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Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by Mre11/Rad50-containing nuclear foci. Activated DNA damage signalling caused stabilization of the tumour suppressor p53, which resulted in cell cycle arrest and apoptosis. When Brn3a was ectopically expressed in primary melanocytes and fibroblasts, anchorage-independent growth was increased. In tumourigenic melanocytes and fibroblasts, Brn3a accelerated tumour growth in vivo. Furthermore, Brn3a cooperated with proliferation pathways such as oncogenic BRAF, by reducing oncogene-induced senescence in non-malignant melanocytes. Together, these results identify Brn3a as a new factor in melanoma that is essential for melanoma cell survival and that promotes melanocytic transformation and tumourigenesis.
Background: Giant cell arteritis (GCA) is the most common systemic vasculitis in persons aged 50 and above (incidence, 3.5 per 100 000 per year). It affects cranial arteries, the aorta, and arteries elsewhere in the body, e.g., in the limbs.
Methods: We selectively review the pertinent literature, including guidelines and recommendations from Germany and abroad.
Results: The typical symptoms of new-onset GCA are bi-temporal headaches, jaw claudiacation, scalp tenderness, visual disturbances, systemic symptoms such as fever and weight loss, and polymyalgia. The diagnostic assessment comprises laboratory testing (erythrocyte sedimentation rate, C-reactive protein), imaging studies (duplex sonography, high-resolution magnetic resonance imaging, positron-emission tomography), and temporal artery biopsy. The standard treatment is with corticosteroids (adverse effects: diabetes mellitus, osteoporosis, cataract, arterial hypertension). A meta-analysis of three randomized controlled trials led to a recommendation for treatment with methotrexate to lower the recurrence rate and spare steroids. Patients for whom methotrexate is contraindicated or who cannot tolerate the drug can be treated with azathioprine instead.
Conclusion: Giant cell arteritis, if untreated, progresses to involve the aorta and its collateral branches, leading to various complications. Late diagnosis and treatment can have serious consequences, including irreversible loss of visual function.