記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/cddis.2017.322

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：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/jid.

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   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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

Background: Atopic dermatitis (AD) is a common chronic eczematous skin disease with severe pruritus. Several new therapeutic agents for AD such as dupilumab, an anti–IL-4Rα antibody, have been developed in recent years. We need to predict which agent is the best choice for each patient, but this remains difficult. Objective: Our aim was to examine clinical background factors and baseline biomarkers that could predict the achievement of improved clinical outcomes in patients with AD treated with dupilumab. Methods: A multicenter, prospective observational study was conducted on 110 patients with AD. The Eczema Area and Severity Index was used as an objective assessment, and the Patient-Oriented Eczema Measure and Numerical Rating Scale for Pruritus were used as patient-reported outcomes. In addition, some clinical background factors were evaluated. Results: The achievement of an absolute Eczema Area and Severity Index of 7 or less was negatively associated with current comorbidity of food allergy and baseline serum lactate dehydrogenase (LDH) levels. There were negative associations between achievement of a Patient-Oriented Eczema Measure score of 7 or less and duration of severe AD and between achievement of an itching Numerical Rating Scale for Pruritus score of 1 or less and current comorbidity of allergic conjunctivitis or baseline serum periostin level. Furthermore, signal detection analysis showed that a baseline serum LDH level less than 328 U/L could potentially be used as a cutoff value for predicting the efficacy of dupilumab. Conclusion: Baseline biomarkers such as LDH and periostin and clinical background factors such as current comorbidity of food allergy and a long period of severe disease may be useful indicators when choosing dupilumab for systemic treatment for AD, as they can predict the efficacy of dupilumab.

DOI： 10.1016/j.jacig.2024.100317

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記述言語：英語  

DOI： 10.1016/j.alit.2024.08.010

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

Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream 1% in Japanese patients aged ≥12 years with atopic dermatitis (AD) in two phase 3 trials, ZBB4-1 and ZBB4-2. ZBB4-1 (N = 216) consisted of an 8-week, double-blind, vehicle-controlled treatment period (period 1) and a 16-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who enrolled in period 2 received tapinarof. ZBB4-2 (N = 291) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBB4-1, the proportion of patients who achieved an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 8 (IGA treatment success, the primary end point) was 20.24% in the tapinarof group and 2.24% in the vehicle group (p = 0.0007). The proportion of patients with ≥75% improvement from baseline in Eczema Area and Severity Index (EASI) score at week 8 (EASI-75 response, the key secondary end point) was 40.3% in the tapinarof group and 4.3% in the vehicle group (p < 0.0001). In ZBB4-2, IGA treatment success rate was 28.1% at week 16, 32.3% at week 24, and 41.3% at week 52, and EASI-75 response rate was 53.3% at week 16, 63.7% at week 24, and 76.6% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis, acne, and headache. In summary, tapinarof cream 1% was effective and generally safe for up to 52 weeks of treatment in Japanese patients with AD.

DOI： 10.1111/1346-8138.17451

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

Tapinarof is a non-steroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream (1%) in Japanese patients aged ≥18 years with plaque psoriasis in two phase 3 trials, ZBA4-1 and ZBA4-2. ZBA4-1 (N = 158) consisted of a 12-week, double-blind, vehicle-controlled treatment period (period 1) and a 12-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who were enrolled in period 2 received tapinarof. ZBA4-2 (N = 305) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBA4-1, the proportion of patients who achieved a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 12 (PGA treatment success, the primary endpoint) was 20.06% in the tapinarof group and 2.50% in the vehicle group (p = 0.0035). The proportion of patients with ≥75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (PASI75 response, a key secondary endpoint) was 37.7% in the tapinarof group and 3.8% in the vehicle group (p < 0.0001). In ZBA4-2, PGA treatment success rate was 30.0% at week 12, 51.3% at week 24, and 56.3% at week 52, and PASI75 response rate was 50.4% at week 12, 77.5% at week 24, and 79.9% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis and contact dermatitis. In summary, tapinarof cream (1%) was efficacious and generally safe for up to 52 weeks of treatment in Japanese patients with plaque psoriasis.

DOI： 10.1111/1346-8138.17423

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出版者・発行元：Journal of Cutaneous Immunology and Allergy  

Background: Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. Tapinarof has been shown to be efficacious and have acceptable safety profile in the treatment of atopic dermatitis (AD). Objective: We sought to evaluate the improvement effect of tapinarof on skin barrier function in patients with AD. Methods: This was an open-label, uncontrolled, single-center study. Japanese patients aged ≥20 years with AD (N = 30) were included in this study. Patients applied tapinarof cream 1% once daily to the target areas on the volar forearm for 8 weeks. The primary endpoints were changes from baseline in stratum corneum hydration (SCH) and transepidermal water loss (TEWL) at the target affected area at week 8. Results: The mean SCH value at the target affected area was 13.656 AU at baseline, 16.904 AU at week 4, and 16.423 AU at week 8. The SCH at the target affected area significantly increased from baseline to week 8, with a mean change of 2.826 AU (p = 0.0433). The mean TEWL value at the target affected area was 17.35 g/m2/hr at baseline, 10.01 g/m2/hr at week 4, and 9.52 g/m2/hr at week 8. The TEWL at the target affected area significantly decreased from baseline to week 8, with a mean change of −8.03 g/m2/hr (p < 0.0001). Clinical signs of AD at the target affected area were improved over time. No serious, severe, or treatment-related AEs were reported. Conclusion: Treatment with tapinarof led to an increase in SCH and a decrease in TEWL in patients with AD, indicating the potential improvement effect of tapinarof on skin barrier function.

DOI： 10.3389/jcia.2024.13418

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記述言語：英語   出版者・発行元：International Journal of Molecular Sciences  

Difamilast, a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective in the treatment of atopic dermatitis (AD), although the mechanism involved remains unclear. Since IL-33 plays an important role in the pathogenesis of AD, we investigated the effect of difamilast on IL-33 activity. Since an in vitro model of cultured normal human epidermal keratinocytes (NHEKs) has been utilized to evaluate the pharmacological potential of adjunctive treatment of AD, we treated NHEKs with difamilast and analyzed the expression of the suppression of tumorigenicity 2 protein (ST2), an IL-33 receptor with transmembrane (ST2L) and soluble (sST2) isoforms. Difamilast treatment increased mRNA and protein levels of sST2, a decoy receptor suppressing IL-33 signal transduction, without affecting ST2L expression. Furthermore, supernatants from difamilast-treated NHEKs inhibited IL-33-induced upregulation of TNF-α, IL-5, and IL-13 in KU812 cells, a basophil cell line sensitive to IL-33. We also found that difamilast activated the aryl hydrocarbon receptor (AHR)–nuclear factor erythroid 2-related factor 2 (NRF2) axis. Additionally, the knockdown of AHR or NRF2 abolished the difamilast-induced sST2 production. These results indicate that difamilast treatment produces sST2 via the AHR–NRF2 axis, contributing to improving AD symptoms by inhibiting IL-33 activity.

DOI： 10.3390/ijms25147910

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

DOI： 10.1111/1346-8138.17318

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記述言語：英語   出版者・発行元：Antioxidants  

Semaphorin 3A (SEMA3A), a nerve-repellent factor produced by keratinocytes, has an inhibitory effect on nerve extension to the epidermis. Epidermal innervation is involved in pruritus in inflammatory skin diseases such as atopic dermatitis (AD) and dry skin. We previously reported that tapinarof, a stilbene molecule, upregulates SEMA3A in human keratinocytes. We also showed that this mechanism is mediated via the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, and the nuclear factor erythroid 2-related factor 2 (NRF2) axis. Since some stilbenes activate AHR and NRF2, we attempted to identify other stilbenes that upregulate SEMA3A. We analyzed normal human epidermal keratinocytes (NHEKs) treated with 11 types of stilbenes and examined SEMA3A expression. We found that resveratrol and pinostilbene, antioxidant polyphenols, upregulated SEMA3A and increased nuclear AHR and NRF2 expression. In addition, AHR knockdown by small interfering RNA (siRNA) transfection abolished the NRF2 nuclear expression. Furthermore, AHR and NRF2 knockdown by siRNA transfection abrogated resveratrol- and pinostilbene-induced SEMA3A upregulation. Finally, we confirmed that resveratrol and pinostilbene increased SEMA3A promoter activity through NRF2 binding using ChIP-qPCR analysis. These results suggest that resveratrol and pinostilbene upregulate SEMA3A via the AHR–NRF2 axis in human keratinocytes.

DOI： 10.3390/antiox13060732

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記述言語：英語   出版者・発行元：一般社団法人日本アレルギー学会  

DOI： 10.1016/j.alit.2023.12.001

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出版者・発行元：Traditional and Kampo Medicine  

Background: Yusho is a 1968 mass food poisoning that was caused by the ingestion of rice oil contaminated with dioxins and related organochlorines. We previously reported that keishibukuryogan (KBG) administration was effective for improvement of the symptoms of Yusho patients. This study used responder analysis to more deeply elucidate the effectiveness of KBG. Method: The data analyzed in the study were collected from our previous clinical study done to predict response to KBG treatment. The patients were divided into responders and non-responders based on whether their symptoms improved after taking KBG. We assessed baseline patient characteristics and the intensity of general fatigue and dermatological, neurological, and respiratory symptoms. Further, we used SF-36 to evaluate Quality of Life (QOL). Results: Of the 42 patients who completed the previous study, 27 were responders and 15 non-responders, with no significant differences in the patient characteristics. The general fatigue, dermatological symptoms, and respiratory symptoms of responders were significantly improved at month 3 of treatment. Analysis of the eight QOL domain profiles of SF-36 showed that the general health of responders was significantly improved from baseline to month 3 compared with non-responders, as was vitality from baseline to month 1. Moreover, the mental health of responders significantly improved from baseline to months 1 and 3. Conclusions: Keishibukuryogan was not only effective for symptoms such as general fatigue, dermatological symptoms, and respiratory symptoms, but also for the mental health of Yusho patients, which indicates that it would be a good first-choice Kampo medicine for the treatment of these patients.

DOI： 10.1002/tkm2.1400

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

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.2023.10.002

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出版者・発行元：協和企画  

DOI： 10.24733/pd.0000003734

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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：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　・体幹に発生し巨大化した皮下腫瘍であり,類表皮嚢腫や粘液癌,脂肪肉腫との鑑別を要した.・全切除標本の病理組織学的診断で診断確定に至った.

記述言語：英語   出版者・発行元：一般社団法人 日本形成外科学会  

<p>Burn, a common injury in daily life, is a potential risk factor for severe sequelae in people, particularly children. Preventing unexpected burn injuries is of the utmost importance. This study examined the current status of pediatric burns in our institute. One hundred children who received intensive therapy in Kyushu University Hospital were analyzed regarding the causes, sites, severity, treatments, and outcomes of burns between 2004 and 2021. The mean patient age was 2.4 years (range: 0-15), and 90% of patients were 6 years old or younger. The mean percent total body surface area was 12.7%. All patients had second- or third-degree burns. The most common cause was scalding (93%), and among them, hot water burns, and kettle burns were predominant in 49.5% and 24.7% of children, respectively. The seasonal fluctuations of occurrence were not remarkable. Basic fibroblast growth factor spray with wet dressing was used, but hypertrophic scars arose in 39 patients. The mean duration of hospitalization was 18.9 ± 18.2 days. This study revealed that more than 90% of pediatric burns were caused by hot liquids, thereby highlighting the importance of educational activities for parents to prevent and reduce pediatric burns because most scalding burns can be avoided with caution.</p>

DOI： 10.53045/jprs.2023-0005

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記述言語：英語   出版者・発行元：(一社)日本形成外科学会  

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  

Interleukin (IL)-33 and IL-37 have been identified as novel cytokines involved in various inflammatory diseases. However, their specific roles remain largely unknown. Recent studies have shown that IL-33, which triggers inflammation, and IL-37, which suppresses it, cooperatively regulate the balance between inflammation and anti-inflammation. IL-33 and IL-37 are also deeply involved in the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis. Furthermore, a signaling pathway by which aryl hydrocarbon receptor (AHR), a receptor for dioxins, regulates the expression of IL-33 and IL-37 has been revealed. Here, we outline recent findings on the mechanisms regulating IL-33 and IL-37 expression in AD and psoriasis. IL-33 expression is partially dependent on mitogen-activated protein kinase (MAPK) activation, and IL-37 has a role in suppressing MAPK in human keratinocytes. Furthermore, IL-33 downregulates skin barrier function proteins including filaggrin and loricrin, thereby downregulating the expression of IL-37, which colocalizes with these proteins. This leads to an imbalance of the IL-33-IL-37 axis, involving increased IL-33 and decreased IL-37, which may be associated with the pathogenesis of AD and psoriasis. Therefore, AHR-mediated regulation of the IL-33-IL-37 axis may lead to new therapeutic strategies for the treatment of AD and psoriasis.

DOI： 10.3390/ijms241914633

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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: Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes. OBJECTIVE: To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes. METHODS: We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast. RESULTS: We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs. CONCLUSION: These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.

DOI： 10.1016/j.jdermsci.2023.04.007

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記述言語：英語   出版者・発行元：エルゼビア・ジャパン(株)  

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

Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly impacts quality of life. The pathogenesis of AD is a complex combination of skin barrier dysfunction, type II immune response, and pruritus. Progress in the understanding of the immunological mechanisms of AD has led to the recognition of multiple novel therapeutic targets. For systemic therapy, new biologic agents that target IL-13, IL-22, IL-33, the IL-23/IL-17 axis, and OX40-OX40L are being developed. Binding of type II cytokines to their receptors activates Janus kinase (JAK) and its downstream signal, namely signal transduction and activator of transcription (STAT). JAK inhibitors block the activation of the JAK-STAT pathway, thereby blocking the signaling pathways mediated by type II cytokines. In addition to oral JAK inhibitors, histamine H4 receptor antagonists are under investigation as small-molecule compounds. For topical therapy, JAK inhibitors, aryl hydrocarbon receptor modulators, and phosphodiesterase-4 inhibitors are being approved. Microbiome modulation is also being examined for the treatment of AD. This review outlines current and future directions for novel therapies of AD that are currently being investigated in clinical trials, focusing on their mechanisms of action and efficacy. This supports the accumulation of data on advanced treatments for AD in the new era of precision medicine.

DOI： 10.3390/biomedicines11051303

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記述言語：日本語   出版者・発行元：福岡医学会  

We performed congener specific analysis of dioxins using HRGC/HRMS and determined their lipid based concentrations in blood samples collected from 175 family members living with certificated Yusho patients and considered as Yusho patients (Family members living with Yusho patients) during annual Yusho examinations between 2013 and 2021. When concentration of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) was compared in eleven Family members living with Yusho patients, undergoing examinations among the nine years, the longitudinal concentrations in the respective individuals hardly changed over these years. Mean concentration of 2,3,4,7,8-PeCDF in blood from 175 Family members living with Yusho patients was calculated as 25 pg/g-fat, which was higher than the mean value of 12 pg/g-fat in blood from 409 Yusho-suspected (non-registered) persons. The rates of persons with blood 2,3,4,7,8-PeCDF concentrations below 50 pg/g-fat in the entire Family members livingwith Yusho patients occupied approx. 90 %, on the other hand, concentrations above 50 pg/g-fat, defined as high concentration in Yusho criteria, were also found in fourteen Family members living with Yusho patients.

DOI： 10.15017/6790822

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記述言語：日本語   出版者・発行元：福岡医学会  

Interleukin (IL)-37 has been identified as an anti-inflammatory cytokine with the ability to suppress inflammation. However, its role remains largely unknown. Recent studies suggest that IL-37 may be a potential new therapeutic target in the treatment of inflammatory skin diseases. It has been shown that the dioxin receptor, the aryl hydrocarbon receptor (AHR), is involved in the pathogenesis of inflammatory skin diseases. In this article, we present the latest findings on the relationship between IL-37 and AHR in inflammatory skin diseases, including our studies. IL-37 is expressed in the granular layer of the skin, together with skin barrier function proteins such as Filaggrin, Loricrin and Involucrin. In lesions of atopic dermatitis and psoriasis, these skin barrier proteins are reduced, consistent with decreased expression of IL-37. We analyzed the expression of IL-37 in normal human epidermal keratinocytes treated with an AHR modulator that promotes keratinocyte differentiation. The therapeutic AHR- modulating agent, Tapinarof, induced IL-37 expression, which mechanism was AHR-dependent. We have revealed that the AHR is the receptor that regulates the expression of IL-37 in the skin. Thus, tapinarof potentially exerts a broad anti-inflammatory effect by inducing IL-37 and is expected to have novel therapeutic effects on inflammatory skin diseases.

DOI： 10.15017/6790818

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記述言語：日本語   出版者・発行元：福岡医学会  

特集号 : 油症とPCB及びダイオキシン関連化合物 / 研究報告第29集 / 責任編集者 辻学

DOI： 10.15017/6790817

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記述言語：日本語   出版者・発行元：福岡医学会  

2013～2021年度に全国油症検診で採取した1224名の血液試料の血中ダイオキシン類を分析し、同居家族認定者175名と従来の油症診断基準で認定された検診認定者640名および未認定者409名の血中濃度を比較した。その結果、同居家族の血中ダイオキシン類濃度は経年推移に明らかな変化は認めず、通常の濃度区分に属し一般人と同等の健康リスクであった。しかし、同居家族において少数ではあるが油症診断基準で典型的な患者と同等の濃度事例を認めた。

記述言語：日本語   出版者・発行元：日本皮膚科学会西部支部  

<p>アトピー性皮膚炎（atopic dermatitis：AD）は臨床現場においてよくみられる慢性皮膚疾患である。その発症や病態形成には，遺伝的，免疫学的，環境的な要因が複雑に絡み合うとされ，近年のさまざまな基礎・臨床研究により，数多くの知見が報告されている。ここでは特に，AD の病態に深く関与する 2 型サイトカインの IL-4 および IL-13 について，その機能や役割，これらを標的にした治療薬の最新知見を概説するとともに，今後望まれる AD 治療戦略について考察した。</p>

DOI： 10.2336/nishinihonhifu.85.5

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記述言語：日本語   出版者・発行元：日本皮膚科学会西部支部  

<p>基礎疾患や家族歴のない 9 歳男児。3 歳時に頭頚部の石灰化上皮腫を5 カ所切除した。数年前から頭頚部，腰部，四肢に皮下結節が出現し，合計 8 カ所の皮下結節を認めた。6 カ所切除し，病理組織学的検査でいずれも石灰化上皮腫の診断となった。過去の報告では，石灰化上皮腫が 6 個以上多発した症例の多くで筋緊張性ジストロフィー，家族性腺腫性ポリポーシス，Turner 症候群，Rubinstein-Taybi 症候群など何らかの症候群を合併している。自験例は遺伝子検査を行っていないが，臨床上これらの症候群を疑う所見はなかった。明らかな症候群や家族歴を伴わない場合でも，β-カテニン遺伝子の変異により多発性石灰化上皮腫を来す可能性がある。β- カテニン遺伝子の変異は悪性腫瘍を生じる可能性がある。自験例は遺伝子変異に関しては明らかではないが，今後の悪性腫瘍の発現に注意して経過をみていく必要がある。</p>

DOI： 10.2336/nishinihonhifu.85.46

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CiNii Research

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

Acral melanoma (AM) is a rare, life-threatening skin cancer. Since AM bears unique features, existing therapies for other types of malignant melanomas have limited effects and the establishment of effective treatments for AM is strongly desired. Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that is frequently elevated in tumors and contributes to tumor progression, so it is considered a promising therapeutic target for tumors. This study was established to evaluate the potential of HER3-targeted therapy to treat AM by investigating the expression and function of HER3. HER3 expression was immunohistochemically analyzed in AM lesions of 72 patients and in AM cell lines. To investigate function of HER3, effects of HER3 inhibition on cell proliferation, apoptosis/survival, anchorage-independent growth, and underlying signals were assessed. HER3 was expressed in patients' AM tissues with various intensities and HER3 expression was significantly correlated with patient's disease-free survival. In vitro analyses revealed that HER3 is more highly expressed in AM cells than in normal epidermal melanocytes. AM cells were also shown to be sensitive to the cytotoxic part of a HER3-targeted antibody-drug conjugate. Inhibition of HER3 did not affect cell proliferation, whereas it decreased the anchorage-independent growth of AM cells likely through affecting the nuclear translocation of Yes-associated protein. It is implied that HER3 may serve as a novel therapeutic target for AM.

DOI： 10.1038/s41420-023-01358-5

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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：日本語   出版者・発行元：日本皮膚科学会-西部支部  

基礎疾患や家族歴のない9歳男児。3歳時に頭頸部の石灰化上皮腫を5ヶ所切除した。数年前から頭頸部,腰部,四肢に皮下結節が出現し,合計8ヶ所の皮下結節を認めた。6ヶ所切除し,病理組織学的検査でいずれも石灰化上皮腫の診断となった。過去の報告では,石灰化上皮腫が6個以上多発した症例の多くで筋緊張性ジストロフィー,家族性腺腫性ポリポーシス,Turner症候群,Rubinstein-Taybi症候群など何らかの症候群を合併している。自験例は遺伝子検査を行っていないが,臨床上これらの症候群を疑う所見はなかった。明らかな症候群や家族歴を伴わない場合でも,β-カテニン遺伝子の変異により多発性石灰化上皮腫を来す可能性がある。β-カテニン遺伝子の変異は悪性腫瘍を生じる可能性がある。自験例は遺伝子変異に関しては明らかではないが,今後の悪性腫瘍の発現に注意して経過をみていく必要がある。(著者抄録)

記述言語：日本語   出版者・発行元：日本皮膚科学会西部支部  

<p>我々は，異なる臨床像を呈した 3 例の Eccrine Angiomatous Hamartoma（EAH）を経験した。症例 1： 78 歳，男性。幼少期から右肘窩部に暗赤色腫瘤を自覚し，緩徐に増大傾向であった。症例 2：41 歳，男性。10 年前から左頰部に淡青灰色局面を自覚していた。局面の大きさは 10 年でほぼ変わりなかった。症例 3：41 歳，女性。8 年前から上腹部に皮下腫瘤を自覚し，2 カ月前から疼痛を伴うようになった。症例 1 と 3 は全切除生検，症例 2 は部分生検を行った。3 症例とも病理組織学的に腫瘍の境界は不明瞭で，真皮にエクリン汗腺や小血管の増生を認め，EAH と診断した。 EAH は比較的まれな腫瘍であり，多彩な臨床像をとる。自験例は初診時に鑑別疾患として EAH は挙がらず，病理組織学的検査で診断がついた。疾患に特徴的な画像所見もこれまで報告されておらず，診断には発症時期や局所多汗などの特徴的な所見を問診することと，皮膚生検が有用と考える。</p>

DOI： 10.2336/nishinihonhifu.84.547

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CiNii Research

記述言語：日本語   出版者・発行元：日本皮膚科学会西部支部  

<p>原発巣切除後 30 年以上経過して転移した悪性黒色腫の症例を 2 例経験した。症例 1 は 72 歳の女性。40 歳で左下腿後面の黒色斑を切除され，悪性黒色腫と診断された。術後にダカルバジンを投与され再発無く経過していたが，32 年後に左鼠径部の腫脹が出現し，生検により悪性黒色腫のリンパ節転移と診断された。症例 2 は 69 歳の男性。38 歳で頸部左側の悪性黒色腫を拡大切除され，術後問題なく経過していた。 31 年後に胃前庭部と両肺野に小結節が出現し，いずれも切除され悪性黒色腫の遠隔転移の診断となった。 悪性黒色腫は稀ではあるが術後長期間経過しての再発もあり，皮膚とリンパ節のセルフチェックに関する教育や長期のフォローが重要である。</p>

DOI： 10.2336/nishinihonhifu.84.556

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CiNii Research

記述言語：日本語   出版者・発行元：日本皮膚科学会-西部支部  

我々は,異なる臨床像を呈した3例のEccrine Angiomatous Hamartoma(EAH)を経験した。症例1:78歳,男性。幼少期から右肘窩部に暗赤色腫瘤を自覚し,緩徐に増大傾向であった。症例2:41歳,男性。10年前から左頬部に淡青灰色局面を自覚していた。局面の大きさは10年でほぼ変わりなかった。症例3:41歳,女性。8年前から上腹部に皮下腫瘤を自覚し,2ヵ月前から疼痛を伴うようになった。症例1と3は全切除生検,症例2は部分生検を行った。3症例とも病理組織学的に腫瘍の境界は不明瞭で,真皮にエクリン汗腺や小血管の増生を認め,EAHと診断した。EAHは比較的まれな腫瘍であり,多彩な臨床像をとる。自験例は初診時に鑑別疾患としてEAHは挙がらず,病理組織学的検査で診断がついた。疾患に特徴的な画像所見もこれまで報告されておらず,診断には発症時期や局所多汗などの特徴的な所見を問診することと,皮膚生検が有用と考える。(著者抄録)

記述言語：日本語   出版者・発行元：日本皮膚科学会-西部支部  

原発巣切除後30年以上経過して転移した悪性黒色腫の症例を2例経験した。症例1は72歳の女性。40歳で左下腿後面の黒色斑を切除され,悪性黒色腫と診断された。術後にダカルバジンを投与され再発無く経過していたが,32年後に左鼠径部の腫脹が出現し,生検により悪性黒色腫のリンパ節転移と診断された。症例2は69歳の男性。38歳で頸部左側の悪性黒色腫を拡大切除され,術後問題なく経過していた。31年後に胃前庭部と両肺野に小結節が出現し,いずれも切除され悪性黒色腫の遠隔転移の診断となった。悪性黒色腫は稀ではあるが術後長期間経過しての再発もあり,皮膚とリンパ節のセルフチェックに関する教育や長期のフォローが重要である。(著者抄録)

記述言語：日本語   出版者・発行元：日本皮膚科学会西部支部  

<p>53 歳，女性。当科初診の20 年前に右拇指球部に自覚症状の伴わない陥凹性紅色局面が出現し，その後拡大した。皮疹部に外傷歴や刺激行為はなかった。ダーモスコピーでは紅色無構造であった。皮膚生検では健常部から病変部にかけて角層が階段状に菲薄化し，それに伴い顆粒層も菲薄化していた。Circumscribed palmar hypokeratosis の診断となった。活性型ビタミン D3 製剤を外用し，治療開始後 2 カ月の時点で辺縁の陥凹がわずかに平坦化した。本疾患は表皮の角化異常，ヒトパピローマウイルス感染，外傷などが原因として考えられているが，確立した見解はない。治療法は活性型ビタミン D3 製剤の外用，液体窒素凍結療法，外科的切除などの報告があるが，保存的治療では奏効しないことも多く確立した見解はない。本疾患は認知度が低く，誤診されることも多いため，中高年女性の掌蹠に生じた陥凹性紅斑を認めた場合，本疾患に留意する必要がある。本疾患の病態の解明や治療の確立のために，今後さらなる症例の蓄積が望まれる。</p>

DOI： 10.2336/nishinihonhifu.84.422

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CiNii Research

記述言語：日本語   出版者・発行元：日本皮膚科学会西部支部  

<p><b>患者</b>：49 歳，男性</p><p><b>主訴</b>：体幹，四肢の紅斑，紅色丘疹</p><p><b>既往歴</b>：糖尿病，糖尿病性網膜症，網膜剥離，糖尿病性腎症，糖尿病性神経障害</p><p><b>現病歴</b>：全身に瘙痒を伴う紅斑が多発しており，長年未治療であった。糖尿病性網膜症に伴う網膜剥離に対して当院眼科入院中に全身の皮疹に対して精査目的に当科紹介となった。 </p><p><b>現症</b>：頭皮，体幹，四肢に痂皮や鱗屑を伴う小紅斑，紅色丘疹が散在していた。痂皮が付着する中央が軽度陥凹した小結節もみられ，同部位より皮膚生検を施行した（<b>図 1 </b>）。</p><p><b>血液検査</b>：BUN 19 mg/dL，Cr 1.14 mg/dL，HbA1c 10.8％</p><p><b>病理組織学的所見</b>：表皮のカップ状の表皮陥凹（<b>図 2 </b>）の中に膠原線維の経表皮排泄像を認めた（<b>図 3 </b>）。陥凹部直上の角層は角栓形成がみられた。真皮は浮腫状であり，真皮上層の血管周囲にリンパ球と少数の好酸球の浸潤を認め，毛細血管の増加と赤血球の血管外漏出を認めた。</p><p><b>診断</b>：後天性反応性穿孔性膠原線維症</p><p><b>治療および経過</b>：当院糖尿病内科でインスリンによる治療が開始され HbA1c は改善傾向となった。当科でヘパリン類似物質クリームによる保湿とベタメタゾン酪酸エステルプロピオン酸エステル軟膏の外用を行い，瘙痒と皮膚症状は改善した。</p>

DOI： 10.2336/nishinihonhifu.84.391

CiNii Research

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 Medicine  

Skincare products play a crucial role in preventing the dry skin induced by various causes. Certain ingredients can help to improve the efficacy of skincare products. Galactomyces ferment filtrate (GFF) is such a functional ingredient. Its use originated from the empirical observation that the hands of sake brewers who deal with yeast fermentation retain a beautiful and youthful appearance. Consequently, skincare products based on GFF are widely used throughout the world. Recent studies have demonstrated that GFF activates an aryl hydrocarbon receptor (AHR) and upregulates the expression of filaggrin, a pivotal endogenous source of natural moisturizing factors, in epidermal keratinocytes. It also activates nuclear factor erythroid-2-related factor 2 (NRF2), the antioxidative master transcription factor, and exhibits potent antioxidative activity against oxidative stress induced by ultraviolet irradiation and proinflammatory cytokines, which also accelerate inflammaging. GFF-mediated NRF2 activation downregulates the expression of CDKN2A, which is known to be overexpressed in senescent keratinocytes. Moreover, GFF enhances epidermal terminal differentiation by upregulating the expression of caspase-14, claudin-1, and claudin-4. It also promotes the synthesis of the antiinflammatory cytokine IL-37 and downregulates the expression of proallergic cytokine IL-33 in keratinocytes. In addition, GFF downregulates the expression of the CXCL14 and IL6R genes, which are involved in inflammaging. These beneficial properties might underpin the potent barrier-protecting and anti-inflammaging effects of GFF-containing skin formulae.

DOI： 10.3390/jcm11216338

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記述言語：日本語   出版者・発行元：日本皮膚科学会-西部支部  

53歳,女性。当科初診の20年前に右拇指球部に自覚症状の伴わない陥凹性紅色局面が出現し,その後拡大した。皮疹部に外傷歴や刺激行為はなかった。ダーモスコピーでは紅色無構造であった。皮膚生検では健常部から病変部にかけて角層が階段状に菲薄化し,それに伴い顆粒層も菲薄化していた。Circumscribed palmar hypokeratosisの診断となった。活性型ビタミンD3製剤を外用し,治療開始後2ヵ月の時点で辺縁の陥凹がわずかに平坦化した。本疾患は表皮の角化異常,ヒトパピローマウイルス感染,外傷などが原因として考えられているが,確立した見解はない。治療法は活性型ビタミンD3製剤の外用,液体窒素凍結療法,外科的切除などの報告があるが,保存的治療では奏効しないことも多く確立した見解はない。本疾患は認知度が低く,誤診されることも多いため,中高年女性の掌蹠に生じた陥凹性紅斑を認めた場合,本疾患に留意する必要がある。本疾患の病態の解明や治療の確立のために,今後さらなる症例の蓄積が望まれる。(著者抄録)

記述言語：日本語   出版者・発行元：日本皮膚科学会西部支部  

<p>66 歳，女性。17 年前に発症した関節リウマチに対し 11 年前よりメトトレキサート（methotrexate：MTX）を内服していた。8 カ月前に右下腿を打撲し同部位に潰瘍を生じたという。改善しないため当科紹介となった。右下腿，右大腿，背部に多発する皮膚潰瘍が認められ，周囲に色素沈着と皮下硬結を伴っていた。また CT では右肺下葉に結節影を認めた。右下腿と背部の皮膚生検で真皮から皮下脂肪織に CD20 陽性の大型異型リンパ球が多数浸潤しており，腫瘍細胞は LMP-1，EBER 陽性で組織学的に EBV 感染を確認した。MTX 中止により皮下硬結の範囲は速やかに縮小し，右大腿と背部の潰瘍は約 1 カ月で上皮化した。肺の結節影も縮小傾向で，病理組織像と臨床経過から MTX 関連リンパ増殖性疾患（methotrexate-associated lymphoproliferative disorders：MTX-LPD）と診断した。右下腿の潰瘍は難治だったため，組織学的にリンパ増殖性疾患の所見のないことを確認し植皮術を行った。その後は寛解を維持し，リンパ増殖性疾患の再発および関節リウマチの増悪はない。MTX-LPD の皮膚潰瘍は多発例が多く，紅斑，結節，腫瘤といった原発疹が存在することを特徴とするが，単発例も存在し下腿は好発部位の一つである。MTX を内服中の患者に下腿潰瘍を生じた場合，MTX-LPD を鑑別に挙げる必要がある。</p>

DOI： 10.2336/nishinihonhifu.84.218

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CiNii Research

記述言語：日本語   出版者・発行元：日本皮膚科学会-西部支部  

66歳,女性。17年前に発症した関節リウマチに対し11年前よりメトトレキサート(methotrexate:MTX)を内服していた。8ヵ月前に右下腿を打撲し同部位に潰瘍を生じたという。改善しないため当科紹介となった。右下腿,右大腿,背部に多発する皮膚潰瘍が認められ,周囲に色素沈着と皮下硬結を伴っていた。またCTでは右肺下葉に結節影を認めた。右下腿と背部の皮膚生検で真皮から皮下脂肪織にCD20陽性の大型異型リンパ球が多数浸潤しており,腫瘍細胞はLMP-1,EBER陽性で組織学的にEBV感染を確認した。MTX中止により皮下硬結の範囲は速やかに縮小し,右大腿と背部の潰瘍は約1ヵ月で上皮化した。肺の結節影も縮小傾向で,病理組織像と臨床経過からMTX関連リンパ増殖性疾患(methotrexate-associated lymphoproliferative disorders:MTX-LPD)と診断した。右下腿の潰瘍は難治だったため,組織学的にリンパ増殖性疾患の所見のないことを確認し植皮術を行った。その後は寛解を維持し,リンパ増殖性疾患の再発および関節リウマチの増悪はない。MTX-LPDの皮膚潰瘍は多発例が多く,紅斑,結節,腫瘤といった原発疹が存在することを特徴とするが,単発例も存在し下腿は好発部位の一つである。MTXを内服中の患者に下腿潰瘍を生じた場合,MTX-LPDを鑑別に挙げる必要がある。(著者抄録)

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  

Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.

DOI： 10.3389/fimmu.2022.745997

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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 Clinical Medicine  

Mask wearing is described as one of the main public health measures against COVID-19. Mask wearing induces various types of subjective and objective facial skin damage, such as hair pore dilatation and redness. Facial pore size and redness show morning-to-evening intra-day fluctuations. It remains unknown whether mask usage affects fluctuations in pore size and redness. We measured facial skin hydration, transepidermal water loss (TEWL), pore size, and redness four times a day for 6 weeks in 20 healthy young women. After a 2-week no-mask-usage period (baseline period), all subjects wore unwoven masks for 2 weeks; then, for the following 2 weeks, they applied masks after the topical application of a moisturizer containing a Galactomyces ferment filtrate (GFF) skin care formula (Pitera™). We demonstrated that mask wearing significantly increased the intra-day fluctuations of pore size, redness, and TEWL. In addition, significant correlations were evident among these three parameters. Notably, these mask-induced skin changes were significantly improved, achieving a return to baseline levels, by the application of a GFF-containing moisturizer. In conclusion, mask wearing aggravates intra-day fluctuations in pore size and redness. Appropriate moisturization can minimize this mask-related skin damage, most likely by normalizing the elevated TEWL.

DOI： 10.3390/jcm11082121

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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  

Atopic dermatitis (AD) is an eczematous skin disorder characterized by type 2 inflammation, barrier disruption, and intense itch. In addition to type 2 cytokines, many other cytokines, such as interferon gamma (IFN-γ), interleukin 17 (IL-17), and interleukin 22 (IL-22), play roles in the pathogenesis of AD. It has been reported that the extracellular signal-regulated kinase (ERK) is downstream of such cytokines. However, the involvement of the ERK pathway in the pathogenesis of AD has not yet been investigated. We examined the expression of p-ERK in mouse and human AD skin. We also investigated the effects of the topical application of an ERK inhibitor on the dermatitis score, transepidermal water loss (TEWL), histological change, and expression of filaggrin, using an AD-like NC/Nga murine model. The effects of an ERK inhibitor on filaggrin expression in normal human epidermal keratinocytes (NHEKs) and on chemokine production from bone marrow-derived dendritic cells (BMDCs) were also evaluated. p-ERK was highly expressed in mouse and human AD skin. Topical application of an ERK inhibitor alleviated the clinical symptoms, histological changes, TEWL, and decrease in expression of filaggrin in the AD-like NC/Nga murine model. The ERK inhibitor also restored the IL-4 induced reduction in the expression of filaggrin in NHEK, and inhibited chemokine production from BMDC induced by IL-4. These results indicate that the ERK pathway is involved in the pathogenesis of AD, and suggest that the ERK pathway has potential as a therapeutic target for AD in the future.

DOI： 10.3390/ijms23073467

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PubMed

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記述言語：日本語   出版者・発行元：一般社団法人 日本アレルギー学会  

DOI： 10.15036/arerugi.71.1143

PubMed

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Psoriasis is a chronic inflammatory skin disease, and its immune mechanism has been profoundly elucidated. Biologics targeting interleukin (IL)-23 have prevented the development of psoriasis. As major sources of IL-23, dendritic cells (DCs) play a pivotal role in psoriasis; however, the regulatory mechanism of IL-23 in DCs remains unclear. IL-36γ was reported to reflect the disease activity of psoriasis. Therefore, we hypothesized that IL-36γ may affect IL-23 production in DCs. To reveal the mechanism by which IL-36γ controls IL-23 production in DCs, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-36γ. IL-36γ stimulation upregulated the mRNA and protein expression of Nfkbiz in BMDCs. Nfkbiz knockdown using siRNA transfection partially inhibited the upregulation of IL-23 mRNA expression induced by IL-36γ stimulation. Since NF-κB signaling regulates Nfkbiz expression and the anti-diabetic agent metformin reportedly modulates NF-κB signaling, we examined the effect of metformin treatment on IL-36γ-induced IL-23 production. Metformin treatment impaired the phosphorylation of NF-κB induced by IL-36γ stimulation with the subsequent downregulation of Nfkbiz, resulting in the inhibition of IL-23 production in BMDCs. These data provided evidence that metformin treatment can inhibit IL-36γ-mediated IL-23 production in BMDCs, which might contribute to the prevention of psoriasis.

DOI： 10.3390/jcm10235610

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2340/actadv.v101.369

記述言語：英語  

DOI： 10.1016/j.jdermsci.2021.09.009

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although long noncoding RNAs (lncRNAs) are transcripts that do not encode proteins by definition, some lncRNAs actually contain small open reading frames that are translated. TINCR (terminal differentiation-induced ncRNA) has been recognized as a lncRNA that contributes to keratinocyte differentiation. However, we here show that TINCR encodes a ubiquitin-like protein that is well conserved among species and whose expression was confirmed by the generation of mice harboring a FLAG epitope tag sequence in the endogenous open reading frame as well as by targeted proteomics. Forced expression of this protein promoted cell cycle progression in normal human epidermal keratinocytes, and mice lacking this protein manifested a delay in skin wound healing associated with attenuated cell cycle progression in keratinocytes. We termed this protein TINCR-encoded ubiquitin-like protein (TUBL), and our results reveal a role for TINCR in the regulation of keratinocyte proliferation and skin regeneration that is dependent on TUBL.

DOI： 10.1371/journal.pgen.1009686

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Young women often complain about the daily fluctuation of their facial skin conditions. However, no objective study has been carried out on such changes. This study is aimed at quantitatively elucidating daily skin fluctuation and evaluating the efficacy of cosmetic skin care treatment. We developed the first portable and self-guided facial skin imaging device (eMR Pro) to reproducibly capture facial images at home. Two 8 week clinical studies were then conducted to analyze daily skin fluctuation of facial pore areas, roughness and redness in young Japanese women (n = 47 in study 1 and n = 57 in study 2) by collecting facial images three times a day, during the morning after wake-up, during the morning after face wash, and during the evening after face wash. After a 4 week baseline measurement period (week -4 to week -1), all subjects applied Galactomyces ferment filtrate (GFF, Pitera®) skin care formula twice a day for 4 weeks (week 1 to week 4). These three skin conditions did exhibit different fluctuation patterns. The pore area and roughness showed the "morning after wake-up"-largest fluctuation pattern, whereas redness showed the "evening after face wash"-largest fluctuation pattern. GFF treatment significantly reduced the net values and delta fluctuation of pore area, roughness, and redness, which were consistently observed in two studies. In conclusion, the daily fluctuation of facial skin conditions is potentially a new target field for investigating healthy skin maintenance.

DOI： 10.3390/jcm10112502

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by mutation in the neurofibromin 1 (NF1) gene. Its hallmarks are cutaneous findings including neurofibromas, benign peripheral nerve sheath tumors. We analyzed the collagen and matrix metalloproteinase 1 (MMP1) expression in Neurofibromatosis 1 cutaneous neurofibroma and found excessive expression of collagen and reduced expression of MMP1. To identify new therapeutic drugs for neurofibroma, we analyzed phosphorylation of components of the Ras pathway, which underlies NF1 regulation, and applied treatments to block this pathway (PD184352, U0126, and rapamycin) and lysosomal processes (chloroquine (CQ), hydroxychloroquine (HCQ), and bafilomycin A (BafA)) in cultured Neurofibromatosis 1 fibroblasts. We found that downregulation of the MMP1 protein was a key abnormal feature in the neurofibromatosis 1 fibroblasts and that the decreased MMP1 was restored by the lysosomal blockers CQ and HCQ, but not by the blockers of the Ras pathway. Moreover, the MMP1-upregulating activity of those lysosomal blockers was dependent on aryl hydrocarbon receptor (AHR) activation and ERK phosphorylation. Our findings suggest that lysosomal blockers are potential candidates for the treatment of Neurofibromatosis 1 neurofibroma.

DOI： 10.1038/s41419-021-03802-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Atopic dermatitis is a common, chronic inflammatory skin disease that is characterized by skin barrier dysfunction, inflammation and intense itch. Although the exact mechanisms behind its pathogenesis remain unclear, it is evident that the complex interplay among barrier dysfunction, inflammation and itch are critical in its development, progression and chronicity. Abnormalities in filaggrin, intercellular lipids and tight junctions induce barrier-disrupted skin, which produces thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33; these in turn promote skin inflammation characterized by type 2 immune deviation. This inflammation then downregulates the expression of filaggrin in keratinocytes and exacerbates epidermal barrier dysfunction. Furthermore, various itch mediators/pruritogens produced during this inflammatory process can act directly on sensory nerves and cause itch. In this review, we summarize the basics and recent advances in our understanding of the pathophysiology of atopic dermatitis focusing on three aspects: barrier dysfunction, skin inflammation and itch.

DOI： 10.1111/1346-8138.15664

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In competing risks settings, the cause-specific cumulative incidence function is of great interest since it quantifies cumulative risk in the presence of other causes. To date, however, long-term cancer- and noncancer-specific mortality in Yusho patients exposed to polychlorinated biphenyls (PCBs) and dioxin-related compounds has not been estimated. METHODS: We identified vital status and cause of death for Yusho patients between 1968 and 2017. Risk of cancer- and noncancer-specific mortality was estimated using a flexible hazards-based regression model, with accounting for competing events. RESULTS: In total, 1664 Yusho patients with 63,566 person-years of follow-up were included in the analysis. 50-year cumulative incidence of cancer mortality was 12.4&#37; (95&#37; confidence interval [CI], 10.5-14.7) in males and 4.7&#37; (95&#37; CI, 3.5-6.4) in females (difference, 7.7 percentage points [95&#37; CI, 5.2-10.2]; adjusted hazard ratio for males, 2.61 [95&#37; CI, 1.93-3.52]). For noncancer, the 50-year cumulative incidence of mortality was 35.4&#37; (95&#37; CI, 32.8-38.3) in males and 35.6&#37; (95&#37; CI, 33.3-38.1) in females (difference, -0.2 percentage points [95&#37; CI, -3.5 to 3.1]; adjusted hazard ratio for males, 1.51 [95&#37; CI, 1.26-1.82]). CONCLUSIONS: These findings confirm that male Yusho patients have a significantly higher risk of cumulative incidence of cancer-specific mortality than female Yusho patients. Our findings might be useful in providing Yusho patients with more accurate information on cancer prognosis and survivorship and help determine more appropriate disease management.

DOI： 10.1016/j.envint.2020.106320

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Poisoning by high concentrations of dioxin and its related compounds manifests variable toxic symptoms such as general malaise, chloracne, hyperpigmentation, sputum and cough, paresthesia or numbness of the extremities, hypertriglyceridemia, perinatal abnormalities, and elevated risks of cancer-related mortality. Such health hazards are observed in patients with Yusho (oil disease in Japanese) who had consumed rice bran oil highly contaminated with 2,3,4,7,8-pentachlorodibenzofuran, polychlorinated biphenyls, and polychlorinated quaterphenyls in 1968. The blood concentrations of these congeners in patients with Yusho remain extremely elevated 50 years after onset. Dioxins exert their toxicity via aryl hydrocarbon receptor (AHR) through the generation of reactive oxygen species (ROS). In this review article, we discuss the pathogenic implication of AHR in dioxin-induced health hazards. We also mention the potential therapeutic use of herbal drugs targeting AHR and ROS in patients with Yusho.

DOI： 10.3390/ijms22020708

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.

DOI： 10.3390/ijms21249412

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The "Guidelines for the management of dermatomycosis" of the Japanese Dermatological Association were first published in Japanese in 2009 and the Guidelines Committee of the Japanese Dermatological Association revised it in 2019. The first guidelines was prepared according to the opinions of the Guidelines Committee members and it was of educational value. The revised version is composed of introductory descriptions of the disease concepts, diagnosis, medical mycology and recent advances in treatment, along with clinical questions (CQ), which is intended to help in general practice for dermatologists. The CQ are limited to those involved in therapy but include some of the recently launched antifungal agents. The level of evidence and the degree of recommendation for each item were reviewed by the committee based on clinical studies published by 2018. For rare dermatomycoses, recommendations by the committee are described in the guidelines. In this field, there are still few good quality studies on treatment. Periodic revision in line with new evidence is necessary.

DOI： 10.1111/1346-8138.15618

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In 1968, the Yusho incident resulted in accidental exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and related compounds in Japan. This study updated the risk of mortality in Yusho patients. METHODS: We obtained updated cohort data for all Yusho patients for the period 1968-2017. We calculated standardized mortality ratios (SMRs) for all-cause and cause-specific mortality over a 50-year follow-up period compared with the general population in Japan. RESULTS: A total of 1664 Yusho patients with 63,566 person-years of follow up were included in the analysis. Among males, excess mortality was observed for all cancers (SMR: 1.22, 95&#37; confidence interval [CI]: 1.02 to 1.45) and lung cancer (SMR: 1.59, 95&#37; CI: 1.12 to 2.19). Among females, increased mortality was observed for liver cancer (SMR: 2.05, 95&#37; CI: 1.02 to 3.67). No significant increase was seen in non-cancer-related mortality compared with the general population. CONCLUSIONS: Carcinogenic risk in humans after exposure to PCBs and PCDFs remains higher among Yusho patients. Our findings suggest the importance of care engagement and optimum management to deal with the burden of Yusho disease.

DOI： 10.1186/s12940-020-00680-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms20164053

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）  

DOI： 10.1111/all.13322

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jaad.2017.12.040

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jdermsci.2017.10.002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/ijms18091948

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.13834

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/modpathol.2016.169

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）  

掲載種別：研究論文（学術雑誌）  

担当ページ：「クロラゾールブラックE染色」Page 160-161   記述言語：日本語   著書種別：学術書

開催年月日： 2015年9月

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Rotterdam   国名：オランダ王国  

開催年月日： 2011年5月

会議種別：口頭発表（一般）  

開催地：Seoul   国名：大韓民国  

開催年月日： 2011年5月

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：Seoul   国名：大韓民国  

開催年月日： 2011年5月

会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：Phoenix   国名：アメリカ合衆国  

開催年月日： 2010年10月 - 2011年7月

会議種別：口頭発表（一般）  

開催地：Fukuoka   国名：日本国  

開催年月日： 2010年9月

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国名：日本国  

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開催地：San Antonio   国名：アメリカ合衆国  

開催年月日： 2010年8月

会議種別：口頭発表（一般）  

開催地：Kobe   国名：日本国  

開催年月日： 2010年5月

会議種別：口頭発表（一般）  

開催地：Atlanta   国名：アメリカ合衆国  

開催年月日： 2009年9月

会議種別：口頭発表（一般）  

開催地：Budapest   国名：ハンガリー共和国  

開催年月日： 2009年5月

開催地：Tokyo   国名：日本国  

開催年月日： 2008年12月

会議種別：口頭発表（一般）  

国名：台湾  

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Edinburgh   国名：グレートブリテン・北アイルランド連合王国(英国)  

記述言語：英語   会議種別：口頭発表（一般）  

開催地：Raleigh,   国名：アメリカ合衆国  

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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：福岡医学会  

IL-37は抗炎症サイトカインとして同定され、最近の研究では炎症性皮膚疾患(ID)において新たな治療標的となる可能性が示唆されている。ダイオキシンの受容体である芳香族炭化水素受容体(AHR)はIDの病態形成に関与することから、IDにおけるIL-37とAHRとの関係性に関する下記の最新の研究について述べた。1)IL-37の構造とシグナル伝達機構、2)皮膚におけるIL-37の発現とAHRによる制御機構、3)IDにおけるIL-37の役割(アトピー性皮膚炎、乾癬、化膿性汗腺炎)、について述べた。

記述言語：日本語   出版者・発行元：日本皮膚科学会-西部支部  

アトピー性皮膚炎(atopic dermatitis:AD)は臨床現場においてよくみられる慢性皮膚疾患である。その発症や病態形成には,遺伝的,免疫学的,環境的な要因が複雑に絡み合うとされ,近年のさまざまな基礎・臨床研究により,数多くの知見が報告されている。ここでは特に,ADの病態に深く関与する2型サイトカインのIL-4およびIL-13について,その機能や役割,これらを標的にした治療薬の最新知見を概説するとともに,今後望まれるAD治療戦略について考察した。(著者抄録)

記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

記述言語：日本語   出版者・発行元：日本皮膚科学会-西部支部  

記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

種別：査読等 

外国語雑誌　査読論文数：5

日本語雑誌　査読論文数：1