Medicine and Health Sciences Commons^™

Targeting The Colchicine Binding Site On Tubulin To Overcome Multidrug Resistance And Anticancer Efficacy Of Selective Survivin Inhibitors, Kinsle E. Arnst

Theses and Dissertations (ETD)

Tubulin inhibitors are widely used as chemotherapeutic agents, and their successis attributed to their ability to target microtubule dynamics and disrupt critical cellular functions including cell signaling, motility, intracellular trafficking, and mitosis. Interference with microtubule dynamics consequently disrupts mitotic progression and ultimately leads to apoptosis, validating microtubule dynamics as an excellent target for anticancer agents. While this class of drug has proven to be effective against many cancer types, the clinical efficacy of current tubulin inhibitors is often limited by the development of multidrug resistance. The most common form of resistance to these agents arises from the overexpression of drug …

Metabolic Regulation Of Cellular Signaling, Rashid John Darbandi

Theses and Dissertations (ETD)

Using the biochemically tractable Xenopus oocyte model system, we have previously characterized a novel metabolic regulation of cell death. We found that glucose-6-phosphate (G6P) via the pentose phosphate pathway leads to increased nicotinamide adenine dinucleotide phosphate (NADPH) levels, a subsequent increase in cytosolic acetyl-coenzyme A and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). We recently identified coenzyme A (CoA), derived from the breakdown of acetyl-CoA, as the key metabolic signal that mediates a novel mechanism of calmodulindependent activation of CaMKII. CoA binds directly to the calmodulin (CaM) binding domain (CaMBD) of CaMKII resulting in its activation and downstream inhibitory phosphorylation …

The Roles Of Nuclear Receptor Nr4a1 In Cancer Cell Proliferation And Skeletal Muscle Differentiation, Alexa Farmer

Theses and Dissertations (ETD)

Nuclear receptors (NRs) constitute a major class of drug targets in the treatment of various cancer types. NRs respond to cellular signals and become activated upon ligand binding to transcriptionally modulate expression of target genes. NR4A1 (Nur77) is a member of the NR4A family of nuclear receptors and displays an oncogenic profile in many cancer models. It is often upregulated in adult solid malignancies and is known to promote cell proliferation and survival. Knockdown studies of NR4A1 in cancer cell lines results in decreased cell growth and angiogenesis and increased apoptosis, suggesting NR4A1 is an oncogenic protein. Due to the …

Novel Oncogenic Drivers In Pediatric Gliomagenesis, Alexander K. Diaz

Theses and Dissertations (ETD)

Pediatric high-grade gliomas (pHGGs), with a two-year survival rate of less than 20%, are some of the most aggressive human cancers. This dissertation begins with our analysis of 127 pHGGs, including brainstem (BS) and non-brainstem (NBS) tumors, from 118 patients using next-generation sequencing technologies. Nearly one-third of BS-HGGs, also known as diffuse intrinsic pontine gliomas (DIPGs), harbored somatic heterozygous missense mutations in ACVR1, coding for a receptor serine-threonine kinase involved in bone morphogenetic protein (BMP) signaling. These alterations led to gain-of-function as evidenced by increased phosphorylation of downstream targets in primary astrocytes and zebrafish embryo ventralization. Whole-genome sequencing and …

Nkg2d Ligands In Cancer, Neha Das Gupta

Theses and Dissertations (ETD)

NK cell transplantation has been increasingly used to treat cancers that are resistant to chemotherapy. However, not all cancers are susceptible to NK cell killing. The prevalence and mechanisms of NK cell resistance have not been well elucidated. Because NKG2D is a major activating receptor on NK cells, we sought to test the hypothesis that NKG2D is the primary pathway in tumor cell recognition. Herein, we comprehensively assessed 20 cancer cell lines representing a broad array of cancer types. In line with our primary hypothesis, no cancer cell lines that expressed low levels of NKG2D ligands were susceptible to NK …

Pain Management In Nursing Home Residents With Cancer And Dementia With And Without Hospice Services, Todd Bryant Monroe

Theses and Dissertations (ETD)

Aims: We sought to identify differences in pain management between two groups; nursing home residents with malignant cancer and dementia with and without hospice services.

Methods: Decedent records from 2003-2009 were assessed for diagnosis of dementia and cause of death as cancer. Ten malignant cancer diagnoses were determined a priori from the CDC 2004 data on the top 10 malignant cancers for all races and genders. Fifty-five decedents from 10 nursing homes were included in the final sample. Four instruments were used: Minimum Data Set (MDS) a standardized assessment tool required of most U.S. nursing homes. A large …

Pax5 Haploinsufficiency Cooperates With Bcr-Abl1 To Induce Acute Lymphoblastic Leukemia, Christopher B. Miller

Theses and Dissertations (ETD)

Acute lymphoblastic leukemia (ALL) is the commonest pediatric malignancy and comprises several distinct subtypes each with its own unique pathogenesis, clinical behavior, and response to therapy. Chromosomal aberrations are a hallmark of ALL but alone fail to induce leukemia. Pediatric ALLs can be divided into several categories based on the expression of several genetically conserved chromosomal translocations including the t(9,22)[BCR-ABL1], t(1,19)[TCF3-PBX1], t(12,21)[ETV6-RUNX1], MLLrearranged leukemia’s, hyperdiploid and hypodiploid karyotypes, and T-lineage leukemia. Each translocation confers a characteristic transforming phenotype within the cell in which it originates but is alone insufficient to induce overt leukemia. …