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Full-Text Articles in Medical Sciences

Injury Induced Neuroplasticity And Cell Specific Targeting Of The Lumbar Enlargement For Gene Therapy., Brandon Lee Brown Aug 2023

Injury Induced Neuroplasticity And Cell Specific Targeting Of The Lumbar Enlargement For Gene Therapy., Brandon Lee Brown

Electronic Theses and Dissertations

This dissertation is an examination of spinal cord injury induced neuroplasticity and tests whether noninvasive gene therapy can successfully target neurons in the lumbar spinal cord. It begins with an overview of neural control of locomotion and a brief summary of therapeutics that are used and/or in development for treating spinal anatomically characterize s subset of neurons in the spinal cord, long ascending propriospinal neurons, that are involved in interlimb coordination. Characterization of these neurons allows for subsequent evaluation of their potential involvement in injury induced neuroplasticity. This dissertation is divided into five chapters, covering spinal cord injury and therapeutics. …


On-Campus Mental Health Service Use Among College Students With Autism: A Case Study Applying The Andersen Behavioral Model Of Health Services Use, Estella C. Lilyquist Jul 2023

On-Campus Mental Health Service Use Among College Students With Autism: A Case Study Applying The Andersen Behavioral Model Of Health Services Use, Estella C. Lilyquist

Electronic Theses and Dissertations

The unique set of impairments and limitations presented by students with autism spectrum disorder (ASD) make the accessing of campus-based nonacademic resources more difficult and complicated than their typically developed peers. Each year, the rate of students entering college with disabilities continues to grow, but their mental well-being is relatively poor. The purpose of this qualitative case study was to apply the conceptual framework of the Andersen behavioral model of health services use (ABMHSU) to the experiences of college students with ASD to understand and predict their utilization of campus-provided mental health resources. The participants were seven college students with …


Irreversible Electroporation Potentiates Beta Glucan Induced Trained Innate Immunity: A Novel Combination Treatment For Pancreatic Adenocarcinoma., Matthew Woeste May 2023

Irreversible Electroporation Potentiates Beta Glucan Induced Trained Innate Immunity: A Novel Combination Treatment For Pancreatic Adenocarcinoma., Matthew Woeste

Electronic Theses and Dissertations

Pancreatic cancer (PC) is a challenging diagnosis yet to benefit from advances in immune oncologic treatments. Irreversible electroporation, a non-thermal method of tumor ablation, is used in treatment of select patients with locally advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate β-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment β-glucan-induced trained immunity in the treatment of PC. β-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and anti-tumor function after exposure to ablated and un-ablated tumor conditioned media. β-Glucan and …


Toward A Comprehensive Account Of Orientation Selectivity In The Retina., Megan Zipperer May 2023

Toward A Comprehensive Account Of Orientation Selectivity In The Retina., Megan Zipperer

Electronic Theses and Dissertations

Retinal Ganglion Cells (RGCs) form functionally distinct signaling channels that selectively encode features of the visual input including direction of motion, contrast polarity, size, and color. A highly conserved visual channel amongst vertebrates conveys orientation selectivity, i.e., the selective firing of neuronal cells in response to elongated stimuli along a preferred orientation. Orientation selectivity is an apparent critical computation and several studies have reported aspects of it, including cell type identity in anatomical reconstructions, and functional characterization of at least four different identified RGC types. But how cell types in the different studies relate is not well resolved; the mechanisms …


Examining The Effects Of Npra Antagonist Anantin On Sci-Induced Ployuria., Lindsey Zipperer Dec 2022

Examining The Effects Of Npra Antagonist Anantin On Sci-Induced Ployuria., Lindsey Zipperer

Electronic Theses and Dissertations

Polyuria, or the over production of urine, is a prevalent condition that significantly impacts the quality of life in individuals suffering from a spinal cord injury (SCI). Post-SCI induced polyuria is thought to have been associated with altered levels of vasopressin (AVP), atrial natriuretic peptide (ANP), and natriuretic peptide receptor A (NPRA). In the present study, the function of NPRA was analyzed in the rat contusion model using anantin, an NPRA antagonist. A daily dose of either 100 µg of anantin or vehicle was administered intraperitoneally immediately following the SCI surgery and continued until termination, 4 weeks post injury (wpi). …


The Mechanisms Of Mitochondrial Dysfunction In T Cell Aging During Chronic Viral Infection, Madison B. Schank Dec 2022

The Mechanisms Of Mitochondrial Dysfunction In T Cell Aging During Chronic Viral Infection, Madison B. Schank

Electronic Theses and Dissertations

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections induce a myriad of disturbances to CD4 T cell functions, including mitochondrial compromise, excessive inflammation, increased telomeric DNA damage and attrition, cellular exhaustion and senescence, and accelerated aging. In this dissertation, the mechanisms underlying metabolic failure, accelerated aging, and cellular dysfunctions were evaluated in CD4 T cells from healthy subjects (HS) treated with a telomere-targeting drug (KML001) or HCV-infected individuals or people living with HIV (PLHIV) compared to HS. We observed that KML001-induced telomere injury resulted in mitochondrial swelling and decreased mitochondrial membrane potential, cellular respiration, mitochondrial DNA (mtDNA) copy …


Investigating The Pi3k/Akt/Atm Pathway, Telomeric Dna Damage, T Cell Death, And Crispr/Cas9-Mediated Gene Editing During Acute And Chronic Hiv Infection, Sushant Khanal Dec 2022

Investigating The Pi3k/Akt/Atm Pathway, Telomeric Dna Damage, T Cell Death, And Crispr/Cas9-Mediated Gene Editing During Acute And Chronic Hiv Infection, Sushant Khanal

Electronic Theses and Dissertations

Human Immunodeficiency Virus (HIV) infection initiates major metabolic and cell- survival complications. Anti-retroviral therapy (ART) is the current approach to suppress active HIV replication to a level of undetected viral load, but it is not a curative approach. Newer and sophisticated gene editing technologies could indeed be a potent antiviral therapy to achieve a clinical sterilization/cure of HIV infection. Chronic HIV patients, even under a successful ART regimen, exhibit a low-grade inflammation, immune senescence, premature aging, telomeric DNA attrition, T cell apoptosis, and cellular homeostasis. In this dissertation, we investigated CD4 T cell homeostasis, degree of T cell apoptosis, an …


Bayesian Methods For Graphical Models With Neighborhood Selection., Sagnik Bhadury Dec 2022

Bayesian Methods For Graphical Models With Neighborhood Selection., Sagnik Bhadury

Electronic Theses and Dissertations

Graphical models determine associations between variables through the notion of conditional independence. Gaussian graphical models are a widely used class of such models, where the relationships are formalized by non-null entries of the precision matrix. However, in high-dimensional cases, covariance estimates are typically unstable. Moreover, it is natural to expect only a few significant associations to be present in many realistic applications. This necessitates the injection of sparsity techniques into the estimation method. Classical frequentist methods, like GLASSO, use penalization techniques for this purpose. Fully Bayesian methods, on the contrary, are slow because they require iteratively sampling over a quadratic …


Metabolic Foundations Of Exercise-Induced Cardiac Growth., Kyle Fulghum Dec 2022

Metabolic Foundations Of Exercise-Induced Cardiac Growth., Kyle Fulghum

Electronic Theses and Dissertations

Regular aerobic exercise promotes physiological cardiac growth, which is an adaptive response thought to enable the heart to meet higher physical demands. Cardiac growth involves coordination of catabolic and anabolic activities to support ATP generation, macromolecule biosynthesis, and myocyte hypertrophy. Although previous studies suggest that exercise-induced reductions in cardiac glycolysis are critical for physiological myocyte hypertrophy, it remains unclear how exercise influences the many interlinked pathways of metabolism that support adaptive remodeling of the heart. In this thesis project, we tested the general hypothesis that aerobic exercise promotes physiological cardiac growth by coordinating myocardial metabolism to promote glucose-supported anabolic pathway …


Stromal Vascular Fraction Restores Vasodilatory Function By Reversing Mitochondrial Dysfunction And Oxidative Stress In Aging-Induced Coronary Microvascular Disease., Evan Paul Tracy Aug 2022

Stromal Vascular Fraction Restores Vasodilatory Function By Reversing Mitochondrial Dysfunction And Oxidative Stress In Aging-Induced Coronary Microvascular Disease., Evan Paul Tracy

Electronic Theses and Dissertations

Background: Coronary Microvascular Disease (CMD) presents in aging post-menopausal women with chronic angina due to microvascular hyperconstriction. The objective was to identify mechanisms of adipose stromal vascular fraction’s (SVF) restorative effects on vasodilation. We hypothesize aging-induced CMD is caused by a) abrogated flow-mediated dilation (FMD) due to loss of nitric oxide signaling and b) ROS-dependent βADR desensitization & internalization, reversible by ameliorating mitochondrial dysfunction and oxidative stress with SVF. Methods: Coronary microvessels were isolated from female rats either young, old, or old with SVF tail-vein injection (OSVF). Pressure myography, RNA-sequencing, immunofluorescence, Western blotting, and morphological analysis were performed to …


Cyclic Di-Gmp Regulates Motility, Biofilm Formation, And Desiccation Tolerance In Acinetobacter Baumannii, Garrett Reynolds Aug 2022

Cyclic Di-Gmp Regulates Motility, Biofilm Formation, And Desiccation Tolerance In Acinetobacter Baumannii, Garrett Reynolds

Electronic Theses and Dissertations

Acinetobacter baumannii is an increasingly multidrug-resistant pathogen contributing to hospital-acquired infections necessitating the discovery of novel treatments. A bacterial second messenger, cyclic diguanosine monophosphate (cyclic di-GMP), can regulate various persistence factors that are potentially advantageous for survival in hospital environments. Cyclic di-GMP–modulating enzymes and cyclic di-GMP–binding effectors predictively are encoded in the Acinetobacter baumannii genome. I hypothesized that cyclic di-GMP controls motility, biofilm formation, and desiccation tolerance in Acinetobacter baumannii. Disrupting cyclic di-GMP–modulating enzymes or cyclic di-GMP–binding effectors should alter the regulatory effectiveness of these phenotypes. I tested the multidrug-resistant isolate Acinetobacter baumannii strain AB5075 and identified several transposon …


The Contribution Of Ethical Governance Of Artificial Intelligence & Machine Learning In Healthcare, Tina Nguyen May 2022

The Contribution Of Ethical Governance Of Artificial Intelligence & Machine Learning In Healthcare, Tina Nguyen

Electronic Theses and Dissertations

With the Internet Age and technology progressively advancing every year, the usage of Artificial Intelligence (AI) along with Machine Learning (ML) algorithms has only increased since its introduction to society. Specifically, in the healthcare field, AI/ML has proven to its end-users how beneficial its assistance has been. However, despite its effectiveness and efficiencies, AI/ML has also been under scrutiny due to its unethical outcomes. As a result of this, two polarizing views are typically debated when discussing AI/ML. One side believes that AI/ML usage should continue regardless of its unsureness, while the other side argues that this technology is too …


Early Detection Of Atypical Motor And Neurobehavior Of Infants At Risk Secondary To Opioid Exposure: A Prospective Study, Kara Boynewicz May 2022

Early Detection Of Atypical Motor And Neurobehavior Of Infants At Risk Secondary To Opioid Exposure: A Prospective Study, Kara Boynewicz

Electronic Theses and Dissertations

Prenatal opioid exposure has been studied in relation to infants' medical outcomes. However, large gaps exist in the literature supporting early identification of atypical neurobehavior and motor development of infants with prenatal opioid exposure. The purpose of the study was to investigate whether prenatal opioid exposure has a negative influence on a newborn infant’s neurobehavior and motor development to aid in the early identification of potential delays. Using a prospective quasi experimental design, infants motor development using the Test of Infant Motor Performance (TIMP) and neurobehavior using the NICU Neonatal Network Scale (NNNS) was assessed on 58 infants in a …


Adipose-Derived Stromal Vascular Fraction Therapy Improves Age-Related Adrenergic Mediated Microvascular Dysfunction And Increases Revascularization Potential Following Injury., Gabrielle Brown May 2022

Adipose-Derived Stromal Vascular Fraction Therapy Improves Age-Related Adrenergic Mediated Microvascular Dysfunction And Increases Revascularization Potential Following Injury., Gabrielle Brown

Electronic Theses and Dissertations

The role of the microcirculation is to balance blood flow and oxygen delivery to meet local metabolic and oxygen demands. With advancing age, the health of the endothelium declines leading to improper augmentation of the microcirculation; decreasing vasoreactivity and angiogenic potential which can further increase the risk of ischemia. The multiple contributing factors that drive the decline in endothelial health with age make traditional pharmacological interventions challenging whereas cell-based therapies can exert multifactorial gains. Adipose-derived stromal vascular fraction (SVF) is an emerging therapeutic for its easily accessible, autologous, anti-inflammatory, and angiogenic properties. It is a heterogenous population comprised of leukocyte …


The Role Of Obesity In Macrophage-Mediated Mechanisms Promoting Early-Onset Colon Cancer., Katharina Marietta Scheurlen May 2022

The Role Of Obesity In Macrophage-Mediated Mechanisms Promoting Early-Onset Colon Cancer., Katharina Marietta Scheurlen

Electronic Theses and Dissertations

Early-onset colon cancer (EOCC) is a leading cause of cancer death among people younger than 50 years of age in the United States and is associated with metabolic dysfunction and obesity. Anti-inflammatory tumor-associated macrophages (TAM) and low Peroxisome Proliferator Activated Receptor Gamma (PPARγ) gene expression in colon cancer (CC) tissue promote tumor progression and decreased patient survival. Obesity-related hormones, such as leptin and adiponectin, have the potential to affect gene expression in TAM to promote CC progression and thereby link obesity and EOCC. The aim of this project was to identify target genes in human CC and to investigate the …


The Impact Of Volume Of Tissue Activation On Cortical-Striatal Networks And Verbal Fluency Declines In Post-Deep Brain Stimulation Parkinson's Disease Patients., Alexander Luke Alley May 2022

The Impact Of Volume Of Tissue Activation On Cortical-Striatal Networks And Verbal Fluency Declines In Post-Deep Brain Stimulation Parkinson's Disease Patients., Alexander Luke Alley

Electronic Theses and Dissertations

This study investigated the cortical-striatal networks of verbal fluency declines in 6-month, post-operative, deep brain stimulation Parkinson’s Disease patients. Nine Parkinson’s disease participants with implanted STN or GPi DBS systems were recruited for this study. Verbal fluency data was obtained from each patient preoperatively and 6- months post implantation. The stimulation-based volume of tissue activated area (VTA) of each target site (STN or GPi) was analyzed using Lead-DBS and Lead-Group. The white matter tracks intersecting each patient’s VTA, terminating in the pre-SMA, SMA, caudate nucleus, and anterior cingulate were investigated and correlated with verbal fluency declines. We found statistically significant …


Knockdown Of C. Elegans Nad Kinases Nadk-1 Or Nadk-2 Induces An Antioxidant Response Without Affecting Lifespan, Henry Gong May 2022

Knockdown Of C. Elegans Nad Kinases Nadk-1 Or Nadk-2 Induces An Antioxidant Response Without Affecting Lifespan, Henry Gong

Electronic Theses and Dissertations

Nearly all multicellular organisms show changes in redox balance with aging leading to oxidative damage of macromolecules. This study investigated the role of the [NADP+]/[NADPH] redox couple in aging. This redox couple plays an important role in maintaining tissue redox balance and becomes slightly more oxidized in aged tissues. NADPH is a major source of reducing equivalents for enzymes that detoxify hydrogen peroxide. However, catalase detoxifies hydrogen peroxide independently of NADPH. But catalase is absent from mitochondria, a major source of hydrogen peroxide, where instead glutathione plays the major role in hydrogen peroxide detoxification in an NADPH-dependent manner. …


Decoding The Mystery Of Antibiotic Persistence, Tahmina Hossain Jan 2022

Decoding The Mystery Of Antibiotic Persistence, Tahmina Hossain

Electronic Theses and Dissertations

This work combines microbiology, molecular biology, Next-Generation Sequencing and system biology approaches to explore the mechanism of antibiotic persistence: a multi-drug tolerant, non-dividing, and metabolically altered state present in a subpopulation of cells due to phenotypic diversity rather than genetic variation (i.e. mutations). Persister can survive lethal antibiotic state and resuscitate after the treatment period is over. They are considered as the major contributing factor behind recurring infections. They also have a high mutation rate, which increases the chances of bacteria gaining antibiotic resistance. The formation of this phenotypic variant (persister) threatens the therapeutic effectiveness of antibiotics and understanding how …


Role Of Meibum And Tear Phospholipids In The Evaporative Water Loss Associated With Dry Eye., Samiyyah M. Sledge Dec 2021

Role Of Meibum And Tear Phospholipids In The Evaporative Water Loss Associated With Dry Eye., Samiyyah M. Sledge

Electronic Theses and Dissertations

It is generally believed that the tear film lipid surface film inhibits the rate of evaporation (Revap) of the underlying tear aqueous. It is also generally believed that changes in the composition of the tear film lipid layer is responsible for an increase in Revap in patients with dry eye. Both of these ideas have never been proven. The purpose of the current studies was to test these ideas. Revap was measured in vitro gravimetrically. Lipid spreading was measured using Raman spectroscopy and microscopy. The influence of the following surface films on the Revap of the sub phase of physiologically …


Preclinical Development Of Epicertin, A Novel Biotherapeutic For The Treatment Of Ulcerative Colitis., Micaela Ann Reeves Dec 2021

Preclinical Development Of Epicertin, A Novel Biotherapeutic For The Treatment Of Ulcerative Colitis., Micaela Ann Reeves

Electronic Theses and Dissertations

Epicertin (EPT) is a recombinant variant of the cholera toxin B subunit with a C-terminal KDEL endoplasmic retention motif. Previously, orally administered EPT demonstrated mucosal healing activity in acute and chronic dextran sulfate sodium colitis models, indicating its therapeutic potential for ulcerative colitis (UC) treatment. However, oral dosing with EPT requires neutralization of gastric acid prior to administration, hindering its facile application in the treatment of chronic diseases like UC. One solution to this issue is that EPT may also be administered intracolonically without losing efficacy. This work describes the determination of a target intracolonic dose of EPT for future …


Assessing The Role Of Arsenic Exposure And Mirna-186 In Skin Tumorigenesis And Chromosomal Instability., Angeliki Lykoudi Dec 2021

Assessing The Role Of Arsenic Exposure And Mirna-186 In Skin Tumorigenesis And Chromosomal Instability., Angeliki Lykoudi

Electronic Theses and Dissertations

Chronic arsenic exposure through drinking water is a global health issue, affecting more than 200 million people. Arsenic is a group I human carcinogen and causes chromosomal instability (CIN). Arsenic exposure is the second most cause of skin cancer after UV radiation. MiR-186 is overexpressed in arsenic-induced squamous cell carcinoma relative to premalignant hyperkeratosis. Predicted targets of miR-186 are cell cycle regulators. Thus, we hypothesize that miR-186 overexpression drives malignant transformation of HaCaT cells by induction of CIN. Stable clones of HaCaT transfected with pEP-miR-186 expression vector or empty vector were maintained under puromycin selection were exposed to 0 or …


An Analysis Of Taste Neuron Morphological Variability: Influences Of Neuron Type And Plasticity., Lisa Christina Ohman Dec 2021

An Analysis Of Taste Neuron Morphological Variability: Influences Of Neuron Type And Plasticity., Lisa Christina Ohman

Electronic Theses and Dissertations

Taste neurons are functionally and molecularly diverse, but their morphological diversity was, until recently, completely unexplored. Taste neurons were considered relay cells, communicating information from taste-transducing cells to the brain without variation in morphology. Instead, individual taste neurons are tremendously morphologically variable. To determine how differences in branching relate to the number and types of taste-transducing cells providing neuronal input, I combined sparse cell genetic labeling with a whole-mount immunohistochemistry and analysis workflow. I found that the maximum number of taste-transducing cells capable of providing convergent input onto individual gustatory neurons varied with a range of 1-22 taste-transducing cells. Consistently, …


Genital Chlamydia Infection Is Influenced By The Female Sex Hormones Estrogen And Progesterone In Vivo, Amy Gail Gravitte Dec 2021

Genital Chlamydia Infection Is Influenced By The Female Sex Hormones Estrogen And Progesterone In Vivo, Amy Gail Gravitte

Electronic Theses and Dissertations

Chlamydia is the most common bacterial sexually transmitted infection in the United States and worldwide. It often goes unnoticed due to lack of symptoms and left untreated it can ascend the female genital tract to cause sequelae like pelvic inflammatory disease and irreversible tubal infertility. In reproductive-aged women, female sex hormones estrogen (E2) and progesterone (P4) concentrations fluctuate during the menstrual cycle and are influenced by hormonal contraceptives and hormone replacement therapy. E2 and P4 influence genital Chlamydia infection in women and mice, but these multifactorial interactions are not entirely mapped out. The complex interplay of E2 and P4 with …


Effects Of Chemosensory Experience And Context On Consummatory Behaviors., Saphira M. Chiu Dec 2021

Effects Of Chemosensory Experience And Context On Consummatory Behaviors., Saphira M. Chiu

Electronic Theses and Dissertations

Eating food generates associations between odors and tastes (i.e., flavor) that guide future choices. Experience with an odor-taste mixture links an odor with a taste’s quality and hedonic value, resulting in a preference for an odor paired with a palatable taste over an odor paired with an unpalatable taste. However, experience with a neutral stimulus (i.e., latent inhibition) or environment (i.e., context) can influence the formation of conditioned associations. Here, I used a two-bottle brief-access task to determine whether rats display an innate preference between unpaired odors (isoamyl acetate and benzaldehyde), how preexposure to the unpaired odors impacts mixture-dependent consummatory …


Decreasing Unintentional Pregnancies For Tennesseans, Paula M. Todd Oct 2021

Decreasing Unintentional Pregnancies For Tennesseans, Paula M. Todd

Electronic Theses and Dissertations

In 2018, 49% of all pregnancies in the United States were unintended, with women with a lower- income status being five times more likely to experience an unplanned pregnancy. Tennessee has a high rate of unintended pregnancies, particularly among the uninsured, low-income, and rural teen populations; some 22% of these unintended pregnancies end in abortion. Oral or transdermal contraceptives that are affordable and accessible for women of childbearing age can reduce unintentional pregnancies. The addressed gap in clinical practice was that contraceptives are not currently available over the counter in Tennessee pharmacies without a prescription, which necessitates a costly medical …


Decreased Kidney Mitochondrial Content And Pgc-1Α Following Repeated Low-Dose Cisplatin-Induced Kidney Injury., Andrew Joseph Orwick Aug 2021

Decreased Kidney Mitochondrial Content And Pgc-1Α Following Repeated Low-Dose Cisplatin-Induced Kidney Injury., Andrew Joseph Orwick

Electronic Theses and Dissertations

Cisplatin is highly effective and one of the most commonly used chemotherapeutic agents in the treatment of a number of different solid organ tumors. Unfortunately, the dose-limiting nephrotoxicity occurs in up to 30% of patients, which requires alterations to treatment regimens that are often less effective. The kidney’s function is to provide fluid homeostasis, and this is an energy-intensive process. Proper renal function is dependent on functional mitochondria. PGC-1α regulates mitochondrial number, respiratory capacity, and mitochondrial proteins in proximal tubule cells. We delivered low-dose cisplatin to mice via intraperitoneal injections once a week for 4 weeks. The mice were then …


Oligodendrocyte Responses After Spinal Cord Injury., George Zach Wei Aug 2021

Oligodendrocyte Responses After Spinal Cord Injury., George Zach Wei

Electronic Theses and Dissertations

Recent studies demonstrate that neuroprotection strategies targeting the proteostasis network and components of its effector signaling pathways improve cell survival and motor recovery outcomes in several models of neuronal injury and degeneration. However, the individual contributions of these signaling pathways to the pathogenesis of spinal cord injury (SCI), white matter damage, and motor recovery have not yet been determined. Here, I explored the role of the HIF prolyl hydroxylase domain proteins (PHD/EGLN), effectors that can modulate stress responses activated by the proteostasis network, on motor function recovery after SCI. Furthermore, I identified previously unknown candidate mechanisms in an unbiased manner …


Metabolic-Epigenetic Regulation Of Macrophage Polarization., Jordan T. Noe Aug 2021

Metabolic-Epigenetic Regulation Of Macrophage Polarization., Jordan T. Noe

Electronic Theses and Dissertations

Tumor-associated macrophages polarized to an M2 phenotype (M2-TAMs) promote neo-angiogenesis, tumor-stromal matrix remodeling, and immuno-evasion, which, collectively, contribute to immunotherapeutic resistance and reduced cancer patient survival. Highly glycolytic “Warburg” cancer cells produce lactate that independently drives naïve M0→immunosuppressive M2 (M0→M2) macrophage polarization, but the mechanisms have not been fully elucidated. The atypical cytokine macrophage migration inhibitory factor (MIF) is a fundamental underlying requirement for immunosuppressive M2 macrophage polarization. Still, it is unknown whether a molecular link exists between lactate-supported and MIF-dependent M2 macrophage polarization. Using a combination of gene expression assays, chromatin immunoprecipitation, and metabolomic analyses, we identified that M2 …


Harnessing The Power Of Trained Immunity In The Setting Of Pancreatic Cancer: A Novel Mechanism Of Immune Trafficking And Tumor Control., Anne Elena Geller May 2021

Harnessing The Power Of Trained Immunity In The Setting Of Pancreatic Cancer: A Novel Mechanism Of Immune Trafficking And Tumor Control., Anne Elena Geller

Electronic Theses and Dissertations

Despite the success of immunotherapy in many types of cancer, pancreatic adenocarcinoma (PDAC) has yet to benefit. Innate immune cells are critical to antitumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Though trained innate immunity has mostly been investigated in the context of infection, the induction of trained innate immunity could also protect against tumors, and specifically pancreatic tumors. Here, we demonstrate that yeast-derived particulate β-glucan, a known inducer of trained immunity, traffics to the pancreas following IP administration. This causes …


Pde4 Inhibition: A Novel Therapeutic Strategy In Liver Fibrosis., Mohamed Elnagdy May 2021

Pde4 Inhibition: A Novel Therapeutic Strategy In Liver Fibrosis., Mohamed Elnagdy

Electronic Theses and Dissertations

Background: Liver fibrosis is accumulation of extracellular matrix (ECM) proteins due to chronic liver injury. Chronic hepatic damage can occur due to multiple causes including, alcohol, non-alcoholic steatohepatitis and chronic viral hepatitis. Liver fibrosis is a critical problem worldwide due to the extremely high incidence of alcohol associated liver damage and chronic viral hepatitis. Moreover, there is no FDA approved therapy for liver fibrosis. Activation and transdifferentiation of quiecent hepatic stellate cells (HSCs) to myofibroblasts (MFBs) is the main event contributing to liver fibrosis. This process involves two phases, the initiation and the perpetuation phases. Hepatocyte injury and inflammatory response …