Oncogenic transformation and hypoxia both induce glut1 mRNA. We studied the interaction between the ras oncogene and hypoxia in up-regulating glut1 mRNA levels using Rat1 fibroblasts transformed with H-ras (Rat1-ras). Transformation with H-ras led to a substantial increase in glut1 mRNA levels under normoxic conditions and additively increased glut1 mRNA levels in concert with hypoxia. Using a luciferase reporter construct containing 6 kilobase pairs of the glut1 promoter, we showed that this effect was mediated at the transcriptional level. Promoter activity was much higher in Rat1-ras cells than in Rat1 cells and could be down-regulated by cotransfection with a dominant negative Ras construct (RasN17). A 480-base pair (bp) cobalt/hypoxia-responsive fragment of the promoter containing a HIF-1 binding site showed significantly higher activity in Rat1-ras cells than in Rat1 cells, suggesting that Ras might mediate its effect through HIF-1 even under normoxic conditions. Consistent with this, Rat1-ras cells displayed higher levels of HIF1-␣ protein under normoxic conditions. In addition, a promoter construct containing a 4-bp mutation in the HIF1 binding site showed lower activity in Rat1-ras cells than a construct with an intact HIF1 binding site. The activity of the latter construct but not the former could be down-regulated by RasN17, supporting the importance of the HIF1 binding site in regulation by Ras. The phosphatidylinositol 3-kinase inhibitor LY29004 down-regulated glut1 promoter activity and mRNA levels under normoxia and also decreased HIF1␣ protein levels in these cells. Collectively these results indicate that H-Ras up-regulates the glut1 promoter, at least in part, by increasing HIF-1␣ protein levels leading to transactivation of promoter through the HIF-1 binding site.Oncogenic transformation of mammalian cells is associated with many alterations in metabolism (see Ref. 1 for review). An increased rate of glucose transport is among the most characteristic biochemical markers of the transformed phenotype. The Glut1 glucose transporter is one of the proteins responsible (reviewed in Ref. 2). A number of oncogenes, including fps, src, and ras have been shown to increase glucose transport and to up-regulate glut1 mRNA and protein levels (3-5). glut1 gene expression and glucose transport are also stimulated in a variety of cells under hypoxic conditions, a response that is mediated by the transcription factor HIF-1.1 HIF-1 binds to a cis-acting binding sites located within the 5Ј-flanking region of the glut1 gene (8, 9).Because hypoxia and oncogenic mutations are both commonly present in tumors, we set out to examine the interaction between the two in up-regulating glut1 mRNA levels. Mutations in Ras are seen in a third of human cancers (6); therefore, as our model system we used Rat1 fibroblasts transformed with H-ras. Transformation with H-ras led to a substantial increase in glut1 mRNA levels under normoxic conditions and additively increased glut1 mRNA levels in concert with hypoxia. Our results ind...

This multi-institutional phase I/II trial demonstrates that high-dose SBRT is safe and effective for the treatment of patients with one to three lung metastases.

Coarse grain (CG) molecular models have been proposed to simulate complex systems with lower computational overheads and longer timescales with respect to atomistic level models. However, their acceleration on parallel architectures such as graphic processing units (GPUs) presents original challenges that must be carefully evaluated. The objective of this work is to characterize the impact of CG model features on parallel simulation performance. To achieve this, we implemented a GPU‐accelerated version of a CG molecular dynamics simulator, to which we applied specific optimizations for CG models, such as dedicated data structures to handle different bead type interactions, obtaining a maximum speed‐up of $14$ on the NVIDIA GTX480 GPU with Fermi architecture. We provide a complete characterization and evaluation of algorithmic and simulated system features of CG models impacting the achievable speed‐up and accuracy of results, using three different GPU architectures as case studies. © 2012 Wiley Periodicals, Inc.