Medical Sciences Commons^™

Integrating Genetic Counseling And Testing In The Pediatric Oncology Setting: Parental Attitudes And Influencing Factors, Lauren Renee Desrosiers

Theses and Dissertations

Cancer predisposition syndromes (CPS), caused by germline pathogenic variants in tumor suppressor genes and oncogenes, are genetic conditions that put an individual at increased risk to develop cancer. It is estimated that 10-15% of children with cancer have an underlying CPS. Although genetic testing for these conditions has become routine in the adult setting, incorporation of germline genomic technologies into pediatric cancer care has not occurred as rapidly. The purpose of this study is to assess desire for genetic counseling and testing services among parents of children with cancer to provide parental insight in the incorporation of genomic technologies in …

Role Of Cox2 In Cellular Senescence, Mingxiao Feng

Theses and Dissertations

The survivors of childhood cancers are often associated with adverse late effects including hypoplasia, fatigue, and infertility, which are characteristics of aging. However, the underlying mechanisms of the late effects of chemotherapy are still elusive. We have found that transgenic cyclooxygenase-2 (COX2) expression causes premature aging phenotypes. Since COX2 expression is highly induced by various chemotherapeutic agents, we further investigated the possible link between COX2 and the late effects of chemotherapy. Treatment of juvenile wild-type mice with doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, resulted in premature aging phenotypes and escalated cellular senescence level in various tissues. We found that tissue …

Spiritual Care In Cancer Genetic Counseling: Patient Perceptions Of Methods, Christopher Michael Spencer

Theses and Dissertations

The integration of spirituality into medical care is a growing area of debate among professionals, involving a delicate balance between serving patients who may benefit from this without alienating those who would not. To date, little research has targeted spirituality in cancer genetic counseling, particularly concerning the various methods a genetic counselor can use to address spirituality with their patients. A paper questionnaire was created and distributed to patients following their cancer genetic counseling appointments to gain insight on their perception of these methods. Fifty-two participants completed this questionnaire. The eight different spiritual integration methods presented each showed positive responses …

Investigating The Role Of Nicotinic Acetylcholine Receptor Agonists In Lung Cancer Progression And Chemosensitivity In The Context Of Treating Chemotherapy-Induced Peripheral Neuropathy, Sarah L. Kyte

Theses and Dissertations

While cancer chemotherapy continues to significantly contribute to the number of cancer survivors, exposure to these drugs can often result in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms in the hands and feet, such as numbness, burning, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a microtubule poison that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, …

Evaluation And Adaptation Of Live-Cell Interferometry For Applications In Basic, Translational, And Clinical Research, Kevin A. Leslie

Theses and Dissertations

Cell mass is an important indicator of cell health and status. A diverse set of techniques have been developed to precisely measure the masses of single cells, with varying degrees of technical complexity and throughput. Here, the development of a non-invasive, label-free optical technique, termed Live-Cell Interferometry (LCI), is described. Several applications are presented, including an evaluation of LCI’s utility for assessing drug response heterogeneity in patient-derived melanoma lines and the measurement of CD3+ T cell kinetics during hematopoietic stem cell transplantation. The characterization of mast cells during degranulation, the measurement of viral reactivation kinetics in Kaposi’s Sarcoma, and drug …

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

Alternative Splicing Of Cytoplasmic Polyadenylation Element Binding Protein 2 Is Modulated Via Serine Arginine Splicing Factor 3 In Cancer Metastasis, James T. Deligio, James Thomas Deligio

Theses and Dissertations

Our laboratory delineated a role for alternative pre-mRNA splicing (AS) in triple negative breast cancer (TNBC). We found the translational regulator cytosolic polyadenylation element binding protein 2 (CPEB2) which has two isoforms, CPEB2A and CPEB2B, is alternatively spliced during acquisition of anoikis resistance (AnR) and metastasis. The splicing event which determines the CPEB2 isoform is via inclusion/ exclusion of exon four in the mature mRNA transcript. The loss of CPEB2A with a concomitant increase in CPEB2B is required for TNBC cells to metastasize in vivo. We examined RNAseq profiles of TNBC cells which had CPEB2 isoforms specifically downregulated to …

Age-Dependent Changes In Oxygen Supply And Demand Of Rat Spinotrapezius Muscle, Sami C. Dodhy

Theses and Dissertations

Because of the aerobic nature of cellular metabolism in mammalian organisms, a continuous supply of oxygen is necessary to maintain normal physiological function. As organisms age, their metabolic rates generally decline and there are accompanying alterations in the structure and function of the microcirculation, as this part of the cardiovascular system is especially important for oxygen exchange. The overall Oxygen Transport System can be considered as being composed of two complementary components: one for Oxygen Demand and one for Oxygen Supply. The purpose of the current work is to describe the age-dependent changes in both oxygen demand and oxygen supply …

The Role Of Adam10 And Adam17 In Humoral And Type 2 Immunity, Joseph C. Lownik

Theses and Dissertations

The proper regulation of inducible costimulator (ICOS) and its ligand (ICOSL) have been shown to be essential for maintaining immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant antibody production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that ADAM10 is the primary physiological sheddase of ICOSL in both mouse and human. Using an in vivo system in which ADAM10 is deleted only on B cells (ADAM10^B-/-), elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is …

Glycosaminoglycan Lyases In The Preparation Of Oligosaccharides, Alhumaidi B. Alabbas

Theses and Dissertations

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date.

An alternative approach is to prepare GAG oligosaccharides using …

Gastrointestinal Microbiota Modulate Antinociceptive Tolerance Development In Mice With Chronic Morphine Exposure, Ryan A. Mischel

Theses and Dissertations

In October 2017, the United States government declared a state of public health emergency in response to the burgeoning prescription opioid epidemic. Opioid analgesics are the gold standard of therapy for moderate to severe pain, but their clinical utility is greatly limited by analgesic tolerance – a primary driver of diminished pain control and opioid dose escalations. Integral in this process are primary afferent sensory neurons in dorsal root ganglia (DRG), the first-order components of nociceptive sensation. With surmounting evidence that morphine and other narcotics can alter gut microbial composition and promote bacterial translocation to other tissues, a question arises …

The Contribution Of Sarm1 To Axonal Degeneration In Cns Inflammatory Disorders, Daniel C. Njoku

Theses and Dissertations

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that results in demyelination and axonal loss. Efficiently targeting mechanisms of axonal degeneration in MS has the potential to reduce disability but remains an unmet need. Prior research has identified the protein sterile alpha and TIR motif containing 1 (SARM1) as a critical factor that promotes axonal destruction in the program of axonal degeneration known as Wallerian degeneration. SARM1 inactivation reduces axonal degeneration in a variety of contexts including traumatic and toxic injury, but it remains unknown to what extent SARM1 is involved in axonal degeneration …

Effects Of The Na-Cl Co-Transporter (Ncc) In Western Diet Induced Metabolic And Cardiac Dysfunction, Zachary S. Cutter

Theses and Dissertations

Interleukin-18 (IL-18) is a pro-inflammatory cytokine known to be involved in maintaining metabolic homeostasis; however, also capable of inducing cardiac dysfunction. Additionally, IL-18, has been shown to bind to a novel receptor, the Na-Cl Co-transporter (NCC). We hypothesized that NCC mediates IL-18 metabolic and cardiac signaling in mice. Using male C57BL/6J mice, we compared the metabolic and cardiac function changes after at least 8 weeks of high-saturated fat high sugar diet (Western Diet) in NCC knockout (NCCKO), IL-18 knockout (IL-18KO), and wild-type mice. We show that NCCKO mice have significantly increased body weight gain from baseline, no difference in fasting …

Advances In Dual-Energy Computed Tomography Imaging Of Radiological Properties, Dong Han

Theses and Dissertations

Dual-energy computed tomography (DECT) has shown great potential in the reduction of uncertainties of proton ranges and low energy photon cross section estimation used in radiation therapy planning. The work presented herein investigated three contributions for advancing DECT applications. 1) A linear and separable two-parameter DECT, the basis vector model (BVM) was used to estimate proton stopping power. Compared to other nonlinear two-parameter models in the literature, the BVM model shows a comparable accuracy achieved for typical human tissues. This model outperforms other nonlinear models in estimations of linear attenuation coefficients. This is the first study to clearly illustrate the …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Understanding The Role Of Phosphoinositide 3-Kinase And Its Function As A Driving Force Behind The Er Stress Response In Fibrostenotic Crohn’S Disease-Affected Ileal Smooth Muscle Cells, Prashant Yadav

Theses and Dissertations

Crohn’s disease (CD) affects about 780,000 people in the United States alone, and it is estimated that 6-15 per 100,000 persons will receive a diagnosis of this disease each year. There currently is no cure for Crohn’s disease, and available medical therapies simply serve to alleviate the inflammation. This does not help treat fibrostenosis that Crohn’s disease patients may develop, which can only be treated surgically. Finding alternatives to treat CD requires an understanding of mechanisms at the biochemical level. In this thesis, we attempted to gain a better understanding of certain pathways found to be active in Crohn’s disease-affected …

Branched Short Chain Fatty Acid Isovaleric Acid Causes Smooth Muscle Relaxation Via Camp/Pka Pathway, Inhibits Gastrointestinal Motility, And Disrupts Peristaltic Movement, Bryan Adam Blakeney

Theses and Dissertations

Isovaleric Acid (IVA) is a 5-carbon branched chain fatty acid present in fermented foods and produced by the fermentation of leucine by colonic bacteria. IVA activates G-protein coupled receptors such as FFAR2, FFAR3, and OR51E1 known to be expressed on enteric neurons and enteroendocrine cells. We previously reported that the shorter, straight chain fatty acids acetate, propionate and butyrate, differentially affect colonic propulsion; however, the effect of branched chain fatty acids on gastrointestinal motility is unknown. We hypothesize that IVA relaxes smooth muscle in a cAMP/PKA dependent manner by direct action on smooth muscle cells. IVA will also decrease peristalsis …

Signaling Components Involved In The Hormone Induced Translocation Of Enac In Cultured Adult Human Fungiform (Hbo) Taste Cells, Deanna Hojati

Theses and Dissertations

The amiloride-sensitive epithelial Na⁺ channel, ENaC, is the Na⁺-specific salt taste receptor in rodents. Compared to rodents, human salt taste perception is amiloride-insensitive. In rodents the ENaC is composed of aβg-subunits. Whereas humans express an additional subunit, the d-ENaC subunit. ENaC in human taste cells is composed of aβg-subunits or dβg-subunits, with the latter being amiloride-insensitive. Currently, it is not known if dβg-ENaC expression and trafficking is regulated by hormones and their downstream intracellular signaling effectors. The aim of this study is to investigate if arginine vasopressin (AVP), aldosterone, and cAMP regulate d-ENaC expression and trafficking in …

Thyroid Hormone As A Method Of Reducing Damage To Donor Hearts After Circulatory Arrest, William P. Adams

Theses and Dissertations

There is a chronic lack of donor hearts to meet the need for heart transplant both in the US and worldwide. Further, the use of available hearts is limited by the short period between collection and implantation during which the heart can be safely preserved ex vivo. Using mid-thermic Langendorff machine perfusion, we have been able to preserve the metabolic function of a healthy heart for up to 8 hours, twice the limit for current static cold storage. We have also been able to preserve the metabolic function of a damaged DCD Heart collected 30 minutes after cardiac arrest …

Modulation Of Pkr Activity During Hiv Infection And Cellular Stress By Pact And Trbp, Evelyn E. Chukwurah

Theses and Dissertations

A crucial component of the cellular response to stress is the attenuation of protein synthesis to allow the cell to dedicate resources for the restoration of homeostasis or towards the induction of apoptotic cell death in case the stressors overwhelm the cell. This process is itself regulated by one of the four eIF2α kinases of which PKR (Protein Kinase R) is responsible for inhibiting general translation during viral infection, oxidative stress, ER stress, heat shock or serum withdrawal.

During viral infection, PKR is transcriptionally induced by interferon but remains latent until it interacts with dsRNA. This interaction induces a conformational …

Radioactive Contamination Of Natural Biological Systems: Oxidative Balance And Genetic Stability, Daniel Einor

Theses and Dissertations

The global demand for nuclear energy grows, and so do the risks of an accidental release of nuclear products into the environment. Therefore, understanding the health and ecological effects of contamination by radionuclides should be of great interest for biomedical specialists and the public. Empirical studies unequivocally show that high doses of ionizing radiation (IR) shift the redox-balance of many biological systems and increase the rates of genetic errors. However, the effects of chronic low doses of radiation vary significantly between tissues and between species. The present dissertation comprises the results of experimental and meta-analytical research of a variety of …

The Perceived Utility Of Personalized Genomic Medicine In Individuals With A Family History Of Heart Disease: A Pilot Study, Dana Margaret Mittag

Theses and Dissertations

According to the World Health Organization (2005), cardiovascular disease (CVD) is the number one cause of death in most countries. Assessing a patient’s risk for heart disease may include incorporating factors such as their gender, age, weight, tobacco history, cholesterol, blood pressure, family history, and more recently, genetics. Genome-wide association studies (GWAS) have made it possible to identify risk loci for many of the common, complex disorders, including coronary artery disease (CAD). As the medical genetics community undergoes a shift from a genetics focus to a genomics oriented focus, genomic medicine is becoming more accessible. Research has begun to examine …

Assessment Of Patient Satisfaction With The Provision Of Fertility Information In Women With Lynch Syndrome, Rachel Elizabeth Hickey

Theses and Dissertations

Lynch Syndrome (LS), one of the most common hereditary cancer syndromes, is primarily known for its substantially increased risks for colorectal cancer. The incidence of gynecologic cancers (endometrial and ovarian cancers) equals or exceeds the incidence of colorectal cancers in female patients with LS. The prevention and treatment methods for these cancers can drastically affect fertility and reproduction. Previous studies with cancer patients have revealed challenges in acquiring information related to these topics; thus far, no research has assessed whether there is an informational gap regarding fertility information for women in the LS population. The purpose of this study was …

Exercise Recommendations For Active Adults At Risk For Sudden Cardiac Death: “Can I Continue To Exercise?”, Kacie Lynn Baker

Theses and Dissertations

Sudden arrhythmic death syndrome (SADS) is due to genetic conditions associated with cardiac ion channelopathies and cardiomyopathies. Many of these conditions have exercise guidelines regarding eligibility and disqualification recommendations for competitive athletes through the American Heart Association and the American College for Cardiology. This study investigates how medical professionals communicate these exercise recommendations to patients, and in turn, how well patients understand these recommendations. The study also explores motivations for either continuing or discontinuing an exercise practice after a diagnosis. A questionnaire was distributed through cardiac disease-focused support groups and organizations. Data from 67 individuals with a SADS condition were …

Effects Of Estrogens On Astrocytes Exposed To Stressors, Bridget N. Smith

Theses and Dissertations

Hormone replacement therapy (HRT), used by many women to alleviate menopausal symptoms such as hot flashes and mood swings, is often a combination of horomones such as estrogens, progesterone, and conjugated equine estrogens (CEE), extracted from the urine of pregnant mares. Previous studies have found positive correlations between estradiol and cellular protection, but recent research has concluded CEE provide less protective mechanisms as compared to endogenous hormones. This research sought to compare the effects of estrogen treatments (single and combined estrogen) on viability when astrocytes were induced with stressors (epinephrine, cortisol, and low oxygen concentration). Cultured human astrocytes were treated …

Comparison Of Atypical Bacteriophages That Infect Caulobacter Crescentus, Doreen Nguyen

Theses and Dissertations

Several Caulobacter bacterial genomes have been recently sequenced, and all of the genomes contained one or more clusters of genes with phage origins. This observation indicates that bacteriophages contribute to the Caulobacter gene pool, so in order to understand bacteria genomes we will need to understand phage genomes as well. As part of understanding the phage genomes, we want to isolate novel bacteriophages and study their genomics. This study resulted in the isolation of 12 new phages, including four that differ from the well-studied CbKlike phages. Two of these novel phages are Podoviruses with icosahedral heads and small tails, and …

Environmental Relationships And Predator-Prey Interactions Within The Snapper-Grouper Complex In The Southeastern U.S. Atlantic – Implications For Fisheries Management, Dawn M. Glasgow

Theses and Dissertations

Stock assessments indicate many valuable fish species are declining, or are considered overfished and/or are undergoing overfishing. Fisheries scientists and managers in the southeastern U.S. typically have utilized a single-species approach, and relied on catch per unit effort data derived from fishery-independent surveys to determine indices of abundance for economically important reef fish. However, catchability for these surveys vary for many reasons including environmental and predator-prey relationships. This research was developed to elucidate environmental influences on reef fish assemblages and distribution of reef-associated marine predators, and examine predator-prey dynamics that may influence relative abundance of large predators based on chevron …

Applications Of Multimedia Resources Developed As Part Of The Virtual Cell Animation Collection In Undergraduate Introductory Biology, Eric Edward Goff

Theses and Dissertations

Calls for reform in undergraduate STEM education have arisen from an increased need for well-trained biology graduates in the future scientific workforce. To address this need, many institutions have focused on a pedagogical restructuring of instructional practices to promote deeper conceptual understanding of core biological concepts. This study investigates the implementation of multimedia resources as a possible reliable supplement to undergraduate introductory biology and aims to provide empirical evidence on the instructional best practices of their use. As a central part of this study, we focus on one specific multimedia package, the Virtual Cell Animation Collection, due to its developmental …

Adoptees’ Experiences With Direct-To-Consumer Genetic Testing: Emotions, Satisfaction, And Motivating Factors, Anna Childers

Theses and Dissertations

Public awareness of the role of genetics in disease continues to expand along with the use of direct-to-consumer genetic testing (DTC-GT). One subset of customers taking advantage of the growing DTC-GT market is adoptees. Prior research has shown that adoptees appear to be more motivated than non-adoptees to learn about their genetic disease risk but have similar responses to health-related information acquired through DTC-GT. In this exploratory qualitative study, fourteen adoptees were asked about their motivations for pursuing DTC-GT; satisfaction with results; emotions throughout the process; and interest in meeting with a genetic counselor. Motivations for pursuing DTCGT fell into …

Pediatric Genetic Counselor Perspective On Serving The Foster Care Population And The Integration Of Genetic Information Within The Health Passport, Angela Rose Douglas

Theses and Dissertations

Many states within the foster care system have adopted a document referred to as the health passport, which provides a condensed summary of a child's health history. This passport is intended to remain with the child as he/she moves between placements to improve communication between foster parents, caseworkers, and medical professionals. This exploratory research study examines the foster care system's utility of a child's health passport and opportunities for improvement through an online survey of the pediatric genetic counselor population. First, counselor perspectives on serving foster children were gathered and summarized into themes. Major elements and/or obstacles of counseling the …