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MELODI is the European platform dedicated to low-dose radiation risk research. From 7 October through 10 October 2013 the Fifth MELODI Workshop took place in Brussels, Belgium. The workshop offered the opportunity to 221 unique participants originating from 22 countries worldwide to update their knowledge and discuss radiation research issues through 118 oral and 44 poster presentations. In addition, the MELODI 2013 workshop was reaching out to the broader radiation protection community, rather than only the low-dose community, with contributions from the fields of radioecology, emergency and recovery preparedness, and dosimetry. In this review, we summarise the major scientific conclusions of the workshop, which are important to keep the MELODI strategic research agenda up-to-date and which will serve to establish a joint radiation protection research roadmap for the future. [ABSTRACT FROM AUTHOR]

Without the protective shielding of Earth's atmosphere, astronauts face higher doses of ionizing radiation in space, causing serious health concerns. Highly charged and high energy (HZE) particles are particularly effective in causing complex and difficult-to-repair DNA double-strand breaks compared to low linear energy transfer. Additionally, chronic cortisol exposure during spaceflight raises further concerns, although its specific impact on DNA damage and repair remains unknown. This study explorers the effect of different radiation qualities (photons, protons, carbon, and iron ions) on the DNA damage and repair of cortisol-conditioned primary human dermal fibroblasts. Besides, we introduce a new measure, the Foci-Integrated Damage Complexity Score (FIDCS), to assess DNA damage complexity by analyzing focus area and fluorescent intensity. Our results show that the FIDCS captured the DNA damage induced by different radiation qualities better than counting the number of foci, as traditionally done. Besides, using this measure, we were able to identify differences in DNA damage between cortisol-exposed cells and controls. This suggests that, besides measuring the total number of foci, considering the complexity of the DNA damage by means of the FIDCS can provide additional and, in our case, improved information when comparing different radiation qualities., (© 2024. The Author(s).)

Periodically, the European Space Agency (ESA) updates scientific roadmaps in consultation with the scientific community. The ESA SciSpacE Science Community White Paper (SSCWP) 9, "Biology in Space and Analogue Environments", focusses in 5 main topic areas, aiming to address key community-identified knowledge gaps in Space Biology. Here we present one of the identified topic areas, which is also an unanswered question of life science research in Space: "How to Obtain an Integrated Picture of the Molecular Networks Involved in Adaptation to Microgravity in Different Biological Systems?" The manuscript reports the main gaps of knowledge which have been identified by the community in the above topic area as well as the approach the community indicates to address the gaps not yet bridged. Moreover, the relevance that these research activities might have for the space exploration programs and also for application in industrial and technological fields on Earth is briefly discussed., (© 2024. The Author(s).)

Purpose: Childhood cancer survivors, in particular those treated with radiation therapy, are at high risk of long-term iatrogenic events. The prediction of risk of such events is mainly based on the knowledge of the radiation dose received to healthy organs and tissues during treatment of childhood cancer diagnosed decades ago. We aimed to set up a standardized organ dose table to help former patients and clinicians in charge of long-term follow-up clinics., Methods and Materials: We performed whole body dosimetric reconstruction for 2646 patients from 12 European countries treated between 1941 and 2006 (median, 1976). Most plannings were 2- or 3-dimensional. A total of 46% of patients were treated using Cobalt 60, and 41%, using a linear accelerator. The median prescribed dose was 27.2 Gy (IQ1-IQ3, 17.6-40.0 Gy). A patient-specific voxel-based anthropomorphic phantom with more than 200 anatomic structures or substructures delineated as a surrogate of each subject's anatomy was used. The radiation therapy was simulated with a treatment planning system based on available treatment information. The radiation dose received by any organ of the body was estimated by extending the treatment planning system dose calculation to the whole body, by type and localization of childhood cancer., Results: The integral dose and normal tissue doses to most of the 23 considered organs increased between the 1950s and 1970s and decreased or plateaued thereafter. Whatever the organ considered, the type of childhood cancer explained most of the variability in organ dose. The country of treatment explained only a small part of the variability., Conclusions: The detailed dose estimates provide very useful information for former patients or clinicians who have only limited knowledge about radiation therapy protocols or techniques, but who know the type and site of childhood cancer, sex, age, and year of treatment. This will allow better prediction of the long-term risk of iatrogenic events and better referral to long-term follow-up clinics., (Copyright © 2024. Published by Elsevier Inc.)

Progress in mechanobiology allowed us to better understand the important role of mechanical forces in the regulation of biological processes. Space research in the field of life sciences clearly showed that gravity plays a crucial role in biological processes. The space environment offers the unique opportunity to carry out experiments without gravity, helping us not only to understand the effects of gravitational alterations on biological systems but also the mechanisms underlying mechanoperception and cell/tissue response to mechanical and gravitational stresses. Despite the progress made so far, for future space exploration programs it is necessary to increase our knowledge on the mechanotransduction processes as well as on the molecular mechanisms underlying microgravity-induced cell and tissue alterations. This white paper reports the suggestions and recommendations of the SciSpacE Science Community for the elaboration of the section of the European Space Agency roadmap "Biology in Space and Analogue Environments" focusing on "How are cells and tissues influenced by gravity and what are the gravity perception mechanisms?" The knowledge gaps that prevent the Science Community from fully answering this question and the activities proposed to fill them are discussed., (© 2024. The Author(s).)

Introduction: Long-term space missions trigger a prolonged neuroendocrine stress response leading to immune system dysregulation evidenced by susceptibility to infections, viral reactivation, and skin irritations. However, due to existing technical constraints, real-time functional immune assessments are not currently available to crew inflight. The in vitro cytokine release assay (CRA) has been effectively employed to study the stimulated cytokine response of immune cells in whole blood albeit limited to pre- and post-flight sessions. A novel two-valve reaction tube (RT) has been developed to enable the execution of the CRA on the International Space Station (ISS). Methods: In a comprehensive test campaign, we assessed the suitability of three materials (silicone, C-Flex, and PVC) for the RT design in terms of biochemical compatibility, chemical stability, and final data quality analysis. Furthermore, we thoroughly examined additional quality criteria such as safety, handling, and the frozen storage of antigens within the RTs. The validation of the proposed crew procedure was conducted during a parabolic flight campaign. Results: The selected material and procedure proved to be both feasible and secure yielding consistent and dependable data outcomes. This new hardware allows for the stimulation of blood samples on board the ISS, with subsequent analysis still conducted on the ground. Discussion: The resultant data promises to offer a more accurate understanding of the stress-induced neuroendocrine modulation of immunity during space travel providing valuable insights for the scientific community. Furthermore, the versatile nature of the RT suggests its potential utility as a testing platform for various other assays or sample types., Competing Interests: MB is employed and MaV was employed by Kayser Italia S.r.l. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Buchheim, Feuerecker, Balsamo, Vukich, Van Walleghem, Tabury, Quintens, Vermeesen, Baselet, Baatout, Rattenbacher, Antunes, Ngo-Anh, Crucian and Choukér.)

Purpose: The radiation protection community has been particularly attentive to the risks of delayed effects on offspring from low dose or low dose-rate exposures to ionizing radiation. Despite this, the current epidemiologic studies and scientific data are still insufficient to provide the necessary evidence for improving risk assessment guidelines. This literature review aims to inform future studies on multigenerational and transgenerational effects. It primarily focuses on animal studies involving in utero exposure and discusses crucial elements for interpreting the results. These elements include in utero exposure scenarios relative to the developmental stages of the embryo/fetus, and the primary biological mechanisms responsible for transmitting heritable or hereditary effects to future generations. The review addresses several issues within the contexts of both multigenerational and transgenerational effects, with a focus on hereditary perspectives., Conclusions: Knowledge consolidation in the field of Developmental Origins of Health and Disease (DOHaD) has led us to propose a new study strategy. This strategy aims to address the transgenerational effects of in utero exposure to low dose and low dose-rate radiation. Within this concept, there is a possibility that disruption of epigenetic programming in embryonic and fetal cells may occur. This disruption could lead to metabolic dysfunction, which in turn may cause abnormal responses to future environmental challenges, consequently increasing disease risk. Lastly, we discuss methodological limitations in our studies. These limitations are related to cohort size, follow-up time, model radiosensitivity, and analytical techniques. We propose scientific and analytical strategies for future research in this field.

The space environment will expose astronauts to stressors like ionizing radiation, altered gravity fields and elevated cortisol levels, which pose a health risk. Understanding how the interplay between these stressors changes T cells' response is important to better characterize space-related immune dysfunction. We have exposed stimulated Jurkat cells to simulated space stressors (1 Gy, carbon ions/1 Gy photons, 1 µM hydrocortisone (HC), Mars, moon, and microgravity) in a single or combined manner. Pro-inflammatory cytokine IL-2 was measured in the supernatant of Jurkat cells and at the mRNA level. Results show that alone, HC, Mars gravity and microgravity significantly decrease IL-2 presence in the supernatant. 1 Gy carbon ion irradiation showed a smaller impact on IL-2 levels than photon irradiation. Combining exposure to different simulated space stressors seems to have less immunosuppressive effects. Gene expression was less impacted at the time-point collected. These findings showcase a complex T cell response to different conditions and suggest the importance of elevated cortisol levels in the context of space flight, also highlighting the need to use simulated partial gravity technologies to better understand the immune system's response to the space environment.

Long bone fractures are a concern in long-duration exploration missions (LDEM) where crew autonomy will exceed the current Low Earth Orbit paradigm. Current crew selection assumptions require extensive complete training and competency testing prior to flight for off-nominal situations. Analogue astronauts (n = 6) can be quickly trained to address a single fracture pattern and then competently perform the repair procedure. An easy-to-use external fixation (EZExFix) was employed to repair artificial tibial shaft fractures during an inhabited mission at the Mars Desert Research Station (Utah, USA). Bone repair safety zones were respected (23/24), participants achieved 79.2% repair success, and median completion time was 50.04 min. Just-in-time training in-mission was sufficient to become autonomous without pre-mission medical/surgical/mechanical education, regardless of learning conditions (p > 0.05). Similar techniques could be used in LDEM to increase astronauts' autonomy in traumatic injury treatment and lower skill competency requirements used in crew selection., (© 2023. Springer Nature Limited.)

The present white paper concerns the indications and recommendations of the SciSpacE Science Community to make progress in filling the gaps of knowledge that prevent us from answering the question: "How Do Gravity Alterations Affect Animal and Human Systems at a Cellular/Tissue Level?" This is one of the five major scientific issues of the ESA roadmap "Biology in Space and Analogue Environments". Despite the many studies conducted so far on spaceflight adaptation mechanisms and related pathophysiological alterations observed in astronauts, we are not yet able to elaborate a synthetic integrated model of the many changes occurring at different system and functional levels. Consequently, it is difficult to develop credible models for predicting long-term consequences of human adaptation to the space environment, as well as to implement medical support plans for long-term missions and a strategy for preventing the possible health risks due to prolonged exposure to spaceflight beyond the low Earth orbit (LEO). The research activities suggested by the scientific community have the aim to overcome these problems by striving to connect biological and physiological aspects in a more holistic view of space adaptation effects., (© 2023. Springer Nature Limited.)

DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ribeiro, Altinisik, Rajan, Verslegers, Baatout, Gopalakrishnan and Quintens.)

Bioprinting in space is the next frontier in tissue engineering. In the absence of gravity, novel opportunities arise, as well as new challenges. The cardiovascular system needs particular attention in tissue engineering, not only to develop safe countermeasures for astronauts in future deep and long-term space missions, but also to bring solutions to organ transplantation shortage. In this perspective, the challenges encountered when using bioprinting techniques in space and current gaps that need to be overcome are discussed. The recent developments that have been made in the bioprinting of heart tissues in space and an outlook on potential future bioprinting opportunities in space are described., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)

The lunar dust problem was first formulated in 1969 with NASA's first successful mission to land a human being on the surface of the Moon. Subsequent Apollo missions failed to keep the dust at bay, so exposure to the dust was unavoidable. In 1972, Harrison Schmitt suffered a brief sneezing attack, red eyes, an itchy throat, and congested sinuses in response to lunar dust. Some additional Apollo astronauts also reported allergy-like symptoms after tracking dust into the lunar module. Immediately following the Apollo missions, research into the toxic effects of lunar dust on the respiratory system gained a lot of interest. Moreover, researchers believed other organ systems might be at risk, including the skin and cornea. Secondary effects could translocate to the cardiovascular system, the immune system, and the brain. With current intentions to return humans to the moon and establish a semi-permanent presence on or near the moon's surface, integrated, end-to-end dust mitigation strategies are needed to enable sustainable lunar presence and architecture. The characteristics and formation of Martian dust are different from lunar dust, but advances in the research of lunar dust toxicity, mitigation, and protection strategies can prove strategic for future operations on Mars.

Although we have sent humans into space for more than 50 years, crucial questions regarding immune response in space conditions remain unanswered. There are many complex interactions between the immune system and other physiological systems in the human body. This makes it difficult to study the combined long-term effects of space stressors such as radiation and microgravity. In particular, exposure to microgravity and cosmic radiation may produce changes in the performance of the immune system at the cellular and molecular levels and in the major physiological systems of the body. Consequently, abnormal immune responses induced in the space environment may have serious health consequences, especially in future long-term space missions. In particular, radiation-induced immune effects pose significant health challenges for long-duration space exploration missions with potential risks to reduce the organism's ability to respond to injuries, infections, and vaccines, and predispose astronauts to the onset of chronic diseases (e.g., immunosuppression, cardiovascular and metabolic diseases, gut dysbiosis). Other deleterious effects encountered by radiation may include cancer and premature aging, induced by dysregulated redox and metabolic processes, microbiota, immune cell function, endotoxin, and pro-inflammatory signal production 1,2 . In this review, we summarize and highlight the current understanding of the effects of microgravity and radiation on the immune system and discuss knowledge gaps that future studies should address., (© 2023. The Author(s).)

The spaceflight environment imposes risks for maintaining a healthy skin function as the observed delayed wound healing can contribute to increased risks of infection. To counteract delayed wound healing in space, a better understanding of the fibroblasts' reaction to altered gravity levels is needed. In this paper, we describe experiments that were carried out at the Large Diameter Centrifuge located in ESA-ESTEC as part of the ESA Academy 2021 Spin Your Thesis! Campaign. We exposed dermal fibroblasts to a set of altered gravity levels, including transitions between simulated microgravity and hypergravity. The addition of the stress hormone cortisol to the cell culture medium was done to account for possible interaction effects of gravity and cortisol exposure. Results show a main impact of cortisol on the secretion of pro-inflammatory cytokines as well as extracellular matrix proteins. Altered gravity mostly induced a delay in cellular migration and changes in mechanosensitive cell structures. Furthermore, 20 × g hypergravity transitions induced changes in nuclear morphology. These findings provide insights into the effect of gravity transitions on the fibroblasts' function related to wound healing, which may be useful for the development of countermeasures., (© 2023. The Author(s).)

The skeletal muscle and the immune system are heavily affected by the space environment. The crosstalk between these organs, although established, is not fully understood. This study determined the nature of immune cell changes in the murine skeletal muscle following (hindlimb) unloading combined with an acute session of irradiation (HLUR). Our findings show that 14 days of HLUR induces a significant increase of myeloid immune cell infiltration in skeletal muscle., (© 2023. The Author(s).)

The radionuclide therapy [ 177 Lu]Lu-PSMA-617 was recently FDA-approved for treatment of metastatic castration-resistant prostate cancer. Salivary gland toxicity is currently considered as the main dose-limiting side effect. However, its uptake and retention mechanisms in the salivary glands remain elusive. Therefore, our aim was to elucidate the uptake patterns of [ 177 Lu]Lu-PSMA-617 in salivary gland tissue and cells by conducting cellular binding and autoradiography experiments. Briefly, A-253 and PC3-PIP cells, and mouse kidney and pig salivary gland tissue, were incubated with 5 nM [ 177 Lu]Lu-PSMA-617 to characterize its binding. Additionally, [ 177 Lu]Lu-PSMA-617 was co-incubated with monosodium glutamate, ionotropic or metabotropic glutamate receptor antagonists. Low, non-specific binding was observed in salivary gland cells and tissues. Monosodium glutamate was able to decrease [ 177 Lu]Lu-PSMA-617 in PC3-PIP cells, mouse kidney and pig salivary gland tissue. Kynurenic acid (ionotropic antagonist) decreased the binding of [ 177 Lu]Lu-PSMA-617 to 29.2 ± 20.6% and 63.4 ± 15.4%, respectively, with similar effects observed on tissues. (RS)-MCPG (metabotropic antagonist) was able to decrease the [ 177 Lu]Lu-PSMA-617 binding on A-253 cells to 68.2 ± 16.8% and pig salivary gland tissue to 53.1 ± 36.8%. To conclude, we showed that the non-specific binding on [ 177 Lu]Lu-PSMA-617 could be reduced by monosodium glutamate, kynurenic acid and (RS)-MCPG.

Although we have sent humans into space for more than 50 years crucial questions regarding kidney physiology, volume regulation and osmoregulation remain unanswered. The complex interactions between the renin-angiotensin-aldosterone system, the sympathetic nervous system, osmoregulatory responses, glomerular function, tubular function, and environmental factors such as sodium and water intake, motion sickness and ambient temperature make it difficult to establish the exact effect of microgravity and the subsequent fluid shifts and muscle mass loss on these parameters. Unfortunately, not all responses to actual microgravity can be reproduced with head-down tilt bed rest studies, which complicates research on Earth. Better understanding of the effects of microgravity on kidney function, volume regulation and osmoregulation are needed with the advent of long-term deep space missions and planetary surface explorations during which orthostatic intolerance complaints or kidney stone formation can be life-threatening for astronauts. Galactic cosmic radiation may be a new threat to kidney function. In this review, we summarise and highlight the current understandings of the effects of microgravity on kidney function, volume regulation and osmoregulation and discuss knowledge gaps that future studies should address., (© 2023. The Author(s).)

Pelvic irradiation-induced mucositis secondarily leads to dysbiosis, which seriously affects patients' quality of life after treatment. No safe and effective radioprotector or mitigator has yet been approved for clinical therapy. Here, we investigated the potential protective effects of fresh biomass of Limnospira indica PCC 8005 against ionizing irradiation-induced mucositis and dysbiosis in respect to benchmark probiotic Lacticaseibacillus rhamnosus GG ATCC 53103. For this, mice were supplemented daily before and after 12 Gy X-irradiation of the pelvis. Upon sacrifice, food supplements' efficacy was assessed for intestinal barrier protection, immunomodulation and changes in the microbiota composition. While both could not confer barrier protection or significant immunomodulatory effects, 16S microbial profiling revealed that L. indica PCC 8005 and L. rhamnosus GG could prevent pelvic irradiation-induced dysbiosis. Altogether, our data show that-besides benchmarked L. rhamnosus GG- L. indica PCC 8005 is an interesting candidate to further explore as a radiomitigator counteracting pelvic irradiation-induced dysbiosis in the presented in vivo irradiation-gut-microbiota platform., Competing Interests: The authors declare no conflict of interest.

The recent incidental discovery of an asymptomatic venous thrombosis (VT) in the internal jugular vein of an astronaut on the International Space Station prompted a necessary, immediate response from the space medicine community. The European Space Agency formed a topical team to review the pathophysiology, risk and clinical presentation of venous thrombosis and the evaluation of its prevention, diagnosis, mitigation, and management strategies in spaceflight. In this article, we discuss the findings of the ESA VT Topical Team over its 2-year term, report the key gaps as we see them in the above areas which are hindering understanding VT in space. We provide research recommendations in a stepwise manner that build upon existing resources, and highlight the initial steps required to enable further evaluation of this newly identified pertinent medical risk., (© 2023. The Author(s).)

Human spaceflight is entering a new era of sustainable human space exploration. By 2030 humans will regularly fly to the Moon's orbit, return to the Moon's surface and preparations for crewed Mars missions will intensify. In planning these undertakings, several challenges will need to be addressed in order to ensure the safety of astronauts during their space travels. One of the important challenges to overcome, that could be a major showstopper of the space endeavor, is the exposure to the space radiation environment. There is an urgent need for quantifying, managing and limiting the detrimental health risks and electronics damage induced by space radiation exposure. Such risks raise key priority topics for space research programs. Risk limitation involves obtaining a better understanding of space weather phenomena and the complex radiation environment in spaceflight, as well as developing and applying accurate dosimetric instruments, understanding related short- and long-term health risks, and strategies for effective countermeasures to minimize both exposure to space radiation and the remaining effects post exposure. The ESA/SciSpacE Space Radiation White Paper identifies those topics and underlines priorities for future research and development, to enable safe human and robotic exploration of space beyond Low Earth Orbit., (© 2023. The Author(s).)

Fibroblast migration is an important aspect of wound healing. Different factors can influence migration and as such proper wound healing. In vitro scratch wound assays are used to examine cellular migration. However, the wide array of techniques available reduces reproducibility of findings. In this paper, we compare two techniques for wound creation; i.e. the exclusion method or scratching of cell monolayers. Furthermore, we investigate if analysis software influences experimental outcome by comparing both commercially and freely available analysis software. Besides, we examine the effect of cortisol on migration behavior of fibroblasts and identify possible caveats in experimental design. Results show a significantly reduced migration of fibroblasts when wounds are created using a cell exclusion method. Furthermore, addition of cortisol to the cell culture media only reduced migration of fibroblast monolayers that had been scratched but not in those where wounds were created using the exclusion method. A possible explanation related to cytokine expression is discussed., Competing Interests: The authors report no conflict of interest., (© 2023 The Authors.)

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.