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Objectives: This study aimed to understand the status quo of medical treatments and pregnancy outcomes in patients with Takayasu arteritis (TAK) and children's birth outcomes., Methods: This study retrospectively enrolled patients with TAK who conceived after the disease onset and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis., Results: This study enrolled 51 cases and 68 pregnancies during 2019-21. Of these, 48 cases and 65 pregnancies resulted in delivery and live-born babies. The median age of diagnosis and delivery was 22 and 31 years, respectively. Preconception therapy included prednisolone (PSL) in 51 (78.5%, median 7.5 mg/day), immunosuppressants in 18 (27.7%), and biologics in 12 (18.5%) pregnancies. Six cases underwent surgical treatment before pregnancy. Medications during pregnancy included PSL in 48 (73.8%, median: 9 mg/day), immunosuppressants in 13 (20.0%), and biologics in 9 (13.8%) pregnancies. TAK relapsed in four (6.2%) and eight (12.3%) pregnancies during pregnancy and after delivery, respectively. Additionally, 13/62 (20.9%) preterm infants and 17/59 (28.8%) low-birth-weight infants were observed, and none had serious postnatal abnormalities., Conclusions: Most pregnancies in TAK were manageable with PSL at ≤10 mg/day. Relapse during pregnancy and postpartum occurred in <20% of pregnancies., (© Japan College of Rheumatology 2024. Published by Oxford University Press. 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.)

Genome-wide association studies (GWASs) have identified thousands of variants associated with complex phenotypes, including neuropsychiatric disorders. To better understand their pathogenesis, it is necessary to identify the functional roles of these variants, which are largely located in non-coding DNA regions. Here, we employ a human mesencephalic neuronal cell differentiation model, LUHMES, with sensitive and high-resolution methods to discover enhancers (NET-CAGE), perform DNA conformation analysis (Capture Hi-C) to link enhancers to their target genes, and finally validate selected interactions. We expand the number of known enhancers active in differentiating human LUHMES neurons to 47,350, and find overlap with GWAS variants for Parkinson's disease and schizophrenia. Our findings reveal a fine-tuned regulation of human neuronal differentiation, even between adjacent developmental stages; provide a valuable resource for further studies on neuronal development, regulation, and disorders; and emphasize the importance of exploring the vast regulatory potential of non-coding DNA and enhancers., Competing Interests: Disclosure and competing interests statement. YM is an inventor on a patent related to the NET-CAGE technology. Other authors declare no competing interests., (© 2025. The Author(s).)

The bovine leukocyte antigen (BoLA) comprises four regions that contain a high density of polymorphic genes and frequently show gene copy number variations (CNV). Therefore, genotyping BoLA using genome-wide resequencing is difficult. This study aimed to develop four probe sets for resequencing of the BoLA region using a hybridization capture target next-generation sequencing (NGS) method. This proof of concept showed and discussed the several applications of the used strategy. DNAs from nine Japanese Black cows and one Holstein cow were genotyped for BoLA-DRB3 using PCR sequence-based typing (SBT). DNA libraries were constructed using the KAPA HyperPlus Kit, and BoLA DNA sequences were enriched using the SeqCap EZ kit and four custom-made probes. Based on preliminary results, the probe set BoLA2 was selected for further analysis. This analysis resulted in a mean coverage of 90.8% with an average depth of 108 reads. A total of 113,646 SNPs and 17,995 indels were detected, several of which have previously been described in the dbSNP database. This allowed the genotyping of class II genes, including BoLA-DRB3. A comparison between target resequencing and PCR-SBT assays did not show conflicts between the BoLA-DRB3 genotyping results. CNV analysis based on read number inferred that the BoLA-DQA1, BoLA-DQA2, BoLA-DQA5, and BoLA-DQB genes would be present in the homozygous or heterozygous states or absent, allowing for the definition of four class II and three class I haplotypes. In addition, CNV of non-classical class I genes were also observed. In conclusion, results show that approach used in this study is a cost-effective strategy for sequencing large samples for many research purposes., (© 2025 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Recent studies have demonstrated that the production of bidirectional enhancer-derived transcripts (eRNAs) is a characteristic of an active Cis-regulatory element (CRE). Higher levels of eRNA synthesis correlate with the activation of histone modifications, a potentially valuable tool for deciphering the complexity of the gene regulatory network. To understand the changes of CREs during gonadal development in mice, we collected gonadal WT1-positive cells from the piggyBac-Wt1-mCherry-2A-EGFP (PBWt1-RG) reporter strain at E13.5, E16.5, and P0 in both sexes and conducted Cap Analysis of Gene Expression analysis (CAGE) which is capable to capture transcriptional starting site (TSS). We compared the levels of intergenic bidirectional RNA, i.e, potentially eRNA, according to sex at each stage (testis somatic cells vs ovary somatic cells at E13.5, E16.5, and P0) and stage in each sex (E13.5 vs E16.5, E16.5 vs P0, and E13.5 vs P0 in testis somatic cells or ovary somatic cells). Intergenic RNAs with significant changes (|Log2FC| > 1, p < 0.05) were selected. The TSS profile of intergenic RNA changed more profoundly in testis somatic cells than in ovary somatic cells, suggesting embryonic testicular development is driven by larger changes in a transcriptional regulatory network than ovarian development. Based on the profiles of the predicted transcription factors (TFs) that would bind to the active CREs during gonadal development, the NR4A, EGR, and TCF3 families would be novel TFs to play pivotal roles in gonadal development. Identifying active CREs using eRNAs would provide a means to comprehensively understand the transcriptional regulatory system, leading to valuable insights into the gonadal development of male and female individuals., (S. Karger AG, Basel.)

Objectives Patients with rheumatoid arthritis (RA) have a high incidence of arteriosclerotic disease. These are partly attributed to high levels of C-reactive protein (CRP) and inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. Tocilizumab (TCZ) is an IL-6 receptor antagonist that lowers CRP levels by directly blocking IL-6 signaling. Tocilizumab has been reported to increase serum lipid levels. However, its effect on arteriosclerosis remains unclear. Therefore, we investigated the effect of TCZ on arteriosclerosis in patients with RA. Methods Eighteen Japanese patients with RA who were administered TCZ were included and assessed at baseline and six and 12 months. The Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR), CRP, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and carotid intima-media thickness (IMT) were measured and analyzed using high-resolution B-mode ultrasonography. Additionally, the effects of concurrent statin administration on any changes in IMT were evaluated. Results From baseline to six or 12 months, TCZ decreased CRP (P < 0.0005) and DAS28-ESR (P < 0.0005) significantly, whereas TC, LDL-C, and HDL-C levels increased significantly (P < 0.005). However, there was no change in the LDL-C/HDL-C ratio (P = 0.821 at six months and P = 0.168 at 12 months), and carotid IMT (P = 0.6874 at six months and P = 0.6951 at 12 months). Comparison of percentage changes in mean IMT revealed no statistical differences between the patient groups with or without statin administration (P = 0.7208 at six months, P = 0.5928 at 12 months). Conclusions According to the 12-month observation data, no significant association was detected between TCZ use and IMT changes in patients with RA, despite its effects on serum lipids. Further long-term studies are needed to confirm that IL-6 receptor blockers have cardiovascular effects., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Medical Research Ethics Committee, Shimane University Faculty of Medicine issued approval (416). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: MT, MH, and YS have nothing to declare. MM has received honoraria for lectures from Ayumi Pharma Corporation, Eisai Co. Ltd, Eli Lilly Japan K.K., Taisyo Pharma Corporation, and Mitsubishi Tanabe Pharma Corporation. YM has received honoraria from for lectures AbbVie Japan GK, Asahi Kasei Pharma Co. Ltd., Astellas Pharma Inc., AstraZeneca, AYUMI Pharma Corp., Bristol Myers Squibb Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi-Tanabe Co Ltd., MSD, Ono Pharmaceutical Co Ltd. and UCB Japan Co. Ltd. MK has received grants from Janssen Pharma K.K., GlaxoSmithKline, K.K., Pfizer Inc., Zenyaku Kogyo Co. Ltd., and Cmic Co. Ltd., and has received speaking fee from Eisai Co. Ltd., Chugai Pharma Co. Ltd., Mitsubishi-Tanabe Pharma, Bristol-Myers Squibb, Janssen Pharma K.K., Astellas Pharma Inc., Takeda Pharma Co. Nippon Kayaku Co. Ltd, Daiichi-Sankyo Co. Ltd, Asahi Kasei Pharma Co. and AbbVie Japan. KI has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the following companies: AstraZeneca K.K., Asahi Kasei Pharma Corporation, GlaxoSmithKline K.K., Eli Lilly Japan K.K., AbbVie G.K., Taisho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Moriyama et al.)

While epidemiological and experimental studies have demonstrated kidney-protective effects of estrogen and female sex in adulthood, some epidemiological data showed deterioration of kidney function during puberty when estrogen production increases. However, molecular mechanisms explaining these conflicting phenomena remain unknown. Here, we showed that the pubertal sex hormone surge in female mice increases susceptibility to kidney ischemia reperfusion injury partly via downregulation of insulin-like growth factor 1 receptor (IGF-1R) expression in proximal tubules. Adult mice ovariectomized pre-pubertally (at postnatal day 21) showed strong tolerance to kidney ischemia, which was partly reversed by the administration of 17β-estradiol, while adult mice ovariectomized post-pubertally (at 8 weeks of age) were vulnerable to kidney ischemia. Kidney tubular IGF-1R protein expression decreased during postnatal growth but was highly expressed in adult mice ovariectomized pre-pubertally and in infant mice, which might be partly explained by different expression of an E3 ligase (MDM2) of IGF-1R. Mice deficient of Igf-1r in proximal tubules (iIGF-1RKO mice) during postnatal kidney growth showed increased susceptibility to ischemic injury. RNA-seq and western blotting analysis using proximal tubular cells from pre-pubertally ovariectomized iIGF-1RKO and control mice revealed altered expression of cell cycle-associated molecules such as cyclin D1. These results suggest that Igf-1r deletion during postnatal growth renders proximal tubular cells susceptible to ischemia possibly via altered cell cycle regulation. Thus, our findings provide evidence that exposure to pubertal sex hormones leads to increased susceptibility to kidney ischemia, which is partly mediated by modulation of IGF-1R signaling., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Repeat expansions cause at least 50 hereditary disorders, including Friedreich ataxia and other diseases known to cause mitochondrial dysfunction. We identified a patient with NAXE-related mitochondrial encephalopathy and novel biallelic GGGCC repeat expansion as long as ~200 repeats in the NAXE promoter region using long-read sequencing. In addition to a marked reduction in the RNA and protein, we found a marked reduction in nascent RNA in the promoter using native elongating transcript-cap analysis of gene expression (NET-CAGE), suggesting transcriptional suppression. Accordingly, CpG hypermethylation was observed in the repeat region. Genetic analyses determined that homozygosity in the patient was due to maternal chromosome 1 uniparental disomy (UPD). We assessed short variants within NAXE including the repeat region in the undiagnosed mitochondrial encephalopathy cohort of 242 patients. This study identified the GGGCC repeat expansion causing a mitochondrial disease and suggests that UPD could significantly contribute to homozygosity for rare repeat-expanded alleles., (© 2024. The Author(s).)

Background: Whether muscle mass and muscle quality affect the prognosis of elderly patients with aspiration pneumonia is unclear. This study aimed to evaluate the relationship between erector spinae muscle mass and muscle quality on the 30-day prognosis of elderly patients with aspiration pneumonia., Methods: Two hundred fifty-eight patients who were diagnosed with aspiration pneumonia and admitted to Sanuki Municipal Hospital for pulmonary rehabilitation intervention were included. The cross-sectional area (ESM CSA /BSA) and CT values (ESM CT ) of the erector spinae muscles at the 12th thoracic vertebra were measured on chest CT images to represent muscle mass and quality, respectively. The primary outcome was defined as 30-day survival., Results: Twenty-six patients died within 30 days after hospitalization. The ESM CSA /BSA ratio was significantly greater in the survival group than in the nonsurvival group (p = 0.001). The cutoff values for 30-day survival were calculated as follows: the ESM CSA /BSA was 11.046 cm 2 /m 2 in male patients and 9.600 cm 2 /m 2 in female patients; the ESM CT was 26.85 HU in male patients and 8.00 HU in female patients. A higher ESM CSA /BSA significantly improved 30-day survival, while ESM CT did not show a significant difference. Cox proportional hazards regression analysis revealed that the ESM CSA /BSA was independently associated with 30-day short-term prognosis (hazard ratio 0.34, p = 0.034)., Conclusion: The short-term prognosis of elderly patients with aspiration pneumonia may be more strongly influenced by muscle mass than by the muscle quality of the erector spinae muscles., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This study aimed to clarify recent clinical features and treatment outcomes in Japanese patients with newly diagnosed Takayasu arteritis (TAK) during the first 2 years of treatment., Methods and Results: A nationwide multicenter retrospective cohort study for TAK was implemented to collect data between 2007 and 2014. The primary outcome of the study was clinical remission at Week 24. Of the 184 participants registered, 129 patients with newly diagnosed TAK were analyzed: 84% were female and the mean age at onset was 35 years. Clinical symptoms at diagnosis were mostly associated with large-vessel lesions. Frequent sites of vascular involvement included the carotid artery, subclavian artery, aortic arch, and descending aorta. The mean initial dose of prednisolone administered was 0.68 mg/kg/day, and 59% and 17% of patients received immunosuppressive drugs and biologics, respectively, by Week 104. Clinical remission at Week 24 and sustained clinical remission with daily prednisolone at ≤10 mg at Week 52 were achieved in 107 (82.9%) and 51 (39.5%) patients, respectively. The presence of signs and symptoms linked to large-vessel lesions was associated with failure to achieve sustained clinical remission at Week 52., Conclusions: We elucidated the clinical characteristics, treatment outcomes, and factors associated with failure to achieve sustained clinical remission in patients with newly diagnosed TAK in Japan during the first 2 years of treatment.

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4 + FOXP3 + regulatory T cells (T regs ) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T regs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1 , which led to destabilization of forkhead box P3 (FOXP3) and T reg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T regs from individuals with MS revealed enriched activating protein-1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and T reg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T regs in autoimmune diseases.

Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4 + T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.

The living body is composed of innumerable fine and complex structures. Although these structures have been studied in the past, a vast amount of information pertaining to them still remains unknown. When attempting to observe these ultra-structures, the use of electron microscopy (EM) has become indispensable. However, conventional EM settings are limited to a narrow tissue area, which can bias observations. Recently, new trends in EM research have emerged, enabling coverage of far broader, nano-scale fields of view for two-dimensional wide areas and three-dimensional large volumes. Moreover, cutting-edge bioimage informatics conducted via deep learning has accelerated the quantification of complex morphological bioimages. Taken together, these technological and analytical advances have led to the comprehensive acquisition and quantification of cellular morphology, which now arises as a new omics science termed 'morphomics'., (© The Author(s) (2023). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Objective: To revise the 2017 clinical practice guidelines (CPG) for the management of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) to reflect advancements in the field., Methods: Similar to the 2017 CPG, the Grading of Recommendations, Assessment, Development, and Evaluation system was adopted for this revision. The intended users of this CPG include patients diagnosed with MPA or GPA in Japan and their families and healthcare professionals, including specialists and non-specialists. Based on a scoping review, four clinical questions (CQs) of the 2017 guidelines were modified, and six new CQs were added., Results: We suggest a combination of glucocorticoid and cyclophosphamide or rituximab for remission induction therapy. In cases where cyclophosphamide or rituximab is used, we suggest the use of avacopan over high-dose glucocorticoid. Furthermore, we suggest against the use of plasma exchange in addition to the standard treatment in severe cases of MPA/GPA. Finally, we suggest the use of glucocorticoid and rituximab over glucocorticoid and azathioprine for remission maintenance therapy., Conclusions: The recommendations have been updated based on patient preference, certainty of evidence, benefit and risk balance, and cost., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In vertebrates, retinal neural circuitry for visual perception is organized in specific layers. The outer plexiform layer is the first synaptic region in the visual pathway, where photoreceptor synaptic terminals connect with bipolar and horizontal cell processes. However, molecular mechanisms underlying cone synapse formation to mediate OFF pathways remain unknown. This study reveals that Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and dendrites of type 4 OFF cone bipolar cells (CBCs). In Necl-1 -/- mouse retina, synapses between cones and type 4 OFF CBCs were dislocated, horizontal cell distribution became abnormal, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were dislocated. Necl-1 -/- mice exhibited aberrant short-wavelength-light-elicited signal transmission from cones to OFF CBCs, which was rescued by AMPA receptor potentiator. Additionally, Necl-1 -/- mice showed impaired optokinetic responses. These findings suggest that Necl-1 regulates cone synapse formation to mediate OFF cone pathways elicited by short-wavelength light in mouse retina., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Objectives: This study elucidated the prognosis and risk factors associated with damage accrual during long-term remission maintenance therapy for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV)., Methods: We obtained data from 120 patients registered in a nationwide prospective cohort study on remission induction therapy in Japanese patients with AAV and rapidly progressive glomerulonephritis (RemIT-JAV-RPGN), who achieved remission at 24 months after treatment initiation and were followed up for additional 24 months. The primary outcome was the vasculitis damage index (VDI) score at Month 48, and the secondary outcome included risk factors associated with increased total VDI at Month 48., Results: The understudied patients comprised 52 men and 68 women aged 68 ± 13 years. Between Months 25 and 48, the patients' survival rate was 95% (114/120). End-stage renal disease developed in seven patients by Month 48, and 64 cases had increased VDI. The multivariable analysis results revealed that oral prednisolone (PSL) doses at Month 24 were associated with damage accrual between Months 24 and 48., Conclusions: VDI accrual was observed in more than half of patients with AAV during maintenance therapy, and increased VDI scores were associated with oral PSL doses 24 months after initiating remission induction therapy in Japan., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The aim is to evaluate the prevention and development of cervical cancer in systemic lupus erythematosus (SLE) patients in Japan and its background based on a questionnaire survey., Methods: The questionnaire was handed to 460 adult female SLE patients at 12 medical institutions. The participants were grouped by age, and data related to their human papillomavirus vaccination status, age at first coitus, cervical cancer screening, and diagnosis of cervical cancer were analysed., Results: A total of 320 responses were received. Patients aged 35-54 years included a higher proportion of patients whose age at first coitus was <20 years. This group also showed a higher rate of cervical cancer/dysplasia. Only nine patients had a human papillomavirus vaccination history. Adequate frequency of cervical cancer screening was slightly higher (52.1%) among SLE patients than in the Japanese general population. However, 23% of the patients had never undergone examination, primarily because of a feeling of troublesome. The incidence of cervical cancer was significantly higher among SLE patients. One reason for this may be associated with the use of immunosuppressants, although the difference was not significant., Conclusions: SLE patients are at a higher risk of cervical cancer and dysplasia. Rheumatologists should proactively recommend vaccination and screening examinations for SLE female patients., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that messenger RNA (mRNA) decay factors regnase-1 (Reg1; Zc3h12a) and regnase-3 (Reg3; Zc3h12c) are essential for determining lymphoid fate and restricting myeloid differentiation in HSPCs. Loss of Reg1 and Reg3 resulted in severe impairment of lymphopoiesis and a mild increase in myelopoiesis in the bone marrow. Single-cell RNA sequencing analysis revealed that Reg1 and Reg3 regulate lineage directions in HSPCs via the control of a set of myeloid-related genes. Reg1- and Reg3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single-cell assay for transposase-accessible chromatin sequencing analysis revealed that Reg1 and Reg3 control the epigenetic landscape on myeloid-related gene loci in early stage HSPCs via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Reg1- and Reg3-mediated Nfkbiz mRNA degradation primed hematopoietic stem cells toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between posttranscriptional control and chromatin remodeling by the Reg1/Reg3-Nfkbiz axis governs HSPC lineage biases, ultimately dictating the fate of lymphoid vs myeloid differentiation., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Gastrointestinal stromal tumors (GISTs) are typically characterized by activating mutations of the KIT proto-oncogene receptor tyrosine kinase (KIT) or platelet-derived growth factor receptor alpha (PDGFRA). Recently, the neurotrophic tyrosine receptor kinase (NTRK) fusion was reported in a small subset of wild-type GIST. We examined trk IHC and NTRK gene expressions in GIST. Pan-trk immunohistochemistry (IHC) was positive in 25 (all 16 duodenal and 9 out of 16 small intestinal GISTs) of 139 cases, and all pan-trk positive cases showed diffuse and strong expression of c-kit. Interestingly, all of these cases showed only trkB but not trkA/trkC expression. Cap analysis of gene expression (CAGE) analysis identified increased number of genes whose promoters were activated in pan-trk/trkB positive GISTs. Imbalanced expression of NTRK2, which suggests the presence of NTRK2 fusion, was not observed in any of trkB positive GISTs, despite higher mRNA expression. TrkB expression was found in duodenal GISTs and more than half of small intestinal GISTs, and this subset of cases showed poor prognosis. However, there was not clear difference in clinical outcomes according to the trkB expression status in small intestinal GISTs. These findings may provide a possible hypothesis for trkB overexpression contributing to the tumorigenesis and aggressive clinical outcome in GISTs of duodenal origin., (© 2024. The Author(s).)

This feasibility study enrolled 20 patients with advanced severe Parkinson's disease (PD) to evaluate somato-cognitive coordination therapy (SCCT) using virtual reality. Focusing on the safety and tolerability of SCCT, 17 patients (76±9 years old and 64.7% male) completed the 3-month trial. Key observations included absence of adverse events and tolerability of the participants to SCCT despite initial apprehensions and minor adjustments in medication. Physical functions showed no significant deterioration, suggesting the safety of SCCT. In conclusion, SCCT emerges as feasible and well-tolerated intervention in advanced severe PD, requiring further research to assess its therapeutic efficacy.

Fibroblast growth factors (Fgfs) play crucial roles in various developmental processes including brain development. We previously identified Fgf22 in zebrafish and found that fgf22 is involved in midbrain patterning during embryogenesis. Here, we investigated the role of Fgf22 in the formation of the zebrafish forebrain. We found that fgf22 was essential for determining the ventral properties of the telencephalon and diencephalon but not for cell proliferation. In addition, the knockdown of fgf22 inhibited the generation of glutamatergic neurons, γ-aminobutyric acid (GABA)ergic interneurons and astrocytes. Recently, Fgf signaling has received much attention because of its importance in the pathogenesis of multiple sclerosis, in which oligodendrocytes and myelin are destroyed. However, the effects of each Fgf on oligodendrocytes remain largely unknown. Therefore, we also investigated the role of Fgf22 in oligodendrocyte development and explored whether there is a difference between Fgf22 and other Fgfs. Knockdown of fgf22 promoted the generation of oligodendrocytes. Conversely, overexpression of fgf22 inhibited the generation of oligodendrocytes. Furthermore, the forebrain phenotypes of fgfr2b knockdown zebrafish were remarkably similar to those of fgf22 knockdown zebrafish. This establishes the Fgf22-Fgfr2b axis as a key ligand‒receptor partnership in neurogenesis and gliogenesis in the forebrain. Our results indicate that Fgf22 has a unique function in suppressing oligodendrocyte differentiation through Fgfr2b without affecting cell proliferation., Competing Interests: Declaration of competing interest We have no conflict of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: We aimed to identify associations between patterns of large-vessel lesions of large-vessel giant cell arteritis (LV-GCA) and treatment outcomes., Methods: We extracted data on 68 newly diagnosed patients with LV-GCA from a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014. Patients with aortic lesions were identified based on the findings from contrast-enhanced computed tomography, magnetic resonance imaging, or positron emission tomography-computed tomography (Group 2, n = 49). Patients without aortic lesions were subdivided into LV-GCA with or without subclavian lesions defined as Group 1 (n = 9) or Group 3 (n = 10), respectively. The primary outcome evaluation was failure to achieve clinical remission by Week 24 and/or relapse within 104 weeks., Results: The mean age and proportion of patients with cranial lesions and polymyalgia rheumatica in Group 2 were numerically lower than in the other two groups. Large-vessel lesions in Group 3 included carotid, pulmonary, renal, hepatic, or mesenteric lesions. The cumulative rate of poor treatment outcomes >2 years was 11.1%, 55.3%, and 88.0% in Groups 1, 2, and 3, respectively (by Kaplan-Meier analysis). The mean time to poor outcome was significantly different between the groups., Conclusions: Classification by subclavian and aortic lesions may be useful to determine treatment strategy., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The aim of this article is to evaluate the effectiveness and safety of rituximab (RTX) for microscopic polyangiitis and granulomatosis with polyangiitis in Japan., Methods: In this prospective observational study, all patients with microscopic polyangiitis and granulomatosis with polyangiitis administered RTX were enrolled at each institution. During the observation period of 2 years, data up to 6 months were analysed. Cox proportional hazards analysis was used to assess the factors associated with an outcome., Results: Of the 75 patients who received RTX for remission induction therapy, 53 achieved remission by the sixth month and 50 were in remission at the sixth month. During therapy, 38 serious adverse events were observed in 24 patients, 21 serious infections in 16 patients, and 9 patients died. No factors were associated with remission; however, there was a significant difference between patients with and without remission in serious adverse events (22.6% vs. 54.5%), serious infections (11.3% vs. 45.4%), and death (1.9% vs. 36.4%). The hazard ratio (95% confidence interval) for serious infection was 3.49 (1.29-9.74) for patients aged ≥ 75 years and 3.53 (1.31-9.53) for pulmonary complications. Four patients maintained remission for 6 months., Conclusions: The effectiveness and safety of RTX for microscopic polyangiitis and granulomatosis with polyangiitis for up to 6 months was demonstrated., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Significance Statement: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms underlying TLT expansion and their effect on renal regeneration remain unclear. The authors report that single-nucleus RNA sequencing and validation experiments demonstrate that TLTs potentially amplify inflammation in aged injured kidneys. Lymphocytes within TLTs promote proinflammatory phenotypes of the surrounding proximal tubules and fibroblasts within the TLTs via proinflammatory cytokine production. These proinflammatory parenchymal cells then interact with immune cells by chemokine or cytokine production. Such cell-cell interactions potentially increase inflammation, expand TLTs, and exacerbate kidney injury. These findings help illuminate renal TLT pathology and suggest potential therapeutic targets., Background: Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms that expand TLTs and underlie exacerbation of kidney injury remain unclear., Methods: We performed single-nucleus RNA sequencing (snRNA-seq) on aged mouse kidneys with TLTs after ischemia-reperfusion injury. The results were validated using immunostaining, in situ hybridization of murine and human kidneys, and in vitro experiments., Results: Using snRNA-seq, we identified proinflammatory and profibrotic Vcam1+ injured proximal tubules (PTs) with NF κ B and IFN-inducible transcription factor activation. VCAM1 + PTs were preferentially localized around TLTs and drove inflammation and fibrosis via the production of multiple chemokines or cytokines. Lymphocytes within TLTs expressed Tnf and Ifng at high levels, which synergistically upregulated VCAM1 and chemokine expression in cultured PT cells. In addition, snRNA-seq also identified proinflammatory and profibrotic fibroblasts, which resided within and outside TLTs, respectively. Proinflammatory fibroblasts exhibited STAT1 activation and various chemokine or cytokine production, including CXCL9/CXCL10 and B cell-activating factor, contributing to lymphocyte recruitment and survival. IFN γ upregulated the expression of these molecules in cultured fibroblasts in a STAT1-dependent manner, indicating potential bidirectional interactions between IFN γ -producing CXCR3 + T cells and proinflammatory fibroblasts within TLTs. The cellular and molecular components described in this study were confirmed in human kidneys with TLTs., Conclusions: These findings suggest that TLTs potentially amplify inflammation by providing a microenvironment that allows intense interactions between renal parenchymal and immune cells. These interactions may serve as novel therapeutic targets in kidney diseases involving TLT formation., (Copyright © 2023 The Author. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

The conjunctival epithelium consists of conjunctival epithelial cells and goblet cells derived from conjunctival epithelial stem/progenitor cells. However, the source of these cells is not well known because no specific markers for conjunctival epithelial stem/progenitor cells have been discovered. Therefore, to identify conjunctival epithelial stem/progenitor cell markers, we performed single-cell RNA sequencing of a conjunctival epithelial cell population derived from human-induced pluripotent stem cells (hiPSCs). The following conjunctival epithelial markers were identified: BST2, SLC2A3, AGR2, TMEM54, OLR1, and TRIM29. Notably, BST2 was strongly positive in the basal conjunctival epithelium, which is thought to be rich in stem/progenitor cells. Moreover, BST2 was able to sort conjunctival epithelial stem/progenitor cells from hiPSC-derived ocular surface epithelial cell populations. BST2-positive cells were highly proliferative and capable of successfully generating conjunctival epithelial sheets containing goblet cells. In conclusion, BST2 has been identified as a specific marker of conjunctival epithelial stem/progenitor cells., Competing Interests: M.K., R.H., and K. Nishida have submitted a patent application on “Conjunctival epithelial markers: BST2, SLC2A3, AGR2, TMEM54, OLR1, and TRIM29.” R.H. is the holder of an Endowed Chair provided by ROHTO Pharmaceutical., (© 2023 The Authors.)

Gene transcription is regulated through complex mechanisms involving non-coding RNAs (ncRNAs). As the transcription of ncRNAs, especially of enhancer RNAs, is often low and cell type specific, how the levels of RNA transcription depend on genotype remains largely unexplored. Here we report the development and utility of a machine-learning model (MENTR) that reliably links genome sequence and ncRNA expression at the cell type level. Effects on ncRNA transcription predicted by the model were concordant with estimates from published studies in a cell-type-dependent manner, regardless of allele frequency and genetic linkage. Among 41,223 variants from genome-wide association studies, the model identified 7,775 enhancer RNAs and 3,548 long ncRNAs causally associated with complex traits across 348 major human primary cells and tissues, such as rare variants plausibly altering the transcription of enhancer RNAs to influence the risks of Crohn's disease and asthma. The model may aid the discovery of causal variants and the generation of testable hypotheses for biological mechanisms driving complex traits., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Mobile genetic elements (MEs) are heritable mutagens that recursively generate structural variants (SVs). ME variants (MEVs) are difficult to genotype and integrate in statistical genetics, obscuring their impact on genome diversification and traits. We developed a tool that accurately genotypes MEVs using short-read whole-genome sequencing (WGS) and applied it to global human populations. We find unexpected population-specific MEV differences, including an Alu insertion distribution distinguishing Japanese from other populations. Integrating MEVs with expression quantitative trait loci (eQTL) maps shows that MEV classes regulate tissue-specific gene expression by shared mechanisms, including creating or attenuating enhancers and recruiting post-transcriptional regulators, supporting class-wide interpretability. MEVs more often associate with gene expression changes than SNVs, thus plausibly impacting traits. Performing genome-wide association study (GWAS) with MEVs pinpoints potential causes of disease risk, including a LINE-1 insertion associated with keloid and fasciitis. This work implicates MEVs as drivers of human divergence and disease risk., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: The introduction of biologic therapies and a treat-to-target approach has transformed the management of rheumatoid arthritis (RA), which has led to improved outcomes for women with RA who wish to become pregnant. However, guidelines for the management of reproductive health in female patients with RA are still lacking., Areas Covered: A task force (Women of Childbearing Age [WoCBA]-Rheumatoid Arthritis in Japan) comprising 10 experts in the fields of rheumatology, obstetrics and orthopedic surgery developed 10 clinical questions (CQ) related to the management of WoCBA with RA. For each CQ, a systematic literature review was conducted to identify relevant evidence. Based on this evidence, a set of recommendations for each CQ were drafted and evaluated using the modified Delphi method. This article describes the agreed recommendations along with the supporting evidence., Expert Opinion: There are many ongoing challenges associated with the provision of reproductive healthcare in WoCBA with RA. It is hoped that the consensus-based recommendations provided here can be implemented in clinical practice in order to increase collaboration between rheumatologists and obstetricians/gynecologists and to improve reproductive health outcomes for WoCBA with RA.

Background: Patients presenting with inoperable colon cancer at first onset (ICF) or at time of relapse (ICR) are considered in unrecoverable. The therapeutic goal for unrecoverable cancer is to prolong overall survival (OS) and maintain a high quality of life (QOL). As data on objective indicators of QOL in cancer patients, such as length of hospitalisation (LOH), outpatient consultation times (OCT), and hospital-free survival (HFS), is limited, this study compared ICF and ICR with respect to OS and QOL over the entire clinical course., Methods: We retrospectively evaluated 90 inoperable colon cancer patients with chemotherapy and compared ICF and ICR in terms of OS, LOH, OCT, and HFS., Results: Patients with ICF had a worse OS than those with ICR. In patients with ICF and ICR, OS and LOH were not correlated but OS and OCT and OS and HFS were strongly correlated. In patients with ICF and ICR, OCT and HFS accounted for approximately 8% and 90% of their OS, respectively., Conclusions: The LOH, OCT, and HFS are important factors for evaluating objective QOL of patients with inoperable colon cancer and should be considered when making treatment decisions., (© 2023. The Author(s).)

Adult T-cell leukemia (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). Microsatellite instability (MSI) has been observed in ATL cells. Although MSI results from impaired mismatch repair (MMR) pathway, no null mutations in the genes encoding MMR factors are detectable in ATL cells. Thus, it is unclear whether or not impairment of MMR causes the MSI in ATL cells. HTLV-1 bZIP factor (HBZ) protein interacts with numerous host transcription factors and significantly contributes to disease pathogenesis and progression. Here we investigated the effect of HBZ on MMR in normal cells. The ectopic expression of HBZ in MMR-proficient cells induced MSI, and also suppressed the expression of several MMR factors. We then hypothesized that the HBZ compromises MMR by interfering with a transcription factor, nuclear respiratory factor 1 (NRF-1), and identified the consensus NRF-1 binding site at the promoter of the gene encoding MutS homologue 2 (MSH2), an essential MMR factor. The luciferase reporter assay revealed that NRF-1 overexpression enhanced MSH2 promoter activity, while co-expression of HBZ reversed this enhancement. These results supported the idea that HBZ suppresses the transcription of MSH2 by inhibiting NRF-1. Our data demonstrate that HBZ causes impaired MMR, and may imply a novel oncogenesis driven by HTLV-1., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masao Matsuoka reports a relationship with Kyowa Kirin Co Ltd that includes: speaking and lecture fees. Masao Matsuoka reports a relationship with Meiji Seika Pharma Co Ltd that includes: speaking and lecture fees. Masao Matsuoka reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Masao Matsuoka reports a relationship with Chugai Pharmaceutical Co Ltd that includes: speaking and lecture fees. Akifumi Takaori-Kondo reports a relationship with Ono Pharmaceutical Co Ltd that includes: funding grants., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Little is known about the biweekly combined use of cetuximab and chemotherapy as second-line treatment of metastatic colorectal cancer (mCRC). Recently, DNA methylation status has been reported to be a new possible predictor of the efficacy from the anti-epidermal growth factor receptor (EGFR) antibody treatment. The purpose of this study was to examine the efficacy and safety of biweekly cetuximab plus mFOLFOX6 or mFOLFIRI as a second-line treatment for KRAS exon 2 wild-type mCRC. We also investigated the predictability of DNA methylation status on the efficacy of the EGFR antibody-containing treatment., Methods: Patients who were refractory or intolerant to the first-line chemotherapy were enrolled and received biweekly cetuximab plus mFOLFOX6 or mFOLFIRI. The primary endpoint was progression-free survival (PFS). Tumor evaluations were performed every 2 months using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Adverse events (AEs) were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. DNA methylation status of colorectal cancer cells was defined by a modified MethyLight assay., Results: Sixty-six cases were enrolled. The median PFS (mPFS) was 5.1 [95% confidence interval (CI), 3.8-7.6] months. The median overall survival (mOS) was 12.7 (95% CI, 7.5-15.3) months. Grade 3 or higher neutropenia occurred in 53.0% of patients, whereas skin disorders with a grade 3 or higher occurred in <15% of patients. In multivariate analysis, DNA methylation status could not be an independent predictor of PFS [hazard ratio (HR), 1.43; P=0.39] and OS (HR, 2.13; P=0.086). However, in RAS/BRAF wild-type patients, the mPFS and mOS in the low-methylated colorectal cancer (LMCC) group was numerically better than those in the highly-methylated colorectal cancer (HMCC) group, although the difference was not statistically significant [mPFS: 8.5 (95% CI, 6.1-10.9) vs. 3.3 (95% CI, 1.2-not reached) months, P=0.79; ΔmPFS, 5.2 months; mOS: 15.3 (95% CI, 11.9-23.5) vs. 6.5 (95% CI, 3.1-not reached) months, P=0.53; ΔmOS, 8.8 months]., Conclusions: Biweekly cetuximab plus mFOLFOX6 or mFOLFIRI is a useful second-line therapy for mCRC. DNA methylation status warrants further exploration as a predictive biomarker for anti-EGFR efficacy in mCRC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-862/coif). ST reports personal fees from Taiho, Chugai, Asahi Kasei, Bristol-Myers Squibb, Bayer, Japan blood products organization, Medicon, Takeda, Yakult, and Daiichi-Sankyo, Eli Lilly, Eisai, and grants and personal fees from Merck Biopharma and Ono, outside the submitted work. TM reports a grant from Repertoire Genesis and stock in Ono Pharmaceutical Co., Ltd. and Japan Post. Masanobu Takahashi reports personal fees from Daiichi-Sankyo, Bristol-Myers Squibb, and grants and personal fees from Chugai and Ono. HO reports personal fees from Yakult, Merck Biopharma, and Kyowa Kirin. Masahiro Takahashi reports grants from Ono and Incyte Bioscience. TY reports personal fees Nipro and grants from AC Medical, A2 Healthcare, EP Croit, ClinChoice, Japan Tabacco, Japan Media, Medidata Solutions, Ono, Kyowa Kirin, Tsumura, Daiichi-Sankyo, Otsuka, Eisai, Asahi Intec, 3H Clinical Trial, Medrio, Nipro, Intellim, Welby, 3H Medi Solution, Baseconnect, Nobori, Puravida Technologies, and Hemp Kitchen, and consulting fees from EP Croit, Japan Tabacco, Medidata Solutions, Ono, Kowa, Chugai, Tsumura, Daiichi-Sankyo, Eisai, Asahi Intec Asahi Kasei Pharma, 3H Clinical Trial, Intellim, Takeda, AstraZeneca, Sonire Therapeutics, and Seikagaku, and participates on a data safety monitoring board of Incyte Biosciences. CI reports grants from Shionogi, Nippon Kayaku, Eisai, Sanofi, Taiho, Chugai, Kyowa Kirin, Asahi Kasei Pharma, Daiichi-Sankyo, Eli Lilly, Yakult, Ono, Takeda, Tsumura, and Bayer, and honoraria from Chugai. The other authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

The paired-like homeobox transcription factor LEUTX is expressed in human preimplantation embryos between the 4- and 8-cell stages, and then silenced in somatic tissues. To characterize the function of LEUTX, we performed a multiomic characterization of LEUTX using two proteomics methods and three genome-wide sequencing approaches. Our results show that LEUTX stably interacts with the EP300 and CBP histone acetyltransferases through its 9 amino acid transactivation domain (9aaTAD), as mutation of this domain abolishes the interactions. LEUTX targets genomic cis-regulatory sequences that overlap with repetitive elements, and through these elements it is suggested to regulate the expression of its downstream genes. We find LEUTX to be a transcriptional activator, upregulating several genes linked to preimplantation development as well as 8-cell-like markers, such as DPPA3 and ZNF280A. Our results support a role for LEUTX in preimplantation development as an enhancer binding protein and as a potent transcriptional activator., Competing Interests: Y.M. is an inventor on a patent related to NET-CAGE technology. Other authors declare no competing interest., (© 2023 The Authors.)

ATM gene mutation carriers are predisposed to estrogen-receptor-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis after ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. After estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes, including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis., Competing Interests: Declaration of interests The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

X-ray microscopes adopting computed tomography enable nondestructive 3D visualization of biological specimens at micron-level resolution without conventional 2D serial sectioning that is a destructive/laborious method and is routinely used for analyzing renal biopsy in clinical diagnosis of kidney diseases. Here we applied a compact commercial system of laboratory-based X-ray microscope to observe a resin-embedded osmium-stained 1-mm strip of a mouse kidney piece as a model of renal biopsy, toward a more efficient diagnosis of kidney diseases. A reconstructed computed tomography image from several hours of data collection using CCD detector allowed us to unambiguously segment a single nephron connected to a renal corpuscle, which was consistent with previous reports using serial sectioning. Histogram analysis on the segmented nephron confirmed that the proximal and distal tubules were distinguishable on the basis of their X-ray opacities. A 3D rendering model of the segmented nephron visualized a convoluted structure of renal tubules neighboring the renal corpuscle and a branched structure of efferent arterioles. Furthermore, another data collection using scientific complementary metal-oxide semiconductor detector with a much shorter data acquisition time of 15 min provided similar results from the same samples. These results suggest a potential application of the compact laboratory-based X-ray microscope to analyze mouse renal biopsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Society of Microscopy.)

Objectives: To evaluate the effectiveness and safety of abatacept over 52 weeks in biologic-naïve rheumatoid arthritis (RA) patients with moderate disease activity in the prospective, 5-year, observational study (ORIGAMI study) in Japan., Methods: Abatacept (125 mg) was administered subcutaneously once a week. Clinical outcomes included Simplified Disease Activity Index (SDAI) remission at Week 52 (primary endpoint), Japanese Health Assessment Questionnaire (J-HAQ), EuroQol 5-Dimension Questionnaire (EQ-5D), treatment retention, and safety. The results were compared with those of conventional synthetic disease-modifying antirheumatic drug (csDMARD) controls from the ongoing Institute of Rheumatology, Rheumatoid Arthritis (IORRA) registry., Results: Overall, 325 patients were enrolled, with a mean age of 66.9 ± 12.7 years. The proportion of patients achieving SDAI remission (≤3.3) at Week 52 was 18.9% (95% CI: 14.3-23.6) and low disease activity (≤11) was 53.3% (95% CI: 47.4-59.1). A significant improvement was observed in J-HAQ and EQ-5D over 52 weeks in both the abatacept and csDMARD groups. The probability of abatacept treatment retention at Week 52 was 69.9% (95% CI: 64.7-75.5). Adverse events and serious adverse events were reported in 50.0% and 12.1% of patients, respectively., Conclusions: Abatacept significantly improved disease activity, physical disability, and quality of life for up to 52 weeks in RA patients in a real-world setting., (© Japan College of Rheumatology 2021. Published by Oxford University Press.)

Objective: The present study was designed to investigate the whole transcriptome of periodontal tissues of both young and aged mice to identify the characteristic up-regulation of protease genes with aging and to localize their translated protein products in the periodontal tissues., Background: The metzincin protease superfamily is composed of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs. Up-regulation of these extracellular matrix-degrading proteases has been implicated in senescence of tissues and organs, including the skin. However, few studies have investigated the expression profiles of these proteases and potential involvement in aging of periodontal tissues., Methods: Periodontal tissues with the surrounding mandibular bones were collected from 50- and 10-week-old mice. Total RNA was extracted from the periodontal tissue and analyzed by cap analysis of gene expression (CAGE) to identify differentially expressed genes encoding the metzincin proteases. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the CAGE results, and the phenotypic expression of proteases involved in aging was localized via immunohistochemical analysis., Results: The CAGE results showed that the expression levels of MMP-3, -10, and -12 were up-regulated at 50 weeks. Subsequent qRT-PCR analysis showed that the gene expression levels of MMP-3 and -10 were significantly increased with age. MMP-10 immunoreactivity was localized exclusively in the cementum and alveolar bone adjacent to the periodontal ligament and was stronger and broader in aged mice than young mice. MMP-3 immunoreactivity was localized in the periodontal ligaments at both 10 and 50 weeks., Conclusion: In the present study, we demonstrated that the expression of MMP-3 and -10 increased with aging and identified their characteristic localizations in aged periodontal tissues., (© 2022 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd.)

Background: To determine the rate of undiagnosed atrial fibrillation (AF) we screened for AF using an oscillometric blood pressure (BP) monitor device followed by a single-lead handheld electrocardiogram (ECG), with confirmation by 12-lead ECG as the reference standard., Methods and results: From October 2017 to August 2019, 1,148 patients were enrolled without known AF, who were aged ≥65 years with moderate-to-high stroke risk, at 71 centers in Japan. After exclusion of 7 patients with confirmed AF at the index visit, 1,141 patients were asked to use an oscillometric BP monitor twice daily for 2 weeks (max: 4 weeks) to detect an irregular pulse. The BP monitor detected an irregular pulse in 481 patients, of which 1 patient had confirmed AF. Thereafter, 480 patients were instructed to acquire ECGs twice daily for an additional 2 weeks (max: 4 weeks) using a single-lead handheld ECG device. The handheld ECG device detected irregular rhythm in 41 patients, of which 1 patient had confirmed AF. In total, undiagnosed AF was confirmed in 9 (0.8%) patients of the overall study cohort during the 24-week follow-up period., Conclusions: Sequential use of a BP monitor and handheld ECG for 4 weeks is a practical strategy for identifying undiagnosed AF in Japanese people at heightened risk of stroke.

The genetic regulation of ovarian development remains largely unclear. Indeed, in most cases of impaired ovarian development-such as 46,XX disorders of sex development (DSD) without SRY, and premature ovarian insufficiency (POI)-the genetic causes have not been identified, and the vast majority of disease-associated sequence variants could lie within non-coding regulatory sequences. In this study, we aimed to identify enhancers of five ovarian genes known to play key roles in early ovarian development, basing our analysis on the expression of enhancer derived transcripts (eRNAs), which are considered to characterize active enhancers. Temporal expression profile changes in mouse WT1-positive ovarian cells were obtained from cap analysis of gene expression at E13.5, E16.5 and P0. We compared the chronological expression profiles of ovarian-specific eRNA with expression profiles for each of the ovarian-specific genes, yielding two candidate sequences for enhancers of Wnt4 and Rspo1. Both sequences are conserved between mouse and human, and we confirmed their enhancer activities using transient expression assays in murine granulosa cells. Furthermore, by sequencing the region in patients with impaired ovarian development in 24 patients, such as POI, gonadal dysgenesis and 46,XX DSD, we identified rare single nucleotide variants in both sequences. Our results demonstrate that combined analysis of the temporal expression profiles of eRNA and mRNA of target genes presents a powerful tool for locating cis-element enhancers, and a means of identifying disease-associated sequence variants that lie within non-coding regulatory sequences, thus advancing an important unmet need in forward human genetics., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Germ cells are unique in engendering totipotency, yet the mechanisms underlying this capacity remain elusive. Here, we perform comprehensive and in-depth nucleome analysis of mouse germ-cell development in vitro, encompassing pluripotent precursors, primordial germ cells (PGCs) before and after epigenetic reprogramming, and spermatogonia/spermatogonial stem cells (SSCs). Although epigenetic reprogramming, including genome-wide DNA de-methylation, creates broadly open chromatin with abundant enhancer-like signatures, the augmented chromatin insulation safeguards transcriptional fidelity. These insulatory constraints are then erased en masse for spermatogonial development. Notably, despite distinguishing epigenetic programming, including global DNA re-methylation, the PGCs-to-spermatogonia/SSCs development entails further euchromatization. This accompanies substantial erasure of lamina-associated domains, generating spermatogonia/SSCs with a minimal peripheral attachment of chromatin except for pericentromeres-an architecture conserved in primates. Accordingly, faulty nucleome maturation, including persistent insulation and improper euchromatization, leads to impaired spermatogenic potential. Given that PGCs after epigenetic reprogramming serve as oogenic progenitors as well, our findings elucidate a principle for the nucleome programming that creates gametogenic progenitors in both sexes, defining a basis for nuclear totipotency., (© 2022 The Authors.)

Crush syndrome (CS) is a potentially lethal condition characterized by muscle cell damage resulting from decompression following compression. Patients with CS can develop cardiac failure, kidney dysfunction, shock, systemic inflammation and sepsis. Salvianolic acid B (SalB) has cardiac and kidney protective effects and anti-oxidative, anti-inflammatory, anti-apoptotic and anti-bacterial properties. The present study aimed to demonstrate the survival benefit of SalB in the CS rat model, which comprised anesthetized rats with bilateral hindlimb compression by a rubber tourniquet for 5 h. The rats examined were randomly divided into four groups: i) Sham; ii) sham treated with SalB; iii) CS rat model without treatment; and iv) CS rat model treated with SalB. Under continuous monitoring and recording of arterial blood pressures, blood and tissue samples were collected for biochemical analyses at designated timepoints before and after reperfusion. SalB administration improved the survival rate, kidney function (by treating shock and metabolic acidosis) and inflammation (by reducing mitochondrial dysfunction and endothelial damage). Reduced incidence of cardiac failure due to hyperkalemia was associated with reduced muscle injury via the prevention of mitochondrial dysfunction. Additionally, indirect antibacterial action by the neutrophil extracellular trap system (NETs) was observed. SalB administration to the CS rat model led to a substantial improvement in survival following CS by decreasing kidney and cardiac dysfunctions, inflammation, and endothelial dysfunction by improving the mitochondrial function and through antibacterial effects via NETs., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Background/aim: This phase II study assessed the efficacy of capecitabine plus cisplatin in patients with advanced gastric cancer refractory to adjuvant S-1., Patients and Methods: This single-arm, open-label, multicenter, phase II study was conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE) in Japan. Patients aged ≥20 years with advanced HER2-negative gastric cancer that was refractory to S-1 were enrolled. Patients received 80 mg/m 2 cisplatin on day 1 intravenously and 1,000 mg/m 2 capecitabine twice daily from day 1 to day 14, in 3-week cycles. The primary endpoint was progression-free survival (PFS). The threshold overall response rate (ORR) was estimated to be 15%. The secondary endpoints were overall survival (OS), time to treatment failure, ORR, and toxicities., Results: In total, 21 patients were enrolled from seven hospitals. The median patient age was 63 years. Nineteen patients received the protocol treatment. Median PFS was 3.7 months [90% confidence interval (CI)=2.7-5.6 months], which did not reach the predefined threshold of 4.0 months. ORR was 5.9% (95%CI=0.0-17.1%). Median OS was 11.9 months (95% CI 6.3-19.4 months). Febrile neutropenia was observed in 5.3% of patients. The most frequently observed grade 3 non-hematologic toxicities were nausea (15.8%) and hyponatremia (15.8%)., Conclusion: The addition of a fluoropyrimidine to a platinum agent after adjuvant therapy is not suitable for gastric cancer., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Double homeobox 4 ( DUX4 ) is expressed at the early pre-implantation stage in human embryos. Here we show that induced human DUX4 expression substantially alters the chromatin accessibility of non-coding DNA and activates thousands of newly identified transcribed enhancer-like regions, preferentially located within ERVL-MaLR repeat elements. CRISPR activation of transcribed enhancers by C-terminal DUX4 motifs results in the increased expression of target embryonic genome activation (EGA) genes ZSCAN4 and KHDC1P1 . We show that DUX4 is markedly enriched in human zygotes, followed by intense nuclear DUX4 localization preceding and coinciding with minor EGA. DUX4 knockdown in human zygotes led to changes in the EGA transcriptome but did not terminate the embryos. We also show that the DUX4 protein interacts with the Mediator complex via the C-terminal KIX binding motif. Our findings contribute to the understanding of DUX4 as a regulator of the non-coding genome., Competing Interests: Y.T. and A.K. are employees of K.K.DNAFORM. Y. T. and Y. M. are inventors on a patent related to NET-CAGE technology., (© 2022 The Authors.)

Background: To evaluate the impact of three risk factors (age [≥75 years], renal impairment [creatinine clearance <50 ml/min], and low body weight [≤50 kg]) on the risk of any bleeding events, all-cause mortality, and stroke, non-central nervous system (non-CNS) systemic embolism (SE), and myocardial infarction (MI) in patients with nonvalvular atrial fibrillation (NVAF) treated with rivaroxaban in a real-world clinical setting., Methods: The Xarelto Post-Authorization Safety and Effectiveness Study in Japanese Patients with Atrial Fibrillation (XAPASS) is a prospective, single-arm, observational study. Enrolled patients were divided into four subgroups by the number of risk factors., Results: Overall, 9823 patients were included: 4299 with low risk, 2816 with moderate risk, 1574 with high risk, and 1134 with very high risk. The hazard ratios (95% confidence interval) (reference: low risk) for the moderate-, high-, and very-high-risk groups were 1.62 (1.19, 2.21) ( p  = 0.002), 2.15 (1.47, 3.15) ( p  < 0.001), and 2.49 (1.60, 3.87) ( p  <0.001) for major bleeding, and 1.98 (1.47, 2.66), 2.29 (1.59, 3.29), and 2.74 (1.81, 4.16) ( p  <0.001 for all) for stroke/non-CNS SE/MI, respectively., Conclusions: Age ≥75 years and renal impairment, but not low body weight, were determinants for major bleeding. The accrual of three risk factors was associated with increased risk for major bleeding and stroke/non-CNS SE/MI in patients with NVAF receiving rivaroxaban; there was no increase in the cumulative risk for these with an increasing number of risk factors., Competing Interests: T. Ikeda, S. Ogawa, T. Kitazono, J. Nakagawara, K. Minematsu, S. Miyamoto, and Y. Murakawa were advisory board members for Bayer Yakuhin. T. Ikeda received research grants from Daiichi Sankyo, Medtronic, and Japan Lifeline, and lecture fees from Bayer Yakuhin, Bristol Myers Squibb, Ono, and Toa Eiyo. T. Kitazono received a research grant from Bayer Yakuhin. J. Nakagawara received a research grant from Nihon Medi‐Physics. K. Minematsu received lecture fees from Astellas, AstraZeneca, Bayer Yakuhin, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Japan Stryker, Kowa, Mitsubishi Tanabe, Nihon Medi‐Physics, Nippon Chemiphar, Otsuka, Pfizer, Sawai, and Sumitomo Dainippon, and was an advisory board member for CSL Behring and Medico's Hirata. S. Miyamoto received research grants from Astellas, Brainlab, Bristol Myers Squibb, Carl Zeiss Meditec, Chugai, CSL Behring, Daiichi Sankyo, Eisai, Medtronic, Meiji Seika, Mitsubishi Tanabe, Mizuho, Merck & Co., Pfizer, Nihon Medi‐Physics, Otsuka, Philips Electronics Japan, Sanofi, Siemens Healthcare, and Takeda. Y. Murakawa received research grants from Bayer Yakuhin, Boehringer Ingelheim, and Daiichi Sankyo, and lecture fees from Bayer Yakuhin, Boehringer Ingelheim, Bristol Myers Squibb, and Daiichi Sankyo. M. Tachiiri, Y. Okayama, T. Sunaya, K. Hirano, and T. Hayasaki are employees of Bayer Yakuhin., (© 2022 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

A 41-year-old woman presented with spinal cord infarction and paraplegia after acute thoracoabdominal aortic dissection. Clinical evaluation revealed the American Spinal Injury Association (ASIA) lower limb exercise score of 0 points and the Functional Assessment for Control of Trunk (FACT) score of 0 points. Conventional physical therapy for 60 days did not significantly improve the paraplegia or FACT score; therefore, belt electrode skeletal muscle electrical stimulation (B-SES) and virtual reality (VR)-guided sitting balance training were introduced for 30 days. She developed independence for all basic movements and her gait was restored using short leg braces and Lofstrand crutches. At discharge, her ASIA lower limb exercise score was 24 and FACT score was 7, with a functional impedance measure motor item of 57, and she could continuously walk for a distance of 150 m. The combination of B-SES and VR-guided balance training may be a feasible therapeutic option after spinal cord infarction., Competing Interests: Competing interests: Yuichiro Murakawa is an employee of mediVR, Inc., a company that holds several patents on VR-guided rehabilitation. Ai Michibata, Miyoko Haraguchi and Hideo Ishikawa have no conflicts of interest to declare., (© BMJ Publishing Group Limited 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)