Medicine and Health Sciences Commons^™

Ischemic Stroke Damage Is Reduced By Inhibition Of Il-6 Signaling With To Cilizumab, Jacob Hudobenko

Dissertations and Theses (Open Access)

Introduction:

Stroke is the leading cause of serious long-term disability and is the 5^th leading cause of death causing approximately 130,000 deaths in the United States every year {1}. Stroke is also the 2^nd leading cause of death in American women {2}. Women are 33% more likely to require nursing home care then men, have a higher lifetime risk of stroke and are 13% less likely to receive thrombolytic (clot busting) treatment than men {2}. Interleukin 6 (IL-6) is a pro-inflammatory cytokine involved in the regulation of the immune system in multiple disease states such as rheumatoid …

Equipment To Address Infrastructure And Human Resource Challenges For Radiotherapy In Low-Resource Settings, Rachel Mccarroll

Dissertations and Theses (Open Access)

Millions of people in low- and middle- income countries (LMICs) are without access to radiation therapy and as rate of population growth in these regions increase and lifestyle factors which are indicative of cancer increase; the cancer burden will only rise. There are a multitude of reasons for lack of access but two themes among them are the lack of access to affordable and reliable teletherapy units and insufficient properly trained staff to deliver high quality care. The purpose of this work was to investigate to two proposed efforts to improve access to radiotherapy in low-resource areas; an upright radiotherapy …

Investigating The Roles Of Tap63 And Tap73 In Cutaneous Squamous Cell Carcinoma And Lung Adenocarcinoma, Andrew J. Davis

Dissertations and Theses (Open Access)

TP63 and TP73 (which encode p63 and p73, respectively) are highly conserved transcription factors with important roles in development and tissue homeostasis. Similar to their homolog, p53, both p63 and p73 have been shown to mediate tumor suppression in multiple tissue types. Interestingly, however, both genes are expressed as multiple isoforms, which appear to have different and, in many cases, antagonistic functions. Through the use of isoform-specific null alleles of p63 and p73 our lab and others have shown that the full-length N-terminal isoforms of p63 and p73 (referred to as TAp63 and TAp73, respectively) exhibit distinct functions in development, …

Trichuris Muris Whey Acidic Protein Induces Type 2 Protective Immunity Against Whipworm, Neima Briggs

Dissertations and Theses (Open Access)

Human whipworm (Trichuris trichiura) infects approximately 1 in 15 people worldwide, representing the leading infectious cause of colitis and subsequent, inflammatory bowel disease (IBD). Current control measures focused on mass deworming have had limited success due to low drug efficacies. Vaccination would be an ideal, cost-effective strategy to induce protective immunity, leading to control of infection and transmission. Here we report the identification of whey acidic protein, a whipworm secretory protein, as a strong immunogen for inducing protective efficacy in a surrogate mouse T. muris infection model. The near full-length recombinant WAP protein (rTm-WAP49), as well …

Ube4b Levels Determine The Efficacy Of Egfr And Stat5 Inhibitors In Treatment Resistant Neuroblastoma, David James Savage

Dissertations and Theses (Open Access)

Neuroblastoma is the most common malignancy in infants. Overexpression of the epidermal growth factor receptor (EGFR) in neuroblastoma tumors can result in enhanced EGFR signaling, uncontrolled proliferation, and may provide a mechanism for chemotherapy resistance. UBE4B, an E3/E4 ubiquitin ligase, ubiquitinates the EGFR and promotes its lysosomal degradation ultimately attenuating EGFR signaling. Interestingly, the UBE4B gene lies in a chromosomal region (1p36) whose loss is correlated with poor patient outcomes due to inefficient EGFR degradation and enhanced cell proliferation. We examined whether depletion of UBE4B in a chemoresistant neuroblastoma cell line would affect tumor responses to drugs that specifically target …

Identification Of Intracranial Lesions With Dual-Energy Computed To Mography And Magnetic Resonance Phase Imaging, Megan C. Jacobsen

Dissertations and Theses (Open Access)

On conventional Single-energy Computed Tomography (SECT), lesions with an attenuation greater than 100 Hounsfield Units (HU) can be definitively diagnosed as calcification. However, low-density calcifications and hemorrhage may have overlapping attenuation ranges between 40 and 100 HU and, therefore, cannot be differentiated with SECT alone. On T2*-weighted Gradient Recalled Echo (GRE) MRI, these lesions appear as “foci of susceptibility” in which their signal is hypointense due to the magnetic susceptibility of the lesions differing from that of the background tissue.

Dual-energy Computed Tomography (DECT) and Phase-Sensitive Magnetic Resonance Imaging (PS-MRI) represent two new imaging paradigms which both have the potential …

Aging Exacerbates Neutrophil Pathogenicity In Ischemic Stroke, Meaghan Roy-O'Reilly

Dissertations and Theses (Open Access)

Ischemic stroke is a major cause of disability and mortality worldwide. As most patients cannot receive the currently approved therapies for ischemic stroke, novel treatments are critically needed. Cerebral ischemia causes irreversible tissue damage, referred to as the “tissue core”, which is surrounded by a salvageable penumbral region. Excitotoxicity, oxidative stress and inflammation can further damage this “tissue-at-risk”, resulting in even greater functional loss and poorer injury outcomes.

Aging represents the single strongest risk factor for high mortality and poor outcome after stroke in patients. This phenotype is also seen in animal models, with aged mice experiencing higher mortality and …

Auto-Delineation Of Oropharyngeal Clinical Target Volumes Using Deep Learning Techniques, Carlos Eduardo Cardenas

Dissertations and Theses (Open Access)

Head and neck intensity modulate radiation therapy allows for the delivery of high-precision radiotherapy by conforming radiation dose to the defined treatment targets achieving more accurate target dose distribution and better sparing of normal tissues. However, producing very precise treatment plans may be ineffective if the target volumes are not defined accurately. Furthermore, there are several reports of significant inter-observer variability when delineating these target volumes for head and neck cancers making this variability one of the largest sources of uncertainty in head and neck radiation therapy.

The purpose of this study was to develop algorithms to automate target delineation …

The Role Of Perivascular Fibrosis In Post-Stroke Glymphatic Impairment And Cerebral Amyloid Angiopathy, Matthew D. Howe

Dissertations and Theses (Open Access)

In healthy brain tissue, toxic amyloid-β (Aβ) proteins are transported by the pulsatile flow of cerebrospinal fluid (CSF) along perivascular drainage pathways. Ischemic stroke may disrupt this process, leading to a perivascular build-up of Aβ, termed cerebral amyloid angiopathy (CAA). I hypothesize that an abnormal pattern of extracellular matrix deposition within the vascular basement membrane, termed fibrosis, impairs Aβ drainage from the aged brain after stroke. I further hypothesize that inhibition of astrocytic transforming growth factor-β (TGF-β) signaling can reverse these phenotypes. Finally, I also hypothesize that serum biomarkers of perivascular fibrosis can be used to diagnose CAA following intracerebral …

Changes In The Testes Following Spinal Cord Injury And The Attenuating Effects Of Licofelone, Ryan Fortune

Dissertations and Theses (Open Access)

Spinal cord injury is a devastating disease that researchers have had very limited success in treating. In addition to interrupted innervation, spinal cord injury causes pathologic changes in a multitude of organ systems. Male infertility is one such complication that is particularly devastating because the patient population is predominantly young men. Our lab has previously shown that the blood testis barrier breaks down after spinal cord injury. This dissertation shows the local metabolomic and mRNA changes that spinal cord injury causes within the testes using a Sprague Dawley rat model, including the elevation in eicosanoids, increased oxidative stress, chronically elevated …

Microrna Functions In Uv-Induced Cutaneous Squamous Cell Carcinoma, Tran Nguyen

Dissertations and Theses (Open Access)

Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer, for which long term UV exposure and chronic wounding are the dominant risk factors. Despite these clinically established connections, little is understood about the early molecular response of human skin to UV exposure and its connection to acute wounding and cuSCC. Thus, our goal is to find common and specific signatures driven by UV-exposure and wounding as a means of developing new approaches for treating and preventing cuSCC.

Here, we perform integrated analyses of RNA-seq and miR-seq on 3 datasets: (1) UV-unexposed and acute UV-exposed human skin, (2) …

Genomic And Transcriptomic Landscape Of Colorectal Premalignancy, Kyle Chang

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most commonly diagnosed cancer among men and women in the United States, with 3 to 5 percent of the cases diagnosed in the background of a hereditary form of the disease. Biologically, CRC is divided into two groups: microsatellite instable (MSI) and chromosomally unstable (CIN). Genomic and transcriptomic characterization of CRC has emerged from large-scale studies in recent years due to the advancement of next-generation sequencing technologies. These studies have identified key genes and pathways altered in CRC and provided insights to the discovery of therapeutic targets. Despite the wealth of knowledge acquired in …

Enhancing Radiation Sensitivity In Non-Small Cell Lung Cancer, Yifan Wang

Dissertations and Theses (Open Access)

Lung cancer is the leading cause of cancer-related death. While radiation therapy is one of the standard treatments for lung cancer, the disease outcome after radiotherapy is still far from satisfactory despite ongoing advances in radiation techniques. Enhancing the radiosensitivity of lung cancer has the potential to improve the disease outcome of radiation treatments. Using a novel high throughput radiation sensitizing screen, previous work in the lab has identified several potent radiation sensitizers. The focus of my dissertation is on two of the identified pathways, HSP90 and MEK, using the potent and clinically relevant inhibitors ganetespib and trametinib. Using both …

The Cross-Talk Between Neurons And Microglia Through Interleukin-4 After Ischemic Injury, Shun-Ming Ting

Dissertations and Theses (Open Access)

After ischemic stroke, the loss of blood supply to the affected region of the brain leads to a series of pathological events known as ischemic cascades, that include excitotoxicity and microglia/macrophage over-activation resulting in damaging inflammatory responses. Studies from our research group suggest that the viable neurons in the ischemic penumbra (location receiving less profound damage, as compare to ischemic core) produce and release a potent anti-inflammatory cytokine, interleukin(IL) -4. We propose that this neuronal response to sublethal ischemia is designed to guide surrounding microglia/macrophages to a reparative and anti-inflammatory (M2) phenotype.

The research included in this study is designed …

The Protective Effects Of Memantine On The Morphology And Activity Of Irradiated Dendritic Spines, Thanh Lam

Dissertations and Theses (Open Access)

Abstract: The Protective Effects of Memantine on the Morphology And

Activity of Irradiated Dendritic Spines

Thanh T. Lam, M.S.

Advisory Professor: David R. Grosshans, M.D, Ph.D.

Although radiotherapy is an effective treatment for brain tumors, the adverse effects of such treatments may result in a decline in cognitive functioning. To prevent or reverse such radiation-induced cognitive dysfunctions, it is critical to understand the cellular and subcellular effects of radiation. In this study, both Thy-1 YFP mice and cultured cortical neurons were used to investigate changes in dendritic spines after cortical neurons were irradiated. The results indicated that irradiation has long-term …

Improved Target Coverage Of Spinal Metastases Through The Use Of Flattening Filter Free Beams, Laura Bennett

Dissertations and Theses (Open Access)

Of the patients that are diagnosed with metastatic disease, up to 40% will develop vertebral osseous metastases. These metastases tend to be located in close proximity to the spinal cord itself, making it difficult to achieve the recommended minimum dose of 14 Gy for single fraction SBRT or 21 Gy¹ for three fraction SBRT while maintaining acceptable doses to the cord and cauda equina. This proximity of the target to critical structures has the potential to compromise the efficacy of the radiation treatment plan in favor of reducing normal tissue dose, resulting in poor local control and tumor recurrence …

Mir-484 Functions As An Onco-Mir In Triple Negative Breast Cancer, Nashwa Kabil

Dissertations and Theses (Open Access)

Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer (BC), with a poor prognosis with currently used therapies, and thus represents an unmet therapeutic challenge. Lack of molecular targets (i.e. ER, PR, HER2) and significant genetic heterogeneity are the major reasons contributing to early relapse and high mortality rates. Numerous studies have indicated that microRNAs (miRs) have an important role in BC progression, invasion, angiogenesis, and metastasis. We analyzed miRNA expression profiles of BC patient data bases and identified that miR-484 is highly upregulated in all subtypes of BC patients, with the highest expression in TNBC …

Design, Fabrication, And Validation Of 3d Printed, Patient-Specific Compensators For Postmastectomy Radiation Therapy, Daniel Craft

Dissertations and Theses (Open Access)

The purpose of this study was to use 3D printed, patient-specific tissue compensators to overcome the 3D planning limitations for postmastectomy radiation therapy (PMRT). Tissue compensators can be used to reduce dose heterogeneity, hot and cold spots at field junctions, and treatment complexity, but are currently seldom used due to the difficulty in designing, fabricating, and validating them.

To produce compensators using 3D printing technology, suitable materials had to be found and characterized. Several materials were found to be promising, but previously unreported material uncertainties were also discovered that must be carefully controlled for in 3D printing studies. A new …

Omics Approaches To Uncover Germline And Somatic Variation Underlying Inherited Sarcomagenesis, Justin Wong

Dissertations and Theses (Open Access)

Sarcomas are rare mesenchymal tumors, making up 15% of all childhood and 1% of all adult tumors. They account for a disproportionate share of mortality in young adults, and if left untreated, are highly likely to metastasize. However, sarcoma etiology is poorly understood, and having numerous histological subtypes has complicated elucidation. To better understand factors underlying sarcomagenesis, we leveraged two rare inherited cancer predisposition syndromes, Li-Fraumeni Syndrome (LFS), and LFS-like (LFSL), both with a high incidence of sarcomas. LFS is caused by mutations in the tumor suppressor gene TP53 (p53), but has variable and incomplete penetrance, suggesting additional acquired …

Characterizing The Recognition Motif And Novel Substrates Of Carm1, Sitaram Gayatri

Dissertations and Theses (Open Access)

A limited pool of proteins attains vast functional repertoire due to posttranslational modifications (PTMs). Arginine methylation is a common posttranslational modification, which is catalyzed by a family of nine protein arginine methyltransferases or PRMTs. These enzymes deposit one or two methyl groups to the nitrogen atoms of arginine side-chains. Elucidating the substrate specificity of each PRMT will promote a better understanding of which signaling networks these enzymes contribute to. Although many PRMT substrates have been identified, and their methylation sites mapped, the optimal target motif for each of the nine PRMTs has not been systematically addressed. Here we describe the …

Dissecting The Molecular Mechanism Of Early Tumor Dissemination In Non-Small Cell Lung Cancer, Xingtong Liu

Dissertations and Theses (Open Access)

Lung cancer is the most common cause of cancer related death in the United States and worldwide. It has been shown that 30%-55% of patients with early stages of non-small cell lung cancer (NSCLC) developed and died of recurrence after curative resection, suggesting that tumor cell dissemination occurred early in those patients before surgery. However, molecular evidence, underline mechanisms and risk factors for the NSCLC relapse remain largely unknown. Addressing these questions will be critical for the development of strategies to stratify the risk of recurrence and approaches to reduce these risks. My thesis focused on dissecting the molecular basis …

Associations Between Physical Activity, Health-Related Quality Of Life, Regimen Adherence, And Glycemic Control In Jordanian Adolescents With Type 1 Diabetes, Yousef Aljawarneh

Dissertations and Theses (Open Access)

Background: Adolescents with Type 1 Diabetes (T1D) display a greater than two-fold higher risk of developing microvascular and macrovascular complications compared with the non-diabetic population and the risk increases markedly as glycated hemoglobin (HbA1c) increases. The majority of the findings on the associated factors with improved glycemic control are geared toward Western population with a clear lack of studies on Middle Eastern populations.

Purpose: This study aimed to examine the effect of Physical Activity (PA), Health-Related Quality of Life (HRQoL), and regimen adherence on glycemic control in Jordanian adolescents with T1D.

Methods: The study utilized a cross-sectional design. Jordanian adolescents …

Factors Influencing Physical Activity Among Immigrants From South India: A Qualitative Descriptive Study, Jaya Abraham

Dissertations and Theses (Open Access)

Background: In the United States (U.S), the percentage of diabetes and coronary artery diseases is higher among Asian Indian immigrants compared to other ethnic groups. Although research has been useful in describing patterns of physical activity among South Asian groups, very little is known about the factors influencing physical activity among Asian South Indian (ASI) immigrants. There is very limited research performed on the individual, social, cultural and environmental factors influencing physical activity among ASI immigrants.

Purpose: The study purpose was to explore the factors influencing physical activity with the following primary and secondary aims: The primary aim …

Relationships Of Moral Distress Among Interprofessional Icu Teams, Heather Vincent

Dissertations and Theses (Open Access)

Background: Moral distress is the psychological response to knowing the right action required by a healthcare professional but being unable to act upon the right course of action due to internal, external, and institutional constraints.

Purpose: The study investigated: 1. the level of moral distress among interprofessional healthcare providers working in four ICUs of a single academic hospital as measured by the 21-item Moral Distress Scale-Revised (MDS-R), 2. the differences in moral distress among interprofessional healthcare providers based on demographic characteristics and rankings of clinical scenario on the MDS-R.

Method: Descriptive, cross-sectional design using survey methodology.

Outcomes: Significant differences in …

Bridging The Gap Between Food Insecurity And Subsequent Child Body Mass: Mediating Effects Of Dietary Quality And Feeding Styles In Low-Income Hispanic Preschoolers, Nipa Kamdar

Dissertations and Theses (Open Access)

Background: Low-income Hispanic preschoolers face disproportionately high prevalence of food insecurity (FI) and obesity. Consumption of low-cost, energy-dense foods to compensate for FI leads to excess body-mass. FI parents may adopt feeding styles that contribute to decline in children’s dietary quality. Feeding style describes the amount of demandingness (i.e., control of children’s eating) and responsiveness (i.e., warmth used to express demandingness). FI may indirectly contribute to obesity through dietary quality and feeding style.

Purpose: This study investigated: 1. if dietary quality mediated the relationship between food security status (FSS) at Time 1 (T1) and child body-mass at Time 2 (T2), …

Structure Based Drug Design Of High Affinity Kras Inhibitors, Michael Mccarthy

Dissertations and Theses (Open Access)

RAS, one of the most well characterized membrane-associated small GTPases, is a notorious oncogene with >15% of all tumors harboring RAS mutations. When RAS is mutated it becomes constitutively active sending cell growth, survival and proliferation into overdrive, which subsequently leads to cancer. Although, RAS has been aggressively targeted with drug design efforts for more than 30 years an FDA approved direct inhibitor has not yet been developed. There are three isoforms of RAS in cells; HRAS, NRAS and KRAS. We focused on KRAS since it is the most frequently mutated isoform in cancer. To identify novel non-covalent small molecules …

The Role Of Merlin And Apicobasal Polarity In Endometrial Development And Homeostasis, Erin Lopez

Dissertations and Theses (Open Access)

Apicobasal polarity and cell adhesion are necessary for the proper formation and organization of epithelial tissues. Merlin couples cell polarity and adhesion through correct localization of the polarity protein Par3 and maturation of apical junctions. Merlin and Par3 are necessary for the development and homeostasis of highly regenerative tissues like the epidermis. The continual repopulation of the endometrium after each menstrual cycle requires a constant reorganization of cell polarity and adhesion. The endometrium consists of a luminal epithelium that postnatally gives rise to the distinct glandular epithelium. Endometrial glands are necessary to secrete nutrients for the pre-implantation embryo. In addition, …

Psychiatric Impact Of Tuberous Sclerosis Complex And Utilization Of Mental Health Treatment, Kate Mowrey

Dissertations and Theses (Open Access)

Tuberous sclerosis complex (TSC) is a multi-system, neurocutaneous disorder with neuropsychiatric features known as TSC-associated neuropsychiatric disorders (TAND). While 90% of individuals with TSC have some TAND features, only 20% receive treatment, leading to a 70% treatment gap. This study evaluated perception of disease severity, presence of anxiety and depression, as well as the utilization and barriers towards mental health services among adults with TSC. Disease severity had a moderate and low-moderate association with anxiety and depression, respectively. Regardless of past utilization, respondents had a positive outlook towards the use of mental health services with the major barrier being cost.

Characteristics Of Individuals Undergoing Panel Genetic Testing For Primary Brain Tumors, Sarah Azam

Dissertations and Theses (Open Access)

Background. Currently, there are no genetic testing guidelines for patients with a primary brain tumor (PBT). This population is largely understudied in terms of the family history, tumor grade, pathology, and their relation to genetic contribution. Our aim was to describe patient-specific characteristics and family histories across mutation-positive, negative, and variant of uncertain significance (VUS) cohorts based on cancer-panel genetic test results among patients with a PBT.

Methods. Subjects were referred for multi-gene panel testing between March 2012 and June 2016. Clinical data were ascertained from test requisition forms. The incidence of pathogenic mutations (including likely pathogenic) and VUS’s were …

Mechanisms And Targeting Of Neurodevelopmental Regulator Rest In Medulloblastoma Dissemination, Keri Callegari

Dissertations and Theses (Open Access)

Molecular subgrouping of medulloblastoma (MB) has produced four subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. While patients with WNT tumors have the best prognosis, patients with SHH tumors have a more variable prognosis concurrent with metastatic disease. This subset of SHH patients have elevated levels of the neurogenic regulator, RE1 Silencing Transcription factor (REST). To understand the role of REST in MB, we utilized a novel transgenic mouse model wherein REST expression can be conditionally elevated during postnatal development in the cells of origin of SHH MB, cerebellar granule neural progenitors (GNPs). While these mice did …