Medicine and Health Sciences Commons^™

Bevacizumab Effect On Topotecan Pharmacokinetics In A Murine Orthotopic Rhabdomyosarcoma Xenograft Model, Zaifang Huang

Theses and Dissertations (ETD)

Increasing evidence suggests that inhibition of vascular endothelial growth factor (VEGF) can transiently normalize tumor vasculature, thereby improving delivery of systemic chemotherapy. Bevacizumab (BEV), an anti-VEGF antibody, has been shown to transiently normalize tumor vasculature by increasing tumor vessel maturity, decreasing tumor vessel permeability, and increasing tumor oxygenation in an Rh30 orthotopic rhabdomyosarcoma xenograft model. However, the effects of BEV on the pharmacokinetics of TPT and the antitumor activity of TPT have not been evaluated. This study aimed to investigate the effect of BEV on TPT systemic and tumoral pharmacokinetics and to determine how these changes affect the efficacy of …

The Association Between Reading Comprehension And Prerequisite Skills For Children In Poverty, Hyo Jin Yoon

Theses and Dissertations (ETD)

The purpose of this study was to investigate the relationship between reading comprehension and the prerequisite skills typically assessed by a school based speech pathologist with a focus on children raised in poverty. Based upon previous studies, three hypotheses were developed. First, children from low socioeconomic status (SES) backgrounds would not perform as well as children from the standardization sample on norm referenced language tests although the language tests would predict reading comprehension. Second, decoding would not be as good a predictor of reading comprehension for children from low SES backgrounds as it is in typically developing children from middle …

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 …

Preclinical Pharmacology Of The Mdm2 Antagonist Nutlin-3a, Fan Zhang

Theses and Dissertations (ETD)

Nutlin-3a is an MDM2-p53 interaction antagonist that is under investigation in preclinical models for a variety of pediatric malignancies, including neuroblastoma, retinoblastoma, leukemia, and rhabdomyosarcoma. In the current research, we conducted preclinical pharmacology studies of nutlin-3a to evaluate the synergistic effect of the nutlin-3a and topotecan combination on neuroblastoma cell growth, to assess the effect of nutlin-3a on breast cancer resistance protein (BCRP), and to characterize the disposition of nutlin-3a in the mouse plasma and multiple tissues.

Activating the p53 pathway might offer a new therapy for neuroblastoma. In the first part of the study, we assessed the effect of …

Nurses Information Appraisal Within The Clinical Setting, Heather D. Carter-Templeton

Theses and Dissertations (ETD)

Information appraisal is foundational to information literacy, a necessary skill to support evidence-based practice. Little discussion in nursing literature exists regarding how nurses appraise information. If nurses lack information appraisal skills they cannot safely and effectively apply evidence in practice. Furthermore, if nurses at all levels are to engage in evidence-based practice, information appraisal in the clinical setting must be understood. The research study used an interpretive description design to define and describe the process of information appraisal in the clinical setting. Participants of this study represented a stratified purposeful sample of 44 registered nurses employed at a regional medical …

Testing Whether Mrp4 (A Camp Efflux Pump) And The Beta 2 Andrenergic Receptor (An Upstream Regulator Of Camp Signaling Pathways, Praveen Kumar Potukuchi

Theses and Dissertations (ETD)

Background and Aim: MRP4/ABCC4 is an ABC transporter that can efflux the second-messenger, cAMP, from cells. MRP4 has a PDZ interacting motif at its carboxy terminal end through which it binds to scaffolding proteins NHERF1 and PDZK1. Previous studies have shown that PDZK1 serves as a scaffold physically coupling MRP4 with the cystic fibrosis transmembrane conductance regulator (CFTR). This protein complex functionally couples cAMP regulation of CFTR function with MRP4 cAMP transporter activity [Li, C., et al., Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia. Cell, 2007. 131(5): p. 940-51]. We hypothesized that the …

The Effects Of Pten Deletion On Cell Size And Plasticity In The Hippocampus, Margaret Sperow

Theses and Dissertations (ETD)

The tumor suppressor phosphatase and tensin homolog (PTEN) is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) -signaling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size and synaptic transmission and plasticity. Neurologic abnormalities such as autism, seizures, and ataxia are associated with inherited PTEN mutations. Yet, how PTEN loss contributes to neurologic dysfunction remains unknown. PTEN loss during early development is associated with extensive deficits in neuronal migration and substantial hypotrophy of neurons and synaptic densities. However, whether its effect on synaptic transmission and plasticity is direct …

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 …

Synthesis And Computational Studies On Hiv-1 Integrase Inhibitors, Horrick Sharma

Theses and Dissertations (ETD)

HIV-1 integrase (IN) is essential for viral replication and offers a promising target for the development of anti-retroviral drugs. Two decades of extensive research has lead to the recent approval of raltegravir as the first IN inhibitor. Advancement of drug candidate elvitegravir, which is currently in Phase III clinical trial, has furthermore accelerated efforts against this potential target for combating HIV. However, the emergence of resistance against raltegravir and elvitegravir demands exploration of novel chemical scaffolds that could circumvent resistance against currently used HIV-1 IN inhibitors. With the goal of discovering new agents targeting HIV, a novel structural class of …

Development And Evaluation Of Nano‑Scale Systems For Targeted Delivery To Treat Liver Fibrosis, Ningning Yang

Theses and Dissertations (ETD)

Excessive deposition of ECM is the common characteristic of liver fibrosis. During hepatic fibrosis, various inflammatory cytokines are released and trigger the activation of quiescent HSCs. The activated HSCs play the major role in producing extra amount collagen. It becomes very crucial to focus on HSCs to find out therapeutics, such as inhibiting collagen synthesis, inhibiting activation to myofibroblasts, or controlling inflammation.

To control excessive collagen synthesis, one triplex forming oligonucleotides (TFO), was systemically administrated to prevent type I collagen mRNA transcription. To enhance circulation time and targeted delivery efficiency, TFO was conjugated to M6P‑HPMA and showed efficient targeted delivery …

Characterization Of The Key Mouse Cochlear Developmental Genes For Auditory Hair Cell Regeneration, Zhiyong Liu

Theses and Dissertations (ETD)

Mammalian inner ear cochlear auditory hair cells (HCs) and adjacent supporting cells (SCs) are believed to derive from the same progenitors during development. However, unlike SCs of nonmammalian vertebrates, mammalian cochlear SCs cannot be converted into functional hair cells (HCs) after damage, thus leading to permanent deafness. To entitle mammals with the ability to restore hearing capacity after HC damage, we first achieved proliferation of SCs by acute ablation of p27 or Sox2. Secondly, we overactivated Notch1 signaling in the mouse inner ear at different developmental stages, and found that the ability of Notch signaling in generating new HCs declines …

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 …

Military Sexual Trauma Exposure And Heart Rate Variability Outcomes In Female Veterans, Elizabeth Ann Davis Lee

Theses and Dissertations (ETD)

Area of Investigation and Hypothesis: Decreased heart rate variability (HRV) has been used as a predictor of cardiac and all-cause mortality. Studies have documented decreased HRV in a variety of conditions, including posttraumatic stress disorder (PTSD), depression, age, coronary artery disease (CAD), diabetes mellitus (DM), and tobacco use but improvement with beta blocker (BB) treatment. No prior study evaluated the relationship between military sexual trauma (MST) exposure and HRV outcomes. The hypothesis of this study was that female veterans exposed to MST would have lower time domain HRV measures than a reference cohort reporting non-exposure. Methods and Procedures: Electronic medical …

Evaluating Dimensional Accuracy And Reliability Of "Stitched" Small Field Of View (Ssfov) Cone Beam Computed Tomography (Cbct) Datasets For Use In Proprietary Dental Implant Guided Surgery Software, Nicholas Luke Egbert

Theses and Dissertations (ETD)

Background: Recently a "stitched" small field of view (SSFOV) cone beam computed tomography (CBCT) extraoral imaging system (Kodak 9000D, Carestream Health Inc, Kodak Dental Systems, Marne‑la‑Vallee, France) has been released. The benefits of the 3D stitching module of stitched SFOV CBCT may include: broader range of applications, affordability, flexibility, safety optimizing radiation dose and improved workflow. With the reduced effective dose of radiation and cost to both the patient and clinician, this superior imaging modality becomes more accessible to the community, potentially elevating the standard of care. Currently, stitched data sets are restricted to diagnostic data gathering only. To date, …

Effect Of Occlusion, Directionality And Age On Horizontal Localization, Lynzee Nicole Alworth

Theses and Dissertations (ETD)

Localization acuity of a given listener is dependent upon the ability discriminate between interaural time and level disparities. Interaural time differences are encoded by low frequency information whereas interaural level differences are encoded by high frequency information. Much research has examined effects of hearing aid microphone technologies and occlusion separately and prior studies have not evaluated age as a factor in localization acuity. Open-fit hearing instruments provide new earmold technologies and varying microphone capabilities; however, these instruments have yet to be evaluated with regard to horizontal localization acuity.

Thus, the purpose of this study is to examine the effects of …

Analysis Of Out-Of-Pocket Expenditures Of Oral Oncologics For Tennessee Recipients Of Medicare Part D, Eve Carolyn Elias

Theses and Dissertations (ETD)

Background: There are few studies that examine patients' costs of oral oncology drugs from Medicare Part D plan providers. These drugs can impose a financial burden to beneficiaries, and, due to their cost, place beneficiaries in the coverage gap in a short period of time. In addition to examining costs, there is little published concerning the potential impact of drug utilization management techniques on access to these drugs in Medicare Part D plans. This study examined the roles of prior authorization, step-therapy, and placement of drugs in higher formulary tiers on patients' out-of-pocket costs, and access to therapy.

Methods …

The Long-Term Stability Of Class Ii Cases Treated In A Private Practice Using A Straightwire Appliance: A Dental Cast Analysis, Lina K. Kulkarni

Theses and Dissertations (ETD)

Achieving long-term stability after orthodontic treatment is a major challenge for orthodontists. The previous literature shows that relapse occurs at a considerable magnitude. The purpose of the present study was to determine the amount and type of long-term, posttreatment relapse that occurs in a homogeneous group of patients treated by a single experienced orthodontist in a private practice setting. Dental casts from a sample of 30 Class II division 1 Caucasian females treated without extractions were evaluated at pretreatment (mean age = 13.1 years), posttreatment (mean age = 15.9 years) and recall (mean age = 28.3 years) to determine the …

Use Of A Spine Robot Employing A Real Time Force Control Algorithm To Develop, Simulate, And Compare Spinal Biomechanical Testing Protocols: Eccentric Loading, Pure Moment, And A Novel Head Weight Protocol, Daniel Mark Wido

Theses and Dissertations (ETD)

In vitro testing provides a critical tool for understanding the biomechanics of the subaxial cervical spine. Previous common testing protocols used to evaluate the subaxial cervical spine include Pure Moment (PM), follower load, and eccentric lever arm (EL) loading methods. Although these methods are widely accepted, there is always a goal to try to better simulate physiologic loading conditions. While the follower load attempts to simulate compression due to muscle activation, no previous protocol has taken into account the constant vertical force vector applied to C2 produced by the weight of the human head. Furthermore, we are unaware of previous …

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 …

Temporal And Aerodynamic Aspects Of Velopharyngeal Coarticulation: Effects Of Age, Gender And Vowel Height, Fadwa Khwaileh

Theses and Dissertations (ETD)

Previous studies on the normal patterns of velopharyngeal coarticulation did not provide a multidimensional description of the phenomenon. The primary objective of this study was to determine the effects of age, gender and vowel height on the temporal and aerodynamic aspects of nasal airflow segments related to velar coarticulation in the normal speech of children and adults. A secondary objective was to determine the within speaker variability of the segments.

Speakers consisted of 20 children between the ages of 5 and 7 years, 20 children between 9 and 11 years and 20 adult speakers 18 years or older. Nasal and …

Rna Interference For Improving The Outcome Of Islet Transplantation And Polymeric Micelle‑Based Nanomedicine For Cancer Therapy, Feng Li

Theses and Dissertations (ETD)

Ex vivo gene transfer has been used to improve the outcome of islet transplantation for treating type I diabetes. RNA interference is an effective approach for reducing gene expressions at the mRNA level. The application of RNA interference to improve the outcome of islet transplantation was reviewed in Chapter 2, where I summarized biological obstacles to islet transplantation, various types of RNAi techniques, combinatorial RNAi in islet transplantation, and different delivery strategies.

Upregulation of inducible nitric oxide synthase (iNOS) and subsequent product of radical nitric oxide (NO) impair islet β cell function. Therefore, we hypothesized that iNOS gene silencing could …

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 …

Pten Function In Postnatal Brain Development And Tumorigenesis, Guo Zhu

Theses and Dissertations (ETD)

PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) is a tumor suppressor gene that is commonly mutated in multiple types of human cancers including endometrial, prostate, breast cancers and glioblastoma multiforme (GBM). PTEN functions as a phospholipid phosphatase antagonizing phosphorylation by phosphatidylinositol‑3‑OH kinases (PI3Ks) and thus serves as a major negative regulator of the PI3K pathway. Homozygous Pten knock-out mice die during embryogenesis. Conditional Pten knock-out in the nervous system showed that Pten negatively regulates self-renewal and proliferation of neural stem cells, negatively controls neuronal size, is required for proper neuronal positioning and is involved in the development and …

Inhibition Of Monocyte Chemotaxis And Chemokine Macrophage Inflammatory Protein-1 Alpha, And Interleukin-8 Secretion By Lipopolysaccharide Isolated From Periodontal Pathogens, Andrew Karl Gray

Theses and Dissertations (ETD)

The vast majority of periodontal pathogens are classified as gram negative bacteria. These bacteria have an outermost membrane consisting of lipopolysaccharide (LPS), a molecule that can act as an endotoxin and elicit an immune response. The lipopolysaccharide structure consists of three major regions: oligosaccharide, core, and lipid A. Oligosaccharide is exposed on the cell surface, and lipid A anchors LPS in the outer membrane. LPS has been known to hinder certain defensive mechanisms of the immune system by secreting products that interfere with signals that promote chemotaxis of leukocytes enabling the pathogens to go unrestricted. When LPS binds to the …

The Design And Synthesis Of Autotaxin Inhibitors And Analogs Of Lysophosphatidic Acid, Renuka Niranjan Gupte

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) is a naturally occurring bioactive phospholipid. It has a wide array of biological effects like cell proliferation, survival, migration, apoptosis invasion, wound healing and angiogenesis. Autotaxin (ATX) was identified as an autocrine tumor cell motility factor from A2058 melanoma conditioned medium. ATX has lysophospholipase D enzyme activity and is responsible for the cleavage of lysophophatidylcholine (LPC) leading to the generation of LPA. Antagonists of Autotaxin would have a potential therapeutic application in cancer research. Chapter 1 is an introduction of LPA and autotaxin. It provides the background and significance of the research. Chapter 2 explores the synthesis …

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 …

A Novel Shear Thinning And Thixotropic Plga Micro Particulate Suspension System For Controlled Drug Delivery, Sonia Bedi

Theses and Dissertations (ETD)

Poly lactide‑co‑glycolide (PLGA) polymer has been the polymer of choice for many parenteral controlled drug release applications. This is mainly due to the inherent advantages of this polymer i.e. biodegradability, biocompatibility and non-toxic nature. The polymer, however, has a characteristic degradation pattern whereby the final erosion phase does not begin until the polymer reaches a certain molecular weight (MW) limit. After this, the accumulated acidic degradation byproducts initiate a bulk erosion phenomenon that leads to a disruption of the polymer matrix and release of the remaining drug in a short period of time. Furthermore, most of the delivery systems or …

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 …

The Relationship Between Lower Extremity Bone Mass And Body Mass Index In A Nhanes Adolescent Population, James Randall Post

Theses and Dissertations (ETD)

The effect of body mass index (BMI) on bone mineral content (BMC) among adolescents has been researched yielding mixed results. This study explored the relationship of left lower extremity (LLE) BMC on BMI across the spectrum of weight in a large nationally representative group of adolescents. This descriptive study used secondary data from the publically accessible, cross-sectional survey files of the 1999-2004 Continuous National Health Assessment and Nutritional Examination Survey (NHANES) that contained whole body dual energy X‑ray absorptiometry (DXA) data as well as BMI calculations looking at the adolescent population 12- to19-year-olds at the time of the exam. The …