Objective Anti-angiogenic therapies (AATs), targeting VEGF-VEGFR pathways, are being used as an adjuvant to normalize glioblastoma (GBM) vasculature. Unexpectedly, clinical trials have witnessed transient therapeutic effect followed by aggressive tumor recurrence. In pre-clinical studies, targeting VEGFR2 with vatalanib, increased GBM growth under hypoxic microenvironment. There is limited understanding of these unanticipated results. Here, we investigated tumor cell associated phenotypes in response to VEGFR2 blockade. Methods Human U251 cells were orthotopically implanted in mice (day 0) and were treated with vehicle or vatalanib on day 8. Tumor specimens were collected for immunohistochemistry and protein array. Nuclear translocation of VEGFR2 was analyzed through IHC and western blot. In vitro studies were performed in U251 (p53 and EGFR mutated) and U87 (p53 and EGFR wildtype) cells following vehicle or vatalanib treatments under normoxia (21% O2) and hypoxia (1% O2). Proliferation, cell cycle and apoptosis assays were done to analyze tumor cell phenotypes after treatments. Results Vatalanib treated animals displayed distinct patterns of VEGFR2 translocation into nuclear compartment of U251 tumor cells. In vitro studies suggest that vatalanib significantly induced nuclear translocation of VEGFR2, characterized in chromatin bound fraction, especially in U251 tumor cells grown under normoxia and hypoxia. Anti-VEGFR2 driven nuclear translocation of VEGFR2 was associated with increased cell cycle and proliferation, decreased apoptosis, and displayed increased invasiveness in U251 compared to U87 cells. Conclusions Study suggests that AAT- induced molecular and phenotypic alterations in tumor cells are associated with mutation status and are responsible for aggressive tumor growth. Therefore, mutation status of the tumor in GBM patients should be taken in to consideration before applying targeted therapy to overcome unwanted effects.

The development of metal matrix composites (MMCs) has set the stage for a new revolution in materials. In this research, Al matrix composites reinforced with SiC nanoparticles were fabricated by a powder metallurgy process and the effects of compaction load and sintering temperature on the mechanical properties of the Al-SiC nano-composite was investigated. The samples were prepared with two different compaction loads, 100 kN and 200 kN, and two different sintering temperatures, 550 °C and 600 °C. Subsequently, their mechanical testing was carried out. The density and hardness of the samples were investigated. The microstructure of the nano-composite was examined by optical microscope. The results showed that the higher compaction load and higher sintering temperature significantly increased the density and hardness of the nano-composite materials.

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