Life Sciences Commons^™

Pyrrolo[2,3-D]Pyrimidine Classical Antifolates For Targeted Cancer Chemotherapy- Applications Of Bioisosteric And Regioisomeric Substitutions For Improved Tumor-Selectivity And Potency, Manasa Punaha Ravindra

Electronic Theses and Dissertations

In 2018, it is estimated that 1,735,350 new cases of cancer and 609,640 deaths from the disease will be diagnosed in the United States alone. Conventional chemotherapy is by far the most successful category of clinical oncology, having cured (complete remission (CR), without return) or provided clinical benefit to millions of people. However, since its earliest discovery, the major causes of failure of conventional cancer chemotherapy have been dose-limiting toxicities and development of resistance. There is a desperate ongoing search for new cancer therapies as tumor-targeted agents (without harming normal cells or tissues) with low propensity for the development of …

Particulate Hexavalent Chromium Does Not Induce Centrosome Amplification In Sperm Whale And Bowhead Whale Cells., Jennifer Haruka Toyoda

Electronic Theses and Dissertations

Hexavalent chromium [Cr(VI)] is a widespread environmental and occupational carcinogen. The mechanism of carcinogenesis remains poorly understood, but chromosome instability (CIN) is the dominant theory. How numerical CIN arises is unclear, but it correlates with centrosome amplification. Both phenotypes are hallmarks of cancers, early events in carcinogenesis, and have been shown to occur after Cr(VI) exposure to human skin and lung fibroblasts. In this study, we investigate numerical CIN and centrosome amplification in whale cells. Whales are our closest marine relatives, have long lifespans, and are exposed to environmental Cr(VI). Importantly, they have low cancer rates and cell culture studies …

The Role Of Cyp2a5 In Cadmium-Induced Liver Injury, Julia Salamat

Electronic Theses and Dissertations

Cadmium is present in food and groundwater. Tobacco smoking and occupational exposure are also major sources for cadmium. Cadmium is primarily accumulated in liver, a major organ metabolizing exogenous chemicals. Chemical metabolism may cause detoxification, but it can also cause bio-activation resulting in liver damage. Cytochrome P450s (CYP) are major liver metabolism enzymes, and cadmium chloride (CdCl2) can induce CYP2A5 in mice. We examined the effect of CYP2A5 on CdCl2-induced liver injury using CYP2A5-knockout (cyp2a5-/-) mice. The cyp2a5-/- mice and their control WT mice were injected CdCl2 intraperitoneally at 5 mg/kg body weight, respectively, to induce liver injury. …

Epidermal Growth Factor-Like Ligands Regulate Dimer Selection., Jamie S. Rush

Electronic Theses and Dissertations

There are thirteen known endogenous EGF-like ligands. We previously reported that Betacellulin (BTC) increases ligand-mediated corneal wound healing more than Epidermal Growth Factor (EGF) [Peterson et al. (2014) IOVS 55(5):2870-80], although the molecular reason for this is unknown. Despite being better at promoting wound healing via enhanced cell migration, BTC has reduced receptor affinity and weaker induction of EGFR phosphorylation. These data indicate that BTC’s response is not due to enhanced affinity or EGFR-kinase activity. Receptor phosphorylation and proximity ligation assays indicate that BTC treatment significantly increases ErbB3 phosphorylation and EGFR:ErbB3 heterodimers. BTC traffics EGFR at a faster rate than …

The Role Of Cathelicidin In The Regulation Of Gut Microbiota And Inflammasome Activation In Alcoholic Liver Disease., Fengyuan Li

Electronic Theses and Dissertations

Alcoholic liver disease (ALD) is characterized by gut dysbiosis and hepatic and intestinal inflammation. Gut microbiota is critically maintained by antimicrobial peptides (AMPs) expressed in the epithelial and immune cells. AMPs are also identified as immune-regulators in various diseases. Previous studies demonstrated that deficiency of AMPs REG3 lectins exacerbated alcoholic steatohepatitis. LL-37 is the sole member of human cathelicidin AMP family, named CRAMP in mouse. Despite of the extensive studies in infectious diseases and in gut-microbiota-related inflammatory bowel disease, the role of LL-37/CRAMP in ALD is yet unknown. Our previous studies showed a decreased intestinal CRAMP in a mouse model …

Effect Of Arsenic Exposure On Early Eye Development In Zebrafish (Danio Rerio), Remy S. Babich

Electronic Theses and Dissertations

Arsenic is a metalloid that contaminates drinking water supplies worldwide. Due to concerns for human health, the World Health Organization (WHO) and the U.S. Environmental Protection Agency (EPA) have established a safe level in drinking water of ≤ 10 ppb. Arsenic has been shown to have carcinogenic effects in humans at high and low doses. Chronic exposure may result in dermal conditions such as hyperkeratosis and hyperpigmentation. Recently, arsenic exposure has also been linked to lower IQ values in children. The effect of arsenic on neurogenesis, specifically eye development, has not been widely explored. This study aimed to examine the …

Molecular Mechanisms Underlying Toxicant Effects On Mast Cell Signaling And Mitochondria, Juyoung Katherine Shim

Electronic Theses and Dissertations

Mast cells contribute to numerous physiological processes and diseases including immunological and neurological roles. Mast cells degranulate, releasing potent mediators, following signaling transduction initiated by receptor crosslinking. Previously, we showed that the environmental toxicant arsenic and the antibacterial agent triclosan inhibit mast cell degranulation; thus, we have investigated the mechanisms underlying their inhibitory action. We have discovered that arsenic targets early steps in the mast cell signaling pathway: it inhibits phosphorylation of early tyrosine kinase Syk and of Syk’s direct substrate PI3K. Arsenic’s tyrosine phosphorylation inhibition causes inhibition of calcium influx into the cytosol, a key event necessary for degranulation. …

Hiv Integrase Inhibitor Pharmacogenetics And Clinical Outcomes: An Exploratory Association Study, Derek E. Murrell

Electronic Theses and Dissertations

As HIV is now primarily a chronic condition, treatment is given life-long with changes as necessitated by alterations in tolerability and efficacy. Thus, personalized medicine may be useful in the prevention of unnecessary drug exposure and avoidable side effects. Three of the four currently available HIV integrase strand transfer inhibitors (INSTIs), raltegravir, elvitegravir, and dolutegravir, are widely utilized antiretrovirals in the USA and exhibit variations in outcomes among subjects. To interrogate differences among subjects receiving these drugs, we investigated the association of several single nucleotide polymorphisms (SNPs) with drug exposure, clinical outcomes, and subject-reported adverse events. HIV+ adults (≥18 years …

Egfr Signaling From The Early Endosome., Julie A. Gosney

Electronic Theses and Dissertations

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is an integral component of proliferative signaling. When activated by a ligand at the plasma membrane, EGFR dimerizes with another ErbB family receptor, leading to kinase domain activation and transphosphorylation of C-terminus tyrosine residues. These phosphotyrosines act as crucial regulators of EGFR signaling as effector proteins dock to the receptor at these sites. The receptor undergoes clathrin-mediated endocytosis into early endosomes, where it can then be trafficked to a lysosome for degradation. However, the kinase domain of EGFR retains its activity during trafficking, suggesting that EGFR can continue …

Wnt/Β-Catenin Mediated Cancer Stem Cell Activation In Hepatocellular Carcinoma., Harshulkumar M. Pandit

Electronic Theses and Dissertations

Hepatocellular carcinoma (HCC) is one of the deadliest cancers, with variable presentation, high chemotherapy resistance and early tumor recurrence. In this dissertation, we have systematically enriched, identified and characterized HCC cancer stem cells (CSCs) from 3 different HCC cell lines (Hepa1-6, HepG2, and Hep3B) using in vitro serum-free culture method. Enriched spheroids acquired CSC properties, primarily self-renewal capability, spheroid formation ability, and drug resistance. Heterogeneous CSCs enriched from Hepa1-6 cells demonstrated higher tumor initiation and proliferation capability in vivo, compared to control HCC cells in orthotopic immunocompetent mouse model. EpCAM+ CSCs were significantly enriched within heterogeneous Hepa1-6 CSC spheroids. Consequently, …

A Novel Fibroblast Growth Factor 1 Variant Reverses Nonalcoholic Fatty Liver Disease In Type 2 Diabetes., Qian Lin

Electronic Theses and Dissertations

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with type 2 diabetes (T2D). Our recently engineered FGF1 partial agonist, carrying triple mutations (FGF1^△HBS) exhibits greatly reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1. This study tests the preventive and therapeutic effects of FGF1^△HBS on NAFLD in db/db T2D and explores potential mechanisms. The results showed that administration of FGF1^△HBS to 2-month-old db/db mice for 2 months constantly lowered blood glucose levels, improved insulin sensitivity, and lowered liver weight, lipid deposition, and …

Deciphering The Role Of Human Arylamine N-Acetyltransferase 1 (Nat1) In Breast Cancer Cell Metabolism Using A Systems Biology Approach., Samantha Marie Carlisle

Electronic Theses and Dissertations

Background: Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme found in almost all tissues. NAT1 can additionally hydrolyze acetyl-coenzyme A (acetyl-CoA) in the absence of an arylamine substrate. NAT1 expression varies inter-individually and is elevated in several cancers including estrogen receptor positive (ER+) breast cancers. Additionally, multiple studies have shown the knockdown of NAT1, by both small molecule inhibition and siRNA methods, in breast cancer cells leads to decreased invasive ability and proliferation and decreased anchorage-independent colony formation. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Additionally, consequences …

Evaluation Of Drug-Loaded Gold Nanoparticle Cytotoxicity As A Function Of Tumor Tissue Heterogeneity., Hunter Allan Miller

Electronic Theses and Dissertations

The inherent heterogeneity of tumor tissue presents a major challenge to nanoparticle-medicated drug delivery. This heterogeneity spans from the molecular to the cellular (cell types) and to the tissue (vasculature, extra-cellular matrix) scales. Here we employ computational modeling to evaluate therapeutic response as a function of vascular-induced tumor tissue heterogeneity. Using data with three-layered gold nanoparticles loaded with cisplatin, nanotherapy is simulated with different levels of tissue heterogeneity, and the treatment response is measured in terms of tumor regression. The results show that tumor vascular density non-trivially influences the nanoparticle uptake and washout, and the associated tissue response. The drug …

Developing A Risk Assessment Protocol To Quantify Distribution And Uptake Of Persistent Organic Pollutants In Glacial Outflows, Kimberley Rain Miner

Electronic Theses and Dissertations

Pollutants released by industrialized nations between 1960 and 2004 have been transported northward through atmospheric processes and deposited into glaciated alpine ecosystems. Many of these chemicals retain their original structure and are absorbed into the biota thousands of miles away from where they were originally utilized. With a warming climate increasing the melt of alpine glaciers, these glaciers may be introducing growing amounts of toxins into the watershed. While studies have demonstrated the existence of resident pollutants within glaciated ecosystems, no one has developed a risk assessment to identify sources and quantity of risk posed by these compounds when released …

Melatonin-Micronutrients Osteopenia Treatment Study (Mots): A Translational Study Assessing The Effects Of Melatonin, Strontium Citrate, Vitamin D3 And Vitamin K2 On Bone Density, Bone Turnover Markers And Health-Related Quality Of Life In Postmenopausal Osteopenic Women Following A One-Year Double-Blind Randomized Placebo-Controlled Trial And On Osteoblast-Osteoclast Co-Cultures, Sifat Maria

Electronic Theses and Dissertations

Objective: The purpose of this study was to assess if a novel combination of melatonin and three other natural bone-aiding micronutrients: strontium citrate, vitamins D₃ and K₂ (MSDK) could improve bone health by modulating the activity of osteoblasts and osteoclasts in favor of balanced bone remodeling and by improving the overall health-related quality of life in postmenopausal osteopenic women.

Methods: The Melatonin-micronutrients Osteopenia Treatment Study (MOTS) is a translational research study that used both clinical and in vitro approaches to assess the efficacy of MSDK on bone health in women and to identify potential mechanisms for its effects. …

The Effects Of Polychlorinated Biphenyls Exposure On Non-Alcoholic Fatty Liver Disease : Role Of Aryl Hydrocarbon Receptor., Hongxue Shi

Electronic Theses and Dissertations

Polychlorinated biphenyls (PCBs) are detectable in serum of 100% of adults in US, and has been associated with fatty liver disease in epidemiological studies. PCBs are classified as either dioxin-like (DL) or non-dioxin-like (NDL) PCB based on their ability to activate the aryl hydrocarbon receptor (AhR). We used exposures that reflect human bioaccumulation patterns, which resembles Aroclor 1260 with a low level of the DL-PCB, PCB 126. Our aim was to determine if this exposure will activate the human and mouse AhR and examine if receptor activation influences these steatotic responses due to PCB exposures. DL-PCBs exposure-induced AhR activation in …

Vinyl Chloride Enhances Diet-Induced Liver Injury Via Metabolic Dyshomeostasis : Critical Role Of Mitochondria., Anna L. Lang

Electronic Theses and Dissertations

Background. Vinyl chloride (VC) is an environmental toxicant and has been shown to be directly hepatotoxic at high exposures. However, recent studies suggest low-level toxicant exposure can cause subtle changes to the liver. Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the United States, it is important to determine the impact of low-level toxicant exposure on the progression of underlying liver injury when combined with other factors. Therefore, the overarching goal of this dissertation was to develop a model of VC co-exposure with high-fat diet (HFD) and to determine the mechanisms by which VC contributes to the …

The Combined Neuropharmacology And Toxicology Of Major 'Bath Salts' Constituents Mdpv, Mephedrone, And Methylone, Serena Allen

Electronic Theses and Dissertations

The synthetic cathinones, 3,4- methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4- methylenedioxymethcathinone (methylone), gained worldwide notoriety as the psychoactive components of ‘bath salts;’ a marketing term used to circumvent federal drug laws and permit their legal sale. Previous studies have shown that these drugs share pharmacological characteristics with cocaine and the amphetamines, however, descriptions of their neurotoxic properties are limited. Moreover, while forensic analysis has revealed that the most frequently abused bath salts ‘brands’ contain binary and ternary mixtures of MDPV, mephedrone, and methylone, the majority of preclinical research has focused on explicating the individual effects of these drugs. Therefore, the …

Loss Of The Na+/H+ Exchange Regulatory Factor 1 Results In Increased Susceptibility To Cisplatin-Induced Acute Kidney Injury., Adrienne M. Bushau-Sprinkle

Electronic Theses and Dissertations

Background. Acute kidney injury (AKI), an abrupt loss of kidney function which carries a high mortality and confers an increased risk of chronic kidney disease, develops in 30% of patients who receive cisplatin, a widely used chemotherapeutic agent [1], [2], [3]. The sodium hydrogen exchange regulatory factor isoform 1 (NHERF1) is a scaffolding protein that anchors multiple membrane proteins, in renal proximal tubules [4]. NHERF-1 deficient mice have aberrant localization of BBM proteins in intracellular compartments [5]. The investigators have recently demonstrated NHERF1 deficient proximal tubule cells have an underlying …

A Model To Study The Effects Of Whole Life Chronic Exposure To Arsenic Or Cadmium On The Development Of Adult Metabolic Syndrome : Initial Characterization Of Hepatic Changes., Jamie L. Young

Electronic Theses and Dissertations

Metabolic syndrome (MetS) is a group of diseases affecting < 30% of adults. Although obesity is a major risk for the development of MetS, it does not account for all cases, suggesting contribution of other risk factors. We hypothesized that early life exposure to arsenic (As) or cadmium (Cd) may represent such a risk. The purpose of this study was to characterize a model to discern the effects of early life exposures to Cd and As on high fat diet (HFD)-induced MetS. Adult C57BL/6J mice were exposed to control or metals containing drinking water. Pregnant dams and offspring were continuously exposed to the same toxicants as their parents. At weaning, offspring were fed LFD or HFD and sacrificed 10 or 24 weeks later. Metal exposure caused time- and sex-dependent alterations in HFD-induced variables of liver damage. The initial results suggest that these toxicants enhanced obesity-induced liver injury.

Examining The Issue Of Compliance With Personal Protective Equipment Among Wastewater Workers Across The Southeast Region Of The United States, Tamara L. Wright

Electronic Theses and Dissertations

Wastewater workers are exposed to different occupational hazards such as chemicals, gases, viruses, and bacteria. Personal Protective Equipment (PPE) is a significant factor that can reduce or increase the probability of an accident from hazardous exposures to chemicals and microbial contaminants. The purpose of this study was to identify wastewater worker’s beliefs and practices on wearing PPE and protections offered by PPE through the integration of the Health Belief Model (HBM). Participants were workers in the wastewater industry, which included wastewater operators, laboratory analysts, maintenance workers, wastewater collection workers, equipment operators, managers, and supervisors (n=272). The instrument was a self-administered …