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We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

DOI： 10.1080/25785826.2024.2430812

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/qjmed/hcae215

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

In systemic lupus erythematosus (SLE) loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here, we set out to dissect layers and hierarchies of autoimmune kidney inflammation in order to identify tissue-specific cellular hubs that amplify auto-inflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blocking and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILC) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signaling in a distinct subset of ILC1 instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILC promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody mNCR1.152) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data support that NKp46+ ILC1 promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1 thus constitutes a previously unrecognized, critical tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies.

DOI： 10.1038/s41586-024-07907-x

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BACKGROUND: The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart. METHODS: Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species. RESULTS: We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. Esm1-lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism. CONCLUSIONS: A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.s.

DOI： 10.1161/CIRCRESAHA.124.324868

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Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.

DOI： 10.1016/j.clim.2024.110255

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Authorship：Corresponding author   Language：English  

DOI： 10.1111/1756-185X.15206

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DOI： 10.55563/clinexprheumatol/std9t8

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DOI： 10.1111/1440-1681.13840

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DOI： 10.1093/rheumatology/kead421

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DOI： 10.1111/1756-185X.15083

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A 27-year-old man presented with quotidian fever, rash, knee arthralgia, sore throat, and bloody diarrhea. Laboratory findings showed neutrophilia, elevated CRP, ferritin, and liver enzyme levels, and decreased hemoglobin levels. Radiological investigations revealed splenomegaly, systemic lymphadenopathy, thickening of the descending colon wall, and an abnormal uptake in the bone marrow and spleen as seen in F-fluorodeoxyglucose positron emission tomography. Malignant lymphoma was initially suspected, but biopsies showed no malignant findings. Colonoscopy revealed mucosal friability, erosions, and shallow ulcers, and pathological findings included crypt abscesses suggestive of either acute infectious colitis or inflammatory bowel disease. The patient was eventually diagnosed with adult-onset Still's disease (AOSD) and started on prednisolone, which resolved bloody diarrhea, leading to the diagnosis of comorbid ulcerative colitis (UC). The combination of AOSD and UC presents a diagnostic challenge due to overlapping symptoms. An accurate diagnosis requires careful exclusion of other diseases and a comprehensive assessment.

DOI： 10.31662/jmaj.2023-0103

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/1756-185X.15029

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Dexmedetomidine (DEX), a highly selective alpha2-adrenoceptors agonist, is not only a sedative drug used during mechanical ventilation in the intensive care unit but also a cardio-protective drug against ischemia-reperfusion injury (IRI). Numerous preclinical in vivo and ex vivo studies, mostly evaluating the effect of DEX pretreatment in healthy rodents, have shown the efficacy of DEX in protecting the hearts from IRI. However, whether DEX can maintain its cardio-protective effect in hearts with comorbidities such as diabetes has not been fully elucidated. Multiple clinical trials have reported promising results, showing that pretreatment with DEX can attenuate cardiac damage in patients undergoing cardiac surgery. However, evidence of the post-treatment effects of DEX in clinical practice remains limited. In this narrative review, we summarize the previously reported evidence of DEX-induced cardio-protection against IRI and clarify the condition of the hearts and the timing of DEX administration that has not been tested. With further investigations evaluating these knowledge gaps, the use of DEX as a cardio-protective drug could be further facilitated in the management of patients undergoing cardiac surgery and might be considered in a broader area of clinical settings beyond cardiac surgery, including patients with acute myocardial infarction.

DOI： 10.1007/s00540-023-03261-w

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Acute kidney injury (AKI) is a common and severe complication of the coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly affects the glomerular and tubular epithelial cells to induce AKI; however, its pathophysiology remains unclear. Here, we explored the underlying mechanisms and therapeutic targets of renal involvement in COVID-19. We developed an in vitro human kidney cellular model, including immortalized tubular epithelial and endothelial cell lines, demonstrating that SARS-CoV-2 directly triggers cell death. To identify the molecular targets in the process of SARS-CoV-2-mediated cell injury, we performed transcriptional analysis using RNA sequencing. Tubular epithelial cells were more prone to dying by SARS-CoV-2 than endothelial cells; however, SARS-CoV-2 did not replicate in renal cells, distinct from VeroE6/transmembrane protease serine 2 cells. Transcriptomic analysis revealed increased inflammatory and immune-related gene expression levels in renal cells incubated with SARS-CoV-2. Toll-like receptor (TLR) 3 in renal cells recognized viral RNA and underwent cell death. Furthermore, analysis of upstream regulators identified several key transcriptional regulators. Among them, inhibition of the interleukin-1 receptor (IL-1R) and TLR4 pathways protects tubular epithelial and endothelial cells from injury via regulation of the signal transducer and activator of transcription protein-3/nuclear factor-kB pathway. Our results reveal that SARS-CoV-2 directly injures renal cells via the proinflammatory response without viral replication, and that IL-1R and TLR4 may be used as therapeutic targets for SARS-CoV-2 mediated kidney injury.

DOI： 10.1038/s41420-023-01584-x

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Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed pro-inflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase (MPO)-ANCA titers with a reduction in NETs formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.

DOI： 10.1172/jci.insight.167486

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DOI： 10.1002/art.42443

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DOI： 10.1093/qjmed/hcad157

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DOI： 10.1093/cercor/bhad120

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DOI： 10.3899/jrheum.220649

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Dupilumab (DUP) is a monoclonal antibody that acts on the interleukin (IL)-4 receptor alpha, which inhibits IL-4 and IL-13 signalling and is approved for type 2 inflammatory diseases such as asthma, chronic rhinosinusitis with nasal polyposis and atopic dermatitis; however, the efficacy of DUP to IgG4-related disease (IgG4-RD) is under discussion due to the controversial outcomes based on the several case reports. Here, we reviewed the efficacy of DUP in four consecutive patients with IgG4-RD in our institute and the previous literature.All patients administered DUP fulfilled the 2019 ACR/EULAR classification criteria for IgG4-RD complicated with severe asthma and chronic rhinosinusitis with nasal polyposis. Two cases were administered DUP without systemic glucocorticoids (GCs), and in 6 months, the volume of swollen submandibular glands (SMGs) was reduced by approximately 70%. Two cases receiving GCs successfully reduced their daily dose of GCs (10 and 50% reduction, respectively) with dupilumab in 6 months. In all four cases, serum IgG4 concentration and IgG4-RD responder index decreased in 6 months.DUP reduced the volume of the swollen SMGs, serum IgG4 levels, responder index and the daily dose of GCs in patients with IgG4-RD with severe asthma or eosinophilic rhinosinusitis in 6 months.The efficacy of DUP to IgG4-RD is under discussion due to the limited case reports with controversial outcomes. Here, we demonstrated that two patients with IgG4-RD treated by DUP without systemic GCs, showed volume reduction of swollen SMGs and two cases showed GC-sparing effects by DUP. DUP can ameliorate the disease activity and be a steroid-sparing agent in patients with IgG4-RD.

DOI： 10.1136/rmdopen-2023-003026

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OBJECTIVES: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multi-organ dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30~40% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue-resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. Herein, we explored new therapeutic targets for NPSLE focusing on microglia. METHODS: RNA sequencing of microglia in MRL/lpr, lupus-prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified and its role on microglial activation and phagocytosis was investigated using specific inhibitors and siRNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL/lpr was also evaluated. RESULTS: Transcriptome analysis revealed the upregulation of Ikbke, which encodes the inhibitor of nuclear factor kappa-B kinase epsilon (IKBKE) in both microglia from MRL/lpr mice and cytokine-stimulated microglia in vitro. Intracerebroventricular administration of an IKBKE inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lpr mice. Mechanistically, IKBKE inhibition reduced glycolysis, which dampened microglial activation and phagocytosis. CONCLUSIONS: These findings suggest that IKBKE plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.

DOI： 10.1002/art.42352

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.

Other Link： https://www.nature.com/articles/s41467-023-36594-x

DOI： 10.1038/s41467-023-36594-x

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A 67-year-old woman with a 5-year history of recurrent swollen eyelids and epistaxis, diagnosed as immunoglobulin4-related diseases (IgG4-RD) based on hyper-IgG4-emia and IgG4-positive cell infiltration to the lesion, was referred to our department due to recurrent symptoms despite corticosteroid therapies. Computed tomography revealed an osteoclastic sinus mass with prominent neutrophil infiltration and necrosis that was incompatible with IgG4-RD histopathologically. Finally, she was diagnosed with a tumefactive fibroinflammatory lesion (TFIL) of the head and neck and treated with high-dose corticosteroids. Physicians should remember that TFIL can mimic IgG4-RD in the head and neck region with prominent neutrophil infiltration and necrosis.

DOI： 10.2169/internalmedicine.9760-22

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Severe coronavirus disease 2019 (COVID-19) is characterized by acute respiratory distress syndrome and multiple organ dysfunction, in which the host immune response plays a pivotal role. Excessive neutrophil activation and subsequent superfluity of neutrophil extracellular traps (NETs) can lead to tissue damage, and several studies have shown the involvement of neutrophils in severe COVID-19. However, the detailed responses of each neutrophil subset to SARS-CoV-2 infection has not been fully described. To explore this issue, we incubated normal-density granulocytes (NDGs) and low-density granulocytes (LDGs) with different viral titers of SARS-CoV-2. NDGs form NETs with chromatin fibers in response to SARS-CoV-2, whereas LDGs incubated with SARS-CoV-2 display a distinct morphology with condensed nuclei and moderate transcriptional changes. Based on these transcriptional changes, we suggest that AGO2 possibly plays a role in LDG regulation in response to SARS-CoV-2.

DOI： 10.1002/2211-5463.13500

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OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis where ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial necrosis occurs. Cyclophilin D (CypD) plays an important role in mediating cell necrosis and inflammation via opening of mitochondrial permeability transition pores (mPTP). Here, we examined the role of CypD in AAV pathogenesis. METHODS: In vitro, the role and mechanism of CypD in ANCA-stimulated neutrophils were assessed by immunostaining and electron microscopy. A comprehensive RNA sequencing analysis was performed on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, an-anti-MPO IgG-transfer AAV model or spontaneous AAV model mice were induced in CypD knockout or wild-type mice. RESULTS: In vitro, pharmacological and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species/cytochrome c release from the mitochondria. The analysis of RNA sequencing in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, and CypD deficiency reduced ANCA-induced alterations in gene expression. Furthermore, the upstream regulator analysis revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that CypD-dependent mPTP opening is associated with ANCA-induced neutrophil activation and NETosis. In both AAV models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSIONS: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.

DOI： 10.1002/art.42314

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Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by the infiltration of IgG4-positive plasma cells and fibrosis in organs throughout the body. IgG4-RD involvement in the gastrointestinal (GI) tract (IgG4-related GI disease; IgG4-GID) is rare, and the disease concept remains unclear. Generally, IgG4-GID has been reported with morphological changes, including ulcers, strictures, and submucosal tumors. Here, we report a case of IgG4-GID with persistent diarrhea and abdominal pain in which typical endoscopic findings were absent. This case suggests the unidentified clinical features of IgG4-GID.

DOI： 10.1016/j.gastha.2023.07.009

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DOI： 10.1101/2022.12.20.517740

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BACKGROUND: Tubarial glands (TGs) are a collection of unidentified salivary glands overlying the torus tubarius in the nasopharyngeal wall. Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibroinflammatory state that often has multiple organ involvement. Involvement of the head and neck, especially the salivary glands, is common in IgG4-RD. AIMS/OBJECTIVES: This study aimed to elucidate the clinical significance of TGs in IgG4-RD. MATERIALS AND METHODS: We investigated the local findings of TGs in ten patients with IgG4-RD. RESULTS: Nasopharyngeal endoscopic examination revealed oedematous swelling of the nasopharyngeal wall surrounding the TGs, which improved after steroid treatment. Moreover, sonotubometry showed a stenotic pattern in three out of seven patients with IgG4-RD. CONCLUSIONS AND SIGNIFICANCE: TGs may be involved in IgG4-RD. The swollen TGs may be responsible for obstructive Eustachian tube dysfunction. Further studies are required to clarify the clinical significance and physiological roles of TGs in IgG4-RD.

DOI： 10.1080/00016489.2022.2104368

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Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, nonischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single-cell resolution. Together, these data illuminate both shared and distinct cellular and molecular architectures of human heart failure and suggest candidate therapeutic targets.

DOI： 10.1126/science.abo1984

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BACKGROUND: Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI). PATIENTS AND METHODS: Structural and resting-state functional MRI data were acquired from patients with IA, patients with osteoarthritis (OA) and heathy controls (HCs). Two datasets were adopted to derive (51 IA, 56 OA, and 17 HCs) and validate (31 IA) the observations. 33 IA patients in the derivation dataset and all the patients in validation dataset required biological treatment and were clinically evaluated before and after therapy. Via whole-brain pair-wise FC analyses, we analyzed IA-specific FC measures relevant to therapeutic response to biologics. RESULTS: The value of FC between left insular cortex (IC) and anterior cingulate cortex (ACC) was significantly low in IA patients compared with OA patients and HCs. We demonstrated that the FC between left anterior long insular gyrus as a subdivision of IC and ACC was significantly associated with therapeutic response to biologics regarding the improvement of patients' global assessment (PGA) in both derivation and validation datasets. CONCLUSION: Disease-specific resting-state FC provides a means to assess the therapeutic improvement of PGA and would be a clinical decision-making tool with predictability for treatment response in both RA and SpA.

DOI： 10.1016/j.semarthrit.2022.151994

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media {LLC}  

OBJECTIVES: Tubarial glands (TGs) are recently refocused gland tissues localized near the tori tubarius in the nasopharynx and their clinical relevance is not clear yet. IgG4-related disease (IgG4-RD) is a progressive fibrosing condition and salivary glands are well-affected lesions. The aim of the present study is to examine [18F]fluorodeoxyglucose ([18F]FDG) accumulation to the tori tubarius in IgG4-related disease (IgG4-RD). METHODS: 48 patients with IgG4-RD who underwent positron emission tomography (PET) scanning with [18F]FDG were included and semi-quantitative analysis of [18F]FDG accumulation to tori tubarius was performed along with the clinical features and histopathological analysis. RESULTS: Of the 48 patients, abnormal [18F]FDG accumulation (metabolic tumour volume ≥ 1) to tori tubarius was observed in 15 (31.3%), all of whom had lesions in other head and neck glands. IgG4-RD patients with abnormal [18F]FDG accumulation to tori tubarius showed swollen nasopharyngeal walls around tori tubarius and forceps biopsy of the lesion revealed acinar cells and IgG4-positive plasma cells histologically. Abnormal [18F]FDG accumulation (maximum standard uptake value, metabolic tumour volume and total lesion glycolysis) to tori tubarius correlated with higher IgG4 and lower IgA serum concentrations. CONCLUSIONS: Abnormal [18F]FDG accumulation to tori tubarius can be observed in patients with IgG4-RD and the abnormal [18F]FDG accumulation to tori tubarius can be a clue of TG involvement in IgG4-RD.

DOI： 10.1007/s12149-021-01691-8

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Type B insulin resistance syndrome (TBIR) is a rare disease characterized by refractory diabetes due to severe insulin resistance caused by anti-insulin receptor autoantibodies, and a standard treatment regimen for TBIR has not been established, leading to therapeutic difficulties and high mortality. Since TBIR is known to be associated with autoimmune diseases such as systemic lupus erythematosus (SLE), glucocorticoids are often used as key immunosuppressive agents. However, glucocorticoids have the potential to exacerbate the pathophysiology of TBIR by worsening insulin sensitivity, which leads to hyperglycemia and muscle wasting. Here, we report a case history of a 66-year-old man who was diagnosed as having TBIR in combination with SLE and Sjögren's syndrome with marked hyperglycemia, ketosis, and muscle wasting. He was successfully treated with combination therapy of double-filtration plasmapheresis (DFPP) and administration of the anti-CD20 monoclonal antibody rituximab without induction of glucocorticoid therapy while using a sensor-augmented insulin pump (SAP) to prevent hypoglycemia. Remission of diabetes was achieved without severe hypoglycemic events and his circulating insulin receptor antibodies became negative after seven months of initiation of these treatments. Based on the successful clinical courses of this case, our report suggests the possibility of an effective therapeutic regimen with DFPP and rituximab under the condition of the use of an SAP for a patient with TBIR without induction of glucocorticoids.

DOI： 10.3389/fendo.2022.997296

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DOI： 10.1093/qjmed/hcac101

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Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.

DOI： 10.1038/s41586-020-2797-4

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DOI： 10.1101/2020.04.03.024075

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Essentials The mechanism of antiphospholipid antibodies (aPL) production remains unclear. We investigated lymphocyte subset, single nucleotide polymorphisms (SNP), and aPL-producing cells. The increase of circulating plasmablasts was associated with type I interferon upregulation. Our novel ex vivo assay revealed circulating plasmablasts as a major source of aPL. SUMMARY: Background/objective Antiphospholipid antibodies (aPL) are pathogenic autoantibodies in antiphospholipid syndrome (APS). This study aimed to clarify the mechanism of aPL production. Methods T cell and B cell subsets were evaluated in peripheral blood mononuclear cells (PBMCs) of 26 primary APS (PAPS), 19 systemic lupus erythematosus-associated APS (SLE/APS) patients and 10 healthy controls. The SLE-related or APS-related single nucleotide polymorphisms (SNP) were analyzed in those patients. Interferon (IFN) score was calculated based on the mRNA expression of Ly6e, Mx1, IFIT1, and IFIT3 in PBMCs. The PBMCs obtained from APS patients were cultured ex vivo following depletion of CD20 positive or negative B cells and the culture supernatants were applied to aPL measurements. Results In PAPS and SLE/APS patients, Th2, Th17, and plasmablasts were increased while regulatory T, memory B, and regulatory B cells were decreased compared to healthy controls. Genetic analysis revealed that the increase of plasmablasts was more pronounced in patients carrying a risk allele of toll like receptor (TLR) 7 SNP rs3853839. The IFN score was significantly higher in the risk allele carriers. Ex vivo experiments showed that aPL were present in the culture supernatant of PBMCs lacking CD20+CD19+ subset, but not in that of cells lacking CD20-CD19+ subset. Conclusions Our data indicate an important role of plasmablasts in the production of aPL. Furthermore, the increase of plasmablasts was associated with TLR 7 and type I IFN, suggesting a common pathophysiology in SLE and APS. Targeting plasmablasts might be a novel immunological therapeutic approach in the treatment of APS.

DOI： 10.1111/jth.14427

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Gene expression in human tissue has primarily been studied on the transcriptional level, largely neglecting translational regulation. Here, we analyze the translatomes of 80 human hearts to identify new translation events and quantify the effect of translational regulation. We show extensive translational control of cardiac gene expression, which is orchestrated in a process-specific manner. Translation downstream of predicted disease-causing protein-truncating variants appears to be frequent, suggesting inefficient translation termination. We identify hundreds of previously undetected microproteins, expressed from lncRNAs and circRNAs, for which we validate the protein products in vivo. The translation of microproteins is not restricted to the heart and prominent in the translatomes of human kidney and liver. We associate these microproteins with diverse cellular processes and compartments and find that many locate to the mitochondria. Importantly, dozens of microproteins are translated from lncRNAs with well-characterized noncoding functions, indicating previously unrecognized biology.

DOI： 10.1016/j.cell.2019.05.010

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Recurrent pregnancy loss (RPL) is often considered idiopathic, however excessive complement activation has been observed in pregnancy related manifestations. Anti-C1q antibodies (anti-C1q) are associated with the activation of complement pathway in lupus patients, while it remains unclear in RPL. Firstly, we showed that both the prevalence and titre of anti-C1q were significantly higher in unexplained RPL than in healthy parous individuals. Secondly, we established the murine model of anti-C1q induced pregnancy loss using a monoclonal anti-mouse C1q antibody, JL-1. In mice treated with JL-1, high ratio of pregnancy loss and fetal growth restriction were frequently observed and complement activation occurred. C5a receptor (C5aR) blockade cancelled these pathogenic changes in mice treated with JL-1. In conclusion, our study reveals an association between the prevalence of anti-C1q and RPL. Additionally, our murine model has indicated that anti-C1q can induce reproductive failure, which might be ameliorated by therapy targeting the C5-C5aR axis.

DOI： 10.1016/j.clim.2019.04.005

PubMed

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Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：{SAGE} Publications  

DOI： 10.1177/0961203318784654

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

Ichushi

J-GLOBAL

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PubMed

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PubMed

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In patients with systemic lupus erythematosus (SLE), neuropsychiatric (NP) symptoms sometimes occur after administration of corticosteroids, making differential diagnosis between NPSLE and steroid-induced psychosis challenging for clinicians. The aim of this study was to clarify the characteristics of post-steroid NP disease (PSNP) in patients with SLE. Clinical courses of 146 patients with SLE and 162 with other systemic autoimmune diseases, all in the absence of NP manifestations on admission, were retrospectively analyzed. Forty-three NPSLE patients on admission (de novo NPSLE) were also investigated. All patients were consecutively recruited and treated with 40mg/day or more of prednisolone in Hokkaido University Hospital between April 2002 and March 2015. The prevalence of PSNP was strikingly higher in SLE patients than other systemic autoimmune diseases (24.7% vs. 7.4%, OR 4.09, 95% CI 2.04-8.22). As independent risk factors to develop PSNP in SLE patients, past history of mental disorder and the presence of antiphospholipid syndrome were identified using multiple logistic regression analysis. In patients with PSNP-SLE, mood disorder was significantly more frequent than in de novo NPSLE (47.2% vs. 20.9%, OR 3.38, 95% CI 1.26-9.04). Of PSNP-SLE patients, two-thirds were with one or more abnormal findings in cerebrospinal fluid, electroencephalogram, MRI or SPECT. Majority of our PSNP-SLE patients received intensified immunosuppressive treatments and experienced improvement in most cases. PSNP-SLE had better relapse-free survival than de novo NPSLE (p<0.05, log rank test). In conclusion, PSNP frequently occurred in patients with SLE and treated successfully with immunosuppressive therapy, indicating that NPSLE is likely to harbor patients with PSNP-SLE.

DOI： 10.1016/j.autrev.2016.03.017

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Invariant natural killer T (iNKT) cells are a subset of innate-like T cells that act as important mediators of immune responses. In particular, iNKT cells have the ability to immediately produce large amounts of IFN-γ upon activation and thus initiate immune responses in various pathological conditions. However, molecular mechanisms that control IFN-γ production in iNKT cells are not fully understood. Here, we report that basic helix-loop-helix transcription factor family, member e40 (Bhlhe40), is an important regulator for IFN-γ production in iNKT cells. Bhlhe40 is highly expressed in stage 3 thymic iNKT cells and iNKT1 subsets, and the level of Bhlhe40 mRNA expression is correlated with Ifng mRNA expression in the resting state. Although Bhlhe40-deficient mice show normal iNKT cell development, Bhlhe40-deficient iNKT cells show significant impairment of IFN-γ production and antitumor effects. Bhlhe40 alone shows no significant effects on Ifng promoter activities but contributes to enhance T-box transcription factor Tbx21 (T-bet)-mediated Ifng promoter activation. Chromatin immunoprecipitation analysis revealed that Bhlhe40 accumulates in the T-box region of the Ifng locus and contributes to histone H3-lysine 9 acetylation of the Ifng locus, which is impaired without T-bet conditions. These results indicate that Bhlhe40 works as a cofactor of T-bet for enhancing IFN-γ production in iNKT cells.

DOI： 10.1073/pnas.1604178113

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2340/00015555-1706

PubMed

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Authorship：Lead author   Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.102.1461

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Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1365-2133.2011.10696.x

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Authorship：Lead author   Language：Japanese   Publisher：The Japanese Society of Hematology  

DOI： 10.11406/rinketsu.52.118

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Authorship：Lead author   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/j.1365-2133.2008.08983.x

PubMed

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

Ichushi

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Language：Japanese   Publisher：東京 : 日本内科学会  

Other Link:： https://ndlsearch.ndl.go.jp/books/R000000004-I033070838

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本リウマチ学会-北海道・東北支部  

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Language：Japanese   Publisher：(一社)日本リウマチ学会-北海道・東北支部  

Ichushi

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Language：Japanese   Publisher：(一社)日本リウマチ学会-北海道・東北支部  

Ichushi

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

Ichushi

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Language：Japanese   Publisher：(公財)先進医薬研究振興財団  

Ichushi

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Language：Japanese   Publisher：(一社)日本リウマチ学会-北海道・東北支部  

Ichushi

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Language：Japanese   Publisher：日本消化器病学会-北海道支部  

Ichushi

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Ichushi

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Ichushi

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Ichushi

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Ichushi

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Language：Japanese   Publisher：(一社)日本臨床免疫学会  

Ichushi

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Language：Japanese   Publisher：(公社)日本医師会  

Ichushi

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Language：Japanese   Publisher：(一社)日本臨床免疫学会  

Ichushi

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Ichushi

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

Ichushi

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Language：Japanese   Publisher：日本臨床免疫学会  

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J01882&link_issn=&doc_id=20171006410111&doc_link_id=%2Fdy4jjoci%2F2017%2F004004%2F112%2F0303-0303%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2017%2F004004%2F112%2F0303-0303%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.40.303c

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

Ichushi

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Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Language：Japanese   Publisher：日本臨床免疫学会  

Other Link:： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01882&link_issn=&doc_id=20160905390119&doc_link_id=%2Fdy4jjoci%2F2016%2F003904%2F119%2F0386-0386%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2016%2F003904%2F119%2F0386-0386%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.39.386a

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Language：Japanese   Publisher：日本臨床免疫学会  

Other Link:： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01882&link_issn=&doc_id=20160905390118&doc_link_id=%2Fdy4jjoci%2F2016%2F003904%2F118%2F0385-0385%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2016%2F003904%2F118%2F0385-0385%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.39.385b

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Ichushi

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Ichushi

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Ichushi

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Language：Japanese   Publisher：(一社)日本リウマチ学会  

Ichushi

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Language：Japanese   Publisher：日本臨床免疫学会  

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J01882&link_issn=&doc_id=20131106410143&doc_link_id=%2Fdy4jjoci%2F2013%2F003605%2F08f%2F0408-0408%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2013%2F003605%2F08f%2F0408-0408%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.36.408a

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Language：Japanese   Publisher：日本臨床免疫学会  

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J01882&link_issn=&doc_id=20131106410142&doc_link_id=%2Fdy4jjoci%2F2013%2F003605%2F08e%2F0407-0407%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdy4jjoci%2F2013%2F003605%2F08e%2F0407-0407%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

DOI： 10.2177/jsci.36.407b

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Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

Ichushi

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Language：Japanese   Publisher：北海道医学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

Ichushi

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Language：Japanese   Publisher：The Japanese Society for Clinical Rheumatology and Related Research  

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J02269&link_issn=&doc_id=20130725110008&doc_link_id=10.14961%2Fcra.25.125&url=https%3A%2F%2Fdoi.org%2F10.14961%2Fcra.25.125&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

DOI： 10.14961/cra.25.125

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Language：Japanese   Publisher：(株)北隆館  

Ichushi

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Other Link:： http://id.nii.ac.jp/1599/00012948/

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Language：Japanese   Publisher：角化症研究会事務局  

Ichushi

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DOI： 10.2177/jsci.36.406b

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DOI： 10.2177/jsci.36.408b

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DOI： 10.2177/jsci.36.421b

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Language：Japanese   Publisher：北海道医学会  

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Language：Japanese   Publisher：(一社)日本臨床内科医会  

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Language：Japanese   Publisher：がんの子供を守る会  

Other Link:： https://search.jamas.or.jp/link/ui/2011331156

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Language：Japanese   Publisher：(NPO)日本小児がん学会  

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2011&ichushi_jid=J00638&link_issn=&doc_id=20110901150007&doc_link_id=%2Fex9syoni%2F2011%2Fs04802%2F001%2F0140-0140%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fex9syoni%2F2011%2Fs04802%2F001%2F0140-0140%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Language：Japanese   Publisher：日本臨床外科学会  

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