Digital Commons Network^™

Targeting The Major Regulator Of Mitosis., J. Mason Hoffman

Electronic Theses and Dissertations

Mitosis-inhibiting chemotherapeutics (e.g. taxanes) are frequently used to treat multiple cancer types. Recently, there has been much concern about the limited success of these drugs due to resistance and a lack of molecular targets. Thus, there is high demand for new drugs with diverse cellular targets. Targeting the regulators of mitosis is a promising approach. The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that controls cell cycle progression at multiple points. The interaction of ANAPC2 and ANAPC11, catalytic core subunits, is necessary for APC/C function. An in silico approach was used to identify compounds predicted to prevent assembly …

The Dlk1-Meg3 Locus In Malignant Cells Of Proposed Primordial Germ Cell Origins., Zachariah Payne Sellers

Electronic Theses and Dissertations

Primordial germ cells (PGCs) are hypothesized to deposit hematopoietic stem cells (HSCs) along their migration route through the embryo during the early stages of embryogenesis. PGCs also undergo global chromatin remodeling, including the erasure and reestablishment of genomic imprints, during this migration. While PGCs do not spontaneously form teratomas, their malignant development into germ cell tumors (GCTs) in vivo is often accompanied by the retention of hypomethylation at the IGF2-H19 imprinting control differentially methylated region (DMR). Previous studies in bimaternal embryos determined that proper genomic imprinting at two paternally imprinted loci was necessary for their growth and development: Igf2-H19 and …

Advances In Tumor-Targeted Therapy Using Nanomedicine., Divya Karukonda

Electronic Theses and Dissertations

Despite continuous improvement and significant progress made in diagnostic and therapeutic approaches for cancer, it is still the leading cause of death worldwide. Although conventional chemotherapy has made significant advances in improving patient survival the indiscriminate destruction of normal cells leads to severe side effects and poor clinical outcomes. Thus, there is a need for effective delivery of drugs to the tumor site avoiding normal tissues to reduce toxicity in the rest of the body. For this reason, a novel multidisciplinary field called Nanotechnology has evolved in recent years and advances in this field have contributed to the development of …

Prevention And Treatment Of Familial Adenomatous Polyposis And Colorectal Cancer By Bilberry-Derived Anthocyanidins., Ashley M. Mudd

Electronic Theses and Dissertations

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths within the United States. Familial adenomatous polyposis (FAP) is an inherited disorder which if left untreated will develop into colon cancer. The family of plant-derived compounds, anthocyanins, show significant therapeutic potential against a variety of diseases, however, they are limited by their instability and poor bioavailability. The goal of my Master’s research project was to determine whether anthocyanidins (non-glycosylated anthocyanins) are more effective than the native anthocyanins, and whether exosomal formulation of anthocyanidins (ExoAnthos) can enhance therapeutic potency compared with free Anthos against both FAP and CRC. The antiproliferative …

The Interaction Of Homoserine Lactones And Paraoxonase 2 Modulates Cell Death Signaling And Cell Proliferation., Aaron Mackallan Neely

Electronic Theses and Dissertations

Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule that functions to facilitate bacteria-bacteria communication. C12 has also been reported to affect many aspects of human host cell physiology, including evoking cell death in various types of cells. However, the signaling pathway(s) leading to C12-triggerred cell death remains unclear. To clarify cell death signaling induced by C12, we examined mouse embryonic fibroblasts (MEFs) deficient in one or more caspases. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in cells, probably through the direct induction of mitochondrial membrane permeabilization. Importantly, C12 induces apoptosis …

Examining The Effects Of Macrophage Populations On Cancerous Tumor Growth., Grace E. Mahlbacher

Electronic Theses and Dissertations

The most abundant immune cell types of the tumor microenvironment macrophages recruited there by tumor-eluted factors. The role of these immune cells in tumor progression, and the interplay between tumor and immune cells is an emerging field of research with potential for novel treatment strategies. Here, a TIE2 expressing macrophage (TEM) subtype is integrated into a virtual tumor model. Within the 2D microenvironment, the TEM will differentiate from an extravasated monocyte precursor, congregate around the abluminal side of the vasculature in response to a chemoattractant gradient, secrete cytokines which favor differentiation of a separate angiogenic macrophage subtype [1]. The effects …

Discovery Of Pyrimidine-Based Heterocycles As Single Agents With Combination Chemotherapy Potential And As Inhibitors Of Purine Nucleotide Biosynthesis For The Treatment Of Cancer, Rishabh Mohan

Electronic Theses and Dissertations

This dissertation describes the design, synthesis and biological evaluation of monocyclic and bicyclic pyrimidine-base heterocycles as single agents with combination chemotherapy potential having both antiangiogenic effects and cytotoxic effects. This dissertation also describes selective tumor targeting with 5-substituted pyrrolo[2,3-d]pyrimidines analogs with heteroatom bridge substitution as GARFTase inhibitors.

The work in this dissertation is centered on identifying structural features that are necessary for inhibition of tubulin polymerization as well as for inhibition of one or more of the receptor tyrosine kinases (RTKs)- vascular endothelial growth factor receptor-2 (VEGFR2), platelet derived growth factor receptor-β (PDGFRβ) and epidermal growth factor receptor …

Application Of The Misclassification Simulation Extrapolation (Mc-Simex) Procedure To Log-Logistic Accelerated Failure Time (Aft) Models In Survival Analysis, Varadan Sevilimedu

Electronic Theses and Dissertations

Survival analysis is the study of time to event outcomes. Accelerated Failure Time models (AFT) serve as a useful tool in survival analysis to study the time of occurrence of an event and its relation to the covariates of interest. The accuracy of estimation of parameters in a model depends upon the correct measurement of covariates. Considering that perfect measurement of covariates is highly unlikely, it is imperative that the performance of the existing bias-correction methods be analyzed in AFT models. However, certain areas of bias-correction in AFT models still remain unexplored. One of these unexplored areas, is a situation …

Assessing The Anticancer Potential Of Natural Health Products (Lemongrass, Hibiscus, And Eleuthero Ginseng) Against Breast Cancer Models, Michael Stanesic

Electronic Theses and Dissertations

Breast cancer is a growing problem worldwide. Currently used cancer therapy is effective against cancer, but also causes cell death in normal cells, thereby causing severe side effects in patients. There is a serious need for the development of more effective and safer alternatives to chemotherapy and radiation. Natural health products have been used for centuries to treat various forms of diseases, although many of the therapeutic benefits have not been scientifically studied for their efficacy and safety. The use of natural health products has led to the development of most of the chemotherapy currently used today. In this thesis, …