Masahisa Shindo

CD27, a member of the tumor necrosis factor receptor superfamily, activates NF-kappaB and stress-activated protein kinase/c-Jun N-terminal kinase via TRAF2, TRAF5, and NF-kappaB-inducing kinase.

CD27 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on T, B, and NK cells. The signal via CD27 plays pivotal roles in T-T and T-B cell interactions. Here we demonstrate that overexpression of CD27 activates NF-κB and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). Deletion analysis of the cytoplasmic domain of CD27 revealed that the C-terminal PIQEDYR motif was indispensable for both NF-κB and SAPK/JNK activation and was also required for the interaction with TNF receptor-associated factor (TRAF) 2 and TRAF5, both of which have been implicated in NF-κB activation by members of the TNF-R superfamily. Co-transfection of a dominant negative TRAF2 or TRAF5 blocked NF-κB and SAPK/JNK activation induced by CD27. Recently, a TRAF2-interacting kinase has been identified, termed NF-κB-inducing kinase (NIK). A kinase-inactive mutant NIK blocked CD27-, TRAF2-, and TRAF5-mediated NF-κB and SAPK/JNK activation. These results indicate that TRAF2 and TRAF5 are involved in NF-κB and SAPK/JNK activation by CD27, and NIK is a common downstream kinase of TRAF2 and TRAF5 for NF-κB and SAPK/JNK activation.

Syringocystadenoma papilliferum on the male nipple

Syringocystadenoma papilliferum is a rare benign adnexal tumor that most frequently arises from an organoid nevus on the head and neck. Occurrence of this tumor on the male breast is extremely rare. A 74‐year‐old Japanese man presented with a nodule on his left nipple. Histopathological findings were typical for syringocystadenoma papilliferum. Ultrastructurally, constituent epithelial cells of the tumor were divided into three types. We focused on one cell type, undifferentiated clear cells, which have been suggested to be pluripotent cells bearing stem cell nature in syringocystadenoma papilliferum. Immunohistochemically, the tumor cells were negative for cytokeratin 15, which is known as a relatively specific marker for multipotent stem cells in the follicular bulge. We speculated that the clear cells are slightly differentiated toward apocrine rather than stem cells. We also ruled out the possibility of a relationship between the clear cells and Toker cells, which have a clear cytoplasm and are present in the areola region. Dermoscopic examination revealed amorphous milky white areas that corresponded to the pathological findings of luminal deposition of the tumor.

Regulatory T cells and skin tumors.

Regulatory T cells (Tregs) are essential for maintaining self-tolerance and also play a pivotal role in diminishing anti-tumor immunoresponse. The frequency and activity of CD4(+)CD25(+)FoxP3(+) Tregs in the circulation and tumor microenvironment is increased in patients with various cancers. Although, the exact role of Tregs in cutaneous tumors remains unclear, Tregs contribute to tumor progression of skin cancers, explaining, in part, why immunotherapy with dendritic cell-based vaccination for melanoma patients has not been satisfactory. Therefore, there has been considerable interest in determining their function in order to treat skin cancers such as malignant melanoma. However, clinical trials with specific antibodies designed to overcome Treg-associated immunosuppression resulted in limited clinical efficacy with some adverse effects. A better understanding of the role of Tregs in the tumor environment might contribute to the development of novel approaches for treating various cutaneous tumors. In this review, we focus on clinical and basic research on Tregs in relation to skin tumors and describe some important patents for the treatment of skin cancers.

Necrotizing Soft-Tissue Infection Caused by Both Candida glabrata and Streptococcus agalactiae

dronate and zoledronic acid. No established guidelines exist for dosing of zoledronic acid in children. Our patient’s severe symptomatic hypocalcemia may have been dose related and/or related to his severe osteopenia. He received 4 mg (0.1 mg/kg) of zoledronic acid, which has been safely used in multiple patients with osteopenia treated by one of us (J.E.H.). Two recent case series of zoledronic acid therapy used to treat a small number of children with osteoporosis or localized bone disease and evidence of active resorption have used initial doses of 0.0125 to 0.025 mg/kg. Owing to the risk for osteopenia and osteoporosis, patients with RDEB should be screened for bone mineral density with dual-energy x-ray absorptiometry. Low serum calcium and 25-hydroxyvitamin D levels should be treated with vigorous supplementation and exercise programs to prevent development of osteopenia. Caution should be used when choosing a zoledronic acid dose: an initial low dose (0.025-0.05 mg/kg) should be considered for patients with severe osteopenia to prevent hypocalcemia, and treatment should be repeated every 3 to 6 months. Further studies of the safest and most effective oral and/or intravenous doses of bisphosphonates in children are needed.

Occipital bone dysplasia associated with diffuse plexiform neurofibroma

ejd.2011.1359 Auteur(s) : Yuichi Yoshida yxy@grape.med.tottori-u.ac.jp, Masahisa Shindo, Osamu Yamamoto Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University, 86 Nishi-cho Yonago-shi, Tottori 683-8503, Japan Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disease characterized by cafe-au-lait spots, neurofibroma, freckling, optic glioma, Lisch nodules, and osseous abnormalities. NF1-associated sphenoid wing dysplasia [...]

Assignment1 of IκB kinase β (IKBKB) to human chromosome band 8p12→p11 by in situ hybridization

NF-ÎB is composed of heteroor homodimers of Rel family proteins and is involved in inflammatory response, growth control, and cell death. In unstimulated cells, NF-ÎB is sequestered in the cytoplasm as a complex with inhibitory proteins called IÎBs. Various stimuli activating NF-ÎB result in phosphorylation of two serines at the N-terminus of IÎB· and IÎBß and subsequent degradation of them, resulting in translocation of NF-ÎB into the nucleus and activation of target genes. A previous study showed that the IÎB kinase (IKK) forms a large complex with a molecular mass of 700 kDa (Lee et al., 1997). Recently, two subunits of the IKK complex, designated IKK· and IKKß, have been identified. Both IKK· and IKKß specifically phosphorylate N-terminal serines of IÎB·, IÎBß and IÎBÂ, and are involved in NF-ÎB activation by TNF, IL-1 and members of the TNF receptor superfamily. (Didonato et al., 1997; Regnier et al., 1997; Zandi et al., 1997; Mercurio et al., 1997; Woronicz et al., 1997; Nakano et al., 1998). IKK· is a previously cloned serine-threonine kinase called CHUK and the human gene (CHUK) was mapped to chromosome 10p25→p24 (Connelly et al., 1995; Mock et al., 1995). Using fluorescence in situ hybridization we have determined the location of the human IKKß gene (IKBKB) at chromosome 8p12→p11.

Chemical burn caused by excrement after ingestion of kerosene

ejd.2011.1345 Auteur(s) : Hiromi Higaki-Mori higaki.h@med.tottori-un.ac.jp, Tessin Watanabe, Masahisa Shindo, Yuichi Yoshida, Osamu Yamamoto Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan We herein describe a case of chemical burn by excrement after accidental ingestion of kerosene. An 84-year-old Japanese woman with slight dementia was referred to our clinic for evaluation of erythema with [...]

A case of zinc deficiency histologically showing spongiform pustules of Kogoj.

An 89-year-old Japanese woman was referred to us for evaluation of multiple scaly erythematous plaques with erosions that had developed over her entire body. She had received enteral feeding because of eating disorders for 9 months. Although she had been treated with topical steroid ointment and oral administration of prednisolone and terbinafine before admission to our department, there was no response. Due to concurrent severe diarrhoea, she was also treated with intravenous antibiotics (imipenem), but the treatment was not effective. Physical examination revealed multiple erythematous plaques with oedema, irregular in shape, on her face, especially around the eyelids, vulva, trunk and extremities (Fig. 1). The centre of each erythema was erosive, and some pustules were observed on the surface. Laboratory examinations demonstrated the following values: white blood cell count 13.2 × 109/l; C-reactive protein 6.9 mg/dl; serum zinc level 5.2 μmol/l (normal range 9.2–20 μmol/l). No fungus was found on the erythema. A biopsy specimen taken from the erythema with pustules showed hyperkeratosis, parakeratosis, acanthosis and subcorneal spongiform pustules of Kogoj (Fig. 2). Based on these findings, a diagnosis of zinc deficiency was made. Supplementation of zinc by oral administration of zinc sulphate for 2 weeks improved the skin lesions.