Cell signaling plays a central role in the etiology of cancer. Numerous therapeutics in use or under development target signaling proteins; however, off-target effects often limit assignment of positive clinical response to the intended target. As direct measurements of signaling protein activity are not generally feasible during treatment, there is a need for more powerful methods to determine if therapeutics inhibit their targets and when off-target effects occur. We have used the Bayesian Decomposition algorithm and data on transcriptional regulation to create a novel methodology, Differential Expression for Signaling Determination (DESIDE), for inferring signaling activity from microarray measurements. We applied DESIDE to deduce signaling activity in gastrointestinal stromal tumor cell lines treated with the targeted therapeutic imatinib mesylate (Gleevec). We detected the expected reduced activity in the KIT pathway, as well as unexpected changes in the p53 pathway. Pursuing these findings, we have determined that imatinib-induced DNA damage is responsible for the increased activity of p53, identifying a novel off-target activity for this drug. We then used DESIDE on data from resected, post-imatinib treatment tumor samples and identified a pattern in these tumors similar to that at late time points in the cell lines, and this pattern correlated with initial clinical response. The pattern showed increased activity of ETS domain-containing protein Elk-1 and signal transducers and activators of transcription 3 transcription factors, which are associated with the growth of side population cells. DESIDE infers the global reprogramming of signaling networks during treatment, permitting treatment modification that leverages ongoing drug development efforts, which is crucial for personalized medicine. [Cancer Res 2009;69(23):9125-32]
The phase properties and deformation behavior of the δ-ferrite and γ-austenite phases of CF-3 and CF-8 cast duplex stainless steels were characterized by nanoindentation and microstructure-based finite element method (FEM) models. The elastic modulus of each phase was evaluated and the results indicate that the mean elastic modulus of the δ-ferrite phase is greater than that of the γ-austenite phase, and the mean nanoindentation hardness values of each phase are approximately the same. The elastic FEM model results illustrate that greater von Mises stresses are located within the δ-ferrite phase, while greater von Mises strains are located in the γ-austenite phase in response to elastic deformation. The elastic moduli calculated by FEM agree closely with those measured by tensile testing. The plastically deformed specimens exhibit an increase in misorientation, deformed grains, and subgrain structure formation as measured by electron backscatter diffraction (EBSD).
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