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Best Practices In A Clinical Development Project Management Office (Pmo) To Achieve A Reference Standard In The Pharmaceutical Industry, Russell Guinto

Dissertations, Masters Theses, Capstones, and Culminating Projects

Medications are developed by the pharmaceutical industry starting with the discovery phase, proceeds to preclinical trials, moves into clinical trials (progressing from Phase I to Phase III), and if the data are positive, may lead to Food and Drug Administration (FDA) approval. Once approved, post-marketing surveillance for safety is required as long as the drug is marketed to consumers. This phase may also include clinical trial Phase IV studies if additional safety testing is required. This process usually takes between ten to fifteen years, with clinical development taking seven to ten years of that time (1). Clinical development can …

Chronic Cadmium Exposure Alters Erα Dependency And Drug Sensitivity Of Breast Cancer Cells, Mathew Bloomfield

Dissertations, Masters Theses, Capstones, and Culminating Projects

The global prevalence of breast cancer in women illustrates the importance of identifying factors that contribute to disease onset and progression. Endogenous and environmental agents that interact with estrogen receptor alpha (ERα) have been shown to play a role in breast cancer etiology. Evidence from epidemiological studies and animal models has suggested that cadmium, a heavy metal that can activate ERα, contributes to the development and progression of breast cancer. Additionally, our lab showed that chronic cadmium exposure altered the expression of several ERα-responsive genes and increased the malignancy of MCF7 breast cancer cells. Although these studies support cadmium’s function …

Loss Of Function Of Gene X Protects Against Α-Dicarbonyl Stress Through The Skn-1 Pathway In C. Elegans, Austin Lim

Dissertations, Masters Theses, Capstones, and Culminating Projects

Diabetes mellitus and Parkinson’s Disease (PD) are debilitating diseases that are increasing in prevalence worldwide. One potential cause of these diseases is the accumulation of advanced glycation end products (AGEs), which are macromolecules that cause irreversible damages. AGEs are a diverse group of highly oxidative byproducts produced from α-dicarbonyl compounds (α-dcs), which are highly reactive molecules that bind indiscriminately to protein and DNA and, are regulated by a conserved glyoxalase system (GLO1 and DJ-1) in humans. Utilizing the conserved glyoxalase system, we were able to establish within a C. elegans model that when this glyoxalase system is impaired, …

Different Methodologies To Characterize And Diagnose Sickle Cell Disease In Both Developed And Developing Nations, Mohammed Alharbi

Dissertations, Masters Theses, Capstones, and Culminating Projects

Sickle cell disease (SCD) is a genetic blood disorder that causes the RBC to become sickle shaped due to a mutation in the β-globin gene encoding the protein hemoglobin. This disease causes reduced oxygen carrying capacity of RBC resulting in painful crisis, hemolytic anemia, and infection susceptibility. SCD affects around 100,000 individuals in USA alone and 14 million people globally. SCD affected individuals have high mortality rates. Early detection and constant monitoring of this disease is essential. The following review focuses on various methodologies that have emerged in the diagnosis of SCD. Also, low cost methods that can be easily …

Specimen Accountability Process Change In A Non-Automated Consolidated Microbiology Laboratory, Michael Monh

Dissertations, Masters Theses, Capstones, and Culminating Projects

The pre-analytical phase contributes 60-70% of total error of the total testing process (TTP) (Plebani 2006). The pre-analytical phase can be further divided into two phases; the ‘pre-preanalytical’ and ‘preanalytical’ phases, which commonly includes tasks performed outside of the laboratory walls, and tasks perform within the laboratory’s walls and control, respectively. Additionally, medical care reimbursement policies in the U.S. along with the need to efficiently produce quality results and reduce the costs to clients, has caused the microbiology lab to move from on-site to more resourcefully abundant consolidate labs (Sautter 2014). Serving many satellite facilities, it is of interest to …

Preclinical Evaluation Of Matrix Metalloproteinase Inhibitors And Protein Kinase C Activators In Cell And Mouse Models Of Huntington’S Disease, Kuruwitage Madushani

Dissertations, Masters Theses, Capstones, and Culminating Projects

Huntington’s disease (HD) is an incurable genetic neurological disorder that affects 1 in 10,000 people, with no treatment that can alter the course of the disease. Neural cell death in the striatum and the cortex results from the accumulation of toxic mutant huntingtin protein (mHTT) fragments. Full length HTT is cleaved by proteases, including caspases, calpains and matrix metalloproteinases (MMPs). Previous research has also shown altered kinase signaling pathways in HD contribute to the localization of mutant huntingtin to the nucleus and to disruption of transcriptional regulation. Currently, there are no drugs that delay the onset or slow the progression …

Targeting Mitochondrial Proline Dehydrogenase (Prodh) With A Suicide Inhibitor As A Novel Anticancer Strategy, Beatrice Becker

Dissertations, Masters Theses, Capstones, and Culminating Projects

Proline dehydrogenase (PRODH) is a p53-inducible inner mitochondrial membrane protein linked to electron transport and capable of generating mitochondrial glutamate and intracellular ATP, especially under cellular stress conditions. Among a panel of 51 human breast cancer cell lines, PRODH and glutaminase (GLS1) expression levels were found to be inversely correlated (1) implicating two independent and alternative mitochondrial pathways supplying anaplerotic glutamate for cancer cell energy production and macromolecular synthesis. Proposing PRODH to be a promising cancer therapeutic target, we compared the in vitro cellular effects of PRODH knockdown by siRNA as well as competitive (L-tetrahydrofuroic acid, THFA; or 5-oxo-2-tetrahydrofurancarboxylic acid, …

Determination Of Adamts13 Susceptibility In Type Iia Von Willebrand Disease, Monica Buselli

Dissertations, Masters Theses, Capstones, and Culminating Projects

von Willebrand Disease (vWD) is a bleeding disorder caused by a deficiency in von Willebrand Factor (vWF), a large glycoprotein that assists in coagulation. Specifically, large vWF multimers in the blood stream are key components in starting the coagulation cascade. vWF is cleaved by the metalloprotease ADAMTS13, regulating the multimers size, which hinders vWF’s ability to function properly. The three main types of vWD —Type I, II, and III— are not well defined, and as a result are all similarly treated with plasma-derived vWF replacement therapy. Plasma-derived vWF is a treatment that does not cure the problem but relieves the …

Identification Of Substrate-Selective Histone Deacetylases And Their Inhibitors That Mediate Her2 Transcript Stability, Mariah Alejo

Dissertations, Masters Theses, Capstones, and Culminating Projects

Breast cancer is the most common malignancy diagnosed in women. 15-20% of these cancers overexpress the HER2 (ERRB2) oncoprotein. HER2-positive breast cancers are generally aggressive and are associated with poor prognosis. Unfortunately, only a mere 30% of HER2-positve patients respond to therapies when they are used as a single agent. Combining therapeutics can potentially lead to synergy and improved anticancer efficacy, and there is clearly a need for the development of new HER2-directed therapeutics. Newer approaches include the utilization of histone deacetylase (HDAC) inhibitors. It has been observed that HDAC inhibitors can induce the rapid decay of oncogenic transcripts such …

Hypophosphatemic Rickets: A Targeted Literature Review To Characterize The Multiple Causes Of Phosphate Wasting Disorders And Identify Potential Disease Biomarkers, Christopher O'Mara

Dissertations, Masters Theses, Capstones, and Culminating Projects

Hypophosphatemic rickets is a rare, renal phosphate wasting disorder that presents various skeletal deformities. Although there are specific clinical presentations and biochemical findings used to identify hypophosphatemic rickets, there are various underlying renal phosphate wasting disorders that can lead to hypophosphatemic rickets making diagnosis extremely difficult. A targeted literature review through electronic search engines (e.g., BMC, PubMed, Google Scholar) was conducted to: 1) consolidate and summarize currently available data regarding the various renal phosphate wasting disorders, 2) identify current obstacles of successful diagnosis and treatment, and 3) propose directions for future hypophosphatemic rickets research into new biomarkers.

Changing Antimalarial Drug Sensitivities In Uganda, Stephanie Alexis Rasmussen

Dissertations, Masters Theses, Capstones, and Culminating Projects

Dihydroartemisinin-piperaquine (DP) has demonstrated excellent efficacy for the treatment and prevention of malaria in Uganda. However, resistance to both components of this regimen has emerged in Southeast Asia. The efficacy of artemether-lumefantrine, the first-line regimen to treat malaria in Uganda, has also been excellent, but continued pressure may select for parasites with decreased sensitivity to lumefantrine. To gain insight into current drug sensitivity patterns, ex vivo sensitivities were assessed and genotypes previously associated with altered drug sensitivity were characterized for 58 isolates collected in Tororo, Uganda from subjects presenting in 2016 with malaria from the community or as part of …

Modeling 3d Retinogenesis In Mouse Embryonic Stem Cells Following Crispr-Mediated Crx Knockdown, Pooja Prasad

Dissertations, Masters Theses, Capstones, and Culminating Projects

An emerging technology known as three-dimensional (3D) tissue engineering has allowed scientists to mimic tissues found in vivo. Previous studies indicate that it is possible to differentiate dissociated mouse embryonic stem cells (mESCs) into 3D retinal tissues in vitro (Bertacchi, 2015; Eiraku, 2012). The newly differentiated retinal tissues are said to encompass all of the major components found in retinal tissues. The generation of in vitro 3D tissues holds great potential in terms of patient-specific disease modeling. Although various diseases have been well-studied in animal models, there are limitations with regards to patient-specificity. The generation of animal models to study …

Novel Effects Of Prefoldin Pathway On Intestinal Homeostasis Via Dietary Restriction In Drosophila Melanogaster, Jesse Simons

Dissertations, Masters Theses, Capstones, and Culminating Projects

The field of medicine research is embroiled in a battle against aging. Particular focus is on the extension of lifespan and health-span. Lifespan duration is affected by many factors, one of which is the maintenance of the intestines of the organism. Homeostasis of the intestines is controlled by the regulation of intestine cell apoptosis and intestine cell proliferation. My research explores the role of two protein subunits found in a complex which may have possible functions in the regulation of these processes. The overall complex is formed from six subunit proteins, some of which are known to assist in other …

The Developmental And Genetic Basis Of Differences In Cave And Surface-Dwelling Forms Of The Crustacean, Asellus Aquaticus, Hafasa Mojaddidi

Dissertations, Masters Theses, Capstones, and Culminating Projects

Currently, there are many gaps in our understanding of the genetic mechanisms responsible for human diseases. One novel method to bridge these gaps is to investigate the naturally occurring variation of wild populations, which is arguably more similar to the genetic complexity present in human disease than artificially induced mutations in model species. Species adapted to subterranean environments often share phenotypic characteristics such as the reduction or complete absence of eyes, reduced pigmentation, and enhanced sensory systems. In order to understand the evolution of these morphological changes, we selected an invertebrate model system the freshwater isopod crustacean Asellus aquaticus, …

The Effects Of Various Therapeutics On Cystine Stone Formation, See Yang

Dissertations, Masters Theses, Capstones, and Culminating Projects

Cystinuria is an autosomal recessive genetic disorder characterized by the defect of a renal transporter involved in cystine reabsorption. When this transporter is deficient, cystine cannot be broken down and reabsorbed by the body and is excreted via urine in high concentrations. The high levels of cystine present in the urine eventually lead to recurrent cystine urolithiasis due to its inability to solubilize. Despite having various forms of treatments such as thiol pharmaceutical therapies such as tiopronin and urine alkalinizing agents like potassium citrate, only few patients with cystinuria are able to successfully decrease cystine urine concentration. We observed the …

Mammalian Cell Line Development Platform For Recombinant Protein Production: Expanding The Protein Expression Toolbox For Research And Drug Discovery Applications, Elizabeth Del Greco

Dissertations, Masters Theses, Capstones, and Culminating Projects

Recombinant proteins have revolutionized the biomedical industry, providing therapeutics for life-threatening diseases and protein reagents for research applications. BioMarin Pharmaceutical Inc. develops recombinant protein therapeutics to treat rare diseases including lysosomal storage disorders (LSDs), a group of about 50 individually rare disorders together affecting 1 in 8,000 live births. With an increase in the number of novel therapeutics in our drug discovery pipeline, there is a high demand to produce a variety of recombinant proteins for early-stage drug development projects. In order to equip our protein production process with the tools and capability for diverse protein expression, it is valuable …

Targeting Estrogen Receptor Negative Breast Cancer Cells Using Diarylthiourea Analogs Of Sheta2, Hongye Zou

Dissertations, Masters Theses, Capstones, and Culminating Projects

Abstract will available after document embargo ends.

Induction Of Human Embryonic Stem Cell Derived Retinal Stem Cells In Vitro Using Transient Overexpression Of Messenger Rna For Blimp, Onecut1 And Otx2, Helen Cifuentes

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

Evaluation Of Seizure Threshold As An Early Behavioral Marker Of Disease Progression In The Mouse Model Of Mucopolysaccharidosis Iiia, Pamela Santiago

Dissertations, Masters Theses, Capstones, and Culminating Projects

Mucopolysaccharidosis IIIA (MPS IIIA) is a lysosomal storage disease caused by a mutation in the gene that codes for the enzyme heparan sulfamidase. The decreased enzyme activity of heparan sulfamidase results in the accumulation of heparan sulfate (HS). HS accumulation in the brain causes severe central nervous system (CNS) complications, including learning and memory deficits and seizure. MPS IIIA patients have short life expectancies and there currently is no cure for the disease. This thesis work was aimed at identifying an early neurological phenotype in the mouse model of MPS IIIA. The data will aid in the design of an …

Transgenerational Epigenetic Inheritance Via Environmental Stress In Caenorhabditis Elegans, Monica A. Arroliga

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

Rac1 And Ire1 Are Required To Prevent Early Loss Of Intestinal Homeostasis In Drosophila Melanogaster, Mauricio M. Ortega

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

Optimizing Pharmacological Lifespan Extension: Testing Chemical Compounds For Additive Effects On Longevity, Elizabeth Chao

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

Evaluating The Performance Of In Silico Predictive Models On Detecting Splice-Altering Variants, Erica Cayton

Dissertations, Masters Theses, Capstones, and Culminating Projects

As with any complex biological pathway, the splicing process has both advantages and obstacles with respect to the diversity and fidelity of protein production. The potential benefits of being able to produce multiple versions of a gene (isoforms) must be weighed against the additional complexity introduced by the noisy and mechanistically complicated process of splicing. Indeed, research has found that errors in splicing can be implicated in an increasing number of disorders. Variants that cause disease may operate by disrupting splicing; however many of the variants are frequently annotated as disrupting function through a missense mutation, or via an unknown …

Synaptic Homeostasis At The Drosophila Neuromuscular Junction: Molecular Mechanisms And Developmental Adaptation, Lindsay A. Gray

Dissertations, Masters Theses, Capstones, and Culminating Projects

No abstract available

Integrity Of The Barrier Epithelium In Drosophila Gut Is Mediated By Factors That Regulate Intestinal Stem Cell Activity, Adam A. Kinion

Dissertations, Masters Theses, Capstones, and Culminating Projects

My thesis work on the Drosophila intestinal epithelium (IE) involved characterizing the mitochondrial unfolded protein response (UPRmt), validating proliferation specific regulatory genes, and proposing gut barrier function–specific genes as regulators of commensal bacteria density. The results from this project have shown that intestinal stem cells (ISCs) respond systemically in the presence of autonomously induced, visceral muscle (VM)-localized UPRmt. A phenotypic correlation between autonomous electron transport chain (ETC) dysfunction was observed in the visceral muscle and the systemic UPRmt response of ISCs in the posterior midgut. Exploratively, two genome-wide association studies (GWAS) using the Drosophila genetic reference panel (DGRP) were performed, …

Efficient In Vitro Development Of Photoreceptors From Human Pluripotent Stem Cells, Joseph C. Reynolds

Dissertations, Masters Theses, Capstones, and Culminating Projects

Degeneration of the rod and cone photoreceptors in the human retina is among the most common causes of blindness. Replacing these damaged photoreceptors may help to restore vision. Repairing the damaged retina relies on the insertion of new, healthy cells. Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are two possible sources of photoreceptors to restore vision. Previous data shows that human ES cells and iPS cells can be differentiated into photoreceptors and transplanted into the eye to restore some vision. However, this process is inefficient, and costly. Here, we show a new method for inducing photoreceptor production …

Modeling Uric Acid Kidney Stones Disease In D. Melanogaster Using Rnai And Dietary Modulation, Hai T.H. Lu

Dissertations, Masters Theses, Capstones, and Culminating Projects

In humans, the major predictor for gout and forming uric acid kidney stones is elevated uric acid in the serum and urine respectively. It is known that uric acid is an end metabolite of purine degradation in humans, but in other species from D. melanogaster to lower apes, uric acid can be further metabolized by urate oxidase into readily excreted allantoin. We hypothesize that if urate oxidase enzyme activity and dietary purine are both critical in uric acid kidney stone formation, then urate oxidase knockdown in combination with dietary purine supplementation will increase uric acid and induce uric acid kidney …

Ectodomain Mutations Alter The Proteolysis Of The Amyloid-Β Precursor Protein (App), Michael S. Mitsumori

Dissertations, Masters Theses, Capstones, and Culminating Projects

Alzheimer’s disease (AD) is the most common form of dementia, affecting over 5 million Americans. In AD patients there is a buildup of amyloid plaque in the brain, which contributes to AD symptoms. The main component of plaques is Amyloid-β (Aβ), a 40-42 length peptide formed from Amyloid-β Precursor Protein (APP) proteolysis. APP proteolysis can result in either anti-trophic or trophic peptides. Several APP polymorphisms exist that cause or protect against AD by altering APP proteolysis. Recently, more polymorphisms in the APP ectodomain have been discovered in patients with late onset AD (LOAD). The proteolysis of APP may be affected …

Oral Wellness: Using Occupational Therapy To Enhance Oral Hygiene Delivery In Long-Term Care, Lauryn J. Banovitz, Liberty Bellah, Rosemarie Lion

Dissertations, Masters Theses, Capstones, and Culminating Projects

Based on current literature, oral health in long-term care (LTC) facilities is frequently of low priority and does not follow evidence-based best practices. Poor oral health reduces the quality of life of older adult residents and patients and can lead to systemic diseases, such as cardiovascular disease, stroke, and pneumonia, the leading cause of death in LTC. Occupational therapists can play an instrumental role as oral care consultants, and educators, and can act as resource guides to raise the standards of oral care in LTC facilities.

This capstone project explored ways in which occupational therapy, a profession traditionally designated for …

Proteins Involved In Hdaci Induced Decay Of Erbb2 Transcripts In Breast Cancer, Sadaf Malik

Dissertations, Masters Theses, Capstones, and Culminating Projects

ERBB2-positive breast cancer is an aggressive disease form that can result in rapid tumor growth and metastasis driven by the overexpression of ERBB2 growth factor receptors present on the cell surface. Currently, approved agents can target and disable ERBB2 receptor function, but as few as 30% of patients with disseminated ERBB2-positive breast cancer will respond to these targeted therapeutics when given as single agents. Even then, many initial responders will soon develop resistance to these agents. Histone deacetylase inhibitors (HDACi) are a powerful new class of epigenetic therapeutics that have demonstrated potent antitumor activity. However, there are several concerns that …