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Full-Text Articles in Medicine and Health Sciences
Transcriptional, Epigenetic, And Signal Events In Antifolate Therapeutics, Alexandra Racanelli
Transcriptional, Epigenetic, And Signal Events In Antifolate Therapeutics, Alexandra Racanelli
Theses and Dissertations
A targeted approach to the development of antifolate therapies has been sought for many years. Central to the success of such development is an understanding of the molecular mechanisms dictating the sensitivity of cells to antifolates and the fundamental differences of these processes between normal and neoplastic phenotypes. This dissertation addressed transcriptional mechanisms and cell-signaling events responsible for the efficacy of antifolate therapies. Transcriptional processes and cell signaling pathways are often aberrant in neoplastic tissues, providing a potential point of distinction between a normal and neoplastic cellular state. Folylpolyglutamate synthetase (FPGS) catalyzes the formation of poly-γ-glutamate derivatives of folates and …
Pax5 Haploinsufficiency Cooperates With Bcr-Abl1 To Induce Acute Lymphoblastic Leukemia, Christopher B. Miller
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. …
Therapeutic Drugs In Cancer And Resistance., Aditi Pandya Martin
Therapeutic Drugs In Cancer And Resistance., Aditi Pandya Martin
Theses and Dissertations
We investigated the mechanism of toxicity and resistance development of small molecule tyrosine kinase inhibitor lapatinib in HCT 116 colon cancer cells. Lapatinib mediated cell death in HCT 116 cells was caspase independent and involved cytosolic release of apoptosis inducing factor. Treatment of HCT 116 cells with 10µM Lapatinib lead to the outgrowth of lapatinib resistant HCT 116 cells. Our studies show that alterations in the expression and activation of Bcl-2 family proteins allow lapatinib resistant HCT 116 cells to resist cytotoxic effects of lapatinib as well as of other commonly used chemotherapeutic agents. In hepatoma and pancreatic cancer cells, …
Human Ribosomal Rna Gene Clusters Are Recombinational Hotspots In Cancer, Dawn Michelle Stults
Human Ribosomal Rna Gene Clusters Are Recombinational Hotspots In Cancer, Dawn Michelle Stults
University of Kentucky Master's Theses
The gene that produces the precursor RNA transcript to the three largest ribosomal RNA molecules (rDNA) is present in multiple copies and organized into gene clusters. They represent 0.5% of the diploid human genome but are critical for cellular viability. The individual genes possess very high levels of sequence identity and are present in high local concentration, making them ideal substrates for genomic rearrangement driven by dysregulated homologous recombination. Our laboratory has developed a sensitive physical assay capable of detecting recombination-mediated genomic restructuring in the rDNA by monitoring changes in lengths of the individual clusters. In order to determine whether …
Regulation Of Redox Signaling By Lipid Electrophiles In Breast Cancer, Anne R. Diers
Regulation Of Redox Signaling By Lipid Electrophiles In Breast Cancer, Anne R. Diers
All ETDs from UAB
A number of steps in breast cancer progression and metastasis are regulated by redox signaling pathways. Electrophilic lipids such as 15-deoxy-delta12,14-Prostaglandin J2 (15d-PGJ2) are mediators of redox signaling pathways because of their ability to modify critical cysteine residues (thiols) in redox-sensitive proteins. In this thesis, we examine the effect of lipid electrophiles such as 15d-PGJ2 and others on redox signaling pathways in breast cancer. Furthermore, we develop new strategies to regulate cancer cell behavior in response to lipid electrophiles using three strategies: 1) through organelle-specific targeting of electrophiles 2) by exploiting the concentration-dependence of effects of electrophiles, and 3) utilizing …
The Peptidyl-Prolyl Isomerase Pin1 Promotes Nf-Kappab And Stat3 Signaling In Glioblastoma, George Prescott Atkinson
The Peptidyl-Prolyl Isomerase Pin1 Promotes Nf-Kappab And Stat3 Signaling In Glioblastoma, George Prescott Atkinson
All ETDs from UAB
Glioblastoma (GBM) is an incurable tumor of the central nervous system (CNS). Over the past 50 years, little progress has made in improving the quality of life and median lifespans of patients who are diagnosed with this devastating disease. However, new insights into the aberrant signaling pathways at the root of GBM pathology are providing new targets for next generation cancer therapies. Two signaling pathways that are commonly upregulated in GBM are NF-kappaB and STAT3. Importantly, tumor models in which NF-kappaB and STAT3 signaling are inhibited have demonstrated the importance of these pathways to GBM growth and proliferation. Therefore, better …
Mouse Modeling Of Pancreatic Ductal Adenocarcinoma (Pdac); Search For Early Diagnostic Markers And Therapeutic Targets, Kyoko Kojima
Mouse Modeling Of Pancreatic Ductal Adenocarcinoma (Pdac); Search For Early Diagnostic Markers And Therapeutic Targets, Kyoko Kojima
All ETDs from UAB
PDAC is a highly malignant neoplasm that carries a very poor prognosis. PDAC development is a multistage transformation process that involves multiple genetic alterations that include activation of EGFR/HER2 and KRAS, and loss-of-function mutations in INK4A/ARF, p53 and SMAD4. In recent years, several genetically engineered mouse models that accurately recapitulate human pancreatic neoplasia have been developed. Histological characterizations of those models have revealed possible roles for the mutated RAS, INK4a/ARF and p53 in pancreatic tumorigenesis. However, the role of SMAD4 mutation, which is associated with late stages of tumor progression, has yet to be explored. Additionally, those models that would …