研究者詳細 - 平井　陽至

論文 - 平井　陽至

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安富陽平, 川上佳夫, 篠倉美理, 平井陽至, 山﨑修, 森実真

西日本皮膚科 83 ( 1 ) 18 - 21 2021年

The aim of the measurement of Epstein-Barr virus DNA in hydroa vacciniforme and hypersensitivity to mosquito bites. 国際誌

Tomoko Miyake, Keiji Iwatsuki, Yoji Hirai, Takenobu Yamamoto, Toshihisa Hamada, Kazuyasu Fujii, Hideaki Imamura, Shin Morizane

Journal of medical virology 92 ( 12 ) 3689 - 3696 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epstein-Barr virus (EBV) DNA load in the blood increases in posttransplant lymphoproliferative disorders and chronic active EBV infection. In this report, we analyzed the EBV DNA load in the peripheral blood mononuclear cells (PBMCs) and plasma of patients with hydroa vacciniforme (HV) and/or hypersensitivity to mosquito bites (HMB) to understand the clinical significance of EBV DNA load. All 30 patients showed high DNA loads in the PBMCs over the cut-off level. Of 16 plasma samples, extremely high in two samples obtained from patients with hemophagocytic lymphohistiocytosis (HLH). The amount of cell-free DNA in plasma was correlated to the serum levels of lactate dehydrogenase and inversely correlated to platelet counts. These results indicate that the EBV DNA load in PBMCs can provide one of the diagnostic indicators for HV and HMB and marked elevation of cell-free EBV DNA in plasma might be related to cytolysis such as that observed in HLH.

DOI： 10.1002/jmv.25811

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Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis. 国際誌

Hayato Nomura, Mutsumi Suganuma, Takuya Takeichi, Michihiro Kono, Yuki Isokane, Ko Sunagawa, Mina Kobashi, Satoru Sugihara, Ai Kajita, Tomoko Miyake, Yoji Hirai, Osamu Yamasaki, Masashi Akiyama, Shin Morizane

International journal of molecular sciences 21 ( 3 ) 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

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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Pediatric-onset annular pustular psoriasis in a patient with Down syndrome. 国際誌

Anri Morita, Yoshio Kawakami, Tatsuya Kaji, Yoji Hirai, Tomoko Miyake, Masayuki Takahashi, Osamu Yamasaki, Kazumitsu Sugiura, Shin Morizane

The Journal of dermatology 46 ( 10 ) e367-e368 2019年10月

TNF-α and IL-17A induce the expression of lympho-epithelial Kazal-type inhibitor in epidermal keratinocytes. 国際誌

Satoru Sugihara, Saeko Sugimoto, Kota Tachibana, Mina Kobashi, Hayato Nomura, Tomoko Miyake, Yoji Hirai, Osamu Yamasaki, Shin Morizane

Journal of dermatological science 96 ( 1 ) 26 - 32 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Serine proteases have important roles in skin barrier function and desquamation, and the aberrant expression or the dysfunction of serine proteases is associated with the pathogenesis of skin diseases. Serine protease activities are tightly regulated by serine proteases such as kallikrein-related peptidases (KLKs) and serine protease inhibitors such as lympho-epithelial Kazal-type related inhibitor (LEKTI). For a better understating of diseases' pathogenesis, the regulation mechanism of serine proteases and the inhibitors' expression in epidermal keratinocytes must be clarified. OBJECTIVES: To investigate the effects of the cytokines on the expression of LEKTI in epidermal keratinocytes. METHODS: Normal human epidermal keratinocytes (NHEKs) were stimulated with panels of inflammatory cytokines. The expression of serine protease inhibitors was analyzed using quantitative real-time PCR and ELISA. LEKTI expression in normal human skin and lesions from psoriasis or atopic dermatitis (AD) were analyzed by immunohistochemically and tape-stripping. Trypsin- and chymotrypsin-like serine protease activities in culture supernatants were measured by using specific substrates. RESULTS: TNF-α and IL-17A significantly induced the expression of LEKTI in NHEKs. The immunohistochemical and tape-stripping analysis revealed that psoriatic skin lesions had higher LEKTI expression compared to normal skin and AD lesions. Trypsin- and chymotrypsin-like protease activities in the culture media were upregulated 3-5 days later but attenuated 6-7 days later period by these cytokines. CONCLUSIONS: In epidermal keratinocytes, the Th1&Th17 cytokines TNF-α and IL-17A induce the expression of serine protease inhibitor LEKTI, and it might occur to suppress the increase in the serine protease activities under inflammation.

DOI： 10.1016/j.jdermsci.2019.08.007

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Clinical manifestations of skin, lung and muscle diseases in dermatomyositis positive for anti-aminoacyl tRNA synthetase antibodies. 国際誌

Hiroko Fukamatsu, Yoji Hirai, Tomoko Miyake, Tatsuya Kaji, Shin Morizane, Emi Yokoyama, Toshihisa Hamada, Takashi Oono, Yoshinobu Koyama, Seiichiro Norikane, Keiji Iwatsuki

The Journal of dermatology 46 ( 10 ) 886 - 897 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Patients with dermatomyositis positive for anti-aminoacyl tRNA synthetase (ARS) antibodies, also known as antisynthetase syndrome (ASS), frequently present with mechanic's hand and interstitial lung disease (ILD). We first screened the antibody profiles of 59 patients with dermatomyositis, and then examined the cutaneous, muscular and pulmonary manifestations characteristic for patients with ASS. The anti-ARS antibodies Jo-1, PL-7, PL-12, EJ and KS, along with antibodies to TIF1-γ, MDA5 and Mi-2, were examined. Among the 59 patients, 20, 21, 15 and three patients were classified into the ASS, non-ASS, myositis-specific antibody-negative and unknown groups, respectively. Five of 16 patients (31%) with ASS had six relatives with a history of collagen diseases, within the second degree of relationship, including two cases of dermatomyositis (vs the non-ASS group, P = 0.018). Patients with ASS more frequently presented with fever and arthralgia, and had elevated levels of C-reactive protein. Nine of the 11 finger lesions (82%) clinically diagnosed as mechanic's hands showed a psoriasiform tissue reaction. ILD was observed in 19 of 20 patients (95%) with ASS, and eight of 21 patients (38%) in the non-ASS group, in which six patients possessed anti-MDA5 antibody. Patients with ASS showed higher serum levels of muscle enzymes, and four of 12 patients (33%) had fasciitis-dominant myopathy, while only one of 11 patients (9%) in the non-ASS group had fasciitis-dominant myopathy. Patients with ASS often present with a psoriasiform tissue reaction in the hand lesions and fasciitis-dominant myopathy, and the relatives of those with ASS are at high risk for collagen diseases.

DOI： 10.1111/1346-8138.15049

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Successful Treatment of Genital Warts with Ingenol Mebutate Monitored with Optical Coherence Tomography and Reflectance Confocal Microscopy. 国際誌

Markus Reinholz, Benjamin M Clanner-Engelshofen, Markus V Heppt, Yoji Hirai, Thomas Ruzicka, Carola Berking, Tanja von Braunmühl

Annals of dermatology 31 ( 4 ) 434 - 437 2019年8月

記述言語：英語

Ingenol mebutate (IM) is approved for the treatment of actinic keratosis and induces cell death in precancerous lesions. The efficacy of IM in the treatment of genital warts was investigated in a therapy-refractory patient. The 74-year-old male was treated with IM gel for three consecutive days. Treatment course and efficacy were evaluated by clinical inspection and non-invasive diagnostics namely optical coherence tomography (OCT) and reflectance confocal microscopy (RCM). Within 24 to 48 hours IM induced a strong local inflammatory reaction. One week later a complete response was observed. OCT and RCM showed a strong reaction after treatment with erosions, swelling of cells, and a subepidermal dark band in representative lesions. IM has the advantage of a short treatment period in contrast to other topical treatments and shows a promising clinical outcome. Larger studies are needed to validate the data.

DOI： 10.5021/ad.2019.31.4.434

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An effective and promising treatment with adalimumab for impetigo herpetiformis with postpartum flare-up. 国際誌

Tamayo Yamashita, Toshihisa Hamada, Yuka Maruta, Ai Kajita, Yoji Hirai, Shin Morizane, Soichiro Watanabe, Kazumitsu Sugiura, Keiji Iwatsuki

International journal of dermatology 58 ( 3 ) 350 - 353 2019年3月

Hydroa vacciniforme: a distinctive form of Epstein-Barr virus-associated T-cell lymphoproliferative disorders. 国際誌

Keiji Iwatsuki, Tomoko Miyake, Yoji Hirai, Takenobu Yamamoto

European journal of dermatology : EJD 29 ( 1 ) 21 - 28 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Hydroa vacciniforme (HV) is a cutaneous subset of Epstein-Barr virus (EBV)-associated T/NK lymphoproliferative disorders (LPDs). Our previous case series study clearly showed a clinical spectrum of EBV-associated T/NK LPDs including HV, hypersensitivity to mosquito bites (HMB), chronic active EBV infection (CAEBV), and hemophagocytic lymphohistiocytosis (HLH). Patients with HV are divided into two groups: a benign subtype designated "classic HV" (cHV) and more serious systemic HV (sHV), also called "HV-like LPD" in the 2017 World Health Organization (WHO) classification. Patients with cHV usually have an increased number of EBV-infected γδT cells and patients with sHV without HMB are further classified into two groups: γδT-cell- and αβT-cell-dominant types. Patients with HMB, with or without HV-like eruptions, have an increased number of EBV-infected NK cells in the blood. Patients with cHV and γδT-cell-dominant sHV show a favourable prognosis, but the other subtypes such as αβT-cell-dominant sHV and HMB have a poor prognosis with mortality rates of 11.5 and 3.51 per 100 person-years, respectively. In addition to the clinical subtypes and the dominant lymphocyte subsets, the poor prognostic indicators include onset age over nine years and expression of the reactivation marker, BZLF1 mRNA. No prognostic correlation has been reported for anti-EBV antibody titres or EBV DNA load. The clinical subtypes and their prognostic factors should be considered for therapeutic interventions.

DOI： 10.1684/ejd.2018.3490

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Autophagy in malnutrition-associated dermatoses. 国際誌

Yoji Hirai, Tomoko Miyake, Toshihisa Hamada, Osamu Yamasaki, Shin Morizane, Tatsuhiko Mori, Keiji Iwatsuki

The Journal of dermatology 46 ( 1 ) 43 - 47 2019年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Malnutrition-associated dermatoses including necrolytic migratory erythema (NME) and pellagra share common clinicopathological features; in particular, necrolytic changes in the upper epidermis. Here, we report the involvement of autophagy in the development of necrolysis in three patients with malnutrition-associated dermatoses. First, we examined an autophagy-specific molecule, microtubule-associated protein light chain 3 (LC3), using a monoclonal antibody. LC3 was strongly expressed in the granular layers of the active border, and less intensely observed in the perilesional areas. Little LC3 staining or only background levels were observed in control skin diseases including atopic dermatitis (n = 4), psoriasis vulgaris (n = 3), basal cell carcinoma with amyloid deposits (n = 3) and squamous cell carcinoma (n = 3). Electron microscopic observations revealed the presence of autophagosome-like structures in the necrolytic areas. No apoptotic signals were observed in the necrolytic lesion using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. Epidermal Langerhans cells determined by anti-CD1a antibody were markedly decreased in number. Our observations suggest the possibility that malnutrition-associated necrolysis, as exemplified by NME and pellagra, may be induced by autophagy.

DOI： 10.1111/1346-8138.14694

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Clinical and Laboratory Markers Associated With Relapse in Cutaneous Polyarteritis Nodosa. 国際誌

Azusa Kato, Toshihisa Hamada, Tomoko Miyake, Shin Morizane, Yoji Hirai, Osamu Yamasaki, Keiji Iwatsuki

JAMA dermatology 154 ( 8 ) 922 - 926 2018年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Importance: In cutaneous polyarteritis nodosa (CPAN), less aggressive treatments can be selected, because CPAN is not associated with life-threatening or progressive outcomes. Although patients with a recurrent clinical course may require additional immunosuppressive therapies, no pretreatment factors associated with a worse prognosis in CPAN have been reported. Objective: To identify clinical or laboratory markers associated with relapse of CPAN. Design, Setting, and Participants: This retrospective case series was performed at a dermatology clinic of a tertiary referral center in Okayama, Japan, from October 1, 2001, through April 30, 2017. Of 30 patients identified with CPAN, the 21 with histopathologic evidence of disease were eligible and enrolled in the study. Main Outcomes and Measures: The medical database was examined for sex, age at diagnosis, affected anatomical sites, type and extent of skin lesion, laboratory data, initial therapies, duration of follow-up, and current status. Relapse was defined as the first reoccurrence or new onset of cutaneous disease that required further escalation of treatment with prednisolone at a dosage of greater than 20 mg/d and/or add-on use of immunosuppressant therapy, more than 6 months after initial treatment. The pretreatment factors were statistically evaluated between the groups without and with relapse. Results: The 21 patients included 5 males and 16 females with a median age of 49 years (range, 11-74 years) at diagnosis. The median follow-up was 42 months (range, 8-374 months). Pretreatment cutaneous ulcer was significantly associated with relapse between the 2 groups (0 of 11 in the nonrelapse group vs 4 of 10 in the relapse group; χ21 = 4.67; P < .05). In the laboratory test results, significantly higher mean (SD) values were observed in the relapse group for C-reactive protein level (0.23 [2.00] vs 6.03 [3.10] mg/dL; standard error of the mean [SEM], 3.40 mg/dL; 95% CI, 0.01-10.8 mg/dL; P = .01), absolute neutrophil count (ANC) (3.4 × 103/μL [1.1 × 103/μL] vs 6.0 × 103/μL [3.2 × 103/μL]; SEM, 2.9 × 103/μL; 95% CI, 1.9 × 103/μL to 14.6 × 103/μL; P = .001), neutrophil-to-lymphocyte ratio (1.4 [0.8] vs 2.8 [0.9]; SEM, 1.2; 95% CI, 1.1-4.9; P = .002), and systemic immune-inflammation index (5.1 × 105 [3.9 × 105] vs 11.7 × 105 [7.7 × 105]; SEM, 7.3 × 105; 95% CI, 3.3 × 105 to 31.1 × 105; P = .007). The estimated 2-year cumulative relapse rate was significantly high in the patients with blood ANC of greater than 4.9 × 103/μL compared with 4.9 × 103/μL or less (9 of 10 [90%] vs 2 of 11 [18%]; 95% CI, 6%-72%). Conclusions and Relevance: Pretreatment status of cutaneous ulcer, the serum C-reactive protein level, the blood ANC, the neutrophil-to-lymphocyte ratio, and the systemic immune-inflammation index are associated with a worse prognosis in CPAN.

DOI： 10.1001/jamadermatol.2018.1601

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Type D (CD8+) lymphomatoid papulosis in a patient with classic (CD4+) mycosis fungoides. 国際誌

Junko Hori-Kosogabe, Toshihisa Hamada, Shin Morizane, Yoji Hirai, Tomoko Miyake, Tadashi Yoshino, Keiji Iwatsuki

European journal of dermatology : EJD 28 ( 2 ) 267 - 268 2018年4月

Epstein-Barr virus-positive mucocutaneous ulcer in a patient with polycythemia vera treated with oral hydroxyurea. 国際誌

Toshihisa Hamada, Mariko Kawata, Yoshinobu Maeda, Tadashi Yoshino, Tomoko Miyake, Shin Morizane, Yoji Hirai, Keiji Iwatsuki

The Journal of dermatology 45 ( 4 ) e82-e83 2018年4月

Clinical outcomes of primary cutaneous anaplastic large cell lymphoma: data from a single Japanese centre. 国際誌

Yuka Maruta, Toshihisa Hamada, Hiroko Fukamatsu, Tatsuya Kaji, Shin Morizane, Yoji Hirai, Tomoko Miyake, Osamu Yamasaki, Tadashi Yoshino, Keiji Iwatsuki

European journal of dermatology : EJD 27 ( 6 ) 669 - 671 2017年12月

皮膚リンパ腫患者の治療抵抗性皮膚病変に対する低線量放射線療法の有用性

浜重純平, 平井陽至, 濱田利久, 岩月啓氏, 勝井邦彰, 金沢右

日本皮膚科学会雑誌 127 ( 2 ) 219 - 219 2017年2月

Comparative study on driver mutations in primary and metastatic melanomas at a single Japanese institute: A clue for intra- and inter-tumor heterogeneity. 国際誌

Tatsuya Kaji, Osamu Yamasaki, Minoru Takata, Masaki Otsuka, Toshihisa Hamada, Shin Morizane, Kenji Asagoe, Hiroyuki Yanai, Yoji Hirai, Hiroshi Umemura, Keiji Iwatsuki

Journal of dermatological science 85 ( 1 ) 51 - 57 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared. RESULTS: Of 77 tissue samples, BRAF V600E was detected in 21 samples (27%), CDK4 R24C in 7, EPHB6 G404S in 6, BRAF V600K in 2, NEK10 E379K in 2, and CDK4 R24H, NRAS Q61K, NRAS Q61R, KRAS G12A, KIT L576P, KIT V559A, ERBB4 E452K, and PDGFRA E996K in one sample each. No driver mutations related to the MAPK cascade including RAS and BRAF were detected in the chronically sun-damaged (CSD) group of melanoma. Dual or triple driver mutations were found in four of 40 (10%) samples from the primary melanomas, and three of 37 (8%) of the metastatic melanomas. Fourteen of 26 (54%) samples of non-CSD melanoma, and 3 of 6 (50%) melanomas of unknown primary origin had the BRAF V600E mutation. Mutations in membrane-bound receptors including KIT, ERBB4 and EPHB6 were detected in 8 of 77 (10%) samples. Of 17 pairs of primary and metastatic melanomas from the same patient, the primary mutation pattern was changed to a novel one in three cases, and only one of the plural mutations in the primary melanoma was found in the metastatic lesions in two cases. CONCLUSIONS: BRAF V600E is a predominant mutation in non-CSD melanoma and melanomas of unknown primary origin. Mutational heterogeneity may exist in the primary melanoma (intra-tumor heterogeneity), and between the primary and metastatic lesions (inter-tumor heterogeneity).

DOI： 10.1016/j.jdermsci.2016.10.006

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Differential diagnosis of herpetiform vesicles by a non-invasive, molecular method using crusts or blister roofs: Sensitivity, specificity and likelihood ratio. 国際誌

Tomoko Miyake, Takenobu Yamamoto, Yoji Hirai, Keiji Iwatsuki

Journal of dermatological science 84 ( 3 ) 358 - 359 2016年12月

手術室映像システムを活用した皮膚科の手術教育

山崎修, 加持達弥, 平井陽至, 梅村啓史, 濱田利久, 岩月啓氏

日本皮膚科学会雑誌 126 ( 11 ) 2137 - 2137 2016年10月

IVIGにより血小板減少をきたした難治性尋常性天疱瘡の1例

浜重純平, 野村隼人, 禅正和真, 河野淳子, 難波裕子, 梶田藍, 平井陽至, 岩月啓氏, 松三友子

日本皮膚科学会雑誌 126 ( 11 ) 2135 - 2136 2016年10月

病院現況および患者視点からみた進行期悪性黒色腫に対する新規治療

山崎修, 加持達弥, 梅村啓史, 平井陽至, 森実真, 濱田利久, 高田実, 岩月啓氏, 勝井邦彰, 合地明

日本皮膚科学会雑誌 126 ( 9 ) 1709 - 1716 2016年8月

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