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Full-Text Articles in Medicine and Health Sciences
Biomarker And Target Discovery In Cancer, Alyncia Dominique Robinson
Biomarker And Target Discovery In Cancer, Alyncia Dominique Robinson
All ETDs from UAB
Cancer is a complex disease characterized by uncontrolled growth of transformed cells that can arise in many tissue types throughout the body (e.g., breast, lung, prostate, pancreas, lymph nodes) and is a major cause of death worldwide. Cancer progression resulting in aggressive or metastatic disease accounts for one of the leading causes of death worldwide, second only to heart disease in the US. Incidentally, cancer-related mortality has been on a steady decline, dropping 25% over the last 25 years [1]. This could be attributed to improved and earlier diagnoses and better treatment options being developed over the past few decades. …
Characterization Of Rna Polymerase I Trigger Loop Mutations, Collin Ainslie
Characterization Of Rna Polymerase I Trigger Loop Mutations, Collin Ainslie
All ETDs from UAB
RNA polymerases are primarily multi-subunit enzymes that synthesize RNAs from template DNA strands. RNA polymerase I (Pol I) is the eukaryotic RNA polymerase that synthesizes the majority of ribosomal RNA (rRNA) for ribosome production. These include the 5.8S, 28S, and 18S rRNAs which are synthesized from a polycistronic gene in the nucleolus. The rRNAs synthesized by Pol I, the 5S rRNA, & ribosomal proteins come together to synthesize ribosomes through ribosome biogenesis. Dysregulation of Pol I activity has been established to contribute to dysregulation of ribosome biogenesis and disease state development. These conditions include but are not limited to Cincinnati …
Rna Polymerase I Elongation Kinetics: A Biochemical And Global Study Of A Cancer Therapeutic Target, Catherine Elizabeth Scull
Rna Polymerase I Elongation Kinetics: A Biochemical And Global Study Of A Cancer Therapeutic Target, Catherine Elizabeth Scull
All ETDs from UAB
My graduate research has focused on understanding the elongation kinetics of RNA polymerase I (Pol I), the enzyme responsible for synthesizing ribosomal RNA (rRNA), and defining how inhibition of ribosome biogenesis may be used as a cancer therapeutic strategy. Here, I have defined key biophysical features of Pol I and I have expanded the field’s understanding of Pol I elongation by: 1) characterizing the enzymatic properties of Pol I by mutational analysis of the polymerase itself, and by 2) elucidating the role of DNA sequence on Pol I arrest and nucleolytic cleavage activity. In recent years, Pol I has become …
Analysis Of The Gtp Cyclohydrolase I/Tetrahydrobiopterin Pathway In Glioblastoma Biology, Anh Tran
Analysis Of The Gtp Cyclohydrolase I/Tetrahydrobiopterin Pathway In Glioblastoma Biology, Anh Tran
All ETDs from UAB
Glioblastomas (GBMs) are the most common primary malignant brain tumors in adults and one of the most aggressive cancers with high rates of recurrence and therapeutic resistance. In GBMs, subpopulations of highly tumorigenic cells called brain tumor initiating cells (BTICs) have the unique capacity to promote tumor maintenance, therapeutic resistance, and angiogenesis. Depending on the level, differentiation state, and tumor stage, reactive nitrogen and oxygen species inhibit or increase cancer growth and BTIC maintenance. GTP cyclohydrolase 1 (GCH1) is the rate limiting enzyme in a pathway that can regulate reactive species production but has not been thoroughly investigated in GBM. …
Overcoming Obesity-Induced Immunotherapeutic Impairment, Shannon Boi
Overcoming Obesity-Induced Immunotherapeutic Impairment, Shannon Boi
All ETDs from UAB
Obesity affects ~40% of United States adults and is linked to the development of multiple health-related complications. Obesity is a major risk factor for developing renal cell carcinoma (RCC), the most common type of renal cancer. Metastatic RCC has poor five-year survivals, therefore, new, efficacious therapeutics are needed. One avenue is immunomodulation to generate tumor-specific, systemic anti-tumor responses that are long-lasting against local, metastatic, and recurrent tumors. Despite encouraging results, immunotherapeutic treatment of RCC is underwhelming. Cytokine therapies are largely toxic, while newly FDA-approved ‘checkpoint blockade’ (CB) antibodies have responses <50%. Here, we present a strategy employing a T cell priming therapy (AdTR/CpG) upstream of CB administration. Combinatorial use resulted in improved anti-tumoral immune responses, significantly reduced tumor burdens, and extended overall survival in pre-clinical RCC. Importantly, this approach was more efficacious than either single agent(s). Pre-clinical therapy development is often accomplished using lean, healthy animals–thus, to improve translatability we examined immune responses in the context of obesity as a major patient comorbidity. Subsequently, we investigated AdTR/CpG/CB in diet-induced obese (DIO) mice. Tumor/treatment-naïve DIO mice exhibited obesity-associated features; i.e., increased leptin/insulin and serum cytokines. These effects were not dependent on high-fat diet administration as mice resistant to weight gain had minimal alterations in these factors, and were similar to mice maintained on standard chow. As previously identified, 80% of DIO mice bearing renal tumors failed to respond to AdTR/CpG. AdTR/CpG/CB-treatment dramatically improved response rates against DIO tumors, however, decreased obese responder percentages were observed in both combinatorial therapies and was independent of high fat diet administration alone. Impaired response rates were not model or immunotherapy-specific as similar reductions in tumor clearance were seen in models of melanoma and sarcoma. Furthermore, responses were not due to initial T cell priming or unequal precursor CD8+ T cell frequencies. Detrimental changes in the tumor microenvironment underscored failure in obese mice and revealed therapeutic success was defined by a T cell-myeloid cell-inversion profile, supported by immunogenetic and flow cytometric analyses. Thus, we demonstrate a novel combinatorial approach for improving checkpoint-based outcomes, and identify the ability of host obesity to impede therapy-induced anti-tumor immunity.
Investigating Phenotypic Severity Associated With Sister Chromatid Cohesion Defects In Human Disease, Stefanie Marie Percival
Investigating Phenotypic Severity Associated With Sister Chromatid Cohesion Defects In Human Disease, Stefanie Marie Percival
All ETDs from UAB
INVESTIGATING PHENOTYPIC SEVERITY ASSOCIATED WITH SISTER CHROMATID COHESION DEFECTS IN HUMAN DISEASE STEFANIE M. PERCIVAL GRADUATE BIOMEDICAL SCIENCES ABSTRACT Sister chromatid cohesion (SCC) is a process that utilizes a proteinaceous ring, cohesin, for accurate chromosome segregation. An essential process in S phase termed cohesion establishment is necessary to stabilize cohesin rings around sister chromatids. Mutations in establishment of cohesion homolog 2 (ESCO2), a protein essential for cohesion establishment, cause a developmental disorder called Roberts Syndrome (RBS). Cytogenetic analysis in patients reveals heterochromatic repulsion (HR), a centromeric puffing, indicative of cohesion defects. The severity of phenotypes varies from preterm lethal to …
Atp6v1c1 Enhances Breast Cancer Growth By Activating V-Atpase Mediated Mtorc1 Signaling And Metastasis By Increasing V-Atpase Activity In Cancer Cells, Matthew J. Mcconnell
Atp6v1c1 Enhances Breast Cancer Growth By Activating V-Atpase Mediated Mtorc1 Signaling And Metastasis By Increasing V-Atpase Activity In Cancer Cells, Matthew J. Mcconnell
All ETDs from UAB
It is known that the vacuolar ATPase has a number of functions related to tumor growth and progression such as involvement in drug resistance, pH regulation, autophagy, and lysosomal acid protease activation, as well as invasion and metastasis. Here we specifically describe the role of ATP6v1c1 in murine and human models of breast cancer. ATP6v1c1 is the dominant isoform of the coordinating subunit (ATP6v1c) involved in the assembly of the vacuolar ATPase complex which plays a key role in cancer growth and progression. We also describe how ATP6v1c1 knockdown impairs tumor nutrient signaling through mTORC1 and tumor cell proliferation, by …
The Sialyltransferase St6gal-I Promotes A Cancer Stem Cell Phenotype, Matthew Jonathan Schultz
The Sialyltransferase St6gal-I Promotes A Cancer Stem Cell Phenotype, Matthew Jonathan Schultz
All ETDs from UAB
Alterations in tumor cell glycosylation have been observed for decades, but the functional consequences of specific glycosyltransferase activity are not well understood. This dissertation focuses on the role of the sialyltransferase ST6Gal-I in driving ovarian and pancreatic cancer development. ST6Gal-I adds a negatively-charged sialic acid sugar in an alpha 2-6 linkage to select receptors, which can alter their function. We show that ST6Gal-I protein is upregulated in ovarian and pancreatic cancers but not expressed in normal epithelial tissue from these organs. ST6Gal-I expression in ovarian cancer correlates with decreased progression-free and overall survival, and we present evidence that ST6Gal-I expression …
The Expression And Function Of Icam-2 In Neuroblastoma, Joseph Feduska
The Expression And Function Of Icam-2 In Neuroblastoma, Joseph Feduska
All ETDs from UAB
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for 15% of all childhood cancer deaths. At the time of initial diagnosis, the majority of patients present with NB that has already metastasized. While initial remission is often achieved following treatment, roughly 50% of these patients will relapse and die from the development of intractable metastatic progression. Intercellular adhesion molecule-2 (ICAM-2) is a transmembrane glycoprotein, normally expressed only in endothelial cells and subsets of leukocytes. ICAM-2 expression in cancer cells had not been previously investigated, until our lab recently reported the novel finding of endogenous ICAM-2 expression …
Role Of The Cystine/Glutamate Exchanger In Glioma Cell Biology, Toyin Adeyemi Ogunrinu
Role Of The Cystine/Glutamate Exchanger In Glioma Cell Biology, Toyin Adeyemi Ogunrinu
All ETDs from UAB
Changes in the glioma microenvironment including oxygen (O2) levels, supply of amino acid such as L-glutamate and L-cystine and glutathione (GSH) concentrations play a critical role in glioma biology. Previous data from our laboratory and others have implicated the L-cystine/L-glutamate exchanger, system xc- in the invasion and proliferation of cancers including glioma. The central aim of this dissertation was to characterize the contribution of L-cystine uptake, GSH synthesis and L-glutamate release to migration and proliferation of glioma cells. In my first study, I examined the role of system xc- mediated L-glutamate release on glioma migration. I show that activation of …
Limited Transplantation Of Antigen-Expressing Hematopoietic Stem Cells Induces Long-Lasting Cytotoxic T Cell Responses And Effect Of Altered Suppressive Myeloid Population On Hiv-Disease Progression, Warren L. Denning
All ETDs from UAB
While each type of cancer and chronic viral infection has its own specific pathology, they share two common mechanisms of immune evasion. The first mechanism is the exhaustion or deletion of antigen-specific T cells. The second mechanism is the formation of an immunosuppressive environment responsible for the block of T cell function. Elicitation of antigen-specific T cells be accomplished by immunotherapy in place of conventional treatments such as HAART and chemotherapy. In addition, immunotherapy can alleviate the side-effects associated with long-term use of conventional therapies while reducing the total cost. The results presented here provide an alternative to conventional methods …
Structural And Functional Studies On Group A Streptococcal Bacteriophage Hyaluronidase, Joo Hyoung Lee
Structural And Functional Studies On Group A Streptococcal Bacteriophage Hyaluronidase, Joo Hyoung Lee
All ETDs from UAB
Aberrant hyaluronan production is frequently associated with tumors where the elevated levels of tumoral hyaluronan are often associated with higher expression levels of cellular hyaluronidases that produce saturated hyaluronan fragments with divergent pro-tumoral activities. In this thesis, we provide evidence that different hyaluronan metabolism of bacteriophage hyaluronidase (HylP) elicits distinct alteration in breast cancer cell behavior. We demonstrate through comparative analysis with bovine testicular hyaluronidase (BTH) that higher enzyme activity, specificity for hyaluronan and production of unsaturated oligosaccharides render HylP to have profound effects on growth, migration and invasion activities of breast carcinoma cells, whereas BTH and its saturated metabolites …
Preclinical Pharmacology Of Novel Synthetic Iminoquinones As Anticancer Agents, Scharri Ezell
Preclinical Pharmacology Of Novel Synthetic Iminoquinones As Anticancer Agents, Scharri Ezell
All ETDs from UAB
Prostate cancer is the most common male malignancy and the second leading cause of cancer related death in the United States. Despite recent advances in the detection, diagnosis, and treatment of prostate cancer, there is a need for more effective therapies. Unfortunately, most conventional therapeutic modalities, such as androgen ablation therapy, frequently result in androgen-independent cancers. These cancers are typically more aggressive, metastatic, and resistant to chemotherapeutic agents than androgen-dependent prostate cancer. Therefore, agents that are effective against both androgen-sensitive and androgen-independent, as well as genetically diverse cancers are critically needed. The objective of the dissertation research was to address …
Brms1 Coordinately Regulates Microrna To Suppress Breast, Mick D. Edmonds
Brms1 Coordinately Regulates Microrna To Suppress Breast, Mick D. Edmonds
All ETDs from UAB
The majority of cancer related mortality is attributed to complications associated with metastatic disease. Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis of multiple cancer types in vivo and loss of nuclear BRMS1 is associated with ER-negative cancers and a high rate of proliferation. Many groups have shown BRMS1 to regulate the expression of multiple metastatic genes, yet until now no one has been able to account for how these many changes in gene expression occur. In this work, we report that BRMS1 regulates a select set of genes called microRNA (miRNA), and these miRNA themselves can regulate metastasis. Using …
The Role Of Gli1 In Eralpha-Negative Breast Cancer: Promoting Survival, Migration, Invasion, And Metastasis, Yeon-Jin Kwon
The Role Of Gli1 In Eralpha-Negative Breast Cancer: Promoting Survival, Migration, Invasion, And Metastasis, Yeon-Jin Kwon
All ETDs from UAB
Glioma-associated oncogene homolog 1 (Gli1) is a well-known oncogene and a transcription factor that mediates several signaling pathways important for tumor progression, such as hedgehog, TGFß, Ras, and EGFR. Although Gli1 is known to play an important role in cancers of brain, skin, prostate, and the pancreas, the role of Gli1 in breast cancer was not previously well-defined. Therefore, this dissertation focuses on defining the role of Gli1 and the mechanism underlying Gli1-mediated transcription in breast cancer. Interestingly, the major findings of the dissertation clearly indicate that Gli1 promotes cell survival and is predictive of a poor outcome in Estrogen …
Molecular Mechanisms Of Breast Cancer Metastasis: Gap Junction Intercellular Communication And The Bone Microenvironment, Thomas Morgan Bodenstine
Molecular Mechanisms Of Breast Cancer Metastasis: Gap Junction Intercellular Communication And The Bone Microenvironment, Thomas Morgan Bodenstine
All ETDs from UAB
Metastatic disease accounts for the overwhelming majority of cancer related deaths. More specifically, breast cancer remains one of the leading causes of death in women and breast cancer cells metastasize to bone more than any other secondary site. Upon arriving within the bone microenvironment, breast cancer cells interact with bone marrow cells, leading to changes in bone biology that favor growth of the cancer cells. Additionally, some cancer cells are capable of direct cellular communication with cells at metastatic sites via dysregulation of a family of proteins known as connexins. This direct, physical communication is known as gap junctional intercellular …
Fiber Modification Of Adenoviral Vectors For Cancer Gene Therapy, Miho Murakami
Fiber Modification Of Adenoviral Vectors For Cancer Gene Therapy, Miho Murakami
All ETDs from UAB
Cancer still remains a major public health concern despite improvements in primary prevention, early detection and advanced treatments. Cancer gene therapy using human adenovirus serotype 5 (HAdV-5) as a vector has been explored as a new therapeutic approach. HAdV-5 infection is initiated by binding to the coxsackie virus and adenovirus receptor (CAR), its primary cellular receptor. However, the levels and patterns of expression of CAR vary greatly in clinical tumor tissue samples, and the expression lev-els tend to decrease as the tumors progress. The low level expression of CAR in target cancer cells diminishes the utility of HAdV-5 as a …
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 …
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 …
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 …