Life Sciences Commons^™

Functionalized Carbon Nanotubes In Hydrophobic Drug Delivery, Kun Chen

Dissertations

The direct incorporation of carboxylated carbon nanotubes (f-CNTs) into hydrophobic drug particles during their formation via anti-solvent precipitation is presented. The approach is tested using two drugs namely antifungal agent Griseofulvin (GF) and antibiotic Sulfamethoxazole (SMZ) that have very different aqueous solubility. It is observed that the f-CNTs dispersed in the water serve as nucleating sites for crystallization and are readily incorporated into the drug particles without altering crystal structure or other properties. The results show that the hydrophilic f-CNTs dramatically enhance dissolution rate for both drugs. The increased degree of functionalization leads to higher hydrophilicity and therefore faster dissolution …

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 …

Effects Of Ambient Air Pollution On Asthma-Related Emergency Department Visits Within The Las Vegas Metropolitan Area, Loiren E. Monardes

UNLV Theses, Dissertations, Professional Papers, and Capstones

The objective of this research was to evaluate the risk for asthma-related Emergency Department visits and their association with ambient air pollution within the Las Vegas metropolitan area. All data were aggregated by date and ZIP Code. The association was analyzed by applying the distributed lag non-linear model in an attempt to identify elevated concentrations of specific air pollutants

as triggers and their delayed effects (lag days). Relative Risk (RR) and 95% confidence intervals were produced, while adjusting for socioeconomic status. This ecological population-based study analyzed daily asthma counts of Emergency Department visits from January 1st, 2009 to December 31st, …

Examining Environmental Hazards In Rental Homes And Habitability Laws In Clark County, Nevada, Jorge Luis Bertran

UNLV Theses, Dissertations, Professional Papers, and Capstones

It is well established that home conditions are linked to the health outcomes of occupants. There are over 880,000 housing units in Clark County, Nevada; nearly half of those are renter-occupied units (ROUs). Currently, there is limited research on the characteristics of environmental hazards found in Clark County ROUs and the strength of habitability statutes created to protect tenants from substandard housing. Understanding how renters in Clark County are affected by environmental hazards in ROUs and the processes by which landlords and tenants resolve grievances related to those hazards would benefit public health. It would enhance the ability to quickly …

Development Of Chloroquine-Containing Hpma Copolymers For Drug Delivery, Fei Yu

Theses & Dissertations

Abstract

Development of Chloroquine-containing HPMA Copolymers for Drug Delivery

Fei Yu, Ph.D.

University of Nebraska Medical Center, 2018

Supervisor: David Oupický, Ph.D.

Synthetic polymers have been extensively explored for improved delivery of anticancer agents. Polymers can be designed as either carriers of existing drugs or as polymeric drugs with intrinsic pharmacological activity. Advantages of such polymeric drugs include common positive features of polymer-drug conjugates, such as targeted delivery of drugs, altered pharmacokinetic and biodistribution, improved drug safety, but also favorable pharmacological activities due to multivalent receptor-ligand interactions.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are safe drugs that have been in clinical …

The Opposing Roles Of Glun2c And Glun2d Nmda Receptor Subunits In Modulating Neuronal Oscillations, Zhihao Mao

Theses & Dissertations

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels consisting of two GluN1 subunits and two other subunits from among GluN2A-2D and GluN3A-3B subunits. NMDARs play critical roles in synaptic plasticity, learning and memory, and higher brain function such as cognition and perception. Dysfunction of NMDARs (hyper-function and hypo-function of NMDARs) are related to various diseases, including stroke, schizophrenia, Alzheimer’s disease, and others. However, to date, NMDARs antagonists have mostly failed in clinical trials due to adverse effects.

NMDARs antagonists replicate the core symptoms of schizophrenia which may underlie its ability to alter neuronal oscillations in the neural circuitry of different brain …

Assessing Biofiltration Without Ozonation For Removal Of Trihalomethane Precursors In Drinking Water At The Beaver Water District Drinking Water Treatment Plant, Sana Ajaz

Graduate Theses and Dissertations

Biofiltration without pre-ozonation has the capability to remove natural organic matter (NOM) fractions that serve as precursors of disinfection byproducts (DBPs), which include the four regulated trihalomethanes (THMs) and dichloroacetonitrile (DCAN). Rapid small-scale column tests (RSSCTs) and Pilot Plant filters operated at empty-bed contact times (EBCTs) of 4, 8, and 16 minutes were used to evaluate the performance of nutrient-amended (free ammonia and phosphorus) biofiltration for THM and DCAN precursor removal, as measured using formation potential (FP) tests. NOM surrogates – which include dissolved organic carbon (DOC), specific ultraviolet absorbance (SUVA254) and fluorescence-PARAFAC components – were measured weekly throughout the …

Analysis Of Synthetic Opioids In Postmortem Blood, Vitreous Humor, And Brain Tissue, Rachel K. Chesser

Student Theses

In the United States, the use of new synthetic opioids (e.g. fentanyl and derivatives) has become an increasing health issue with thousands of overdose deaths being observed since 2013. With the high mortality rate associated with these substances, postmortem analyses and interpretation of synthetic opioids has become extremely important. However, due to the novelty of these compounds, the available data is limited and provides challenges to toxicologists. The focus of this project was to examine the postmortem distribution of new synthetic opioids in blood, vitreous humor, and brain tissue. New methods were developed and validated to quantify 13 synthetic opioids …

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 …

Toxicity Of Formulated Insecticide Mixtures To Apis And Non-Apis Bees, Joseph Edward Belsky

Graduate Theses and Dissertations

This work investigates ecotoxicology of new insecticide mixtures to Apis and non-Apis bees. Previous studies have demonstrated the acute and sub-lethal toxicity of individual active ingredient insecticides to honey bees and to a lesser extent non-Apis bees. However, the contact toxicity of formulated premix insecticides containing multiple active ingredients to bees has not been thoroughly assessed. To address this void, laboratory studies simulating exposure to four premix insecticides under different field-realistic scenarios were conducted for two bee species.

Honey bee, Apis mellifera (Linnaeus) contact exposure was examined by simulating three scenarios: (1) when bees continuously forage in a field and …

Inducible Dna Cross-Linking Agents: Design, Synthesis, Mechanism, And Anticancer Activity, Heli Fan

Theses and Dissertations

This thesis focuses on investigating the reactivity of DNA towards a wide variety of aromatic compounds as novel DNA cross-linking agents and exploring their biomedical applications.

In the first part, we synthesized three series of bifunctional aromatic compounds with various core structures, aromatic substituents, and benzylic leaving groups and investigated their reactivity towards DNA. Most of these compounds efficiently form DNA interstrand cross-links (ICLs) via carbocations generated upon irradiation at 350 nm. The efficiency of DNA ICL formation and the pathway of carbocation formation strongly depend on core structures, aromatic substituents and leaving groups. Mono benzene analogues bearing an electron …

Targeting Ph Domain Proteins For Cancer Therapy, Zhi Tan

Dissertations & Theses (Open Access)

Targeted therapy has been one of the most promising treatment options for cancer during the past decade. Discoveries of potent and selective small molecule inhibitors are critical to new and promising targeted therapy. Pleckstrin Homology (PH) domain proteins are one of the biggest protein families in the human proteome. However, no drugs have been achieved to the late development stages, let alone getting to the market. Thus, a deeper understanding of this protein family is required and there is an urgent need to develop novel small molecule compounds targeting these proteins.

Studies of PH domains began around two decades ago …

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 …

Expression Of Hepatic Cytochrome P450 Drug Metabolizing Enzymes In Diabetes And Diabetic Nephropathy, Cheng Jay Fang

Electronic Thesis and Dissertation Repository

The prevalence of diabetes worldwide is rapidly increasing. Polypharmacy, along with a high risk of adverse drug reactions, is common in diabetic patients. Cytochrome P450 (CYP) 3A and 2C drug metabolizing enzymes are reduced in chronic kidney disease (CKD), altering drug pharmacokinetics and contributing to adverse drug reactions. A large fraction of commonly prescribed drugs are metabolized by CYP3A and CYP2C. Approximately 40% of all CKD cases are attributed to diabetic nephropathy (DN) and early DN presents as mild kidney disease. This study aims to evaluate the impact of diabetes and DN on levels and activity of hepatic CYP3A and …

The Use Of Current Steering During Subthalamic Deep Brain Stimulation To Alleviate Upper Limb Symptoms Of Parkinson's Disease, Shabna Iftikar Mohideen

Electronic Thesis and Dissertation Repository

Subthalamic (STN) deep brain stimulation (DBS) is an established treatment to alleviate the appendicular motor symptoms of Parkinson's Disease (PD). Current steering during DBS allows the unequal fractionation of current between two electrodes on the lead, resulting in a non-spherical electrical field. It is hypothesized that the way the electrical field is shaped will affect a patient’s upper limb symptom alleviation. Seven PD patients who underwent bilateral STN-DBS were tested over four weeks post-operation. 16 current fractionation settings were tested each week at an amplitude that increased weekly. Optimal setting was defined as the setting that provided the best …

Silver Nanoparticles In Environmental And Biological Systems: Source, Transformation, And Detection, Huiyuan Guo

Doctoral Dissertations

Silver nanoparticles (AgNPs) are the most commonly used nanoparticles in consumer products. Concerns over human exposure to and risk from these particles have resulted in increased interest in novel strategies to detect manufactured AgNPs. This dissertation investigated the feasibility of SERS as a technique for the detection and quantification of manufactured AgNPs in different matrices. By using ferbam as an indicator molecule that binds strongly onto the nanoparticles, AgNPs detection and discrimination were achieved based on the signature SERS response of AgNPs-ferbam complex. AgNPs coated with citrate and polyvinylpirrolidone (PVP) showed strong interactions with ferbam and induced high SERS signals. …

Resilience Of The Nigerian Coastal Socio-Ecological System: Case Study Of The Niger Delta Region, Chinenye Joy Ijiomah

World Maritime University Dissertations

No abstract provided.

Assesing Port Reception Facilities For Ship Generated Solid Waste: The Case Of The Port Of Walvis Bay, Namibia., Shapua Randy Mandela Kalomo

World Maritime University Dissertations

No abstract provided.

Evaluating The Toxicity And Formation Of Halobenzoquinones In Point-Of-Use Chlorinated Drinking Water, Stephanie Hung

Masters Theses

Chlorine has effectively reduced the prevalence of waterborne diseases, however there are secondary consequences to this public health advancement. Disinfection byproducts (DBPs) are chemicals formed when chlorine reacts with natural organic matter (NOM) in water. A new class of DBPs, halobenzoquinones (HBQs), has recently been identified and data suggests it could be potentially carcinogenic and up to 1000 times more toxic than some regulated DBPs. So far, in vitro studies have assessed HBQ toxicity without taking into account its transformation in cell media into potentially less toxic compounds. This study evaluated the toxic effects of one HBQ, 2,6-DCBQ, and its …

Modulation Of The Redox Environment During Sensitive Developmental Periods Impairs Pancreatic Organogenesis In The Zebrafish (Danio Rerio), Haydee Jacobs

Masters Theses

The developing pancreas has been identified as a potentially sensitive target for oxidative damage caused by environmental toxicant exposure in the developing zebrafish, Danio rerio. The objectives of this study were to 1) investigate the effects of exposure to a common pro-oxidizing toxicant, Mono(2-ethylhexyl) phthalate (MEHP), on pancreatic development, and 2) elucidate redox-sensitive temporal windows of pancreatic organogenesis in the zebrafish. We also investigated the involvement of Nrf2 (Nfe2l2), a transcription factor involved in the oxidative stress response, in toxicant-mediated pancreatic toxicity. In aim one, zebrafish embryos were exposed to 0 or 200 µg/L MEHP beginning at 3 hours post …

Direct Quantification Of Deubiquitinating Enzyme Activity In Single Intact Cells, Nora Safabakhsh

LSU Doctoral Dissertations

Challenges in drug efficacy occur during the treatment of most types of cancer due to the heterogeneity of the tumor microenvironment. This has led to the development of personalized medicine. Due to the clinical success of the proteasome inhibitors Bortezomib and Carfilzomib in treatment of multiple myeloma, interest has shifted towards molecularly-targeted chemotherapeutics for ubiquitin-proteasome system (UPS). Deubiquitinating enzymes (DUBs) are an essential part of this pathway which have been found to promote Bortezomib resistance in multiple myeloma patients. Unfortunately, there is a lack of specific, high throughput biochemical assays to characterize DUB activity in patient samples before and after …

Development Of Macromolecular Prodrug Conjugates For The Diagnosis And Treatment Of Musculoskeletal Diseases, Xin Wei

Theses & Dissertations

Macromolecular prodrug conjugate is a promising strategy for better diagnosis and treatment of musculoskeletal diseases. Our lab has pioneered this effort and has successfully developed multiple prodrug formulations. The general approach we have taken is to incorporate active ingredient (AI, including imaging probe or therapeutic agents) containing monomers into water-soluble and biocompatible polymers, such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers. Structural parameters of these polymeric prodrugs, such as molecular weight (MW), drug loading, prodrug activation mechanism and the selection of drug payload may greatly affect therapeutic efficacy and the safety of the macromolecular prodrugs. To investigate the impact of these …

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. …

Development And Evaluation Of Biocompatible Engineered Nanoparticles For Use In Ophthalmology, Bedia Begum Karakocak

McKelvey School of Engineering Theses & Dissertations

The synthesis and design of biocompatible nanoparticles for targeted drug delivery and bioimaging requires knowledge of both their potential toxicity and their transport. For both practical and ethical reasons, evaluating exposure via cell studies is a logical precursor to in vivo tests. As a step towards clinical trials, this work extensively investigated the toxicity of gold nanoparticles (Au NPs) and carbon dot (CD) nanoparticles as a prelude to their in vivo application, focusing specifically on ocular cells. As a further step, it also evaluated their whole-body transport in mice. The research pursued two approaches in assessing the toxicity of engineered …

Detection Of In-Utero Ethanol Exposure Via Etg And Ets Analysis In Umbilical Cord And Placenta, Jennifer Hanna

Student Theses

Alcohol exposure during pregnancy constitutes one of the leading preventable causes of birth defects, mental retardation and neurodevelopmental disorders in exposed children. According to the 2016 National Survey on Drug Use and Health, alcohol was the second most prevalent substance (8.3%) after tobacco (10%), being this alcohol prevalence higher among 26-44 years old pregnant women than in the 18-25 years old group (9.1 vs 6.5%) (Center for Behavioral Health Statistics and Quality, 2017). The ethanol marker ethyl glucuronide (EtG) has proven to be a specific long-term marker of ethanol in-utero exposure in meconium; however, currently there are scarce or no …

Inhibition Of Ribosome Biogenesis Through Genetic And Chemical Approaches, Leonid Anikin

Graduate School of Biomedical Sciences Theses and Dissertations

In order to maintain the ability to generate proteins, proliferating cells must continuously generate ribosomes, designating up to 80% of their energy to ribosome biogenesis (RBG). RBG involves transcription of rDNA by RNA polymerases I (Pol I) and III (Pol III), expression of approximately 80 ribosomal proteins, and assembly of these components in a process referred to as ribosome maturation. During maturation, the Pol I transcribed 47S pre-rRNA undergoes a number of processing events, while simultaneously interacting with processing factors and ribosomal proteins that drive pre-ribosome assembly. Inhibition of RBG has become one of the pursued targets for cancer therapy …

The Role Of Perivascular Fibrosis In Post-Stroke Glymphatic Impairment And Cerebral Amyloid Angiopathy, Matthew D. Howe

Dissertations & Theses (Open Access)

In healthy brain tissue, toxic amyloid-β (Aβ) proteins are transported by the pulsatile flow of cerebrospinal fluid (CSF) along perivascular drainage pathways. Ischemic stroke may disrupt this process, leading to a perivascular build-up of Aβ, termed cerebral amyloid angiopathy (CAA). I hypothesize that an abnormal pattern of extracellular matrix deposition within the vascular basement membrane, termed fibrosis, impairs Aβ drainage from the aged brain after stroke. I further hypothesize that inhibition of astrocytic transforming growth factor-β (TGF-β) signaling can reverse these phenotypes. Finally, I also hypothesize that serum biomarkers of perivascular fibrosis can be used to diagnose CAA following intracerebral …

Macrophytes And Atrazine In Ponds Of Southwest Missouri, Christine Michelle Cornish

MSU Graduate Theses

Wetlands are often the ultimate destination of agrochemicals. The increased use of these pollutants has resulted in their increased transport, via runoff and spray drift, into wetlands. Atrazine, a commonly used herbicide, has been detected in surface water, groundwater, soil, and sediment, and has shown to have adverse impacts on aquatic biota, such as fish and amphibians. Few studies have reported on the relationships between atrazine and macrophytes. I measured atrazine concentrations in surface sediments in agricultural, conservation, and golf course ponds of southwest Missouri, and investigated how those concentrations might be related to macrophyte communities, and pond environmental characteristics. …