EMMPRIN Promotes Melanoma Cells Malignant Properties through a HIF-2alpha Mediated Up-Regulation of VEGF-Receptor-2

EMMPRIN's expression in melanoma tissue was reported to be predictive of poor prognosis. Here we demonstrate that EMMPRIN up-regulated VEGF receptor-2 (VEGFR-2) in two different primary melanoma cell lines and consequently increased migration and proliferation of these cells while inhibiting their apoptosis. SiRNA inhibition of VEGFR-2 expression abrogated these EMMPRIN effects. EMMPRIN regulation of VEGFR-2 was mediated through the over-expression of HIF-2α and its translocation to the nucleus where it forms heterodimers with HIF-1β. These results were supported by an in vivo correlation between the expression of EMMPRIN with that of VEGFR-2 in human melanoma tissues as well as with the extent of HIF-2α localization in the nucleus. They demonstrate a novel mechanism by which EMMPRIN promotes tumor progression through HIF-2α/VEGFR-2 mediated mechanism, with an autocrine role in melanoma cell malignancy. The inhibition of EMMPRIN in cancer may thus simultaneously target both the VEGFR-2/VEGF system and the matrix degrading proteases to block tumor cell growth and invasion

Phase I dose escalation study of telatinib (BAY 57-9352) in patients with advanced solid tumours

Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. In this multicentre phase I dose escalation study, 71 patients with refractory solid tumours were enroled into 14 days on/7 days off (noncontinuous dosing) or continuous dosing groups to receive telatinib two times daily (BID). Hypertension (23%) and diarrhoea (7%) were the most frequent study drug-related adverse events of CTC grade 3. The maximum-tolerated dose was not reached up to a dose of 1500 mg BID continuous dosing. Telatinib was rapidly absorbed with median tmax of 3 hours or less. Geometric mean Cmax and AUC0−12 increased in a less than dose-proportional manner and plateaued in the 900–1500 mg BID dose range. Two renal cell carcinoma patients reached a partial response. Tumour blood flow measured by contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing AUC0−12 of telatinib. Telatinib is safe and well tolerated up to a dose of 1500 mg BID continuous dosing. Based on pharmacokinetic and pharmacodynamic criteria, 900 mg telatinib BID continuously administered was selected as the recommended phase II dose

Alterações inflamatórias provocadas pelo metronidazol em feridas: estudo experimental em ratos Inflammatory alterations provoked by metronidazole in wounds: an experimental study in rats

CONTEXTO: Cerca de 2,7% da população brasileira tem úlceras crônicas nos pés e nas pernas, porcentagem que chega a 10% nos diabéticos e que representa a segunda causa de afastamento do trabalho no Brasil. Isso demonstra a necessidade de se encontrar um produto de baixo custo que favoreça a cicatrização dessas feridas. OBJETIVO: Avaliar os efeitos do metronidazol na cicatrização de feridas por segunda intenção. MÉTODOS: Utilizaram-se 80 ratos machos, em cujos dorsos se produziu uma ferida, distribuindo-se, os animais, em dois grupos de 40. Os ratos do grupo-controle tiveram suas feridas tratadas com solução de NaCl 0,9%, e os pertencentes ao grupo-experimento, com metronidazol 4%. No terceiro, sétimo, 14º e 21º dias, avaliou-se o processo cicatricial por parâmetros macroscópicos, histológicos e imunoistoquímicos. RESULTADOS: A concentração de colágeno foi maior nas cicatrizes dos animais do grupo-experimento em todos os tempos examinados. A concentração de colágeno do tipo I também foi significante no sétimo dia (p = 0,020) e no 21º dia (p = 0,016). O colágeno tipo III mostrou concentração semelhante nos tempos iniciais e apresentou-se com maior concentração no 21º dia (p = 0,005). A angiogênese, avaliada pelo anti-CD34, demonstrou maior número de vasos, no grupo-experimento, com diferença significante no terceiro dia (p < 0,001) e no 14º dia (p = 0,003). CONCLUSÃO: O metronidazol contribui para a cicatrização de feridas por segunda intenção, estimulando a produção de colágeno e a angiogênese.<br>CONTEXT: Chronic feet and leg ulcers affect about 2.7% of the Brazilian population, 10% of diabetic patients. The condition represents the second most frequent cause of absence from work in Brazil. This shows the need for a product that promotes healing of these wounds at a low cost. OBJECTIVE: To evaluate the effects of metronidazole on ulcer healing by second intention. METHODS: Eighty male rats divided into two groups of 40 had a wound made on their dorsum. The control group was treated with a 0.9% NaCl solution and the experimental group was treated with 4% metronidazole. On the third, seventh, 14th and 21st days, the healing process was assessed through macroscopical, histological and immunohistochemical parameters. RESULTS: Collagen concentration was higher in wounds in the experimental group in all samples. Concentration of type I collagen was also significant on the 7th (p = 0.020) and 21st (p = 0.016) days. Concentration of type III collagen was similar in both groups in the initial phase, but it was higher in the experimental group on the 21st day (p = 0.005). Angiogenesis, assessed with anti-CD34, revealed a larger number of vessels in the experimental group, with a significant difference on the third (p < 0.001) and 14th (p = 0.003) days. CONCLUSION: Metronidazole contributes to healing wounds by second intention and stimulates collagen production and angiogenesis