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Sine Oculis Homeobox Homolog 1 (Six1) Plays A Critical Role In The Progression Of Pulmonary Fibrosis., Cory Wilson

Dissertations and Theses (Open Access)

Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia with a median survival time of 2-4 years after diagnosis. The alarming mortality rate is due to the lack of effective treatments. IPF is a chronic disease that is characterized by alveolar destruction due to increasing extracellular matrix deposition that leads to poor lung compliance, impaired gas exchange, and ultimately respiratory failure. Repetitive alveolar epithelial injury is a central process to the underlying pathology with injury to the type II alveolar epithelial cells (AT2) specifically being a key player in the pathogenesis of IPF. Recent studies have shown that …

Investigation Of The Functional Impact Of Anti-Pd-1 On Tumor-Infiltrating Lymphocytes (Til) And Mapping Of Tumor Genomic Features Relevant For Response To Til Therapy, Caitlin Creasy

Dissertations and Theses (Open Access)

With the growing use of both cellular and antibody-based immunotherapies, it has become more important to uncover biomarkers to predict patient response to therapy and ideally aid in patient selection for specific therapeutics, thereby enhancing treatment outcome. At MD Anderson, we have a 43% response rate to therapy when treating metastatic melanoma patients with adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL), but it is unknown what makes the other 57% of patients not respond to therapy. It is further unknown how particularly early doses of checkpoint inhibitors, like anti-PD-1, attribute to TIL functionality, adding another confounding factor in determining …

Elucidating The Roles Of Il-15 In The Tumor Microenvironment, Rosa Maria Santana Carrero

Dissertations and Theses (Open Access)

ELUCIDATING THE ROLES OF IL-15 IN THE TUMOR MICROENVIRONMENT

Rosa M. Santana Carrero, B.S.

Advisory Professors: Shao-Cong Sun, Ph.D. & Kimberly S. Schluns, Ph.D.

Interleukin-15 (IL-15) is a factor that promotes activation, proliferation, cytotoxicity, and survival of CD8 T cells and NK cells, and has been shown to have anti-tumor effects. Moreover, loss of IL-15 expression in human colorectal tumors correlates with increased risk of relapse, diminished survival, decreased density and proliferation of T cells. All together these findings suggest that IL-15 expressed locally in the tumor microenvironment (TME) is an important mediator of anti-tumor responses by tumor infiltrating lymphocytes …

The Genome-Wide Roles Of The Lung Lineage Transcription Factor Nkx2-1 In The Regulation Of Opposing Cell Fates In Vivo, Danielle Renae Little

Dissertations and Theses (Open Access)

Lineage transcription factors mark, promote, and maintain multiple distinct cell types originating from a common progenitor. Despite their essential role, how such factors function and bind genome wide to orchestrate the epigenetic changes necessary to form and maintain these identities in vivo is unclear. One lineage transcription factor NK Homeobox 2-1 (NKX2-1) is expressed throughout the lung epithelium during development and was thought to be lost in the extraordinarily thin cell type required for gas exchange– the alveolar type 1 (AT1) cell. Complementing precise genetic knockouts with cell type-specific ChIP-seq, ATAC-seq, and scRNA-seq, our study shows that AT1 and AT2 …

The Role Of Daam1 In Kidney Development, Vanja Krneta-Stankic

Dissertations and Theses (Open Access)

Kidneys, like most organs in our bodies, consist of a network of epithelial tubules. Kidney tubules are called nephrons, and their morphology is important for kidney function. Nephrons develop from mesodermally derived aggregates of progenitor cells. The nephric progenitors organize into nephric tubules lined with hair-like sensory projections called cilia. Many diseases of the kidney are characterized by abnormal nephron morphology with current treatment aimed at symptom control. To understand the mechanisms underlying kidney diseases and achieve the development of novel therapies, a better understanding of how nephrons develop is needed. Although the actin cytoskeleton is critical for cell behaviors …

Micrornas Associated With Melanoma Inflammation And Response To Pd-1 Inhibition, Robert Szczepaniak Sloane

Dissertations and Theses (Open Access)

Melanoma is an aggressive malignancy of melanocytes with historically poor outcomes. Melanoma therapy has improved markedly over the past decade with advances in molecularly targeted agents and immunotherapies. Immune checkpoint inhibitors achieve T-cell mediated anti-tumor efficacy by blocking engagement of inhibitory checkpoints on T-cells to overcome immunosuppressive signals from tumor cells and the broader microenvironment. Despite these advances, there are a significant proportion of patients who do not benefit from existing immunotherapy strategies making it a priority to identify and target the mechanisms that confer resistance to therapy. We demonstrate that microRNAs are accurate markers of microenvironment composition with prognostic …

Nuclear-Targeted Gold Nanoparticles Enhance The Effects Of Radiation Therapy With And Without Liposomal Delivery, Maureen Aliru

Dissertations and Theses (Open Access)

Less that 10% of pancreatic cancer patients are eligible for curative resection, and clinical trials evaluating chemoradiation in locally advanced patients with unresectable disease have been largely disappointing. New and creative therapeutic approaches are needed to address the unment need for treatment options. The objective of this thesis is to advance radiosensitization of treatment-resistant densely desmoplastic pancreatic cancer using nanoparticles to surmount biological barriers to effective particle distribution for DNA-targeting.

Clinical translation of radiosensitizing nanoparticles has stalled owing to technical challenges. Current strategies to use AuNPs for radiosensitization require large quantities of gold, kilovoltage x-rays, immediate irradiation after intravenous administration, …

The Role Of Daam1 In Kidney Development, Vanja Krneta-Stankic

Dissertations and Theses (Open Access)

Kidneys, like most organs in our bodies, consist of a network of epithelial tubules. Kidney tubules are called nephrons, and their morphology is important for kidney function. Nephrons develop from mesodermally derived aggregates of progenitor cells. The nephric progenitors organize into nephric tubules lined with hair-like sensory projections called cilia. Many diseases of the kidney are characterized by abnormal nephron morphology with current treatment aimed at symptom control. To understand the mechanisms underlying kidney diseases and achieve the development of novel therapies, a better understanding of how nephrons develop is needed. Although the actin cytoskeleton is critical for cell behaviors …

Packaging And Secretion Of Airway Mucins, Oanh Ngoc Hoang

Dissertations and Theses (Open Access)

In the conducting airways of the lungs, the mobile mucus gel layer sits on top of the airway epithelium, and through ciliary beating it is propelled up the trachea into the pharynx where it is swallowed and cleared. This gel layer is composed of secreted mucins that become hydrated once reaching the airway lumen. Mucins are secreted at a baseline rate and at a stimulated rate, dependent on the amount of agonist. Baseline secretion is responsible for steady clearance of inhaled particles and pathogens. Stimulated secretion is thought to play a role in trapping helminths though mucus occlusion in small …

Great Expectations: Phosph(On)Ate Prodrugs In Drug Design—Opportunities And Limitations, Victoria Yan

Dissertations and Theses (Open Access)

Phosphate and phosphonates are chemical moieties with historical precedence in anticancer and antiviral nucleotide analogues. Synchronous to modern efforts identifying novel therapeutic targets in cancer, such chemical moieties are being investigated in the design of novel inhibitors with antineoplastic potential. A central challenge to the delivery of phosph(on)ate-containing drugs is their anionic character at physiological pH, which portends poor membrane permeability. This limitation has been successfully overcome through the use of prodrugs. When attached to the phosph(on)ate moiety, prodrugs mask the negative charge and easily enable cell permeability. Upon cellular entry, the promoieties are enzymatically or environmentally cleaved to unveil …

Qki-Mediated Cholesterol Biosynthesis In Eye Lens And Myelin Of The Central Nervous System, Seula Shin, Seula Shin

Dissertations and Theses (Open Access)

Cells obtain cholesterol in two ways, de novo biosynthesis and uptake from circulation. While most tissues utilize both sources, eye lens and brain depend extensively on cholesterol biosynthesis due to the limited supply from circulation. Lens cell membrane consists of highest portion of cholesterol. Brain is the most cholesterol-rich organ, which accounts for 23% of total cholesterol. Genetic mutations of cholesterol biosynthesis enzymes in humans and animal models present cataracts and hypomyelinating disorders linked to neurological impairment. Yet, it remains unclear how gene expression of cholesterol biosynthesis is regulated in lens and brain. Therefore, studying cholesterol biosynthesis in both tissues …

Decoding The Evolutionary Response To Prostate Cancer Therapy Using Plasma Genome Sequencing, Naveen Ramesh

Dissertations and Theses (Open Access)

Investigating genome evolution in response to therapy is difficult in human tissue samples due to the difficulty in accessing metastatic tumor sites and logistical challenges of collecting longitudinal samples. To overcome these issues, we developed an unbiased whole-genome plasma DNA sequencing approach called PEGASUS that concurrently measures genomic copy number and exome mutations from archival cryostored plasma samples. This approach was applied to study longitudinal blood plasma samples from prostate cancer patients. A molecular characterization of archival plasma DNA from 233 patients and genomic profiling of 101 patients identified clinical correlations of aneuploid plasma DNA profiles with poor survival, increased …

Ionic Mechanism Of Lysosomal Function And Cell Metabolism, Jian Xiong

Dissertations and Theses (Open Access)

Two Pore Channels (TPCs) are endolysosomal ion channels that are permeable to sodium and calcium. Defects in TPCs have been implicated to impair vesicle trafficking, autophagy and cell metabolism control; however, the detailed mechanism remains largely unknown. In this study, I show that TPCs are critical for appropriate cargo delivery to the lysosomes and deletion of either TPC1 or TPC2 leads to delayed clearance of autophagosomes, resulting in enlarged lysosomes and accumulated contents inside the lysosomes. Cells with both TPC deleted also exhibit 50% reduction in lysosomal amino acids under normal culture conditions, leading to reduced homeostatic mTORC1 activation.

Glutamine …

Fibroblast Heterogeneity In Pancreatic Cancer Immunity, Josephine Darpolor

Dissertations and Theses (Open Access)

Fibroblasts are a unique cell type defined by their mesenchymal phenotype and exclusion from epithelial, immune, and endothelial cell subsets. Although well studied in wound healing, cancer associated fibroblasts (CAFs) are incredibly heterogeneous, leading to contradictions as to the roles CAFs play in the tumor microenvironment (TME). CAFs were thought to be a barrier to treatment of pancreatic ductal adenocarcinoma (PDAC). However, general stromal targeting strategies have largely failed in the clinic likely due to the heterogeneity of CAFs in the TME. Therefore, our groups and others have worked to unravel the heterogeneity of CAFs in PDAC. In the works …

Investigation Of Proliferation Suppressors In Genetic Fitness Screens, Walter Frank Lenoir Iv

Dissertations and Theses (Open Access)

Innovation of CRISPR gene-editing technology has provided scientists genome manipulation tools that allowed rapid advancement of scientific capabilities and thus improved our ability to systematically study mammalian genetic functional profiles. Genome-wide CRISPR knockout screens conducted in collections of human cell lines can knock out genes at multiple loci, and have provided new insights into functional roles for independent genes. This method has launched massive efforts in looking across genetic backgrounds for context specific genetic vulnerabilities within cancer. Much of the research effort thus far has been spent on optimizing phenotype distinctions between essential, genes required for cell fitness, and non-essential, …

Combined Inhibition Of Ddr1 And Cdk4/6 Induces Synergistic Effects In Er-Positive, Her2-Negative Breast Cancer With Pik3ca/Akt1 Mutations, Maryam Shariati, Maryam Shariati

Dissertations and Theses (Open Access)

COMBINED INHIBITION OF DDR1 AND CDK4/6 INDUCES SYNERGISTIC EFFECTS IN ER-POSITIVE, HER2-NEGATIVE BREAST CANCER WITH PIK3CA/AKT1 MUTATIONS

Maryam Shariati, M.S. Advisory Professor: Funda Meric-Bernstam, M.D.

Molecular alterations in the phosphatidylinositol 3‑kinase (PI3K)/ serine/threonine protein kinase B (AKT) signaling pathway occur frequently in estrogen receptor–positive (ER-positive) breast tumors. Patients with ER-positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer are often treated with cyclin-dependent kinase (CDK4/6) inhibitors such as palbociclib in combination with endocrine therapy. Although this is a very effective regimen, disease progression ultimately occurs in most patients. Further, the modulators of palbociclib sensitivity remain unclear. The purpose …

Qki-Mediated Cholesterol Biosynthesis In Eye Lens And Myelin Of The Central Nervous System, Seula Shin, Seula Shin

Dissertations and Theses (Open Access)

Cells obtain cholesterol in two ways, de novo biosynthesis and uptake from circulation. While most tissues utilize both sources, eye lens and brain depend extensively on cholesterol biosynthesis due to the limited supply from circulation. Lens cell membrane consists of highest portion of cholesterol. Brain is the most cholesterol-rich organ, which accounts for 23% of total cholesterol. Genetic mutations of cholesterol biosynthesis enzymes in humans and animal models present cataracts and hypomyelinating disorders linked to neurological impairment. Yet, it remains unclear how gene expression of cholesterol biosynthesis is regulated in lens and brain. Therefore, studying cholesterol biosynthesis in both tissues …

Howard's "Showing: What Pregnancy Tells Us About Being Human" (Book Review), Kyle D. Diroberts

The Christian Librarian

No abstract provided.

Detecting Mens Rea In The Brain, Owen D. Jones, Read Montague, Gideon Yaffe

Vanderbilt Law School Faculty Publications

What if the widely used Model Penal Code (MPC) assumes a distinction between mental states that doesn’t actually exist? The MPC assumes, for instance, that there is a real distinction in real people between the mental states it defines as “knowing” and “reckless.” But is there?

If there are such psychological differences, there must also be brain differences. Consequently, the moral legitimacy of the Model Penal Code’s taxonomy of culpable mental states – which punishes those in defined mental states differently – depends on whether those mental states actually correspond to different brain states in the way the MPC categorization …

A Case For Zoning, Christopher Serkin

Vanderbilt Law School Faculty Publications

Due to a remarkable convergence of criticisms from both the right and the left, zoning is under more sustained attack than at any time in the last seventy-five years. A consensus is building that zoning is what ails America. Simultaneously, the traditional justifications for zoning like separating incompatible uses, have become increasingly anachronistic in an age of mixed-use development and a desire for vibrant, dynamic places. This Article offers an updated defense of zoning, and in particular density regulations. Today, local governments deploy zon- ing not primarily to keep industry (or apartment buildings) out of residential neighborhoods, but to preserve …

Designing Law To Enable Adaptive Governance Of Modern Wicked Problems, J. B. Ruhl, Barbara A. Cosens A. Cosens, Niko Soininen, Lance Gunderson

Vanderbilt Law School Faculty Publications

This Article contributes to the development of adaptive governance theory by articulating and situating the role of formal law and government as the facilitator, but not central controller, of adaptive governance. To advance the understanding of adaptive governance, we argue that it can be understood in the broader context of scholarship covering the observed emergence of new governance, the efforts to develop theoretical understandings through decentered theory, and the refinement of constitutional understanding through democratic experimentalism. Synthesis of these three themes in turn informs the role of law and government in working with emergent governance responses to complexity to manage …

Introduction: Governing Wicked Problems, J. B. Ruhl, J. Salzman

Vanderbilt Law School Faculty Publications

“Wicked problems.” It just says it all. Persistent social problems—poverty, food insecurity, climate change, drug addiction, pollution, and the list goes on—seem aptly condemned as wicked. But what makes them wicked, and what are we to do about them? The concept of wicked problems as something more than a generic description has its origins in the late 1960s. Professor Horst Rittel of the University of California, Berkeley, Architecture Department posed the term in a seminar to describe “that class of social system problems which are ill-formulated, where the information is confusing, where there are many clients and decision makers with …

An Integrative Approach Concerning Radiological Protection Of The Environment: Plant Influence On Biogeochemistry And Transport, Plant Uptake, And Non-Human Biota Dosimetry For Select Radionuclides, Dawn Angel Montgomery

All Dissertations

The fields of radioecology and environmental radiation protection encompass a multitude of interdisciplinary specialties relating to the use, transport, and effects associated with radioactive substances in the environment, which often must inform each other in an integrated and iterative manner. As these fields have begun to consider a more holistic approach to environmental radiation protection, there is not only a need to evaluate fate and transport of radionuclides in the environment, but also a need to consider the dose and impacts to non-human biota residing in contaminated (or potentially contaminated) areas. Thus, the overall objective of this work was to …

High Sulfur-Content Materials From Free Fatty Acids, Ashlyn Dennis Smith

All Dissertations

The consumption of traditional plastics continues to climb to meet increasing consumer needs, despite growing awareness that these petrochemical-derived materials are detrimental to the environment. Sustainability scientists are faced with the task of trying to replace some of these materials with sustainably sourced compounds, leading the industry away from fossil fuel-derived monomers. Fatty acid derivatives have proven to be versatile sources for monomers. As constituents of several high-volume and low value waste streams and, given their origins in plant and animal sources, fatty acid derivatives are an ideal starting material. The presence of alcohol, carboxylic acid and olefin functional groups …

Reading With Daddy: Parent Gender, Joint Book Reading, And Emergent Literacy Growth, Julia Kate Bentley

All Dissertations

For decades, educational researchers have reported joint book reading with caregivers promotes children’s emergent literacy development (Bus et al., 1995; Demir-Lira et al., 2019; NELP, 2008; Pelligrini et al., 1990). However, the bulk of this research has been conducted with mothers (Bingham, 2007; Bojczyk, 2016; Roberts et al., 2005). Mothers have been the focus of such research because, historically, the primary responsibility for caring for young children was placed on them (Fagot et al., 2012). Recent societal changes have resulted in fathers taking on more childcare roles (Banchefsky & Park, 2016). Yet, their contributions are rarely noted in literacy research. …

Understanding Corrosion In Modular Acetabular Tapers: Retrieval Analysis, In Vitro Testing And Cell-Material Interactions, Aarti Shenoy

All Dissertations

Modular metal-on-metal acetabular tapers comprise two overarching design categories: a titanium shell and a metal/ceramic/polymer liner pair, or a dual-mobility articulation design with an added polymeric insert containing a freely rotating femoral head. Both designs often include a metal-on-metal (MoM) or modular dual-mobility (MDM) shell-liner interfaces, which is prone to corrosion and associated local effects. The goals of this dissertation were to document and distinguish between corrosion modes at this modular junction, to design in vitro test methods to characterize mechanical modes, and to examine their interactions with macrophages, which represent a critical part of the immune response. Through retrieval …

Novel Low Dimensional Sensors For Rapid Disease Diagnosis And Efficient Biomolecular Detection, Bipin Sharma

All Dissertations

Nanomaterials have been used in diverse biosensing applications over the years for their unique properties compared to their ‘bulk’ counterparts. The quantum effects observed in nanomaterials of different dimensions have been exploited, in particular, for fluorescence sensing using surface plasmons. The present work is directed towards the understanding of these effects and the physics behind such plasmons and its application.

In the first chapter (Chapter 1), a succinct introduction to quantum confinement and fluorescence biosensors has been presented, followed by a brief overview of the applications of nanomaterials in biosensing. Chapter 2 focuses on the various analytical and characterization techniques …

Investigating The Extent Of The Problem: Injury Epidemiology In Cross-Country And Track & Field, Christopher Lee Hopkins

All Dissertations

This dissertation aims to explore the problem of injuries in high school and collegiate cross-country and track and field by systematically reviewing and analyzing data from previous epidemiologic studies, comparing injury rates from a large dataset of collegiate track and field injuries, examining the psychology of injury reporting among adolescent runners, and identifying directions for future research in the field of sports injury epidemiology. Cross-country and track and field are popular modes of physical activity for many adolescents, but as with many sports, they have inherent injury risks that may lead participants to quit or increase their risk of conditions …

Comparison Of Papillary Renal Cell Carcinoma Type 1 And Type 2: A Secondary Data Analysis Using The Cancer Genome Atlas, Melissa Paquin

All Dissertations

The first chapter in this manuscript serves as an overview of the background, significance, and theological framework of this study, comparison of papillary renal cell carcinoma type 1 and type 2: a secondary analysis. The body of this work focuses on the topics of the current knowledge, genetic variations and syndromes, demographics, increased risk factors, and pathways associated with type 1 and type 2 papillary renal cell carcinoma.

The second chapter is a review of the literature to discuss the current working knowledge on papillary renal cell carcinoma including genetic underpinnings, disease management and histological subtyping. This chapter was designed …

Simulated And Applied Precision Feeding System Of High And Low Forage Diets With Different Fat Sources And Sequences Of Dietary Fat Concentration In In-Vitro And In-Vivo Studies, Saad Ali M. Hussein

All Dissertations

Controlling dry matter intake (DMI) is one strategy to meet the animal’s requirements while reducing feed costs and increasing feed efficiency. Controlling intake through precision-feeding provides a more nutrient-dense diet, allowing an increase in energy and nutrient utilization efficiency while decreasing nutrient loss. The literature about precision feeding has provided information regarding optimal N intake and different dietary fiber proportions, but more information needs to be addressed. This is one of the first attempts to further our knowledge through the use of fat inclusion. In the present dissertation, a total of 4 in-vitro and in-vivo experiments were conducted. Simulated and …