Medicine and Health Sciences Commons^™

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

Novel Insights Into Ubiquitin-Like Protein E1-E2 Interactions, Asad Taherbhoy

Theses and Dissertations (ETD)

Posttranslational modification of macromolecules by ubiquitin-like proteins (UBLs) such as ubiquitin, Sumo and NEDD8 regulate a vast array of processes in the cell. Transfer of UBLs to their target generally occurs by a series of molecular handoffs down an E1‑E2‑E3 cascade. We are interested in understanding how E1‑E2 pairs interact and mediate UBL transfer. To this effect, we studied two E1‑E2 pairs: the Sumo pathway (Sumo utilizes a canonical E1 and E2) and the Atg8 pathway (Atg8 is a UBL involved in autophagy that utilizes a non-canonical E1‑E2 pair).

Sumo conjugation is initiated by the heterodimeric Aos1‑Uba2 E1 enzyme (in …

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 …

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, …

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 …

Eccentric Interchangeability Of The Semi‑Adjustable Articulator: A Pilot Study, Mark James Hopkins

Theses and Dissertations (ETD)

Background: Dental articulation is a method of approximating the patient's mandibular motion in order to allow for analysis of dental relations and fabrication of appliances. The most prevalent method used in teaching institutions is the semi-adjustable articulator. Several of these instruments claim interchangeability without loss of clinical accuracy and studies have supported this claim. No studies to date have assessed the interchangeability of the articulators in any relation other than hinge axis closure. Assessment of the accuracy of interchangeability of calibrated articulators will inform the profession of this parameter of articulation and allow for informed decisions on whether or not …

Efficacy Of Temporary Fixed Retention Following Comprehensive Orthodontic Treatment, Mark J. Owens

Theses and Dissertations (ETD)

Instability of the occlusion is a common problem following orthodontic treatment. The purpose of the present research was to evaluate posttreatment relapse at long-term recall (> 10 years) in cases (A) treated with temporary fixed mandibular retention plus Hawley retainers compared to (B) a similar group retained with just removable retention (standard Hawley type retainers alone). Fixed retainers were removed after having been in place for about 2.5 years. Following this period, use of removable retention was left up to the discretion of the patient in both groups. Data consisted of orthodontic records of 166 American whites, all of whom …

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 …

The Influence Of Patient-Reported Provider Availability Factors On Nonurgent Emergency Department Use, Cheryl Anne Dewood

Theses and Dissertations (ETD)

Purpose. The purpose of this study was to examine the influence of patient‑perceived provider availability on nonurgent emergency department use (NUEDU). The study population consisted of a nationally‑representative population of non‑elderly adults who were continuously privately insured (CPI) for at least a year before an emergency department visit that was determined to be nonurgent, and who reported having a regular source of care (RSC).

Methods. Data were obtained from a nationally‑representative longitudinal survey, the Medical Expenditure Panel Survey (MEPS). The classification of ED visits as nonurgent was based on patient report using a method developed for this study. Patient­‑perceived provider …

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 …

Activity Of Epithelial Defensin Hbd-3 Against A Periodontal Pathogen, Norman B. Fine

Theses and Dissertations (ETD)

Defensins are cationic (positive-charged) peptides with broad-spectrum antibiotic activity. In humans, there are two types of defensins, alpha (α) and beta (β). Human neutrophils contain four α-defensins known as Human Neutrophil Peptide (HNP) 1-4. Epithelial cells produce four β-defensins known as Human Beta Defensin (HBD) 1-4. Gram-negative anaerobic bacteria that are associated with periodontal disease are resistant to human α-defensins, but are killed by β-defensins.

HBD-3 is the most active β-defensin. HBD-3 is a longer peptide than HNP 1-4. HBD-3 has additional amino acid residues with hydrophobic side chains near the N-terminus and residues with cationic side chains at the …

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 …

Craniofacial Changes Following Nonextraction Orthodontic Treatment: A Long-Term Cephalometric Analysis, James Austin Rahaim

Theses and Dissertations (ETD)

Long-term posttreatment cephalometric changes from late adolescence into early adulthood were analyzed in this study. Lateral cephalometric radiographs from a sample of 30 Class II division 1 Caucasian females treated without extractions were evaluated at posttreatment (mean age = 15.9 years) and recall (mean age = 28.3 years). All of the subjects were treated in the private practice of a single, experienced practitioner. The cephalograms were examined to investigate changes in the cranial base, midface, maxilla, mandible, maxillomandibular relationships, dental relationships, and the soft tissue profile that occurred at an average of 12.4 years posttreatment. Descriptive and inferential statistics were …

Evaluating Consumer Preferences For Medicare Part D Using Conjoint Analysis, La'marcus Wingate

Theses and Dissertations (ETD)

The establishment of an outpatient prescription drug benefit in Medicare, Medicare Part D, was one of the more significant events in United States healthcare reform history. Many seniors have chosen to enroll in the plan as the program has an enrollment of over 27 million. One central premise of Medicare Part D was that the plan would be administered entirely through private insurance plans. Because many plans would be competing against one another for potential beneficiaries, it was expected that companies would offer seniors plans with high quality benefits at lower costs that would presumably be attractive to seniors. However, …

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 …

Biomechanical Comparison Of Traditional Laminectomy And Minimally‑Invasive Facetectomies, Karen Sedacki

Theses and Dissertations (ETD)

The facet joints of the lumbar spine are one of the sources of low‑back pain that affects a great portion of the population. Minimally‑invasive (MI) procedures have been becoming more popular in the surgical decompression of the spine because they offer shorter recovery time and involve removal of smaller amounts of important structures. With these features, it is believed that MI procedures lead to less clinical instability, and the functionality of the segment is maintained. Another important factor is how the facet angle in the lumbar segments affects the biomechanical instability. In spite of all this interest in MI procedures, …

Use Of A Multi-Axis Robotic Testing Platform To Investigate The Sagittal Mechanics Of The Multi-Body Lumbar Spine, Jessica Rose Stubbs

Theses and Dissertations (ETD)

A biomechanical study was performed to compare range of motion of the multi-body lumbar spine using three different protocols: pure moment, eccentric loading, and a new method called combined loading moment. The objectives of the study were to introduce a new protocol that overcomes the limitations of previous methods by applying more realistic loading conditions and to compare the range of motion of this new protocol to those of eccentric loading and pure moment protocols within the same specimen pool. The second objective of this study was to compare the data sets of these three protocols to both in vivo …