Medicine and Health Sciences Commons^™

Striving For Appropriate Antibiotic Use: A Biomarker Initiative, And Outcomes Associated With Azithromycin Exposure, Amanda Gusovsky

Theses and Dissertations--Pharmacy

The introduction of antibiotics into clinical practice is considered the greatest medical breakthrough of the 20^thcentury. However, the use of antibiotics can contribute to the development of resistance. In the United States (U.S.), approximately 2.8 million people are infected with antibiotic-resistant bacteria each year, and more than 35,000 people die as a result. Moreover, some antibiotics are known to cause cardiac side effects including QT prolongation, hypotension, and ventricular arrythmias. The U.S. Centers for Disease Control and Prevention (CDC) defines appropriate antibiotic use as the effort to use “the right antibiotic, at the right dose, for the right …

Self-Assembled Ternary Polypeptide Nanoparticles With Improved Biostability For Drug Delivery In Cancer Therapy, Preye Mike Agbana

Theses and Dissertations--Pharmacy

Cancer remains a real and present threat to global health. In the United States, according to cancer statistics, almost 40% of people will be diagnosed with cancer at some point in their lifetime. Conventional chemotherapy has become the mainstay for cancer treatment option. However, chemotherapeutic agents are plagued with problems such as poor aqueous solubility, chemical degradation, Bio instability, and off-site toxicity due to non-specificity. New drug modalities are needed to tackle the ever-growing burden on cancer. In recent times, the promise of nanotechnology has aided to develop drug delivery vehicles to facilitate the administration of potent chemotherapeutics. Nanoformulations such …

Investigation Of Folate-Poly(Glutamic Acid)/Polyethylenimine/Dna Complexes For In Vitro Gene Delivery, Caleb Akers

Theses and Dissertations--Pharmacy

Gene therapy is currently being studied as a treatment for a variety of indications, including cancer, infectious disease, and cardiovascular diseases, among others. While many of the early treatments in the field involved the use of viral delivery methods, various safety, ethical, and financial concerns limit the potential uses of this methodology. As such, more recent research has focused on developing non-viral delivery platforms to alleviate some of the issues inherent in viral delivery. Recently, the release of the COVID-19 vaccines from Pfizer and Moderna represents a promising use of non-viral delivery as both utilized a lipid-based delivery vector.

Despite …

Developing A Biocatalytic Toolbox To Aid In Understanding Nucleoside Antibiotics, Jasmine Brianna Woods

Theses and Dissertations--Pharmacy

Antibiotic resistance happens when bacteria develop the ability to survive medications that normally terminate them. Instead, these super germs are able to survive in the body and produce a community of antibiotic resistance germs which can cause human fatalities. It is important to discover and develop new compounds and molecules that will improve this clinical obstacle. This research focused on analyzing the biosynthesis that incorporates distinctive chemical characteristic of various nucleoside antibiotics, ß-hydroxy amino acids and α-methyl-amino acids. ß-hydroxy amino acids and α-methyl-amino acids are considered an important class of industrially useful compounds, particularly for pharmaceutical development, and are found …

New Tools For Biocatalysis: Studies On The Carminomycin 4-O-Methyltransferase Dnrk, Elnaz Jalali

Theses and Dissertations--Pharmacy

Methyltransferases (MTs) are ubiquitous enzymes commonly involved in biosynthesis and regulation. The fundamental goal of this thesis was to explore the permissive nature of methyltransferases and leverage this unique biocatalytic feature to develop a new platform for chemoselective intramolecular cyclization reactions. To realize this ambitious goal, this thesis project set out to probe the substrate specificity of multiple natural product tailoring enzymes (MTs and glycosyltransferases), identify model substrates common to multiple such tailoring enzymes and subsequently establish multi-enzyme tandem reactions that would set the stage for a subsequent chemoselective intramolecular cyclization reaction. Chapter One highlights current state of the art …

Optimization Of Orally Bioavailable Inhibitors Of Defective In Cullin Neddylation 1 (Dcn-1), Leah Kovalic

Theses and Dissertations--Pharmacy

Ubiquitin (UB) and ubiquitin-like protein (UBL) pathways have emerged as important targets for oncology drug discovery based on the success of proteasome inhibitors (bortezomib or carfilzomib), E3 inhibitors, and the NEDD8 E1 inhibitor pevonedistat (MLN42924). Chemical inhibitors have also proven to be useful probes for identifying and dissecting multifactor UB and UBL regulatory networks. Toward this end, we have pursued approaches to target NEDD8 ligation to Cullins, through developing small molecule inhibitors of DCN1 (defective in Cullin Neddylation 1). DCN1 was discovered as a potentiating RBX1-dependent NEDD8-ligation, through recognizing the acetylated N-terminal methionine of the NEDD8 E2s UBE2M and UBE2F. …

Genetic And Pharmacogenetics Associations Of Cancer Disparities In Appalachia, Nan Lin

Theses and Dissertations--Pharmacy

Individuals residing in Appalachian regions have significant health disparities, including higher cancer incidence and mortality rates. Previous studies have addressed the impact of socioeconomic status and environmental risk factors on Appalachia cancer disparities, while few studies have evaluated genetic risk factors.

Germline whole exome sequencing samples from 7,078 individuals with cancer (759 Appalachians) were evaluated. Demographics and relatedness were assessed using KING. Ethnicity was verified by principal component analysis using TRACE, which included 6,034 individuals (85%) of European genetic ancestry. After QC filtering, 5,980 individuals were analyzed. To assess the overall predisposition of hereditary disease, gene level frequency of likely …

An Epidemiological And Pharmacokinetic-Pharmacodynamic Investigation Into The Impact Of Carbapenem-Resistant Enterobacterales, Justin Clark

Theses and Dissertations--Pharmacy

Background: According to the 2019 CDC Antibiotic Resistance Threats Report, more than 2.8 million antibiotic-resistant infections occur in the United States each year, leading to more than 35,000 deaths. Among the most urgent threats identified by the CDC are carbapenem-resistant Enterobacterales (CRE). Despite efforts to control the spread of these organisms, the number of estimated cases between 2012 and 2017 remained stable. In 2017, an estimated 13,100 hospitalized cases of CRE led to approximately 1,100 deaths and $130 million attributable healthcare costs. This dissertation seeks to address this issue from both a pharmacokinetic/pharmacodynamic and epidemiological perspective.

Methods: We evaluated the …

Bioinformatic Analysis Of Proteomic And Genomic Data From Nsclc Tumors On Prognostic And Predictive Factors Of Immunotherapy Treatment, Mark Wuenschel

Theses and Dissertations--Pharmacy

Recent lung cancer research has led to advancements in molecular immunology, resulting in development of small molecule inhibitors, or immune checkpoint inhibitors, that propagate an anti-tumor T cell response. Despite increased overall and progression-free survival with reduced adverse effects compared to traditional chemotherapy, treating advanced stage lung adenocarcinoma patients remains non-curative, and evidence of non-responders or tumor recurrence to immune checkpoint inhibitor therapy is growing. Also, compared to traditional chemotherapy, there is a lower percentage of patients who respond to small molecule inhibitors. In this analysis of proteomic and genomic data from The Cancer Proteome Atlas and Global Data Commons …