Proton and alpha radiation-induced mutational profiles in human cells

Ionizing radiation is known to be DNA damaging and mutagenic, however less is known about which mutational footprints result from exposures of human cells to different types of radiation. We were interested in the mutagenic effects of particle radiation exposures on genomes of various human cell types, in order to gauge the genotoxic risks of galactic cosmic radiation, and of certain types of tumor radiotherapy. To this end, we exposed cultured cell lines from the human blood, breast and lung to fractionated proton and alpha particle (helium nuclei) beams at doses sufficient to considerably affect cell viability. Whole-genome sequencing revealed that mutation rates were not overall markedly increased upon proton and alpha exposures. However, there were modest changes in mutation spectra and distributions, such as the increases in clustered mutations and of certain types of indels and structural variants. The spectrum of mutagenic effects of particle beams may be cell-type and/or genetic background specific. Overall, the mutational effects of repeated exposures to proton and alpha radiation on human cells in culture appear subtle, however further work is warranted to understand effects of long-term exposures on various human tissues.© 2023. The Author(s)

Spectroscopic properties and radiation damage investigation of a diamond based Schottky diode for ion-beam therapy microdosimetry

In this work, a detailed analysis of the properties of a novel microdosimeter based on a synthetic single crystal diamond is reported. Focused ion microbeams were used to investigate the device spectropscopic properties as well as the induced radiation damageeffects. A diamond based Schottky diode was fabricated by chemical vapor deposition with a very thin detecting region, about 400 nm thick (approximately 1.4 μm water equivalent thickness), corresponding to the typical size in microdosimetric measurements. A 200 × 200 μm2 square metallic contact was patterned on the diamond surface by standard photolithography to define the sensitive area. Experimental measurements were carried out at the Ruder Boškovic′ Institute microbeam facility using 4 MeV carbon and 5 MeV silicon ions. Ion beam induced charge maps were employed to characterize the microdosimeter response in terms of its charge collection properties. A stable response with no evidence of polarization or memory effects was observed up to the maximum investigated ion beam flux of about 1.7 × 109 ions·cm−2·s−1. A homogeneity of the response about 6% was found over the sensitive region with a well-defined confinement of the response within the active area. Tests of the radiation damageeffect were performed by selectively irradiating small areas of the device with different ion fluences, up to about 1012 ions/cm2. An exponential decrease of the charge collection efficiency was observed with a characteristic decay constant of about 4.8 MGy and 1 MGy for C and Si ions, respectively. The experimental data were analyzed by means of GEANT4 Monte Carlo simulations. A direct correlation between the diamond damaging effect and the Non Ionizing Energy Loss (NIEL) fraction was found. In particular, an exponential decay of the charge collection efficiency with an exponential decay as a function of NIEL is observed, with a characteristic constant of about 9.3 kGy-NIEL for both carbon and silicon ions

An ultra-thin diamond membrane as a transmission particle detector and vacuum window for external microbeams

Several applications of external microbeam techniques demand a very accurate and controlled dose delivery. To satisfy these requirements when post-sample ion detection is not feasible, we constructed a transmission single-ion detector based on an ultra-thin diamond membrane. The negligible intrinsic noise provides an excellent signal-to-noise ratio and enables a hit-detection efficiency of close to 100%, even for energetic protons, while the small thickness of the membrane limits beam spreading. Moreover, because of the superb mechanical stiffness of diamond, this membrane can simultaneously serve as a vacuum window and allow the extraction of an ion microbeam into the atmosphere

Measurement and modelling of anomalous polarity pulses in a multi-electrode diamond detector

In multi-electrode detectors, the motion of excess carriers generated by ionizing radiation induces charge pulses at the electrodes, whose intensities and polarities depend on the geometrical, electrostatic and carriers transport properties of the device. The resulting charge sharing effects may lead to bipolar currents, pulse height defects and anomalous polarity signals affecting the response of the device to ionizing radiation. This latter effect has recently attracted attention in commonly used detector materials, but different interpretations have been suggested, depending on the material, the geometry of the device and the nature of the ionizing radiation. In this letter, we report on the investigation in the formation of anomalous polarity pulses in a multi-electrode diamond detector with buried graphitic electrodes. In particular, we propose a purely electrostatic model based on the Shockley-Ramo-Gunn theory, providing a satisfactory description of anomalous pulses observed in charge collection efficiency maps measured by means of Ion Beam Induced Charge (IBIC) microscopy, and suitable for a general application in multi-electrode devices and detectors.Comment: 8 pages, 4 figure

Commissioning of an ultra-high dose rate pulsed electron beam medical LINAC for FLASH RT preclinical animal experiments and future clinical human protocols.

To present the acceptance and the commissioning, to define the reference dose, and to prepare the reference data for a quality assessment (QA) program of an ultra-high dose rate (UHDR) electron device in order to validate it for preclinical animal FLASH radiotherapy (FLASH RT) experiments and for FLASH RT clinical human protocols. The Mobetron <sup>®</sup> device was evaluated with electron beams of 9 MeV in conventional (CONV) mode and of 6 and 9 MeV in UHDR mode (nominal energy). The acceptance was performed according to the acceptance protocol of the company. The commissioning consisted of determining the short- and long-term stability of the device, the measurement of percent depth dose curves (PDDs) and profiles at two different positions (with two different dose per pulse regimen) and for different collimator sizes, and the evaluation of the variability of these parameters when changing the pulse width and pulse repetition frequency. Measurements were performed using a redundant and validated dosimetric strategy with alanine and radiochromic films, as well as Advanced Markus ionization chamber for some measurements. The acceptance tests were all within the tolerances of the company's acceptance protocol. The linearity with pulse width was within 1.5% in all cases. The pulse repetition frequency did not affect the delivered dose more than 2% in all cases but 90 Hz, for which the larger difference was 3.8%. The reference dosimetry showed a good agreement within the alanine and films with variations of 2.2% or less. The short-term (resp. long-term) stability was less than 1.0% (resp. 1.8%) and was the same in both CONV and UHDR modes. PDDs, profiles, and reference dosimetry were measured at two positions, providing data for two specific dose rates (about 9 Gy/pulse and 3 Gy/pulse). Maximal beam size was 4 and 6 cm at 90% isodose in the two positions tested. There was no difference between CONV and UHDR mode in the beam characteristics tested. The device is commissioned for FLASH RT preclinical biological experiments as well as FLASH RT clinical human protocols

Localized holes and delocalized electrons in photoexcited inorganic perovskites: Watching each atomic actor by picosecond X-ray absorption spectroscopy

We report on an element-selective study of the fate of charge carriers in photoexcited inorganic CsPbBr3 and CsPb(ClBr)3 perovskite nanocrystals (NCs) in toluene solutions using time-resolved X-ray absorption spectroscopy with 80 ps time resolution. Probing the Br K-edge, the Pb L3-edge and the Cs L2-edge, we find that holes in the valence band are localized at Br atoms, forming small polarons, while electrons appear as delocalized in the conduction band. No signature of either electronic or structural changes are observed at the Cs L2-edge. The results at the Br and Pb edges suggest the existence of a weakly localized exciton, while the absence of signatures at the Cs edge indicates that the Cs+ cation plays no role in the charge transport, at least beyond 80 ps. These results can explain the rather modest charge carrier mobilities in these materials.Comment: 19 pages, 3 figure

Charge multiplication effect in thin diamond films

Herein, we report on the enhanced sensitivity for the detection of charged particles in single crystal chemical vapour deposition (scCVD) diamond radiation detectors. The experimental results demonstrate charge multiplication in thin planar diamond membrane detectors, upon impact of 18MeV O ions, under high electric field conditions. Avalanche multiplication is widely exploited in devices such as avalanche photo diodes, but has never before been reproducibly observed in intrinsic CVD diamond. Because enhanced sensitivity for charged particle detection is obtained for short charge drift lengths without dark counts, this effect could be further exploited in the development of sensors based on avalanche multiplication and radiation detectors with extreme radiation hardnes

Antitumor Effect by Either FLASH or Conventional Dose Rate Irradiation Involves Equivalent Immune Responses.

The capability of ultrahigh dose rate FLASH radiation therapy to generate the FLASH effect has opened the possibility to enhance the therapeutic index of radiation therapy. The contribution of the immune response has frequently been hypothesized to account for a certain fraction of the antitumor efficacy and tumor kill of FLASH but has yet to be rigorously evaluated. To investigate the immune response as a potentially important mechanism of the antitumor effect of FLASH, various murine tumor models were grafted either subcutaneously or orthotopically into immunocompetent mice or in moderately and severely immunocompromised mice. Mice were locally irradiated with single dose (20 Gy) or hypofractionated regimens (3 × 8 or 2 × 6 Gy) using FLASH (≥2000 Gy/s) and conventional (CONV) dose rates (0.1 Gy/s), with/without anti-CTLA-4. Tumor growth was monitored over time and immune profiling performed. FLASH and CONV 20 Gy were isoeffective in delaying tumor growth in immunocompetent and moderately immunodeficient hosts and increased tumor doubling time to >14 days versus >7 days in control animals. Similar observations were obtained with a hypofractionated scheme, regardless of the microenvironment (subcutaneous flank vs ortho lungs). Interestingly, in profoundly immunocompromised mice, 20 Gy FLASH retained antitumor activity and significantly increased tumor doubling time to >14 days versus >8 days in control animals, suggesting a possible antitumor mechanism independent of the immune response. Analysis of the tumor microenvironment showed similar immune profiles after both irradiation modalities with significant decrease of lymphoid cells by ∼40% and a corresponding increase of myeloid cells. In addition, FLASH and CONV did not increase transforming growth factor-β1 levels in tumors compared with unirradiated control animals. Furthermore, when a complete and long-lasting antitumor response was obtained (>140 days), both modalities of irradiation were able to generate a long-term immunologic memory response. The present results clearly document that the tumor responses across multiple immunocompetent and immunodeficient mouse models are largely dose rate independent and simultaneously contradict a major role of the immune response in the antitumor efficacy of FLASH. Therefore, our study indicates that FLASH is as potent as CONV in modulating antitumor immune response and can be used as an immunomodulatory agent