Linear Energy Transfer Radiation Research Articles

Biological outcomes of γ-radiation induced DNA damages in breast and lung cancer cells pretreated with free radical scavengers

Purpose: Investigation of effects on DNA of γ-irradiated human cancer cells pretreated with free radical scavengers is aimed to create reference data which would enable assessment of the relative efficiency of high linear energy transfer (LET) radiations used in hadron therapy, i.e. protons and carbon ions.Materials and methods: MCF-7 breast and HTB177 lung cancer cells are irradiated with γ-rays. To minimize indirect effects of irradiation, dimethyl sulfoxide (DMSO) or glycerol are applied as free radical scavengers. Biological response to irradiation is evaluated through clonogenic cell survival, immunocytochemical and cell cycle analysis, as well as expression of proteins involved in DNA damage response.Results: Examined cell lines reveal similar level of radioresistance. Application of scavengers leads to the rise of cell survival and decreases the number of DNA double strand breaks in irradiated cells. Differences in cell cycle and protein expression between the two cell lines are probably caused by different DNA damage repair mechanisms that are activated.Conclusion: The obtained results show that DMSO and glycerol have good scavenging capacity, and may be used to minimize DNA damage induced by free radicals. Therefore, they will be used as the reference for comparison with high LET irradiations, as well as good experimental data suitable for validation of numerical simulations.

Hyperthermia: The Optimal Treatment to Overcome Radiation Resistant Hypoxia.

Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination.

Hyperthermia with photon radiotherapy is thermoradiobiologically analogous to neutrons for tumors without enhanced normal tissue toxicity

The depth dose profiles of photons mirror those of fast neutrons. However, in contrast to the high linear energy transfer (LET) characteristics of neutrons; photons exhibit low LET features. Hyperthermia (HT) inhibits the repair of radiation-induced DNA damage and is cytotoxic to the radioresistant hypoxic tumor cells. Thus, thermoradiobiologically, HT simulates high LET radiation with photons. At temperatures of 39–45 °C, the physiological vasodilation allows rapid heat dissipation from normal tissues. On the contrary, the chaotic and relatively rigid tumor vasculature results in heat retention leading to higher intratumoural temperatures. Consequently, the high LET attributes of HT with photon radiations are mostly limited to the confines of the heated tumor while the normothermic normal tissues would be irradiated with low LET photons. HT thereby augments photon therapy by conferring therapeutic advantages of high LET radiations to the tumors akin to neutrons, while the ‘heat-sink’ effect spares the normal tissues from thermal radiosensitization. Thus, photon thermoradiotherapy imparts radiobiological advantages selectively to tumors analogous to neutrons without exaggerating normal tissue morbidities. The later has been the major concern with clinical fast neutron beam therapy. Outcomes reported from several clinical trials in diverse tumor sites add testimony to the enhanced therapeutic efficacy of photon thermoradiotherapy.

Radiolytic Degradation of Uranyl-Loaded Tributyl Phosphate by High and Low LET Radiation

ABSTRACT Understanding and characterizing the radiolytic degradation of solvents used for treatment of used nuclear fuel is an ongoing topic of research. In the work presented here, degradation constants for the radiolysis of tributyl phosphate (TBP) as a function of various process variables, such as the inclusion of nitric acid and uranyl ions on the TBP, were determined. Degradation constants were determined for both high linear energy transfer (LET) and low LET (gamma) radiation exposure. Results indicate that susceptibility to gamma radiolysis is roughly twice that of high LET and that acid uptake by TBP has little effect on the overall degradation for both high and low LET irradiations. The inclusion of a metal ion affects the degradation of TBP by forming complexes that absorb a portion of the energy deposited by radiation. These TBP–metal complexes break down during irradiation, and the degradation constants for the complex were found to be higher compared to free TBP, for both high and low LET radiations suggesting that the TBP–uranyl complex is more susceptible to radiation than free TBP.

Laser-Generated Au Nanoparticles for Bio-Medical Applications

BackgroundThe present study it is part of the study of the applications of biocompatible nanoparticles in a biological environment. Nowadays, in fact, nanoparticles are making it possible to reach surprising results in the field of biomaterials, drug delivery and their transport in the blood flux, as the use of the contrast medium for medical imaging and to be injected in tumors before to apply radio and thermal therapy. Nanoparticles modify the chemical and physical properties of solids, liquids, and gases and in particular of physiological liquids, soft and hard biological tissues. MethodsThe present article focalizes on the role of Au nanoparticles for biological and medical applications in which their insertion in cells, tissues, and organs may improve the diagnostic imaging contrast with traditional X-ray imaging and the absorbed doses due to radio- and thermal-therapies. Their injection in the tissue, in fact, increases the effective atomic number of the tissue, thus the increment of the electron density of the medium causes higher radiation LET (linear energy transfer) with the increment of released dose and major effects of radiotherapy expositions. Main findingsThe present paper shows the possibility to generate spherical gold nanoparticles with an average diameter of about 5 nm, pure and not agglomerated, biocompatible, stable and without the addition of chemical agents, by laser ablation of gold material in water. The solution can be directly injected in the extracellular liquid of cell cultures or directly in the blood flux of mice to be transported inside the complex living system. Here it is accumulated in specific organs in which the up-take and decay can be measured using suitable images of fluorescence of the organs of the mouse. ConclusionsThe aim of this research is to transport the nanoparticles in places where tissue disease exists and reduce their concentration in healthy tissues. This permit a better observation of the diseased tissues and their preparation as targeting for radio- and thermal-therapy to be applied to damage tumor cells saving healthy tissues.

Using Persistent Homology as a New Approach for Super-Resolution Localization Microscopy Data Analysis and Classification of γH2AX Foci/Clusters.

DNA double strand breaks (DSB) are the most severe damages in chromatin induced by ionizing radiation. In response to such environmentally determined stress situations, cells have developed repair mechanisms. Although many investigations have contributed to a detailed understanding of repair processes, e.g., homologous recombination repair or non-homologous end-joining, the question is not sufficiently answered, how a cell decides to apply a certain repair process at a certain damage site, since all different repair pathways could simultaneously occur in the same cell nucleus. One of the first processes after DSB induction is phosphorylation of the histone variant H2AX to γH2AX in the given surroundings of the damaged locus. Since the spatial organization of chromatin is not random, it may be conclusive that the spatial organization of γH2AX foci is also not random, and rather, contributes to accessibility of special repair proteins to the damaged site, and thus, to the following repair pathway at this given site. The aim of this article is to demonstrate a new approach to analyze repair foci by their topology in order to obtain a cell independent method of categorization. During the last decade, novel super-resolution fluorescence light microscopic techniques have enabled new insights into genome structure and spatial organization on the nano-scale in the order of 10 nm. One of these techniques is single molecule localization microscopy (SMLM) with which the spatial coordinates of single fluorescence molecules can precisely be determined and density and distance distributions can be calculated. This method is an appropriate tool to quantify complex changes of chromatin and to describe repair foci on the single molecule level. Based on the pointillist information obtained by SMLM from specifically labeled heterochromatin and γH2AX foci reflecting the chromatin morphology and repair foci topology, we have developed a new analytical methodology of foci or foci cluster characterization, respectively, by means of persistence homology. This method allows, for the first time, a cell independent comparison of two point distributions (here the point distributions of two γH2AX clusters) with each other of a selected ensample and to give a mathematical measure of their similarity. In order to demonstrate the feasibility of this approach, cells were irradiated by low LET (linear energy transfer) radiation with different doses and the heterochromatin and γH2AX foci were fluorescently labeled by antibodies for SMLM. By means of our new analysis method, we were able to show that the topology of clusters of γH2AX foci can be categorized depending on the distance to heterochromatin. This method opens up new possibilities to categorize spatial organization of point patterns by parameterization of topological similarity.

Morphological Analysis of Amoeboid–Mesenchymal Transition Plasticity After Low and High LET Radiation on Migrating and Invading Pancreatic Cancer Cells

Cell migration and invasion are fundamental components of tumor cell metastasis that represent the biggest threat to the survival and quality of life of cancer patients. There is clear evidence that ionizing radiation can differently modulate migration and invasiveness of cancer cells depending on the cell lines, the doses and the radiation types investigated. This suggests that motile cells are able to adopt different migration strategies according to their molecular characteristics and external signals. In this study, a morphological analysis was performed on pancreatic cancer Aspc-1 cells to evaluate the amoeboid-mesenchymal mobility transition in several experimental conditions considering the role played by factors released by normal and tumor cells, in basal conditions and after low and high Linear Energy Transfer (LET) irradiation. The migratory behavior of Aspc-1 cells is modulated by factors released by normal fibroblasts and tumor cells, and this is in turn modulated by both the radiation dose and the radiation quality.

Abstract 3212: Nuclear-targeted gold nanoparticles as radiosensitizers

Abstract Purpose Intracellular localization of gold nanoparticles has been shown to enhance the effects of radiation. However, few studies have investigated the effect of subcellular localization of these particles on enhancing the radiosensitization effect in cells treated with radiation of varying energies and linear energy transfer (LET) levels. Herein, we evaluate the radiosensitization potential of nuclear-targeted gold nanoparticles across a spectrum of energies and LETs. Methods Gold nanospheres (AuNSs) were functionalized with a nuclear localization sequence (NLS) peptide to enhance the nuclear accumulation of these particles. Internalization of the particles into the cells was achieved using a cell penetrating peptide (CPP). Cellular and nuclear internalization were assessed in Panc-1 human pancreatic adenocarcinoma cancer cells using western blot (WB), transmission electron microscopy, dark field microscopy and inductively-coupled plasma mass spectrometry (ICP-MS). DNA damage due to radiation was evaluated through γH2AX and 53BP1 foci staining. Clonogenic cell survival assay was performed to evaluate the radiosensitization effect after irradiation with 250-kVp X-rays, Cs-137, Co-60, 6 MV and 100 MeV protons (LET 2.5 and 7.7 keV/µm). Results Nuclear-targeted particles (nAuNS) and non-targeted particles (PEGylated, pAuNS) demonstrated similar cellular internalization. However, enhanced uptake of nuclear-targeted particles was observed in the nucleus when compared to non-targeted particles. This was confirmed using dark field microscopy, WB and ICP-MS analysis. DNA double strand breaks through γH2AX and 53BP1 foci staining revealed significantly higher numbers of foci at early (1 hour) and late (24 hour) time points following radiation and nAuNS compared to radiation and pAuNS treatment. Clonogenic cell survival assay revealed significantly higher radiosensitization enhancement factor (REF) at 10% survival fraction for nAuNS compared to pAuNS for all beams assessed. Protons with higher LETs resulted in greater clonogenic cell death and nAuNS further increased radiosensitization whereas pAuNS did not. Conclusion Our data demonstrates that, across a spectrum of radiation energies and LETs, nuclear-targeted gold nanoparticles enhance radiosensitization beyond that achievable with strictly intracytoplasmic gold nanoparticles. Citation Format: Sunil Krishnan, Maureen Aliru. Nuclear-targeted gold nanoparticles as radiosensitizers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3212.

Radiosensitization Effect of Talazoparib, a Parp Inhibitor, on Glioblastoma Stem Cells Exposed to Low and High Linear Energy Transfer Radiation

Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro. Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising.

Histone Deacetylase Inhibitor Induced Radiation Sensitization Effects on Human Cancer Cells after Photon and Hadron Radiation Exposure

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells.

Radiation Measured for Chinese Satellite SJ‐10 Space Mission

AbstractsSpace biological effects are mainly a result of space radiation particles with high linear energy transfer (LET); therefore, accurate measurement of high LET space radiation is vital. The radiation in low Earth orbits is composed mainly of high‐energy galactic cosmic rays (GCRs), solar energetic particles, particles of radiation belts, the South Atlantic Anomaly, and the albedo neutrons and protons scattered from the Earth's atmosphere. CR‐39 plastic nuclear track detectors sensitive to high LET are the best passive detectors to measure space radiation. The LET method that employs CR‐39 can measure all the radiation LET spectra and quantities. CR‐39 detectors can also record the incident directions and coordinates of GCR heavy ions that pass through both CR‐39 and biosamples, and the impact parameter, the distance between the particle's incident point and the seed's spore, can then be determined. The radiation characteristics and impact parameter of GCR heavy ions are especially beneficial for in‐depth research regarding space radiation biological effects. The payload returnable satellite SJ‐10 provided an excellent opportunity to investigate space radiation biological effects with CR‐39 detectors. The space bio‐effects experiment was successfully conducted on board the SJ‐10 satellite. This paper introduces space radiation in low Earth orbits and the LET method in radiation‐related research and presents the results of nuclear tracks and biosamples hitting distributions of GCR heavy ions, the radiation LET spectra, and the quantities measured for the SJ‐10 space mission. The SJ‐10 bio‐experiment indicated that radiation may produce significant bio‐effects.

Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation.

High linear energy transfer (LET) radiation or heavy ion such as carbon ion radiation is used as a method for advanced radiotherapy in the treatment of cancer. It has many advantages over the conventional photon based radiotherapy using Co-60 gamma or high energy X-rays from a Linear Accelerator. However, charged particle therapy is very costly. One way to reduce the cost as well as irradiation effects on normal cells is to reduce the dose of radiation by enhancing the radiation sensitivity through the use of a radiomodulator. PNKP (polynucleotide kinase/phosphatase) is an enzyme which plays important role in the non-homologous end joining (NHEJ) DNA repair pathway. It is expected that inhibition of PNKP activity may enhance the efficacy of the charged particle irradiation in the radioresistant prostate cancer cell line PC-3. To test this hypothesis, we investigated cellular radiosensitivity by clonogenic cell survival assay in PC-3 cells.12Carbon ion beam of62 MeVenergy (equivalent 5.16 MeV/nucleon) and with an entrance LET of 287 kev/μm was used for the present study. Apoptotic parameters such as nuclear fragmentation and caspase-3 activity were measured by DAPI staining, nuclear ladder assay and colorimetric caspase-3method. Cell cycle arrest was determined by FACS analysis. Cell death was enhanced when carbon ion irradiation is combined with PNKPi (PNKP inhibitor) to treat cells as compared to that seen for PNKPi untreated cells. A low concentration (10μM) of PNKPi effectively radiosensitized the PC-3 cells in terms of reduction of dose in achieving the same survival fraction. PC-3 cells underwent significant apoptosis and cell cycle arrest too was enhanced at G2/M phase when carbon ion irradiation was combined with PNKPi treatment. Our findings suggest that combined treatment of carbon ion irradiation and PNKP inhibition could enhance cellular radiosensitivity in a radioresistant prostate cancer cell line PC-3. The synergistic effect of PNKPi and carbon ion irradiation could be used as a promising method for carbon-ion therapy in radioresistant cells.

Processing-Challenges Generated by Clusters of DNA Double-Strand Breaks Underpin Increased Effectiveness of High-LET Radiation and Chromothripsis.

Whereas most endogenous and exogenous DNA damaging agents typically generate lesions that are relatively isolated and can be repaired easily, ionizing radiation (IR) also induces clustered lesions causing DNA double strand breaks (DSBs). Moreover, forms of IR characterized by high linearenergytransfer (LET) induce not only isolated DSBs but also DSB clusters- multiple DSBs in close proximity -that pose increased risks for the cell. DSB clusters can destabilize chromatin locally and compromise processing of individual DSBs within the cluster. Since the discovery of chromothripsis, a phenomenon whereby multiple DSBs locally generated by a catastrophic event causes genomic rearrangements that feed carcinogenesis, DSB clusters receive increased attention also in the field of cancer. While formation of DSB clusters after exposure to high LET is a direct and inherent consequence of the spatial distribution of the constituting energy deposition events, also called track structure, the sources of local genomic shattering underpinning chromothripsis are under investigation. Notably, many consequences of DSB clusters in the affected genome reflect processing by pathways that have evolved to repair DSBs, but which operate with widely different degrees of fidelity. The molecular underpinnings and the basis of the underlying repair pathway choices that ultimately lead to the observed consequences from DSB clusters remain unknown. We developed a tractable model of DSB clustering that allows direct analysis in cells of the consequences of certain configurations of DSB clusters. We outline the rationale for the development of this model and describe its key characteristics. We summarize results suggesting that DSB clusters compromise the first-line DSB-processing pathways of c-NHEJ and HRR, increasing as a consequence the contribution of alt-EJ, which has high propensity of generating chromosomal rearrangements. The results suggest a mechanism for the increased toxicity of high LET radiation and the extensive genomic rearrangements associated with chromothripsis.

Localized hydroxyl radical generation at mmol/L and mol/L levels in water by photon irradiation.

The generation of localized hydroxyl radical (•OH) in aqueous samples by low linear energy transfer irradiation was investigated. Several concentrations of 5,5-dimethyl-1-pyrroline-N-oxid solution (from 0.5 to 1,680 mmol/L) were prepared and irradiated with an identical dose of X-ray or γ-ray. The density of •OH generation in aqueous solution was evaluated by the electron paramagnetic resonance spin-trapping technique using 5,5-dimethyl-1-pyrroline-N-oxid as an electron paramagnetic resonance spin-trapping agent. The relationship between the molecular density of 5,5-dimethyl-1-pyrroline-N-oxid in the samples and the concentration of 5,5-dimethyl-1-pyrroline-N-oxid-OH generated in the irradiated samples was analyzed. Two different characteristic linear trends were observed in the 5,5-dimethyl-1-pyrroline-N-oxid-OH/5,5-dimethyl-1-pyrroline-N-oxid plots, which suggested •OH generation in two fashions, i.e., mmol/L- and mol/L-level local concentrations. The dose, dose rate, and/or the energy of photon irradiation did not affect the shapes of the 5,5-dimethyl-1-pyrroline-N-oxid-OH/5,5-dimethyl-1-pyrroline-N-oxid plots. Moreover, the addition of 5 mmol/L caffeine could cancel the contribution of mmol/L-level •OH generation, leaving a trace of mol/L-level •OH generation. Thus, the localized mmol/L- and mol/L-level generations of •OH, which were independent of experimental parameters such as dose, dose rate, and/or the energy of photon of low linear energy transfer radiation, were established.

Dependence of Immunogenic Modulation of Tumor Cells by Proton Radiation on the Linear Energy Transfer

Radiation therapy has been shown to induce immune-mediated tumor regression by multiple mechanisms. One of the mechanisms is to trigger an immunogenic phenotype characterized by upregulation of cell surface immune co-stimulators, antigen presenting machinery and checkpoint molecules that primes cells for subsequent elimination by cytotoxic T cells. The LET of the proton beam varies with the depth of dose deposition. Prior studies comparing proton radiation to photon radiation have failed to identify a stronger immunogenic phenotype with protons. However, the linear energy transfer (LET) was comparable for both modalities. We asked whether immunogenic phenotype induction would be different with higher LET, one that is typically noted towards the end of the Bragg peak of protons. Murine CT26 colorectal cancer cells were irradiated with 8Gy proton beams at 1.09keV/um (low), 2.58keV/um (medium) and 7.7keV/um (high) LET. 48hours after irradiation the cells were stained for surface expression of OX40L, ICOSL, CD40, CD70, 41BBL (immune co-stimulators), MHC-I, Calreticulin (antigen presenting machinery), ICAM-1 (cell adhesion molecule), PDL-1, CTLA-4 (immune checkpoint molecules) using a multiplexed flow staining panel. The treated cells were also plated on 8 well glass chamber slides and immunofluorescence (IF) staining for 41BBL, OX40L, CD40, MHC-1 and calreticulin was evaluated. Freshly extracted mouse splenocytes were used as biological positive control for both flow cytometry and immunofluorescence. We observed increase in percentage expression of OX40L, CD40, ICAM-1 and MHC-I, and drop in PDL-1 expression in the cells irradiated in the high LET region compared to low LET region of the proton beam as shown in the following table.Abstract 3444Treatment groupsMarker % expressionControl8Gy Low LET8Gy Medium LET8Gy High LETOX40L0.70.2360.6187.79CD4073.1383.292.5596.73MHC-I91.1195.1195.998.62ICAM-13.125.660.9627.42PDL-110.3256.4650.2138.36 Open table in a new tab This data is the average of independent experiments performed under same conditions. The other immune markers did not show statistically significant difference between the low and high LET proton radiation although the expression increased compared to the untreated controls. There was increased expression of 41BBL, OX40L, CD40, Calreticulin and MHC-I in the high LET group compared to low LET on immunofluorescence staining, which was assessed qualitatively. High LET proton radiation can be used to stimulate better immunogenic phenotype in tumor cells compared to low LET proton radiation. This preliminary data will form the foundation for future in vivo testing on animal models, to see if high LET proton therapy improves the local control and elicits a stronger systemic immune response compared to low LET radiation.

Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome

BackgroundSpace travel is associated with continuous low dose rate exposure to high linear energy transfer (LET) radiation. Pathophysiological manifestations after low dose radiation exposure are strongly influenced by non-cytocidal radiation effects, including changes in the microbiome and host gene expression. Although the importance of the gut microbiome in the maintenance of human health is well established, little is known about the role of radiation in altering the microbiome during deep-space travel.ResultsUsing a mouse model for exposure to high LET radiation, we observed substantial changes in the composition and functional potential of the gut microbiome. These were accompanied by changes in the abundance of multiple metabolites, which were related to the enzymatic activity of the predicted metagenome by means of metabolic network modeling. There was a complex dynamic in microbial and metabolic composition at different radiation doses, suggestive of transient, dose-dependent interactions between microbial ecology and signals from the host’s cellular damage repair processes. The observed radiation-induced changes in microbiota diversity and composition were analyzed at the functional level. A constitutive change in activity was found for several pathways dominated by microbiome-specific enzymatic reactions like carbohydrate digestion and absorption and lipopolysaccharide biosynthesis, while the activity in other radiation-responsive pathways like phosphatidylinositol signaling could be linked to dose-dependent changes in the abundance of specific taxa.ConclusionsThe implication of microbiome-mediated pathophysiology after low dose ionizing radiation may be an unappreciated biologic hazard of space travel and deserves experimental validation. This study provides a conceptual and analytical basis of further investigations to increase our understanding of the chronic effects of space radiation on human health, and points to potential new targets for intervention in adverse radiation effects.

Chromatin organization revealed by nanostructure of irradiation induced \u03b3H2AX, 53BP1 and Rad51 foci

The spatial distribution of DSB repair factors γH2AX, 53BP1 and Rad51 in ionizing radiation induced foci (IRIF) in HeLa cells using super resolution STED nanoscopy after low and high linear energy transfer (LET) irradiation was investigated. 53BP1 and γH2AX form IRIF with same mean size of (540 ± 40) nm after high LET irradiation while the size after low LET irradiation is significantly smaller. The IRIF of both repair factors show nanostructures with partial anti-correlation. These structures are related to domains formed within the chromatin territories marked by γH2AX while 53BP1 is mainly situated in the perichromatin region. The nanostructures have a mean size of (129 ± 6) nm and are found to be irrespective of the applied LET and the labelled damage marker. In contrast, Rad51 shows no nanostructure and a mean size of (143 ± 13) nm independent of LET. Although Rad51 is surrounded by 53BP1 it strongly anti-correlates meaning an exclusion of 53BP1 next to DSB when decision for homologous DSB repair happened.

LET Monitoring Using Liquid Ionization Chambers

Relative biological effectiveness (RBE) is an important quantity in planning particle beam cancer therapy. In general, the RBE describes the biological effectiveness of a given primary beam with respect to a reference photon irradiation. RBE varies not only for different primary beams but also with depth in the target for a given beam modality. It is not a quantity that easily lends itself to measurements or computation as it depends on many biological and physical quantities. Numerous experiments in vitro using various cell lines and irradiation modalities have shown that a general relationship between RBE and the physical quantity Linear Energy Transfer (LET) exists. Several groups have proposed including LET in the radiation therapy treatment planning instead of the more complicated and elusive RBE. It has been shown that LET is an important quantity to consider in treating radio-resistant tumors. The concept of LET painting has been proposed with the goal of improving tumor control probability (TCP) for hypoxic tumors by focusing high LET radiation on the hypoxic region of the tumor while restricting the surrounding normal tissue to low LET radiation. In order to properly incorporate LET in clinical treatment, it is important to be able to experimentally measure and verify LET distribution. We propose a novel method for measuring LET using a dual chamber methodology exploiting the difference in the observed recombination between air filled ionization chambers (IC) and liquid filled ionization chambers (LIC). The resulting difference in the measured signals will be used to directly extract the relative LET of an actual treatment beam in real time. This paper describes our initial studies of this method, presents preliminary results, and discusses further improvements toward a practical real-time LET measuring device.

Recent advances in radiation research for human health and environment

The 1st International Conference on Radiation Research: Impact on Human Health and Environment (2016) and First Biennial Meeting of Society for Radiation Research was organized at Bhabha Atomic Research Centre in Mumbai (India). Recent developments in molecular, translational, and clinical radiobiology were discussed among basic and translational scientists as well as clinicians. The meeting has covered the topics ranging from the most recent insight into the paradigm shift from DNA-based radiation health effects (epigenetics), radiation biology from laboratory clinic, radiobiologically relevant redox metabolism, hypoxia, stem cell biology, hyperthermia to advances in dose deposition, and understanding the molecular biological effects of high linear energy transfer (LET) radiation. Mechanism of radiobiological effects of actinides, and the search for novel radiosensitizers, radiation countermeasures, and efficient actinide decorporation agents were discussed for further improvement in cancer radiotherapy, radiation protection, and medical management of internal contamination in humans. This report summarizes the key points of recent observations/results presented in the meeting, and highlights their importance in view of human health and environment. This document would also help in understanding the significance of synergistic interaction among radiation researchers, scientists, clinicians, medical physicists, and radiation environmentalists for harnessing the real potential of radiation/radioactivity for better care of human health and environment.

Hydrogen Emission and Macromolecular Radiation-Induced Defects in Polyethylene Irradiated under an Inert Atmosphere: The Role of Energy Transfers toward trans-Vinylene Unsaturations

This article is aimed at studying the evolution of H2 release as well as radiation-induced defects in polyethylene (PE), as a function of the irradiation dose under anoxic conditions. We analyze the influence of the energy transfers and trapping toward radiation-induced defects on the evolution of the radiation chemical yields with dose. One key objective herein is to quantify the contribution of these transfers toward trans-vinylene (TV) on H2 emission. For this purpose, pure PE was irradiated in a large dose domain and H2 emission was compared to that in predoped PEs containing chemically inserted TV groups irradiated at low doses. In parallel, evolutions of the concentrations of the TV groups and minor defects (vinyl and trans-trans-diene) as a function of dose were considered. Moreover, measuring simultaneously H2 and unsaturated groups had allowed inferring the cross-linking evolution with dose. With this methodology, we have succeeded in quantifying the efficiency of TVs and cross-links as energy traps and, using simple models, in fully describing the evolution of all of the radiation chemical yields. Besides, irradiations were performed using either low linear energy transfer irradiations (electron beams, γ rays) or ion beams, with the objective to assess the influence of the high ionization and excitation densities induced by the latter on PE ageing and energy transfer processes.