Medicine and Health Sciences Commons^™

Feature Selection From Clinical Surveys Using Semantic Textual Similarity, Benjamin Warner

McKelvey School of Engineering Theses & Dissertations

Survey data collected from human subjects can contain a high number of features while having a comparatively low quantity of examples. Machine learning models that attempt to predict outcomes from survey data under these conditions can overfit and result in poor generalizability. One remedy to this issue is feature selection, which attempts to select an optimal subset of features to learn upon. A relatively unexplored source of information in the feature selection process is the usage of textual names of features, which may be semantically indicative of which features are relevant to a target outcome. The relationships between feature names …

Synthesis, Radiolabeling And Evaluation Of A Suite Of Tracers With 44Sc For Detecting Extracellular Dna, Zhiyao Li

McKelvey School of Engineering Theses & Dissertations

Neutrophil extracellular traps involve the rapid translocation of DNA to the outside of the cell under certain stimuli. This structure forms a fibrous network that is able to limit the spread of pathogens and to kill microorganisms. It has also been shown to be present in various pathological processes such as inflammation, autoimmune diseases, and cancer metastasis. Currently, the formation process of NETs in vivo is being extensively studied. However noninvasive detection and quantitation has yet to be achieved. A class of PET tracers are described here that consists of a DNA dye as the backbone that is labeled with …

Functional Analysis Of Recurrent Non-Coding Variants In Human Melanoma, Paula Maria Godoy

Arts & Sciences Electronic Theses and Dissertations

Worldwide incidence rates of cutaneous melanoma are increasing, and while survival rates for early stages of melanoma are high, rates drop precipitously for metastatic melanomas or those that are unable to be targeted by currently available treatments. As melanomas have a propensity to quickly metastasize, understanding the contributions of melanoma initiation remains critical for early intervention. Onset of melanoma is characterized most by mutations that stimulate mitogen-activated protein kinase (MAPK) signaling, disrupt DNA damage checkpoints, and trigger mechanisms to bypass senescence through elongation of telomeres. Additionally, in zebrafish melanoma models, the earliest cluster of melanoma-initiating cells activate expression of a …

Tissue Resident Macrophages Drive Fibrosis During Pancreas Inflammatory Injury And Pancreatic Ductal Adenocarcinoma, John Baer

Arts & Sciences Electronic Theses and Dissertations

The immune system, and especially macrophages, are central in responding to infections, as well as providing a wide array of functions in other pathologies, especially in responding to inflammation. It is established that macrophages will accumulate within tissues during inflammation, many times secreting cytokines and chemokines central to the inflammatory response. This is particularly true during pancreatitis, or inflammation of the pancreas, where it has been shown that macrophages and monocytes accumulate in the pancreas to have various roles in further promoting inflammation. It is not well established, however, whether there are divergent roles for the distinct macrophage subsets that …

Evaluation And Clinical Implementation Of A Dual-Energy Ct Stopping-Power Ratio Mapping Technique For Proton-Therapy Treatment Planning, Maria Jose Medrano Matamoros

McKelvey School of Engineering Theses & Dissertations

Proton radiotherapy has the potential to treat tumors with better conformal dose distribution than competing modalities when the rapid dose falloff at the end of the proton-beam range is correctly aligned to the edge of the clinical target volume (CTV). However, its clinical potential is dependent on the accurate localization of the Bragg-peak position from predicted stopping-power ratio maps. The method that is most commonly used in today’s clinical practice for predicting stopping-power ratio (SPR) consists of a stoichiometric calibrationtechnique based on single-energy CT (SECT) for direct estimation of patient-specific SPR distribution from vendor-reconstructed Hounsfield Unit (HU) images. Unfortunately, this …

Cancer Survivors’ Participation In Meaningful Life Activities, A Mixed Methods Approach, Allison Jean L'Hotta

Arts & Sciences Electronic Theses and Dissertations

A new cancer diagnosis dramatically impacts an individual’s daily life. While data describing cancer-related symptoms (e.g. fatigue) and impairments (e.g. weakness) are abundant, there remains limited data detailing the impact of cancer on survivors’ daily life participation. Advancement in participation research is challenged by the lack of a universally accepted definition of participation and a standard approach to measurement. Previous research evaluating participation among cancer survivors is limited by small sample sizes, cross-sectional data including only a single disease group, and assessing participation exclusively among individuals who have completed active cancer treatment. The purpose of the presented dissertation was to …

Macrophage-Based Immunotherapies For The Treatment Of Multiple Myeloma, Jennifer Sun

McKelvey School of Engineering Theses & Dissertations

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematologic malignancy in the world. Despite an array of novel therapy approvals, MM remains to be incurable. Most patients ultimately relapse and become refractory to previous treatments, which lowers the median survival to only 5–15 months. Recently, cancer immunotherapy has gained attention as a promising approach to enhance the body’s natural immune responses to fight cancer. Currently, immunotherapies in MM have largely focused on engaging the T cells; however, many are challenged by insufficient responses, high cost, and/or extensive adverse …

Nanoparticle T Cell Engagers As A Modular Platform For Cancer Immunotherapy, Kinan Alhallak

McKelvey School of Engineering Theses & Dissertations

Immunotherapy has advanced significantly in recent years due to its promising clinical outcomes in a variety of malignancies and holds great promise in becoming the “cure” for cancer. Cancer immunotherapy is the treatment that stimulates a person’s own immune system to recognize, target, and eliminate cancer cells. As the field progresses with emerging and novel strategies, the ability to manipulate the immune system while mitigating toxicities is the goal for clinical translation. To control for both efficacy and safety, biomaterials have been incorporated into immunotherapies to achieve tissue- and/or cell-specific immunomodulation, overcome immunosuppression, and address tumor microenvironment heterogeneity.T cell-based immunotherapy, …

Investigation Of Ifnγ-Induced Control Of Intracellular Pathogens, Michael Mcallaster

Arts & Sciences Electronic Theses and Dissertations

Genes required for the lysosomal degradation pathway of autophagy play key roles in topologically distinct cellular processes with significant physiologic importance. One of the first-described of these ATG gene-dependent processes is the requirement for a subset of ATG genes in interferon-γ (IFNγ)-induced inhibition of norovirus and Toxoplasma gondii replication. In this dissertation we identified novel components that are required for or that negatively regulate this immune mechanism. Enzymes involved in the conjugation of UFM1 to target proteins including UFC1 and UBA5, negatively regulated IFNγ-induced inhibition of norovirus replication via effects of Ern1. We identified and confirmed that IFNγ-induced inhibition of …

The Immunoregulation Of Autoimmune Diabetes, Hao Hu

Arts & Sciences Electronic Theses and Dissertations

How autoimmune diseases are regulated is a long-term research topic in the autoimmunity field. We use autoimmune diabetes as a model to study this. Autoimmune diabetes is a T cell-dependent autoimmune syndrome. The functions of T cells are regulated during their development and activation. Developmentally, T cells will undergo a stringent thymic selection: a process that self-reactive T cells are tolerized to become thymic derived Tregs or can be deleted by apoptosis based on binding affinity and avidity between the TCRs and self-peptide:MHC complexes. After T cells mature, they can also be tolerized in the periphery in many other ways, …

Exploring Β-Cell Function And Heterogeneity In Obese Sm/J Mice, Mario Alejandro Miranda

Arts & Sciences Electronic Theses and Dissertations

Pancreatic β-cells perform glucose-stimulated insulin secretion, a process required to maintain systemic glucose homeostasis. Obesity promotes glycemic and inflammatory stress, causing β-cell death and dysfunction, resulting in diabetes. Efforts to improve β-cell function in obesity have been hampered by observations that β-cells are highly heterogeneous, varying in morphology, function, and gene expression. There is great need to understand the breadth of β-cell heterogeneity in health and obesity to improve diabetic therapies.High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study β-cell adaptation. Here, we show that as they resolve hyperglycemia, obese SM/J …

Metabolic Control And Immune Barriers Of Hematopoietic Stem Cells, Hannah Pizzato

Arts & Sciences Electronic Theses and Dissertations

Hematopoietic stem cells (HSCs) have the unique ability to self-renew for life, to differentiate into mature blood lineages, and to readily engraft upon intravenous transplantation. As such, they are the only types of stem cells in routine clinical use. Understanding HSCs and hematopoietic development can provide many lessons for other types of stem cells as they near clinical utility. Through bone marrow transplantation, it was discovered that cells exist with regenerative potential. This led to the search to purify these cells and to determine the function of other hematopoietic cells. By isolating and transplanting cells expressing different combinations of surface …

Exploring The Intrinsic And Extrinsic Factors That Regulate Breast Cancer Cell Dormancy, Qihao Ren

Arts & Sciences Electronic Theses and Dissertations

Breast cancer can recur in patients months to decades after initial diagnosis and treatment. There is mounting evidence that dormant breast disseminated tumor cells (DTCs) exist in distant organs, whose reactivation results in cancer recurrence. However, the mechanisms that control tumor cell dormancy remain poorly understood, making it difficult to predict which patients will recur and develop cancer recurrence. Unfortunately, the extreme rarity of dormant DTCs has been the major obstacle to their study. To overcome this challenge, we developed an efficient system to isolate and study rare dormant tumor cells from metastatic organs. Using this system and single cell …

Discovery Of Sex Differences In Response To P53 Loss And Gain-Of-Function In Glioblastoma, Nathan Cuyle Rockwell

Arts & Sciences Electronic Theses and Dissertations

The tumor suppressor TP53 (p53) is the most frequently mutated gene in cancer and among the most mutated genes in brain cancer. Functionally, p53 is a transcription factor that, when activated by an array of stress stimuli, regulates a complex transcriptional program that contributes to a variety of antiproliferative pathways. The loss of p53 function (LOF), either through mutation, deletion, or inhibition by alterations in the proteins that regulate p53, removes an essential barrier to the unfettered proliferation and genomic instability that drive transformation. Unlike most tumor suppressors, many p53 mutations are missense mutations that lead to stable expression of …

Investigating The Role Of Bladder Epithelial Stem Cells In Bladder Mucosal Remodeling And Defense Against Infection, Seongmi Kim Russell

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTIs) can be highly recurrent, and the mechanism(s) governing recurrence susceptibility are mostly unknown. Here I demonstrate bladder epithelial (urothelial)-intrinsic trained immunity as part of a differential mucosal remodeling response to an initial UTI. I established urothelial stem cell (USC) lines from isogenic mice with different UTI histories (naïve, chronic, or self-resolving) and discovered 2880 differential genome-accessible regions, indicating differential epigenetic reprogramming dependent on infection history. Differentiation of USC lines in vitro resulted in polarized urothelial cultures that recapitulated distinct remodeling morphologies seen in vivo and exhibited altered gene expression, including genes involved in cell death pathways. …

Regulation Of Host-Microbe Interactions In Autoimmunity And Antiviral Immunity By Cytosolic Nucleic Acid Sensing And Interferon Signaling, Derek Jerome Platt

Arts & Sciences Electronic Theses and Dissertations

Cytosolic nucleic acid sensing and interferon (IFN) signaling are central to the host immune response to microbial pathogens. However, dysregulation of immunological pathways such as these can result in devastating autoimmune disease. In order to provide a robust immune response to pathogen without causing harm to self, the host immune system must engage in a delicate balancing act, interacting with microbes and determining whether they are commensal or pathogenic. The cGAS-STING pathway is a key regulator of host-microbe interactions by cytosolic nucleic sensing and IFN signaling. Loss of function in the cGAS-STING pathway leads to increased susceptibility to pathogenic threats, …

Uncovering A Myc-Driven Tumor-Suppressive Program In Proliferating Lymphocytes, Elena Tonc

Arts & Sciences Electronic Theses and Dissertations

Rapid cell proliferation is a hallmark feature of adaptive immune cells lymphocytes. It is essential for the establishment of diverse antigen receptor repertoires and amplification of antigen-specific immune responses. While such proliferation is beneficial for host protection from infections and cancers, it inevitably elevates the risk of oncogenic transformation. In developing and germinal center B lymphocytes, the risk is further increased by endogenous, genomic insults due to antigen receptor rearrangements and somatic mutations, with which expression of the proto-oncogene c-MYC is closely associated. Nonetheless, frequencies of cancers originated from B lymphocytes are relatively low, suggesting that they are protected from …

Peripheral Nerve Macrophages And Their Implications In Neuroimmunity, Peter Leon Wang

Arts & Sciences Electronic Theses and Dissertations

Macrophages are innate immune cells that protect against pathogens and maintain tissue integrity. In vertebrates, macrophages reside in every tissue where they perform specific functions from early development through adulthood. While macrophages provide important functions across all tissues, a major focus in recent years has been the role of resident brain macrophages, known as microglia, in neurodegeneration. As microglia have been shown to affect brain development, homeostasis, and disease, they demonstrate how immune cells critically mediate neurological health and point to the broader significance of neuroimmune interactions, or the coordinated actions of the nervous and immune systems for maintaining tissue …

Transcriptional Control Of Dendritic Cell Function And Development, David Alexander Anderson Iii

Arts & Sciences Electronic Theses and Dissertations

Dendritic cells (DCs) are innate immune cells of the myeloid lineage that are specialized at pathogen recognition, cytokine production, and antigen presentation. Their functions and developmental pathways are largely conserved between mice and humans and mice. The DC lineage is composed of two major subsets, known as plasmacytoid DCs (pDCs) and classical DCs (cDCs). Research conducted to date suggests that the function of pDCs, limited to viral antigen recognition and type I interferon production, can be compensated by other immune cell lineages. On the other hand, there is a consensus that diversified subsets cDCs in mice and humans are essential …

Dissecting The Role And Regulation Of Transcription Factor Zeb2 In Hematopoiesis, Xiao Huang

Arts & Sciences Electronic Theses and Dissertations

A potent immune response requires crosstalk and collaboration between the innate and adaptive immune systems, both of which contain highly specialized immune lineages. All immune lineages arise during adult life are generated from the differentiation of hematopoietic stem cells (HSCs) in the process of hematopoiesis. Normal hematopoiesis under steady state and emergency hematopoiesis during immune response are orchestrated precisely by transcriptional networks formed by transcription factors (TFs) to direct multipotent progenitors into specific fate. TFs required for the development of single or multiple lineages within the hematopoietic system has been identified, such as Irf8 for type I classical dendritic cells …

Regulation Of Gut Commensal-Specific T Cell Differentiation By Dendritic Cell Subsets, Emilie Russler-Germain

Arts & Sciences Electronic Theses and Dissertations

The mammalian gastrointestinal tract can harbor both beneficial commensal organisms important for host health, but also pathogenic organisms capable of intestinal damage. It is therefore important that the host immune system mounts appropriate responses to different intestinal organisms – promoting tolerance to some, controlling the colonization of others, and inducing sterilizing immunity in cases of noxious pathogens. Failure to induce tolerance to commensal organisms may underlie immune-mediated diseases such as human inflammatory bowel disease, while inappropriate tolerance to more harmful organisms has the potential to result in infection, inflammation, or even malabsorption. Adaptive immune responses to intestinal commensal organisms are …

Glial Inflammatory Responses Regulate Neurocognitive Recovery Following Viral Encephalitis, Allison Luen Soung

Arts & Sciences Electronic Theses and Dissertations

The concept of the brain as an immune privileged organ has been slowly shifting as an in-creasing number of studies have demonstrated that even under homeostatic conditions, commu-nication between the nervous and immune system is essential for proper brain function. Given their roles in innate and adaptive immunity, glial cells and infiltrating immune cells have been placed at the center of this communication axis. Microglia, astrocytes, and T cells have all been shown to receive and convey information to all neural cell types in a coordinated effort to re-spond to injury and infection and initiate reparative mechanisms as well as …

Magnetic Resonance-Guided High Intensity Focused Ultrasound (Mrghifu) Induced Hyperthermia (Ht) For Treatment Of Cervical Cancer, Lifei Zhu

McKelvey School of Engineering Theses & Dissertations

Hyperthermia (HT), which refers to increasing the temperature of the tumor tissue to 40–45°C for an extended period of time, has been reported to be one of the most effective sensitizers for radiation therapy (RT) and/or chemotherapy. High intensity focused ultrasound (HIFU) has been developed as a non-invasive and non-ionizing tool to induce localized HT. Magnetic resonance thermometry (MR thermometry) is one of the most reliable methods for non-invasively and precisely measuring the in vivo volumetric temperature in real time. The integration of MR thermometry with HIFU has been implemented in commercially available magnetic resonance guided high intensity focused ultrasound …

Retinal Ganglion Cells Underlying Visual Perception And Predation In Mice, Keith Patrick Johnson

Arts & Sciences Electronic Theses and Dissertations

The spike trains of retinal ganglion cells (RGCs) are the sole source of visual information to the brain. In mice, more than 40 RGC types send signals to more than 50 brain areas. RGCs that perform nonlinear operations to extract specific visual features (e.g., the motion of an object against a background) are called feature detectors. Those that linearly integrate local changes in light inten-sity are known as pixel encoders. Most mouse RGC types are feature detectors. In the first part of my dissertation, I discovered a pixel encoder RGC type in mice, the PixON-RGC. I revealed how the unique …

Etv2/Myct1 Axis In The Regulation Of Tumor Angiogenesis And Anti-Tumor Immunity, Ashraf Ul Kabir

Arts & Sciences Electronic Theses and Dissertations

Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there …

A Novel Function Of Plasmacytoid Dendritic Cells In Regulating Type 2 Immune Responses, Hannah Leigh Miller

Arts & Sciences Electronic Theses and Dissertations

The generation of an allergic response is particularly perplexing, as the mucosal immune system is exposed to a myriad of antigens on a daily basis, the majority of which do not elicit inflammation. However, for the growing population of patients impacted by allergic diseases, there is a clear breakdown of normal tolerance to innocuous antigens, resulting in symptoms mediated by antigen specific T helper 2 (Th2) cells. In addition to their well-established role in early antiviral immunity via production of type I interferon, plasmacytoid dendritic cells (pDC) have been implicated in the generation of immune tolerance in a variety of …

The Roles Of Capsular Polysaccharides And Diet In The Immune Response To A Bacteroides Thetaiotaomicron Antigen, Samantha Hsieh

Arts & Sciences Electronic Theses and Dissertations

The environment is well recognized to modulate immune responses within the intestinal mucosa in a general fashion. However, the connection between the effects of the environment on the immune response directed towards specific intestinal microbes is unclear. Progress in this area has been hampered by the lack of a model system in which the immune responses to a specific antigen in a gut symbiont can be examined. To this end, we developed a novel CD4+ T cell model, termed BθOM, that is specific for a dominant antigen in the gut symbiont Bacteroides thetaiotaomicron (B. theta). In this work, we use …

Mechanisms Of Natural Killer Cell Anti-Tumor Function And Homeostasis, Julia Alexandra Wagner

Arts & Sciences Electronic Theses and Dissertations

Natural killer (NK) cells are innate lymphoid cells (ILCs) that mediate anti-tumor and anti-viral immune responses. They do so via two primary effector functions: cytokine production and direct cytotoxicity. Unlike adaptive T and B lymphocytes, NK cells do not rearrange their DNA to express a predominant antigen-specific receptor, and instead express a variety of stochastically-expressed, germline DNA-encoded activating and inhibitory receptors whose signals integrate to govern their functional responses. What results is a diverse repertoire of NK cells capable of recognizing a variety of malignantly-transformed or virally-infected cells. Studies from several groups have established the anti-tumor potential of NK cells, …

Examining Early Interactions Between Innate Airway Resident Immune Cells And Mtb-Specific Factors During Pulmonary Infection With Mycobacterium Tuberculosis, Micah D. Dunlap

Arts & Sciences Electronic Theses and Dissertations

Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent in the world today, infecting roughly one quarter of humans. Despite this, the mechanisms of early pathogenesis and host protective innate immune responses remain poorly understood and uncharacterized.

Lung resident Alveolar Macrophages (AMs) are the first host contact with Mtb bacilli after inhalation and are thus key mediators of the early pulmonary immune response. AMs are generally believed to reside entirely in the airway, but it was recently demonstrated that they have the capacity to egress and enter into granulomas during pulmonary infection with hypervirulent Mtb. Furthermore, …

Contribution Of Tgf-B Signaling To The Pathogenesis Of Myeloproliferative Neoplasms, Juo-Chin Yao

Arts & Sciences Electronic Theses and Dissertations

TGF-b expression is increased in most cases of myeloproliferative neoplasms (MPNs); however, its contribution to disease pathogenesis is not well understood. Here, we explore two specific hypotheses. First, we hypothesize that increased TGF-b signaling in mesenchymal stromal cells contributes to the development of myelofibrosis. Second, we hypothesize that Jak2 mutated hematopoietic stem cells (HSCs) are resistant to the growth suppressive effect of TGF-b, conferring a fitness advantage that contributes to their expansion in MPNs and clonal hematopoiesis. To test the first hypothesis, we abrogated TGF-b signaling in mesenchymal stem/progenitor cells by deleting Tgfbr2 using a doxycycline-repressible Osterix-Cre transgene (Osx-Cre), which …