受賞区分：国内学会・会議・シンポジウム等の賞  受賞国：日本国

受賞区分：国内外の国際的学術賞  受賞国：日本国

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17182

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17165

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17367

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17370

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17382

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17128

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17319

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

Background: No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism. Objectives: To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC. Methods: We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097). Results: We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation. Conclusions: CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC.

DOI： 10.1093/bjd/ljae193

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17081

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出版者・発行元：Oral Oncology Reports  

DOI： 10.1016/j.oor.2024.100356

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Rheumatology (United Kingdom)  

DOI： 10.1093/rheumatology/kead649

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17073

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.17014

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the American Academy of Dermatology  

DOI： 10.1016/j.jaad.2023.10.070

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Allergology International  

DOI： 10.1016/j.alit.2023.12.001

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記述言語：英語   出版者・発行元：Experimental Dermatology  

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype–phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).

DOI： 10.1111/exd.15072

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the American Academy of Dermatology  

DOI： 10.1016/j.jaad.2023.10.056

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Allergy and Clinical Immunology: Global  

Background: To develop precision medicine for atopic dermatitis (AD), it is critical to establish relevant biomarkers. However, the characteristics of various biomarkers have not been fully understood. We previously carried out the Biomarkers to Predict Clinical Improvement of AD in Patients Treated with Dupilumab (B-PAD) study, a comprehensive nationwide study in Japan, to explore biomarkers for AD. Objective: The aim of this study is to find biomarkers associated with objective and subjective clinical findings in patients with moderate-to-severe AD based on the B-PAD study and to identify biomarkers sensitive enough to assess the severity of AD. Methods: We performed the B-PAD study as a consortium composed of 19 medical facilities in Japan, enrolling 110 patients with moderate-to-severe AD. We evaluated the Eczema Area and Severity Index (EASI) for objective assessment as well as the Patient-Oriented Eczema Measure (POEM) and a numeric rating scale for pruritus (pruritis-NRS) for subjective assessment, measuring 19 biomarkers at baseline. Results: We found that 12, 6, and 7 biomarkers showed significant and positive associations with the EASI, POEM, and pruritis-NRS, respectively. Most of the biomarkers associated with either the POEM or the pruritis-NRS were included among the biomarkers associated with EASI. Of the biomarkers examined, CCL26/eotaxin-3 and SCCA2 were the most capable of assessing severity for EASI, as shown by the 2 kinds of receiver operating characteristic analyses, respectively, whereas lactate dehydrogenase was the best for both the POEM and pruritis-NRS, again using the 2 analyses. Conclusion: We found biomarkers associated with the EASI, POEM, and pruritis-NRS, respectively, based on the B-PAD study. Moreover, we identified CCL26/eotaxin-3 and/or SCCA2 as the biomarkers having the greatest ability to assess severity in the EASI; lactate dehydrogenase did the same for the POEM and pruritis-NRS. These findings will be useful in treating patients with moderate-to-severe AD.

DOI： 10.1016/j.jacig.2023.100175

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16968

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatological Science  

Background: Congenital ichthyoses sometimes present with severe skin symptoms that significantly affect the patient's quality of life (QOL). Symptomatic treatments are the mainstay therapies, and their efficacy is limited and inadequate. Objective: To assess the disease severity and QOL in patients with congenital ichthyoses, and to investigate the effectiveness of current treatments. Methods: We conducted a questionnaire-based Japan-wide epidemiological survey of patients with congenital ichthyosis who received medical care from 1 January 2016–31 December 2020. Effectiveness of past and current treatments was assessed. The outcomes were the physician's assessment, disease severity assessed using the clinical ichthyosis score (CIS), and the disease burden estimated using the Dermatology Life Quality Index (DLQI), the Children's Dermatology Life Quality Index (CDLQI), and the Infants’ Dermatitis Quality of Life Index. Results: One hundred patients with 14 ichthyosis subtypes from 47 institutes were included in the final analysis. The CDLQI score showed a positive correlation with CIS (rs = 0.59, p = 0.004), while the DLQI score showed no significant correlation (rs = 0.13, p = 0.33). All existing medications were effective for many patients. Etretinate improved QOL and reduced CIS, but side effects including bone growth retardation were reported. Decreased treatment willingness was observed in patients with very low and very high CIS. Conclusion: QOL scores were found to correlate with CIS in children, but not in adults. Considering the adverse events, it is speculated that etretinate is not indicated for children with mild cases. Petrolatum was the most commonly used medication, even in patients who were reluctant to receive treatment.

DOI： 10.1016/j.jdermsci.2023.11.002

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

Pathogenic variants in ABCA12 are important causative genetic defects for autosomal recessive congenital ichthyoses (ARCI), which include congenital ichthyosiform erythroderma (CIE), harlequin ichthyosis, and lamellar ichthyosis. In addition, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. We previously reported siblings who carried an ABCA12 variant but did not show a “congenital” phenotype. They were considered to have pityriasis rubra pilaris (PRP). Here, we present a further patient with ABCA12 variants whose phenotype was not congenital ichthyosis, in an independent family. Notably, these three patients had geographic unaffected areas. Such areas are not usually found in patients with ARCI who have ABCA12 variants, suggesting mild phenotypes for these patients. Interestingly, the histological features of the ichthyotic lesions in these patients resembled those of PRP. All three patients had homozygous pathogenic missense variants in ABCA12. Our findings expand the phenotypic spectrum of patients with ABCA12 variants.

DOI： 10.1111/1346-8138.16967

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JDDG - Journal of the German Society of Dermatology  

DOI： 10.1111/ddg.15273_g

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Biochimie  

Epidermal lipids play important roles in skin homeostasis and diseases. Psoriasis is an inflammatory disease characterized by keratinocyte hyperproliferation and Th17 immune responses. We previously reported that ethanolamine-type lysoplasmalogen (P-LPE), preferentially produced by group IIF secreted PLA2 (sPLA2-IIF/PLA2G2F) that is expressed in the suprabasal epidermis, promotes epidermal hyperplasia in psoriatic inflammation. Herein, we show that forcible degradation of epidermal P-LPE by topical application of recombinant lysophospholipase D (LyPls-PLD) from Thermocrispum, a lysoplasmalogen-specific hydrolase, attenuated epidermal hyperplasia and inflammation in imiquimod-induced and K5.Stat3C-transgenic mouse psoriasis models. In humans, P-LPE levels were elevated in the tape-stripped stratum corneum of patients with psoriasis. Moreover, in primary cultured human epidermal keratinocytes, aberrant cell proliferation and activation by psoriatic cytokines were sPLA2-IIF/P-LPE-dependent and were suppressed by the addition of LyPls-PLD with a decrease in P-LPE. These findings confirm that the sPLA2-IIF/P-LPE axis in the epidermis indeed regulates psoriasis, that P-LPE is a lipid biomarker that predicts the severity of psoriasis, and that pharmacological removal of this bioactive lipid is useful to prevent the disease. Thus, our study may lead to the development of drug discovery and diagnostic techniques based on this pathway.

DOI： 10.1016/j.biochi.2023.09.027

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担当区分：責任著者   記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16880

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16857

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1093/bjd/ljad207

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAMA Dermatology  

DOI： 10.1001/jamadermatol.2023.1417

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Experimental Dermatology  

Pathogenic variants in MPO, which encodes the myeloperoxidase, were reported as causative genetic defects in several cases of generalised pustular psoriasis (GPP) in addition to patients with myeloperoxidase deficiency in 2020. However, which clinical subtypes of GPP patients have pathogenic variants in MPO remains largely undetermined, and elucidating this is clinically important. The present report outlines a mild case of GPP with a rare missense heterozygous variant, c.1810C>T p.(Arg604Cys), in MPO. Our structural analysis and functional assays to measure myeloperoxidase activity suggest that the present MPO substitution is a hypomorphic variant in MPO. Thus, the mild phenotype of the present GPP patient might be associated with an incomplete hypomorphic loss-of-function variant in MPO. Additionally, the severe intractable edematous pustules and erythema improved dramatically after five rounds of granulocyte and monocyte adsorption apheresis (GMA) therapy. This is the first report of GMA treatment for GPP associated with a pathogenic variant in MPO, as far as we know. Our findings suggest that GMA might be a useful and powerful tool for controlling GPP in patients with myeloperoxidase deficiency.

DOI： 10.1111/exd.14846

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16798

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記述言語：英語   出版者・発行元：International Journal of Rheumatic Diseases  

DOI： 10.1111/1756-185X.14654

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

The kinesin superfamily protein 20B (KIF20B), also known as M-phase phosphoprotein-1, is a plus-end-directed motor enzyme for cytokinesis. Anti-KIF20B antibodies have been reported in idiopathic ataxia, but no previous studies have examined anti-KIF20B antibodies in systemic autoimmune rheumatic diseases (SARDs). We aimed to establish methods for detecting anti-KIF20B antibodies and to investigate the clinical significance of these antibodies in SARDs. Serum samples from 597 patients with various SARDs and 46 healthy controls (HCs) were included. Fifty-nine samples that had been examined by immunoprecipitation using the recombinant KIF20B protein produced by in vitro transcription/translation were used for establishing the ELISA cutoff with the same recombinant protein for measuring the anti-KIF20B antibodies. The ELISA performed well, showing close agreement with the immunoprecipitation results (Cohen's κ >0.8). The ELISA results for 643 samples showed the prevalence of anti-KIF20B to be higher in the systemic lupus erythematosus (SLE) patients than in the HCs (18/89 vs. 3/46, P = 0.045). Since no SARD other than SLE had higher frequencies of anti-KIF20B antibodies than those of the HCs, we investigated the clinical characteristics of anti-KIF20B antibody-positive cases in SLE. The score on the SLE Disease Activity Index-2000 (SLEDAI-2K) was significantly higher for the anti-KIF20B-positive SLE patients than for the anti-KIF20B-negative SLE patients (P = 0.013). In a multivariate regression analysis of the anti-single-stranded deoxyribonucleic acid, anti-double-stranded deoxyribonucleic acid, and anti-KIF20B antibodies, the presence of anti-KIF20B antibody was significantly associated with high SLEDAI-2K scores (P = 0.003). Anti-KIF20B antibodies were found in ~20% of patients with SLE and were associated with high SLEDAI-2K scores. Much larger cohort and longitudinal studies are needed to confirm the association between anti-KIF20B antibodies and SLE.

DOI： 10.1111/1346-8138.16813

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担当区分：責任著者   記述言語：英語   出版者・発行元：Journal of Dermatological Science  

DOI： 10.1016/j.jdermsci.2023.06.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Investigative Dermatology  

Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced β1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of β1 integrins, and depleting PLOD2 in T231M-RhoE–expressing cells reduced T231M-RhoE–mediated β1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.

DOI： 10.1016/j.jid.2023.01.019

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1093/bjd/ljad122

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1093/bjd/ljad082

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16726

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2302/kjm.2023-0008-IR

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

Darier's disease (DD) is a rare autosomal dominantly inherited disorder. DD patients usually present with widespread keratotic eruptions with itching in the seborrheic regions that are exacerbated by various factors, including heat, sweat, and physical trauma. The SARS-CoV-2 (COVID-19) pandemic has stirred confusion among the medical community, including dermatologists, as this infection has been implicated in various skin conditions. Only a handful of reports have documented DD associated with COVID-19. Here, we report a 30-year-old male with Darier's disease whose symptoms were exacerbated following both COVID-19 vaccination and COVID-19 infection. The patient had noticed slight eruptions 7 years prior, but was not particularly concerned. After COVID-19 vaccination and infection, he had erythematous maculopapular lesions in large areas of the trunk and extremities. The previously reported pathogenic variant c.2255_2257del (p.(Ile752_Tyr753delinsAsn)) in ATP2A2 was detected in the present patient. Oral etretinate greatly improved his DD manifestations. As far as we know, the present patient is the first genetically confirmed DD case who showed both COVID-19 infection- and vaccination-related DD exacerbations independently. We think that the further accumulation of DD cases exacerbated by COVID-19 infection/vaccination is needed to clarify the mechanisms of DD aggravation.

DOI： 10.1111/1346-8138.16725

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16704

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/1346-8138.16704

記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16707

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担当区分：責任著者   記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.18894

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1093/bjd/ljac036

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

In dermatology, biologics that block signaling pathways of TNF-α, IL-4/IL13, IL-17s, and IL-23 are widely used for the treatment of several inflammatory skin diseases, such as atopic dermatitis and psoriasis. They have shown excellent efficacy with an acceptable safety profile. However, these biologics targeting pathogenic cytokines and their receptors could modulate immunological balance, leading to the development of other inflammatory or autoimmune skin diseases in some cases. In this study, we present a patient who suffered pemphigus vegetans and showed an exacerbation of pemphigus foliaceus after secukinumab loading for the treatment of complicated generalized pustular psoriasis and pyoderma gangrenosum.

DOI： 10.1111/1346-8138.16563

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記述言語：英語   出版者・発行元：Clinical and Experimental Allergy  

DOI： 10.1111/cea.14267

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16618

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記述言語：英語   出版者・発行元：Nagoya Journal of Medical Science  

Blockade of the secretion of immunoglobulins leads to their accumulation in plasma cells, resulting in condensed immunoglobulins in the rough endoplasmic reticulum of plasma cells, termed Russell bodies. They are sometimes found in lymphoplasmacellular inflammation of the intestinal mucosa and in lymphoid cell malignancies, but only very rarely in skin diseases. Here, we report an 86-year-old female who presented with a lesion with the prominent accumulation of Russell bodies underlying pseudocarcinomatous hyperplasia with fungal infection in the face. Immunohistochemical staining showed the cells containing Russell bodies to be positive for CD138 and the Russell bodies to be positive for immunoglobulin k and l light chains. The present case suggests that when inflammatory cell infiltration with abundant round intracellular eosinophilic materials is observed in the dermis, the dermal accumulation of Russell bodies should be considered in cases with reactive pseudocarcinomatous hyperplasia with fungal infection.

DOI： 10.18999/nagjms.85.1.123

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16601

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記述言語：英語   出版者・発行元：Clinical and Experimental Rheumatology  

DOI： 10.55563/clinexprheumatol/fnrck0

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16587

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2023.4414

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記述言語：英語  

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記述言語：英語   出版者・発行元：Journal of Immunological Methods  

DOI： 10.1016/j.jim.2022.113400

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記述言語：英語   出版者・発行元：Autoimmunity Reviews  

Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are useful for identifying a clinical subset of patients with inflammatory myopathies. Since the myositis of anti-ARS-positive patients is characterized by a unique set of non-myopathic manifestations, including interstitial lung disease, mechanic's hands, and arthralgia, the patients are classified as having anti-synthetase syndrome. Autoantibodies have been identified to eight kinds of ARSs. Of the other 12 ARSs, eight are components of the “OJ” multi-synthetase complex. Autoantibodies to the four remaining ARSs (CysARS, ValARS, SerARS, and TrpARS) have not been reported to be present in patients with inflammatory myopathies. In this study, we first screened samples from more than 300 Japanese patients majorly consisting of those with dermatomyositis (DM) by our established in-house ELISA to find autoantibodies against the four ARSs described above. Since sera from two DM patients specifically reacted to CysARS or ValARS, we determined their reactivities by immunoprecipitation (IP) with the corresponding recombinant proteins and IP–Western blotting with cellular extract. One patient had several features found in anti-synthetase syndrome, but the other did not. The clinical differences among the various anti-ARS antibodies should be explored in a future work.

DOI： 10.1016/j.autrev.2022.103204

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Lipid Research  

Self-healing collodion baby (SHCB), also called “self-improving collodion baby”, is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79*))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432-Cys))/ c.1138delG (p.(Asp380Thrfs*3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79*) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

DOI： 10.1016/j.jlr.2022.100308

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatological Science  

Background: Sjögren–Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. Objectives: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. Methods: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. Results: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. Conclusion: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

DOI： 10.1016/j.jdermsci.2022.08.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Rheumatology (United Kingdom)  

DOI： 10.1093/rheumatology/keac170

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16402

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16399

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

Darier disease (DD), also called keratosis follicularis, is an autosomal dominant hereditary keratinization disorder that manifests as keratotic papules with plaques in seborrheic areas. There are no validated curative treatments for DD, with the majority of cases treated symptomatically. We report the efficacy of a topical over-the-counter agent which contains retinyl palmitate, vitamin E, and urea for a patient with DD. A 13-year-old girl had brown papules on her scalp, neck, shoulders, and axillae since entering elementary school. A skin biopsy revealed hyperkeratosis, suprabasal acantholysis, and dyskeratosis manifested as corps ronds and grains in the epidermis. Sanger sequencing found the previously reported heterozygous mutation c.1484C>T in ATP2A2. The application of an over-the-counter topical agent containing retinyl palmitate 2750 μg/g (5000 IU/g), tocopheryl acetate 20 mg/g, urea 200 mg/g, and monoammonium glycyrrhizinate 5 mg/g twice daily for 2 months improved the papules without serious adverse events. Oral or topical aromatic vitamin A analogs (retinoids) are often used to treat DD. However, several adverse events are associated with retinoid treatment, and many patients only undergo their intermittent use or discontinue the treatments. Retinyl palmitate is more stable and has a lower irritative profile than other retinoic acids. When applied topically, however, retinyl palmitate cannot penetrate the skin as well as retinol can. Some reports have noted that vitamin E increases the biological availability of vitamin A and that urea helps mechanical percutaneous drug delivery. Our case suggests that retinyl palmitate has a sufficient therapeutic effect when combined with vitamin E and urea. In conclusion, we propose that topical agents containing retinyl palmitate, vitamin E, and urea might have a satisfactory effect on the skin lesions of DD patients, without the serious risks of adverse events.

DOI： 10.1111/1346-8138.16395

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16348

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth. We report the clinical manifestations of two patients from a Japanese family with SEI caused by a hotspot mutation, p.Glu487Lys, in KRT2. In addition, we summarize previous reports on SEI patients with the identical mutation. One of the two patients had disease onset at the age of 7 months. The other patient’s age of onset is unknown, but it was in childhood. Neither of the two patients showed erythroderma. To perform deep phenotyping, we studied the age of onset and the frequency of erythroderma in 34 reported SEI cases with the p.Glu487Lys mutation, including the present cases. Among the cases with sufficient clinical information, 44.4% of the cases that were due to p.Glu487Lys in KRT2 occurred at birth. Erythroderma was observed in 11.1% of the cases with p.Glu487Lys in KRT2.

DOI： 10.3390/ijms23147791

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Immunology  

NLRP1 (NACHT and leucine-rich repeat-containing protein family, pyrin domain-containing protein 1) is an innate immune sensor that is involved in the formation of inflammasome complexes. NLRP1 hyperactivity has been reported to cause inherited autoinflammatory diseases including familial keratosis lichenoides chronica and NLRP1-associated autoinflammation with arthritis and dyskeratosis. We generated Nlrp1b (the mouse homologue of human NLRP1) gain-of-function knock-in (Nlrp1b KI) mice with UVB irradiation-induced autoinflammatory skin lesions. We demonstrated that UVB irradiation induces IL-1β upregulation and IL-1β-dependent inflammation via caspase-1 activation in these Nlrp1b KI mice. RNA sequencing revealed the upregulation of inflammasome pathway-related genes, keratinocyte stress marker genes, and keratinocyte differentiation marker genes in the Nlrp1b KI mice after UVB irradiation. The skin inflammation and hyperkeratosis from UVB irradiation in the Nlrp1b KI mice were inhibited by both intraperitoneal and subcutaneous administration of anti-IL-1β antibodies before UVB irradiation. UVB irradiation and the IL-1β pathway are important in the pathogenesis of NLRP1-associated autoinflammatory skin lesions.

DOI： 10.3389/fimmu.2022.876390

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記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.17890

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Rheumatology (United Kingdom)  

Objective: Anti-NOR90 antibodies are usually found in patients with SSc; however, their clinical relevance remains obscure. We developed an ELISA for measuring them to investigate the clinical features of patients with anti-NOR90 antibodies. Methods: Serum samples from 1252 patients with various conditions from Nagoya University Hospital and 244 patients with idiopathic interstitial pneumonia (IIP) from Tosei General Hospital were included. Anti-NOR90 antibodies were assayed by an ELISA using the recombinant protein produced by in vitro transcription/translation. Results: Five (0.4%) patients in the Nagoya University Hospital cohort had anti-NOR90 antibodies. One patient with diffuse cutaneous SSc, three with limited cutaneous SSc, and one with Raynaud's disease were positive for anti-NOR90 antibodies. Anti-NOR90 antibodies were found more frequently in patients with systemic scleroderma-spectrum disorders (SSDs) than without SSDs (5/316 vs 0/936, P <0.00101) and were found more frequently in patients with SSc than without SSc (4/249 vs 0/528, P <0.0104) in the systemic autoimmune rheumatic diseases cohort. Three of the four anti-NOR90-positive SSc patients had interstitial lung disease (ILD), and two of those four had cancer. Three (1.2%) patients in the Tosei General Hospital cohort had anti-NOR90 antibodies. All three of the anti-NOR90-positive IIP patients had gastrointestinal tract involvement, and two of those three had cancer or skin lesions observed in SSc. Conclusions: Although anti-NOR90 antibodies are rarely found in clinics, our ELISA is useful for their detection. Further studies are needed to confirm the association of anti-NOR90 antibodies with ILD and cancer in SSc and IIP patients.

DOI： 10.1093/rheumatology/keab575

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.16277

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記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.17752

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Investigative Dermatology  

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.

DOI： 10.1016/j.jid.2021.07.154

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記述言語：英語   出版者・発行元：Arthritis and Rheumatology  

DOI： 10.1002/art.41945

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記述言語：英語  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers in Immunology  

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.

DOI： 10.3389/fimmu.2021.737747

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出版者・発行元：Nishinihon Journal of Dermatology  

DOI： 10.2336/nishinihonhifu.84.9

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出版者・発行元：Nishinihon Journal of Dermatology  

DOI： 10.2336/nishinihonhifu.84.418

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記述言語：英語   出版者・発行元：Immunology Letters  

DOI： 10.1016/j.imlet.2021.08.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Arthritis and Rheumatology  

DOI： 10.1002/art.41775

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2021.4138

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15976

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記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.17201

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15951

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記述言語：英語   出版者・発行元：Journal of Dermatological Science  

DOI： 10.1016/j.jdermsci.2021.06.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Autoimmunity  

Objective: Anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies are useful for identifying a clinical subset of patients with idiopathic inflammatory myopathies (IIMs). Anti-OJ antibodies, which recognize multi-enzyme synthetase complexes including isoleucyl-tRNA synthetase (IARS) and lysyl-tRNA synthetase (KARS), are among the anti-ARS antibodies. Although testing antibodies to other ARSs have been used clinically, no validated immunoassays for detecting anti-OJ antibodies are available. We aimed to establish an anti-OJ ELISA. Methods: Serum samples were collected from 279 patients with IIMs and 22 patients with idiopathic interstitial pneumonia. Sixty-four of the samples that had been confirmed to be negative for anti-OJ by standard immunoprecipitation were used as the negative control, and 12 anti-OJ-positive reference sera were used as the positive control. Antibodies to IARS and KARS were assayed by ELISA using biotinylated recombinant proteins generated by in vitro transcription/translation. Results: The anti-OJ-positive sera strongly reacted with the KARS and IARS recombinant proteins in ELISA. Although all 12 reference sera were positive in the anti-KARS ELISA, 4 of the 64 anti-OJ-negative sera were also weakly positive. The sensitivity and the specificity were 100% and 93.8%, respectively. Since our anti-KARS ELISA performed well, showing a high agreement with the results for immunoprecipitation (Cohen's κ > 0.8), the remaining 237 samples were also tested. Thirteen anti-KARS-positive sera were newly found by ELISA, all of which were anti-OJ positive by immunoprecipitation. Conclusion: Immunoassays for detecting anti-OJ antibodies using KARS and IARS recombinant proteins were developed. Our ELISAs performed well, with very high agreement of the results by immunoprecipitation and can be applied to the first reliable, easy-to-use measurement assays for anti-OJ antibodies.

DOI： 10.1016/j.jaut.2021.102680

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-3844

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder. Clinicians must be aware of the diverse clinical features of this disorder in order to provide optimal care for it. We have set up an NF1 in-hospital medical care network of specialists regardless of patient age, launching a multidisciplinary approach to the disease for the first time in Japan. From January 2014 to December 2020, 246 patients were enrolled in the NF1 patient list and medical records. Mean age was 26.0 years ranging from 3 months to 80 years. The number of patients was higher as age at first visit was lower. There were 107 males (41%) and 139 females. After 2011, the number of patients has increased since the year when the medical care network was started. Regarding orthopedic signs, scoliosis was present in 60 cases (26%), and bone abnormalities in the upper arm, forearm, and tibia in 8 cases (3.5%). Neurofibromas other than cutaneous neurofibromas were present in 90 cases (39%), and MPNST in 17 cases (7.4%). We launched a multidisciplinary NF1 clinic system for the first time in Japan. For patients with NF1, which is a hereditary and systemic disease associated with a high incidence of malignant tumors, it will be of great benefit when the number of such clinics in Japan and the rest of Asia is increased.

DOI： 10.1038/s41598-021-91345-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Journal of Human Genetics  

Revertant mosaicism, or “natural gene therapy,” refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only approximately 50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli, such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.

DOI： 10.1016/j.ajhg.2021.04.021

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Investigative Dermatology  

DOI： 10.1016/j.jid.2020.09.035

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the American Academy of Dermatology  

DOI： 10.1016/j.jaad.2020.07.131

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記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.17098

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記述言語：英語   出版者・発行元：Journal of Dermatological Science  

DOI： 10.1016/j.jdermsci.2021.03.003

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記述言語：英語   出版者・発行元：Nagoya Journal of Medical Science  

Basal cell nevus syndrome (BCNS) is an autosomal dominant skin disorder characterized by multiple basal cell nevi. Patients with BCNS tend to develop basal cell carcinoma (BCC) and frequently show skeletal abnormalities. Most cases of BCNS are caused by mutations in patched 1 (PTCH1). PTCH1 encodes a transmembrane receptor protein for the secreted molecule sonic hedgehog, which plays a key role in the development of animals ranging from insects to mammals. We analyzed two Japanese BCNS patients from two independent families. Both of our patients had multiple jaw keratocysts. In one patient, these were the key to noticing his BCNS, as he had no skin tumors. The early detection of PTCH1 mutations would enable BCNS patients to be carefully followed up for the occurrence of BCC. The diagnosis of BCC at the early stage leads to prompt surgical treatments, resulting in a good prognosis. The present cases suggest that keratocysts of the jaw might be an important clue for diagnosing BCNS.

DOI： 10.18999/nagjms.83.2.393

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15795

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15777

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記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.16990

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記述言語：英語   出版者・発行元：Journal of Cutaneous Immunology and Allergy  

Systemic sclerosis (SSc) is a multi-system autoimmune disease. Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against enzymes found within primary granules of neutrophils and lysosomes in monocytes. Although up to 12% of SSc patients have ANCA, only a minority of these patients develop an overlap syndrome with ANCA-associated vasculitis. We summarize previous reports on SSc patients with ANCA-associated neuropathy. In all the reported cases, the SSc diagnosis preceded the ANCA-associated neuropathy diagnosis. Seven of the eight patients with limited cutaneous SSc had interstitial lung disease (ILD). Thus, patients with ANCA-associated neuropathy in lSSc may be prone to complication with ILD.

DOI： 10.1002/cia2.12153

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2021.4017

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-3764

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Modern Rheumatology Case Reports  

A 55-year-old man who had been diagnosed with autoimmune pancreatitis five years earlier was referred to our department because of finger swelling, finger stiffness and the presence of interstitial lung disease (ILD). The patient was diagnosed with Sjögren’s syndrome according to the pathological findings of minor salivary glands and positive anti-SS-A antibodies. Later, at age 58, he was hospitalised due to the exacerbation of the ILD. Serum IgG4 level was checked and was found to be elevated (417 mg/dL). After the introduction of cyclosporine in addition to the prednisolone, at age 60, the ILD disease activity stabilised. However, at age 62, fever, myalgia and mechanic’s hands appeared. His serum creatine kinase level was high, and magnetic resonance imaging showed inflammatory findings of muscle. In-house ELISA clarified that his serum carried anti-PL-7 antibody among anti-aminoacyl-tRNA synthetase antibodies. This is a unique case who had overlapping features of IgG4-related autoimmune pancreatitis, Sjögren’s syndrome and anti-synthetase syndrome. Although the aetiology of the complications in this patient is obscure, autoimmunity might have played a significant role in the disease conditions and prognosis of the present case with IgG4-related disease.

DOI： 10.1080/24725625.2020.1816675

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記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.16799

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15612

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15645

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2020.3956

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記述言語：英語   出版者・発行元：Journal of Dermatological Science  

DOI： 10.1016/j.jdermsci.2020.05.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The myositis-specific autoantibodies that characterise certain forms of idiopathic inflammatory myopathy (IIM) are useful for diagnosing dermatomyositis (DM) / polymyositis (PM) and predicting its prognosis. The autoantibody to phenylalanyl-tRNA synthetase (anti-Zo) has been identified as a disease marker antibody for anti-synthetase syndrome only in a UK cohort. Here we aim to establish an ELISA for the measurement of anti-Zo and to characterise the clinical features of Japanese patients who have this autoantibody. METHODS: Anti-Zo was investigated by immunoprecipitation with recombinant phenylalanyl-tRNA synthetase α/β proteins. The results were confirmed by immunoprecipitation-Western blotting with cell extract. Sera from patients with DM/PM (n=224) were screened by an ELISA with the recombinant proteins. Medical records were retrospectively reviewed to obtain detailed information on the clinical phenotypes of the anti-Zo-positive patients. RESULTS: Only two male patients were confirmed to have anti-Zo. Both patients had fever, myopathy, interstitial lung disease, and mechanic's hands, and these clinical features are consistent with those of anti-synthetase syndrome. Another patient's serum showed a higher level than the cut-off value for anti-phenylalanyl-tRNA synthetase α by our in-house ELISA, but was judged to be negative for anti-Zo by immunoprecipitation-Western blotting. CONCLUSIONS: This is the first report of anti-Zo-positive IIM patients from Asia. Although Japanese patients with anti-Zo have a clinical phenotype similar to that of Caucasian patients, further large cohort studies are necessary to confirm the frequency of anti-Zo in Japanese IIM patients. Our newly developed ELISA should be validated for sensitivity and specificity in large cohorts.

DOI： 10.55563/clinexprheumatol/q70vmh

PubMed

記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15525

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記述言語：英語   出版者・発行元：Journal of Cutaneous Immunology and Allergy  

DOI： 10.1002/cia2.12132

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記述言語：英語   出版者・発行元：Journal of Dermatological Science  

DOI： 10.1016/j.jdermsci.2020.08.008

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15513

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAMA Dermatology  

DOI： 10.1001/jamadermatol.2020.2195

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Medicine (United States)  

Background:Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab.Methods:Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment."Discussion:This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.

DOI： 10.1097/MD.0000000000022043

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2020.3868

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15476

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Cutaneous Immunology and Allergy  

DOI： 10.1002/cia2.12122

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2020.3812

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-3570

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記述言語：英語   出版者・発行元：Journal of Dermatological Science  

Among the components of the barrier structure of the stratum corneum in human skin, the corneocyte lipid envelope (CLE) is extremely important for the skin barrier. The importance of the CLE and esterified ω-hydroxy sphingosine (CerEOS), its main precursor, has been suggested from the fact that mutations in a number of genes involved in CerEOS synthesis and CLE formation have been identified as genetic causes of congenital ichthyoses, which are severe genetic skin disorders. However, the molecule/mechanism involved in the covalent binding of CerEOS to proteins on the outer surface of the cornified cell envelope had been a missing part. Very recently, we proposed new potential modes of protein binding by covalent reactions of CerEOS-epoxy-enone. We revealed the biochemical function of short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7), encoded by SDR9C7, as catalyzing the dehydrogenation of the lipoxygenase products that are esterified in CerEOS. Epoxy-enone produced by SDR9C7 covalently binds to proteins on the outer extracellular surface of the cornified cell envelope. Importantly, our recent striking findings were derived from the detailed lipid analysis of only one ARCI patient with SDR9C7 mutation. The combination of detailed analyses of precious samples from a rare patient and the establishment of corresponding animal models is an effective and powerful tool for analyzing rare inherited diseases. This review summarizes this newly revealed mechanism in skin barrier formation, describes the characteristic features of patients with SDR9C7 mutations, and introduces the clinical value of non-invasive analyses for patients with very rare intractable skin diseases.

DOI： 10.1016/j.jdermsci.2020.03.005

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：英語   出版者・発行元：Frontiers in Immunology  

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists. Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis. There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion. Proteasome maturation protein (POMP), encoded by POMP, is an ubiquitously expressed protein that functions as a chaperone for proteasome maturation. KLICK syndrome is caused by a reduction in POMP levels that leads to proteasome insufficiency in differentiating keratinocytes. It is noteworthy that POMP is also known to be the causative gene for proteasome-associated autoinflammatory syndrome-2 (PRAAS2). It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome. Inflammation caused by the hyperactivation of innate immunity occasionally leads to inflammatory diseases of the skin, recently denoted as autoinflammatory keratinization diseases (AiKDs). We propose that KLICK syndrome caused by the specific 1-bp nucleotide deletion mutation in the regulatory region of POMP might be in a spectrum of proteasome-associated phenotypes.

DOI： 10.3389/fimmu.2020.00641

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cancers  

Extramammary Paget’s disease (EMPD) is a neoplastic skin disease of indeterminate origin with an unknown genetic cause. We performed a comprehensive genetic analysis or targeted gene sequencing in 48 patients with EMPD. We identified FOXA1 mutations, a GAS6–FOXA1 fusion gene, and somatic hotspot mutations in the FOXA1 promoter region in 11 of the 48 EMPD patients (11/48, 23%). Additional mutations were identified in PIK3CA (six patients) and in HIST1H2BB, HIST1H2BC, and SMARCB1 (one patient each), but none were found in other frequently mutated genes in cancer. A global gene expression analysis using EMPD clinical samples found the upregulation of PI3 kinase–AKT–mTOR signaling. ABCC11, which is specifically expressed in the apocrine secretory cells and is necessary for their sweat secretion, was upregulated in the EMPD samples. This upregulation suggests that Paget cells originate from apocrine secretory cells. Immunohistochemical staining revealed that FOXA1 expression was prevalent in all of the EMPD samples analyzed and was associated with estrogen receptor expression. Our genetic analysis indicates that EMPD frequently involves FOXA1 mutations. FOXA1 is a transcriptional pioneer factor for the estrogen receptor, and the present results suggest that certain treatments for hormone-dependent cancers could be effective for EMPD.

DOI： 10.3390/cancers12040820

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記述言語：英語   出版者・発行元：American Journal of Clinical Dermatology  

Generalized pustular psoriasis (GPP) is a chronic, systemic inflammatory disease accompanied by high fever and general malaise. Diffuse erythema and swelling of the extremities occur, with multiple sterile pustules all over the body in GPP patients. GPP often relapses over the lifetime and can be life-threatening. Recent discoveries of the underlying molecular genetic basis of many cases of this disorder have provided major advances to clinicians and researchers towards an understanding of the pathomechanism of GPP. However, the therapeutic management of GPP still faces many challenges and much uncertainty, and an evidence-based review summarizing the available clinical data on the management of this heterogeneous disease is needed. The present review addresses challenges regarding the precise clinical diagnosis and evaluation of clinical symptoms in GPP. In addition, we update and briefly summarize the current understanding of molecular pathomechanisms behind GPP as an autoinflammatory keratinization disease. Recent publications have clarified the genetic backgrounds of patients with GPP and ethnic differences in predisposing factors. Although there are ethnic differences in the prevalences of these pathogenic alleles, from recent reports, at most 60.5% (IL36RN), 5.9% (CARD14), and 10.8% (AP1S3) of GPP patients have the mutations/variations of these genes. All the reported biologics studied seemed effective and relatively well tolerated. Although it is difficult to evaluate therapeutic efficacy from studies on just a few cases, recent findings suggest that biologics can be a useful, powerful tool for controlling skin and systemic inflammation in GPP and for improving the quality of life of GPP patients.

DOI： 10.1007/s40257-019-00492-0

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15210

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15228

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記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1684/ejd.2019.3681

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Clinical Investigation  

The corneocyte lipid envelope, composed of covalently bound ceramides and fatty acids, is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7-KO model, we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative liquid chromatography-mass spectometry (LC-MS) assays revealed almost complete loss of a species of ω-Oacylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy- 11E-13-ketone, a reactive moiety known for its nonenzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.

DOI： 10.1172/JCI130675

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記述言語：英語   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.18445

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Journal of Molecular Sciences  

The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin-and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC's serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD.

DOI： 10.3390/ijms21030913

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記述言語：英語   出版者・発行元：Clinical and Experimental Dermatology  

DOI： 10.1111/ced.13938

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記述言語：英語   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.15892

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatological Science  

Background: NIPAL4, encoding the NIPA-like domain containing 4 protein (NIPAL4), is one of the causative genes of autosomal recessive congenital ichthyosis (ARCI). The physiological role of NIPAL4 and the pathogenetic mechanisms of ARCI caused by NIPAL4 mutations remain unclear. Objective: To clarify the changes of ceramide components in the lesional stratum corneum (SC) and the gene expression profile in the lesional skin of an ARCI patient with a novel frameshift mutation in NIPAL4. Methods: We performed ultrastructural and immunohistochemical analyses of the skin. We used RNA sequencing to determine the mRNA expression in the skin of the patient and healthy individuals. We investigated ceramide components using tape stripped SC samples from the patient. Results: mRNA expression profiling in the patient's skin showed significant upregulation of IL-17/TNFα-related genes (IL17C, IL36A, IL36G, S100A7A, S100A9) and psoriasis hallmark genes (VNN3, LCE3D, PLA2G4D), and significant downregulation of lipid-associated genes (GAL, HAO2, FABP7). Ceramide analysis in the patient's SC revealed amounts of CER[NS] with carbon chain-length (C) 32–52 were increased, while amounts of most acylceramide with C66:2 - C72:2 were reduced relatively to those in healthy individuals. After the retinoid treatment, CER[NS] with carbon chains C46–54, CER[EOH] and CER[EOP] increased. Conclusion: IL-17C and IL-36 family cytokines might be involved in the pathogenetic process of ARCI with NIPAL4 mutations. Reduced amounts of the acylceramides in the SC are associated with the skin phenotype due to NIPAL4 mutations. Efficacy of the oral retinoid treatment might be due to restored amounts of CER[EOH] and CER[EOP] in the SC.

DOI： 10.1016/j.jdermsci.2019.12.001

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.15110

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記述言語：英語   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.18343

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-3277

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記述言語：英語   出版者・発行元：Clinical and Experimental Dermatology  

DOI： 10.1111/ced.13979

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記述言語：英語   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14905

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記述言語：英語  

DOI： 10.1016/j.jid.2019.07.196

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14748

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14777

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記述言語：英語   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.17405

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Allergy and Clinical Immunology  

DOI： 10.1016/j.jaci.2018.11.044

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14666

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14613

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14626

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Cutaneous Immunology and Allergy  

Psoriasis is a common skin disorder that is characterized by hyperkeratosis, epidermal hyperplasia, T-cell and neutrophil recruitment, and changes in the vascular endothelial system. The several upregulated variable lipid mediators, including the eicosanoids, in psoriatic keratinocytes were described previously, although some results were contradictory. Since hepoxilin is less stable than other eicosanoids such as hydroxyeicosatetraenoic acid (HETE), the measurement of hepoxilin is difficult. In this study, to clarify the relationship between hepoxilin/hepoxilin-related fatty acid derivatives and psoriasis vulgaris, we evaluated the amount of production of lipid mediators including hepoxilins in skin tissues of patients with psoriasis vulgaris in comparison with normal controls by high-performance liquid chromatography/mass spectrometry. Most of the hepoxilins and related lipids evaluated in this study tended to be more abundant in the lesional skin from the psoriasis patient group (PPG) than in the skin from controls. Interestingly, 12R-HETE was markedly higher in the skin samples from the PPG. In addition, the lipids produced in the lipoxygenase pathway, including hepoxilin, were elevated in the skin lesions of the PPG compared with those of normal controls, whereas the lipids produced in the cyclooxygenase pathway were decreased in the skin lesions from the PPG. Our results suggest that an imbalance between the lipoxygenase and cyclooxygenase pathways may contribute to psoriatic pathomechanisms.

DOI： 10.1002/cia2.12039

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記述言語：日本語  

DOI： 10.2336/nishinihonhifu.81.382

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.11406/rinketsu.60.1641

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Lipid Research  

Neu-Laxova syndrome (NLS) is a very rare autosomal recessive congenital disorder characterized by disturbed development of the central nervous system and the skin and caused by mutations in any of the three genes involved in de novo l-serine biosynthesis: PHGDH, PSAT1, and PSPH. l-Serine is essential for the biosynthesis of phosphatidylserine and sphingolipids. The extracellular lipid of the stratum corneum, of which sphingolipid constitutes a significant part, plays a primary role in skin barrier function. Here, we describe a Japanese NLS pedigree with a previously unreported nonsense mutation in PHGDH and a unique inversion of chromosome 1. In addition, the levels of 11 major ceramide classes in the tape-stripped stratum corneum of the NLS patient’s skin were assessed by LC/MS. Notably, lower amounts of ceramides of all classes were found in the patient’s stratum corneum than in those of controls. This is the first report to demonstrate the reduction of ceramides in the stratum corneum of an NLS patient due to PHGDH mutations. The clinical findings and a detailed analysis of ceramides from the stratum corneum in the family extend the spectrum of clinical anomalies and give us a clue to the pathomechanisms of ichthyosis in NLS patients with phosphoglycerate dehydrogenase deficiency.—Takeichi, T., Y. Okuno, A. Kawamoto, T. Inoue, E. Nagamoto, C. Murase, E. Shimizu, K. Tanaka, Y. Kageshita, S. Fukushima, M. Kono, J. Ishikawa, H. Ihn, Y. Takahashi, and M. Akiyama. Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency.

DOI： 10.1194/jlr.P087536

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.16823

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.15004

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14350

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2018.3415

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatological Science  

Background: Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently. Objective: To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) Methods: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0–30) and clinical ichthyosis score (range of 0–100). Results: Netherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8–71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearman's correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (P < 0.05). Conclusion: We confirmed that Netherton syndrome and KID syndrome patients have a higher risk of allergy to food or environmental allergens and of skin infections, respectively. QOL impairment correlates with disease severity in HI and ISFs patients.

DOI： 10.1016/j.jdermsci.2018.08.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.16895

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.14330

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.15076

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Germline missense mutations in GJB2 encoding connexin (Cx) 26 have been found in keratitis, ichthyosis and deafness (KID) syndrome. We explored the effects of three mouse Cx26 mutants (Cx26-G12R, -G45E and -D50N) corresponding to KID syndrome-causative human mutants on hemichannel activities leading to cell death and the expression of immune response-associated genes. We analyzed the 3D images of cells expressing wild-type (WT) or mutant Cx26 molecules to demonstrate clearly the intracellular localization of Cx26 mutants and hemichannel formation. High extracellular Ca2+ conditions lead to the closure of gap junction hemichannels in Cx26-G12R or Cx26-G45E expressing cells, resulting in prohibition of the Cx26 mutant-induced cell death. Fluorescent dye uptake assays revealed that cells with Cx26-D50N had aberrantly high hemichannel activities, which were abolished by a hemichannel blocker, carbenoxolone and 18α-Glycyrrhetinic acid. These results further support the idea that abnormal hemichannel activities play important roles in the pathogenesis of KID syndrome. Furthermore, we revealed that the expressions of IL15, CCL5, IL1A, IL23R and TLR5 are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.

DOI： 10.1038/s41598-018-30757-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.16610

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.16712

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2018.3313

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.16375

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nagoya Journal of Medical Science  

Dyschromatosis symmetrica hereditaria (DSH) is one of the genetic pigmentation disorders and shows characteristic mixture of hyper- and hypo-pigmented small macules on the extremities. Heterozygous mutations in the adenosine deaminase acting on RNA1 gene (ADAR1) cause DSH. In the present study, we report five cases of DSH and identify a distinct known mutation in each patient. Furthermore, we review previously described cases with the five ADAR1 mutations found in the present study. We reviewed clinical and molecular findings in the present and previously reported cases and found an identical mutation can result in various phenotypic severities, even in one family. We found novel phenotype-genotype correlations between the presence/absence of facial lesions and the ADAR1 mutation c.3286C>T. The absence of frecklelike macules in the face was found to be more commonly associated with the mutation c.3286C>T than with the other 4 ADAR1 mutations (odds ratio = 0.056 [95% CI: 0.007-0.47, p < 0.005]). We objectively evaluated the severity of skin manifestations in the extremities using our definition of severity levels for such manifestations. This is the first semi-quantitative evaluation of skin manifestations in DSH. Using our definition, we found that patients with facial lesions with or without hypopigmented macules tend to show more severe symptoms on the extremities than patients without facials lesions show. Furthermore, no significant difference in the severity of the skin lesions was observed between the upper and the lower extremities, suggesting that sun exposure does not affect significantly the pathogenesis of DSH skin lesions.

DOI： 10.18999/nagjms.80.2.267

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jid.2018.03.264

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2018.3259

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.14307

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jdermsci.2018.01.017

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jdermsci.2018.01.012

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.15869

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

DOI： 10.1111/1346-8138.13851

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.14531

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.14241

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.14439

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

Patients with deficiency of interleukin-36 receptor antagonist (DITRA), due to mutation of IL36RN, exhibit psoriatic phenotypes, typically generalized pustular psoriasis (GPP). We report a paediatric patient with DITRA, whose cutaneous lesions varied from psoriasis vulgaris in infancy to annular pustular psoriasis with acute exacerbation to GPP at 13 years of age. Conventional systemic treatments for GPP, which include oral retinoids, ciclosporin and methotrexate, are controversial in paediatric cases, because of their adverse effects and uncertain long-term consequences. Granulocyte monocyte apheresis, a process associated with few adverse events, promptly controlled the GPP of our paediatric patient, and has potential as a suitable alternative treatment for paediatric patients with DITRA.

DOI： 10.1111/bjd.15509

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatological Science  

DOI： 10.1016/j.jdermsci.2017.05.012

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Dermatology  

Adult-onset Still's disease (AOSD) is characterized by multiple systemic inflammation of unknown etiology. Although the typical eruption of AOSD is salmon-pink rheumatoid rash on the trunk and extremities, persistent pruritic papules and plaques have also been reported. Correlations between serum cytokines, including interleukin-6 and -18, and disease activity in AOSD have been reported. Activated signal transducer and activator of transcription 3 (STAT3) is transported into the nucleus, where it functions as a transcription factor that regulates genes involved in cell survival and inflammation. To assess whether STAT3 was phosphorylated in skin samples from AOSD patients, we conducted immunohistochemical analysis of affected and unaffected lesions from four AOSD patients in comparison with 10 normal controls. Quantitative analysis was conducted by measuring the ratio of epidermal keratinocytes with phosphorylated STAT3 (p-STAT3)-positive nuclei to total epidermal keratinocytes. p-STAT3 was found to be more strongly expressed in the nuclei in the epidermis of AOSD than in normal controls. Quantification of the data revealed significant differences in staining for p-STAT3 between AOSD and normal skin. Our findings suggest that phosphorylation of STAT3 may be a potential therapeutic target for AOSD.

DOI： 10.1111/1346-8138.13888

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bjd.15442

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-2729

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Investigative Dermatology  

DOI： 10.1016/j.jid.2017.04.036

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/bjd.15315

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.15070

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2017.3049

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記述言語：英語  

DOI： 10.1016/j.jid.2017.02.908

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-2549

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.13906

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：European Journal of Dermatology  

DOI： 10.1684/ejd.2016.2920

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-2553

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：British Journal of Dermatology  

DOI： 10.1111/bjd.14845

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of the European Academy of Dermatology and Venereology  

DOI： 10.1111/jdv.13877

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Acta Dermato-Venereologica  

DOI： 10.2340/00015555-2501

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1001/jamadermatol.2016.3601.

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pgen.1004276

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞出生週数37週1日の経腟分娩の新生児(男児).出生時より四肢体幹に水疱,表皮剥離を認めた.患児の母,祖母にも同様のエピソードがあった.常染色体顕性(優性)遺伝形式の表皮水疱症を考えて,全エクソーム解析,および/または,Sangerシークエンシングによる病因遺伝子変異検索を行い,患児とその母親,母方祖母のケラチン14をコードする遺伝子KRT14にミスセンスバリアントc. 368A>G(p.(Asn123Ser))を同定し,単純型表皮水疱症(重症型)(旧病型分類名,Dowling-Meara型)と診断した.診断の結果を踏まえ,患部の洗浄,ワセリン塗布,創傷被覆材による保護などの保存的治療と,感染対策を行った.NICUでの感染対策,創部の管理など,表皮水疱症の保存的治療の注意点について,最近の知見を交えて考察し,報告する.表皮水疱症を疑った際には,速やかな診断の確定ならびに治療方針の決定や,遺伝カウンセリングのための病因遺伝子変異の同定と病型分類を目的とした全エクソーム解析が有効である.

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：角化症研究会事務局  

記述言語：日本語   出版者・発行元：(一社)日本歯内療法学会  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：日本脂質生化学会  

記述言語：日本語   出版者・発行元：日本脂質生化学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

記述言語：日本語   出版者・発行元：(NPO)日本歯科保存学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(株)南江堂  

＜文献概要＞・副腎皮質ステロイド外用薬は多様な皮膚疾患に用いられている.・五つのランクに分類され,病状,外用部位,年齢によって使い分ける.・局所的な副作用に注意して使用する.・適切なランクの副腎皮質ステロイドを使用しても改善しない場合は,皮膚科専門医への紹介が望ましい.

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00974&link_issn=&doc_id=20230414290022&doc_link_id=issn%3D0022-1961%26volume%3D131%26issue%3D4%26spage%3D604&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D131%26issue%3D4%26spage%3D604&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(株)協和企画  

＜文献概要＞症例のポイント ・出生直後からのNICU管理,早期からのレチノイド全身投与を行った.・胸郭挙上不良による換気障害があれば角層の減張切開を検討する.・指趾の虚血や拘縮が疑われれば,角層の減張切開を検討する.・救命とともに,後遺症を最小限に抑えることも肝要である.

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：中部リウマチ学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(一社)日本皮膚免疫アレルギー学会  

記述言語：日本語   出版者・発行元：加齢皮膚医学研究会  

記述言語：日本語   出版者・発行元：加齢皮膚医学研究会  

老人性乾皮症は、皮脂および汗の分泌が減退し、皮膚が乾燥して光沢を失い粗造になった状態をいう。皮膚バリア機能の低下のため冬季では湿疹性病変を合併し、強いそう痒を伴うことがある。本研究では、老人性乾皮症ならびにアトピー性皮膚炎と診断された、既知のFLG遺伝子変異を有しない10名の患者の血液からDNAを抽出し、whole-exome sequence解析法を用いて、SDR9C7遺伝子のバリアント解析、SNP解析を行った。今回解析を行った老人性乾皮症ならびにアトピー性皮膚炎患者の10名の中には、SDR9C7遺伝子の変異/バリアントを有する症例は同定されなかった。本研究では、老人性乾皮症におけるSDR9C7分子の病態への関与は明らかにならなかった。今後、解析症例数を増やすことを検討している。(著者抄録)

記述言語：日本語   出版者・発行元：加齢皮膚医学研究会  

記述言語：日本語   出版者・発行元：(株)協和企画  

＜文献概要＞症例のポイント ・長島型掌蹠角化症とアトピー性皮膚炎が併存していた.・自験例においてSERPINB7遺伝子変異を同定した.

記述言語：日本語   出版者・発行元：(株)全日本病院出版会  

汎発性膿疱性乾癬(generalized pustular psoriasis:GPP)は、寛解と増悪を繰り返し、ときに生命を脅かす、重篤で稀な炎症性皮膚疾患である。家族性GPPの原因がインターロイキン(IL)36受容体阻害因子の欠損であるという2011年の報告に始まり、近年、遺伝学的素因に関連したGPPの自己炎症性の側面が明らかになってきた。最近我々は、その自己炎症に着目し、GPPの一部を自己炎症性角化症として捉えることを提唱している。自己炎症性疾患の主な病態は自然免疫系の賦活化によるもので、好中球やリンパ球からのIL-1βやTNF-αなどの炎症性サイトカインを介して引き起こされる、皮膚を含む全身性の慢性炎症とされる。本稿では、最近報告されたGPPと好中球についての新知見を紹介するとともに、好中球関連皮膚疾患としてのGPPの病態メカニズムに迫る。(著者抄録)

記述言語：日本語   出版者・発行元：角化症研究会事務局  

記述言語：日本語   出版者・発行元：角化症研究会事務局  

記述言語：日本語   出版者・発行元：角化症研究会事務局  

記述言語：日本語   出版者・発行元：加齢皮膚医学研究会  

記述言語：日本語   出版者・発行元：日本小児皮膚科学会  

7歳男児。1歳頃より嗄声に気づき、6歳時に近医耳鼻科受診。声帯の結節性病変を指摘され、その後病理所見から慢性喉頭炎および軽度〜中等度異形成と診断された。7歳頃より両上眼瞼に白色を帯びた、直径約1mmの平滑な丘疹が数珠状に多数並ぶようになり、当科紹介受診。初診時、舌にも白色斑がみられた。眼瞼皮疹の病理では真皮乳頭に好酸性無構造物質が沈着していた。歯牙の異常なし。両親、妹弟に同症状はない。Extracellular matrix protein 1(ECM1)をコードするECM1遺伝子にホモ接合性c.879G>A変異あり、lipoid proteinosis(LP:リポイドタンパク症)と診断した。父親にはヘテロ接合性に同遺伝子変異があり、母親は野生型であった。3年間経過観察したところ、両頬粘膜に萎縮性白色斑が新たに出現した。本症は稀な疾患で特に小児例の報告は少ないことからその皮膚粘膜症状について報告する。(著者抄録)

記述言語：日本語   出版者・発行元：角化症研究会事務局  

記述言語：日本語   出版者・発行元：角化症研究会事務局  

記述言語：日本語   出版者・発行元：角化症研究会事務局  

記述言語：日本語   出版者・発行元：加齢皮膚医学研究会  

記述言語：日本語   出版者・発行元：加齢皮膚医学研究会  

記述言語：日本語   出版者・発行元：加齢皮膚医学研究会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(一社)日本小児神経学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本整形外科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会