Fujio Otsuka

Attenuation of UVB-Induced Sunburn Reaction and Oxidative DNA Damage with no Alterations in UVB-Induced Skin Carcinogenesis in Nrf2 Gene-Deficient Mice

UV radiation is an important environmental factor in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with generation of reactive oxygen species. Cellular antioxidants prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. The transcription factor Nrf2 (NF-E2-related factor 2) and its negative regulator protein, Keap1 (Kelch-like-ECH-associated protein 1), are central regulators of cellular antioxidant responses. We used nrf2-null mice to investigate the roles of the Nrf2-Keap1 system in protection of skin from harmful effects of UVB irradiation. A single irradiation with UVB induced stronger and longer lasting sunburn reaction in nrf2-null mice. Histological changes, including epidermal necrosis, dermal edema, inflammatory cell infiltration, sunburn cell formation, TUNEL-positive apoptotic cell formation, and accumulation of oxidative DNA products such as 8-hydroxy-2-deoxyguanosine after UVB irradiation, were more prominent in nrf2-null mice. These findings indicate that the Nrf2-Keap1 pathway plays an important role in protection of the skin against acute UVB reactions, including cutaneous cell apoptosis and oxidative damage. However, there were no significant differences in skin carcinogenesis between nrf2-null and wild-type mice exposed to chronic UVB irradiation, suggesting that there is a complex and subtle balance between factors promoting and preventing photocarcinogenesis. Journal of Investigative Dermatology (2008) 128, 1773-1779; doi:10.1038/sj.jid.5701245; published online 17 January 2008.

Severe local skin reactions to interferon beta-1b in multiple sclerosis-improvement by deep subcutaneous injection

Severe local skin reactions to subcutaneous injection of interferon beta-1b in multiple sclerosis are rare, and only 12 cases of severe skin reaction due to interferon beta-1b have been reported to date. We report two cases of severe skin reactions in multiple sclerosis patients following the injection of subcutaneous interferon beta-1b. In case 1, after five years of treatment, a painful indurated erythematous lesion appeared at the injection site on the left buttock. On histological analysis, the lesion showed septal and lobular panniculitis with lymphocytic infiltration. In case 2, cutaneous ulceration was surrounded by painful induration, which developed at the injection site on the right thigh after four years of treatment. The lesions resolved rapidly after discontinuation of interferon beta-1b treatment in both cases. Here, we review cases of similar lesions caused by interferon beta-1b reported in the literature, and discuss the characteristics, mechanism, treatment, and prevention of such lesions.

The combination of ubiquitous transcription factors AP-1 and Sp1 directs keratinocyte-specific and differentiation-specific gene expression in vitro

Abstract:u2002 Previous studies of epidermal‐specific gene promoters suggested that a limited set of transcription factors regulate keratinocyte‐specific and differentiation‐specific gene expression in the epidermis. In the present study, we investigated the functional importance of AP‐1‐ and Sp1‐binding elements in the determination of cell type‐specific and differentiation‐specific gene expression by transient transfection into undifferentiated and differentiated keratinocytes as well as into various non‐epidermal cell lines. Synthesized short AP‐1‐ and/or Sp1‐binding elements were inserted into a minimal reporter vector, and the artificial promoter containing both AP‐1 and Sp1 elements showed high levels of transcriptional activity only when transfected into differentiated keratinocytes. Promoters containing either the AP‐1 or the Sp1 motif alone showed little activity in any of the cells examined. We also found that close proximity of the Sp1 and AP‐1 sites is essential for transcriptional activity, suggesting that the physical interaction between Sp1 and AP‐1 factors is important for functional activity. These results clearly demonstrate that the combination of ubiquitously expressed transcription factors AP‐1 and Sp1 confers keratinocyte specificity and differentiation specificity on the gene expression. Our findings also provide a simple model of the mechanisms underlying regulation of cell type‐specific and cell differentiation‐specific gene expression by ubiquitously expressed transcription factors.

Chronically Recurrent and Disseminated Tinea Faciei/Corporis—Autoinoculation from Asymptomatic Tinea Capitis Carriage

Abstract:u2002 We report clinical findings in a 12‐year‐old girl with long‐term recurrent and disseminated multiple eruptions of tinea faciei and tinea corporis, which persisted for 10u2003years. Mycological examination revealed the dermatophyte Trichophyton tonsurans in both scale samples from the body lesions and in brushing samples from her asymptomatic scalp, suggesting that she was an asymptomatic dermatophyte carrier on the scalp, and autoinoculation of the dermatophyte was responsible for the recurrent and disseminated tinea faciei/corporis.

Modified gluteal‐fold flap for the reconstruction of vulvovaginal defects

Backgroundu2002 Reconstruction of vulvovaginal defects after tumor excision requires good‐quality skin cover because of the cosmetic and functional importance of this region. Although numerous techniques for vulvovaginal reconstruction have been described, an ideal approach has yet to be widely accepted.

The induction of tumor‐specific CD4+ T cells via major histocompatibility complex class II is required to gain optimal anti‐tumor immunity against B16 melanoma cell line in tumor immunotherapy using dendritic cells

Abstract:u2002 We have demonstrated that dendritic cells (DCs) genetically modified to express tumor‐associated antigens (TAAs) with retroviral vectors elicit more potential anti‐tumor effect than those loaded with peptides because they can prime antigen‐specific CD4+ T cells resulting in production of tumor‐specific antibody. In this study, we showed the importance of antigen presentation via a major histocompatibility complex (MHC) class II molecule in cancer immunity against non‐membrane bound TAAs such as the melanoma antigen gp100 by using DCs derived from MHC class II‐deficient mice (C2KO). DCs were prepared by transduction of gp100 cDNA into haematopoietic progenitor cells obtained from C2KO followed by differentiation with cytokines (C2KO‐gp/DCs). When C2KO‐gp/DCs were inoculated into immunocompetent mice, the mice scarcely primed the antigen‐specific Th1 cells and developed fewer CD8 T cells than did those inoculated with transduced DCs prepared from normal mice. The attenuated anti‐tumor effect was also confirmed in a postimmunization setting where, while two of eight control mice eradicated the pre‐existing melanoma cell line B16 (25%), no mice inoculated with C2KO‐gp/DCs did. These results suggested not only the limitation of current protocols using MHC class I‐restricted tumor peptides but also the usefulness of DCs expressing gp100 in vaccine therapy against melanoma.

Tumor lysis syndrome after transcatheter arterial infusion of cisplatin and embolization therapy for liver metastases of melanoma

Backgroundu2002 Tumor lysis syndrome (TLS) is rare in the treatment of solid tumors, but it may occur in myelolymphoproliferative diseases.

Overexpression of the Transcription Factor Yin-Yang-1 Suppresses Differentiation of HaCaT Cells in Three-Dimensional Cell Culture

Yin-Yang-1 (YY1) is a member of the GLI-Krüppel family of transcription factors, and both YY1 mRNA and protein expression have been identified in a number of different tissues and cell types suggesting that it is expressed both constitutively and ubiquitously. In epidermal tissue, however, we reported previously that YY1 protein is expressed at high levels in undifferentiated basal keratinocytes and is downregulated during differentiation toward the suprabasal layers. This differential expression pattern during keratinocyte differentiation suggests that YY1 may have an important role in regulating keratinocyte differentiation. In this study, we examined the role of YY1 in differentiation of the human keratinocyte cell line HaCaT using air-liquid interface three-dimensional culture. The constitutive overexpression of YY1 in HaCaT cells during air exposure-induced differentiation resulted in an undifferentiated phenotype, thickening of the stratified layers, suppression of differentiation marker expression, and retention of proliferative activity. These findings suggested that YY1 may have an important role in maintenance of the undifferentiated phenotype of keratinocytes in the basal epidermal layer, and that reduction of YY1 expression in the suprabasal layers may allow keratinocytes to differentiate and move toward the upper layers of the epidermis.

Multiple microvenular hemangiomas in a healthy child.

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Complete long-term response of angiosarcoma of the scalp with cervical lymph node metastases treated with a combination of weekly and monthly docetaxel.

MADAM, Cutaneous angiosarcoma is a rare malignant tumour of vascular endothelial cells that usually affects the face and scalp regions, most often in elderly men. It usually follows an aggressive course with a tendency for progressive local invasion and early lung metastasis. In a recent study, a median survival rate of 16 months and cumulative survival rates at 2 and 5 years of 31% and 8%, respectively, were reported. Because of the rarity of this malignancy, the optimal treatment is not clearly defined and remains difficult. We describe a patient with angiosarcoma of the scalp with cervical lymph node metastases who was treated with combined weekly and monthly docetaxel and showed a complete long-term response over 40 months. A 69-year-old woman presented with skin lesions of the scalp that had started to develop 1 month previously. She had no significant personal or family history. A physical examination revealed multifocal red nodules and two ulcerated plaques of 8 · 8 cm and 7 · 6 cm on the scalp (Fig. 1a). A computed tomography (CT) scan showed irregularly shaped, swollen cervical lymph nodes (Fig. 1b), indicating cervical lymph node metastasis. A biopsy specimen of her scalp revealed irregular vascular channels with haemorrhage, lined by atypical, enlarged pleomorphic endothelial cells infiltrating the dermis (Fig. 1c). Immunohistochemistry revealed that these cells were positive for CD31 and CD34. Cervical lymph node biopsy was not performed because of the patient’s refusal. The pathological and immunohistochemical findings led to a diagnosis of angiosarcoma of the scalp. The diagnosis of cervical lymph node metastases was based on the CT findings. Treatment options including surgery, radiation and chemotherapy were offered. The patient elected to undergo chemotherapy with docetaxel. She was started on weekly intravenous docetaxel at a dose of 25 mg m on an outpatient basis. The cycle was repeated every 7 days for 3 weeks, followed by a 1-week interval between courses. After nine cycles, the red nodules were almost flat and the ulcerated plaques had significantly decreased in size. She received additional monthly docetaxel at a dose of 60 mg m. After five cycles, the docetaxel was stopped because of peripheral neuropathy. The lesions had almost disappeared, leaving slight pigmentation and depigmentation of the skin (Fig. 2a). A CT scan also showed that the swollen cervical lymph nodes had disappeared (Fig. 2b). Biopsy specimens taken from different sites of the patient’s scalp after chemotherapy revealed no atypical endothelial cells or irregular vascular tissue (Fig. 2c). Forty-four months after the diagnosis and initiation of docetaxel therapy, the patient has no evidence of local recurrence or metastasis. Angiosarcoma has usually been treated with combined radical surgical excision and radiotherapy. However, over 60% of patients ultimately develop distant metastases. Furthermore, many patients present with extensive disease for which surgery is not an option. Thus, there has been interest in other treatment options, including chemotherapy. Recent studies have shown a favourable response of angiosarcoma of the scalp or face to paclitaxel. Although a randomized, phase II study concluded that weekly docetaxel was ineffective in the treatment of soft tissue sarcoma, including angiosarcoma, the effec(a) (b)