Medicine and Health Sciences Commons^™

Cxcr2 Expression In Tumor Cells Is A Poor Prognostic Factor And Promotes Invasion And Metastasis In Lung Adenocarcinoma, Erminia Massarelli

Dissertations & Theses (Open Access)

CXC chemokine receptor 2 (CXCR2) is a G-protein coupled receptor which mediates signaling by binding to CXC chemokines CXCL1-3 and 5-8. In non-small cell lung cancer CXCR2 has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. However, there is controversial data in the literature about CXCR2 expression in tumor cells and its role in the tumor microenvironment. We hypothesized that tumoral expression of CXCR2 and its ligands promote tumor invasion and metastasis in non-small cell lung cancer. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from …

Adenylyl Cyclase 2 Selectively Regulates Il-6 Expression In Human Bronchial Smooth Muscle Cells, Amy Sue Bogard

Theses and Dissertations (ETD)

Adenylyl cyclase (AC) catalyzes the formation of the ubiquitous second messenger cAMP. AC isoforms differ in their tissue distribution, cellular localization, regulation, and protein interactions, and most cells express multiple isoforms. We hypothesized that cAMP produced by different AC isoforms regulates unique cellular responses. Overexpression of individual isoforms had distinct effects on forskolin (Fsk)-induced expression of a number of known cAMP-responsive genes in human bronchial smooth muscle cells (BSMC) and human embryonic kidney cells (HEK-293). Most notable, in BSMC overexpression and activation of AC2 enhanced interleukin 6 (IL-6) expression, but overexpression of AC3 or AC6 had no effect. IL-6 production …

Enhanced Pancreatic Beta-Cells Proliferation And Functionality, Hanan Abdulaziz Alismail

Graduate Theses and Dissertations

Biologically functional beta-cells proliferate at an extremely low rate with limited turnover capacity. This cellular property hinders cell-based therapy for clinical applications. Many attempts have been made to develop techniques that allow large quantities of production of clinically relevant islet β-cells in vitro. A line of studies demonstrates that functional beta-cells can proliferate under certain circumstances, providing hope for generating and expanding these cells in vitro and transplanting them into the recipient. In this study, we showed that a membrane substrate offers a better niche for beta cell proliferation and insulin secretion. Mouse beta cells were grown on a tissue …

Regulation Of Secretory Phospholipase A2 By Thyroid Hormone, Pragya Sharma

Theses and Dissertations (ETD)

Rationale: Low grade inflammation has been correlated with elevated risk of hepatic steatosis and atherosclerosis. Secretory phospholipase A2 group IIA (PLA2g2a) enhances the progression of several chronic inflammatory diseases including arthritis and atherosclerosis. The potential linkage of hypothyroidism with inflammation led us to examine the modulation of sPLA2 expression by thyroid hormone (T3) in liver.

Objective: Most of the studies of phospholipase A2 group IIA (PLA2g2a) have been conducted with macrophages and vascular smooth muscle cells with regard to atherosclerosis. The liver is one of the major contributors to the total pool of extracellular PLA2g2a. The aim of the present …

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 …

Vascular Stem Cells In Diabetic Complications, Emily C. Keats

Electronic Thesis and Dissertation Repository

Diabetes leads to a variety of secondary complications. At the heart of these complications lies endothelial cells (ECs) – cells that take up unregulated plasma glucose, experience various biochemical alterations, and provide the basis for whole organ vascular dysfunctions. With the purpose of generating new vascular networks for the treatment of these chronic complications, my initial work focused on vascular stem cells (VSCs). VSCs have the ability to differentiate into both endothelial (EPC) and mesenchymal (MPC) progenitor cells, both of which are necessary for the creation of stable and functional blood vessels. To establish whether these progenitor populations retain their …

Macromolecular Complexes Of Cystic Fibrosis Transmembrane Conductance Regulator Alter Fluid Transport In Inflammatory Bowel Disorders, Kavisha Arora

Theses and Dissertations (ETD)

Macromolecular complexes of cystic fibrosis transmembrane conductance regulator (CFTR) comprise of network of proteins that can regulate cAMP-/cGMP-activated CFTR chloride channel function. We report the physical and functional coupling of CFTR with nitric oxide (NO) producing enzyme-inducible nitric oxide synthase (iNOS) at the apical plasma membrane in inflammatory bowel disease (IBD). The complex formation requires the scaffolding protein Na+ /H+ exchanger regulatory factor 2 (NHERF2). We demonstrate that iNOS is overexpressed at or near the apical plasma membrane of gut epithelial cells in IBD and, through the stimulation of the NO-cGMP pathway, generates compartmentalized cGMP underneath the plasma membrane. This …

The Protumorigenic Role Of Caspase-8 In Neuroblastoma, Devin Drew Twitchell

Theses and Dissertations (ETD)

Neuroblastoma (NB), the most common extracranial solid tumor in children, accounts for 15% of cancer-related deaths in pediatric patients. Caspase-8 (casp8), a proapoptotic protein, is silenced in approximately, 50-70% of neuroblastoma patient samples. Loss of casp8 has been suggested to increase NB metastasis and correlated, in some studies, with advanced-stage NB. Furthermore, decreased casp8 expression may facilitate neuroblastoma tumorigenesis by protecting cells from cell death mediated by either integrins or chemotherapeutics. Paradoxically, casp8 expression is maintained in 30-50% of NB patient samples giving rise to the possibility that casp8 may provide selective advantages for NB tumorigenesis. Caspase-8 is shown to …

Diabetes Mellitus And Hypercholesterolemia Are Risk Factors For Alzheimer’S Disease And Appear To Affect The Integrity Of The Blood Brain Barrier, Jacqueline Dash

Graduate School of Biomedical Sciences Theses and Dissertations

Studies have shown that the vascular risk factors common to diabetes mellitus and hypercholesterolemia are also risk factors for Alzheimer’s disease (AD). It is currently unknown how these diseases are associated with AD, but they may cause a leak in the blood brain barrier (BBB), which is one of the hallmarks of AD. In this preliminary study, over 150 pig brain slides were tested for the expression levels of tight junction proteins occludin and claudin V in the BBB microvasculature. There were three groups of pig brains used in this study namely, control pigs, pigs with diabetes mellitus and hypercholesterolemia …

Associations Between Alcohol Consumption And Fasting Blood Glucose In Young Adults, Julie Ann Lucca

Master's Theses

Current research shows moderate alcohol consumption is associated with decreased risk of diabetes and excessive consumption or binge drinking can cause insulin resistance and diabetes. In 2010, diabetes was the seventh leading cause of death in the United Statesand was responsible for significant health complications: blindness, kidney failure, and limb amputations, and is a large national economic burden. Fasting blood glucose (FBG) is a tool used to help diagnose diabetes. Abnormally high FBG, ≥100 mg/dl, is indicative of diabetes and pre-diabetes. Few studies have observed diabetic prevalence among young adults or college students. Studying young adults can help provide added …

Delayed Thrombus Resolution And Fibroproliferative Vascular Wound Healing From Deficiency Of Type Iii Collagen: A Paradoxical Mechanism For Tissue Fragility, Amy J. Reid

Dissertations & Theses (Open Access)

Vascular Ehlers-Danlos syndrome is a heritable disease of connective tissue caused by mutations in COL3A1, conferring a tissue deficiency of type III collagen. Cutaneous wounds heal poorly in these patients, and they are susceptible to spontaneous and catastrophic rupture of expansible hollow organs like the gut, uterus, and medium-sized to large arteries, which leads to premature death. Although the predisposition for organ rupture is often attributed to inherent tissue fragility, investigation of arteries from a haploinsufficient Col3a1 mouse model (Col3a1^+/-) demonstrates that mutant arteries withstand even supraphysiologic pressures comparably to wild-type vessels. We hypothesize that injury …

Functional Study Of Hemogen Knockout Mouse Model, Peng Gao

Theses and Dissertations (ETD)

Mouse Hemogen (Hemgn) is regarded as a homologue of human Erythroid Differentiation Associated Gene (EDAG). EDAG overexpression has been postulated for association with some leukemia cases. Meanwhile, Hemgn has been found to contribute to Hoxb4 mediated hematopoietic stem cell expansion. Based on these postulations and evidences, a Hemgn knockout mouse model has been generated to study its function in normal and stress hematopoiesis. I confirmed the Hemgn expression in hematopoietic organs including bone marrow and spleen, as well as round spematids in testis. Hemgn is expressed in mouse hematopoietic stem cells and erythroid progenitor cells. Moreover, Hemgn was also found …

Characterizing Stomatin-Like Protein 2 And Its Role In Neuron Survival, Lisa A. Foris

Electronic Thesis and Dissertation Repository

Stomatin-like Protein 2 (SLP-2) has been identified as a stress-inducible transcript and has been shown to interact with and stabilize mitochondrial proteins. Since mitochondria are critical for neuronal function, we hypothesized that SLP-2 regulates neuron survival in response to stressful stimuli. A conditional SLP-2 knockout mouse (deletion) and the SN56 cell line (upregulation) were employed to study the role of SLP-2 in mitochondrial dynamics and neuron survival. SLP-2 deficient primary cortical neurons displayed significantly decreased levels of various mitochondrial respiratory chain proteins, indicating SLP-2 contributes to maintenance of mitochondrial membrane integrity. SLP-2 was up-regulated in response to oxidative stress and …

The Role Of Dax-1 In Regulating Pluripotency In Mouse Embryonic Stem Cells, Anthony Torres

Master's Theses

The orphan receptor Dax-1 is highly expressed in pluripotent embryonic stem (ES) cells and shows a correlative reduction in expression as these cells differentiate. While it is known that Dax-1 is expressed in pluripotent mouse ES cells, the precise function of Dax-1 in these cells is not as well understood. Recent studies employing RNA interference (RNAi) to specifically reduce the expression of the Dax-1 gene in mouse ES cells found that upon the knock down of Dax-1, ES cells differentiated. These findings indicate that Dax-1 functions in a novel role in the maintenance of a relatively undifferentiated state in ES …

Role Of Iron In Ethanol Derived Hepatic Stress, Jesse A. Thornton

Theses, Dissertations and Capstones

Chronic alcohol abuse is the third leading cause of preventable death in the United States. Ethanol metabolism causes liver injury through alterations in hepatic metabolic state, redox status, and acetaldehyde adduct formations. Increased iron absorption is associated with chronic ethanol consumption and may play a role in ethanol induced oxidative stress. We tested the hypothesis that normal labile iron in the liver plays a role in ethanol related pathological stress, using C57/Bl6 mice pair-fed Lieber-DeCarli liquid ethanol diets for 11 and 22 weeks. Normal iron group mice received 55mg/kg iron as ferric citrate, whereas the low iron groups received 5mg/kg. …

Multifactorial Modulation Of The Blood-Brain Barrier: Relationship To Stroke, Bei Zhang

Theses and Dissertations--Nutritional Sciences

The blood-brain barrier (BBB) is a dynamic interface, mainly consisting of highly specialized brain microvascular endothelial cells (BMECs) that segregate the central nervous system (CNS) from the peripheral circulation. Impairment of the BBB, due to disruption of tight junction (TJ) proteins and inflammatory responses, may initiate and/or contribute to the progress of CNS disorders, including stroke. Stroke is the second leading cause of death worldwide. It has been shown that aging and environmental pollutants can induce brain endothelium dysfunction, and are considered as risk factors for stroke.

Deficiency of telomerase is highly linked with aging-associated vascular diseases. Evidence indicates that …

Generation And Characterization Of Peptide Fusion Proteins, Brianna L. Probasco

Graduate School of Biomedical Sciences Theses and Dissertations

Pathogenic Th17 cells drive progression of many autoimmune diseases. Th17 cells develop from naïve T cells in the immune system after antigen-driven stimulation in a specific cytokine environment. Normally, T cells act to fight off infection, but when not properly controlled, they can cause disease. The cytokine interleukin-23 (IL-23) plays an essential role in the expansion of pathogenic Th17 cells. IL-23 is a heterodimeric protein, composed of a p19 alpha chain and a p40 beta chain. The p40 is also part of IL-12 and binds to the IL-12 receptor beta 1 (IL-12Rβ1) subunit. Thus, it follows that the IL-23 receptor …

Amalgamation Of Nucleosides And Amino Acids In Antibiotic Biosynthesis, Sandra H. Barnard

Theses and Dissertations--Pharmacy

The rapid increase in antibiotic resistance demands the identification of novel antibiotics with novel targets. One potential antibacterial target is the biosynthesis of peptidoglycan cell wall, which is both ubiquitous and necessary for bacterial survival. Both the caprazamycin-related compounds A-90289 and muraminomicin, as well as the capuramycin-related compounds A-503083 and A-102395 are potent inhibitors of the translocase I enzyme, one of the key enzymes required for cell wall biosynthesis. The caprazamycin-related compounds contain a core nonproteinogen b-hydroxy-a-amino acid referred to as 5’-C-glycyluridine (GlyU). Residing within the biosynthetic gene clusters of the aforementioned compounds is a shared open reading …

Redox-Regulated Relb-Ar Axis Mediates Prostate Specific Antigen Expression: Insight In Prostate Cancer Response To Radiation Therapy, Lu Miao

Theses and Dissertations--Toxicology and Cancer Biology

Although the prostate specific antigen (PSA) test is widely used in clinical settings for prostate cancer (PCa) diagnosis and post-treatment follow-up monitoring, false positive PSA test results, which contribute to over-diagnosis of PCa, and false negative results, which miss some patients with aggressive PCa, remain problems of clinical importance.

Our study demonstrates that radiation therapy, which is widely used for treatment of localized PCa, generates TNF-α in tumor cells and stromal fibroblasts, redox dependently. Interestingly, TNF-α rapidly and transiently triggers the RelA-mediated NF-κB canonical pathway, but its effect on RelB expression is more robust and long lasting, which leads to …

Novel Insights Into The Function And Regulation Of Group X Secretory Phospholipase A2, Joseph D. Layne Jr

Theses and Dissertations--Nutritional Sciences

Group X secretory phospholipase A₂ (GX sPLA₂) hydrolyzes membrane phospholipids producing free fatty acids and lysophospholipids. Previous studies from our lab suggest that mice with targeted deletion of GX sPLA₂ (GX KO) have increased age-related weight gain due to an increase in overall adiposity. Paradoxically, this increased adiposity is associated with improved age-related glucose intolerance. GX KO mice also demonstrate a reduced inflammatory response to lipopolysaccharide injection. In vitro studies indicate this phenotype may be attributable to blunted macrophage mediated inflammatory responses. Given the role of macrophages in promoting adipose tissue (AT) inflammation and metabolic dysfunction …

Discovery Of New Biomarkers Of Mild Cognitive Impairment And Alzheimer's Disease Risk In Buccal Cells Using Laser Scanning Cytometry, Maxime Francois

Theses: Doctorates and Masters

Previous studies have shown that mild cognitive impairment (MCI) may reflect the early stages of more pronounced neurodegenerative disorders such as Alzheimer’s disease (AD). In clinical practice, patients with AD are not usually identified until the disease has progressed to a stage when primary prevention is no longer possible. Therefore there is a need for a minimally invasive and inexpensive diagnostic to identify those who exhibit cellular pathology indicative of MCI and AD risk so that they can be prioritised for primary prevention. Human buccal cells are accessible in a minimally invasive manner, and exhibit cytological and nuclear morphologies that …