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Purpose: Radiological examinations are critical in the evaluation of patients with haematological malignancies for diagnosis and treatment. Any dose of radiation has been shown in studies to be harmful. In this regard, we assessed the radiation exposure of 3 types of haematological malignancies (diffuse large B-cell lymphoma [DLBCL], acute myeloid leukaemia [AML], and multiple myeloma [MM]) in our centre during the first year after diagnosis. Material and methods: In the first year after diagnosis we retrospectively reviewed the radiation exposure data of 3 types of haematological malignancies (DLBCL, AML, and MM). The total and median CED value (cumulative effective radiation dose in millisieverts [mSv]) of each patient was used. Each patient's total and median estimated CED value was calculated using a web-based calculator and recorded in millisieverts (mSv). Results: The total radiation doses in one year after diagnosis (CED value) were 46.54 +/- 37.12 (median dose: 36.2) in the AML group; 63.00 +/- 42.05 (median dose: 66.4) in the DLBCL group; and 28.04 +/- 19.81 (median dose: 26.0) in the MM group (p = 0.0001). There was a significant difference between DLBCL and MM groups. Conclusions: In all 3 haematological malignancies, the radiation exposure was significant, especially in the DBLCL group, within the first year of diagnosis. It is critical to seek methods to reduce these dosage levels. In diagnostic radiology, reference values must be established to increase awareness and self-control and reduce patient radiation exposure. This paper is also the first to offer thorough details on the subject at hand, and we think it can serve as a guide for further investigation.

To assess the number of life-bearing worlds in astrophysical environments, it is necessary to take the intertwined processes of abiogenesis (birth), extinction (death), and transfer of life (migration) into account. We construct a mathematical model that incorporates this trio of mechanisms and accordingly derive the probability distribution function and other statistical properties (e.g., mean) for the number of worlds with biospheres. We show that a given astrophysical setting may become eventually saturated with life if the rate of successful transfers of organisms is higher than the extinction rate of biospheres. Based on the available data, we suggest that this criterion might be fulfilled for star-forming clusters (and perhaps the Galactic bulge under optimal circumstances), thereby indicating that such regions could constitute promising abodes for hosting and detecting life., 8 pages, 3 figures. Published on 28 October 2021 in MNRAS

The escape fraction of Lyman-continuum (LyC) photons ($f_{esc}$) is a key parameter for determining the sources of cosmic reionization at $z\geq 6$. At these redshifts, owing to the opacity of the intergalactic medium, the LyC emission cannot be measured directly. However, LyC leakers during the epoch of reionization could be identified using indirect indicators that have been extensively tested at low and intermediate redshifts. These include a high [OIII]/[OII] flux ratio, high star-formation surface density, and compact sizes. In this work, we present observations of 29 $4.5 \leq z \leq 8$ gravitationally lensed galaxies in the Abell 2744 cluster field. From a combined analysis of JWST-NIRSpec and NIRCam data, we accurately derived their physical and spectroscopic properties: our galaxies have low masses $(\log(M_\star)\sim 8.5)$, blue UV spectral slopes ($\beta \sim -2.1$), compact sizes ($r_e \sim 0.3-0.5$ kpc), and high [OIII]/[OII] flux ratios. We confirm that these properties are similar to those characterizing low-redshift LyC leakers. Indirectly inferring the fraction of escaping ionizing photons, we find that more than 80% of our galaxies have predicted $f_{esc}$ values larger than 0.05, indicating that they would be considered leakers. The average predicted $f_{esc}$ value of our sample is 0.12, suggesting that similar galaxies at $z\geq 6$ have provided a substantial contribution to cosmic reionization., Comment: Accepted for publication in the 4. Extragalactic astronomy section of A&A, 12 pages, 8 figures

Introduction: In the event of a radiation accident detecting γ-H2AX foci is being accepted as fast method for triage and dose assessment. However, due to their disappearance kinetics, published calibrations have been constructed at specific post-irradiation times. - Objectives: To develop a surface, or tridimensional, model to estimate doses at times not included in the calibration analysis, and to validate it. - Materials and methods: Calibration data was obtained irradiating peripheral mononucleated cells from one donor with radiation doses ranging from 0 to 3 Gy, and γ -H2AX foci were detected microscopically using a semi-automatic method, at different post-irradiation times from 0.5 to 24 h. For validation, in addition to the above-mentioned donor, blood samples from another donor were also used. Validation was done within the range of doses and post-irradiation times used in the calibration. - Results: The calibration data clearly shows that at each analyzed time, the γ-H2AX foci frequency increases as dose increases, and for each dose this frequency decreases with post-irradiation time. The γ-H2AX foci nucleus distribution was clearly overdispersed, for this reason to obtain bidimensional and tridimensional dose-effect relationships no probability distribution was assumed, and linear and non-linear least squares weighted regression was used. In the two validation exercises for most evaluated samples, the 95% confidence limits of the estimated dose were between ±0.5 Gy of the real dose. No major differences were observed between donors. - Conclusion: In case of a suspected overexposure to radiation, the surface model here presented allows a correct dose estimation using γ-H2AX foci as biomarker. The advantage of this surface model is that it can be used at any post-irradiation time, in our model between 0.5 and 24 h.

The iconic Viking Landers that landed on Mars in 1976 demonstrated that the Martian surface is an extreme place, dominated by high UV fluxes and regolith chemistry capable of oxidizing organic molecules. From follow-on missions, we have learned that Mars was much warmer and wetter in its early history, and even some areas of Mars (such as crater lakes, possibly with sustained hydrothermal activity) were habitable places (e.g. Grotzinger et al. (2014). Science (New York, N.Y.) 343; Mangold et al. (2021). Science (New York, N.Y.). However, based on the Viking results we have learnt that the search for life and its remains is challenged by abiotic breakdown and alteration of organic material. In particular, the harsh radiation climate at the Martian surface that directly and indirectly could degrade organics has been held accountable for the lack of organics in the Martian regolith. Recent work simulating wind-driven erosion of basalts under Mars-like conditions has shown that this process, comparable to UV- and ionizing radiation, produces reactive compounds, kills microbes and removes methane from the atmosphere. and thereby could equally jeopardize the success of life-seeking missions to Mars. In this review, we summarize and discuss previous work on the role of physical and chemical mechanisms that affect the persistence of organics, and their consequences for the detection of life and/or its signatures in the Martian regolith and in the atmosphere.

We report the discovery of J0121+0025, an extremely luminous and young star-forming galaxy (M_UV = -24.11, log[L_Lya / erg s^-1] = 43.8) at z = 3.244 showing copious Lyman continuum (LyC) leakage (f_esc,abs ~ 40%). High signal-to-noise ratio rest-frame UV spectroscopy with the Gran Telescopio Canarias reveals a high significance (7.9 sigma) emission below the Lyman limit (< 912A), with a flux density level f_900A = 0.78 +/- 0.10 uJy, and strong P-Cygni in wind lines of OVI 1033A, NV 1240A and CIV 1550A that are indicative of a young age of the starburst (, 16 pages, 8 figures, 2 tables. Accepted for publication in MNRAS. v2: reference list updated

Astronauts can develop psychological stress (PS) during space flights due to the enclosed environment, microgravity, altered light-dark cycles, and risks of equipment failure or fatal mishaps. At the same time, they are exposed to cosmic rays including high atomic number and energy (HZE) particles such as iron-56 (Fe) ions. Psychological stress or radiation exposure can cause detrimental effects in humans. An earlier published pioneering study showed that chronic restraint-induced psychological stress (CRIPS) could attenuate Trp53 functions and increase carcinogenesis induced by low-linear energy transfer (LET) γ rays in Trp53-heterozygous (Trp53+/-) mice. To elucidate possible modification effects from CRIPS on high-LET HZE particle-induced health consequences, Trp53+/- mice were received both CRIPS and accelerated Fe ion irradiation. Six-week-old Trp53+/- C57BL/6N male mice were restrained 6 h per day for 28 consecutive days. On day 8, they received total-body Fe-particle irradiation (Fe-TBI, 0.1 or 2 Gy). Metaphase chromosome spreads prepared from splenocytes at the end of the 28-day restraint regimen were painted with the fluorescence in situ hybridization (FISH) probes for chromosomes 1 (green), 2 (red) and 3 (yellow). Induction of psychological stress in our experimental model was confirmed by increase in urinary corticosterone level on day 7 of restraint regimen. Regardless of Fe-TBI, CRIPS reduced splenocyte number per spleen at the end of the 28-day restraint regimen. At 2 Gy, Fe-TBI alone induced many aberrant chromosomes and no modifying effect was detected from CRIPS on induction of aberrant chromosomes. Notably, neither Fe-TBI at 0.1 Gy nor CRIPS alone induced any increase in the frequency of aberrant chromosomes, while simultaneous exposure resulted in a significant increase in the frequency of chromosomal exchanges. These findings clearly showed that CRIPS could enhance the frequency of chromosomal exchanges induced by Fe-TBI at a low dose of 0.1 Gy.

Proton radiotherapy (PRT) has the potential to reduce the normal tissue toxicity associated with conventional photon-based radiotherapy (X-ray therapy, XRT) because the active dose can be more directly targeted to a tumor. Although this dosimetric advantage of PRT is well known, the molecular mechanisms affected by PRT remain largely elusive. Here, we combined the molecular toolbox of the eukaryotic model Saccharomyces cerevisiae with a systems biology approach to investigate the physiological effects of PRT compared to XRT. Our data show that the DNA damage response and protein stress response are the major molecular mechanisms activated after both PRT and XRT. However, RNA-Seq revealed that PRT treatment evoked a stronger activation of genes involved in the response to proteotoxic stress, highlighting the molecular differences between PRT and XRT. Moreover, inhibition of the proteasome resulted in decreased survival in combination with PRT compared to XRT, not only further confirming that protons induced a stronger proteotoxic stress response, but also hinting at the potential of using proteasome inhibitors in combination with proton radiotherapy in clinical settings. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:10 ispartof: location:Switzerland status: published

Even though a detailed understanding of the proliferative characteristics of T lymphocytes is imperative in many research fields, prior studies have never reached a consensus on these characteristics, and on the corresponding cell cycle kinetics specifically. In this study, the general proliferative response of human T lymphocytes to phytohaemagglutinin (PHA) stimulation was characterized using a carboxyfluorescein succinimidyl ester-based flow cytometric assay. We were able to determine when PHA-stimulated T lymphocytes complete their first division, the proportion of cells that initiate proliferation, the subsequent division rate of the cells, and the impact of irradiation on these proliferative properties. Next, we accurately visualized the cell cycle progression of dividing T lymphocytes cultured in whole blood using an adapted 5-ethynyl-2’-deoxyuridine pulse-chase method. Furthermore, through multiple downstream analysis methods, we were able to make an estimation of the corresponding cell cycle kinetics. We also visualized the impact of X-rays on the progression of the cells through the cell cycle. Our results showed dose-dependent G2 arrest after exposure to irradiation, and a corresponding delay in G1 phase-entry of the cells. In conclusion, utilizing various flow cytometric assays, we provided valuable information on T lymphocyte proliferation characteristics starting from first division to fully dividing cells.

Radiotherapy can induce an immunological response. One limiting factor is side effects on normal tissue. Using FLASH radiotherapy, side effects could possibly be reduced. The efficacy of FLASH in relation to conventional radiotherapy (CONV-RT) has not been extensively explored in fully immunocompetent animals. Fully immunocompetent Fischer 344 rats were inoculated with NS1 glioblastoma cells subcutaneously or intracranially. Radiotherapy was delivered with FLASH or CONV-RT at 8 Gy × 2 (subcutaneous tumors) and 12.5 Gy × 2 (intracranial tumors). Cured animals were re-challenged in order to explore long-term anti-tumor immunity. Serum analytes and gene expression were explored. The majority of animals with subcutaneous tumors were cured when treated with FLASH or CONV-RT at 8 Gy × 2. Cured animals could reject tumor re-challenge. TIMP-1 in serum was reduced in animals treated with FLASH 8 Gy × 2 compared to control animals. Animals with intracranial tumors survived longer when treated with FLASH or CONV-RT at 12.5 Gy × 2, but cure was not reached. CONV-RT and FLASH were equally effective in fully immunocompetent animals with glioblastoma. Radiotherapy was highly efficient in the subcutaneous setting, leading to cure and long-term immunity in the majority of the animals.

Radiotherapy is a cancer treatment that applies high doses of ionizing radiation to induce cell death, mainly by triggering DNA double-strand breaks. The outcome of radiotherapy greatly depends on radiosensitivity of cancer cells, which is determined by multiple proteins and cellular processes. In this review, we summarize current knowledge on the role of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in determining the response to radiation. Non-coding RNAs modulate ionizing radiation response by targeting key signaling pathways, including DNA damage repair, apoptosis, glycolysis, cell cycle arrest, and autophagy. Additionally, we indicate miRNAs and lncRNAs that upon overexpression or inhibition alter cellular radiosensitivity. Current data indicate the potential of using specific non-coding RNAs as modulators of cellular radiosensitivity to improve outcome of radiotherapy.

We present results on the star cluster properties from a series of high resolution smoothed particles hydrodynamics (SPH) simulations of isolated dwarf galaxies as part of the GRIFFIN project. The simulations at sub-parsec spatial resolution and a minimum particle mass of 4 $\mathrm{M_\odot}$ incorporate non-equilibrium heating, cooling and chemistry processes, and realise individual massive stars. All the simulations follow feedback channels of massive stars that include the interstellar-radiation field, that is variable in space and time, the radiation input by photo-ionisation and supernova explosions. Varying the star formation efficiency per free-fall time in the range $\epsilon_\mathrm{ff}$ = 0.2 - 50$\%$ neither changes the star formation rates nor the outflow rates. While the environmental densities at star formation change significantly with $\epsilon_\mathrm{ff}$, the ambient densities of supernovae are independent of $\epsilon_\mathrm{ff}$ indicating a decoupling of the two processes. At low $\epsilon_\mathrm{ff}$, more massive, and increasingly more bound star clusters are formed, which are typically not destroyed. With increasing $\epsilon_\mathrm{ff}$ there is a trend for shallower cluster mass functions and the cluster formation efficiency $\Gamma$ for young bound clusters decreases from $50 \%$ to $\sim 1 \%$ showing evidence for cluster disruption. However, none of our simulations form low mass ($< 10^3$ $\mathrm{M_\odot}$) clusters with structural properties in perfect agreement with observations. Traditional star formation models used in galaxy formation simulations based on local free-fall times might therefore not be able to capture low mass star cluster properties without significant fine-tuning., Comment: 17 pages, 13 figures. Accepted to be published in MNRAS. Comments welcome

Radiotherapy in cancer treatment involves the use of ionizing radiation for cancer cell killing. Although radiotherapy has shown significant improvements on cancer recurrence and mortality, several radiation-induced adverse effects have been documented. Of these adverse effects, radiation-induced cardiovascular disease (CVD) is particularly prominent among patients receiving mediastinal radiotherapy, such as breast cancer and Hodgkin’s lymphoma patients. A number of mechanisms of radiation-induced CVD pathogenesis have been proposed such as endothelial inflammatory activation, premature endothelial senescence, increased ROS and mitochondrial dysfunction. However, current research seems to point to a so-far unexamined and potentially novel involvement of epigenetics in radiation-induced CVD pathogenesis. Firstly, epigenetic mechanisms have been implicated in CVD pathophysiology. In addition, several studies have shown that ionizing radiation can cause epigenetic modifications, especially DNA methylation alterations. As a result, this review aims to provide a summary of the current literature linking DNA methylation to radiation-induced CVD and thereby explore DNA methylation as a possible contributor to radiation-induced CVD pathogenesis., Graphical abstract

Simple SummaryImmunotherapy provides the unprecedented opportunity to prolong the survival of cancer patients and even cure patients with previously untreatable malignancies. Preclinical and clinical studies show that standard photon-based radiotherapy and immunotherapy can synergize in order to promote both local and systemic anti-tumor immunity and that there is still ample room for improvement. Charged particle radiation is thought to have greater immunogenic potential compared to photon radiotherapy due to more lethal unrepaired damage, higher ionization density and thus more complex clustered DNA lesions. In this review, several factors determining the success of radiotherapy combined with immunotherapies, such as composition of the tumor, radiotherapy scheme and schedule, radiation dose, the type of radiation, are addressed. Furthermore, the theoretical basis, first pieces of evidences and new insights supporting a favorable immunogenicity profile of charged particle radiation are examined, including a depiction of best of knowledge for the immune-related responses triggered by charged particles and prospective clinical trials.Radiotherapy (RT) has been shown to interfere with inflammatory signals and to enhance tumor immunogenicity via, e.g., immunogenic cell death, thereby potentially augmenting the therapeutic efficacy of immunotherapy. Conventional RT consists predominantly of high energy photon beams. Hypofractionated RT regimens administered, e.g., by stereotactic body radiation therapy (SBRT), are increasingly investigated in combination with cancer immunotherapy within clinical trials. Despite intensive preclinical studies, the optimal dose per fraction and dose schemes for elaboration of RT induced immunogenic potential remain inconclusive. Compared to the scenario of combined immune checkpoint inhibition (ICI) and RT, multimodal therapies utilizing other immunotherapy principles such as adoptive transfer of immune cells, vaccination strategies, targeted immune-cytokines and agonists are underrepresented in both preclinical and clinical settings. Despite the clinical success of ICI and RT combination, e.g., prolonging overall survival in locally advanced lung cancer, curative outcomes are still not achieved for most cancer entities studied. Charged particle RT (PRT) has gained interest as it may enhance tumor immunogenicity compared to conventional RT due to its unique biological and physical properties. However, whether PRT in combination with immune therapy will elicit superior antitumor effects both locally and systemically needs to be further investigated. In this review, the immunological effects of RT in the tumor microenvironment are summarized to understand their implications for immunotherapy combinations. Attention will be given to the various immunotherapeutic interventions that have been co-administered with RT so far. Furthermore, the theoretical basis and first evidences supporting a favorable immunogenicity profile of PRT will be examined.

Simple Summary Immunotherapy provides the unprecedented opportunity to prolong the survival of cancer patients and even cure patients with previously untreatable malignancies. Preclinical and clinical studies show that standard photon-based radiotherapy and immunotherapy can synergize in order to promote both local and systemic anti-tumor immunity and that there is still ample room for improvement. Charged particle radiation is thought to have greater immunogenic potential compared to photon radiotherapy due to more lethal unrepaired damage, higher ionization density and thus more complex clustered DNA lesions. In this review, several factors determining the success of radiotherapy combined with immunotherapies, such as composition of the tumor, radiotherapy scheme and schedule, radiation dose, the type of radiation, are addressed. Furthermore, the theoretical basis, first pieces of evidences and new insights supporting a favorable immunogenicity profile of charged particle radiation are examined, including a depiction of best of knowledge for the immune-related responses triggered by charged particles and prospective clinical trials. Abstract Radiotherapy (RT) has been shown to interfere with inflammatory signals and to enhance tumor immunogenicity via, e.g., immunogenic cell death, thereby potentially augmenting the therapeutic efficacy of immunotherapy. Conventional RT consists predominantly of high energy photon beams. Hypofractionated RT regimens administered, e.g., by stereotactic body radiation therapy (SBRT), are increasingly investigated in combination with cancer immunotherapy within clinical trials. Despite intensive preclinical studies, the optimal dose per fraction and dose schemes for elaboration of RT induced immunogenic potential remain inconclusive. Compared to the scenario of combined immune checkpoint inhibition (ICI) and RT, multimodal therapies utilizing other immunotherapy principles such as adoptive transfer of immune cells, vaccination strategies, targeted immune-cytokines and agonists are underrepresented in both preclinical and clinical settings. Despite the clinical success of ICI and RT combination, e.g., prolonging overall survival in locally advanced lung cancer, curative outcomes are still not achieved for most cancer entities studied. Charged particle RT (PRT) has gained interest as it may enhance tumor immunogenicity compared to conventional RT due to its unique biological and physical properties. However, whether PRT in combination with immune therapy will elicit superior antitumor effects both locally and systemically needs to be further investigated. In this review, the immunological effects of RT in the tumor microenvironment are summarized to understand their implications for immunotherapy combinations. Attention will be given to the various immunotherapeutic interventions that have been co-administered with RT so far. Furthermore, the theoretical basis and first evidences supporting a favorable immunogenicity profile of PRT will be examined.

Hadron therapy by proton beams represents an advanced anti-cancer strategy due to its highly localized dose deposition allowing a greater sparing of normal tissue and/or organs at risk compared to photon/electron radiotherapy. However, it is not clear to what extent non-targeted effects such as transcriptional modulations produced along the beamline may diffuse and impact the surrounding tissue. In this work, we analyze the transcriptome of proton-irradiated mouse skin and choose two biomarker genes to trace their modulation at different distances from the beam's target and at different doses and times from irradiation to understand to what extent and how far it may propagate, using RNA-Seq and quantitative RT-PCR. In parallel, assessment of lipids alteration is performed by FTIR spectroscopy as a measure of tissue damage. Despite the observed high individual variability of expression, we can show evidence of transcriptional modulation of two biomarker genes at considerable distance from the beam's target where a simulation system predicts a significantly lower adsorbed dose. The results are compatible with a model involving diffusion of transcripts or regulatory molecules from high dose irradiated cells to distant tissue's portions adsorbing a much lower fraction of radiation.

Previous studies suggested a causal link between pre-natal exposure to ionizing radiation and birth defects such as microphthalmos and exencephaly. In mice, these defects arise primarily after high-dose X-irradiation during early neurulation. However, the impact of sublethal (low) X-ray doses during this early developmental time window on adult behavior and morphology of central nervous system structures is not known. In addition, the efficacy of folic acid (FA) in preventing radiation-induced birth defects and persistent radiation-induced anomalies has remained unexplored. To assess the efficacy of FA in preventing radiation-induced defects, pregnant C57BL6/J mice were X-irradiated at embryonic day (E)7.5 and were fed FA-fortified food. FA partially prevented radiation-induced (1.0 Gy) anophthalmos, exencephaly and gastroschisis at E18, and reduced the number of pre-natal deaths, fetal weight loss and defects in the cervical vertebrae resulting from irradiation. Furthermore, FA food fortification counteracted radiation-induced impairments in vision and olfaction, which were evidenced after exposure to doses ≥0.1 Gy. These findings coincided with the observation of a reduction in thickness of the retinal ganglion cell and nerve fiber layer, and a decreased axial length of the eye following exposure to 0.5 Gy. Finally, MRI studies revealed a volumetric decrease of the hippocampus, striatum, thalamus, midbrain and pons following 0.5 Gy irradiation, which could be partially ameliorated after FA food fortification. Altogether, our study is the first to offer detailed insights into the long-term consequences of X-ray exposure during neurulation, and supports the use of FA as a radioprotectant and antiteratogen to counter the detrimental effects of X-ray exposure during this crucial period of gestation. ispartof: Frontiers In Behavioral Neuroscience vol:14 pages:1-21 ispartof: location:Switzerland status: published

Kyrgyzstan still suffers from the past practices of radioactive industry operated by the Soviet Union that caused significant impact on ecosystems in this region, especially related with storage of uranium in inadequate conditions. There are at least 50 abandoned sites used as radioactive waste dumps in the country. Due to the pressure of natural and anthropogenic reasons, the structural foundations of mine waste dumps are gradually losing their integrities. Here, particular interest of our research is to reveal current state of radioactive contamination and to make evaluation on the radiological impacts of pollution caused by uranium mine waste dump, one is situated near Kaji-Say Village in Issyk Kul Region-Kyrgyzstan. In this study, the leaf, stem, and root parts of Perovskia abrotanoides Kar. and their co-located soils as study materials collected from five different localities were used for investigation of existent alterations on element uptake and genetic material in the plant using ICP-MS and ISSR marker technique. Also, radioactivity readings were recorded using Geiger counter. The data showed that the levels of radiation (in mR/h) were found to be significantly high in comparison with normal acceptable limits. Uptake patterns of certain elements in P. abrotanoides grown in the uranium waste dump site were modified extensively as reductions and increments due to strong radioactive leakage in comparison with the control. Also, the results indicated that changes in ISSR profiles from exposed plant leaf samples included variation in band intensities, losses of normal bands, and the appearances of new bands compared to unexposed (control) plant leaf sample. Considering people living around the area where the research was conducted, the consequences of contamination as our data suggest could cause health problems through radioactive leakage. Kyrgyz-Turkish Manas University, Commission of Scientific Research Project [KTMU-BAP-2018.FBE.01] This work was supported by the Kyrgyz-Turkish Manas University, Commission of Scientific Research Project [KTMU-BAP-2018.FBE.01].

Radiotherapy for head and neck cancer is associated with impairment of salivary gland function and consequent xerostomia, which has a devastating effect on the quality of life of the patients. The mechanism of radiation-induced salivary gland damage is not completely understood. Cellular senescence is a permanent state of cell cycle arrest accompanied by a secretory phenotype which contributes to inflammation and tissue deterioration. Genotoxic stresses, including radiation-induced DNA damage, are known to induce a senescence response. Here, we show that radiation induces cellular senescence preferentially in the salivary gland stem/progenitor cell niche of mouse models and patients. Similarly, salivary gland-derived organoids show increased expression of senescence markers and pro-inflammatory senescence-associated secretory phenotype (SASP) factors after radiation exposure. Clearance of senescent cells by selective removal of p16Ink4a-positive cells by the drug ganciclovir or the senolytic drug ABT263 lead to increased stem cell self-renewal capacity as measured by organoid formation efficiency. Additionally, pharmacological treatment with ABT263 in mice irradiated to the salivary glands mitigates tissue degeneration, thus preserving salivation. Our data suggest that senescence in the salivary gland stem/progenitor cell niche contributes to radiation-induced hyposalivation. Pharmacological targeting of senescent cells may represent a therapeutic strategy to prevent radiotherapy-induced xerostomia.

Radiotherapy is a cancer treatment that applies high doses of ionizing radiation to induce cell death, mainly by triggering DNA double-strand breaks. The outcome of radiotherapy greatly depends on radiosensitivity of cancer cells, which is determined by multiple proteins and cellular processes. In this review, we summarize current knowledge on the role of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in determining the response to radiation. Non-coding RNAs modulate ionizing radiation response by targeting key signaling pathways, including DNA damage repair, apoptosis, glycolysis, cell cycle arrest, and autophagy. Additionally, we indicate miRNAs and lncRNAs that upon overexpression or inhibition alter cellular radiosensitivity. Current data indicate the potential of using specific non-coding RNAs as modulators of cellular radiosensitivity to improve outcome of radiotherapy.

Radiotherapeutic treatment consists of targeted application of radiation beams to a tumor but exposure of surrounding healthy tissue is inevitable. In the brain, ionizing radiation induces breakdown of the blood–brain barrier by effects on brain microvascular endothelial cells. Damage from directly irradiated cells can be transferred to surrounding non-exposed bystander cells, known as the radiation-induced bystander effect. We investigated involvement of connexin channels and paracrine signaling in radiation-induced bystander DNA damage in brain microvascular endothelial cells exposed to focused X-rays. Irradiation caused DNA damage in the directly exposed area, which propagated over several millimeters in the bystander area. DNA damage was significantly reduced by the connexin channel-targeting peptide Gap26 and the Cx43 hemichannel blocker TAT-Gap19. ATP release, dye uptake, and patch clamp experiments showed that hemichannels opened within 5 min post irradiation in both irradiated and bystander areas. Bystander signaling involved cellular Ca2+ dynamics and IP3, ATP, ROS, and NO signaling, with Ca2+, IP3, and ROS as crucial propagators of DNA damage. We conclude that bystander effects are communicated by a concerted cascade involving connexin channels, and IP3/Ca2+, ATP, ROS, and NO as major contributors of regenerative signal expansion.

A growing body of evidence indicates that the expression of TERT, the catalytic subunit of telomerase, is a biological marker of progression in several cancers. We investigated the predictive and prognostic role of TERT levels and telomere length in tissues and peripheral blood in patients with head and neck squamous cell carcinoma (HNSCC). High TERT levels in cancer tissues were independently associated with worse response to therapy (odds ratio [OR]:6.26), regional failure (hazard ratio [HR]:5.75), progression (HR:2.12), and death (HR:3.53). Longer telomeres in the mucosa surrounding the tumor (SM) were independently associated with a lower risk of mucosal failure (HR:0.39). While telomere length in peripheral blood mononuclear cells (PBMC) significantly decreased with age, no correlation was found between age and telomere length in SM. No associations were found between TERT levels in plasma and telomere length in PBMC and the prognostic variables. High levels of TERT transcripts in cancer cells represent a reliable prognostic marker for identifying HNSCC patients with risk of progression. The altered relationship of telomere length to age in SM compared with PBMC suggests that in a subset of cases the phenotypically normal SM constitutes an acquired telomere-shortened epithelial field prone to genetic instability.

Background and Purpose Up to 50-60% of all cancer patients receive radiotherapy as part of their treatment strategy. However, the mechanisms accounting for increased vascular risks after irradiation are not completely understood. Mitochondrial dysfunction has been identified as a potential cause of radiation-induced atherosclerosis. Materials and Methods Assays for apoptosis, cellular metabolism, mitochondrial DNA content, functionality and morphology were used to compare the response of endothelial cells to a single 2 Gy dose of X-rays under basal conditions or after pharmacological treatments that either reduced (EtBr) or increased (rosiglitazone) mitochondrial content. Results Exposure to ionizing radiation caused a persistent reduction in mitochondrial content of endothelial cells. Pharmacological reduction of mitochondrial DNA content rendered endothelial cells more vulnerable to radiation-induced apoptosis, whereas rosiglitazone treatment increased oxidative metabolism and redox state and decreased the levels of apoptosis after irradiation. Conclusion Pre-existing mitochondrial damage sensitizes endothelial cells to ionizing radiation-induced mitochondrial dysfunction. Rosiglitazone protects endothelial cells from the detrimental effects of radiation exposure on mitochondrial metabolism and oxidative stress. Thus, our findings indicate that rosiglitazone may have potential value as prophylactic for radiation-induced atherosclerosis. This work was funded by EU FP7 DoReMi network of excellence (grant #249689), EU FP7 project ProCardio (grant #295823),the Belgian Federal Agency for Nuclear Control FANC-AFCN (grant #CO-90-13-3289-00) and the Belgian Fonds National de la Recherche Scientifique (F.R.S.-FNRS). BB, NB, and EC are supported by a doctoral SCK CEN grant. PS is a F.R.S.-FNRS Senior Research Associate. Aerts, A (reprint author), Belgian Nucl Res Ctr SCK CEN, Inst Environm Hlth & Safety, Radiobiol Unit, Mol, Belgium. an.aerts@sckcen.be

Purpose The aim of this study was to explore the effects of chronic low-dose-rate gamma-radiation at a multi-scale level. The specific objective was to obtain an overall view of the endothelial cell response, by integrating previously published data on different cellular endpoints and highlighting possible different mechanisms underpinning radiation-induced senescence. Materials and methods Different datasets were collected regarding experiments on human umbilical vein endothelial cells (HUVECs) which were chronically exposed to low dose rates (0, 1.4, 2.1 and 4.1 mGy/h) of gamma-rays until cell replication was arrested. Such exposed cells were analyzed for different complementary endpoints at distinct time points (up to several weeks), investigating cellular functions such as proliferation, senescence and angiogenic properties, as well as using transcriptomics and proteomics profiling. A mathematical model was proposed to describe proliferation and senescence. Results Simultaneous ceasing of cell proliferation and senescence onset as a function of time were well reproduced by the logistic growth curve, conveying shared equilibria between the two endpoints. The combination of all the different endpoints investigated highlighted a dose-dependence for prematurely induced senescence. However, the underpinning molecular mechanisms appeared to be dissimilar for the different dose rates, thus suggesting a more complex scenario. Conclusions This study was conducted integrating different datasets, focusing on their temporal dynamics, and using a systems biology approach. Results of our analysis highlight that different dose rates have different effects in inducing premature senescence, and that the total cumulative absorbed dose also plays an important role in accelerating endothelial cell senescence.

Individual variability in response to radiation exposure is recognised and has often been reported as important in treatment planning. Despite many efforts to identify biomarkers allowing the identification of radiation sensitive patients, it is not yet possible to distinguish them with certainty before the beginning of the radiotherapy treatment. A comprehensive analysis of genome-wide single-nucleotide polymorphisms (SNPs) and a transcriptional response to ionising radiation exposure in twins have the potential to identify such an individual. In the present work, we investigated SNP profile and CDKN1A gene expression in blood T lymphocytes from 130 healthy Caucasians with a complex level of individual kinship (unrelated, mono- or dizygotic twins). It was found that genetic variation accounts for 66% (95% CI 37–82%) of CDKN1A transcriptional response to radiation exposure. We developed a novel integrative multi-kinship strategy allowing investigating the role of genome-wide polymorphisms in transcriptomic radiation response, and it revealed that rs205543 (ETV6 gene), rs2287505 and rs1263612 (KLF7 gene) are significantly associated with CDKN1A expression level. The functional analysis revealed that rs6974232 (RPA3 gene), involved in mismatch repair (p value = 9.68e−04) as well as in RNA repair (p value = 1.4e−03) might have an important role in that process. Two missense polymorphisms with possible deleterious effect in humans were identified: rs1133833 (AKIP1 gene) and rs17362588 (CCDC141 gene). In summary, the data presented here support the validity of this novel integrative data analysis strategy to provide insights into the identification of SNPs potentially influencing radiation sensitivity. Further investigations in radiation response research at the genomic level should be therefore continued to confirm these findings. Electronic supplementary material The online version of this article (10.1007/s10142-019-00658-3) contains supplementary material, which is available to authorized users.

We apply Bayesian statistics to perform model selection on different reionisation scenarios via the Multinest algorithm. Initially, we recover the results shown by 21CMMC for the parameter estimation of 21cmFAST models. We proceed to test several toy models of the Epoch of Reionisation (EoR) defined in contrasting morphology and scale. We find that LOFAR observations are unlikely to allow model selection even with long integration times. HERA would require 61 dipoles to perform the same analysis in 1080 hours, and becomes comparable to the SKA with 217 dipoles. We find the SKA requires only 324 hours of observation to conclusively distinguish between our models. Once model selection is achievable, an analysis of observational priors is performed finding that neutral fraction checks at specific redshifts add little to no inference. We show the difficulties in model selection at the level of distinguishing fiducial parameters within a model or distinguishing galaxies with a constant versus power law mass-to-light ratio. Finally, we explore the use of the Savage-Dickey density ratio to show the redundancy of the parameter Rmfp within 21cmFAST., Comment: 20 pages, 16 figures - Accepted for publication by MNRAS

The sensitive infrared telescopes, Spitzer and Herschel, have been used to target low-metallicity star-forming galaxies, allowing us to investigate the properties of their interstellar medium (ISM) in unprecedented detail. Interpretation of the observations in physical terms relies on careful modeling of those properties. We have employed a multiphase approach to model the ISM phases (HII region and photodissociation region) with the spectral synthesis code Cloudy. Our goal is to characterize the physical conditions (gas densities, radiation fields, etc.) in the ISM of the galaxies from the Herschel Dwarf Galaxy Survey. We are particularly interested in correlations between those physical conditions and metallicity or star-formation rate. Other key issues we have addressed are the contribution of different ISM phases to the total line emission, especially of the [CII]157um line, and the characterization of the porosity of the ISM. We find that the lower-metallicity galaxies of our sample tend to have higher ionization parameters and galaxies with higher specific star-formation rates have higher gas densities. The [CII] emission arises mainly from PDRs and the contribution from the ionized gas phases is small, typically less than 30% of the observed emission. We also find correlation - though with scatter - between metallicity and both the PDR covering factor and the fraction of [CII] from the ionized gas. Overall, the low metal abundances appear to be driving most of the changes in the ISM structure and conditions of these galaxies, and not the high specific star-formation rates. These results demonstrate in a quantitative way the increase of ISM porosity at low metallicity. Such porosity may be typical of galaxies in the young Universe., Accepted in A&A. 20 pages, 12 figures, 5 tables plus appendices

Objective To determine patient, institution, and machine characteristics that contribute to variation in radiation doses used for computed tomography (CT). Design Prospective cohort study. Setting Data were assembled and analyzed from the University of California San Francisco CT International Dose Registry. Participants Standardized data from over 2.0 million CT examinations of adults who underwent CT between November 2015 and August 2017 from 151 institutions, across seven countries (Switzerland, Netherlands, Germany, United Kingdom, United States, Israel, and Japan). Main outcome measures Mean effective doses and proportions of high dose examinations for abdomen, chest, combined chest and abdomen, and head CT were determined by patient characteristics (sex, age, and size), type of institution (trauma center, care provision 24 hours per day and seven days per week, academic, private), institutional practice volume, machine factors (manufacturer, model), country, and how scanners were used, before and after adjustment for patient characteristics, using hierarchical linear and logistic regression. High dose examinations were defined as CT scans with doses above the 75th percentile defined during a baseline period. Results The mean effective dose and proportion of high dose examinations varied substantially across institutions. The doses varied modestly (10-30%) by type of institution and machine characteristics after adjusting for patient characteristics. By contrast, even after adjusting for patient characteristics, wide variations in radiation doses across countries persisted, with a fourfold range in mean effective dose for abdomen CT examinations (7.0-25.7 mSv) and a 17-fold range in proportion of high dose examinations (4-69%). Similar variation across countries was observed for chest (mean effective dose 1.7-6.4 mSv, proportion of high dose examinations 1-26%) and combined chest and abdomen CT (10.0-37.9 mSv, 2-78%). Doses for head CT varied less (1.4-1.9 mSv, 8-27%). In multivariable models, the dose variation across countries was primarily attributable to institutional decisions regarding technical parameters (that is, how the scanners were used). Conclusions CT protocols and radiation doses vary greatly across countries and are primarily attributable to local choices regarding technical parameters, rather than patient, institution, or machine characteristics. These findings suggest that the optimization of doses to a consistent standard should be possible. Study registration Clinicaltrials.gov NCT03000751 .

Numerous studies have demonstrated that the martian surface environment is hostile to life because of its rough radiation climate and the reactive chemistry of the regolith. Physical processes such as erosion and transport of mineral particles by wind-driven saltation have hitherto not been considered as a life hazard. We report a series of experiments where bacterial endospores (spores of Bacillus subtilis) were exposed to a simulated saltating martian environment. We observed that 50% of the spores that are known to be highly resistant to radiation and oxidizing chemicals were destroyed by saltation-mediated abrasion within one minute. Scanning electron micrographs show that the spores were not only damaged by abrasion but were eradicated during the saltation process. We suggest that abrasion mediated by wind-driven saltation should be included as a factor that defines the habitability of the martian surface environment. The process may efficiently protect the martian surface from forward contamination with terrestrial microbial life-forms. Abrasion mediated by wind-driven saltation should also be considered as a major challenge to indigenous martian surface life if it exists/existed.

Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate). In the present study we focus on the development of lysine (K) acetyltransferase inhibitors (KATi) targeting the MYST family member Tip60 (Kat5), an essential protein, designed or discovered through screening libraries. Importantly, Tip60 has been demonstrated to be significantly down-regulated in many cancers which urgently require new treatment options. We highlight current and future efforts employing these KATi as cancer treatments and their ability to synergize and enhance current cancer treatments. We investigate the different methods of KATi production or discovery, their mechanisms and their validation models. Importantly, the utility of KATi is based on a key concept: using KATi to abrogate the activity of an already down-regulated essential protein (effectively creating a lethal knockout) provides another innovative mechanism for targeting cancer cells, while significantly minimizing any off-target effects to normal cells. This approach, combined with the rapidly developing interest in KATi, suggests that KATi have a bright future for providing truly personalized therapies.

Metformin (Met) is an approved antidiabetic drug currently being explored for repurposing in cancer treatment based on recent evidence of its apparent chemopreventive properties. Met is weakly cationic and targets the mitochondria to induce cytotoxic effects in tumor cells, albeit not very effectively. We hypothesized that increasing its mitochondria-targeting potential by attaching a positively charged lipophilic substituent would enhance the antitumor activity of Met. In pursuit of this question, we synthesized a set of mitochondria-targeted Met analogues (Mito-Mets) with varying alkyl chain lengths containing a triphenylphosphonium cation (TPP+). In particular, the analogue Mito-Met10, synthesized by attaching TPP+ to Met via a 10-carbon aliphatic side chain, was nearly 1,000 times more efficacious than Met at inhibiting cell proliferation in pancreatic ductal adenocarcinoma (PDAC). Notably, in PDAC cells, Mito-Met10 potently inhibited mitochondrial complex I, stimulating superoxide and AMPK activation, but had no effect in nontransformed control cells. Moreover, Mito-Met10 potently triggered G1 cell-cycle phase arrest in PDAC cells, enhanced their radiosensitivity, and more potently abrogated PDAC growth in preclinical mouse models, compared with Met. Collectively, our findings show how improving the mitochondrial targeting of Met enhances its anticancer activities, including aggressive cancers like PDAC in great need of more effective therapeutic options. Cancer Res; 76(13); 3904–15. ©2016 AACR.

Every year, cervical cancer affects similar to 500,000 women worldwide, and similar to 275,000 patients die of this disease. The addition of platin-based chemotherapy to primary radiotherapy has increased 5-year survival of advanced-stage cervical cancer patients, which is, however, still only 66%. One of the factors thought to contribute to treatment failure is the ability of tumor cells to repair chemoradiotherapy-induced DNA damage. Therefore, sensitization of tumor cells for chemoradiotherapy via inhibition of the DNA damage response (DDR) as a novel strategy to improve therapy effect, is currently studied pre-clinically as well as in the clinic.Almost invariably, cervical carcinogenesis involves infection with the human papillomavirus (HPV), which inactivates part of the DNA damage response. This HPV-mediated partial inactivation of the DDR presents therapeutic targeting of the residual DDR as an interesting approach to achieve chemoradio-sensitization for cervical cancer. How the DDR can be most efficiently targeted, however, remains unclear. The fact that cisplatin and radiotherapy activate multiple signaling axes within the DDR further complicates a rational choice of therapeutic targets within the DDR. In this review, we provide an overview of the current preclinical and clinical knowledge about targeting the DDR in cervical cancer. (C) 2015 Elsevier Ltd. All rights reserved.

Every year, cervical cancer affects similar to 500,000 women worldwide, and similar to 275,000 patients die of this disease. The addition of platin-based chemotherapy to primary radiotherapy has increased 5-year survival of advanced-stage cervical cancer patients, which is, however, still only 66%. One of the factors thought to contribute to treatment failure is the ability of tumor cells to repair chemoradiotherapy-induced DNA damage. Therefore, sensitization of tumor cells for chemoradiotherapy via inhibition of the DNA damage response (DDR) as a novel strategy to improve therapy effect, is currently studied pre-clinically as well as in the clinic. Almost invariably, cervical carcinogenesis involves infection with the human papillomavirus (HPV), which inactivates part of the DNA damage response. This HPV-mediated partial inactivation of the DDR presents therapeutic targeting of the residual DDR as an interesting approach to achieve chemoradio-sensitization for cervical cancer. How the DDR can be most efficiently targeted, however, remains unclear. The fact that cisplatin and radiotherapy activate multiple signaling axes within the DDR further complicates a rational choice of therapeutic targets within the DDR. In this review, we provide an overview of the current preclinical and clinical knowledge about targeting the DDR in cervical cancer. (C) 2015 Elsevier Ltd. All rights reserved.

Recent numerical and analytic work has highlighted some shortcomings in our understanding of the dynamics of H II region expansion, especially at late times, when the H II region approaches pressure equilibrium with the ambient medium. Here we reconsider the idealized case of a constant radiation source in a uniform and spherically symmetric ambient medium, with an isothermal equation of state. A thick-shell solution is developed which captures the stalling of the ionization front and the decay of the leading shock to a weak compression wave as it escapes to large radii. An acoustic approximation is introduced to capture the late-time damped oscillations of the H II region about the stagnation radius. Putting these together, a matched asymptotic equation is derived for the radius of the ionization front which accounts for both the inertia of the expanding shell and the finite temperature of the ambient medium. The solution to this equation is shown to agree very well with the numerical solution at all times, and is superior to all previously published solutions. The matched asymptotic solution can also accurately model the variation of H II region radius for a time-varying radiation source., 8 pages, 5 figures. Authors' original version, revised version with minor changes accepted for publication in MNRAS