The Health Risks of Extraterrestrial Environments
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THREE Bibliography

Characterization of solar energetic particle radiation dose to astronaut crew on deep-space exploration missions
Mertens CJ, Slaba TC. Space Weather. 2019 Dec;17(12):1650-8.
Summary:
Human radiation exposure from solar energetic particle (SEP) events during deep-space exploration missions has a greater impact on mission planning and operations compared to spaceflight missions to low Earth orbit. In this paper, radiation dose to the blood forming organs (BFO) of astronaut crew are calculated from a set of historical SEP events, using the design of the Orion Multi-Purpose Crew Vehicle (MPCV). The analysis of the BFO doses from the historical events presented in this paper will assist in the design of future space weather architectures by identifying models and measurements needed to expand and extend NASA's existing SEP radiation risk tools.
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Ethical challenges in human space missions: A space refuge, scientific value, and human gene editing for space.
Szocik K, Norman Z, Reiss MJ. Sci Eng Ethics. 2019 Sep 3. [Epub ahead of print]
Summary:
This article examines some selected ethical issues in human space missions including human missions to Mars, particularly the idea of a space refuge, the scientific value of space exploration, and the possibility of human gene editing for deep-space travel. Each of these issues may be used either to support or to criticize human space missions. We conclude that while these issues are complex and context-dependent, there appear to be no overwhelming obstacles such as cost effectiveness, threats to human life or protection of pristine space objects, to sending humans to space and to colonize space. The article argues for the rationality of the idea of a space refuge and the defensibility of the idea of human enhancement applied to future deep-space astronauts.
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Research plans in Europe for radiation health hazard assessment in exploratory space missions.
Walsh L, Schneider U, Fogtman A, Kausch C, McKenna-Lawlor S, Narici L, Ngo-Anh J, Reitz G, Sabatier L, Santin G, Sihver L, Straube U, Weber U, Durante M. Life Sci Space Res. 2019 May;21,73-82.
Summary:
The European Space Agency (ESA) is currently expanding its efforts in identifying requirements and promoting research towards optimizing radiation protection of astronauts. Space agencies use common limits for tissue (deterministic) effects on the International Space Station. However, the agencies have in place different career radiation exposure limits (for stochastic effects) for astronauts in low-Earth orbit missions. Moreover, no specific limits for interplanetary missions are issued. Harmonization of risk models and dose limits for exploratory-class missions are now operational priorities, in view of the short-term plans for international exploratory-class human missions. The purpose of this paper is to report on the activity of the ESA Topical Team on space radiation research, whose task was to identify the most pertinent research requirements for improved space radiation protection and to develop a European space radiation risk model, to contribute to the efforts to reach international consensus on dose limits for deep space. The Topical Team recommended ESA to promote the development of a space radiation risk model based on European-specific expertise in: transport codes, radiobiological modelling, risk assessment, and uncertainty analysis. The model should provide cancer and non-cancer radiation risks for crews implementing exploratory missions. ESA should then support the International Commission on Radiological Protection to harmonize international models and dose limits in deep space, and guarantee continuous support in Europe for accelerator-based research configured to improve the models and develop risk mitigation strategies.
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Current status of space radiobiological studies in China
Pei W, Hu W, Chai Z, Zhou G. Life Sci Space Res. 2019 May 8.
Summary:
After successfully launching two space laboratories, Tiangong-1 and Tiangong-2, China has announced her next plan of constructing the China Space Station (CSS) in 2022. The CSS will provide not only platforms for Chinese scientists to carry out experimental studies in outer space but also opportunities for open international cooperation. In this article, we review the development of China's manned space exploration missions and the preliminary plan for CSS. Besides, China has initiated space radiation research decades ago with both ground-based simulation research platform and space vehicles and has made noticeable progresses in several aspects. These include the studies for human health risk assessment using mammalian cell cultures and animals as models. Furthermore, there have been numerous studies in assessing the space environment in plant breeding.
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On the decision making criteria for cis-lunar reference mission scenarios.
El-Jaby S, Lewis BJ, Tomi L. Life Sci Space Res. 2019 Feb 28. [Article in Press]
Summary:
Space agencies are currently developing reference mission scenarios to determine if occupational dose limits, already adopted for low-Earth orbit (LEO) missions to the International Space Station (ISS), are also applicable for deep space cis-lunar missions. These cis-lunar missions can potentially last upwards of a year, during which astronauts will experience a daily low-dose from galactic cosmic radiation (GCR) and a potentially high-dose from single, or multiple, solar particle events (SPEs). Unlike GCR exposure, SPEs are difficult to predict and model due to their sporadic nature. Consequently, mission planners have decided to rely on historical SPE spectra to prepare for the 'worst case' scenario. Assuming a spherical aluminum shell as a reference spacecraft, this paper demonstrates how the choice of SPE parametric model, shield thickness, dose metric, and radiation transport code can impact the decision-making criteria for the worst case SPE, the estimated GCR dose, and consequently whether current LEO dose limits are applicable.
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Comparing HZETRN, SHIELD, FLUKA and GEANT transport codes.
John W. Norbury, Tony C. Slaba, Nikolai Sobolevsky, Brandon Reddell. NASALife Sciences in Space Research 14 (2017) 64-73.
Summary:
This paper represents the first direct comparisons of the American (NASA) and Russian (ROSCOSMOS) space radiation transport codes, HZETRN and SHIELD. Flux spectra of neutrons, light ions, heavy ions and pions were calculated for galactic cosmic ray projectiles incident on Aluminum. Some comparison calculations with the GEANT4 and FLUKA transport codes were also shown. Overall, the biggest differences between transport codes occur below the several hundred MeV region, which may be due to the differences in nuclear models employed in the different codes.
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SHIELD and HZETRN comparisons of pion production cross sections.
John W. Norburya, Nikolai Sobolevsky, Charles M. Werneth. Nuclear Inst, and Methods in Physics Research B 418 (2018) 13-17.
Summary:
The present work represents the second time that NASA and ROSCOSMOS calculations have been directly compared, and the focus here is on models of pion production cross sections used in the HZETRN (NASA) and SHIELD (ROSCOSMOS) transport codes. It was found that these models are in moderate agreement with each other and with experimental data, and further model improvements would be worthwhile.
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Comparison of space radiation GCR models to recent AMS data.
John W. Norbury, Kathryn Whitman, Kerry Lee, Tony C. Slaba, Francis F. Badavi. Life Sciences in Space Research 18 (2018) 64-71.
Summary:
This paper is the third in a series of comparisons of American (NASA) and Russian (ROSCOSMOS) space radiation calculations. The present work focuses on calculation of fluxes of galactic cosmic rays (GCR), which are a constant source of radiation that constitutes one of the major hazards during deep space exploration missions for both astronauts/cosmonauts and hardware. In this work, commonly used GCR models are compared with recently published measurements of cosmic ray Hydrogen, Helium, and the Boron-to-Carbon ratio from the Alpha Magnetic Spectrometer (AMS). All of the models were developed and calibrated prior to the publication of the AMS data; therefore this an opportunity to validate the models against an independent data set. Overall, the different GCR models are in good agreement with AMS data in energy regions important for space radiation.
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HZETRN radiation transport validation using balloon-based experimental data.
Warner JE, Norman RB, Blattnig SR. Life Sci Space Res. 2018 Feb 21.
Summary:
The deterministic radiation transport code HZETRN (High charge (Z) and Energy TRaNsport) was developed by NASA to study the effects of cosmic radiation on astronauts and instrumentation shielded by various materials. This work presents an analysis of computed differential flux from HZETRN compared with measurement data from three balloon-based experiments over a range of atmospheric depths, particle types, and energies. Model uncertainties were quantified using an interval-based validation metric that takes into account measurement uncertainty both in the flux and the energy at which it was measured. Average uncertainty metrics were computed for the entire dataset as well as subsets of the measurements (by experiment, particle type, energy, etc.) to reveal any specific trends of systematic over- or under-prediction by HZETRN. The distribution of individual model uncertainties was also investigated to study the range and dispersion of errors beyond just single scalar and interval metrics.
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Solar particle event storm shelter requirements for missions beyond low Earth orbit.
Townsend LW, Adams JH, Blattnig SR, Clowdsley MS, Fry DJ, Jun I, McLeod CD, Minow JI, Moore DF, Norbury JW, Norman RB, Reames DV, Schwadron NA, Semones EJ, Singleterry RC, Slaba TC, Werneth CM, Xapsos MA. Life Sci Space Res. 2018 Feb 21.
Summary:
Protecting spacecraft crews from energetic space radiations that pose both chronic and acute health risks is a critical issue for future missions beyond low Earth orbit (LEO). Chronic health risks are possible from both galactic cosmic ray and solar energetic particle event (SPE) exposures. However, SPE exposures also can pose significant short term risks including, if dose levels are high enough, acute radiation syndrome effects that can be mission- or life-threatening. In order to address the reduction of short term risks to spaceflight crews from SPEs, we have developed recommendations to NASA for a design-standard SPE to be used as the basis for evaluating the adequacy of proposed radiation shelters for cislunar missions beyond LEO. Four SPE protection requirements for habitats are proposed: (1) a blood-forming-organ limit of 250 mGy-equivalent for the design SPE; (2) a design reference SPE environment equivalent to the sum of the proton spectra during the October 1989 event series; (3) any necessary assembly of the protection system must be completed within 30 minutes of event onset; and (4) space protection systems must be designed to ensure that astronaut radiation exposures follow the ALARA (As Low As Reasonably Achievable) principle.
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Microgravity validation of a novel system for RNA isolation and multiplex quantitative real time PCR analysis of gene expression on the International Space Station
Parra M, Jung J, Boone TD, Tran L, Blaber EA, Brown M, et al. (2017) PLoS ONE 12(9): e0183480.
Summary:
This manuscript describes the WetLab-2 validation flight results. This work, conducted during SPX-8, is the first peer-reviewed publication of the major NASA accomplishment of successfully conducting genomic and molecular biology studies end-to-end, sample-to-data, on ISS. The WetLab-2 system allows ISS experimenters to use biological samples collected on station and in the same day extract RNA, and obtain quantitative gene expression data by PCR analysis, potentially for science, medical diagnostics, and environmental monitoring. The WetLab-2 facility now provides a novel operational on-orbit research capability for molecular biology and demonstrates the feasibility of more complex wet bench experiments in the ISS National Lab environment.
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Cosmic-ray interaction data for designing biological experiments in space.
Straume T, Slaba TC, Bhattacharya S, Braby LA. Life Sciences in Space Research, Volume 13, May 2017, Pages 51-59
Summary:
This paper provides physical cosmic-ray interaction data and related information useful to biologists who may be planning biological experiments beyond low-Earth orbit (LEO). Nuclide-specific flux and dose rates were calculated using OLTARIS and these results were used to determine particle traversal rates and doses in hypothetical biological targets. Comparisons are provided between GCR in interplanetary space and inside the ISS. Calculated probabilistic estimates of dose from solar particle events are also presented.
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Myth-free space advocacy Part I-The myth of innate exploratory and migratory urges.
Schwartz JSJ. Acta Astronaut. 2017 Aug;137:450-60.
Summary:
Space advocates often argue that we ought to explore space because we are by nature an exploring species, but this is problematic for a number of reasons. Research in biology and genetics has revealed genes associated with exploratory behavior, but `exploratory behavior' is a general term covering a wide range of information- and novelty-seeking activities and does not refer always or exclusively to, e.g., acts of discovery or migration. Though existing work recognizes a link between these genes and prehistoric human migration, the data suggest they did not impel migration but instead were selected for subsequent to migration. Additionally, exploration is not an universal in human history or culture. In cases where societies or nations have engaged in extensive exploration, including the exploration of space, it has seldom been conducted for its own sake but instead as an accessory to other ambitions, e.g., conquest, resource acquisition, prestige. In no sense relevant to space exploration is there good evidence that humans (or human societies) are innately exploratory.
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Optimal shielding thickness for galactic cosmic ray environments.
Slaba TC, Bahadori AA, Reddell BD, Singleterry RC, Clowdsley MS, Blattnig SR. Life Sci Space Res. 2017 Feb;12:1-15. Epub 2016 Dec 27.
Summary:
It has been widely thought that passive shielding strategies are inefficient for protecting astronauts from galactic cosmic rays (GCR) on long duration missions in deep space, and the mass required to appreciably reduce exposure levels is not practical given current launch and cost constraints. An implicit assumption within this shield design paradigm is that adding mass only decreases exposures levels. However, recent studies with NASAs deterministic radiation transport code, HZETRN, have shown that GCR-induced dose equivalent values initially decline over the first 20 g/cm2 of aluminum shielding and then increase substantially, revealing a previously unseen local minimum. If such a result can be verified and validated, current shield design strategies could be substantially altered. In this work, four Monte Carlo simulation codes and 3DHZETRN are used to verify the existence of a local minimum in slab geometry. It is shown that neutron and light ion interactions dominate the buildup in dose equivalent values beyond the local minimum. Future work will examine the effect of leakage and water absorbers on exposure estimates in detail to provide more informative exposure assessments for early phase vehicle design and optimization studies.
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NEUDOSE: A CubeSat mission for dosimetry of charged particles and neutrons in low-Earth orbit
Hanu AR, Barberiz J, Bonneville D, Byun SH, Chen L, Ciambella C, Dao E, Deshpande V, Garnett R, Hunter SD, Jhirad A, Johnston EM, Kordic M, Kurnell M, Lopera L, McFadden M, Melnichuk A, Nguyen J, Otto A, Scott R, Wagner DL, Wiendels M. NEUDOSE: A CubeSat mission for dosimetry of charged particles and neutrons in low-Earth orbit. Radiat Res. 2016 Dec 21. [Epub ahead of print]
Summary:
This articles introduces the NEUtron DOSimetry & Exploration (NEUDOSE) CubeSat mission that intends to further our understanding of lonterm exposure to space radiation by investigating how charged and neutral particles contribute to the human equivalent dose during low-Earth orbit missions. The NEUDOSE CubeSat is equipped with the Charged & Neutral Particle Tissue Equivalent Proportional Counter (CNP-TEPC) which is an advanced radiation monitoring instrument that uses active coincidence techniques to separate the interactions of charged particles and neutrons in real time. In the article we describe the CNP-TEPC instrument design, the NEUDOSE CubeSat and how the measurements will be used to accurately characterize the dose and quality factors typical of unshielded radiation exposure in low-Earth orbit.
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Cosmic radiation measurements on the Foton-M4 satellite by passive detectors.
Strádi A, Pálfalvi JK, Szabó J, Pázmándi T, Ivanova OA, Shurshakov VA. Acta Astronaut. 2017 Feb;131:110-2.
Summary:
The Russian Foton spacecraft was designed to deliver scientific experiments to low Earth orbit and return them safely to the ground for further analysis. During the 44-d Foton-M4 satellite mission in 2014 several passive cosmic ray detectors were exposed outside (in a single holder) and inside (in 4 locations) the recoverable capsule to study the radiation field. Within the paper the obtained absorbed dose rates has been compared to those measured on the previous Foton-M flights, during the Bion-M1 mission and in the Columbus module of the International Space Station.
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Initial report on International Space Station radiation environment monitor performance.
Stoffle N, Keller J, Semones E. Houston, TX: NASA Johnson Space Center, 2016 Sep. 44 p. NASA/TM-2016-219278.
Summary:
The International Space Station Radiation Environment Monitor (ISS REM) is a small, low-power, hybrid-pixel radiation detector based on the CERN Timepix tech- nology. Five detectors were flown aboard ISS beginning in late 2012. This document contains the initial results from the first year of operation as reviewed in late 2013, including hardware issues, detector performance, and development efforts.
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THESEUS Consortium, European Science Foundation. Towards Human Exploration of Space: a EUropean Strategy - Roadmap

Summary:
Online report on an integrated life sciences research roadmap enabling European human space exploration in synergy with the ESA strategy, taking advantage of the expertise available in Europe and identifying the potential of non-space applications and dual research and development.
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Space Radiation and Human Exposures, A Primer.
Gregory A. Nelson 2016) Radiation Research: April 2016, Vol. 185, No. 4, pp. 349-358.
Summary:
This article focuses on the various components of the space radiation environment and the human exposures that it creates, including sources of these particles, estimation of human health risks, informed by radiobiological experiments and epidemiology studies, leading to models of cancer-associated and non-cancer risks.
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The March 2016 Boice Report (No. 46) on “Mars Matters” has been released.
Summary:
Professor John Boice of the Vanderbilt University School of Medicine is the President of the National Council of Radiation Protection and Measurements and publishes a monthly column in Health Physics. This column lays out the substance of his talk to the Human Research Program workshop held in Galveston in February, 2016.
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The Space Radiation Environment | Track Structure | Interactions of Radiation with Matter | Shielding

The Space Radiation Environment

Occam's broom* and the dirty DSB: Cytogenetic perspectives on cellular response to changes in track structure and ionization density
Cornforth MN. Int J Radiat Biol. 2020 Jan 23. [Epub ahead of print] Review.
Summary:
Given equal doses, it is well-known that densely ionizing radiations are more potent in causing a number of biological effects compared to sparsely ionizing radiations, such as x- or gamma rays. According to classical models of radiation action, this results from differences in the spatial distribution of lesions along charged particle tracks. In recent years it has become fashionable instead to explain RBE/LET relationships as being due to "qualitative" differences in the types of molecular lesions that each type of radiation produces at the nanometer level. There is likely a kernel of truth to this idea, but to ignore the fact that such differences result from the distribution of lesions that span sub-micrometer cellular distances is an unjustifiably narrow stance tantamount to employing Occam’s Broom. From a cytogenetic perspective, not only are such spatial considerations indispensable in explaining the impact of ionization density upon higher order biological endpoints, the explanations they provide render arguments based principally on the quality of IR damage largely superfluous.
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Update on Galactic Cosmic Ray Integral Flux Measurements in Lunar Orbit With CRaTER
Zeitlin C, Schwadron NA, Spence HE, Jordan AP, Looper MD, Wilson J, Mazur JE, Townsend LW. Space Weather. 19 June 2019:17.
Summary:
We report measurements of increasing intensities of Galactic Cosmic Ray protons and helium ions from 2015 through the end of 2018. The overall decrease in solar activity in this period has led to an increased flux of energetic particles, to levels that are approaching those observed during the previous solar minimum in 2009/2010, which was the deepest minimum of the Space Age. The data have implications for human exploration of deep space, and may provide useful benchmarks for models of cosmic ray fluxes as a function of solar modulation.
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Experimental Assessment of Lithium Hydride's Space Radiation Shielding Performance and Monte Carlo Benchmarking.
Schuy C, La Tessa C, Horst F, Rovituso M, Durante M, Giraudo M, Bocchini L, Baricco M, Castellero A, Fioreh G, Weber U. Radiation Research, 191(2):154-161 (2018).
Summary:
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.
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Pion-heavy ion scattering total and inelastic cross sections for space radiation applications
Francis A. Cucinotta, Myung-Hee Y. Kim, Premkumar B. Saganti Nuclear Inst. and Methods in Physics Research B 438 (2019) 14-19.
Summary:
Secondary pions are produced by cosmic ray proton and heavy ion induced collisions with spacecraft shielding materials and tissue. In this paper we describe methods for compiling a data-base of energy dependent pion-heavy ion inelastic sections for interactions of pions with common shielding and tissue atoms over a wide energy range (20 MeV to 100 GeV). We report on extensive comparisons to experimental data for energy dependent total and absorption (inelastic) cross sections. General agreement between model and experiments within 20% is found.
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Synergy Theory in Radiobiology.
Ham DW, Song B, Gao J, Yu J. and Sachs RK. Radiat. Res. 189, 225-237 (2018).
Summary:
We characterize, exemplify, compare and critically evaluate mathematical/computational synergy analysis methods currently used in biology, and used or potentially applicable in radiobiology. No new experimental results are presented. As examples, we consider dose-effect relations (DERs) for single ions simulating components of the galactic cosmic ray mixed field. The endpoints are murine Harderian gland tumors or in vitro chromosome aberrations. Baseline no-synergy/no-antagonism mixture DERs are then calculated from the one-ion DERs. Synergy analysis of mixed radiation field action when components' individual DERs are very curvilinear should not consist of simply comparing to the sum of the components' effects. Many different synergy analysis theories are currently used in biology to replace simple effect additivity synergy theory. Marked curvilinearity must often be allowed for in current radiobiology, especially when studying possible non-targeted ("bystander") effects. We give evidence that for most synergy experiments and observations, incremental effect additivity is the appropriate replacement. It has a large domain of applicability, being useful even when pronounced individual DER curvilinearity is a confounding factor. It allows calculation of 95% confidence intervals for baseline mixture DERs taking into account parameter correlations; if non-targeted effects are important this gives much tighter intervals than neglecting the correlations. Incremental effect additivity always obeys two consistency conditions that simple effect additivity usually fails to obey: a ''mixture of mixtures principle'' and the standard ''sham mixture principle''. The mixture of mixtures principle is important in radiobiology because even nominally single-ion radiations are usually mixtures when they strike the biological target, due to intervening material.
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Atmospheric Cosmic-Ray Variation and Ambient Dose Equivalent Assessments Considering Ground Level Enhancement Thanks to Coupled Anisotropic Solar Cosmic Ray and Extensive Air Shower Modeling.
Hubert G and Aubry S. Radiation Research: Nov 2017;188(5):517-531.
Summary:
This work investigates the impact of Forbush decrease (FD) and ground-level enhancement (GLE) in the atmosphere, based on solar and galactic cosmic-ray models and the extensive air shower simulations. The calculated ambient dose equivalents were compared with flight measurements in quiet solar conditions. Doses induced by extreme GLE events were investigated specifically for London to New York flights.
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The radiation environment on the surface of Mars - Numerical calculations of the galactic component with GEANT4/PLANETOCOSMICS.
Matthiä D, Berger T. Life Sci Space Res. 2017 Apr 1. [Article in Press]
Summary:
The article describes the methodology and the results of a simulation of the GCR induced radiation environment on the surface of Mars. The simulation was performed with the Monte-Carlo package GEANT4 for the time period between 15 November 2015 and 15 January 2016. The pressure and shielding provided by the atmosphere were derived from measurements and backscattering from the Martian regolith was considered. The article presents calculated particle intensities for neutrons, protons and heavy ions as well as for photons, muons, electrons/positrons and pions. An analysis of the upward and downward directed components of these particles is performed and interactions of the particles with the atmosphere are discussed. The particle fluxes are used to calculate the total dose rate and dose equivalent rate and the individual particle contributions.
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Solar Energetic Particles:A Modern Primer on Understanding Sources, Acceleration and Propagation.
Reames, Donald V., ( ISBN 978-3-319-50870-2)., Springer Lecture Notes in Physics Vol. 932, 127 p. (2017)
Summary:
Solar Energetic Particles is a modern primer on the sources, acceleration, and transport of solar energetic particles (SEPs). In a field with beautiful images of the Sun, SEPs are virtually invisible, and only recently have we found that the abundances of the elements, isotopes, ionization states, and spectra of elements from H all the way up through Pb, carry a wealth of information on their acceleration, transport and even the temperature of the plasma at their sources. The book discusses the varied and controversial history of SEP theory, the physics of magnetic reconnection and wave-particle interactions in the "impulsive" SEP events from solar flares and jets, the large, "gradual" SEP events accelerated at shock waves driven out from the Sun by coronal mass ejections, and the recent summary of the fluence and spectra of GeV protons in the largest SEP events and the radiation hazard they pose.
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Using spectral shape and predictor fluence to evaluate temporal dependence of exposures from solar particle events.
Kim, M.-H. Y., S. R. Blattnig, M. C. Clowdsley, and R. B. Norman (2017), Space Weather,15, doi:10.1002/2016SW001552.
Summary:
This paper introduces a process of rapidly estimating temporal exposures to SPEs by implementing the distributions of the organ doses and the spectral-shape characterization of the major SPEs. Simultaneously, the unconditional probability exceeding the NASA 30 day limit of a blood-forming organ dose is estimated by taking into account the variability of detailed spectra of SPEs for a given predictor fluence. These temporal evaluations of SPEs can be applied to the development of real-time guidance and protection systems on improving mitigation of adverse effects during space missions.
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Solar proton exposure of an ICRU sphere within a complex structure Part I: Combinatorial geometry.
Wilson JW, Slaba TC, Badavi FF, Reddell BD, Bahadori AA. Life Sci Space Res. 2016 May 24. [Article in Press]
Summary:
Highly efficient three dimensional (3D) transport procedures for neutrons and light ions were recently developed for NASAs space radiation transport code, HZETRN. The improved model, referred to as 3DHZETRN, was tested in simplified spherical geometry and compared against Monte Carlo simulations in prior publications. This article describes an extension of 3DHZETRN to allow transport in more complex combinatorial geometry (i.e. combinations of cylinders, spheres, boxes, and ellipsoids). The updated code is compared to Monte Carlo simulations for the case of a tissue sphere surrounded by a cylindrical shell with additional internal geometric objects. It is shown that 3DHZETRN agrees with the Monte Carlo codes to the extent they agree with each other and is several orders of magnitude faster for this application.
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Life science experiments performed in space in the ISS/Kibo facility and future research plans.
Ohnishi T., J Radiat Res. 2016 Apr 29. [Epub ahead of print]
Summary:
Experiments in the Japanese ‘Kibo’ facility in the International Space Station (ISS) have been performed 2009, and two additional experiments are currently in progress. This paper is a review of these experiments, including new information from space-based experiments involving radiation biology.
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Extreme solar event of AD775: Potential radiation exposure to crews in deep space.
Townsend LW, Porter JA, deWet WC, Smith WJ, McGirl NA, Heilbronn LH, Moussa HM. Acta Astronaut. 2016 Jun-Jul;123:116-20.
Summary:
Over the present era of human travels in space, the issue regarding what constitutes a reasonable "worst-case solar particle event" has often arisen. Within the space radiation protection community, three aspects of such an event are usually considered: 1. What event magnitude event is reasonable? 2. How probable is its occurrence? 3. What are its potential health effects on space-faring crews/ This article seeks to address these questions by investigating an extreme event that scientific evidence suggests occurred approximately 1200 years ago.
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Dose and dose-rate effects of ionizing radiation: a discussion in the light of radiological protection.
Ruhm W, Woloschak GE, et al. Radiation and Environmental Biophysics, November 2015, Volume 54, Issue 4, pp 379-401. First online: 05 September 2015
Summary:
This is a summary of a dedicated workshop on this topic held in May 2015 in Kyoto, Japan. This paper describes the historical development of the DDREF concept in light of emerging scientific evidence on dose and dose-rate effects, summarizes the conclusions recently drawn by a number of international organizations (e.g., BEIR VII, ICRP, SSK, UNSCEAR, and WHO), mentions current scientific efforts to obtain more data on low-dose and low-dose-rate effects at molecular, cellular, animal and human levels, and discusses future options that could be useful to improve and optimize the DDREF concept for the purpose of radiological protection.
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Neutron yields and effective doses produced by galactic cosmic ray interactions in shielded environments in space.
Heilbronn LH, Borak TB, Townsend LW, Tsai P-E, Burnham CA, McBeth RA. Life Sci Space Res. 2015 Oct 23. [Article in Press]
Summary:
The intent of the research reported in this paper was to investigate what ranges of neutron energies are important for the measurement of neutron fluence and neutron effective dose in shielded environments in space. The methodology utilized transport model calculations of a GCR spectrum incident on simple shielding configurations made of aluminum and water. The results show that a significant fraction of the effective dose and fluence lies above the 20-50 MeV range that is the limit to where a majority of the neutron instrumentation flown previously in space respond. An interesting secondary outcome of the research shows that a simple two component proton+helium or three component proton+helium+oxygen input spectrum in transport model calculations can reproduce the neutron spectrum generated by the full, 26-element GCR spectrum using the same simple spectrum across both shielding materials and across all thicknesses.
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Badhwar-O'Neill 2014 galactic cosmic ray flux model description.
O'Neill PM, Golge S, Slaba TC. Houston, TX: NASA Johnson Space Center, 2015 Mar. 32 p. NASA/TP-2015-218569.
Summary:
The Badhwar-O'Neill (BON) Galactic Cosmic Ray (GCR) model is based on GCR measurements from particle detectors. The model has mainly been used by NASA to certify microelectronic systems and for the analysis of radiation health risks to astronauts in space missions. The BON14 model numerically solves the Fokker-Planck differential equation to account for particle transport in the heliosphere due to diffusion, convection, and adiabatic deceleration under the assumption of a spherically symmetric heliosphere. The model also incorporates an empirical time delay function to account for the lag of the solar activity to reach the boundary of the heliosphere. This technical paper describes the most recent improvements in parameter fits to the BON model (BON14). Using a comprehensive measurement database, it is shown that BON14 is significantly improved over the previous version, BON11.
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Evaluation of the new radiation belt AE9/AP9/SPM model for a cislunar mission.
Badavi FF, Walker SA, Santos Koos LM. Acta Astronaut. 2014;102:156-68.
Summary:
A multi-vehicle mission is planned for the epoch of February 2020 from LEO to the Earth-moon Lagrange-point two (L2), located approximately 63,000km beyond the orbit of the Earth-Moon binary system. During the LEO-GEO transit, the crew and cargo vehicles will encounter exposure from trapped particles and attenuated GCR, followed by free space exposure due to GCR and SEP. In this work, the amount of exposure acquired within the trapped field, along the design trajectory of the crew vehicle, using the new AE9/AP9/SPM model is evaluated against the older AE8/AP8 model. The analysis is then extended to the GCR dominated en-route, cislunar L2 space and return trajectories in order to provide cumulative exposure estimates for the duration of the mission.
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Validation of the new trapped environment AE9/AP9/SPM at low Earth orbit.
Badavi FF. Adv Space Res. 2014;54(6):917-28.
Summary:
One goal of this paper is to validate the older AE8/AP8 and the new AE9/AP9/SPM trapped radiation models against ISS dosimetric measurements for a silicon based detector, and to assess the improvements in the AE9/AP9/SPM model as compared to AE8/AP8 using both isotropic and anisotropic spectra. For angular validation AP8 and AP9 are compared with measurements from the compact environment anomaly sensor (CEASE) science instrument package, flown June 2000-July 2006. Particular emphasis is put on the validation of proton flux profiles at differential 40 MeV and integral >40 MeV, in the vicinity of the South Atlantic Anomaly, where protons exhibit east-west (EW) anisotropy and have a relatively narrow pitch angle distribution.
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Does the worsening galactic cosmic radiation environment observed by CRaTER preclude future manned deep space exploration?
N. A. Schwadron, J. B. Blake, A. W. Case, C. J. Joyce1, J. Kasper, J. Mazur, N. Petro, M. Quinn, J. A. Porter, C.W. Smith, S. Smith, H. E. Spence, L.W. Townsend, R. Turner, J. K.Wilson, and C. Zeitlin. Space Weather (online), 11, doi:10.1002/2014SW001084
Summary:
Data from a cosmic ray telescope onboard NASA's Lunar Reconnaissance Orbiter show that while increasing fluxes of cosmic rays "are not a show stopper for long duration missions (e.g., to the Moon, an asteroid, or Mars), galactic cosmic radiation remains a significant and worsening factor that limits mission durations."
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Cosmic rays are intensifying. Galactic cosmic rays are a mixture of high-energy photons and subatomic particles accelerated to near-light speed by violent events such as supernova explosions. Astronauts are protected from cosmic rays in part by the sun: solar magnetic fields and the solar wind combine to create a porous 'shield' that fends off energetic particles from outside the solar system. The problem is "The sun and its solar wind are currently exhibiting extremely low densities and magnetic field strengths, representing states that have never been observed during the Space Age. As a result of the remarkably weak solar activity, we have also observed the highest fluxes of cosmic rays in the Space Age."
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The shielding action of the sun is strongest during solar maximum and weakest during solar minimum. At the moment we are experiencing Solar Max, which should be a good time for astronauts to fly. However, the solar maximum of 2011-2014 is the weakest in a century, allowing unusual numbers of cosmic rays to penetrate the solar system.
This situation could become even worse if, as some researchers suspect, the sun is entering a long-term phase of the solar cycle characterized by relatively weak maxima and deep, extended minima. In such a future, feeble solar magnetic fields would do an extra-poor job keeping cosmic rays at bay, further reducing the number of days astronauts can travel far from Earth.
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Active magnetic radiation shielding system analysis and key technologies.
S.A. Washburn, S.R. Blattnig, R.C. Singleterry, and S.C. Westoverc, published in Life Sciences in Space Research 4 (2015) 22-34.
Summary:
Washburn et al. performed a trade study on active magnetic radiation shielding in order to assess feasibility and to derive requirements for technology development needed to enable the concept considered. In order to be able to cover the trade space in a reasonable amount of computations time, rapid approximate calculation methodology was used that decoupled the magnetic deflection of particles from the transport through passive shielding which was performed using HZETRN. It was found that the type of active shielding considered was not practical due to the large structural masses needed to control the stresses and pressures associate with the fields and that major breakthrough in materials technologies would be needed to enable the concept.
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Track Structure

Track structure model of microscopic energy deposition by protons and heavy ions in segments of neuronal cell dendrites represented by cylinders or spheres.
Alp M, Cucinotta FA.. Life Sci Space Res. 2017 Apr 2. [Article in Press]
Summary:
The purpose of the present work is to develop computational methods to evaluate microscopic energy deposition (ED) in volumes representative of neuron cell structures, including segments of dendrites and spines, using a stochastic track structure model. We consider cylindrical and spherical microscopic volumes of varying geometric parameters and aspect ratios from 0.5 to 5 irradiated by protons, and 3He and 12C particles at energies corresponding to a distance of 1 cm to the Bragg peak, which represent particles of interest in Hadron therapy as well as space radiation exposure.
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Time-lapse monitoring of DNA damage colocalized with particle tracks in single living cells.
McFadden CH, Hallacy TM, Flint DB, Granville DA, Asaithamby A, Sahoo N, Akselrod MS, Sawakuchi GO. Int J Radiat Oncol Biol Phys. 2016 Sep 1;96(1):221-7.
Summary:
Understanding the DNA damage and repair induced by high-energy charged particles such as protons and heavier ions is crucial for developing novel strategies to maximize the use of particle therapy to treat cancer patients as well as to understand the effects of space radiation in humans. However, spatiotemporal studies of DNA damage and repair for beam energies relevant to particle therapy and radiation protection in space have been challenging. We report a technique that enables spatiotemporal measurement of radiation-induced damage in live cells and colocalization of this damage with charged particle tracks over a broad range of beam energies. The technique uses novel fluorescence nuclear track detectors with a custom-built fluorescence confocal laser scanning microscope to visualize particle track traversals within the subcellular compartments of live cells within seconds after injury. Our custom-built microscope can be shipped and installed in any beam line (horizontal and vertical beams) including particle therapy beams and beam lines used for space radiation research such as the NASA Space Radiation Laboratory. This technique makes possible investigations of DNA damage response processes that happen immediately after DNA damage in high-energy beams that are not available in microbeam facilities.
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Experimental microdosimetry: History, applications and recent technical advances.
Braby LA. Radiat Prot Dosimetry. 2015 Apr 15. [Epub ahead of print]
Summary:
This paper summarizes the 50 year development of microdosimetry detectors from delicate laboratory research instruments to rugged detectors that can be used in a wide variety of radiation environments. The relative biological risk presented by different types of ionizing radiation can be estimated based on the amount of energy each type deposits in small volumes such as a cell nucleus. Radiations which deposit a large amount of energy in a few small volumes tend to be more damaging than radiations that deposit a small amount of energy in a large number of small volumes, even though the total amount of energy deposited in an organ is the same. The characterization of energy deposition in small volumes, known as microdosimetry, has been the basis of a sequence of instruments used to evaluate radiation exposure on the STS and ISS for nearly two decades.
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Description and Verification of an Algorithm for Obtaining Microdosimetric Quantities for High-LET Radiation Using a Single TEPC without Pulse Height Analysis.
Thomas B. Borak and Phillip L. Chapman (2014) Radiation Research: October 2014, Vol. 182, No. 4, pp. 396-407.
Summary:
Microdosimetric spectra of single event distributions have been used to provide estimates of quality factors for radiation protection of high LET radiation. It becomes difficult to measure, record and store energy deposition from single events in situations with high dose rates. An alternative approach is to store random energy deposition events in a sequence of fixed time intervals that does not require recording single events. This can be accomplished with one detector without pulse shaping or pulse height analysis. We present the development of the algorithm using expectation analyses of the statistical estimators for moments of lineal energy. The method can provide prompt real-time information in circumstances that restrict detector configurations in terms of size, mass and power consumption such as personal dosimetry during an EVA It can be adapted for measurements of any quantity that is linearly related to absorbed dose, such as estimation of dose averaged LET.
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Biophysics of NASA Radiation Quality Factors.
Francis A. Cucinotta. Radiat Prot Dosimetry (2015) doi: 10.1093/rpd/ncv144. First published online: April 16, 2015
Summary:
NASA has implemented new radiation quality factors (QFs) for projecting cancer risks from space radiation exposures to astronauts. The NASA QFs are based on particle track structure concepts with parameters derived from available radiobiology data, and NASA introduces distinct QFs for solid cancer and leukaemia risk estimates. A key feature of the NASA QFs is to represent the uncertainty in the QF assessments and evaluate the importance of the QF uncertainty to overall uncertainties in cancer risk projections. In this article, the biophysical basis for the probability distribution functions representing QF uncertainties is reviewed, and approaches needed to reduce uncertainties are discussed.
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Interactions of Radiation with Matter

Physical characteristics at the turnover-points of relative biological effect (RBE) with linear energy transfer (LET).
Jones B, Hill MA. Phys Med Biol. 2019 Oct 30. [Epub ahead of print]
Summary:
This article shows that ions of each lighter element (up to Ferric ions) exert their maximum relative biological effect (RBE) at unique values of ionisation clustering (denoted by a linear energy transfer of LETU). This is the LET value at which RBE (and radiosensitivity) begins to fall with further increases of LET. At LETU the ions are at 0.99 of their fully expressed nuclear charge and share some kinematic properties: a velocity of 3-4 nm.fs-1 per nucleon, or around 6-8 nm.fs-1 per unit Z, dimensions that are relevant to radiochemical changes and to DNA and nucleosome.
These findings differ from conclusions drawn from pooled ionic RBE data, which have previously assumed that the maximum bio-effect of all light ions occured at a LET of around 120 keV per micrometre. There are potential implications for future RBE estimations (based on LET and absorbed dose) in radiotherapy, radioprotection and space travel.
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Enhanced GEANT4 Monte Carlo simulations of the space radiation effects on the International Space Station and Apollo missions using high-performance computing environment.
Lund M, Jevremovic T. Acta Astronaut. 2019 Dec;165:219-28. Epub 2019 Sep 19.
Summary:
This paper introduces a new simulation model and application using GEANT4 with multithreading and Message Passing Interface (MPI) that greatly reduces computational time to hours instead of weeks without any post simulation processing based on high-performance computing. This paper also introduces a new set of GEANT4 computational detectors for calculating dose distribution, besides the historically used International Commission of Radiation Units simulation spheres. The computational detectors include a thermoluminescent detector, tissue equivalent proportional counter, and human phantom, along with additional new scorers to calculate dose equivalence based on the International Commission of Radiation Protection standards. This study presents GEANT4 simulations of the dose deposition for the International Space Station and the Apollo 11 and 14 missions, which replicate well the dose measurements during these missions. The simulations of both Apollo missions show consistent doses from galactic cosmic rays and radiation belts with a small variation in dose distribution across the Apollo capsule. The greatest contributor to radiation dose for both Apollo missions in the simulations came from galactic cosmic rays. Simulations of historical solar particle events during an Apollo missions show a solar particle event would not be fatal and below mission limits. These GEANT4 models also provides the values of the dose deposition and dose equivalent for various organs within a human phantom in the International Space Station and Apollo command module, which are developed for the first time using this GEANT4 based application.
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Evaluating the effectiveness of common aerospace materials at lowering the whole body effective dose equivalent in deep space.
Bond DK, Goddard B, Singleterry RC Jr, Bilbao y Leóna S. Acta Astronaut. 2019 Aug 22. [Article in Press]
Summary:
Materials have a primary purpose in the design of space vehicles, such as fuels, walls, racks, windows, etc. Additionally, each will also affect space radiation protection. The shielding capabilities of 59 materials are evaluated for deep space travel, in terms of whole body effective dose equivalent, ED, and number of nucleons per volume#ofNucleonsVolume. The hydrogen rich materials are evaluated further using the number of Hydrogen Atoms per mass and number of Hydrogen Atoms per volume. All evaluated materials, through density, composition, and shielding ability, can be categorized into three groups: metals, polymers and composites, and fuels, hydrides, and liquid gases. The analyses presented in the article shows that a "magic" material is not possible; however polymers and composites should be used instead of metals, if they can serve their primary purpose. Polyethylene and magnesium borohydride are shown to be the best feasible materials from this sample. Thermal neutron absorbers, 6Li and 10B, do not have a significant effect on ED. Alloying of materials, such as aluminum, for strengthening purposes, do not increase ED. Ultimately, a space vehicle is a system of systems and radiation protection must be one of them.
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Advances in space radiation physics and transport at NASA.
Norbury JW, Slaba TC, Aghara S, Badavi FF, Blattnig SR, Clowdsley MS, Heilbronn LH, Lee K, Maung KM, Mertens CJ, Miller J, Norman RB, Sandridge CA, Singleterry R, Sobolevsky N, Spangler JL, Townsend LW, Werneth CM, Whitman K, Wilson JW, Xu SX, Zeitlin C. Life Sci Space Res. 2019 Jul 10. [Article in Press] Review.
Summary:
This paper describes significant new discoveries and advances made in space radiation physics and transport over the past decade. Some of the most important new developments include the following: 1) The discovery of a minimum in the dose-equivalent versus depth curve; 2) A large contribution to dose from pions; 3) A large contribution of neutrons and light ions to dose equivalent for realistic shield thickness; 4) A realization that there are large and significant gaps in cross section measurements needed for space radiation; 5) Development of 3-dimensional deterministic transport methods; 6) Development of a fully relativistic nuclear fragmentation model; 7) Development of a GCR simulation capability at the NASA Space Radiation Laboratory; 8) Development of an On-Line Tool for the Assessment of Radiation In Space (OLTARIS); 9) Development of a Nowcast of Atmospheric Ionizing Radiation for Aviation Safety (NAIRAS) model. Each of these advances contribute significantly to improving our knowledge of space radiation and will help achieve safer long term space travel. The paper is coauthored by 22 scientists from various NASA centers, universities and commercial companies, and includes work funded by NASA's Human Research Program and Advanced Exploration Systems.
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Thick target neutron yields from 100- and 230- MeV/nucleon helium ions bombarding water, PMMA, and iron
P. Tsai, L. Heilbronn, B. Lai, Y. Iwata, T. Murakami, R. Sheu. Nuclear Instruments and Methods in Physics Research B. 2019;449,62-70.
Summary:
The yields of secondary neutrons produced from 100- and 230-MeV/nucleon 4He ions, respectively, stopping in thick natFe, PMMA and water targets were measured. Double-differential thick target neutron yields, angular distributions, and total neutron yields per ion were benchmarked against model calculations with the PHITS, FLUKA, and MCNP Monte Carlo simulation codes. Our results indicate that significant improvements are needed in the physics models used to describe 4He-induced nuclear reactions for predictions of neutron production.
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Shielding

Radiation engineering analysis of shielding materials to assess their ability to protect astronauts in deep space from energetic particle radiation
Acta Astronaut. 2020 Feb 15. Manning B, Singleterry R.
Summary:
This paper is a continuation of a paper written in 2013 (Same title, AA V.91 p.49-54). These papers together look at launch mass to LEO to get astronauts to Mars and back within a GCR proxy total mission exposure limit of 150 mSv effective dose. This paper (AA 2020-Feb-15 preprint) focuses on the difference between spherical vehicles (the original paper) and right circular cylinder vehicles. It also analyzes a whole body personal protection system and the tanking of shielding materials. A newer version of OLTARIS was used along with the latest GCR environment model. As in the previous paper, liquid hydrogen, liquid methane, water, polyethylene, and aluminum are used in the analyses. This paper shows that a single SLS launch of material will get the astronauts to their total proxy limit in about 180 days. No single launch configuration of materials will get an astronaut to 400 days (a typical Mars mission duration in transit). This prompted another study reported on in AIAA SPACE 2018-5360 "Maintaining Human Health for Human-Mars" by Robert Moses, Dennis Bushnell, et. al. that showed it is possible to get humans to and from Mars within the proxy limit; however, transit times of 60 days one-way are necessary. The last item touched on in this paper is an initial investigation of the ray tracing approximation used to convert CAD models of spacecraft to radiation analysis models that can be used in codes like OLTARIS. This is prompting new research in this area.
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Design and dosimetry of a facility to study health effects following exposures to fission neutrons at low dose rates for long durations.
Int J Radiat Biol. 2019 Nov 5. [Epub ahead of print] Borak TB, Heilbronn L, Krumland N, Weil MM.
Summary:
We developed a vivarium in which rodents could be irradiated with neutrons for protracted periods of time. The neutron source is a panoramic irradiator containing 252Cf located in a concrete shielded vault with a footprint of 53 m2. The vault can accommodate sufficient caging to simultaneously irradiate 900 mice and 60 rats for durations up to 400 d at a dose rate of 1 mGy/d and is approved for extended animal husbandry. Mixed field dosimetry was performed using a miniature GM counter and CaF2:Dy thermoluminescent dosimeters (TLD) for photons and tissue-equivalent proportional counters for neutrons. The photon contribution is 20% of the total dose. The uncertainty in the delivered dose is estimated to be ±20%. The dose averaged LET for the charged particle recoil nuclei is 68 keV/µ.
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Applied nuclear physics at the new high-energy particle accelerator facilities
Durante M, Golubev A, Park W-Y, Trautmann C. Physics Reports. 2019;800,1-37.
Summary:
New, large accelerator facilities are currently under construction in Europe, Asia, and USA. The upcoming facilities open new opportunities for research in biomedical applications, such as particle radiography, radioactive beam imaging, ultra-high dose rates and new ions for therapy. Moreover, space radiation research and materials science can successfully exploit these new centers. The new facilities can pave the way to many future applications of nuclear physics for the benefit of the society. In this paper we will summarize the current status of applied sciences at high-energy accelerators, describe the characteristics of some of the machines under construction (FAIR, NICA, RAON, ELI) and discuss the new opportunities offered by these facilities in applied sciences.
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GCR Simulator Reference Field and a Spectral Approach for Laboratory Simulation
Slaba TC, Blattnig SR, Norbury JW, Rusek A, Tessa CL, and Walker SA. NASA Technical Publication NASA/TP-2015-218698, March 2015.
Summary:
The galactic cosmic ray (GCR) simulator at the NASA Space Radiation Laboratory (NSRL) is intended to deliver the broad spectrum of particles and energies encountered in deep space to biological targets in a controlled laboratory setting. In this work, certain aspects of simulating the GCR environment in the laboratory are discussed. A single reference field for deep space missions is identified and an approach for selecting beams at NSRL to simulate the designated reference field is presented. Drawbacks of the proposed methodology are discussed and weighed against alternative simulation strategies. The neutron component and track structure characteristics of the simulated field are discussed in this context.
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Proceedings of the National Cancer Institute Workshop on Charged Particle Radiobiology.
Mohan R, Held KD, Story MD, Grosshans D, Capala J. Int J Radiat Oncol Biol Phys. 2018 Mar 15;100(4):816-31.
Summary:
In April 2016, the National Cancer Institute hosted a multidisciplinary workshop to discuss the current knowledge of the radiobiological aspects of charged particles used in cancer therapy to identify gaps in that knowledge that might hinder the effective clinical use of charged particles and to propose research that could help fill those gaps. The workshop was organized into 10 topics ranging from biophysical models to clinical trials and included treatment optimization, relative biological effectiveness of tumors and normal tissues, hypofractionation with particles, combination with immunotherapy, "omics," hypoxia, and particle-induced second malignancies. Discussion also included the potential advantages of heavier ions, notably carbon ions, because of their increased biological effectiveness, especially for tumors frequently considered to be radiation resistant, increased effectiveness in hypoxic cells, and potential for differentially altering immune responses.
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Overview of the NASA space radiation laboratory.
Chiara La Tessa, Michael Sivertz, I-Hung Chiang , Derek Lowenstein, Adam Rusek. Life Sciences in Space Research 11 (2016) 18-23
Summary:
The NASA Space Radiation Laboratory (NSRL) is a multidisciplinary center for space radiation research funded by NASA and located at the Brookhaven National Laboratory (BNL), Upton NY. Operational since 2003, the scope of NSRL is to provide ion beams in support of the NASA Humans in Space program in radiobiology, physics and engineering to measure the risk and ameliorate the effect of radiation in space. Recently, it has also been recognized as the only facility in the U.S. currently capable of contributing to heavy ion radiotherapy research. This work contains a general overview of NSRL structure, capabilities and operation.
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Twenty years of space radiation physics at the BNL AGS and NASA Space Radiation Laboratory.
J. Miller and C. Zeitlin. Life Sciences in Space Research 9 (2016) 12-18
Summary:
Highly ionizing atomic nuclei HZE in the GCR will be a significant source of radiation exposure for hu- mans on extended missions outside low Earth orbit. Accelerators such as the LBNL Bevalac and the BNL AGS, designed decades ago for fundamental nuclear and particle physics research, subsequently found use as sources of GCR-like particles for ground-based physics and biology research relevant to space flight. The NASA Space Radiation Laboratory at BNL was constructed specifically for space radiation re- search. Here we review some of the space-related physics results obtained over the first 20 years of NASA-sponsored research at Brookhaven.
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Genesis of the NASA Space Radiation Laboratory
Schimmerling W. Life Sci Space Res. 2016. Epub 2016 Mar 7.
Summary:
A personal recollection of events leading up to the construction and commissioning of NSRL, including reference to precursor facilities and the development of the NASA Space Radiation Program.
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Galactic cosmic ray simulation at the NASA Space Radiation Laboratory.
John W. Norbury, Walter Schimmerling, Tony C. Slaba, Edouard I. Azzam, Francis F. Badavi, Giorgio Baiocco, Eric Benton, Veronica Bindi, Eleanor A. Blakely, Steve R. Blattnig, David A. Boothman, Thomas B. Borak, Richard A. Britten, Stan Curtis, Michael Dingfelder, Marco Durante, William S. Dynan, Amelia J. Eisch, S. Robin Elgart, Dudley T. Goodhead, Peter M. Guida, Lawrence H. Heilbronn, Christine E. Hellweg, Janice L. Huff, Amy Kronenberg, Chiara La Tessa, Derek I. Lowenstein, Jack Miller, Takashi Morita, Livio Narici, Gregory A. Nelson, Ryan B. Norman, Andrea Ottolenghi, Zarana S. Patel, Guenther Reitz, Adam Rusek, Ann-Sofie Schreurs, Lisa A. Scott-Carnell, Edward Semones, Jerry W. Shay, Vyacheslav A. Shurshakov, Lembit Sihver, Lisa C. Simonsen, Michael D. Story, Mitchell S. Turker, Yukio Uchihori, Jacqueline Williams, Cary J. Zeitlin.
Life Sciences in Space Research 8, 1-68 (February 2016)
Summary:
Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation.
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Reference field specification and preliminary beam selection strategy for accelerator-based GCR simulation.
Slaba TC, Blattnig SR, Norbury JW, Rusek A, La Tessa C Life Sci Space Res. 2016 Feb;8:52-67.
Summary:
The galactic cosmic ray (GCR) simulator at the NASA Space Radiation Laboratory (NSRL) is intended to deliver the broad spectrum of particles and energies encountered in deep space to biological targets in a controlled laboratory setting. In this work, certain aspects of simulating the GCR environment in the laboratory are discussed. Reference field specification and beam selection strategies at NSRL are the main focus, but the analysis presented herein may be modified for other facilities and possible biological considerations.
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Issues for Simulation of Galactic Cosmic Ray Exposures for Radiobiological Research at Ground Based Accelerators.
Kim Myung-Hee Y, Rusek Adam, Cucinotta Francis A. Frontiers in Oncology. 2015. Vol 5(00122).
Summary:
We performed extensive simulation studies using the stochastic transport code, GERMcode (GCR Event Risk Model) to define a GCR reference field using 9 HZE particle beam-energy combinations each with a unique absorber thickness to provide fragmentation and 10 or more energies of proton and 4He beams. A kinetics model of HZE particle hit probabilities suggests that experimental simulations of several weeks will be needed to avoid high fluence rate artifacts, which places limitations on the experiments to be performed. Ultimately risk estimates are limited by theoretical understanding, and focus on improving knowledge of mechanisms and development of experimental models to improve this understanding should remain the highest priority for space radiobiology research.
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A lifetime in biophysics
Blakely E., CERN COURIER. Aug 26, 2014
Summary:
Eleanor Blakely talks about her work at Berkeley that began with pioneering research into the use of ion beams for hadron therapy.
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The German Aerospace Center M-42 radiation detector—A new development for applications in mixed radiation fields.
Berger T, Marsalek K, Aeckerlein J, Hauslage J, Matthiä D, Przybyla B, Rohde M, Wirtz M. Rev Sci Instrum. 2019 Dec 1;90(12):125115.
Summary:
In the last years the Biophysics working group of the Institute of Aerospace Medicine at DLR started the development of a small low power consumption radiation detector system for the measurement of the absorbed dose to be applied in various environments as onboard aircraft, in space and also as a demonstration tool for students. These so called DLR M-42 detectors are based on an electronics design which can easily be adjusted to the user- and mission requirements. M-42 systems were already applied for measurements in airplanes, during two DLR-MAPHEUS rocket missions and have already worked flawlessly on a NASA Balloon flight over New Mexico. In addition, they will be part of the dosimetry suite of the upcoming MARE ( https://www.dlr.de/me/mare) experiment on the NASA Artemis I mission.
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Accelerator-Based Tests of Shielding Effectiveness of Different Materials and Multilayers using High-Energy Light and Heavy Ions.
Martina Giraudo, Christoph Schuy, Uli Weber, Marta Rovituso, Giovanni Santin, John W. Norbury, Emanuele Tracino, Alessandra Menicucci, Luca Bocchini, Cesare Lobascio, Marco Durante, and Chiara La Tessa Radiation Research 2018 190 (5), 526-537
Summary:
Short- and long-term effects caused by exposure to cosmic radiation are among the main health risks of space travel. One of the current strategies is to find multifunctional materials that combine excellent mechanical properties with a high shielding effectiveness to minimize the overall load. In this work, the shielding effectiveness of a wide variety of single and multilayer materials of interest for different mission scenarios has been characterized. The results are presented in terms of Bragg curves and dose reduction per unit area density. To isolate the shielding effectiveness only due to nuclear fragmentation, a correction for the energy loss in the material is also considered. The output of this investigation represents a useful database for benchmarking Monte Carlo and deterministic transport codes used for space radiation transport calculations.
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A preliminary study on radiation shielding using Martian magnetic anomalies.
Emoto K, Takao Y, Kuninaka H. Biol Sci Space. 2018 Apr 28;32:1-5.
Summary:
We propose radiation shielding using Martian magnetic anomalies to protect human crews on the Martian surface. We have simulated the trajectories of energetic protons using the Buneman-Boris method to measure how magnetic anomalies affect the impact rate on the Martian surface. Protons from the west can be completely eliminated, while those from the east are concentrated on the area between the magnetic poles. This would mean crews would need to concern themselves about radiation from the vertex and east only. A Martian magnetic anomaly can therefore be used to realize continuous and efficient radiation shielding.
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Evaluation of HZETRN on the Martian surface: Sensitivity tests and model results.
Slaba TC, Stoffle NN. Life Sci Space Res. 2017 Aug;14:29-35.
Summary:
The Mars Science Laboratory Radiation Assessment Detector (MSLRAD) provides continuous measurements of dose, dose equivalent, and particle flux on the surface of Mars. Various radiation physics and transport models have been compared to the MSLRAD data, and in June 2016, a workshop was held in Boulder, CO to have a "blind" comparison between models and new MSLRAD measurements. Certain aspects of the environmental conditions on the Martian surface were provided to the modeling teams such as the time period over which the measurements occurred and the atmospheric column density. Other details were intentionally left unspecified. For example, each team was free to choose a model to describe the primary GCR particle spectra, atmosphere and regolith composition, and other related factors. Leveraging the high degree of computational efficiency and accuracy associated with HZETRN, sensitivity tests were performed to determine to what extent some of the unspecified factors influence quantities of interest on the Martian surface. Results of these tests are useful in providing context for the summary comparison paper of Matthia et al. (2017) (contained within the same issue as this paper) so that variation between codes and differences against MSLRAD data can be more clearly interpreted. This paper appears in a special issue of Life Sciences in Space Research along with several other modeling, measurement data analysis, and summary papers.
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Simulation of the GCR spectrum in the Mars Curiosity Rover's RAD detector using MCNP6.
Ratliff HN, Smith MBR, Heilbronn L. Life Sci Space Res. 2017 Aug;14:43-50.
Summary:
The paper presents results from MCNP6 simulations modeling the radiation environment induced by galactic cosmic rays (GCRs) on the surface of Mars as seen by the Radiation Assessment Detector (RAD) onboard NASA's Curiosity rover. The detector had two separate particle acceptance angles, 4π and 30° off zenith. All ions with Z = 1 through Z = 28 were tracked in both scenarios while some additional secondary particles were only tracked in the 4π cases. This work was part of a collaborative workshop hosted by the Southwest Research Institute comparing RAD measurements with the simulated results of five modeling teams each using a different particle transport code.

-HEDS fall well within the experimental uncertainty. The calculated results for alpha particles and the heavy ion groups Z=3-5, Z=6-8, Z=9-13 and Z>24 are in the best agreement, each with an average relative difference from measured data of less than 40%. Predictions for neutrons, protons, deuterons, tritons, Helium-3, and the heavy ion group Z=14-24 have differences from the measurements, in some cases, greater than 50%. Future updates to the secondary light particle production methods in the nuclear model within HETC-HEDS are expected to improve light ion flux predictions.
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Radiation transport simulation of the Martian GCR surface flux and dose estimation using spherical geometry in PHITS compared to MSL-RAD measurements.
Flores-McLaughlin J. Life Sci Space Res. 2017 Aug;14:36-42.
Summary:
The Martian surface radiation environment is composed of galactic cosmic radiation, secondary particles produced by their interaction with the Martian atmosphere, albedo particles from the Martian regolith and occasional solar particle events. Despite this complex physical environment with potentially significant locational and geometric dependencies, computational resources often limit radiation environment calculations to a one-dimensional or slab geometry specification. To better account for Martian geometry, spherical volumes with respective Martian material densities are adopted in this model. This physical description is modeled with the PHITS radiation transport code and compared to a portion of measurements from the Radiation Assessment Detector of the Mars Science Laboratory. Particle spectra measured between 15 November 2015 and 15 January 2016 and PHITS model results calculated for this time period are compared. Results indicate good agreement between simulated dose rates, proton, neutron and gamma spectra. This work was originally presented at the 1st Mars Space Radiation Modeling Workshop held in 2016 in Boulder, CO.
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A calculation of the radiation environment on the Martian surface.
de Wet WC, Townsend LW. Life Sci Space Res. 2017 Aug;14:51-6.
Summary:
The radiation environment on the Martian surface, as produced by galactic cosmic radiation incident on the atmosphere, is modeled using the Monte Carlo radiation transport code, High Energy Transport Code-Human Exploration and Development in Space (HETC-HEDS). Calculated fluxes for neutrons, protons, deuterons, tritons, helions, alpha particles, and heavier ions up to Fe are compared with measurements taken by the Radiation Assessment Detector (RAD) instrument aboard the Mars Science Laboratory over a period of 2 months. The degree of agreement between measured and calculated surface flux values over the limited energy range of the measurements is found to vary significantly depending on the particle species or group. However, in many cases the fluxes predicted by HETC-HEDS fall well within the experimental uncertainty. The calculated results for alpha particles and the heavy ion groups Z=3-5, Z=6-8, Z=9-13 and Z>24 are in the best agreement, each with an average relative difference from measured data of less than 40%. Predictions for neutrons, protons, deuterons, tritons, Helium-3, and the heavy ion group Z=14-24 have differences from the measurements, in some cases, greater than 50%. Future updates to the secondary light particle production methods in the nuclear model within HETC-HEDS are expected to improve light ion flux predictions.
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The radiation environment on the surface of Mars - Summary of model calculations and comparison to RAD data.
Matthiä D, Hassler DM, de Wet W, Ehresmann B, Firan A, Flores-McLaughlin J, Guo J, Heilbronn LH, Lee K, Ratliff H, Rios RR, Slaba TC, Smith MA, Stoffle NN, Townsend LW, Berger T, Reitz G, Wimmer-Schweingruber RF, Zeitlin C. Life Sci Space Res. 2017 Aug;14:57-63. Epub 2017 Jun 28.
Summary:
This article summarizes the results of a workshop held in June 2016 in Boulder, CO. The goal of the workshop was validating models and simulations of the radiation environment originating from galactic cosmic rays on the Martian surface with data recorded by the Radiation Assessment Detector (RAD) on the Curiosity rover of the Mars Science Laboratory (MSL). For this purpose, a time period (15 Nov 2015 to 15 Jan 2016) was selected for which the model calculations were performed; measurements taken by RAD during the same time were used for the comparison. The paper presents differential particle fluxes calculated using different galactic cosmic ray spectra in combination with particle transport codes: GEANT4, HETC-HEDS, HZETRN, MCNP6, and PHITS. The results of the numerical models are compared to charged particle spectra stopping in the RAD detector in the energy range between a few tens and a few hundred MeV per nucleon and neutral particle spectra, i.e. photons and neutrons, between 10 MeV and 1 GeV. Dose rates and dose equivalent rates as well as the corresponding quality factors from models and measurement are presented as well.
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Comparing HZETRN, SHIELD, FLUKA and GEANT transport codes.
J. Norbury, T. Slaba, N. Sobolevsky, B. Reddell Life Sciences in Space Research, vol. 14, pp. 64-73, 2017.
Summary:
The space radiation transport codes, HZETRN, SHIELD, FLUKA and GEANT are compared to each other for heavy-ion, light-ion (isotopes of Hydrogen and Helium) and pion production after the galactic cosmic ray spectrum is transported through various aluminum shield thicknesses. The paper shows that the biggest differences among the codes occurs for light-ion production.
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Mars science laboratory radiation assessment detector (MSL/RAD) modeling workshop proceedings.
Hassler DM, Norbury JW, Reitz G. Life Sci Space Res. 2017 Aug;14:1-2.
Summary:
This paper is an introduction to the special issue of Life Sciences in Space Research devoted to comparisons of space radiation transport codes with recent measurements made by the Mars Science Laboratory Radiation Assessment Detector.
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Ballooning for Biologists: Mission Essentials for Flying Life Science Experiments to Near Space on NASA Large Scientific Balloons.
Smith DJ and Sowa MB. Gravitational and Space Research, Volume 5(1), July 2017, Pages 52-73
Summary:
This review paper was written for space biology and radiation research teams, addressing the logistics and benefits of flying life science experiments on large scientific balloons. Earth's stratosphere has a naturally broad, low, and sustained background radiation spectrum; thus long duration biology experiments flown on balloons can avoid limitations otherwise associated with ground simulation chambers and radiation facilities. The authors provide an overview of balloon operations (Part 1), biology topics that can be uniquely addressed in the stratosphere's radiation environment (Part 2), and a roadmap for developing payloads to fly with NASA (Part 3).
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Measurements of the neutral particle spectra on Mars by MSL/RAD from 2015-11-15 to 2016-01-15.
Guo J, Zeitlin C, Wimmer-Schweingruber R, Hassler DM, Köhler J, Ehresmann B, Böttcher S, Böhm E, Brinza DE. Life Sci Space Res. 2017 Jun 16. [Article in Press]
Summary:
This paper updates the earlier work by Koehler et al. published in JGR Planets in 2013 (10.1002/2013JE004539). We have studied the time period specified for the RAD Modeling Workshop (see http://www.boulder.swri.edu/rad_modeling_workshop/) using the same inversion technique as before, but with an improved algorithm for normalizing the neutron and gamma-ray spectra. We find smaller dose and dose equivalent rates than were found previously. The spectral shapes are very similar to what was found previously, and are again well-fit by power laws with spectral indices close to those found in the earlier work.
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Calibration and characterization of the radiation assessment detector (rad) on curiosity.
C. Zeitlin, D. Hassler, R. Wimmer-Schweingruber, B. Ehresmann, J. Appel, T. Berger, E. Böhm, S. Böttcher, D. Brinza, S. Burmeister, et al. Space Sci. Rev., 201 (1-4) (2016), pp. 201-233
Summary:
This paper documents the calibration of the MSL-RAD instrument, which has been operating in transit to and on Mars since December 2011. Initial calibration parameters were determined on the ground and have been refined using flight data. In addition to calibration, RAD has several hundred parameters that are adjustable in flight; the settings for most of these are documented as well, showing the effects of threshold changes and calibration tweaks that have been performed over the course of the mission to date.
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High dose rates obtained outside ISS in June 2015 during SEP event
T.P. Dachev et al., High dose rates obtained outside ISS in June 2015 during SEP event, Life Sciences in Space Research (2016) Apr 27. [Article in Press]
Summary:
The Bulgarian-built R3DR2 instrument on the European Space Agency (ESA) EXPOSE-R2 platform outside the Russian “Zvezda” module of the International Space Station (ISS) is described. The dosimetric characteristics of the solar energetic particles (SEP) event, observed on 22 June 2015 were analyzed and the main finding of the study is that SEP protons produced high dose rates outside ISS, reaching values > 5000 μGy/h. SEP events similar to that observed on 22 June 2015 could be the most dangers events for the cosmonauts/astronauts involved in extravehicular activity (EVA).
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Solar modulation of the deep space galactic cosmic ray lineal energy spectrum measured by CraTER, 2009-2014.
Zeitlin, C, et al. Space Weather, 14,247-258.
Summary:
The Cosmic Ray Telescope for the Effects of Radiation (CRaTER) is an energetic particle detector flying aboard the Lunar Reconnaissance Orbiter. Since arriving at the Moon in 2009, CRaTER has observed the deep solar minimum of solar cycle 23, the ascending phase of cycle 24, the very weak maximum of cycle 24, and in recent months, what appears to be the start of the descending phase of cycle 24. In earlier work, we presented lineal energy spectra of galactic cosmic rays (GCRs) at solar minimum for different shielding depths. The long period of CRaTER observations allows us to study the evolution of these spectra as a function of solar modulation. As solar modulation increases, the total flux of GCRs decreases, and lower-energy ions are preferentially removed from the spectrum of ions that arrive in the inner heliosphere. These effects lead to modest variations in the lineal energy spectrum as a function of time. GCR fluxes at the 2009/2010 solar minimum were high by historical standards and at solar maximum remained high compared to earlier maxima.
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Evaluation of the spectrometric and dose characteristics of neutron fields inside the Russian segment of the ISS by fission detectors.
V. A. Shurshakov, I. B. Vorob'ev, V. A. Nikolaev, V. I. Lyagushin, Yu. A. Akatov, V. V. Kushin. Cosmic Research March 2016, Volume 54, Issue 2, pp 111-117 First online: 07 April 2016
Original Russian Text © V.A. Shurshakov, I.B. Vorob'ev, V.A. Nikolaev, V.I. Lyagushin, Yu.A. Akatov, V.V. Kushin, 2016, published in Kosmicheskie Issledovaniya, 2016, Vol. 54, No. 2, pp. 119-125.
Summary:
The results of measuring the dose and the energy spectrum of neutrons inside the Russian segment of the International Space Station (ISS) from March 21 until November 10, 2002 are presentedStatistically reliable results of measurement are obtained by using thorium- and uranium-based fission detectors with cadmium and boron filtersRecommendations on how to improve the procedure for using the fission detectors to measure the characteristics of neutron fields inside the compartments of space stations are formulated.
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A semiconductor radiation imaging pixel detector for space radiation dosimetry.
Kroupa M, Bahadori A, Campbell-Ricketts T, Empl A, Hoang SM, Idarraga-Munoz J, Rios R, Semones E, Stoffle N, Tlustos L, Turecek D, Pinsky L. . Life Sci Space Res. 2015 Jul 3.
Summary:
A new generation of compact low-power active dosimeters is introduced. These new devices use state-of-the-art semiconductor technology to provide precise particle-by-particle measurements for environment evaluation. This article presents the core ideas of using this technology for space radiation monitoring along with a glimpse of developments to come.
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Compact tissue-equivalent proportional counter for deep space human missions.
Straume T, Braby LA, Borak TB, Lusby T, Warner DW, Perez-Nunez D. Health Phys. 2015 Oct;109(4):277-83.
Summary:
Instruments using tissue equivalent proportional counters operating at low gas pressure have been used to measure absorbed dose and dose equivalent on the space shuttle and ISS for many years However, those instruments, which measure the spectrum of energy deposition events in order to determine the radiation quality, require complex electronics which makes them too large and heavy to be used during deep space missions. An instrument which uses the same type of detector, but evaluates only the mean of the energy deposition spectrum, has been built using much simpler electronics resulting in a much smaller package and lower power consumption
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Simulated response of a tissue-equivalent proportional counter on the surface of Mars.
Northum JD, Guetersloh SB, Braby LA, Ford JR. Health Phys2015 Oct;109(4):284-95.
Summary:
The dose equivalent on the surface of Mars is the result of cosmic ray particles penetrating the atmosphere, secondary particles (fragmentation products) produced in the atmosphere, and secondary particles produced in the Martian soil and emitted back to the surface. Tissue equivalent proportional counters are frequently used to measure the energy deposition and evaluate the dose equivalent in such complex radiation fields. Monte Carlo calculations were used to track cosmic ray particles through the atmosphere and into the Martian soil, and to calculate the energy deposited in detectors located at the Martian surface. The results show that the dose equivalent is slightly less than one fifth of the dose equivalent in free space above Mars.
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Simulation of the charge migration in DNA under irradiation with heavy ions.
Belov OV, Boyda DL, Plante I, Shirmovsky SE. Biomed Mater Eng. 2015 Aug 17;26 Suppl 1:S1937-44.
Summary:
Ionizing radiation results in DNA lesions of different types. High charged (Z) and energy (E) particles (HZE) of high linear energy transfer (LET) typically result in more complex DNA damage than low-LET radiation such as X- or gamma-rays. Following DNA ionization, positive charges resulting from ionizations can migrate to different bases. In this work, charge migration was simulated by using a quantum-classical nonlinear model of the DNA-charge system. It was shown that charges can cross potential barriers, suggesting a quantum tunnel effect. Therefore, charge migration can influence the type of DNA damage resulting from ionizing radiation.
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Measurements of the neutron spectrum in transit to Mars on the Mars Science Laboratory.
Köhler J, Ehresmann B, Zeitlin C, Wimmer-Schweingruber RF,J, Böttcher S, Böhm E, Burmeister S, Guo J, Lohf H, Martin C, Posner A, Rafkin S. Life Sci Space Res. 2015 Mar 24. [Article in Press] Article citation (from SPACELINE):
Summary:
The Mars Science Laboratory spacecraft, containing the Curiosity rover, was launched to Mars on 26 November 2011. Although designed for measuring the radiation on the surface of Mars, the Radiation Assessment Detector (RAD) used this unique opportunity to measure the radiation environment inside the spacecraft during the 253-day cruise to Mars.RAD measures neutral particles with two scintillators enclosed by an anti-coincidence. One of the scintillators has a high-Z and therefore a high sensitivity for gamma-rays, the other scintillator has a high proton content and therefore a high sensitivity for neutrons. In this work an inversion method is applied to the RAD neutral particle measurements to obtain the neutron and gamma spectra as well as neutron dose and dose equivalent.
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Overview of the Liulin type instruments for space radiation measurement and their scientific results.
T.P. Dachev, J.V. Semkova, B.T. Tomov, Yu.N. Matviichuk, P.G. Dimitrov, R.T. Koleva, St.Malchev, N.G. Bankov, V.A. Shurshakov, V.V. Benghin, E.N. Yarmanova, O.A. Ivanova, D.-P. Hä der, M. Lebert, M.T. Schuster, G. Reitz, G. Horneck, Y. Uchihori, H. Kitamura, O. Ploc, J. Cubancak, I. Nikolaev, Life Sciences in Space Research, Volume 4, January 2015, Pages 92-114.
Summary:
The paper presents an overview of the different modifications of the Liulin type spectrometer-dosimeters, which were developed in the late 1980s and have been in use since then. Up to now Liulin type instruments were developed for 14 experiments in space: 1 on Mir space station, 6 on ISS, and other 7 on different satellites including Chandrayaan-1 satellite at 100 km orbit around the Moon. 2 of them were lost on Mars-96 and Phobos-Grunt missions. Currently there are 3 active Liulin type experiments on ISS. The data analysis procedure allows characterization of the different main space radiation sources as GCR, inner radiation belt protons and outer radiation belt electrons. There are two major discoveries in the ISS radiation environment: the first is the large outside doses from relativistic electrons in the outer radiation belt, while the second is the decrease in the ISS SAA dose rate during the US space shuttle dockings. Liulin spectrometers were also used by different scientific groups for monitoring of the radiation environment on thousands of aircraft flights and balloons. The main advantages of the Liulin type spectrometers are their low weight (100-500 g), low power consumption (100-500 mW) and low cost.
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Experimental microdosimetry: History, applications and recent technical advances.
Braby LA. Radiat Prot Dosimetry. 2015 Apr 15. [Epub ahead of print]
Summary:
This paper summarizes the 50 year development of microdosimetry detectors from delicate laboratory research instruments to rugged detectors that can be used in a wide variety of radiation environments. The relative biological risk presented by different types of ionizing radiation can be estimated based on the amount of energy each type deposits in small volumes such as a cell nucleus. Radiations which deposit a large amount of energy in a few small volumes tend to be more damaging than radiations that deposit a small amount of energy in a large number of small volumes, even though the total amount of energy deposited in an organ is the same. The characterization of energy deposition in small volumes, known as microdosimetry, has been the basis of a sequence of instruments used to evaluate radiation exposure on the STS and ISS for nearly two decades.
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Description and Verification of an Algorithm for Obtaining Microdosimetric Quantities for High-LET Radiation Using a Single TEPC without Pulse Height Analysis.
Thomas B. Borak and Phillip L. Chapman (2014) Radiation Research: October 2014, Vol. 182, No. 4, pp. 396-407.
Summary:
Microdosimetric spectra of single event distributions have been used to provide estimates of quality factors for radiation protection of high LET radiation. It becomes difficult to measure, record and store energy deposition from single events in situations with high dose rates. An alternative approach is to store random energy deposition events in a sequence of fixed time intervals that does not require recording single events. This can be accomplished with one detector without pulse shaping or pulse height analysis. We present the development of the algorithm using expectation analyses of the statistical estimators for moments of lineal energy. The method can provide prompt real-time information in circumstances that restrict detector configurations in terms of size, mass and power consumption such as personal dosimetry during an EVA. It can be adapted for measurements of any quantity that is linearly related to absorbed dose, such as estimation of dose averaged LET.
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Simulation of the charge migration in DNA under irradiation with heavy ions.
Belov OV, Boyda DL, Plante I, Shirmovsky SE. Biomed Mater Eng. 2015 Aug 17;26 Suppl 1:S1937-44.
Summary:
Ionizing radiation results in DNA lesions of different types. High charged (Z) and energy (E) particles (HZE) of high linear energy transfer (LET) typically result in more complex DNA damage than low-LET radiation such as X- or gamma-rays. Following DNA ionization, positive charges resulting from ionizations can migrate to different bases. In this work, charge migration was simulated by using a quantum-classical nonlinear model of the DNA-charge system. It was shown that charges can cross potential barriers, suggesting a quantum tunnel effect. Therefore, charge migration can influence the type of DNA damage resulting from ionizing radiation
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Simulation of the radiolysis of water using Green's functions of the diffusion equation.
Plante I, Cucinotta FA. Radiat Prot Dosimetry. 2015 Apr 20. [Epub ahead of print]
Summary:
Green's functions of the diffusion equation (GFDEs) for partially diffusion-controlled reactions represent the probability distribution for a pair of particles to be separated by the inter-particle distance r at time t, assuming that they were initially at separation distance r0. The integral is the survival probability of the pair. In this paper, the first simulation results obtained for the radiolysis of water by 300-MeV protons are presented, using radiation track structures calculated by the code RITRACKS as a starting point for the simulation.
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Binary-Encounter-Bethe direct effect of ionising radiation.
Plante I, Cucinotta FA Radiat Prot Dosimetry. 2015 Apr 13. [Epub ahead of print]
Summary:
This paper describes the Binary-Encounter-Bethe (BEB) model of cross sections for ionization of DNA bases, sugars and phosphates by electrons. In this model, the differential cross section is calculated for each electron using the electron binding energy, the mean kinetic energy and the occupancy number of each orbital as parameters. Additionally, the paper reports two sampling algorithm. The first is used to determine the energy loss occurring during an ionization event in DNA using the BEB model. The second algorithm is used to determine the distance of an electron to the next interaction when it crosses media with different cross sections, which is the case when the trajectory of an electron intersects DNA.
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Mathematical model of ATM activation and chromatin relaxation by ionizing radiation
Li Y, Cucinotta FA. Int J Mol Sci. 2020 Feb 12;21(4):E1214.
Summary:
We propose a comprehensive mathematical model to study the dynamics of ionizing radiation induced Ataxia-telangiectasia mutated (ATM) activation that consists of ATM activation through dual mechanisms: the initiative activation pathway triggered by the DNA damage-induced local chromatin relaxation and the primary activation pathway consisting of a self-activation loop by interplay with chromatin relaxation. The model is expressed as a series of biochemical reactions, governed by a system of differential equations and analyzed by dynamical systems techniques. Radiation induced double strand breaks (DSBs) cause rapid local chromatin relaxation, which is independent of ATM but initiates ATM activation at damage sites. Key to the model description is how chromatin relaxation follows when active ATM phosphorylates KAP-1, which subsequently spreads throughout the chromatin and induces global chromatin relaxation. Additionally, the model describes how oxidative stress activation of ATM triggers a self-activation loop in which PP2A and ATF2 are released so that ATM can undergo autophosphorylation and acetylation for full activation in relaxed chromatin. In contrast, oxidative stress alone can partially activate ATM because phosphorylated ATM remains as a dimer. The model leads to predictions on ATM mediated responses to DSBs, oxidative stress, or both that can be tested by experiments.
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Translational research in radiation-induced DNA damage signaling and repair.
Nickoloff JA, Boss M-K, Allen CP, LaRue SM. Transl Can Res. 2017 Jul;6 Suppl 5:S875-S891. Review.
Summary:
A review that focuses on how insights into molecular mechanisms of DNA damage response pathways are translated to small animal preclinical studies, to clinical studies of naturally occurring tumors in companion animals, and finally to human clinical trials.
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Low Dose Radiation Affects Cardiac Physiology: Gene Networks and Molecular Signaling in Cardiomyocytes.
Matthew A. Coleman, Sharath P. Sasi, Jillian Onufrak, Mohan Natarajan, Krishnan Manickam, John Schwab, Sujatha Muralidharan, Leif E. Peterson, Yuriy O. Alekseyev, Xinhua Yan, David A. Goukassian. American Journal of Physiology: Heart and Circulatory Physiology, September 25, 2015, ajpheart.00050.2015. doi: 10.1152/ajpheart. 00050.2015. [Epub ahead of print] PMID: 26408534
Summary:
We examined molecular responses using transcriptome profiling in left ventricular murine CM isolated from mice that were exposed to 90 cGy, 1 GeV proton (1H) and 15 cGy, 1 GeV/nucleon iron (56Fe) over 28 days after exposure Our data present several new findings - (1) at 90 cGy, 1 GeV dose of 1H-IR, gene expression in CMs is not significantly affected over 28 days; (2)at 15 cGy, 1 GeV/n dose of 56Fe-IR, CMs exhibit a time dependent and cyclical change in gene expression in the inflammatory, free radical scavenging and CV development and function pathways; (3)differential genes were predictive for modulation of transcription factors (STAT-3, GATA-4, TBX5, MEF2C, NF-kB, NFATc4) and p38 MAPK signaling; (4)there was a significant transcript overlap between neurodegenerative disease and cardiac muscle disorder specific pathways that may support a possibility of common underlying molecular mechanism for radiation-induced neurodegenerative and cardio-degenerative diseases/disorders; (5) 14 days after a single 56Fe-IR, the activation of several developmental transcription factors, such as TBX5, GATA-4, MEF2C, that are required for the maintenance of cardiac homeostasis strongly suggest activation of cardio-protective and regeneration responses in 56Fe-IR exposed hearts
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Data integration reveals key homeostatic mechanisms following low dose radiation exposure.
Susan C. Tilton, Melissa M. Matzke, Marianne B. Sowa, David L. Stenoien, Thomas J. Weber, William F. Morgan, and Katrina M. Waters, Toxicol Appl Pharmacol. 2015 Feb 2. pii: S0041-008X(15)00042-3. doi: 10.1016/j.taap.2015.01.019. [Epub ahead of print].
Summary:
This study develops a systems approach to define pathways regulated by low dose radiation exposures and to understand how a complex biological system responds to subtle perturbations in its environment. We have examined the temporal response of the dermal and epidermal layers of an irradiated 3D full thickness skin model using transcriptomic, proteomic, phosphoproteomic and metabolomic strategies to generate a significant amount of heterogeneous data. The integration of these varied data sets using both top down and bottom up approaches identified novel signaling pathways that would not be clearly observed by any single 'omic technology and suggests persistent alterations in cellular and tissue homeostatic regulation occur following low dose radiation exposures in skin. The goal of these systems approaches is to enable a transition from qualitative observations to a quantitative and ultimately predictive science.
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New tricks for an old fox: impact of TGFβ on the DNA damage response and genomic stability.
M. H. Barcellos-Hoff, F. A. Cucinotta, (2014) Sci. Signal. 7, re5.
Summary:
Transforming growth factor beta is a pleiotropic growth factor necessary for homeostasis and responses to injury. TGFbeta activity is controlled by its secretion as a latent complex that is extracellularly activated by reactive oxygen species, engendering rapid and persistent mediation of tissue responses to radiation. Here, the authors review how TGFb signaling is also involved in the efficient execution of the DNA damage response, which ties the intrinsic molecular mechanisms maintaining DNA integrity to extrinsic control of tissue function.
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Mary Helen Barcellos-Hoff's NASA Space Radiation Summer School lecture Systems Radiation Biology and Radiation Induced Cell Signals has been posted to the THREE Encyclopedia - Tissue Biology and Pathology.
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Role of Endoplasmic Reticulum and Mitochondrion in Proton Microbeam Radiation-Induced Bystander Effect
Chen Dong, Wenzhi Tu, Mingyuan He, Jiamei Fu, Alisa Kobayashi, Teruaki Konishi, and Chunlin Shao. Radiation Research: January 2020, Vol. 193, No. 1, pp. 63-72.
Summary:
When a small portion of cells in a population of human lung fibroblast MRC-5 cells were precisely irradiated through either the nuclei or cytoplasm with counted microbeam protons, the yield of micronuclei (MN) and the levels of intracellular reactive oxygen species (ROS) in nonirradiated cells neighboring irradiated cells were significantly increased. Our results suggest that the organelles of mitochondria and ER have different roles in RIBE with respect to nuclear and cytoplasmic irradiation, and the function of ER is a prerequisite for mitochondrial activation.
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Comparison of signaling profiles in the low dose range following low and high LET radiation
Sridharan DM, Chien L-C, Cucinotta FA, Pluth JM. Life Sci Space Res. 2020 Feb
Summary:
In this study we have investigated the kinetics and dose response of DNA double strand breaks (DSB's) for low doses of three different ions at various energies covering a wide spectrum of LET's (11 radiation qualities in all). We performed the work using three different phospho-proteins known to localize to DNA DSB's (γH2AX, pATF2, pSMC1). These phospho-proteins have unique primary activating kinases, which showed novel patterns dependent on dose and radiation quality, with solely ATM mediated phospho-proteins showing a greater persistence.
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Particle radiation-induced dysregulation of protein homeostasis in primary human and mouse neuronal cells
Shaler T, Lin HT, Bakke J, Chen S, Grover A, Chang P. Life Sci Space Res. 2020 Feb 21.
Summary:
Space particle radiations may cause significant damage to proteins and oxidative stress in the cells within the central nervous system and pose a potential health hazard to humans in long-term manned space explorations. Dysregulation of the ubiquitin-proteasome system as evidenced by abnormal accumulation of polyubiquitin (pUb) chain linkages has been implicated in several age-related neurodegenerative disorders by mechanisms that may involve the inter-neuronal spread of toxic misfolded proteins, the induction of chronic neuroinflammation, or the inappropriate inhibition or activation of key enzymes, which could lead to dysfunction in, for example, proteolysis, or the accumulation of post-translationally-modified substrates.In this study, we employed a quantitative proteomics method to evaluate the impact of particle-radiation induced alterations in three major pUb-linked chains at lysine residues Lys-48 (K-48), Lys-63 (K-63), and Lys-11 (K-11), and probed for global proteomic changes in mouse and human neural cells that were irradiated with low doses of 250 MeV proton, 260 MeV/u silicon or 1 GeV/u iron ions. We found significant accumulation in K-48 linkage after 1 Gy protons and K-63 linkage after 0.5 Gy iron ions in human neural cells. Cells derived from different regions of the mouse brain (cortex, striatum and mesencephalon) showed differential sensitivity to particle radiation exposure. Although none of the linkages were altered after proton exposure, both K-48 and K-63 linkages in mouse striatal neuronal cells were elevated after 0.5 Gy of silicon or iron ions. Changes were also seen in proteins commonly used as markers of neural progenitor and stem cells, in DNA binding/damage repair and cellular redox pathways. In contrast, no significant changes were observed at the same time point after proton irradiation. These results suggest that the quality of the particle radiation plays a key role in the level, linkage and cell type specificity of protein homeostasis in key populations of neuronal cells.
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Prediction of Cell Survival after Exposure to Mixed Radiation Fields with the Local Effect Model
Radiation Research 193(2), 130-142, (5 December 2019), Tabea Pfuhl, Thomas Friedrich, and Michael Scholz
Summary:
In this paper, the Local Effect Model (LEM) is applied to simulate cell survival after simultaneous irradiation with ions and X-rays. To evaluate the precision of the LEM, the simulation results are compared to existing experimental data. Furthermore, the results are compared to the microdosimetric model by Zaider and Rossi and the Lesion Additivity model by LAM.
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Nitric Oxide Is Involved in Heavy Ion-Induced Non-Targeted Effects in Human Fibroblasts
Hada M, Saganti PB, Cucinotta FA. Int J Mol Sci. 2019, 20, 4327.
Summary:
We measured chromosomal aberrations (CA) with and without nitric oxide (NO) scavenger in normal skin fibroblasts cells after exposure to 600 MeV/u and 1 GeV/u 56Fe ions, and less than one direct particle traversal per cell nucleus (NO has been reported as a candidate for intercellular signaling for non-targeted effect (NTE) in many studies). Yields of CA were significantly lower in fibroblasts exposed to the NO scavenger compared to controls, suggesting involvement of NO in cell signaling for induction of CA. Media transferred from irradiated cells induced CA in non-irradiated cells, and this effect was abrogated with NO scavengers. Our results strongly support the importance of NTE contributions in the formation of CA at low-particle fluence in fibroblasts.
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RITCARD: Radiation-Induced Tracks, Chromosome Aberrations, Repair and Damage
Plante I, Ponomarev A, Patel Z, Slaba T, Hada M. Radiation Research. September 2019, Vol. 192, No. 3, pp. 282-298.
Summary:
Chromosome aberrations (CAs) are one of the effects of radiation exposure and can have implications for human health in the space environment, since they are related to cancer risk. To shed light on the formation and quality of chromosome aberrations in the space environment, many experiments and simulations have been performed using chromosome aberrations in human cells, induced by heavy ions, which are present in galactic cosmic rays (GCRs). In this work, the new simulation program, radiation-induced tracks, chromosome aberrations, repair and damage (RITCARD), is presented. RITCARD is comprised of four parts: a random walk (RW) algorithm for simulating chromosomes in a nucleus; a deoxyribonucleic acid (DNA) damage algorithm; a break repair process; and a function to assess and count chromosome aberrations. Prior to running RITCARD, the code relativistic ion tracks (RITRACKS), is used to simulate detailed radiation track structure and calculate time-dependent differential voxel dose maps in a parallelepiped centered on a cell nucleus. The RITCARD program reads the pre-calculated voxel dose and locates the intersections between the voxels and the chromosomes. Radiation-induced breaks occur strictly at these intersections. When a break occurs in the random walk, the corresponding chromosome piece is cut into two fragments where each has a free end at the position of the break. In the next step, the algorithm simulates the time-dependent rejoining of free end pairs, using different probabilities for pairs originating from a given break (proper) or from different breaks (improper), which results in the formation of fragment sequences. By grouping these sequences, the program determines the number and types of aberrations, based on the criteria used in our experiment. The new program is used to assess the yields of various types of chromosome aberrations in human fibroblast cells for several ions (1H+, 4He2+, 12C6+, 16O8+,20Ne10+, 28Si14+, 48Ti22+ and 56Fe26+) with energies varying from 10 to 1,000 MeV/n. The results show linear and linear-quadratic dose dependence for most chromosome aberrations types. The calculation results were compared with those obtained by fluorescence in situ hybridization (FISH) experiments that were performed by our group. The simulation results also show that the coefficient of the linear part of the dose-dependence curve peaks at an LET value of approximately 100 keV/μm, which evokes a relative biological effectiveness (RBE) peak.
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Dose, LET and Strain Dependence of Radiation-Induced 53BP1 Foci in 15 Mouse Strains Ex Vivo. Introducing Novel DNA Damage Metrics
Penninckx S, Cekanaviciute E, Degorre C, Guiet E, Viger L, Lucas S and Costes SV. Radiation Research, 2019:192;1-12.
Summary:
A comprehensive 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, totaling 5 million skin fibroblast cells imaged by three-dimensional highthroughput conventional microscopy. Non-immortalized primary skin fibroblasts derived from 76 mice were subjected to increasing doses of both low- and high-LET radiation (X rays; 350 MeV/n 40Ar; 600 MeV/n 56Fe), which are relevant to carcinogenesis and human space exploration. All 15 strains showed the same dose and LET dependence, but strain differences were preserved under various experimental conditions, indicating that the number and sizes of repair domains are modulated by the genetic background of each strain.
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HMGB1 mediated autophagy protects glioblastoma cells from carbon-ion beam irradiation injury
Lei R, Yan L, Deng Y, Xu J, Zhao T, Awan MUF, Li Q, Zhou G, Wang X, Ma H., Acta Astronaut. 2019 Mar 19.
Summary:
The present study investigated autophagy changes and the expression of HMGB1 in human glioblastoma cells, responding to carbon-ion beam irradiation (35 keV/μm, 80.55 MeV/u). U251 cells were irradiated with carbon-ion beams and cell proliferation was measured by counting the number of living cells. A high level of autophagy was induced 24 h after irradiation with 1 Gy carbon ions and then decreased in a time- and dose-dependent manner. The expression of the whole HMGB1 showed correlation with the dynamic autophagic level. In summary, carbon-ion beam irradiation could elevate autophagy and HMGB1 expression efficiently, which would protect the cells from programmed cell death via autophagy. Apoptosis as measured by expression of caspase activities increased as the dose increased, which was accompanied with decreased levels of LC3B and HMGB1.
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Genetic variation and radiation quality impact cancer promoting cellular phenotypes in response to HZE exposure.
Sridharan DM, Enerio S, Wang C, LaBarge MA, Stampfer MR, Pluth JM. Life Sci Space Res. 2018 Oct 21.
Summary:
There exists a wide degree of genetic variation within the normal human population which includes disease free individuals with heterozygote defects in major DNA repair genes. A lack of understanding of how this genetic variation impacts cellular phenotypes that inform cancer risk post heavy ion exposure poses a major limitation in developing personalized cancer risk assessment of astronauts. We initiated a pilot study with Human Mammary Epithelial Cell strains (HMEC) and various genetic variants that were heterozygote for DNA repair genes; BRCA1, BRCA2 and ATM. The centrosome aberration frequency increases with dose, complexity of the lesion generated by different radiation qualities and age of the individual. This increase in genomic instability correlates with elevated check-point activation post radiation exposure. These results will have significant implications in estimating cancer susceptibility in genetically variant individuals exposed to HZE particles.
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Radiation-induced genomic instability, epigenetic mechanisms and the mitochondria: A dysfunctional mé nage a trois?
Baulch JE. Int J Radiat Biol. 2018 Nov 19. [Epub ahead of print] [2/5]
Summary:
This article presents a perspective examining the evidence for a link between radiation-induced genomic instability, epigenetic mechanisms and mitochondrial dysfunction. Significant evidence suggests that mitochondrial dysfunction accompanies radiation-induced genomic instability. Similarly, it is well recognized that mitochondria synthesize the methyl, acetyl and phosphate donors necessary for covalent DNA and histone modifications. Although we have long invoked epigenetic mechanisms as drivers of persistent genomic instability, most studies arguably provide only correlative data to support this assertion.
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Clustered DNA double-strand break formation and the repair pathway following heavy-ion irradiation
Hagiwara Y, Oike T, Niimi A, Yamauchi M, Sato H, Limsirichaikul S, Held KD, Nakano T, and Shibata A. J Radiat Res, 2018, pp. 1-11.
Summary:
Photons, such as X- or γ-rays, induce DNA damage (distributed throughout the nucleus) as a result of low-density energy deposition. In contrast, particle irradiation with high linear energy transfer (LET) deposits high-density energy along the particle track. High-LET heavy-ion irradiation generates a greater number and more complex critical chromosomal aberrations, such as dicentrics and translocations, compared with X-ray or γ irradiation. In addition, the formation of >1000 bp deletions, which is rarely observed after X-ray irradiation, has been identified following high-LET heavy-ion irradiation. Previously, these chromosomal aberrations have been thought to be the result of misrepair of complex DNA lesions, defined as DNA damage through DNA double-strand breaks (DSBs) and single-strand breaks as well as base damage within 1-2 helical turns (<3-4 nm). In this review, we summarize the latest findings regarding the hallmarks of DNA damage structure and the repair pathway following heavy-ion irradiation. Furthermore, we discuss the mechanism through which high-LET heavy-ion irradiation may induce dicentrics, translocations and large deletions.
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DETRIMENTS IN NEURON MORPHOLOGY FOLLOWING HEAVY ION IRRADIATION: WHAT'S THE TARGET?
Francis A. Cucinotta, Murat Alp, and Eliedonna Cacao. Radiation Protection Dosimetry (2018), pp. 1-6.
Summary:
Neuron cells consist of the soma or cell body, axons, dendritic arbor with multiple branches, and dendritic spines which are the substrates for memory storage and synaptic transmission. Detriments in neuron morphology are suggested to play a key role in cognitive impairments following brain irradiation. Multiple molecular mechanisms are involved in the regulation and stability of neuron morphology, while the effects of radiation on these processes have not been studied extensively. In this report, we consider possible biological targets in neurons for energy deposition (ED) by charged particles that could lead to neuron morphology detriments, and the resulting dose and radiation quality dependence of such detriments. The track structures of heavy ions including high charge and energy (HZE) particles consists of core of high-ED events and a penumbra of sparse ED from δ-ray electrons produced in ionization of target molecules. We consider the role of track structure relative to possible targets causative in the degradation of morphology.
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Analysis of radiation-induced chromosomal aberrations on a cell-by-cell basis after alpha-particle microbeam irradiation: Experimental data and simulations.
Testa A, Ballarini F, Giesen U, Gil OM, Carante MP, Tello J, Langner F, Rabus H, Palma V, Pinto M, Patrono C. Radiation Research 189(6):597-604. 2018.
Summary:
An experimental and theoretical analysis was carried out on chromosomal aberrations in CHO-K1 cells, which were exposed to 5.5 MeV and 17.8 MeV α-particles (LET: ~85 keV/mm and ~36 keV/mm, respectively) generated by a microbeam available at PTB in Braunschweig (Germany), and analyzed by an ad hoc in situ protocol. The 5.5 MeV α-particles were more effective than the 17.8 MeV α-particles; for instance, the yield of total aberrations increased by a factor of ~2. The experimental data were compared with Monte Carlo simulations based on a biophysical model called BIANCA (BIophysical ANalysis of Cell death and chromosomal Aberrations). In particular, the higher aberration yields observed at the higher LET were explained by taking into account that each particle was much more effective at inducing DNA critical damage (Cluster Lesions, or CLs), thus leading to an increased yield of CLs/cell that was consistent with the increased yield of total aberrations observed in the experiments.
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NASA GeneLab Project: Bridging Space Radiation Omics with Ground Studies.
Afshin Beheshti, Jack Miller, Yared Kidane, Daniel Berrios, Samrawit G. Gebre, and Sylvain V. Costes. Radiation Research: June 2018, Vol. 189, No. 6, pp. 553-559.
Summary:
An original research article led by NASA Ames Research Center, Space Biosciences Research Branch scientists, titled "NASA GeneLab Project: Bridging Space Radiation Omics with Ground Studies" was published in the April 2018 issue of Radiation Research. This paper provides a comprehensive review of the data available on NASA's GeneLab platform (genelab.nasa.gov). The NASA GeneLab project aims to provide a detailed library of omics datasets associated with biological samples exposed to space radiation. The GeneLab Data System (GLDS) includes datasets from both spaceflight and ground-based studies, a majority of which involve exposure to ionizing radiation. GeneLab is the first comprehensive omics database for space-related research from which an investigator can generate hypotheses to direct future experiments, utilizing both ground and space biological radiation data. In this manuscript, the authors provide a detailed summary of the data available on GeneLab which include a description of the ground radiation studies including ion type, total dose, dose rate, and LET. In addition, they describe in detail the data available on GeneLab from experiments done on the space shuttle that have complete information on the amount of radiation the samples were exposed to during spaceflight. This manuscript is a good starting point for investigators interested in performing space radiation related research.
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Exposure of the bone marrow microenvironment to simulated solar and galactic cosmic radiation induces biological bystander effects on human hematopoiesis.
Almeida-Porada G, Rodman C, Kuhlman B, Brudvik E, Moon J, George S, Guida P, Sajuthi SP, Langefeld CD, Walker SJ, Wilson PF, Porada CD. Stem Cells Dev. 2018 Apr 26. [Epub ahead of print]
Summary:
We recently reported that direct exposure of human hematopoietic stem cells (HSC) to simulated solar energetic particle (SEP) and galactic cosmic ray (GCR) radiation dramatically altered the differentiative potential of these cells, and that simulated GCR exposures can directly induce DNA damage and mutations within human HSC, which led to leukemic transformation when these cells repopulated murine recipients. In this study, we performed the first in-depth examination to define changes that occur in mesenchymal stem cells present in the human BM niche following exposure to accelerated protons and iron ions and assess the impact these changes have upon human hematopoiesis. Our data provide compelling evidence that simulated SEP/GCR exposures can also contribute to defective hematopoiesis/immunity through so-called "biological bystander effects" by damaging the stromal cells that comprise the human marrow microenvironment, thereby altering their ability to support normal hematopoiesis.
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Mice lacking RIP3 kinase are not protected from acute radiation syndrome.
Castle KD, Daniel AR, Moding EJ, Luo L, Lee CL, Kirsch DG. Radiat Res. 2018 Apr 10 [Epub ahead of print]
Summary:
To facilitate the development of medical countermeasures that prevent the acute radiation syndrome, it is essential to characterize cell death pathways that mediate radiation injury in distinct organ systems. Recent studies have shown that pharmacological inhibition of necroptosis can mitigate death from the acute radiation syndrome in mice. In this study, we utilized mice lacking a critical regulator of necroptosis, receptor interacting protein 3 (RIP3) kinase, to characterize the role of RIP3 in normal tissue toxicity following irradiation. Our results suggest that RIP3-mediated signaling is not a critical driver of the hematopoietic or gastrointestinal acute radiation syndrome.
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Effect of densely ionizing radiation on cardiomyocyte differentiation from human-induced pluripotent stem cells.
Baljinnyam E, Venkatesh S, Gordan R, Mareedu S, Zhang J, Xie LH, Azzam EI, Suzuki CK, Fraidenraich D. Physiol Rep. 2017 Aug;5(15):e13308.
Summary:
Studies with human hearts are not feasible as cardiac biopsies are extremely rare. Thus, innovative approaches are greatly needed to investigate human cardiac cell biology in a dish. To achieve this, we developed a system whereby human induced pluripotent stem cells (hiPSCs) maintained in culture, were used to evaluate the effects of densely ionizing radiation on cardiac differentiation. hiPSCs were exposed to low fluences of 3.7 MeV a particles (mean linear energy transfer ~109 keV/mm), and then differentiated into beating cardiomyocytes (hiPSC-CMs), permitting us to conduct molecular, morphological, and functional assessments. We report that low mean absorbed doses of a particles (0.5-10 cGy) applied to hiPSCs does not affect their capacity to become beating cardiomyocytes, but has direct consequences on the generation of arrhythmic profiles and on the number of differentiated cells.

The results obtained in the study have broader implications for future investigations. For example, hiPSCs can be generated using fibroblasts or blood lymphocytes, or even urine from astronauts before and after space travel. These astronaut-derived hiPSCs may be invaluable for further characterizations. Another exciting therapeutic possibility is the prospect of using astronaut-derived pre-mission hiPSCs, as these cells can be differentiated into cardiomyocytes, and subsequently transplanted back into the astronaut in a personalized manner to correct for unexpected pathologies resulting from deep space travel.
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Low- and high-LET ionizing radiation induces delayed homologous recombination that persists for two weeks before resolving.
Allen CP, Hirakawa H, Nakajima N, Moore S, Nie J, Sharma N, Sugiura M, Hoki Y, Araki R, Abe M, Okayasu R, Fujimori A, Nickoloff JA. Radiation Research July 2017, Volume 188, pages 82-93.
Summary:
Ionizing radiation has immediate effects on cells and tissues, causing DNA damage, mutations, and cell death that are evident within minutes to days of exposure. Ionizing radiation also causes delayed effects observed weeks to years after exposure, including delayed death and delayed chromosomal instability. The Morgan laboratory pioneered studies of ionizing radiation-induced delayed chromosomal instability, demonstrating that it can persist for years after cells survive low to moderate doses of low LET ionizing radiation. Subsequently, low LET ionizing radiation was shown to induce a mechanistically distinct form of delayed genomic instability, revealed as hyper-homologous recombination. This study extends those findings, revealing that delayed homologous recombination is also induced by high LET carbon ions. Genome instability is a hallmark (and often a driver) of cancer, so genome instability associated with hyper-homologous recombination is concerning, both for environmental and radiotherapy radiation exposures. Importantly, similar levels of hyper-homologous recombination were induced by low and high LET radiation, and in both cases it persists for only two weeks before resolving. These results indicate that this form of genome instability is not as persistent as delayed chromosomal instability, and that the risk of genome instability associated with homologous recombination after high LET carbon ion radiation is no greater than that induced by low LET X-rays.
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Genomic instability induced in distant progeny of bystander cells depends on the connexins expressed in the irradiated cells.
de Toledo SM, Buonanno M, Harris AL, Azzam EI. Int J Radiat Biol. 2017 Jun 1:1-49. [Epub ahead of print]
Summary:
Using a layered cell culture system, the study examines the time window during which intercellular signaling though gap junctions mediates the propagation of harmful effects from irradiated normal or tumor cells that express specific connexins to contiguous bystander normal human fibroblasts. The irradiated cells were exposed to moderate mean absorbed doses of 3.7 MeV a particle, 1000 MeV/u iron ions, 600 MeV/u silicon ions, or 137Cs γ rays. Increased frequency of chromosomal damage and enhanced oxidative changes were observed in bystander cells exposed to either the sparsely ionizing (137Cs γ rays) or densely ionizing (a particles, energetic iron or silicon ions) radiations. Notably, the distant progeny of isolated bystander cells also exhibited increased levels of spontaneous chromosomal damage, and the effect was dependent on the type of junctional channels that coupled the irradiated donor cells with the bystander cells. Together, the results inform the roles that intercellular communication play under stress conditions, and aid assessment of the health risks of exposure to ionizing radiation.
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Very low doses of heavy oxygen ion radiation induce premature ovarian failure.
Mishra B, Ripperdan R, Ortiz L, Luderer U. Reproduction. 2017 May 20. [Epub ahead of print]
Summary:
Women are born with a finite number of eggs, which are contained in ovarian follicles. Low linear energy transfer radiation used to treat cancer is known to destroy ovarian follicles, leading to premature menopause, but the effects of high linear energy transfer space radiation on the ovary are largely unknown. This study showed that the ovaries are highly sensitive to exposure to charged oxygen particles typical of space radiation. One week after a single dose of 5 cGy fewer than 30% of follicles remained in the ovaries of exposed mice, and essentially no follicles remained after doses of 30 and 50 cGy. Destruction of ovarian follicles was preceded by dose-dependent increases in DNA double strand breaks, oxidative damage, and levels of the proapoptotic protein PUMA in follicles, consistent with DNA-damage induced apoptosis as the mechanism of follicle destruction. The findings of this study and the authors' prior study showing similar effects of charged iron particles raise concerns that exposure to charged particles during travel in deep space may lead to high risk of premature menopause in female astronauts.
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28Si total body irradiation injures bone marrow hematopoietic stem cells via induction of cellular apoptosis.
Chang J, Feng W, Wang Y, Allen AR, Turner J, Stewart B, Raber J, Hauer-Jensen M, Zhou D, Shao L Life Sci Space Res. 2017 Apr 5. [Article in Press]
Summary:
In this study, the effects of whole body 28Si ion irradiation (600 MeV/n; 0.3, 0.6, or 0.9 Gy) on the hematopoietic system (hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs)) of C57BL/6J mice exposed at 6 months of age was assessed 4 weeks after exposure. 28Si ion irradiation reduced the frequencies and numbers of HSCs, compared to non-irradiated controls, in a radiation dose-dependent manner, and impaired their clonogenic ability, while not affecting HPCs. The effects on HSCs may be due to radiation-induced apoptosis; HSCs, but not HPCs, from irradiated mice showed an increase in apoptosis in a radiation dose-dependent fashion. Thus, 28Si ion irradiation causes damage of HSCs.
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A mimic of the tumor microenvironment: A simple method for generating enriched cell populations and investigating intercellular communication.
Domogauer JD, de Toledo SM, Azzam EI. J Vis Exp. 2016 Sep 20(115).
Note: This article may be obtained online without charge. The video component can be found at http://www.jove.com/video/54429/
Summary:
This report describes a simple method to examine intercellular communications in a population consisting of different cell types. Although, the study described in the manuscript focusses on the cross- talk between cells in the tumor microenvironment, it is amenable to the study of the role of diverse bi-directional modes of cell-cell interactions in the spread of stressful effects from irradiated normal cells to bystander cells in their vicinity. Notably, the method readily permits isolation of highly enriched individual cell populations from a mixed co-culture, under non-perturbing conditions, for further study. The technique is likely to be useful in studies of different aspects of the bystander effect of space radiation.
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Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation.
Lorat Y, Timm S, Jakob B, Taucher-Scholz G, Rübe CE. Radiother Oncol. 2016 Sep 13. [Epub ahead of print]
Summary:
Understanding the radiobiological effects of high-energy charged particles such as carbon ions is crucial for developing novel strategies to maximize the use of particle therapy to treat cancer patients as well as to understand the effects of space radiation on humans. A prevailing hypothesis is that the high energy deposition along particle trajectories induces complex and clustered DNA lesions that are challenging to repair. Here, we report on electron microscopic techniques that enable spatiotemporal studies of DNA damage and repair at the nanoscale level for beam energies relevant to particle therapy and radiation protection in space. Using gold-labelled DNA-repair factors we analyzed the induction and repair of single-strand breaks, double-strand breaks, and clustered lesions in combination with terminal dUTP nick-end labelling of DNA breaks. These techniques permit the visualization of the radiation-induced DNA-damage pattern in the chromatin ultrastructure of cell nuclei after exposure to different radiation qualities.
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Novel biological approaches for testing the contributions of single DSBs and DSB clusters to the biological effects of high LET radiation.
Mladenova V, Mladenov E, Iliakis G. . Front Oncol. 2016 Jun 28;6:163.
Summary:
DSB-cluster formation in radiation action is discussed in the light of novel biological technologies that allow the generation of enzymatic DSBs at random or in well-defined locations in the genome. This article describes new ways of exploiting the I-SceI endonuclease to generate DSB-clusters at random locations in the genome, the possible utility of Zn-finger nucleases and of TALENs in generating DSBs at defined genomic locations, and ways to harness CRISPR/Cas9 technology to advance our understanding of the biological effects of DSBs. Collectively, these approaches promise to improve the focus of mathematical modeling of radiation action by providing testing opportunities for key assumptions on the underlying biology.
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Proton and light ion RBE for the induction of direct DNA double strand breaks.
Pater P, Backstom G, Villegas F, Ahnesjo A, Enger SA, Seuntjens J, El Naqa I. Med Phys. 2016 May; 43(5):2131.
Summary:
The creation of DNA double strand breaks (DSBs) following irradiation is considered an important, fate-deciding event in the life of cells. The yields of DSBs, particularly those created by the direct action of radiation, is a relevant biological endpoint, by which one can compare the effectiveness of various radiation qualities in inducing cellular death. Tedious and somewhat uncertainty-filled experimental measurements of DSBs yields can be enhanced by the use of Monte Carlo (MC) based simulation tools. In this work, the MC code Geant4 is used to generate the detailed patterns of energy depositions (i.e. tracks) of protons and light ions of various linear energy transfer (LET). These tracks are then overlaid on a simple arrangement of nucleosomes (a DNA sub-unit) in order to estimate DNA damage yields. This work presents the simulation methodology we designed in order to achieve good statistics in reasonable computation times and comparisons of the biological effectiveness of the studied particles. A notable result of this work is to show that protons are more damaging than higher atomic number ions (alpha, carbon, etc.) of the same LET.
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Charged particle mutagenesis at low dose and fluence in mouse splenic T cells.
Grygoryev D, Gauny S, Lasarev M, Ohlrich A, Kronenberg A, Turker MS.
Mutat Res. 2016 Mar 29. [Epub ahead of print]
Summary:
High-energy heavy charged particles (HZE ions) are found in the deep space environment and can significantly affect human health by inducing mutations and related cancers. Current estimates are that 1 in 3 cells in the human body will be traversed by a single heavy ion track during a three-year mission in deep space. This report considers the risk of autosomal mutation in mouse splenic T cells exposed to two representative HZE ions at low fluence (Ti ions, 1 GeV/amu, LET=107 keV/μm and Fe ions, 1 GeV/amu, LET=151 keV/μm). Proton exposure (1 GeV, LET= 0.24 keV/μm) was used as a sparsely ionizing control radiation. At the lowest fluences tested for the densely ionizing HZE ions (an average of 1 or 2 particle traversals/cell nucleus) radiation signature mutations were identified. Interestingly, the frequencies of these mutations peaked at a fluence of 2 HZE ions per cell nucleus and declined at higher levels.
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New insight into quantitative modeling of DNA double-strand break rejoining.
Herr L, Shuryak I, Friedrich T, Scholz M, Durante M, Brenner DJ Radiat Res. 2015 Aug 25. [Epub ahead of print]
Summary:
For the assessment of radiation risks for patients during radiotherapy or for astronauts on space missions, accurate, reliable and mechanistically plausible models are of great value. Amongst others, the radiation effect on tissue or on its constituting cells depends on the timing of the exposure. Cells are potentially able to mitigate damage when the time-scale of the exposure is comparable to or larger than the cellular repair time-scale. Therefore, depending on the dose, the linear energy transfer and the dose rate, radiation risks for humans, organs and cells will vary. Ten models of DNA double-strand break rejoining, accounting only for the time-dependence after radiation exposure, were investigated. A bi-exponential model with two discrete rejoining rates and a model with a gamma-distributed rejoining rate best describe 61 selected experimental data sets, and might be favorable for integration into more complex models for the estimation of radiation risks.
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Accelerated Ti ions induce autosomal mutations in mouse kidney epithelium at low dose and fluence.
Hryciw G, Grygoryev D, Lasarev M, Ohlrich A, Dan C, Madhira R, Eckelmann B, Gauny S, Kronenberg A, Turker MS, published in Radiat Res. 2015. Epub 2015 Sep 23
Summary:
Radiation limits for astronauts on long duration missions depend, in part, on understanding the risks of low fluence exposure to heavy ions (Z>2) in the GCR. In space, cells at risk for the development of fatal cancers will be traversed by a single heavy ion about once every few months. This report considers the risk of autosomal mutation from low fluence exposure to a representative heavy ion (Ti ions, 1 GeV/amu, LET=107 keV/μm) in a normal epithelium. At the lowest fluences (an average of 1 or 2 particle traversals/cell nucleus) characteristic radiation-induced mutations were identified that are typified by large-scale changes affecting one or more chromosomes. Cells with such changes are retained in the tissue for many months after exposure.
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Radiation dose-rate effects on gene expression in a mouse biodosimetry model.
Paul S, Smilenov LB, Elliston CD, Amundson SA. Radiat Res. 2015 Jul;184(1):24-32. Epub 2015 Jun 26.
Summary:
Gene expression in peripheral blood is a promising approach to radiation biodosimetry, but most studies have considered only acute exposures Many exposures, such as those involving radioactive fallout or long missions in Space, will involve protraction of all or part of the dose over time This study demonstrates for the first time the potential of gene expression profiling to distinguish between acute and low dose-rate exposures. Further development of this aspect of radiation biodosimetry, either as part of a complete gene expression approach, or as an adjunct to other methods, could provide important information for risk assessment and medical management.
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Evolved cellular mechanisms to respond to genotoxic insults: Implications for radiation-induced hematologic malignancies.
Fleenor CJ, Higa K, Weil MM, DeGregori J. Radiat Res. 2015 Sep 28. [Epub ahead of print] Review.
Summary:
Ionizing radiation exposure results in both acute and persistent health effects, including an increased risk of cancerThe damaging effects of radiation have conventionally been attributed to the direct generation of mutations resulting from radiation-induced DNA damage. New studies have uncovered -radiation-induced cellular programs that positively or negatively regulate tissue homeostasis and carcinogenesis, depending on the extent of damage received. In this review, these cellular programs, apoptosis, senescence, and differentiation, are highlighted in the context of irradiation-induced carcinogenesis.
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Proteomic profiling of hematopoietic stem/progenitor cells after a whole body exposure of CBA/CaJ mice to titanium (48Ti) ions.
Rithidech K, Tungjai M, Jangiam W, Honikel L, Gordon C, Lai X, Witzmann F. Proteomes. 2015 Sep;3(3):132.
Summary:
We used the label-free quantitative mass spectrometry (LFQMS) proteomic approach (developed in our laboratory) to determine the expression of proteins in HSPC-derived myeloid colonies (the known target for radiation-induced myeloid leukemia) obtained at an early time-point (one week) and a late time-point (six months) after an acute whole-body exposure of CBA/CaJ mice to a total dose of 0, 0.1, 0.25, or 0.5 Gy of 48Ti ions. Alterations of expression levels of proteins detected in samples collected at one week post-irradiation reflects acute effects of exposure to 48Ti ions, while those detected in samples collected at six months post-irradiation represent protein expression profiles involved in the induction of late-occurring damage (normally referred to as genomic instability).
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The role of DNA cluster damage and chromosome aberrations in radiation-induced cell killing: A theoretical approach.
Ballarini F, Altieri S, Bortolussi S, Carante M, Giroletti E, Protti N. Radiat Prot Dosimetry. 2015 Apr 15. [Epub ahead of print]
Summary:
This paper presents a biophysical model of radiation cell killing called BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations), which assumes that certain chromosome aberrations ("lethal aberrations") lead to cell death, and that chromosome aberrations are due to mm-scale rejoining of chromosome fragments deriving from DNA "cluster lesions" (CLs); the CL yield and the threshold distance governing chromosome-fragment rejoining are adjustable parameters. The agreement between simulated survival curves and experimental data on human and hamster cells exposed to photons, light ions and heavier ions suggests that lethal aberrations may play an important role in cell killing for different cell lines and different radiation types. Furthermore, the results are consistent with the hypothesis that the critical DNA lesions leading to cell death and other endpoints are DSB clusters at sub-micrometric scale (possibly involving DNA fragments with size at the kilo-bp scale), and that the effects of such critical lesions are modulated by mm-scale proximity effects during DNA-damage processing.
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Low-dose energetic protons induce adaptive and bystander effects that protect human cells against DNA damage caused by a subsequent exposure to energetic iron ions.
Buonanno M, De Toledo SM, Howell RW, Azzam EI. J Radiat Res. 2015 Mar 23.
Summary:
Buonanno et al. measured DNA damage in normal human cells exposed to protons followed at a subsequent time by energetic HZE particles. The spread of signaling events from low dose proton-irradiated cells to non-irradiated cells in their vicinity (i.e. bystanders), and the ensuing response of the latter cells to a challenge by HZE particles, was also examined. The results suggest that these studies should be extended to evaluate cytogenetic effects and other endpoints following exposures to mixed fields of space radiation delivered chronically at low dose rates.
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Particle Radiation-Induced Non-targeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells.
Goukassian DA, Sasi SP, Park D, Muralidharan S, Wage J, Kiladjian A, Onufrak J, Enderling H, Yan X. Stem Cell International, May 2015 [In press].
Summary:
Our studies show that exposure to single low-dose proton (90 cGy, 1 GeV) or iron (15 cGy, 1 GeV/n) radiation culminated in persistent IR-induced DNA damage in BM-EPCs over a period of one month; increased levels of cytokine and chemokine expression over 24 h along with a cyclical increase in apoptosis over 28 days post-IR. This may lead to BM-EPC dysfunction and eventually contribute to the increased risk for development of cardiovascular and neurodegenerative diseases. Therefore, identifying the role of specific cytokines responsible for IR-induced NTE in BM may allow development of mitigating factors to prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu.
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Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy - The heavy burden to repair.
Rübe CE, Lorat Y, Brunner CU, Schanz S, Jakob B, Taucher-Scholz G. DNA Repair (Amst). 2015 Jan 28. pii: S1568-7864(15)00019-1. doi: 10.1016/j.dnarep.2015.01.007.
Summary:
The spatial distribution of energy deposition on the scale of DNA, cells and tissue for both low- and high-LET radiation is important in determining the subsequent biological response in DNA, cells and ultimately people. In irradiated cells, the biological response has been shown to be critically dependent on the clustering of DNA damage on the nanometer scale, with high-LET radiation not only producing a higher frequency of complex DNA damage but also typically producing damage sites of greater complexity than those produced by low-LET radiation.
Here, using a new approach based on electron microscopic detection of immunogold-labeled repair factors we visualized different types of DNA lesions (SSBs, DSBs, clustered lesions) in the chromatin ultrastructure of human cells and characterized the spatio-temporal DNA damage pattern at the nanometer scale after low-LET and high-LET radiation. We show that high-LET radiation produced highly clustered DNA lesions within the particle trajectories, with multiple DSBs localized in regions of compact heterochromatin. Compared to sparsely ionizing radiation, high-LET radiation induced clearly higher yields of DSBs with up to ~500 DSBs per μm3 track volume. These clustered DNA lesions were repaired with slower kinetics and large fractions of these heterochromatic DSBs remained unrepaired. These unrepaired and/or misrepaired DNA lesions may contribute to the observed higher relative biological effectiveness for cell killing, chromosomal aberrations, mutagenesis, and carcinogenesis in high-LET radiated cells.
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Understanding Cancer Development. Processes after HZE-Particle Exposure: Roles of ROS, DNA Damage Repair, and Inflammation.
Sridharan, D. M., Asaithamby, A., Bailey, S. M., Costes, S., Doetsch, P. W., Dynan, W., Kronenberg, A., Rithidech, K. N.,Saha, J., Snijders, A. M., Werner, E., Wiese, C., Cucinotta, F.A. and Pluth, J. M. Radiat. Res. 183, 1-26 (2015).
Summary:
Oxidative stress appears to play a central role in DNA damage, telomere dysfunction and inflammation as redox reactions regulate several critical biological processes. We have attempted to clarify how redox regulation is central in influencing biological response, cell fate and potentiating cancer risk especially in cells exposed to space radiation. This review summarizes our current understanding of some critical areas within the DNA damage and oxidative arena that are key aspects to more fully elucidate in order to obtain useful robust tools to accurately model cancer risk.
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Effect of Radiation Quality on Mutagenic Joining of Enzymatically-Induced DNA Double-Strand Breaks in Previously Irradiated Human Cells. Radiation Research.
Zhentian Li, Huichen Wang, Ya Wang, John P. Murnane, and William S. Dynan (2014) November 2014, Vol. 182, No. 5, pp. 573-579.
Summary:
Prior work has shown that exposure of mammalian cells to HZE-particle radiation predisposes them to inaccurately repair new DNA double-strand breaks induced experimentally at various times during recovery. The effect was seen originally when a human tumor reporter cell line was exposed to 600 MeV/u 56Fe particles (LET = 174 keV/micron), then challenged by expression of the rare-cutting endonuclease, I-SceI. HZE particle irradiation increased the frequency of I-SceI-mediated deletions and translocations relative to non-irradiated, or low-LET irradiated, controls. Here, we tested two additional ions, 1000 MeV/u 48Ti (LET = 108 keV/micron) and 300 MeV/u 28Si (LET = 69 keV/micron). Exposure to 48Ti increased the frequency of translocations, but not deletions, whereas the 28Si ions had no measurable effect on either endpoint. There was a close correlation between the induction of the mutagenic repair phenomenon and the frequency of micronuclei in the targeted population, whereas there was no apparent correlation with radiation-induced cell inactivation. Together, results better define the radiation quality dependence of the mutagenic repair phenomenon and establish its correlation, or lack of correlation, with other endpoints.
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Induction of Chromosomal Aberrations at Fluences of Less Than One HZE Particle per Cell Nucleus.
Megumi Hada, Lori J.
Chappell, Minli Wang, Kerry A. George, and Francis A. Cucinotta (2014) Radiation Research: October 2014, Vol. 182, No. 4, pp. 368-379.
Summary:
We investigated the dose response for chromosomal aberrations for exposures corresponding to less than one particle traversal per cell nucleus by high-energy charged (HZE) nuclei. Nonlinear regression models were used to evaluate possible linear and nonlinear dose-response models based on these data. Dose responses for simple exchanges for human fibroblasts were best fit by nonlinear models motivated by a nontargeted effect (NTE). The best fits for dose response data for human lymphocytes were a linear response model for all particles. Our results suggest that simple exchanges in normal human fibroblasts have an important NTE contribution at low-particle fluence. The current and prior experimental studies provide important evidence against the linear dose response assumption used in radiation protection for HZE particles and other high-LET radiation at the relevant range of low doses.
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Radiation Quality and Mutagenesis in Human Lymphoblastoid Cells. Radiation Research.
Howard L. Liber, Rupa Idate, Christy Warner, and Susan M. Bailey (2014) October 2014, Vol. 182, No. 4, pp. 390-395.
Summary:
It seems logical that after exposures to low doses of HZE particles, damage to individual cells should be distributed as described by Poisson statistics. Cells with the most traversals and thus the highest probability of experiencing induced mutations would also be more likely to grow slowly during the expression period; these cells would be "diluted" by more rapidly growing, less damaged cells. This would lead to an underestimation of the actual level of induced mutations. In the manuscript, we showed that this was true, and went on to characterize induced mutations as a function of radiation quality - silicon at 400 MeV/n was the most mutagenic ion/energy. Interestingly, we found that induction of non-targeted mutagenesis had a pattern which appeared to be the mirror-image of that seen for direct effects.
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Telomeres and telomerase in the radiation response: implications for instability, reprograming, and carcinogenesis.
Sishc BJ, Nelson CB, McKenna MJ, Battaglia CL, Herndon A, Idate R, Liber HL, Bailey SM. Front Oncol. 2015 Nov 24;5:257.
Summary:
To gain a deeper understanding of the roles telomeres and telomerase play in the response of human cells to ionizing radiations of different qualities, changes in telomeric end-capping function, telomere length, and telomerase activity were monitored in panels of mammary epithelial and hematopoietic cell lines exposed to low linear energy transfer (LET) gamma(γ)-rays or high LET high charge, high energy (HZE) particles, delivered either acutely or at low dose rates. In addition to demonstrating that dysfunctional telomeres contribute to IR-induced mutation frequencies and genome instability, non-canonical roles for telomerase were suggested, in that telomerase activity was required for IR-induced enrichment of mammary epithelial putative stem/progenitor cell populations; separate modeling efforts support contribution of cellular reprogramming for such enrichment (Gao et al., manuscript in preparation). Results establish the critical importance of telomeres and telomerase in the radiation response and as such, have compelling implications not only for accelerated tumor repopulation following radiation therapy, but for carcinogenic potential following low dose exposures as well, including those of relevance to spaceflight-associated galactic cosmic radiations.
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Particle Radiation-Induced Non-targeted Effects in Bone-Marrow-Derived Endothelial Progenitor Cells
Goukassian DA, Sasi SP, Park D, Muralidharan S, Wage J, Kiladjian A, Onufrak J, Enderling H, Yan X. Stem Cell International, May 2015 [In press].
Summary:
Our studies show that exposure to single low-dose proton (90 cGy, 1 GeV) or iron (15 cGy, 1 GeV/n) radiation culminated in persistent IR-induced DNA damage in BM-EPCs over a period of one month; increased levels of cytokine and chemokine expression over 24 h along with a cyclical increase in apoptosis over 28 days post-IR. This may lead to BM-EPC dysfunction and eventually contribute to the increased risk for development of cardiovascular and neurodegenerative diseases. Therefore, identifying the role of specific cytokines responsible for IR-induced NTE in BM may allow development of mitigating factors to prevent long-term and cyclical loss of stem and progenitors cells in the BM milieu.
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Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles
Baulch JE, Craver BM, Tran KK, Yu L, Chmielewski N, Allen BD, Limoli CL. Redox Biol. 2015 Aug 11;5:24-32. Epub 2015 Mar 11.
Summary:
In this study we investigated whether space relevant fluences of charged particles caused oxidative stress in cultures of human neural stem cells that was proportional to the microdosimetric properties of the incident particle. Dose and temporal responses for radiation-induced oxidative stress were probed through the use of intracellular fluorogenic dyes that exhibit relative specificity for certain reactive species. Increased fluorescent signals derived from the oxidation of selected redox sensitive dyes provided a quantitative measure of oxidative stress after exposure. Data showed that the total dose, rather than particle energy and/or LET was the predominate factor dictating the extent and duration of oxidative stress in irradiated populations of human neural stem cells.
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New tricks for an old fox: impact of TGFβ on the DNA damage response and genomic stability.
M. H. Barcellos-Hoff, F. A. Cucinotta, (2014) Sci. Signal. 7, re5.
Summary:
Transforming growth factor beta is a pleiotropic growth factor necessary for homeostasis and responses to injury. TGFbeta activity is controlled by its secretion as a latent complex that is extracellularly activated by reactive oxygen species, engendering rapid and persistent mediation of tissue responses to radiation. Here, the authors review how TGFb signaling is also involved in the efficient execution of the DNA damage response, which ties the intrinsic molecular mechanisms maintaining DNA integrity to extrinsic control of tissue function.
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Induction of Chromosomal Aberrations at Fluences of Less Than One HZE Particle per Cell Nucleus.
Megumi Hada, Lori J. Chappell, Minli Wang, Kerry A. George, and Francis A. Cucinotta (2014) Radiation Research: October 2014, Vol. 182, No. 4, pp. 368-379.
Summary:
We investigated the dose response for chromosomal aberrations for exposures corresponding to less than one particle traversal per cell nucleus by high-energy charged (HZE) nuclei. Nonlinear regression models were used to evaluate possible linear and nonlinear dose-response models based on these data. Dose responses for simple exchanges for human fibroblasts were best fit by nonlinear models motivated by a nontargeted effect (NTE). The best fits for dose response data for human lymphocytes were a linear response model for all particles. Our results suggest that simple exchanges in normal human fibroblasts have an important NTE contribution at low-particle fluence. The current and prior experimental studies provide important evidence against the linear dose response assumption used in radiation protection for HZE particles and other high-LET radiation at the relevant range of low doses.
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Radiation Quality and Mutagenesis in Human Lymphoblastoid Cells. Radiation Research
Howard L. Liber, Rupa Idate, Christy Warner, and Susan M. Bailey (2014) October 2014, Vol. 182, No. 4, pp. 390-395.
Summary:
It seems logical that after exposures to low doses of HZE particles, damage to individual cells should be distributed as described by Poisson statistics. Cells with the most traversals and thus the highest probability of experiencing induced mutations would also be more likely to grow slowly during the expression period; these cells would be "diluted" by more rapidly growing, less damaged cells. This would lead to an underestimation of the actual level of induced mutations. In the manuscript, we showed that this was true, and went on to characterize induced mutations as a function of radiation quality - silicon at 400 MeV/n was the most mutagenic ion/energy. Interestingly, we found that induction of non-targeted mutagenesis had a pattern which appeared to be the mirror-image of that seen for direct effects.
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Models | CNS Effects | Degenerative Effects | Solid Cancers | Leukemia

Models

NASA GeneLab platform utilized for biological response to space radiation in animal models
McDonald JT, Stainforth R, Miller J, Cahill T, da Silveira WA, Rathi KS, Hardiman G, Taylor D, Costes SV, Chauhan V, Meller R, Beheshti A. Cancers (Basel). 2020 Feb 7;12(2):E381
Summary:
This paper uses the largest number of GeneLab datasets and provides space radiation predictions of biological responses in animal studies. Twenty-eight GeneLab omics datasets were analyzed, associated with both ground-based and spaceflight radiation studies that included in vivo and in vitro approaches. A range of ions from protons to iron particles with doses from 0.1 to 1.0 Gy for ground studies, as well as samples flown in low-Earth orbit with total doses of 1.0 mGy to 30 mGy, were utilized. Distinct biological signatures associating specific ions with specific biological responses due to radiation exposure in space were identified.
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Simulating galactic cosmic ray effects: Synergy modeling of murine tumor prevalence after exposure to two one-ion beams in rapid sequence
Huang EG, Wang R, Xie L, Chang P, Yao G, Zhang B, Ham DW, Lin Y, Blakely E, Sachs R. Life Sci Space Res. 2020 Jan 7. [Article in Press]
Summary:
Recent upgrades at the Brookhaven NASA Space Radiation Laboratory (NSRL) now allow mixtures in the form of different one-ion beams delivered in rapid sequence. This paper uses the results of three two-ion mixture experiments to illustrate conceptual, mathematical, computational, and statistical aspects of synergy analyses and also acts as an interim report on the mixture experiments' results. The results were interpreted using the following: (a) accumulated data from HG one-ion accelerator experiments; (b) incremental effect additivity synergy theory rather than simple effect additivity synergy theory; (c) parsimonious models for one-ion dose-effect-relations; and (d), computer-implemented numerical methods encapsulated in freely available open-source customized R software. The main conclusions are the following. As yet, the murine HG tumorigenesis experimental studies show synergy in only one case out of three. Moreover, some theoretical arguments suggest GCR-simulating mixed beams are not likely to be synergistic.
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Synergy theory for murine Harderian gland tumours after irradiation by mixtures of high-energy ionized atomic nuclei
Huang EG, Lin Y, Ebert M, Ham DW, Zhang CY, Sachs RK. Radiat Environ Biophys. 2019 Feb 2. doi:10.1007/s00411-018-00774-x. [Epub ahead of print]
Summary:
Experimental studies reporting murine Harderian gland tumorigenesis induced by accelerator beams of ions in the galactic cosmic ray (GCR) spectrum have been a NASA concern for many years. It is not currently known whether GCR have significant synergy. Synergy would increase the health risks of astronaut voyages in interplanetary space. This paper uses in silico synergy theory to analyze prospective GCR-simulating ion-mixture experiments. The "obvious" simple effect additivity (SEA) approach of comparing an observed mixture dose-effect relationship (DER) to the sum of the components' DERs is known from other fields of biology to be unreliable when the components' DERs are highly curvilinear, so many different replacements are now being used. Such curvilinearity may be present at low fluxes in the one-ion Harderian gland experiments due to non-targeted ('bystander') effects, in which case a replacement for SEA synergy theory is needed. This paper uses a recently introduced, arguably optimal, replacement for SEA: incremental effect additivity (IEA). It is based on numerical integration of non-linear ordinary differential equations. Unlike SEA and almost all its replacements, IEA synergy theory obeys the mixture of mixtures principle, important because even a one-ion beam on entry often becomes mixed due to interactions with intervening matter. To illustrate IEA synergy theory, prospective experiments using rapidly-sequential beams are studied with customized open-source software. Tight 95% confidence intervals are calculated taking into account adjustable parameter correlations. Arguments are presented against NASA emphasizing accelerator experiments with mixed beams whose mixture composition is standardized rather than being adjustable to take biological variability into account.
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GeneLab database analyses suggest long-term impact of space radiation on the cardiovascular system by the activation of FYN through reactive oxygen species.
Beheshti A, McDonald JT, Miller J, Grabham P, Costes SV. Int J Mol Sci. 2019 Feb 3;20(3):E661.
Summary:
Three GeneLab datasets were used to provide a potentially novel mechanism for space radiation induced cardiovascular risk directly linking radiation ground studies to spaceflight. Two of the datasets encompassed simulated space radiation ground studies and one was an in vitro spaceflight study focusing on the cardiovascular system. The following novel findings emerged from this study: 1) Space radiation causes downregulation of reactive oxygen species (ROS) functions in the cardiovascular system; 2) Astronauts and samples on the ISS are experiencing more proton radiation than any other type of space radiation; and 3) From our study we hypothesize that a feedback loop occurs from the oxidative stress caused by space radiation that upregulates a key driving gene called FYN, which in turn reduces ROS levels and thus ROS pathways, preventing cell death of cardiovascular related cells and thus protecting the cardiovascular systems.
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Mechanistic modeling predicts no significant dose rate effect on heavy-ion carcinogenesis at dose rates relevant for space exploration
Shuryak I, Brenner DJ. Radiat Prot Dosimetry. 2018 Dec 11. [Epub ahead of print]
Summary:
Based on a mix of experimental carcinogenesis data from rodent models and epidemiological studies of uranium miners, we generated model-based quantitative estimates of dose-rate-effects, relative to acute exposures, for densely-ionizing GCR-induced lung carcinogenesis. We used a mechanistically-motivated biophysical model which includes and quantifies both targeted and non-targeted radiation effects. These dose rates effects are predicted to depend both on dose rate and fluence. At the CGR fluences/dose rates expected during a Mars mission, very small dose-rate effects were predicted, i.e. the risks estimated for prolonged exposure were similar to those for acute exposures. Heavy ion carcinogenesis estimates from moderate/high dose-rate experimental data may be applicable to doses/dose rates relevant for space exploration.
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Comparative profiling of microRNAs reveals the underlying toxicological mechanism in mice testis following carbon ion radiation.
He Y, Zhang Y, Li H, Zhang H, Li Z, Xiao L, Hu J, Ma Y, Zhang Q, Zhao X. Dose Response. 2018 Apr-Jun;16(2):1559325818778633.
Summary:
This study investigated the toxicity of heavy ion radiation to mice testis by microRNA (miRNA) sequencing and bioinformatics analyses. Testicular indices and histology were measured following enterocoelia irradiation with a 2 Gy carbon ion beam, with the testes exhibiting the most serious injuries at 4 weeks after carbon ion radiation (CIR) exposure. Illumina sequencing technology was used to sequence small RNA libraries of the control and irradiated groups at 4 weeks after CIR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses implicated differential miRNAs in the regulation of target genes involved in metabolism, development, and reproduction. Here, 8 miRNAs, including miR-34c-5p, miR-138, and 6 let-7 miRNA family members previously reported in testis after radiation, were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) to validate miRNA sequencing data. The differentially expressed miRNAs described here provided a novel perspective for the role of miRNAs in testis toxicity following CIR.
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Biodosimetric transcriptional and proteomic changes are conserved in irradiated human tissue.
Keam, S.P., Gulati, T., Gamell, C. et al. Radiat Environ Biophys (2018) 57: 241.
Summary:
Transcriptional dosimetry is an emergent field of radiobiology aimed at developing robust methods for detecting and quantifying absorbed doses using radiation-induced fluctuations in gene expression. A combination of RNA sequencing, array-based and quantitative PCR transcriptomics in cellular, murine and various ex vivo human models has led to a comprehensive description of a fundamental set of genes with demonstrable dosimetric qualities. However, these are yet to be validated in human tissue due to the scarcity of in situ-irradiated source material. In this study, we present a novel evaluation of a previously reported set of dosimetric genes in human tissue exposed to a large therapeutic dose of radiation. To do this, we evaluated the quantitative changes of a set of dosimetric transcripts consisting of FDXR, BAX, BCL2, CDKN1A, DDB2, BBC3, GADD45A, GDF15, MDM2, SERPINE1, TNFRSF10B, PLK3, SESN2 and VWCE in guided pre- and post-radiation (2 weeks) prostate cancer biopsies from seven patients. We confirmed the prolonged dose-responsivity of most of these transcripts in in situ-irradiated tissue. BCL2, GDF15, and to some extent TNFRSF10B, were markedly unreliable single markers of radiation exposure. Nevertheless, as a full set, these genes reliably segregated non-irradiated and irradiated tissues and predicted radiation absorption on a patient-specific basis.
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Genetically engineered mouse models for studying radiation biology.
Castle KD, Chen M, Wisdom AJ, Kirsch DG. Transl Can Res. 2017 Jul;6 Suppl 5:S900-S913. Review.
Summary:
Genetically engineered mouse models (GEMMs) are valuable research tools that have transformed the understanding of cancer development. Castle and colleagues summarize the history of the development of GEMMs and discuss contemporary model systems with techniques such as in vivo short hairpin RNA (shRNA) knockdown, inducible gene expression, site-specific recombinases to delete genes, and dual recombinase systems. They explore the strengths and limitations of these models to study radiation biology for rigorous and reproducible preclinical research. These systems can be applied to investigate mechanisms and to develop mitigators of carcinogenesis from space radiation.
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Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome.
Casero D, Gill K, Sridharan V, Koturbash I, Nelson G, Hauer-Jensen M, Boerma M, Braun J, Cheema AK. Microbiome. 2017 Aug 18;5(1):105.
Summary:
Pathophysiological manifestations after low dose radiation exposure are strongly influenced by non-cytocidal radiation effects, including changes in the microbiome and host gene expression. Although the importance of the gut microbiome in the maintenance of human health is well established, little is known about the role of radiation in altering the microbiome during deep-space travel. Using a mouse model for exposure to high LET radiation, we observed substantial changes in the composition and functional potential of the gut microbiome. These were accompanied by changes in the abundance of multiple metabolites, which were related to the enzymatic activity of the predicted metagenome by means of metabolic network modeling. The implication of microbiome-mediated pathophysiology after low dose ionizing radiation may be an unappreciated biologic hazard of space travel and deserves experimental validation.
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Developing Human Radiation Biodosimetry Models: Testing Cross-Species Conversion Approaches Using an Ex VivoModel System.
Jin G. Park, Sunirmal Paul, Natalia Briones, Jia Zeng, Kristin Gillis, Garrick Wallstrom, Joshua LaBaer, and Sally A. Amundson (2017) Radiation Research: June 2017, Vol. 187, No. 6, pp. 708-721.
Summary:
Because non-human primates (NHP) are the animals most closely related to man, they have generally been accepted to be the most relevant animal model of human biological responses. However, responses in NHP should not be assumed to be identical to those of humans. This study begins to assess the differences in gene expression responses to radiation exposure in NHP and humans in the context of developing radiation biodosimetry. Several approaches are tested for applying dose prediction models developed in NHP to humans. It was found that an NHP biodosimetry model built using interspecies-correlated genes could accurately predict dose to human samples when a multiple regression-based cross-species conversion was applied to the gene expression values.
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Non-targeted effects models predict significantly higher Mars mission cancer risk than targeted effects models.
Cucinotta FA, Cacao E. Sci Rep. 2017 May 12;7(1):1832.
Summary:
Using the mouse Harderian gland tumor experiment, a particle track structure model of tumor prevalence is used to investigate the effects of non-targeted effects (NTE) in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model.
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Simulating Space Radiation-Induced Breast Tumor Incidence Using Automata.
A. C. Heuskin, A. I. Osseiran, J. Tang, and S. V. Costes, Radiat Res. 2016 Jul;186(1):27-38.
Summary:
We introduce the first of its kind automata-based computer breast tissue model, where individual cells live in an organized sheet and can be exposed to radiation in silico. Women are simulated from the age of 20 to 70 years old and cancer occurs via two separate random consecutive mutation events: initiation and transformation. Cell proliferation and mutation rates are derived empirically to fit the normal incidence of breast cancer observed in human populations. Radiation is then introduced in the model as a perturbation by applying multiplicative factors for both mutation and cell death rates. Multiplicative factors are derived directly from published in vitro experimental data assuming they only impact the cells present in the tissue and do not last in time. Such assumption is not sufficient to explain the excess relative cancers observed in Japanese women who received an acute dose ranging from 0.1 to 1 Gy at Hiroshima and Nagasaki. The model must add multiplicative factors reflecting chronic inflammation to fit the A-bomb data. The duration and intensity of the inflammation is found to be dose independent and increase either mutation rates or cell death rates for as long as 100 days post exposure. Such systemic effect is often referred as non-targeted effects (NTE), which have been shown to follow a step-like-dose-function which is both dose and LET independent. Using the same formalism for cosmic radiation by applying RBE for cell death and cell mutation, this model predicts for the first time breast cancer RBE in humans for any LET of interest, suggesting the most deleterious LET in space would be around 220 keV/μm.
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Addressing the Symptoms or Fixing the Problem? Developing Countermeasures against Normal Tissue Radiation Injury.
Jacqueline P. Williams, Laura Calvi, Joe V. Chakkalakal, Jacob N. Finkelstein, M. Kerry O'Banion, and Edward Puzas, Radiat Res. 2016 Jul;186(1):1-16.
Summary:
This review provides an overview of the approaches that have been used in the development of countermeasures against radiation-induced normal tissue injuries, addressing outcomes that result from both high doses (e.g. therapy or accidental exposure) and low chronic exposures (e.g. space). Importantly, the authors discuss the obstacles that have made progress difficult to date and provide an intriguing hypothesis as an explanation for the lack of significant progress - that radiation induces dysregulation across a broad array of cellular systems, all of which may require stabilization in order to restore homeostasis. This idea offers opportunities for a combination approach to countering normal tissue damage that may have broad implications across a number of fields, including space radiation research.
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Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.
Wang J, Zhang X, Wang P, Wang X, Farris III AB, Wang Y. Life Sci Space Res. 2016 May 24. [Article in Press]
Summary:
In this article, the authors suggest a better mouse model for studying the risk of space radiation-induced lung tumorigenesis. The authors based their results on using different transgenic mouse strains: oncogene (miR-21) knock-in or tumor suppressor (Gprc5a) deficient mice, and concluded that wild type mice with lowly spontaneous tumorigenesis frequency are the better mouse model choice.
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The Trp53 delta proline (Trp53ΔP) mouse exhibits increased genome instability and susceptibility to radiation-induced, but not spontaneous, tumor development.
Adams CJ, Yu JS, Mao JH, Jen KY, Costes SV, Wade M, Shoemake J, Aina OH, Del Rosario R, Menchavez PT, Cardiff RD, Wahl GM, Balmain A. Mol Carcinog. 2015 Aug 27. [Epub ahead of print].
Summary:
The Trp53ΔP mouse, which carries a germline deletion of the N-terminal proline-rich domain, on a mixed 129/Sv and C57Bl/6 background does not develop spontaneous tumors, yet is highly sensitive to a single dose of 4 Gy gamma total body radiation and develops a broad spectrum of tumor types in a wide range of tissues. Basal levels of aneuploidy in TrpΔ53 cells and tissues are elevated similar to that of the Trp53-/- (null) mice, yet this high level of genomic instability is still insufficient to drive spontaneous tumorigenesis. The lack of spontaneous tumors renders this Trp53ΔP model ideal for the study of the causal role of radiation in cancer induction.
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Induction of non-targeted stress responses in mammary tissues by heavy ions.
Wang TJ, Wu CC, Chai Y, Lam RK, Hamada N, Kakinuma S, Uchihori Y, Yu PK, Hei TK. PLoS One. 2015 Aug 28;10(8):e0136307.
Summary:
Charged particles such as protons and heavy ions are increasingly being used in clinical radiotherapy and their biological effects are also of interest to the space research community due to potential health effects of these ions to astronauts. As part of the International Open Laboratories program of the National Institute of Radiological Sciences in Chiba, Japan, Wang et al. examined the potential of carbon and argon ions in the induction of non-targeted, out of field response in mammary tissues. Irradiation of a small area in the lower abdomen of well shielded mice with either carbon or argon ions results in the induction of inflammatory response characterized by cyclooxygenase-2 induction and oxidative DNA damages in out of field breast tissues. This abscopal or out of field phenomenon indicates that non-targeted effects coordinate in a complex interplay involving cells, tissues and organs and may pose new challenges to evaluate the risks associated with radiation exposure and understanding radiation-induced side effects.Therefore, continuing to investigate the consequences of heavy ion radiation-induced bystander effects may lead to better understanding of both acute and late-side effects in a clinical setting.
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Dermatopathology effects of simulated SPE radiation exposure in the porcine model.
Sanzari JK, Diffenderfer ES, Hagan S, Billings PC, Gridley DS, Seykora JT, Kennedy AR, Cengel KA. Dermatopathology the porcine model. Life Sci Space Res. 2015 Jun 18.
Summary:
Solar particle event radiation increases an astronaut's risk of the acute radiation syndrome, prodromal effects, and/or skin damage. In this article, solar particle event-like radiation was simulated with either electron or proton radiation. Minipig skin was microscopically evaluated after nonhomogenous, total body radiation exposure at skin doses as high as 10 Gy. Maximum melanin deposition occurred at 14 days post-radiation with increased proliferation and skin thickening as well as DNA damage as late as 7 days post-radiation, indicative of post-inflammatory hyperpigmentation. These acute changes may be part of or trigger a larger inflammatory response, which may pose a hazard during deep space travel, especially if exacerbated by additional space environment factors.
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Data integration reveals key homeostatic mechanisms following low dose radiation exposure
Susan C. Tilton, Melissa M. Matzke, Marianne B. Sowa, David L. Stenoien, Thomas J. Weber, William F. Morgan, and Katrina M. Waters, Toxicol Appl Pharmacol. 2015 Feb 2. pii: S0041-008X(15)00042-3. doi: 10.1016/j.taap.2015.01.019. [Epub ahead of print].
Summary:
This study develops a systems approach to define pathways regulated by low dose radiation exposures and to understand how a complex biological system responds to subtle perturbations in its environment. We have examined the temporal response of the dermal and epidermal layers of an irradiated 3D full thickness skin model using transcriptomic, proteomic, phosphoproteomic and metabolomic strategies to generate a significant amount of heterogeneous data. The integration of these varied data sets using both top down and bottom up approaches identified novel signaling pathways that would not be clearly observed by any single 'omic technology and suggests persistent alterations in cellular and tissue homeostatic regulation occur following low dose radiation exposures in skin. The goal of these systems approaches is to enable a transition from qualitative observations to a quantitative and ultimately predictive science.
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CNS Effects

Multi-domain cognitive assessment of male mice shows space radiation is not harmful to high-level cognition and actually improves pattern separation
Whoolery CW, Yun S, Reynolds RP, Lucero MJ, Soler I, Tran FH, Ito N, Redfield RL, Richardson DR, Shih HY, Rivera PD, Chen BPC, Birnbaum SG, Stowe AM, Eisch AJ. Sci Rep. 2020 Feb 17;10(1):2737
Summary:
It is understandable that HZE particle exposure is presumed to have a negative influence on some lower and high-level cognitive functions, as many studies support this conclusion. However, our study shows this is not universally true. Mature male mice that receive whole-body exposure to two different HZE particles perform similarly to control mice on many high-level cognitive tasks, reflecting the functional integrity of key neural circuits. Strikingly, mice irradiated with either 56Fe or 28Si actually perform "better" than control mice in both appetitive and aversive pattern separation tasks. Our work urges revisitation of the generally-accepted conclusion that space radiation is detrimental to cognition.
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Particle radiation-induced dysregulation of protein homeostasis in primary human and mouse neuronal cells
Shaler T, Lin HT, Bakke J, Chen S, Grover A, Chang P. Life Sci Space Res. 2020 Feb 21.
Summary:
Space particle radiations may cause significant damage to proteins and oxidative stress in the cells within the central nervous system and pose a potential health hazard to humans in long-term manned space explorations. Dysregulation of the ubiquitin-proteasome system as evidenced by abnormal accumulation of polyubiquitin (pUb) chain linkages has been implicated in several age-related neurodegenerative disorders by mechanisms that may involve the inter-neuronal spread of toxic misfolded proteins, the induction of chronic neuroinflammation, or the inappropriate inhibition or activation of key enzymes, which could lead to dysfunction in, for example, proteolysis, or the accumulation of post-translationally-modified substrates.In this study, we employed a quantitative proteomics method to evaluate the impact of particle-radiation induced alterations in three major pUb-linked chains at lysine residues Lys-48 (K-48), Lys-63 (K-63), and Lys-11 (K-11), and probed for global proteomic changes in mouse and human neural cells that were irradiated with low doses of 250 MeV proton, 260 MeV/u silicon or 1 GeV/u iron ions. We found significant accumulation in K-48 linkage after 1 Gy protons and K-63 linkage after 0.5 Gy iron ions in human neural cells. Cells derived from different regions of the mouse brain (cortex, striatum and mesencephalon) showed differential sensitivity to particle radiation exposure. Although none of the linkages were altered after proton exposure, both K-48 and K-63 linkages in mouse striatal neuronal cells were elevated after 0.5 Gy of silicon or iron ions. Changes were also seen in proteins commonly used as markers of neural progenitor and stem cells, in DNA binding/damage repair and cellular redox pathways. In contrast, no significant changes were observed at the same time point after proton irradiation. These results suggest that the quality of the particle radiation plays a key role in the level, linkage and cell type specificity of protein homeostasis in key populations of neuronal cells.
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The Potential Effects of Radiation on the Gut-Brain Axis
Carli B. Jones, Catherine M. Davis, and Karen S. Sfanos.Radiation Research: March 2020, Vol. 193, No. 3, pp. 209-222
Summary:
Over the course of a lifetime, humans may be exposed to different types of radiation, typically in the form of low-linear energy transfer (LET) radiation, which is used, for example, in cancer treatment. In addition, astronauts may be exposed to high-LET radiation in outer space. Here, we propose that alterations to the gastrointestinal (GI) microbiota may occur when exposure to either low- or high-LET radiation, and that these alterations may perturb important relationships that exist between the GI microbiota and human health. For example, the GI microbiota can communicate with the brain via various pathways and molecules, such as the enteric nervous system, the vagus nerve, microbial metabolites and the immune system. This relationship has been termed the "gut-brain axis". Alterations to the composition of the GI microbiome can lead to alterations in its functional metabolic output and means of communication, therefore potentially causing downstream cognitive effects. Consequently, studying how radiation can affect this important network of communication could lead to new and critical interventions, as well as prevention strategies. Herein, we review the evidence supporting a relationship between radiation exposure and disruption of the gut-brain axis as well as summarize strategies that may be used to counter the effects of radiation exposure on the GI microbiome.
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Effects of chronic exposure to a mixed field of neutrons and photons on behavioral and cognitive performance in mice.
Perez R, Younger S, Bertheau E, Fallgren C, Weil M, Raber J. Behav Brain Res. 2019 Nov 22. [Epub ahead of print]
Summary:
In this study, the effects of high LET radiation delivered at low dose rate which may have relevance to space radiation exposures received by astronauts beyond low Earth orbit were assessed. More specifically, we assessed the effects chronic neutron exposure starting at 60 days of age on behavioral and cognitive performance of BALB/c female and C3H male mice at 600 and 700 days of age. Dose- and time point-dependent effects on various distinct measures of behavioral and cognitive performance of BALB/c female and C3H male mice were revealed. Different outcome measures show distinct dose-response relationships, with some anticipated to worsen performance during space missions, like increased measures of anxiety, while other anticipated to enhance performance, such as increased nest building and object recognition.
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Cranial irradiation mediated spine loss is sex-specific and complement receptor-3 dependent in male mice.
Hinkle JJ, Olschowka JA, Love TM, Williams JP, O'Banion MK. Sci Rep. 2019 Dec 11;9(1):18899.
Summary:
Previous rodent studies demonstrated that irradiation induces significant loss in dendritic spine number and alters spine morphology; these changes are associated with behavioral task deficits. In the current study sexual dimorphisms in irradiation-mediated alterations of microglia activation markers and dendritic spine density are described. Moreover, the significant dendritic spine loss observed in male mice following irradiation was complement receptor 3 (CR3)-dependent, revealing a specific and targetable mechanism for radiation effects on synaptic structure.
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Microgravity and cosmic radiations during space exploration as a window into neurodegeneration on Earth.
Sprugnoli G, Cagle YD, Santarnecchi E. JAMA Neurol. 2019 Nov 25. [Epub ahead of print]
Summary:
Astronauts involved in long-duration spaceflight missions are exposed to microgravity and cosmic radiations, considered responsible of profound changes in brain structure and function. In particular, microgravity is related to cephalad fluid shift that potentially affects protein clearance mechanisms, while cosmic radiations seem to promote the accumulation of amyloid-β in mouse models, and consequently alter hippocampus-related cognition. A pattern of "spaceflight-induced accelerated brain aging" emerges, raising on one hand important issues about astronauts' health, while, on the other, offering the opportunity to deepen the understanding of neurodegenerative diseases on Earth and develop potential countermeasures.
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Meta-analysis of Cognitive Performance by Novel Object Recognition after Proton and Heavy Ion Exposures.
Eliedonna Cacao and Francis A. Cucinotta Radiation Research: November 2019, Vol. 192, No. 5, pp. 463-472.(2019)
Summary:
Experimental studies of cognitive detriments in mice and rats after proton and heavy ion exposures have been performed by several laboratories to investigate possible risks to astronauts exposed to cosmic rays in space travel and patients treated for brain cancers with proton and carbon beams in Hadron therapy. However, distinct radiation types and doses, cognitive tests and rodent models have been used by different laboratories, while few studies have considered detailed dose-response characterizations, including estimates of relative biological effectiveness (RBE). Here we report on the first quantitative meta-analysis of the dose response for proton and heavy ion rodent studies of the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our study reveals that linear or linear-quadratic dose-response models of relative risk (RR) do not provide accurate descriptions. However, good descriptions for doses up to 1 Gy are provided by exponentially increasing fluence or dose-response models observed with an LET dependence similar to a classical radiation quality response, which peaks near 100-120 keV/µm and declines at higher LET values. Exponential models provide accurate predictions of experimental results for NOR in mice after mixed-beam exposures of protons and 56Fe, and protons, 16O and 28Si. RBE estimates are limited by available X-ray or gamma-ray experiments to serve as a reference radiation. RBE estimates based on use of data from combined gamma-ray and high-energy protons of low-LET experiments suggest modest RBEs, with values <8 for most heavy ions, while higher values <20 are based on limited gamma-ray data. In addition, we consider a log-normal model for the variation of subject responses at defined dose levels. The log-normal model predicts a heavy ion dose threshold of approximately 0.01 Gy for NOR-related cognitive detriments.
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Predictions of cognitive detriments from galactic cosmic ray exposures to astronauts on exploration missions
Cucinotta FA, Cacao E. Life Sci Space Res. 2019 Oct 16. [Article in Press]
Summary:
For the first-time we report on predictions on cognitive detriments from galactic cosmic ray (GCR) exposures on long-duration space missions outside the protection of the Earth's magnetosphere and solid body shielding. Estimates are based on a relative risk (RR) model of the fluence response for proton and heavy ion in rodent studies using the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our recent meta-analysis showed that linear and linear-quadratic dose response models were not accurate, while exponential increasing fluence response models based on particle track structure provided good descriptions of rodent data for doses up to 1 Gy. Using detailed models of the GCR environment and particle transport in shielding and tissue, we predict the excess relative risk (ERR) for NOR detriments for several long-term space mission scenarios. Predictions suggest ERR < 0.15 for most space mission scenarios with ERR<0.1 for 1-year lunar surface missions, and about ERR~0.1 for a 1000 day Mars mission for average solar cycle conditions. We discuss possible implications of these ERR levels of cognitive performance detriments relative to other neurological challenges such as rodent models of Alzheimer's disease (AD), Parkinson's disease (PD) and traumatic brain injury (TBI). Comparisons suggest a small but potentially clinically significant risk for possible space mission scenarios.
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Space-like 56Fe irradiation manifests mild, early sex-specific behavioral and neuropathological changes in wildtype and Alzheimer's-like transgenic mice.
Liu B, Hinshaw RG, Le KX, Park MA, Wang S, Belanger AP, Dubey S, Frost JL, Shi Q, Holton P, Trojanczyk L, Reiser V, Jones PA, Trigg W, Di Carli MF, Lorello P, Caldarone BJ, Williams JP, O'Banion MK, Lemere CA. Sci Rep. 2019 Aug 20;9(1):12118.
Summary:
This study investigated the effects of exposure to space radiation on behavioral and neuropathological changes in mice. Four-month old Alzheimer's disease (AD)-like transgenic (Tg) mice and wildtype (WT) littermates were irradiated with a single, whole-body dose of 10 or 50 cGy 56Fe ions (1 GeV/u) at Brookhaven National Laboratory. Sex-, genotype-, and dose-dependent changes in locomotor activity, contextual fear conditioning, grip strength, and motor learning were observed 1.5 months later mostly in Tg mice but not WT mice. Few changes were seen in general health, depression, or anxiety. MicroPET imaging of the translocator protein ligand 2 months post-irradiation showed no radiation-specific change in neuroinflammation, while brain examination indicated that radiation reduced cerebral amyloid-β levels and microglia activation in female Tg mice, modestly increased microhemorrhages in 50 cGy irradiated male WT mice and did not affect synaptic marker levels compared to sham controls. In summary, specific short-term changes in neuropathology and behaviour induced by 56Fe irradiation were observed, possibly having implications for long-term space travel.
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New concerns for neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation
Acharya MM, Baulch JE, Klein PM, Baddour AAD, Apodaca LA, Kramar EA, Alikhani L, Garcia C Jr, Angulo MC, Batra RS, Fallgren CM, Borak TB, Stark CEL, Wood MA, Britten RA, Soltesz I, Limoli CL. eNeuro 5 August 2019, 6 (4). 10.1523/ENEURO.0094-19.2019.
Summary:
Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors.
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Comments on "New concerns for neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation."
Bevelacqua JJ, Welsh J, Mortazavi S. eNeuro. 2019 Dec 17. [Epub ahead of print]
Summary:
Evaluations of the biological effects of space radiation must carefully consider the biological system response and the specific nature of the source term. Acharya et al. review neurocognitive function during deep space exposures to chronic, low dose rate, neutron radiation, but do not utilize a source term that reflects the actual space environment in terms of radiation types and their respective energies. In addition, important biological effects including adaptive response to the space radiation environment are not addressed.
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Effects of exposure to 12C and 4He particles on cognitive performance of intact and ovariectomized female rats.
Rabin BM, Miller MG, Larsen A, Spadafora C, Zolnerowich NN, Dell'Acqua LA, Shukitt-Hale B. Life Sci Space Res. 2019 Jul 10.
Summary:
Exploratory class missions to other planets will include both male and female astronauts. Previous research has indicated that female subjects do not show a disruption of cognitive performance following exposure to HZE particles. Because estrogen can function as a neuroprotectant, the cognitive performance of intact and ovariectomized female rats with estradiol or vehicle implants was tested following exposure to 12C (290 MeV/n) or 4He particles (300 MeV/n). The results indicated that exposure to 12C or 4He particles did not disrupt operant performance in the intact rats. Estradiol implants exacerbated the disruptive effects of radiation on performance. Although estrogen does not appear to function as a neuroprotectant following exposure to space radiation, the data suggest that intact females may be less responsive to the deleterious effects of exposure to space radiation on cognitive performance, possibly due to the effects of estrogen on cognitive performance.
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Risks of cognitive detriments after low dose heavy ion and proton exposures
Cucinotta FA, Cacao E. Int J Radiat Biol. 2019 May 23. [Epub ahead of print]
Summary:
Purpose: Heavy ion and proton brain irradiations occur during space travel and in Hadron therapy for cancer. Heavy ions produce distinct patterns of energy deposition in neuron cells and brain tissues compared to X-rays leading to large uncertainties in risk estimates. We make a critical review of findings from research studies over the last 25 years for understanding risks at low dose.
Conclusions: A large number of mouse and rat cognitive testing measures have been reported for a variety of particle species and energies for acute doses. However tissue reactions occur above dose thresholds and very few studies were performed at the heavy ion doses to be encountered on space missions (<0.04 Gy/y) or considered dose-rate effects, such that threshold doses are not known in rodent models. Investigations of possible mechanisms for cognitive changes have been limited by experimental design with largely group specific and not subject specific findings reported. Persistent oxidative stress and activated microglia cells are common mechanisms studied, while impairment of neurogenesis, detriments in neuron morphology, and changes to gene and protein expression were each found to be important in specific studies. Future research should focus on estimating threshold doses carried out with experimental designs aimed at understating causative mechanisms, which will be essential for extrapolating rodent findings to humans and chronic radiation scenarios, while establishing if mitigation are needed.
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Radiation-induced DNA damage cooperates with heterozygosity of TP53 and PTEN to generate high grade gliomas
Todorova PK, Fletcher-Sananikone E, Mukherjee B, Kollipara R, Vemireddy V, Xie XJ, Guida PM, Story MD, Hatanpaa K, Habib AA, Kittler R, Bachoo R, Hromas R, Floyd JR, Burma S. Cancer Res. 2019 May 14. pii: canres.0680.2019 [Epub ahead of print]
Summary:
Using transgenic mouse models, this study uncovers mechanisms by which ionizing radiation, especially particle radiation, promotes the development of lethal brain cancers called glioblastoma. Of special relevance to long-distance space missions, the study clearly shows that high-LET heavy ions carry a much greater carcinogenic risk compared to low-LET protons or X-rays. Importantly, the paper describes a versatile mouse model that can be used in the future for the testing of countermeasures to prevent brain cancer development from radiation exposure.
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Behavioral effects of space radiation: A comprehensive review of animal studies
Kiffer F, Boerma M, Allen A. Life Sci Space Res. 2019 Feb 19. [Article in Press]
Summary:
This article provides a comprehensive review of prior published work on the effects of protons, helium and heavy ions on cognitive function in mouse and rat models. As this field of research is currently in a transition towards studying mixed ion fields, this review is intended as a reference of prior results of behavioral assays after single ion exposures.
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Neurochemical insights into the radiation protection of astronauts: Distinction between low- and moderate-LET radiation components
Belov OV, Belokopytova KV, Kudrin VS, Molokanov AG, Shtemberg AS, Bazyan AS. Phys Med. 2019 Jan;57:7-16.
Summary:
Radiation protection of astronauts remains an ongoing challenge in preparation of deep space exploratory missions. Exposure to space radiation consisting of multiple radiation components is associated with a significant risk of experiencing central nervous system (CNS) detriments, potentially influencing the crew operational decisions. Developing of countermeasures protecting CNS from the deleterious exposure requires understanding the mechanistic nature of cognitive impairments induced by different components of space radiation. The current study was designed to identify differences in neurochemical modifications caused by exposure to low- and moderate-LET radiations and to elucidate a distinction between the observed outcomes. We exposed rats to accelerated protons (170 MeV; 0.5 keV/μm) or to carbon ions (12C; 500 MeV/u; 10.5 keV/μm) delivered at the same dose of 1 Gy. Neurochemical alterations were evaluated 1, 30, and 90 days after exposure via indices of the monoamine metabolism measured in five brain structures, including prefrontal cortex, hypothalamus, nucleus accumbens, hippocampus and striatum. We obtained the detailed patterns of neurochemical modifications after exposure to the mentioned radiation modalities. Our data show that the enhancement in the radiation LET from relatively low to moderate values leads to different neurochemical outcomes and that a particular effect depends on the irradiated brain structure. We also hypothesized that exposure to the moderate-LET radiations can induce a hyperactivation of feedback neurochemical mechanisms, which blur metabolic deviations and lead to the delayed impairments in brain functions. Based on our findings we discuss possible contribution of the observed changes to behavioural impairments.
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Exposure to ≤15 cGy of 600 MeV/n 56Fe Particles Impairs Rule Acquisition but not Long-Term Memory in the Attentional Set-Shifting Assay
Jewell JS, Duncan VD, Fesshaye A, Tondin A, Macadat E, and Britten RA. Radiation Research. 190(6):565-575, 2018.
Summary:
This paper describes our study of the impact of 56Fe ions (a major component of Galactic Cosmic rays) on the ability of rats to perform attentional set shifting (ATSET), one form of executive function. In this study we used rats that were maintained on a rigorous exercise regimen and that were prescreened for competency in the ATSET test. We discovered that the rats maintained a good working memory of the rules of the ATSET test for at least 6 months, even after irradiation, but that the irradiated rats had an impaired ability to learn a new set of rules when presented with a modified version of the ATSET test. Should similar effects occur in astronauts, exposure to space radiation may only impact the astronauts' ability to solve problems that they have not previously encountered.
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The final frontier: Transient microglia reduction after cosmic radiation exposure mitigates cognitive impairments and modulates phagocytic activity
Rosi S. Brain Circ. 2018 Jul-Sep;4(3):109-13. Review.
Summary:
Here, we discuss the potential of transient microglia depletion after the brain irradiation to reset the altered immune system activation and eliminate any potential long-term cognitive effects. Temporary microglia depletion showed promise in preventing any deleterious cognitive impairments following exposure to elements of cosmic radiation, such as helium and high-charge nuclei. The understanding of long-term radiation-induced cognitive impairments is vital for the protection of future astronauts and equally as important for current cancer patients.
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Psycho-emotional status but not cognition is changed under the combined effect of ionizing radiations at doses related to deep space missions
Kokhan VS, Shakhbazian EV, Markova NA. Behav Brain Res. 2019 Jan 15;362:311-8.
Summary:
Initially, the paradigm about the strictly negative impact of ionizing radiation (IR) on the central nervous system dominated. However, data on the stimulating effect of moderate doses of ionizing radiation on cognitive abilities, as well as on the anxiolytic and antidepressant effects of IR, gradually accumulated. In the present work, a study was conducted of the serotonergic system in the brain structures that are closely involved in the implementation of the response to stress. The results revealed an anxiogenic and, at the same time, antidepressant effect of IR. At the same time, the positive effect of IR on the spatial learning performance of rats was obtained. Obviously, we are seeing a number of neurocompensatory and neuroadaptive CNS reactions to the effect of IR. Within the limits of sensitivity of the tests used and within the limits of doses of the combination of ionizing radiations used (comparable to that in the implementation of the 860-day Mars mission), we conclude that IR is relatively safe for CNS functions.
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Effects of head-only or whole-body exposure to very low doses of 4He (1000 MeV/n) particles on neuronal function and cognitive performance
Rabin BM, Poulose SM, Bielinski DF, Shukitt-Hale B. Life Sci Space Res. 2019 Feb 5. [Article in Press]
Summary:
A significant portion of the total dose experienced by astronauts may be expected to come from exposure to low LET 4He particles. Changes in neuronal function and cognitive performance could be observed following both head-only and whole-body exposures to 4He particles at doses as low as 0.01-0.025 cGy. These results, therefore, suggest the possibility that astronauts on exploratory class missions may be at a greater risk for HZE-induced deficits than previously anticipated.
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Modeling Reveals the Dependence of Hippocampal Neurogenesis Radiosensitivity on Age and Strain of Rats.
Cacao E, Kapukotuwa S and Cucinotta FA. Front. Neurosci. 12:980.
Summary:
Cognitive dysfunction following radiation treatment for brain cancers in both children and adults have been correlated to impairment of neurogenesis in the hippocampal dentate gyrus. In this paper, we have extended our previous mathematical model of radiation-induced hippocampal neurogenesis impairment of C57BL/6 mice to delineate the time, age, and dose dependent alterations in neurogenesis of a diverse strain of rats. We considered four compartments to model hippocampal neurogenesis and its impairment following radiation exposures: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN), and (4) glioblasts (GB). Additional consideration of dose and time after irradiation dependence of microglial activation and a possible shift of NSC proliferation from neurogenesis to gliogenesis at higher doses is established. A major result of this work is predictions of the rat strain and age dependent differences in radiation sensitivity and sub-lethal damage repair that can be used for predictions for arbitrary dose and dose-fractionation schedules.
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Female mice are protected from space radiation-induced maladaptive responses
Krukowski K, Grue K, Frias ES, Pietrykowski J, Jones T, Nelson G, Rosi S. Brain Behav Immun. 2018 Aug 11.
Summary:
A single exposure to simulated GCR induces long-term cognitive and behavioral deficits only in the male cohorts but not in female. Mechanistically, the maladaptive behavioral responses observed only in the male cohorts correspond with microglia activation and synaptic loss in the hippocampus, a brain region involved in the cognitive domains reported here. Our findings suggest that GCR exposure can regulate microglia activity and alter synaptic architecture, which in turn leads to a range of cognitive alterations in a sex dependent manner.
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Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits.
Krukowski K, Feng X, Paladini MS, Chou A, Sacramento K, Grue K, ..., Rosi S. Scientific Reports, 8, 7857 (2018).
Summary:
Temporary microglia depletion, one week after cosmic radiation, prevents the development of long-term memory deficits. The repopulated microglia present a modified functional phenotype with reduced phagocytic activity shown to be involved in microglia-synapses interaction. Our data provide mechanistic evidence for the role of microglia in the development of cognitive deficits after cosmic radiation exposure. To our knowledge this is the first report to identify a therapeutic approach for treating GCR-induced deficits.
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Detrimental effects of helium ion irradiation on cognitive performance and cortical levels of MAP-2 in B6D2F1 mice.
Raber J, Torres ERS, Akinyeke T, Lee J, Weber Boutros SJ, Turker MS, Kronenberg A. Int J Mol Sci. 2018 Apr 20;19(4):E1247.
Summary:
The space radiation environment includes helium (4He) ions that may impact brain function. As little is known about the effects of exposures to 4He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J x DBA2/J F1 (B6D2F1) mice three months following irradiation with 4He ions (250 MeV/n; linear energy transfer (LET) = 1.6 keV/μm; 0, 21, 42 or 168 cGy). 4He ion irradiation impaired cognitive function and reduced the levels of the dendritic marker microtubule-associated protein 2 (MAP-2) in the cortex.
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Impaired attentional set-shifting performance after exposure to 5 cGy of 600 MeV/n (28)Si particles.
Britten RA, Jewell JS, Duncan VD, Hadley MM, Macadat E, Musto AE, La Tessa C. Radiat Res. Epub 2018 Jan 8. 2018 Mar;189(3):273-282.
Summary:
The long lag time for communication on a deep space mission will require that astronauts work more autonomously than on previous missions, and thus their ability to perform executive functions could be critical to mission success. Executive functions are a set of higher order cognitive abilities that animals utilize to assess changing situation and to achieve a desired goal in the most efficient and acceptable way (Assess, Adapt, Achieve!). In this paper we have determined that low doses (5 cGy) of 600 MeV/n 28Si ions impairs one executive function (cognitive flexibility, specifically the simple discrimination task in the attentional set shifting test). If astronauts were to experience GCR-induced simple discrimination impairments, they would be unable to identify key factors to successfully resolve a situation. Si ions impaired attentional set shifting performance at lower doses than the heavier ions we have previously studied, but when iso-fluences of the Si, Ti and Fe ions were compared, there were no significant differences in the severity of the impaired performance, but there were ion-specific decrements in the ability of rats to perform within the various stages of the test. This study further supports the notion that "mission-relevant" doses of HZE particles (<20 cGy) can impair certain aspects of attentional set shifting performance, but there may be some ion-specific changes in the specific cognitive domains impaired.
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Late effects of 1H irradiation on hippocampal physiology.
Kiffer F, Howe AK, Carr H, Wang J, Alexander T, Anderson JE, Groves T, Seawright JW, Sridharan V, Carter G, Boerma M, Allen AR. Life Sci Space Res. 2018 Mar 15. [Article in Press]
Summary:
This study examined the effects of protons, an abundant charged particle in both galactic cosmic rays and solar particle events, on cognitive function and hippocampus morphology in adult male C57BL/6 mice. Nine months after exposure to protons (150 MeV), mice showed a reduced ability to distinguish novel objects in a Novel Object Recognition test, indicative of reduced non-spatial memory. These results coincided with decreases in spine density and dendrite morphology in the hippocampus. The results suggest that proton irradiation caused late changes in neuronal morphology necessary for normal hippocampal processing.
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Early effects of 16O radiation on neuronal morphology and cognition in a murine model.
Carr H, Alexander TC, Groves T, Kiffer F, Wang J, Price E, Boerma M, Allen AR. Life Sci Space Res. 2018 Mar 14. [Article in Press]
Summary:
There is concern about potential adverse effects of high atomic number and energy (HZE) radiation on brain morphology. In this study, adult male C57BL/6 mice were exposed to oxygen ions (600 MeV/n, 0.1 - 1 Gy) and the hippocampus was examined two weeks after irradiation. Significant changes in spine density of neurons and in the expression of receptors that modulate synaptic function were observed, suggesting that oxygen ions have early deleterious effects on mature neurons that are associated with hippocampal learning and memory.
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Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice.
Parihar VK, Maroso M, Syage A, Allen BD, Angulo MC, Soltesz I, Limoli CL. Exp Neurol. 2018 Mar 11. [Epub ahead of print]
Summary:
Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic-radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post-irradiation intervals.
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Whole-Body Oxygen (16O) Ion-Exposure-Induced Impairments in Social Odor Recognition Memory in Rats are Dose and Time Dependent.
Ami Mange, Yuqing Cao, SiYuan Zhang, Robert D. Hienz, and Catherine M. Davis (2018) Whole-Body Oxygen (16O) Radiation Research: March 2018, Vol. 189, No. 3, pp. 292-299.
Summary:
Our paper reports dose- and time-dependent effects of acute exposure to 16O ions (5 and 25 cGy, 1000 MeV/n) on a social odor recognition memory test in male rats. At 30-days after radiation exposure, all exposed rats displayed a memory deficit, however, at 6-months following radiation exposure, this deficit was only evident in the 25 cGy exposed group. No differences in Ki67 staining, a marker of cell proliferation, were found in the subventricular zone between the sham controls, 5 cGy or 25 cGy exposed rats when assessed at 6-months following radiation exposure. This work demonstrates that low-dose HZE exposure can significantly impair memory for social odors in rats, which suggests that HZE exposure might negatively affect social processing.
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Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons.
Alp M and Cucinotta FA. (2018) Radiation Research: March 2018, Vol. 189, No. 3, pp. 312-325.
Summary:
Exposure to heavy-ion radiation during cancer treatment or space travel may cause cognitive detriments that have been associated with changes in neuron morphology and plasticity. Observations in mice of reduced neuronal dendritic complexity have revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. In this work we used morphological data for mouse dentate granular cell layer (GCL) neurons and a stochastic model of particle track structure and microscopic energy deposition (ED) to develop a predictive model of high-charge and energy (HZE) particle-induced morphological changes to the complex structures of dendritic arbors.
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Stem cell therapies for the resolution of radiation injury to the brain.
Smith SM, Limoli CL. Curr Stem Cell Rep. 2017 Dec;3(4):342-7. Review.
Summary:
Transplantation of human stem cells in the irradiated brain was first shown to resolve radiation-induced cognitive dysfunction in a landmark paper by Acharya et al., appearing in PNAS in 2009. Since that time, work from the same laboratory as well as other groups have reported on the beneficial (as well as detrimental) effects of stem cell grafting after cranial radiation exposure. Improved learning and memory found many months after engraftment has since been associated with a preservation of host neuronal morphology, a suppression of neuroinflammation, improved myelination and increased cerebral blood flow.
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Whole-Body Exposure to 28Si-Radiation Dose-Dependently Disrupts Dentate Gyrus Neurogenesis and Proliferation in the Short Term and New Neuron Survival and Contextual Fear Conditioning in the Long Term.
Whoolery CW, Walker AK, Richardson DR, Lucero MJ, Reynolds RP, Beddow DH, Clark KL, Shih HY, LeBlanc JA, Cole MG, Amaral WZ, Mukherjee S, Zhang S, Ahn F, Bulin SE, DeCarolis NA, Rivera PD, Chen BPC, Yun S, Eisch SJ. Radiation Research: Nov 2017;188(5):532-551.
Summary:
To compare the influence of 28Si exposure on indices of neurogenesis and hippocampal function with previous studies on 56Fe exposure, 9-week-old C57BL/6J and Nestin-GFP mice received whole-body 28Si-particle-radiation exposure. In contrast to the clearly observed radiation-induced, dose-dependent reductions in the short-term group across all markers, only a few neurogenesis indices were changed in the long-term irradiated groups. Compared to previously reported studies, present data suggest that 28Si-radiation exposure damages neurogenesis, but to a lesser extent than 56Fe radiation and that low-dose 28Si exposure induces abnormalities in hippocampal function, disrupting fear memory but also inducing anxiety-like behavior. Furthermore, exposure to 28Si radiation decreased new neuron survival in long-term male groups but not females suggests that sex may be an important factor when performing brain health risk assessment for astronauts traveling in space.
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Low-dose proton radiation effects in a transgenic mouse model of Alzheimer's disease - Implications for space travel.
Rudobeck E, Bellone JA, Szücs A, Bonnick K, Mehrotra-Carter S, Badaut J, Nelson GA, Hartman RE, Vlkolinsky R. PLoS One. 2017 Nov 29;12(11):e0186168.
Summary:
Space radiation represents a significant health risk for astronauts and it may accelerate the onset of Alzheimer's disease (AD). Although protons represent the main constituent in the space radiation spectrum, their effects on AD-related pathology have not been tested. We irradiated 3-month-old APP/PSEN1 transgenic (TG) and wild type (WT) mice with protons (150 MeV; 0.1-1.0 Gy; whole body) and evaluated functional and biochemical hallmarks of AD. We performed behavioral tests in the water maze (WM) before irradiation and in the WM and Barnes maze at 3 and 6 months post-irradiation to evaluate spatial learning and memory. We also performed electrophysiological recordings in vitro in hippocampal slices prepared 6 and 9 months post-irradiation to evaluate excitatory synaptic transmission and plasticity. Next, we evaluated amyloid β (Aβ) deposition in the contralateral hippocampus and adjacent cortex using immunohistochemistry. In cortical homogenates, we analyzed the levels of the presynaptic marker synaptophysin by Western blotting and measured pro-inflammatory cytokine levels (TNFα, IL-1β, IL-6, CXCL10 and CCL2) by bead-based multiplex assay. TG mice performed significantly worse than WT mice in the WM. Irradiation of TG mice did not affect their behavioral performance, but reduced the amplitudes of population spikes and inhibited paired-pulse facilitation in CA1 neurons. These electrophysiological alterations in the TG mice were qualitatively different from those observed in WT mice, in which irradiation increased excitability and synaptic efficacy. Irradiation increased Aβ deposition in the cortex of TG mice without affecting cytokine levels and increased synaptophysin expression in WT mice (but not in the TG mice). Although irradiation with protons increased Aβ deposition, the complex functional and biochemical results indicate that irradiation effects are not synergistic to AD pathology.
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Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation.
Patel R, Arakawa H, Radivoyevitch T, Gerson SL and Welford SM. Radiation Research. 2017; 188(6):672-680.
Summary:
Across a range of LET sources, we found that different ion species have different detrimental impacts at extended time points post exposure that can lead sustained declines in behavioral performances. A significant dose effect was observed on recognition memory and activity levels measured 9 months postirradiation, regardless of radiation source. In contrast, we observed that each ion species had a distinct effect on anxiety, motor coordination and spatial memory at extended time points.
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Irradiation of Neurons with High-Energy Charged Particles: An In Silico Modeling Approach
Alp M, Parihar VK, Limoli CL, Cucinotta FA (2015) PLoS Comput Biol 11(8): e1004428.
Summary:
This paper describes the spatial dependence of a particle's microscopic dose deposition events on a detailed neuron structure. Heavy ions including iron, carbon and hydrogen particles, and energetic electrons that are common in space radiation exposures are considered. The computational model covers the stochastics of the generation of energy deposition events, delivery of particle beams and possible encounter schemes of microscopic dose and neuronal morphology. Results from this in silico study can be used to consider experimental studies in order to understand structural and functional neuronal damage following irradiation.
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Bi-directional and shared epigenomic signatures following proton and 56Fe irradiation
Impey, S., Jopson, T, Pelz, C., Tafessu, A, Fareh, F., Zuloaga, D., Marzulla, T., Riparip, L., Stewart, B., Rosi, S, Turker, M.S., Raber, J. Scientific Reports, 7, 10227 (2017)
Summary:
As the brain's response to radiation exposure is an important concern for patients undergoing cancer therapy and astronauts on long missions in deep space. We assessed whether this response is specific and prolonged and is linked to epigenetic mechanisms, focusing on the response of the hippocampus at early (2-weeks) and late (20-week) time points following whole body proton irradiation. Significant overlap was observed between DNA methylation changes at the 2 and 20-week time points, demonstrating specificity and retention of changes in response to radiation and a novel class of DNA methylation change was observed following space irradiation characterized by both increased and decreased cytosine hydroxymethylation (5hmC) levels along the entire gene body. These changes mapped to genes encoding neuronal functions including postsynaptic gene ontology categories, indicating that the brain's response to proton irradiation is both specific and prolonged and involves novel remodeling of non-random regions of the epigenome.
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Changes in the Hippocampal Proteome Associated with Spatial Memory Impairment after Exposure to Low (20 cGy) Doses of 1 GeV/n 56Fe Radiation.
Richard A. Britten, Jessica S. Jewell, Leslie K. Davis, Vania D. Miller, Melissa M. Hadley, O. John Semmes, György Lonart, and Sucharita M. Dutta (2017) . Radiation Research: March 2017, Vol. 187, No. 3, pp. 287-297.
Summary:
This paper is the first to apply an unbiased proteomic profiling approach to identify the mechanisms underlying neurocognitive impairment by GCR. This approach provides a snapshot of the composition of the brain (in this case the hippocampus) , the data can then be mined to determine what pathways are active in the irradiated versus unirradiated individuals. Importantly, not all irradiated individuals develop neurocognitive impairment, suggesting that some individuals are able to ameliorate the deleterious effects of the GCR while others are unable to do so. This situation provides a unique opportunity to increase our understanding of how GCR impacts upon neurophysiology, what adaptive responses can be invoked to prevent the emergence of GEFI, as well as the pathways that are altered when neurocognitive impairment occurs. It may be possible to use such knowledge to develop two alternative countermeasure strategies, one that preserves critical pathways prophylactically and one that invokes restorative pathways after GCR exposure.
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Epigenetic determinants of space radiation-induced cognitive dysfunction.
Acharya MM, Baddour AA, Kawashita T, Allen BD, Syage AR, Nguyen TH, Yoon N, Giedzinski E, Yu L, Parihar VK, Baulch JE. Sci Rep. 2017 Feb 21;7:42885.
Summary:
While it has been clearly shown that space radiation exposures induce dramatic alterations in CNS function, the mechanisms that contribute to radiation-induced cognitive dysfunction are poorly understood. This study tested the hypothesis that neuroepigenetic mechanisms underlie, at least in part, these radiation-induced cognitive impairments. We demonstrated that mice exposed to 20 cGy of 28Si particles had elevated levels of DNA methylation that correlated with impaired ability to perform behavioral tasks that measure episodic, spatial and temporal memory. Inhibition of DNA methylation by disruption of S-adenylmethionine metabolism protected against and mitigated the changes in global DNA methylation in the irradiated brain and improved cognition, supporting the hypothesis that neuroepigenetic aberrations contribute to cognitive deficits following space relevant radiation exposures.
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Neurogenic effects of low-dose whole-body HZE (Fe) ion and gamma irradiation.
Sweet TB, Hurley SD, Wu MD, Olschowka JA, Williams JP, O'Banion MK. Radiat Res. 2016 Dec 01. [Epub ahead of print]
Summary:
Although it is well known that radiation adversely impacts adult hippocampal neurogenesis and this has been suggested as one factor contributing to cognitive deficits following brain radiation exposure, the dose threshold for radiation effects on neurogenesis has not been thoroughly investigated. Using doses ranging from 1 to 300 cGy of iron HZE particles (1 GeV/n) or gamma irradiation from a cesium source with young C57BL/6 mice, acute decreases in hippocampal neurogenesis were detected at doses of 30 and 100 cGy for iron ions and gamma radiation, respectively. Significant reduction in doublecortin-positive, newly differentiated neurons was observed at 100 cGy for both radiation types. These data complement an earlier study of proton exposure (1 GeV) that showed effects on both acute cell division and long-term neurogenesis at 50 cGy (Sweet et al., Radiat. Res. 182:18, 2014) and will aide in our understanding of radiation effects on central nervous system function.
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Neurophysiology of space travel: Energetic solar particles cause cell type-specific plasticity of neurotransmission.
Lee SH, Dudok B, Parihar VK, Jung KM, Zöldi M, Kang YJ, Maroso M, Alexander AL, Nelson GA, Piomelli D, Katona I, Limoli CL, Soltesz I. Brain Struct Funct. 2016 Nov 30. [Epub ahead of print]
Summary:
Evidence that energetic solar particles cause cell type-specific and persistent alterations in neurotransmission. Specifically, irradiation caused a significant increase in GABA release from cannabinoid receptor 1 (CB1) expressing basket cells onto pyramidal cell neurons in the CA1, an effect that could be abolished by CB1 blockade. The nature of these synaptic changes are consistent with the observed disruptions in cognitive dysfunction and point to the possibility of developing targeted therapeutic interventions to mitigate radiation-induced space brain during interplanetary travel.
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Modeling Heavy-Ion Impairment of Hippocampal Neurogenesis after Acute and Fractionated Irradiation.
Cacao, E. and Cucinotta, F. A. Radiat. Res. 186, Published on-line ahead of print (2016).
Summary:
Radiation-induced impairment of neurogenesis in the hippocampal dentate gyrus is a concern due to its reported association with cognitive detriments after radiotherapy for brain cancers and the possible risks to astronauts chronically exposed to space radiation. We used a system of nonlinear ordinary differential equations (ODEs) to represent age, time after exposure and dose-dependent changes to several cell populations participating in neurogenesis, as reported in mouse experiments. We compared our model to experimental data for X rays, and protons, carbon and iron particles, including data for fractionated iron-particle irradiation.
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Cosmic radiation exposure and persistent cognitive dysfunction.
Parihar VK, Allen BD, Caressi C, Kwok S, Chu E, Tran KK, Chmielewski NN, Giedzinski E, Acharya MM, Britten RA, Baulch JE, Limoli CL, published in Scientific Reports 6, Article number: 34774 (2016).
Summary:
A study from the laboratory of Professor Charles Limoli has found that exposures to low doses of charged particles found in galactic cosmic rays causes long-term impairments in learning and memory. These cognitive deficits are associated with significant reductions in the structural complexity of neurons and elevated neuroinflammation. These findings highlight the importance of understanding space radiation effects on the brain, and point to the unique hazards associated with such exposures.
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Individual variations in dose response for spatial memory learning among outbred Wistar rats exposed from 5 to 20 cGy of Fe particles.
Wyrobek AJ, Britten RA. Environ Mol Mutagen. 2016 May 30. [Epub ahead of print]
Summary:
A report on measurements of spatial memory learning among genetically outbred male Wistar rats exposed to graded doses of (56) Fe particles (sham, 5, 10, 15, and 20 cGy; 1 GeV/n), assessed on a Barnes maze. The findings suggest that genetically diverse individuals can vary substantially in their spatial memory learning, and that exposures at low doses appear to preferentially impact poor learners.
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Contrasting the effects of proton irradiation on dendritic complexity of subiculum neurons in wild type and MCAT mice.
Chmielewski NN, Caressi C, Giedzinski E, Parihar VK, Limoli CL. Environ Mol Mutagen. 2016 Mar 20. [Epub ahead of print]
Summary:
Our most recent findings extend our prior work previously published in Antioxidants & Redox Signaling (ref below) and now shows that similar protective effects can be demonstrated in the subiculum after proton irradiation by increasing mitochondrial antioxidant capacity. Our findings support the overall idea that altered redox homeostasis in the irradiated brain contributes to impaired neurotransmission that adversely affects cognitive function.
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Proton irradiation induces persistent and tissue-specific DNA methylation changes in the left ventricle and hippocampus.
Soren Impey, Carl Pelz, Amanuel Tafessu, Tessa Marzulla, Mitchell S. Turker and Jacob Raber. BMC Genomics 2016 17:273
Summary:
Persistent epigenetic changes that result from environmental exposures include gains or losses of DNA methylation of cytosine, which can impact gene expression. In this unbiased genome-wide DNA methylation study, we compared the long-term epigenetic effects of whole body proton irradiation in the mouse hippocampus and left ventricle. The DNA methylation data showed tissue-dependent effects of proton irradiation. Many regions affected in the ventricle mapped to genes involved in cardiovascular function pathways, whereas many regions affected in the hippocampus mapped to genes involved in neuronal functions. Importantly, the DNA methylation data revealed significant major pathway changes in response to a single proton irradiation that are related to known pathophysiologic processes.
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Impaired spatial memory performance in adult Wistar rats exposed to low (5-20 cGy) doses of 1 GeV/n Fe particles.
Britten RA, Jewell JS, Miller VD, Davis LK, Hadley MM, Wyrobek AJ. Radiat Res. 2016 Mar 185(3):332-7.
Summary:
Our paper reports on the impact that mission relevant doses of 1 GeV/n 56Fe particles has on spatial memory performance ( a cognitive function that is highly dependent upon the hippocampus). When the overall population is considered there is a significant impairment of cognitive function, but there are individual rats that retain the ability to conduct spatial memory. A novel aspect of this paper is that we analyzed the effects of radiation-induced impairments on spatial memory performance using traditional metrics based on cohort means, but also used a metric that reflects the performance of each individual rat, and then determined the proportion of individuals in each experimental cohort whose performances are impaired (Z score of >2). We believe that presenting the data in this format will be more useful to NASA when they conduct a Probabilistic Risk Analysis for this issue.
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Sex- and dose-dependent effects of calcium ion irradiation on behavioral performance of B6D2F1 mice during contextual fear conditioning training.
Raber J, Weber S, Kronenberg A, Turker MS. Life Sci Space Res. 2016 Mar 22. [Article in Press]
Summary:
In this study, the effects of 40Ca ion irradiation on behavioral and cognitive performance were assessed for the first time. 40Ca ion irradiation reduced the activity of the mice in a novel environment in a dose-dependent fashion and reduced the response to shock in female, but not male, mice. In contrast, 40Ca ion irradiation did not affect fear learning, fear memory, or extinction of fear memory. These data suggest that brain areas involved in emotional reactions to novelty and aversive environmental stimuli might be particularly susceptible to effects of 40Ca ion irradiation.
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56Fe irradiation alters spine density and dendritic complexity in the mouse hippocampus.
Allen AR, Raber J, Chakraborti A, Sharma S, Fike JR. Radiat Res. 2015 Nov 18. [Epub ahead of print]
Summary:
Health risks associated with high-LET space radiation exposure include cognitive injury, which may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology in the hippocampus, a brain area important for cognitive performance. Mice were either whole-body irradiated with 0.5 Gy 56Fe (600 MeV/n) or sham irradiated and three months later they were tested for locomotor activity and habituation and their brains analyzed for hippocampal spine morphology. Compared to sham-irradiated mice, irradiated mice moved less when first introduced to the environment and showed a compromised dendritic architecture and reduced spine density in the hippocampus. Future studies are warranted to determine the molecular mechanism underlying the deleterious effects of high-LET radiation on mature neurons associated with hippocampal learning and memory.
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Irradiation of neurons with high-energy charged particles: An in silico modeling approach.
Alp M, Parihar VK, Limoli CL, Cucinotta FA. PLoS Comput Biol. 2015 Aug; 11(8): e1004428.
Summary:
This paper describes the spatial dependence of a particle’s microscopic dose deposition events on a detailed neuron structure. Heavy ions including iron, carbon and hydrogen particles, and energetic electrons are considered. Results show that the heterogeneity of heavy particle tracks at low doses, compared to the more uniform dose distribution of electrons, juxtaposed with neuron morphology make it necessary to model the spatial dose painting for specific neuronal components.
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Fractionated radiation exposure of rat spinal cords leads to latent neuro-inflammation in brain, cognitive deficits, and alterations in apurinic endonuclease.
Suresh Kumar MA, Peluso M, Chaudhary P, Dhawan J, Beheshti A, Manickam K, Thapar U, Pena L, Natarajan M, Hlatky L, Demple B, Naidu M. 1. PLoS One. 2015 Jul 24;10(7):e0133016.
Summary:
Spinal cords of rat were used as an in vivo model for measuring possible latent effects of protons and particle radiation on the differentiation oligodendrocyte precursor cells (OPC), using low LET (X-rays and protons (1 Gy)) and high LET (28Si/ 56Fe) radiation. This study focused on the role of the base excision repair protein Apurinic Endonuclease-1 (APE1) in the rat spinal cords OPC differentiation. Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induced increases in APE1 with single dose, which then decreased with fractionation.
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A single low dose of proton radiation induces long-term behavioral and electrophysiological changes in mice.
Bellone JA, Rudobeck E, Hartman RE, Szücs A, Vlkolinský R. Radiat Res. 2015 Jul 24. [Epub ahead of print]
Summary:
Exposure to high-LET charged particles, at doses similar to those anticipated during deep space missions, was previously shown in transgenic (TG) mice to promote Alzheimer’s disease (AD)-like neurodegeneration. The authors found that proton radiation impaired reversal learning in the water maze and increased synaptic excitability in CA1 neurons, but suppressed their propensity for epileptiform activity. These baseline radiation responses to protons in healthy subjects suggest that astronauts traveling outside Earth’s magnetosphere may be at increased risk of developing long-term decrements associated with hippocampal dysfunction.
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Acute effects of exposure to Fe and O particles on learning and memory.
Rabin BM, Poulose SM, Carrihill-Knoll KL, Ramirez F, Bielinski DF, Heroux N, Shukitt-Hale B. Radiat Res. 2015 Jul 24. [Epub ahead of print]
Summary:
The experiments reported in this paper were designed to determine (1) the acute effects (24-48 hr) of exposure to 16O and 56Fe on cognitive performance; (2) whether exposure to HZE particles affected learning or memory; and (3) the relationship between HZE particle-induced oxidative stress and neuroinflammation in specific brain regions and cognitive performance. The results indicated that the acute effects of irradiation on cognitive performance are on memory, not learning. The effects of exposure to HZE particles on oxidative stress and neuroinflammation and their relationship to cognitive performance indicated that, although the effects of exposure are widespread, only changes in specific regions of the brain may be related to changes in cognitive function.
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(28)Silicon irradiation impairs contextual fear memory in B6D2F1 mice.
Raber J, Marzulla T, Stewart B, Kronenberg A, Turker MS. Radiat Res. 2015 Jun; 183(6):708-12. Epub 2015 May 26.
Summary:
In mouse studies, C57Bl6/J homozygous wild-type mice and genetic mutant mice on a C57Bl6/J background have typically been used for assessing effects of space radiation on cognition and little is known about the radiation response of mice on a heterozygous background. In the study published in the June issue of Radiation Research, 28Si irradiation was shown to impair hippocampus-dependent contextual fear memory in C57Bl6/J x DBA2/J F1 (B6D2F1) mice three months following irradiation. In contrast, in an earlier study contextual fear memory was enhanced three months following irradiation of C57Bl6/J mice with 28Si. Thus, B6D2F1 mice seem more susceptible than C57Bl6/J mice to detrimental effects of 28Si irradiation and underline the importance of considering strains with distinct genetic backgrounds for evaluating the effects of space irradiation on the brain.
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Lack of reliability in the disruption of cognitive performance following exposure to protons.
Rabin, B. M., Heroux, N. A., Shukitt-Hale, B., Carrihill-Knoll, K. L., Beck, Z., & Baxter, C. (2015 Radiation and Environmental Biophysics, 54: 285-295.
Summary:
A series of three replications were run to determine the reliability with which exposure to protons produces a disruption of cognitive performance, using a novel object recognition task and operant responding on an ascending fixed-ratio task. For the first two replications, rats were exposed to head-only exposures to 1000 MeV/n protons at the NASA Space Radiation Laboratory. For the third replication, subjects were given head-only or whole-body exposures to both 1000 and 150 MeV/n protons. The results were characterized by a lack of consistency in the effects of exposure to protons on the performance of these cognitive tasks, both within and between replications.
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What happens to your brain on the way to Mars?
Vipan K. Parihar, Barrett Allen, Katherine K. Tran, Trisha G. Macaraeg,Esther M.Chu, Stephanie F.Kwok, Nicole N. Chmielewski, Brianna M. Craver, Janet E. Baulch, Munjal M. Acharya, Francis A.Cucinotta, Charles L. Limoli. published Sci. Adv. 2015;1:e1400256 1 May 2015.
Summary:
Our study provides evidence that suggests exposure to space radiation poses a risk for developing cognitive decrements. Mice subjected to low doses of charged particles showed impaired learning and memory when subjected to behavioral testing 6 weeks later. Cognitive deficits coincided with a range of structural and synaptic alterations to neurons located in the medial prefrontal cortex. Reductions in dendritic complexity and spine density can directly disrupt neurotransmission and cognition. Our findings suggest that similar types of cognitive complications may arise in astronauts subjected to the space radiation environment during a long term deep space mission to Mars.
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Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles.
Baulch JE, Craver BM, Tran KK, Yu L, Chmielewski N, Allen BD, Limoli CL. Redox Biol. 2015 Aug 11;5:24-32. Epub 2015 Mar 11.
Summary:
In this study we investigated whether space relevant fluences of charged particles caused oxidative stress in cultures of human neural stem cells that was proportional to the microdosimetric properties of the incident particle. Dose and temporal responses for radiation-induced oxidative stress were probed through the use of intracellular fluorogenic dyes that exhibit relative specificity for certain reactive species. Increased fluorescent signals derived from the oxidation of selected redox sensitive dyes provided a quantitative measure of oxidative stress after exposure. Data showed that the total dose, rather than particle energy and/or LET was the predominate factor dictating the extent and duration of oxidative stress in irradiated populations of human neural stem cells.
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Space radiation risks to the central nervous system. (Review)
Cucinotta, F.A., Alp, M., Sulzman, F.M., Wang, M. Life Sci. Space Res, 2014;2:54-69
Summary:
In this report we summarize recent space radiobiology studies of CNS effects from particle accelerators simulating space radiation using experimental models, and make a critical assessment of their relevance with respect to doses and the dose rates to be incurred on a Mars Mission. Prospects for understanding dose, dose-rate and radiation quality dependencies of CNS effects and extrapolation to human risk assessments are described.

Novel images and novel locations of familiar images as sensitive translational cognitive tests in humans.
J. Raber. published in Behav Brain Res. 2015 Feb 2. [Epub ahead of print].
Summary:
Cognitive tests involving preferential exploration of familiar objects in novel locations and of novel objects are particularly sensitive to detect effects of space irradiation in rodents. Based on the rodent test of object recognition, a human test of object recognition was developed, the Novel Image Novel Location (NINL) test, containing panels with three images each. As this test does not involve language and is sensitive to detect of apolipoprotein E4, a risk factor for age-related cognitive decline and Alzheimer's disease, in the healthy oldest-old (mean age 81 years), it would also be good to consider the NINL test for assessing cognitive performance in astronauts during and/or following space missions.
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Impact of breathing 100% oxygen on radiation-induced cognitive impairment.
Wheeler K, Payne V, D' Agostino R, Walb M, Munley M, Metheny-Barlow L, Robbins M. Radiation Research: November 2014, Vol. 182, No. 5, pp. 580-585
Summary:
Astronauts are exposed to space radiations while breathing 100% oxygen during an EVA. Given that brain irradiation can cause cognitive impairment and oxygen is a potent radiosensitizer, astronauts may have a greater risk of developing radiation-induced cognitive impairment during an EVA. In this study, unanesthetized and unrestrained rats were whole-body irradiated with 18 MV X-rays at a low dose rate of ~425 mGy/min while breathing either air or 100% oxygen for 30 min before, during and 2 h postirradiation. Within the study's limitations, breathing 100% oxygen under simulated EVA conditions, increased rather than decreased, cognitive function at all doses when compared to irradiated air-breathing rats. Thus, astronauts are not likely to be at a greater risk of developing cognitive impairment when exposed to space radiations while breathing 100% oxygen during an EVA.
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Acute effects of exposure to Fe and O particles on learning and memory.
Rabin BM, Poulose SM, Carrihill-Knoll KL, Ramirez F, Bielinski DF, Heroux N, Shukitt-Hale B. Radiat Res. 2015 Jul 24. [Epub ahead of print]
Summary:
The experiments reported in this paper were designed to determine (1) the acute effects (24-48 hr) of exposure to 16O and 56Fe on cognitive performance; (2) whether exposure to HZE particles affected learning or memory; and (3) the relationship between HZE particle-induced oxidative stress and neuroinflammation in specific brain regions and cognitive performance. The results indicated that the acute effects of irradiation on cognitive performance are on memory, not learning. The effects of exposure to HZE particles on oxidative stress and neuroinflammation and their relationship to cognitive performance indicated that, although the effects of exposure are widespread, only changes in specific regions of the brain may be related to changes in cognitive function.
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A single low dose of proton radiation induces long-term behavioral and electrophysiological changes in mice.
Bellone JA, Rudobeck E, Hartman RE, Szücs A, Vlkolinský R. Radiat Res. 2015 Jul 24. [Epub ahead of print]
Summary:
Exposure to high-LET charged particles, at doses similar to those anticipated during deep space missions, was previously shown in transgenic (TG) mice to promote Alzheimer's disease (AD)-like neurodegeneration. The authors found that proton radiation impaired reversal learning in the water maze and increased synaptic excitability in CA1 neurons, but suppressed their propensity for epileptiform activity. These baseline radiation responses to protons in healthy subjects suggest that astronauts traveling outside Earth's magnetosphere may be at increased risk of developing long-term decrements associated with hippocampal dysfunction.
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Degenerative Effects

Changes in one-carbon metabolism and DNA methylation in the hearts of mice exposed to space environment-relevant doses of oxygen ions (16O)
Miousse IR, Skinner CM, Sridharan V, Seawright JW, Singh P, Landes RD, Cheema AK, Hauer-Jensen M, Boerma M, Koturbash I. Life Sci Space Res. 2019 August; 22, 8-15.
Summary:
Cardiovascular disease constitutes an important threat to humans after space missions beyond the Earth's magnetosphere. We investigated the effects of 16O on the cardiac methylome and one-carbon metabolism in male C57BL/6 J mice. Left ventricles were examined 14 and 90 days after exposure to space-relevant doses of 0.1, 0.25, or 1 Gy of 16O (600 MeV/n). DNA methylation in repetitive elements was elevated, particularly after 90 days, while expression showed first a decrease followed by an increase in transcript abundance. Metabolomics analysis revealed that metabolites involved in homocysteine remethylation, central to DNA methylation, were unaffected by radiation, but the transsulfuration pathway was impacted after 90 days, with a large increase in cystathione levels at the lowest dose.
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Radiation-induced cardiovascular disease: Mechanisms and importance of linear energy transfer.
Sylvester CB, Abe JI, Patel ZS, Grande-Allen KJ. Front Cardiovasc Med. 2018 Jan 31;5:5. Review.
Summary:
The link between radiation and CVD is well established in human cohorts at doses greater than 0.5 Gy. Most knowledge about radiation-induced cardiovascular disease (RICVD) comes from populations exposed to low-linear energy transfer (LET) photons. More recently, high-LET radiation is being tested as a therapy for cancer. High-LET therapy more closely replicates the high energy and atomic weight component of space radiation to which astronauts will be subjected, but how high-LET radiation affects the cardiovascular system is not yet completely understood. This review examines the clinical, molecular, and animal studies that investigate the effects of high-LET radiation on the cardiovascular system and compares those results to current knowledge of low-LET radiation. It further elaborates on how advances within NASA's research program as well as within the terrestrial work with cancer therapy can inform both the risk of RICVD and mitigation strategies.
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Low doses of oxygen ion irradiation cause long-term damage to bone marrow hematopoietic progenitor and stem cells in mice.
Wang Y, Chang J, Li X, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L. PLoS One: 2017 Dec 12;12(12):e0189466.
Summary:
While high energy charged particle irradiation as found in space is known to have short-term adverse effects on the hematopoietic system, long-term effects are not well studied. This experiment used a mouse model of oxygen ion exposure to assess stem and progenitor cells isolated from the bone marrow at three months after exposure. The cells of irradiated animals showed increased levels of reactive oxygen species and reduced performance in cell function assays. These results suggest that high energy charged particle irradiation can have long-term adverse effects on the hematopoietic system.
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Dose- and ion-dependent effects in the oxidative stress response to space-like radiation exposure in the skeletal system.
Alwood JS, Tran LH, Schreurs AS, Shirazi-Fard Y, Kumar A, Hilton D, Tahimic CGT, Globus RK. Int J Mol Sci. 2017 Oct 10;18(10):E2117.
Summary:
This article reports on impairment of osteoblastogenesis in 16-weeks old, male, C57BL6/J mice by protons (150 MeV/n) 56Fe ions (600 MeV/n) using either low (5 or 10 cGy) or high (50 or 200 cGy) doses at NASA's Space Radiation Lab. The authors' conclusion is that high-LET irradiation at 200 cGy impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss.
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Different sequences of fractionated low-dose proton and single iron-radiation-induced divergent biological responses in the heart.
Sasi SP, Yan X, Zuriaga-Herrero M, Gee H, Lee J, Song J, Onufrak J, Morgan J, Enderling H, Walsh K, Kishore R, Goukassian DA. Radiat Res. August 2017, Vol. 188, No. 2, pp. 191-203.(2017).
Summary:
We previously reported the effects of a single, whole-body, low-dose 1H (0.5 Gy, 1 GeV) and 56Fe (0.15 Gy, 1 GeV/nucleon) ion irradiation on the CV system during normal aging and under ischemic conditions. These studies signified the long-term (up to 10 months) negative effects of irradiation on systolic and diastolic functions of the heart accompanied by increased hypertrophic signaling contributing to heart failure. In the model of acute myocardial infarct, the cardiac tissue recovery and regeneration after exposure to 0.15 Gy 56Fe radiation demonstrated long-lasting detrimental effects including loss of cardiac function and worsened cardiac remodeling over the period of 10 months. On the other hand, 0.5 Gy 1H irradiation induced positive effects during recovery after a MI event, which may be attributed to a possible ischemic preconditioning-like effect of low-proton irradiation of the heart in case of possible adverse cardiac event, such as acute myocardial infarct (AMI). Because there is essentially no data available on the effects of different sequential, fractionated low-dose charged particle (SPE-like proton and HZE) irradiations to the CV system, we used same murine models to examine the effects of acute, whole-body fractionated low-dose 1H exposure by itself and in combination with a single low dose of 56Fe radiation before or after fractionated 1H to emulate a possible space-like environment. Our1H vs. a single 56Fe-IR. These findings also provide initial mechanistic insight into the development of CV morbidity and mortality induced by mixed charged particle radiation in the heart tissue. Additionally, they emphasize the necessity to determine underlying molecular mechanisms responsible for this significant mix ion fractionation and sequence-dependent divergent responses in the heart during aging and in case of a possible ischemic cardiovascular event.
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Heart Disease Mortality in the Life Span Study, 1950-2008.
Ikuno Takahashi, Yukiko Shimizu, Eric J. Grant, John Cologne, Kotaro Ozasa, and Kazunori Kodama (2017). Radiation Research: March 2017, Vol. 187, No. 3, pp. 319-332.
Summary:
Cardiovascular disease (CVD), i.e., stroke and heart disease consists of various subtypes that have potentially different radiation dose responses, as well as subtype-specific risks that have not been fully evaluated. The goal of this study was to clarify the radiation risk of subtype-specific heart disease over different time periods. Radiation dose response was examined for mortality from several heart disease subtypes in 86,600 members of the Life Span Study (LSS) cohort during 1950-2008. These subtypes included ischemic heart disease (IHD), valvular heart disease (VHD), hypertensive organ damage (HOD) and heart failure (HF).
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Short-term effects of low-LET radiation on the endothelial barrier: Uncoupling of PECAM-1 and the production of endothelial microparticles.
Templin T, Sharma P, Guida P, Grabham P. Radiat Res. 2016 Dec 1. [Epub ahead of print]
Summary:
A study from the laboratory of Dr Peter Grabham is one of the first published reports of the production and release of "cell dust" also known as endothelial micro-particles (EMPs) by the microvasculature in response to radiation. The response was first recognized as an acute dip in trans-endothelial electrical resistance 3 hours after exposure to doses as low as 2 Gy Gamma radiation. The report shows that photons (Gamma and X rays), but not low-LET charged particles (Protons and Helium ions), caused the acute uncoupling of the cell adhesion molecule PECAM-1 and the production and release of EMPs containing PECAM-1 from human endothelial monolayers and 3-D microvessel models. This response occurs at two physiological extremes and is thus likely to occur in vivo under any conditions. Considering the recent interest in PECAM-1 positive EMPs and their possible role in pathological related processes such as platelet aggregation and leukocyte extravasation, the photon-induced uncoupling of PECAM-1 and the production and release of EMPs into the blood stream has the potential to be of highly significant clinical importance.
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Apollo lunar astronauts show higher cardiovascular disease mortality: Possible deep space radiation effects on the vascular endothelium.
Delp MD, Charvat JM, Limoli CL, Globus RK, Ghosh P. Sci Rep. 2016 Jul 28;6:29901.
Summary:
The primary purpose of this study was to determine whether mortality rates due to cardiovascular disease (CVD), cancer, accidents and all other causes of death differ in (1) astronauts who never flew orbital missions in space, (2) astronauts who flew only in low Earth orbit (LEO), and (3) Apollo lunar astronauts, the only humans to have traveled beyond Earth's magnetosphere. Results show there were no differences in CVD mortality rate between non-flight (9%) and LEO (11%) astronauts. However, the CVD mortality rate among Apollo lunar astronauts (43%) was 4-5 times higher than in non-flight and LEO astronauts. Measurements of simulated weightlessness and space-relevant total-body irradiation on vascular responsiveness in mice are interpreted to show that irradiation may lead to occlusive artery disease, and may be an important risk factor for CVD among astronauts exposed to deep space radiation.
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No evidence for an increase in circulatory disease mortality in astronauts following space radiation exposures.
F.A. Cucinotta et al., Life Sciences in Space Research (2016).
Summary:
Important deficiencies in the methods and assumptions on radiation exposures used by Delp et al. are discussed and judged to cast serious doubt on their conclusions.
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Mechanisms of phosphene generation in ocular proton therapy as related to space radiation exposure.
Chuard D, Anthonipillai V, Dendale R, Nauraye C, Khan E, Mabit C, De Marzi L, Narici L, Life Sci Space Res. 2016, Jul 7. [Article in Press]
Summary:
Cosmic rays are well known to produce anomalous visual percepts in astronauts. Nevertheless, we do not yet have a detailed idea of the mechanisms by which this happens. The development of ground-based medical facilities using proton beams represents a great opportunity to study this phenomenon much more easily than in space. This article is about a study carried out at ICPO, a proton therapy centre in France. About 60% of the patients treated there report anomalous light flashes. Our analysis suggests a possible twofold mechanism of phosphene generation based on (i) light due to nuclear interactions and radioactive decay and (ii) direct excitation of the nerve fibres in the back of the eye and/or chemiluminescence near the retina.
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Effects of High-LET Radiation Exposure and Hindlimb Unloading on Skeletal Muscle Resistance Artery Vasomotor Properties and Cancel- lous Bone Microarchitecture in Mice.
Ghosh, P., Behnke, B. J., Stabley, J. N., Kilar, C. R., Park, Y., Narayanan, A., Alwood, J. S., Shirazi-Fard, Y., Schreurs, A-S., Globus, R. K. and Delp, M. D. . Radiat. Res. 185, 257- 266 (2016).
Summary:
Both hindlimb unloading, a rodent model to simulate a weightless environment, and high-LET total-body irradiation, an exposure paradigm to simulate deep space radiation, have been previously shown to induce endothelial cell dysfunction in arterial vessels. The purpose of this study was to determine whether the combination of these two environmental factors has a greater impact on vascular function than each produce individually. Both hindlimb unloading and total-body irradiation depressed endothelium-dependent vasodilation, and the combination of the two induced an even greater endothelial dysfunction. If these findings translate to humans, the results suggest that the interaction of weightlessness and deep space radiation to impair vascular endothelial cell function may create greater risk for occlusive arterial disease in astronauts than previously estimated.
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Space radiation and cardiovascular disease risk.
Boerma M, Nelson GA, Sridharan V, Mao XW, Koturbash I, Hauer-Jensen M. World J Cardiol. 2015 Dec 26;7(12):882-8. Review.
Summary:
This review article provides an overview of our current knowledge of the effects of space radiation on the cardiovascular system. To introduce this topic, general characteristics of ionizing radiation are described, and cardiovascular effects of ionizing radiation on Earth are summarized. While knowledge of the health effects of exposure to ionizing radiation on Earth can be obtained from clinical and epidemiological studies, estimates of the health risks of space radiation are largely obtained from animal and cell culture models. Because these types of experiments have begun fairly recently, the identification of potential pharmacological countermeasures to prevent or mitigate these effects is still in its infancy.
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A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation.
Ramadan SS, Sridharan V, Koturbash I, Miousse IR, Hauer-Jensen M, Nelson GA, Boerma M., published in Life Sci Space Res. 2016 Dec 14. [Article in Press]
Summary:
This study used a mouse model to examine some of the potential effects of space radiation on the heart. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we examined the effects of a low dose of protons (0.1 Gy, 150 MeV) to a subsequent higher dose of iron ions (0.5 Gy, 600 MeV/n). The two radiation exposures were 24 hours apart. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine the expression of protein markers. Exposure to iron ions caused an increase in markers of cardiac remodeling, inflammatory infiltration, and cell death. Exposure to protons 24 hours before iron ions prevented all of the responses to iron ions. These results indicate that a low dose of protons may prime the heart to respond differently to a subsequent exposure to heavy ions.
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Solid Cancers

Protons show greater relative biological effectiveness for mammary tumorigenesis with higher ERα and HER2 positive tumors relative to γ-rays in APCMin/+ mice
Suman S, Shuryak I, Kallakury B, Brenner DJ, Fornace AJ Jr, Johnson MD, Datta K. Int J Radiat Oncol Biol Phys. 2020 Feb 6. [Epub ahead of print]
Summary:
This study provides insight into proton radiation-induced mammary carcinogenesis that has implications for long-duration deep space missions and breast cancer risk in astronauts. In this paper, we demonstrated that the APCMin/+ mouse model has a good signal-to-noise ratio for proton-induced mammary tumorigenesis, which also correlates with dysregulated APC observed in a substantial portion of human breast cancer patients. Our study also establishes that estrogen signaling through ERα and HER2 are actively involved in promoting breast cancer after radiation exposures, so this can provide leads for developing strategies to block aspects of the estrogenic response, which could benefit astronauts as well as radiotherapy patients. Although this study establishes the female APCMin/+ mouse as a relevant model for space radiation-induced mammary tumorigenesis studies, further experiments using GCR and SPE beams are required to address the uncertainties in breast cancer risk modeling for long duration space missions.
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Aggressive mammary cancers lacking lymphocytic infiltration arise in irradiated mice and can be prevented by dietary intervention.
Omene C, Ma L, Moore J, Ouyang H, Illa-Bochaca I, Chou W, Patel MS, Sebastiano C, Demaria S, Mao JH, Karagoz K, Gatza ML, Barcellos-Hoff MH. Cancer Immunol Res. 2019 Dec 12. [Epub ahead of print]
Summary:
Using a radiation-genetic mammary chimera model we developed to evaluate how carcinogenesis is affected by radiation-induced, non-mutational processes, we examined the relationship between tumor microenvironment (TME) components and breast cancer phenotypes arising from Trp53-null mammary chimeras as a function of two factors, radiation type and host age. Densely ionizing radiation (DIR), which is present in the space radiation environment and used in radiation oncology, has potentially greater carcinogenic effect compared to sparsely ionizing radiation (SIR) that is prevalent on earth. Because occupational exposure (e.g. astronauts) and most radiotherapy occur in adults, here, we considered age at exposure as a factor. Here we show that compared to our prior studies in 10 week-old mice, the effect of radiation quality was greater in aged mice (10 months old), demonstrating that DIR was more effective than SIR at inducing aggressive tumors. However, tumors arising in both DIR- and SIR-irradiated hosts were characterized by rapid growth rate and an immunosuppressive TME, both of which we have previously reported in young mice. Only tumors arising in irradiated mice were devoid of lymphocytic infiltrates, suggesting that non-mutational, radiation effects promoted immune evasion. This prompted us to use caffeic acid phenethyl ester (CAPE), the major active component in propolis, a honeybee product that possesses immunomodulatory (anti-inflammatory) and anti-cancer properties. CAPE administered post-radiation in the diet of 10-week old mice prevented establishment of aggressive tumors with an immunosuppressive TME. These studies suggest that systemic inflammation and erosion of antitumor immunity elicited by radiation can be targeted after exposure to prevent aggressive tumors.
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Lung cancer progression using fast switching multiple ion beam radiation and countermeasure prevention
Luitel K, Kim SB, Barron S, Richardson JA, Shay JW. Life Sci Space Res. 2019 Aug 1. [Article in Press]
Summary:
We exposed the whole body of a lung cancer susceptible mouse model (K-rasLA-1) to three sequential ion beams: Protons (H) (120 MeV/n) 20 cGy, Helium (He) (250 MeV/n) 5.0 cGy, and Silicon (Si) (300 MeV/n) 5.0 cGy with a dose rate of 0.5 cGy/min and a total dose of 30 cGy in two different orders: 3B-1 (H→He→Si) and 3B-2 (Si→He→H) and used 30 cGy H single-ion beam as a reference. In this study we show that whole-body irradiation with H→He→Si increases the incidence of premalignant lesions and systemic oxidative stress in mice 100 days post-irradiation more than (Si→He→H) and H only irradiation. Additionally, we observed an increase in adenomas with atypia and adenocarcinomas in H→He→Si irradiated mice but not in (Si→He→H) or H (30 cGy) only irradiated mice. When we used the H→He→Si irradiation sequence but skipped a day before exposing the mice to Si, we did not observe the increased incidence of cancer initiation and progression. We also found that a non-toxic anti-inflammatory, anti-oxidative radioprotector (CDDO-EA) reduced H→He→Si induced oxidative stress and cancer initiation almost back to baseline. Thus, exposure to H→He→Si elicits significant changes in lung cancer initiation that can be mitigated using CDDO-EA.
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Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
Kumar S, Suman S, Fornace AJ Jr, Datta K., published in Proc Natl Acad Sci U S A. 2018 Oct 1. [Epub ahead of print]
Summary:
Kumar report that HZE ion radiation leads to important long-term perturbations in intestinal function. The Georgetown group showed ten years ago that HZE ions induce a persistent oxidative-stress state and pro-inflammatory phenotype in gastrointestinal (GI) and other tissues. The Shay laboratory (a member of their GI NSCOR program) further expanded on this in a 2015 report in Oncogene showing changes in gene expression in GI tissues reminiscent of the senescence-associated inflammatory response (SIR) after space radiation. In the current publication, the authors now show that HZE ions trigger perturbations in key proteins and often their transcript levels that are known to control normal GI epithelial cell maturation and function. Interestingly, cell migration along the crypt-villus axis in small intestine was persistently decreased after a low dose of 56Fe radiation relative to control and γ-rays. Wnt/β-catenin and its downstream EphrinB/EphB signaling are key to GI epithelial proliferation and positioning during migration, and both were upregulated. In addition, factors involved in cell polarity, cell adhesion, and cell-extracellular matrix interactions were persistently downregulated. These changes were accompanied by changes in barrier function and nutrient absorption factors, as well as increased intestinal tumorigenesis. Along with these changes, increasing levels of oxidative stress and DNA damage were seen up to a year after irradiation. These effects correlated with higher levels of senescent cells in GI crypts and features of the senescence-associated secretory phenotype (SASP) and the SIR. A working model was proposed whereby HZE ions cause sufficient damage to induce senescent GI cells, and that senescent-cell associated signaling molecules trigger long-term oxidative stress and a feedback loop leading to a gradual increase in senescent cells in GI crypts with increasing levels of DNA damage.
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Exposure to galactic cosmic radiation compromises DNA repair and increases the potential for oncogenic chromosomal rearrangement in bronchial epithelial cells.
Li Z, Jella KK, Jaafar L, Li S, Park S, Story MD, Wang H, Wang Y, Dynan WS. Sci Rep. 2018 Jul 23;8(1):11038.
Summary:
The authors of this study investigated persistent effects of galactic cosmic ray exposure on DNA repair capacity in human lung-derived epithelial cells, Replicate cell cultures were irradiated with 48-Ti ions or reference γ-rays, then challenged by expression of a Cas9/sgRNA pair that creates double-strand breaks simultaneously in the EML4 and ALK loci. Misjoining, which creates an EML4-ALK fusion oncogene, was significantly elevated in 48-Ti-irradiated populations relative to controls or γ-ray-irradiated samples and was frequently accompanied by deletions, consistent with a shift toward error-prone alternative nonhomologous end joining repair.
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Charged-Iron-Particles Found in Galactic Cosmic Rays are Potent Inducers of Epithelial Ovarian Tumors.
Mishra B, Lawson GW, Ripperdan R, Ortiz L, Ludere U. Radiation Research 190(2):142-150. 2018.
Summary:
Astronauts traveling in deep space are exposed to radioactive particles, such as iron ions, from galactic cosmic rays. We previously showed that irradiation of adult female mice with iron ions destroys ovarian follicles, causing premature ovarian failure, and we hypothesized that these mice would subsequently develop ovarian tumors. To test this, we aged female mice for 15 months after irradiation with 50 cGy iron ions, which is about the total dose of radiation astronauts would receive during a 3 year Mars mission. Irradiated mice had a 4-fold increased incidence of ovarian tumors compared to non-irradiated controls. The tumors were positive for cytokeratin, indicating that they were epithelial tumors. Most human ovarian cancers are also epithelial. These results raise concerns about ovarian tumors as possible late consequences of deep space travel in female astronauts.
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High-LET Radiation Increases Tumor Progression in a K-Ras-Driven Model of Lung Adenocarcinoma.
Asselin-Labat ML, Rampersad R, Xu X, Ritchie ME, Michalski J, Huang L, Onaitis MW. Radiation Research. Nov 2017; 188(5):562-570.
Summary:
A mouse model of lung adenocarcinoma driven by oncogenic K-Ras was used to ascertain the effect of low- and high-LET radiation on tumor formation. We observed increased tumor progression and tumor cell proliferation after single dose or fractionated high-LET doses, which was not observed in mice exposed to low-LET radiation. Location of the tumor nodules was not affected by radiation, indicating that the cell of origin of K-Ras-driven tumors was the same in irradiated or nonirradiated mice. Gene expression analysis revealed an upregulation of genes involved in cell proliferation and DNA damage repair. This study provides evidence that exposure to a single dose or fractionated doses of high-LET radiation induces molecular and cellular changes that accelerate lung tumor growth.
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Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells.
Sridharan DM, Enerio S, Pluth JM. Aging (Albany NY). 2017 Feb 28. [Epub ahead of print]
Summary:
Age is a key parameter that impacts cancer susceptibility to carcinogenic exposures. However the effects of complexity of the damage induced on mechanisms that maintain genomic integrity and its relationship to age are unclear. In recent work published in the Aging Journal, titled "Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells", Dr Janice Pluth's lab at LBL have attempted to address this gap by employing radiation as a tool to generate lesions of different complexity in a wide cohort of normal primary human mammary epithelial cell strains derived from women of various ages. They note unique dose and age related changes in the frequency of centrosome aberrations and stem cell populations following exposures that cause complex damages. These studies suggest that complex damages can threaten the genome stability of the stem cell population in older people. These effects will likely be exacerbated by age-associated deterioration in function and accentuate age-related cancer predisposition.
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High energy particle radiation-associated oncogenic transformation in normal mice: Insight into the connection between activation of oncotargets and oncogene addiction.
Aravindan N, Aravindan S, Manickam K, Natarajan M. Sci Rep. 2016 Nov 23;6:37623.
Summary:
This article describes a possible course of oncogenic transformation of normal tissue in wild type C57BL/6 mice after high energy particle radiation exposure. The study identified a tissue-specific molecular blue print pertaining to oncogene adduction that could mediate radiogenic cell transformation after high LET radiation. This response was found to be relatively distinct from the low LET radiation response at similar dose equivalence. In addition, this study underscores some of the potential biomarkers that can be pursued to determine the differential response of major organs to different qualities of radiation. The study provides valuable insight in determining human health risk in space and protracted post-treatment normal tissue toxicity.
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Harderian Gland Tumorigenesis: Low-Dose and LET Response.
Polly Y. Chang, Francis A. Cucinotta, Kathleen A. Bjornstad, James Bakke, Chris J. Rosen, Nicholas Du, David G. Fairchild, Eliedonna Cacao, and Eleanor A. Blakely (2016) Radiation Research: May 2016, Vol. 185, No. 5, pp. 449-460.
Summary:
This study fills gaps in the historical Harderian gland tumorigenesis data at 260 MeV/u silicon (LET ~70 keV/μm) and 1,000 MeV/u titanium (LET ~100 keV/μm, single doses and fractionated exposures to simulate chronic exposure). Modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.
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Radiation promotes colorectal cancer initiation and progression by inducing senescence-associated inflammatory responses.
Kim SB, Bozeman RG, Kaisani A, Kim W, Zhang L, Richardson JA, Wright WE, Shay JW. Oncogene. 2015 Oct 19. [Epub ahead of print]
Summary:
We used a mouse model of colon cancer susceptibility (CPC;Apc) to determine the biological effects of equivalent doses of proton (2Gy, 50 MeV/n, 20 cGy/min), protons provided at a lower dose rate as a solar particle event (SPE) simulation (2 Gy, 50-150 MeV/n, 1.7 cGy/min), and as x-rays (2 Gy 250 kVp, 20 cGy/min). While the unirradiated control mice had a 6.3% invasive cancer incidence, the x-ray treated cohort had a slight increase to 8.0% invasive cancers. The single acute dose proton irradiated mice had an 11.1% incidence of invasive cancers suggesting that protons may cause a modest increase in advanced cancers compared to terrestrial radiation in a mouse model of colon cancer susceptibility. Significantly, the SPE simulation (2 Gy protons provided over 2 hrs in 62 mice) resulted in a highly significant increase in the incidence of invasive colon cancers (25.8%). In the tumor-adjacent normal colonic tissues in the mice exposed to the SPE simulation (100 days post-irradiation) there was an increase in a panel of senescence-associated inflammatory response genes (SIRs). To test if inflammatory responses were involved in the increase in invasive cancers in the SPE irradiated mice we provided in lab chow an anti-inflammatory, anti-oxidant countermeasure (CDDO-EA, a synthetic triterpenoid) 3 days prior to SPE irradiation without additional CDDO-EA following irradiation. We observed a decreases in the inflammatory responses and the frequency of invasive cancers in the SPE treated mice, which was reduced to 15.2% with no side effects to any mice. CDDO analogs are currently in several human clinical trials with a good safety profile and may be important in reducing proton and HZE-ion exposure-associated tumor initiation and progression. Experiments are in progress using lower SPE simulation doses and other HZE-ions in a mouse model of colon cancer or lung cancer susceptibility. In addition, experiments to test if CDDO-EA is also a mitigator of radiation exposure are in progress.
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Combined exposure to protons and 56Fe leads to overexpression of Il13 and reactivation of repetitive elements in the mouse lung.
Nzabarushimana E, Prior S, Miousse IR, Pathak R, Allen AR, Latendresse J, Olsen RHJ, Raber J, Hauer-Jensen M, Nelson GA, Koturbash I..Life Sci Space Res. 2015 Aug 18.
Summary:
While previous studies have been devoted primarily to the effects of a single source of space radiation, there is an imperative need to utilize exposures to two or more sources to better simulate the occupational exposure that will be encountered by astronauts. In this study, the authors aimed to investigate the pro-fibrotic and epigenetic effects of exposure to protons and/or 56Fe ions in the dose range relevant to a space mission in the mouse lung 1 month after irradiation. Combined exposure to protons and 56Fe did not lead to detectable histopathological changes and increased expression of Tgfβ1 in the mouse lung. At the same time, combined exposure to protons and 56Fe resulted in substantially increased levels of Il13, a gene whose overexpression alone is sufficient to induce non-allergic asthma or induction of fibrosis, independently of Tgfβ1. Furthermore, decreased expression of the major maintenance DNA methyltransferase Dnmt1 and reactivation of repetitive elements - retrotransposons LINE-1 and SINE B1, and major and minor satellites were detected in the lungs of mice exposed to protons and 56Fe. The results of this study indicate that combined exposure to protons and 56Fe ions in the dose range relevant to a space mission may exert more severe pulmonary effects than exposure to either of these sources alone.
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Elucidation of changes in exposed human bronchial epithelial cells to radiations of increasing LET.
Ding LH, Park S, Xie Y, Girard L, Minna JD, Story MD. Mutagenesis. 2015 May 22. [Epub ahead of print]
Summary:
In this study, we investigated the role of ionizing radiation with increasing LETs in transforming human bronchial epithelial cells that varied in their oncogenic potential because of their genetic background. HBEC3KT cell lines were immortalized by overexpressing CDK4 and hTERT while the syngeneic HBEC3KT-R53RAS contain an additional p53 knockdown vector and overexpress mutant kRAS. Baseline transformation frequency for HBEC3KT is 10 times lower than its progressed counterpart HBEC3KT-P53RAS. As early as 6 day post-IR, cellular transformation was 1-2 logs higher increased in the oncogenically progressed HBEC3KT-p53RAS cells while gene expression profiles identified pathways that contribute to transformation including HIF-1α, mTOR, IGF-1, RhoA and the ERK/MAPK pathways upregulated in the progressed cell line. Our data suggested greater risk of lung cancer for heavy particles exposure in individuals harboring cancer-prone genetic changes.
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Ionizing radiation stimulates expression of pro-osteoclastogenic genes in marrow and skeletal tissue.
Alwood JS, Shahnazari M, Chicana B, Schreurs AS, Kumar A, Bartolini A, Shirazi-Fard Y, Globus RK. J Interferon Cytokine Res. 2015 Mar 3. [Epub ahead of print]
Summary:
Irradiation causes a very rapid loss of mineralized bone tissue via increased resorption by osteoclasts. In this study, adult mice were exposed to HZE (56Fe) or 137Cs radiation to evaluate expression levels of genes known to mediate osteoclastogenesis. This work shows a time-dependent, radiation-induced increase in skeletal expression of Rankl, the obligate cytokine for osteoclast differentiation, as well as other pro-resorption cytokines (Mcp1, Tnf, Csf1, Il6), markers of osteoclast activation (Acp5, Ctk, NfatC1), and oxidative stress responses (nfe2l2). These molecular responses to radiation preceded (< 3 days) the manifestation of bone loss (3-7 days). The findings have relevance to skeletal fragility caused by radiation exposure either on Earth or in space.
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Relative Effectiveness at 1 Gy after Acute and Fractionated Exposures of Heavy Ions with Different Linear Energy Transfer for Lung Tumorigenesis.
Ya Wang, Xiang Wang, Alton B. Farris III, Ping Wang, Xiangming Zhang, Hongyan Wang, and (2015), Radiation Research: February 2015, Vol. 183, No. 2, pp. 233-239.
Summary:
Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death in humans; therefore, studying radiation-induced lung tumorigenesis is critical for estimating the risk of space radiation to astronauts. In this study, we show that all these tested HZE particles (iron, silicon, oxygen) induced a higher incidence of lung tumorigenesis than x-rays, the relative effectiveness at 1 Gy was > 6 and silicon exposure induced more aggressive lung tumors.
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Low- and High-LET Radiation Drives Clonal Expansion of Lung Progenitor Cells In Vivo.
Farin, A. M., Manzo, N. D., Terry, K. L., Kirsch, D. G. and Stripp, B. R. Radiat. Res. 183,124-132 (2015).
Summary:
Astronauts are exposed to varying doses and qualities of ionizing radiation during space travel. However, little is known about the effects of ionizing radiation on epithelial progenitor cells that maintain the respiratory system. We hypothesized that ionizing radiation exposure would compromise progenitor cell function leading to changes in their capacity for epithelial maintenance. We assessed progenitor cell function and capacity for clonal expansion following exposure to either X-rays or 56Fe using genetic lineage tracing in combination with in vitro and in vivo assays. We found that progenitor cells were lost in a radiation dose and quality-dependent manner, but surviving progenitor cells undergo significant clonal expansion for epithelial maintenance. Based on our data, we propose a model in which radiation induces a dose-dependent decrease in the pool of available progenitor cells, leaving fewer progenitors able to maintain the airway long-term.
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Densely Ionizing Radiation Acts via the Microenvironment to Promote Aggressive Trp53 Null Mammary Carcinomas.
Illa-Bochaca I, Ouyang H, Tang J, Sebastiano C, Mao JH, Costes SV, Demaria S, Barcellos-Hoff MH. Cancer Res. 2014 Oct 10. pii: canres.1212.2014.
Summary:
Ionizing radiation is a complete carcinogen, able to both initiate malignant transformation by causing mutations in cells and to promote cancer progression by acting systemically via the tissue microenvironment. Here, the authors use a radiation mammary chimera, in which the host is irradiated but the mammary epithelium is not, to demonstrate that densely ionizing radiation (350 MeV/amu Si) acts via the microenvironment to promotes development of aggressive mammary tumors. Compared to sham-irradiated mice, a class of hormone receptor negative tumors grew faster and were more metastic in Si-particle irradiated mice. This study suggests that the response of tissues to densely ionizing radiation is an important component of its carcinogenic action; unlike mutations per se, the response of the microenvironment is amenable to countermeasures.
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Dermatopathology effects of simulated SPE radiation exposure in the porcine model.
Sanzari JK, Diffenderfer ES, Hagan S, Billings PC, Gridley DS, Seykora JT, Kennedy AR, Cengel KA. Dermatopathology the porcine model. Life Sci Space Res. 2015 Jun 18.
Summary:
Solar particle event radiation increases an astronaut's risk of the acute radiation syndrome, prodromal effects, and/or skin damage. In this article, solar particle event-like radiation was simulated with either electron or proton radiation. Minipig skin was microscopically evaluated after nonhomogenous, total body radiation exposure at skin doses as high as 10 Gy. Maximum melanin deposition occurred at 14 days post-radiation with increased proliferation and skin thickening as well as DNA damage as late as 7 days post-radiation, indicative of post-inflammatory hyperpigmentation. These acute changes may be part of or trigger a larger inflammatory response, which may pose a hazard during deep space travel, especially if exacerbated by additional space environment factors.
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Leukemia

Effects of High- and Low-LET Radiation on Human Hematopoietic System Reconstituted in Immunodeficient Mice.
Hoehn D, Pujol-Candell M, Young EF, Serban G, Shuryak I, Maerki J, Xu Z, Chowdhury M, Luna AM, Vlad G and Smilenov LB. Radiat Res. 191, 162-175 (2019).
Summary:
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.
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Pathological effects of ionizing radiation: endothelial activation and dysfunction
Baselet B, Sonveaux P, Baatout S, Aerts A. Cell Mol Life Sciences, Feb 2019, 76 (4): 699-728.
Summary:
The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.
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Dried plum diet protects from bone loss caused by ionizing radiation.
Bib section: Health Effects
Schreurs AS, Shirazi-Fard Y, Shahnazari M, Alwood JS, Truong TA, Tahimic CG, Limoli CL, Turner ND, Halloran B, Globus RK. Dried plum diet protects from bone loss caused by ionizing radiation. Sci Rep. 2016 Feb 11;6:21343.
Summary:
This study used a mouse model (C56Bl/6J, 16-mo old, males) to screen for interventions that can protect mineralized tissues from the detrimental effects of ionizing radiation. Candidate treatments with antioxidant or anti-inflammatory activities (antioxidant cocktail, dihydrolipoic acid, ibuprofen, dietary dried plum) were tested for their ability to blunt expression of degradation-related genes after irradiation with either gamma rays (photons, 2 Gy) or simulated space radiation (protons and heavy ions, 1 Gy total dose), and to prevent subsequent bone loss. Dried plum, which is rich in polyphenols and anti-oxidant activity, was most effective of the candidate interventions. These results indicate that with further research, dried plum or its constituents may prove useful.
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Concepts and challenges in cancer risk prediction for the space radiation environment.
Barcellos-Hoff MH, Blakely EA, Burma S, Fornace AJ Jr, Gerson S, Hlatky L, Kirsch DG, Lederer U, Shay J, Wang Y, Weil MM. Life Sci Space Res. 2015. Epub 2015 Jul 17.
Summary:
This white paper from scientists who receive funding from the NASA Space Radiation Program addresses the current state of the cancer biology and issues related to animal models used to study the effects of space radiation on carcinogenesis. Given that inherent uncertainties limit accurate cancer risk quantification for astronauts for deep space exploration, it is important to understand the biological mechanisms that increase cancer after radiation exposure and determine whether they impact risk modeling. New experimental data suggest that radiation quality may increase the incidence of cancers with poor prognosis (e.g. metastatic); if so, determining the underlying biology may also provide routes to effective countermeasures.
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The Future of Low Dose Radiation Research in the United States: Proceedings of a Symposium. Washington, DC: The National Academies Press, 2019
National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Nuclear and Radiation Studies Board; Ourania Kosti, Rapporteur
Summary:
Exposures at low doses of radiation, generally taken to mean doses below 100 millisieverts, are of primary interest for setting standards for protecting individuals against the adverse effects of ionizing radiation. However, there are considerable uncertainties associated with current best estimates of risks and gaps in knowledge on critical scientific issues that relate to low dose radiation. The Nuclear and Radiation Studies Board of the National Academies hosted the symposium on The Future of Low Dose Radiation Research in the United States on May 8 and 9, 2019. The goal of the symposium was to provide an open forum for a national discussion on the need for a long-term strategy to guide a low dose radiation research program in the United States. The symposium featured presentations on low dose radiation programs around the world, panel discussions with representatives from governmental and nongovernmental organizations about the need for a low dose radiation research program, reviews of low dose radiation research in epidemiology and radiation biology including new directions, and lessons to be learned from setting up large research programs in non-radiation research fields. This publication summarizes the presentation and discussion of the symposium.
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The Combination of Particle Irradiation With the Hedgehog Inhibitor GANT61 Differently Modulates the Radiosensitivity and Migration of Cancer Cells Compared to X-Ray Irradiation
Konings K, Vandevoorde C, Belmans N, Vermeesen R, Baselet B, Walleghem MV, Janssen A, Isebaert S, Baatout S, Haustermans K, Moreels M. Frontiers in Oncology, May 2019, 9, Article N°: 391.
Summary:
Metastasis is still an important cause of mortality in cancer patients and evidence has shown that conventional radiotherapy can increase the formation of metastasizing cells. An important pathway involved in the process of metastasis is the Hedgehog (Hh) signaling pathway. Here, we investigated the effect of X-rays, protons and carbon ions on cell survival, migration and Hh pathway gene expression in prostate cancer (PC3) and medulloblastoma (DAOY) cell lines.
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Proton radiation-induced cancer progression
Luitel K, Bozeman RG, Kaisani A, Kim SB, Barron S, Richardson JA, Shay JW. Life Sci Space Res. 2018 Aug 18.
Summary:
In this study, the long-term side effects of proton radiation are compared to equivalent doses of X-rays in the initiation and progression of premalignant lesions in a lung cancer susceptible mouse model (K-rasLA1). Exposure to proton irradiation enhances the progression of premalignant lesions to invasive carcinomas through persistent DNA damage, chronic oxidative stress, and immunosuppression.
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A lifetime in biophysics
Blakely E., CERN COURIER. Aug 26, 2014
Summary:
Eleanor Blakely talks about her work at Berkeley that began with pioneering research into the use of ion beams for hadron therapy.
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Reproductive hazards of space travel in women and men.
Mishra B, Luderer U. Nat Rev Endocrinol. 2019 Oct 14. [Epub ahead of print].
Summary:
This paper reviews the effects of space flight in low earth orbit, cosmic radiation, microgravity, and hypergravity on the reproductive systems of females and males. Studies performed on Earth in which rodents were exposed to experimentally generated high charge and energy particles like those found in cosmic radiation have shown that developing eggs in the ovaries and developing sperm cells in the testes are highly sensitive to destruction by these particles. Exposure to microgravity during space flight and experimental microgravity on Earth disrupts sperm development and testosterone production in rodents, while the male reproductive system seems to adapt to moderate hypergravity. Exposure to microgravity during the second half of pregnancy does not cause major disruptions of fetal development or parturition in rodents. Many gaps remain in our understanding of the reproductive hazards of space travel.
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Positive impact of low-dose, high-energy radiation on bone in partial- and/or full-weightbearing mice
Bokhari RS, Metzger CE, Black JM, Franklin KA, Boudreaux RD, Allen MR, Macias BR, Hogan HA, Braby LA, Bloomfield SA. npj Microgravity. 2019 Jun 4;5(1):13.
Summary:
We provide evidence for persistent positive impacts of high-LET radiation exposure preceding a period of full or partial weightbearing on bone mass and microarchitecture in the distal femur and, for full weightbearing mice only and more transiently, cortical bone energy absorption values.
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Radiation and microgravity - Associated stress factors and carcinogenesis.
Moreno-Villanueva M, Wu H. REACH. 2019 Mar;13:100027.
Summary:
Defects in signaling networks that regulate cellular activities, such as growth and survival can lead to cancer development. Space environment affects signal molecules and genes involve in DNA damage response, cell proliferation, cell metabolism, and cytoskeleton signaling among others. Reduced gravity and exposure to harmful radiation are the main stress factors encountered in space. While a potential risk of tumor initiation has been extensively investigated for space-radiation, research efforts on the effects of microgravity on cancer cells have focused mainly on tumor progression and migration. However, the space environment comprises both cosmic radiation and reduced gravity, and, therefore, potential additive or synergistic effects need to be considered. For instance, impaired DNA repair processes due to lack of gravity can compromise the cellular response to radiation, which in turn leads to accumulation of DNA damage and increase of the risk of tumor initiation and progression. In this review, recent research aiming at identifying the association between space radiation, microgravity or the combination of both with tumor development and the possible underlying cellular mechanisms is summarized. Furthermore, space-associated stress factors, such as psychological stress, sleep disturbances or the potential role of the immune system in tumor initiation and development in space are discussed.
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Genome wide expression profiling of cancer cell lines cultured in microgravity reveals significant dysregulation of cell cycle and microRNA gene networks.
Vidyasekar P, Shyamsunder P, Arun R, Santhakumar R, Kapadia NK, Kumar R, Verma RS. PLoS One. 2015 Aug 21;10(8):e0135958.
Summary:
Zero gravity causes several changes in metabolic and functional aspects of the human body and experiments in space flight have demonstrated alterations in cancer growth and progression. This study reports the genome wide expression profiling of a colorectal cancer cell line-DLD-1, and a lymphoblast leukemic cell line-MOLT-4, under simulated microgravity in an effort to understand central processes and cellular functions that are dysregulated among both cell lines.
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NASA Program Documents | Reports | Articles

NASA Program Documents

The Human Health and Performance Risks for Space Exploration Missions book is a collection of the evidence base for potential astronaut health and performance risks on future exploration missions. The book contains risks in twelve different areas. There are four chapters on the risks of space radiation:
Risk of Radiation Carcinogenesis Risk of Acute Radiation Syndromes Due to Solar Particle Events
Risk of Acute or Late Central Nervous System Effects from Radiation
Risk of Degenerative Tissue or Other Health Effects from Radiation

Predictions of space radiation fatality risk for exploration missions.
Cucinotta FA, To K, Cacao E. Predictions of space radiation fatality risk for exploration missions. Life Sci Space Res. 2017 Feb 1. [Article in Press]
Summary:
In this paper we describe revisions to the NASA Space Cancer Risk (NSCR) model focusing on updates to probability distribution functions (PDF) representing the uncertainties in the radiation quality factor (QF) model parameters and the dose and dose-rate reduction effectiveness factor (DDREF).
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Biophysics of NASA Radiation Quality Factors.
Francis A. Cucinotta. Radiat Prot Dosimetry (2015) doi: 10.1093/rpd/ncv144. First published online: April 16, 2015
Summary:
NASA has implemented new radiation quality factors (QFs) for projecting cancer risks from space radiation exposures to astronauts. The NASA QFs are based on particle track structure concepts with parameters derived from available radiobiology data, and NASA introduces distinct QFs for solid cancer and leukaemia risk estimates. A key feature of the NASA QFs is to represent the uncertainty in the QF assessments and evaluate the importance of the QF uncertainty to overall uncertainties in cancer risk projections. In this article, the biophysical basis for the probability distribution functions representing QF uncertainties is reviewed, and approaches needed to reduce uncertainties are discussed.
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Reports

A Report on Animal Experimentation at the Frontiers of Molecular, Cellular, and Tissue Radiobiology
A select panel, chaired by Mina Bissell, Lawrence Berkeley National Laboratory, evaluated the extent to which experiments with animal models are essential for the development of new and more accurate predictions of risks associated with exposure to HZE particles. The report was published October 7, 1996.
Posted to Background, May 17, 2011.
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A report of a joint NASA-NCI Workshop on lung cancer risk has been published as a Meeting Report in Cancer Research, requiring a subscription, or payment, to view the article: From Mice and Men to Earth and Space: Joint NASA-NCI Workshop on Lung Cancer Risk Resulting from Space and terrestrial Radiation was written by Jerry Shay, Francis Cucinotta, Frank Sulzman, Norman Coleman, and John Minna.
Posted November 15, 2011
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Reviews of Modern Physics has published an extensive review of the Physical basis of radiation protection in space trave, by Marco Durante and Francis Cucinotta. The article provides a detailed review of the space radiation environment, space radiation transport, and shielding.
Posted November 15, 2011
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Articles

Acute radiation risk assessment and mitigation strategies in near future exploration spaceflights.
Hu S, Barzilla JE, Semones E. Life Sci Space Res. 2019 Oct 31. [Article in Press]
Summary:
A brief summary of the features of radiation exposure if astronauts encounter severe SPEs beyond Low Earth Orbit (LEO), the evidence of ARS radiobiological studies at exposure levels close to recommended limits, and the shortcomings of previous dose projection approaches for ARS risk assessment. Some ARS biomathematical models, particularly those pertinent to the dose ranges that severe SPEs beyond LEO could generate, are reviewed and evaluated, focusing on their capability to predict the incidence of performance incapacitation and time-phased health effects with subsequent medical care recommendations. Using onboard active dosimeter input for estimating organ doses and likely clinical outcomes for SPEs in real time, a new strategy for ARS assessment and mitigation is described to cope with the potential threats of severe SPEs for planned deep space missions.
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On prognostic estimates of radiation risk in medicine and radiation protection
Ulanowski A, Kaiser JC, Schneider U, Walsh L. Radiation and Environmental Biophysics. August 2019, Volume 58, Issue 3, pp 305-319.
Summary:
Exposure to ionising radiation is known to increase risks of harmful health effects, of which malignant neoplasms receive special attention due to deadly hazards they bring. In many situations of unavoidable radiation exposure, either occupational or medical, risks of additional future health effects are estimated and compared with spontaneous incidence observed in the contemporary population. Correspondingly, the conventional techniques of radiation risk assessment are bound to use of the contemporary demographic and health data and are representative for an average member of the current general population. However, medical patients treated with radiation are unlikely to be similar to the average, mostly healthy, member of the general population; people exposed occupationally, like astronauts, are often selected based on their health status, they undergo periodical medical checks and screenings and due to these they can be hardly represented by the average population member. Use of current, cross-sectional, population statistics for projection of lifetime radiation risks also brings significant uncertainties to the risk estimates due to unknown future changes of health and vital statistics This paper reviews the conventional metrics used to express future radiation risks, demonstrates their limitations and difficulties with their use, and suggest an alternative quantity to express the risk, which is insensitive to competing risks and robust against unknown future changes in the population's health and demographic data. The authors examine which risk metrics better represent atypical groups, like medical patients or astronauts; are robust to variability of individual properties, pre-selection and screening; and allow risk projections with unknown secular trends.
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What does radiation biology tell us about potential health effects at low dose and low dose rates.
Azzam EI. J Radiol Prot. 2019 Jun 19. [Epub ahead of print]
Summary:
The health risks to humans exposed to low dose and low dose rate ionizing radiation remain ambiguous and are the subject of debate. The need to establish risk assessment standards based on the mechanisms underlying low dose/low fluence radiation exposures has been recognized by scholarly and regulatory bodies as critical for reducing the uncertainty in predicting adverse health risks of human exposure to low doses of radiation. Here, a brief review of laboratory-based evidence of molecular and biochemical changes induced by low doses and low dose rates of radiation is presented. In particular, two phenomena, namely bystander effects and adaptive responses that may impact low level radiation health risks are discussed together with the need for further studies. The expansion of this knowledge by considering the important variables that affect the radiation response (e.g., genetic susceptibility, time after exposure), and using the latest advances in experimental models and bioinformatics tools, may guide epidemiological studies towards reducing the uncertainty in predicting the potential health hazards of exposure to low dose radiation.
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Funding for radiation research: past, present and future
Cho K, Imaoka T, Klokov D, Paunesku T, Salomaa S, Birschwilks M, Bouffler S, Brooks AL, Hei TK, Iwasaki T, Ono T, Sakai K, Wojcik A, Woloschak GE, Yamada Y, Hamada N. International Journal of Radiation Biology. 2019;95,1-25.
Summary:
For more than a century, ionizing radiation has been indispensable mainly in medicine and industry. Radiation research is a multidisciplinary field that investigates radiation effects. Radiation research was very active in the mid- to late 20th century, but has then faced challenges, during which time funding has fluctuated widely. Here we review historical changes in funding situations in the field of radiation research, particularly in Canada, European Union countries, Japan, South Korea, and the US. We also provide a brief overview of the current situations in education and training in this field. A better understanding of the biological consequences of radiation exposure is becoming more important with increasing public concerns on radiation risks and other radiation literacy. Continued funding for radiation research is needed, and education and training in this field are also important.
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Fluence-to-effective dose conversion coefficients for male astronauts.
Timoshenko GN, Belvedersky MI. J Radiol Prot. 2019 Jun;39(2),511-21.
Summary:
The problem of the reliable estimation of astronauts' radiation exposure doses in deep space is very important and relevant in connection with the accepted space research programmes. The effective dose value based on ICRP Publication 103 presents too conservative an estimate of an astronaut's radiation risk. A more realistic dose can be calculated on the basis of relationships between the radiation quality factor and linear energy transfer or linear energy or Z*2/β 2, according to the NASA concept. In addition, it is reasonable to use a set of tissue weighting coefficients (normalised relative detriments) that have been averaged over a cohort of working age males similar to the male astronaut cohort. The closest to the male astronauts is the NASA cohort of males aged 30-60 years who have never smoked. The fluence-to-effective dose equivalent conversion coefficients calculated specially for male astronauts are compared. Different approaches to radiation risk estimation for astronauts are discussed.
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The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight
Garrett-Bakelman FE et al. Science. 2019;364,eaau8650.
Summary:
The research is featured on the cover of the journal issue with the caption: "A study of identical twins identifies molecular, physiological, and cognitive changes specific to one twin who spent a year living aboard the International Space Station. The cover depicts the twins and their respective Earth-bound and space residencies, with a rocket and the International Space Station in the background."
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The Million Person Study, whence it came and why.
Boice JD Jr, Cohen SS, Mumma MT, Ellis ED. Int J Radiat Biol. 2019 Mar 4. [Epub ahead of print]
Summary:
The study of low dose and low-dose rate exposure is of immeasurable value in understanding the possible range of health effects from prolonged exposures to radiation. The Million Person Study of Low-Dose Health Effects (MPS) was designed to evaluate radiation risks among healthy American workers and veterans who are more representative of today's populations than are the Japanese atomic bomb survivors exposed briefly to high-dose radiation in 1945. A million persons were needed for statistical reasons to evaluate low-dose and dose-rate effects, rare cancers, intakes of radioactive elements, and differences in risks between women and men.
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The Million Person Study relevance to space exploration and Mars
Boice JD Jr. Int J Radiat Biol. 2019 Mar 4. [Epub ahead of print]
Summary:
Understanding the health consequences of exposure to radiation received gradually over time is critically needed. The National Aeronautics and Space Administration (NASA) bases its safety standards on the acute exposures received by Japanese atomic bomb survivors. Such a brief exposure differs appreciably from the chronic radiation received during a two to three year mission to Mars. NASA also applies an individual risk-based system for radiation protection that accounts for age, sex, smoking history and individual life styles. Because the Japanese life span study (LSS) reports women to be at 2 to 3 times greater lifetime risk of developing cancer than men, female astronauts are allowed less time in space. Another concern is the potential behavioral and cognitive impairments from galactic cosmic radiation (GCR) impinging on the nervous system that might jeopardize the mission, and, possibly, lead to dementia later in life. GCR are high-velocity heavy ions traveling through space. There are no human circumstances/analogs similar to GCR that can provide direct information on the possible effects of such high-LET exposure to brain tissue.
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Hibernation and Radioprotection: Gene Expression in the Liver and Testicle of Rats Irradiated under Synthetic Torpor
Tinganelli W, Hitrec T, Romani F, Simoniello P, Squarcio F, Stanzani A, Piscitiello E, Marchesano V, Luppi M, Sioli M, Helm A, Compagnone G, Morganti AG, Amici R, Negrini M, Zoccoli A, Durante M and Cerri M. Int J Mol Sci. 2019, 20, 352-364.
Summary:
Hibernation has been proposed as a tool for human space travel. In recent years, a procedure to induce a metabolic state known as "synthetic torpor" in non-hibernating mammals was successfully developed. Synthetic torpor may not only be an efficient method to spare resources and reduce psychological problems in long-term exploratory-class missions, but may also represent a countermeasure against cosmic rays. Here we show the preliminary results from an experiment in rats exposed to ionizing radiation in normothermic conditions or synthetic torpor. Animals were irradiated with 3 Gy X-rays and organs were collected 4 h after exposure. Histological analysis of liver and testicle showed a reduced toxicity in animals irradiated in torpor compared to controls irradiated at normal temperature and metabolic activity. The expression of ataxia telangiectasia mutated (ATM) in the liver was significantly downregulated in the group of animals in synthetic torpor. In the testicle, more genes involved in the DNA damage signaling were downregulated during synthetic torpor. These data show for the first time that synthetic torpor is a radioprotector in non-hibernators, similarly to natural torpor in hibernating animals. Synthetic torpor can be an elective strategy to protect humans during long term space exploration of the solar system.
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Evaluation of statistical modeling approaches for epidemiologic studies of low dose radiation health effects
Golden AP, Cohen SS, Chen H, Ellis ED, Boice JD Jr. Int J Radiat Biol. 2018 Nov 30. [Epub ahead of print]
Summary:
This study compares radiation risk estimates for leukemia other than chronic lymphocytic leukemia (non-CLL) and ischemic heart disease (IHD) produced by both Cox and Poisson regression models for time-dependent dose-response analyses of occupational exposure. The results from one cohort, the Nuclear Power Plant workers (NPP) are presented, although the evaluation considered five cohorts of varying size and exposure as part of the Million Worker Study. Cox Proportional Hazards models, with age as the underlying timescale for hazard, were conducted using three computer software programs: SAS, R, and Epicure. Doses lagged 2 years for non-CLL and 10 years for ischemic heart disease were treated as time-dependent exposures at the annual level and were examined both in categories and as a continuous term. Hazard ratios (HR) and 95% confidence intervals (CI) were reported for each model in SAS and R, while the Peanuts program of Epicure was utilized to produce Excess Relative Risk (ERR) estimates and 95% CI. All models were adjusted for gender and year of birth. Four piece-wise exponential Poisson models (log-linear regression for rate) were developed with varying cutpoints for age strata from very fine to broad categories using both R and the Amfit program in Epicure for ERR estimates. Comparable estimates of risk (both RR and ERR) were observed from Cox and Poisson models, regardless of software utilized, as long as appropriately narrow categories of age were utilized to control the confounding of age in Poisson models. The ERR estimates produced in Epicure tended to agree very closely with the HR or RR estimates, and the statistical software program used had no impact to risk estimates for the same model. The results of this evaluation support the use of the Cox proportional hazards or the ungrouped Poisson approach to analyzing time-dependent dose-response relationships to ensure that maximum control over the confounding of age is achieved in studies of mortality for cohorts occupationally exposed to radiation.
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Non-Targeted Effects Lead To A Paridigm Shift In Risk Assessment For A Mission To The Earth's Moon Or Martian Moon Phobos
Francis A. Cucinotta, Eliedonna Cacao, Myung-Hee Y. Kim and Premkumar B. Saganti. Radiation Protection Dosimetry (2018), pp. 1-6.
Summary:
Many studies suggest non-targeted effects (NTEs) occur for low doses of high-linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. We investigate corrections to quality factors (QF) for NTEs, which are used in predictions of fatal cancer risks for exploration missions. Prediction of fatal cancer risks for missions to the Martian moon, Phobos of 500-d and the Earth's moon of 365-d for average solar minimum condition show increases of 2- to 4-fold higher in the NTE model compared with the conventional model. Limitations in estimating uncertainties in NTE model parameters due to sparse radiobiology data at low doses are discussed.
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How Safe Is Safe Enough? Radiation Risk for a Human Mission to Mars
Francis A. Cucinotta, Myung-Hee Y. Kim, Lori J. Chappell, Janice L. Huff. PLoS ONE 8(10):e74988, 10/16/2013.
Summary:
Astronauts on a mission to Mars would be exposed for up to 3 years to galactic cosmic rays (GCR) - made up of high-energy protons and high charge (Z) and energy (E) (HZE) nuclei. GCR exposure rate increases about three times as spacecraft venture out of Earth orbit into deep space where protection of the Earth's magnetosphere and solid body are lost. NASA's radiation standard limits astronaut exposures to a 3% risk of exposure induced death (REID) at the upper 95% confidence interval (CI) of the risk estimate. Fatal cancer risk has been considered the dominant risk for GCR, however recent epidemiological analysis of radiation risks for circulatory diseases allow for predictions of REID for circulatory diseases to be included with cancer risk predictions for space missions. Using NASA's models of risks and uncertainties, we predicted that central estimates for radiation induced mortality and morbidity could exceed 5% and 10% with upper 95% CI near 10% and 20%, respectively for a Mars mission. Additional risks to the central nervous system (CNS) and qualitative differences in the biological effects of GCR compared to terrestrial radiation may significantly increase these estimates, and will require new knowledge to evaluate.
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Should NASA collect astronauts' genetic information for occupational surveillance and research?
Reed RD, Antonsen EL. AMA J Ethics. 2018 Sep 1;20(9):E849-56.
Summary:
Humans exploring beyond low-Earth orbit face environmental challenges coupled with isolation, remote operations, and extreme resource limitations in which personalized medicine, enabled by genetic research, might be necessary for mission success. With little opportunity to test personalized countermeasures broadly, the National Aeronautics and Space Administration (NASA) will likely need to rely instead on collection of significant amounts of genomic and environmental exposure data from individuals. This need appears at first to be in conflict with the statutes and regulations governing the collection and use of genetic data. In fact, under certain conditions, the Genetic Information Nondiscrimination Act (GINA) of 2008 allows for the use of genetic information in both occupational surveillance and research and in the development of countermeasures such as personalized pharmaceuticals.
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Cancer and circulatory disease risks for a human mission to Mars: Private mission considerations.
Cucinotta FA, Cacao E, Kim M-HY, Saganti PB. Acta Astronaut. 2018 Aug 13.
Summary:
There is growing interest in private missions to Mars and other deep space destinations within the next decade. Private missions could consider persons not restricted by radiation limits; however there remains an interest in the level of risk to be encountered. Astronauts and cosmonauts are typically above 40-y, while younger aged persons could participate in private space missions. This paper describes cancer and circulatory disease risks for a 940 d Mars mission for average solar minimum conditions for persons of varying ages from 20 to 60 years. For the first-time NTEs are considered in Mars mission cancer risk predictions. We find much higher importance of cancer risk compared to circulatory disease risks for persons participating in space missions.
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Vive la radioré sistance!: Converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization.
Cortese F, Klokov D, Osipov A, Stefaniak J, Moskalev A, Schastnaya J, Cantor C, Aliper A, Mamoshina P, Ushakov I, Sapetsky A, Vanheaelen Q, Alchinova I, Karganov M, Kovalchuk O, Wilkins RC, Shtemberg A, Moreels M, Baatout S, Izumchenko E, de Magalhães JP, Artemov AV, Costes SV, Beheshti A, Mao XW, Pecaut MJ, Kaminskiy D, Ozerov IV, Scheibye-Knudsen M, Zhavoronkov A. Oncotarget. 2018 Feb 9.
Summary:
Roadmap proposed by an international team of researchers toward enhancing human radioresistance for space exploration and colonization. The roadmap outlines possible future research directions toward the goal of enhancing human radioresistance, including upregulation of endogenous repair and radioprotective mechanisms, possible leeways into gene therapy in order to enhance radioresistance via the translation of exogenous and engineered DNA repair and radioprotective mechanisms, the substitution of organic molecules with fortified isoforms, the coordination of regenerative and ablative technologies, and methods of slowing metabolic activity while preserving cognitive function. The paper concludes by presenting the known associations between radioresistance and longevity, and articulating the position that enhancing human radioresistance is likely to extend the healthspan of human spacefarers as well.
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Men, Women, and Space Travel: Gene-Linked Molecular Networks, Human Countermeasures, and Legal and Ethical Considerations
Schmidt MA, Bailey SM, Goodwin TJ, Jones JA, Killian JP, Legato MJ, Limoli C, Moussa S, Ploutz-Snyder L. Gend Genome. 2017 Jun 1;1(2):54-67.
Summary:
A roundtable discussion to consider the extensive differences between men and women, including both their strengths and vulnerabilities, in preparing professional astronauts for space travel.
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Solid Cancer Incidence among the Life Span Study of Atomic Bomb Survivors: 1958-2009.
Eric J. Grant, Alina Brenner, Hiromi Sugiyama, Ritsu Sakata, Atsuko Sadakane, Mai Utada, Elizabeth K. Cahoon, Caitlin M. Milder, Midori Soda, Harry M. Cullings, Dale L. Preston, Kiyohiko Mabuchi and Kotaro Ozasa. Radiation Research 187(5):513-537. 2017
Summary:
The Radiation Effects Research Foundation (RERF) and its forerunner, the Atomic Bomb Casualty Commission (ABCC), have been estimating the long-term health effects of radiation among the Life Span Study (LSS) cohort of atomic bomb survivors since that study's inception in 1950. Cancer incidence has been followed since the establishment of local cancer registries in 1958.

In the accompanying article, 105,444 LSS cohort members were followed from 1958 through 2009. The primary exposure was the radiation dose to the colon, calculated by a weighted sum of gamma and neutron doses. The primary outcome was a first primary solid cancer. Excess relative risk models (ERR) and excess absolute rate models (EAR) were constructed while adjusting for smoking consumption, the first time ABCC/RERF have made such an adjustment in one of their major reports. Radiation risks were allowed to be modified by sex, age at the time of bombing, and attained age.

The most important finding was that the effects of radiation exposure in 1945 continue to be observed more than 60 years since the time of exposure. The most notable finding was a curvilinear dose response among males, while the female response remained linear. Until this paper's publication (the previous report was made in 2007), the dose responses in both sexes had been linear. The emergence of a curved response in our study was somewhat surprising, and we are now working to ascertain if this is an artifact of the types of cancers occurring among a now elderly population or if it has underlying mechanistic implications for those exposed at young ages.

The paper also reports other findings that may be of interest to the NASA community. First, the lowest dose range for which a sex-averaged linear dose model showed a statistically increased risk in solid cancer was 0-100 mGy. Also, due to the curvilinear response in males, the female-to-male ratio of excess relative risks has increased slightly in comparison with earlier reports.

This manuscript investigated solid cancers in aggregate. We are currently in the process of writing other manuscripts looking at individual organs and organ systems. The first manuscript in that series of reports (on respiratory cancers) was recently published (http://www.bioone.org/doi/abs/10.1667/RR14583.1).
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Scaling human cancer risks from low LET to high LET when dose-effect relationships are complex.
Shuryak I, Fornace AJ Jr, Datta K, Suman S, Kumar S, Sachs RK, Brenner DJ. Radiat Res. 2017 Feb 20. [Epub ahead of print]
Summary:
Reliable methods are needed for scaling low-LET to high-LET radiation risks for humans, based on animal or in vitro studies comparing these radiations. The current standard metric, relative biological effectiveness (RBE) compares iso-effect doses of two radiations. By contrast, a proposed new metric, radiation effects ratio (RER), compares effects of two radiations at the same dose. This definition of RER allows direct scaling of low-LET to high-LET radiation risks in humans at the dose or doses of interest. By contrast to RBE, RER can be used without need for detailed information about dose response shapes for compared radiations. This property of RER allows animal carcinogenesis experiments to be simplified by reducing the number of tested radiation doses. Values of RBE and RER and uncertainties are estimated for tumors in a mouse model for intestinal cancer. Since non-targeted effects and the like, particularly at low doses, may contribute to non-linear dose responses, this approach offers a direct assessment at a particular dose.
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Space: The final frontier-Research relevant to Mars.
Boice JD Jr. Health Phys. 2017 Apr;112(4):392-7.
Summary:
The National Council on Radiation Protection and Measurements (NCRP) is active in the developmment of guidance for radiation protection in the US. The author, who is president of the NCRP, discusses the relevance of the ongoing Million Person Study for reducing the uncertainty in NASA risk estimates, narrowing the 95% confidence interval, and thus allowing more time in space for astronauts.
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Ionizing radiation sensitivity of the ocular lens and its dose rate dependence.
Hamada N. Int J Radiat Biol. 2016 Nov 30:1-32. [Epub ahead of print]
Summary:
This paper reviews the current knowledge on the radiosensitivity of the lens and the dose rate dependence of radiation cataractogenesis, and discusses its mechanisms. Further biological and epidemiological studies are warranted to gain deeper knowledge on the radiosensitivity of the lens and dose rate dependence of radiation cataractogenesis.
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Hibernation for space travel: Impact on radioprotection.
Cerri M, Tinganelli W, Negrini M, Helm A, Scifoni E, Tommasino F, Sioli M, Zoccoli A, Durante M. Life Sci Space Res. 2016 Sep 13. [Article in Press]
Summary:
This article reviews the mechanisms of increased radioprotection in hibernation, and discusses its possible impact on human space exploration. The idea of exploiting hibernation for space exploration is becoming more realistic, thanks to the introduction of specific methods to induce hibernation-like conditions (synthetic torpor) in non-hibernating animals. In addition to the expected advantages in long-term exploratory-class missions in terms of resource consumptions, aging, and psychology, hibernation may provide protection from cosmic radiation damage to the crew. Data from over half century ago in animal models suggest indeed that radiation effects are reduced during hibernation.
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Evaluation of superconducting magnet shield configurations for long duration manned space missions.
Ambroglini F, Battiston R, Burger WJ. Front Oncol. 2016 Jun 8;6:97.
Summary:
A series of the three studies based on high-temperature superconductors, estimate the mass of the coils and supporting structure of engineering designs based on the current and expected near-future performance of the superconducting materials. In each case, the dose reduction was calculated with a 3-dimensional Monte Carlo simulation of the electromagnetic and hadronic interactions of the galactic-cosmic rays, and the secondary particles they produce in the materials of the shield and spacecraft.
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PMMA/MWCNT nanocomposite for proton radiation shielding applications.
Li Z, Chen S, Nambiar S, Sun Y, Zhang M, Zheng W, Yeow JT. Nanotechnology. 2016 Jun 10;27(23):234001. Epub 2016 Apr 29.
Summary:
In this study, poly(methyl-methacrylate)/multi-walled carbon nanotube (PMMA/MWCNT) nanocomposite was fabricated. The role of MWCNTs embedded in PMMA matrix, in terms of radiation shielding effectiveness, was experimentally evaluated by comparing the proton transmission properties and secondary neutron generation of the PMMA/MWCNT nanocomposite with pure PMMA and aluminum. The results showed that the addition of MWCNTs in PMMA matrix can further reduce the secondary neutron generation of the pure polymer, while no obvious change was found in the proton transmission property. On the other hand, both the pure PMMA and the nanocomposite were 18%-19% lighter in weight than aluminum for stopping the protons with the same energy and generated up to 5% fewer secondary neutrons. Furthermore, the use of MWCNTs showed enhanced thermal stability over the pure polymer, and thus the overall reinforcement effects make MWCNT an effective filler material for applications in the space industry.
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Personalized Cancer Risk Assessments for Space Radiation Exposures.
Locke PA, Weil MM. Front Oncol. 2016 Feb 22;6:38
Summary:
This article examines the effect of risk or risk reduction factors that have the potential to personalize risk estimates for individual astronauts and could influence the determination of safe days in space, and explores how the provisions of the federal Genetic Information Non-discrimination Act could impact the collection, dissemination and use of this information by NASA.
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Space Radiation Quality Factors and the Delta Ray Dose and Dose-Rate Reduction Effectiveness Factor.
Cucinotta, Francis A.; Cacao, Eliedonna; Alp, Murat, Health Physics. 110(3):262-266, March 2016.
Summary:
In this paper, the authors recommend that the dose and dose-rate effectiveness factor used for space radiation risk assessments should be based on a comparison of the biological effects of energetic electrons produced along a cosmic ray particles path in low fluence exposures to high dose-rate gamma-ray exposures of doses of about 1 Gy. Methods to implement this approach are described.
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Concepts and challenges in cancer risk prediction for the space radiation environment.
Barcellos-Hoff MH, Blakely EA, Burma S, Fornace AJ Jr, Gerson S, Hlatky L, Kirsch DG, Lederer U, Shay J, Wang Y, Weil MM. Life Sci Space Res. 2015. Epub 2015 Jul 17.
Summary:
This white paper from scientists who receive funding from the NASA Space Radiation Program addresses the current state of the cancer biology and issues related to animal models used to study the effects of space radiation on carcinogenesis. Given that inherent uncertainties limit accurate cancer risk quantification for astronauts for deep space exploration, it is important to understand the biological mechanisms that increase cancer after radiation exposure and determine whether they impact risk modeling. New experimental data suggest that radiation quality may increase the incidence of cancers with poor prognosis (e.g. metastatic); if so, determining the underlying biology may also provide routes to effective countermeasures.
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Safe days in space with acceptable uncertainty from space radiation exposure.
Francis A. Cucinotta, Murat Alp, Blake Rowedder, Myung-Hee Y. Kim. Life Sciences in Space Research. Volume 5, April 2015, Pages 31-38
Summary:
In this paper, we evaluate probability distribution functions and the number or “safe days” in space, which are defined as the mission length where risk limits are not exceeded, for several mission scenarios at different acceptable levels of uncertainty. In addition, we briefly discuss several important issues in risk assessment including non-cancer effects, the distinct tumor spectra and lethality found in animal experiments for HZE particles compared to background or low LET radiation associated tumors, and the possibility of non-targeted effects (NTE) modifying low dose responses and increasing relative biological effectiveness (RBE) factors for tumor induction.
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A New Approach to Reduce Uncertainties in Space Radiation Cancer Risk Predictions.
Cucinotta, F.S. 2015;PLOS ONE 10.1371/journal.pone.0120717
Summary:
The prediction of space radiation induced cancer risk carries large uncertainties with two of the largest uncertainties being radiation quality and dose-rate effects. In risk models the ratio of the quality factor (QF) to the dose and dose-rate reduction effectiveness factor (DDREF) parameter is used to scale organ doses for cosmic ray proton and high charge and energy (HZE) particles to a hazard rate for γ-rays derived from human epidemiology data.. Here I report on an analysis of a maximum QF parameter and its uncertainty using mouse tumor induction data. Because experimental data for risks at low doses of γ-rays are highly uncertain which impacts estimates of maximum values of relative biological effectiveness (RBEmax), I developed an alternate QF model, denoted QFγAcute where QFs are defined relative to higher acute γ-ray doses (0.5 to 3 Gy). The alternate model reduces the dependence of risk projections on the DDREF, however a DDREF is still needed for risk estimates for high-energy protons and other primary or secondary sparsely ionizing space radiation components. In addition, I discuss how a possible qualitative difference leading to increased tumor lethality for HZE particles compared to low LET radiation and background tumors remains a large uncertainty in risk estimates.
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NCRP Commentary No. 23, Radiation Protection for Space Activities: Supplement to Previous Recommendations.
National Council on Radiation Protection and Measurements. Bethesda, MD. November 18, 2014.
Summary:
This Commentary supplements previous recommendations from NCRP that underlie the current National Aeronautics and Space Administration (NASA) standards for radiation protection of crew members during space activities. This Commentary focuses on the implications of extended LEO missions in a general manner, particularly with regard to uncertainties in the knowledge of the health effects and the biological effectiveness of exposures to galactic cosmic rays in space, and includes a discussion of ethical considerations and principles that may bear on the application of NCRP advice on radiation protection for space activities. The Commentary is available from the NCRP website.
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On April 21, 2011, the International Commission on Radiological Protection (ICRP) issued new recommendations on radiological protection. The Commission has now reviewed recent epidemiological evidence suggesting that there are some tissue reaction effects, particularly those with very late manifestation, where threshold doses are or might be lower than previously considered. For the lens of the eye, the threshold in absorbed dose is now considered to be 0.5 Gy. Accordingly, (3) For occupational exposure in planned exposure situations the Commission now recommends an equivalent dose limit for the lens of the eye of 20 mSv in a year, averaged over defined periods of 5 years, with no single year exceeding 50 mSv. In part, the new recommendations are based on research reported by NASA scientists:

The full draft report may be found at Annals of the ICRP.
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Evaluating Biomarkers To Model Cancer Risk Post Cosmic Ray Exposure.
Sridharan DM, Asaithamby A, Blattnig SR, Costes SV, Doetsch PW, Dynan WS, Hahnfeldt P, Hlatky L, Kidane Y, Kronenberg A, Naidu MD, Peterson LE, Plante I, Ponomarev AL, Saha J, Snijders AM, Srinivasan K, Tang J, Werner E, Pluth JM, Life Sci Space Res. 2016 May 21. [Article in Press]
Summary:
Prediction of cancer risk from radiation exposure is a goal for NASA's HRP as astronauts are subjected to protracted cosmic ray exposure. The spectrum of doses, dose rates, radiation qualities, energies and particle flux in the space radiation environment complicate risk assessment. One approach to unravel uncertainties contributed by each of these factors is to identify sensitive biomarkers that can serve as inputs for modeling an individual's risk of cancer. To assist in these modeling efforts, a collaborative effort was undertaken by NASA scientists to critically evaluate candidate biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions and its ultimate impact on cancer development. The authors highlight qualities and limitations of various biomarkers and assess their ability to contribute to biomarker-driven models that can be used to estimate cancer risk from radiation exposure.
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Issues for Simulation of Galactic Cosmic Ray Exposures for Radiobiological Research at Ground Based Accelerators
Kim Myung-Hee Y, Rusek Adam, Cucinotta Francis A. Frontiers in Oncology. 2015. Vol 5(00122).
Summary:
We performed extensive simulation studies using the stochastic transport code, GERMcode (GCR Event Risk Model) to define a GCR reference field using 9 HZE particle beam-energy combinations each with a unique absorber thickness to provide fragmentation and 10 or more energies of proton and 4He beams. A kinetics model of HZE particle hit probabilities suggests that experimental simulations of several weeks will be needed to avoid high fluence rate artifacts, which places limitations on the experiments to be performed. Ultimately risk estimates are limited by theoretical understanding, and focus on improving knowledge of mechanisms and development of experimental models to improve this understanding should remain the highest priority for space radiobiology research.
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Does the worsening galactic cosmic radiation environment observed by CRaTER preclude future manned deep space exploration?
N. A. Schwadron, J. B. Blake, A. W. Case, C. J. Joyce1, J. Kasper, J. Mazur, N. Petro, M. Quinn, J. A. Porter, C.W. Smith, S. Smith, H. E. Spence, L.W. Townsend, R. Turner, J. K.Wilson, and C. Zeitlin. Space Weather (online), 11, doi:10.1002/2014SW001084
Summary:
Data from a cosmic ray telescope onboard NASA's Lunar Reconnaissance Orbiter show that while increasing fluxes of cosmic rays "are not a show stopper for long duration missions (e.g., to the Moon, an asteroid, or Mars), galactic cosmic radiation remains a significant and worsening factor that limits mission durations." Cosmic rays are intensifying. Galactic cosmic rays are a mixture of high-energy photons and subatomic particles accelerated to near-light speed by violent events such as supernova explosions. Astronauts are protected from cosmic rays in part by the sun: solar magnetic fields and the solar wind combine to create a porous 'shield' that fends off energetic particles from outside the solar system. The problem is "The sun and its solar wind are currently exhibiting extremely low densities and magnetic field strengths, representing states that have never been observed during the Space Age. As a result of the remarkably weak solar activity, we have also observed the highest fluxes of cosmic rays in the Space Age." The shielding action of the sun is strongest during solar maximum and weakest during solar minimum. At the moment we are experiencing Solar Max, which should be a good time for astronauts to fly. However, the solar maximum of 2011-2014 is the weakest in a century, allowing unusual numbers of cosmic rays to penetrate the solar system. This situation could become even worse if, as some researchers suspect, the sun is entering a long-term phase of the solar cycle characterized by relatively weak maxima and deep, extended minima. In such a future, feeble solar magnetic fields would do an extra-poor job keeping cosmic rays at bay, further reducing the number of days astronauts can travel far from Earth.
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Revisions to the NASA projection model for lifetime cancer risks from space radiation and new estimates of model uncertainties are described in NASA/TP-2011- 216155, Space Radiation Cancer Risk Projections and Uncertainties - 2010 by Francis A. Cucinotta, Myung-Hee Y. Kim, Lori J. Chappell.
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Updates to Astronaut Radiation Limits: Radiation Risks for Never-Smokers was published online by Rad Res, May 16, 2011. The article from the Space Radiation Program Laboratory at NASA Johnson Space Center recommends dose limits for astronauts that take into consideration age- and gender-specific dose limits for never-smokers.
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A new text by Dr. Olga Smirnova, Environmental Radiation Effects on Mammals: A Dynamical Modeling Approach , has been published by Springer. Read more. Posted to the Archive, May 27, 2011.
Feature article on Radiation Risk in Technology Innovation, NASA's magazine for Business & Technology, Volume 15 Number 3, 2010. Posted to the Archive, May 17, 2011.
Mitigating Astronauts' Health Risks from Space Radiation
Francis A. Cucinotta, Ph.D.
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TOPAS-nBio: An Extension to the TOPAS Simulation Toolkit for Cellular and Sub-cellular Radiobiology
Schuemann J, McNamara AL, Ramos-Mé ndez J, Perl J, Held KD, Paganetti H, Incerti S and Faddegon B. Radiat Res. 191, 125-138 (2019).
Summary:
The TOPAS Monte Carlo (MC) system provides detailed simulations of patient scale properties; however, the fundamental unit of the biological response to radiation is a cell. TOPAS-nBio is an extension of TOPAS that extends TOPAS to model radiobiological experiments. TOPAS-nBio is based on and extends Geant4- DNA. It explicitly simulates every particle interaction (i.e., without using condensed histories) and propagates radiolysis products. A graphical user interface 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. Additionally, we expanded the chemical reactions and species provided in Geant4-DNA and developed a new method based on independent reaction times (IRT). Chemical stage simulations using IRT were a factor of 145 faster than with step-by-step tracking. 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.
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