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Background: Atrial cardiomyopathy (AtCM) has drawn attention as the pathophysiology related to cardiovascular events such as atrial tachyarrhythmia, congestive heart failure, and embolic stroke. As the concept of AtCM is relatively recent, the long-term clinical course of AtCM has not been reported., Case Summary: Here, we describe a 78-year-old patient diagnosed with end-stage AtCM. He had started to visit our hospital due to paroxysmal atrial fibrillation (AF) and hypertrophic cardiomyopathy over three decades since the age of 45. During follow-up, he experienced cardiogenic embolism and pacemaker implantation due to sick sinus syndrome. At this time, he complained of palpitation due to AF and underwent catheter ablation. Regardless of de novo ablation, left atrial voltage mapping showed ultimately extensive scar in left atrium and pulmonary vein, suggesting that conventional AF ablation strategy was ineffective. From this finding, he was diagnosed with end-stage AtCM. In the review of the previous 12-lead electrocardiogram, P-wave amplitude was decreased, and PR duration was prolonged gradually. We performed only cavotricuspid isthmus ablation and ended the ablation session. After six months, he complained of dyspnoea on effort due to pacing-induced cardiomyopathy. Furthermore, before the cardiac resynchronization therapy with a defibrillator (CRT-D) upgrade, left atrial appendage thrombus was detected even under the administration of apixaban. After thrombolysis with warfarin, CRT-D upgrade the left ventricular ejection fraction was improved., Discussion: In this case, the patient slowly developed end-stage AtCM and experienced multiple cardiovascular events related to severe AtCM. We should care for the disease progression of AtCM with vigilance., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

This study presents a case of a 72-year-old man diagnosed with non-small cell lung cancer (cT4N0M0) referred to our hospital for possible surgical treatment of a solitary nodule detected in the mesorectum. The patient had received combined chemoradiotherapy and achieved a complete response 13 months before the presentation. On examination, the mesorectal nodule was incidentally detected during surveillance computed tomography, and the maximum standardized uptake value of the nodule was 10.3. Because of the potential malignancy and need for en-bloc resection of the nodule, we performed laparoscopically assisted high anterior resection of the rectum. The postoperative course was uneventful. Notably, while pathological examination revealed that the mesorectal nodule comprised an intravenous organized thromboembolism, malignancy was not observed. These findings suggest that although positron emission tomography/computed tomography with 18 F-fluorodeoxyglucose is useful for the diagnosis of malignant diseases, surgical resection might be the most reliable option for complex cases such as ours., Competing Interests: The authors declare that they have no conflict of interest., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background: Disturbances in the cardiovascular system, bone and skeletal muscle are independent risk factors for death among patients receiving haemodialysis (HD). However, the combined impact of disorders of these three organs on morbidity and mortality is unclear in the HD population., Methods: A total of 3031 Japanese patients on maintenance HD were prospectively followed. The outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and bone fracture. Patients were divided into four groups (G1-G4) according to the baseline number of diseased organs represented as histories of cardiovascular disease and bone fractures and the presence of low skeletal muscle mass as follows: G1, no organ; G2, one organ; G3, two organs; G4, three organs. Multivariable-adjusted survival models were used to analyse associations between the number of diseased organs and outcomes., Results: During a 4-year follow-up, 499 deaths, 540 MACE and 140 bone fractures occurred. In the Cox proportional hazards model, the risk for all-cause mortality was significantly higher in G2, G3 and G4 than in G1 as the reference {hazard ratio: G2, 2.16 [95% confidence interval (CI) 1.65-2.84], G3, 3.10 [95% CI 2.27-4.23] and G4, 3.11 [95% CI 1.89-5.14]}. Similarly, the risks for developing MACE and bone fractures were significantly elevated as the number of organ disorders increased., Conclusions: Multiple disorders of the cardiovascular-bone-skeletal muscle axis are strong predictors of morbidity and mortality in patients undergoing HD., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic membranous nephropathy (MN). Anti-PLA2R antibodies are mainly of the immunoglobulin G (IgG) subclass IgG4, although other IgG subclass depositions in glomeruli may also be detected. However, the importance of the subclass of the IgG deposit has not been proven. Thus we investigated clinical findings from patients with idiopathic MN in relation to glomerular PLA2R deposition and IgG subclass., Methods: We enrolled 132 Japanese patients with biopsy-proven idiopathic MN in a multicentre retrospective observational study. We investigated the complete remission rate as the primary outcome and the development of end-stage kidney disease (ESKD) as the secondary outcome in relation to glomerular PLA2R deposition. Moreover, we evaluated prognostic factors, including glomerular IgG subclass, in the PLA2R-positive group., Results: The percentage of cases with glomerular PLA2R deposition was 76.5% ( n  = 101). The first complete remission rate of the PLA2R-positive group was worse than that of the PLA2R-negative group (logrank test P  < .001). ESKD incidence did not significantly differ between the glomerular PLA2R-negative and PLA2R-positive MN groups (logrank test P  = .608). In the PLA2R-positive group, higher PLA2R intensities and IgG2 staining were associated with a poorer first complete remission rate (logrank test P  < .001 and P  = .032, respectively). Cox proportional hazards analysis also showed that strong PLA2R deposition and positive IgG2 staining were significantly associated with a failure to reach complete remission [hazard ratio 2.09 ( P  = .004) and 1.78 ( P  = .030), respectively]., Conclusions: Our results suggest that intense glomerular PLA2R and IgG2 positivity predict a poor proteinuria remission rate in idiopathic MN., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

The mammalian oviductal lumen is a specialized chamber that provides an environment that strictly regulates fertilization and early embryogenesis, but the regulatory mechanisms to gametes and zygotes are unclear. We evaluated the oviductal regulation of early embryonic development using Ovgp1 (encoding an oviductal humoral factor, OVGP1)-knockout golden hamsters. The experimental results revealed the following: (1) female Ovgp1-knockout hamsters failed to produce litters; (2) in the oviducts of Ovgp1-knockout animals, fertilized eggs were sometimes identified, but their morphology showed abnormal features; (3) the number of implantations in the Ovgp1-knockout females was low; (4) even if implantations occurred, the embryos developed abnormally and eventually died; and (5) Ovgp1-knockout female ovaries transferred to wild-type females resulted in the production of Ovgp1-knockout egg-derived OVGP1-null litters, but the reverse experiment did not. These results suggest that OVGP1-mediated physiological events are crucial for reproductive process in vivo, from fertilization to early embryonic development. This animal model shows that the fate of the zygote is determined not only genetically, but also by the surrounding oviductal microenvironment., (© The Author(s) 2023. Published by Oxford University Press behalf of Society for the Study of Reproduction.)

Drought stress is a major threat leading to global plant and crop losses in the context of the climate change crisis. Brassinosteroids (BRs) are plant steroid hormones, and the BR signaling mechanism in plant development has been well elucidated. Nevertheless, the specific mechanisms of BR signaling in drought stress are still unclear. Here, we identify a novel Arabidopsis gene, BRZ INSENSITIVE LONG HYPOCOTYL 9 (BIL9), which promotes plant growth via BR signaling. Overexpression of BIL9 enhances drought and mannitol stress resistance and increases the expression of drought-responsive genes. BIL9 protein is induced by dehydration and interacts with the HD-Zip IV transcription factor HOMEODOMAIN GLABROUS 11 (HDG11), which is known to promote plant resistance to drought stress, in vitro and in vivo. BIL9 enhanced the transcriptional activity of HDG11 for drought-stress-resistant genes. BIL9 is a novel BR signaling factor that enhances both plant growth and plant drought resistance., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Epidemiological studies have identified smoking as an independent risk factor for development of chronic kidney disease. However, the early renal pathological lesions have not been clearly elucidated., Methods: We investigated time-zero biopsy specimens from 547 living kidney donors and evaluated the relationships between smoking and renal histological changes, including arteriolar hyalinization, intimal thickening of small-medium arteries, global glomerulosclerosis, and interstitial fibrosis and tubular atrophy (IF/TA)., Results: A total of 199 subjects (36.4%) had smoking history; 92 (16.8%) and 107 (19.6%) subjects had <20 pack-years and ≥20 pack-years of smoking, respectively. Cumulative smoking dose was significantly associated with prevalence of arteriolar hyalinization: the multivariable-adjusted odds ratio (OR) per 20 pack-year increase was 1.50 (95% confidence interval 1.15-1.97). The ORs for smokers with <20 pack-years and ≥20 pack-years versus never-smokers were 1.76 (1.01-3.09) and 2.56 (1.48-4.44), respectively. Smoking was also associated with prevalence of >10% global glomerulosclerosis: the OR per 20 pack-year increase was 1.24 (0.96-1.59). The ORs for smokers with <20 pack-years and ≥20 pack-years versus never-smokers were 1.50 (0.98-2.78) and 2.11 (1.18-3.79), respectively. The ORs for these pathological changes increased significantly depending on cumulative smoking dose. Intimal thickening of small-medium arteries and IF/TA were not associated with smoking status. The prevalence of arteriolar hyalinization remained higher in patients with ≥10 years since smoking cessation than in never-smokers [OR 2.23 (1.03-4.83)]., Conclusions: Subclinical pathological injury caused by smoking is potentially associated with renal arteriolar hyalinization and glomerular ischaemia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma., Methods: SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo., Results: High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells., Conclusions: High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer., Methods: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given., Results: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies., Conclusion: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347)., (Published by Oxford University Press 2022.)

Brassinosteroids (BRs), a kind of phytohormone, have various biological activities such as promoting plant growth, increasing stress resistance, and chloroplast development. Though BRs have been known to have physiological effects on chloroplast, the detailed mechanism of chloroplast development and chlorophyll biosynthesis in BR signaling remains unknown. Here we identified a recessive pale green Arabidopsis mutant, Brz-insensitive-pale green1 (bpg1), which was insensitive to promoting of greening by BR biosynthesis-specific inhibitor Brz in the light. BPG1 gene encoded chlorophyll biosynthesis enzyme, 3, 8-divinyl protochlorophyllide a 8-vinyl reductase (DVR), and bpg1 accumulated divinyl chlorophylls. Chloroplast development was suppressed in bpg1. Brz dramatically increased the expression of chlorophyll biosynthesis enzyme genes, including BPG1. These results suggest that chlorophyll biosynthesis enzymes are regulated by BR signaling in the aspect of gene expression and BPG1 plays an important role in regulating chloroplast development., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Brassinolide (BL) is a possible plant growth regulator in agriculture, but the presence of a steroid skeleton hampers the field application of BL in agriculture because of its high synthetic cost. We discovered NSBR1 as the first nonsteroidal BL-like compound using in silico technology. Searching for more potent BL-like compounds, we modified the structure of NSBR1 with respect to 2 benzene rings and the piperazine ring. The activity of synthesized compounds was measured in Arabidopsis hypocotyl elongation. The propyl group of butyryl moiety of NSBR1 was changed to various alkyl groups, such as straight, branched, and cyclic alkyl chains. Another substituent, F, at the ortho position of the B ring toward the piperazine ring was changed to other substituents. A methyl group was introduced to the piperazine ring. Most of the newly synthesized compounds with the 3,4-(OH)2 group at the A ring significantly elongated the hypocotyl of Arabidopsis., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Castration-resistant prostate cancer shows resistance to not only androgen deprivation therapy (ADT) but also X-ray therapy. On the other hand, carbon ion beams have a high biological effect and are used for various cancers showing resistance to X-ray therapy. The purposes of this study are to clarify the difference in the sensitivity of Castration-resistant prostate cancer to X-ray and carbon ion beams and to elucidate the mechanism. The androgen-insensitive prostate cancer cell line LNCaP-LA established by culturing the androgen-sensitive prostate cancer cell line LNCaP for 2 years in androgen-free medium was used for this study. First, colony formation assays were performed to investigate its sensitivity to X-ray and carbon ion beams. Next, DNA mutation analysis on 409 cancer-related genes and comprehensive transcriptome analysis (RNA-seq) were performed with a next-generation sequencer. Lethal dose 50 values of X-rays for LNCaP and LNCaP-LA were 1.4 Gy and 2.8 Gy, respectively (P < 0.01). The Lethal dose 50 values of carbon ion beams were 0.9 Gy and 0.7 Gy, respectively (P = 0.09). On DNA mutation analysis, AR mutation was observed specifically in LNCaP-LA. From RNA-seq, 181 genes were identified as differentially expressed genes (DEGs; FDR <0.10, P < 0.00076) between LNCaP and LNCaP-LA. Function analysis suggested that cell death was suppressed in LNCaP-LA, and pathway analysis suggested that the NRF2-pathway involved in intracellular oxidative stress prevention was activated in LNCaP-LA. LNCaP-LA showed X-ray resistance compared to LNCaP and sensitivity to carbon ion beams. The AR mutation and the NRF2-pathway were suggested as causes of resistance., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cryopyrin-associated periodic syndrome (CAPS) is a rare inherited autoinflammatory disease caused by gain-of-function mutations in the NLRP3 gene, with a genotype-phenotype correlation. The clinical presentation of each mutation has been previously studied. However, very few studies have reported on the clinical characteristics and treatment effectiveness across different generations within a family with the same mutation. A detailed investigation of family members of patients with CAPS may help in the appropriate diagnosis and treatment of undiagnosed CAPS. Herein, we report a 2-year-old boy (proband), his father, and his grandmother who presented with several symptoms of CAPS, such as persistently positive inflammatory reactions and hearing impairment. All three patients had the same pathogenic mutation in the NLRP3 gene (c.1049C > T (p.Thr350Met) heterozygous mutation) and were diagnosed with CAPS. With canakinumab treatment, the laboratory data of all three patients improved, the proband and father's skin rash disappeared, and his grandmother's arthropathy improved. The proband's hearing also showed slight improvement but not in his father or grandmother. Among the various non-specific symptoms associated with CAPS, chronic ocular hyperaemia is a finding that can be easily identified by non-ophthalmologists. Diagnosis of CAPS should be considered when eye symptoms are present in a combination of hyperinflammatory response, arthropathy, or skin symptoms. Thorough family history records, physical examinations, and close collaboration between paediatricians and adult rheumatologists are important for prompt diagnosis and appropriate treatment of inherited autoinflammatory diseases., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Behçet's disease (BD) is often associated with neutrophilic dermatosis. However, BD is rarely associated with aseptic abscesses in the spleen or liver. A 2-year-old girl presented to our hospital with a 2-week history of fever, abdominal pain, and a skin ulcer on her leg. Each time her skin was punctured with a needle for a blood test or spinal fluid test, she developed intractable aseptic abscesses on her skin. She was diagnosed with intestinal BD based on gastrointestinal endoscopy findings and was treated with prednisolone, mesalazine, and elemental diet therapy. Although these were effective for her colon ulcers, low-grade fever and mild abdominal pain persisted. Abdominal computed tomography revealed a low-density area in the spleen. Although it is recommended to check the contents with puncture drainage, it was difficult due to the risk of bleeding and pathergy. The abscess expanded despite antimicrobial therapy. We discontinued antimicrobial therapy and switched to intensified immunosuppressive therapy for BD [intravenous infliximab (IFX)]. After administration of IFX, the splenic abscess gradually disappeared, and all her symptoms improved. In cases of BD with splenic abscesses resistant to antimicrobial therapy, intensifying immunosuppressive therapy can be expected to shrink the abscesses and avoid splenectomy., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We herein report a retrospective analysis of the efficacy of a combination therapy of pelvic irradiation that excluded the common iliac lymph nodes region and image-guided brachytherapy (IGBT) for non-bulky (≤4 cm) cervical cancer. Thirty-three patients with stage I-II cervical squamous cell carcinoma (≤4 cm) and without pelvic/para-aortic lymphadenopathy who were treated with definitive radiotherapy alone between February 2009 and September 2016 were included. The radiotherapy consisted of CT-based small-pelvis irradiation (whole pelvis minus common iliac lymph node area) of 20 Gy/10 fractions followed by pelvic irradiation with a midline block of 30 Gy/15 fractions and IGBT of 24 Gy/4 fractions (6 Gy/fraction for high-risk [HR] clinical target volume [CTV] D90%). In-room computed tomography (CT) imaging with applicator insertion was used for brachytherapy planning, with physical examinations and diagnostic magnetic resonance imaging (MRI) also being referred to for determination of HR CTV. Over a median follow-up of 60.5 months (range, 7-89), two patients developed distant recurrence and one developed local and distant recurrence. Two patients died from cervical cancer, one from hepatocellular carcinoma and one from non-cancerous disease. The 2/5-year local control (LC), progression-free survival (PFS) and overall survival (OS) rates were 100%/96.7%, 93.8%/90.6% and 93.9%/93.9%, respectively. No pelvic/para-aortic lymph node recurrence was observed. There were no late complications of grade 3 or higher in the small bowel, large bowel/rectum, or bladder. Our results suggest that a combination therapy of IGBT plus small-pelvis irradiation excluding common iliac lymph nodes provides reasonable clinical outcomes and can be a treatment option in non-bulky (≤4 cm) cervical squamous cell carcinoma., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The self-face advantage has been demonstrated not only at the supraliminal level, but also at the subliminal level. However, it remains unclear whether subliminal self-face processing involves the same neural networks as those for supraliminal self-face processing. Here, we show that the ventral tegmental area, a center of the dopamine reward pathway, exhibited greater activation to subliminal presentations of the self-face than those of the others' faces, whereas subliminal presentations of the others' faces induced activation in the amygdala, which generally responds to unfamiliar information. This self-other difference in brain response was consistently observed even when the facial configuration was modified without changing the shape of the facial parts. The present findings suggest that the dopamine reward pathway is involved in automatic self-advantage in face processing, and the subliminal self-other facial discrimination does not depend on information of the precise facial configuration., (© The Author(s) 2021. Published by Oxford University Press.)

We aimed to compare the outcomes of high-dose-rate brachytherapy (HDR-BT) boost and external beam radiation therapy (EBRT) alone for high-risk prostate cancer. This was a single-center, retrospective and observational study. Consecutive patients who underwent initial radical treatment by HDR-BT boost or EBRT alone from June 2009 to May 2016 at the Niigata University Medical and Dental Hospital, Japan were included. A total of 96 patients underwent HDR-BT boost, and 61 underwent EBRT alone. The prescription dose of HDR-BT boost was set to 18 Gy twice a day with EBRT 39 Gy/13 fractions. The dose for EBRT alone was mostly 70 Gy/28 fractions. The high-risk group received >6 months of prior androgen deprivation therapy. Overall survival, biochemical-free survival, local control and distant metastasis-free survival rates at 5 years were analyzed. The incidence of urological and gastrointestinal late adverse events of Grade 2 and above was also summarized. In the National Comprehensive Cancer Network (NCCN) high-risk calssification, HDR-BT boost had a significantly higher biochemical-free survival rate at 5 years (98.9% versus 90.7%, P = 0.04). Urethral strictures were more common in the HDR-BT boost group. We will continuously observe the progress of the study patients and determine the longer term results., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

The aim of this study was to assess the feasibility of planning dose-volume histogram (DVH) parameters in computed tomography-based 3D image-guided brachytherapy for locally advanced cervical cancer. In a prospective multi-institutional study, 60 patients with stage IIA2-IVA cervical cancer from eight institutions were treated with external beam radiotherapy using central shielding and intracavitary or hybrid (combined intracavitary/interstitial) brachytherapy (HBT). The dose constraints were set as a cumulative linear quadratic equivalent dose (EQD2) of at least 60 Gy for high-risk clinical target volume (HR-CTV) D90, D2cc ≤ 75 Gy for rectum, D2cc ≤ 90 Gy for bladder and D2cc ≤ 75 Gy for sigmoid. The median HR-CTV D90 was 70.0 Gy (range, 62.8-83.7 Gy) in EQD2. The median D2cc of rectum, bladder and sigmoid was 57.1 Gy (range, 39.8-72.1 Gy), 68.9 Gy (range, 46.5-84.9 Gy) and 57.2 Gy (range, 39.2-71.2 Gy) in EQD2, respectively. In 76 of 233 sessions (33%), 23 patients underwent HBT, and the median number of interstitial needles was 2 (range, 1-5). HBT for a bulky HR-CTV (≥40 cm3) significantly improved the HR-CTV D90 compared with intracavitary brachytherapy alone (P = 0.010). All patients fulfilled the dose constrains for target and at risk organs by undergoing HBT in one-third of sessions. We conclude that the planning DVH parameters used in our protocol are clinically feasible., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Identifying the depth of invasion (DOI) of superficial esophageal squamous cell carcinoma (SESCC) is crucial to determine the indication for endoscopic resection. This retrospective, single-center study aimed to evaluate the diagnostic efficacy of magnifying blue laser imaging (M-BLI) compared with white-light imaging (WLI) or magnifying narrow-band imaging (M-NBI) for identifying the DOI of SESCC. A total of 160 consecutive patients with SESCCs who underwent endoscopic submucosal dissection were enrolled in this study. Still images of the lesion were obtained using WLI, M-BLI and M-NBI prior to endoscopic submucosal dissection. Three endoscopists retrospectively evaluated the DOI using WLI according to non-magnifying findings and using M-BLI and M-NBI images according to the magnifying endoscopic classification of the Japan Esophageal Society. The diagnostic accuracy of each modality was compared using the chi-square test. The DOIs in 160 SESCCs evaluated pathologically were as follows: invasion to the epithelium or lamina propria mucosa in 130, invasion to the lamina muscularis mucosa or submucosa to a depth ≤ 200 μm in 18, and invasion to the submucosa to a depth > 200 μm in 12. The overall diagnostic accuracy rates of WLI, M-BLI, M-NBI, WLI with M-BLI (WLI + M-BLI), and WLI with M-NBI (WLI + M-NBI) were 86.9, 91.2, 90.6, 95.6 and 94.4%, respectively. Significant differences were found between WLI and WLI + M-BLI or WLI + M-NBI (P = 0.006 and P = 0.021, respectively). The concordance of intrapapillary capillary loops between M-BLI and M-NBI was 91.2%. The kappa coefficients for interobserver variability of the three endoscopists for M-BLI and M-NBI were 0.728/0.649/0.792 and 0.729/0.666/0.791, respectively, while those for intraobserver variability were 0.919/0.746/0.778 and 0.736/0.720/0.745, respectively. Similar to M-NBI, M-BLI was useful in predicting the DOI of SESCCs., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cardiovascular disease (CVD) is a major cause of death in kidney transplant (KT) recipients. To improve their long-term survival, it is clinically important to estimate the risk of CVD after living donor KT via adequate pre-transplant CVD screening., Methods: A derivation cohort containing 331 KT recipients underwent living donor KT at Kyushu University Hospital from January 2006 to December 2012. A prediction model was retrospectively developed and risk scores were investigated via a Cox proportional hazards regression model. The discrimination and calibration capacities of the prediction model were estimated via the c-statistic and the Hosmer-Lemeshow goodness of fit test. External validation was estimated via the same statistical methods by applying the model to a validation cohort of 300 KT recipients who underwent living donor KT at Tokyo Women's Medical University Hospital., Results: In the derivation cohort, 28 patients (8.5%) had CVD events during the observation period. Recipient age, CVD history, diabetic nephropathy, dialysis vintage, serum albumin and proteinuria at 12 months after KT were significant predictors of CVD. A prediction model consisting of integer risk scores demonstrated good discrimination (c-statistic 0.88) and goodness of fit (Hosmer-Lemeshow test P = 0.18). In a validation cohort, the model demonstrated moderate discrimination (c-statistic 0.77) and goodness of fit (Hosmer-Lemeshow test P = 0.15), suggesting external validity., Conclusions: The above-described simple model for predicting CVD after living donor KT was accurate and useful in clinical situations., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

The feasibility and efficacy of hypofractionated salvage radiotherapy (HS-RT) for prostate cancer (PC) with biochemical recurrence (BR) after prostatectomy, and the usefulness of prostate-specific antigen (PSA) kinetics as a predictor of BR, were evaluated in 38 patients who received HS-RT without androgen deprivation therapy between May 2009 and January 2017. Their median age, PSA level and PSA doubling time (PSA-DT) at the start of HS-RT were 68 (53-74) years, 0.28 (0.20-0.79) ng/ml and 7.7 (2.3-38.5) months, respectively. A total dose of 60 Gy in 20 fractions (three times a week) was three-dimensionally delivered to the prostate bed. After a median follow-up of 62 (30-100) months, 19 (50%) patients developed a second BR after HS-RT, but only 1 patient died before the last follow-up. The 5-year overall survival and BR-free survival rates were 97.1 and 47.4%, respectively. Late grade 2 gastrointestinal and genitourinary morbidities were observed in 0 and 5 (13%) patients, respectively. The PSA level as well as pathological T-stage and surgical margin status were regarded as significant predictive factors for a second BR by multivariate analysis. BR developed within 6 months after HS-RT in 11 (85%) of 13 patients with a PSA-DT < 10 months compared with 1 (17%) of 6 with a PSA-DT ≥ 10 months (median time to BR: 3 vs 14 months, P < 0.05). Despite the small number of patients, our HS-RT protocol seems feasible, and PSA kinetics may be useful for predicting the risk of BR and determining the appropriate follow-up schedule., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM)., Methods: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM., Results: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08)., Conclusions: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly., Key Points: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array., Methods: We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction., Results: In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02)., Conclusions: IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

3D image-guided brachytherapy (3D-IGBT) has become a standard therapy for cervical cancer. However, the use of 3D-IGBT is limited in East and Southeast Asia. This study aimed to clarify the current usage patterns of 3D-IGBT for cervical cancer in East and Southeast Asia. A questionnaire-based survey was performed in 11 countries within the framework of the Forum for Nuclear Cooperation in Asia. The questionnaire collected the treatment information of patients with cervical cancer who underwent 3D-IGBT. The cumulative external beam radiotherapy and 3D-IGBT doses were summarized and normalized to a biological equivalent dose of 2 Gy per fraction (EQD2) using a linear-quadratic model. Of the 11 institutions representing the participating countries, six (55%) responded to the questionnaire. Overall, data of 36 patients were collected from the six institutions. Twenty-one patients underwent whole-pelvic irradiation and 15 underwent whole-pelvic irradiation with central shielding. Patients received a median of four treatment sessions of 3D-IGBT (range, 2-6). All 3D-IGBT sessions were computed tomography (CT)-based and not magnetic resonance image-based. The median doses to the high-risk clinical target volume D90, bladder D2cc, rectum D2cc and sigmoid colon D2cc were 80.9 Gy EQD2 (range, 58.9-105.9), 77.7 Gy EQD2 (range, 56.9-99.1), 68.0 Gy EQD2 (range, 48.6-90.7) and 62.0 Gy EQD2 (range, 39.6-83.7), respectively. This study elucidated the current patterns of 3D-IGBT for the treatment of cervical cancer in East and Southeast Asia. The results indicate the feasibility of observational studies of CT-based 3D-IGBT for cervical cancer in these countries., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Polyglutamylation is a reversible protein modification that commonly occurs in tumor cells. Methotrexate (MTX) in tumor cells is polyglutamylated and strongly binds to dihydrofolate reductase (DHFR) without competitive inhibition by leucovorin. Therefore, tumor cells with high polyglutamylation levels are supposed to be selectively killed, whereas normal cells with lower polyglutamylation are rescued by leucovorin. This study investigated the combined effects of MTX plus histone deacetylase inhibitors (HDACIs), which upregulate MTX polyglutamylation, in primary central nervous system lymphoma (PCNSL)., Methods: We evaluated cell viability after MTX treatment and leucovorin rescue and compared the expression of folylpolyglutamate synthetase (FPGS), γ-glutamyl hydrolase (GGH), and DHFR in 2 human PCNSL-derived cell lines (HKBML and TK) and a human Burkitt lymphoma cell line (TL-1). Combination treatments were created using 4 HDACIs: panobinostat, vorinostat, sodium butyrate, and valproic acid. The expression of DHFR was examined as well as ratios of FPGS/GGH expression. The combined effects of MTX plus HDACIs were evaluated using a cell viability assay, mass spectroscopy imaging, and subcutaneous and intracranial xenograft models., Results: HDACIs upregulated the ratio of FPGS/GGH expression resulting in increased polyglutamylation of MTX, but also downregulated expression of the target molecule of MTX: DHFR. The combination of MTX and vorinostat decreased cell viability in vitro ( P < .05) and tumor volumes in a subcutaneous model ( P < .0001), and prolonged survival in an intracranial model ( P < .01), relative to controls., Conclusion: HDACIs enhanced the therapeutic effect of MTX through increased polyglutamylation of MTX and concomitant downregulation of DHFR expression., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: The utility of the Columbia classification (Col-class) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven., Methods: We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class., Results: The patients were classified into the following variants: not otherwise specified [NOS; n = 121 (60.1%)], perihilar [n = 31 (15.4%)], cellular [n = 19 (9.5%)], tip [n = 17 (8.5%)] and collapsing [n = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P = 0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P = 0.539)., Conclusions: The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Angiosperms have three PsbQ-like (PQL) proteins in addition to the PsbQ subunit of the oxygen-evolving complex of photosystem II. Previous studies have shown that two PQL proteins, PnsL2 and PnsL3, are subunits of the chloroplast NADH dehydrogenase-like (NDH) complex involved in the photosystem I (PSI) cyclic electron flow. In addition, another PsbQ homolog, PQL3, is required for the NDH activity; however, the molecular function of PQL3 has not been elucidated. Here, we show that PQL3 is an assembly factor, particularly for the accumulation of subcomplex B (SubB) of the chloroplast NDH. In the pql3 mutant of Arabidopsis thaliana, the amounts of NDH subunits in SubB, PnsB1 and PsnB4, were decreased, causing a severe reduction in the NDH-PSI supercomplex. Analysis using blue native polyacrylamide gel electrophoresis suggested that the incorporation of PnsL3 into SubB was affected in the pql3 mutant. Unlike other PsbQ homologs, PQL3 was weakly associated with thylakoid membranes and was only partially protected from thermolysin digestion. Consistent with the function as an assembly factor, PQL3 accumulated independently in other NDH mutants, such as pnsl1-3. Furthermore, PQL3 accumulated in young leaves in a manner similar to the accumulation of CRR3, an assembly factor for SubB. These results suggest that PQL3 has developed a distinct function as an assembly factor for the NDH complex during evolution of the PsbQ protein family in angiosperms., (© The Author(s) 2020. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In Parkinson's disease, a precursor phenomenon to visual hallucinations presents as 'pareidolias' which make ambiguous forms appear meaningful. To evoke and detect pareidolias in patients, a noise pareidolia test was recently developed, although its task-dependent mechanisms are yet to be revealed. When subjected to this test, we hypothesized that patients exhibiting pareidolias would show altered top-down influence of visual processing allowing us to demonstrate the influence of pareidolic illusionary behaviour in Parkinson's disease patients. To that end, we evaluated eye-movement strategies and fixation-related presaccadic activity on scalp EEG when participants performed the test. Twelve healthy controls and 21 Parkinson's disease patients, evaluated for cognitive, visuo-spatial and executive functions, took a modified computer-based version of the noise pareidolia test in a free-viewing EEG eye-tracking experiment. Eye-tracking metrics (fixation-related durations and counts) documented the eye movement behaviour employed in correct responses (face/noise) and misperceptions (pareidolia/missed) during early and late visual search conditions. Simultaneously, EEG recorded the presaccadic activity in frontal and parietal areas of the brain. Based on the noise pareidolia test scores, we found certain Parkinson's disease patients exhibited pareidolias whereas others did not. ANOVA on eye-tracking data showed that patients dwelled significantly longer to detect faces and pareidolias which affected both global and local search dynamics depending on their visuo-perceptual status. Presaccadic activity in parietal electrodes for the groups was positive for faces and pareidolias, and negative for noise, though these results depended mainly on saccade size. However, patients sensitive to pareidolias showed a significantly higher presaccadic potential on frontal electrodes independent of saccade sizes, suggesting a stronger frontal activation for pareidolic stimuli. We concluded with the following interpretations (i) the noise pareidolia test specifically characterizes visuo-perceptual inadequacies in patients despite their wide range of cognitive scores, (ii) Parkinson's disease patients dwell longer to converge attention to pareidolic stimuli due to abnormal saccade generation proportional to their visuo-perceptual deficit during early search, and during late search, due to time-independent alteration of visual attentional network and (iii) patients with pareidolias show increased frontal activation reflecting the allocation of attention to irrelevant targets that express the pareidolic phenomenon. While the disease per se alters the visuo-perceptual and oculomotor dynamics, pareidolias occur in Parkinson's disease due to an abnormal top-down modulation of visual processing that affects visual attention and guidance to ambiguous stimuli., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

In green plants, photosystem II (PSII) forms multisubunit supercomplexes (SCs) containing a dimeric core and light-harvesting complexes (LHCs). In this study, we show that Arabidopsis thaliana PsbP-like protein 1 (PPL1) is involved in the assembly of the PSII SCs and is required for adaptation to changing light intensity. PPL1 is a homolog of PsbP protein that optimizes the water-oxidizing reaction of PSII in green plants and is required for the efficient repair of photodamaged PSII; however, its exact function has been unknown. PPL1 was enriched in stroma lamellae and grana margins and associated with PSII subcomplexes including PSII monomers and PSII dimers, and several LHCII assemblies, while PPL1 was not detected in PSII-LHCII SCs. In a PPL1 null mutant (ppl1-2), assembly of CP43, PsbR and PsbW was affected, resulting in a reduced accumulation of PSII SCs even under moderate light intensity. This caused the abnormal association of LHCII in ppl1-2, as indicated by lower maximal quantum efficiency of PSII (Fv/Fm) and accelerated State 1 to State 2 transitions. These differences would lower the capability of plants to adapt to changing light environments, thereby leading to reduced growth under natural fluctuating light environments. Phylogenetic and structural analyses suggest that PPL1 is closely related to its cyanobacterial homolog CyanoP, which functions as an assembly factor in the early stage of PSII biogenesis. Our results suggest that PPL1 has a similar function, but the data also indicate that it could aid the association of LHCII with PSII., (© The Author(s) 2020. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The current study aimed to evaluate the outcomes of patients with adenocarcinoma (AC) of the uterine cervix after definitive radiotherapy (RT) and to evaluate prognostic factors, including immunity-related molecules. A total of 71 patients with AC of the uterine cervix from multiple Japanese institutions were retrospectively analysed. Histological subtypes were diagnosed according to the 2014 World Health Organization classification. All patients underwent definitive RT comprising external beam RT and intracavitary brachytherapy with or without concurrent chemotherapy. Immunohistochemical studies were performed to detect the expression of programmed cell death-ligand 1(PD-L1) and CD8. The 5-year locoregional control (LC), overall survival (OS) and progression-free survival (PFS) rates for all patients were 61.8, 49.7 and 36.1%, respectively. The LC, OS and PFS rates were not significantly different among the histological subtypes. Membranous PD-L1 expression was not significantly associated with prognosis. Patients with CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) in the tumor nests had significantly better OS than patients without CD8+TILs in the tumor nests (5-year OS: 53.8 vs 23.8%, P = 0.038). As expected, the International Federation of Gynecology and Obstetrics (FIGO) stage (2008) III-IVA and maximum tumor diameter > 40 mm were significantly associated with worse prognosis. In summary, the presence of CD8+TILs in the tumor nests has the potential to be an independent favorable prognostic factor for patients with AC of the uterine cervix after definitive RT., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Ionizing radiation produces clustered DNA damage that contains two or more lesions in 10-20 bp. It is believed that the complexity of clustered damage (i.e., the number of lesions per damage site) is related to the biological severity of ionizing radiation. However, only simple clustered damage containing two vicinal lesions has been demonstrated experimentally. Here we developed a novel method to analyze the complexity of clustered DNA damage. Plasmid DNA was irradiated with densely and sparsely ionizing Fe-ion beams and X-rays, respectively. Then, the resulting DNA lesions were labeled with biotin/streptavidin and observed with atomic force microscopy. Fe-ion beams produced complex clustered damage containing 2-4 lesions. Furthermore, they generated two or three clustered damage sites in a single plasmid molecule that resulted from the hit of a single track of Fe-ion beams. Conversely, X-rays produced relatively simple clustered damage. The present results provide the first experimental evidence for complex cluster damage., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The aim of the study was to compare incidences of late gastrointestinal adverse events and clinical outcomes between 3D conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) after radical hysterectomy for cervical cancer patients. Between March 2007 and May 2014, 73 cervical cancer patients with high-risk prognostic factors (pelvic lymph node metastasis and/or parametrial invasion) underwent postoperative pelvic radiation therapy (RT) after radical hysterectomy. Of these patients, 33 (45%) and 40 (55%) received 3DCRT and IMRT, respectively. Because the gastrointestinal obstruction rate after postoperative pelvic 3DCRT was high, no concurrent chemotherapy was applied until 2015. The median follow-up period for patients with 3DCRT and IMRT was 82 months (6-113) and 50 months (5-74), respectively. There was no significant difference in overall survival (OS) (4-year OS: 85% vs 78%, P = 0.744) or disease-free survival (DFS) (4-year DFS: 73% vs 64%, P = 0.696) between the two groups. Eleven (33%) and 13 (33%) patients experienced recurrence after 3DCRT and IMRT, respectively. The patients who had vaginal invasion from the postoperative pathological finding more frequently had loco-regional recurrence than the patients who did not have vaginal invasion (2.3% vs 17%, P = 0.033). Gastrointestinal obstruction was observed in 9 (27%) and 3 (7.5%) patients for 3DCRT and for IMRT, respectively (P = 0.026). Severe gastrointestinal obstruction that required surgery was observed in 6 (19%) patients, all of whom received adjuvant RT by 3DCRT. IMRT could reduce the incidence of late severe gastrointestinal obstruction after postoperative pelvic RT with a non-inferior clinical efficacy compared with 3DCRT., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

PIWI-interacting RNAs (piRNAs), a subclass of germ cell-specific noncoding small RNAs, are essential for de novo DNA methylation of retrotransposon genes in embryonic testes. PIWIL2/MILI, one of three mouse PIWI family members, is indispensable for piRNA production, DNA methylation of retrotransposons presumably via piRNA, and normal spermatogenesis. In vitro analysis using germline stem cells (GS cells) revealed that glycerol-3-phosphate acyltransferase 2 (GPAT2), which is a mitochondrial outer membrane protein involved in generation of lysophosphatidic acid (LPA) and highly expressed in testes, plays important roles in spermatogenesis. Namely, GPAT2 binds to PIWIL2 and is closely involved in the biogenesis of piRNAs; this process is independent of its enzymatic activity on LPA. However, GS cells recapitulate only a limited phase of spermatogenesis and the biological functions of GPAT2 remain largely unknown. In this study, we generated GPAT2-deficient mice and conducted comprehensive analyses. The deficient mice showed defective piRNA production and subsequent de-silencing of IAP and Line-1 retrotransposons in fetal testes. In addition, apoptosis of pachytene spermatocytes was observed. These abnormalities were all common to the phenotype of PIWIL2-deficient mice, in which piRNA production was impaired. GPAT2-deficient mice exhibited apoptosis in spermatogonia at the neonatal stage, which was not observed in PIWIL2-deficient mice. These data show that GPAT2 plays a critical role in preventing apoptosis in spermatogonia., (© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction.)

The use of human induced pluripotent stem cells (hiPSCs) and recent advances in cell engineering have opened new prospects for cell-based therapy. However, there are concerns that must be addressed prior to their broad clinical applications and a major concern is tumorigenicity. Suicide gene approaches could eliminate wayward tumor-initiating cells even after cell transplantation, but their efficacy remains controversial. Another concern is the safety of genome editing. Our knowledge of human genomic safe harbors (GSHs) is still insufficient, making it difficult to predict the influence of gene integration on nearby genes. Here, we showed the topological architecture of human GSH candidates, AAVS1, CCR5, human ROSA26, and an extragenic GSH locus on chromosome 1 (Chr1-eGSH). Chr1-eGSH permitted robust transgene expression, but a 2 Mb-distant gene within the same topologically associated domain showed aberrant expression. Although knockin iPSCs carrying the suicide gene, herpes simplex virus thymidine kinase (HSV-TK), were sufficiently sensitive to ganciclovir in vitro, the resulting teratomas showed varying degrees of resistance to the drug in vivo. Our findings suggest that the Chr1-eGSH is not suitable for therapeutic gene integration and highlight that topological analysis could facilitate exploration of human GSHs for regenerative medicine applications. Our data indicate that the HSV-TK/ganciclovir suicide gene approach alone may be not an adequate safeguard against the risk of teratoma, and suggest that the combination of several distinct approaches could reduce the risks associated with cell therapy. Stem Cells Translational Medicine 2019;8:627&638., (© 2019 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Definitive radiotherapy for cervical cancer consists of external-beam radiotherapy (EBRT) and brachytherapy. In EBRT, a central shield (CS) reduces the dose to the rectum and bladder. The combination of whole-pelvic (WP)- and CS-EBRT and brachytherapy is the standard radiotherapy protocol in Japan. Despite clinical studies, including multi-institutional clinical trials, showing that the Japanese treatment protocol yields favorable treatment outcomes with low rates of late radiation toxicities, dose-volume parameters for the Japanese treatment protocol remain to be established. We conducted a retrospective dose-volume analysis of 103 patients with uterine cervical cancer treated with the Japanese protocol using computed tomography-based adaptive brachytherapy. The 2-year overall survival and 2-year local control rates according to FIGO stage were 100% and 100% for Stage I, 92% and 94% for Stage II, and 85% and 87% for Stage III-IV, respectively. Late adverse effects in the rectum and bladder were acceptable. Receiver operating characteristic analysis discriminated recurrence within the high-risk clinical target volume (HR-CTV) (n = 5) from no local recurrence (n = 96), with the optimal response obtained at a dose of 36.0 GyEQD2 for HR-CTV D90 and 28.0 GyEQD2 for HR-CTV D98. These values were used as cut-offs in Fisher exact tests to show that high HR-CTV D90 and HR-CTV D98 doses for brachytherapy sessions were significantly associated with tumor control within the HR-CTV. These data suggest a contribution of brachytherapy to local tumor control in WP- and CS-EBRT and brachytherapy combination treatment, warranting validation in multi-institutional prospective studies., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

It is important to confirm the dose distribution and its biophysiological response in patients subjected to carbon-ion radiotherapy (CIRT) by using medical imaging methods. In this study, the correlation between the signal intensity changes of muscles observed in magnetic resonance imaging (MRI) after CIRT and planned dose distribution was evaluated. Seven patients were arbitrarily selected from among localized prostate cancer patients on whom CIRT was performed in our facilities in 2010. All subjects received the same dose of CIRT, namely, 57.6 Gy relative biological effectiveness (RBE) in 16 fractions. The following two types of images were acquired for each subject: planning computed tomography (CT) images overlaying the dose distribution of CIRT and MRI T2-weighted images (T2WI) taken 1 year after CIRT. The fusion image of the planning CT and MRI images was registered by using a treatment-planning system, and the CIRT dose distribution was compared with changes observed in the MRI of the obturator internus muscles located near the prostate. The signal changes in the axial image passing through the isocenter of the planning target volume were digitized, and a scatter diagram was created showing the relationship between the radiation dose and digitized signal changes. A strong correlation between the radiation dose and the MRI signal intensity changes was observed, and a quadratic function was found to have the best fit. However, estimating the dose distribution from the normalized MRI signal intensity is difficult at this point, owing to the wide variation. Therefore, further investigation is required., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background and Aims: Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn's disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel., Methods: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions., Results: Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10-26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, pmeta = 3.56 × 10-19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [p <1 × 10-6], and rs488200 located upstream of RAP1A was significantly associated with CD [pcombined = 4.36 × 10-8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression., Conclusions: RAP1A is a novel susceptibility locus for CD in the Japanese population., (Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. 
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There are no quantitative selection criteria for identifying high-grade glioma (HGG) patients who are suited for volumetric-modulated arc therapy (VMAT). This study aimed to develop selection criteria that can be used for the selection of the optimal treatment modality in HGG. We analyzed 20 patients with HGG treated by 3D conformal radiotherapy (3DCRT). First, VMAT plans were created for each patient retrospectively. For each plan, the normal tissue complication probability (NTCP) for normal brain was calculated. We then divided the patients based on the NTCPs of the 3DCRT plans for normal brain, using the threshold of 5%. We compared the NTCPs of the two plans and the gross tumor volumes (GTVs) of the two groups. For the GTVs, we used receiver operating characteristic curves to identify the cut-off value for predicting NTCP < 5%. We determined the respective correlations between the GTV and the GTV's largest cross-sectional diameter and largest cross-sectional area. In the NTCP ≥ 5% group, the NTCPs for the VMAT plans were significantly lower than those for the 3DCRT plans (P = 0.0011). The NTCP ≥ 5% group's GTV was significantly larger than that of the NTCP < 5% group (P = 0.0016), and the cut-off value of the GTV was 130.5 cm3. The GTV was strongly correlated with the GTV's largest cross-sectional diameter (R2 = 0.82) and largest cross-sectional area (R2 = 0.94), which produced the cut-off values of 7.5 cm and 41 cm2, respectively. It was concluded that VMAT is more appropriate than 3DCRT in cases in which the GTV is ≥130.5 cm3., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Neoadjuvant chemotherapy (NAC) is administered to many patients with esophageal squamous cell carcinoma (ESCC) prior to surgery, but it is also true that some of these patients demonstrated no response to the therapy following surgery. In addition, the prognosis of advanced case such as ESCC patients with lymph node metastasis has remained relatively low. Programmed death ligand-1 (PD-L1) in conjunction with tumor-infiltrating lymphocytes (TILs) has been studied as a potential mechanism of "immune escape" in several human malignancies. Therefore, in this study, we studied PD-L1 status in carcinoma cells and forkhead box protein 3 (FOXP3) and CD8 status among TILs in the residual tumors of primary and metastatic sites following NAC. We also studied the association of these factors with the clinicopathological findings in 44 patients with ESCC harboring lymph node metastasis. There was discordance in the pathological response to chemotherapy between the primary tumor and lymph node metastasis, and histologically identified resistance to NAC in lymph node metastases tended to be correlated with an adverse clinical outcome (P = 0.0765) than resistance in the primary tumor. Both univariate and multivariate analyses for disease-specific survival (DSS) revealed that the PD-L1 status of carcinoma cells in metastatic lymph nodes and a higher FOXP3/CD8 ratio in the primary tumor were both significantly correlated with an eventual adverse clinical outcome of the patients (P = 0.0178, P = 0.0463, respectively). These results all indicated that the PD-L1 status of carcinoma cells in metastatic lymph nodes and the FOXP3/CD8 ratio in primary tumors could predict eventual clinical outcomes in ESCC patients with NAC., (© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Objective: To evaluate the efficacy and safety of sirukumab, a human anti-interleukin six monoclonal antibody, in Japanese patients with rheumatoid arthritis who were refractory to anti-tumor necrosis factor therapy., Methods: This subgroup analysis, based on a double-blind, placebo-controlled, 52-week phase 3, global study (SIRROUND-T) assessed the American College of Rheumatology (ACR) 20 response at week 16 (primary endpoint). Secondary endpoints: ACR 50, Disease Activity Score in 28 joints-C reactive protein, Health Assessment Questionnaire-Disability Index and safety were assessed. Results 116/878 patients received sirukumab 50 mg/4 weeks (q4w, n = 35), 100 mg/2 weeks (q2w, n = 44) or placebo (n = 37) subcutaneously. Significantly more patients achieved ACR 20 response at week 16 with sirukumab (50 mg q4w:20 [57.1%]; p < .001, 100 mg q2w:24 [54.5%]; p = .001) versus placebo (7 [18.9%]); consistent significant improvement in secondary endpoints at week 24 and 52 was observed. At week 24, incidence of treatment-emergent adverse events (TEAEs) was numerically higher with sirukumab groups (50 mg q4w:29 [82.9%]; 100 mg q2w:38 [86.4%] versus placebo (28 [75.7%]); however, at week 52, sirukumab combined groups had comparable incidence of TEAEs., Conclusion: Efficacy findings through 52 weeks were comparable between sirukumab doses in Japanese patients and consistent with primary SIRROUND-T study results. No new safety signals were observed.

Objectives: This study was performed to analyse the surgical results of total anomalous pulmonary venous connection (TAPVC) repair at a single institution and to identify trends and variables associated with mortality and morbidity, particularly predictors of recurrent pulmonary venous obstruction (PVO)., Methods: Our surgical database contained 256 patients with biventricular anatomy who underwent surgical repair for TAPVC from 1981 to 2016. The anatomic TAPVC subtypes in this study were as follows: 114 supracardiac (44.5%), 56 cardiac (21.9%), 64 infracardiac (25.0%) and 22 mixed (8.6%) types. The follow-up for the entire study ranged from 1.6 months to 28.2 years (median 10.4 years). Preoperative PVO was present in 128 patients (50.0%). All patients with TAPVC with single-ventricle anatomy were excluded from the analysis. Data were retrospectively reviewed., Results: Seven (2.7%) early deaths and 26 (10.1%) late deaths occurred. The actuarial survival rate at 20 years postoperatively was 85.3%. The preoperative predictors of operative mortality were younger age and the era of TAPVC repair (before 1998). In addition to these variables, associated cardiac anomalies were predictors of late mortality. Those for postoperative PVO were younger age, lower weight and being an emergency case. The actuarial survival rate at 20 years was 38.6% for patients with postoperative PVO and 92.2% for patients without postoperative PVO (P < 0.001)., Conclusions: The long-term outcomes after TAPVC repair in patients with biventricular anatomy were satisfactory. Mortality was significantly associated with the rate of progression of postoperative PVO, and careful follow-up was required especially within 6 months after the primary operation., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Photons, such as X- or γ-rays, induce DNA damage (distributed throughout the nucleus) as a result of low-density energy deposition. In contrast, particle irradiation with high linear energy transfer (LET) deposits high-density energy along the particle track. High-LET heavy-ion irradiation generates a greater number and more complex critical chromosomal aberrations, such as dicentrics and translocations, compared with X-ray or γ irradiation. In addition, the formation of >1000 bp deletions, which is rarely observed after X-ray irradiation, has been identified following high-LET heavy-ion irradiation. Previously, these chromosomal aberrations have been thought to be the result of misrepair of complex DNA lesions, defined as DNA damage through DNA double-strand breaks (DSBs) and single-strand breaks as well as base damage within 1-2 helical turns (<3-4 nm). However, because the scale of complex DNA lesions is less than a few nanometers, the large-scale chromosomal aberrations at a micrometer level cannot be simply explained by complex DNA lesions. Recently, we have demonstrated the existence of clustered DSBs along the particle track through the use of super-resolution microscopy. Furthermore, we have visualized high-level and frequent formation of DSBs at the chromosomal boundary following high-LET heavy-ion irradiation. In this review, we summarize the latest findings regarding the hallmarks of DNA damage structure and the repair pathway following heavy-ion irradiation. Furthermore, we discuss the mechanism through which high-LET heavy-ion irradiation may induce dicentrics, translocations and large deletions.

Objective: To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs., Methods: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints)., Results: A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p < .001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, p = .024; 100 mg q2w: 0.0, p = .002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52., Conclusion: Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.

Polyinosinic-polycytidylic acid (PIC), a double-stranded RNA that induces innate immunity in mammals, is a candidate immunopotentiator for pharmaceuticals. The potency and adverse effects of PIC are strongly correlated with the nucleotide length, and the inability to precisely control the length in PIC production limits its practical use. Length extension during the annealing process is the major factor underlying the lack of control, but tuning the annealing conditions is insufficient to resolve this issue. In this study, we developed a novel method to produce accurate nucleotide length PIC at an industrial scale. The length extension was significantly suppressed by the assembly of multiple short polyinosinic acid molecules with one long polycytidylic acid molecule. A newly developed PIC, uPIC100-400, demonstrated a reproducible length and better storage stability than that of corresponding evenly structured PIC. Human dsRNA receptors exhibited equivalent responsiveness to uPIC100-400 and the evenly structured PIC with the same length.