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NASA NTRS2012

Developing an Open Source, Reusable Platform for Distributed Collaborative Information Management in the Early Detection Research Network

For the past decade, the NASA Jet Propulsion Laboratory, in collaboration with Dartmouth University has served as the center for informatics for the Early Detection Research Network (EDRN). The EDRN is a multi-institution research effort funded by the U.S. National Cancer Institute (NCI) and tasked with identifying and validating biomarkers for the early detection of cancer. As the distributed network has grown, increasingly formal processes have been developed for the acquisition, curation, storage, and dissemination of heterogeneous research information assets, and an informatics infrastructure has emerged. In this paper we discuss the evolution of EDRN informatics, its success as a mechanism for distributed information integration, and the potential sustainability and reuse benefits of emerging efforts to make the platform components themselves open source. We describe our experience transitioning a large closed-source software system to a community driven, open source project at the Apache Software Foundation, and point to lessons learned that will guide our present efforts to promote the reuse of the EDRN informatics infrastructure by a broader community.

Early Detection Research Network (EDRN)↗

NASA NTRS2013

Correlated Uncertainties in Radiation Shielding Effectiveness

The space radiation environment is composed of energetic particles which can deliver harmful doses of radiation that may lead to acute radiation sickness, cancer, and even death for insufficiently shielded crew members. Spacecraft shielding must provide structural integrity and minimize the risk associated with radiation exposure. The risk of radiation exposure induced death (REID) is a measure of the risk of dying from cancer induced by radiation exposure. Uncertainties in the risk projection model, quality factor, and spectral fluence are folded into the calculation of the REID by sampling from probability distribution functions. Consequently, determining optimal shielding materials that reduce the REID in a statistically significant manner has been found to be difficult. In this work, the difference of the REID distributions for different materials is used to study the effect of composition on shielding effectiveness. It is shown that the use of correlated uncertainties allows for the determination of statistically significant differences between materials despite the large uncertainties in the quality factor. This is in contrast to previous methods where uncertainties have been generally treated as uncorrelated. It is concluded that the use of correlated quality factor uncertainties greatly reduces the uncertainty in the assessment of shielding effectiveness for the mitigation of radiation exposure.

Werneth, Charles M.↗

NASA NTRS2013

Estimation of the Dose and Dose Rate Effectiveness Factor

Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

Chappell, L.↗

NASA NTRS2014

Overview of NASARTI (NASA Radiation Track Image) Program: Highlights of the Model Improvement and the New Results

This presentation summarizes several years of research done by the co-authors developing the NASARTI (NASA Radiation Track Image) program and supporting it with scientific data. The goal of the program is to support NASA mission to achieve a safe space travel for humans despite the perils of space radiation. The program focuses on selected topics in radiation biology that were deemed important throughout this period of time, both for the NASA human space flight program and to academic radiation research. Besides scientific support to develop strategies protecting humans against an exposure to deep space radiation during space missions, and understanding health effects from space radiation on astronauts, other important ramifications of the ionizing radiation were studied with the applicability to greater human needs: understanding the origins of cancer, the impact on human genome, and the application of computer technology to biological research addressing the health of general population. The models under NASARTI project include: the general properties of ionizing radiation, such as particular track structure, the effects of radiation on human DNA, visualization and the statistical properties of DSBs (DNA double-strand breaks), DNA damage and repair pathways models and cell phenotypes, chromosomal aberrations, microscopy data analysis and the application to human tissue damage and cancer models. The development of the GUI and the interactive website, as deliverables to NASA operations teams and tools for a broader research community, is discussed. Most recent findings in the area of chromosomal aberrations and the application of the stochastic track structure are also presented.

Ponomarev, Artem L.↗

NASA NTRS2015

NASA Space Radiation Program Integrative Risk Model Toolkit

NASA Space Radiation Program Element scientists have been actively involved in development of an integrative risk models toolkit that includes models for acute radiation risk and organ dose projection (ARRBOD), NASA space radiation cancer risk projection (NSCR), hemocyte dose estimation (HemoDose), GCR event-based risk model code (GERMcode), and relativistic ion tracks (RITRACKS), NASA radiation track image (NASARTI), and the On-Line Tool for the Assessment of Radiation in Space (OLTARIS). This session will introduce the components of the risk toolkit with opportunity for hands on demonstrations. The brief descriptions of each tools are: ARRBOD for Organ dose projection and acute radiation risk calculation from exposure to solar particle event; NSCR for Projection of cancer risk from exposure to space radiation; HemoDose for retrospective dose estimation by using multi-type blood cell counts; GERMcode for basic physical and biophysical properties for an ion beam, and biophysical and radiobiological properties for a beam transport to the target in the NASA Space Radiation Laboratory beam line; RITRACKS for simulation of heavy ion and delta-ray track structure, radiation chemistry, DNA structure and DNA damage at the molecular scale; NASARTI for modeling of the effects of space radiation on human cells and tissue by incorporating a physical model of tracks, cell nucleus, and DNA damage foci with image segmentation for the automated count; and OLTARIS, an integrated tool set utilizing HZETRN (High Charge and Energy Transport) intended to help scientists and engineers study the effects of space radiation on shielding materials, electronics, and biological systems.

Kim, Myung-Hee Y.↗

NASA NTRS2015

RBE of Energetic Iron Ions for the Induction of Early and Late Chromosome Aberrations in Different Cell Types

Numerous published studies have reported the Relative Biological Effectiveness (RBE) values for chromosome aberrations induced by charged particles of different LET. The RBE for chromosome aberrations in human lymphocytes exposed ex vivo has been suggested to show a similar relationship as the quality factor for cancer induction. Therefore, increased chromosome aberrations in the astronauts' white blood cells post long-duration missions are used to determine the biological doses from exposures to space radiation. However, the RBE value is known to be very different for different types of cancer. Previously, we reported that, even though the RBE for initial chromosome damages was high in human lymphocytes exposed to Fe ions, the RBE was significantly reduced after multiple cell divisions post irradiation. To test the hypothesis that RBE values for chromosome aberrations are cell type dependent, and different between early and late damages, we exposed human lymphocytes ex vivo, and human mammary epithelial cells in vitro to various charged particles. Chromosome aberrations were quantified using the samples collected at first mitosis post irradiation for initial damages, and the samples collected after multiple generations for the remaining or late arising aberrations. Results of the study suggested that the effectiveness of high-LET charged particles for late chromosome aberrations may be cell type dependent, even though the RBE values are similar for early damages.

Zhang, Ye↗

NASA NTRS2015

2014 Space Radiation Standing Review Panel

The 2014 Space Radiation Standing Review Panel (from here on referred to as the SRP) participated in a WebEx/teleconference with members of the Space Radiation Program Element, representatives from the Human Research Program (HRP), the National Space Biomedical Research Institute (NSBRI), and NASA Headquarters on November 21, 2014 (list of participants is in Section XI of this report). The SRP reviewed the updated Research Plan for the Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure (Degen Risk). The SRP also received a status update on the Risk of Acute and Late Central Nervous System Effects from Radiation Exposure (CNS Risk), the Risk of Acute Radiation Syndromes Due to Solar Particle Events (ARS Risk), and the Risk of Radiation Carcinogenesis (Cancer Risk). The SRP thought the teleconference was very informative and that the Space Radiation Program Element did a great job of outlining where the Element is with respect to our state of knowledge on the risks of carcinogenesis, central nervous system effects, and the risk of cardiovascular disease and other degenerative tissue effects from exposure to space radiation. The SRP was impressed with the quality of research that is being conducted and the progress the Space Radiation Program Element has made in the past year. While much work has been done, the SRP had a few remaining questions regarding the broad applicability of these findings to a manned deep space mission (in terms of cognitive function, the paradigms were still hippocampal based and also using Alzheimer disease models). The SRP believes that NASA should consider developing an approach to follow astronauts long-term (beyond retirement) for potential side-effects/risks of space exposure that may be unknown. Radiation toxicities often occur decades after exposure, and potential consequences would be missed if intensified exams stop after retirement of the astronauts. In addition, while cancer is one consequence of radiation exposure that is monitored, potential other side effects (CNS, Alzheimer Disease, loss of cognitive function, etc.) are not included in long-term studies and would be missed. Inclusion of long-term data would be of benefit to the astronauts themselves who have given their service to the corps but also to future astronauts and the future of space exploration.

Steinberg, Susan↗

NASA NTRS2015

Evidence Report: Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation Exposure

Occupational radiation exposure from the space environment may result in non-cancer or non-CNS degenerative tissue diseases, such as cardiovascular disease, cataracts, and respiratory or digestive diseases. However, the magnitude of influence and mechanisms of action of radiation leading to these diseases are not well characterized. Radiation and synergistic effects of radiation cause DNA damage, persistent oxidative stress, chronic inflammation, and accelerated tissue aging and degeneration, which may lead to acute or chronic disease of susceptible organ tissues. In particular, cardiovascular pathologies such as atherosclerosis are of major concern following gamma-ray exposure. This provides evidence for possible degenerative tissue effects following exposures to ionizing radiation in the form of the GCR or SPEs expected during long-duration spaceflight. However, the existence of low dose thresholds and dose-rate and radiation quality effects, as well as mechanisms and major risk pathways, are not well-characterized. Degenerative disease risks are difficult to assess because multiple factors, including radiation, are believed to play a role in the etiology of the diseases. As additional evidence is pointing to lower, space-relevant thresholds for these degenerative effects, particularly for cardiovascular disease, additional research with cell and animal studies is required to quantify the magnitude of this risk, understand mechanisms, and determine if additional protection strategies are required.The NASA PEL (Permissive Exposure Limit)s for cataract and cardiovascular risks are based on existing human epidemiology data. Although animal and clinical astronaut data show a significant increase in cataracts following exposure and a reassessment of atomic bomb (A-bomb) data suggests an increase in cardiovascular disease from radiation exposure, additional research is required to fully understand and quantify these adverse outcomes at lower doses (less than 0.5 gray (SI unit for ionizing radiation dosage, i.e. one joule of radiation energy per one kilogram of matter)) to facilitate risk prediction. This risk has considerable uncertainty associated with it, and no acceptable model for projecting degenerative tissue risk is currently available. In particular, risk factors such as obesity, alcohol, and tobacco use can act as confounding factors that contribute to the large uncertainties. The PELs could be violated under certain scenarios, including following a large SPE (solar proton event) or long-term GCR (galactic cosmic ray) exposure. Specifically, for a Mars mission, the accumulated dose is sufficiently high that epidemiology data and preliminary risk estimates suggest a significant risk for cardiovascular disease. Ongoing research in this area is intended to provide the evidence base for accurate risk quantification to determine criticality for extended duration missions. Data specific to the space radiation environment must be compiled to quantify the magnitude of this risk to decrease the uncertainty in current PELs and to determine if additional protection strategies are required. New research results could lead to estimates of cumulative radiation risk from CNS and degenerative tissue diseases that, when combined with the cancer risk, may have major negative impacts on mission design, costs, schedule, and crew selection. The current report amends an earlier report (Human Research Program Requirements Document, HRP-47052, Rev. C, dated Jan 2009) in order to provide an update of evidence since 2009.

Patel, Zarana↗

NASA NTRS2015

Evidence Report: Risk of Acute and Late Central Nervous System Effects from Radiation Exposure

Possible acute and late risks to the central nervous system (CNS) from galactic cosmic rays (GCR) and solar particle events (SPE) are a documented concern for human exploration of space. Acute CNS risks include: altered cognitive function, reduced motor function, and behavioral changes, all of which may affect performance and human health. Late CNS risks include neurological disorders such as Alzheimer's disease (AD), dementia and premature aging. Although detrimental CNS changes are observed in humans treated with high-dose radiation (e.g., gamma rays and protons) for cancer and are supported by experimental evidence showing neurocognitive and behavioral effects in animal models, the significance of these results on the morbidity to astronauts has not been elucidated. There is a lack of human epidemiology data on which to base CNS risk estimates; therefore, risk projection based on scaling to human data, as done for cancer risk, is not possible for CNS risks. Research specific to the spaceflight environment using animal and cell models must be compiled to quantify the magnitude of CNS changes in order to estimate this risk and to establish validity of the current permissible exposure limits (PELs). In addition, the impact of radiation exposure in combination with individual sensitivity or other space flight factors, as well as assessment of the need for biological/pharmaceutical countermeasures, will be considered after further definition of CNS risk occurs.

Nelson, Gregory A.↗

NASA NTRS2016

Proton and Fe Ion-Induced Early and Late Chromosome Aberrations in Different Cell Types

An early stage of cancer development is believed to be genomic instability (GI) which accelerates the mutation rate in the descendants of the cells surviving radiation exposure. To investigate GI induced by charged particles, we exposed human lymphocytes, human fibroblast cells, and human mammary epithelial cells to high energy protons and Fe ions. In addition, we also investigated GI in bone marrow cells isolated from CBA/CaH (CBA) and C57BL/6 (C57) mice, by analyzing cell survival and chromosome aberrations in the cells after multiple cell divisions. Results analyzed so far from the experiments indicated different sensitivities to charged particles between CBA/CaH (CBA) and C57BL/6 (C57) mouse strains, suggesting that there are two main types of response to irradiation: 1) responses associated with survival of damaged cells and 2) responses associated with the induction of non-clonal chromosomal instability in the surviving progeny of stem cells. Previously, we reported that the RBE for initial chromosome damages was high in human lymphocytes exposed to Fe ions. Our results with different cell types demonstrated different RBE values between different cell types and between early and late chromosomal damages. This study also attempts to offer an explanation for the varying RBE values for different cancer types.

Wu, Honglu↗

NASA NTRS2015

2015 Space Radiation Standing Review Panel

The 2015 Space Radiation Standing Review Panel (from here on referred to as the SRP) met for a site visit in Houston, TX on December 8 - 9, 2015. The SRP met with representatives from the Space Radiation Element and members of the Human Research Program (HRP) to review the updated research plan for the Risk of Radiation Carcinogenesis Cancer Risk. The SRP also reviewed the newly revised Evidence Reports for the Risk of Acute Radiation Syndromes Due to Solar Particle Events (SPEs) (Acute Risk), the Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure (CNS Risk), and the Risk of Cardiovascular Disease and Other Degenerative Tissue Effects from Radiation (Degen Risk), as well as a status update on these Risks. The SRP would like to commend Dr. Simonsen, Dr. Huff, Dr. Nelson, and Dr. Patel for their detailed presentations. The Space Radiation Element did a great job presenting a very large volume of material. The SRP considers it to be a strong program that is well-organized, well-coordinated and generates valuable data. The SRP commended the tissue sharing protocols, working groups, systems biology analysis, and standardization of models. In several of the discussed areas the SRP suggested improvements of the research plans in the future. These include the following: It is important that the team has expanded efforts examining immunology and inflammation as important components of the space radiation biological response. This is an overarching and important focus that is likely to apply to all aspects of the program including acute, CVD, CNS, cancer and others. Given that the area of immunology/inflammation is highly complex (and especially so as it relates to radiation), it warrants the expansion of investigators expertise in immunology and inflammation to work with the individual research projects and also the NASA Specialized Center of Research (NSCORs). Historical data on radiation injury to be entered into the Watson “big data” study must be used with caution. The general scientific issues of reproducibility, details of experimental methods and data analysis from preclinical and basic research laboratories have been raised broadly over the last few years (not specific to this work) and indicate that caution must be applied in the ways these data are used. This pertains to preclinical data and also to phase 3 clinical trials in radiation oncology and medical oncology. Of course, appropriate use and analysis of these “big-data” sets also offer the potential of pinpointing limitations and extracting remaining useful information. Emphasis should be placed on the latter possibility. A key target is risk reduction from radiation exposure. Progress of the entire space program, now moving towards the Mars mission, requires timely answers to key components of human risk, which are known to be complex. Periodic review of progress should be conducted with additional resources directed into achieving critical milestones. Turning the long red bars to yellow and green (or for some risks such as CNS possibly to grey) must be high priority. That such progress will require new science and not engineering means that it should be viewed in a knowledge-based light. The technology-based aspects of engineering issues are certainly as important, however, science and knowledge-based problems are solved in a different way than engineering. Timelines for engineering are more predictable, while for science, progress can be methodical with occasional major incremental findings that can rapidly change the rate of progress. As opportunities for rapid incremental changes arise, periodic enhancement of investment is strongly recommended to enable such new knowledge to be quickly and efficiently exploited. Collaborations and linkages with National Institute of Allergy and Infectious Diseases (NIAID), the Biomedical Advanced Research and Development Authority (BARDA) and the Department of Defense (DoD) are in place and more are encouraged, where possible, with the radiation injury and medical countermeasure studies. This could include utilizing some of their animal model testing contracts to facilitate obtaining results using common platforms. Such approach will facilitate the comparison of results among laboratories, and will facilitate and accelerate the development of medical countermeasures. It is particularly noteworthy that the NASA Space Radiation Element is reaching out to the Multidisciplinary European Low Dose Initiative (MELODI) platform coordinating low dose radiation risk research, and to other international agencies that are studying low dose radiation effects in an effort to fill the void generated by the cancelation of the Department of Energy (DOE) low dose radiation program. While NASA is working actively with NIAID and BARDA to integrate their relevant findings of radiation mitigator investigations to NASA programs, the committee notes its disappointment that the United States currently lacks a dedicated low dose radiation program with clear mechanistic orientation and aimed at the quantification and mitigation of human radiation risk on Earth. This void gives to the NASA Space Radiation Program Element special societal value, but also makes its overall design more challenging.

Steinberg, Susan↗

NASA NTRS2016

Evidence Report: Risk of Acute and Late Central Nervous System Effects from Radiation Exposure

Possible acute and late risks to the central nervous system (CNS) from galactic cosmic rays (GCR) and solar particle events (SPE) are concerns for human exploration of space. Acute CNS risks may include: altered cognitive function, reduced motor function, and behavioral changes, all of which may affect performance and human health. Late CNS risks may include neurological disorders such as Alzheimer's disease (AD), dementia and premature aging. Although detrimental CNS changes are observed in humans treated with high-dose radiation (e.g., gamma rays and 9 protons) for cancer and are supported by experimental evidence showing neurocognitive and behavioral effects in animal models, the significance of these results on the morbidity to astronauts has not been elucidated. There is a lack of human epidemiology data on which to base CNS risk estimates; therefore, risk projection based on scaling to human data, as done for cancer risk, is not possible for CNS risks. Research specific to the spaceflight environment using animal and cell models must be compiled to quantify the magnitude of CNS changes in order to estimate this risk and to establish validity of the current permissible exposure limits (PELs). In addition, the impact of radiation exposure in combination with individual sensitivity or other space flight factors, as well as assessment of the need for biological/pharmaceutical countermeasures, will be considered after further definition of CNS risk occurs.

Nelson, Gregory A.↗

NASA NTRS2018

Effect of Ex Vivo Ionizing Radiation on Static and Fatigue Properties of Mouse Vertebral Bodies

For a variety of medical and scientific reasons, human bones can be exposed to a wide range of ionizing radiation levels. In vivo radiation therapy (0.05 kGy) is used in cancer treatment, and ex vivo irradiation (25-35 kGy) is used to sterilize bone allografts. Ionizing radiation in these applications has been shown to increase risk of fracture, decrease bone quality and degrade collagen integrity. Past studies have investigated the deleterious effects of radiation on cortical or trabecular bone specimens individually, but to date no studies have examined whole bones containing both cortical and trabecular tissue. Furthermore, a clear relationship between the dose and the mechanical and biochemical response of bone's extracellular matrix has yet to be established for doses ranging from cancer therapy to allograft sterilization (0.05-35 kGy). To gain insight into these issues, we conducted an ex vivo radiation study to investigate non-cellular (i.e. matrix) effects of ionizing radiation dose on vertebral whole bone mechanical properties, over a range of radiation doses (0.05-35 kGy), with a focus on any radiation-induced changes in collagen. With underlying mechanisms of action in mind, we hypothesized that any induced reductions in mechanical properties would be associated with changes in collagen integrity. METHODS: 20-week old female mice were euthanized and the lumbar spine was dissected using IACUC approved protocols. The lumbar vertebrae (L1- S1) were extracted from the spine via cuts through adjacent intervertebral discs, and the endplates, posterior processes, surrounding musculature, and soft tissues were removed (approx. 1.5mm diameter, approx. 2mm height). Specimens were randomly assigned to one of five groups for ex vivo radiation exposure: x-ray irradiation at 0.05, 1, 17, or 35 kGy, or a 0 kGy control. Following irradiation, the vertebrae were imaged using microcomputed tomography (micro-CT) and then subjected to either monotonic compressive loading to failure or uniform cyclic compressive loading. During cyclic testing, samples were loaded in force control to a force level that corresponded to a strain of 0.46%, as determined in advance by a linearly elastic micro-CT-based finite element analysis for each specimen. Tests were stopped at imminent fracture, defined as a rapid increase in strain. The main outcome for the monotonic test was the strength (maximum force); for cyclic testing it was the fatigue life (log of the number of cycles of loading at imminent failure). A fluorometric assay was used on the S1 vertebrae to measure the number of non-enzymatic collagen crosslinks[4]. A one-way ANOVA was performed on mechanical properties and collagen crosslinks; means were compared with controls using Dunnett's method, with a Tukey-Kramer post-hoc analysis when significance was found (p < or = 0.05). RESULTS: Compared to the unirradiated control group, the concentration of non-enzymatic collagen crosslinks was significantly increased for all irradiated groups (p < 0.0001), and being higher by at least 50% (Figure 1a). By contrast, the radiation effects on the collagen were only evident at the higher doses. For irradiation exposures of 17 kGy or more, strength decreased substantially as the radiation level was increased, but no effect was evident below 17 kGy (Figure 1b). There was no significant change in the stiffness or maximum displacement for any radiation dose (p>0.05). The finite element analysis prescribed force level for cyclic loading exceeded the measured (monotonic) strength of the 17 and 35 kGy irradiated groups (mean +/- SD, 20.6 +/- 5.6 N; 13.2 +/- 3.7 N, respectively) and therefore these groups were eliminated from the fatigue study. The fatigue life for the 0.05 and 1 kGy groups were similar to each other and were not statistically significantly different from the control group (Figure 1c).

radiation↗

NASA NTRS2018

Radiation and the Immune System

Radiation has profound effects on the immune system. This makes it particularly important to study in order to protect astronauts venturing into deep space and cancer patients considering radiotherapy treatments. Beyond the Earth's magentic field lies galactic cosmic radiation, which contains heavy ion based rays. Immune alterations in response to radiation depends on factors such as the type and amount of radiation, and potentially even the genes of the individual being exposed. In order to study the effects of cosmic radiation on the immune system, we are exposing primary human immune cells to various types and amounts of radiation. To measure sensitivity to radiation, we are quantifying the DNA damage within the cells before irradiation, 4 hours after irradiation, and 24 hours after irradiation. DNA damage is visualized by fluorescently staining for known DNA repair proteins, which get recruited to the site of damage within a cell. These results will be analyzed to search for correlations between immune cell responses and the type of radiation, amount of radiation, or any genetic markers present in the human blood donors. We will also be attempting to determine which specific immune cells are most suspectible to radiation damage. These correlations and discoveries will contribute to making long duration human deep space exploration a possibility, and can even be used to design more personalized and effective radiation treatments for cancer patients.

Malkani, Sherina S.↗

NASA NTRS2018

Variability in Galactic Cosmic Radiation- Induced DNA Damage Response in Inbred Mice Is Modulated by Genetics

In radiation biology, the ability to predict cancer risk associated with exposure to low doses of high-LET (Linear Energy Transfer) ionizing radiation remains a challenge. Epidemiological methods lack the sensitivity and power to provide detailed risk estimates for cancer and ignore individual sensitivity. We have hypothesized that DNA repair capacity is the primary factor differentiating peoples radiation sensitivity. We previously showed in immortalized human cell lines that characterizing the dose and time dependence of p53-binding protein 1 (53BP1) foci formation in the nucleus following X-rays exposure is sufficient to predict DNA repair response to any other LET in the same cell line. We now tested this hypothesis across a population of mice with different genetic background. Fibroblast cells were extracted and cultivated from 76 individual mice from 15 different strains and exposed to HZE (high (H) atomic number (Z) and energy (E) galactic cosmic ray particles) particles and X-rays. Individual radiation sensitivities were investigated by high throughput measurement of DNA repair kinetics that evaluated 53bp1 foci numbers as a surrogate for DNA double-strand breaks at various times post-irradiation. Instead of just counting foci which can be hard to distinguish for high-LET or high doses, we also took into account the track structure of high-LET particles to compute the remaining number of unrepaired tracks as a function of time post-irradiation. As expected, the percentage of unrepaired track over a 48 hours follow-up period increased with LET. In addition, repair rate was modulated by genetics, with animals from the same strain showing small variance while large rate differences were observed between strains. Radiation strain sensitivity ranking was estimated based on repair rates from exposure to each LET evaluated in this work, and ranking for high-LET correlated better with ranking from high dose of X-ray, not low dose. At the in-vivo level, drops in T-cells and B-cells number measured 24 hours after 0.1 Gy (Gray) X-ray exposure, correlated with slower DNA repair kinetic in fibroblast cells of the same strains of mice. At the genomic level, mouse genome wide association (GWA) analysis identified seven significant genetic loci on chromosomes 2, 3, 7, 10, 11, 13 and 19 with different significance depending on the LET. Interestingly, for the two highest LET, a common locus on Chromosome 10 was identified with high enrichment for DNA repair associated genes.Overall, this work suggests that repair kinetics of primary skin fibroblasts is a good surrogate marker for in-vivo radiation sensitivities in other tissues and that this response is modulated by genetics. Our study also confirms that DNA repair kinetics following high doses of X-ray can be used to predict radiation sensitivity to high-LET.

High-LET Radiation↗

NASA NTRS2018

Ionizing Radiation from Ex Vivo Sterilization Diminishes Collagen Integrity and Vertebral Body Mechanics

Clinical exposure to ionizing radiation could put cancer radiotherapy or bone allograft patients at an increased risk of fracture. In these applications, ionizing radiation levels can range from accumulative 50 Gy for radiotherapy cancer treatment, to acute 35,000 Gy for allograft sterilization. Ionizing radiation has been shown to decrease bon equality through reduced strength and post-yield properties and degrade collagen integrity through either increased crosslinks (advanced glycation end products, AGEs)or fragmentation. It is unclear which collagen structural change accounts for reduced strength. The dose-dependent effect of ionizing radiation on mechanical and biochemical properties of whole bones are not well understood, particularly for ex vivo doses ranging from 50 to 35,000 Gy.

Radiation↗

NASA NTRSDate not supplied

Dose, LET, time and strain dependence of radiation-induced 53BP1 foci in 15 mouse strains ex vivo and associations to in vivo radiation susceptibility

We present a comparative analysis on the repair of radiation-induced DNA damage ex vivo in 15 strains of mice, including 5 inbred reference strains and 10 collaborative-cross strains, of both sexes. Non-immortalized primary skin fibroblasts derived from 76 mice were subjected to both low- and high-LET radiation (0.1, 1 and 4 Gy of X rays; 1.1 and 3 particles/100μm2 of 350 MeV/n 40Ar and 600 MeV/n 56Fe). Automated image quantification of 53BP1 radiation-induced foci (RIF) during the first 4-48 h post-irradiation was performed as a function of dose and LET. Similarly to what we had previously reported for immortalized human cell lines [1], we observed a saturation of RIF number with dose at 4h post-irradiation, with more RIF/Gy for lower LET (X rays and 40Ar) compared to 56Fe. However at later time points (24h and above), the trend was inverted with more RIF/Gy for higher LET. Our data suggest that multiple DSBs cluster into RIF: as the linear density of DSBs increases with LET, so does the probability of having more DSBs per RIF, which makes it more difficult for cells to fully resolve high-LET-induced RIF, explaining the hypersensitivity to high-LET radiation despite a low number of RIF. Taking into account the amount of clustering at a given dose and LET, but also the kinetics of DNA damage repair, we introduced a novel mathematical formalism to evaluate the number of remaining RIF over time. We showed that the newly introduced kinetic metrics can be used as surrogate biomarkers for in vivo radiation toxicity, with potential applications in radiotherapy and human space exploration. In particular, we observed an association between the repairable fraction of RIF measured in vitro and survival levels of immune cells collected from irradiated mice. Moreover, the speed of DNA damage repair correlated with spontaneous cancer incidence data collected from the Mouse Tumor Biology database, suggesting a relationship between the efficiency of DSB repair after irradiation and cancer risk. In addition to the efficacy of repair and persistent RIF levels, even the amount of spontaneous foci without irradiation was shown to be strain dependent, indicating that these phenotypes are at least partially driven by genetics, and supporting their potential as indicators of individual radiation sensitivity. [1] Neumaier, T., et al., PNAS, 2012 (8) 109:443

Radiation, DNA damage, repair kinetics↗

NASA NTRSDate not supplied

Medical Countermeasure Requirements for Meeting Permissible Radiation Exposure Limits in Space

The space radiation environment consists of ionizing radiation that poses healthrisks to crew members who embark on a mission to Mars. NASA requiresthat astronaut career radiation limits for the Risk of Exposure Induced Death(REID) should not exceed 3% at the upper 95% confidence level for cancermortality. However, the lifetime career limit is likely to be exceeded for eventhe shortest round-trip mission scenario to Mars. As such, approaches fordirectly reducing the radiation risk, despite the large uncertainties, are beinginvestigated. A recent study showed that medical countermeasures (MCM)which reduced background cancer mortality rates may be effective in mitigatingthe REID, where the data employed in the sensitivity analysis were limited tocohort studies of aspirin and warfarin. The present work addresses the generalMCM requirements that are needed to meet the lifetime career exposure limitsby examining modifications to the background cancer mortality rates, radiationquality factor, and low-LET radiation risk models for a Mars mission scenario.These results may be used to help inform decision-makers about potentialexperimental measurements that facilitate the greatest propensity for MCM risk reduction.

Charles M Werneth↗