Medicine and Health Sciences Commons^™

The Regulation And Mechanisms Of Egfr-Mediated Apoptosis In Mda-Mb-468 Cells., Nicole Marion Jackson

Electronic Theses and Dissertations

Background: The Epidermal Growth Factor Receptor (EGFR) is a 170- kilodalton transmembrane protein that belongs to the ErbB family of receptor tyrosine kinases. Upon ligand-mediated activation, the EGFR responsible for cell growth, proliferation, and tissue homeostasis in epithelial cells; however, the EGFR is overexpressed in many human malignancies including MDA-MB-468 cells, a metastatic breast epithelial cell line. Previous studies have indicated that within the MDA-MB-468 cell line, receptors at the cell surface promote cell growth when activated with Epidermal Growth Factor (EGF) ligand. Activated receptors that are internalized to the endosomes however induce apoptosis. This contrasting response at different cellular …

Suramin Protects From Cisplatin-Induced Acute Kidney Injury., Tess Dupre

Electronic Theses and Dissertations

In rodent models, suramin improves recovery following acute kidney injury (AKI). We hypothesized that suramin would be useful in protection against cisplatin-induced AKI. This hypothesis was tested by pre-treating C57BL/6j mice with suramin prior to cisplatin. Our data indicates that suramin protects the kidney from injury by decreasing cisplatininduced decreases in kidney function. Renal histology indicated that suramin significantly protected from cisplatin-induced AKI. Data indicate that suramin pretreatment attenuated mRNA expression of pro-inflammatory cytokines and chemokines following cisplatin treatment, while also decreasing markers of cell stress and cell death. We utilized the same experimental design with 10-month old FVB mice …

Identifying Hepatocellular Carcinoma (Hcc) Cells With Cancer Stem Cell-Like Properties., Harshulkumar M. Pandit

Electronic Theses and Dissertations

Hepatocellular Carcinoma (HCC) is a challenging condition to treat in the clinic due to its distinct tumor phenotype, aggressive growth, and chemotherapy resistance. Cancer Stem Cells (CSCs) are a poorly differentiated subpopulation of cells within the tumor microenvironment, and role of CSCs in tumor initiation and chemotherapy resistance is not well understood in HCC. In this study, we have successfully identified HCC cells with CSC-like properties that showed resistance to Doxorubicin. Using the established serum free culture techniques, we have enriched CSC-like cells among hepatocellular cancer cells. These enriched cells exhibit all CSC-like properties i.e. self-renewal capability, anchorage independent growth …

Searching For Novel Ligands For The Cannabinoid And Related Receptors., Pritesh Prakash Kumar

Electronic Theses and Dissertations

The first purpose of the present dissertation was to apply a high throughput assay to systematically screen a library of food and drug administration (FDA)-approved drugs as potential ligands for the cannabinoid receptor 2 (CB2). A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring changes in intracellular cAMP levels was validated and found to be suitable for testing ligands that may act on CB2. Among the 640 FDA-approved drugs screened, raloxifene, a drug used to treat/prevent post-menopausal osteoporosis, was identified for the first time to be a novel CB2 inverse agonist. The dissertation reporting these results demonstrated that by …

Improved Oncolytic Virotherapy By Increasing Virus Spread Within Tumors., Stephen Wechman

Electronic Theses and Dissertations

Oncolytic adenoviruses (Ads) have great therapeutic potential for lung cancer. Cancer selective E1b-deleted Ads are safe, however their efficacy remains limited clinically. To improve E1b-deleted Ads, Adhz60 was selected for greater anti-cancer efficacy by a process called bioselection, producing AdUV. AdUV preferentially lysed A549 and H1299 lung cancer cells more effectively than both the cancer selective Adhz60 and non-selective Ad5. AdUV induced greater LC3-II expression, relative to LC3-I, indicating that AdUV (30.9-fold) induced autophagy more effectively than Ad5 (12.2-fold) and Adhz60 (7.8-fold) in A549 cells. Mice treated with AdUV had significantly smaller tumors (p-value < 0.001) and prolonged survival (p-value = 0.0005) than mice treated with the negative control AdGFP. These results suggest that AdUV efficiently lyses lung cancer cells in vitro and in vivo.

Chronic Ethanol Exposure Sensitizes The Lung In A Mouse Model Of Endotoxemia-Induced Acute Lung Injury : Potential Role Of Plasminogen Activator Inhibitor-1., Lauren G. Poole

Electronic Theses and Dissertations

The goal of this project is to characterize a new mouse model of alcohol-enhanced acute lung injury (ALI) and to determine the role of plasminogen activator inhibitor-1 (PAI-1) in this model. Male mice (WT and PAI-1-/-) were exposed to ethanol-containing Lieber-DeCarli diet or pair-fed control diet for 6 weeks; some animals were administered intraperitoneal lipopolysaccharide (LPS) prior to sacrifice. Chronic alcohol feeding enhanced induction of the chemokines MIP-2 and KC (murine IL-8 homologues) after LPS injection in wild type animals. This enhanced chemokine expression did not correlate with enhanced pulmonary neutrophil infiltration, however animals exposed to chronic ethanol showed sustained …

Regulation Of Receptor Tyrosine Kinases By Ubiquilin1., Zimple Kurlawala

Electronic Theses and Dissertations

Receptor Tyrosine Kinases (RTK’s) like EGFR, Insulin Receptor, IGF1R and others mediate growth, proliferation and balance between apoptosis and survival. Dysregulation of RTK activity has been identified in a wide range of cancers and contributes to initiation, progression and metastasis of tumors. Ubiquilins (UBQLN) are fairly novel proteins and are studied mostly in the field of neurodegenerative disorders. Our laboratory recently discovered a link between UBQLN1 function and tumorigenesis. UBQLN1 is lost in about 50% of non-small cell lung cancer (NSCLC) cases. We have identified an interaction between UBQLN1 and IGF1R. Furthermore, UBQLN1 regulates activity of IGF1R and EGFR. Following …

Metabolomics Of Transformed Mda-Mb-231 Cell Lines Expressing Different Levels Of Human Arylamine N-Acetyltransferase 1 (Nat1)., Samantha Marie Carlisle

Electronic Theses and Dissertations

Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme that is found in almost all tissues of the body. Expression of NAT1 is commonly elevated in several cancers including breast cancer. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Three MDA-MB-231 breast adenocarcinoma cell lines that stably express wild-type, increased, and decreased levels of human NAT1 have been constructed and characterized for NAT1 mRNA, NAT1 acetylation activity, cell doubling rates, and endogenous acetyl-CoA levels. Differences in polar metabolic profile between these three cell lines were investigated using a comprehensive GC×GC−TOF …

Promoting Differentiation And Survival Of Human C-Kit+ Cardiac Progenitor Cells Ex Vivo., Tareq Al-Maqtari

Electronic Theses and Dissertations

c-kit+ cardiac progenitor cells (CPCs) have recently gained much attention due to the therapeutic effects they exert on cardiac function following their administration into the infarcted heart as evidenced by animal studies and by a recent clinical trial (SCIPIO). However, injecting these cells in the heart is associated with poor differentiation into specialized cardiac cell types and with rapid death of the engrafted cells. With the ultimate goal of advancing cardiac stem cell therapy, we sought to facilitate the differentiation of human CPCs into cardiac cell types (e.g. cardiomyocytes, smooth muscle cells, endothelial cells and cardiac fibroblasts) by overexpressing selected …

Exploring The Roles Of Host And Tumor Cell Α4 And Α7 Nicotinic Acetylcholine Receptors In Lung Cancer., John Caleb Greenwell

Electronic Theses and Dissertations

Lung cancer is the leading cause of cancer death in men and women worldwide. Tobacco exposure represents the major risk factor. Nicotine, an addictive plant alkaloid found in tobacco, has been demonstrated to stimulate lung carcinoma cells directly via nicotinic acetylcholine receptors (nAChRs) that trigger downstream signals capable of promoting lung cancer growth and progression. Attention has been given to α7 nAChRs, while less is known about α4 nAChRs. However, most studies evaluating these receptors relied on chemical inhibitors notorious for their off-target effects. Consequently, the true role of α4 and α7 nAChRs in lung cancer remains unclear. To address …

Novel Delivery Systems For Iron Replenishment, Naresh Modepalli

Electronic Theses and Dissertations

Iron is an integral part of hemoglobin and essential for the production of red blood cells. Iron deficiency and the resulting anemia are major nutritional deficiency disorders. The majority of patient populations suffering from iron deficiency anemia (IDA) are women of child bearing age and children of all ages. Iron deficiency is a complication of various other chronic conditions. Oral iron salts or colloidal parenteral iron formulations are treatment options for iron replenishment since several decades, but they are associated with severe side effects along with other patient noncompliance issues. Transdermal delivery of iron could be a potential alternative to …

Health Utility Assessment Among Caregivers Of Individuals With Multiple Sclerosis, Namita Joshi

Electronic Theses and Dissertations

OBJECTIVES The study objectives were to evaluate psychometric properties of the EuroQoL–five–dimensional questionnaire (EQ–5D–3L) among caregivers of individuals with multiple sclerosis (MS), assess caregiver utilities and determine predictors of utilities, and compare caregiver utilities obtained from the EQ–5D–3L and the SF–6D. METHODS A web–based survey was administered to MS caregivers via Qualtrics survey software using assistance from a MS patient registry– North American Research Committee on MS (NARCOMS). Measurement properties including convergent, discriminant, and known–groups validity, reliability, and ceiling and floors effects of the EQ–5D–3L were tested. Caregiver health utilities were estimated using the EQ–5D–3L and compared with population norms; …

Design, Synthesis And Cannabinoid Receptor Activity Of Benzofuran Ligands, Eric William Bow

Electronic Theses and Dissertations

The endocannabinoid system is a complex homeostatic signaling system controlled through the actions of two g-protein coupled receptors, cannabinoid receptor 1 (cb1) and cannabinoid receptor 2 (cb2). Significant neuronal expression and distribution of cb1 throughout the brain establishes its function as a major synaptic signaling receptor, and in regards to the actions of cannabis sativa, it is the primary mediator of the psychotropic effects of marijuana. Conversely, cb2 expression is confined to microglial cells in the brain and predominantly peripheral immune cells. The expression of cb2 provides a pharmacological basis for the well-documented immunomodulatory effects of cannabis, providing a potential …

Endangered Plant Species For Potential Drug Leads And Anticancer Prototypes For Treatment Of Breast And Pancreatic Cancers, Joonseok Oh

Electronic Theses and Dissertations

No abstract provided.

Transdermal Iontophoretic Delivery Of Lipophilic Drugs, Abhishek Juluri

Electronic Theses and Dissertations

Iontophoresis is one of the most widely studied active technique for enhancing transdermal delivery of drugs. However, its ability to enhance the delivery of highly lipophilic compounds is poor due to lack of any charge and poor water solubility of molecules. Propofol, a sedative and anesthetic drug was chosen as a one of the model lipophilic drug in this study. Initially, feasibility of delivery of propofol phosphate, a water soluble prodrug of propofol, via transdermal route using iontophoresis in combination with chemical permeation enhancers was investigated. Cathodal iontophoresis in combination with 0.1% sodium dodecyl sulphate synergistically enhanced the flux of …

Discovery Of Alternative Artemisinin Binding Sites In Plasmodium Falciparum Atpase-6, Shuneize Elizabeth Slater

Electronic Theses and Dissertations

Malaria is a fatal yet preventable and treatable disease. It is commonly spread through the bite of an infected Anopheles mosquito. Malaria parasites belong to the Plasmodium genus and can be caused by the falciparum, malariae, ovale, vivax, and knowlesi species. Artemisinin is an endoperoxide lactone extracted from qinghaosu (Artemisia annua L. or sweet wormwood). It and its derivatives possess uncharacteristically rapid action against Plasmodium falciparum. Artemisinin is unique in its effectiveness in deadly cerebral malaria. The endoperoxide bridge is crucial for its antimalarial activity; however, how it aids in killing the parasite is unknown. While there are multiple suggested …

Influence Of Novel Techniques On Solubility, Mechanical Properties And Permeability Via Hot Melt Extrusion Technology, Eman A. Ashour

Electronic Theses and Dissertations

Hot melt extrusion (HME) was evaluated as a continuous processing technology for the manufacture of solid dispersions. The aim of the current research project was to study the effect of pressurized carbon dioxide (P-CO2) on the physico-mechanical properties of three different grades of cellulose polymers, Klucel™ ELF, EF and LF hydroxypropylcellulose (HPC) resulting from hot melt extrusion techniques, and to assess the plasticization effect of P-CO2 on the tested polymers. The physico-mechanical properties as well as the tablet characteristics of the extrudates with and without injection of P-CO2 and with non-extruded polymers were examined. P-CO2 acted as plasticizer for Klucel™ …

Non-Invasive Drug Delivery To The Posterior Segment Of The Eye: Development Of Formulation Strategies And Evaluation Of Ocular Distribution And Pharmacological Activity, Goutham Reddy Adelli

Electronic Theses and Dissertations

Diseases of the posterior segment of the eye such as diabetic retinopathy, age related macular degeneration and glaucoma are the leading causes for blindness throughout the world. Topical eye drops is the most convenient formulation for daily application. The human eye, however, presents major physiological and dynamic barriers for the topically administered drug/molecule from reaching the retina. Similarly, the blood-retinal and blood-aqueous barriers restricts passage of drug from systemic circulation into the eye. Although intravitreal injections are the gold standards for the treatment of posterior segment ocular diseases, they are associated with pain, inflammation, endopthalmitis and infection. So there is …

Lipid & Surfactant Based Systems For Improved Delivery Of Poorly Soluble Apis, Sri Satyasai Nagendra Babu Punyamurthula

Electronic Theses and Dissertations

A large number of pharmaceutical compounds belong to class II and IV of biopharmaceutical classification of drug (BCS). Class II compounds are limited by their poor aqueous solubility, while class IV compounds suffer from poor solubility and permeability. This translates to poor absorption and low plasma levels post oral administration. Lipids comprise of fatty acids and their derivatives and are considered a biocompatible option for drug delivery. In the studies discussed in following chapters, lipid based drug delivery systems (LBDDS) have been utilized in improving the handling, ease of formulation, solubility and bioavailability of three compounds. In the first study, …

Protein-Ligand Interaction Studies And Identification Of New Drug-Like Hits As Cannabinoid Receptor Modulators, Pankaj Pandey

Electronic Theses and Dissertations

The cannabinoid receptors (CB1 and CB2) belong to the family of class A GPCRs. The CB1 receptor is predominately found in the central nervous system and regulates various neuromodulatory and physiological processes while CB2 receptors are found in peripheral tissues, particularly in the immune system tissues. This dissertation reports several projects including: (1) an examination of the putative binding modes of Cannabis-derived ligands with CB1 and CB2 receptors, (2) the identification of novel CB1 inverse agonists, and (3) the identification of allosteric site(s) in the CB2 receptor and screening of new CB2 allosteric modulators (AMs).

Chapter 1 describes background information …

Predictors Of Use Of Hydroxyurea And Its Impact On Clinical And Economic Outcomes Among Children With Sickle Cell Disease, Manasi Datar

Electronic Theses and Dissertations

Objective: The objective of this study was to assess the prevalence and predictors of use of hydroxyurea (HU) and its impact on clinical and economic outcomes in pediatric patients with sickle cell disease (SCD) enrolled in Medicaid. Methods: A cohort of patients with SCD was identified in 2006 using ICD-9-CM codes from Medicaid claims from 40 US states. Patients who filled three prescriptions of HU in within 6 months in 2007 were identified as HU users. HU users were then matched with non-users and the impact of HU use on the presence of crises and economic outcomes including presence of …

Influence Of Hot Melt Extrusion Processing Parameters On The Properties Of A Pharmaceutical Formulation, Saad M. Alshahrani

Electronic Theses and Dissertations

Hot melt extrusion (HME) is an old technology that has been recently adapted to be used in the pharmaceutical industry. HME is a continuous process that is widely used to produce a solid dispersion matrix. The aim of this dissertation is to evaluate different factors that will affect the pharmaceutical formulation properties that are produced using HME. For HME, there are different variables that will affect the product quality such as processing parameters, material selection, material ratio, and the presence of gas or moisture. One aim of this study is to find the most significant factor that affects the product …

Ehtnobotanical- And Chemometric-Guided Investigation Of Phytolacca Americana L., Michael Chan

Electronic Theses and Dissertations

No abstract provided.

Development Of The Medication Non-Adherence Scale (Mnas) And The Medication Non-Persistence Scale (Mnps), Amod Sudhir Athavale

Electronic Theses and Dissertations

No abstract provided.

Evaluation Of Novel Ligands For Opioid Receptors, Amer Hussien Tarawneh

Electronic Theses and Dissertations

No abstract provided.

Design, Synthesis, And Biological Evaluation Of Sigma Receptors (Σrs) Ligands As Potential Pharmacotherapy For Cancer And Drug Addiction, Walid Alsharif

Electronic Theses and Dissertations

Sigma receptors are a well-defined unique class of receptors and are highly expressed in the central nervous system and also widely distributed in peripheral organs and tissues. There are two subtypes of sigma receptors: sigma-1 and sigma-2. These receptors are thought to be associated with functions and disorders such as inflammation, depression, anxiety, Alzheimer’s disease, epilepsy and drug abuse. The sigma-1 receptor has been demonstrated to be involved in acute and chronic effects of cocaine and methamphetamine toxicities. However, the role of sigma-2 receptors is less clear due to the lack of availability of detailed protein structural information and truly …

Versatility Of Hot-Melt Extrusion For Dosage Form Design, Sultan Mohammad Alshehri

Electronic Theses and Dissertations

Recently, Hot Melt Extrusion (HME) has attracted the attention of pharmaceutical companies and scientists as a technique for manufacturing a variety of dosage forms. In this research, HME was applied in different ways to achieve different goals, such as solubility enhancement, taste masking, solid state stability enhancement, and sustained release formulations for oral drug delivery, using one model drug, mefenamic acid. For solubility enhancement and taste masking formulations, Eudragit EPO was blended with MA in different ratios (20, 25, 30, and 40% of drug loads) and processed by a hot melt extruder to produce a solid dispersion system. FT-IR analysis …

Solubility Enhancement, Mechanical Properties And Taste Masking Of Poorly Water Soluble Compounds By Optimizing Hot Melt Extrusion Processing, Abdullah Saud Alshetaili

Electronic Theses and Dissertations

Pharmaceutical research includes investigation and development of a new drug and determination of the delivery route and delivery system, as well as the technology to create the delivery system. It can also consist of a combination of these steps. Researchers studying potential delivery routes have explored oral, nasal, dermal, transdermal, transmucosal, pulmonary, and injection routes for their ability to deliver large and small drug molecules. This research project focuses on the oral route, which is generally accepted as an effective delivery route for many drug products with a large market share, and studies the use of this route for the …

Impact Of Refill Synchronization On Medication Adherence For Chronic Diseases, Divya Verma

Electronic Theses and Dissertations

Objectives: The objective of this study is to assess the impact of medication synchronization (med sync) on medication adherence for three drug classes under the CMS Star Rating system i.e. oral diabetes, hypertension and cholesterol. Methods: A quasi-experimental pre-post study design was employed using pharmacy prescription fill data from various independent community pharmacies located in different regions of Mississippi. Using Proportion of Days Covered (PDC), medication adherence before and after the med sync was calculated. Total study period of one year for each patient including six months of pre-period and post-period was used for the analysis. Descriptive statistics were calculated. …