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Matsuya, Yusuke; Sato, Tatsuhiko; Kusumoto, Tamon*; Yachi, Yoshie*; Seino, Ryosuke*; Miwa, Misako*; Ishikawa, Masayori*; Matsuyama, Shigeo*; Fukunaga, Hisanori*
Scientific Reports (Internet), 14, p.16696_1 - 16696_14, 2024/07
Times Cited Count：2 Percentile：84.90(Multidisciplinary Sciences)Boron neutron capture therapy (BNCT) is a unique radiotherapy to selectively eradicate tumor cells using boron compounds (e.g., 4-borono-L-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. However, the impacts of tempo-spatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector, cell cycle analysis, and biophysical simulations, we demonstrated the cell cycle-dependent heterogenicity of BPA uptake and following biological impacts of 
B(n, 
)
Li reactions in HeLa cells expressing Fluorescent Ubiquitination-based Cell Cycle Indicators (FUCCI), as well as its modification effects of polyvinyl alcohol (PVA). As a result, we revealed that the intracellular BPA concentration in the S/G2/M phase was higher than that in the G1/S phase and that PVA modified the cell cycle dependence. Further, these findings lead to the development of the first BPA-PVA-based model for predicting BNCT treatment effects. These outcomes may contribute to more precision of therapeutic efficacy, when BNCT is combined with PVA and/or cell cycle-specific anticancer agents.
Matsuya, Yusuke; Sato, Tatsuhiko; Yachi, Yoshie*; Date, Hiroyuki*; Hamada, Nobuyuki*
Scientific Reports (Internet), 14, p.12160_1 - 12160_14, 2024/05
Times Cited Count：1 Percentile：0.00(Multidisciplinary Sciences)Understand mechanisms of radiation cataracts that are of concern in the field of radiation protection and radiation therapy. However, biological effects in HLEC following protracted exposure have not yet fully been explored. Here, we investigated the temporal kinetics of DNA double-strand breaks (DSBs) and cell survival of HLEC after exposure to photon beams at various dose rates, compared to those of human lung fibroblasts (WI-38). In parallel, we quantified the recovery for DSB and cell survival using a biophysical model. The study revealed that HLEC cells have a lower repair rate than WI-38 cells. There is no significant impact of dose rate on cell survival in both cell lines in the dose-rate range of 0.033-1.82 Gy/min. On the other hand, the experimental residual DSBs showed inverse dose rate effects (IDREs) compared to the model prediction, highlighting the importance of the IDREs in evaluating radiation effects on the ocular lens.
Matsuya, Yusuke; McMahon, S. J.*; Butterworth, K. T.*; Yachi, Yoshie*; Saga, Ryo*; Sato, Tatsuhiko; Prise, K. M.*
Physics in Medicine & Biology, 68(9), p.095008_1 - 095008_12, 2023/04
Times Cited Count：3 Percentile：60.63(Engineering, Biomedical)Hypoxia induces radioresistance in tumors, leading to malignant progression in intensity-modulated radiation therapy. To date, it has been shown that intercellular signalling between cells positioned inside and outside radiation field impacts on cellular radiosensitivity under hypoxia and normoxia. However, the mechanistic role of intercellular communication in hypoxia remains to be fully understood. In this study, we modelled the cell-killing effects of intercellular signalling in hypoxia to better understand the underlying mechanisms of response. We used the oxygen enhancement ratio (OER) given from early DSB yields and modelled the in- and out-of-field radiosensitivity. As a result, the model analysis provides an mechanistical interpretation that the probability of hits for releasing cell-killing signals is dependent on oxygen. Our data also suggested that the field-type independent OER value, which can be given by uniform-field exposure, can be applied when predicting both in- and out-of-field radiosensitivity. These results would contribute to more precise understanding of intercellular signalling under heterogeneous exposure to intensity-modulated radiation fields.
-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：4 Percentile：56.48(Biochemistry & Molecular Biology)When 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.
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：2 Percentile：27.95(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：7 Percentile：58.79(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：12 Percentile：81.91(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; 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：6 Percentile：49.19(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.
Yachi, Yoshie*; Yoshii, Yuji*; Matsuya, Yusuke; Mori, Ryosuke*; Oikawa, Joma*; Date, Hiroyuki*
Scientific Reports (Internet), 9(1), p.17649_1 - 17649_8, 2019/11
Times Cited Count：9 Percentile：41.30(Multidisciplinary Sciences)Radiation weighting factor for photon and electron is defined as 1.0 independently these energies. However, it should be noted that the biological effects after 29 kVp X-rays is relative higher than standard 200 kVp X-rays at the endpoint of 
. And it is of importance to evaluate electrons generated via interaction of photons with matter. Here, we evaluated the energy concentration along electron track (dose-mean lineal energy) on chromosome (micron-meter) scales by Monte Carlo simulation, and measured the DNA double-strand breaks (DSBs) induction. From the cell experiments, the DSBs induction after diagnostic X-rays exposure (60-100 kVp) is higher than those with therapeutic X-rays (6 MV). In the relation between the dose-mean lineal energy and the number of DSBs, it was shown that lower energy photons might induce more biological impact due to the interaction by low energy electron. This study implies that radiation weighting factor for photon and electron should not be unity.
Matsuya, Yusuke; Kai, Takeshi; Yoshii, Yuji*; Yachi, Yoshie*; Naijo, Shingo*; Date, Hiroyuki*; Sato, Tatsuhiko
Journal of Applied Physics, 126(12), p.124701_1 - 124701_8, 2019/09
Times Cited Count：33 Percentile：81.13(Physics, Applied)Biological effects after ionizing radiation exposure arise from initial DNA strand breaks. DNA damage can be estimated from the simulation with both track structure analysis and diffusion of free radicals; however, the simulation is a time-consuming process. In this study, we present a simple model for estimating yields of strand breaks based only on spatial patterns of inelastic interactions (i.e., ionization and electronic excitation) generated by electrons, which are evaluated by PHITS code without considering the production and diffusion of free radicals. In this model, the number of events per track and that of the two events pair within 3.4 nm (corresponding to 10 base pair) were stochastically sampled for calculating SSB and DSB yields, respectively. The calculated results agreed well with other simulations and experimental data on DSB yield and yield ratio of DSB/SSB for the exposure to mono-energetic electrons. The present model also can demonstrate the relative biological effectiveness at the DSB endpoint for various photon exposures. This study indicated that the spatial pattern of inelastic events composed of ionization and electronic excitation is sufficient to obtain the impact of electrons on initial induction to DNA strand break.
Matsuya, Yusuke; Kai, Takeshi; Yoshii, Yuji*; Yachi, Yoshie*; Date, Hiroyuki*; Sato, Tatsuhiko
no journal, ,
DNA damage induced under exposure to ionizing radiation is related with track structure of electrons in liquid water (physical process) and diffusion of free radicals (chemical process). By using the computational simulation considering both processes, we can estimate DNA damage and expect to evaluate biological effects after exposure; however, the simulation is a time-consuming process. In this study, we used the electron track structure mode released recently, and developed a simple model for estimating yields of strand breaks based only on aggregation index of inelastic interactions (i.e., ionization and electronic excitation) generated by electrons. In the present model, the number of linkages within 10 base pair (corresponding to 3.4 nm) were stochastically sampled for calculating double-strand break (DSB) yields as a fatal DNA damage. The calculated DSB yield shows maximum for 300 eV electron irradiation, and agreed well with the other simulation and experimental data for both electron and photon irradiations. This work suggests that the spatial pattern of inelastic events composed of ionization and electronic excitation along electron track is sufficient to estimate the impact of electrons (and photons) on yield of DNA strand break. In the future, based on this developed approach, we are planning to estimate DSB yields after irradiation with proton or carbon.
Fukunaga, Hisanori*; Matsuya, Yusuke; Yachi, Yoshie*; Date, Hiroyuki*
no journal, ,
Boron neutron capture therapy (BNCT) is a radiotherapy which enables eradicating tumor by the dose concentration on tumor cells by rays and Li ions generated from the nuclear reaction between thermal neutrons and boron. With the development of accelerator-based neutron sources and the Japanese insurance listing, it is expected that accelerator-based BNCT will be installed in many medical institutions in the future. In the accelerator-based BNCT, boron-containing compounds, i.e., BPA, are administered by intravenous injection and are taken up into tumor cells, so it is expected that cellular BPA concentration becomes spatially heterogeneous. However, the effects of such heterogenous BPA concentration on the therapeutic effects remains unclear. In this study, we measured the heterogenous distribution of BPA in tumor cells (cell cycle dependence) using CR-39 detector. As a result, the number of reactions per unit area in the BPA-administered cells was increased by about 20% in S/G
/M phase cells compared to that in G
/S phase. This outcome revealed the cell-cycle dependence on the intercellular BPA concentration and the boron dose, suggesting that such heterogeneity might affect the curative effects for BNCT.
Matsuya, Yusuke; Yachi, Yoshie*; Kai, Takeshi
no journal, ,
MR linac radiotherapy, which combines a linac accelerator and MRI, can enhance the contrast between normal soft tissues and solid tumors during real-time imaging. The track structure of charged particles such as electrons is altered by the Lorentz force in a magnetic field, but the biological effects (especially initial DNA damage yields) remain unclear. We have previously developed an electron track-structure model (PHITS-ETS model) that simulates each atomic interaction (e.g., ionization and excitation) and a DNA damage estimation model based on the spatial patterns in the PHITS code. In recent years, we have also made it possible to estimate the physical properties of charged particles in a magnetic field and the subsequent biological effects by considering the magnetic field effect in the PHITS-ETS model. In this presentation, we present the physical properties of electrons in a magnetic field (i.e., range and dose distribution) and the DNA damage yields (double-strand breaks and the complexity), and finally propose a theoretical method for planning MR linac radiotherapy.
