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Background: This study aims to present the feasibility of developing a synchrotron-based proton ultra-high dose rate (UHDR) pencil beam scanning (PBS) system. Methods: The RF extraction power in the synchrotron system was increased to generate 142.4 MeV pulsed proton beams for UHDR irradiation at ~100 nA beam current. The charge per spill was measured using a Faraday cup. The spill length and microscopic time structure of each spill was measured with a 2D strip transmission ion chamber. The measured UHDR beam fluence was used to derive the spot dwell time for pencil beam scanning. Absolute dose distributions at various depths and spot spacings were measured using Gafchromic films in a solid-water phantom. Results: For proton UHDR beams at 142.4 MeV, the maximum charge per spill is 4.96 ± 0.10 nC with a maximum spill length of 50 ms. This translates to an average beam current of approximately 100 nA during each spill. Using a 2 × 2 spot delivery pattern, the delivered dose per spill at 5 cm and 13.5 cm depth is 36.3 Gy (726.3 Gy/s) and 56.2 Gy (1124.0 Gy/s), respectively. Conclusions: The synchrotron-based proton therapy system has the capability to deliver pulsed proton UHDR PBS beams. The maximum deliverable dose and field size per pulse are limited by the spill length and extraction charge.

A proton beam therapy (PBT) system has been designed which dedicates to spot-scanning and has a gating function employing the fluoroscopy-based real-time-imaging of internal fiducial markers near tumors. The dose distribution and treatment time of the newly designed real-time-image gated, spot-scanning proton beam therapy (RGPT) were compared with free-breathing spot-scanning proton beam therapy (FBPT) in a simulation. In-house simulation tools and treatment planning system VQA (Hitachi, Ltd., Japan) were used for estimating the dose distribution and treatment time. Simulations were performed for 48 motion parameters (including 8 respiratory patterns and 6 initial breathing timings) on CT data from two patients, A and B, with hepatocellular carcinoma and with clinical target volumes 14.6 cc and 63.1 cc. The respiratory patterns were derived from the actual trajectory of internal fiducial markers taken in X-ray real-time tumor-tracking radiotherapy (RTRT). With FBPT, 9/48 motion parameters achieved the criteria of successful delivery for patient A and 0/48 for B. With RGPT 48/48 and 42/48 achieved the criteria. Compared with FBPT, the mean liver dose was smaller with RGPT with statistical significance (p<0.001); it decreased from 27% to 13% and 28% to 23% of the prescribed doses for patients A and B, respectively. The relative lengthening of treatment time to administer 3 Gy (RBE) was estimated to be 1.22 (RGPT/FBPT: 138 s/113 s) and 1.72 (207 s/120 s) for patients A and B, respectively. This simulation study demonstrated that the RGPT was able to improve the dose distribution markedly for moving tumors without very large treatment time extension. The proton beam therapy system dedicated to spot-scanning with a gating function for real-time imaging increases accuracy with moving tumors and reduces the physical size, and subsequently the cost of the equipment as well as of the building housing the equipment.

The current monochromatic beam mode (i.e., uHDR irradiation mode) of the scanned carbon-ion beam lacks a dedicated dose monitor, making the beam control challenging. We developed and characterized a dedicated dose monitor for uHDR-scanned carbon-ion beams. Furthermore, a simple measurable dose rate (dose rate per spot (DR spot )) was suggested by using the developed dose monitor and experimentally validating quantities relevant to the uHDR scanned carbon-ion beam. A large plane-parallel ionization chamber (IC) with a smaller electrode spacing was used to reduce uHDR recombination effects, and a dedicated operational amplifier was manufactured for the uHDR-scanned carbon-ion beam. The dose linearity of the IC was within ± 1% in the range of 1.8–12.3 Gy. The spatial inhomogeneity of the dose response of the IC was ± 0.38% inside the ± 40-mm detector area, and a systematic deviation of approximately 2% was measured at the edge of the detector. uHDR irradiation with beam scanning was tested and verified for different doses at the corresponding dose rates (in terms of both the average dose rate and DR spot ). We confirmed that the dose monitor can highlight the characteristics (i.e., dose, dose rate, and dose profile) of uHDR-scanned carbon-ion beams at several dose levels in the monochromatic beam mode.

While the FLASH radiotherapy (FLASH RT) using ultra-high-dose-rate (UHDR) proton beams has the potential to achieve more effective cancer treatment, reliable and practical dosimetry of UHDR beams remains challenging. Although the commercial radiochromic films, named “Gafchromic film,” can be promising tools for the measurements of UHDR beam profiles, these films have some unfavorable features such as scanning orientation effects and lateral response artifacts. In this study, we examined the scanning orientation effects of Gafchromic EBT3 films irradiated with UHDR proton beams. The square sheets (5.5 × 5.5 cm2) of EBT3 film were irradiated with 8.7–8.8 Gy(H2O) at the plateau region of 139 MeV proton beams in the treatment room at the Nagoya Proton Therapy Center (NPTC) at three different dose rates: 0.29 Gy s−1, 170 Gy s−1, and 720 Gy s−1. The irradiated films were scanned in the reference and perpendicular orientations using two scanners: a flatbed scanner (FBS) (GT-X980, Seiko Epson Corp.) and an overhead scanner (OHS) (Aura, CZUR Tech Co., Ltd.). At the conventional dose rate (0.29 Gy s−1), the inverted red and green color profiles acquired by FBS in the perpendicular orientation were significantly lower than those in the reference orientation, as observed in previous studies using photon beams. Unexpectedly, such orientation effects were not observed in the FBS images of the EBT3 films irradiated with UHDR beams. The scanning orientation did not affect the color profiles of the OHS images at any dose rate tested. These results imply that the scanning orientation effect of the Gafchromic film is not a concern in beam profile measurements for FLASH RT. More comprehensive studies are needed to explain the mechanisms underlying these phenomena and to confirm the universality of the findings obtained in this study.Article highlightsThe scanning orientation effects of the EBT3 film were examined for ultra-high-dose-rate (UHDR) proton beams.The scanning orientation effects in the flatbed scanner images were not observed for the UHDR proton beams.The overhead scanner images stably presented fewer orientation effects than the flatbed scanner images.

There are only a few studies on dosimetry with ultrahigh-dose-rate (uHDR) scanned carbon-ion beams. This study investigated the characteristics of four types of ionization chambers for the uHDR beam. We employed a newly developed large-plane parallel chamber to monitor a 208.3-MeV/u uHDR scanned carbon-ion beam with a 110-Gy/s average dose rate. The ionization chambers used were the Advanced Markus chamber (AMC), PinPoint 3D chamber (PPC), Farmer chamber (FC), and large-plane parallel chamber (StingRay). The AMC and StingRay surfaces and the PPC and FC geometric centers were aligned to the radiation isocenter using treatment room lasers. Using the voltage range stated in the instruction manuals, we obtained the saturation curves of the chambers. From these curves, we obtained the ion recombination correction factors using the two-voltage and three-voltage linear methods. The dose linearity was evaluated using five measurement points, and the chamber repeatability was verified by conducting repeated measurements for different dose values. Although all chambers, except for AMC, reached saturation when specified voltages were applied, they exhibited excellent linearity for different dose values. The ion recombination correction factors of the AMC obtained using the aforementioned linear methods were nearly 1. Additionally, all chambers exhibited excellent repeatability. Although the standard deviation of the PPC for the lowest dose was ~1.5%, those of all the other chambers were <1.0%. All ionization chambers can be used for measuring the relative dose, and absolute dose can be conveniently measured using the AMC with an uHDR carbon-ion scanned beam.

Abstract Two chemical dosimeters, lithium formate monohydride (LFM) and L-alanine (ALA), were first evaluated under ultra-high dose rate (UHDR) proton irradiation conditions, known as ‘FLASH’, which has the potential to reduce the impact on normal tissue while effectively killing tumors, using electron spin resonance (ESR) spectroscopy. Both ALA and LFM demonstrated a significant linear increase in ESR peaks that correlated with the physical dose when comparing conventional radiation (CONV) to UHDR radiation. The relative effectiveness (RE: the ratio of the amount of free radicals produced by each type of proton irradiation to the amount produced by 60Co γ-ray irradiation) was determined for CONV, UHDR-Plateau and UHDR-Peak, yielding RE values of 0.849, 0.731 and 0.661 for LFM and 0.834, 0.692 and 0.624 for ALA, respectively. The decrease in RE values was likely due to the combination of UHDR and the increase of linear energy transfer (LET) to facilitate the recombination of radicals formed within the crystal during CONV and UHDR of proton beams. When using the height of the ESR central peak as an indicator of sensitivity, LFM was assessed to be ~20% more sensitive than ALA.

The focus of this report is establishing an irradiation arrangement to realize an ultra-high dose-rate (uHDR; FLASH) of scanned carbon-ion irradiation possible with a compact commonly available medical synchrotron. Following adjustments to the operation it became possible to extract ≥1.0×10 carbon ions at 208.3 MeV/u (86 mm in range) per 100 ms. The design takes the utmost care to prevent damage to monitors, particularly in the nozzle, achieved by the uHDR beam not passing through this part of the apparatus. Doses were adjusted by extraction times, using a function generator. After one scan by the carbon-ion beam it became possible to create a field within the extraction time. The Advanced Markus chamber (AMC) and Gafchromic film are then able to measure the absolute dose and field size at a plateau depth, with the operating voltage of the chamber at 400 V at the uHDR for the AMC. The beam scanning utilizing this uHDR irradiation could be confirmed at a dose of 6.5±0.08 Gy (±3% homogeneous) at this volume over at least 16×16 mm corresponding to a dose-rate of 92.3 Gy/s (±1.3%). The dose was ca. 0.7, 1.5, 2.9, and 5.4 Gy depending on dose-rate and field size, with the rate of killed cells increasing with the irradiation dose. The compact medical synchrotron achieved FLASH dose-rates of >40 Gy/s at different dose levels and in useful field sizes for research with the apparatus and arrangement developed here.

A compact proton synchrotron using combined function magnets is proposed to help realize the wider availability of charged particle cancer therapy facilities. This combined function magnet was designed with the help of three-dimensional magnetic field calculations to take account of a realistic fringe and the interference among the magnetic poles. An evaluation scheme for tune values based on particle tracking was developed to improve the magnet design. To verify the magnet design, a model magnet was fabricated and measured. In order to achieve a tune value evaluation from the measured magnetic field, schemes for accurate field mapping and field interpolation were developed. From the tune value evaluation of the measured magnetic field, it was thought that the performance of the model magnet was good enough to construct a synchrotron. In this paper, we report details of the design and the evaluation scheme for the combined function magnet and the results of the field measurements of the model magnet.

The presence of redox-active molecules containing catenated sulfur atoms (supersulfides) in living organisms has led to a review of the concepts of redox biology and its translational strategy. Glutathione (GSH) is the body’s primary detoxifier and antioxidant, and its oxidized form (GSSG) has been considered as a marker of oxidative status. However, we report that GSSG, but not reduced GSH, prevents ischemic supersulfide catabolism-associated heart failure in male mice by electrophilic modification of dynamin-related protein (Drp1). In healthy exercised hearts, the redox-sensitive Cys644 of Drp1 is highly S-glutathionylated. Nearly 40% of Cys644 is normally polysulfidated, which is a preferential target for GSSG-mediated S-glutathionylation. Cys644 S-glutathionylation is resistant to Drp1 depolysulfidation-dependent mitochondrial hyperfission and myocardial dysfunction caused by hypoxic stress. MD simulation of Drp1 structure and site-directed mutagenetic analysis reveal a functional interaction between Cys644 and a critical phosphorylation site Ser637, through Glu640. Bulky modification at Cys644 via polysulfidation or S-glutathionylation reduces Drp1 activity by disrupting Ser637-Glu640-Cys644 interaction. Disruption of Cys644 S-glutathionylation nullifies the cardioprotective effect of GSSG against heart failure after myocardial infarction. Our findings suggest a therapeutic potential of supersulfide-based Cys bulking on Drp1 for ischemic heart disease. The oxidized glutathione (GSSG) has been considered as a marker of oxidative status. Here the authors show that GSSG, but not GSH, improves ischemic heart failure by inhibiting mitochondrial fission through polysulfur-based S-glutathionylation of Drp1 at Cys644.

(+)-Sesamin, a furofuran class lignan, is widespread in vascular plants and represented by Sesamum spp. (+)-Sesamin has been of rapidly growing interest because of its beneficial biological effects in mammals, but its biosynthesis and physiological roles in plants remain to be clarified. It is speculated to be synthesized from (+)-pinoresinol by means of (+)-piperitol by formation of two methylenedioxy bridges mediated by two distinct Sesamum indicum cytochrome P450 (SiP450) proteins. Here, we report an SiP450, CYP81Q1, that alone catalyzes (+)-sesamin biosynthesis from (+)-pinoresinol by means of (+)-piperitol by forming two methylenedioxy bridges. The CYP81Q1 gene expression profile was temporally consistent with the accumulation pattern of (+)-sesamin during seed development. The CYP81Q1-GFP chimera protein was colocalized with an endoplasmic reticulum (ER)-targeting chimera protein, indicating that (+)-sesamin biosynthesis occurs on the ER cytoplasmic surface. Moreover, we isolated two CYP81Q1 homologs from other Sesamum spp. Sesamum radiatum CYP81Q2 showed dual (+)-piperitol/(+)-sesamin synthetic activity. CYP81Q2, as well as CYP81Q1, therefore, corresponds to a (+)-piperitol/(+)-sesamin synthase in lignan biosynthesis. In contrast, Sesamum alatum CYP81Q3 showed no activity, in accord with (+)-sesamin being deficient in S. alatum. Our findings not only provide insight into lignan biosynthesis but also unravel a unique mode of cytochrome P450 action.