Takaoki Ishiji

Transcriptional enhancer factor (TEF)-1 and its cell-specific co-activator activate human papillomavirus-16 E6 and E7 oncogene transcription in keratinocytes and cervical carcinoma cells.

The human papillomavirus (HPV)‐16 oncogenes, E6 and E7, are transcribed preferentially in keratinocytes and cervical carcinoma cells due to a 5′ enhancer. An abundant peptide binding to a 37 nt enhancer element was purified from human keratinocytes by sequence‐specific DNA chromatography. This protein was identified as transcriptional enhancer factor (TEF)‐1 by complex mobility, binding to wild‐type and mutant SV40 and HPV‐16 enhansons and antigenic reactivity with two anti‐TEF‐1 antibodies. TEF‐1 is cell‐specific, but its transactivation also depends on a limiting, cell‐specific TEF‐1 ‘co‐activator’. We show that both TEF‐1 and the TEF‐1 co‐activator are active in human keratinocytes and essential for HPV‐16 transcription. TEF‐1 binding in vivo was necessary for HPV‐16 P97 promoter activity. Excess TEF‐1 and chimeric GAL4‐TEF‐1 specifically inhibited the P97 promoter by ‘squelching’, indicating that HPV‐16 transcription also requires a limiting TEF‐1 co‐activator. TEF‐1 and the TEF‐1 co‐activator functions mirrored HPV‐16 transcription by their presence in keratinocytes and cervical carcinoma cells and their absence from lymphoid B‐cells, but also functioned in liver cells where the HPV‐16 promoter is inactive. TEF‐1 and its associated co‐activator are thus part of a complex mechanism which determines the restricted cell range of the HPV‐16 E6 and E7 oncogene promoter.

Molecular mechanism of carcinogenesis by human papillomavirus-16.

Human papillomaviruses (HPVs) are common DNA viruses in humans. Recently, epithelial cancers associated with HPV infection have been used as models of virus‐induced carcinogenesis. HPVs can be divided into two groups, mucosal and cutaneous. HPV‐16 is the most frequent mucosal type associated with cervical cancer. Although the molecular mechanisms of carcinogenesis by HPV‐16 have not been completely elucidated, it is apparent that HPV infection is the major risk factor in cervical carcinogenesis. Two viral early genes, E6 and E7, and an upstream regulatory region (URR) are preserved in cervical carcinoma cell lines as well as in clinical samples of cervical cancer, indicating that these regions are important in cancer development. E6 and E7 function as transforming genes. E6 protein binds to and promotes degradation of the tumor suppressor protein, p53, while E7 protein complexes and inactivates the Rb protein; together, they disrupt cell cycle regulation. E6 and E7 are transcribed from a promoter, P97. P97 is regulated by complex interactions between multiple, positive and negative, cellular factors and the viral E2 product. E2 disruption caused by the integration into the cellular genome may induce overexpression of E6 and E7. The E6 and E7 proteins are thought to act as critical factors in cervical carcinogenesis by inactivating the two tumor suppressor proteins, p53 and Rb, which are commonly mutated in other human cancers.

Impact of disease severity on work productivity and activity impairment in Japanese patients with atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disease that is characterized by chronic and persisting pruritic and eczematous lesions. There has been no study of work productivity and activity in AD patients in relation to disease severity. The purpose of this study was to examine the impact of disease severity on work productivity and activity impairment (WPAI) in adult AD patients using the Japanese version of the questionnaire. Data were collected from 112 AD patients who visited the Jikei University Hospital. Outcomes as measured by the questionnaire included employment status, total work productivity impairment (TWPI) and total activity impairment (TAI). We investigated the correlation between TWPI or TAI scores and severity scoring of AD (SCORAD) for disease severity and dermatology life quality index (DLQI) for quality of life impairment. Both TWPI and TAI scores were significantly correlated with the SCORAD and DLQI scores (P < 0.001), indicating disease severity is significantly associated with WPAI in Japanese adult AD patients. Further studies are necessary to evaluate the effects of treatments on WPAI for severe AD patients.

Cutaneous lymphomas in Tokyo: analysis of 62 cases in a dermatology clinic

Abstract

A Case of Pemphigus Vulgaris Successfully Treated with Single Filtration Plasmapheresis: A Correlation of Clinical Disease Activity with Serum Antibody Levels

We report a patient with pemphigus vulgaris (PV) successfully treated with single filtration plasmapheresis. A 40‐year‐old man with PV was started on therapy with prednisolone (PSL). Although the dosage of PSL was doubled, and both cyclosporin A (CyA) and pulse therapy were added, the disease was not controlled. After single filtration plasmapheresis began, most of the eroded lesions on the trunk reepithelialized. A switch to double filtration was followed by recurrence. Finally, additional treatments with single filtration plasmapheresis were required to obtain remission. To evaluate the efficacy of the treatment, circulating antibodies were measured by immunofluorescence (IIF) and enzyme‐linked immunosorbent assays (ELISAs) using recombinant desmoglein (Dsg) 3. IIF titer and the ELISA scores correlated with the clinical disease activity. It is suggested that ELISA was more sensitive than IIF.

The truncated C-terminal E2 (E2-TR) protein of bovine papillomavirus (BPV) type-1 is a transactivator that modulates transcription in vivo and in vitro in a manner distinct from the E2-TA and E8^E2 gene products.

The E2 open reading frame of bovine papillomavirus (BPV)-1 encodes a 410 amino acid (aa) transcriptional activator, E2-TA, and collinear polypeptides--E2-TR (243 aa) and E8^E2 (196 aa). E8^E2 and E2-TR share the DNA-binding domain of E2-TA, and both have been defined as transcriptional repressors. Although purified E2-TR and E8^E2 proteins specifically bound E2 sites with similar affinities, only the E2-TR stimulated transcription. Here we show that E2-TR trans-activates E2-dependent promoters 5 to 10-fold in cooperation with cellular factors and in a dose-dependent fashion in epithelial cells and fibroblasts of animal or human origin while E2-TA activated >100-fold and the E8^E2 had no effect. However, in contrast to E2-TA, E2-TR activated transcription from a promoter-proximal position. E2-TR also partially inhibited the BPV-1 P89 or heterologous promoters whereas E8^E2 led to complete repression. Thus, the BPV-1 E2-TR modulates viral gene expression in a manner distinct from other E2 proteins.

Skin ultrasound examination proves useful in diagnosing two cases of solid cystic hidradenoma

two cases of solid cystic hidradenoma Editor, Solid cystic hidradenoma is an uncommon, benign, skin adenexal tumor of sweat gland origin. This tumor has been reported under various designations, such as clear cell hidradenoma, nodular hidradenoma, and eccrine acrospiroma. It usually occurs on the head, neck, or limbs, and presents as a solitary, slow-growing, solid or cystic nodule. Because this tumor is usually removed without imaging studies, typical radiological findings have not yet been well established. To the best of our knowledge, only five cases have been reported based on ultrasound examinations from the fields of breast surgery or radiology. Herein, we present two cases of solid cystic hidradenoma on the leg and groin, respectively, in which skin ultrasound examination was useful in the diagnosis. A 48-year-old Japanese man presented with a lesion on the left leg. The lesion represented a skin-colored, elastic, soft, subcutaneous nodule measuring 25 · 20 mm and had developed over two years (Fig. 1a). Its clinical features led to a suspected diagnosis of an epidermal cyst or sweat gland tumor. Skin ultrasound examination using a Philips iU22 US system (Koninklijke Philips Electronics NV, Amsterdam, the Netherlands) with 5–12-MHz probes disclosed a well-demarcated, echo-lucent area with a high echo component protruding from the edge wall (Fig. 1b). There was no vascular signal on color Doppler evaluation. Histological examination of the excised nodule revealed the cystic structure as a whole mixed with a solid portion protruding from the cyst wall (Fig. 1c). The solid portion was composed of fibrous tissue at the base and poroid cells and cuticular cells forming lumina at the tip (Fig. 1d). A solid cystic hidradenoma was diagnosed. A 42-year-old Japanese man presented with a lesion in the right groin area. This appeared as a light red– brown, dome-shaped, elastic, soft skin nodule measuring 12 · 6 mm that had developed gradually over three years (Fig. 2a). Skin ultrasound examination revealed an echolucent area with a high echo component (Fig. 2b). Histological examination disclosed the cystic structure with a solid portion protruding from the cyst wall (Fig. 2c). The solid portion was composed of poroid cells and cuticular cells intermingled with fibrous tissue (Fig. 2d). A solid cystic hidradenoma was diagnosed. Five cases of solid cystic hidradenoma diagnosed using ultrasound have been reported. In three cases, the tumor was located on the breast. In the other two cases the tumors were located on the hand and thigh, respectively. The ultrasound findings of eccrine acrospiroma of

Bowen's carcinoma of the penis with sebaceous differentiation associated with human papillomavirus type 16.

type 16 Editor, In Bowen’s disease, a carcinoma in situ occasionally progresses to become invasive Bowen’s carcinoma. Human papillomavirus (HPV) infection is thought to be associated with Bowen’s disease and is also implicated in carcinogenesis in Bowen’s carcinoma, in which HPV types 16 and 82 have been detected. Sebaceous differentiation in Bowen’s disease or sebaceous carcinoma associated with or arising from Bowen’s disease is very rare, and, to the best of our knowledge, only three cases have been reported. Herein, we present the first case of Bowen’s carcinoma of the penis with sebaceous differentiation associated with HPV type 16. A 64-year-old Japanese man presented with erythema and nodules on the penis which had first become evident one year earlier and which had slowly enlarged. The reddish nodule had been biopsied by a previous doctor and was suspected to be sebaceous carcinoma. Physical examination revealed circumferential erythematous plaque on the foreskin and glans of the penis, with two bright redcolored papillomatous nodules, measuring 15 9 13 mm and 7 9 7 mm in diameter, respectively (Fig. 1a,b). Histological examination of skin biopsy specimens obtained from the erythematous plaque and papillomatous nodule disclosed Bowen’s disease and Bowen’s carcinoma with sebaceous differentiation, respectively. Blood tests were within normal limits, and computed tomography disclosed no metastasis to lymph nodes or other organs. On the patient’s request that we preserve the penis, we resected the tumor circumferentially with a 5-mm margin at the level of the tunica albuginea, partially including the corpus spongiosum, and followed this with skin grafts. Histopathology of the erythematous plaque showed full-thickness keratinocytic atypia, numerous mitoses, multinucleation, and focal dyskeratosis, compatible with typical features of Bowen’s disease (Fig. 1c). In papillomatous nodules, some tumor cells had invaded the dermis (Fig. 1d), and a few keratinocytes showed sebaceous differentiation in the form of a cluster of sebocytes (Fig. 2a), some of which were stained by epithelial membrane antigen and adipophilin (Fig. 2b,c). The margins of a resected sample were tumor cell-negative both vertically and horizontally. HPV type 16 in situ hybridization (GeneticLab Co. Ltd, Sapporo, Japan) disclosed that keratinocytes in the upper layer of the epidermis were positive for viral DNA in both the erythematous plaque and the papillomatous nodules (Fig. 2d). We diagnosed this case as Bowen’s carcinoma of the penis with sebaceous differentiation associated with HPV type 16. Ten months have passed since the resection without recurrence or metastasis.

A Cardiac Allograft Recipient with Bowen's Disease on a Finger and Concurrent Perianal Bowenoid Papulosis

We report a patient who developed Bowens disease of the finger and bowenoid papulosis of the perianal area after cardiac transplantation. Human papillomavirus (HPV) type 16 only, not any skin‐related or epidermodysplasia verruciformis‐related types, was detected in both lesions by in situ hybridization and polymerase chain reaction. The same virus type was identified in both the tumor of the finger and the perianal area, which suggests contact transmission. HPV 16 has often been associated with malignant changes and may be at least one source of the malignancies that are more common in immunosuppressed patients. The presence of a potentially oncogenic type of the HPV in an immunosuppressed patient highlights the importance of regular follow‐up of such patients.

Spontaneous regression of Merkel cell carcinoma developed in a patient with epidermodysplasia verruciformis

1 Song YC, Oh BH, Ko JH et al. A case of fibroelastolytic papulosis on the neck of a young man. Ann Dermatol 2011; 23: 193–197. 2 Cannav o SP, Rongioletti F, Guarneri F et al. Fibroelastolytic papulosis of the neck: two new cases with an ultrastructural study. G Ital Dermatol Venereol 2007; 142: 607–611. 3 Jagdeo J, Ng C, Ronchetti IP, Wilkel C, Bercovitch L, Robinson-Bostom L. Fibroelastolytic papulosis. J Am Acad Dermatol 2004; 51: 958–964. 4 Watson RE, Craven NM, Kang S, Jones CJ, Kielty CM, Griffiths CE. A short-term screening protocol, using fibrillin-1 as a reporter molecule, for photoaging repair agents. J Invest Dermatol 2001; 116: 672–678. 5 Schwartz E, Cruickshank FA, Lebwohl MG. Elastase-like protease and elastolytic activities expressed in cultured dermal fibroblasts derived from lesional skin of patients with pseudoxanthoma elasticum, actinic elastosis, and cutis laxa. Clin Chim Acta 1988; 176: 219–224.