Medicine and Health Sciences Commons^™

Using Mouse Models To Define How The P53 R72p Polymorphism Impacts The Adverse Effects Of Doxorubicin And Ionizing Radiation, Emily Dominguez

Dissertations and Theses (Open Access)

The single nucleotide polymorphism (SNP) at codon 72 of the tumor suppressor gene p53 codes for either an arginine (R) or proline (P) (p53 R72P). This SNP may impact how cells respond to genotoxic insult. Studies in cell culture and in tissues from mouse models of the SNP indicate that, in response to gentoxic treatment, the two variants may differentially induce apoptosis and expression of p53 target genes. In epidemiological studies, the P variant is associated with decreased cancer survival and increased risk of side-effects from genotoxic cancer treatment. Genotoxic therapy is still the mainstay of cancer treatment, and doxorubicin …

The Role Of Streptococcus Gallolyticus Subspecies Gallolyticus In Colon Cancer Development, Jennifer L. Herold

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the third most common cancer in men and women and is also the third most common cause of cancer death. A large body of evidence points towards the possibility that bacteria can have a significant impact on the development of cancer. It has been suggested that Streptococcus gallolyticus subsp. gallolyticus, a group D streptococci, may play a role in the development of CRC. Sg, formerly S. bovis biotype I, has been shown to be highly associated with CRC. In observing patients with either Sg bacteremia or endocarditis it was found that 25-80% of …

Concomitant Targeting Of The Mtor/Mapk Pathways: Novel Therapeutic Strategy In Subsets Of Non-Small Cell Lung Cancer, Dennis Ruder

Dissertations and Theses (Open Access)

Over the last decade, a paradigm-shift in lung cancer therapy has evolved into targeted-driven medicinal approaches. However, patients frequently relapse and develop resistance to available therapies. Herein, we utilized genomic mutation data from advanced chemorefractory non-small cell lung cancer (NSCLC) patients enrolled in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-2) clinical trial to characterize novel actionable genomic alterations potentially of clinical relevance. We identified RICTOR alterations (mutations, amplifications) in 17% of lung adenocarcinomas and found RICTOR expression correlates to worse overall survival. There was enrichment of MAPK pathway genetic aberrations in key oncogenes (e.g. KRAS, BRAF, …

Maguk Scaffolds Organize A Key Synaptic Complex In Horizontal Cell Processes Contacting Photoreceptors, Alejandro Vila, Ph.D.

Dissertations and Theses (Open Access)

Synaptic processes and plasticity of synapses are mediated by large suites of proteins. In most cases, many of these proteins are tethered together by synaptic scaffold proteins. Scaffold proteins have a large number and typically a variety of protein interaction domains that allow many different proteins to be assembled into functional complexes. As each scaffold protein has a different set of protein interaction domains and a unique set of interacting partners, the presence of synaptic scaffolds can provide insight into the molecular mechanisms that regulate synaptic processes. In studies of rabbit retina, we found SAP102 and Chapsyn110 selectively localized in …

Characterization Of Vesicular Monoamine Transporter 2 And Its Role In Parkinson's Disease Pathogenesis Using Drosophila, Antonio Joel Tito Jr., Sheng Zhang

Dissertations and Theses (Open Access)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the Substantia nigra pars compacta region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes induce …

Her4 Promotes A Stem-Like Phenotype In Osteosarcoma, Rocio K. Rivera-Valentin

Dissertations and Theses (Open Access)

Metastatic disease to the lungs is the primary cause of death for patients with pediatric osteosarcoma (OS). OS has a high degree of heterogeneity and genomic instability, making understanding the pathogenesis and drivers of metastasis of this disease challenging. In an effort to explain tumoral heterogeneity, the tumor initiating cell model (TIC) states that tumors are composed of cells that form the majority of the tumor and are terminally differentiated. This model however, attributes tumorigenesis, metastasis and chemoresistance to a distinct cell population with a stem-like phenotype that can be identified using selective markers. OS appears to follow this model …

Determination Of Thermal Dose Model Parameters Using Magnetic Resonance Imaging, Christopher James Maclellan

Dissertations and Theses (Open Access)

Magnetic Resonance Temperature Imaging (MRTI) is a powerful technique for noninvasively monitoring temperature during minimally invasive thermal therapy procedures. When coupled with thermal dose models, MRTI feedback provides the clinician with a real-time estimate of tissue damage by functioning as a surrogate for post-treatment verification imaging. This aids in maximizing the safety and efficacy of treatment by facilitating adaptive control of the damaged volume during therapy. The underlying thermal dose parameters are derived from laboratory experiments that do not necessarily reflect the surrogate imaging endpoints used for treatment verification. Thus, there is interest and opportunity in deriving model parameters from …

Organ Specific Vascular Response To Fibrosis Affects Breast Cancer Metastatic Organotropism, Eliot S. Fletcher, Eliot S. Fletcher

Dissertations and Theses (Open Access)

The solid tumor microenvironment, pre-metastatic niche, and fibrotic environment are known to have significant biochemical and biomechanical similarities to the fibrotic environment. All have significantly increased levels of factors such as TGFβ, HIF1α, TNFα, PDGF, VEGF, FGF, interleukins and other growth factors that are known to be pro-tumorigenic. Clinical and basic science research has shown that fibrosis presents an environment that favors tumor growth, such as hepatocellular carcinoma being commonly preceded by liver cirrhosis, or bleomycin induced lung fibrosis enhancing pulmonary metastasis in mouse models of breast cancer. In addition to the evidence indicating that fibrosis enhances primary tumor growth …

Long-Term Survival In Metastatic Melanoma Patients With Leptomeningeal Disease Treated With Intrathecal Interleukin-2, Isabella C. Glitza Oliva

Dissertations and Theses (Open Access)

BACKGROUND: Metastatic melanoma patients with leptomeningeal disease (LMD) have an extremely poor prognosis and a paucity of effective treatment options. We assessed the safety and efficacy of intrathecal interleukin-2 (IT IL-2) in metastatic melanoma patients with LMD.

METHODS: We reviewed the outcomes of 43 consecutive metastatic melanoma patients with LMD who were treated with IT IL-2 from 2006 to 2014 in a Compassionate Investigational New Drug Study. All patients had evidence of LMD based on cerebrospinal fluid (CSF) cytology, radiology, and/or surgical pathology. IL-2 at a dose of 1.2 mIU was administered intrathecally via Ommaya reservoir up to 5 times …

Nucleotide Excision Repair, Crosslink Repair And Transcriptional Function Of Xpa In Human Cells, Mandira Mananadhar

Dissertations and Theses (Open Access)

Nucleotide excision repair (NER) in mammalian cells includes xeroderma pigmentosum group A protein (XPA) as a core factor. XPA and other NER proteins have been detected previously at some active promoters, and NER deficiency is reported to decrease activated transcription of selected genes. To determine the global extent of XPA influence on transcription, we analyzed the human transcriptome by RNA sequencing. We first confirmed that XPA is confined to the cell nucleus even in the absence of external DNA damage, in contrast to previous reports that XPA is normally resident in the cytoplasm and is imported following DNA damage. We …

Microenvironment-Induced Pten Loss By Exosomal Microrna Primes Brain Metastasis Outgrowth, Lin Zhang

Dissertations and Theses (Open Access)

Development of life-threatening cancer metastases at distant organs requires disseminated tumor cells’ adaptation to and co-evolution with the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interplay between metastatic tumor cells and extrinsic signals at individual metastatic organ sites critically impacts the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumor cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that primary tumor cells with normal expression of PTEN, an important …

Investigation Of Radiation Injury In The Esophagus From Definitive Chemoradiation Therapy Using Novel Imaging Biomarkers, Joshua S. Niedzielski

Dissertations and Theses (Open Access)

Radiation injury in the esophagus occurs with high frequency from the treatment of non-small cell lung cancer (NSCLC). Radiation esophagitis is an acute normal tissue toxicity that negatively affects treatment efficacy by limiting dose and potentially interrupting radiation therapy. Clinical quantification of this toxicity is typically achieved by utilizing physician grading scales, assigning complication severity on an ordinal scale of symptom presentation and/or physician chosen interventions. These criteria are subjective in nature, both from the physician assigning the grade and the patient reporting the symptom. Furthermore, radiation therapy planning guidelines for the esophagus are derived from toxicity prediction models utilizing …

Novel Simulation To Avoid Bias In Measurement Of Hyperpolarized Pyruvate: Demonstrated In Phantom And In Vivo, Christopher M. Walker

Dissertations and Theses (Open Access)

Dynamic nuclear polarization creates a transient hyperpolarized nuclear state that can dramatically increase the signal detected by magnetic resonance imaging. This signal increase allows real-time spectroscopic imaging of specific metabolites in vivo by magnetic resonance. Real-time imaging of both the spatial and chemical fate of hyperpolarized metabolites is showing great promise to meaningfully benefit clinical care of cancer patients. Imaging of hyperpolarized agents will have a larger clinical impact if it can function as a quantitative modality upon which clinical decisions can be made. However, quantitative measurement of hyperpolarized agents is currently difficult due to the restrictions imposed by the …

Assessing The Potential Clinical Impact Of Variable Biological Effectiveness In Proton Radiotherapy, Christopher R. Peeler Ph.D.

Dissertations and Theses (Open Access)

It has long been known that proton radiotherapy has an increased biological effectiveness compared to traditional x-ray radiotherapy. This arises from the clustered nature of DNA damage produced by the energy deposition of protons along their tracks in medium. This effect is currently quantified in clinical settings by assigning protons a relative biological effectiveness (RBE) value of 1.1 corresponding to 10% increased effectiveness compared to photon radiation. Numerous studies have shown, however, that the RBE value of protons is variable and can deviate substantially from 1.1, but experimental data on RBE and clinical evidence of its variability remains limited.

The …

Datagauge: A Model-Driven Framework For Systematically Assessing The Quality Of Clinical Data For Secondary Use, Jose Franck Diazvasquez

Dissertations and Theses (Open Access)

There is growing interest in the reuse of clinical data for research and clinical healthcare quality improvement. However, direct analysis of clinical data sets can yield misleading results. Data Cleaning is often employed as a means to detect and fix data issues during analysis but this approach lacks of systematicity. Data Quality (DQ) assessments are a more thorough way of spotting threats to the validity of analytical results stemming from data repurposing. This is because DQ assessments aim to evaluate ‘fitness for purpose’. However, there is currently no systematic method to assess DQ for the secondary analysis of clinical data. …

The Power Of Reasoning: How Student Nurses Develop Confidence In Reasoning, Michael F. Brown

Dissertations and Theses (Open Access)

Background

Clinical Reasoning (CR) is the intellectual capacity to understand the value of patient data related to current knowledge, skills, and experiences within a dynamic domain of patient care with reflective analysis relating the new experience and understanding into new knowledge to be applied in future clinical situations. Poorly developed CR skills inhibit effective problem-solving abilities of nursing students producing levels of unexpected confusion and loss of confidence impeding their adaptability and effectiveness in dynamic healthcare environments. This study explored the effectiveness of human patient simulation (HPS) as an innovative method to facilitate the development of CR in undergraduate nursing …

Repetitive, Pre-Anesthetic Fasting And Malnutrition In A Pediatric Oncology Population Undergoing Radiation Therapy, Laura P. Santibáñez

Dissertations and Theses (Open Access)

Background: Pediatric oncology patients often experience nutritional status changes, particularly malnutrition, which may adversely affect their outcomes. Although the consequences of malnutrition are elucidated, its causes remain unclear. A possible cause of malnutrition in pediatric oncology patients is repetitive, pre-anesthetic fasting prior to non-invasive procedures and treatments, such as anesthesia-assisted radiation therapy (AART). This exploratory study investigated the association between repetitive, pre-anesthetic fasting and non-fasting days and malnutrition in pediatric oncology patients receiving AART.

Procedure: A retrospective cohort of 138 pediatric oncology patients (£ 10 years of age) who received any type of radiation therapy (RT) with or without anesthesia …

Treatment Recidivism In Adolescents With Mental Illness: A Focused Applied Medical Ethnography, Chukwudi C. Ekwemalor

Dissertations and Theses (Open Access)

Background

Treatment recidivism, described as frequent unplanned relapse readmissions, is a national problem predominant in adolescents with mental illness with significant socioeconomic consequences. Adolescents living with mental illness are a sub-culture of adolescence, the critical growth period of developmental and social transition from childhood to adulthood. The main triggers of treatment recidivism in this population are not fully understood from previous studies.

Purpose

The study purpose was to explore treatment recidivism with the following aims:

1. To illuminate treatment recidivism from the perspectives of recidivist adolescents with mental illness.

2. To describe the main factors that contribute to treatment recidivism …

Experiences Of Stress And Coping Over Time By Caregivers Of Stroke Survivors: A Mixed-Methods Approach, Fang Ye

Dissertations and Theses (Open Access)

Background/ Objectives: Caregivers of stroke survivors often experience physical and mental stress, decreased physical and emotional well-being, high burden of care, social isolation, and neglecting self-care. The majority of previous research studies have identified caregiver experiences during the first one-to-two years post stroke. Little is known about caregiver experiences beyond the first two years of the post- stroke recovery trajectory, indicating a need for longitudinal study of their experiences over time. Therefore, the objectives of this study were to 1) investigate caregiver experiences of stress and coping over 5-7 years post stroke using quantitative methods, and 2) explore through …

Role Of Stress And Social Resources On Biomarkers And Fatigue In Staff Nurses: A Biobehavioral Approach, Mona Cockerham

Dissertations and Theses (Open Access)

Purpose

Consecutive 12-hr workdays can contribute to increased stress and fatigue and negative biological responses in nurses, potentially compromising quality of patient care and safety. The primary purpose of this study was to assess changes in stress, fatigue, and biological responses (salivary cortisol and alpha-amylase) over three consecutive 12-hr workdays in acute care nurses and how stress and social resources function in predicting fatigue and biological responses.

Methods

In a prospective study, 81 acute care nurses completed questionnaires and provided saliva samples four times: pre-shifts and post-shifts of day 1 and day 3.

Results

Although stress and biological responses did …

Influences On Self-Care In Women With Heart Failure: A Pilot Study, Joy Corcione

Dissertations and Theses (Open Access)

Background: Heart Failure self-care becomes exceedingly difficult to perform as the disease progresses; therefore social support becomes important in facilitating heart failure self-care. Woman with heart failure represent a significant and growing vulnerable population. Women tend to have lower self-confidence in providing self-care, experience greater negative emotions, decreased social support, experience more adverse psychosocial factors affecting self-care and experience greater psychosocial adversity than do men. Self-care is vital in managing heart failure and social support greatly facilitates self-care behaviors.

Purpose: The purpose of this pilot study was to gain a deeper understanding about the sources of perceived social support and …

Mechanistic And Functional Characterization Of B And T Lymphocyte Attenuator (Btla) In Cd8 Tumor Infiltrating Lymphocytes, Krit Ritthipichai

Dissertations and Theses (Open Access)

This dissertation project focused on understanding the functional role of BTLA on CD8⁺ Tumor Infiltrating Lymphocytes (TIL) from metastatic melanoma patients. Clinical trials of adoptive T-cell therapy (ACT) using autologous ex vivo expanded TIL have demonstrated the great potential of this immunotherapy with an overall clinical response rate 40-50% for stage IV metastatic melanoma patients. We have investigated a number of biomarkers in both the infused TIL and the tumor microenvironment for their association with clinical response. Surprisingly, a subset of CD8⁺ TIL expressing the co-inhibitory molecule BTLA (B-and-T lymphocyte attenuator) was highly associated with clinical response, while …

Identifying Treatment Planning System Errors In Iroc-Houston Head And Neck Phantom Irradiations, James Kerns

Dissertations and Theses (Open Access)

Treatment Planning System (TPS) errors can affect large numbers of cancer patients receiving radiation therapy. Using an independent recalculation system, the Imaging and Radiation Oncology Core-Houston (IROC-H) can identify institutions that have not sufficiently modelled their linear accelerators in their TPS model. Linear accelerator point measurement data from IROC-H’s site visits was aggregated and analyzed from over 30 linear accelerator models. Dosimetrically similar models were combined to create “classes”. The class data was used to construct customized beam models in an independent treatment dose verification system (TVS). Approximately 200 head and neck phantom plans from 2012 to 2015 were recalculated …

Bias And Variability In Image-Based Volumetric Yttrium-90 Dosimetry, Wendy Siman

Dissertations and Theses (Open Access)

90Y-microsphere therapy has been widely accepted as a treatment option for both primary and metastatic liver tumors where the patients are ineligible for surgical resection and external beam radiation therapy. The prognosis of untreated patient having liver cancer is very poor with life expectancy less than a year at advance stage. Hence the ability to predict treatment efficacy right after the treatment from post-therapy imaging will help personalize treatment strategies and achieve better outcome. Such prediction can be modeled from correlation of dose and tumor response metrics.

It has been shown that local dose deposition method can generate dose map …

Circumventing Cisplatin Resistance In Ovarian Cancers Through Reactivation Of P53 By Non-Cross-Resistant Platinum Analogs, Michelle Martinez-Rivera

Dissertations and Theses (Open Access)

Abstract

CIRCUMVENTING CISPLATIN RESISTANCE IN OVARIAN CANCERS THROUGH REACTIVATION OF P53 BY NON-CROSS-RESISTANT PLATINUM ANALOGS

Michelle Martinez-Rivera, B.S.

Advisory Professor: Zahid H. Siddik, Ph.D.

Cisplatin (cis-Pt), an anticancer platinum (Pt) drug, is used widely in the treatment of several malignancies, such as ovarian cancer. This Pt compound induces DNA damage, which results in p53 activation through post-translational modifications, mainly phosphorylation, culminating in execution of programmed cell-death. However, despite initial therapeutic response to cis-Pt, clinical resistance to this drug emerges leading to disease progression. Pt-resistance phenotypes have been associated with dysfunction in the p53 signaling pathway. Therefore, an effort to understand …

Determining Mechanisms Of Response To Polo-Like Kinase 1 Inhibition In Non-Small Cell Lung Cancer, Ruchitha Goonatilake

Dissertations and Theses (Open Access)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. The discovery of genetic alterations in some patients (~15%) has made it possible to use targeted therapies without the use of chemotherapy. To identify potential therapeutic targets in NSCLC, we systematically evaluated two cancer cell line databases with sensitivity data for a broad range of drugs. We identified polo-like kinase 1 (Plk1) as the most promising target for further investigation based on a subset of sensitive cell lines and inhibitors that were in advanced clinical development. To identify potential biomarkers of response and mechanisms of Plk1 inhibitor-induced …

Regulation Of Breast Cancer Initiation And Progression By 14-3-3zeta, Chia-Chi Chang

Dissertations and Theses (Open Access)

14-3-3ζ is a ubiquitously expressed family member of proteins that have been implicated to have oncogenic potential through its interactions and involvement in cancer initiation and progression. 14-3-3ζ belongs to the highly conserved 14-3-3ζ protein family and modulates numerous pathways in cancer. Overexpression of 14-3-3ζ is an early event, occurs in more than 40% of human breast cancer cases, and is associated with disease recurrence and poor prognosis. Metabolic reprogramming is a hallmark of cancer. Cancer cells elevate aerobic glycolysis to produce metabolic intermediates and reducing equivalents, thereby facilitating cellular adaptation to the adverse environment and sustaining fast proliferation. Interestingly, …

A Phase I Dose-Escalation Study Of The Braf Inhibitor Vemurafenib In Combination With The Mtor Inhibitor Everolimus In Subjects With Advanced Cancer, Javier Munoz

Dissertations and Theses (Open Access)

Vemurafenib has been approved in the United States for the treatment of relapsed or refractory BRAF mutation positive malignant melanoma and is being investigated in various other malignancies. The RAS/RAF/MEK/ERK (MAPK) pathway is critical to cell proliferation in many human cancers. The mTOR inhibitors are well known to exert profound anticancer effects across malignancies through inhibition of the PTEN/PI3K/AKT/mTOR (mTOR) pathway. We hypothesize that the toxicity profile of the combination of vemurafenib and everolimus will be well tolerated. The primary objective is to find the maximum tolerated dose (MTD) and the toxicity of the combination of vemurafenib and everolimus following …

The Impact Of Cortical State On Neural Coding And Behavior, Charles Beaman

Dissertations and Theses (Open Access)

The brain is never truly silent – up to 80% of its energy budget is expended during ongoing activity in the absence of sensory input. Previous research has shown that sensory neurons are not exclusively influenced by external stimuli but rather reflect interactions between sensory inputs and the ongoing activity of the brain. Yet, whether fluctuations in the state of cortical networks influence sensory coding in neural circuits and the behavior of the animal are unknown. To shed light on this issue, we conducted multi-unit electrophysiology experiments in visual areas V1 and V4 of behaving monkeys. First, we studied the …

Development Of An In Silico Kir Genotyping Algorithm And Its Application To Population And Cancer Immunogenetic Analyses, Howard Rosoff

Dissertations and Theses (Open Access)

Gene content determination and variant calling in the complex KIR genomic region are useful for immune system function analysis, pathogenesis and disease risk factor elucidation, immunotherapy development, evolutionary investigations, and human migration modeling. Sequence-specific oligonucleotide and sequence-specific primer PCR methods are the de facto standards for KIR presence/absence identification, but the current platforms are unsuitable for SNP calling, impractical for KIR typing large cohorts of DNA samples, and inapplicable for typing repositories in which sequence data, but not cells or cell analytes, are available. Alternative typing methods, such as in silico sequence-based typing, can address the problems associated with amplicon-based …