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Human spaceflight is associated with several health-related issues as a result of long-term exposure to microgravity, ionizing radiation, and higher levels of psychological stress. Frequent reported skin problems in space include rashes, itches, and a delayed wound healing. Access to space is restricted by financial and logistical issues; as a consequence, experimental sample sizes are often small, which limits the generalization of the results. Earth-based simulation models can be used to investigate cellular responses as a result of exposure to certain spaceflight stressors. Here, we describe the development of an in vitro model of the simulated spaceflight environment, which we used to investigate the combined effect of simulated microgravity using the random positioning machine (RPM), ionizing radiation, and stress hormones on the wound-healing capacity of human dermal fibroblasts. Fibroblasts were exposed to cortisol, after which they were irradiated with different radiation qualities (including X-rays, protons, carbon ions, and iron ions) followed by exposure to simulated microgravity using a random positioning machine (RPM). Data related to the inflammatory, proliferation, and remodeling phase of wound healing has been collected. Results show that spaceflight stressors can interfere with the wound healing process at any phase. Moreover, several interactions between the different spaceflight stressors were found. This highlights the complexity that needs to be taken into account when studying the effect of spaceflight stressors on certain biological processes and for the aim of countermeasures development. [ABSTRACT FROM AUTHOR]

Immunotherapy and targeted therapy are now commonly used in clinical trials in combination with radiotherapy for several cancers. While results are promising and encouraging, the molecular mechanisms of the interaction between the drugs and radiation remain largely unknown. This is especially important when switching from conventional photon therapy to particle therapy using protons or heavier ions. Different dose deposition patterns and molecular radiobiology can in fact modify the interaction with drugs and their effectiveness. We will show here that whilst the main molecular players are the same after low and high linear energy transfer radiation exposure, significant differences are observed in post-exposure signalling pathways that may lead to different effects of the drugs. We will also emphasise that the problem of the timing between drug administration and radiation and the fractionation regime are critical issues that need to be addressed urgently to achieve optimal results in combined treatments with particle therapy. [ABSTRACT FROM AUTHOR]

The increasing application of charged particles in radiotherapy requires a deeper understanding of early and late side effects occurring in skin, which is exposed in all radiation treatments. We measured cellular and molecular changes related to the early inflammatory response of human skin irradiated with carbon ions, in particular cell death induction and changes in differentiation and proliferation of epidermal cells during the first days after exposure. Model systems for human skin from healthy donors of different complexity, i.e., keratinocytes, coculture of skin cells, 3D skin equivalents, and skin explants, were used to investigate the alterations induced by carbon ions (spread-out Bragg peak, dose-averaged LET 100 keV/μm) in comparison to X-ray and UV-B exposure. After exposure to ionizing radiation, in none of the model systems, apoptosis/necrosis was observed. Carbon ions triggered inflammatory signaling and accelerated differentiation of keratinocytes to a similar extent as X-rays at the same doses. High doses of carbon ions were more effective than X-rays in reducing proliferation and inducing abnormal differentiation. In contrast, changes identified following low-dose exposure (≤0.5 Gy) were induced more effectively after X-ray exposure, i.e., enhanced proliferation and change in the polarity of basal cells. [ABSTRACT FROM AUTHOR]

Purpose: To characterise the radiation response of human hematopoietic stem and progenitor cells (HSPC) with respect to X and carbon ion irradiation. Materials and methods: HSPC from peripheral blood of healthy donors treated with granulocyte-colony stimulating factor (G-CSF) were enriched for the transmembrane glycoprotein CD34 (cluster of differentiation) and irradiated with X rays or carbon ions (29 keV/μm monoenergetic beam and 60-85 keV/μm spread-out Bragg peak), mimicking radiotherapy conditions. Apoptotic cell death, cell cycle progression and the frequency of chromosomal aberrations were determined. Results: After radiation exposure no inhibition in the progression of the cell cycle was detected. However, an enhanced frequency of apoptotic cells and an increase in aberrant cells were observed, both effects being more pronounced for carbon ions than X rays, resulting in a relative biological effectiveness (RBE) of 1.4–1.7. The fraction of complex-type aberrations was higher following carbon ion exposure. Conclusions: RBE values of carbon ions are low, as expected for radiosensitive cells. The observed frequencies of apoptotic cells and chromosome aberrations in HSPC are similar to those reported for human peripheral blood lymphocytes suggesting that at least with respect to apoptosis and chromosomal aberrations mature lymphocytes reflect the respective radiation responses of their proliferating progenitors. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: The goal of the present study was to investigate aging and genetic instability in the progeny of human fibroblasts exposed to X-rays and carbon ions. Materials and methods: Following irradiation, cells were regularly subcultured until senescence. At selected time-points BrdU-labelling index, expression of cell cycle related proteins, cell differentiation pattern and chromosome aberrations were assessed. Results: After exposure, an immediate cell cycle arrest occurred followed by a period of a few weeks where premature differentiation and senescence were observed. In all cultures cycling cells expressing low levels of cell cycle inhibiting proteins were present and finally dominated the populations. About 5months after exposure, the cellular and molecular changes attributed to differentiation and senescence reappeared and persisted. Concurrently, genetic instability was observed, but the aberration yields and types differed between repeated experiments. The descendants of cells exposed to carbon ions did not senesce earlier and displayed a similar rate of genetic instability as the X-ray progeny. For high doses an impaired cell cycle regulation and extended life span was observed, but finally cell proliferation ceased in all populations. Conclusions: The descendants of irradiated fibroblasts undergo stepwise senescence and differentiation. Genetic instability is frequent and an extension of the life span may occur. [Copyright &y& Elsevier]

In radiation-induced acute myeloid leukemia (rAML), clonal chromosomal abnormalities are often observed in bone marrow cells of patients, suggesting that their formation is crucial in the development of the disease. Since rAML is considered to originate from hematopoietic stem and progenitor cells (HSPC), we investigated the frequency and spectrum of radiation-induced chromosomal abnormalities in human CD34 + cells. We then measured stable chromosomal abnormalities, a possible biomarker of leukemia risk, in clonally expanded cell populations which were grown for 14 days in a 3D-matrix (CFU-assay). We compared two radiation qualities used in radiotherapy, sparsely ionizing X-rays and densely ionizing carbon ions (29 and 60–85 keV/μm, doses between 0.5 and 4 Gy). Only a negligible number of de novo arising, unstable aberrations (≤0.05 aberrations/cell, 97% breaks) were measured in the descendants of irradiated HSPC. However, stable aberrations were detected in colonies formed by irradiated HSPC. All cells of the affected colonies exhibited one or more identical aberrations, indicating their clonal origin. The majority of the clonal rearrangements (92%) were simple exchanges such as translocations (77%) and pericentric inversions (15%), which are known to contribute to the development of rAML. Carbon ions were more efficient in inducing cell killing (maximum of ∼30–35% apoptotic cells for 2 Gy carbon ions compared to ∼25% for X-rays) and chromosomal aberrations in the first cell-cycle after exposure (∼70% and ∼40% for 1 Gy of carbon ions and X-rays, respectively), with a higher fraction of non-transmissible aberrations. In contrast, for both radiation qualities the percentage of clones with chromosomal abnormalities was similar (40%). Using the frequency of colonies with clonal aberrations as a surrogate marker for the leukemia risk following radiotherapy of solid tumors, charged particle therapy is not expected to lead to an increased risk of leukemia in patients. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we set out to investigate cytogenetic changes in the progeny of two normal human fibroblast cell strains after exposure to sparsely or densely ionizing irradiation (X-rays or 9.8MeVu−1 carbon ions). The cells were regularly subcultured up to senescence. The transition to senescence was determined by measurement of population doubling numbers and senescence associated (SA) β-galactosidase activity. Chromosomal changes (structural aberrations, tetraploidy) were investigated by solid staining. In temporal proximity to senescence, we observed for all populations of the two fibroblasts cell strains an increase in the fraction of cells with structural and numerical aberrations. The observed changes in the yield of structural chromosomal aberrations were similar for the progeny of controls and irradiated cells, except that a previous irradiation with a high, fractionated X-ray dose resulted in a stronger increase. Noteworthy, delayed tetraploidy in the descendants of irradiated cells exceeded the level in control cells. In addition, tetraploidy and the time of onset of senescence were significantly correlated for all populations, regardless of a preceding radiation exposure. However, the time of the onset of senescence depends on previous exposure to radiation. We conclude that the occurrence of tetraploidy is associated with senescence independently of exposure to radiation. [Copyright &y& Elsevier]