Radiation Response Research Articles

Direct Tumor Irradiation Potentiates Adoptive NK Cell Targeting Against Parental and Stemlike Cancer in Human Liver Cancer Models

Radiation therapy (RT) has been shown to effectively induce the expression of intercellular adhesion molecule-1 (ICAM-1), which is recognized by lymphocyte function-associated antigen 1 (LFA-1) expressed on natural killer (NK) cells. However, the potential synergistic antitumor immune response of tumor irradiation and administered NK cells has not been explored in intractable human liver cancers. Furthermore, NK cell targeting against both parental and cancer stemness has never been investigated. Highly activated ex vivo NK cells were administered into the human liver tumor-bearing mice. Tumor direct RT was optimized according to tumor bearing site. HepG2 and Hep3B ICAM-1 knockout cells were generated using CRISPR/CAS9. Stemness tumor spheres were generated. NK cell cytolysis against parental and tumor sphere was evaluated using flow cytometry and real-time cytotoxicity assay. A combination of adoptive NK cell therapy with RT significantly improved therapeutic efficacy over monotherapies against subcutaneous, orthotopic, and metastatic human liver tumor models. Direct tumor irradiation potentiated NK cell recognition and conjugation against liver cancer through the LFA-1/ICAM-1 axis. Suppression of immune synapse formation on NK cells using high-affinity LFA-1 inhibitors or ICAM-1 knockout liver cancer induced "outside-in" signal blocking in NK cells, resulting in failure to eliminate liver tumor despite the combination therapy. NK cells effectively recognized and targeted triple-high epithelial cell adhesion molecule+CD133+CD24+ liver cancer expressing upregulated ICAM-1 in the irradiated tumor microenvironment, which led to prevention of the initiation of metastasis, improving survival in a metastatic model. In addition, the LFA-1/ICAM-1 axis interruption between NK cells and stemness liver tumor spheres significantly diminished NK cell cytolysis. Consistent with our preclinical data, the LFA-1/ICAM-1 axis correlated with survival outcomes in patients with metastatic cancer from the The Cancer Genome Atlas databases. NK cells in combination with tumor irradiation can provide synergistic therapeutic effects for NK cell recognition and elimination against both parental and stemlike liver cancer through LFA-1/ICAM-1.

Determination of Uniformity Value Response and Calibration Factors TLD Chips Using GAMMA Sources

The response of the Thermoluminescence Dosimeter (TLD) varies from one type of TLD to another depending on the material, thickness, holder, filter/absorber on each chip, type of radiation, energy and direction of radiation. This research was conducted to determine the uniformity value of the TLD chip response and to determine the calibration factor of the TLD chip using a gamma radiation source. The TLD response must be known so that the measurement results are accurate. TLD-100 irradiation in this study used a radiation source Cesium – 137. TLD used as many as 150 pieces with a large irradiation dose of 5 mSv. The irradiated TLD-100 response resulted in a standard deviation of 1% to 5% with each response corresponding to its standard deviation value. The results of the irradiation in this study the value of the calibration factor obtained for the standard deviation values of 1%, 2%, 3%, 4%, and 5% which ranged between 0,121 mSv/nC – 0,206 mSv/nC. With a large uniformity of variation in the range of 2,25% - 14%.

The role of hypoxia and radiation in developing a CTCs-like phenotype in murine osteosarcoma cells.

Introduction: Cancer treatment has evolved significantly, yet concerns about tumor recurrence and metastasis persist. Within the dynamic tumor microenvironment, a subpopulation of mesenchymal tumor cells, known as Circulating Cancer Stem Cells (CCSCs), express markers like CD133, TrkB, and CD47, making them radioresistant and pivotal to metastasis. Hypoxia intensifies their stemness, complicating their identification in the bloodstream. This study investigates the interplay of acute and chronic hypoxia and radiation exposure in selecting and characterizing cells with a CCSC-like phenotype. Methods: LM8 murine osteosarcoma cells were cultured and subjected to normoxic (21% O2) and hypoxic (1% O2) conditions. We employed Sphere Formation and Migration Assays, Western Blot analysis, CD133 Cell Sorting, and CD133+ Fluorescent Activated Cell Sorting (FACS) analysis with a focus on TrkB antibody to assess the effects of acute and chronic hypoxia, along with radiation exposure. Results: Our findings demonstrate that the combination of radiation and acute hypoxia enhances stemness, while chronic hypoxia imparts a cancer stem-like phenotype in murine osteosarcoma cells, marked by increased migration and upregulation of CCSC markers, particularly TrkB and CD47. These insights offer a comprehensive understanding of the interactions between radiation, hypoxia, and cellular responses in the context of cancer treatment. Discussion: This study elucidates the complex interplay among radiation, hypoxia, and cellular responses, offering valuable insights into the intricacies and potential advancements in cancer treatment.

Radiation Response of Perfluorinated Polymer Optical Fibers (CYTOP) to Low Doses of X-Rays, Protons, and Neutrons

Radiation Response of Perfluorinated Polymer Optical Fibers (CYTOP) to Low Doses of X-Rays, Protons, and Neutrons

Development of an interatomic potential for L12 precipitates in Fe–Ni–Al alloys

Fe–Ni-based alloys have been considered as candidate structural materials for advanced nuclear reactors, and some of their excellent properties are particularly associated with L12 precipitates dispersed in the alloys. For a better understanding of the irradiation response, classical molecular dynamics is an essential tool to simulate the irradiation-induced defect formation and subsequent microstructural evolution. We here develop an interatomic potential for L12(Ni,Fe)3Al precipitates in the ternary Fe–Ni–Al system. The fitting parameters are tuned to describe the lattice and elastic constants of NiFe solid solutions and defect formation/vacancy migration energies in the fcc matrix. Furthermore, the lattice properties and defect energies of L12(Ni,Fe)3Al are considered for the fitting. We demonstrate the developed potential reproduces the lattice and defect properties with reasonable accuracy by comparison with density functional theory calculations, existing empirical potentials, and experimental data. This potential will be useful to investigate the defect formation and evolution of (Ni,Fe)3Al precipitates in the alloys under irradiation, which would provide critical insights into the materials design strategy to achieve enhanced properties.

Influence of Peptide Bioregulators on Indicators of Hemostasis in Blood of Irradiated Experimental Animals at Low Altitude Conditions

In modern biology and medicine, much attention is paid to the study of the hemostasis regulation of some cell populations by substances of a peptide nature. They have the ability to regulate the functional and proliferative activity of cells and ensure communication in normal and pathological conditions. Research data showed that significant violations of the hemostatic system also occur with radiation damage to the body. One of the first radiation responses involves the coagulation cascade's activation, which leads to the breakdown of fibrinogen and the formation of fibrin clots. The potential threat of this is quite evident due to the existence of uranium mining tailings in several regions of the Kyrgyz Republic. Considering that significant disturbances of the hemostatic system occur during radiation damage to the body, and effective means are clearly not enough, the study of the effect of bioregulatory peptides in these conditions is of great importance. In the study, we carried out the total X-ray irradiation of laboratory animals on the X-ray therapeutic apparatus RUM-17. Peptide bioregulators peptide-1 and peptide-2 were administered intramuscularly to irradiated animals. Throughout the research, we used methods characterizing all links of hemostasis: vascular-platelet hemostasis, coagulation hemostasis, and fibrinolysis. The study has shown that the use of the peptide bioregulators in the background of acute radiation pathology leads to a decrease in the intensity of the chronic course of post-radiation thrombo hemorrhagic syndrome, contributing to an increase in the content of antithrombin III in the blood and modulating the versatile effects of endogenous heparin, which undoubtedly have a beneficial effect on the pathogenesis of radiation sickness.

RBIO-09. HMGB2 INHIBITION RADIO-SENSITIZES GLIOBLASTOMA CELLS INDEPENDENTLY OF THEIR TP53-MUTATION STATUS

Abstract Alterations in TP53 are major drivers of radiation resistance in gliomas. High Mobility Group Box 2 (HMGB2) has been implicated in resistance to temozolomide through p53-phosphorylation during DNA double-strand break repair and in silico analysis suggests its involvement in the p53-p21-RB signaling pathway. Nevertheless, the role of HMGB2 in radiation response has not been fully explored in gliomas. While HMGB2 is virtually not expressed in the normal adult brain, increasing expression with histopathological glioma grade correlates with poor patient survival. We confirmed increased HMGB2 expression in grade 3 compared to grade 2 gliomas using ClariomD and observed spatial heterogeneous HMGB2 expression in glioblastomas (GBMs) in histopathology-targeted supervised proteomic analysis employing liquid chromatography tandem mass spectroscopy (LC-MS-MS). Here, we aimed to study HMGB2 effects in cell proliferation and response to radiation in a set of molecularly distinct genetically engineered GBM cell lines (IDHwt). Using an established U87 GBM cell line and isogenic primary GBM cell lines GBM3359 TP53wt and CRISPR/Cas9-engineered mutant TP53 (R248W) generated in our laboratory, we successfully produced clones with either HMGB2 shRNA knockdown (KD – over 70% reduction) or HMGB2 lentiviral-mediated overexpression (OE – 3-76x higher expression). HMGB2-KD reduced cell proliferation (10% in U87; 20-25% in isogenic GBM3359 cell lines) and colony formation (more than 50% reduction), which was further rescued with HMGB2 OE in all cell lines. Half maximal inhibitory concentration (IC50) for radiation was determined by methylene blue cell proliferation and clonogenic assays, which showed that HMGB2-KD decreased the IC50 while rescued HMGB2 OE increased RT resistance of all clones. Taken together, our data suggest that HMGB2 inhibition may improve radiation response independently of TP53 status in gliomas. Further mechanistic studies to elucidate the relationship between HMGB2 and TP53 are underway to unfold the contribution of heightened HMGB2 expression to radiation resistance mechanisms in gliomas.

Radiation response properties of Ce-doped CaF2 transparent ceramics

We report on the luminescence properties of CaF2 transparent ceramics having various concentrations of CeF3 (0.1 %, 0.5 %, and 1 %). Scintillation emissions centered at approximately 318, 345, and 386 nm derived from the 5d→4f transition of Ce3+ were detected, and scintillation light yields were determined to be 8600 photons/MeV (0.1 % CeF3), 1930 photons/MeV (0.5 % CeF3), and 1850 photons/MeV (1 % CeF3) under gamma-ray irradiation from 241Am. The Ce-doped CaF2 transparent ceramics showed thermally stimulated luminescence (TSL) with a broad glow peak at around 115–145 °C, and their dose response curves were determined over a broad dose range (0.01–3 mGy). Moreover, optically stimulated luminescence (OSL) exponential decay curves were obtained under 500 nm stimulation light, and dose response curves were obtained in the dose range of 0.1–100 mGy. The minimum detectable dose was estimated to be 0.1 mGy. A direct correlation between scintillation light yields under gamma-ray irradiation and TSL/OSL intensities was demonstrated.

RADT-28. DISRUPTION OF BIOENERGETICS ENHANCES RADIO-SENSITIVITY OF PATIENT-DERIVED GLIOBLASTOMA TUMORSPHERES

Abstract INTRODUCTION Glioblastoma (GBM), the most common primary brain tumor, has been associated with poor prognosis despite various treatment modalities, the surgical resection accompanied by chemotherapy and radiotherapy. Although the importance of radiotherapy is well known, its combination with bioenergetics regulators has not been established in clinical practice. Here, we hypothesized that bioenergetics regulators improve the radio-sensitivity of GBM-tumorspheres (TS). METHODS Gene expression profiles of GBM patient-derived TSs were obtained from microarray. In vitro efficacies of the treatment were evaluated using clonogenic assay, 3D invasion assay, neurosphere-formation assay, and apoptosis-analysis. Protein expression was evaluated by western blot, and immunofluorescence was performed for detection of γH2AX foci. In vivo efficacies were confirmed using a mouse orthotopic-xenograft model. RESULTS GBM TSs with high-radioresistant or low-radioresistant were selected according to expression levels of radiation response associated genes. In order to select the bioenergetics regulators that significantly increased the radiotherapy effect of GBM-TSs, five bioenergetics regulators were combined which are oxidative-phosphorylation (OxPhos) inhibitor (IM156A), aldehyde-dehydrogenase inhibitor (gossypol) + OxPhos inhibitor (phenformin), fatty acid oxidation inhibitor (etomoxir), pentose-phosphate pathway inhibitor (dehydroepiandrosterone; DHEA) and glycolysis inhibitor (2-deoxy-D-glucose; 2DG). Amongst of these five bioenergetics regulators, DHEA and 2DG significantly augmented the therapeutic efficacies of ionizing radiation (IR) by reducing the survival fraction, stemness, and invasiveness in both high-radioresistant and low-radioresistant GBM TSs. IR combined with bioenergetics regulators (DHEA or 2DG) induced DNA damage response and apoptosis in low-radioresistant GBM TSs. In vivo experiments using a mouse orthotopic-xenograft model confirmed the tendency to prolong survival period and reduced the size in tumor after the combined treatment of 2DG with IR in low-radioresistant GBM TS. CONCLUSION These data proposes that the combination of bioenergetics regulators and radiotherapy is more effective than IR monotherapy itself. We expect that this combination regimen can strategically establish as a future treatment practice of GBM.

DDDR-26. INHIBITION OF RAD52 ACTIVITY ENHANCES THE RADIOSENSITIVITY IN DIPG

Abstract Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating childhood cancers that limited response to radiation therapy, resulting in median overall survival of approximately 10 months. There is a critical need for new therapeutics that enhance the radiation effect while enabling the use of lower doses of radiation to limit long-term side effects in young patients. We, therefore, tested the hypothesis that targeting RAD52 activity sensitizes the radiation response of DIPG. Genome-wide CRISPR/Cas9 screening identified RAD52 as potential therapeutic target in DIPG cells. RAD52 inhibition, using shRNA mediated RAD52 depletion and treatment with RAD52 inhibitor, D-I03, suppressed DIPG cell proliferation. Importantly, RAD52 inhibition in combination with radiation therapy further increased radiosensitivity of DIPG cells. Immunocytochemistry of DNA double-strand breaks (DSB) marker γH2AX and repair marker 53BP1 showed that RAD52 inhibition sustained DNA damage with high levels of γH2AX at 24 hours following radiation while the level of 53BPI was decreased, thereby inhibiting DNA DSB repair. Western blotting also revealed that RAD52 inhibition causes a sustained level of phosphorylated Rad50 and γH2AX in irradiated DIPG cells. DNA repair assay showed that RAD52 inhibition suppressed DNA DSB repair through a homologous recombination pathway. RNA sequencing showed that RAD52 inhibition downregulated genes associated with the DNA repair pathway. Finally, the combination therapy of D-I03 RAD52 inhibitor and radiation inhibited tumor growth and significantly increased survival of mice bearing DIPG patient-derived xenografts, outperforming either monotherapy. Together, these results highlight RAD52 inhibitor as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

Simulating tumor volume dynamics in response to radiotherapy: Implications of model selection

From the beginning of the usage of radiotherapy (RT) for cancer treatment, mathematical modeling has been integral to understanding radiobiology and for designing treatment approaches and schedules. There has been extensive modeling of response to RT with the inclusion of various degrees of biological complexity. In this study, we compare three models of tumor volume dynamics: (1) exponential growth with RT directly reducing tumor volume, (2) logistic growth with direct tumor volume reduction, and (3) logistic growth with RT reducing the tumor carrying capacity with the objective of understanding the implications of model selection and informing the process of model calibration and parameterization. For all three models, we: examined the rates of change in tumor volume during and RT treatment course; performed parameter sensitivity and identifiability analyses; and investigated the impact of the parameter sensitivity on the tumor volume trajectories. In examining the tumor volume dynamics trends, we coined a new metric – the point of maximum reduction of tumor volume (MRV) – to quantify the magnitude and timing of the expected largest impact of RT during a treatment course. We found distinct timing differences in MRV, dependent on model selection. The parameter identifiability and sensitivity analyses revealed the interdependence of the different model parameters and that it is only possible to independently identify tumor growth and radiation response parameters if the underlying tumor growth rate is sufficiently large. Ultimately, the results of these analyses help us to better understand the implications of model selection while simultaneously generating falsifiable hypotheses about MRV timing that can be tested on longitudinal measurements of tumor volume from pre-clinical or clinical data with high acquisition frequency. Although, our study only compares three particular models, the results demonstrate that caution is necessary in selecting models of response to RT, given the artifacts imposed by each model.

Overview of DISCOVER22 experiment in the framework of INFN-LNGS Cosmic Silence activity: challenges and improvements in underground radiobiology

One of the most intriguing and still pending questions in radiobiology is to understand whether and how natural environmental background radiation has shaped Life over millions of years of evolution on Earth. Deep Underground Laboratories (DULs) represent the ideal below-background exposure facilities where to address such a question. Among the few worldwide DULs, INFN-Laboratorio Nazionale del Gran Sasso (LNGS) is one of the largest in terms of size and infrastructure. Designed and built to host neutrino and dark matter experiments, since the 1990 s the LNGS has been one of the first DULs to systematically host radiobiology experiments. Here we present the DISCOVER22 (DNA Damage and Immune System Cooperation in VEry low Radiation environment 2022) experiment recently started at LNGS. DISCOVER22 aims at investigating how the low radiation background modulates the Immune System (IS) response in in vitro and in vivo models. Underground radiobiology experiments are particularly complex and tricky to design and perform. In these studies, the accurate characterization of exposure scenarios is mandatory, but a challenging aspect is to understand how the very few ionizing tracks in the ultra-Low Radiation Environment (LRE) interact with the living matter in space and time in order to trigger different biological responses. In this Perspective, we describe these challenges and how we address them through a microdosimetric and a radiobiological approaches. We aim at linking physical microdosimetric measurements and the corresponding biological radiation responses by using radiation biophysical models that could shed light on many as yet unresolved questions.

RBIO-08. GTP SIGNALING LINKS ALTERED METABOLISM, DNA REPAIR AND TREATMENT RESISTANCE IN GLIOBLASTOMA

Abstract OBJECTIVE We sought to define the mechanisms by which purines regulate DNA repair and therapy response. METHODS Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after radiation (RT) and antibodies generated against novel sites. Animal models of glioblastoma (GBM) and normal tissues were used to assess DNA repair and treatment responses in vivo. RESULTS Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT by inhibiting the activity of non-homologous end joining, but not homologous recombination. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced double-strand break (DSB) repair, and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to G protein Rac1. Expression of constitutively active Rac1 promoted but dominant negative Rac1 blocked the dephosphorylation of Abi-1 (S323) and DSB repair. Knock-down or inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. In GBM PDX samples, p-Abi-1 (S323) levels negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibiting Rac1 enhanced RT responses and suppressed Abi-1 (S323) dephosphorylation. Abi-1 knockout enhanced efficacy of genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in non-malignant cells and protected mice from RT-mediated gastrointestinal injury and bleomycin-induced pulmonary fibrosis. CONCLUSION The GTP-Rac1-PP5-Abi-1 signaling axis links metabolism and DNA repair. Disrupting this pathway can overcome GBM resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues.

Comparative of HPHT and CVD diamond: performance and defect analysis for alpha radiation detector

Currently, the high-purity single crystal diamond preparation is still a challenging task, which restricts the application of diamond in electronics. In this paper, the chemical vapor deposition (CVD) IIa type single crystal diamond was prepared on the IIa type high pressure high temperature (HPHT) substrate by combining the chamber design with the plasma purifying technology, and the performance of diamond detectors using both IIa type single crystal diamonds were compared based on the defect analysis. The dislocations in diamonds were directly observed by synchrotron radiation X-ray white-beam topography. The CVD diamond shows the comparatively low dislocation density resulting from the high-quality HPHT diamond substrate. No observable NV impurity could be found in photoluminescence (PL) spectrum. The trace impurity of substitutional nitrogen (Ns) was characterized by electron paramagnetic resonance (EPR). It shows the very low concentration in the CVD diamond (2.1 ppb) compared with the several tens ppb in HPHT diamond. This value is comparable with the electronic-grade diamond reported by Element Six. Furthermore, both of the HPHT and CVD single crystal diamonds were packaged as the α-particle radiation detectors with the typical sandwich structure and used Ni/Al (50 nm/500 nm) as metal electrodes. The energy resolution of HPHT and CVD diamond detectors were 2.04% and 0.86%, respectively. Based on Schottky contact and defect regulation, at 0 voltage, the CVD diamond detector achieved response of α-particle radiation and the charge collection efficiency (CCE) was 10.76%. Under positive voltage, the CCE of HPHT and CVD diamond detectors were 38.11% and 86.65%, respectively. The deep level trapping effect of Ns impurities on charge carriers resulted in low CCE of HPHT diamond detector. The spatial polarization effect caused by defects leaded to the formation of an internal electric field, which was the main reason affecting the transport of charge carriers in CVD diamond.

Response of ZrC to swift heavy ion irradiation

Zirconium carbide (ZrC) is commonly used for energy sector research, as well as a surrogate for the proposed advanced nuclear fuel candidate uranium carbide. This study investigates structural modifications to nanocrystalline and microcrystalline ZrC resulting from dense electronic excitations induced by swift heavy ion exposure. Samples were irradiated with 946 MeV Au ions to various fluences up to 6 × 1013 ions cm−2 and characterized using synchrotron-based x-ray diffraction. The evolution of the unit-cell parameter and heterogeneous microstrain were evaluated as a function of fluence and compared with those of nanocrystalline and microcrystalline CeO2 (a surrogate for UO2 fuel) irradiated under identical conditions. Distinct differences were observed in the radiation responses of the carbide and oxide across both grain sizes. Most notably, microcrystalline ZrC exhibits swelling characterized by two distinct regimes, which does not result in saturation at the ion fluences achieved. This contrasts with CeO2, which exhibits the well-documented direct-impact defect accumulation mechanism, reaching a steady-state saturation of swelling at higher fluences. Nanocrystalline CeO2 undergoes more pronounced swelling compared with microcrystalline CeO2, in contrast to nanocrystalline ZrC, which exhibits only minimal unit-cell changes. These results demonstrate that swift heavy ion-induced structural changes can be quite different in carbides and oxides, which must be considered when extrapolating fission-fragment type damage in current fuels to advanced fuels.

Expression of ZNF281 in colorectal cancer correlates with response to radiotherapy and survival

Background The treatment of Colorectal cancer (CRC) is extremely complex and survival rates vary depending on the stage of the disease at the time of diagnosis. Neoadjuvant chemoradiotherapy (NACRT), is the conventional treatment for locally advanced rectal cancer (LARC); however, the resistance to chemoradiotherapy in LARC is difficult to predict. Materials and methods In this study, clinical data of 126 LARC patients were collected and analyzed, and relevant validation was performed using GEO database and in vitro and in vivo experiments, including Western blotting and Real-time quantitative PCR, immunohistochemistry, immunofluorescence, clonogenic cell survival assays, and nude-mouse xenograft models. Results In patients with LARC who were treated with neoadjuvant radiotherapy (NART), higher ZNF281 expression in malignant tissue was associated with a poorer prognosis and lesser degree of tumor regression. Cell and mouse experiments have shown that ZNF281 reduces the damage caused by X-rays to CRC cells and tumors grown in mice. Conclusion We found that the expression of ZNF281 predicted the radiation response of CRC cells and suggested the prognosis of patients with LARC who received neoadjuvant radiation therapy.

Moving the Needle Forward in Genomically-Guided Precision Radiation Treatment.

Radiation treatment (RT) is a mainstay treatment for many types of cancer. Recommendations for RT and the radiation plan are individualized to each patient, taking into consideration the patient's tumor pathology, staging, anatomy, and other clinical characteristics. Information on germline mutations and somatic tumor mutations is at present rarely used to guide specific clinical decisions in RT. Many genes, such as ATM, and BRCA1/2, have been identified in the laboratory to confer radiation sensitivity. However, our understanding of the clinical significance of mutations in these genes remains limited and, as individual mutations in such genes can be rare, their impact on tumor response and toxicity remains unclear. Current guidelines, including those from the National Comprehensive Cancer Network (NCCN), provide limited guidance on how genetic results should be integrated into RT recommendations. With an increasing understanding of the molecular underpinning of radiation response, genomically-guided RT can inform decisions surrounding RT dose, volume, concurrent therapies, and even omission to further improve oncologic outcomes and reduce risks of toxicities. Here, we review existing evidence from laboratory, pre-clinical, and clinical studies with regard to how genetic alterations may affect radiosensitivity. We also summarize recent data from clinical trials and explore potential future directions to utilize genetic data to support clinical decision-making in developing a pathway toward personalized RT.

Influence of high fluence heavy ion irradiation on the performance of single crystal diamond detectors

Radiation detectors based on diamond are highly favored for particle physics research due to their superior radiation hardness. In this work, the performance of single crystal diamond detectors under high fluence heavy ion radiation has been investigated. After irradiation by Fe13+ and Xe20+ ion beams with a high particle fluence of 1.2 × 1015 cm-2, the properties of unirradiated and irradiated intrinsic single crystal chemical vapor deposition (CVD) diamond detectors are compared by means of the spectroscopic energy resolution, charge collection efficiency (CCE), mobility-lifetime (μτ) product and time response using a 241Am alpha (α) particle source. The experimental results of the unirradiated sample with respect to I-V dark current levels, showed an ohmic behaviour of the Al and Cr/Au contact, CCE of 100%, fast response with a rise time of 750 ps and a fall time of 600 ps as well as drift velocities of 6.67 × 104 m/s and 4.72 × 104 m/s for holes and electrons respectively. In the case of the irradiated samples, the CCE, μτ product and time response pulse amplitude of holes and electrons were all degraded, indicating that high density trappings for both kinds of carriers were created under the diamond crystal surface and the trapping probability of holes and electrons was equal, which was different from the previous reports in the literature where only higher trapping probability of holes were observed under heavy ions irradiation. In particular, the spectroscopic performance as well as μτ product of holes and electrons in Fe13+ irradiated sample decreased more than those in Xe20+ irradiated sample, which implied that the recombination of electrons and holes increased in Fe13+ irradiated sample with greater penetration depth than that in Xe20+ irradiated sample when radiation fluence was up to 1015 cm-2, despite the lower density of lattice vacancies in Fe13+ irradiated sample. Moreover, the rise time of holes was slightly different, but the drift velocity was basically the same as that of the unirradiated sample, and so was that of the electrons. Anyway, the presented results showed that the diamond detectors irradiated by heavy ions at a high fluence of 1015 cm-2 still retained their good spectroscopic and very fast time response properties.

Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer.

There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of patients with MIBC homogeneously treated with TMT. Pretreatment tumors from 76 patients with MIBC underwent whole-exome sequencing; 67 underwent matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation. With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS [HR, 0.15; 95% confidence interval (CI), 0.06-0.37; P = 0.030] and improved BI-EFS, an endpoint that includes all-cause mortality (HR, 0.33; 95% CI, 0.15-0.68; P = 0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wild-type cells. Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts.

Suppressed grain growth and enhanced irradiation resistance of nano-grained waste form under electronic energy loss

The effects of both nuclear energy loss and electronic energy loss need to be taken into consideration in the ceramic-based waste forms under repository environment. However, the irradiation responses of ceramic-based waste forms to each type of energy loss are somewhat different. In this study, the microstructure evolutions of ultrafine nano and micro Gd2Zr2O7-based waste forms were systematically studied under predominant electronic energy loss simulated by multi-energy He+ irradiation, and compared to those under predominant nuclear energy loss. The results reveal that the fewer He bubble chains, ribbon-like He bubbles and smaller microcracks were observed in the irradiated nano-grained sample. Additionally, nano-grained sample displayed a lower degree of amorphization and higher atomic order compared to micro-grained samples when subjected to predominant electronic energy loss. Moreover, the irradiation dominated by nuclear energy loss can easily induce the grain growth of nano-grained Gd2Zr2O7-based waste form, but in the present study this phenomenon was not observed under multi-energy He+ irradiation. Consequently, under predominant electronic energy loss, the thermodynamic instability and driving force for grain growth due to excess surface energy in the ultrafine nano sample can be suppressed. As a result, the sample demonstrated enhanced irradiation resistance due to the more efficient absorption and elimination of defects at grain boundaries induced by electronic excitation. We elucidated that enhanced irradiation resistance of the waste forms by tailoring the grain size requires the consideration of the effects of electronic energy loss and nuclear energy loss, which can provide guidance for the design and optimization of highly irradiation-resistant nuclear waste forms.