RESUMEN
The BMP/TGFß-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína Morfogenética Ósea 6/metabolismo , Células Endoteliales/metabolismo , Neovascularización Fisiológica , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Secuencia de Bases , Proteína Morfogenética Ósea 2/metabolismo , Hipoxia de la Célula , Núcleo Celular/metabolismo , Vía de Señalización Hippo , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Biológicos , Transporte de Proteínas , Porcinos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: High grade serous ovarian carcinoma (HGSOC) is the most common subtype of epithelial ovarian cancers (EOC) with poor prognosis. In most cases EOC is widely disseminated at the time of diagnosis. Despite the optimal cytoreductive surgery and chemotherapy most patients develop chemoresistance, and the 5-year overall survival being only 25-35%. METHODS: Here we analyzed the gene expression profiles of 10 primary HGSOC tumors and 10 related omental metastases using RNA sequencing and identified 100 differentially expressed genes. RESULTS: The differentially expressed genes were associated with decreased embryogenesis and vasculogenesis and increased cellular proliferation and organismal death. Top upstream regulators responsible for this gene signature were NR5A1, GATA4, FOXL2, TP53 and BMP7. A subset of these genes were highly expressed in the ovarian cancer among the cancer transcriptomes of The Cancer Genome Atlas. Importantly, the metastatic gene signature was suggestive of poor survival in TCGA data based on gene enrichment analysis. CONCLUSION: By comparing the gene expression profiles of primary HGSOC tumors and their matched metastasis, we provide evidence that a signature of 100 genes is able to separate these two sample types and potentially predict patient survival. Our study identifies functional categories of genes and transcription factors that could play important roles in promoting metastases and serve as markers for cancer prognosis.
Asunto(s)
Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Perfilación de la Expresión Génica , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Transcriptoma , Carcinoma Epitelial de Ovario/mortalidad , Línea Celular Tumoral , Biología Computacional/métodos , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias Ováricas/mortalidadRESUMEN
The effect of surfactant on the rheological properties of some cream formulations was studied. Two surfactants from two different series were combined to determine the combination which yielded the most viscoelastic structure for creams. The surfactants were the soybean derivatives soya sterol, polyethylene glycol 10 soya sterol and polyethylene glycol 25 soya sterol and the sorbitol derivatives sorbitan monooleate and sorbitan trioleate. The rheological properties of the creams were studied using oscillation stress sweep, oscillation frequency sweep and viscosity tests. Droplet size distribution and conductivity of the creams were also determined. The combination polyethylene glycol 10 soya sterol and sorbitan trioleate yielded the most viscoelastic structure with linearly viscoelastic behaviour.
Asunto(s)
Pomadas/química , Reología/métodos , Tensoactivos/química , Conductividad Eléctrica , Excipientes , Enlace de Hidrógeno , Tamaño de la Partícula , ViscosidadRESUMEN
The effects of graded doses of ethyl alcohol on defence behaviour were studied in nine cats: 0.25 g/kg of body weight had a slight but not significant excitatory effect, 0.5 and 1.0 g/kg had no effect and 1.5 g/kg significantly depressed some behavior components. When taking the scores for all the manifestations combined as an index of gross behaviour, 0.25 significantly intensified, 0.5 and 1.0 did not change and 1.5 g alcohol/kg significantly depressed defence. These results are consistent with the expected effects of alcohol on physiological functions in general.