Browsing by Subject "Tumor"
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Item Model selection for tumor growth with nonlinear mechanical effects(2019-05-10) Perez, Xoab; Yankeelov, Thomas E.Accurately modeling in vivo tumor growth is a persistent challenge due to the complexity of tumors and their environments. Accurate models are sought after for their potential to guide treatments and help researchers discover or better understand the underlying biological processes. Previous research has identified a reaction-diffusion formulation coupled with mechanical forces that performs well at modeling tumor growth. The focus of the current research was a similar formulation with a nonlinear constitutive equation instead of a linear constitutive equation for the mechanical forces. In this study the models performed similarly, with the nonlinear model predictions being slightly closer to the actual actual tumor growth on average. This indicates that the linear model may be a sufficiently close approximation, though the parameter estimation procedure needs improvement. Then other nonlinear models can be studied easily using the code developed for this work.Item Regulation of ATG5 and the ATG12–ATG5-ATG16L1 complex in prostate cancer(2015-05) Wible, Daric John; Wright, Casey Wyatt; Bratton, Shawn B.; Tang, Dean G; De Lozanne, Arturo; Fischer, Janice AAutophagy is a highly conserved pathway in which an autophagosome envelops cytoplasmic cargo and delivers it to the lysosome for degradation in order to maintain cellular homeostasis or survival in response to stress. The ATG12–ATG5-ATG16L1 complex functions as an essential regulator of autophagosome formation. We have discovered that DU145 prostate cancer (PCa) cells have a splice donor-site mutation that triggers aberrant splicing of ATG5 and leads to the proteasomal degradation of ATG12 and ATG16L1, thus completely inactivating autophagy. We demonstrate that ATG5, ATG12, and ATG16L1 are coordinately degraded when not associated with the complex and that the ATG5-ATG16L1 interaction is essential for preventing ubiquitination and turnover, thereby facilitating ATG12 conjugation. We also show that this interaction can be disrupted through alternative ATG5 splicing and by ATG5 genetic mutations that have been identified in human tumors. Meta-analysis of available mRNA expression data indicates that ATG5 is significantly downregulated in PCa. We confirmed previous reports that found prostate cancers have frequent deletions of the 6q21 locus containing ATG5. However, mRNA expression of neighboring genes is largely unaffected, indicating ATG5 can also be selectively downregulated though other mechanisms. Together, this suggests that ATG5 functions as a tumor suppressor gene that can be inactivated by a variety of different mechanisms. ATG5 is more significantly underexpressed than many established PCa tumor suppressor genes and is also underexpressed in PCa metastases compared to primary tumors. This implies that ATG5 is also a tumor suppressor in advanced PCa. ATG5 re-expression in ATG5-deficient DU145 PCa cells resulted in dramatic suppression of xenograft tumor growth, indicating that ATG5 is a functional PCa tumor suppressor gene. Therefore, autophagy may actually be tumor suppressive at both early and late stages of prostate tumorigenesis, which suggests that autophagy inhibition may be counterproductive for the treatment of advanced prostate cancers.Item Targeted nanoparticle formulation for a poorly water soluble Gemcitabine derivative and its in vivo and in vitro anti-tumor activity(2012-08) Sandoval, Michael Anthony; Cui, Zhengrong; Williams, Robert O; Walkow, Janet CCancer is a collection of over one hundred different types of diseases and is responsible for the leading cause of death in the United States. More strikingly, cancer mortality rates have remained relatively unchanged for the past several decades, indicating significant clinical demand for improved cancer therapy. Gemcitabine, known clinically as Gemzar®, is used to treat a variety of human cancers, however, clinical efficacy is modest due to it’s brief blood circulation, rapid clearance, manifestation of tumor-drug resistance, and lack of drug specificity. This thesis sought to develop a solid lipid nanoparticle-based platform to passively and actively target a gemcitabine lipophilic derivative, 4-(N)-stearoyl gemcitabine, into tumor cells over-expressing epidermal growth factor receptor (EGFR) after intravenous injection. Considering gemcitabine is hydrophilic and the core of the nanoparticle is solid (hydrophobic), we lipophilized gemcitabine by conjugating a stearoyl group to its N-terminus to form 4-(N)-stearoyl gemcitabine. Second, we incorporated stearoyl gemcitabine into lecithin-based nanoparticles. The nanoparticle formulation was prepared from lecithin/glyceryl monostearate-in-water emulsions. Third, we grafted the gemcitabine nanoparticles with polyethylene glycol chains with reactive end groups that are capable of conjugating with a targeting moiety on the surface to actively target tumors that over-express EGFR. Taken together, the overall objective of the research presented in this thesis is to develop, characterize, and evaluate the anti-tumor performance in vitro as well as in mice against both human and mouse tumor models.