Medicine and Health Sciences Commons^™

Genetic Determinants Underlying Rare Diseases Identified Using Next-Generation Sequencing Technologies, Rosettia Ho

Electronic Thesis and Dissertation Repository

Rare disorders affect less than one in 2000 individuals, placing a huge burden on individuals, families and the health care system. Gene discovery is the starting point in understanding the molecular mechanisms underlying these diseases. The advent of next-generation sequencing has accelerated discovery of disease-causing genetic variants and is showing numerous benefits for research and medicine. I describe the application of next-generation sequencing, namely LipidSeq™ ‒ a targeted resequencing panel for the identification of dyslipidemia-associated variants ‒ and whole-exome sequencing, to identify genetic determinants of several rare diseases. Utilization of next-generation sequencing plus associated bioinformatics led to the discovery of …

Clinical And Pharmacogenetic Determinants Of Plasma Factor Xa Inhibitor Systemic Exposure, Markus Gulilat

Electronic Thesis and Dissertation Repository

Inhibition of blood coagulation via oral anticoagulant therapy is the mainstay for preventing a cardioembolic stroke in patients with atrial fibrillation (AF). Factor Xa inhibitors (FXaIs), rivaroxaban and apixaban, represent a new class of oral anticoagulants that are now widely prescribed in AF patients as an alternative to traditional warfarin therapy. An important advantage of these drugs is that routine monitoring of anticoagulation response is not necessary. Nevertheless, because of their mechanism of action, FXaI antithrombotic effect can be inferred based on the observed drug plasma concentration, with prolonged periods of elevated FXaI systemic exposure associated with increased risk for …

Integration Of Complementary And Alternative Medicine Into The Healthcare System In The United States, Nikki Lu

Global Honors Theses

Chronic diseases are a prevalent issue around the world and chronic diseases are hard to prevent due to various systemic factors in the healthcare system. This paper mainly focused on socioeconomic issues and highlighted a few systemic factors in the US healthcare system. These factors have created various health disparities, inequities among socially constructed groups, and financial expenditures in the US healthcare system. Socioeconomic factors significantly impact the health and healthcare among socially constructed groups. Additionally, in this paper there are current approaches in addressing these healthcare factors such as social determinants of health and precision medicine as well as …

The State Of The Translational Chaperone Icd-1 During Apoptosis In Caenorhabditis Elegans, Kyle Cicalese

Senior Honors Projects, 2010-2019

The unfolded protein response (UPR) is a signal transduction cascade that mitigates low levels of misfolded protein stress in the endoplasmic reticulum (ER) in an effort to save the affected cell, while prolonged and/or acute ER stress leads to UPR-initiated apoptosis (programmed cell death). One putative step driving apoptosis is the cleavage of chaperones, proteins tasked to help misfolded proteins refold, by caspases, proteases essential to the execution of apoptosis. We are studying the nascent polypeptide-associated complex (NAC), a heterodimeric chaperone complex essential for viability, to determine if its beta subunit is cleaved by caspases during apoptosis to prevent the …

Somatic Mutation Detection In Leukemia-Derived Circulating Dna: Utility In Monitoring Clonal Dynamics And Disease Response In Pediatric Acute Lymphoblastic Leukemia, Sarah Hisham Abdelaziz Youssef

Theses and Dissertations (ETD)

Despite the improved outcome associated with current treatment strategies ofpediatric acute lymphoblastic leukemia (ALL), relapse still represents a major challenge. Pediatric ALL demonstrates branched evolution in response to selective pressure exerted by therapy; relapse founder clones emerge from pre-leukemic clones or minor subclones present at diagnosis. It is hence crucial to develop biomarkers capable of tracking subclones throughout therapy. Current practices for monitoring disease response in leukemia rely on the analysis of BM biopsy sample at specific time points throughout therapy. Not only the invasiveness of the BM biopsy hinders the sequential sampling, but also, the currently implied techniques are …

Outcomes Of Genetic Testing In A Genitourinary Genetics Clinic, Annelise Pace

Dissertations & Theses (Open Access)

Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU-related hereditary cancer syndromes but there is limited research on the clinical picture of these patients, including their cancerous and non-cancerous features, the genetic testing strategy for this population, and the probability of having a positive germline mutation if testing is performed. The purpose of this study is to determine the most common indications for ordering genetic testing in a GU Genetics Clinic and evaluate whether there is a relationship between the indication for genetic testing …

Optimization Of Braf V600 Assay As A 2-Step Real-Time Pcr Protocol, Mimi Phuong

Dissertations, Masters Theses, Capstones, and Culminating Projects

The QClamp® BRAF Codon Specific Mutation Detection Kit is a real-time PCR assay for the detection of somatic mutations in codon 600 Valine at exon 15 in the BRAF gene which encodes the serine/threonine protein kinase, using purified DNA. The V600E mutation is the most common BRAF gene mutation found in human cancers. This mutation leads to production of a BRAF protein that is abnormally active, which disrupts regulation of cell growth and division. Mutations in this gene have been found in cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, papillary thyroid carcinoma, non-small-cell lung carcinoma, gastric cancer, and even …

Tumor Immunotherapy: Mechanisms Of Acquired Resistance And Characterization Of Immune Related Toxicities, Ashvin Jaiswal

Dissertations & Theses (Open Access)

Tumor immunotherapy has shown very promising clinical benefit across an array of cancers; however, two major challenges remain unresolved in the field. First, many patients do not respond to therapy at all or relapse after a period of remission. Second, there are often dose-limiting immune related adverse effects associated with immunomodulation.

In order to understand the mechanisms employed by tumors to evade immunotherapeutic responses, we established a murine model of melanoma designed to elucidate the molecular mechanisms underlying immunotherapy resistance. Through multiple in vivo passages, we selected a B16 melanoma tumor line that evolved complete resistance to combination blockade of …

Designer Babies: A Paired Analysis Of The Technological Advances And Ethical Implications Of Genetic Selection, Alexandra Schmerge 18

Honor Scholar Theses

No abstract provided.

Microrna 1207-3p In Prostate Cancer, Dibash Das

Dissertations, Theses, and Capstone Projects

Prostate cancer (PCa) is the most commonly diagnosed male cancer and the second leading cause of cancer-related death for men in the United States. Understanding the molecular mechanisms involved in progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC) is a major challenge. MicroRNAs (miRNAs), are known to be dysregulated in PCa. MicroRNA-1207-3p (miR-1207-3p) is encoded by the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of miR-1207-3p in PCa is unclear. We have discovered that miR-1207-3p is significantly underexpressed in PCa cell lines …

Role Of Mycobacterium Avium Paratuberculosis (Map) And Tnfsf15 Snps On Tl1a In Cd, Sayf Al-Deen Hassouneh

Electronic Theses and Dissertations

Tumor Necrosis Factor-Like Ligand 1a (TL1A) is a cytokine encoded by Tumor Necrosis Factor Super Family 15 gene (TNFSF15) gene mostly in endothelial cells which binds to T-cells and foments the production of pro-inflammatory cytokines including TNF-α, IL-6, IL-1b, IFN- γ and IL-13. TL1A level is elevated in inflammatory diseases including Crohn's Disease (CD). Although Single Nucleotide Polymorphisms (SNPs) in TNFSF15 have been reported in CD, no studies have investigated the effect of these SNPs on TL1A, inflammation, and susceptibility to Mycobacterium avium subspecies paratuberculosis (MAP) infection. MAP is a strong candidate in CD pathogenesis. This study is designed to …

Assessing The Barriers To Cardiac Care In Carriers Of Duchenne And Becker Muscular Dystrophy, Lauren Renae Eekhoff

Theses and Dissertations

Duchenne and Becker muscular dystrophy (DBMD) are X-linked conditions due to mutations within the dystrophin gene that cause progressive muscle weakness, respiratory insufficiency, and cardiomyopathy in affected males. Approximately twothirds of women who have a son with DBMD are carriers of the condition. Carriers typically do not manifest muscular symptoms but are at risk for cardiac abnormalities such as dilated cardiomyopathies. The American Academy of Pediatrics (AAP) recommends that carriers of DBMD receive a complete cardiac evaluation by a cardiologist that includes an echocardiogram and electrocardiogram (EKG) with reevaluation every five years. According to a recent study33, as many as …

Parental Experience With Whole Exome Sequencing Reanalysis And Its Impact On The Diagnostic Odyssey, Nicole D. Lucas

Theses and Dissertations

Advances in genomic technology and an increase in the number of gene-disease associations have helped reduce the number of individuals living without a diagnosis. Whole exome sequencing (WES) analyzes the entire human exome in an attempt to determine if there is a molecular etiology for individuals who remain undiagnosed after other clinical or molecular investigations. Still, WES leaves most individuals undiagnosed, resulting in feelings of disappointment and uncertainty. Individuals who remain undiagnosed after WES can subsequently undergo WES reanalysis later due to improvements in bioinformatics, software updates, and an increase in known genedisease associations. This is the first study, to …

Is Current Fragile X Syndrome Counseling Enough? Expanding The Clinical Phenotype Of Fragile X In Premutation And Intermediate Allele Carriers, Zahra Saadat Girnary

Theses and Dissertations

Fragile X syndrome (FXS) is caused by a triplet repeat expansion on the FMR1 gene. Individuals with >200 repeats have FXS, while individuals between 45-54 and 55- 200 repeats have the FMR1 intermediate allele and premutation, respectively. FXS is characterized by autism and intellectual disability while the premutation is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). However, recent research shows that the premutation may be associated with psychiatric manifestations. Currently, there are no established clinical features associated with the intermediate allele. This study sought to 1) study knowledge regarding FXTAS, FXPOI, as well …

The Impact Of Communication Deficits On Puberty And Sexual Development In Adolescents On The Autism Spectrum, Ashton Wolfe

Theses and Dissertations

Transitioning into a sexually mature adult is a challenging time for both an adolescent with autism spectrum disorder (ASD) and his or her family. Sexual development begets challenges due to the demands it places on the social and communication skills needed to explore developmental changes that are occurring physically, emotionally and hormonally. A diagnosis of ASD is largely established by quantifying impediments in social and communication skills through observation. With deficits in these skills, one can assume that social and communication difficulties can create obstacles in the sexual development of affected individuals. Our study used quantitative and qualitative measures to …

Discussing History Of Mental Illness During Prenatal Genetic Counseling: Patient Interest And Comfort, Sarah Nimrichter

Theses and Dissertations

Purpose: This study aimed to explore patient interest in and comfort with discussing a personal and/or family history of mental illness with a genetic counselor during a prenatal genetic counseling session. Methods: Participants included pregnant women who met with a genetic counselor for routine prenatal screening/testing counseling at Palmetto Health USC Medical Group Department of OB/GYN. Following their appointment, they were given a copy of the invitation to participate, questionnaire, and mental health resource page by the genetic counselor who performed their genetic counseling. Results: Forty participants completed questionnaires. 70% of participants indicated some level of interest in discussing mental …

Studying Vascular Morphologies In The Aged Human Brain Using Large Autopsy Datasets, Eseosa T. Ighodaro

Theses and Dissertations--Neuroscience

Cerebrovascular disease is a major cause of dementia in elderly individuals, especially Black/African Americans. Within my dissertation, we focused on two vascular morphologies that affect small vessels: brain arteriolosclerosis (B-ASC) and multi-vascular profiles (MVPs). B-ASC is characterized by degenerative thickening of the wall of brain arterioles. The risk factors, cognitive sequelae, and co-pathologies of B-ASC are not fully understood. To address this, we used multimodal data from the National Alzheimer’s Coordinating Center, Alzheimer’s Disease Neuroimaging Initiative, and brain-banked tissue samples from the University of Kentucky Alzheimer’s Disease Center (UK-ADC) brain repository. We analyzed two age at death groups separately: < 80 years and ≥ 80 years. Hypertension was a risk factor in the < 80 years at death group. In addition, an ABCC9 …