gli-1 Oncogene is highly expressed in granulomatous skin disorders, including sarcoidosis, granuloma annulare, and necrobiosis lipoidica diabeticorum.

BACKGROUND: Sarcoidosis, which occurs most commonly in African American women, is a granulomatous multisystem disorder affecting the skin, lungs, and central nervous system. In a previous immunohistochemistry study of keloids, a scar granuloma stained highly positive for glioma-associated oncogene homologue (gli)-1. OBSERVATION: This observation led us to study whether gli-1, one of the vertebrate zinc finger transcription factor genes of the gli superfamily, is expressed in granulomatous skin disorders such as cutaneous sarcoidosis, granuloma annulare (GA), and necrobiosis lipoidica diabeticorum (NLD). Immunohistochemistry studies for gli-1 were performed on biopsy specimens from patients with cutaneous sarcoidosis, GA, and NLD. All sarcoid lesions were highly positive for gli-1 expression, and 75% of the cells demonstrated positivity with a stain intensity of 3 on a scale of 1 to 3. The gli-1 expression was confined to cutaneous granulomas. CD68 staining was highly positive in the sarcoid lesions as well. Similarly, GA and NLD lesions were uniformly positive for gli-1 expression. CONCLUSIONS: We found that gli-1 is inappropriately expressed in granulomatous lesions of the skin such as cutaneous sarcoidosis, GA, and NLD. These findings provide a rationale for clinical trials of inhibitors of gli-1 signaling, including tacrolimus and sizolimus, for the treatment of cutaneous sarcoidosis and other granulomatous disorders of the skin.

Mitogen-actived protein kinase activation is an early event in melanoma progression.

PURPOSE: Melanoma is the most common cause of death from cutaneous malignancy, and is the cancer that is most rapidly rising in incidence. Because current therapeutic methods for metastatic melanoma are poorly efficacious, enhanced understanding of signal transduction in melanoma progression is warranted. Prior experimental studies in murine models and human tissues have shown a correlation among activation of mitogen activated protein kinase (MAPK) signaling, angiogenesis, and tumorigenesis. Because of these findings, we wanted to assess the role of MAPK signaling in melanoma progression and angiogenesis. EXPERIMENTAL DESIGN: We studied expression of phosphorylated (active) MAPK and two target genes known to be induced by MAPK signaling, tissue factor and vascular endothelial growth factor, in 131 melanocytic lesions, ranging from atypical nevi to metastatic melanoma. RESULTS: We observed little staining for activated (phosphorylated) MAPK and low amounts of angiogenesis in atypical nevi, but angiogenesis and MAPK activation were activated in radial growth melanoma and in later stage lesions. CONCLUSIONS: Our findings implicate MAPK activation as an early event in melanoma progression, and MAPK may be a potential target for pharmacologic intervention.

Cutaneous manifestations of Wegener's granulomatosis: a clinicopathologic study of 17 patients and correlation to antineutrophil cytoplasmic antibody status.

BACKGROUND: Wegener's granulomatosis (WG), a systemic vasculitis, can be associated with cutaneous signs and symptoms before, during or after the diagnosis of systemic disease. METHODS: We reviewed clinical and histologic features of cutaneous lesions from 17 patients with WG. The temporal relationship between development of cutaneous symptoms and onset of systemic disease was determined, and antineutrophil cytoplasmic antibody (ANCA) status of the patients was also established. RESULTS: In six patients, systemic and cutaneous disease developed concurrently. In eight patients, cutaneous disease developed after patients received the diagnosis of systemic disease. In three patients, cutaneous disease preceded systemic disease. Cytoplasmic ANCA or proteinase-3-ANCA [c-ANCA/proteinase 3 (PR3)-ANCA] serologic test results were negative for one patient when cutaneous disease developed, and one patient had c-ANCA/PR3-ANCA seroconversion a year before systemic disease developed. Histopathologic features of cutaneous WG were not limited to leukocytoclastic vasculitis; they also included acneiform perifollicular and dermal granulomatous inflammation and palisaded neutrophilic and granulomatous inflammation. CONCLUSIONS: Patients with WG can present initially with cutaneous symptoms. Histopathologic patterns vary, but leukocytoclastic vasculitis is most commonly noted. Patients with WG and skin lesions are likely to have positive c-ANCA/PR3-ANCA serologic test results.

Reactive oxygen signaling and MAPK activation distinguish Epstein-Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma.

Burkitt's lymphoma (BL) is an aggressive B cell neoplasm, which is one of the most common neoplasms of childhood. It is highly widespread in East Africa, where it appears in endemic form associated with Epstein-Barr virus (EBV) infection, and around the world in a sporadic form in which EBV infection is much less common. In addition to being the first human neoplasm to be associated with EBV, BL is associated with a characteristic translocation, in which the Ig promoter is translocated to constitutively activate the c-myc oncogene. Although many BLs respond well to chemotherapy, a significant fraction fails to respond to therapy, leading to death. In this article, we demonstrate that EBV-positive BL expresses high levels of activated mitogen-activated protein kinase and reactive oxygen species (ROS), and that ROS directly regulate NF-kappaB activation. EBV-negative BLs exhibit activation of phosphoinositol 3-kinase, but do not have elevated levels of ROS. Elevated reactive oxygen may play a role in diverse forms of viral carcinogenesis in humans, including cancers caused by EBV, hepatitis B, C, and human T cell lymphotropic virus. Our findings imply that inhibition of ROS may be useful in the treatment of EBV-induced neoplasia.

Cutaneous lesions of secondary syphilis are highly angiogenic.

BACKGROUND: The role of angiogenesis in infectious processes is poorly studied. Some viruses have been linked to angiogenesis, but the role of bacteria and protozoa in inducing angiogenesis in chronic infections is poorly understood. OBJECTIVES: We examined the role of angiogenesis in syphilis, a common and often difficult-to-treat infectious disease, especially in the setting of HIV/AIDS. METHOD: Microvessel counts were performed on 27 paraffin-fixed sections of secondary syphilis by staining with monoclonal antibodies against CD31. In addition, immunohistochemistry was performed using antibodies against vascular endothelial growth factor (VEGF) to determine whether increased angiogenesis may be mediated, in part, through increased production of VEGF. RESULTS: The CD31 mean microvessel count in secondary syphilis sections was significantly higher than in normal control sections. VEGF intensity appeared increased in the patients with secondary syphilis. CONCLUSIONS: Infection with Treponema pallidum results in increased angiogenesis in secondary syphilis. The mechanism for increased angiogenesis may involve elaboration of angiogenic cytokines, such as VEGF and epidermal growth factor.