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Urinary toxicities are one of the serious complications of radiotherapy for prostate cancer, and dose-volume histogram of prostatic urethra has been associated with such toxicities in previous reports. Previous research has focused on estimating the prostatic urethra, which is difficult to delineate in CT images; however, these studies, which are limited in number, mainly focused on cases undergoing brachytherapy uses low-dose-rate sources and do not involve external beam radiation therapy (EBRT). In this study, we aimed to develop a deep learning-based method of determining the position of the prostatic urethra in patients eligible for EBRT. We used contour data from 430 patients with localized prostate cancer. In all cases, a urethral catheter was placed when planning CT to identify the prostatic urethra. We used 2D and 3D U-Net segmentation models. The input images included the bladder and prostate, while the output images focused on the prostatic urethra. The 2D model determined the prostate's position based on results from both coronal and sagittal directions. Evaluation metrics included the average distance between centerlines. The average centerline distances for the 2D and 3D models were 2.07 ± 0.87 mm and 2.05 ± 0.92 mm, respectively. Increasing the number of cases while maintaining equivalent accuracy as we did in this study suggests the potential for high generalization performance and the feasibility of using deep learning technology for estimating the position of the prostatic urethra., Competing Interests: Declarations. Conflict of interest: There is no conflict of interest with regard to this manuscript. Ethical approval: This study was conducted with the approval of the Ethics Committee Tohoku University Graduate School of Medicine., (© 2024. The Author(s).)

The lack of circulating biomarkers for tumor monitoring is a major problem in Ewing sarcoma management. The development of methods for accurate tumor monitoring is required, considering the high recurrence rate of drug-resistant Ewing sarcoma. Here, we describe a sensitive analytical technique for tumor monitoring of Ewing sarcoma by detecting circulating extracellular vesicles secreted from Ewing sarcoma cells. Proteomic analysis of Ewing sarcoma cell-derived extracellular vesicles identified 564 proteins prominently observed in extracellular vesicles from three Ewing sarcoma cell lines. Among these, CD99, SLC1A5, and ENO-1 were identified on extracellular vesicles purified from sera of patients with Ewing sarcoma before treatment but not on extracellular vesicles from those after treatment and healthy individuals. Notably, not only Ewing sarcoma-derived extracellular vesicles but also Ewing sarcoma cells demonstrated proteomic expression of CD99 and ENO-1 on their surface membranes. ENO-1 + CD63 + extracellular vesicle detection was reduced after tumor resection while both CD99 + CD63 + and ENO-1 + CD63 + extracellular vesicles were detected in serum from Ewing sarcoma-bearing mice. Finally, the accuracy of liquid biopsy targeting these candidates was assessed using extracellular vesicles from the sera of patients with Ewing sarcoma. Elevated ENO-1 + CD81 + extracellular vesicles in the serum of patients before treatments distinguished patients with Ewing sarcoma from healthy individuals with an area under the curve value of 0.92 (P < 0.001) and reflected the tumor burden in patients with Ewing sarcoma during multidisciplinary treatments. Collectively, circulating ENO-1 + CD81 + extracellular vesicle detection could represent a novel tool for tumor monitoring of Ewing sarcoma., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: We investigated the effects of outdoor access for one-hour per day (ODA) on milk yield and composition and behaviors of tethered dairy cows., Methods: Eleven all-day tethered dairy cows were treated with ODA for two weeks. To evaluate the effect of ODA on milk yield, we first calculated the average daily milk yield of each cow for three days during two weeks before the ODA, three days before the ODA, three days at the end of the ODA, and three days during two weeks after the ODA. We then compared the milk yield change during the ODA with that for two weeks before and two weeks after the ODA. The effects of ODA on milk compositions and behaviors were evaluated by comparing the average values for each composition and behavior for the three days before the ODA and the last three days of the ODA., Results: The decrease of milk yield during the two weeks of ODA was significantly higher than that during the two weeks before ODA (p<0.01). The milk fat rate was significantly higher during ODA than before ODA (p<0.05). Lactose rate was significantly lower during ODA than before ODA (p<0.05). The concentrations of milk urea nitrogen, ketone bodies, and free fatty acids in the milk were significantly higher during ODA than before ODA (p<0.05). The mean total duration per day of lying during ODA was significantly lower than that before ODA (p<0.05). The walking steps per one-hour outdoor access were 158.4±54.7. The social behavior during the one-hour outdoor access of the 11 cows was 53 times/h/herd., Conclusion: Our results suggested that ODA promotes the expression of normal behavior in dairy cows, but even one hour of ODA decreases milk production in cows, which may drop producers' profits without some financial supplementation.

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas., Competing Interests: Y.U. is the President and CEO of Oncolys BioPharma, Inc. H.T. and Tos.F. are consultants of Oncolys BioPharma, Inc. The other authors have no potential conflicts of interest to disclose., (Copyright: © 2024 Uotani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The Unity magnetic resonance (MR) linear accelerator (MRL) with MR-guided adaptive radiotherapy (MRgART) is capable of online MRgART where images are acquired on the treatment day and the radiation treatment plan is immediately replanned and performed. We evaluated the MRgART plan quality and plan reproducibility of the Unity MRL in patients with prostate cancer. There were five low- or moderate-risk and five high-risk patients who received 36.25 Gy or 40 Gy, respectively in five fractions. All patients underwent simulation magnetic resonance imaging (MRI) and five online adaptive MRI. We created plans for 5, 7, 9, 16, and 20 beams and for 60, 100, and 150 segments. We evaluated the target and organ doses for different number of beams and segments, respectively. Variation in dose constraint between the simulation plan and online adaptive plan was measured for each patient to assess plan reproducibility. The plan quality improved with the increasing number of beams. However, the proportion of significantly improved dose constraints decreased as the number of beams increased. For some dose parameters, there were statistically significant differences between 60 and 100 segments, and 100 and 150 segments. The plan of five beams exhibited limited reproducibility. The number of segments had minimal impact on plan reproducibility, but 60 segments sometimes failed to meet dose constraints for online adaptive plan. The optimization and delivery time increased with the number of beams and segments. We do not recommend using five or fewer beams for a reproducible and high-quality plan in the Unity MRL. In addition, many number of segments and beams may help meet dose constraints during online adaptive plan. Treatment with the Unity MRL should be performed with the appropriate number of beams and segments to achieve a good balance among plan quality, delivery time, and optimization time., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

In external radiotherapy of head and neck (HN) cancers, the reduction of irradiation accuracy due to HN volume reduction often causes a problem. Adaptive radiotherapy (ART) can effectively solve this problem; however, its application to all cases is impractical because of cost and time. Therefore, finding priority cases is essential. This study aimed to predict patients with HN cancers are more likely to need ART based on a quantitative measure of large HN volume reduction and evaluate model accuracy. The study included 172 cases of patients with HN cancer who received external irradiation. The HN volume was calculated using cone-beam computed tomography (CT) for irradiation-guided radiotherapy for all treatment fractions and classified into two groups: cases with a large reduction in the HN volume and cases without a large reduction. Radiomic features were extracted from the primary gross tumor volume (GTV) and nodal GTV of the planning CT. To develop the prediction model, four feature selection methods and two machine-learning algorithms were tested. Predictive performance was evaluated by the area under the curve (AUC), accuracy, sensitivity and specificity. Predictive performance was the highest for the random forest, with an AUC of 0.662. Furthermore, its accuracy, sensitivity and specificity were 0.692, 0.700 and 0.813, respectively. Selected features included radiomic features of the primary GTV, human papillomavirus in oropharyngeal cancer and the implementation of chemotherapy; thus, these features might be related to HN volume change. Our model suggested the potential to predict ART requirements based on HN volume reduction ., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: We investigated the effects of outdoor access for 1 h per day on the animal welfare (AW) of tethered cows, in terms of lying and sleeping postures, and immune function., Methods: A total of five dry cows were tethered all day indoors (tethering) for 30 days and then tethered indoors with 1 h daily outdoor access (ODA-1h) for 30 days. To analyze the effects of ODA-1h, we calculated the total duration and bout frequency per day, and bout duration of lying and sleeping postures during the last five days of each treatment period. We also analyzed the populations of T cells, B cells, and NK cells in peripheral blood mononuclear cells (PBMC) by fluorescence-activated cell sorting and determined the concanavalin A (Con A) -induced proliferation rate of T cells., Results: The mean total time per day of lying during the ODA-1h treatment was significantly shorter than that during the tethering treatment (p<0.001). The Con A-induced proliferation rate of T cells during the ODA-1h treatment was significantly higher than that during the tethering treatment (p = 0.007). The proportion of NK cells in PBMC during the ODA-1h treatment tended to be higher than that during the tethering treatment (p = 0.062)., Conclusion: Although ODA-1h may decrease lying time, it increases the available space for tethered cows towards that typically found in grazing and free barn feeding systems. This increased available space promotes the expression of normal behaviors such as walking and social behaviors except lying and may also improve the immune function of tethered dry cows, thereby improving their overall welfare.

The ionic current blockades when poly(dT) 60 or dNTPs passed through SiN nanopores in an aqueous solution containing (NH 4 ) 2 SO 4 were investigated. The dwell time of poly(dT) 60 in the nanopores in an aqueous solution containing (NH 4 ) 2 SO 4 was significantly longer compared to that in an aqueous solution that did not contain (NH 4 ) 2 SO 4 . This dwell time prolongation effect due to the aqueous solution containing (NH 4 ) 2 SO 4 was also confirmed when dCTP passed through the nanopores. In addition, when the nanopores were fabricated via dielectric breakdown in the aqueous solution containing (NH 4 ) 2 SO 4 , the dwell time prolongation effect for dCTP still occurred even after the aqueous solution was displaced with the aqueous solution without (NH 4 ) 2 SO 4 . Furthermore, we measured the ionic current blockades when the four types of dNTPs passed through the same nanopore, and the four types of dNTPs could be statistically identified according to their current blockade values., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Radiotherapy for breast cancer has attracted attention in Western countries because radiation to the heart can cause cardiac events. The purposes of this study were to evaluate the relationship between radiotherapy after breast-conserving surgery and the frequency of cardiac events in Japanese patients and to investigate the risk factors of cardiac events after postoperative radiotherapy in those patients. Female patients who received postoperative radiotherapy following breast-conserving surgery between 2007 and 2012 at our hospital were evaluated. In this study, we estimated the cumulative incidence of cardiac events including angina pectoris, myocardial infarction, ischemic heart disease, heart failure and cardiomyopathy after radiotherapy. Of 311 eligible patients, 7.1% of the patients had a smoking history, 20.3% of the patients were obese and 22.2% of the patients had hypertension. The median follow-up period was 118 months (interquartile range, 102-132 months). Twelve patients (3.9%) experienced cardiac events after treatment. The mean time to cardiac events was 126 months. The 10-year cumulative incidences of cardiac events after treatment were 4.2% and 4.3% for patients with left-sided and right-sided breast cancer, respectively, without a significant difference. Multivariate analysis showed that only hypertension was a risk factor for cardiac events (hazard ratio = 16.67, P = 0.0003). In conclusion, postoperative radiotherapy for breast cancer did not increase the incidence of cardiac events. Since at least 2007, postoperative radiotherapy for breast cancer has been safely performed without effects on the heart., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This study aimed to develop and validate a collapsed cone convolution for magnetic resonance-guided radiotherapy (CCCMR). The 3D energy deposition kernels (EDKs) were generated in water in a 1.5-T transverse magnetic field. The CCCMR corrects the inhomogeneity in simulation geometry by referring to the EDKs according to the mass density between the interaction and energy deposition points in addition to density scaling. Dose distributions in a water phantom and in slab phantoms with inserted inhomogeneities were calculated using the Monte Carlo (MC) and CCCMR. The percentage depth dose (PDD) and off-axis ratio (OAR) were compared, and the gamma passing rate (3%/2 mm) was evaluated. The CCCMR simulated asymmetric dose distributions in the simulation phantoms, especially the water phantom, and all PDD and OAR profiles were in good agreement with the findings of the MC. The gamma passing rates were >99% for each field size and for the entire region. In the inhomogeneity phantoms, although the CCCMR underestimated dose in the low mass density regions, it could reconstruct dose changes at mass density boundaries. The gamma passing rate for the entire region was >95% for the field size of 2 × 2 cm2, but it was 68.9-86.7% for the field sizes of ≥5 × 5 cm2. Conclusively, in water, the CCCMR can obtain dose distributions comparable to those with the MC. Although the dose differences between them were mainly in inhomogeneity regions, the possibility of the effective use of the CCCMR in small field sizes was demonstrated., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Shifts in protein production methods are an emerging challenge toward realizing a sustainable society. This paper aims to examine preferences among Japanese consumers regarding attributes of beef mince and its substitutes, to develop consumer segments based on these preferences, and to explore the segment with higher acceptance of replacement from conventional products. This paper also aims to explain intersegment differences from consumer heterogeneity in human values, scientific literacy, and sociodemographic viewpoints for a deeper understanding of consumer behavior in each segment. The results of an online choice experiment involving 4421 consumers in Japan, using food labels on mince showed that Japanese-origin organic beef was associated with the highest utility among the five production methods mentioned. Five consumer segments were identified with latent class analysis: novelty accepters, generous customers, attribute-economy balancers, price-conscious, and conservatives, which vary in preference in choice behavior, sociodemographic, human values, and scientific literacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/aim: An association between leukotriene receptor antagonists (LTRA) and cancer has been previously reported, but the relationship between LTRA use and cancer prevention remains controversial. This study aimed to clarify the cancer-preventive effect of LTRA in Japanese patients with bronchial asthma., Patients and Methods: We obtained information from a large populationbased medical information database to analyze data on patients who were newly diagnosed with bronchial asthma between 2006 and 2015. Eligible participants were patients who were prescribed an LTRA for at least 30 days (LTRA users) and those who were not using LTRA (LTRA non-users) during the objective period. LTRA users and LTRA non-users were matched 1:1 using propensity scores., Results: The 1:1 propensity score matching of LTRA users and LTRA nonusers facilitated the inclusion of 3,744 participants each, in these two subgroups. The results of the Cox proportional hazards model after adjustment for covariates showed no significant difference in the cancer risk between LTRA users and non-users [adjusted hazard ratio (HR)=0.83, 95% confidence interval (CI)=0.59-1.16]. The subgroup analysis showed no significant difference in the cancer risk between the LTRA low-cumulative dose group and LTRA non-users, or between the LTRA medium-cumulative dose group and LTRA non-users. In contrast, the LTRA high-cumulative dose group had a significantly lower risk of developing cancer compared with LTRA non-users (adjusted HR=0.57, 95% CI=0.33-0.98)., Conclusion: LTRA use may prevent cancer in patients with bronchial asthma., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Early regression-the regression in tumor volume during the initial phase of radiotherapy (approximately 2 weeks after treatment initiation)-is a common occurrence during radiotherapy. This rapid radiation-induced tumor regression may alter target coordinates, necessitating adaptive radiotherapy (ART). We developed a deep learning-based radiomics (DLR) approach to predict early head and neck tumor regression and thereby facilitate ART. Primary gross tumor volume (GTVp) was monitored in 96 patients and nodal GTV (GTVn) in 79 patients during treatment. All patients underwent two computed tomography (CT) scans: one before the start of radiotherapy for initial planning and one during radiotherapy for boost planning. Patients were assigned to regression and nonregression groups according to their median tumor regression rate (ΔGTV/treatment day from initial to boost CT scan). We input a GTV image into the convolutional neural network model, which was pretrained using natural image datasets, via transfer learning. The deep features were extracted from the last fully connected layer. To clarify the prognostic power of the deep features, machine learning models were trained. The models then predicted the regression and nonregression of GTVp and GTVn and evaluated the predictive performance by 0.632 + bootstrap area under the curve (AUC). Predictive performance for GTVp regression was highest using the InceptionResNetv2 model (mean AUC = 0.75) and that for GTVn was highest using NASNetLarge (mean AUC = 0.73). Both models outperformed the handcrafted radiomics features (mean AUC = 0.63 for GTVp and 0.61 for GTVn) or clinical factors (0.64 and 0.67, respectively). DLR may facilitate ART for improved radiation side-effects and target coverage., (© 2022. The Author(s).)

Background: To protect developing brain from any unfavorable effects, it is necessary to construct experimental techniques that can sensitively detect and evaluate developmental toxicity. We have previously shown that brain perivascular tissues, especially perivascular macrophages (PVMs), respond sensitively even to weak stimuli by foreign toxicants such as low-dose exposure to nanoparticle. This paper shows the protocol of a novel staining method that enables easy detection and rapid evaluation of brain perivascular abnormalities. Methods: As weak stimulus, low-dose of carbon black nanoparticle (95 μg/kg) or titanium dioxide nanoparticle (100 μg/kg) was intranasally administered to pregnant mice at gestational days 5 and 9. The offspring brains were used to confirm the properties of PVMs and to find suitable protocols for the detection and evaluation of the mild denaturation of PVMs. Furthermore, various procedures of novel combinational double staining including periodic acid-Schiff (PAS) staining and immunohistochemistry were examined. In addition, we checked the alterations in neurotransmitter levels and the behaviors of the offspring. Results and discussion: Maternal exposure to low-dose of nanoparticle at levels where no significant effects on the brain were observed, such as abnormal behavior, alteration of neurotransmitter levels, or microglial activation, resulted in mild denaturation of the PVMs, which was captured by PAS staining. However, it was difficult to detect and determine slight histopathological alterations. Therefore, we established PAS-immunohistochemical double-staining method for the brain. This double staining method enabled easy detection and rapid evaluation of brain perivascular abnormalities and the relationship between PVMs and the surrounding cells. In addition, this double staining allows evaluation of the histopathological denaturation of the PVMs and the associated abnormalities in the surrounding tissues in the same section. Conclusion: The slight responses of brain perivascular tissues, such as mild denaturation of PVMs, were sensitively and easily determined by the PAS-immunohistochemical double-staining method. This double staining method is a powerful tool to assess brain perivascular injuries including PVM denaturation and the relationship between the expression of various molecules and the morphology of PVMs. We propose that the observation of the tissue around brain blood vessels using the double staining provides potential endpoints to evaluate developmental neurotoxicity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Onoda, Hagiwara, Kubota, Yanagita, Takeda and Umezawa.)

Objective: Endoplasmic reticulum (ER) stress engages the unfolded protein response (UPR) that serves as an important mechanism for modulating hepatic fatty acid oxidation and lipogenesis. Chronic fasting in mice induced the UPR activation to regulate lipid metabolism. However, there is no direct evidence of whether negative energy balance (NEB) induces ER stress in the liver of cows. This study aimed to elucidate the relationship between the NEB attributed to feed deprivation and ER stress in bovine hepatocytes., Methods: Blood samples and liver biopsy tissues were collected from 6 non-lactating cows before and after their starvation for 48 h. The blood non-esterified fatty acids (NEFA), β-hydroxybutyric acid (BHBA) and glucose level were analyzed. Real-time quantitative polymerase chain reaction and Western blotting were used to explore the regulation of genes associated with UPR and lipid metabolism., Results: The starvation increased the plasma BHBA and NEFA levels and decreased the glucose level. Additionally, the starvation caused significant increases in the mRNA expression level of spliced X-box binding protein 1 (XBP1s) and the protein level of phosphorylated inositol-requiring kinase 1 alpha (p-IRE1α; an upstream protein of XBP1) in the liver. The mRNA expression levels of peroxisome proliferator-activated receptor alpha and its target fatty acid oxidation- and ketogenesis-related genes were significantly upregulated by the starvation-mediated NEB. Furthermore, we found that the mRNA expression levels of lipogenic genes were not significantly changed after starvation., Conclusion: These findings suggest that in the initial stage of NEB in dairy cows, the liver coordinates an adaptive response by activating the IRE1 arm of the UPR to enhance ketogenesis, thereby avoiding a fatty liver status.

To analyze limb pain in tethered dairy cows, we compared three cow floor mat materials (pasture mat® [PM], KKM rubber mat® [RM], and woodchip [WC]) with soil ground considering the pressure applied to the anterior knee of Holstein cows. Three Holstein dry cows (791.3 ± 44.6 kg, 3.8 ± 1.1 years old) moored at the Education and Research Center of Alpine Field Science of the Faculty of Agriculture, Shinshu University, were tested. Pressure applied to the anterior knee of the cow by four different floor mat materials was compared using a commercially available pressure measurement sheet. The sustained pressures applied to the anterior knee of the test cow were 7.2 ± 1. 5, 29.3 ± 5.1, 17.0 ± 1.4, and 27.7 ± 2.5 MPa in the control, RM, PM, and WC, respectively, showing significant lower values (P < 0.05) than in the control. Sustained pressure was significantly lower in the PM than in the other treatments (P < 0.05). The RM was 41.7% cheaper than the PM. The pressure applied to the anterior knee of cow is lower on PM than on RM and WC. PM was more costly than RM but the sustained pressure was much lower on PM., (© 2022 Japanese Society of Animal Science.)

Purpose: To evaluate the accuracy of electron transport in the magnetic field of Electron Gamma Shower version 5 (EGS5) by using the special Fano cavity test., Methods: To simulate electron transport in the magnetic field, the trajectory of the electron was reconstructed with a short step length to restrict fractional energy loss, and the maximum user step length (mxustep) was set at 0.01 cm or 0.001 cm. For the special Fano cavity test, three-layer slab Fano test geometry was used, and uniform and isotropic per unit mass mono-energetic electrons with 0.01, 0.1, 1.0, and 10 MeV were permitted from the central axis of geometry in 0.35 T and 1.5 T. Furthermore, the magnetic field strength was scaled based on the mass density of the material. The relative difference between the calculated dose to gap and the theoretical value was evaluated. Furthermore, the special Fano cavity test was also performed using EGSnrc with the electron-enhanced electric and magnetic field macros under the same conditions, and the results were compared with those of EGS5., Results: Deviations in 0.35 T were within 0.3% regardless of the parameter settings. In 1.5 T, stable results within 0.3% were obtained using 0.001 cm as the mxustep, except for one at 10 MeV. Further, the accuracy of EGSnrc was within 0.2%, except for 10 MeV for a 0.2-cm gap in 1.5 T., Conclusions: EGS5 with the appropriate parameter settings enable electron transport in magnetic fields similar with the accuracy of EGSnrc., (Copyright © 2021. Published by Elsevier Ltd.)

Background/aim: Recent experimental studies have reported that leukotriene receptor antagonists (LTRAs) might protect against dementia. However, few clinical studies have examined this in humans. This study assessed whether the use of LTRAs can prevent the onset of dementia in humans., Patients and Methods: A large population-based retrospective cohort study was conducted using a health insurance claims database in Japan, which included patients newly diagnosed with bronchial asthma between 2006 and 2015. Each of these patients that was LTRA user was matched with a randomly selected LTRA non-user according to age, sex, and bronchial asthma diagnostic year., Results: There were 10,471 patients in both the LTRA user and the LTRA non-user group. Using Cox proportional hazards models, a significant reduction in the risk of developing dementia was observed in the LTRA user group compared to the non-user group (adjusted hazard ratio=0.42, 95% confidence interval=0.20-0.87, p=0.019)., Conclusion: Our data suggest that the use of LTRAs may prevent the onset of dementia in asthmatic patients., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background and Objectives: Titanium dioxide nanoparticles (TiO 2 -NP) are important materials used in commercial practice. Reportedly, TiO 2 -NP exposure during pregnancy can affect the development of the central nervous system in mouse offspring; however, the underlying mechanism remains unknown. In the present study, we investigated the impact of prenatal TiO 2 -NP exposure on global DNA methylation and mRNA expression patterns in the brains of neonatal mice. Materials and Methods: Pregnant C57BL/6J mice were intratracheally administered a TiO 2 -NP suspension (100 μg/mouse) on gestational day 10.5, and brains were collected from male and female offspring at day 1 postpartum. After extraction of methylated DNA by immunoprecipitation, the DNA methylation profile was analyzed using a mouse CpG island microarray. Total RNA was obtained, and mRNA expression profiles were comprehensively assessed using microarray analysis. Results: Among genes in the CpG island microarray, DNA methylation was increased in 614 and 2,924 genes and decreased in 6,220 and 6,477 genes in male and female offspring, respectively. Combined with mRNA microarray analysis, 88 and 89 genes were upregulated (≥1.5-fold) accompanied by demethylation of CpG islands, whereas 13 and 33 genes were downregulated (≤0.67-fold) accompanied by methylation of CpG islands in male and female offspring mice, respectively. Gene Set Enrichment Analysis (GSEA) revealed that these genes were enriched in gene ontology terms related to the regulation of transcription factors, cell proliferation, and organism development. Additionally, MeSH terms related to stem cells and morphogenesis were enriched. Conclusion: Prenatal TiO 2 -NP exposure induced genome-wide alterations in DNA methylation and mRNA expression in the brains of male and female offspring. Based on GSEA findings, it can be speculated that prenatal TiO 2 -NP exposure causes adverse effects on brain functions by altering the DNA methylation state of the fetal brain, especially neural stem cells, resulting in the subsequent abnormal regulation of transcription factors that modulate development and differentiation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tachibana, Kawazoe, Onoda, Umezawa and Takeda.)

Air pollution is associated with significant adverse health effects. Recent studies support the idea that inhalation of fine particles can instigate extrapulmonary effects on the cardiovascular system through several pathways. The systemic transfer of ultrafine particles (UFPs) or soluble particle components (organic compounds and metals) is of particular concern. An integral role of reactive oxygen species (ROS)-dependent pathways has been suggested in systemic inflammatory responses and vascular dysfunction at the molecular level. Accumulating lines of evidence suggest that fine particles affect fetal development, giving rise to low birth weight and a reduction in fetal growth, and also affect the immune, cardiovascular, and central nervous systems. Oxidative stress plays an important role in fine particles toxicity; pre-treatment with antioxidants partially suppresses the developmental toxicity of fine particles. On the other hand, Nuclear factor erythroid-derived 2-like 2 (Nfe2l2), also known as NRF2, is a transcription factor essential for inducible and/or constitutive expression of phase II and antioxidant enzymes. Studies using Nrf2 -knockout mice revealed that NRF2 dysfunction is intimately involved in the pathogenesis of various human diseases. Multiple single nucleotide polymorphisms (SNPs) have been detected in human NRF2 locus. An NRF2 gene SNP (-617C > A; rs6721961), located in the upstream promoter region, affects the transcriptional level of NRF2 and thereby the protein level and downstream gene expression. It has been reported that the SNP-617 is associated with various diseases. The onset and exacerbation of the diseases are regulated by genetic predisposition and environmental factors; some people live in the air-polluted environment but are not affected and remain healthy, suggesting the presence of individual differences in the susceptibility to air pollutants. NRF2 polymorphisms may also be associated with the fetal effects of fine particles exposure. Screening high-risk pregnant women genetically susceptible to oxidative stress and prevention by antioxidant interventions to protect fetal development in air-polluted areas should be considered. This article reviews the recent advances in our understanding of the fetal health effects of fine particles and describes potential chemoprevention via the NRF2 pathway to prevent the developmental and reproductive toxicity of fine particles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Takeda, Yamamoto and Kawada.)

We assessed the accuracy of deformable image registration (DIR) accuracy between CT and MR images using an open-source software (Elastix, from Utrecht Medical Center) and a commercial software (Velocity AI Ver. 3.2.0 from Varian Medical Systems, Palo Alto, CA, USA) software. Five male patients' pelvic regions were studied using publicly available CT, T1-weighted (T1w) MR, and T2-weighted (T2w) MR images. In the cost function of the Elastix, we used six DIR parameter settings with different regularization weights (Elastix0, Elastix0.01, Elastix0.1, Elastix1, Elastix10, and Elastix100). We used MR Corrected Deformable algorithm for Velocity AI. The Dice similarity coefficient (DSC) and mean distance to agreement (MDA) for the prostate, bladder, rectum and left and right femoral heads were used to evaluate DIR accuracy. Except for the bladder, most algorithms produced good DSC and MDA results for all organs. In our study, the mean DSCs for the bladder ranged from 0.75 to 0.88 (CT-T1w) and from 0.72 to 0.76 (CT-T2w). Similarly, the mean MDA ranges were 2.4 to 4.9 mm (CT-T1w), 4.6 to 5.3 mm (CT-T2w). For the Elastix, CT-T1w was outperformed CT-T2w for both DSCs and MDAs at Elastix0, Elastix0.01, and Elastix0.1. In the case of Velocity AI, no significant differences in DSC and MDA of all organs were observed. This implied that the DIR accuracy of CT and MR images might differ depending on the sequence used., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Radiotherapy for esophageal cancer entails high-dose irradiation of the myocardium owing to its close anatomical proximity to the esophagus. This study aimed to evaluate the dosimetric impact of functional avoidance planning for the myocardium with volumetric-modulated arc therapy (VMAT) in patients with esophageal cancer and determine the feasibility of functional planning. Ten patients with early stage esophageal cancer were included in this study. The prescribed dose was 60 Gy administered in 30 fractions. An experienced physician contoured the left ventricle (LV) of the myocardium. For each patient, an anatomical plan (non-LV-sparing plan) and a functional plan (LV-sparing plan) were created using the VMAT. In the functional plan, the mean percentage of LV volume receiving a dose of ≥ 30 and ≥ 40 Gy was 6.0% ± 6.7% and 2.4% ± 2.7%, respectively, whereas in the anatomical plan, they were 11.7% ± 13.1% and 4.9% ± 6.5%, respectively. There were no significant differences with respect to the dose to the hottest 1 cm 3 of the planning target volume (PTV) and the minimum dose of the gross tumor volume and the dosimetric parameters of other normal tissues between the anatomical and functional plans. We compared the anatomical and functional plans of patients with esophageal cancer undergoing VMAT. Our results demonstrated that the functional plan reduced the dose to the LV with no significant differences in the organs at risk and PTV, indicating that avoidance planning can be safely performed when administering VMAT in patients with esophageal cancer., (© 2021. Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Intractable late urinary toxicity is a serious complication after radiotherapy for patients with localized prostate cancer (LPC). We assessed clinical factors correlated with severe late urinary toxicity in LPC treated with curative image-guided intensity-modulated radiation therapy (IMRT). A total of 452 patients with LPC treated with IMRT between 2002 and 2016 were retrospectively analyzed. Among them, 432 patients received androgen deprivation therapy (ADT). The median total irradiated doses were 80 (range, 76-80) Gy. Each daily dose was 2 Gy per fraction. The median follow-up was 83 (range, 4-210) months. Late urinary toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03. Grade 3 late urinary toxicity was observed in 27 patients. No cases with grade ≥ 4 late urinary toxicity were observed. The 5-, 10-, and 12.5-year grade 3 late urinary toxicity-free survival rates were 97%, 91.8% and 88.1%, respectively. Age, risk classification, total irradiated dose, ADT duration, antithrombotic therapy (AT), cardiovascular disease, hypertension (HT), diabetes mellitus (DM), dyslipidemia (DL), prior transurethral resection of the prostate (TURP) and prior high-intensity focused ultrasound (HIFU) were investigated for correlations with grade 3 late urinary toxicity. In univariate analysis, AT and prior HIFU and no other studied factors, were correlated with grade 3 late urinary toxicity. AT and prior HIFU appear to be predictive of grade 3 late urinary toxicity. Patients with LPC with these relevant clinical factors should be carefully followed up by sharing detailed information with the urology department., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Introduction: Particulate air pollution, containing nanoparticles, enhances the risk of pediatric allergic diseases that is potentially associated with disruption of neonatal immune system. Previous studies have revealed that maternal exposure to carbon black nanoparticles (CB-NP) disturbs the development of the lymphoid tissues in newborns. Interestingly, the CB-NP-induced immune profiles were observed to be different depending on the gestational period of exposure. It is important to identify the critical exposure period to prevent toxic effects of nanoparticles on the development of the immune system. Therefore, the present study was aimed to investigate the effect of CB-NP on the development of neonatal lymphoid tissues in mice, depending on the gestational period of exposure. Methods: Pregnant ICR mice were treated with a suspension of CB-NP (95 μg/kg body weight) by intranasal instillation; the suspension was administered twice during each gestational period as follows: the pre-implantation period (gestational days 4 and 5), organogenesis period (gestational days 8 and 9), and fetal developmental period (gestational days 15 and 16). The spleen and thymus were collected from offspring mice at 1, 3, and 5-days post-partum. Splenocyte and thymocyte phenotypes were examined by flow cytometry. Gene expression in the spleen was examined by quantitative reverse transcription-polymerase chain reaction. Results: The numbers of total splenocytes and splenic CD3 - B220 - phenotype (non-T/non-B lymphocytes) in offspring on postnatal day 5 were significantly increased after exposure to CB-NP during the organogenesis period compared with other gestational periods of exposure and control (no exposure). In contrast, expression levels of mRNA associated with chemotaxis and differentiation of immune cells in the spleen were not affected by CB-NP exposure during any gestational period. Conclusion: The organogenesis period was the most susceptible period to CB-NP exposure with respect to lymphoid tissue development. Moreover, the findings of the present and previous studies suggested that long-term exposure to CB-NP across multiple gestational periods including the organogenesis period, rather than acute exposure only organogenesis period, may more severely affect the development of the immune system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Onoda, Okamoto, Shimizu, El-Sayed, Watanabe, Ogawa, Abe, Kamimura, Soga, Tachibana, Takeda and Umezawa.)

In our previous studies, ultrathin SiN membranes down to 3 nm in thickness were fabricated using the poly-Si sacrificial layer process, and nanopores were formed in those membranes. The region of the SiN membrane fabricated using this process was small, and the poly-Si sacrificial layer remained throughout the other region. On the other hand, to reduce the noise of the current through the nanopore, it is preferable to reduce the capacitance of the nanopore chip by replacing the poly-Si layer with an insulator with low permittivity, such as SiO 2 . Thus, in this study, the fabrication of SiN membranes with thicknesses of 3-7 nm using the SiO 2 sacrificial layer process was examined. SiN membranes with thicknesses of less than 5 nm could not be formed when the thickness of the top SiN layer deposited onto the sacrificial layer was 100 nm. In contrast, SiN membranes down to 3.07 nm in thickness could be formed when the top SiN layer was 40 nm in thickness. This is thought to be due to the difference in membrane stress. Nanopores were then fabricated in the membranes via dielectric breakdown. The current noise of the nanopore membranes was approximately 3/5 that of membranes fabricated using the poly-Si sacrificial layer process. Last, ionic current blockades were measured when poly(dT) 60 passed through the nanopores, and the effective thickness of the nanopores was estimated based on those current-blockade values. The effective thickness was approximately 4.8 nm when the deposited thickness of the SiN membrane was 6.03 nm. On the other hand, the effective thickness and the deposited thickness were almost the same when the deposited thickness was 3.07 nm. This suggests it became difficult to form a shape in which the thickness of the nanopore edge was thinner than the deposited membrane thickness as the deposited thickness decreased., (© 2021 IOP Publishing Ltd.)

In recent years, an apparent decline in human sperm quality has been observed worldwide. One in every 5.5 couples suffers from infertility, with male reproductive problems contributing to nearly 40% of all infertility cases. Although the reasons for the increasing number of infertility cases are largely unknown, both genetic and environmental factors can be contributing factors. In particular, exposure to chemical substances during mammalian male germ cell development has been linked to an increased risk of infertility in later life owing to defective sperm production, reproductive tract obstruction, inflammation, and sexual disorders. Prenatal exposure to nanomaterials (NMs) is no exception. In animal experiments, maternal exposure to NMs has been reported to affect the reproductive health of male offspring. Male germ cells require multiple epigenetic reprogramming events during their lifespan to acquire reproductive capacity. Given that spermatozoa deliver the paternal genome to oocytes upon fertilization, we hypothesized that maternal exposure to NMs negatively affects male germ cells by altering epigenetic regulation, which may in turn affect embryo development. Small non-coding RNAs (including microRNAs, PIWI-interacting RNAs, tRNA-derived small RNAs, and rRNA-derived small RNAs), which are differentially expressed in mammalian male germ cells in a spatiotemporal manner, could play important regulatory roles in spermatogenesis and embryogenesis. Thus, the evaluation of RNAs responsible for sperm fertility is of great interest in reproductive toxicology and medicine. However, whether the effect of maternal exposure to NMs on spermatogenesis in the offspring (intergenerational effects) really triggers multigenerational effects remains unclear, and infertility biomarkers for evaluating paternal inheritance have not been identified to date. In this review, existing lines of evidence on the effects of prenatal exposure to NMs on male reproduction are summarized. A working hypothesis of the transgenerational effects of sperm-derived epigenomic changes in the F1 generation is presented, in that such maternal exposure could affect early embryonic development followed by deficits in neurodevelopment and male reproduction in the F2 generation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yokota, Takeda and Oshio.)

The purpose of this retrospective study was to investigate survival outcomes and irradiated tumor control (local control [LC]) and locoregional control (LRC) after stereotactic body radiotherapy (SBRT) for T1 or recurrent T1 (rT1) kidney cancer. Twenty-nine nonconsecutive patients with 30 tumors were included. SBRT doses of 70 Gy, 60 Gy or 50 Gy in 10 fractions were prescribed with a linear accelerator using daily image guidance. The Kaplan-Meier method was used to estimate time-to-event outcomes, and the log-rank test was used to compare survival curves between groups divided by each possible factor. The median follow-up periods for all patients and survivors were 57 months and 69.6 months, respectively. The five-year LC rate, LRC rate, progression-free survival (PFS) rate, disease-specific survival (DSS) rate and overall survival (OS) rate were 94%, 88%, 50%, 96% and 68%, respectively. No significant factor was related to OS and PFS. Three of 24 non-hemodialysis (HD) patients had new-onset-HD because of the progression of underlying kidney disease. Grade 3 or higher toxicities from SBRT did not occur. In conclusion, SBRT for kidney cancer provided a high rate of LC, LRC and DSS with minimal toxicities, but patient selection and indication for SBRT should be done carefully considering the relatively low OS rate., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Radiomics is a new technology to noninvasively predict survival prognosis with quantitative features extracted from medical images. Most radiomics-based prognostic studies of non-small-cell lung cancer (NSCLC) patients have used mixed datasets of different subgroups. Therefore, we investigated the radiomics-based survival prediction of NSCLC patients by focusing on subgroups with identical characteristics., Methods: A total of 304 NSCLC (Stages I-IV) patients treated with radiotherapy in our hospital were used. We extracted 107 radiomic features (i.e., 14 shape features, 18 first-order statistical features, and 75 texture features) from the gross tumor volume drawn on the free breathing planning computed tomography image. Three feature selection methods [i.e., test-retest and multiple segmentation (FS1), Pearson's correlation analysis (FS2), and a method that combined FS1 and FS2 (FS3)] were used to clarify how they affect survival prediction performance. Subgroup analysis for each histological subtype and each T stage applied the best selection method for the analysis of All data. We used a least absolute shrinkage and selection operator Cox regression model for all analyses and evaluated prognostic performance using the concordance-index (C-index) and the Kaplan-Meier method. For subgroup analysis, fivefold cross-validation was applied to ensure model reliability., Results: In the analysis of All data, the C-index for the test dataset is 0.62 (FS1), 0.63 (FS2), and 0.62 (FS3). The subgroup analysis indicated that the prediction model based on specific histological subtypes and T stages had a higher C-index for the test dataset than that based on All data (All data, 0.64 vs. SCC all , 060; ADC all , 0.69; T1, 0.68; T2, 0.65; T3, 0.66; T4, 0.70). In addition, the prediction models unified for each T stage in histological subtype showed a different trend in the C-index for the test dataset between ADC-related and SCC-related models (ADC T1 -ADC T4 , 0.72-0.83; SCC T1 -SCC T4 , 0.58-0.71)., Conclusions: Our results showed that feature selection methods moderately affected the survival prediction performance. In addition, prediction models based on specific subgroups may improve the prediction performance. These results may prove useful for determining the optimal radiomics-based predication model.

We investigated the inhibitory effect of capsaicin fertilizer on feeding in deer. We tested four captive adult female deer. In Experiment 1, in addition to the treatment (intact) containing only a solid feed (HC), we mixed the fertilizer not containing capsaicin (F) or the capsaicin fertilizer (CF) in the solid feed. In addition, the solid feed was put on a wire net that capsaicin fertilizer was placed 5 cm below (SCF). We investigated their feeding behavior response. In Experiment 2, we changed the amount of substance (fertilizer and capsaicin fertilizer) mixed in the HC. We mixed different amounts (0, 50, 100, and 200 g) of the treatments other than the intact with HC and presented them to the deer, and investigated their feeding behavior response. In Experiment 1, intake in the F and CF decreased (p < .05). In Experiment 2, HC intake was significantly lower in the 100 and 200 g CF (p < .05). However, HC intake relatively increased by the last day in the CF 200 g too. The capsaicin fertilizer decreased the feeding behavior of deer by directly touching the mucous membranes of the deer nose and lips. However, the effects were decreased over time., (© 2021 Japanese Society of Animal Science.)

We compared predictive performance between dose volume histogram (DVH) parameter addition and deformable image registration (DIR) addition for gastrointestinal (GI) toxicity in cervical cancer patients. A total of 59 patients receiving brachytherapy and external beam radiotherapy were analyzed retrospectively. The accumulative dose was calculated by three methods: conventional DVH parameter addition, full DIR addition and partial DIR addition. ${D}&#95;{2{cm}^3}$, ${D}&#95;{1{cm}^3}$ and ${D}&#95;{0.1{cm}^3}$ (minimum doses to the most exposed 2 cm3, 1cm3 and 0.1 cm3 of tissue, respectively) of the rectum and sigmoid were calculated by each method. V50, V60 and V70 Gy (volume irradiated over 50, 60 and 70 Gy, respectively) were calculated in full DIR addition. The DVH parameters were compared between toxicity (≥grade1) and non-toxicity groups. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves were compared to evaluate the predictive performance of each method. The differences between toxicity and non-toxicity groups in ${D}&#95;{2{cm}^3}$ were 0.2, 5.7 and 3.1 Gy for the DVH parameter addition, full DIR addition and partial DIR addition, respectively. The AUCs of ${D}&#95;{2{cm}^3}$ were 0.51, 0.67 and 0.57 for DVH parameter addition, full DIR addition and partial DIR addition, respectively. In full DIR addition, the difference in dose between toxicity and non-toxicity was the largest and AUC was the highest. AUCs of V50, V60 and V70 Gy were 0.51, 0.63 and 0.62, respectively, and V60 and V70 were high values close to the value of ${D}&#95;{2{cm}^3}$ of the full DIR addition. Our results suggested that the full DIR addition may have the potential to predict toxicity more accurately than the conventional DVH parameter addition, and that it could be more effective to accumulate to all pelvic irradiation by DIR., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: This study aimed to develop a deep convolutional neural network (CNN)-based dose distribution conversion approach for the correction of the influence of a magnetic field for online MR-guided adaptive radiotherapy., Methods: Our model is based on DenseNet and consists of two 2D input channels and one 2D output channel. These three types of data comprise dose distributions without a magnetic field (uncorrected), electron density (ED) maps, and dose distributions with a magnetic field. These data were generated as follows: both types of dose distributions were created using 15-field IMRT in the same conditions except for the presence or absence of a magnetic field with the GPU Monte Carlo dose in Monaco version 5.4; ED maps were acquired with planning CT images using a clinical CT-to-ED table at our institution. Data for 50 prostate cancer patients were used; 30 patients were allocated for training, 10 for validation, and 10 for testing using 4-fold cross-validation based on rectum gas volume. The accuracy of the model was evaluated by comparing 2D gamma-indexes against the dose distributions in each irradiation field with a magnetic field (true)., Results: The gamma indexes in the body for CNN-corrected uncorrected dose against the true dose were 94.95% ± 4.69% and 63.19% ± 3.63%, respectively. The gamma indexes with 2%/2-mm criteria were improved by 10% in most test cases (99.36%)., Conclusions: Our results suggest that the CNN-based approach can be used to correct the dose-distribution influences with a magnetic field in prostate cancer treatment., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

In the present study, we investigated the role of Nrf2 in airway immune responses induced by diesel exhaust (DE) inhalation in mice. C57BL/6J Nrf2 +/+ and Nrf2 -/- mice were exposed to DE or clean air for 8 h/day and 6 days/week for 4 weeks. After DE exposure, the number of neutrophils and macrophage inflammatory protein (MIP)-2 level in bronchoalveolar lavage fluid (BALF) and interleukin (IL)-17 level in the lung tissue increased in Nrf2 -/- mice compared with Nrf2 +/+ mice; however, the lack of an increase in the level of tumor necrosis factor (TNF)-α in the lung tissue in Nrf2 +/+ mice and mild suppression of the level of TNF-α in Nrf2 -/- mice were observed; the level of granulocyte macrophage colony-stimulating factor (GM-CSF) in the lung tissue decreased in Nrf2 -/- mice than in Nrf2 +/+ mice; the number of DE particle-laden alveolar macrophages in BALF were larger in Nrf2 -/- mice than in Nrf2 +/+ mice. The results of electron microscope observations showed alveolar type II cell injury and degeneration of the lamellar body after DE exposure in Nrf2 -/- mice. Antioxidant enzyme NAD(P)H quinone dehydrogenase (NQO)1 mRNA expression level was higher in Nrf2 +/+ mice than in Nrf2 -/- mice after DE exposure. Our results suggested that Nrf2 reduces the risk of pulmonary disease via modulating the airway innate immune response caused by DE in mice.

We evaluated four-dimensional cone beam computed tomography (4D-CBCT) ventilation images (VI CBCT ) acquired with two different linear accelerator systems at various gantry speeds using a deformable lung phantom. The 4D-CT and 4D-CBCT scans were performed using a computed tomography (CT) scanner, an X-ray volume imaging system (Elekta XVI) mounted in Versa HD, and an On-Board Imager (OBI) system mounted in TrueBeam. Intensity-based deformable image registration (DIR) was performed between peak-exhale and peak-inhale images. VI CBCT - and 4D-CT-based ventilation images (VI CT ) were derived by DIR using two metrics: one based on the Jacobian determinant and one on changes in the Hounsfield unit (HU). Three different DIR regularization values (λ) were used for VI CBCT . Correlations between the VI CBCT and VI CT values were evaluated using voxel-wise Spearman's rank correlation coefficient (r). In case of both metrics, the Jacobian-based VI CBCT with a gantry speed of 0.6 deg/sec in Versa HD showed the highest correlation for all the gantry speeds (e.g., λ = 0.05 and r = 0.68). Thus, the r value of the Jacobian-based VI CBCT was greater or equal to that of the HU-based VI CBCT . In addition, the ventilation accuracy of VI CBCT increased at low gantry speeds. Thus, the image quality of VI CBCT was affected by the change in gantry speed in both the imaging systems. Additionally, DIR regularization considerably influenced VI CBCT in both the imaging systems. Our results have the potential to assist in designing CBCT protocols, incorporating VI CBCT imaging into the functional avoidance planning process., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Functional lung avoidance during radiotherapy can help reduce pulmonary toxicity. This study assessed the potential impact of four-dimensional computed tomography (4DCT)-ventilation imaging-guided proton radiotherapy (PT) on stereotactic body radiotherapy (SBRT) by comparing it with three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT), which employ photon beams. Thirteen lung cancer patients who received SBRT with 3D-CRT were included in the study. 4DCT ventilation was calculated using the patients' 4DCT data, deformable image registration, and a density-change-based algorithm. Three functional treatment plans sparing the functional lung regions were developed for each patient using 3D-CRT, VMAT, and PT. The prescribed doses and dose constraints were based on the Radiation Therapy Oncology Group 0618 protocol. We evaluated the region of interest (ROI) and functional map-based dose-function metrics for 4DCT ventilation and the irradiated dose. Using 3D-CRT, VMAT, and PT, the percentages of the functional lung regions that received ≥ 5 Gy (fV5) were 26.0%, 21.9%, and 10.7%, respectively; the fV10 were 14.4%, 11.4%, and 9.0%, respectively; and fV20 were 6.5%, 6.4%, and 6.6%, respectively, and the functional mean lung doses (fMLD) were 5.6 Gy, 5.2 Gy, and 3.8 Gy, respectively. These results indicated that PT resulted in a significant reduction in fMLD, fV5, and fV10, but not fV20. The use of PT reduced the radiation to highly functional lung regions compared with those for 3D-CRT and VMAT while meeting all dose constraints.

Purpose: The purpose of this prospective study was to evaluate radiation-induced myocardial damage after mediastinal radiation therapy (RT) using late gadolinium-enhancement (LGE) magnetic resonance imaging (MRI)., Methods and Materials: We enrolled 19 patients with esophageal cancer who were expected to have long-term survival by definitive treatment. They underwent delayed contrast-enhanced MRI (19 patients before treatment, 19 patients 6 months after treatment, and 12 patients 1.5 years after treatment). Dose distribution of the left ventricle was made using computed tomography, and the dose volume histogram of the left ventricle was calculated. Myocardial signal intensities in individual MRIs were normalized by the mean values in regions receiving low doses (<5 Gy). Changes in the normalized signal intensities after mediastinal radiation therapy were compared among regions where irradiation doses were 0 to 10 Gy, 10 to 20 Gy, 20 to 30 Gy, 30 to 40 Gy, 40 to 50 Gy, and 50 to 60 Gy, and we investigated whether intensity change was detected in a dose-dependent manner., Results: The registered patients were treated with concurrent chemoradiotherapy with a median total dose of 60 Gy (50.4-66 Gy). Chemotherapy consisting of cisplatin and 5-fluorouracil was administered. In the population-based dose-response curve, dose-dependent intensity changes progressively increased in regions receiving more than 30 Gy. The averages of relative intensity change at 6 months and 1.5 years after treatment were 1.1% and -1.9% at 20 to 30 Gy and 37.5% and 17.5% at 40 to 50 Gy, respectively. LGE in regions receiving more than 30 Gy was detected in 68% (13/19) of the patients., Conclusions: A dose-dependent relationship for myocardial signal intensity change was found by using LGE MRI. It may be necessary to reduce the volume of the myocardium receiving more than 30 Gy., (© 2020 The Author(s).)

The uptake of boron into tumor cells is a key factor in the biological effects of boron neutron capture therapy (BNCT). The uptake of boron agents is suppressed in hypoxic conditions, but the mechanism of hypoxia-induced modulation of suppression of boron uptake is not clear. Therefore, we evaluated whether hypoxia-inducible factor 1α (HIF-1α) contributes to attenuation of the antitumor effects of BNCT in hypoxic tumor cells. We also tested whether YC-1, a HIF-1α-targeting inhibitor, has therapeutic potential with BNCT. To elucidate the mechanism of attenuation of the effects of BNCT caused by hypoxia, deferoxamine (DFO) was used in experiments. Cells were incubated in normal oxygen, hypoxic conditions (1% O2) or 5 μM DFO for 24 h. Then, cells were treated with 10B-boronophenylalanine (BPA) for 2 h and boron accumulation in cells was evaluated. To clarify the relationship between HIF-1α and L-type amino acid transporter 1 (LAT1), gene expression was evaluated by a using HIF-1α gene knockdown technique. Finally, to improve attenuation of the effects of BNCT in hypoxic cells, BNCT was combined with YC-1. Boron uptake was continuously suppressed up to 2 h after administration of BPA by 5 μM DFO treatment. In cells treated with 5 μM DFO, LAT1 expression was restored in HIF-1α-knocked down samples in all cell lines, revealing that HIF-1α suppresses LAT1 expression in hypoxic cells. From the results of the surviving fraction after BNCT combined with YC-1, treatment with YC-1 sensitized the antitumor effects of BNCT in cells cultured in hypoxia., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: Accurate identification of the prostatic urethra and bladder can help determine dosing and evaluate urinary toxicity during intensity-modulated radiation therapy (IMRT) planning in patients with localized prostate cancer. However, it is challenging to locate the prostatic urethra in planning computed tomography (pCT). In the present study, we developed a multiatlas-based auto-segmentation method for prostatic urethra identification using deformable image registration accuracy prediction with machine learning (ML) and assessed its feasibility., Methods: We examined 120 patients with prostate cancer treated with IMRT. All patients underwent temporary urinary catheter placement for identification and contouring of the prostatic urethra in pCT images (ground truth). Our method comprises the following three steps: (a) select four atlas datasets from the atlas datasets using the deformable image registration (DIR) accuracy prediction model, (b) deform them by structure-based DIR, (3) and propagate urethra contour using displacement vector field calculated by the DIR. In (a), for identifying suitable datasets, we used the trained support vector machine regression (SVR) model and five feature descriptors (e.g., prostate volume) to increase DIR accuracy. This method was trained/validated using 100 patients and performance was evaluated within an independent test set of 20 patients. Fivefold cross-validation was used to optimize the hype parameters of the DIR accuracy prediction model. We assessed the accuracy of our method by comparing it with those of two others: Acostas method-based patient selection (previous study method, by Acosta et al.), and the Waterman's method (defines the prostatic urethra based on the center of the prostate, by Waterman et al.). We used the centerlines distance (CLD) between the ground truth and the predicted prostatic urethra as the evaluation index., Results: The CLD in the entire prostatic urethra was 2.09 ± 0.89 mm (our proposed method), 2.77 ± 0.99 mm (Acosta et al., P = 0.022), and 3.47 ± 1.19 mm (Waterman et al., P < 0.001); our proposed method showed the highest accuracy. In segmented CLD, CLD in the top 1/3 segment was highly improved from that of Waterman et.al. and was slightly improved from that of Acosta et.al., with results of 2.49 ± 1.78 mm (our proposed method), 2.95 ± 1.75 mm (Acosta et al., P = 0.42), and 5.76 ± 3.09 mm (Waterman et al., P < 0.001)., Conclusions: We developed a DIR accuracy prediction model-based multiatlas-based auto-segmentation method for prostatic urethra identification. Our method identified prostatic urethra with mean error of 2.09 mm, likely due to combined effects of SVR model employment in patient selection, modified atlas dataset characteristics and DIR algorithm. Our method has potential utility in prostate cancer IMRT and can replace use of temporary indwelling urinary catheters., (© 2020 American Association of Physicists in Medicine.)

Nano-particulate air pollution threatens developing brains and is epidemiologically related to neurodegenerative diseases involving deposition of misfolded proteins. However, the mechanism underlying developmental neurotoxicity by nanoparticles remains unknown. Here, we report that maternal exposure to low doses of carbon black nanoparticle (CB-NP) induces endoplasmic reticulum (ER) stress associated with accumulation of misfolded proteins. Notably, offspring specifically showed high induction of ER stress in perivascular macrophages and reactive astrocytes only around brain blood vessels, along with accumulation of β-sheet-rich proteins regarded as misfolded proteins. Our results suggest that maternal CB-NP exposure induced ER stress in PVMs and reactive astrocytes around blood vessels in the brain of offspring in mice. The induction of ER stress accompanied by the perivascular accumulation of misfolded proteins is likely to be associated with perivascular abnormalities and neurodegeneration, and development of neurodegenerative diseases related to particulate air pollution.

Purpose: Radiomics is a new technique that enables noninvasive prognostic prediction by extracting features from medical images. Homology is a concept used in many branches of algebra and topology that can quantify the contact degree. In the present study, we developed homology-based radiomic features to predict the prognosis of non-small-cell lung cancer (NSCLC) patients and then evaluated the accuracy of this prediction method., Methods: Four datasets were used: two to provide training and test data and two for the selection of robust radiomic features. All the datasets were downloaded from The Cancer Imaging Archive (TCIA). In two-dimensional cases, the Betti numbers consist of two values: b 0 (zero-dimensional Betti number), which is the number of isolated components, and b 1 (one-dimensional Betti number), which is the number of one-dimensional or "circular" holes. For homology-based evaluation, computed tomography (CT) images must be converted to binarized images in which each pixel has two possible values: 0 or 1. All CT slices of the gross tumor volume were used for calculating the homology histogram. First, by changing the threshold of the CT value (range: -150 to 300 HU) for all its slices, we developed homology-based histograms for b 0 , b 1 , and b 1 /b 0 using binarized images. All histograms were then summed, and the summed histogram was normalized by the number of slices. 144 homology-based radiomic features were defined from the histogram. To compare the standard radiomic features, 107 radiomic features were calculated using the standard radiomics technique. To clarify the prognostic power, the relationship between the values of the homology-based radiomic features and overall survival was evaluated using LASSO Cox regression model and the Kaplan-Meier method. The retained features with nonzero coefficients calculated by the LASSO Cox regression model were used for fitting the regression model. Moreover, these features were then integrated into a radiomics signature. An individualized rad score was calculated from a linear combination of the selected features, which were weighted by their respective coefficients., Results: When the patients in the training and test datasets were stratified into high-risk and low-risk groups according to the rad scores, the overall survival of the groups was significantly different. The C-index values for the homology-based features (rad score), standard features (rad score), and tumor size were 0.625, 0.603, and 0.607, respectively, for the training datasets and 0.689, 0.668, and 0.667 for the test datasets. This result showed that homology-based radiomic features had slightly higher prediction power than the standard radiomic features., Conclusions: Prediction performance using homology-based radiomic features had a comparable or slightly higher prediction power than standard radiomic features. These findings suggest that homology-based radiomic features may have great potential for improving the prognostic prediction accuracy of CT-based radiomics. In this result, it is noteworthy that there are some limitations., (© 2020 American Association of Physicists in Medicine.)

Nanopore-based biosensors have attracted attention as highly sensitive microscopes for detecting single molecules in aqueous solutions. However, the ionic current noise through a nanopore degrades the measurement accuracy. In this study, the magnitude of the low-frequency noise in the ionic current through a silicon nitride nanopore was found to change depending on the metal ion species in the aqueous solution. The order of the low-frequency noise magnitudes of the alkali metal ionic current was consistent with the order of the adsorption affinities of the metal ions for the silanol surface of the nanopore (Li 2 aqueous solution with a CsCl aqueous solution, indicating that Ca ions continued being adsorbed onto silanol groups even after removing the aqueous solution.

Nanopore DNA sequencing offers a new paradigm owing to its extensive potential for long-read, high-throughput detection of nucleotide modification and direct RNA sequencing. Given the remarkable advances in protein nanopore sequencing technology, there is still a strong enthusiasm in exploring alternative nanopore-sequencing techniques, particularly those based on a solid-state nanopore using a semiconductor material. Since solid-state nanopores provide superior material robustness and large-scale integrability with on-chip electronics, they have the potential to surpass the limitations of their biological counterparts. However, there are key technical challenges to be addressed: the creation of an ultrasmall nanopore, fabrication of an ultrathin membrane, control of the ultrafast DNA speed and detection of four nucleotides. Extensive research efforts have been devoted to resolving these issues over the past two decades. In this review, we briefly introduce recent updates regarding solid-state nanopore technologies towards DNA sequencing. It can be envisioned that emerging technologies will offer a brand new future in DNA-sequencing technology.

The purpose of the study was to compare a 3D convolutional neural network (CNN) with the conventional machine learning method for predicting intensity-modulated radiation therapy (IMRT) dose distribution using only contours in prostate cancer. In this study, which included 95 IMRT-treated prostate cancer patients with available dose distributions and contours for planning target volume (PTVs) and organs at risk (OARs), a supervised-learning approach was used for training, where the dose for a voxel set in the dataset was defined as the label. The adaptive moment estimation algorithm was employed for optimizing a 3D U-net similar network. Eighty cases were used for the training and validation set in 5-fold cross-validation, and the remaining 15 cases were used as the test set. The predicted dose distributions were compared with the clinical dose distributions, and the model performance was evaluated by comparison with RapidPlan™. Dose-volume histogram (DVH) parameters were calculated for each contour as evaluation indexes. The mean absolute errors (MAE) with one standard deviation (1SD) between the clinical and CNN-predicted doses were 1.10% ± 0.64%, 2.50% ± 1.17%, 2.04% ± 1.40%, and 2.08% ± 1.99% for D2, D98 in PTV-1 and V65 in rectum and V65 in bladder, respectively, whereas the MAEs with 1SD between the clinical and the RapidPlan™-generated doses were 1.01% ± 0.66%, 2.15% ± 1.25%, 5.34% ± 2.13% and 3.04% ± 1.79%, respectively. Our CNN model could predict dose distributions that were superior or comparable with that generated by RapidPlan™, suggesting the potential of CNN in dose distribution prediction., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

For nanopore sensing of various-sized molecules with high sensitivity, the size of the nanopore should be adjusted according to the size of each target molecule. For solid-state nanopores, a simple and inexpensive nanopore fabrication method utilizing dielectric breakdown of a membrane is widely used. This method is suitable for fabricating a small nanopore. However, it suffers two serious problems when attempting to fabricate a large nanopore: the generation of multiple nanopores and the non-opening failure of a nanopore. In this study, we found that nanopore fabrication by dielectric breakdown of a SiN membrane under high-pH conditions (pH ≥ 11.3) could overcome these two problems and enabled the formation of a single large nanopore up to 40 nm in diameter within one minute. Moreover, the ionic-current blockades derived from streptavidin-labelled and non-labelled DNA passing through the fabricated nanopore were clearly distinguished. The current blockades caused by streptavidin-labelled DNA could be identified even when its concentration is 1% of the total DNA.

We evaluated an anthropomorphic head and neck phantom with tissue heterogeneity, produced using a personal 3D printer, with quality assurance (QA), specific to patients undergoing intensity-modulated radiation therapy (IMRT). Using semi-automatic segmentation, 3D models of bone, soft tissue, and an air-filled cavity were created based on computed tomography (CT) images from patients with head and neck cancer treated with IMRT. For the 3D printer settings, polylactide was used for soft tissue with 100% infill. Bone was reproduced by pouring plaster into the cavity created by the 3D printer. The average CT values for soft tissue and bone were 13.0 ± 144.3 HU and 439.5 ± 137.0 HU, respectively, for the phantom and 12.1 ± 124.5 HU and 771.5 ± 405.3 HU, respectively, for the patient. The gamma passing rate (3%/3 mm) was 96.1% for a nine-field IMRT plan. Thus, this phantom may be used instead of a standard shape phantom for patient-specific QA in IMRT.

Nanopore DNA sequencing with a solid-state nanopore requires deceleration of the ultrafast translocation speed of single-stranded DNA (ssDNA). We report an unexpected phenomenon: controlled dielectric breakdown (CBD) with a divalent metal cation, especially Ca2+, provides a silicon nitride nanopore with the ability to decelerate ssDNA speed to 100 μs per base even after solution replacement. This speed is two orders of magnitude slower than that for CBD with a conventional monovalent metal cation. Temperature dependence experiments revealed that the enthalpic barrier for a nanopore created via CBD with Ca2+ is 25-30kBT, comparable to that of a biological nanopore. The slowing effect originates from the strong interaction between ssDNA and divalent cations, which were coated on the sidewall of the nanopore during the CBD process. In addition, we found that the nanopore created via CBD with Ca2+ can decelerate the speed of even single-nucleotide monomers, dNMPs, to 0.1-10 ms per base. The four single nucleotides could be statistically identified according to their blockade currents. Our approach is simple and practical because it simultaneously allows nanopore fabrication, ssDNA deceleration and the identification of nucleotide monomers.