotherapy protocols were compared: TomoTLI (n = 5) and TomoTLI/total-body irradiation (TBI) (n = 2). Five of seven animals developed mixed chimerism. Three of five animals given the TomoTLI protocol generated transient mixed chimerism with no graft-versus-host disease (GVHD) with survival of 33, 152 and >180 days. However, the inclusion of belatacept in addition to a single fraction of TBI resulted in total chimerism and fatal GVHD in both animals, indicating an unacceptable conditioning regimen.

The biological effects and regulatory mechanisms of low-dose and low-dose-rate radiation are still rather controversial. Therefore, in this study we investigated the effects of low-dose-rate radiation on zebrafish neurodevelopment and the role of miRNAs in radiation-induced neurodevelopment. Zebrafish embryos received prolonged gamma-ray irradiation (0 mGy/h, 0.1 mGy/h, 0.2 mGy/h, 0.4 mGy/h) during development. Neurodevelopmental indicators included mortality, malformation rate, swimming speed, as well as the morphology changes of the lateral line system and brain tissue. Additionally, spatiotemporal expression of development-related miRNAs (dre-miR-196a-5p, dre-miR-210-3p, dre-miR-338) and miRNA processing enzymes genes (Dicer and Drosha) were assessed by qRT-PCR and whole mount in situ hybridization (WISH). The results revealed a decline in mortality, malformation and swimming speed, with normal histological and morphological appearance, in zebrafish that received 0.1 mGy/h; however, increased mortality, malformation and swimming speed were observed, with pathological changes, in zebrafish that received 0.2 mGy/h and 0.4 mGy/h. The expression of miRNA processing enzyme genes was altered after irradiation, and miRNAs expression was downregulated in the 0.1 mGy/h group, and upregulated in the 0.2 mGy/h and 0.4 mGy/h groups. Furthermore, ectopic expression of dre-miR-210-3p, Dicer and Drosha was also observed in the 0.4 mGy/h group. In conclusion, the effect of low-dose and low-dose-rate radiation on neurodevelopment follows the threshold model, under the regulation of miRNAs, excitatory effects occurred at a dose rate of 0.1 mGy/h and toxic effects occurred at a dose rate of 0.2 mGy/h and 0.4 mGy/h.

Radiotherapy is an important method for the treatment of malignant tumors. It can directly or indirectly lead to the formation of free radicals and DNA damage, resulting in a series of biological effects, including tumor cell death and normal tissue damage. These radiation effects are typically accompanied by the abnormal expression of sirtuin 1 (Sirt1), which deacetylates histones and non-histones. These Sirt1 substrates, including transcription factors and some catalytic enzymes, play a crucial role in anti-oxidative stress, DNA damage repair, autophagy regulation, anti-senescence, and apoptosis, which are closely related to triggering cell defense and survival in radiation-induced damage. In this article, we review the mechanisms underlying cellular responses to ionizing radiation and the role of Sirt1 in the process, with the aim of providing a theoretical basis for protection against radiation by Sirt1 as well as novel targets for developing radioprotective agents.

Recently, a new technology of low-energy ultrashort-pulsed electron beam (UPEB) accelerators has been developed opening new directions for radiobiology and biomedical research. The purpose of this study was to reveal the lethal dose, LD50 (lethal dose, 50%) delivered by low-energy UPEB whole-body exposure on an organismal level. Wistar rats were exposed to low-energy UPEB whole-body irradiation with different doses and pulse repetition rates to find the LD50 and in silico computer simulations were performed to conduct numerical dose calculations. Survival rate, body weight and water consumption were monitored over the 30-day observation period postirradiation. The LD50 was observed after a 2 Gy dose and pulse repetition rate of 2 Hz. In this group, 50% of the animals survived 30 days postirradiation. The groups of animals exposed to low-energy UPEB radiation at higher doses and pulse repetition rates demonstrated higher mortality rates. We demonstrated that the LD50 dose for the low-energy UPEB whole body irradiation in Wistar rats corresponds to 2 Gy with a pulse repetition rate of 2 Hz. Moreover, we showed that the pulse repetition rate is a very important parameter in the experiments with UPEB and should be assessed in the experiments with such kind of novel irradiation sources.

Treatment of accidental radiation-induced myelosuppression is primarily based on supportive care and requires specific treatment based on hematopoietic growth factors injection or hematopoietic cell transplantation for the most severe cases. The cytokines used consisted of pegylated erythropoietin (darbepoetin alfa) 500 IU once per week, pegylated G-CSF (pegfilgrastim) 6 mg × 2 once, stem cell factor 20 µg.kg^–1 for five days, and romiplostim (TPO analog) 10 µg.kg ^–1 once per week, with different combinations depending on the accidents. As the stem cell factor did not have regulatory approval for clinical use in France, the French regulatory authorities (ANSM, formerly, AFSSAPS) approved their compassionate use as an investigational drug “on a case-by-case basis”. According to the evolution and clinical characteristics, each patient's treatment was adopted on an individual basis. Daily blood count allows initiating G-CSF and SCF delivery when granulocyte <1,000/mm³, TPO delivery when platelets <50,000/mm³, and EPO when Hb<80 g/L. The length of each treatment was based on blood cell recovery criteria. The concept of “stimulation strategy” is linked to each patient's residual hematopoiesis, which varies among them, depending on the radiation exposure's characteristics and heterogeneity. This paper reports the medical management of 8 overexposed patients to ionizing radiation. The recovery of bone marrow function after myelosuppression was accelerated using growth factors, optimized by multiple-line combinations. Particularly in the event of prolonged exposure to ionizing radiation in dose ranges inducing severe myelosuppression (in the order of 5 to 8 Gy), with no indication of hematopoietic stem cell transplantation.

Stem cell responses in tissues after exposure to radiation are of significance for maintaining tissue functions. From the point of view of stem cell characteristics, this article seeks to illustrate some contributions of microbeam research to spatially fractionated radiotherapy (SFRT), such as grid radiotherapy and microbeam radiotherapy. Although the tissue-sparing response after SFRT was first reported more than a century ago, current radiation dose–volume metrics are still unable to accurately predict such tissue-level changes in response to spatially fractionated radiation fields. However, microbeam approaches could contribute to uncovering the mechanisms of tissue response, significantly improving the outcomes of SFRT and reducing its adverse effects. Studies with microbeams have shown that the testicular tissue-sparing effect for maintaining spermatogenesis after exposure to spatially fractionated radiation depends on biological parameters, such as the radiation dose distribution at the microscale level for tissue-specific stem cells and the microenvironment, or niche. This indicates that stem cell survival, migration, and repopulation are involved in the tissue-level changes during or after SFRT. The illustration of microbeam applications in this article focuses on the stem cell migration as a possible mechanism of the tissue-sparing effect for preserving functionality.

Exposure to high dose radiation causes life-threatening acute and delayed effects. Defining the mechanisms of lethal radiation-induced acute toxicity of gastrointestinal and hematopoietic tissues are critical steps to identify drug targets to mitigate and protect against the acute radiation syndrome (ARS). For example, one rational approach would be to design pharmaceuticals that block cell death pathways to preserve tissue integrity in radiation-sensitive organ systems including the gastrointestinal tract and hematopoietic compartment. A previous study reported that the inflammasome pathway, which mediates inflammatory cell death through pyroptosis, promotes ARS. However, we show that mice lacking the inflammatory executioner caspases, caspase-1 and caspase-11, are not protected from ARS when compared directly to littermates expressing caspase-1 and caspase-11. These results suggest that alternative pathways will need to be targeted by drugs that successfully mitigate and protect against the ARS.