Diseases Commons^™

Molecular Characterization Of Glioblastoma Cancer Stem Cells, Jo Meagan Garner

Theses and Dissertations (ETD)

Malignant gliomas are locally aggressive, highly vascular tumors that have an overall survival time less than 14 months, and current therapies provide little improvement in the disease course and outcome. While glioblastoma multiforme (GBM) patients present uniform histological phenotypes, the molecular determinants of the disease vary considerably between individual cases resulting in complicated prognosis. The heterogeneity, aggressiveness and rapid tumor relapse of GBM is believed to be sustained by cancer stem-like cell populations that are able to initiate and maintain tumors. Although CSCs represent only a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance …

The Health-Related Quality Of Life Of Adults With Down Syndrome, Rebecca Jermyn Graves

Theses and Dissertations (ETD)

Purpose. The purpose of this study was to examine the health-related quality of life (HRQOL) and factors associated with the HRQOL of adults with Down syndrome (DS) as reported by adults with DS and their caregivers. The study was designed to compare measures of HRQOL, health problems, health risks, and health-care utilization of adults with DS based on self-report with those from caregiver-report and to explore associations between HRQOL and health problems, health risks, health-care utilization, adaptive behavior, and demographic characteristics. Background. The life expectancy of individuals with DS has lengthened from approximately 30 years around 1960 to over 50 …

Toll-Like Receptors 2 And 9 Are Important For Innate Immune Cell Activation And Recruitment In Hypersensitivity Pneumonitis, Kelly J. Andrews

Theses and Dissertations (ETD)

Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by repeated inhalation of environmental antigens. The disease is characterized by alveolitis and granuloma formation; however, some patients develop chronic HP (CHP), a restrictive lung disease characterized by fibrosis. Previous studies revealed that neutrophils are recruited into the lung via a MyD88- dependent pathway and regulate disease severity through cytokine production. Toll-like receptors (TLRs) 2 and 9 recognize conserved molecular patterns present in bacteria, and signal through the adaptor molecule MyD88. The goal of my project is to investigate the role of TLRs 2 and 9 in the pathogenesis of HP …

Development And Characterization Of A Recombinant Vesicular Stomatitis Virus (Rvsv) For The Treatment Of Glioblastoma, Erika A. Dillard

Theses and Dissertations (ETD)

Background: Over the past 30 years, little has changed in the treatment modalities and prognosis of patients suffering from Glioblastoma multiforme (GBM), the most common and by far the most devastating adult primary malignant brain tumor. Conventional therapies provide only a marginal increase in survival of GBM patients, post-diagnosis. Therefore, more novel means of treating GBM are needed to increase long-term survival and quality of life for those affected. Replication competent oncolytic viruses (OVs) have recently emerged as a possible option for treatment of high-grade gliomas. Particularly, recombinant vesicular stomatitis virus (rVSV), an enveloped, negative strand RNA virus, has shown …

A Novel Mechanism Of Enhanced Susceptibility To Bacterial Pneumonia In Influenza-Infected Hosts, Hazem Elsayed Ghoneim

Theses and Dissertations (ETD)

Viruses such as influenza suppress host immune function by a variety of methods. This may result in a significant morbidity through several pathways, including facilitation of secondary bacterial pneumonia from pathogens such as Streptococcus pneumoniae. Lungresident alveolar macrophages (AMs) act as the first line of innate cellular immunity against respiratory bacterial pathogens, including pneumococcus. Therefore, they represent an attractive target for study Before investigating the impact of influenza infection on resident AMs, we first characterized different subsets of lung-resident macrophages in naïve mice using a novel in vivo labeling approach in conjunction with multicolor flow cytometric analysis and confocal microscopic …

Nkg2d Ligands In Cancer, Neha Das Gupta

Theses and Dissertations (ETD)

NK cell transplantation has been increasingly used to treat cancers that are resistant to chemotherapy. However, not all cancers are susceptible to NK cell killing. The prevalence and mechanisms of NK cell resistance have not been well elucidated. Because NKG2D is a major activating receptor on NK cells, we sought to test the hypothesis that NKG2D is the primary pathway in tumor cell recognition. Herein, we comprehensively assessed 20 cancer cell lines representing a broad array of cancer types. In line with our primary hypothesis, no cancer cell lines that expressed low levels of NKG2D ligands were susceptible to NK …

Tetraspanin Cd9: Contributions To Cancer Cell And Vascular Cell Phenotypes From The Sixth Man, Michael James Herr Ii

Theses and Dissertations (ETD)

Cancer and vascular disease are the two most predominant causes of mortality in the United States. Potential regulatory mechanisms for these two diseases have consumed research interests. Tetraspanins are cell surface proteins that organize the cell membrane. Cellular membrane organization is a prerequisite for cellular signaling to occur. Deregulation of cellular signaling often precedes the formation of cancer or vascular disease phenotypes. This insinuates the necessity to understand how tetraspanins contribute to membrane organization and subsequent downstream signaling. This work examines tetraspanin CD9 contributions in a model of cancer cell invasion and vascular cell contraction. The findings presented here demonstrate …

Attenuation Of Parenteral Nutritionassociated Liver Disease By Omega-3 Long-Chain Polyunsaturated Fatty Acids, Emma Monique Tillman

Theses and Dissertations (ETD)

No abstract provided.

Signal Transduction And Transcriptional Regulation Pathways Essential For Azole Resistance In Candida Albicans, Erin M. Vasicek

Theses and Dissertations (ETD)

Candida albicans is the most prevalent human fungal pathogen, found as a commensal organism in the mucosa, gastrointestinal, and urogenital tracts of humans. This pathogenic fungus causes a wide spectrum of diseases, including the mucosal infection oropharyngeal candidiasis (OPC) which frequently effects patients with human immunodeficiency virus (HIV). The azole antifungals (such as fluconazole) are the most widely used and important ergosterol biosynthesis inhibitors (EBIs) for the treatment of Candida infections, including OPC. However, the azoles are fungistatic against C. albicans and therefore have limited efficacy against this organism, especially for immunocompromised patients. In C. albicans, the transcription factor Upc2 …

Erg11-Mediated Azole Resistance In Candida Albicans, Stephanie Ann Flowers

Theses and Dissertations (ETD)

Although many medically important Candida species are commensal to the gut or colonizers of the skin, these organisms have the propensity to cause disease in the event of a waning immune system. Clinical manifestations of infections with Candida species can range from superficial mucosal infections to deep organ involvement usually resulting from haematogenous spread of infection. Despite significant progress made in the management of patients with fungal infections, the emergence of antifungal resistant clinical isolates creates significant problem in regards to antifungal prophylaxis and empirical treatment strategies. Antifungal resistance is associated with high mortality rates and hefty medical costs. The …

Identification Of Novel Hif1a Target Genes That Regulate Tumor Progression And Metastasis, Danielle L. Peacock

Theses and Dissertations (ETD)

Hypoxia is a hallmark of most solid tumors. In response to hypoxic stress tumor cells adapt by regulating survival, metabolism and angiogenesis. The heterodimeric HypoxiaInducible Factor (HIF) transcription factors are the master regulators of this response. HIFs play key roles in many critical aspects of cancer biology including angiogenesis, stem cell maintenance, metabolic reprogramming, invasion, metastasis and resistance to radiation therapy and chemotherapy. Overexpression of HIF-1α and HIF-2α has been documented in multiple human cancers and HIF-1 protein is over-expressed in ~30% of primary breast tumors and ~70% of metastases, which independently correlates with poor prognosis and decreased survival in …

A Multidisciplinary Approach To The Prevention Of Infant Torticollis And Plagiocephaly, Anne H. Zachry, S. K. Slaughter

Faculty Presentations

Research suggests that parents are more likely to carry out positioning recommendations from a health care professional than any other source. Occupational therapy practitioners can play an important role in educating parents, caregivers, and healthcare providers about the importance of providing tummy time and limiting infant time spent in baby gear.

Macromolecular Complexes Of Cystic Fibrosis Transmembrane Conductance Regulator Alter Fluid Transport In Inflammatory Bowel Disorders, Kavisha Arora

Theses and Dissertations (ETD)

Macromolecular complexes of cystic fibrosis transmembrane conductance regulator (CFTR) comprise of network of proteins that can regulate cAMP-/cGMP-activated CFTR chloride channel function. We report the physical and functional coupling of CFTR with nitric oxide (NO) producing enzyme-inducible nitric oxide synthase (iNOS) at the apical plasma membrane in inflammatory bowel disease (IBD). The complex formation requires the scaffolding protein Na+ /H+ exchanger regulatory factor 2 (NHERF2). We demonstrate that iNOS is overexpressed at or near the apical plasma membrane of gut epithelial cells in IBD and, through the stimulation of the NO-cGMP pathway, generates compartmentalized cGMP underneath the plasma membrane. This …

The Protumorigenic Role Of Caspase-8 In Neuroblastoma, Devin Drew Twitchell

Theses and Dissertations (ETD)

Neuroblastoma (NB), the most common extracranial solid tumor in children, accounts for 15% of cancer-related deaths in pediatric patients. Caspase-8 (casp8), a proapoptotic protein, is silenced in approximately, 50-70% of neuroblastoma patient samples. Loss of casp8 has been suggested to increase NB metastasis and correlated, in some studies, with advanced-stage NB. Furthermore, decreased casp8 expression may facilitate neuroblastoma tumorigenesis by protecting cells from cell death mediated by either integrins or chemotherapeutics. Paradoxically, casp8 expression is maintained in 30-50% of NB patient samples giving rise to the possibility that casp8 may provide selective advantages for NB tumorigenesis. Caspase-8 is shown to …

Functional Study Of Hemogen Knockout Mouse Model, Peng Gao

Theses and Dissertations (ETD)

Mouse Hemogen (Hemgn) is regarded as a homologue of human Erythroid Differentiation Associated Gene (EDAG). EDAG overexpression has been postulated for association with some leukemia cases. Meanwhile, Hemgn has been found to contribute to Hoxb4 mediated hematopoietic stem cell expansion. Based on these postulations and evidences, a Hemgn knockout mouse model has been generated to study its function in normal and stress hematopoiesis. I confirmed the Hemgn expression in hematopoietic organs including bone marrow and spleen, as well as round spematids in testis. Hemgn is expressed in mouse hematopoietic stem cells and erythroid progenitor cells. Moreover, Hemgn was also found …

The Role Of The Yxxφ Motif In Cd82 Trafficking And Function, Mekel Marie Richardson

Theses and Dissertations (ETD)

CD82, a tetraspanin, is a tumor metastasis suppressor. Tetraspanins are membrane spanning proteins that play critical roles in diverse biological and pathological processes, e.g., the regulation of cancer metastasis. CD82 is ubiquitously expressed in various types of tissues, but its expression becomes down-regulated or lost in a majority of metastatic tumors. It inhibits tumor metastasis without affecting primary tumor growth. Cancer patients whose tumors contain CD82 exhibit minimal metastasis. We know that CD82 functions as a tumor metastasis suppressor but the mechanism by which this occurs is largely unknown. CD82 can be found on the plasma membrane as well as …

Inhibition Of Breast Cancer Angiogenesis And Metastasis Ay Targeting Hypoxia-Inducible Factor-1Α, Chikezie O. Madu

Theses and Dissertations (ETD)

The current clinical chemotherapy agents are not ideal for breast cancer as they are not curative, but only provide a modest extension of survival with sometimes a severely adverse effect on the patient’s quality of life. There is, therefore, an urgent need to search for new and more effective anti-breast cancer drugs. However, the existing screening system is inefficient and time-consuming despite the extremely large amount of small molecule compounds in database currently available, and thereby hindering the effort for selecting new and effective anti-cancer drugs.

The majority of locally advanced solid tumors contain regions of reduced oxygen availability. Hypoxia …

Discovery Of Dihydroartemisinin And Dasatinib Drug Combination To Cure Pooroutcome Bcr-Abl+ Acute Lymphoblastic Leukemia, Harpreet Singh

Theses and Dissertations (ETD)

Oncogenic signaling by the Philadelphia chromosome-encoded BCR-ABL fusion kinase initiates and drives both Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Food and Drug Administration (FDA)- approved BCR-ABL-specific kinase inhibitors (BCR-ABL–KIs) imatinib, dasatinib and nilotinib induce prolonged remissions in CML but poor leukemia-reduction and relapse-control in Ph+ ALL. The relative primary BCR-ABL–KI-resistance in Ph+ ALL patients carrying predominantly BCR-ABLWT disease cannot be attributed to drug-resistant BCR-ABL mutations (BCR-ABLMUTANTS), and remains poorly understood.

We established a cell-based platform to evaluate the modulation of anti-Ph+ ALL activity of drugs by both tumor-extrinsic cytokines normally present in the leukemia …

Acetaldehyde And Epithelial Junctions: Role Of Pp2a And Occludin Phosphorylation, Mitzi Dunagan

Theses and Dissertations (ETD)

Chronic alcohol consumption causes health problems including cancers, liver damage, and cirrhosis.These problems are exacerbated by endotoxins from the bacterial population of the colon, which can enter the bloodstream when gastrointestinal tight junctions, protein complexes that prevent paracellular passage of molecules, are compromised. The mechanisms of this barrier disruption are the subject of current study.

Acetaldehyde, produced as a result of ethanol breakdown by intestinal microflora as well as intestinal epithelia, is a known carcinogen. It compromises the barrier function of intestinal epithelial cells by causing irregularities in the phosphorylation of tight junction proteins. It also reacts with proteins, lipids, …

The Molecular Basis Of Fitness And Transmissibility Of Neuraminidase Inhibitor Resistant Influenza A Viruses, Susu Duan

Theses and Dissertations (ETD)

Neuraminidase (NA) inhibitors including oral oseltamivir and inhaled zanamivir are among the first line of defense against influenza virus infection. Development of resistance to NA inhibitors is a huge drawback for limited options for the control of influenza. During the first decade of NA inhibitor use, the detection rates of resistance to both NA inhibitors had remained low in circulating influenza viruses. However, the 2008~2009 season was marked by a radical increase of prevalence of oseltamvir resistance from <1% to >90% in worldwide surveillance in less than a year. The resistance was solely linked to NA H275Y variants of seasonal H1N1 viruses, …

Phenotypic And Electrophysiologic Characterization Of A Mouse Model Of Fragile X Syndrome, Snigdha Roy

Theses and Dissertations (ETD)

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. It is caused by a mutation in the fragile X mental retardation (FMR1) gene on the X chromosome. Many children with FXS exhibit autistic behaviors and deficits in motor coordination including speech articulation deficits. The development of the FMR1 knockout (Fmr1 KO) mouse, in which the Fmr1 gene is inactivated, has provided an animal model that can be used to investigate underlying neuro-physiological mechanisms associated with FXS as well as to evaluate potential therapeutic treatments. In this study, quantitative behavioral assays were used, such as long term …

Beta-2-Adrenergic Receptor Regulates Insulin Signaling To Reduce Cell Death In Müller Cells, Robert Jason Walker

Theses and Dissertations (ETD)

No abstract provided.

Autoimmune Consequences Of Histone Deimination During Neutrophil Activation, Nishant Dwivedi

Theses and Dissertations (ETD)

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins, thus, are crucial questions for the understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death deserves attention because it occurs as a consequence of neutrophil activation, requires the post-translational modification of histones and results in the extracellular release of chromatin. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4) creating structures that capture or "trap" bacterial pathogens. Neutrophil …

Spatial Distribution Of Obesity Among West Virginia 5th Grade Children: Analysis Of The Socioeconomic, Physical, And Personal Environment, Sherry Roper

Theses and Dissertations (ETD)

Childhood obesity defined as a body mass index (BMI) at or above the 95th percentile for children of the same age and sex, is considered an epidemic in the United States. Biology and lifestyle behaviors have been identified as important factors in the development of childhood obesity; however, researchers are beginning to place more emphasis upon the impact that continual environmental exposures have upon obesity development. Environmental risk factors associated with obesity are distributed continuously over space, yet evidence suggests that burden of risk may not be evenly dispersed across a community. West Virginia (WV), a rural Appalachian community has …

Characterization Of The Mechanism Of Pparγ-Mediated Neointima Formation In Rodents, Ryoko Tsukahara

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) and its ether analog alkyl glycerophosphate (AGP) elicit arterial wall remodeling when applied intralumenally into the uninjured carotid artery. LPA is the ligand of eight GPCRs and the peroxisome proliferator-activated receptor γ (PPARγ). We pursued a gene knockout strategy to identify the LPA receptor subtypes necessary for the neointimal response in a non-injury model of carotid remodeling and also compared the effects of AGP and the PPARγ agonist rosiglitazone (ROSI) on balloon injury-elicited neointima development. In the balloon injury model AGP significantly increased neointima; however, rosiglitazone application attenuated it. AGP and ROSI were also applied intralumenally for …

Compound 49b: A Novel Beta-Adrenergic Receptor Agonist In The Treatment Of Diabetic Retinopathy, Kimberly Williams-Guy

Theses and Dissertations (ETD)

Diabetic retinopathy is the leading cause of blindness in working Americans. While there are therapeutic regimens for the disease, more effective methods are needed. We have previously shown that a non-specific beta-adrenergic receptor agonist, isoproterenol, was effective in preventing functional and morphological changes associated with diabetic retinopathy in the rat. Isoproterenol also produced left ventricle remodeling suggesting it entered the systemic circulation. We therefore synthesized various novel beta-adrenergic receptor compounds and screened these compounds in vitro for their ability to reduce markers of inflammation and apoptosis. Of the various compounds tested, Compound 49b was able to reduce both inflammation and …

Inflammatory Proteins, Genetic Variation, And Environmental Influences On Health Care Associated Infection Development In Sepsis, Reba Antoinette Umberger

Theses and Dissertations (ETD)

The purpose of this study was to determine the impact of baseline systemic inflammation (pro‑inflammatory cytokine, anti‑inflammatory cytokine, and their ratio), genetic variability, and environment on the development of health care associated infections (HAI) among sepsis patients during their ICU stay (up to 28 days).

Methods: A prospective observation study was conducted at the Veterans Affairs Medical Center in the Medical Intensive Care Unit over an 18 month period. A total of 78 patients were enrolled within 72 hours of presenting to the ICU with sepsis. Patient were excluded if they were receiving immunosuppressants (chemotherapy or greater than one mg/kg …

Characterization Of The Sigma Factor Proteins And The Dna Binding Protein Euo Of Chlamydia, Cory L. Blackwell

Theses and Dissertations (ETD)

Chlamydia spp. are prokaryotic obligate intracellular pathogens with a unique, biphasic developmental cycle in which an infectious, extracellular form termed the elementary body (EB) interconverts with a metabolically active intracellular reticulate body (RB) within host cells. Subsets of genes are differentially expressed during the developmental cycle, and these genes are believed to be responsible for the transitions between the EB and RB forms. The goal of these studies was to explore two potential mechanisms that may function in regulating developmental cycle stage‑specific gene expression in chlamydiae: a cascade of sigma factor expression and the binding of the early stage protein …

Impact Of Adjuvants On The Antibody Responses To Pre-Pandemic H5n1 Influenza Vaccines, Ali Hassan Ellebedy

Theses and Dissertations (ETD)

Human influenza pandemics occur when influenza viruses to which the population has little or no immunity emerge and acquire the ability to transmit among humans. Since their emergence in 1996, human infections with highly pathogenic avian influenza A (H5N1) viruses presented a serious public health challenge. Additionally, H5N1 viruses caused significant agricultural and economic losses in the communities it has affected. Human infections with these viruses are rare but when they occur, these infections are highly fatal. A greater public health concern stems from the rapid evolution displayed by these viruses so far, which in turn might result in viruses …

Insights Into P53-Dependent Apoptotic Signaling And Cell Fate Vis-A-Vis Functional Cooperation Among Bcl-Xl, Cytoplasmic P53, And Puma, John C. Fisher

Theses and Dissertations (ETD)

Following DNA damage, nuclear p53 induces the expression of PUMA (p53 upregulated modulator of apoptosis), a BH3‑only protein that binds and inhibits the anti‑apoptotic BCL‑2 repertoire, including BCL‑xL. Structural investigations of PUMA and the BCL‑xL×PUMA BH3 domain complex by X‑ray crystallography and nuclear magnetic resonance (NMR) spectroscopy reveal a novel, PUMA‑induced, domain‑swapped dimerization of BCL‑xL that requires a π‑stacking interaction between PUMA W71 and BCL‑xL H113. PUMA is an intrinsically disordered protein, but upon interaction with BCL‑xL, PUMA W71 and the PUMA BH3 domain residues fold into an alpha helix and subtly remodel BCL‑xL to trigger its dimerization. Wild type …