Digital Commons Network^™

Drugging The Histone Acetyltransferase Ep300 Modulates Alternative Splicing At Schizophrenia Risk Genes, Shravani Malay

Theses and Dissertations

Purpose. We will evaluate the effects of drugging the epigenetic histone acetyltransferase (HAT) enzyme p300, encoded by the schizophrenia risk gene EP300, on genome-wide gene expression in neural cells. We hypothesize that drugging p300 will affect gene expression and alternative splicing of other schizophrenia risk genes. Our motivation is to identify potential new epigenetic treatment avenues for schizophrenia.

Methods. Prior to my joining the lab, an experiment was conducted using the novel p300 HAT inhibitor, A-485, to modulate genomic regulation in a neural cell line (SH-SY5Y). SH-SY5Y cells were exposed to 10μM of A-485 or vehicle (DMSO) for 24 …

Testing The Efficacy And Synergistic Components Of Sesamol And Black Rice Extract On Human Colon Cancer Cells, Sera Lim, Philip M. Gerk

Undergraduate Research Posters

Purpose: Systemic treatment of colorectal cancer involves chemotherapeutic agents which elicit serious and negative side effects from the toxicity of the drug. To address this issue, we are testing dietary supplements for their efficacy against human colon cancer cell lines and also their potential synergistic effects when combined with conventional chemotherapy. Dietary supplements (specifically sesamol and black rice extract) exhibit anticancer, anti-inflammatory, and chemo-preventive properties. Meanwhile, one of the cancer resistance mechanisms is the upregulation of drug elimination mechanisms, leading to multi-drug resistance. We hypothesize that dietary compounds will act as chemo-enhancers, thus enhancing potency of the chemotherapy drug(s) on …

Role Of Histone Deacetylase (Hdac) In Epithelial To Mesenchymal Transition (Emt) In A Human Cholangiocyte Model Of Ischemic Cholangiopathy, Priyanshi Pragnesh Parikh

Theses and Dissertations

Organ transplants are a vital intervention for many diseases that result in end stage organ failure. Currently, the donation pool is not meeting the demands of the transplant list. Expanding this pool to include donation after cardiac death (DCD) is highly sought-after. However, the use of DCD livers can lead to increased odds of graft failure and ischemic cholangiopathy. The loss of epithelialization and fibrosis that occurs during ischemic cholangiopathy is characteristic of these cells undergoing epithelial-to-mesenchymal transition (EMT). The biological changes the cell experiences enhance migratory capacity, invasiveness, and increased resistance to apoptosis. Our earlier studies have shown differential …

Assessing Drug Development Proporties Of Antithrombotic And Anti - Cancer Agents, Elsamani I. Abdelfadiel

Theses and Dissertations

The current GAG anticoagulants such as heparin, heparin derivatives, and vitamin K antagonists, such as warfarin continue to be the backbone of anticoagulant therapy. These drugs act through an indirect mechanism to convey inhibition of several coagulation enzymes. However, xv their use leads to several serious adverse effects, such as excessive bleeding risk and unpredictability of patient response. Regardless of their clinical achievement, every individual agent is accompanied by several side effects, particularly major/minor bleeding, thrombocytopenia, drug-food or drug-drug interactions, or absence of antidote. Of all these side effects, bleeding, and a lack of an effective antidote to reverse excessive …

Genetic Assessment Of Hyperuricemia And Gout In Asian, Native Hawaiian, And Pacific Islander Subgroups Of Pregnant Women: Biospecimens Repository Cross-Sectional Study, Ali Alghubayshi, Alison Edelman, Khalifa Alrajeh, Youssef Roman

Pharmacotherapy and Outcomes Science Publications

Background

Gout, an inflammatory condition, is characterized by the precipitation of monosodium urate crystals (MSU) in or around distal joints. The latter is caused by chronic hyperuricemia (HU)—high urate levels in the blood. Genetic variations in urate transporters play a significant role in determining urate levels within the human body, rendering some racial and ethnic groups more or less susceptible to developing either HU or gout. This study aims to estimate the frequencies of HU and gout risk alleles in Asian, Native Hawaiian, and Pacific Islander subgroups, using biorepository DNA samples.

Methods

The biospecimens repository at the University of Hawai’i …

Development And Optimization Of A Low Volume Air-Jet Dry Powder Inhaler (Dpi) Platform For The Delivery Of High Dose Aerosolized Powder To Infants, Connor Howe

Theses and Dissertations

The goal of this research project was to develop an infant air-jet dry powder inhaler (DPI) platform for high-efficiency nose-to-lung (N2L) aerosol administration to infants through optimization of individual system components followed by expansion of the system to higher doses and different formulations using a new approach. Primary challenges associated with aerosol delivery to infants using the N2L route include the extremely narrow extrathoracic airways, short inspiratory times (~0.2 sec), low safe airway pressure (H₂O), and very low volumes of air (~10 mL) available to form the aerosol. The infant air-jet DPI system was comprised of three main …

Trajectories Of Medication Non-Adherence With Time-Varying Predictors And Association With Health Outcomes: A Comparison Of Classical Statistical Methods With Machine Learning Algorithms, Vasco Pontinha

Theses and Dissertations

Background: Medication adherence is a major obstacle to improving health care outcomes in long-term therapies for chronic diseases. According to the World Health Organization, interventions for improving medication adherence can have a higher impact on the health of the population than any other advance in medical treatments. Approximately 125,000 individuals die every year in the U.S. because of non-adherence to medication, representing societal costs of $100-289 billion. Previous research has successfully used group-based trajectories methods to identify similar longitudinal medication adherence trajectories. However, medication adherence is not an isolated behavior and is influenced by many factors that current interventions fail …

Structure-Based Drug Discovery And Development Of Protein Structure Prediction Tools Using An Empirical Force Field, Noah B. Herrington

Theses and Dissertations

Traditional drug discovery has rapidly accelerated thanks to development of computational molecular modeling. The crucial component that these computational studies hinge upon is having a well-defined, and energetically favorable structure. Structures of proteins and ligands that meet these criteria are important for accurately simulating models used to study drug binding. To demonstrate the role of accurate structure simulation in the study of these events, this thesis presents, first, a story examining the problem of accurate structure modeling of ionizable residues within protein structures, specifically aspartic acid, glutamic acid, and histidine. I present our method, which uses the HINT force field …

Modified Ysk12-Mend-Sirna In Dendritic Cells For Cancer Immunotherapy, Syed S. Alam

Undergraduate Research Posters

Tumors may induce tolerogenesis through signaling dendritic cells to produce tolerogenic molecules, such as indoleamine 2, 3-dioxygenase 1 (IDO1). Tumor-associated immunosuppression is associated with higher mortality in patients. Small interfering RNA (siRNA) has been shown to silence specific target genes in the target cell. The siRNA associated with these genes could support a gene knockdown of these immunosuppressors and reduce mortality. Delivery of these therapeutic nucleic acids is difficult in vivo because siRNA is easily broken down inside the cell and the bloodstream through present nucleases. Use of liposome polymers has been reviewed extensively in literature. YSK12-C4, a lipid nanoparticle …

The Economic Value Of Pharmacist-Physician Collaborative Care Models In Hypertension Management, Jessica S. Jay

Theses and Dissertations

Background: Hypertension is highly prevalent in the United States, affecting nearly half of all adults (43%). Studies have shown that pharmacy-physician collaborative care models (PPCCM) for hypertension management significantly improve blood pressure (BP) control rates and provide consistent control of BP. Time in target range (TTR) for systolic BP is a novel measure of BP control consistency that is independently associated with decreased cardiovascular (CV) risk. There is no evidence observed improvement in TTR for systolic BP with PPCCM is cost effective.

Objective: This study aimed to compare the cost-effectiveness of PPCCM with usual care for the management of hypertension …

Protein Structure And Interaction: The Role Of Aromatic Residues In Protein Structure And Interactions Between Pyridoxine 5'-Phosphate Oxidase/Dopa Decarboxylase, Mohammed H. Al Mughram

Theses and Dissertations

Naturally developed proteins are capable of carrying out a wide variety of molecular functions due to their highly precise three-dimensional structures, which are determined by their genetically encoded sequences of amino acids. A thorough knowledge of protein structures and interactions at the atomic level will enable researchers to get a deep foundational understanding of the molecular interactions and enzymatic processes required for cells, resulting in more effective therapeutic interventions. This dissertation intends to use structural knowledge from solved protein structures for two distinct objectives.

In the first project, we conducted a bioinformatics structural analysis of experimental protein structures using our …

Budget Impact Analysis Of Upadacitinib For The Management Of Moderate-To-Severe Atopic Dermatitis In Patients Treated With Systemic Therapies In The United States, Haya O. Alobaid

Theses and Dissertations

Objective: This study evaluated the budget impact of introducing upadacitinib for patients with uncontrolled moderate-to-severe atopic dermatitis (AD) from a United States (U.S.) private payer perspective.

Methods: The model estimated costs before and after the adoption of upadacitinib for a hypothetical one million covered lives over 3 years. The model included immunosuppressant agents and dupilumab. Market uptake was assumed to be 2% per year. Treatments incur a cost for drug acquisition, and the costs associated with drug administration, laboratory testing, and clinic visits. The model calculated the impact on the budget in 2022 U.S. dollars. Various assumptions on market …

Examining Ayahuasca Constituents At 5-Ht2a Receptors In Search Of Antidepressant Action, Jeremy D. Rolquin

Theses and Dissertations

Recently, it has been reported that ligands of the 5-HT_2A receptor can have drastic and fast-acting efficacy towards a number of different mental health disorders, such as depression and anxiety. A mixture of Amazonian plants calledayahuasca contains multiple compounds which have been shown to interact with the serotonergic system, and the 5-HT_2Areceptor in particular.

The structurally similar compounds (DMT, harmine, harmaline, and tetrahydroharmine) found in ayahuasca were examined for differences in their physiochemical properties that might contribute to their binding affinity for the 5-HT_2Areceptor. 3D Molecular modeling and docking studies of these compounds were …

Pharmacists' Role In Opioid Use Disorder And Overdose Prevention And Treatment And Their Attitudes And Perceptions Towards Distributing Naloxone Under A Standing Order, Stephen C. Ijioma

Theses and Dissertations

Background: Opioids are a class of drugs that bind to opioid receptors (mu, delta, and kappa), located in the central and peripheral nervous systems, to exert responses such as analgesia, respiratory depression, euphoria, and miosis. The opioid epidemic is characterized in large part by an increase in opioid overdose deaths. Community pharmacists are one of the most accessible healthcare professionals who frequently interact with patients and can implement OUD and opioid overdose prevention strategies. Treatment for opioid overdose and OUD include naloxone for overdose deaths as well as medication-assisted treatment for OUD.

Objective: The specific aims of this thesis include …

The Water Solubility Of Ursolic Acid Complexes At Different Choline Concentrations, Sera Lim, Renjie Zhan, Phillip M. Gerk

Undergraduate Research Posters

No abstract provided.

Acute Fish Oil Supplementation And Aspirin Treatment Modulates Lipid Profile In Platelet Rich Plasma: A Randomized Pilot Trial, Joshua M. Morriss, Lisa A. Turner, Danielle M. Mccormack, Daniel Contaifer, Naren Gajenthra Kumar, Saidheeraj Paravataneni, Monther Alsultan, Suad Alshammari, Silas Contaifer, Parthasarathy Madurantakam, Dayanjan Wijesinghe

Pharmacotherapy and Outcomes Science Publications

Aims: Platelet rich plasma (PRP) has been used in tissue repair to treat numerous inflammatory pathophysiologies. Recent studies have elucidated that the bioactive lipid fraction of PRP significantly contributes towards the resolution of inflammation. There has been great interest in how therapeutics could modulate the PRP lipidome to formulate a more pro-resolving matrix. Many of the pathways used to produce either pro-resolving or pro-inflammatory lipids are shared between ω-3 and ω-6 polyunsaturated fatty acids (PUFA). Here, we explored the separate and interacting effects acute exogenous ω-3 PUFA supplementation and aspirin had on the lipidome of PRP within 6 hours.

Methods: …

Frequency Of Genetic Polymorphisms Of Cyp2c19 In Native Hawaiian, And Asian And Pacific Islander Subgroups: Implications For Personalized Medicine, Khalifa Y. Alrajeh, Youssef Roman Dr

Graduate Research Posters

Pharmacogenetic testing, where prescriptions are tailored to the individual patient based on his/her genetic makeup, increases the ability to predict individual drug response. However, little is known about the prevalence of clinically actionable pharmacogenes in diverse populations. This study seeks to assess the prevalence of select drug-gene alleles that are implicated in the metabolism of commonly prescribed drugs, so-called Very Important Pharmacogenes (VIPs). The results of this study will fill in the gaps of knowledge of VIPs in underrepresented populations and characterize their potential risk for drug adverse events or due to their underlying genetic polymorphisms, especially in patients of …

Peptidomimetic And Non- Peptidomimetic Derivatives As Possible Sars-Cov-2 Main Protease (Mpro) Inhibitors, Mohammed A. Al Awadh, Mohini S. Ghatge Ph.D, Mona A. Al Khairi, Faik N. Musayev, Akua K. Donkor, Mohammed H. Al Mughram, Abdelsattar M. Omar Ph.D, Moustafa M. El-Araby Ph.D, Martin K. Safo Ph.D

Graduate Research Posters

To design novel inhibitors of the SARS-CoV-2 main protease (Mpro), we investigated the binding mode of the recently reported α-ketoamide inhibitors of this enzyme. Following, we utilized in-silico screening to identify 168 peptidomimetic and non-peptidomimetic compounds that are high probability Mpro binding candidates. The compounds were synthesized in 5 to 10 mg for initial screening for their potential inhibition of Mpro using Fluorescence Resonance Energy Transfer (FRET) assay. The study was conducted using the main protease, MBP-tagged (SARS-CoV-2) Assay Kit (BPS Bioscience, #79955-2), and the fluorescence due to enzymatic cleavage of substrate measured using BMG LABTECH CLARIOstar™, a fluorescent microplate …

Pharmacogenomics And Ssris Appropriateness In Older Community Dwelling African Americans, Wint War Phyo, Lana Sargent, Elvin T. Price

Graduate Research Posters

Background: Depressive and anxiety disorders are among the most common illnesses experienced by older adults (age > 60). The selective serotonin reuptake inhibitors (SSRIs) are preferred class of antidepressants for these disorders due to their high efficacy and safety profiles among older adults. However, SSRIs are metabolized by highly polymorphic cytochrome P450 enzymes, specifically CYP2D6 and CYP2C19. This can lead to variable dose-response outcomes, especially among older African American population.

Objective: Analyze the frequency of CYP2D6 and CYP2C19 polymorphisms in African American older adults who are taking SSRIs and identify potential inappropriate use of SSRIs in these older adults using the …

Development Of An Online Warfarin Dosing Platform Using R Programming Language To Facilitate Healthcare Professional Duties And Limit Medication Related Errors., Monther Alsultan

Graduate Research Posters

Development of an online warfarin dosing platform using R programming language to facilitate healthcare professional duties and limit medication related errors.

Monther Alsultan, Joshua M. Morriss, Daniel Contaifer Jr, Suad Alshammari; Silas Contaifer, Rachel W Flurie, Dayanjan S. Wijesinghe^#

Department of Pharmacotherapy and Outcome Sciences

Objective: 1) Gain experience in developing platform agnostic, fully operational and clinically relevant web applications for effective pharmacist led patient care. 2) Create a decision- support tool using open source software to facilitate evidence-based management therapy of warfarin in clinical settings where it is available for everyone to use at anytime and anywhere.

Introduction: …

Formulation, Characterization And Pharmacokinetic Modelling Of Excipient Enhanced Growth Spray-Dried Inhalation Powders, Serena Bonasera

Theses and Dissertations

The overall aim of this research project was to evaluate effects of spray drying parameters and storage conditions on solid-state characteristics and aerosol performance of excipient enhanced growth (EEG) powders and to formulate a stable and highly dispersible tobramycin EEG powder to be delivered to pediatric cystic fibrosis subjects using a novel positive pressure dry powder inhaler.

Micrometer-sized albuterol sulfate EEG powders were produced using a medium-sized nebulizer and optimized spray drying conditions. Using trileucine as the dispersion enhancer improved the aerosol performance but showed increased moisture absorption compared to the L-leucine formulation.

The optimized spray drying conditions were then …

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Exploring The Dopamine Transporter Utilizing A Two-Pronged Approach With Novel Cathinone Analogs And Mutant Dopamine Transporters, Charles B. Jones Iii

Theses and Dissertations

The dopamine transporter (DAT) is responsible for the removal of the neurotransmitter from the synaptic gap and a therapeutic target for a multitude of drugs. While the ortholog Drosophila melanogaster dopamine transporter (dDAT) and human serotonin transporter (hSERT) have resolved structures, the human dopamine transporter (hDAT) does not. A 3-D computational homology model of hDAT was constructed for the study of molecular interactions with agents within the central binding site (S1) of the transporter.

Synthetic cathiones are a class of abused stimulant drugs that primarily target DAT. Greater than 150 cathinones have been identified on the clandestine market but there …

Development Of Sam-Based Chemical Probes For Methyltransferases, Daniel V. Mongeluzi

Theses and Dissertations

Fig.1. SAM analog for the profiling of MTase activity. A. Chemical structure of probe 1; B. General scheme of the labeling and capture strategy.

A

B

Methylation is a fundamental mechanism used in the biological system to modify the structure and function of biomolecules such as proteins, DNA, RNA, and metabolites.¹ Methyl groups are installed by a large and diverse class of S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTases), which transfer the sulfonium methyl group of SAM to either carbon, nitrogen, oxygen, or other heteroatoms on biomolecules.² Dysregulated MTase activity contributes to numerous diseases, including cancer, metabolic disorders, neurodegenerative diseases. …

Health Outcomes And Utilization Associated With Renal Diseases In Patients With Cancer In The United States, Mitisha Dedhia

Theses and Dissertations

Background: Adverse events and impairments associated with cancer and its treatments causes worse outcomes. Increased incidence of renal diseases among cancer patients is of particular concern. Objective: To determine the risk factors for renal disease in cancer patients and compare healthcare costs, utilization and health-related quality of life (HRQoL) of cancer patients with a renal disease and cancer patients without renal diseases. Methods: Medical Expenditure Panel Survey files from 2009 – 2018 for cancer patients was used for this study. Multiple logistic regression, generalized linear model, Poisson regression and multiple linear regression for analyses after adjusting for demographic, socioeconomic and …

Nebulizer-Based Systems To Improve Pharmaceutical Aerosol Delivery To The Lungs, Benjamin M. Spence

Theses and Dissertations

Combining vibrating mesh nebulizers with additional new technologies leads to substantial improvements in pharmaceutical aerosol delivery to the lungs across therapeutic administration methods. In this dissertation, streamlined components, aerosol administration synchronization, and/or Excipient Enhanced Growth (EEG) technologies were utilized to develop and test several novel devices and aerosol delivery systems. The first focus of this work was to improve the poor delivery efficiency, e.g., 3.6% of nominal dose (Dugernier et al. 2017), of aerosolized medication administration to adult human subjects concurrent with high flow nasal cannula (HFNC) therapy, a form of continuous-flow non-invasive ventilation (NIV). The developed Low-Volume Mixer-Heater (LVMH) …

Bisphosohoglycertae Mutase: A Potential Target For Sickle Cell Disease, Anfal S. Aljahdali

Theses and Dissertations

Bisphosphoglycerate mutase (BPGM) is a part of the erythrocyte glycolysis system. Specifically, it is a central enzyme in the Rapoport-Leubering pathway, a side glycolytic pathway involved in the regulation of the concentration of the natural allosteric effector of hemoglobin (Hb), 2,3-bisphosphoglycerate (2,3-BPG). BPGM catalyses the synthesis and hydrolysis of 2,3-BPG through its synthase and phosphatase activities. The synthase activity is the main role of BPGM, while the phosphatase activity is low and is activated by the physiological effector, 2-phosphoglycolate (2-PG) with the latter mechanism poorly understood.

BPGM activity and 2,3-BPG levels in red blood cells (RBCs) have a significant role …

Reward-Related Effects Of Amphetamines Administered By Electronic Cigarette, Lucas Wohler

Theses and Dissertations

While e-cigarette vaporizers are primarily used for the delivery of nicotine, they can also be used to administer a wide range of other substances of abuse including stimulants such as d-amphetamine and methamphetamine. Methamphetamine and prescription amphetamines are widely abused throughout the United States and across the world leading us to believe there may be abuse potential with vaping methamphetamine as vaping becomes increasingly popular. In the present study, methamphetamine and amphetamine vapor were assessed using vapor capture methods. The vapor samples were then analyzed using liquid chromatography mass spectroscopy (LC-MS). Three experiments were carried out to examine the abuse …

An Analytical Perspective On Determination Of Free Base Nicotine In E-Liquids, Vinit V. Gholap, Rodrigo S. Heyder, Leon Kosmider, Matthew S. Halquist

Pharmaceutics Publications

In electronic cigarette users, nicotine delivery to lungs depends on various factors. One of the important factors is e-liquid nicotine concentration. Nicotine concentration in e-liquids ranges from 0 to >50 mg/mL. Furthermore, nicotine exists in protonated and unprotonated (“free base”) forms. The two forms are believed to affect the nicotine absorption in body. Therefore, in addition to total nicotine concentration, e-liquids should be characterized for their free base nicotine yield. Two approaches are being used for the determination of free base nicotine in e-liquids. The first is applying a dilution to e-liquids followed by two methods: Henderson–Hasselbalch theory application or …

Local Lung Targeting Of Tumor Associated Macrophages Combined With Cytoreductive Therapy Decrease Tumor Burden In A Secondary Lung Cancer Model, Sulaiman Alhudaithi, Hanming Zhang, Rashed Almuqbil, Wei Du, Fatemah Sunbul, Paula Bos, Sandro Da Rocha

Graduate Research Posters

Backgrounds. The efficacy of a locally administered small molecule colony stimulating factor 1 receptor inhibitor (CSF-1Ri), PLX3397, alone or in combination with cytoreductive therapy (paclitaxel) in reducing the tumor burden of an in vivo model of secondary lung cancer was investigated in this work. Local administration of immunotherapy to the lungs may enhance lung biodistribution of such therapies and reduce potential unwanted off-target toxicity. In addition, combination of such therapy with low dose standard of care chemotherapy may offer improved anti-tumor effects.

Methods. Murine breast cancer cells (4T1, known to be highly metastasized to the lungs) were transduced to …