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-H2AX focus formation assay based on track-structure simulationYachi, Yoshie*; Matsuya, Yusuke*; Yoshii, Yuji*; Fukunaga, Hisanori*; Date, Hiroyuki*; Kai, Takeshi
International Journal of Molecular Sciences (Internet), 24(2), p.1386_1 - 1386_14, 2023/01
Times Cited Count：0When living cells are irradiated with radiation and complex damage is formed within a few nanometers of DNA, it is believed to induce biological effects such as cell death. In general, complex DNA damage formed in cells can be detected experimentally by fluorescence microscopy, because the area around the damage site emits light like a focus point when a fluorophore is used. However, this detection method has not been able to analyze the degree of complexity of DNA damage. Therefore, in this study, we addressed on the measured focus size and evaluated the degree of complexity of DNA damage using a track structure analysis code. As a result, we found that as DNA damage becomes more complex, the focus size also increases. Our findings are expected to provide a new analytical method for elucidating the initial factors of radiation biological effects.
Kai, Takeshi; Toigawa, Tomohiro; Matsuya, Yusuke*; Hirata, Yuho; Tezuka, Tomoya*; Tsuchida, Hidetsugu*; Yokoya, Akinari*
RSC Advances (Internet), 13(11), p.7076 - 7086, 2023/00
Scientific insights of water radiolysis are widely used in the life sciences and so on, however, the formation mechanism of radicals, a product of water radiolysis, is still not well understood. We are challenging to develop a simulation code to solve this formation mechanism from the viewpoint of radiation physics. Our first-principles calculations have revealed that the behavior of secondary electrons in water is governed not only by collisional effects but also by polarization effects. Furthermore, from the predicted ratio of ionization to electronic excitation, based on the spatial distribution of secondary electrons, we successfully reproduce the initial yield of hydrated electrons predicted in terms of radiation chemistry. The code provides us a reasonable spatiotemporal connection from radiation physics to radiation chemistry. Our findings are expected to provide newly scientific insights for understanding the earliest stages of water radiolysis.
dataSaga, Ryo*; Matsuya, Yusuke; Sato, Hikari*; Hasegawa, Kazuki*; Obara, Hideki*; Komai, Fumio*; Yoshino, Hironori*; Aoki, Masahiko*; Hosokawa, Yoichiro*
Radiotherapy and Oncology, p.109444_1 - 109444_9, 2023/00
When treating non-small cell lung cancer (NSCLC), stereotactic body radiotherapy (SBRT) with high-dose irradiation is often utilized. The fractionation schemes and curative effects can be evaluated by mathematical models for predicting cell survival curve. Such model parameters can be determined from in vitro experiment, but they are empirically determined based on experiences in clinics. As such, there is a large gap between in vitro and clinical study. As such background, translational study between in vitro cell survival and clinical curative effects is necessary. In this study, explicitly considering existence of cancer stem-like cells (CSCs), we developed an all-in-one model for predicting both in vitro cell survival and clinical curative effects (integrated microdosimetric-kinetic (IMK) model) and performed retrospective evaluation of clinical outcomes following SBRT for NSCLC in Hirosaki University Hospital. As a result, the IMK model successfully reproduced both in vitro cell survival and the tumor control probability with various fractionation schemes (i.e., 6-10 Gy per fraction). The developed model would contribute on precisely understanding the impact of CSCs on curative effects after SBRT for NSCLC with high precision.
Ogawa, Tatsuhiko; Hirata, Yuho; Matsuya, Yusuke; Kai, Takeshi
Isotope News, (784), p.13 - 16, 2022/12
Track-structure calculation, a method to simulate every secondary electron production reaction explicitly, has been extensively used as an important techniques in various fields such as radiation biology, material irradiation effect, and radiation detection. However, it requires the dielectric function of the target materials, which is not well known except for liquid water. Therefore we developed a model to perform track-structure calculation based on a systematic formula of secondary electron production cross section and that of stopping power. The model can therefore perform track-structure calculation regardless of the availability of dielectric function measurement data. Stopping range, and energy deposition radial distribution calculated by this model agreed well with the earlier experimental data and calculation by precedent codes. The lineal energy in tissue-equivalent gas calculated by this model agreed with measurement data taken from literature, showing distinct difference from that in liquid water. This model was implemented to PHITS Ver3.25, the general-purpose radiation transport simulation code of JAEA, being distributed to users as the first track-structure calculation model applicable to arbitrary materials available in general-purpose transport code.
Matsuya, Yusuke; Kai, Takeshi; Parisi, A.*; Yoshii, Yuji*; Sato, Tatsuhiko
Physics in Medicine & Biology, 67(21), p.215017_1 - 215017_13, 2022/11
Times Cited Count：1 Percentile：0.01(Engineering, Biomedical)Proton beam therapy allows to irradiate tumor volumes with reduced side effects on normal tissues with respect to X-ray radiotherapy. Biological effects such as cell killing after proton beam irradiations depend on the proton kinetic energy, which is intrinsically related in the early DNA damage induction. As such, the estimation of DNA damage yields based on Monte Carlo simulations is a research topic of worldwide interest. In this study, we investigate the possibility of applying a simple model developed for electron to proton without any modification. The yields of single-strand breaks (SSB), double-strand breaks (DSB) and the complex DSB were assessed as a function of the proton kinetic energy. The PHITS-based estimation accurately reproduced the experimental and simulated yields of various DNA damage types induced by protons with linear energy transfer (LET) up to about 30 keV/
m. These results suggest that current DNA damage model implemented in PHITS is sufficient for estimating DNA lesion yields induced after protons irradiation except for lower energies than MeV.
Hirata, Yuho; Kai, Takeshi; Ogawa, Tatsuhiko; Matsuya, Yusuke; Sato, Tatsuhiko
Japanese Journal of Applied Physics, 61(10), p.106004_1 - 106004_6, 2022/10
Times Cited Count：0 Percentile：0(Physics, Applied)Some radiation effects such as pulse-height defects and soft errors can cause problems in silicon (Si) devices. Local energy deposition in microscopic scales is essential information to elucidate the mechanism of these radiation effects. We, therefore, developed an electron track-structure model, which can simulate local energy deposition down to nano-scales, dedicated to Si and implemented it into PHITS. Then, we verified the accuracy of our developed model by comparing the ranges and depth-dose distributions of electrons obtained from this study with the corresponding experimental values and other simulated results. As an application of the model, we calculated the mean energies required to create an electron-hole pair, the so-called epsilon value. We found that the threshold energy for generating secondary electrons reproducing the epsilon value is 2.75 eV, consistent with the corresponding data deduced from past theoretical and computational studies. Since the magnitudes of the radiation effects on Si devices largely depend on the epsilon value, the developed code is expected to contribute to precisely understanding the mechanisms of pulse-height defects and semiconductor soft errors.
Papadopoulos, A.*; Kyriakou, I.*; Matsuya, Yusuke; Incerti, S.*; Daglis, I. A.*; Emfietzoglou, D.*
Applied Sciences (Internet), 12(18), p.8950_1 - 8950_20, 2022/09
Times Cited Count：0 Percentile：0(Chemistry, Multidisciplinary)The quality factor (Q) is the index which is used when evaluating the stochastic (e.g., carcinogenic) risk of diverse ionizing radiations. While the Q value can be commonly determined from the Linear Energy Transfer (LET), more elaborate approaches are based on the microdosimetric parameter lineal energy (y) calculated either by analytical model or Monte Carlo (MC) simulations. However, the developing of the model for determining the Q value is still ongoing worldwide for realizing the precise risk assessment. In this study, various generalized analytical models that account for both 
-ray transport and energy-loss straggling effects are utilized to evaluate the Q values over the proton energy range 1-250 MeV. The results revealed that the LET-based ICRP Report 60 recommendations underestimate the microdosimetric-based Q values of protons with energy below 100 MeV, which was also confirmed by using MC simulation data on the y values. The present work shows that analytic models may offer a practical alternative to computer-intensive MC simulations for calculating Q values based on the microdosimetric methodologies. In future study, we are planning to compare the y spectra and subsequent calculations of Q based on new MC data with the latest versions of Geant4-DNA and PHITS track structure codes which make use of different physics models.
Sato, Tatsuhiko; Matsuya, Yusuke; Hamada, Nobuyuki*
International Journal of Radiation Oncology, Biology, Physics, 114(1), p.153 - 162, 2022/09
Times Cited Count：1 Percentile：68.37(Oncology)The microdosimetric kinetic model, which was originally developed for estimating cell surviving fractions for various radiations, was improved to be capable of estimating the mean and uncertainty of RBE for skin reactions. The parameter used in the model was independently determined from in vitro measurements of dermal cell survival and in vivo measurements of skin reactions taken from 8 and 23 papers, respectively. Our model quantitatively revealed that RBE for skin reactions tend to be higher than that for dermal cell survival. RBE of various mono-energetic radiations calculated from this model confirmed that the past evaluations made by ICRP and NCRP a few decades ago are still supported by recent experimental data. Conclusions: Our model can play important roles not only in medical physics for avoiding unnecessary skin reactions in particle therapy and BNCT but also in radiation protection for future decision making of the recommended RBE values.
Yachi, Yoshie*; Kai, Takeshi; Matsuya, Yusuke; Hirata, Yuho; Yoshii, Yuji*; Date, Hiroyuki*
Scientific Reports (Internet), 12, p.16412_1 - 16412_8, 2022/09
Times Cited Count：1 Percentile：0(Multidisciplinary Sciences)Recently, magnetic resonance-guided radiotherapy (MRgRT) which can visualize tumors in real time has been developed and installed in several clinical facilities. It is known that Lorentz force modulate macroscopic dose distribution by a charged particle, however, the impact by the force on microscopic radiation-track structure and early DNA damage induction remain unclear. In this study, we simulated the electron-track structure in a static magnetic field using a PHITS, and estimated features of biological effects. We indicated that the macroscopic dose distributions are changed by the force, while early DNA damage such as double strand breaks is attributed to the secondary electrons below a few tens of eV which are independent of the force. We expect that our insight significantly contributes to the MRgRT.
Matsuya, Yusuke; Kusumoto, Tamon*; Yachi, Yoshie*; Hirata, Yuho; Miwa, Misako*; Ishikawa, Masayori*; Date, Hiroyuki*; Iwamoto, Yosuke; Matsuyama, Shigeo*; Fukunaga, Hisanori*
AIP Advances (Internet), 12(2), p.025013_1 - 025013_9, 2022/02
Times Cited Count：1 Percentile：59.23(Nanoscience & Nanotechnology)Boron Neutron Capture Therapy (BNCT) is a radiation therapy, which can selectively eradicate solid tumors by 
-particles and Li ions generated through the nuclear reaction between thermal neutron and 
B in tumor cells. With the development of accelerator-based neutron sources that can be installed in medical institutions, accelerator-based boron neutron capture therapy is expected to become available at several medical institutes around the world in the near future. Lithium is one of the targets that can produce thermal neutrons from the 
Li(p,n)Be near-threshold reaction. Particle and Heavy Ion Transport code System (PHITS) is a general-purpose Monte Carlo code, which can simulate a variety of diverse particle types and nuclear reactions. The latest PHITS code enables simulating the generation of neutrons from the Li(p,n)Be reactions by using Japanese Evaluated Nuclear Data Library (JENDL-4.0/HE). In this study, we evaluated the neutron fluence using the PHITS code by comparing it to reference data. The subsequent neutron transport simulations were also performed to evaluate the boron trifluoride (BF
) detector responses and the recoiled proton fluence detected by a CR-39 plastic detector. As a result, these comparative studies confirmed that the PHITS code can accurately simulate neutrons generated from an accelerator using a Li target. The PHITS code has a significant potential for contributing to more precise evaluating accelerator-based neutron fields and understandings of therapeutic effects of BNCT.
Matsuya, Yusuke; Hamada, Nobuyuki*; Yachi, Yoshie*; Satou, Yukihiko; Ishikawa, Masayori*; Date, Hiroyuki*; Sato, Tatsuhiko
Cancers (Internet), 14(4), p.1045_1 - 1045_15, 2022/02
Times Cited Count：4 Percentile：93.76(Oncology)An insoluble cesium-bearing microparticle (Cs-BMP) was discovered after the incident at the Fukushima nuclear power plant. Radiation risk by intake of internal exposure to radioactive cesium is conventionally estimated from organ dose, assuming that soluble cesium is uniformly distributed throughout human body. Meanwhile, such Cs-BMPs are assumed to adhere in the long term to normal tissue, leading to chronic non-uniform exposure. In this study, to clarify the normal tissue effects for Cs-BMP exposure, we investigated the relationship between the inflammatory responses and DNA damage induction. From experiments focusing on the inflammatory signaling pathways such as NF-
B p65 and COX-2, compared to the uniform exposure to -rays, NF-B p65 tended to be more activated in the cells proximal to the Cs-BMP, while both NF-B p65 and COX-2 were significantly activated in the distal cells. Experiments with inhibitors for NF-B p65 and COX-2 suggested involvement of such inflammatory responses both in the reduced radiosensitivity of the cells proximal to Cs-BMP and the enhanced radiosensitivity of the cells distal from Cs-BMP. These results suggested that radiation effects for Cs-BMP exposure can differ from that estimated based on conventional uniform exposure to normal tissues.
Matsuya, Yusuke; Kai, Takeshi; Sato, Tatsuhiko; Ogawa, Tatsuhiko; Hirata, Yuho; Yoshii, Yuji*; Parisi, A.*; Liamsuwan, T.*
International Journal of Radiation Biology, 98(2), p.148 - 157, 2022/02
Times Cited Count：6 Percentile：74.47(Biology)When investigating radiation-induced biological effects, it is essential to perform detailed track-structure simulations explicitly by considering each atomic interaction in liquid water (which is equivalent to human tissues) at sub-cellular and DNA scales. The Particle and Heavy Ion Transport code System (PHITS) is a Monte Carlo code which can be used for track structure calculations by employing an original electron track-structure mode (etsmode) and the world-famous KURBUC algorithms (PHITS-KURBUC mode) for protons and carbon ions. In this study, the physical features (i.e., range, radial dose and microdosimetry) of these modes have been verified by comparing to the available experimental data and Monte Carlo simulation results reported in literature. In addition, applying the etsmode to radiobiological study, we estimated the yields of single-strand breaks (SSBs), double-strand breaks (DSBs) and complex DSBs, and evaluated the dependencies of DNA damage yields on incident electron energy. As a result, the simulations suggested that DNA damage types are intrinsically related with the spatial patterns of ionization and electronic excitations and that approximately 500 eV electron can cause much complex DSBs. In this paper, we show the development status of the PHITS track-structure modes and its application to radiobiological research, which would be expected to identify the underlying mechanisms of radiation effects based on physics.
Fukui, Roman*; Saga, Ryo*; Matsuya, Yusuke; Tomita, Kazuo*; Kuwahara, Yoshikazu*; Ouchi, Kentaro*; Sato, Tomoaki*; Okumura, Kazuhiko*; Date, Hiroyuki*; Fukumoto, Manabu*; et al.
Scientific Reports (Internet), 12(1), p.1056_1 - 1056_12, 2022/01
Times Cited Count：3 Percentile：92.7(Multidisciplinary Sciences)Alive cancer cells after fractionated irradiations with 2 Gy X-rays per day for more than 30 days show clinically relevant radioresistant. Such radioresistance is experimentally interpreted to attributed to the increment of stem-like cell content. However, only an experimental approach cannot clarify the cell responses (DNA damage and cell death induction) of cancer stem cells, so the radioresistant mechanisms remain uncertain. In addition to the conventional cell experiments using radio-resistant cell lines established after fractionated irradiations, in this study we developed a mathematical model (so called integrated microdosimetric-kinetic (IMK) model) explicitly considering cancer stem-like cell content and DNA damage responses and investigated radioresistant mechanisms acquired after fractionated irradiations. The IMK model analysis suggested that the changes of stem-like cell fraction and DNA repair efficiency play important roles of radioresisitance acquired after irradiations. Considering these into the IMK model, we successfully reproduced the experimental survival of various cell lines and various irradiation conditions. This work would contribute to not only the precise understanding of the radioresistant mechanisms induced after irradiation but also predicting curative effects with high precision.
Ogawa, Tatsuhiko; Hirata, Yuho; Matsuya, Yusuke; Kai, Takeshi
Scientific Reports (Internet), 11(1), p.24401_1 - 24401_10, 2021/12
Times Cited Count：5 Percentile：69.76(Multidisciplinary Sciences)Track-structure calculation, a method to simulate every secondary electron production reaction explicitly, has been extensively used as an important techniques in various fields such as radiation biology, material irradiation effect, and radiation detection. However, it requires the dielectric function of the target materials, which is not well known except for liquid water. Therefore we developed a model to perform track-structure calculation based on a systematic formula of secondary electron production cross section and that of stopping power. The model can therefore perform track-structure calculation regardless of the availability of dielectric function measurement data. Stopping range, and energy deposition radial distribution calculated by this model agreed well with the earlier experimental data and calculation by precedent codes. The lineal energy in tissue-equivalent gas calculated by this model agreed with measurement data taken from literature, showing distinct difference from that in liquid water. This model was implemented to PHITS Ver3.25, the general-purpose radiation transport simulation code of JAEA, being distributed to users as the first track-structure calculation model applicable to arbitrary materials available in general-purpose transport code.
Matsuya, Yusuke; Kai, Takeshi; Ogawa, Tatsuhiko; Hirata, Yuho; Sato, Tatsuhiko
Hoshasen Kagaku (Internet), (112), p.15 - 20, 2021/11
Particle and Heavy Ion Transport code System (PHITS) is a general-purpose Monte Carlo code enabling radiation kinetics, which is often used in diverse research fields, such as atomic energy, engineering, medicine and science. After released in 2010, the PHITS code has been developed to expand its functions and to improve its convenience. In the few years, track-structure mode has been introduced in PHITS that can simulate each atomic interaction by electrons, positions, protons and carbon ions in liquid water. Thanks to the development of track-structure mode, the latest PHITS code enables microscopic dose calculations by decomposing it to the scale of DNA. Aiming at realizing the track-structure mode with high precision, the further developments of electron and ion track-structure mode for arbitrary materials are recently ongoing. This review shows the development history and future prospect of PHITS track-structure mode, which can expect to be further applied to the research fields of atomic physics, radiation chemistry, and quantum life science.
Fukunaga, Hisanori*; Matsuya, Yusuke
Hoshasen Seibutsu Kenkyu, 56(2), p.208 - 223, 2021/06
Boron Neutron Capture Therapy (BNCT) is one of the radiation therapies, enabling selectively eradicating tumors by short-range a-particles and Li ions generated through the nuclear reaction between thermal neutron and B within tumor cells. With the development of the accelerator-based neutron source in the recent decades, it is expected that BNCT will be available in many medical facilities worldwide in the future. BNCT irradiation needs a relatively long dose-delivery time after taking up boron drug into tumor cells by intravenous injection. During the period, it is suspected that the boron drug is heterogeneously taken up into cells and its concentration changes continuously, leading to the modification of curative effects from the pharmacological and biological viewpoints. However, the model development for precisely predicting curative effects after BNCT irradiation is still ongoing. Here, we introduce the forefront of model development for estimating the curative effects during BNCT irradiation with high accuracy. This review can create the synergetic effects through an interdisciplinary research approach that can connect the fields of physics, pharmacology, biology and medicine, and would pave the way for new era of BNCT.
Matsuya, Yusuke; McMahon, S. J.*; Butterworth, K. T.*; Naijo, Shingo*; Nara, Isshi*; Yachi, Yoshie*; Saga, Ryo*; Ishikawa, Masayori*; Sato, Tatsuhiko; Date, Hiroyuki*; et al.
Physics in Medicine & Biology, 66(7), p.075014_1 - 075014_11, 2021/04
Times Cited Count：2 Percentile：26.93(Engineering, Biomedical)Hypoxic cancer cells within solid tumours show radio-resistance, leading to malignant progression in fractionated radiotherapy. When prescribing dose to tumours under heterogeneous oxygen pressure with intensity-modulated radiation fields, intercellular signalling could have an impact on radiosensitivity between in-field and out-of-field cells. However, the impact of hypoxia on radio-sensitivity under modulated radiation intensity remains uncertain. In this study, we investigate the impact of hypoxia on in-field and out-of-field radio-sensitivities using two types of cancer cells. These in vitro measurements indicate that hypoxia apparently impacts out-of-field cells, although the OER values in out-of-field cells were smaller compared to those for in-field and uniformly irradiated cells. These decreased radio-sensitivities of out-of-field cells were shown as a consistent tendency for both DSB and cell death endpoints, suggesting that radiation-induced intercellular communication is of importance in treatment planning with intensity-modulated radiotherapy.
Saga, Ryo*; Matsuya, Yusuke; Takahashi, Rei*; Hasegawa, Kazuki*; Date, Hiroyuki*; Hosokawa, Yoichiro*
Scientific Reports (Internet), 11(1), p.8258_1 - 8258_10, 2021/04
Times Cited Count：3 Percentile：60.67(Multidisciplinary Sciences)Hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) is a candidate of radiosensitizers in X-ray therapy. The curative effects under such 4-MU administration have been investigated in vitro; however, the radiosensitizing mechanisms remain unclear. Here, we investigated the radiosensitizing effects under 4-MU treatment from cell experiments and model estimations. We generated experimental surviving fractions of human fibrosarcoma cells (HT1080) after 4-MU treatment combined with X-ray irradiation. Meanwhilst, we also modelled the pharmacological effects of 4-MU treatment and theoretically analyzed the synergetic effects between 4-MU treatment and X-ray irradiation. The results show that the enhancement of cell killing by 4-MU treatment is the greatest in the intermediate dose range of around 4 Gy, which indicates the involvement of intercellular communication. In addition, the oxidative stress level, which leads to DNA damage induction, significantly increased under 4-MU treatment, and the radiosensitization by 4-MU can be suppressed by the inhibitors for intercellular communication. These findings suggest that the synergetic effects between 4-MU treatment and irradiation are predominantly attributed to intercellular communication and provide more efficient tumour control than conventional X-ray therapy.
Matsuya, Yusuke; Kai, Takeshi; Sato, Tatsuhiko; Liamsuwan, T.*; Sasaki, Kohei*; Nikjoo, H.*
Physics in Medicine & Biology, 66(6), p.06NT02_1 - 06NT02_11, 2021/03
Times Cited Count：11 Percentile：93.42(Engineering, Biomedical)A general-purpose Monte Carlo radiation transport simulation code, Particle and Heavy Ion Transport code System (PHITS), has the ability to handle diverse particle types over a wide range of energy. In PHITS version 3.20, ion track structure mode has been developed based on the algorithms in the KURBUC code, which enables to simulate the atomic interactions by primary ion and secondary particles (named as PHITS-KURBUC mode). In this study, we compared the range, radial dose distributions, and microdosimetric distributions calculated using the PHITS-KURBUC mode to the corresponding data obtained from the original KURBUC and from other studies. These comparative studies confirm the successful inclusion of the KURBUC code in the PHITS code. As results of the synergistic effect between the macroscopic and microscopic radiation transport codes, this implementation enabled the detailed calculation of the microdosimetric and nanodosimetric quantities under complex radiation fields, such as proton beam therapy with the spread-out Bragg peak. This PHITS-KURBUC mode is expected to pave the way for next-generation radiation researches, such as radiation physics, radiological protection, medical physics, and radiation biology.
assessment in case of the V79 cell line exposed to ions from 
H to 
UParisi, A.*; Sato, Tatsuhiko; Matsuya, Yusuke; Kase, Yuki*; Magrin, G.*; Verona, C.*; Tran, L.*; Rosenfeld, A.*; Bianchi, A.*; Olko, P.*; et al.
Physics in Medicine & Biology, 65(23), p.235010_1 - 235010_20, 2020/12
Times Cited Count：17 Percentile：89.29(Engineering, Biomedical)A new biological weighting function (IBWF) is proposed to phenomenologically relate microdosimetric lineal energy probability density distributions with the relative biological effectiveness (RBE) for the in vitro clonogenic cell survival (survival fraction = 10%) of the most commonly used mammalian cell line, i.e. the Chinese hamster lung fibroblasts (V79). The RBE values assessed by the IBWF were found to be consistent and in good agreement with the ones calculated in combination with computer-simulated microdosimetric spectra, with an average relative deviation of 0.8% and 5.7% for H and C ions respectively.
