The TOPAS Monte Carlo (MC) system is used in radiation therapy and medical imaging research, having played a significant role in making Monte Carlo simulations widely available for proton therapy related research. While TOPAS provides detailed simulations of patient scale properties, the fundamental unit of the biological response to radiation is a cell. Thus, our goal was to develop TOPAS-nBio, an extension of TOPAS dedicated to advance understanding of radiobiological effects at the (sub-)cellular, (i.e., the cellular and sub-cellular) scale. TOPAS-nBio was designed as a set of open source classes that extends TOPAS to model radiobiological experiments. TOPAS-nBio is based on and extends Geant4-DNA, which extends the Geant4 toolkit, the basis of TOPAS, to include very low-energy interactions of particles down to vibrational energies, explicitly simulates every particle interaction (i.e., without using condensed histories) and propagates radiolysis products. To further facilitate the use of TOPAS-nBio, a graphical user interface was developed. TOPAS-nBio offers full track-structure Monte Carlo simulations, integration of chemical reactions within the first millisecond, an extensive catalogue of specialized cell geometries as well as sub-cellular structures such as DNA and mitochondria, and interfaces to mechanistic models of DNA repair kinetics. We compared TOPAS-nBio simulations to measured and published data of energy deposition patterns and chemical reaction rates (G values). Our simulations agreed well within the experimental uncertainties. Additionally, we expanded the chemical reactions and species provided in Geant4-DNA and developed a new method based on independent reaction times (IRT), including a total of 72 reactions classified into 6 types between neutral and charged species. Chemical stage simulations using IRT were a factor of 145 faster than with step-by-step tracking. Finally, we applied the geometric/chemical modeling to obtain initial yields of double-strand breaks (DSBs) in DNA fibers for proton irradiations of 3 and 50 MeV and compared the effect of including chemical reactions on the number and complexity of DSB induction. Over half of the DSBs were found to include chemical reactions with approximately 5% of DSBs caused only by chemical reactions. In conclusion, the TOPAS-nBio extension to the TOPAS MC application offers access to accurate and detailed multiscale simulations, from a macroscopic description of the radiation field to microscopic description of biological outcome for selected cells. TOPAS-nBio offers detailed physics and chemistry simulations of radiobiological experiments on cells simulating the initially induced damage and links to models of DNA repair kinetics.

We quantitated age-related accumulation of senescent cells in irradiated Fanconi anemia (FA) (Fanca^-/- mouse cell lines in vitro, and monitored the effect of continuous administration (via drinking water) of the water-soluble radiation mitigator, MMS350, on tissues in vivo over one year after 7.5 Gy total-body irradiation (TBI). Irradiated Fanca^-/- mouse bone marrow stromal cell lines showed increased numbers of beta-galactosidase- and p21-positive senescent cells compared to Fanca^+/+ cell lines, which was reduced by MMS350. One week after 7.5 Gy TBI, Fanca^-/- mice showed increased numbers of senescent cells in spleen compared to Fanca^+/+ controls, decreased bone marrow cellularity, failure of explanted bone marrow to proliferate in vitro to form a hematopoietic microenvironment and no detectable single stromal cell cloning capacity. There was no detectable amelioration by MMS350 administration at one week. In contrast, one year post-TBI, Fanca^-/- mice demonstrated fewer senescent cells in brain and spleen compared to Fanca^+/+ controls. While Fanca^-/- mouse bone marrow stromal cells explanted one year post-TBI still failed to proliferate in vitro, continuous oral administration of 400 µM, MMS350 in drinking water restored explanted stromal cell proliferation. The data indicate that continuous administration of MMS350 modulated several properties of TBI-accelerated aging in Fanca^-/- mice as well as control mice, and support further study of MMS350 as a modulator of radiation late effects.

The harmful effects of space radiation pose a serious health risk to astronauts participating in future long-term missions. Such radiation effects must be considered in the design phase of space vessels as well as in mission planning. Crew radioprotection during long periods in deep space (e.g., transit to Mars) represents a major challenge, especially because of the strong restrictions on the passive shielding load allowed on-board the vessel. Novel materials with better shielding performance compared to the “gold standard” high-density polyethylene are therefore greatly needed. Because of the high hydrogen content of hydrides, lithium hydride has been selected as a starting point for further studies of promising candidates to be used as passive shielding materials. In the current experimental campaign, the shielding performance of lithium hydride was assessed by measuring normalized dose, primary beam attenuation and neutron ambient dose equivalent using 430 MeV/u ¹²C, 600 MeV/u ¹²C and 228 MeV proton beams. The experimental data were then compared to predictions from the Monte Carlo transport codes PHITS and GRAS. The experimental results show an increased shielding effectiveness of lithium hydride compared to reference materials like polyethylene. For instance, the attenuation length for 600 MeV/u ¹²C primary particles in lithium hydride is approximately 20% shorter compared to polyethylene. Furthermore, the comparison results between both transport codes indicates that the standard Tripathi-based total reaction cross-section model of PHITS cannot accurately reproduce the presented experimental data, whereas GRAS shows reasonable agreement.

Over the last 50 years, a number of important physiological changes in humans who have traveled on spaceflights have been catalogued. Of major concern are the short- and long-term radiation-induced injuries to the hematopoietic system that may be induced by high-energy galactic cosmic rays encountered on interplanetary space missions. To collect data on the effects of space radiation on the human hematopoietic system in vivo, we used a humanized mouse model. In this study, we irradiated humanized mice with 0.4 Gy of 350 MeV/n ²⁸Si ions, a dose that has been shown to induce tumors in tumor-prone mice and a reference dose that has a relative biological effectiveness of 1 (1 Gy of 250-kVp X rays). Cell counts, cell subset frequency and cytogenetic data were collected from bone marrow spleen and blood of irradiated and control mice at short-term (7, 30 and 60 days) and long-term (6–7 months) time points postirradiation. The data show a significant short-term effect on the human hematopoietic stem cell counts imparted by both high- and low-LET radiation exposure. The radiation effects on bone marrow, spleen and blood human cell counts and human cell subset frequency were complex but did not alter the functions of the hematopoietic system. The long-term data acquired from high-LET irradiated mice showed complete recovery of the human hematopoietic system in all hematopoietic compartments. The combined results demonstrate that, in spite of early perturbation, the longer term effects of high-LET radiation are not detrimental to human hematopoiesis in our system of study.

Nuclear factor-erythroid-2-related factor 2 transcription factor (Nrf2) is activated by reactive oxygen species (ROS) and binds to antioxidant response elements in the promoter regions of its target genes involved in redox regulation and antioxidative functions. In this study, we elucidated the relationship between radiation dose and the expression response of Nrf2 target genes involved in oxidative stress, such as heme oxygenase 1, ferritin heavy polypeptide 1 (Fth1), NADPH dehydrogenase quinone 1, glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, glutathione reductase (Gsr) and thioredoxin reductase 1 genes, in peripheral blood from X-ray irradiated mice. Whole-body radiation doses ranged from 0.5 to 3 Gy, and gene expressions were analyzed using reverse transcription quantitative polymerase chain reaction. A significant relationship was observed only for one gene: a statistically significant positive correlation between radiation dose and Fth1 mRNA expression was detected. However, Fth1 did not show any correlations with the biological damages induced by radiation tested in this study. Furthermore, while Gsr expression was significantly associated with spleen weight loss, splenic cell number reduction and bone marrow cell death apoptosis, no significant correlation was observed between Gsr expression and radiation dose. Together these results indicate that Nrf2 target gene expression is closely related to radiation dose and its level may reflect biological damages induced by ionizing radiation. These findings suggest the possibility for application of these target genes as a bio-dosimeter and/or damage marker in individuals exposed to ionizing radiation.

MicroRNAs (miRNAs) are a non-coding regulatory RNAs that play significant roles in plant growth and development, especially in the stress response. Low-energy ion radiation, a type of environmental stress, can cause multiple biological effects. To understand the roles of miRNAs in response to low-energy N⁺ ion radiation in Oryza sativa, high-throughput sequencing of small RNAs was carried out to detect the expression of miRNAs in the shoots of the rice after 2 × 10¹⁷ N+/cm² irradiation. The differentially expressed 28 known miRNAs were identified, 17 of these identified miRNAs were validated by real-time quantitative fluorescent PCR (q-PCR), including 9 up-regulated miRNAs (miR1320-3p, miR1320-5p, miR156b-3p, miR156c-5p, miR156c-3p/g-3p, miR1561-5p, miR398b and miR6250) and 8 down-regulated miRNAs (miR156a/e/i, miR156k, miR160f-5p, miR166j-5p, miR1846e and miR399d). In addition, 45 novel radiationresponsive miRNAs were predicted, and 8 of them were verified by q-PCR. The target genes of radiation-responsive miRNAs were predicted and gene function enrichment analysis was performed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of 9 targets of 4 known miRNA families (miR156, miR399, miR1320 and miR398) and 2 targets of 2 novel miRNAs were quantified by q-PCR, and a strong negative regulation relation between miRNAs and their targets were observed. Those targets including SQUAMOSA promoterbinding-like protein (SPL) genes, copper/zinc superoxide dismutase (Cu/Zn-SOD), copper chaperone for SOD (CCS1) and electron transporter/ heat-shock protein binding protein (HSP), which are involved in growth and defense against various stresses, especially associated with reactive oxygen species (ROS) scavenging. This work provides important information for understanding the ROS generation and elimination mechanisms closely related to miRNAs in rice seedlings after low-energy N⁺ radiation exposure.

Individuals with significant intakes of plutonium (Pu) are typically treated with chelating agents, such as the trisodium salt form of calcium diethylenetriaminepentaacetate (CaNa₃-DTPA, referred to hereafter as Ca-DTPA). Currently, there is no recommended approach for simultaneously modeling plutonium biokinetics during and after chelation therapy. In this study, an improved modeling system for plutonium decorporation was developed. The system comprises three individual model structures describing, separately, the distinct biokinetic behaviors of systemic plutonium, intravenously injected Ca-DTPA and in vivo-formed Pu-DTPA chelate. The system was linked to ICRP Publication 100, “Human Alimentary Tract Model for Radiological Protection” and NCRP Report 156, Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedures for Their Assessment, Dosimetry and Treatment.” Urine bioassay and chelation treatment data from an occupationally-exposed individual were used for model development. Chelation was assumed to occur in the blood, soft tissues, liver and skeleton. The coordinated network for radiation dosimetry approach to decorporation modeling was applied using a chelation constant describing the secondorder, time-dependent kinetics of the in vivo chelation reaction. When using the proposed system of models for plutonium decorporation, a significant improvement of the goodness-of-fit to the urinary excretion data was observed and more accurate predictions of postmortem plutonium retention in the skeleton, liver and wound site were achieved. © 2019 by Radiation Research Society

Increased understanding of radiation-induced secondary bystander effect (RISBE) is relevant to radiation therapy since it likely contributes to normal tissue injury and tumor recurrence, subsequently resulting in treatment failure. In this work, we developed a simple method based on proton microbeam radiation and a transwell insert co-culture system to elucidate the RISBE between irradiated human lung cancer cells and nonirradiated human normal cells. A549 lung cancer cells received a single dose or fractionated doses of proton microbeam radiation to generate the primary bystander cells. These cells were then seeded on the top of the insert with secondary bystander WI-38 normal cells growing underneath in the presence or absence of gap junction intercellular communication (GJIC) inhibitor, 18-α-glycyrrhetnic acid (AGA). Cells were co-cultured before harvesting and assayed for micronuclei formation. The results of this work showed that fractionated doses of protons caused less DNA damage in the secondary bystander WI-38 cells compared to a single radiation dose, where the means differ by 20%. However, the damaging effect in the secondary bystander normal cells could be eliminated when treated with AGA. This novel work reflects our effort to demonstrate that GJIC plays a major role in the RISBE generated from the primary bystander cancer cells.