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THREE Bibliography

Exploration, as understood by the space community, implies a human presence in space. The purpose of this section is to provide a context for this presence, branching out from the NASA perspective to a history of the space exploration efforts of the other spacefaring nations.

The rationale for the US space effort has been evolving continuously since President Kennedy called for putting a man on the moon in response to Sputnik. “Visions” have been iterated several times, reflecting changing perceptions of national purpose. However, the elements of foreseeable missions have been defined and can be expected to be a part of whatever future strategies are adopted.

Space exploration is a truly international effort. It is intended that this section will also host descriptions of the efforts of NASA’s partners in the future.

In addition to joint efforts with the US Department of Energy described in the current articles, NASA has a long history of collaboration with other agencies of the Federal Government. More articles describing this collaboration are also planned.

Walter Schimmerling
THREE Chief Editor

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

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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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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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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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. Häder, 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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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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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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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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Models | CNS Effects | Degenerative Effects | Solid Cancers

Models

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 (Trp53∆P) 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 Trp53∆P 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 Trp∆53 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 Trp53∆P 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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CNS Effects

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

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

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. < br /> 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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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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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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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

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

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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