Medicine and Health Sciences Commons^™

A Cell Culture Model To Study Tobacco Associated Oral Cancer Progression And Treatment Resistance, Amanda Busch

Theses & Dissertations

Head and Neck Squamous cell carcinoma is the 6^th most common cancer in the world. Risk factors for HNSCC include alcohol and tobacco consumption, infection with Human Papilloma Virus, and exposure to environmental toxins. Unlike many other cancers, the incidence of HNSCC is growing, yet the treatment options and outcomes have not been significantly improved for decades. An increased understanding of the molecular mechanisms of these cancers is needed for improvement in early diagnosis, enhanced treatment effectiveness, and cancer prevention. 4-nitroquinoline 1-oxide (4NQO) is a well-tested, tobacco mimicking, carcinogen. 4NQO produces similar histological and chemical changes found in human …

A Survey Of Speech-Language Pathologists' Academic Preparation In Craniofacial Anomalies, Francesca Myerski

Honors Theses

Craniofacial anomalies occur in 1 of 750 newborns a year with the three main types being cleft lip, cleft palate, and cleft lip and/or cleft palate. There are six main factors that affect craniofacial anomalies that are focused on in this research, including genetics, environmental factors, medications, diet, health risks, and surgical procedures/surgeons. The research found that there is a lot of information on craniofacial anomalies and speech-language pathologists need to learn about as much as possible. The lack of knowledge and academic preparations speech-language pathologists have in craniofacial anomalies has decreased their awareness in the birth defect and has …

Med12 Is A Critical Regulator Of Neural Crest Lineage And Nervous System Myelination, Fatma Betul Aksoy Yasar

Dissertations & Theses (Open Access)

The Mediator complex (MED) is a multi-subunit protein complex integral to the eukaryotic transcription machinery. MED12 is a Cdk8- regulatory kinase module subunit directly implicated in human disease and is genetically altered in neurological disease and cancer. Numerous attempts at generating an in vivo system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of Med12 gene. To understand the cellular and molecular processes associated with its role in disease, we generated multiple mouse models with targeted depletion of MED12 in distinct cellular lineages. Our genetically engineered models with induced and conditional …

Differential Impacts Of Hhv-6a Versus Hhv-6b Infection In Differentiated Human Neural Stem Cells, Elham Bahramian

Graduate Theses and Dissertations

Within the family Herpesviridae, sub-family β-herpesvirinae, and genus Roseolovirus, there areonly three human herpesviruses that have been described: HHV-6A, HHV-6B, and HHV-7. Initially, HHV-6A and HHV-6B were considered as two variants of the same virus (i.e., HHV6). Despite high overall genetic sequence identity (~90%), HHV-6A and HHV-6B are now recognized as two distinct viruses. Sequence divergence (e.g., >30%) in key coding regions and significant differences in physiological and biochemical profiles (e.g., use of different receptors for viral entry) underscores the conclusion that HHV-6A and HHV-6B are distinct viruses of the β-herpesvirinae. Despite these viruses being implicated as causative agents in …

Dpc29 Promotes Mitochondrial Translation Post-Initation In Saccharomyces Cerevisiae, Kyle Andrew Hubble

Graduate School of Biomedical Sciences Theses and Dissertations

Although the cytosolic and bacterial translation systems are well studied, much less is known about translation in mitochondria. In the yeast Saccharomyces cerevisiae, mitochondrial gene expression is predominately regulated by translational activators. These regulators are thought to promote translation by binding the elongated 5’-UTRs on their target mRNAs. Since mammalian mitochondrial mRNAs generally lack 5’-UTRs, they must regulate translation by other mechanisms. As expected, most yeast translational activators lack orthologues in mammals. Recently, a mitochondrial gene-specific translational activator, TACO1, was reported in mice and humans. To better define its role in mitochondrial translation I examined the yeast TACO1 orthologue, DPC29. …

Seeing The Big Picture: System Architecture Trends In Endoscopy And Led-Based Hyperspectral Subsystem Intergration, Craig M. Browning

<strong> Theses and Dissertations </strong>

Early-stage colorectal lesions remain difficult to detect. Early development of neoplasia tends to be small (less than 10 mm) and flat and difficult to distinguish from surrounding mucosa. Additionally, optical diagnosis of neoplasia as benign or malignant is problematic. Low rates of detection of these lesions allow for continued growth in the colorectum and increased risk of cancer formation. Therefore, it is crucial to detect neoplasia and other non-neoplastic lesions to determine risk and guide future treatment. Technology for detection needs to enhance contrast of subtle tissue differences in the colorectum and track multiple biomarkers simultaneously. This work implements one …

Synthesis And Biological Testing Of Small-Molecule Mitochondrial Complex I Inhibitors, Willough Sloan

Undergraduate Honors Theses

This thesis delineates two main projects: the first outlines the structure elucidation efforts toward a Diels-Alder adduct of a novel reaction for the synthesis of chimaphilin, a naphthoquinone-based natural product with apoptotic or antiproliferative activity in certain cancer cells^1,2. The structure elucidation extends to derivatives of chimaphilin synthesized by the same cyclization reaction. While Diels-Alder reactions are usually regioselective, ¹H-NMR and ¹³C-NMR of the adducts was inconclusive and indicated the possibility of regioisomer presence, with one regioisomer being chimaphilin (or derivatives). A multitude of crystallization methods were carried out in order to be able to analyze …

Ankyrin Dependent Mitochondrial Function And Bioenergetics In The Heart, Janani Subramaniam, Janani Subramaniam

Dissertations & Theses (Open Access)

ANK2 mutations in patients are associated with numerous arrhythmias, cardiomyopathies, and other heart defects. In the heart, AnkB, the protein encoded by ANK2, clusters relevant ion channels and cell adhesion molecules in several important domains; however, its role at Mitochondria Associated ER/SR Membranes (MAMs) has yet to be investigated. MAMs are crucial to mitochondrial function and metabolism and are signaling hubs implicated in various cardiac pathologies. Among several functions, these sites mediate the direct transfer of calcium from the ER/SR to the mitochondria to modulate ATP synthesis. Given that mitochondrial function and energy production are paramount to cardiovascular heath, …

Screening Tcf19 And Kif18b To Determine Co-Regulation With Mybl1 In Triple Negative Breast Cancer Patient Tissues, Tyra Sharda Ivory

Theses (2016-Present)

The aggressive behavior in triple-negative breast cancer (TNBC) is due to genetic signaling events, which call for the comprehensive analyses of genes differentially regulated in the cancers. Our laboratory previously found that MYBL1 was over-expressed in a fraction of the TNBC, compared to some luminal, and other breast cancer subtypes. The MYBL1 gene is a proto-oncogene that serves as a strong transcriptional activator. The gene is involved in signaling events related to cell cycle signaling, differentiation, proliferation, and apoptosis, all which are differentially regulated in cancers. Because MYBL1 is a transcription regulator, involved in cancer-related mechanisms and differentially expressed in …

Dual Mechanisms Implemented By Lin-28 For Positive Regulation Of Hbl-1 Are Necessary For Proper Development Of Distinct Tissues In Caenorhabditis Elegans, Madeleine Minutillo

Graduate School of Biomedical Sciences Theses and Dissertations

In Caenorhabditis elegans, the heterochronic pathway is comprised of a hierarchy of genes that control the proper timing of developmental events. hbl-1 (Hunchback Like-1) encodes an Ikaros family zinc-finger transcription factor that promotes the L2 stage cell fate events of the hypodermis. The downregulation ofhbl-1 is a crucial step for the transition from the L2 to the L3 stage. There are two known processes through which negative regulation of hbl-1 occurs: suppression of hbl-1 expression by 3 let-7 miRNAs through the hbl-1 3’UTR and inhibition of HBL-1 activity by LIN-46. The mechanisms by which hbl-1 is positively regulated have not …

Yap And Taz Are Required For Neural Crest-Derived Cardiovascular Development, Shannon Erhardt

Dissertations & Theses (Open Access)

Congenital heart defects (CHDs) are the most common human birth defect, occurring in ~1/100 newborns, and are a leading cause of early infant death. Cardiac neural crest cells (NCCs) are a migratory and multipotent cell population known to aid in the development of the cardiac outflow tract (OFT), valves, and interventricular septum, during embryogenesis. Yap and Taz are downstream effectors of the fundamental Hippo signaling pathway and are vital for proper organ and tissue development, yet their role in neural crest (NC)-derived heart formation is still largely unknown. We generated Yap and Taz conditional knockout (CKO) mice using a Cre-lox …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Roles Of Oxidative Stress And Dna Methylation In Cigarette Smoking-Induced Accelerated Acute Myeloid Leukemia Progression, Mary Figueroa

Dissertations & Theses (Open Access)

Acute myeloid leukemia (AML) is a commonly diagnosed cancer in smokers. When current or former smokers have AML, they have worse survival compared to never smoking patients. This has been observed clinically for decades, but then it is unknown how smoking leads to worsened AML survival. Smoking causes oxidative stress and altered DNA methylation that persists for decades in peripheral blood mononuclear cells, but these changes from smoking have not been evaluated in the context of AML. We hypothesize that smoking-induced molecular changes, including altered DNA methylation associated with poor AML prognosis, promote AML. We developed a novel model to …

The Novel Role Of Dnmbp In Kidney Development, Brandy Walker

Dissertations & Theses (Open Access)

Congenital anomalies of the kidney and urinary tract (CAKUT) accounts for nearly one-fourth of all birth defects and more than 40% of pediatric end-stage renal disease, yet only 10-20% of CAKUT cases have a known monogenetic cause. Human kidneys are composed of up to a million epithelial tubules called nephrons. Disruption of nephron development is one of the many congenital anomalies that cause CAKUT, often resulting in chronic or end-stage renal disease which requires transplant. During nephron epithelialization, the formation of stable cadherin-mediated adhesion junctions is essential for maintaining cell-cell contacts. To understand the cell behaviors underlying abnormalities in renal …

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

Extrinsic And Intrinsic Factors Influencing Homeostasis And Repair In Oral Tissues, Georgia Nikoloudaki

Electronic Thesis and Dissertation Repository

The oral tissues, including gingiva and buccal mucosa, heal rapidly with minimal scar formation. Although in the oral cavity, the palatal mucosa is associated with excessive scarring in response to injury. In this thesis, first, I investigated the complex relationship between cells and their microenvironment using wound healing models in which extracellular matrix composition and mechanical stiffness affect cellular responses during acute wound repair. I also determined how intrinsic differences of cells recruited during healing contribute to wound resolution.

In Chapter 2, I first investigated cell-extrinsic factors, specifically the influence of the pro-fibrotic matricellular protein periostin on palatal healing. Using …

The Role Of Reactive Oxygen Species In The Accumulation Of Driver Mutations In B Cell Acute Lymphoblastic Leukemia, Mia P. Sams

Electronic Thesis and Dissertation Repository

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated …

Primary Cilia Of The Cardiac Neural Crest & Hedgehog-Mediated Mechanisms Of Congenital Heart Disease, Lindsey A. Fitzsimons

Electronic Theses and Dissertations

Elimination of primary cilia in cardiac neural crest cell (CNCC) progenitors is hypothesized to cause a variety of congenital heart defects (CHDs), including atrioventricular septal defects, and malformations of the developing cardiac outflow tract. We present an in vivo model of CHD resulting from the conditional elimination of primary cilia from CNCC using multiple, Wnt1:Cre-loxP, neural crest-specific systems, targeting two distinctive, but critical, primary cilia structural genes: Intraflagellar transport protein 88 (Ift88) or kinesin family member 3A (Kif3a). CNCC loss of primary cilia leads to widespread CHD, where homozygous mutant embryos (MUT) display a variety of outflow tract malformations, septation …

Characterization Of 1,1-Diarylethylene Foxm1 Inhibitors Against High-Grade Serous Ovarian Carcinoma Cells, Cassie Liu

Theses & Dissertations

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases, and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell …

Plant Based Polyphenols Decrease Cell Migration And Inhibit Proliferation Of Human Pancreatic Cancer Cells, Mary Gathoni

Electronic Theses & Dissertations

Pancreatic cancer is one of the most highly malignant tumors of the digestive tract. Both the incidence and death rate of pancreatic cancer have increased since 2000. The disease has a poor prognosis with a relative 5-year survival rate of 10%. Pancreatic cancer-related mortality can be mainly attributed to lack of early diagnosis, tumor metastasis, lack of effective treatment strategies and drug resistance. There has been a mounting interest on the use of plant-based compounds such as polyphenols in cancer treatment therapies. This is mainly due to their low toxicity and fewer side effects compared to the conventional chemotherapeutic options …

Novel Regulators Of Cellular Secretion Alter The Tumor Microenvironment To Drive Metastasis, Rakhee Bajaj

Dissertations & Theses (Open Access)

Lung cancer is a highly aggressive disease responsible for ~25% of all cancer-related deaths, due in part to its proclivity to metastasize. Treating metastasis holds potential for improving patient survival but requires a deeper investigation into the underlying mechanisms. Some of these processes that can regulate metastasis are: (1) Oncogenic targets of epithelial micro-RNAs (miRNAs) are epigenetically de-repressed upon loss of the miRNAs during epithelial-to-mesenchymal transition (EMT) and in cancer. EMT confers plasticity and fitness to cancer cells promoting their survival through the metastatic cascade. This cascade and EMT are initiated by loss of the miRNA200 family (miR-200) and the …

Regulation Of C-C Chemokine Receptor 7 (Ccr7) Ligand-Mediated Internalization And Chemotaxis By G Protein-Coupled Receptor Kinase Family 4 (Grk-4, 5, 6) In Human Pediatric T-Cell Acute Lymphoblastic Leukemia (T-All), Eduardo Elias Chaib

Open Access Theses & Dissertations

Background and Significance: The Hispanic population is disproportionally affected by T-ALL (T-cell acute lymphoblastic leukemia) when compared to other races in the US. C-C Chemokine Receptor 7 (CCR7) in T-ALL is used during disease progression, and may lead to migration of cancerous cells into the Central Nervous System (CNS) of patients. Goals and Objectives: This project aims to find relevant rates and risk factors for T-ALL for the Hispanic population in the US/Mexico border region. The other aim is to assess the effect of the G protein-coupled Receptor Kinase 4 (GRK-4) family proteins on migration and receptor internalization through CCR7 …

Hyper Stable Variants Of Fgf-1-Fgf-2 Dimer, Madison Shields Mcclanahan

Chemistry & Biochemistry Undergraduate Honors Theses

Fibroblast Growth Factors (FGFs), including FGF-1 and FGF-2, are proteins that play a crucial role in cell proliferation, cell differentiation, cell migration, and tissue repair. FGF-1 and FGF-2 are useful in accelerating the healing process in the human body; however, these proteins are naturally thermally unstable, resulting in a relatively low half-life in vivo. 1,8 In efforts to improve the stability of this protein, FGF-1 and FGF-2 proteins are engineered by combining the amino acid sequences of the two proteins to form a heterodimer and obtain novel properties. These two FGF variants are chosen for their specific wound healing capabilities. …

Development Of New Treatments For Asthma And Neuropathic Pain Based On Ɣ-Aminobutyric Acid A Receptor (Gabaar) Ligands, Nicolas Mark Zahn

Theses and Dissertations

The γ-aminobutyric acid A receptor (GABAAR) is a ligand-gated pentameric chloride channel consisting of several identified subunits: α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3.1-2 Typical arrangement of subunits consists of two α subunits, two β subunits, and one γ subunit.3 GABAARs have two binding sites for the endogenous ligand γ-aminobutyric acid (GABA), between the α and β subunits. GABAARs also have a binding site for positive allosteric modulators, such as benzodiazepines, between the α and γ subunits.4-5 Due to their ability to treat anxiety, epilepsy, insomnia, and muscle relaxation, benzodiazepines are widely prescribed pharmaceuticals.6-7 Still, adverse effects result from …

The Effects Of Metronomic And Maximum-Tolerated Dose Chemotherapy In Colorectal Cancer Angiogenesis: A Combined Approach Using Endoscopic Diffuse Reflectance Spectroscopy And Mrna Expression, Ariel Isaac Mundo Ortiz

Graduate Theses and Dissertations

Colorectal cancer (CRC) continues to be one of the most incident and deadliest types of cancer worldwide. Chemotherapy has proven effective to reduce tumor burden for CRC patients, but there are several disadvantages associated with the use of mainstay maximtolerated dose (MTD) chemotherapeutic strategies. Metronomic chemotherapy (MET) has been developed as an alternative that addresses the shortcomings of maximum-tolerated dose chemotherapy but so far its effectiveness as a neoadjuvant strategy for CRC has not been explored.

This dissertation uses a combined optics and molecular biology approach (using diffuse reflectance spectroscopy and mRNA expression) to study the changes in angiogenesis and …

Modulation Of Kras Structure And Dynamics By Kras Ubiquitination And Membrane Depolarization, Vinay Nair

Dissertations & Theses (Open Access)

KRAS, a 21 kDa small GTPase protein, functions as a molecular switch playing a key role in regulating cell proliferation. Dysregulation of KRAS signaling by oncogenic mutations leads to uncontrolled cell proliferation, a hallmark of cancer cells. Attempts to therapeutically target oncogenic KRAS have led to limited success resulting in a need to identify new mechanisms to targeting KRAS. The interaction of KRAS with its regulators, effectors, and the membrane present one such avenue. In this study, we investigated how post-translational covalent and environmental modifications could modulate these interactions of KRAS. Using computational molecular dynamics simulations, nuclear magnetic resonance spectroscopy …

Characterization Of Gangliosides And Fatty Acids In Extracellular Vesicles From Human Milk, Aliya Amin

Food Science (MS) Theses

Extracellular vesicles (EVs) are bioactive components of human milk that may impact functionality to regulate growth, cognitive development, metabolism, and immunity in newborns. The biogenesis of EVs and the mechanism by which EVs elicit biologic effects in vivo have not been characterized entirely. Gangliosides and fatty acids are integral in the formation, release, stability, and functionalities of EVs. Presumably, EV function is related to EV composition and lipids in EVs influence the bioavailability of EV cargo and downstream functions of EVs. The objective of this research was to characterize the fatty acid and ganglioside composition of EVs in human milk. …

Cannabinoids And Retinal Fibrotic Disorders., Lucy June Sloan

Electronic Theses and Dissertations

Retinal fibrosis is detrimental to vision. Retinal pigment epithelial (RPE) cells contribute to several retinal fibrotic diseases. Upon exposure to TGF-β, a key fibrotic cytokine, RPE cells trans-differentiate to myofibroblasts marked by the integration of α-SMA fibers into F-actin stress fibers, which confer strong contractility. Myofibroblasts produce and contract the collagen-rich fibrotic scar and disrupt retinal architecture. In this study, we investigated the in vitro effects of the putative endocannabinoid compound N-oleoyl dopamine (OLDA) on TGF-β2 induced porcine RPE cell contraction and α-SMA expression. Using an in vitro collagen matrix contraction assay, we found that OLDA inhibited TGF-β2 induced contraction …

Differential Expression Of Cellular And Exosomal Microrna Isolated From Oral Cancer Cells And Their Resistance To Chemotherapy, Brady Petersen

UNLV Theses, Dissertations, Professional Papers, and Capstones

Introduction: MicroRNAs are abundant small non-coding RNA with a variety of known functions, including transcriptional activation and inhibition. Recent evidence has suggested that microRNA expression may influence the responsiveness of some cancers to chemotherapy, including liver and lung cancers. Some evidence has now suggested that specific microRNAs, such as miR-21, miR-155, and miR-375, may influence oral cancer responsiveness to chemotherapy – although much remains to be discovered.

Objective: Based upon the lack of evidence in this area, the primary objective of this study was to evaluate microRNA expression and responsiveness among oral cancers.

Methods: Five commercially available oral cancer cell …

Integration Of Biomedical Imaging And Translational Approaches For Management Of Head And Neck Cancer, Abdallah Mohamed, Abdallah Mohamed

Dissertations & Theses (Open Access)

The aim of the clinical component of this work was to determine whether the currently available clinical imaging tools can be integrated with radiotherapy (RT) platforms for monitoring and adaptation of radiation dose, prediction of tumor response and disease outcomes, and characterization of patterns of failure and normal tissue toxicity in head and neck cancer (HNC) patients with potentially curable tumors. In Aim 1, we showed that the currently available clinical imaging modalities can be successfully used to adapt RT dose based-on dynamic tumor response, predict oncologic disease outcomes, characterize RT-induced toxicity, and identify the patterns of disease failure. We …