Radiation research最新文献

Radiological nuclear scenarios remain a persistent threat due to civil use and military possession of radiation sources. Therefore, it is crucial to be prepared for events involving a large number of patients exposed to radiation. In such cases, it is important to quickly and simply predict whether potential patients will develop severe, mild, or no Acute Radiation Syndrome (ARS). To address this challenge, the Bundeswehr Institute of Radiobiology developed the H-module, a prediction module that estimates the severity of ARS based on peripheral blood cell counts in the context of an exposure event. For accurate predictions, correct blood counts, especially lymphocyte and granulocyte counts, are essential. Mobile hematology analyzers (HA) are a possible portable and easy-to-learn solution for assessing patient blood counts. These analyzers use impedance measurements to identify cell populations, with cell volume primarily responsible for providing differential blood cell counts. We investigated the influence of alterations in leukocyte size after irradiation on the performance of this method. Whole blood samples from healthy donors were irradiated with different doses (0, 1, and 5 Gy). The samples were analyzed after 0, 1, 6, and 24 h post-irradiation. At each time point, a blood count was performed using impedance measurements via HA, and in parallel, a differential blood count of white blood cells (WBC) was performed using imaging-based flow cytometry. Lymphocytes and granulocytes were differentiated using CD15, CD3, and CD19 markers, by their different side scatter, and by their size in brightfield mode. In addition, peripheral blood mononuclear cells were monitored using a live-cell imaging system equipped with image acquisition and cell size measurement. The HA indicated a discrete increase in the lymphocyte fraction when blood counts were performed 24 h after irradiation, whereas at earlier time points, all WBC fractions remained comparable between both methods. These findings demonstrate that morphological changes in WBC do not impair the ability of the device to distinguish granulocytes from lymphocytes, provided that measurements are performed promptly. However, after 24 h, a reduction in cell size, due to delayed handling of the samples, resulted in an artificial increase in the lymphocyte fraction, potentially masking the lymphocyte depletion characteristic of H-ARS. Thus, timely sample processing when using a HA is essential to ensure diagnostic accuracy.

Hyper-radiosensitivity refers to increased cellular sensitivity at low doses of ionizing radiation and is not accurately captured by classical radiobiological models. Although predominantly studied in the context of low-LET radiation, such as photons, its behavior under high-LET conditions remains less well characterized. In this work, we introduce an analytical formulation of the minimum mutation load (MML) model. This model explains hyper-radiosensitivity and induced radioresistance as a self-protective tissue strategy that minimizes long-term mutational burden by selectively eliminating heavily damaged cells. Overall cell survival can then be modeled as the product of two independent mechanisms: conventional radiation-induced cell killing, described by the linear-quadratic (LQ) model, and programmed cell death, governed by mutation load minimization, as captured by the MML framework. To extend the model to high-LET radiation, we integrate the local effect model (LEM), which predicts the LET dependence of both cell survival and mutation induction. This combined approach is applied to a curated dataset of 93 experimental survival curves and validated against ion irradiation data for helium and carbon ions. A key result is the progressive compression of hyper-radiosensitivity and induced radioresistance with increasing LET, where the characteristic transition from increased to decreased cell survival at low doses shifts to an initial steeper decline in survival without recovery. Because low-dose ion irradiation data remain scarce, we discuss the model assumptions considering corresponding biological evidence.

A cohort mortality study was conducted of 123,401 industrial radiographers in the United States to estimate risks following protracted radiation exposures. The cohort was constructed from the Nuclear Regulatory Commission Radiation Exposure Information Reporting System and the Landauer, Inc. dosimetry databases. Workers were monitored between 1939 and 2011 and were exposed mainly to external gamma radiation from 192Ir and 60Co. Causes of death were obtained from the National Death Index and state mortality files with follow-up through 2019. The mean duration of follow-up was 27.7 years. Nearly 19% of workers were monitored for more than 10 years. There were 30,617 (24.8%) who worked at shipyards and 5,071 (4.1%) at nuclear power plants with the potential for asbestos exposure. The mean radiation dose to the red bone marrow (RBM) was 15.2 mGy (maximum 1.24 Gy; percent >100 mGy was 3.6%), 17.2 mGy to lung, 18.1 mGy to colon, 11.9 mGy to brain, and 18.1 mGy to heart. Overall, 30,537 deaths occurred; the Standardized Mortality Ratio and 95% confidence interval for all-cause mortality was 0.92 (0.91, 0.93); for all solid cancers 1.01 (0.99, 1.03; n = 7,734); for ischemic heart disease (IHD) 0.83 (0.81; 0.85; n = 5,820); for cerebrovascular disease (CeVD) 0.88 (0.83, 0.93; n = 1,257); for mesothelioma 6.08 (5.35, 6.89; n = 248); and for asbestosis 13.4 (11.2, 15.9; n = 134). The linear excess relative risk (ERR) per 100 mGy (95% CI) for leukemia (excluding CLL) was 0.45 (0.05, 0.85) and for non-Hodgkin lymphoma (NHL) was 0.33 (0.04; 0.62). For all solid cancers it was 0.06 (0.02, 0.10); lung cancer 0.11 (0.04, 0.19); all solid cancers excluding lung cancer and mesothelioma 0.02 (-0.03, 0.07); Parkinson's disease 0.24 (-0.13, 0.61); IHD -0.03 (-0.06, 0.01); and CeVD 0.05 (-0.08, 0.17). The ERR per 100 mGy for chronic obstructive pulmonary disease (COPD) was 0.19 (0.08, 0.30) and was similar in magnitude to that for lung cancer. This finding suggests that residual confounding by smoking may have influenced the results, warranting cautious interpretations. No significant association was found between cumulative radiation exposure and all solid cancers after excluding lung cancer and mesothelioma, nor for IHD or CeVD. The marginally non-significant increased risk of Parkinson's disease, also seen in other Million Person Study cohorts, requires further investigation. Early workers monitored entirely before 1979 had the same linear ERR per 100 mGy for solid cancers [0.06 (0.00, 0.12) n = 3,587] as for all other more contemporary workers monitored after 1978 [0.07 (0.01,0.13) n = 4,150]. This report provides convincing evidence that low-dose and low-dose-rate exposures over time significantly increases the risk of leukemia (excluding CLL) following cumulative doses up to 200 mGy while also providing information on early versus contemporary workers.

Radiation dose assessment in exposed individuals relies on the dicentric assay, the gold-standard cytogenetic biodosimeter that quantifies radiation-induced chromosomal aberrations. Although fully automated methods have been proposed, their accuracy remains suboptimal for large-scale emergency response. Here, we present a hybrid, semi-automatic framework that couples a deep-learning-based dicentric classifier with expert review. Among 2 000 metaphase images analyzed with a semi-automatic method, the specificity was 99.8%, the accuracy 98.7%, and the area under the curve (AUC) 0.977. For radiation dose estimation, the system achieved a minimal deviation of 9.25% and a maximal deviation of 15%. By integrating rapid AI triage with targeted human confirmation, the platform improves the high throughput required for population-scale triage while preserving the diagnostic rigor demanded by retrospective dose reconstruction.

Radiotherapy may cause acute and late damage to off-target abscopal tissues, and the underlying signaling factors need further exploration. This study aimed to investigate whether local irradiation could induce damage in non-irradiated abscopal lung tissues using a murine model subjected to fractionated irradiation (8 Gy per fraction over three days) targeted to the right lung. It was found that unilateral fractionated thoracic irradiation could induce progressive tissue injury in the contralateral lung. The exclusion of scattered radiation as a contributor to the observed structural injury and acute DNA damage was confirmed. Notably, unilateral fractionated thoracic irradiation increased macrophages with NF-κB activation. Therapeutic inhibition of NF-κB, as well as administration of cimetidine, markedly mitigated radiation-induced pneumonitis and fibrosis in the contralateral lung. These results demonstrate that abscopal lung injury following unilateral irradiation may be driven by increased macrophages, offering novel mechanistic insight and a potential treatment for lung injury associated with thoracic radiotherapy.

Radiation-induced senescence (RIS) is thought to be one mechanism by which tumor cells can survive radiation-induced cell death. Accumulating evidence suggests that therapy-induced senescence (TIS) (triggered by both chemotherapy and/or irradiation) also facilitates tumor cell recovery, thereby contributing to disease recurrence. Furthermore, the factors secreted by senescent tumor cells (the senescence-associated secretory phenotype (SASP)) have, in some cases, been reported to be tumor-promoting, immunosuppressive, and potentially responsible for some of the adverse effects of radiation. Given these largely undesirable attributes of RIS in tumor cells, the use of senolytic agents to eliminate senescent tumor cells has been investigated in preclinical studies. An analysis of the available literature on RIS in cell culture models tends to support the utility of the Bcl-xL/Bcl-2/Bcl-w-targeting agent ABT-263 (navitoclax), in combination with a single high-dose of radiation and, in some cases, with fractionated irradiation. However, because drug action has also been reported when administered prior to irradiation, prior tumor cell entry into senescence may not be obligatory for enhancement of radiation sensitivity by ABT-263. This conclusion is also consistent with drug action against tumor cells with low RIS levels, such as those induced by fractionated irradiation. While a relatively small number of studies in tumor-bearing animals demonstrate the effectiveness of ABT-263 in combination with radiation in vivo, once the drug pressure has been relaxed, the tumor cells likely still retain the capacity to recover proliferative capacity. Since ABT-263 is unlikely to be approved for the clinical treatment of solid tumors due to both on-target (thrombocytopenia) and off-target (neutropenia) toxicities, the few studies indicating improved radiosensitivity with ABT-199 (venetoclax) are intriguing, suggesting that targeting of Bcl-xL may not be a strict requirement for the combination strategy. Finally, it is worth noting that senolytic agents have the potential to protect normal tissue from radiation-induced damage, which may prove to be the most clinically relevant observation for this class of drugs.

The U.S. Radiologic Technologists (USRT) study investigates cancer and other serious disease risks associated with low-dose occupational radiation exposure. The previous dose system (URDS13) for the full cohort was based on badge dose records through 1997, three self-reported questionnaires administered between 1983 and 2005, and historical estimates from the literature. In this article, we describe an extended (23 additional calendar years, 1998-2020), updated and enhanced dosimetry system for the USRT cohort (URDS25). We incorporated 1,156,584 newly acquired annual badge dose readings (1977-2020) obtained by integrating annual summary data (1977-2011) and monthly badge reading data (2004-2020), bringing the total to 1,416,420 annual badge dose readings (1960-2020) for 81,885 technologists. To enhance the individualization of dose estimates, we also utilized detailed work history and protection practice data from the fourth survey, administered in 2012-2013, along with supplementary work history modules for technologists who performed nuclear medicine and assisted with fluoroscopically guided interventional procedures. Based on all badge readings and work history data collected to date, we re-evaluated the URDS13 badge dose estimates prior to 1997 and reconstructed the estimates from 1998 to 2020, resulting in a total of 3.27 million estimated annual badge doses for 110,374 technologists for the years 1916-2020. Each annual badge dose was reconstructed as a probability distribution using Monte Carlo simulation, generating 1,000 realizations to account for uncertainty in the true dose. Compared to the previous version (URDS13, 1916-1997), this update (URDS25, 1916-2020) resulted in a slight increase in the mean cumulative dose estimates for the entire cohort, from 76 mSv (median: 47 mSv; range: 0.19-3,000 mSv) to 79 mSv (median: 48 mSv; range: 0.12-3,000 mSv), and a mean absolute change of the individual cumulative dose estimates of 26% per technologist. Organ absorbed doses will also be updated based on these revised badge dose estimates and detailed, self-reported work history information and, along with updated follow-up data, will be used in future dose-response analyses to more precisely investigate radiation-associated cancer and non-cancer disease risks.

Previous ophthalmological studies among atomic-bomb survivors and other radiation-exposed populations have shown a significant association between radiation exposure and cataract, particularly posterior subcapsular cataract (PSC). However, reports of radiation effects on nuclear and cortical cataract are inconsistent. In the current study, we reexamined the issue of radiation effects on cataractogenesis using modern methods and well-defined diagnostic criteria. A questionnaire on ophthalmologic diseases was obtained from 2,439 atomic bomb survivors who were exposed at age 15 or younger and participated in biennial health examinations between November 2015 and March 2020. 684 participants (28%) had already undergone lens extraction in both eyes, and 930 participants and 1,773 eyes were examined by an ophthalmologist at the Radiation Effects Research Foundation. Of these, 876 participants with at least one eye evaluable for cataracts, comprising 1,658 eyes, were the subject of this analysis. Lens images were photographed using a slit lamp, a Scheimpflug camera, and a retro-illumination camera. Nuclear cataract was diagnosed by Scheimpflug images and cortical cataract, PSC, retrodots, waterclefts, vacuoles and those center lens (VCC) was evaluated by retro-illumination images. Odds ratio (OR) at 1 Gy was calculated by generalized estimating equations logistic regression. A significant association between radiation and PSC and VCC was observed (OR: 1.68, 95% confidence intervals (CI): 1.13, 2.50, OR: 1.28, 95% CI: 1.04, 1.57, respectively). No significant associations were observed for nuclear or cortical cataracts (OR: 1.29, 95%CI: 0.93, 1.79, OR: 0.87, 95%CI: 0.67, 1.13, respectively). For other subtypes (retrodots, waterclefts, and vacuoles), there was also no clear evidence of association with radiation. Radiation effects were observed on PSC and VCC, which is the precursor lesion of PSC, even 70 years after exposure. Long-term observation, particularly in other radiation-exposed populations, may be needed to fully appreciate the relationship between radiation and development of cataract.

Left unmitigated, high-dose ionizing radiation causes DNA damage resulting in cell death and manifestation of the acute radiation syndrome (ARS). Activation of the lysophosphatidic acid receptor subtype 2 (LPAR2) is one mechanism by which radiation damage can be mitigated. Our laboratory has previously developed 5-chloro-2-(N-(4-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)butyl)sulfamoyl)benzoic acid, designated as Radioprotectin-1 (RP-1), which is a potent LPAR2-specific agonist and radiation mitigator. We previously reported that an aqueous (AQ) formulation of RP-1 provides significant survival advantage in a murine gastrointestinal ARS (GI-ARS) model when given in a three-day regimen of twice-daily subcutaneous injections administered starting 24 h after irradiation. To improve the dosing formulation suitable for the field treatment of mass casualties, an extended-release dosing regimen was developed utilizing a water-in-oil-in-water (W/O/W) multilayered microemulsion (ME) formulation. The ME significantly extended plasma half-life, mean residence time, and exposure time while slowing plasma clearance compared to the AQ formulation in C57BL/6J mice as well as in non-human primates (NHP). This formulation provides a significant survival advantage in a GI-ARS model with only two subcutaneous injections at 24 and 72 h postirradiation. Additionally, RP-1 ME treatment protects intestinal crypts in irradiated mice, resulting in an increase in both total and actively regenerating crypts at day 5 postirradiation. Finally, LPAR2 activation by RP-1 leads to prolonged and sustained activation of the pro-survival kinases ERK1/2 and Akt up to 16 h postirradiation and reduces caspase-mediated apoptosis in irradiated mouse embryonic fibroblasts, providing a mechanism for RP-1 radiation mitigation.

Radiation-associated pain (RAP) after head and neck cancer treatment often results in significant discomfort, yet the mechanisms underlying this pain remain poorly understood. Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8) channels, known to mediate cold sensation, have been implicated in RAP. Previous studies suggested that inhibition of TRPM8 might offer a therapeutic approach for alleviating radiation-induced pain. We tested the effects of PBMC, a small molecule inhibitor of TRPM8, on radiation-induced glossitis and associated pain behaviors in C57BL/6J mice following tongue irradiation. We evaluated the impact of phenylethyl(2-aminoethyl)(4-(benzyloxy)-3-methoxybenzyl)carbamate (PBMC) on weight loss, burrowing, grooming behavior, and nest building. Additionally, mRNA expression of TRPM8 and other relevant ion channels was assessed in the trigeminal ganglion (TG) using qRT-PCR and in situ hybridization (ISH). Irradiated mice exhibited significant glossitis, weight loss, and altered behaviors, including impaired burrowing and grooming. PBMC treatment provided no measurable protection against glossitis and only weakly mitigated weight loss and abnormal burrowing behavior. Exposure to radiation led to downregulation of TRPM8 expression in the TG, contrasting with previous findings of upregulation. Interestingly, female mice showed greater susceptibility to RAP than males, highlighting a sex-dependent response. Our findings suggest that TRPM8 inhibition with PBMC does not alleviate radiation-induced pain or glossitis in the C57BL/6J murine model. The observed downregulation of TRPM8 expression challenges prior assumptions, and our results suggest that compensatory mechanisms or model-specific factors may contribute to the failure of PBMC to impact pain outcomes. Future studies incorporating genetic models and evaluating protein expression are necessary to better understand the role of TRPM8 in radiation-induced pain and to explore more effective therapeutic strategies.