Crack tip stress study for elastic-perfectly plastic materials with some applications

The problems of plasticity and non-linear fracture mechanics have been generally recognized as the most difficult problems of solid mechanics. The present dissertation is devoted to some problems on the intersection of both plasticity and non-linear fracture mechanics. The crack tip is responsible for the crack growth and therefore is the focus of fracture science. The problem of crack has been studied by an army of outstanding scholars and engineers in this century, but has not, as yet, been solved for many important practical situations. The aim of this investigation is to provide an analytical solution to the problem of plasticity at the crack tip for elastic-perfectly plastic materials and to apply the solution to a classical problem of the mechanics of composite materials.^ In this work, the stresses inside the plastic region near the crack tip in a composite material made of two different elastic-perfectly plastic materials are studied. The problems of an interface crack, a crack impinging an interface at the right angle and at arbitrary angles are examined. The constituent materials are assumed to obey the Huber-Mises yielding condition criterion. The theory of slip lines for plane strain is utilized. For the particular homogeneous case these problems have two solutions: the continuous solution found earlier by Prandtl and modified by Hill and Sokolovsky, and the discontinuous solution found later by Cherepanov. The same type of solutions were discovered in the inhomogeneous problems of the present study. Some reasons to prefer the discontinuous solution are provided. The method is also applied to the analysis of a contact problem and a push-in/pull-out problem to determine the critical load for plasticity in these classical problems of the mechanics of composite materials.^ The results of this dissertation published in three journal articles (two of which are under revision) will also be presented in the Invited Lecture at the 7$\rm\sp{th}$ International Conference on Plasticity (Cancun, Mexico, January 1999). ^

The role of redox signaling in the molecular mechanism of tamoxifen resistance in breast cancer.

The emergence of tamoxifen or aromatase inhibitor resistance is a major problem in the treatment of breast cancer. The molecular signaling mechanism of antiestrogen resistance is not clear. Understanding the mechanisms by which resistance to these agents arise could have major clinical implications for preventing or circumventing it. Therefore, in this dissertation we have investigated the molecular mechanisms underlying antiestrogen resistance by studying the contributions of reactive oxygen species (ROS)-induced redox signaling pathways in antiestrogen resistant breast cancer cells. Our hypothesis is that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with a progressive shift towards a pro-oxidant environment of cells as a result of oxidative stress. The hypothesis of this dissertation was tested in an in vitro 2-D cell culture model employing state of the art biochemical and molecular techniques, including gene overexpression, immunoprecipitation, Western blotting, confocal imaging, ChIP, Real-Time RT-PCR, and anchorage-independent cell growth assays. We observed that tamoxifen (TAM) acts like both an oxidant and an antioxidant. Exposure of tamoxifen resistant LCC2 cell to TAM or 17 beta-estradiol (E2) induced the formation of reactive oxidant species (ROS). The formation of E2-induced ROS was inhibited by co-treatment with TAM, similar to cells pretreated with antioxidants. In LCC2 cells, treatments with either E2 or TAM were capable of inducing cell proliferation which was then inhibited by biological and chemical antioxidants. Exposure of LCC2 cells to tamoxifen resulted in a decrease in p27 expression. The LCC2 cells exposed to TAM showed an increase in p27 phosphorylation on T157 and T187. Conversely, antioxidant treatment showed an increase in p27 expression and a decrease in p27 phosphorylation on T157 and T187 in TAM exposed cells which were similar to the effects of Fulvestrant. In line with previous studies, we showed an increase in the binding of cyclin E-Cdk2 and in the level of p27 in TAM exposed cells that overexpressed biological antioxidants. Together these findings highly suggest that lowering the oxidant state of antiestrogen resistant LCC2 cells, increases LCC2 susceptibility to tamoxifen via the cyclin dependent kinase inhibitor p27.