Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47 phox , a subunit of NOX1 to plasma membrane. Of note, PKCd, when it was activated by PDPK1, directly bound to the SH3-N domain of p47 phox and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 phox C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47 phox -NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCd, p47 phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCd, p47 phox or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/ PDPK1/PKCd/p47 phox /NOX1 for ROS generation and consequent malignant cellular transformation.

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NPWT is useful treatment option for open fractures, to bridge between initial debridement and final microsurgical tissue transfer. Considering patient comfort, the costs related to the NPWT, and the final flap results, a 7-day interval between changes of the NPWT is acceptable.

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The ZnO nano-particles were made in the polyimide dielectric matrix by using the chemical reaction between the zinc metal film and polyamic acid. The concentration of the ZnO particle is about 1.5 3 10 12 cm ÿ2 , with average size below 10 nm, and its shapes are almost spherical. Then, the polyimide layer is a stable dielectric material with a dielectric constant of 2.9. To investigate the electrical properties of ZnO particles in the polyimide insulator film, we fabricated a metal-insulator-semiconductor (MIS) structure and measured capacitance-voltage (C-V) with temperature modulation. At room temperature, C-V hysteresis with a voltage gap of 2.8 V appeared in the MIS structure using SiO 2 /Si substrate. As the measuring temperature decreased, the C-V curves were shifted slightly to the accumulation region with gate bias. It was considered that the electrical charging may occur dominantly in nanoparticles, having only a few defects at the interface of the polyimide/SiO 2 and the polyimide/ZnO.