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The cell cycle dependence of radiosensitivity has yet to be fully determined, as it is technically difficult to achieve a high degree of cell cycle synchronization in cultured cell systems and accurately detect the cell cycle phase of individual cells simultaneously. We used human cervical carcinoma HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators (FUCCI), and employed the mitotic harvesting method that is one of the cell cycle synchronization methods. The imaging analysis confirmed that the cell cycle is highly synchronized after mitotic cell harvesting until 18–20 h of the doubling time has elapsed. Also, flow cytometry analysis revealed that the S and G2 phases peak at approximately 12 and 14–16 h, respectively, after mitotic harvesting. In addition, the clonogenic assay showed the changes in surviving fractions following exposure to X-rays according to the progress through the cell cycle. These results indicate that HeLa-FUCCI cells become radioresistant in the G1 phase, become radiosensitive in the early S phase, rapidly become radioresistant in the late S phase, and become radiosensitive again in the G2 phase. Our findings may contribute to the further development of combinations of radiation and cell cycle-specific anticancer agents.

Complex DNA double-strand break (DSB), which is defined as a DSB coupled with additional strand breaks within 10 bp in this study, induced after ionizing radiation or X-rays, is recognized as fatal damage which can induce cell death with a certain probability. In general, a DSB site inside the nucleus of live cells can be experimentally detected using the gamma-H2AX focus formation assay. DSB complexity is believed to be detected by analyzing the focus size using such an assay. However, the relationship between focus size and DSB complexity remains uncertain. In this study, using Monte Carlo (MC) track-structure simulation codes, i.e., an in-house WLTrack code and a Particle and Heavy Ion Transport code System (PHITS), we developed an analytical method for qualifying the DSB complexity induced by photon irradiation from the microscopic image of gamma-H2AX foci. First, assuming that events (i.e., ionization and excitation) potentially induce DNA strand breaks, we scored the number of events in a water cube (5.03 x 5.03 x 5.03 nm(3)) along electron tracks. Second, we obtained the relationship between the number of events and the foci size experimentally measured by the gamma-H2AX focus formation assay. Third, using this relationship, we evaluated the degree of DSB complexity induced after photon irradiation for various X-ray spectra using the foci size, and the experimental DSB complexity was compared to the results estimated by the well-verified DNA damage estimation model in the PHITS code. The number of events in a water cube was found to be proportional to foci size, suggesting that the number of events intrinsically related to DSB complexity at the DNA scale. The developed method was applicable to focus data measured for various X-ray spectral situations (i.e., diagnostic kV X-rays and therapeutic MV X-rays). This method would contribute to a precise understanding of the early biological impacts of photon irradiation by means of the gamma-H2AX focus formation ass

The cell cycle is a series of events in the process of one cell giving rise to two daughter cells. The mitotic harvesting method, established by Terasima and Tolmach in the 1960s, causes minimal physiological stress on the cells and achieves a high degree of cell cycle synchrony by collecting only mitotic cells from a cultured cell system. The purpose of the present study is to validate the versatility of the mitotic harvesting method using human cervical cell line HeLa cells expressing Fluorescent Ubiquitination-based Cell Cycle Indicators (FUCCI) and to estimate the cell cycle-dependent changes in radiosensitivity in HeLa-FUCCI cells. The image analysis showed that cell cycle synchrony was maintained for at least 24 hours after mitotic cell collection. Also, the clonogenic assay demonstrated changes in radiosensitivity that were cell cycle dependent. These results indicate that the mitotic harvesting method using FUCCI-expressing cells has high versatility in the field of radiation cell biology.

The genotoxicity of radiation on germ cells may be passed on to the next generation, thus its elucidation is not only a scientific issue but also an ethical, legal, and social issue in modern society. In this article, we briefly overview the effects of radiation on spermatogenesis and its associated genotoxicity, including the latest findings in the field of radiobiology. The potential role of transgenerational effects is still poorly understood, and further research in this area is desirable. Furthermore, from the perspective of oncofertility, we discuss the historical background and clinical importance of preserving male fertility during radiation treatment and the potential of microbeam radiotherapy. We hope that this review will contribute to stimulating further discussions and investigations for therapies for pediatric and adolescent/young adult patients.

Accelerator-based neutron sources have been developed and installed in recent decades for boron neutron capture therapy (BNCT) in several clinical facilities. Lithium is one of the targets that can produce epithermal neutrons from the 7 Li(p,n)7 Be near-threshold reaction, and accelerator-based BNCT systems employing a Li target are promising for cancer treatment. The accurate evaluation of the characteristics of an accelerator-based neutron source is a key to estimating the therapeutic effects of the accelerator-based BNCT. 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 7 Li(p,n)7 Be reactions by using the Japanese Evaluated Nuclear Data Library 4.0 high-energy file. Thus, the PHITS code can be adopted for dose estimation during treatment planning for the accelerator-based BNCT. In this study, we evaluated the neutron fluence using the PHITS code by comparing it to reference data. The subsequent neutron transport simulations were performed to evaluate the boron trifluoride detector responses and the recoiled proton fluence detected by a CR-39 plastic detector. 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 a detailed evaluation of neutron fields and for predicting the therapeutic effects of the accelerator-based BNCT.

Simple Summary Spermatogenesis is one of the most important processes for the propagation of life; however, the testes' ability to form sperm via this differentiation process is highly radiosensitive and easily impacted by exposure to environmental, occupational, or therapeutic radiation. Furthermore, the possibility that radiation effects on the gonads can be passed on from generation to generation should not be overlooked. This review focuses on the radiation-induced effects on spermatogenesis and the transgenerational effects. We also explore the potential of novel radiobiological approaches to improve male fertility preservation during radiotherapy. The genotoxicity of radiation on germ cells may be passed on to the next generation, thus its elucidation is not only a scientific issue but also an ethical, legal, and social issue in modern society. In this article, we briefly overview the effects of radiation on spermatogenesis and its associated genotoxicity, including the latest findings in the field of radiobiology. The potential role of transgenerational effects is still poorly understood, and further research in this area is desirable. Furthermore, from the perspective of oncofertility, we discuss the historical background and clinical importance of preserving male fertility during radiation treatment and the potential of microbeam radiotherapy. We hope that this review will contribute to stimulating further discussions and investigations for therapies for pediatric and adolescent/young adult patients.

Accelerator-based neutron sources have been developed and installed in recent decades for boron neutron capture therapy (BNCT) in several clinical facilities. Lithium is one of the targets that can produce epithermal neutrons from the Li-7(p,n)Be-7 near-threshold reaction, and accelerator-based BNCT systems employing a Li target are promising for cancer treatment. The accurate evaluation of the characteristics of an accelerator-based neutron source is a key to estimating the therapeutic effects of the accelerator-based BNCT. 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-7(p,n)Be-7 reactions by using the Japanese Evaluated Nuclear Data Library 4.0 high-energy file. Thus, the PHITS code can be adopted for dose estimation during treatment planning for the accelerator-based BNCT. In this study, we evaluated the neutron fluence using the PHITS code by comparing it to reference data. The subsequent neutron transport simulations were performed to evaluate the boron trifluoride detector responses and the recoiled proton fluence detected by a CR-39 plastic detector. 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 a detailed evaluation of neutron fields and for predicting the therapeutic effects of the accelerator-based BNCT.

Following the Fukushima nuclear accident in March 2011, decontamination and related works have been carried out over a wide area, mainly in Fukushima Prefecture. In November 2013, the Radiation Dose Registration and Management System for Decontamination Workers was established to manage the occupational exposure doses of workers engaged in such work. The Radiation Effects Association mainly operates the registration system. This paper summarizes existing reports on this system and occupational health issues among decontamination workers. We collected previous reports and related regulatory laws on occupational health management for decontamination workers working in Fukushima Prefecture, summarized the outline of the radiation dose registration and management system for these decontamination workers, and discussed future issues related to their health management. Approximately 100 000 decontamination workers were registered in the system as of 2020, but none showed radiation doses that exceeded the dose limit. To our knowledge, there have been no reports of decontamination workers presenting physical symptoms suspected to be related to radiation exposure. On the other hand, heatstroke countermeasures and anxiety about radiation exposure have been reported as possible issues in the occupational health management of decontamination workers. Although decontamination workers are unlikely to experience biological effects from radiation exposure, epidemiological studies are needed to examine this evidence. Further analysis is also needed on non-radiation effects, which pose occupational health concerns for decontamination workers. The registration system would allow for tracking decontamination workers, providing data for analyzing radiological and non-radiological effects.

Following the Fukushima nuclear accident in March 2011, decontamination and related works have been carried out over a wide area, mainly in Fukushima Prefecture. In November 2013, the Radiation Dose Registration and Management System for Decontamination Workers was established to manage the occupational exposure doses of workers engaged in such work. The Radiation Effects Association mainly operates the registration system. This paper summarizes existing reports on this system and occupational health issues among decontamination workers. We collected previous reports and related regulatory laws on occupational health management for decontamination workers working in Fukushima Prefecture, summarized the outline of the radiation dose registration and management system for these decontamination workers, and discussed future issues related to their health management. Approximately 100 000 decontamination workers were registered in the system as of 2020, but none showed radiation doses that exceeded the dose limit. To our knowledge, there have been no reports of decontamination workers presenting physical symptoms suspected to be related to radiation exposure. On the other hand, heatstroke countermeasures and anxiety about radiation exposure have been reported as possible issues in the occupational health management of decontamination workers. Although decontamination workers are unlikely to experience biological effects from radiation exposure, epidemiological studies are needed to examine this evidence. Further analysis is also needed on non-radiation effects, which pose occupational health concerns for decontamination workers. The registration system would allow for tracking decontamination workers, providing data for analyzing radiological and non-radiological effects.

Microbeam radiotherapy (MRT) is the delivery of spatially fractionated beams that have the potential to offer significant improvements in the therapeutic ratio due to the delivery of micron-sized high dose and dose rate beams. They build on longstanding clinical experience of GRID radiotherapy and more recently lattice-based approaches. Here we briefly overview the preclinical evidence for MRT efficacy and highlight the challenges for bringing this to clinical utility. The biological mechanisms underpinning MRT efficacy are still unclear, but involve vascular, bystander, stem cell and potentially immune responses. There is probably significant overlap in the mechanisms underpinning MRT responses and FLASH radiotherapy that needs to be further defined. (c) 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

The non-targeted effects of radiation have been known to induce significant alternations in cell survival. Although the effects might govern the progression of tumor sites following advanced radiotherapy, the impacts on the intercellular control of the cell cycle following radiation exposure with a modified field, remain to be determined. Recently, a fluorescent ubiquitination-based cell-cycle indicator (FUCCI), which can visualize the cell-cycle phases with fluorescence microscopy in real time, was developed for biological cell research. In this study, we investigated the non-targeted effects on the regulation of the cell cycle of human cervical carcinoma (HeLa) cells with imperfect p53 function that express the FUCCI (HeLa-FUCCI cells). The possible effects on the cell-cycle phases via soluble factors were analyzed following exposure to different field configurations, which were delivered using a 150 kVp X-ray irradiator. In addition, using synchrotron-generated, 5.35 keV monochromatic X-ray microbeams, high-precision 200 mu m-slit microbeam irradiation was performed to investigate the possible impacts on the cell-cycle phases via cell-cell contacts. Collectively, we could not detect the intercellular regulation of the cell cycle in HeLa-FUCCI cells, which suggested that the unregulated cell growth was a malignant tumor. Our findings indicated that there was no significant intercellular control system of the cell cycle in malignant tumors during or after radiotherapy, highlighting the differences between normal tissue and tumor characteristics.

Background:The Hokkaido Study on Environment and Children’s Health is an ongoing study consisting of twobirth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives areto (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birthdefects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioraldevelopmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-riskgroups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of variouschemicals, including tobacco.Methods:The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarizerecent results, and suggest future directions. In particular, this report provides the latest details from questionnairesurveys, face-to-face examinations, and a collection of biological specimens from children and measurements oftheir chemical exposures.Results:The latest findings indicate different risk factors of parental characteristics on birth outcomes and themediating effect between socioeconomic status and children that are small for the gestational age. Maternal serumfolate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birthsize and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones.We also found significant associations between the chemical levels and neuro development, asthma, and allergies.Conclusions:Chemical exposure to children can occur both before and after birth. Longer follow-up for children iscrucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast,considering shifts in the exposure levels due to regulation is also essential, which may also change the associationto health outcomes. Thi

Mitochondrial dysfunction is known to contribute to mitochondrial diseases, as well as to a variety of aging-based pathologies. Mitochondria have their own genomes (mitochondrial DNA (mtDNA)) and the abnormalities, such as point mutations, deletions, and copy number variations, are involved in mitochondrial dysfunction. In recent years, several epidemiological studies and animal experiments have supported the Developmental Origin of Health and Disease (DOHaD) theory, which states that the environment during fetal life influences the predisposition to disease and the risk of morbidity in adulthood. Mitochondria play a central role in energy production, as well as in various cellular functions, such as apoptosis, lipid metabolism, and calcium metabolism. In terms of the DOHaD theory, mtDNA copy number may be a mediator of health and disease. This paper summarizes the results of recent epidemiological studies on the relationship between environmental factors and mtDNA copy number during pregnancy from the perspective of DOHaD theory. The results of these studies suggest a hypothesis that mtDNA copy number may reflect environmental influences during fetal life and possibly serve as a surrogate marker of health risks in adulthood.

Boron neutron capture therapy (BNCT) is a type of radiation therapy for eradicating tumor cells through a B-10(n,alpha)Li-7 reaction in the presence of B-10 in cancer cells. When delivering a high absorbed dose to cancer cells using BNCT, both the timeline of B-10 concentrations and the relative long dose-delivery time compared to photon therapy must be considered. Changes in radiosensitivity during such a long dose-delivery time can reduce the probability of tumor control; however, such changes have not yet been evaluated. Here, we propose an improved integrated microdosimetric-kinetic model that accounts for changes in microdosimetric quantities and dose rates depending on the B-10 concentration and investigate the cell recovery (dose-rate effects) of melanoma during BNCT irradiation. The integrated microdosimetric-kinetic model used in this study considers both sub-lethal damage repair and changes in microdosimetric quantities during irradiation. The model, coupled with the Monte Carlo track structure simulation code of the Particle and Heavy Ion Transport code System, shows good agreement with in vitro experimental data for acute exposure to Co-60 gamma -rays, thermal neutrons, and BNCT with B-10 concentrations of 10 ppm. This indicates that microdosimetric quantities are important parameters for predicting dose-response curves for cell survival under BNCT irradiations. Furthermore, the model estimation at the endpoint of the mean activation dose exhibits a reduced impact of cell recovery during BNCT irradiations with high linear energy transfer (LET) compared to Co-60 gamma -rays irradiation with low LET. Throughout this study, we discuss the advantages of BNCT for enhancing the killing of cancer cells with a reduced dose-rate dependency. If the neutron spectrum and the timelines for drug and dose delivery are provided, the present model will make it possible to predict radiosensitivity for more realistic dose-delivery schemes in BNCT irradiations.

Boron neutron capture therapy (BNCT) is a type of radiation therapy for eradicating tumor cells through a B-10(n,alpha)Li-7 reaction in the presence of B-10 in cancer cells. When delivering a high absorbed dose to cancer cells using BNCT, both the timeline of B-10 concentrations and the relative long dose-delivery time compared to photon therapy must be considered. Changes in radiosensitivity during such a long dose-delivery time can reduce the probability of tumor control; however, such changes have not yet been evaluated. Here, we propose an improved integrated microdosimetric-kinetic model that accounts for changes in microdosimetric quantities and dose rates depending on the B-10 concentration and investigate the cell recovery (dose-rate effects) of melanoma during BNCT irradiation. The integrated microdosimetric-kinetic model used in this study considers both sub-lethal damage repair and changes in microdosimetric quantities during irradiation. The model, coupled with the Monte Carlo track structure simulation code of the Particle and Heavy Ion Transport code System, shows good agreement with in vitro experimental data for acute exposure to Co-60 gamma -rays, thermal neutrons, and BNCT with B-10 concentrations of 10 ppm. This indicates that microdosimetric quantities are important parameters for predicting dose-response curves for cell survival under BNCT irradiations. Furthermore, the model estimation at the endpoint of the mean activation dose exhibits a reduced impact of cell recovery during BNCT irradiations with high linear energy transfer (LET) compared to Co-60 gamma -rays irradiation with low LET. Throughout this study, we discuss the advantages of BNCT for enhancing the killing of cancer cells with a reduced dose-rate dependency. If the neutron spectrum and the timelines for drug and dose delivery are provided, the present model will make it possible to predict radiosensitivity for more realistic dose-delivery schemes in BNCT irradiations.