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Timing And Duration Of Folate Restriction Differentially Impacts Colon Carcinogenesis., Ali M. Fardous

Wayne State University Dissertations

Colorectal cancer (CRC) constitutes a major burden on the healthcare system as the second most commonly diagnosed cancer in the developed world. Dietary folate is considered an important modulator of colorectal cancer. Folate restriction has been implicated in increasing CRC incidence by disrupting nucleotide synthesis, Impacting DNA methylation and inducing genetic instability. Our research shows that the timing and duration of dietary folate restriction can differentially impact Colorectal cancer initiation. Acclimating mice to folate restriction for 8 weeks results in a reduced number of preneoplastic lesions compared to mice placed of folate restriction for 1 week prior to initiating the …

Biochemical And Cellular Studies Of Apobec3 Family Dna-Cytosine Deaminases, Sachini Umedi Siriwardena

Wayne State University Dissertations

The AID/APOBEC family of enzymes deaminate cytosines in single-stranded DNA to uracils leading to base substitutions and strand breaks. Members of APOBEC3 family in humans are induced by cytokines produced during the body's inflammatory response to infections and provide innate immunity against viruses. However, there is emerging consensus that these enzymes can cause mutations in the cellular genome depending on the physiological state of the cell and the phase of the cell cycle they are expressed. Since aberrant expression of APOBEC3B was recently identified as a possible source of cancer, we initiated a study to determine the maximally active catalytic …

Missing Heritability And Novel Germline Risk Loci In Hereditary Ovarian Cancer: Insights From Whole Exome Sequencing And Functional Analyses, Jaime Lyn Stafford

Wayne State University Dissertations

While 25% of ovarian cancer (OVCA) cases are due to inherited factors, most of the genetic risk remains unexplained. This study addressed this gap by identifying previously undescribed OVCA risk loci through the whole exome sequencing (WES) of 48 BRCA1/BRCA2 wild type women diagnosed with OVCA, selected for high risk of genetic inheritance. Five clearly pathogenic variants were identified in this sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, a high impact variant in FANCM (R1931*) was identified. FANCM has been recently implicated in familial breast cancer risk but is not …

Transferrin Receptor Targeted Delivery Of Sirna For Gene Therapy, Yuran Xie

Wayne State University Dissertations

Gene therapy is thought to be a solution for various difficult to treat diseases such as cancer. Small interfering RNA (siRNA) as a promising anti-sense molecule can specifically silence disease related gene have been exploit in different diseases. However, lack of safe and efficient siRNA delivery systems limits the application of siRNA therapy in clinic. Transferrin receptor (TfR) is an essential transmembrane receptor involved in iron uptake. TfR universally express in most cells/ tissues but upregulated in certain cells, for example, many cancer cells and activated T cells (ATCs). To overcome the biological barriers and increase siRNA delivery efficiency, in …

Structural Characterization And Therapeutic Utility Of The Proton-Coupled Folate Transporter, Michael Roy Wilson

Wayne State University Dissertations

Folate is a B9 vitamin essential to DNA synthesis. The proton-coupled folate transporter (PCFT) is a newly discovered proton/folate symporter with an acidic pH optimum and broad expression across a variety of solid tumor types, with limited expression in normal tissues. Several antifolate molecules have been developed as cancer therapeutics, although these classical antifolates display numerous off-target effects due to transport by the ubiquitous reduced folate carrier (RFC). In this dissertation, we determine the roles of multiple PCFT structure/function domains, and develop PCFT-specific antifolates to target solid tumors. We utilize substituted cysteine accessibility methods (SCAM) to identify a novel reentrant …

The Impact Of Folate Restriction On Cancer And Aging: A Mechanistic Analysis, Safa Beydoun

Wayne State University Dissertations

Aging is a multifactorial process associated with alterations in several physiological functions. It increases susceptibility to disease and ultimately results in mortality. Since the associated diseases of aging are highly prevalent in the geriatric population, targeting the aging process as a whole may provide a better way to delay these age related diseases, in turn delaying aging. Various interventions have been shown to delay aging and age related diseases. They impact a major nutrient sensing pathway, mTOR. mTOR signaling is altered in many cancers and its downregulation was shown to delay aging. Other interventions extend lifespan by altering the one …

Imaging Anti-Proliferative Compounds With Flt-Pet, Christopher Mchugh

Wayne State University Dissertations

Imaging is critical in the detection and management of malignancies, and positron emission tomography (PET) is an imaging approach that provides information regarding cancer physiology through the tracking of molecular pathways and receptors. 3’-fluoro-3’-deoxythymidine (FLT) is a PET tracer designed to image cellular proliferation, which is a hallmark of cancer. FLT has been used to study the response of cancer to a variety of treatments such as chemotherapy, targeted agents, and radiation.

Here we explored FLT retention as a biomarker to monitor the anti-proliferative effect of the synthetic glucocorticoid (GC) dexamethasone (Dex) on non-small cell lung cancer (NSCLC). The basis …

Molecular Studies On The Anti-Tumor Effects Of Metal-Based Complexes: Involvement Of The Ubiquitin-Proteasome And Apoptotic Pathways, Sara M. Schmitt

Wayne State University Dissertations

The ubiquitin-proteasome pathway is crucial to normal cellular function, and as such, has been extensively investigated as a potential target for cancer therapeutics. Many compounds have been tested for their proteasome inhibitory ability, including various small peptide aldehydes, and, following the success of cisplatin, several metal-containing complexes. The efficacy of these compounds in preclinical studies ultimately resulted in the development and approval of the first-in-class proteasome inhibitor bortezomib, the use of which, unfortunately, has been hindered by toxicity and resistance. These limitations have led to a massive push toward designing and developing new, less toxic proteasome inhibitors for clinical use. …

The Impact Of Folate Deficiency On The Base Excision Repair Pathway: Analysis Of Enzyme Coordination In Response To Dna Damage And Imbalanced Repair, Amanda Pilling

Wayne State University Dissertations

The condition of folate deficiency has been implicated in carcinogenesis, with the strongest evidence formulated in colon cancer. The role of folate in DNA repair, DNA synthesis and methylation reactions renders this nutrient an valuable target for studying the onset and progression of cancer. Using molecular techniques to determine gene and protein expression, enzyme activity and methylation status elucidates the mechanism of DNA repair and damage in folic acid deficient animals in response to carcinogen. The findings presented in this study indicate failure to remove and repair damage in the condition of folate deficiency and suggest that the accumulation of …

Hedgehog Signaling: A Potential Therapeutic Target For Non-Small Cell Lung Cancer, Ma'in Yehya Maitah

Wayne State University Dissertations

The American Cancer Society estimated that 222,520 Americans were diagnosed with lung cancer and 157,300 died of lung cancer in 2010 (Jemal et al. 2009, 225-249;Jemal et al. 2011, 69-90). The clinical outcome of patients diagnosed with non-small cell lung cancer (NSCLC), the major lung cancer sub-types, is very poor, which calls for innovative research for finding novel therapeutic targets and agents for better treatment outcome.

Emerging evidences have suggested that a phenomenon called Epithelial-to-Mesenchymal Transition (EMT), which shares similar molecular characteristics with cancer stem-like cells, contributes to lung cancer treatment failure. In view of the fact that EMT process …

Molecular Mechanisms Of Pressure-Stimulated Cancer Cell Signaling, Christina Downey

Wayne State University Dissertations

ABSTRACT

MOLECULAR MECHANISMS OF PRESSURE-STIMULATED CANCER CELL SIGNALING

by

CHRISTINA DOWNEY

June 2010

Advisor: Dr. Marc Basson, MD, PhD

Major: Cancer Biology

Degree: Doctor of Philosophy

Increased extracellular pressure stimulates cancer cell adhesion by a mechanism that is dependent upon beta-1-integrin activation, an intact cytoskeleton, and FAK and Src activation. By a different mechanism, increased extracellular pressure modulates cancer cell proliferation in a manner that is regulated by protein kinase C, but not Src or an intact cytoskeleton. Previous studies from our laboratory have shown that paxillin is a necessary mediator in the pathway by which pressure stimulates adhesion; however, …

Regulatory And Functional Aspects Of Foxo3a Transcription Factor And Their Implications In Prostate Cancer, Melissa Elise Dobson

Wayne State University Dissertations

The P13K/Akt pathway is a critical mediator of growth factor signaling involving many cellular functions. The deregulation of this pathway has been shown to be involved in the development of various cancers. One of the main targets of this pathway is FoxO3a, a transcription factor whose target genes are involved in important cellular processes such as apoptosis, cell cycle control, and glucose metabolism. FoxO3a is regulated by various post translational modifications including acetylation, ubiquitination and phosphorylation. The transcription factor is directly phosphorylated by Akt on 3 residues: Threonine 32, Serine 253 and Serine 315. Phosphorylation by Akt generates binding sites …