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Introduction: Heavy ions of the galactic cosmic radiation dominate the radiation risks and biological effects for plants under spaceflight conditions. However, the biological effects and sensitive genes caused by heavy ions with different linear energy transfer (LET) values have not been thoroughly studied. Methods: To comprehensively analyze the biological effects of heavy ions with different LET values on rice under spaceflight conditions, we utilized the Shijian-10 recoverable satellite (SJ-10) to transport the dehydrated rice seeds on a 12.5-day mission in a 252 km low Earth orbit (LEO), and obtained rice plants hit by individual heavy ions with LET values ranging from 18 keV/μm to 213 keV/μm. The transcriptome and methylation sequencing were conducted on above plants, and a bioinformatics pipeline based on single-sample networks (SSNs) and genetic algorithms (GA) was developed to analyze the multi-omics expression profiles in this work. Note that SSNs can depict the gene interaction patterns within a single sample. The LET regression models were constructed from both gene expression and interaction pattern perspectives respectively, and the radiation response genes that played significant roles in the models were identified. We designed a gene selection algorithm based on GA to enhance the performance of LET regression models. Results: The experimental results demonstrate that all our models exhibit excellent regression performance (R2 values close to 1), which indicates that both gene expressions and interaction patterns can reflect the molecular changes caused by heavy ions with different LET values. LET-related genes (genes exhibiting strong correlation with LET values) and radiation-responsive genes were identified, primarily involved in DNA damage and repair, oxidative stress, photosynthesis, nucleic acid metabolism, energy metabolism, amino acid/protein metabolism, and lipid metabolism, etc. DNA methylation plays a crucial role in responding to heavy ions stressors and regulates the aforementioned processes. Discussion: To the best of our knowledge, this is the first study to report the multi-omics changes in plants after exposure to heavy ions with different LET values under spaceflight conditions. [ABSTRACT FROM AUTHOR]

To overcome chondrosarcoma's (CHS) high chemo- and radioresistance, we used polyethylene glycol-encapsulated iron oxide nanoparticles (IONPs) for the controlled delivery of the chemotherapeutic doxorubicin (IONPDOX) to amplify the cytotoxicity of proton radiation therapy. Human 2D CHS SW1353 cells were treated with protons (linear energy transfer (LET): 1.6 and 12.6 keV/µm) with and without IONPDOX. Cell survival was assayed using a clonogenic test, and genotoxicity was tested through the formation of micronuclei (MN) and γH2AX foci, respectively. Morphology together with spectral fingerprints of nuclei were measured using enhanced dark-field microscopy (EDFM) assembled with a hyperspectral imaging (HI) module and an axial scanning fluorescence module, as well as scanning electron microscopy (SEM) coupled with energy-dispersive X-Ray spectroscopy (EDX). Cell survival was also determined in 3D SW3153 spheroids following treatment with low-LET protons with/without the IONPDOX compound. IONPDOX increased radiosensitivity following proton irradiation at both LETs in correlation with DNA damage expressed as MN or γH2AX. The IONPDOX–low-LET proton combination caused a more lethal effect compared to IONPDOX–high-LET protons. CHS cell biological alterations were reflected by the modifications in the hyperspectral images and spectral profiles, emphasizing new possible spectroscopic markers of cancer therapy effects. Our findings show that the proposed treatment combination has the potential to improve the management of CHS. [ABSTRACT FROM AUTHOR]

Background: Ultra high dose rate (UHDR) radiotherapy using ridge filter is a new treatment modality known as conformal FLASH that, when optimized for dose, dose rate (DR), and linear energy transfer (LET), has the potential to reduce damage to healthy tissue without sacrificing tumor killing efficacy via the FLASH effect. Purpose: Clinical implementation of conformal FLASH proton therapy has been limited by quality assurance (QA) challenges, which include direct measurement of UHDR and LET. Voxel DR distributions and LET spectra at planning target margins are paramount to the DR/LET‐related sparing of organs at risk. We hereby present a methodology to achieve experimental validation of these parameters. Methods: Dose, DR, and LET were measured for a conformal FLASH treatment plan involving a 250‐MeV proton beam and a 3D‐printed ridge filter designed to uniformly irradiate a spherical target. We measured dose and DR simultaneously using a 4D multi‐layer strip ionization chamber (MLSIC) under UHDR conditions. Additionally, we developed an "under‐sample and recover (USRe)" technique for a high‐resolution pixelated semiconductor detector, Timepix3, to avoid event pile‐up and to correct measured LET at high‐proton‐flux locations without undesirable beam modifications. Confirmation of these measurements was done using a MatriXX PT detector and by Monte Carlo (MC) simulations. Results: MC conformal FLASH computed doses had gamma passing rates of >95% (3 mm/3% criteria) when compared to MatriXX PT and MLSIC data. At the lateral margin, DR showed average agreement values within 0.3% of simulation at 100 Gy/s and fluctuations ∼10% at 15 Gy/s. LET spectra in the proximal, lateral, and distal margins had Bhattacharyya distances of <1.3%. Conclusion: Our measurements with the MLSIC and Timepix3 detectors shown that the DR distributions for UHDR scenarios and LET spectra using USRe are in agreement with simulations. These results demonstrate that the methodology presented here can be used effectively for the experimental validation and QA of FLASH treatment plans. [ABSTRACT FROM AUTHOR]

In applying fluorescent nuclear track detectors for heavy ion measurement, the fluorescence intensity directly influences linear energy transfer (LET) estimation. However, the conventional analysis highly depends on the analyzed depth and the reference frames from the optical readout. To improve the accuracy of measurements of heavy ions, the gradient of intensity and moving average fluorescence intensity were acquired and calculated to optimize the measurement conditions. The results indicate that the intensity gradient is an alternative quantity to discriminate ions with different LET, and the moving average fluorescence intensity is readily differentiated among individual ions without overlapping values in fluorescence intensity. The scanned range of 25–45 μm is suggested to be the most suitable depth for measurement. To exclude the impact of the variation in fluorescence intensity on evaluation, it is recommended to use the quantities calculated in moving averages with depth in the future. [ABSTRACT FROM AUTHOR]

The article discusses a special debate on systemic radiotherapy using targeted isotopes as a promising approach to advancing curative radiation therapy. The debate involves arguments for and against this proposition, highlighting the potential of radiopharmaceutical therapy (RPT) to overcome challenges such as microscopic disease, radioresistance, and harnessing the immune system. While proponents emphasize the benefits of RPT in targeting cancer cells throughout the body, opponents raise concerns about logistical, radiobiological, and dosimetric challenges that need to be addressed for broader adoption. Both sides acknowledge the need for further research and development to optimize the effectiveness of RPT in treating various cancer types. [Extracted from the article]

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the "dose and LET" physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LETd) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LETd. However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LETd (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LETd alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line–specific mechanistic model. [ABSTRACT FROM AUTHOR]

Nanodroplets have demonstrated potential for the range detection of hadron radiotherapies. Our formulation uses superheated perfluorobutane (C4F10) stabilized by a poly(vinyl-alcohol) shell. High-LET (linear energy transfer) particles vaporize the nanodroplets into echogenic microbubbles. Tailored ultrasound imaging translates the generated echo-contrast into a dose distribution map, enabling beam range retrieval. This work evaluates the response of size-sorted nanodroplets to carbon-ion radiation. We studied how thesize of nanodroplets affects their sensitivity at various beam-doses and energies, as a function of concentration and shell cross-linking. First, we show the physicochemical characterization of size-isolated nanodroplets by differential centrifugation. Then, we report on the irradiations of the nanodroplet samples in tissue-mimicking phantoms. We compared the response of large (≈900 nm) and small (≈400 nm) nanodroplets to different carbon-ions energies and evaluated their dose linearity and concentration detection thresholds by ultrasound imaging. Additionally, we verified the beam range detection accuracy for the nanodroplets samples. All nanodroplets exhibited sensitivity to carbon-ions with high range verification precision. However, smaller nanodroplets required a higher concentration sensitivity threshold. The vaporization yield depends on the carbon-ions energy and dose, which are both related to particle count/spot. These findings confirm the potential of nanodroplets for range detection, with performance depending on nanodroplets' properties and beam parameters. [ABSTRACT FROM AUTHOR]

This work investigated the single-event effects (SEE) of NiO/β-Ga2O3 heterojunction diodes (HJDs) irradiated by 1.86 GeV tantalum ions with linear energy transfer over 80 MeV cm2/mg. The HJDs exhibited radiation responses with the early single-event leakage current (SELC) degradation until the fatal single-event burnout (SEB) failure, which was far below their breakdown voltages. Meanwhile, the surface morphology revealed the SELC damage expressed as burnout of topside NiO and metal stacks, while the SEB damage was observed as a burned hole in the β-Ga2O3 epitaxial layer. According to technology computer aided design simulations, the thicker p-type region in HJDs could further alleviate the electric field crowding effect exacerbated by the heavy-ion strike because of the extension of charge distribution in the p-type region. The SEB threshold was raised to 250 V by thickening the NiO layer to 300 nm. As for the SELC degradation process along with the burnout of topside stacks in HJDs, we supposed the probable reason was the intolerance of NiO to the high electric field under the SEE. This paper analyzed the SEE mechanism in β-Ga2O3 diodes and paved the way for heavy-ion irradiation hardening. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusions Boron neutron capture therapy (BNCT) is a targeted radiotherapy that relies on the 10B (n, α) 7Li reaction, which produces secondary particles with high linear energy transfer (LET), leading to a high relative biological effectiveness (RBE) in tumors. The biological effectiveness of BNCT is influenced by factors such as boron distribution and concentration, necessitating improved methods for assessing its radiobiological effects and clarifying the sensitivity of the differences in different factors to the biological effects.This paper introduces a method to evaluate the biological effects of BNCT using the cellular repair model. This method aims to overcome some of the limitations of current evaluation approaches. The primary goal is to provide guidance for clinical treatments and the development of boron drugs, as well as to investigate the impact of the synergistic effects of mixed radiation fields in BNCT on treatment outcomes.The approach involves three key steps: first, extending the radial energy deposition distribution of BNCT secondary particles using Geant4‐DNA. This allows for the calculation of initial DNA double‐strand breaks (DSBs) distributions for a given absorbed dose. Next, the obtained initial DSB distributions are used for DNA damage repair simulations to generate cell survival curves, then thereby quantifying RBE and compound biological effectiveness (CBE). The study also explores the synergistic effects of the mixed radiation fields in BNCT on assessing biological effects were also explored in depth.The results showed that the RBE of boronophenylalanine (BPA) and sodium borocaptate (BSH) drugs at cell survival fraction 0.01 was 2.50 and 2.15, respectively. The CBE of the boron dose component was 3.60 and 0.73, respectively, and the RBE of the proton component was 3.21, demonstrating that BPA has a significantly higher biological impact than BSH due to superior cellular permeability. The proton dose significance in BNCT treatment is also underscored, necessitating consideration in both experimental and clinical contexts. The study demonstrates that synergistic effects between disparate radiation fields lead to increased misrepairs and enhanced biological impact. Additionally, the biological effect diminishes with rising boron concentration, emphasizing the need to account for intercellular DNA damage heterogeneity.This methodology offers valuable insights for the development of new boron compounds and precise assessment of bio‐weighted doses in clinical settings and can be adapted to other therapeutic modalities. [ABSTRACT FROM AUTHOR]

Background Purpose Methods Results Conclusion In carbon ion radiotherapy, accurate measurement of the three‐dimensional (3D) absorbed dose distribution is critical for effectively targeting tumors. Although micellar gel dosimeters exhibit considerable potential for measuring 3D absorbed dose distributions, few studies have focused on radiotherapy using carbon ion beams.This study investigated the applicability of the surfactant hydrogel dosimeter (SHD), a micellar gel dosimeter, to measuring a 3D dose absorbed through carbon ion beam irradiation.A cubic target region of 34 mm per side was established at a depth of 46 mm below the upper surface of an SHD specimen. Scanning irradiation was performed using a pencil beam of carbon ions at the Ion‐beam Radiation Oncology Center in Kanagawa (“i‐ROCK”), Japan, under irradiation conditions set by the treatment planning system (“Monaco for Carbon”, Ver. 5.20, Elekta AB, Sweden) to create a spread‐out Bragg peak within the target. The physical dose was set to 10 Gy at the isocenter, situated at the center of the target. The SHD responsiveness was measured twice using optical computed tomography (CT) (“Vista 15”, Modus Medical Devices, Canada) for three irradiated specimens, and six types of measured optical attenuation coefficient (OAC) were obtained. To assess whether the OAC represented the absorbed dose expected in the treatment plan, we compared the relative distribution of the OAC and that of the absorbed dose. Relative fraction (RF) was used to measure the difference between the relative value of the OAC and that of the absorbed dose. Moreover, the distribution of OH radical (•OH) concentration obtained by Monte Carlo simulation (“PHITS” ver. 3.24 JAEA, Japan) and that of the OAC were compared.In the direction of beam travel, the relative distribution of the OAC was lower than that of the absorbed dose. This discrepancy could be attributed to a decrease in the concentration of •OH produced by irradiation owing to the recombination reaction, which does not accurately reflect the absorbed dose. By contrast, the distributions in the plane perpendicular to the beam travel were consistent. The RF increased from ± 3% to ± 13% along the beam travel direction. The small RF in the plane perpendicular to the beam travel could be attributed to the constant distribution of linear energy transfer, regardless of the irradiation position, and the generation of radicals proportionally to the absorbed dose. The increase in RF along the beam travel direction was ascribed to ring artifacts in the irradiated region.The measurement of the absorbed dose distribution in the beam travel direction should be improved. The observed discrepancy is attributed to the reduced reactivity of the SHD due to a high liner energy transfer near the Bragg peak. However, the absorbed dose distribution can be effectively evaluated in the plane perpendicular to the direction of beam travel. [ABSTRACT FROM AUTHOR]

Background: Phenomenological relative biological effectiveness (RBE) models for proton therapy, based on the dose‐averaged linear energy transfer (LET), have been developed to address the apparent RBE increase towards the end of the proton range. The results of these phenomenological models substantially differ due to varying empirical assumptions and fitting functions. In contrast, more theory‐based approaches are used in carbon ion radiotherapy, such as the microdosimetric kinetic model (MKM). However, implementing microdosimetry‐based models in LET‐based proton therapy treatment planning systems poses challenges. Purpose: This work presents a LET‐based version of the MKM that is practical for clinical use in proton radiotherapy. Methods: At first, we derived an approximation of the Mayo Clinic Florida (MCF) MKM for relatively‐sparsely ionizing radiation such as protons. The mathematical formalism of the proposed model is equivalent to the original MKM, but it maintains some key features of the MCF MKM, such as the determination of model parameters from measurable cell characteristics. Subsequently, we carried out Monte Carlo calculations with PHITS in different simulated scenarios to establish a heuristic correlation between microdosimetric quantities and the dose averaged LET of protons. Results: A simple allometric function was found able to describe the relationship between the dose‐averaged LET of protons and the dose‐mean lineal energy, which includes the contributions of secondary particles. The LET‐based MKM was used to model the in vitro clonogenic survival RBE of five human and rodent cell lines (A549, AG01522, CHO, T98G, and U87) exposed to pristine and spread‐out Bragg peak (SOBP) proton beams. The results of the LET‐based MKM agree well with the biological data in a comparable or better way with respect to the other models included in the study. A sensitivity analysis on the model results was also performed. Conclusions: The LET‐based MKM integrates the predictive theoretical framework of the MCF MKM with a straightforward mathematical description of the RBE based on the dose‐averaged LET, a physical quantity readily available in modern treatment planning systems for proton therapy. [ABSTRACT FROM AUTHOR]

This study conducts a comparative analysis of cystamine (RSSR), a disulfide, and cysteamine (RSH), its thiol monomer, to evaluate their efficacy as radioprotectors and antioxidants under high linear energy transfer (LET) and high-dose-rate irradiation conditions. It examines their interactions with reactive primary species produced during the radiolysis of the aqueous ferrous sulfate (Fricke) dosimeter, offering insights into the mechanisms of radioprotection and highlighting their potential to enhance the therapeutic index of radiation therapy, particularly in advanced techniques like FLASH radiotherapy. Using Monte Carlo multi-track chemical modeling to simulate the radiolytic oxidation of ferrous to ferric ions in Fricke-cystamine and Fricke-cysteamine solutions, this study assesses the radioprotective and antioxidant properties of these compounds across a variety of irradiation conditions. Concentrations were varied in both aerated (oxygen-rich) and deaerated (hypoxic) environments, simulating conditions akin to healthy tissue and tumors. Both cystamine and cysteamine demonstrate radioprotective and strong antioxidant properties. However, their effectiveness varies significantly depending on the concentration employed, the conditions of irradiation, and whether or not environmental oxygen is present. Specifically, excluding potential in vivo toxicity, cysteamine substantially reduces the adverse effects of ionizing radiation under aerated, low-LET conditions at concentrations above ~1 mM. However, its efficacy is minimal in hypoxic environments, irrespective of the concentration used. Conversely, cystamine consistently offers robust protective effects in both oxygen-rich and oxygen-poor conditions. The distinct protective capacities of cysteamine and cystamine underscore cysteamine's enhanced potential in radiotherapeutic settings aimed at safeguarding healthy tissues from radiation-induced damage while effectively targeting tumor tissues. This differential effectiveness emphasizes the need for personalized radioprotective strategies, tailored to the specific environmental conditions of the tissue involved. Implementing such approaches is crucial for optimizing therapeutic outcomes and minimizing collateral damage in cancer treatment. [ABSTRACT FROM AUTHOR]

Purpose: Based on considerable interest to enlarge the experimental database of radioresistant cells after their irradiation with helium ions, HTB140, MCF-7 and HTB177 human malignant cells are exposed to helium ion beams having different linear energy transfer (LET). Materials and methods: The cells are irradiated along the widened 62 MeV/u helium ion Bragg peak, providing LET of 4.9, 9.8, 23.4 and 36.8 keV/µm. Numerical simulations with the Geant4 toolkit are used for the experimental design. Cell survival is evaluated and compared with reference γ-rays. DNA double strand breaks are assessed via γ-H2AX foci. Results: With the increase of LET, surviving fractions at 2 Gy decrease, while RBE (2 Gy, γ) gradually increase. For HTB140 cells, above the dose of 4 Gy, a slight saturation of survival is observed while the increase of RBE (2 Gy, γ) remains unaffected. With the increase of LET the increase of γ-H2AX foci is revealed at 0.5 h after irradiation. There is no significant difference in the number of foci between the cell lines for the same LET. From 0.5 to 24 h, the number of foci drops reaching its residual level. For each time point, there are small differences in DNA DSB among the three cell lines. Conclusion: Analyses of data acquired for the three cell lines irradiated by helium ions, having different LET, reveal high elimination capacity and creation of a large number of DNA DSB with respect to γ-rays, and are between those reported for protons and carbon ions. [ABSTRACT FROM AUTHOR]

Background: In radiotherapy, it is essential to deliver prescribed doses to tumors while minimizing damage to surrounding healthy tissue. Accurate measurements of absorbed dose are required for this purpose. Gafchromic® external beam therapy (EBT) radiochromic films have been widely used in radiotherapy. While the dosimetric characteristics of the EBT3 model film have been extensively studied for photon and charged particle beams (protons, electrons, and carbon ions), little research has been done on α$\alpha$‐particle dosimetry. α$\alpha$‐emitting radionuclides have gained popularity in cancer treatment due to their high linear energy transfer, short range in tissue, and ability to spare surrounding organs at risk, thereby delivering a more localized dose distribution to the tumor. Therefore, a dose‐calibration film protocol for α$\alpha$‐particles is required. Purpose: This study aimed to develop a dose‐calibration protocol for the α$\alpha$‐particle emitting radionuclide 241Am, using Monte Carlo (MC) simulations and measurements with unlaminated EBT3 films. Methods: In this study, a MC‐based user code was developed using the Geant4 simulation toolkit to model and simulate an 241Am source and an unlaminated EBT3 film. Two simulations were performed: one with voxelized geometries of the EBT3 active volume composition and the other using water. The dose rate was calculated within a region of interest in the voxelized geometries. Unlaminated EBT3 film pieces were irradiated with the 241Am source at various exposure times inside a black box. Film irradiations were compared to a 6‐MV photon beam from a Varian TrueBeam machine. The simulated dose rate was used to convert the exposure times into absorbed doses to water, describing a radiochromic‐film‐based reference dosimetry protocol for α$\alpha$‐particles. The irradiated films were scanned and through an in‐house Python script, the normalized pixel values from the green‐color channel of scanned film images were analyzed. Results: The 241Am energy spectra obtained from the simulations were in good agreement with IAEA and NIST databases, having differences <$<$0.516% for the emitted γ$\gamma$‐rays and produced characteristic x‐rays and <$<$0.006% for the α$\alpha$‐particles. Due to the short range of α$\alpha$‐particles, there was no energy deposition in the voxels outside the active 241Am source region projected onto the film surface. Thus, the total dose rate within the voxels covering the source was 0.847 ±$\pm$ 0.003 Gy/min within the sensitive layer of the film (LiPCDA) and 0.847 ±$\pm$ 0.004 Gy/min in water, indicating that the active volume can be considered water equivalent for the 241Am beam quality. A novel approach was employed in α$\alpha$‐film dosimetry using an exponential fit for the green channel, which showed promising results by reducing the uncertainty in dose estimation within 5%. Although the statistical analysis did not reveal significant differences between the 6‐MV photon beam and the α$\alpha$ calibration curves, the dose–response curves exhibited the expected behavior. Conclusions: The developed MC user code simulated the experimental setup for α$\alpha$‐dosimetry using radiochromic film with acceptable uncertainty. Unlaminated EBT3 film is suitable for the dosimetry of α$\alpha$‐radiation at low doses and can be used in conjunction with other unlaminated GafChromic® films for quality assurance and research purposes. [ABSTRACT FROM AUTHOR]

Background: Previous study proposed a method to measure linear energy transfer (LET) at specific points using the quenching magnitude of thin film solar cells. This study was conducted to propose a more advanced method for measuring the LET distribution. Purpose: This study focuses on evaluating the feasibility of estimating the proton LET distribution in proton therapy. The feasibility of measuring the proton LET and dose distribution simultaneously using a single‐channel configuration comprising two solar cells with distinct quenching constants is investigated with the objective of paving the way for enhanced proton therapy dosimetry. Methods: Two solar cells with different quenching constants were used to estimate the proton LET distribution. Detector characteristics (e.g., dose linearity and dose‐rate dependency) of the solar cells were evaluated to assess their suitability for dosimetry applications. First, using a reference beam condition, the quenching constants of the two solar cells were determined according to the modified Birks equation. The signal ratios of the two solar cells were then evaluated according to proton LET in relation to the estimated quenching constants. The proton LET distributions of six test beams were obtained by measuring the signal ratios of the two solar cells at each depth, and the ratios were evaluated by comparing them with those calculated by Monte Carlo simulation. Results: The detector characterization of the two solar cells including dose linearity and dose‐rate dependence affirmed their suitability for use in dosimetry applications. The maximum difference between the LET measured using the two solar cells and that calculated by Monte Carlo simulation was 2.34 keV/µm. In the case of the dose distribution measured using the method proposed in this study, the maximum difference between range measured using the proposed method and that measured using a multilayered ionization chamber was 0.7 mm. The expected accuracy of simultaneous LET and dose distribution measurement using the method proposed in this study were estimated to be 3.82%. The signal ratios of the two solar cells, which are related to quenching constants, demonstrated the feasibility of measuring LET and dose distribution simultaneously. Conclusion: The feasibility of measuring proton LET and dose distribution simultaneously using two solar cells with different quenching constants was demonstrated. Although the method proposed in this study was evaluated using a single channel by varying the measuring depth, the results suggest that the proton LET and dose distribution can be simultaneously measured if the detector is configured in a multichannel form. We believe that the results presented in this study provide the envisioned transition to a multichannel configuration, with the promise of substantially advancing proton therapy's accuracy and efficacy in cancer treatment. [ABSTRACT FROM AUTHOR]

Chondrosarcoma is a rare malignant tumor that forms in bone and cartilage. The primary treatment involves surgical removal of the tumor with a margin of healthy tissue. Especially if complete surgical removal is not possible, radiation therapy and chemotherapy are used in conjunction with surgery, but with a generally low efficiency. Ongoing researches are focused on understanding the genetic and molecular basis of chondrosarcoma following high linear energy transfer (LET) irradiation, which may lead to treatments that are more effective. The goal of this study is to evaluate the differential effects of DNA damage repair inhibitors and high LET irradiation on chondrosarcoma versus chondrocyte cells and the LET-dependency of the effects. Two chondrosarcoma cell lines with different IDH mutation status and one chondrocyte cell line were exposed to low LET (X-ray) and high LET (carbon ion) irradiation in combination with an Olaparib PARP inhibitor. Cell survival and DNA repair mechanisms were investigated. High LET irradiation drastically reduced cell survival, with a biological efficiency three times that of low LET. Olaparib significantly inhibited PARylation in all the tested cells. A significant reduction in cell survival of both chondrosarcoma and chondrocyte cells was observed following the treatment combining Olaparib and X-ray. PARP inhibition induced an increase in PARP-1 expression and a reduced effect on the cell survival of WT IDH chondrosarcoma cells. No radiosensitizing effect was observed in cells exposed to Olaparib paired with high LET irradiation. NHEJ was activated in response to high LET irradiation, neutralizing the PARP inhibition effect in both chondrosarcoma cell lines. When high LET irradiation is not available, PARP inhibition could be used in combination with low LET irradiation, with significant radiosensitizing effects on chondrosarcoma cells. Chondrocytes may be affected by the treatment combination too, showing the need to preserve normal tissues from radiation fields when this kind of treatment is suggested. [ABSTRACT FROM AUTHOR]

Our objective was to develop a methodology for assessing the linear energy transfer (LET) and relative biological effectiveness (RBE) in clinical proton and helium ion beams using fluorescent nuclear track detectors (FNTDs). FNTDs were exposed behind solid water to proton and helium (4He) ion spread-out Bragg peaks. Detectors were imaged with a confocal microscope, and the LET spectra were derived from the fluorescence intensity. The track- and dose-averaged LET (LET F and LET D , respectively) were calculated from the LET spectra. LET measurements were used as input on RBE models to estimate the RBE. Human alveolar adenocarcinoma cells (A549) were exposed at the same positions as the FNTDs. The RBE was calculated from the resulting survival curves. All measurements were compared with Monte Carlo simulations. For protons, average relative differences between measurements and simulations were 6% and 19% for LET F and LET D , respectively. For helium ions, the same differences were 11% for both quantities. The position of the experimental LET spectra primary peaks agreed with the simulations within 9% and 14% for protons and helium ions, respectively. For the RBE models using LET D as input, FNTD-based RBE values ranged from 1.02 ± 0.01 to 1.25 ± 0.04 and from 1.08 ± 0.09 to 2.68 ± 1.26 for protons and helium ions, respectively. The average relative differences between these values and simulations were 2% and 4%. For A549 cells, the RBE ranged from 1.05 ± 0.07 to 1.47 ± 0.09 and from 0.89 ± 0.06 to 3.28 ± 0.20 for protons and helium ions, respectively. Regarding the RBE-weighted dose (2.0 Gy at the spread-out Bragg peak), the differences between simulations and measurements were below 0.10 Gy. This study demonstrates for the first time that FNTDs can be used to perform direct LET measurements and to estimate the RBE in clinical proton and helium ion beams. [ABSTRACT FROM AUTHOR]

The repair of DNA double-strand breaks is a crucial yet delicate process which is affected by a multitude of factors. In this study, our goal is to analyse the influence of the linear energy transfer (LET) on the DNA repair kinetics. By utilizing the database of repair of DNA and aggregating the results of 84 experiments, we conduct various model fits to evaluate and compare different hypothesis regarding the effect of LET on the rejoining of DNA ends. Despite the considerable research efforts dedicated to this topic over the past decades, our findings underscore the complexity of the relationship between LET and DNA repair kinetics. This study leverages big data analysis to capture overall trends that single experimental studies might miss, providing a valuable model for understanding how radiation quality impacts DNA damage and subsequent biological effects. Our results highlight the gaps in our current understanding, emphasizing the pressing need for further investigation into this phenomenon. [ABSTRACT FROM AUTHOR]

One of the factors causing the failure of spacecraft integrated circuits is exposure to heavy charged particles. The entry of heavy charged particles into electronic devices leads to the appearance of single event transients (short current pulses), which in analog microcircuits manifest themselves in distortion of the output signal shape, and in digital microcircuits can cause a single event upset. The article discusses a technique for circuit mode-ling of the effect of heavy charged particles on bipolar analog microcircuits, including the developed equivalent electrical circuit of a bipolar transistor for LTSpice and the procedure for modeling transient processes. Despite the simplifications adopted, namely: failure to take into account the dependence of the duration of the rise and fall of the current pulse generated by a charged particle on the parameters of the transistor structure, the assumption that the entire charge is generated in the active base and the space charge regions of the emitter and collector junctions, an equivalent circuit has been developed made it possible to determine that the shape of the collector current pulse for circuit with a common emitter when exposed to a heavy charged particle is determined by the speed of the transistor and its operating mode. Using the developed methodology, the “critical” transistors of the two studied analog microcircuits were determined, and the need to bypass the current-setting resistors with a small capacitor was justified.

Objective. This study aims to assess the composition of scattered particles generated in proton therapy for tumors situated proximal to some titanium (Ti) dental implants. The investigation involves decomposing the mixed field and recording Linear Energy Transfer (LET) spectra to quantify the influence of metallic dental inserts located behind the tumor. Approach. A therapeutic conformal proton beam was used to deliver the treatment plan to an anthropomorphic head phantom with two types of implants inserted in the target volume (made of Ti and plastic, respectively). The scattered radiation resulted during the irradiation was detected by a hybrid semiconductor pixel detector MiniPIX Timepix3 that was placed distal to the Spread-out Bragg peak. Visualization and field decomposition of stray radiation were generated using algorithms trained in particle recognition based on artificial intelligence neural networks (AI NN). Spectral sensitive aspects of the scattered radiation were collected using two angular positions of the detector relative to the beam direction: 0° and 60°. Results. Using AI NN, 3 classes of particles were identified: protons, electrons & photons, and ions & fast neutrons. Placing a Ti implant in the beam's path resulted in predominantly electrons and photons, contributing 52.2% of the total number of detected particles, whereas for plastic implants, the contribution was 65.4%. Scattered protons comprised 45.5% and 31.9% with and without metal inserts, respectively. The LET spectra were derived for each group of particles identified, with values ranging from 0.01 to 7.5 keV μ m−1 for Ti implants/plastic implants. The low-LET component was primarily composed of electrons and photons, while the high-LET component corresponded to protons and ions. Significance. This method, complemented by directional maps, holds the potential for evaluating and validating treatment plans involving stray radiation near organs at risk, offering precise discrimination of the mixed field, and enhancing in this way the LET calculation. [ABSTRACT FROM AUTHOR]

Featured Application: The integration of supercritical water (SCW) technology in proposed Generation IV nuclear reactors marks a significant advancement in the evolution of nuclear energy. To achieve optimal water chemistry control and enhance reactor efficiency, safety, and sustainability, it is critical to thoroughly understand the radiation chemistry and behavior of transient species within the reactor core. This knowledge is particularly vital for the development of SCW-cooled reactor (SCWR) designs, including their SCW-cooled small modular reactor (SCW-SMR) variants. These reactors are designed to operate at temperatures between 300 and 600 °C and at a nominal pressure of 25 MPa. Our study focuses on the radiolysis of de-aerated, pure water by 2 MeV monoenergetic neutrons, mirroring the fast-neutron flux in a typical reactor setting. We provide a detailed analysis of the time-dependent chemical yields (G values) for both radical (e−aq, H●, and ●OH) and molecular (H2 and H2O2) primary species that are either formed or destroyed from 1 picosecond (ps) to 1 millisecond (ms). Given the unique operating conditions of SCWRs/SMRs, our findings are expected to be highly relevant and valuable to those working in the SCWR and SCW-SMR field. (1) Background: Supercritical water-cooled reactors (SCWRs) and their smaller modular variants (SMRs) are part of the 'Generation IV International Forum' (GIF) on advanced nuclear energy systems. These reactors operate beyond the critical point of water (tc = 373.95 °C and Pc = 22.06 MPa), which introduces specific technical challenges that need to be addressed. The primary concerns involve the effects of intense radiation fields—including fast neutrons, recoil protons/oxygen ions, and γ rays—on the chemistry of the coolant fluid and the integrity of construction materials. (2) Methods: This study employs Monte Carlo simulations of radiation track chemistry to investigate the yields of radiolytic species in SCWRs/SMRs exposed to 2 MeV neutrons. In our calculations, only the contributions from the first three recoil protons with initial energies of 1.264, 0.465, and 0.171 MeV were considered. Our analysis was conducted at both subcritical (300 and 350 °C) and supercritical temperatures (400–600 °C), maintaining a constant pressure of 25 MPa. (3) Results: Our simulations provide insights into the radiolytic formation of chemical species such as e−aq, H●, H2, ●OH, and H2O2 from ~1 ps to 1 ms. Compared to data from radiation with low linear energy transfer (LET), the G(e−aq) and G(●OH) values obtained for fast neutrons show a similar temporal dependence but with smaller amplitude—a result demonstrating the high LET nature of fast neutrons. A notable outcome of our simulations is the marked increase in G(●OH) and G(H2), coupled with a corresponding reduction in G(H●), observed during the homogeneous chemical stage of radiolysis. This evolution is attributed to the oxidation of water by the H● atom according to the reaction H● + H2O → ●OH + H2. This reaction acts as a significant source of H2, potentially reducing the need to add extra hydrogen to the reactor's coolant water to suppress the net radiolytic production of oxidizing species. Unlike in subcritical water, our simulations also indicate that G(H2O2) remains very low in low-density SCW throughout the interval from ~1 ps to 1 ms, suggesting that H2O2 is less likely to contribute to oxidative stress under these conditions. (4) Conclusions: The results of this study could significantly impact water-chemistry management in the proposed SCWRs and SCW-SMRs, which is crucial for assessing and mitigating the corrosion risks to reactor materials, especially for long-term operation. [ABSTRACT FROM AUTHOR]

Background: For proton therapy, a relative biological effectiveness (RBE) of 1.1 is widely applied clinically. However, due to abundant evidence of variable RBE in vitro, and as suggested in studies of patient outcomes, RBE might increase by the end of the proton tracks, as described by several proposed variable RBE models. Typically, the dose averaged linear energy transfer (LETd$\text{LET}_d$) has been used as a radiation quality metric (RQM) for these models. However, the optimal choice of RQM has not been fully explored. Purpose: This study aims to propose novel RQMs that effectively weight protons of different energies, and assess their predictive power for variable RBE in proton therapy. The overall objective is to identify an RQM that better describes the contribution of individual particles to the RBE of proton beams. Methods: High‐throughput experimental set‐ups of in vitro cell survival studies for proton RBE determination are simulated utilizing the SHIELD‐HIT12A Monte Carlo particle transport code. For every data point, the proton energy spectra are simulated, allowing the calculation of novel RQMs by applying different power levels to the spectra of LET or effective Q$Q$ (Qeff$Q_\mathrm{eff}$) values. A phenomenological linear‐quadratic‐based RBE model is then applied to the in vitro data, using various RQMs as input variables, and the model performance is evaluated by root‐mean‐square‐error (RMSE) for the logarithm of cell surviving fractions of each data point. Results: Increasing the power level, that is, putting an even higher weight on higher LET particles when constructing the RQM is generally associated with an increased model performance, with dose averaged LET3$\text{LET}^3$ (i.e., dose averaged cubed LET, cLETd$\mathrm{cLET}_d$) resulting in a RMSE value 0.31, compared to 0.45 for a model based on (linearly weighted) LETd$\text{LET}_d$, with similar trends also observed for track averaged and Qeff$Q_\mathrm{eff}$‐based RQMs. Conclusions: The results indicate that improved proton variable RBE models can be constructed assuming a non‐linear RBE(LET) relationship for individual protons. If similar trends hold also for an in vitro‐environment, variable RBE effects are likely better described by cLETd$\mathrm{cLET}_d$ or tracked averaged cubed LET (cLETt$\mathrm{cLET}_t$), or corresponding Qeff$Q_\mathrm{eff}$‐based RQM, rather than linearly weighted LETd$\text{LET}_d$ or LETt$\text{LET}_t$ which is conventionally applied today. [ABSTRACT FROM AUTHOR]

Background: In radiopharmaceutical therapies (RPT) involving beta emitters, absorbed dose (Dabs) calculations often employ the use of dose voxel kernels (DVK). Such methods are faster and easier to implement than Monte Carlo (MC) simulations. Using DVK methods implies a non‐stochastic distribution of particles. This is a valid assumption for betas where thousands to tens of thousands of particles traversing the cell nucleus are required to achieve cell kill. However, alpha particles have linear energy transfers (LET) that are ∼500 times higher than LETs of betas. This results in a significant probability of killing a cell from even a single traversal through its nucleus. Consequently, the activity used for therapy involving alphas is very low, and the use of DVKs for estimating Dabs will generate results that may be erroneous. Purpose: This work aims at illustrating how use of DVKs affect the resulting Dabs in small tumors when irradiated with clinically relevant amounts of beta‐ and alpha‐emitters. The results are compared with those from using a Monte Carlo method where the energy deposition from individual tracks is simulated. Methods: To illustrate the issues associated with DVK for alpha radiopharmaceutical therapies at the microscale, a tumor cluster model was used to compare beta (177Lu) and alphas (211At, 225Ac, and 227Th) irradiations. We used 103 beta particles and 20 alpha particles per cell, which is within the range of the required number of particle traversals through its nucleus to sterilize a cell. Results from using both methods were presented with Dabs histograms, dose volume histograms, and Dabs error maps. Results: For beta‐emitter (177Lu) irradiating the modeled tumor cluster, resulting Dabs was similar for both DVK and MC methods. For all alpha emitters, the use of DVK led to an overestimation of Dabs when compared to results generated using a MC approach. Conclusions: Our results demonstrate that the use of DVK methods for alpha emitters can lead to an overestimation in the calculated Dabs. The use of DVKs for therapies involving alpha emitters may therefore not be appropriate when only referring to the mean Dabs metric. [ABSTRACT FROM AUTHOR]

Background: Proton minibeam radiation therapy (pMBRT) can deliver spatially fractionated dose distributions with submillimeter resolution. These dose distributions exhibit significant heterogeneity in both depth and lateral directions. Accurate characterization of pMBRT doses requires dosimetry devices with high spatial resolution and a wide dynamic range. Furthermore, the dependency of dosimetric measurements on Linear Energy Transfer (LET), as observed in conventional proton therapy, is also present in pMBRT depth dosemeasurements. Purpose: This work demonstrates the process of performing comprehensive dosimetric measurements to characterize the pMBRT collimator on a clinical single-gantry proton machine, utilizing commercially available dosimetry devices. Methods: The minibeam collimator is designed to be mounted on the clinical nozzle as a beam-modifying accessory. Three collimators, each with a slit opening of 0.4 mm, are thoroughly evaluated. The center-to-center (c-t-c) distances of the slits for these collimators are 2.8 mm, 3.2 mm, and 4.0 mm, respectively. High spatial resolution dosimetry devices are essential for PMBRT dose characterizations. To meet this requirement, two-dimensional (2D) dose measurement devices, Gafchromic films, are used to measure lateral profiles at various depths. Films are also used for depth dose profile measurements in solid water. Additionally, high-resolution point dose detectors, microDiamond, and Razor diode detectors are employed for lateral profile measurements at various depths. Percent depth dose (PDD) measurements of pMBRT in solid water, with various proton energies, collimators, and air gaps, are performed using Gafchromic films. The film's LET dependency for proton beams is corrected to ensure accurate pMBRT PDD measurements. The Monte Carlo simulation tool TOPAS is utilized to compare and validate all experimental measurements. Results: At depths where LET is not a concern, film dose measurements were consistent with microDiamond and Razor diode point measurements. The point detectors need to be orientated with the thin side aligned to the incoming beam. Comparison of the lateral dose profiles extracted from TOPAS simulations, films, microDiamond, and Razor diode detectors shows a passing rate exceeding 98% in 1D gamma analysis at 3% 0.1 mm criteria. However, when the microDiamond detector is orientated to face the pMBRT beam, its spatial resolution may not be sufficient to capture the peak and valley dose accurately. Nevertheless, an accuracy within 2% can still be achieved when comparing the average dose. The PDD measurements show that the peak valley dose ratio (PVDR) of pMBRT can be altered at different depths with different air gaps using the same collimator or different collimators of different c-t-c distances. Conclusion: Our study demonstrates that comprehensive dose measurements for pMBRT can be conducted using standard clinical dose measurement devices. These measurements are indispensable for guiding and ensuring accurate dose reporting in pre-clinical studies using the pMBRT technique. [ABSTRACT FROM AUTHOR]

The effect of ionizing radiation on cells is a complex process dependent on several parameters. Cancer treatment commonly involves the use of radiotherapy. In addition to the effective killing of cancer cells, another key aspect of radiotherapy is the protection of healthy cells. An interesting position is occupied by heavy ion radiation in the field of radiotherapy due to its high relative biological effectiveness, making it an effective method of treatment. The high biological efficiency of heavy ion radiation can also pose a danger to healthy cells. The extent of cell death induced by heavy ion radiation in cells was investigated using statistical learning methods in this study. The objective was to predict the healthy cell survival rate based on the physical parameters of the available ionizing radiation. This paper is based on secondary research utilizing the PIDE database. Throughout this study, a local regression and a random forest model were generated. Their predictions were compared to the results of a linear-quadratic model commonly utilized in the field of ionizing radiation using various metrics. The relationship between dose and cell survival rate was examined using the linear-quadratic (LQM) model and local regression (LocReg). An R2 value of 88.43% was achieved for LQM and 89.86% for LocReg. Upon incorporating linear energy transfer, the random forest model attained an R2 value of 96.85%. In terms of RMSE, the linear-quadratic model yielded 9.5910−2, the local regression 9.2110−2, and the random forest 1.96 × 10−2 (lower values indicate better performance). All of these methods were also applied to a log-transformed dataset to decrease the right skewedness of the distribution of the datapoints. This significantly reduced the estimates made with LQM and LocReg (28% decrease in the case of R2), while the random forest retained nearly the same level of estimation as the untransformed data. In conclusion, it can be inferred that dose alone provides a somewhat satisfactory explanatory power for cell survival rate, but the inclusion of linear energy transfer can significantly enhance prediction accuracy in terms of variance and explanatory power. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated the remarkable resistance of bdelloid rotifers to ionizing radiation, making them an interesting model system for studying radiation effects on living organisms. In this study, we use simulations, instead of direct experimental exposures, to examine whether all bdelloids are affected equally by radiation exposure and to explore the relationship between biological data and energy deposition patterns induced by low and high linear energy transfer (LET) radiation. To this end, tool for particle simulation (TOPAS) a simulation tool, widely used in the field of medical physics and radiation therapy, was utilized. Using simulations for proton, iron ions, and X-ray exposure, our findings showed that all individuals, cells, and nuclei were effectively hit by the administered doses of 4 MeV protons, 0.5 GeV/n 56Fe, and X-ray radiation. The results support that the impact on survival and fertility rate measured in Adineta vaga is caused by radiation-induced damage rather than the absence of hits in certain individuals or germinal cells. Notably, simulations revealed significant differences between low- and high-LET radiation concerning irradiated individuals' nuclei. Specifically, for an equivalent dose, high-LET radiation requires fewer incident particles compared to low-LET radiation, resulting in a sparser distribution of radiation hits on the nucleus surface. In conclusion, the study supports the idea that reduced fertility described in high-LET exposed samples is associated with complex DNA damage caused by the condensed energy deposition pattern of high-LET radiation compared to low-LET. [ABSTRACT FROM AUTHOR]

Background: Proton linear energy transfer (LET) is associated with the relative biological effectiveness of radiation on tissues. Monte Carlo (MC) simulations have been known to be the preferred method to calculate LET. Detectors have also been built to measure LET, but they need to be calibrated with MC simulations. Purpose: To propose and test a MC‐free method for determining LET from the measured integral depth dose (LFI) of the protons of interest. Method and materials: LFI consists of three steps: (1) IDD measurements, (2) extraction of energy spectrum (ES) from the IDD, and (3) LET determination from the extracted ES and the stopping power of each energy. To validate the accuracy of the extraction of ES, we use Gaussian ES to synthesize IDD, extract ES from the synthesized IDD, and then compare the original (ground truth) and extracted ES. LETs calculated from the original and extracted ES are also compared. To obtain the LET of protons of interest, we measure IDDs by a large‐area plane‐parallel ionization chamber in water. Finally, TOPAS MC is employed to simulate IDDs, ES, and LETs. From the simulated IDD, the extracted ES and LET are compared with the simulations from TOPAS MC. Results: From the synthesized IDDs, the LETs agreed excellently when the peak energies ≥10 and 1.25 MeV with depth resolutions 0.1 and 0.01 mm, respectively. For energy <1.25 MeV, even higher depth resolution than 0.01 mm is required. From the MC simulated IDDs, our track‐averaged LET excellently agreed with MC simulation, but not the LETd. Our LETd was smaller than MC simulated LETd in the shallow region but larger in the distal Bragg peak region. Conclusion: LET can be accurately determined from the IDD. This method can be used in the clinic to commission or validate LETs from other measurement methods or a treatment planning system. [ABSTRACT FROM AUTHOR]

A first of its kind experimental verification of dose-averaged linear energy transfer (LET d) optimized treatment plans for proton therapy has been carried out using a silicon-on-insulator microdosimeter at the Massachusetts General Hospital (MGH), Boston, USA. Three clinical treatment plans of a typical ependymoma structure set were designed using the standard clinical approach, the proposed protocol approach, and a one-field approach. The plans were then reoptimized to reduce the LET d -weighted dose in the brain stem. All six plans were delivered in a solid water phantom and the experimental y D ‾ measured. After LET d optimization, a reduction in y D ‾ was found within the brain stem by an average of 12%, 19%, and 4% for the clinical, protocol, and one-field plans, respectively, while maintaining adequate coverage of the tumor structure. The experimental LET d -weighted doses were in agreement with the treatment planning system calculations and Monte Carlo simulations and reinforced the improvement of the optimization. This work demonstrates the first experimental verification of the clinical implementation of LET d optimization for patient treatment with proton therapy. [ABSTRACT FROM AUTHOR]

Proton relative biological effectiveness (RBE) is a dynamic variable influenced by factors like linear energy transfer (LET), dose, tissue type, and biological endpoint. The standard fixed proton RBE of 1.1, currently used in clinical planning, may not accurately represent the true biological effects of proton therapy (PT) in all cases. This uncertainty can contribute to radiation-induced normal tissue toxicity in patients. In late-responding tissues such as the spinal cord, toxicity can cause devastating complications. This study investigated spinal cord tolerance in mice subjected to proton irradiation and characterized the influence of fractionation on proton- induced myelopathy at entrance (ENT) and Bragg peak (BP) positions. Cervical spinal cords of 8-week-old C57BL/6J female mice were irradiated with single- or multi-fractions (18x) using lateral opposed radiation fields at 1 of 2 positions along the Bragg curve: ENT (dose-mean LET = 1.2 keV/μm) and BP (LET = 6.9 keV/μm). Mice were monitored over 1 year for changes in weight, mobility, and general health, with radiation-induced myelopathy as the primary biological endpoint. Calculations of the RBE of the ENT and BP curve (RBE ENT/BP) were performed. Single-fraction RBE ENT/BP for 50% effect probability (tolerance dose (TD 50), grade II paresis, determined using log-logistic model fitting) was 1.10 ± 0.06 (95% CI) and for multifraction treatments it was 1.19 ± 0.05 (95% CI). Higher incidence and faster onset of paralysis were seen in mice treated at the BP compared with ENT. The findings challenge the universally fixed RBE value in PT, indicating up to a 25% mouse spinal cord RBE ENT/BP variation for multifraction treatments. These results highlight the importance of considering fractionation in determining RBE for PT. Robust characterization of proton-induced toxicity, aided by in vivo models, is paramount for refining clinical decision-making and mitigating potential patient side effects. [ABSTRACT FROM AUTHOR]

The recently proposed Integrated Physical Optimization Intensity Modulated Proton Therapy (IPO-IMPT) framework allows simultaneous optimization of dose, dose rate, and linear energy transfer (LET) for ultra-high dose rate (FLASH) treatment planning. Finding solutions to IPO-IMPT is difficult because of computational intensiveness. Nevertheless, an inverse solution that simultaneously specifies the geometry of a sparse filter and weights of a proton intensity map is desirable for both clinical and preclinical applications. Such solutions can reduce effective biologic dose to organs at risk in patients with cancer as well as reduce the number of animal irradiations needed to derive extra biologic dose models in preclinical studies. Unlike the initial forward heuristic, this inverse IPO-IMPT solution includes simultaneous optimization of sparse range compensation, sparse range modulation, and spot intensity. The daunting computational tasks vital to this endeavor were resolved iteratively with a distributed computing framework to enable Simultaneous Intensity and Energy Modulation and Compensation (SIEMAC). SIEMAC was demonstrated on a human patient with central lung cancer and a minipig. SIEMAC simultaneously improves maps of spot intensities and patient-field–specific sparse range compensators and range modulators. For the patient with lung cancer, at our maximum nozzle current of 300 nA, dose rate coverage above 100 Gy/s increased from 57% to 96% in the lung and from 93% to 100% in the heart, and LET coverage above 4 keV/µm dropped from 68% to 9% in the lung and from 26% to <1% in the heart. For a simple minipig plan, the full-width half-maximum of the dose, dose rate, and LET distributions decreased by 30%, 1.6%, and 57%, respectively, again with similar target dose coverage, thus reducing uncertainty in these quantities for preclinical studies. The inverse solution to IPO-IMPT demonstrated the capability to simultaneously modulate subspot proton energy and intensity distributions for clinical and preclinical studies. [ABSTRACT FROM AUTHOR]

Carbon-ion irradiation is increasingly used at the skull base and spine near the radiation-sensitive spinal cord. To better characterize the in vivo radiation response of the cervical spinal cord, radiogenic changes in the high-dose area were measured in rats using magnetic resonance imaging (MRI) diffusion measurements in comparison to conventional photon irradiations. In this longitudinal MRI study, we examined the gray matter (GM) of the cervical spinal cord in 16 female Sprague-Dawley rats after high-dose photon (n = 8) or carbon-ion (12C) irradiation (n = 8) and in 6 sham-exposed rats until myelopathy occurred. The differences in the diffusion pattern of the GM of the cervical spinal cord were examined until the endpoint of the study, occurrence of paresis grade II of both forelimbs was reached. In both radiation techniques, the same order of the occurrence of MR-morphological pathologies was observed – from edema formation to a blood spinal cord barrier (BSCB) disruption to paresis grade II of both forelimbs. However, carbon-ion irradiation showed a significant increase of the mean apparent diffusion coefficient (ADC; P = 0.031) with development of a BSCB disruption in the GM. Animals with paresis grade II as a late radiation response had a highly significant increase in mean ADC (P = 0.0001) after carbon-ion irradiation. At this time, a tendency was observed for higher mean ADC values in the GM after 12C irradiation as compared to photon irradiation (P = 0.059). These findings demonstrated that carbon-ion irradiation leads to greater structural damage to the GM of the rat cervical spinal cord than photon irradiation due to its higher linear energy transfer (LET) value. [ABSTRACT FROM AUTHOR]

The ionizing radiation with high linear energy transfer (LET), such as a heavy ion beam, induces more serious biological effects than low LET ones, such as gamma- and X-rays. This indicates a difference in the DNA damage produced by low and high LET radiations and their biological effects. We have been studying the differences in DNA damage produced by gamma-rays and carbon ion beams. Therefore, we analyze mutations induced by both ionizing radiations to discuss the differences in their biological effects in this study. pUC19 plasmid DNA was irradiated by carbon ion beams in the solution containing 1M dimethyl sulfoxide to mimic a cellular condition. The irradiated DNA was cloned in competent cells of Escherichia coli. The clones harboring some mutations in the region of lacZα were selected, and the sequence alterations were analyzed. A one-deletion mutation is significant in the carbon-irradiated DNA, and the C:G↔T:A transition is minor. On the other hand, the gamma-irradiated DNA shows mainly G:C↔T:A transversion. These results suggest that carbon ion beams produce complex DNA damage, and gamma-rays are prone to single oxidative base damage, such as 8-oxoguanine. Carbon ion beams can also introduce oxidative base damage, and the damage species is 5-hydroxycytosine. This was consistent with our previous results of DNA damage caused by heavy ion beams. We confirmed the causal DNA damage by mass spectrometry for these mutations. [ABSTRACT FROM AUTHOR]

Purpose: Carbon ion radiotherapy (CIRT) relies on relative biological effectiveness (RBE)‐weighted dose calculations. Japanese clinics predominantly use the microdosimetric kinetic model (MKM), while European centers utilize the local effect model (LEM). Despite both models estimating RBE‐distributions in tissue, their physical and mathematical assumptions differ, leading to significant disparities in RBE‐weighted doses. Several European clinics adopted Japanese treatment schedules, necessitating adjustments in dose prescriptions and organ at risk (OAR) constraints. In the context of these two clinically used standards for RBE‐weighted dose estimation, the objective of this study was to highlight specific scenarios for which the translations between models diverge, as shortcomings between them can influence clinical decisions. Methods: Our aim was to discuss planning strategies minimizing those discrepancies, ultimately striving for more accurate and robust treatments. Evaluations were conducted in a virtual water phantom and patient CT‐geometry, optimizing LEM RBE‐weighted dose first and recomputing MKM thereafter. Dose‐averaged linear energy transfer (LETd) distributions were also assessed. Results: Results demonstrate how various parameters influence LEM/MKM translation. Similar LEM‐dose distributions lead to markedly different MKM‐dose distributions and variations in LETd. Generally, a homogeneous LEM RBE‐weighted dose aligns with lower MKM values in most of the target volume. Nevertheless, paradoxical MKM hotspots may emerge (at the end of the range), potentially influencing clinical outcomes. Therefore, translation between models requires great caution. Conclusions: Understanding the relationship between these two clinical standards enables combining European and Japanese based experiences. The implementation of optimal planning strategies ensures the safety and acceptability of the clinical plan for both models and therefore enhances plan robustness from the RBE‐weighted dose and LETd distribution point of view. This study emphasizes the importance of optimal planning strategies and the need for comprehensive CIRT plan quality assessment tools. In situations where simultaneous LEM and MKM computation capabilities are lacking, it can provide guidance in plan design, ultimately contributing to enhanced CIRT outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose: Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities. Materials and methods: Radiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated. Results: For the index cases, which developed toxicities at low dose levels (mean, 50 GyRBE), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 GyRBE/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 GyRBE/s. LET-related metrics were not substantially different between the index and non-toxicity cases. Conclusions: Our observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury. [ABSTRACT FROM AUTHOR]

Objective. This study characterized optically-stimulated luminescent dosimeter (OSLD) nanoDots for use in a therapeutic carbon beam using the Imaging and Radiation Oncology Core (IROC) framework for remote output verification. Approach. The absorbed dose correction factors for OSLD (fading, linearity, beam quality, angularity, and depletion), as defined by AAPM TG 191, were characterized for carbon beams. For the various correction factors, the effect of linear energy transfer (LET) was examined by characterizing in both a low and high LET setting. Main results. Fading was not statistically different between reference photons and carbon, nor between low and high LET beams; thus, the standard IROC-defined exponential function could be used to characterize fading. Dose linearity was characterized with a linear fit; while low and high LET carbon linearity was different, these differences were small and could be rolled into the uncertainty budget if using a single linearity correction. A linear fit between beam quality and dose-averaged LET was determined. The OSLD response at various angles of incidence was not statistically different, thus a correction factor need not be applied. There was a difference in depletion between low and high LET irradiations in a primary carbon beam, but this difference was small over the standard five readings. The largest uncertainty associated with the use of OSLDs in carbon was because of the k Q correction factor, with an uncertainty of 6.0%. The overall uncertainty budget was 6.3% for standard irradiation conditions. Significance. OSLD nanoDot response was characterized in a therapeutic carbon beam. The uncertainty was larger than for traditional photon applications. These findings enable the use of OSLDs for carbon absorbed dose measurements, but with less accuracy than conventional OSLD audit programs. [ABSTRACT FROM AUTHOR]

Background: Carbon ion beams are well accepted as densely ionizing radiation with a high linear energy transfer (LET). However, the current clinical practice does not fully exploit the highest possible dose‐averaged LET (LETd) and, consequently, the biological potential in the target. This aspect becomes worse in larger tumors for which inferior clinical outcomes and corresponding lower LETd was reported. Purpose: The vicinity to critical organs in general and the inferior overall survival reported for larger sacral chordomas treated with carbon ion radiotherapy (CIRT), makes the treatment of such tumors challenging. In this work it was aimed to increase the LETd in large volume tumors while maintaining the relative biological effectiveness (RBE)‐weighted dose, utilizing the LETd optimization functions of a commercial treatment planning system (TPS). Methods: Ten reference sequential boost carbon ion treatment plans, designed to mimic clinical plans for large sacral chordoma tumors, were generated. High dose clinical target volumes (CTV‐HD) larger than 250cm3$250 \,{\rm cm}^{3}$ were considered as large targets. The total RBE‐weighted median dose prescription with the local effect model (LEM) was DRBE,50%=73.6Gy$\textrm {D}_{\rm RBE, 50\%}=73.6 \,{\rm Gy}$ in 16 fractions (nine to low dose and seven to high dose planning target volume). No LETd optimization was performed in the reference plans, while LETd optimized plans used the minimum LETd (Lmin) optimization function in RayStation 2023B. Three different Lmin values were investigated and specified for the seven boost fractions: Lmin=60keV/μm$\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$, Lmin=80keV/μm$\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$ and Lmin=100keV/μm$\textrm {L}_{\rm min}=100 \,{\rm keV}/{\umu }{\rm m}$. To compare the LETd optimized against reference plans, LETd and RBE‐weighted dose based goals similar to and less strict than clinical ones were specified for the target. The goals for the organs at risk (OAR) remained unchanged. Robustness evaluation was studied for eight scenarios (±3.5%$\pm 3.5\%$ range uncertainty and ±3mm$\pm 3 \,{\rm mm}$ setup uncertainty along the main three axes). Results: The optimization method with Lmin=60keV/μm$\textrm {L}_{\rm min}=60 \,{\rm keV}/{\umu }{\rm m}$ resulted in an optimal LETd distribution with an average increase of LETd,98%${\rm {LET}}_{{\rm {d,}}98\%}$ (and LETd,50%${\rm {LET}}_{{\rm {d,}}50\%}$) in the CTV‐HD by 8.9±1.5keV/μm$8.9\pm 1.5 \,{\rm keV}/{\umu }{\rm m}$ (27%$27\%$) (and 6.9±1.3keV/μm$6.9\pm 1.3 \,{\rm keV}/{\umu }{\rm m}$ (17%$17\%$)), without significant difference in the RBE‐weighted dose. By allowing ±5%$\pm 5\%$ over‐ and under‐dosage in the target, the LETd,98%${\rm {LET}}_{{\rm {d,}}98\%}$ (and LETd,50%${\rm {LET}}_{{\rm {d,}}50\%}$) can be increased by 11.3±1.2keV/μm$11.3\pm 1.2 \,{\rm keV}/{\umu }{\rm m}$ (34%$34\%$) (and 11.7±3.4keV/μm$11.7\pm 3.4 \,{\rm keV}/{\umu }{\rm m}$ (29%$29\%$)), using the optimization parameters Lmin=80keV/μm$\textrm {L}_{\rm min}=80 \,{\rm keV}/{\umu }{\rm m}$. The pass rate for the OAR goals in the LETd optimized plans was in the same level as the reference plans. LETd optimization lead to less robust plans compared to reference plans. Conclusions: Compared to conventionally optimized treatment plans, the LETd in the target was increased while maintaining the RBE‐weighted dose using TPS LETd optimization functionalities. Regularly assessing RBE‐weighted dose robustness and acquiring more in‐room images remain crucial and inevitable aspects during treatment. [ABSTRACT FROM AUTHOR]

The Korean Radiation Workers Study (KRWS) cohort was established in 2022 to assess the risk of cancer and non-cancer diseases due to occupational radiation exposure. The cohort consists of 196,379 workers, with the majority being men and around 60% born before 1980. Data on cancer, non-cancer diseases, cause of death, and various confounders were obtained from national resources. The study aims to update radiation doses and disease status every 5-10 years and welcomes proposals for further data analyses. The study found that 3.1% of workers had been diagnosed with cancer, with thyroid cancer being the most prevalent type. The most common causes of death were malignant neoplasms, external causes, and circulatory diseases. The incidence of cancer and mortality was higher in men, except for thyroid cancer, which was more common in women. The cohort provided a total of 2.5 million person-years for cancer incidence and 2.8 million person-years for mortality. The Korean Radiation Workers Study (KRWS) is a large-scale national cohort study that aims to investigate the long-term health effects of radiation exposure in Korean workers. The cohort includes both retired and newly hired workers and is designed for long-term follow-up. The study collects comprehensive health information from national registries, ensuring accuracy and completeness of data. The cohort has strengths such as regular updates, availability of confounding factors, and monitoring of cancer incidence. However, limitations include a relatively small [Extracted from the article]

(1) Background: DNA damage is of great importance in the understanding of the effects of ionizing radiation. Various types of DNA damage can result from exposure to ionizing radiation, with clustered types considered the most important for radiobiological effects. (2) Methods: The code RITRACKS (Relativistic Ion Tracks), a program that simulates stochastic radiation track structures, was used to simulate DNA damage by photons and ions spanning a broad range of linear energy transfer (LET) values. To perform these simulations, the transport code was modified to include cross sections for the interactions of ions or electrons with DNA and amino acids for ionizations, dissociative electron attachment, and elastic collisions. The radiochemistry simulations were performed using a step-by-step algorithm that follows the evolution of all particles in time, including reactions between radicals and DNA structures and amino acids. Furthermore, detailed DNA damage events, such as base pair positions, DNA fragment lengths, and fragment yields, were recorded. (3) Results: We report simulation results using photons and the ions 1H+, 4He2+, 12C6+, 16O8+, and 56Fe26+ at various energies, covering LET values from 0.3 to 164 keV/µm, and performed a comparison with other codes and experimental results. The results show evidence of DNA protection from damage at its points of contacts with histone proteins. (4) Conclusions: RITRACKS can provide a framework for studying DNA damage from a variety of ionizing radiation sources with detailed representations of DNA at the atomic scale, DNA-associated proteins, and resulting DNA damage events and statistics, enabling a broader range of future comparisons with experiments such as those based on DNA sequencing. [ABSTRACT FROM AUTHOR]

Based on the characteristics of space particle radiation in the Sun-synchronous orbit (SSO), a space particle radiation effect comprehensive measuring instrument (SPRECMI) was installed on the orbital platform of the upper stage of the Chinese CZ-4C carrier rocket, which can acquire the high-energy proton energy spectra, linear energy transfer (LET) spectra of particles, and radiation dose rate. The particle radiation detection data were obtained at 1000 km altitude for the first time, which can be used mainly for scientific research of the space environment, in-orbit fault analysis, and the operational control management of spacecraft, and can also serve as reference data for component validation tests. After SPRECMI's development, accelerator calibration and simulations were conducted, and the results demonstrated that all the measured indicators, including the high-energy proton spectra (energy range: 21.8–275.0 MeV, precision: <3.3%), total radiation dose (dose range: 0–1.04 × 106 rad, sensitivity: 6.2 µrad/h), and the LET spectra (range: 0.001–37.20 MeV/(mg/cm2), >37.2 MeV/(mg/cm2)), met the relevant requirements. Furthermore, the in-orbit flight test revealed that the detection results of the load components were consistent with the physical characteristics of the particle radiation environment of the spacecraft's orbit. [ABSTRACT FROM AUTHOR]

This study delves into the impact of lithium (Li3+) and silver (Ag7+) ion irradiation on the structure and luminescence of Dy3+ doped and Dy3+/Eu3+ co-doped Gd2MoO6 phosphors, synthesized via the hydrothermal method. To explore the influence of ions with varied mass and energy, 30 MeV Li3+ and 100 MeV Ag7+ ions were employed at different fluences. We elucidate the induced effects based on defect formation and the role of these ions' linear energy transfer (LET) within the irradiated material. SRIM software estimates the depth profile of the ions. Irradiation of the Gd2MoO6 phosphors with Li3+ and Ag7+ ions resulted in the formation of disordered lattices or tracks, modifying their structural, optical, and luminescence properties, which were analyzed by various techniques, including X-ray diffraction, scanning electron microscopy, diffuse reflectance, and photoluminescence. Thermoluminescence (TL) tests and calculations of trapping parameters were conducted to evaluate the dosimetric potential. The findings reveal a more pronounced effect of silver ions compared to lithium ions on the structural and luminescence behavior of doped and codoped Gd2MoO6 phosphors due to their higher atomic weight. [ABSTRACT FROM AUTHOR]

Background: Local recurrence in locally advanced pancreatic cancer (LAPC) after carbon‐ion radiotherapy (CIRT) may partly attribute to low dose‐averaged linear energy transfer (LETd), despite high CIRT dose. Purpose: This study aimed to investigate the approaches to up‐modulate the CIRT LETd and to evaluate the corresponding oxygen enhancement ratio (OER) reduction. Methods: 10 LAPCs that had been irradiated by CIRT with 67.5 Gy (RBE) in 15 fractions were selected. Their original plans were taken as the control plan for the LETd and OER investigations. Our considerations for up‐modulating LETd were: (1) to deliver high doses to gross tumor volume core (GTVcore), while keeping dose constraints of the gastrointestinal (GI) tract in tolerance; (2) to put more Bragg‐peak (BP) within the modulated targets; (3) to increase the BP density, high doses were necessary; (4) CIRT LETd could be effectively increased to small volumes; and (5) simultaneous integrated boost technique (SIB) could achieve the aforementioned tasks. The LETd and the corresponding OER distributions of each type of SIB plan were evaluated. Results: We delivered up to 100 Gy (RBE) to GTVcore using SIB. The mean LETd of GTV increased significantly by 21.3% from 47.8 to 58.0 keV/μm (p < 0.05). Meanwhile, the mean OER of GTVcore decreased by 6.6%, from 1.51 to 1.41 (p < 0.05). The GI LETdS in all modulated plans were not more than those in the original plans. Conclusions: SIB could effectively increase CIRT LETd to LAPC, thus producing reduced OER, which may effectively overcome the radioresistance of LAPCs. [ABSTRACT FROM AUTHOR]

IntroductionHeavy ions of the galactic cosmic radiation dominate the radiation risks and biological effects for plants under spaceflight conditions. However, the biological effects and sensitive genes caused by heavy ions with different linear energy transfer (LET) values have not been thoroughly studied.MethodsTo comprehensively analyze the biological effects of heavy ions with different LET values on rice under spaceflight conditions, we utilized the Shijian-10 recoverable satellite (SJ-10) to transport the dehydrated rice seeds on a 12.5-day mission in a 252 km low Earth orbit (LEO), and obtained rice plants hit by individual heavy ions with LET values ranging from 18 keV/μm to 213 keV/μm. The transcriptome and methylation sequencing were conducted on above plants, and a bioinformatics pipeline based on single-sample networks (SSNs) and genetic algorithms (GA) was developed to analyze the multi-omics expression profiles in this work. Note that SSNs can depict the gene interaction patterns within a single sample. The LET regression models were constructed from both gene expression and interaction pattern perspectives respectively, and the radiation response genes that played significant roles in the models were identified. We designed a gene selection algorithm based on GA to enhance the performance of LET regression models.ResultsThe experimental results demonstrate that all our models exhibit excellent regression performance (R2 values close to 1), which indicates that both gene expressions and interaction patterns can reflect the molecular changes caused by heavy ions with different LET values. LET-related genes (genes exhibiting strong correlation with LET values) and radiation-responsive genes were identified, primarily involved in DNA damage and repair, oxidative stress, photosynthesis, nucleic acid metabolism, energy metabolism, amino acid/protein metabolism, and lipid metabolism, etc. DNA methylation plays a crucial role in responding to heavy ions stressors and regulates the aforementioned processes.DiscussionTo the best of our knowledge, this is the first study to report the multi-omics changes in plants after exposure to heavy ions with different LET values under spaceflight conditions.

Background and Purpose: Radiotherapy for paediatric posterior fossa tumours may cause complications in the brainstem and upper spinal cord due to high doses. With proton therapy (PT) this risk may increase due to higher relative biological effectiveness (RBE) from elevated linear energy transfer (LET). This study assesses variations in LET in the brainstem and spinal cord in proton treatment plans from European centres. Materials and Methods: Ten European PT centres using spot-scanning PT planned two paediatric posterior fossa cases: One overlapping partly with the brainstem and upper spinal cord, prescribed 54 Gy(RBE), and the second wrapping around these organs, prescribed 59.4 Gy(RBE). Dose-averaged LET distributions were assessed in volumes of the brainstem and spinal cord irradiated to over 50 Gy(RBE = 1.1). The maximum hinge angle effect on near-maximum RBE-weighted doses using the Unkelbach RBE model was also investigated. Results: In the first case, the mean LET in brainstem volumes receiving more than 50 Gy(RBE = 1.1) ranged from 2.8 keV/µm to 3.6 keV/µm across centres (median: 3.3 keV/µm). In the second case, treatment plans showed a narrower range of mean LET in the brainstem, from 2.5 keV/µm to 2.8 keV/µm (median: 2.7 keV/µm). There was no statistically significant impact of the maximum hinge angle. Conclusions: LET distributions vary across centres due to different techniques but are also influenced significantly by factors like shape and position of the target volume.

The model of lateral β-Ga2O3 metal–oxide–semiconductor field-effect transistor (MOSFET) was established using Sentaurus Technology Computer Aided Design software. The gate-to-drain distance of the device was 13.7 μm, and the breakdown voltage was 1135 V. The single event effect simulation model caused by heavy ion irradiation was introduced, and the effects of heavy ions' incident position, angle, drain bias voltage, and linear energy transfer on the single event effect were studied. It is found that x = 7.7 μm is the sensitive location of the single event effect at the gate corner near the drain side and the peak value of the transient current is 177 mA/mm. The effect of the terminal structure of the field plate on the transient effect of the single event effect of β-Ga2O3 MOSFET is studied. It is also found that the sensitive position of the single event effect of the conventional structure, gate-field plate structure, and gate–source composite field plate structure is around x = 7.7 μm when VDS = 10 V. The peak transient currents obtained are 177, 161, and 148 mA/mm. The single event effect pulse current of the three structures increases with an increase in the drain bias voltage, while the peak pulse current of the conventional structure is larger than that of the gate-field plate structure and the gate–source composite structure. The research shows that the terminal structure of the field plate is reliable means to reduce the single particle effect. [ABSTRACT FROM AUTHOR]

Background: A significant challenge in cancer therapy lies in eradicating hidden disseminated tumor cells. Within Nuclear Medicine, Targeted Alpha Therapy is a promising approach for cancer treatment tackling disseminated cancer. As tumor size decreases, alpha-particles gain prominence due to their high Linear Energy Transfer (LET) and short path length. Among alpha-particle emitters, 211At stands out with its 7.2 hour half-life and 100% alpha emission decay. However, optimizing the pharmacokinetics of radiopharmaceuticals with short lived radionuclides such as 211At is pivotal, and in this regard, pretargeting is a valuable tool. This method involves priming the tumor with a modified monoclonal antibody capable of binding both the tumor antigen and the radiolabeled carrier, termed the "effector molecule. This smaller, faster-clearing molecule improves efficacy. Utilizing the Diels Alder click reaction between Tetrazine (Tz) and Trans-cyclooctene (TCO), the Tz-substituted effector molecule combines seamlessly with the TCO-modified antibody. This study aims to evaluate the in vivo biodistribution of two Poly-L-Lysine-based effector molecule sizes (10 and 21 kDa), labelled with 211At, and the in vitro binding of the most favorable polymer size, in order to optimize the pretargeted radioimmunotherapy with 211At. Results: In vivo results favor the smaller polymer's biodistribution pattern over the larger one, which accumulates in organs like the liver and spleen. This is especially evident when comparing the biodistribution of the smaller polymer to a directly labelled monoclonal antibody. The smaller variant also shows rapid and efficient binding to SKOV-3 cells preloaded with TCO-modified Trastuzumab in vitro, emphasizing its potential. Both polymer sizes showed equal or better in vivo stability of the astatine-carbon bond compared to a monoclonal antibody labelled with the same prosthetic group. Conclusions: Overall, the small Poly-L-Lysine-based effector molecule (10 kDa) holds the most promise for future research, exhibiting significantly lower uptake in the kidneys and spleen compared to the larger effector (21 kDa) while maintaining an in vivo stability of the astatine-carbon bond comparable to or better than intact antibodies. A proof of concept in vitro cell study demonstrates rapid reaction between the small astatinated effector and a TCO-labelled antibody, indicating the potential of this novel Poly-L-Lysine-based pretargeting system for further investigation in an in vivo tumor model. [ABSTRACT FROM AUTHOR]

Radiation therapy, one of the most effective methods for cancer treatment, is still limited by the tolerances of normal tissues surrounding the tumor. Innovative techniques like spatially fractionated radiation therapy (SFRT) have been shown to increase normal tissue dose resistance. Heavy ions also offer high-dose conformity and increased relative biological effectiveness (RBE) when compared to protons and X-rays. The alliance of heavy ions and spatial fractionation of the dose has the potential to further increase the therapeutic index for difficult-to-treat cases today. In particular, the use of β-delayed multiple-particle emitters might further improve treatment response, as it holds the potential to increase high linear energy transfer (LET) decay products in the valleys of SFRT (low-dose regions) at the end of the range. To verify this hypothesis, this study compares β-delayed multiple-particle emitters (8Li, 9C, 31Ar) with their respective stable isotopes (7Li, 12C, 40Ar) to determine possible benefits of β-delayed multiple-particle emitters minibeam radiation therapy (β-MBRT). Monte Carlo simulations were performed using the GATE toolkit to assess the dose distributions of each ion. RBE-weighted dose distributions were calculated and used for the aforementioned comparison. No significant differences were found among carbon isotopes. In contrast, 8Li and 31Ar exhibited improved RBE-weighted dose distributions with an approximately 12-20% increase in the Bragg-peak-to-entrance dose ratio (BEDR) for both peaks and valleys, which favors tissue sparing. Additionally, 8Li and 31Ar exhibited a lower peak-to-valley dose ratio (PVDR) in normal tissues and higher PVDR in the tumor than 7Li and 40Ar. Biological experiments are needed to conclude whether the differences observed make β-delayed multiple-particle emitters advantageous for MBRT. [ABSTRACT FROM AUTHOR]

Background: Interpatient variation of tumor radiosensitivity is rarely considered during the treatment planning process despite its known significance for the therapeutic outcome. Purpose: To apply our mechanistic biophysical model to investigate the biological robustness of carbon ion radiotherapy (CIRT) against DNA damage repair interference (DDRi) associated patient‐to‐patient variability in radiosensitivity and its potential clinical advantages against conventional radiotherapy approaches. Methods and Materials: The "UNIfied and VERSatile bio response Engine" (UNIVERSE) was extended by carbon ions and its predictions were compared to a panel of in vitro and in vivo data including various endpoints and DDRi settings within clinically relevant dose and linear energy transfer (LET) ranges. The implications of UNIVERSE predictions were then assessed in a clinical patient scenario considering DDRi variance. Results: UNIVERSE tests well against the applied benchmarks. While in vitro survival curves were predicted with an R2 > 0.92, deviations from in vivo RBE data were less than 5.6% The conducted paradigmatic patient plan study implies a markedly reduced significance of DDRi based radiosensitivity variability in CIRT (13% change of D50${{D}_{50}}$ in target) compared to conventional radiotherapy (62%) and that boosting the LET within the target further amplifies this robustness of CIRT (8%). In the case of heightened tumor radiosensitivity, a dose de‐escalation strategy for photons allows a reduction of the maximum effective dose within the normal tissue (NT) from a D2${{D}_2}$ of 2.65 to 1.64 Gy, which lies below the level found for CIRT (D2${{D}_2}$ = 2.41 Gy) for the analyzed plan and parameters. However, even after de‐escalation, the integral effective dose in the NT is found to be substantially higher for conventional radiotherapy in comparison to CIRT (Dmean${{D}_{mean}}$ of 0.75, 0.46, and 0.24 Gy for the conventional plan, its de‐escalation and CIRT, respectively). Conclusions: The framework offers adequate predictions of in vitro and in vivo radiation effects of CIRT while allowing the consideration of DRRi based solely on parameters derived from photon data. The results of the patient planning study underline the potential of CIRT to minimize important sources of interpatient divergence in therapy outcome, especially when combined with techniques that allow to maximize the LET within the tumor. Despite the potential of de‐escalation strategies for conventional radiotherapy to reduce the maximum effective dose in the NT, CIRT appears to remain a more favorable option due to its ability to reduce the integral effective dose within the NT. [ABSTRACT FROM AUTHOR]

Background: Diffusing alpha‐emitters radiation therapy (DaRT) is a novel brachytherapy technique that leverages the diffusive flow of 224Ra progeny within the tumor volume over the course of the treatment. Cell killing is achieved by the emitted alpha particles that have a short range in tissue and high linear energy transfer. The current proposed absorbed dose calculation method for DaRT is based on a diffusion‐leakage (DL) model that neglects absorbed dose from beta particles. Purpose: This work aimed to couple the DL model with dose point kernels (DPKs) to account for dose from beta particles as well as to consider the non‐local deposition of energy. Methods: The DaRT seed was modeled using COMSOL multiphysics and the DL model was implemented to extract the spatial information of the diffusing daughters. Using Monte–Carlo (MC) methods, DPKs were generated for 212Pb, 212Bi, and their progenies since they were considered to be the dominant beta emitters in the 224Ra radioactive decay chain. A convolution operation was performed between the integrated number densities of the diffusing daughters and DPKs to calculate the total absorbed dose over a 30‐day treatment period. Both high‐diffusion and low‐diffusion cases were considered. Results: The calculated DPKs showed non‐negligible energy deposition over several millimeters from the source location. An absorbed dose >10 Gy was deposited within a 1.8 mm radial distance for the low diffusion case and a 2.2 mm radial distance for the high diffusion case. When the DPK method was compared with the local energy deposition method that solely considered dose from alpha particles, differences above 1 Gy were found within 1.3 and 1.8 mm radial distances from the surface of the source for the low diffusion and high diffusion cases, respectively. Conclusions: The proposed method enhances the accuracy of the dose calculation method used for the DaRT technique. [ABSTRACT FROM AUTHOR]

Based on the need for radiobiological databases, in this work, we mined experimental ionizing radiation data of human cells treated with X-rays, γ-rays, carbon ions, protons and α-particles, by manually searching the relevant literature in PubMed from 1980 until 2024. In order to calculate normal and tumor cell survival α and β coefficients of the linear quadratic (LQ) established model, as well as the initial values of the double-strand breaks (DSBs) in DNA, we used WebPlotDigitizer and Python programming language. We also produced complex DNA damage results through the fast Monte Carlo code MCDS in order to complete any missing data. The calculated α/β values are in good agreement with those valued reported in the literature, where α shows a relatively good association with linear energy transfer (LET), but not β. In general, a positive correlation between DSBs and LET was observed as far as the experimental values are concerned. Furthermore, we developed a biophysical prediction model by using machine learning, which showed a good performance for α, while it underscored LET as the most important feature for its prediction. In this study, we designed and developed the novel radiobiological 'RadPhysBio' database for the prediction of irradiated cell survival (α and β coefficients of the LQ model). The incorporation of machine learning and repair models increases the applicability of our results and the spectrum of potential users. [ABSTRACT FROM AUTHOR]