Radiation worker studies provide direct estimates of cancer risk after protracted low-dose exposures to external X-ray and gamma-ray irradiations. The National Registry for Radiation Workers (NRRW) started in 1976 and has become the largest epidemiological program of research on nuclear workers in the UK. Here, we report on the relationship between solid cancer incidence and external radiation at the low-dose levels in 172,452 NRRW cohort members of whom (90%) were men. This study is based on 5.25 million person-years of follow-up from 1955 through the end of 2011. In the range of accumulated low doses two-thirds of workers have doses of less than 10 mSv. This study is an updated analysis of solid cancer incidence data with an additional 10 years of follow-up over the previous analysis of the NRRW cohort (NRRW-3). A total of 18,310 cases of solid cancers based on a 10-year lag were registered and of these 43% of the solid cancer cases occurred during the latest 10 years. Poisson regression was used to investigate the relationship between solid cancers risk and protracted chronic low-dose radiation exposure. This study demonstrated for solid cancers a rapid decrease of risk at high external doses that appeared to be driven by the workers who were monitored for potential exposure to internal emitters and who had also received relatively high external doses. Among cohort members only exposed to external radiation, a strong association was found between external dose and solid cancers (ERR/Sv = 0.52, 95% CI: 0.11; 0.96, based on 13,199 cases). A similar pattern is also seen for lung cancer. Excluding lung cancer from the grouping of all solid cancers resulted in evidence of a linear association with external radiation dose (ERR/Sv = 0.24, 95% CI: 0.01; 0.49, based on 15,035 cases), so suggesting some degree of confounding by smoking. Statistically significantly increasing trends with dose were seen for cancers of the colorectal, bladder and pleura cancer. Some of these results should be treated with caution because of the limited corroborating evidence from other published studies. Information on internal doses as well as non-radiation factors such smoking would be helpful to make more definitive inferences.

Radiation biodosimetry based on transcriptomic analysis of peripheral blood is a valuable tool to detect radiation exposure after a radiological/nuclear event and obtain useful biological information that could predict tissue and organismal injury. However, confounding factors, including chronic inflammation or immune suppression, can potentially obscure the predictive power of the method. Members of the p38 mitogen-activated protein kinase (MAPK) family respond to pro-inflammatory signals and environmental stresses, whereas genetic ablation of the p38 signaling pathway in mice leads to reduced susceptibility to collagen-induced arthritis and experimental autoimmune encephalomyelitis that model human rheumatoid arthritis and multiple sclerosis, respectively. p38 is normally regulated by the MAP3K-MAP2K pathway in mammalian cells. However, in T cells there is an alternative pathway for p38 activation that plays an important role in antigen-receptor-activated T cells and participates in immune and inflammatory responses. To examine the role of p38 in response to radiation, we used two mouse models expressing either a p38α dominant negative (DN) mutation that globally suppresses p38 signaling or a p38αβ double-knock-in (DKI) mutant, which inhibits specifically T-cell receptor activation. We exposed p38 wild-type (p38WT) and mutant male mice to 7 Gy X rays and 24 h later whole blood was isolated subjected to whole-genome microarray and gene ontology analysis. Irradiation of p38WT mice led to a significant overrepresentation of pathways associated with morbidity and mortality, as well as organismal cell death. In contrast, these pathways were significantly underrepresented in p38DN and p38DKI mutant mice, suggesting that p38 attenuation may protect blood cells from the deleterious effects of radiation. Furthermore, radiation exposure in p38 mutant mice resulted in an enrichment of phagocytosis-related pathways, suggesting a role for p38 signaling in restricting phagocytosis of apoptotic cells after irradiation. Finally, despite the significant changes in gene expression, it was still feasible to identify a panel of genes that could accurately distinguish between irradiated and control mice, irrespective of p38 status.

The proposed mission to Mars will expose astronauts to space radiation that is known to adversely affect cognition and tasks that rely on fine sensorimotor function. Space radiation has also been shown to affect the microglial and neurogenic responses in the central nervous system (CNS). We recently reported that a low dose of 5 cGy 600 MeV/n ²⁸Si results in impaired cognition and skilled motor behavior in adult rats. Since these tasks rely at least in part on the proper functioning of the striatum, we examined striatal microglial cells in these same subjects. Using morphometric analysis, we found that ²⁸Si exposure increased activated microglial cells in the striatum. The majority of these striatal Iba1⁺ microglia were ED1^–, indicating that they were in an alternatively activated state, where microglia do not have phagocytic activity but may be releasing cytokines that could negatively impact neuronal function. In the other areas studied, Iba1⁺ microglial cells were increased in the subventricular zone (SVZ), but not in the dentate gyrus (DG). Additionally, we examined the relationship between the microglial response and neurogenesis. An analysis of new neurons in the DG revealed an increase in doublecortin-positive (DCX⁺) hilar ectopic granule cells (hEGC) which correlated with Iba1⁺ cells, suggesting that microglial cells contributed to this aberrant distribution which may adversely affect hippocampal function. Taken together, these results indicate that a single dose of ²⁸Si radiation results in persistent cellular effects in the CNS that may impact astronauts both in the short and long-term following deep space missions.

Clonogenic assays are the gold standard for measuring cell clonogenic survival and enable quantification of a cell line's radiosensitivity through the calculation of the surviving fraction, the ratio of cell clusters (colonies) formed after radiation exposure compared to the number formed without exposure. Such studies regularly utilize Cs-137 irradiators. While uncertainties for specific procedural aspects have been described previously, a comprehensive review has not been completed. We therefore quantified uncertainties associated with clonogenic assays performed using a Cs-137 Shepherd irradiator, and a recently established brachytherapy afterloader in vitro radiation delivery apparatus (BAIRDA), through a series of experiments and a literature review. The clonogenic assay is subject to uncertainties that affect the determination of the surviving fraction (e.g., accuracy of the number of cells seeded, potential effects of hypothermia, and the threshold number of cells for a cluster to be identified as a colony). Furthermore, dose delivery uncertainties related to both the Cs-137 irradiator and BAIRDA were also quantified. The combined standard (k = 1) uncertainty was ± 6.0% in the surviving fraction for the Cs-137 irradiator (±6.3% for BAIRDA), up to ± 2.2% in the dose delivered by the Cs-137 irradiator, and up to ± 4.3% in the dose delivered by BAIRDA. The largest individual uncertainties were associated with the number of cells seeded on a plate (3.4%) and inter-observer variability in counting (4.1%), suggesting that effective reduction of uncertainties in the conduct of the clonogenic assay may provide the greatest relief on the uncertainty budget. Finally, measurable impact on experimental findings was assessed by applying this uncertainty to clonogenic assays of SW756 cells using either a Cs-137 irradiator or BAIRDA, introducing a maximum shift in the reported radiobiological parameters α/β and T_1/2 of 0.3 Gy and 0.4 h, respectively, while the 95% confidence interval increased by 0.5 Gy and decreased by 0.4 h, respectively. Though the overall impact on radiobiological parameter estimation was small, the individual uncertainties could have a significant influence in other applications of in vitro experiments in radiation biology. Hence, better understanding of the uncertainties associated with both clonogenic assays and the radiation source used can improve the accuracy of experimental analysis and reproducibility of the results.

The purpose of this study was to characterize today's radiation and cancer biology educators of radiation oncology residents, and the biology courses they teach. An e-mail list of 133 presumptive resident biology educators was compiled, and they were invited to participate in a 46-item survey. Survey questions were designed to collect information about the educational and academic backgrounds of the educators, how they self-identify, characteristics of the courses they teach, the value that they assign to their teaching activities, their level of satisfaction with their courses and how they see these courses being taught in the future. Findings of this survey were compared and contrasted with prior surveys of biology educators (conducted 12 and 20 years ago, respectively), and with more recent surveys of radiation oncology residents and radiation oncology residency program directors conducted in 2018 and 2019. A total of 67 survey responses were received. Biology educators range in age, academic rank and years of teaching experience from junior (18%) to quite senior (45%). Only about 40% self-identify as radiation biologists, biophysicists or chemists, compared to 56% in 2001. The majority of the others consist of cancer biologists (15%), radiation oncologists (15%) and radiation oncology physician-scientists (16%). Educators prioritize their resident teaching as important or very important. Biology courses are widely variable in contact hours between programs and have not changed significantly over the past 20 years. About 75% of the courses are team-taught, including 15% involving multiple training programs. An average biology course consists of about 42% foundational (“classical”) radiobiology, 28% clinical radiobiology and 28% cancer biology. While biology educators and radiation oncology program directors are highly satisfied with their biology courses, approximately a third of residents report being not very, or not at all, satisfied. That fewer biology educators are radiobiologists by training and their courses have remained quite variable in length and content over long periods point to the need for a consensus core curriculum for resident education in radiation and cancer biology. Both current educators and program directors also support making online teaching resources available, diversifying course instructors and consolidating biology teaching across multiple training programs.

Here we show an interplay between the structures present in ionization tracks and nucleocapsid RNA structural biology, using fast ion-beam inactivation of the severe acute respiratory syndrome coronavirus (SARS-CoV) virion as an example. This interplay could be a key factor in predicting dose-inactivation curves for high-energy ion-beam inactivation of virions. We also investigate the adaptation of well-established cross-section data derived from radiation interactions with water to the interactions involving the components of a virion, going beyond the density-scaling approximation developed previously. We conclude that solving one of the grand challenges of structural biology — the determination of RNA tertiary/quaternary structure — is linked to predicting ion-beam inactivation of viruses and that the two problems can be mutually informative. Indeed, our simulations show that fast ion beams have a key role to play in elucidating RNA tertiary/quaternary structure.

Previous epidemiological studies have demonstrated elevated susceptibility to ionizing radiation in some families, thus suggesting the presence of genetic components that conferred increased rate of radiation-associated meningioma (RAM). In this study, we exome-sequenced and investigated the segregation pattern of rare deleterious variants in 11 RAM pedigrees. In addition, we performed a rare-variant association analysis in 92 unrelated familial cases of RAM that were ancestry-matched with 88 meningioma-free controls. In the pedigree analysis, we found that each family carried mostly a unique set of rare deleterious variants. A follow-up pathway analysis of the union of the genes that segregated within each of the 11 pedigrees identified a single statistically significant (q value = 7.90E-04) “ECM receptor interaction” set. In the case-control association analysis, we observed no statistically significant variants or genes after multiple testing correction; however, examination of ontological categories of the genes that associated with RAM at nominal P values <0.01 identified biologically relevant pathways such as DNA repair, cell cycle and apoptosis. These results suggest that it is unlikely that a small number of highly penetrant genes are involved in the pathogenesis of RAM. Substantially larger studies are needed to identify genetic risk variants and genes in RAM.

Oral administration (gavage) of a second-generation probiotic, Lactobacillus reuteri (L. reuteri), that releases interleukin-22 (LR-IL-22) at 24 h after total-body irradiation (TBI) mitigates damage to the intestine. We determined that LR-IL-22 also mitigates partial-body irradiation (PBI) and whole-abdomen irradiation (WAI). Irradiation can be an effective treatment for ovarian cancer, but its use is limited by intestinal toxicity. Strategies to mitigate toxicity are important and can revitalize this modality to treat ovarian cancer. In the present studies, we evaluated whether LR-IL-22 facilitates fractionated WAI in female C57BL/6 mice with disseminated ovarian cancer given a single fraction of either 15.75 Gy or 19.75 Gy or 4 daily fractions of 6 Gy or 6.5 Gy. Mice receiving single or multiple administrations of LR-IL-22 during WAI showed improved intestinal barrier integrity (P = 0.0167), reduced levels of radiation-induced intestinal cytokines including KC/CXCL1 (P = 0.002) and IFN-γ (P = 0.0024), and reduced levels of plasma, Eotaxin/CCL11 (P = 0.0088). LR-IL-22 significantly preserved the numbers of Lgr5+GFP+ intestinal stem cells (P = 0.0010) and improved survival (P < 0.0343). Female C57BL/6MUC-1 mice with widespread abdominal syngeneic 2F8cis ovarian cancer that received LR-IL-22 during 6.5 Gy WAI in 4 fractions had reduced tumor burden, less intestinal toxicity, and improved 30-day survival. Furthermore, LR-IL-22 facilitated WAI when added to Paclitaxel and Carboplatin chemotherapy and further increased survival. Oral administration (gavage) of LR-IL-22 is a potentially valuable intestinal radioprotector, which can facilitate therapeutic WAI for widespread intra-abdominal ovarian cancer.