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The precision in electron holography studies on electrostatic and magnetic fields depends on the image quality of an electron hologram. Enhancing the image quality of electron holograms is essential for the comprehensive analysis of weak electromagnetic fields; however, extended electron beam irradiation can lead to undesirable radiation damage and contamination. Recent studies have demonstrated that noise reduction using the wavelet hidden Markov model (WHMM) can improve the precision of phase analysis for limited thin-foiled crystals. In this study, we examine the effects of WHMM-based denoising on the electron holography data of weakly charged nanoparticles collected under low-electron-dose conditions. The results indicate that effective noise reduction with the WHMM allows for a reduction in the magnitude of the electron dose by approximately half relative to data collection without WHMM denoising, while maintaining the same level of the charge determination precision: less than one elementary charge. Notably, at a low electron dose of 0.40 e-/pixel, WHMM denoising enables the clear visualization of a weak stray electric field outside a charged latex sphere. This method offers significant advantages for electron holography studies of electron-beam-sensitive materials requiring minimal time for electron exposure., (© The Author(s) 2025. Published by Oxford University Press on behalf of The Japanese Society of Microscopy.)

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The charge state of supported metal catalysts is the key to understand the elementary processes involved in catalytic reactions. However, high-precision charge analysis of the metal catalysts at the atomic level is experimentally challenging. To address this critical challenge, high-sensitivity electron holography has recently been successfully applied for precisely measuring the elementary charges on individual platinum nanoparticles supported on a titanium dioxide surface. In this review, we introduce the latest advancements in high-precision charge analysis and discuss the mechanisms of charge transfer at the metal-support interface. The development of charge measurements is entering a new era, and charge analyses under conditions closer to practical working environments, such as real-time, real-space, and reactive gas environments, are expected to be realized in the near future., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Eosinophils are typical effector cells associated with type 2 immune responses and play key roles in the pathogenesis of allergic diseases. These cells are activated by various stimuli, such as cytokines, chemokines, and growth factors, but the regulatory mechanisms of eosinophil effector functions remain unclear. Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), a transmembrane protein belonging to the tumor necrosis factor (TNF) receptor superfamily, is a well-known regulatory molecule for T cell activation. Here, we show that GITR is also constitutively expressed on eosinophils and functions as a costimulatory molecule for these cells. Although degranulation was unaffected by GITR engagement of murine bone marrow-derived eosinophils, secretion of inflammatory cytokines such as interleukin (IL)-4, IL-6, and IL-13 from IL-33-activated bone marrow-derived eosinophils was augmented by anti-mouse GITR agonistic antibody (DTA-1). In conclusion, our results provide a new regulatory pathway of cytokine secretion from eosinophils in which GITR functions as a costimulatory molecule., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Perovskite oxides, ABO3, are potential catalysts for the oxygen evolution reaction, which is important in the production of hydrogen as a sustainable energy resource. Optimizing the chemical composition of such oxides by substitution or doping with additional elements is an effective approach to improving the activity of such catalysts. Here, we characterized the crystal and electronic structures of fluorine-doped La0.5Sr0.5CoO3-δ particles using scanning transmission electron microscopy (STEM) and electron energy-loss spectroscopy (EELS). High-resolution STEM imaging demonstrated the formation of a disordered surface phase caused by fluorine doping. In addition, spatially resolved EELS data showed that fluorine anions were introduced into the interiors of the particles and that Co ions near the surfaces were slightly reduced by fluorine doping in conjunction with the loss of oxygen ions. Peak fitting of energy-loss near-edge structure data demonstrated an unexpected nanostructure in the vicinity of the surface. An EELS characterization comprising elemental mapping together with an energy-loss near-edge structure analysis indicated that this nanostructure could not be assigned to Co-based materials but rather to the solid electrolyte BaF2. Complementary structural and electronic characterizations using STEM and EELS as demonstrated herein evidently have the potential to play an increasingly important role in elucidating the nanostructures of functional materials., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study evaluated the prognostic impact of the quality of dose distribution using dosiomics in patients with prostate cancer, stratified by pretreatment prostate-specific antigen (PSA) levels and Gleason grade (GG) group., Methods: A total of 721 patients (Japanese Foundation for Cancer Research [JFCR] cohort: N = 489 and Tokyo Radiation Oncology Clinic [TROC] cohort: N = 232) with localized prostate cancer treated by intensity-modulated radiation therapy were enrolled. Two predictive dosiomic features for biochemical recurrence (BCR) were selected and patients were divided into certain groups stratified by pretreatment PSA levels and GG. Freedom from biochemical failure (FFBF) was estimated using the Kaplan-Meier method based on each dosiomic feature and univariate discrimination was evaluated using the log-rank test. As an exploratory analysis, a dosiomics hazard (DH) score was developed and its prognostic power for BCR was examined., Results: The dosiomic feature extracted from planning target volume (PTV) significantly distinguished the high- and low-risk groups in patients with PSA levels >10 ng/mL (7-year FFBF: 86.7% vs 76.1%, P < .01), GG 4 (92.2% vs 76.9%, P < .01), and GG 5 (83.1% vs 77.8%, P = .04). The DH score showed significant association with BCR (hazard score: 2.04; 95% confidence interval: 1.38-3.01; P < .001)., Conclusion: The quality of planned dose distribution on PTV may affect the prognosis of patients with poor prognostic factors, such as PSA levels >10 ng/mL and higher GGs., Advances in Knowledge: The effects of planned dose distribution on prognosis differ depending on the patient's clinical background., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cancer patients often have impaired renal and hepatic function. Opioids are essential to relieve painful symptoms in cancer patients. However, it is unknown which opioids are first prescribed for cancer patients with renal and hepatic impairment. The objective is to investigate the association between the type of first prescribed opioids and the renal/hepatic function of cancer patients., Methods: We used a multicenter database from 2010 to 2019. The number of days from the first opioid prescription to the death was defined as the prognostic period. This period was divided into six categories. The prevalence of opioid prescriptions was calculated for each assessment of renal and hepatic function, divided into prognostic periods. Multinomial logistic regression analysis was used to explore the influence of renal and hepatic function on the first opioid choice., Results: The study included 11 945 patients who died of cancer. In all prognostic period categories, the patients with worse renal function received fewer morphine prescriptions. No trend was observed in hepatic function. The odds ratio of oxycodone to morphine with reference to estimated glomerular filtration rate (eGFR) ≥90 was 1.707 (95% confidence interval: 1.433-2.034) for estimated glomerular filtration rate <30. The odds ratio of fentanyl to morphine with reference to estimated glomerular filtration rate ≥90 was 1.785 (95% confidence interval: 1.492-2.134) for estimated glomerular filtration rate <30. No association was identified between hepatic function and the choice of prescribed opioids., Conclusion: Cancer patients with renal impairment tended to avoid morphine prescriptions, and no specific trend was observed in cancer patients with hepatic impairment., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

This paper proposes a method that provides a phase image related to the demagnetization field (Hd) within a thin-foil permanent magnet using electron holography. The observation of Hd remains a significant challenge because electron holography in principle allows only imaging of the magnetic flux density (B), which is a mixture of the contributions from magnetization (M), stray magnetic field (Hs) outside of the specimen and Hd inside of the specimen. The phase map approximating Hd, which was determined by processing of the electron holography observation from a Nd2Fe14B single-crystalline specimen, showed a good agreement with the prediction by micromagnetic theory. With respect to permanent magnets, this method can be applied to examinations about the coercivity mechanism, which is sensitive to the demagnetization field. Graphical Abstract., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study aimed to investigate the effect of androgen deprivation therapy (ADT) on the survival of intermediate-risk prostate cancer (IR-PCA) patients treated with dose-escalated external beam radiation therapy (DE-EBRT), and to determine the group that will benefit from ADT., Methods: We analysed 620 IR-PCA patients treated with DE-EBRT at two institutions. Variables were adjusted using the stabilised inverse probability of treatment weighting method (sIPTW) between radiation therapy (RT) and RT plus ADT groups. Biochemical relapse-free survival (bRFS) rate and overall survival (OS) rate were compared using Kaplan-Meier analysis and log-rank test. Cox proportional hazard analysis (CPH) was conducted to detect unfavorable risk factors., Results: This study included 405 patients; with 217 and 188 patients in the RT and RT plus ADT groups, respectively. The prescribed radiation dose was 78 Gy in 39 fractions. The median follow-up time was 82.0 months. After sIPTW-adjustment, 214.3 and 189.7 patients were assigned to the RT and RT plus ADT groups, respectively. The 7-year bRFS and OS were 89.3% and 94.6% in RT group and 92.3% and 91.0% in RT plus ADT group, respectively. Before and after sIPTW adjustment, no statistically significant differences were found in these endpoints between treatment groups. Multivariate CPH for bRFS revealed Gleason score (GS) 4 + 3 as an unfavorable risk factor, and ADT improved biochemical control of them., Conclusion: ADT may not always be effective in all Japanese IR-PCA patients treated with DE-EBRT, but it can improve biochemical control in patients with GS 4 + 3., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study assessed the efficacy of chemoradiotherapy for squamous cell carcinoma of the anal canal (SCCAC). Patients with T1-4N0-3M0 SCCAC received chemoradiotherapy with 5-fluorouracil (5-FU, 800 mg/m2/day, 96-h infusion) and mitomycin-C (MMC, 10 mg/m2 bolus). Patients treated with 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) were administered 36.0 Gy in 20 fractions or 49.5 Gy in 33 fractions for elective nodal irradiation and 59.4 Gy in 33 fractions for primary tumor and metastatic nodal irradiation. The sample size was considered sufficient to estimate 95% confidence intervals (CIs) for the true 2-year disease-free survival (DFS) within a width of +15% when the expected true 2-year DFS was 70%. The primary endpoint was 2-year DFS. The secondary endpoints were 2-year overall survival (OS), locoregional control (LC), colostomy-free survival (CFS) and adverse events. Thirty-one patients were enrolled between January 2014 and July 2019. The median follow-up was 33.3 months (range, 16.2-65.8 months). Among the 31 patients, 13%, 32%, 16% and 39% had stage I, II, IIIA and IIIB disease, respectively. Thirty patients were treated with IMRT. Complete response (CR) was achieved in 27 patients. The 2-year DFS, OS, LC and CFS rates were 77.4% (95% CI, 58.4-88.5%), 93.5% (95% CI, 76.6-98.3%), 83.9% (95% CI, 65.5-92.9%) and 80.6% (95% CI, 61.9-90.8%), respectively. One patient experienced grade 3 late adverse events; however, no grade ≥ 4 late adverse events occurred. Good DFS with a low rate of late adverse events was observed. Chemoradiotherapy with 5-FU and MMC was effective for SCCAC., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Upper urinary tract urothelial carcinoma is a rare cancer that has been associated with mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2. In addition, patients with pathogenic variants of cancer-predisposing genes such as BRCA1 and BRCA2 have been reported. However, how cancer-predisposing genes affect the risk of upper urinary tract urothelial carcinoma in the Japanese population remains unclear. Thus, we performed a case-control sequencing study of 27 cancer-predisposing genes in 208 upper urinary tract urothelial carcinoma patients and 37 727 controls. Only MSH6 and MSH2 were observed with a value of P < 0.05. However, there was no difference in the prevalence of pathogenic variants of BRCA1/2, which does not support the use of a poly adenosine diphosphate-ribose polymerase inhibitor in patients with upper urinary tract urothelial carcinoma. Only mismatch repair genes were associated with patients with upper urinary tract urothelial carcinoma, but the prevalence of pathogenic variants in mismatch repair genes was lower than that reported in previous studies from other populations., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Consumption of opioids, essential drugs for pain relief, has seen rapid growth worldwide. In Japan, where total opioid consumption still remains low among developed countries, little is known about trends in the clinical patterns of opioids in terminally ill cancer patients., Methods: Patients who died of cancer from 2010 to 2019 were included in this study. Morphine, oxycodone, fentanyl, tapentadol, methadone and hydromorphone were examined as opioids for cancer pain. We calculated the prevalence of prescribed opioids prior to death by year and age group and the average opioid dose 30 days before death., Results: The total number of patients was 221 598. We found that the prescription prevalence of opioids increased from 60.8 to 65.9% (5.1%). Morphine was most prescribed in 2010 but had decreased prevalence (-9.0%) during the 10-year period. Oxycodone had the highest increase in prescription prevalence (13.7%), and fentanyl prevalence decreased (-4.9%). In the subgroup comparison, the prescription prevalence of opioids in the elderly was lower than that in the younger group; however, the increasing trend in the elderly was greater than that in the younger group. The percentage of patients prescribed low-dose opioids (<60 mg/day) during the 30 days before death increased by 4.9% and was the highest throughout the study period., Conclusion: The prevalence of opioid prescriptions for terminally ill cancer patients has increased from 2010 to 2019 in Japan. The opioid-specific trends were similar to the global trend but differed by palliative care specialty., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Centromeres of most eukaryotes consist of two distinct chromatin domains: a kinetochore domain, identified by the histone H3 variant, CENP-A, and a heterochromatic domain. How these two domains are separated is unclear. Here, we show that, in Schizosaccharomyces pombe, mutation of the chromatin remodeler RSC induced CENP-ACnp1 misloading at pericentromeric heterochromatin, resulting in the mis-assembly of kinetochore proteins and a defect in chromosome segregation. We find that RSC functions at the kinetochore boundary to prevent CENP-ACnp1 from spreading into neighbouring heterochromatin, where deacetylated histones provide an ideal environment for the spread of CENP-ACnp1. In addition, we show that RSC decompacts the chromatin structure at this boundary, and propose that this RSC-directed chromatin decompaction prevents mis-propagation of CENP-ACnp1 into pericentromeric heterochromatin. Our study provides an insight into how the distribution of distinct chromatin domains is established and maintained., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objectives: To propose deep-learning (DL)-based predictive model for pathological complete response rate for resectable locally advanced esophageal squamous cell carcinoma (SCC) after neoadjuvant chemoradiotherapy (NCRT) with endoscopic images., Methods and Material: This retrospective study analyzed 98 patients with locally advanced esophagus cancer treated by preoperative chemoradiotherapy followed by surgery from 2004 to 2016. The patient data were split into two sets: 72 patients for the training of models and 26 patients for testing of the model. Patients was classified into two groups with the LC (Group I: responder and Group II: non-responder). The scanned images were converted into joint photographic experts group (JPEG) format and resized to 150 × 150 pixels. The input image without imaging filter (w/o filter) and with Laplacian, Sobel, and wavelet imaging filters deep-learning model to predict the pathological CR with a convolution neural network (CNN). The accuracy, sensitivity, and specificity, the area under the curve (AUC) of the receiver operating characteristic were evaluated., Results: The average of accuracy for the cross-validation was 0.64 for w/o filter, 0.69 for Laplacian filter, 0.71 for Sobel filter, and 0.81 for wavelet filter, respectively. The average of sensitivity for the cross-validation was 0.80 for w/o filter, 0.81 for Laplacian filter, 0.67 for Sobel filter, and 0.80 for wavelet filter, respectively. The average of specificity for the cross-validation was 0.37 for w/o filter, 0.55 for Laplacian filter, 0.68 for Sobel filter, and 0.81 for wavelet filter, respectively. From the ROC curve, the average AUC for the cross-validation was 0.58 for w/o filter, 0.67 for Laplacian filter, 0.73 for Sobel filter, and 0.83 for wavelet filter, respectively., Conclusions: The current study proposed the improvement the accuracy of the DL-based prediction model with the imaging filters. With the imaging filters, the accuracy was significantly improved. The model can be supported to assist clinical oncologists to have a more accurate expectations of the treatment outcome., Advances in Knowledge: The accuracy of the prediction for the local control after radiotherapy can improve with the input image with the imaging filter for deep learning.

Background: Approximately 20% of lung adenocarcinoma (LUAD) is negative for the lineage-specific oncogene Thyroid transcription factor 1 (TTF-1) and exhibits worse clinical outcome with a low frequency of actionable genomic alterations. To identify molecular features associated with TTF-1-negative LUAD, we compared the transcriptomic and proteomic profiles of LUAD cell lines. SRGN , a chondroitin sulfate proteoglycan Serglycin, was identified as a markedly overexpressed gene in TTF-1-negative LUAD. We therefore investigated the roles and regulation of SRGN in TTF-1-negative LUAD., Methods: Proteomic and metabolomic analyses of 41 LUAD cell lines were done using mass spectrometry. The function of SRGN was investigated in 3 TTF-1-negative and 4 TTF-1-positive LUAD cell lines and in a syngeneic mouse model (n = 5 to 8 mice per group). Expression of SRGN was evaluated in 94 and 105 surgically resected LUAD tumor specimens using immunohistochemistry. All statistical tests were 2-sided., Results: SRGN was markedly overexpressed at mRNA and protein levels in TTF-1-negative LUAD cell lines (P < .001 for both mRNA and protein levels). Expression of SRGN in LUAD tumor tissue was associated with poor outcome (hazard ratio = 4.22, 95% confidence interval = 1.12 to 15.86, likelihood ratio test, P = .03), and with higher expression of Programmed cell death 1 ligand 1 (PD-L1) in tumor cells and higher infiltration of Programmed cell death protein 1-positive lymphocytes. SRGN regulated expression of PD-L1 as well as proinflammatory cytokines, including Interleukin-6, Interleukin-8, and C-X-C motif chemokine 1 in LUAD cell lines; increased migratory and invasive properties of LUAD cells and fibroblasts; and enhanced angiogenesis. SRGN was induced by DNA demethylation resulting from Nicotinamide N-methyltransferase-mediated impairment of methionine metabolism., Conclusions: Our findings suggest that SRGN plays a pivotal role in tumor-stromal interaction and reprogramming into an aggressive and immunosuppressive tumor microenvironment in TTF-1-negative LUAD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Complexes of p24 proteins act as cargo receptors for the transport of COPII vesicles from the endoplasmic reticulum (ER). The major cargos of p24 complexes are hydrophilic proteins tethered to the ER membrane via a covalently attached glycosylphosphatidylinositol (GPI) or fatty acid. Each p24 complex is known to contain members from all four p24 subfamilies (p24α, p24β, p24γ and p24δ). However, it remains unclear how the cargo specificities of p24 complexes are influenced by member stoichiometry. Here, we report the subunit compositions of mammalian p24 complexes involved in the transport of GPI-anchored proteins and Wnt1. We show that at least one p24α is required for the formation of p24 complexes and that a p24 complex consisting of p24α2, p24β1, p24γ2 and p24δ1 is required for the efficient transport of GPI-anchored proteins. On the other hand, a p24 complex containing p24α2, p24α3, p24β1, p24γ and p24δ1 is involved in the transport of Wnt1. Further, interactions between p24α2 and p24α3 are critical for Wnt1 transport. Thus, p24α and p24γ subfamily members are important for cargo selectivity. Lastly, our data fit with an octamer, rather than a tetramer, model of p24 complexes, where each complex consists of two proteins from each p24 subfamily., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Background: The use of volumetric modulated arc therapy is gradually widespread for locally advanced non-small cell lung cancer. The purpose of this study was to identify the factors that caused ≥ grade 2 radiation pneumonitis and evaluate the impact of using volumetric modulated arc therapy on the incidence of ≥ grade 2 radiation pneumonitis by comparing three-dimensional conformal radiation therapy., Methods: We retrospectively evaluated 124 patients who underwent radical radiotherapy for locally advanced non-small cell lung cancer in our institution between 2008 and 2019. The following variables were analysed to detect the factors that affected ≥ grade 2 radiation pneumonitis; age, sex, the presence of interstitial lung disease, pulmonary emphysema, tumour location, stage, PTV/lung volume, lung V20Gy, total dose, concurrent chemoradiotherapy, adjuvant immune checkpoint inhibitor, radiotherapy method. Radiation pneumonitis was evaluated using the common terminology criteria for adverse events (version 5.0)., Results: A total of 84 patients underwent three-dimensional conformal radiation therapy (3D-CRT group) and 40 patients underwent volumetric modulated arc therapy (VMAT group). The cumulative incidence of ≥ grade 2 radiation pneumonitis at 12 months was significantly lower in the VMAT group than in the 3D-CRT group (25% vs. 49.1%). The use of volumetric modulated arc therapy was a significant factor for ≥ grade 2 radiation pneumonitis (HR:0.32, 95% CI: 0.15-0.65, P = 0.0017) in addition to lung V20Gy (≥ 24%, HR:5.72 (95% CI: 2.87-11.4), P < 0.0001) and total dose (≥ 70 Gy, HR:2.64 (95% CI: 1.39-5.03), P = 0.0031) even after adjustment by multivariate analysis., Conclusions: We identified factors associated with ≥ grade 2 radiation pneumonitis in radiotherapy for patients with locally advanced non-small cell lung cancer. Volumetric modulated arc therapy has potential benefits to reduce the risk of ≥ grade 2 radiation pneumonitis., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

An automated hologram acquisition system for big-data analysis and for improving the statistical precision of phase analysis has been upgraded with automated particle detection technology. The coordinates of objects in low-magnification images are automatically detected using zero-mean normalized cross-correlation with preselected reference images. In contrast with the conventional scanning acquisitions from the whole area of a microgrid and/or a thin specimen, the new method allows efficient data collections only from the desired fields of view including the particles. The acquisition time of the cubic/triangular nanoparticles that were observed was shortened by about one-fifty eighth that of the conventional scanning acquisition method because of efficient data collections. The developed technology can improve statistical precision in electron holography with shorter acquisition time and is applicable to the analysis of electromagnetic fields for various kinds of nanoparticles., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An image identification method was developed with the aid of a deep convolutional neural network (CNN) and applied to the analysis of inorganic particles using electron holography. Despite significant variation in the shapes of α-Fe2O3 particles that were observed by transmission electron microscopy, this CNN-based method could be used to identify isolated, spindle-shaped particles that were distinct from other particles that had undergone pairing and/or agglomeration. The averaging of images of these isolated particles provided a significant improvement in the phase analysis precision of the electron holography observations. This method is expected to be helpful in the analysis of weak electromagnetic fields generated by nanoparticles showing only small phase shifts., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

It is often challenging to determine the accurate size and shape of oral lesions through computed tomography (CT) or magnetic resonance imaging (MRI) when they are very small or obscured by metallic artifacts, such as dental prostheses. Intraoral ultrasonography (IUS) has been shown to be beneficial in obtaining precise information about total tumor extension, as well as the exact location and guiding the insertion of catheters during interstitial brachytherapy. We evaluated the role of IUS in assessing the clinical outcomes of interstitial brachytherapy with 198Au grains in tongue cancer through a retrospective medical chart review. The data from 45 patients with T1 (n = 21) and T2 (n = 24) tongue cancer, who were mainly treated with 198Au grain implants between January 2005 and April 2019, were included in this study. 198Au grain implantations were carried out, and positioning of the implants was confirmed by IUS, to ensure that 198Au grains were appropriately placed for the deep border of the tongue lesion. The five-year local control rates of T1 and T2 tongue cancers were 95.2% and 95.5%, respectively. We propose that the use of IUS to identify the extent of lesions and the position of implanted grains is effective when performing brachytherapy with 198Au grains., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: To propose the prediction model for degree of differentiation for locally advanced esophageal cancer patients from the planning CT image by radiomics analysis with machine learning., Methods: Data of 104 patients with esophagus cancer, who underwent chemoradiotherapy followed by surgery at the Hiroshima University hospital from 2003 to 2016 were analyzed. The treatment outcomes of these tumors were known prior to the study. The data were split into 3 sets: 57/16 tumors for the training/validation and 31 tumors for model testing. The degree of differentiation of squamous cell carcinoma was classified into two groups. The first group (Group I) was a poorly differentiated (POR) patients. The second group (Group II) was well and moderately differentiated patients. The radiomics feature was extracted in the tumor and around the tumor regions. A total number of 3480 radiomics features per patient image were extracted from radiotherapy planning CT scan. Models were built with the least absolute shrinkage and selection operator (LASSO) logistic regression and applied to the set of candidate predictors. The radiomics features were used for the input data in the machine learning. To build predictive models with radiomics features, neural network classifiers was used. The precision, accuracy, sensitivity by generating confusion matrices, the area under the curve (AUC) of receiver operating characteristic curve were evaluated., Results: By the LASSO analysis of the training data, we found 13 radiomics features from CT images for the classification. The accuracy of the prediction model was highest for using only CT radiomics features. The accuracy, specificity, and sensitivity of the predictive model were 85.4%, 88.6%, 80.0%, and the AUC was 0.92., Conclusion: The proposed predictive model showed high accuracy for the classification of the degree of the differentiation of esophagus cancer. Because of the good prediction ability of the method, the method may contribute to reducing the pathological examination by biopsy and predicting the local control., Advances in Knowledge: For esophageal cancer, the differentiation of degree is the import indexes reflecting the aggressiveness. The current study proposed the prediction model for the differentiation of degree with radiomics analysis.

Preoperative chemoradiotherapy with capecitabine or 5-fluorouracil is a standard treatment for locally advanced rectal cancer (LARC). S-1, a prodrug of 5-fluorouracil, is a candidate for this chemoradiotherapy regimen in Japan; however, treatment outcomes after S-1 treatment alone are not clear. This study aimed to assess the efficacy and tolerability of preoperative chemoradiotherapy with S-1 alone for LARC. We retrospectively evaluated 54 LARC patients who underwent preoperative chemoradiotherapy with S-1 alone in our institution between 2005 and 2017. The clinical tumor stage was cT2-3 in 31 patients and cT4 in 23 patients, and lymph node metastases were clinically evident in 31 patients. S-1, at a dose of 80 mg/m2/day, was orally administered during radiotherapy. A total dose of 45-50.4 Gy was delivered in 25-28 fractions (median: 50.4 Gy). Surgical resections were scheduled 6-10 weeks after chemoradiotherapy completion. The 3- and 5-year overall survival rates were 92.4 and 72.8%, respectively, with a median follow-up time of 51 months. The 3- and 5-year local control rates were 96.2 and 85.9%, respectively. A pathological complete response was observed in 7 patients (13.0%) at the time of surgery. Ten patients (18.5%) had grade 3 acute toxicities and 5 patients (9.3%) had grade 3 late toxicities. No grade 4 or 5 toxicities were observed. Preoperative chemoradiotherapy with S-1 alone followed by total mesorectal excision resulted in a low incidence of toxicities and comparable clinical results. Therefore, S-1 alone can be a treatment option for preoperative chemoradiotherapy in LARC patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Few studies have examined sensory quality changes during the storage of pasteurized drinking yogurt (PDY), and the cause of off-flavor development is unclear. Off-flavors generated during 90-d ambient storage (25 °C) of PDY from reconstituted skim milk were investigated by sensory evaluation, volatile component analysis with gas chromatography-mass spectroscopy, and gas chromatography-olfactometry. Rancid off-flavor was induced by increased fatty acid concentration due to fat decomposition by heat-stable lipase. Masking of off-flavors was inhibited by degradation of diacetyl, which originally contributed to yogurt-like flavors. Maillard reaction particular to ambient storage of PDY resulted in changes in the furaneol and sotolon levels, which may be involved in enhancement of off-flavors. Finally, our findings indicated that production of 4-vinylguaiacol may be involved in off-flavor development. The results of this study will contribute to the development of PDY with a longer shelf life and superior flavor., (© The Author(s) 2020. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

This review examines methods of magnetic flux density measurements from the narrow grain boundary (GB) regions, the thickness of which is of the order of nanometers, produced in Nd-Fe-B-based sintered magnets. Despite of the complex crystallographic microstructure and the significant stray magnetic field of the sintered magnet, recent progress in electron holography allowed for the determination of the intrinsic magnetic flux density due to the GB which is embedded in the polycrystalline thin-foil. The methods appear to be useful as well for intensive studies about interface magnetism in a variety of systems., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We present here the second complete genome of anaerobic ammonium oxidation (anammox) bacterium, Candidatus (Ca.) Brocadia pituitae, along with those of a nitrite oxidizer and two incomplete denitrifiers from the anammox bacterial community (ABC) metagenome. Although NO2- reduction to NO is considered to be the first step in anammox, Ca. B. pituitae lacks nitrite reductase genes (nirK and nirS) responsible for this reaction. Comparative genomics of Ca. B. pituitae with Ca. Kuenenia stuttgartiensis and six other anammox bacteria with nearly complete genomes revealed that their core genome structure contains 1,152 syntenic orthologues. But nitrite reductase genes were absent from the core, whereas two other Brocadia species possess nirK and these genes were horizontally acquired from multiple lineages. In contrast, at least five paralogous hydroxylamine oxidoreductase genes containing candidate ones (hao2 and hao3) encoding another nitrite reductase were observed in the core. Indeed, these two genes were also significantly expressed in Ca. B. pituitae as in other anammox bacteria. Because many nirS and nirK genes have been detected in the ABC metagenome, Ca. B. pituitae presumably utilises not only NO supplied by the ABC members but also NO and/or NH2OH by self-production for anammox metabolism., (© The Author(s) 2020. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

Purpose: The present study aimed to evaluate the long-term results of definitive chemoradiotherapy (CRT) for unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC)., Materials and Methods: We analyzed eighty patients with unresectable LA-ESCC, who underwent definitive CRT between 2001 and 2014. The 5-year overall survival (OS), cause-specific survival (CSS), and progression-free survival (PFS) rates were calculated, and we investigated the prognostic factors and adverse events., Results: The median age was 66 years (range, 41-83 years). Histologically, all patients had squamous cell carcinoma. The most common tumor site was the middle thoracic esophagus in 43 (54%) patients. According to the eighth edition of the Union for International Cancer Control TNM classification, sixty-six patients (83%) had T4 disease, 59 (74%) had regional lymph node (LN) metastases, and 35 (44%) had distant LN metastases beyond the regional LN (M1 LYM) disease. Forty-five (56%) and 35 (44%) patients belong to clinical stages IVA and IVB, respectively. The median follow-up period for survivors was 86 months. The 5-year OS, CSS, and PFS rates were 20.2%, 25.7%, and 18.4%, respectively. On univariate analysis, only the performance status score was significantly associated with better overall survival (p = 0.026). Grade 3 or higher late adverse events were observed in 12 (15%) patients, and these included cardiopulmonary adverse events in 6 (8%) patients. Treatment-related death occurred in 3 (4%) patients., Conclusion: We showed the long-term results of definitive CRT for unresectable LA-ESCC. The survivals are still poor and new treatment strategies need to be developed., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This study aimed to clarify the motivations and timing of the decision to become radiation oncologists., Materials and Methods: We conducted an online survey for new members of the Japanese Society for Radiation Oncology (JASTRO)., Results: The response rate was 43.3%. Data of the 79 respondents who wanted to obtain a board-certification of JASTRO were analysed. We divided the respondents into two groups: Group A, those who entered a single radiation oncology department, and Group B, those who joined a radiology department in which the radiation oncology department and diagnostic radiology department were integrated. The most common period when respondents were most attracted to radiation oncology was "5th year of university" in Group A and "2nd year of junior residency" and "senior residency" in Group B. Furthermore, 79.5% of Group A and 40% of Group B chose periods before graduation from a university with a significant difference. The most common period when respondents made up their minds to become radiation oncologists was "2nd year of junior residency" in both groups. Internal medicine was the most common department to consider if they did not join the radiation oncology or radiology department., Conclusion: To increase the radiation oncologists, it is crucial to enhance clinical training in the fifth year of university for Group A and to continue an active approach to maintain interest in radiation oncology until the end of junior residency. In Group B facilities, it is desirable to provide undergraduates more opportunities to come in contact with radiation oncology., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

This study aimed to investigate whether the use of molecular-targeted agents could affect gastrointestinal (GI) toxicity in palliative radiotherapy (RT) for metastatic bone tumors in the abdominopelvic region. We collected data of patients who received palliative RT for bone metastases in the abdominopelvic region between 2013 and 2014 from six institutions. Data of 395 patients were collected and184 patients received molecularly targeted therapy, of whom 80 received vascular endothelial growth factor (VEGF)-targeted agents. For 556 lesions, 410 sessions of irradiation were undergone. GI toxicity of ≥G3 was observed in 3.8% of patients. The incidence rates of ≥G3 GI toxicity in patients without targeted agents use, in those using VEGF-targeted agents and in those using non-VEGF-targeted agents were 3.8, 7.5 and 1.0%, respectively. Regarding risk factors of the occurrence of ≥G3 GI toxicity, univariate analysis in all patients showed that a history of abdominopelvic surgery was a significant risk factor (P = 0.01), and the use of VEGF-targeted agents showed a trend of high incidence (P = 0.06). In patients using VEGF-targeted agents, both univariate and multivariate analysis showed that combined anticoagulant use (P = 0.03 and 0.01) and agent use between 1 week before and after RT (P = 0.046 and 0.03) were significant risk factors. In conclusion, the history of abdominopelvic surgery was associated with ≥G3 GI toxicity and the use of VEGF-targeted agents showed a trend for high incidence. When using VEGF-targeted agents, caution should be exercised in the combined use of anticoagulants and in the agent use between 1 week before and after RT., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

The present study aimed to analyze treatment outcomes after induction chemotherapy followed by chemoradiotherapy (CRT) using volumetric-modulated arc therapy (VMAT) in patients with stage IVA-B oropharyngeal cancer (OPC) or hypopharyngeal cancer (HPC), with long-term observation, including examination of larynx preservation. A total of 60 patients with stage IVA-B OPC or HPC, who underwent induction TPF chemotherapy (a combination regimen consisting of docetaxel, cisplatin, and 5-fluorouracil) followed by CRT using VMAT were analyzed. Overall survival (OS), progression-free survival (PFS), laryngoesophageal dysfunction-free survival (LEDFS), and locoregional control (LRC) were calculated and compared. Univariate and multivariate analyses were performed to determine statistical differences in OS and LEDFS. The median follow-up period at the time of evaluation was 61 months. Twenty-six (43%) patients had OPC and 34 (57%) had HPC. The 5-year OS, PFS, LEDFS, and LRC rates were 57%, 52%, 52%, and 68%, respectively. Response to TPF therapy was the only significant predictive factor of OS and LEDFS in multivariate analyses. Regarding long-term toxicities, grade ≥ 2 late toxicities accounted for 15%. No patients experienced grade ≥ 3 xerostomia, and 5% of all patients developed grade 3 dysphagia. With long-term observation, the OS, PFS, and LEDFS rates were relatively good, and the incidence of late toxicities was low. TPF followed by CRT using VMAT was feasible and more effective in those who responded to induction chemotherapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Trichosporon species are some of the most common pathogenic yeasts in Asia, and many are resistant to echinocandin antifungal drugs. Effective treatment of fungal infections requires the selection of appropriate antifungals and the accurate identification of the causal organism. However, in histopathological specimens Trichosporon spp. are often misidentified as Candida species due to morphological similarities. In situ hybridization (ISH) is a useful technique for identifying fungal species in formalin-fixed and paraffin-embedded (FFPE) tissue sections. Although many novel probes for ISH are available, the practical use of ISH for identification of fungi remains limited, in part due to the lack of adequate verifications. We conducted a two-center retrospective observational study in which the ISH technique was used to differentiate Trichosporon spp. and C. albicans in FFPE tissue from autopsy specimens. The study included 88 cases with blood stream yeast infection without Cryptococci extracted from 459 autopsy files of cases with proven invasive fungal infection (IFI). Positive signals for the Trichosporon spp. protein nucleic acid (PNA) probe and C. albicans PNA probe were seen for 7 and 35 cases, respectively, whereas the remaining 46 were negative for both. For the Trichosporon spp.- positive specimens, 5/7 were reported as candidiasis in autopsy records. Our results suggested that accurate histological identification of fungal infections remains challenging, but ISH may be a suitable approach to support histological findings. In addition, this retrospective study suggested that trichosporonosis may have high prevalence among cases of bloodstream yeast infections in Japan., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Elucidation of natural selection signatures and relationships with phenotype spectra is important to understand adaptive evolution of modern humans. Here, we conducted a genome-wide scan of selection signatures of the Japanese population by estimating locus-specific time to the most recent common ancestor using the ascertained sequentially Markovian coalescent (ASMC), from the biobank-based large-scale genome-wide association study data of 170,882 subjects. We identified 29 genetic loci with selection signatures satisfying the genome-wide significance. The signatures were most evident at the alcohol dehydrogenase (ADH) gene cluster locus at 4q23 (PASMC = 2.2 × 10-36), followed by relatively strong selection at the FAM96A (15q22), MYOF (10q23), 13q21, GRIA2 (4q32), and ASAP2 (2p25) loci (PASMC < 1.0 × 10-10). The additional analysis interrogating extended haplotypes (integrated haplotype score) showed robust concordance of the detected signatures, contributing to fine-mapping of the genes, and provided allelic directional insights into selection pressure (e.g., positive selection for ADH1B-Arg48His and HLA-DPB1*04:01). The phenome-wide selection enrichment analysis with the trait-associated variants identified a variety of the modern human phenotypes involved in the adaptation of Japanese. We observed population-specific evidence of enrichment with the alcohol-related phenotypes, anthropometric and biochemical clinical measurements, and immune-related diseases, differently from the findings in Europeans using the UK Biobank resource. Our study demonstrated population-specific features of the selection signatures in Japanese, highlighting a value of the natural selection study using the nation-wide biobank-scale genome and phenotype data., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: High-grade glioma is the most pervasive and lethal of all brain malignancies. Despite advances in imaging technologies, discriminating between gliomas and other brain diseases such as multiple sclerosis (MS) often requires brain biopsy. Several reports show that protein tyrosine phosphatase receptor Z (PTPRZ) is highly expressed in glioblastoma, and we found that a soluble cleaved form of PTPRZ (sPTPRZ) was present in the cerebrospinal fluid (CSF). The aim of this study was to determine whether the sPTPRZ level in CSF has utility as a diagnostic marker for glioma., Methods: Microarray datasets from normal brain tissue and brain tumors were obtained from the Gene Expression Omnibus. PTPRZ protein expression in clinical specimens was evaluated by immunohistochemistry. Semiquantitative western blotting was used to measure sPTPRZ levels in CSF samples from patients with glioma, schwannoma, MS, or nontumor disorders., Results: Expression of PTPRZ mRNA and protein was markedly increased in glioblastoma, astrocytoma, oligodendroglioma, and schwannoma tissues compared with control brain tissue. sPTPRZ was present at significantly elevated levels in the CSF of patients with glioma (grades 1-4), but not in patients with schwannoma or MS, compared with the control samples. Receiver operating characteristic curve analysis showed that sPTPRZ in CSF could discriminate between glioma and MS patients (area under the curve 0.9676; P < .0001)., Conclusions: sPTPRZ in CSF is a promising diagnostic biomarker for glioma and could reduce the need for a surgical biopsy., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

An automated acquisition system for collecting a large number of electron holograms, to improve the statistical precision of phase analysis, was developed. A technique for shifting the electron beam in combination with stage movement allows data to be acquired over a wide area of a TEM-specimen grid. Undesired drift in the hologram position, which may occur during the hologram acquisition, can be corrected in real time by automated detection of the interference-fringe region in an image. To demonstrate the usefulness of the developed automated hologram acquisition system, gold nanoparticles dispersed on a carbon foil were observed with a 1.2-MV atomic resolution holography electron microscope. The system could obtain 1024 holograms, which provided phase maps for more than 500 nanoparticles with a lateral resolution of 0.14 nm, in just 1 h. The observation results revealed an anomalous increase in mean inner potential for a particle size smaller than 4 nm. The developed automated hologram acquisition system can be applied to improve the precision of phase measurement by averaging many phase images, as demonstrated by single particle analysis for biological entities. Moreover, the system makes it possible to study electrostatic potential of catalysts and other functional nanoparticles at atomic resolution., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Genetic testing has been conducted in patients with prostate cancer (PCa) using multigene panels, but no centralized guidelines for genetic testing exist. To overcome this limitation, we investigated the demographic and clinical characteristics of patients with pathogenic variants., Methods: We sequenced eight genes associated with hereditary PCa in 7636 unselected Japanese patients with PCa and 12 366 male, cancer-free control individuals. We assigned clinical significance for all 1456 variants using the American College of Medical Genetics and Genomics guidelines and ClinVar. We compared the frequency of carriers bearing pathogenic variants between cases and control participants with calculated PCa risk in each gene and documented the demographic and clinical characteristics of patients bearing pathogenic variants. All statistical tests were two-sided., Results: We identified 136 pathogenic variants, and 2.9% of patients and 0.8% of control individuals had a pathogenic variant. Association with PCa risk was statistically significant for variants in BRCA2 (P < .001, odds ratio [OR] = 5.65, 95% confidence interval [CI] = 3.55 to 9.32), HOXB13 (P < .001, OR = 4.73, 95% CI = 2.84 to 8.19), and ATM (P < .001, OR = 2.86, 95% CI = 1.63 to 5.15). We detected recurrent new pathogenic variants such as p.Gly132Glu of HOXB13. Patients with pathogenic variants were 2.0 years younger at diagnosis and more often had smoking and alcohol drinking histories as well as family histories of breast, pancreatic, lung, and liver cancers., Conclusions: This largest sequencing study of PCa heredity provides additional evidence supporting the latest consensus among clinicians for developing genetic testing guidelines for PCa., (© The Author(s) 2019. Published by Oxford University Press.)

This study aimed to evaluate the relationship between cardiac toxicity after definitive chemoradiotherapy (CRT) for esophageal cancer and the dose-volume histogram (DVH) of organs at risk (OARs) [using biological effective dose (BED)]. We analyzed the data of 83 patients with esophageal cancer treated using definitive CRT between 2001 and 2016. Furthermore, we evaluated pericardial effusion (PE) as a measure of cardiac toxicity. The median total irradiation dose was 60 (50.4-71) Gy. Symptomatic PE was observed in 12 (14%) patients. The heart and pericardium V5-V100-BED were significantly higher in patients with symptomatic PE than in those without symptomatic PE (heart: V5-V95-BED, P < 0.001; V100-BED, P = 0.0053, and pericardium: V5-V40-BED, V55-V95-BED, P < 0.001; V45-50-BED, V100-BED, P < 0.05, respectively). Receiver operating characteristic curve analysis showed that the dose-volume parameter of the pericardium and the heart that was most strongly associated with an adverse cardiac event was V80-BED, and the mean dose and the cut-off value were 27.38% and 61.7 Gy-BED, respectively. Multivariate analysis showed that the pericardium V80-BED and the mean heart dose-BED were risk factors for symptomatic PE (P < 0.001, respectively). We revealed the relationship between the irradiated dose of the OARs and symptomatic PE using a BED-based dose-volume histogram. Pericardium V80-BED and mean heart dose-BED were the most relevant risk factors for symptomatic PE., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Precise regulation of cytoskeletal dynamics is important in many fundamental cellular processes such as cell shape determination. Actin and microtubule (MT) cytoskeletons mutually regulate their stability and dynamics. Nonmuscle myosin II (NMII) is a candidate protein that mediates the actin-MT crosstalk. NMII regulates the stability and dynamics of actin filaments to control cell morphology. Additionally, previous reports suggest that NMII-dependent cellular contractility regulates MT dynamics, and MTs also control cell morphology; however, the detailed mechanism whereby NMII regulates MT dynamics and the relationship among actin dynamics, MT dynamics and cell morphology remain unclear. The present study explores the roles of two well-characterized NMII isoforms, NMIIA and NMIIB, on the regulation of MT growth dynamics and cell morphology. We performed RNAi and drug experiments and demonstrated the NMII isoform-specific mechanisms-NMIIA-dependent cellular contractility upregulates the expression of some mammalian diaphanous-related formin (mDia) proteins that suppress MT dynamics; NMIIB-dependent inhibition of actin depolymerization suppresses MT growth independently of cellular contractility. The depletion of either NMIIA or NMIIB resulted in the increase in cellular morphological dynamicity, which was alleviated by the perturbation of MT dynamics. Thus, the NMII-dependent control of cell morphology significantly relies on MT dynamics., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

TLRs respond to a variety of microbial products and initiate defense responses against bacteria and viruses. A variety of pathogens invade into and control the endosomal compartment to survive in host cells. On the other hand, host cells deploy cell surface and endosomal TLRs to pathogen-containing vesicles to mount defense responses. The endosomal compartment is a site for pathogen-sensing. As TLR-dependent defense responses are accompanied with a shift to the anabolic state, TLR responses need to be under metabolic control. Cellular metabolic state is monitored by sensing lysosomal metabolites by the mammalian target of rapamycin complex 1 (mTORC1). Type I IFN production induced by endosomal TLRs requires mTORC1. Recent studies have demonstrated that the interaction between TLRs and mTORC1 depends on their anterograde movement to the cell periphery. In a nutrient-sufficient state, a molecular complex called Ragulator recruits and activates mTORC1 in lysosomes. In parallel, Ragulator allows the small GTPase Arl8b to drive lysosomes to the cell periphery. Nutrient-activated mTORC1 in peripheral lysosomes is constitutively associated with type I IFN signaling molecules such as TRAF3 and IKKα. On the other hand, TLR7 and TLR3 are activated in the endosomal compartment and induce trafficking of TLR-containing vesicles to the cell periphery in a manner dependent on Arl8b or another GTPase Rab7a, respectively. Lysosomal trafficking helps TLR7 and TLR3 to interact with nutrient-activated mTORC1 and type I IFN signaling molecules. The endosomal compartments serve as platforms where metabolic sensing machinery licenses TLRs to initiate type I IFN responses., (©2019 Society for Leukocyte Biology.)

Self-assembled dendronized CdS nanoparticles have been attracting considerable attention because of their photoluminescence properties depending on annealing treatments. In this study, their annealing-induced self-assembled structure was investigated via scanning transmission electron microscopy; thin foil specimens of self-assembled dendronized CdS nanoparticles were prepared by ultramicrotomy and the STEM images revealed their ordered structure and the effect of the annealing treatment. In addition, a structural order belonging to the P213 space group was identified via an autocorrelation analysis. The results indicated that this structural order could be achieved only over a few tens of nanometers., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The aim of the current study is to evaluate the effectiveness of reduction metal artifacts using kV-CT image with the single-energy based metal artefact reduction (SEMAR) technique by single-energy reconstruction, monochromatic CT and rED reconstructed by dual-energy reconstruction., Methods: Seven different metal materials (brass, aluminum, copper, stainless, steel, lead and titanium) were placed inside the water-based PMMA phantom. After DECT-based scan, the artefact index (AI) were evaluated with the kV-CT images with and without SEMAR by single-energy reconstruction, and raw-data based electron density (rED), monochromatic CT images by dual-energy reconstruction. Moreover, the AI with evaluated with rED and the converted ED images from the kV-CT and monochromatic CT images., Results: The minimum average value of the AI with all-metal inserts was approximately 80 keV. The AI without SEMAR was larger than that with SEMAR for the 80 kV and 135 kV CT images. In the comparison of the AI for the rED and ED images that were converted from 80 kV and 135 kV CT images with and without SEMAR, the monochromatic CT images of the PMMA phantom with inserted metal materials at 80 keV revealed that the kV-CT with SEMAR reduced the metal artefact substantially., Conclusion: The converted ED from the kV-CT and monochromatic CT images could be useful for a comparison of the AI using the same contrast scale. The kV-CT image with SEMAR by single-energy reconstruction was found to substantially reduce metal artefact., Advances in Knowledge: The effectiveness of reduction of metal artifacts using single-energy based metal artefact reduction (SEMAR) technique and dual-energy CT (DECT) was evaluated the electron density conversion techniques., (© 2019 The Authors. Published by the British Institute of Radiology.)

Heterochromatin is a condensed and transcriptionally silent chromatin structure and that plays important roles in epigenetic regulation of the genome. Two types of heterochromatin exist: constitutive heterochromatin is primarily associated with trimethylation of histone H3 at lysine 9 (H3K9me3), and facultative heterochromatin with trimethylation of H3 at lysine 27 (H3K27me3). The methylated histones are bound by the chromodomain of histone code 'reader' proteins: HP1 family proteins for H3K9me3 and Polycomb family proteins for H3K27me3. Each repressive reader associates with various 'effector' proteins that provide the functional basis of heterochromatin. Heterochromatin regulation is primarily achieved by controlling histone modifications. However, recent studies have revealed that the repressive readers are phosphorylated, like other regulatory proteins, suggesting that phosphorylation also participates in heterochromatin regulation. Detailed studies have shown that phosphorylation of readers affects the binding specificities of chromodomains for methylated histone H3, as well as the binding of effector proteins. Thus, phosphorylation adds another layer to heterochromatin regulation. Interestingly, casein kinase 2, a strong and predominant kinase within the cell, is responsible for phosphorylation of repressive readers. In this commentary, I summarize the regulation of repressive readers by casein kinase 2-dependent phosphorylation and discuss the functional meaning of this modification., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Advanced glycation end products (AGEs) are implicated in the development of diabetic complications via the receptor for AGEs (RAGE). We have reported that the 3-hydroxypyridinium (3HP)-containing AGEs derived from α-hydroxyaldehydes physically interact with RAGE and show cytotoxicity. Lactaldehyde (LA) is formed from a reaction between threonine and myeloperoxidase, but no LA-derived AGEs have been characterized. Here, we identify the structure and physiological effects of an AGE derived from LA. We isolated a novel 3HP derivative, 2-acetamido-6-(3-hydroxy-5-methyl-pyridin-1-ium-1-yl)hexanoate, named as N-acetyl-LAPL (lactaldehyde-derived pyridinium-type lysine adduct), from a mixture of LA with N α -acetyl-L-lysine. LAPL was also detected in the LA-modified protein. LAPL elicited toxicity in PC12 neuronal cells, but the effect was suppressed by the soluble form of RAGE as a decoy receptor. Moreover, surface plasmon resonance-based analysis revealed that LAPL specifically binds to recombinant RAGE. These results indicate that LA generates an AGE containing the 3HP moiety and contributes to RAGE-dependent cytotoxicity. Abbreviations: AGEs: advanced glycation end products; RAGE: receptor for advanced glycation end products; 3HP: 3-hydroxypyridinium; LA: lactaldehyde; LAPL: lactaldehyde-derived pyridinium-type lysine adduct; BSA: bovine serum albumin; GLAP: glyceraldehyde-derived pyridinium; MPO: myeloperoxidase; HFBA: heptafluorobutyric acid; TFA: trifluoroacetic acid; HPLC: high performance liquid chromatography; LC-ESI-QTOF-MS: liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry; NMR: nuclear magnetic resonance; LA-BSA: lactaldehyde-modified bovine serum albumin; PBS: phosphate buffered saline, GST, glutathione S-transferase; SPR: surface plasmon resonance; OP-lysine: 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate; GLO1: glyoxalase 1; MG, methylglyoxal.

Purpose: We recently reported the results from a multi-institutional retrospective outcome study involving 814 patients with renal cell carcinomas (RCCs) who had undergone radical surgery and whose diagnoses were confirmed via a central pathological review. This study aimed to clarify the impact of tumor size on survival outcomes in patients with pT3aN0M0 RCC after radical nephrectomy using this cohort., Methods: Using the Kaplan-Meier method, overall survival (OS), cancer-specific survival (CSS) and relapse-free survival (RFS) were estimated for 103 pT3aN0M0 patients. The differences in the OS, CSS and RFS according to tumor size were evaluated using the log-rank test. To identify independent prognostic factors that affected each survival outcome, clinicopathological factors were examined using univariate and multivariate analyses, and the Cox proportional hazards model., Results: The OS, CSS and RFS rates for 26 patients with pT3a RCCs ≤4 cm were significantly better than those for 77 patients with pT3a RCCs that were 4-7 cm or >7 cm (P = 0.0064, 0.0169 and 0.0001, respectively). Tumor size and venous invasion were independent prognosticators for OS, CSS and RFS. The OS and CSS for patients with pT3a tumors ≤4 cm were comparable with those for patients with pT1 RCCs, and the RFS for patients with pT3a RCCs ≤4 cm was similar to that for patients with pT1b RCCs., Conclusions: Tumor size significantly influenced the prognosis for patients with pT3aN0M0 RCC. This study's results suggest that the postoperative management of pT3a RCCs could be individualized according to tumor size., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The prognostic value of histologic variants (HV) after radical cystectomy (RC) remains controversial. We evaluated the clinicopathological features and prognosis in patients with pure urothelial carcinoma (UC) and HV following RC., Methods: From 1990 to 2015, 286 patients with bladder cancer were treated with RC at six Kitasato University-affiliated hospitals. All patients were divided into two groups: pure UC and HV, which contained pure variants and mixed-type UC with variant pattern. A comparison of patient characteristics between the two groups was made to assess the clinicopathological features, and statistical analyses were performed to investigate prognosis in the two groups., Results: Of the 286 patients, 226 (79%) had pure UC, while 60 (21%) had HV. Of all HV, pure variants accounted for 45% (n = 27). The prevalence of lymph node involvement, locally advanced stage (≥ pT3), positive soft tissue surgical margin and lymphovascular invasion were significantly higher in patients with HV than in those with pure UC. Patients with HV showed worse disease-free survival and cancer-specific survival than those with pure UC (P = 0.009 and 0.003, respectively). In multivariate analysis, HV and lymph node involvement were independent predictors of worse disease-free survival (P = 0.017 and 0.001, respectively). HV, locally advanced stage, lymph node involvement, and positive soft tissue surgical margin were also confirmed as independent predictors of worse cancer-specific survival (P = 0.011, 0.012, 0.003 and 0.010, respectively.)., Conclusions: HV was associated with greater biological aggressiveness and worse prognosis than pure UC., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Worksite-based programs present a simple and effective approach to facilitate weight reduction in employees. Despite the importance of 1-year weight loss maintenance, studies have generally focused on the short-term effects of weight reduction programs. In addition, little is known about the long-term weight maintenance outcomes in Asian populations. We examined the long-term maintenance effects of a worksite-based weight reduction program among Japanese men with cardiovascular risk factors., Methods: The study sample comprised 58 overweight men with cardiovascular risk factors who had voluntarily participated in a randomized crossover trial involving a 3-month weight reduction program. Participants were followed up for 1 year after the trial concluded, and both groups were merged for the analysis. We compared the changes in body weight before the post-trial follow-up and after 12 months to examine the long-term maintenance effects of the program. Changes in other cardiovascular risk factors (eg, waist circumference, blood pressure, lipid measures, and diabetes-related measures) were also examined., Results: Both groups of study participants achieved weight loss during the weight reduction program. Total 53 participants (91.4%) completed the 12-month post-trial follow-up. There were no significant changes in mean body weight (mean: -0.11, 95% confidence interval: -0.7-0.49 kg) and other cardiovascular risk factors between the beginning and end of the follow-up period., Conclusions: This study showed that the worksite-based weight reduction program not only enabled short-term weight loss, but that the participants were able to successfully maintain their weight for 1 year after the program without any supplementary interventions., (© 2019 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

The coherency of a 1.2-MV transmission electron microscope was evaluated through illumination semiangles calculated from lengths over which Fresnel fringes can be observed. These lengths were determined from the diameters of circular holes fully filled with Fresnel fringes, i.e. this method allows lengths to be accurately measured even if micrographs are subjected to distortions. The smallest illumination semiangle of 4.0 × 10-9 rad was obtained for a circular hole with a diameter of 191 μm. In addition, electron beam brightness was estimated to be approximately 3 × 1014 A/m2·sr from the obtained illumination semiangle values and current densities. The results provide us with essential information that can be referred to in future electron holography studies aimed at detecting weak electromagnetic fields in materials.

Background: Although circulating exosomes in blood play crucial roles in cancer development and progression, difficulties in quantifying exosomes hamper their application for reliable clinical testing. By combining the properties of nanobeads with optical disc technology, we have developed a novel device named the ExoCounter to determine the exact number of exosomes in the sera of patients with various types of cancer., Method: In this system, individual exosomes were captured in the groove of an optical disc coated with antibodies against exosome surface antigens. The captured exosomes were labeled with antibody-conjugated magnetic nanobeads, and the number of the labeled exosomes was counted with an optical disc drive., Results: We showed that the ExoCounter could detect specific exosomes derived from cells or human serum without any enrichment procedures. The detection sensitivity and linearity with this system were higher than those with conventional detection methods such as ELISA or flow cytometry. In addition to the ubiquitous exosome markers CD9 and CD63, the cancer-related antigens CD147, carcinoembryonic antigen, and human epidermal growth factor receptor 2 (HER2) were also used to quantify cancer cell line-derived exosomes. Furthermore, analyses of a cross-sectional cohort of sera samples revealed that HER2-positive exosomes were significantly increased in patients with breast cancer or ovarian cancer compared with healthy individuals and those with noncancer diseases., Conclusions: The ExoCounter system exhibits high performance in the direct detection of exosomes in cell culture and human sera. This method may enable reliable analysis of liquid biopsies., (© 2018 American Association for Clinical Chemistry.)

Stratification of the vaginal epithelium is regulated by stromal factors. To analyze the mechanisms of stratification in vitro, 3 dimensional (3D) co-culture models were established with clonal cell lines. In the models, stromal cells were embedded in collagen gel and epithelial cells were seeded on the gel. In the 3D co-culture, stromal SV-6c4a1b cells induced epithelial stratification but stromal MV-1e6g1a cells did not, suggesting that SV-6c4a1b cells secrete molecules to induce stratification. Microarray analyses of these stromal cell lines identified chordin-like 1 (Chrd1) and WNT1 inducible signaling pathway protein 2 (Wisp2) as candidate genes inducing stratification. Chrdl1 variant1 and variant2 mRNAs were expressed not only in stromal SV-6c4a1b and MV-1e6g1a cells but also in epithelial SV-4b6b cells. Wisp2-overexpressing MV-1e6g1a cells, secreting WISP2 as much as SV-6c4a1b cells, induced stratification of epithelial cells. In addition, Wisp2-knockdowned SV-6c4a1b cells were unable to induce epithelial stratification. These results suggest that WISP2 is one of the stromal factors inducing stratification of the mouse vaginal epithelium.

Objective:: The purpose of the current study is to create a contrast medium extraction method using raw-data-based electron density (rED) and CT number from dual-energy CT (DECT) for automatic delineation of the contrast region., Methods:: A CT-ED phantom containing tissue-equivalent inserts and an acrylic phantom with an iodinated contrast medium were scanned by DECT. The contrast medium extraction system was created using Python. The accuracy of the contrast medium extraction was evaluated by measuring the diameter in terms of the full width at half maximum (FWHM) and the ratio of the volume (ROV)., Results:: Mean-2SD CT numbers and the difference of the CT numbers (DCT) of the contrast medium at 0-130 mg ml -1 contrast medium concentration and the bone materials were more than -33 and -20 HU, respectively. In the correlation of rED and CT number, the gradient with the contrast medium phantom was greater than that with the CT-ED phantom. The accuracy of the contrast medium at 80 kV/135 kV and 100 kV/135 kV tube voltages. The gradient of the CT-ED and contrast medium phantoms were different. The gradient in the CT-ED phantom and the contrast medium was 0.0012 and 0.0003 at 80 kV/135 kV, and 0.0015 and 0.0005 at 100 kV/135 kV tube voltages, respectively. The ratio of the measured to the actual diameter in FWHM and ROV was 0.98-1.00 at 2-130 mg ml -1 . At a tube voltage of 100 kV/135 kV. The ratio of the measured to the actual diameter in ROV was 0.66 and FWHM was 0.90 at 2 mg ml -1 contrast medium concentration. The ratio of the measured to the actual diameter in FWHM and ROV was 0.98-1.00 at 3-130 mg ml -1 ., Conclusion:: We created the contrast medium extraction method with rED and CT number images. The contrast medium extraction method could be used with DECT images at 80 kV/135 kV. The method is expected to only extract images from the region containing the contrast medium., Advances in Knowledge:: We created the contrast medium extraction method using raw-data-based electron density and CT number from DECT and it is expected to only extract information from the region containing the contrast medium.

Advanced glycation end-products (AGEs) elicit inflammatory responses via the receptor for AGEs (RAGE) and participate in the pathogenesis of diabetic complications. An earlier study showed that 3-hydroxypyridinium (3-HP), a common moiety of toxic AGEs such as glyceraldehyde-derived pyridinium (GLAP) and GA-pyridine, is essential for the interaction with RAGE. However, the physiological significance of 3-HP recognition by RAGE remains unclear. We hypothesized that pyridinoline (Pyr), a collagen crosslink containing the 3-HP moiety, could have agonist activity with RAGE. To test this hypothesis, we purified Pyr from bovine achilles tendons and examined its cytotoxicity to rat neuronal PC12 cells. Pyr elicited toxicity to PC12 cells in a concentration-dependent manner, and this effect was attenuated in the presence of either the anti-RAGE antibody or the soluble form of RAGE. Moreover, surface plasmon resonance-based analysis showed specific binding of Pyr to RAGE. These data indicate that Pyr is an intrinsic ligand for RAGE., Abbreviations: AGEs: advanced glycation end-products; RAGE: receptor for advanced glycation end-products; DAMPs: damage-associated molecular patterns; PRR: pattern recognition receptor; TLR: toll-like receptor; GLAP: glyceraldehyde-derived pyridinium; 3-HP: 3-hydroxypyridinium; Pyr: pyridinoline; HFBA: heptafluorobutyric acid; GST: glutathione S-transferase; SPR: surface plasmon resonance; ECM: extracellular matrix; EMT: epithelial to mesenchymal transition.