Medical Sciences Commons^™

Molecular Basis Of Cell Membrane Adaption Against Daptomycin In Enterococcus Faecalis, April Nguyen

Dissertations and Theses (Open Access)

Daptomycin is a last-resort lipopeptide antibiotic that disrupts cell membrane (CM) and peptidoglycan homeostasis (Grein et al., 2020a; Müller et al., 2016a). Enterococcus faecalis has developed a sophisticated mechanism to avoid daptomycin killing by redistributing CM anionic phospholipids away from the septum. The CM changes are orchestrated by a three-component regulatory system, designated LiaFSR, with a possible contribution of cardiolipin synthase (Cls) (Cesar A Arias et al., 2011a; Khan et al., 2019b; Palmer et al., 2011a; Panesso et al., 2015a; Reyes et al., 2015a). However, the mechanism by which LiaFSR controls the cell membrane response and the role of Cls …

Dissecting The Relationship Between Mucin 5ac And The Lung/Gut Microbiome In The Pathogenesis Of K-Ras Mutant Lung Cancer, Maria T. Grimaldo

Dissertations and Theses (Open Access)

Non-small cell lung cancer, including its most common subtype, lung adenocarcinoma (LUAD), is the leading cause of cancer-related deaths worldwide. In LUAD patients, KRAS mutations are the most common oncogenic driver alteration. Given KRAS is upstream to many signaling pathways involved in cell survival and cytokine production, interventions against KRAS-mutant lung cancers are prone to develop acquired resistance. Thus, there is a need to develop alternate targeting strategies and test combination therapies for improved intervention. Previously, we have found that KRAS-mutant LUAD (KM-LUAD) patients whose tumors harbor high expression of Mucin 5 AC (MUC5AC), a main airway secretory mucin, have …

Downregulation Of Mir-10a-5p As A Potential Therapeutic Target To Improve The Detrimental Effects Of Post-Stroke Social Isolation, Patrick Mooz

Dissertations and Theses (Open Access)

Introduction

Social isolation is detrimental to health. Isolation and loneliness are linked to all-cause mortality and accelerated disease progression in patients with cancer, dementia, and vascular disease. The number of individuals that live alone is increasing in our society, especially in the elderly, and loneliness and isolation represent a profound growing public health challenge. Previous studies have found that the detrimental effects of social isolation can be recapitulated in animal models. Mice that are socially isolated (SI) prior to an experimental stroke have larger infarcts and significantly worse outcomes. Importantly, animals that remain pair housed (PH) when an experimental stroke …

A Novel Ngs Assay To Detect Any Kmt2a Fusion Transcript At Low Levels, Ghayas Issa

Dissertations and Theses (Open Access)

Measurable residual disease (MRD) detection is associated with cancer relapse. Leukemias with rearrangement of the lysine methyltransferase 2 A gene (KMT2Ar) have an adverse prognosis with more than 80 possible fusion partner genes (FPG) identified. With the advent of effective targeted therapies for KMT2Ar leukemia such as menin inhibitors, there is an unmet need for sensitive assays to detect these various fusions. Standard next-generation sequencing (NGS) methods cannot accurately detect genetic alterations at low frequencies because of inherent technical errors and the need for high sequencing depth. Blocker Displacement Amplification (BDA) technology enables selective detection of such rare …

Effect Of Body Mass Index Percentile On Complicated Appendicitis, Postoperative Complications And Health Service Utilization Among Pediatric Patients In The United States, Nutan Hebballi

Dissertations and Theses (Open Access)

While overweight and obesity have been extensively studied for complicated appendicitis, postoperative complications, and health service utilization, the effects of being underweight are unknown. This dissertation assesses the associations between the body mass index (BMI) spectrum with complicated appendicitis, postoperative complications, and healthcare service utilization in pediatric patients.  A retrospective review of pediatric patients who underwent appendectomy surgery (01/01/2016-12/31/2020) was conducted using the National Surgical Quality Improvement Program database. Computed age and gender-specific BMI percentiles were categorized into underweight, normal weight, overweight and obese. The 30-day postoperative complications were grouped into minor, major, and any. Healthcare service utilizations were compared …

The Development Of Artificial Intelligence-Based To Ols For Expert Peer Review Of Radiotherapy Treatment Plans, Mary Gronberg

Dissertations and Theses (Open Access)

Creating a patient-specific radiation treatment plan is a time-consuming and operator-dependent manual process. The treatment planner adjusts the planning parameters in a trial-and-error fashion in an effort to balance the competing clinical objectives of tumor coverage and normal tissue sparing. Often, a plan is selected because it meets basic organ at risk dose thresholds for severe toxicity; however, it is evident that a plan with a decreased risk of normal tissue complication probability could be achieved. This discrepancy between “acceptable” and “best possible” plan is magnified if either the physician or treatment planner lacks focal expertise in the disease site. …

Role Of Phosphorylated Dicer1 In Tumor Progression, Raisa Reyes-Castro

Dissertations and Theses (Open Access)

DICER1 is a multidomain enzyme discovered and widely recognized for its function in small non-coding microRNA (miRNA) synthesis. In cancer development, DICER1 functions as a haploinsufficient tumor suppressor which regulates miRNAs and Epithelial-to-Mesenchymal Transition (EMT). The Arur laboratory discovered that DICER1 is phosphorylated by active ERK and that ERK-mediated phosphorylation triggers DICER1 to translocate from the cytoplasm to the nucleus of cells in worms, mice and humans. Further, a heterozygous allele of a genetically engineered mouse model of phosphomimetic Dicer1 when combined with heterozygous Kras oncogenic background contributes to lung tumor progression in vivo. Mechanisms through which phosphomimetic Dicer1 …

Lymphatic Dysfunction And Associated Systemic Inflammation In Lymphedema, Assessed By Nirf-Li Imaging And Plasma Cytokine/Chemokine Analysis, Anna Vang

Dissertations and Theses (Open Access)

Breast cancer-related lymphedema (BCRL) manifests as swelling of the upper extremities and trunk as a result of lymphatic fluid buildup due to radiation therapy (RT), surgical lymph node removal, or chemotherapy. As there is currently no cure, BCRL treatment aims to improve quality of life (QOL). First-line treatment involves specialized massage therapy and the use of compression garments. Second-line treatments include reparative lymphatic microsurgeries such as lymphovenous bypass (LVB) and/or vascularized lymph node transplant (VLNT). There is a need for better understanding of the etiology of BCRL and lymphatic microsurgery outcomes. Blood specimens and near-infrared fluorescent lymphatic imaging (NIRF- LI)data …

Adipocytes And Innate Immunity In Systemic Sclerosis, Nancy Wareing

Dissertations and Theses (Open Access)

Systemic sclerosis (SSc; scleroderma) is a chronic systemic autoimmune and connective tissue disorder characterized by vasculopathy, autoimmune phenomena, and widespread fibrosis. Skin thickening and tightening is the cardinal feature of SSc and is responsible, in part, for the considerable morbidity of this disease. There are currently no targeted treatments for skin manifestations in SSc, primarily due to our fragmented understanding of its pathophysiologic mechanisms. In PART I, we report a previously unappreciated link between aberrant expression of the developmental gene sine oculis homeobox homolog 1 (SIX1) in skin-associated adipocytes in SSc skin and the early loss of dermal white adipose …

Uncovering Novel Mechanism Of Immune Modulation Of Invariant Natural Killer T Cells By Liposomal Α-Galactosylceramide, Alexandra S. Flegle

Dissertations and Theses (Open Access)

Invariant Natural Killer T cells (iNK-T cells) are a powerful regulatory immune cell that can recruit both innate and adaptive immune cells. Unlike conventional T cells (CD4⁺ and CD8α⁺), they recognize glycolipid antigens via the MHC-class-I like molecule, CD1d. A synthetically derived glycolipid from the marine sponge, Agelas mauritianus, alpha-Galactosylceramide (α-GalCer) potently activates iNK-T cells. Within a few hours after activation, iNK-T cells produce high quantities of T_H1 and T_H2 type cytokines, thus shape subsequent adaptive immunity towards inflammation (T_H1) or immune-suppression (T_H2). Structural modification of α-GalCer’s phytosphingosine …

The Impact Of Treatment With Palynziq® On Quality Of Life For Individuals With Pku, Teresa Heller

Dissertations and Theses (Open Access)

Management for phenylketonuria (PKU) has traditionally involved adhering to a strict low-protein diet to maintain phenylalanine (Phe) levels within the recommended range (μmol/L). The time commitment and financial, emotional, and social burdens of adhering to a restrictive diet, as well as the neurocognitive symptoms associated with elevated Phe levels, make it challenging to manage PKU and lead to reductions in quality of life. Palynziq^® is an enzyme substitution therapy used to lower blood Phe levels and liberate individuals with PKU from their restrictive diets. Previous studies have demonstrated the safety and efficacy of Palynziq^®, but our study …

Automating The Radiation Therapy Treatment Planning Process For Pediatric Patients With Medulloblastoma, Soleil Hernandez

Dissertations and Theses (Open Access)

Over the past 50 years, pediatric cancer 5-year survival rates increased from 20% to 80% in high-income countries, however, these trends have not been mirrored in low-and-middle-income countries (LMICs). This is due in part to delayed diagnosis, higher rates of advanced disease at presentation and a growing lack of access to high quality medical personnel and technology necessary to deliver complex treatments.

The long-term goal of this study was to alleviate demanding workflows and increase global access to high-quality pediatric radiation therapy by harnessing the power of artificial intelligence to automate the radiation therapy treatment planning process for pediatric patients …

Quantifying The Magnitude Of To Tal Dose Deviation Caused By Various Sources Of Error Among Iroc Phantom Irradiation Results, Sharbacha S. Edward

Dissertations and Theses (Open Access)

The Imaging and Radiation Oncology Core (IROC) phantoms are used as an end-to-end test of an institution’s radiotherapy processes, and for clinical trial credentialing. Phantoms are treated like patients, and evaluation of the doses received by the thermoluminescent dosimeters (TLDs) inside the phantom, reflects the accuracy with which an institution can image, plan and irradiate a phantom or patient. Recent phantom results show that among the hundreds of various IROC phantoms irradiated annually, 8-17% of institutions fail this test. The purpose of this work was to investigate the various types of errors that may occur during the treatment process and …

Infrastructure Development For Personalized Risk Prediction To Reduce Cardiovascular Disease In Childhood Cancer Survivors, Suman Shrestha

Dissertations and Theses (Open Access)

Although childhood cancer survivors have lengthy life expectancies, they run the risk of experiencing long-term health issues as a result of their treatment. The most frequent non-cancerous cause of morbidity and mortality for these survivors is cardiac disease. Radiation therapy (RT) has been linked in numerous cohort studies to a higher chance of developing a late cardiac disease in these survivors, and this risk rises with higher mean heart doses and increased RT exposure to larger cardiac volumes. Since, the heart is a heterogeneous organ made up of several distinct substructures, RT dose received by the entire heart does not …

Risk-Factor Induced Changes In The Breast Microenvironment Facilitate Inflammatory Breast Cancer Progression And Lymphovascular Invasion, Wintana Balema, Wintana Balema

Dissertations and Theses (Open Access)

Inflammatory breast cancer (IBC) is a rapidly progressing, rare and highly lethal form of breast cancer. IBC is a clinical diagnosis, requiring >1/3 involvement on the affected breast and/or skin by erythema, and disease onset of < 6 months. The clinical symptoms of IBC vary in severity and presentation, these include redness, warmth, skin thickening and bruised or pink/purple discoloration appearance and skin changes such as peau d’orange. These skin symptoms are not attributed to inflammation, rather IBC is characterized by florid lymphovascular tumor emboli clogging dermal lymphatics. This leads to “classic” symptoms of breast swelling and skin edema or discoloration. To date, unique genomic drivers which differentiate IBC from non-IBC invasive breast cancers have not been identified highlighting a role for the microenvironment. Several epidemiological studies have unveiled subtype-specific risk factors associated with IBC that are known to alter the microenvironment. Obesity is an established risk factor for all subtypes of IBC. Never-breastfeeding increases risk for developing the most aggressive, triple-negative IBC. Further, never breastfeeding is associated with later clinical stage and worse outcomes. We worked to model these overlapping risk factors to understand microenvironment changes that may lead to the lymphatic change’s indicative of IBC.

First, we investigated the association of a “classic” triad of clinical IBC signs with overall survival among patients to demonstrate the most overt clinical findings of lymphatic involvement were impacting prognosis. We evaluated a triad of IBC signs, including swollen involved breast, nipple change, and diffuse skin change, using breast medical photographs from patients enrolled on a prospective IBC registry. We reported that the …

Defining The Cooperation Between Mhc-I And Mhc-Ii Neoantigen-Driven T Cell Responses To Develop Effective Personalized Immunotherapies, Charmelle Williams

Dissertations and Theses (Open Access)

Immune checkpoint therapy (ICT) (e.g. anti-CTLA-4 (α-CTLA-4), anti-PD-1 (α-PD-1)) enables durable T cell-dependent anti-tumor immunity in certain cancer patients. Since a subset of patients respond to ICT, this work aims at developing a more in-depth understanding of T-cell responses to MHC class I (MHC-I) and MHC class II (MHC-II) tumor antigens that are derived from aberrant expression of non-mutant antigens or driver and passenger somatic alterations that can function as tumor neoantigens. We used a poorly immunogenic Braf^v600e Pten^-/- Cdkn2a^-/- YUMM1.7 (Y1.7) murine melanoma line with a paucity of endogenous neoantigens that is unresponsive to ICT, and …

Absolute Quantification Of Tc-99m Activity Distributions Using A Planar Molecular Breast Imaging Commercial System, Benjamin P. Lopez

Dissertations and Theses (Open Access)

Molecular breast imaging (MBI) uses two dedicated-breast semiconductor detectors to visualize the preferential uptake of technetium-99m-sestamibi (^99mTc-sestamibi) by breast cancer cells relative to surrounding benign breast tissues. Clinically, MBI is used primarily as a supplementary tool to standard-of-care mammography because of its improved detection of breast cancers, especially in women with mammographically-dense breasts. Because of a lack of image corrections, MBI applications are currently limited to qualitative evaluations of relative pixel intensities between image regions with suspected lesions and normal tissue.

The objective of this dissertation was to use Monte Carlo simulations to better characterize the MBI imaging …

Bhlhe40: Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery Salmon, Avery J. Salmon

Dissertations and Theses (Open Access)

Advancements in immunotherapy treatments have become essential in the treatment of various cancers, such as those with high tumor burden like melanoma(Brahmer et al., 2012; Hodi et al., 2010). Immunotherapy, specifically immune checkpoint therapy (ICT) provides antagonist effect on specific immune checkpoints to control effector T cell functions(Pardoll, 2012). This therapy allows for the modulation of anti-tumor responses through the use of monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1 that block the receptors from binding with their ligands, thus allowing for CD4⁺ and CD8⁺ T cell priming and activation(Wei et al., 2017). However, the required epigenetic and transcriptional …

Cell-Free Dna Sequencing In Multiple Myeloma, Russell Irwin

Dissertations and Theses (Open Access)

Multiple myeloma (MM) is an incurable plasma cell dyscrasia. Recent advances in MM therapy, including CAR-T therapy, have increased survival and shown the value of assessing treatment response with great sensitivity, both in acute and long-term settings. Cell-free DNA, DNA fragments which are released into circulation as a part of normal cellular turnover, is a useful and dynamic biomarker in cancer patients due to the presence of circulating tumor DNA (ctDNA), which is readily identified using next generation sequencing. Here we report the analytical sensitivity, applicability, consistency, and prognostic ability of M5Seq, a novel hybrid capture panel designed for MM …

Development Of Advanced Mr-Guided Adaptive Radiation Therapy Methods For Head & Neck Cancers On The 1.5t Mr-Linac, Brigid Mcdonald

Dissertations and Theses (Open Access)

The 1.5T hybrid MRI/linear accelerator (MR-linac) has recently been introduced into clinical practice and used for the treatment of head and neck cancers (HNC). This device enables on-line adaptive radiation therapy (ART) based on anatomical changes throughout treatment and variations in patient position. This novel technology also has the potential for advanced ART strategies such as dose-optimized ART, in which the treatment plan is optimized based on the accumulated dose over previous fractions, or biological image-guided ART, in which the plan is adapted based on individual tumor response as measured through quantitative imaging techniques such as diffusion-weighted imaging (DWI). The …

Yap And Taz Are Required For Neural Crest-Derived Cardiovascular Development, Shannon Erhardt

Dissertations and Theses (Open Access)

Congenital heart defects (CHDs) are the most common human birth defect, occurring in ~1/100 newborns, and are a leading cause of early infant death. Cardiac neural crest cells (NCCs) are a migratory and multipotent cell population known to aid in the development of the cardiac outflow tract (OFT), valves, and interventricular septum, during embryogenesis. Yap and Taz are downstream effectors of the fundamental Hippo signaling pathway and are vital for proper organ and tissue development, yet their role in neural crest (NC)-derived heart formation is still largely unknown. We generated Yap and Taz conditional knockout (CKO) mice using a Cre-lox …

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Induced Cytotoxicity In Crebbp/Ep300mut Head And Neck Squamous Cell Carcinoma, Thomaia Pamplin

Dissertations and Theses (Open Access)

INDUCED CYOTOXICTY IN CREBBP/EP300mut HEAD AND NECK SQUAMOUS CELL CARCINOMA

Thomaia Pamplin

Advisor: Curtis Pickering, Ph.D.

Background: Head and neck squamous cell carcinoma HNSCC is the most common malignancy in the head and neck. Most cases are found in advanced stages and depending on the location can be treated with surgical resection and/or radiation (XRT), chemotherapy, or chemoradiation. Our lab groups have identified that HNSCC with a mutation in its CREBBP/EP300 genes can be sensitized to XRT when the histone acetyltransferase activity of CREBBP/EP300 is inhibited. This radiosensitization manifests in the form of increased cell death for …

Leveraging Single Cell Technologies For The Characterization And Treatment Of Refractory Pancreatic Cancer, Maria Monberg

Dissertations and Theses (Open Access)

Heterogeneity is a hallmark of cancer, and the advent of multimodal single-cell technologies has helped uncover heterogeneity in a high-throughput manner in different cancers across varied contexts at an unprecedented resolution. In an effort to improve precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy with a mere 11% 5-year survival rate, this dissertation focuses on first questioning the assumptions of the most basic models used to study PDAC via multimodal single-cell characterization methods at multiple levels of biological organization (scCNVseq and snATACseq for DNA assays, scRNAseq for transcriptomics, and paired protein assays such as multiplexed immunofluorescence …

Atr-Mediated Cd47 And Pd-L1 Upregulation Restricts Radiotherapy-Induced Immune Priming And Abscopal Responses In Colorectal Cancer, Cheng-En Hsieh, Cheng-En Hsieh

Dissertations and Theses (Open Access)

Radiotherapy of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, incidences of abscopal tumor remission are extremely rare, and the post-irradiation immune escape mechanisms in CRC remain elusive. We report that CRC cells utilize a common DNA repair signaling pathway — ATR/Chk1/STAT3 — to upregulate both CD47 and PD-L1 in response to radiotherapy, which through engagement of SIRPα and PD-1 suppresses the capacity of antigen-presenting cells to phagocytose them thereby preventing TAA cross-presentation and innate immune activation. This post-irradiation CD47 and PD-L1 upregulation can be observed across various human solid tumor cells. Concordantly, …

Targeting Metabolic Adaptations To Anti-Angiogenic Therapy In Ovarian Cancer, Deanna M. Glassman, Deanna Glassman

Dissertations and Theses (Open Access)

ABSTRACT

Background: Ovarian cancer is the most lethal gynecologic malignancy. Despite modest clinical improvements with anti-VEGF antibody (AVA) therapy, adaptive resistance is nearly ubiquitous and additional therapeutic options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance.

Purpose: To assess the efficacy of a glutaminase inhibitor as a means of exploiting the metabolic vulnerability of glutamine dependence that develops as a result of adaptive resistance to AVA therapy.

Experimental Design: We used a glutaminase inhibitor (GLSi) synthesized at MD Anderson Cancer Center for all in vitro and in vivo experiments. …

Hdac6 Inhibition Reverses Long-Term Doxorubicin-Induced Cognitive Dysfunction By Restoring Microglia Homeostasis, Blake Mcalpin

Dissertations and Theses (Open Access)

One in 8 women in the US will be diagnosed with breast cancer. Currently, doxorubicin is one of the most effective chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed, and executive functioning. Currently, no interventions for CICD have been approved by the US Food and Drug Administration. I show here that a 14-day treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor successfully reverses long-term CICD following a therapeutic doxorubicin dosing schedule in female mice, as assessed by the puzzle box test …

Nanoparticles For Biomedical Applications, Joseph Kim

Dissertations and Theses (Open Access)

This thesis presents development and evaluation of the potential of three new nanoparticles for biomedical applications. With the rapid growth of the field of nanoscience, researchers have explored developing nanoparticles for various biomedical applications, including imaging, therapy, and drug delivery. This thesis demonstrates the development of two C­₆₀ fullerene based nanoparticles and one boron based nanoparticle to answer key questions related to their biological potential.

In the first part of the thesis, we describe synthesis and characterization of a pure boron nanoparticle containing asolectin phospholipid-based liposome construct prepared using a water-in-oil emulsion method, as a novel alternative agent for …

The Tca Cycle As A Nexus Of Metabolic Vulnerabilities In Cancer, Sunada Khadka

Dissertations and Theses (Open Access)

Uncontrolled proliferation of cancer cells necessitates rewiring of metabolic pathways to meet biosynthetic and bioenergetic demands of proliferation and fortify redox homeostasis. An increasing body of literature suggests that mitochondrial metabolism (tricarboxylic acid cycle (TCA) and oxidative phosphorylation) is imperative for cancer cell growth and proliferation. The scope of the works presented in this dissertation is to explore the importance of mitochondrial metabolism, and primarily the TCA cycle—the anabolic factory of cancer cells and leverage it as a targetable vulnerability in cancer. Cancer cells consume anabolic nutrients that are used to generate biosynthetic precursors in the TCA cycle. Continuous efflux …

Mechanism Of Rare Variant In Acta2, P.Arg149cys, Driving Diverse Vascular Disease, Kaveeta Kaw

Dissertations and Theses (Open Access)

Heterozygous variants in ACTA2 (smooth muscle (SM) α-actin) predispose to thoracic aortic aneurysms and dissections (TAAD) and early-onset coronary artery disease (CAD). The most common ACTA2 mutation is a genetic alteration of arginine 149 to a cysteine, ACTA2 p.Arg149Cys, which accounts for disease in 24% of all ACTA2 mutation carriers.(1) ACTA2 p.Arg149Cys mutation carriers present with either TAAD or CAD but rarely have both diseases. To identify the molecular mechanisms dictating whether an individual with ACTA2 p.Arg149Cys develops TAAD or CAD, CRISPR/Cas9 technology was used to generate the mutant mouse, Acta2^R149C/+, in a C57BL6 background. Acta2^R149C/+ mice …