54 research outputs found

    Extracellular Heat Shock Protein (Hsp)70 and Hsp90α Assist in Matrix Metalloproteinase-2 Activation and Breast Cancer Cell Migration and Invasion

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    Breast cancer is second only to lung cancer in cancer-related deaths in women, and the majority of these deaths are caused by metastases. Obtaining a better understanding of migration and invasion, two early steps in metastasis, is critical for the development of treatments that inhibit breast cancer metastasis. In a functional proteomic screen for proteins required for invasion, extracellular heat shock protein 90 alpha (Hsp90α) was identified and shown to activate matrix metalloproteinase 2 (MMP-2). The mechanism of MMP-2 activation by Hsp90α is unknown. Intracellular Hsp90α commonly functions with a complex of co-chaperones, leading to our hypothesis that Hsp90α functions similarly outside of the cell. In this study, we show that a complex of co-chaperones outside of breast cancer cells assists Hsp90α mediated activation of MMP-2. We demonstrate that the co-chaperones Hsp70, Hop, Hsp40, and p23 are present outside of breast cancer cells and co-immunoprecipitate with Hsp90α in vitro and in breast cancer conditioned media. These co-chaperones also increase the association of Hsp90α and MMP-2 in vitro. This co-chaperone complex enhances Hsp90α-mediated activation of MMP-2 in vitro, while inhibition of Hsp70 in conditioned media reduces this activation and decreases cancer cell migration and invasion. Together, these findings support a model in which MMP-2 activation by an extracellular co-chaperone complex mediated by Hsp90α increases breast cancer cell migration and invasion. Our studies provide insight into a novel pathway for MMP-2 activation and suggest Hsp70 as an additional extracellular target for anti-metastatic drug development

    The effect of surcharge loading adjacent to piles

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    Breakage of an artificial crushable material under loading

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    The mechanical behaviour of granular materials depends on their grading. Crushing of particles under compression or shear modifies the grain size distribution, with a tendency for the percentage of fine material to increase. It follows that the frictional properties of the material and the critical states are modified as a consequence of the changes in grain size distribution and the available range of packing densities. This paper illustrates an extended experimental investigation of the evolution of the grading of an artificial granular material, consisting of crushed expanded clay pellets under different loading conditions. The changes of grading of the material after isotropic, one-dimensional and constant mean effective stress triaxial compression were described using a single parameter based on the ratio of the areas under the current and an ultimate cumulative particle size distribution, which were both assumed to be consistent with self similar grading with varying fractal dimension. Relative breakage was related to the total work input for unit of volume. For poorly graded samples, the observed maximum rate of breakage is practically independent of initial uniformity. Further experiments at higher confining stress are required to investigate the mechanics of breakage of better graded samples. © 2013 Springer-Verlag Berlin Heidelberg

    Centrifuge modeling of spread-base integral bridge abutments

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    Integral bridge abutments are attracting increasing interest in many countries around the world. Maintenance costs due to damage from assorted agents to bearings and expansion joints can be greatly reduced. However, adverse temperature effects on the performance of these bridges are of concern to many engineers. This paper describes some centrifuge model tests on, and numerical modeling of, spread-base integral bridge abutments subjected to cyclic deformation, which simulated the expansion and contraction of the bridge deck as effective temperature of the bridge deck changed. Significant settlements were observed behind the abutment resulting from soil densification, "strain" ratchetting, horizontal sliding, and the rocking motion of the abutment. The measured lateral earth pressure increased with the amplitude of the passive displacements and the number of cycles, but at a decreasing rate. Under the serviceability and ultimate limit conditions, the measured lateral earth pressure was less than the K-p value, although the measured value was significantly higher than K-o. A triangular failure wedge developed behind the abutment wall under the ultimate limit conditions

    The behaviour of bridge abutments on clay

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