Megumi Furuichi

SOD/catalase mimetic platinum nanoparticles inhibit heat-induced apoptosis in human lymphoma U937 and HH cells

Abstract Platinum nanoparticles (Pt-NPs) are known to possess anti-tumouric activity and the ability to scavenge superoxides and peroxides indicating that they can act as superoxide dismutase (SOD)/catalase mimetics. These potentials seem useful in the protection and/or amelioration of oxidative stress-associated pathologies, but, when they are combined with a therapeutic modality that depends upon the mediation of reactive oxygen species in cell killing induction, the effect of Pt-NPs might be questionable. Here, the effects of polyacrylic acid-capped Pt-NPs (nano-Pts) on hyperthermia (HT)-induced apoptosis and the underlying molecular mechanisms were investigated in human myelomonocytic lymphoma U937 and human cutaneous T-cell lymphoma HH cells. The results showed that the pre-treatment with nano-Pts significantly inhibited HT-induced apoptosis in a dose-dependent manner. Superoxide, but not peroxides, was suppressed to varying extents. All pathways involved in apoptosis execution were also negatively affected. The results reveal that the combination of nano-Pts and HT could result in HT-desensitization.

The Traditional Japanese Formula Keishibukuryogan Inhibits the Production of Inflammatory Cytokines by Dermal Endothelial Cells

Keishibukuryogan (KBG) is one of the traditional herbal formulations widely administered to patients with blood stagnation for improving blood circulation; currently, it is the most frequently prescribed medicine in Japan. KBG has been reported to improve conjunctional microcirculation. The aim of this study was to evaluate the role of KBG and paeoniflorin, a bioactive compound of KBG, in inhibiting the production of inflammatory cytokines using human dermal microvessel endothelial cells (HDMECs). The authors observed that lipopolysaccharide (LPS; 1 μg/mL) stimulated the secretion of proinflammatory cytokines in HDMECs. KBG treatment (10 mg/mL) significantly suppressed the mRNA levels of migration inhibitory factor (MIF), interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α in LPS-stimulated cultured HDMECs. Similarly, paeoniflorin significantly suppressed the mRNA levels of these cytokines in LPS-stimulated cultured HDMECs. ELISA showed that KBG and paeoniflorin suppressed the production of MIF, IL-6, IL-8, and TNF-α in LPS-stimulated HDMECs. Moreover, KBG and paeoniflorin decreased the expression of cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) in these cells. These results suggest that KBG may be useful for improving microvascular inflammation in patients with skin diseases.

A case of giant vascular eccrine spiradenoma with unusual clinical features

Giant vascular eccrine spiradenoma (GVES) is a rare, highly vascular variant of eccrine spiradenoma (ES). To our knowledge, only five such cases have been previously reported in the literature. We report a Japanese patient with GVES on his right shoulder. A 76-year-old Japanese man presented with a tumour involving his right shoulder, which had been present for about 3 years and had gradually increased in size. On physical examination, a pale red pedunculated tumour measuring 50 · 34 · 26 mm was seen, which had erosive lesion on the surface (Fig. 1a). The patient had no pain and reported no other symptoms except bleeding from the lesion. There was no regional lymph-node involvement. The blood test results were almost within normal limits. Enhanced computed tomography showed some high-density nodules in the peripheral region of the tumour (Fig. 1b); in contrast, the central region of the tumour was low density and was not enhanced. The patient underwent total excision of the lesion. Histological examination of the excised tumour showed a prominent blood-filled vascular space and clearly delimited cords (Fig. 2a), showing two types of cell: cells with large pale nuclei in the centre and basaloid cells with small, dark nuclei at the periphery (Fig. 2b). Dilated vascular spaces containing red blood cells were present in the stroma. Immunohistochemically, the luminal large, pale epithelial cells were strongly positive for cytokeratin 19, carcinoembryonic antigen and epithelial membrane antigen, and the outer layer of small basaloid cells was negative. In addition, the cells lining the vascular space were positive for vimentin, CD31 and CD34. Mindbomb homologue (MIB)-1, an antibody against Ki67, was expressed on 3% of the tumour cells. These histological findings were diagnostic of GVES. ES is a benign, adnexal tumour originating from the eccrine sweat glands. It occurs commonly as a subcutaneous solitary nodule, or rarely as multiple lesions. The tumour usually measures < 10 to > 50 mm in diameter. Most of the lesions follow a benign clinical course, and gradually increase in size. In addition, malignant degeneration may also rarely occur. GVES is a rare variant of ES and was first described by Cotton et al. in 1986. Only five such cases have been previously reported in the literature. According to those reports, the lesions were dome-shaped tumours, measuring 20–50 mm in size with a marked degree of vascularity. However, our case was a unique pedunculated tumour, and the clinical features were different (a)

Detection of antibodies to epidermal transglutaminase but not tissue transglutaminase in Japanese patients with dermatitis herpetiformis

MADAM, Dermatitis herpetiformis (DH) is an intensely pruritic, chronic, recurrent, papulovesicular disease. It is commonly thought to be a cutaneous manifestation of a gluten-sensitive enteropathy (GSE). These symptoms were strongly associated with HLA-DQ2 and DQ8. Although DH is a relatively common disease in caucasian populations, it is rare in Asian populations including the Japanese. In addition, several differences between caucasian and Japanese DH have been reported. Japanese DH shows a high frequency of fibrillar IgA deposition, rare GSE and no HLA-DQ2 ⁄DQ8 haplotype. Recently epidermal transglutaminase (eTG) and tissue transglutaminase (tTG) were considered to be autoantigens in caucasian DH. We herein investigated the levels of antibodies to eTG and tTG in two Japanese patients with DH. Patient 1 was a 78-year-old Japanese man, referred to us because of pruritic oedematous erythema, red papules and erosions on the elbows, knees and trunk (Fig. 1a). There was no history of GSE. The HLA haplotypes were A24, A26, B15, B48, DRB1*04 and DRB1*09. A histological examination of the lesions revealed subepidermal blisters with an infiltration of eosinophils and neutrophils (Fig. 1b). Direct immunofluorescence (IF) showed fibrillar IgA depositions in the papillary dermis (Fig. 1c). No positive signal was detected by indirect IF using normal human skin tissues. Patient 2 was a 65-year-old Japanese man referred to us because of small vesicles on the elbows and knees, which were intensely itchy (Fig. 1d). He had never had GSE. The HLA haplotypes were A2, A31, B52, B60, DR4 and DR15. Histological and immunological findings of patient 2 were almost the same as those of patient 1 (Fig. 1e, f). Both patients were diagnosed as having DH. The skin lesions of patient 1 disappeared following treatment with dapsone 100 mg daily and those of patient 2 have been improved by treatment with topical corticosteroids. Both patients refused an intestinal biopsy and treatment with a gluten-free diet (GFD). We next measured IgA reactivity for eTG and tTG by enzyme-linked immunosorbent assay (both from Immundiagnostik, Bensheim, Germany) in these patients. Both assays were performed following the manufacturer’s instructions. The level of IgA antibodies against eTG was markedly increased in both patients (patient 1, 71 U mL; patient 2,

Squamous cell carcinoma arising from Darier's disease

Darier s disease (DD; OMIM 124000) is an autosomal dominant keratinization disorder characterized by the loss of adhesion between epidermal cells, thus resulting in abnormal keratinization. A mutation in the ATP2A2 gene, encoding the sarcoplasmic ⁄ endoplasmic reticulum Ca ATPase (SERCA)2, has previously been identified as the cause of this disease. Squamous cell carcinoma (SCC) arising from DD has not been commonly reported. We report a case of SCC developing in a patient with DD. A 62-year-old Japanese woman, who had been diagnosed as having DD, which had been treated with oral etretinate for the previous 25 years, presented with a 3-month history of a skin tumour on her head. On physical examination, a red erosive tumour measuring 20 · 20 mm in size was seen on the top right of the head. The tumour and its surrounding skin had the appearance of DD. The lesion was excised. Histological examination of the excised tumour found that the irregular tumour mass proliferated downward into the dermis (Fig. 1b). The invading tumour mass was composed of atypical squamous cells and mitotic cells. Acantholysis was also seen within the tumour nest, which is characteristic of DD (Fig. 1c). Immunohistochemically, most of the tumour cells were positive for p53 (Fig. 1d). In addition, MIB-1 was expressed in approximately 50% of all tumour cells. These histological findings indicated a diagnosis of SCC. After obtaining the patient s informed consent, ATP2A2 gene analysis was performed. A heterozygous missense mutation (p.T700A) at exon 15 was found (Fig. 2a). We did not find it in 100 healthy Japanese controls, indicating that it is a pathogenic mutation, not a neutral polymorphism. To our knowledge, this mutation has not been previously described. In this tumour, the cell-specific loss of wild-type ATP2A2 expression was not seen in the genomic DNA, which was isolated from the tumour cells by lasercapture microdissection (Fig. 2b). In addition, no missense mutation in either the H-ras or p53 gene was detected, and there was no evidence of human papilloma virus (HPV) in the tumour cells. SCC arising from DD seems to be rare, and only four such cases have been reported to date. Some of these cases suggested HPV infection to be the cause of carcinogenesis. Recently, heterozygous mutant (ATP2A2 ⁄ ) mice have been reported to develop SCCs on the fore stomach or on the skin, thereby suggesting that SERCA2 haploinsufficiency predisposes keratinocytes to develop neoplasia. Furthermore, loss of heterozygosity was not involved in the carcinogenesis, and the levels of p53 protein in the SCCs increased even though no mutations were found in the p53 gene. Our case is consistent with these reports. In addition, alterations in the ATP2A2 gene have also been reported to lead to the development of various human carcinomas, such as colon and lung cancer. Therefore, our case suggests that SERCA2 haploinsufficiency might cause SCC and thus, this may be a new model of skin carcinogenesis.

Novel mutation of the KRT 10 gene in a Japanese patient with epidermolytic hyperkeratosis

toderma and knuckle pad-like keratoses. J Dermatol 2005; 32: 500–502. 10 Chiu HC, Jee SH, Sheen YS, Chu CY, Lin PJ, Liaw SH. Mutation of keratin 9 (R163W) in a family with epidermolytic palmoplantar keratoderma and knuckle pads. J Dermatol Sci 2007; 45: 63–65. 11 Li M, Yang LJ, Hua HK, Zhu XH, Dai XY. Keratin-9 gene mutation in epidermolytic palmoplantar keratoderma combined with knuckle pads in a large Chinese family. Clin Exp Dermatol 2009; 34: 26–28. 12 Codispoti A, Colombo E, Zocchi L et al. Knuckle pads, in an epidermal palmoplantar keratoderma patient with Keratin 9 R163W transgrediens expression. Eur J Dermatol 2009; 19: 114–118. 13 Lu X, Lane EB. Retrovirus-mediated transgenic keratin expression in cultured fibroblasts: specific domain functions in keratin stabilization and filament formation. Cell 1990; 62: 681–696. 14 Rothnagel JA, Wojcik S, Liefer KM et al. Mutations in the 1A domain of keratin 9 in patients with epidermolytic palmoplantar keratoderma. J Invest Dermatol 1995; 104: 430–433. 15 Funakushi N, Mayuzumi N, Sugimura R et al. Epidermolytic palmoplantar keratoderma with constriction bands on bilateral fifth toes. Arch Dermatol 2009; 145: 609–610.

Giant cystic basal cell carcinoma mimicking epidermal cyst

Dear Editor, Basal cell carcinoma (BCC) is the most common malignant tumor composed of basaloid cells that arise from the basal cells of the epidermis or the epithelial structures of the adnexa. BCC has many different clinical and histological presentations. We herein report a case of cystic BCC which was clinically similar to epidermal cyst. A 91-year-old Japanese man presented with a 4-year history of a soft tumor involving his right cheek. It had recently rapidly increased in size. The physical examination revealed a cystic tumor measuring 5.0 cm · 5.0 cm, including a dark-brown lesion on the center of the surface and irregular telangiectasia on the peripheral area (Fig. 1a). No regional lymph node involvement was detectable. The blood test findings were almost completely normal. Magnetic

Effective treatment of angiosarcoma on the nose by combination treatment with electron beam irradiation, recombinant interleukin‐2 and docetaxel

Angiosarcoma is an uncommon malignant vascular neoplasm. It commonly develops on the head and neck, but it rarely affects the nose. Complete surgical excision of angiosarcoma on the nose is difficult because of cosmetic and functional issues. We describe a patient with angiosarcoma on the nose, which was treated by combination therapy including the administration of docetaxel. A 71-year-old man presented with an 8-month history of an ill-defined, painful, erythematous plaque on his nose and right cheek (Fig. 1a). He had injured his nose in a traffic accident 40 years previously. Histological examination of a skin biopsy taken from the lesion revealed infiltration of spindle-shaped cells to the dermis, and numerous unusual vascular spaces lined by atypical endothelial cells (Fig. 1b,c). Immunohistochemical staining found that the atypical cells were positive for CD31 and CD34 (Fig. 1d), and the mindbomb homologue (MIB)-1 index for the atypical cells was 50%. These histological findings indicated a diagnosis of angiosarcoma. Computed tomography (CT) of the patient s neck and chest and gallium scintigraphy found no evidence of metastasis. Results of all laboratory tests were normal. Owing to the extensive facial involvement, surgical excision was excluded as a treatment option. The patient was initially treated with 50 Gy of electron-beam irradiation to the tumour, followed by subcutaneous injection of recombinant interleukin (IL)-2 (4 · 10 U ⁄ day). These treatments yielded a partial response; however, the tumour gradually redeveloped on the nose and lung metastases were confirmed by CT 18 months later (Fig. 2a).