Medicine and Health Sciences Commons^™

A License To Kill: Understanding Natural Killer Cell Licensing To Fight Cancer, Jolie Schafer

Dissertations and Theses (Open Access)

Natural killer (NK) cell education is an essential developmental process for NK cell effector function, that renders some NK cells “licensed” and others “unlicensed” (with heightened or lowered effector function potential, respectively) against tumor and targets lacking self-molecules. However, the underlying mechanisms responsible for the heightened effector responses of licensed cells remain unknown. Using NK cells derived from humans and expanded ex vivo we performed high-throughput protein expression analysis, and identified multiple proteins that are differentially regulated in licensed and unlicensed human NK cells before and after inhibition by killer-cell immunoglobulin-like receptors (KIRs) and activation by the NKp46 natural cytotoxicity …

Evaluating The Therapeutic Efficacy Of Restoring Wild-Type P53 Activity In P53-Mutant Tumors, Connie A. Larsson

Dissertations and Theses (Open Access)

The p53 transcription factor is the most frequently altered in human cancers usually via missense mutations that undermine its transcriptional activity. Clinically, TP53 mutations have been shown to be remarkably predictive of refractoriness to treatment, resulting in poor outcome. Consequently, the development of p53 pathway activating agents is rapidly evolving and gaining more attention in cancer therapeutics research, with several small molecule compounds currently in preclinical and clinical trials. However, it remains largely unknown what types or proportions of p53-mutant tumors will respond to p53 restoration-based therapies.

Using a mouse model of Li Fraumeni syndrome, we genetically restored wild-type …

Mechanism Of Candida Albicans Biofilm And Virulence Inhibition By A Bacterial Secreted Factor, Carrie Graham

Dissertations and Theses (Open Access)

The human microbiome is a diverse polymicrobial population comprised of both fungi and bacteria. Perturbations of the normal microbiome can have a profound impact on health, including the development of infections. Exploitation of these polymicrobial interactions has the potential to provide novel treatment and prevention strategies for infectious diseases. Enterococcus faecalis, a Gram-positive bacterium, and Candida albicans, a polymorphic fungus, occupy overlapping niches as ubiquitous constituents of the gastrointestinal and oral microbiome. Both species are also amongst the most important and problematic, opportunistic nosocomial pathogens and are often co-isolated during infection. Surprisingly, these two species antagonize each other’s …

Serum Microrna-27b As A Screening Biomarker For Left Ventricular Hypertrophy, Yan Wang, Shuyan Chen, Yanhong Gao, Song Zhang

The Texas Heart Institute Journal

MicroRNA-27b (miR-27b) is frequently upregulated in pressure-overloaded hypertrophic hearts. The clinical implications of aberrant circulating miR-27b in the diagnosis and management of left ventricular hypertrophy warrant study. We investigated whether serum miR-27b is a biomarker for left ventricular hypertrophy (LVH).

We used stem-loop reverse-transcription quantitative polymerase chain reaction techniques to analyze serum miR-27b levels in 200 hypertensive patients with LVH, 100 hypertensive patients without LVH, and 100 healthy volunteers. We found that serum miR-27b levels were significantly higher in the hypertensive patients with LVH than in the hypertensive patients without LVH and in the healthy volunteers. Upon receiver operating characteristic …

A Blueprint For Life And Love, Marilyn Todd

The Texas Heart Institute Journal

No abstract provided.

Computational Identification Of Noncoding Driver Mutations Based On Impact On Rna Processing, Kevin Zhu

Dissertations and Theses (Open Access)

Despite the prevalence of mutations in the noncoding regions of the DNA, their effects on cancer development remain largely uninvestigated. This is especially evident when compared to coding mutations, which have been relatively well-studied and, in certain cases, been identified as driver mutations for cancer. Recent studies, however, have identified noncoding mutations that frequently appear in certain types of cancer, which may be evidence that those mutations are important to cancer development. Nonetheless, the role of noncoding mutations in cancer remains unclear. A potential vector for understanding this mechanism is through observing the relation between noncoding mutations and functional RNA …

Integrative Cancer Immunogenomic Analysis Of Serial Melanoma Biopsies Reveals Correlates Of Response And Resistance To Sequential Ctla-4 And Pd-1 Blockade Treatment, Whijae Roh

Dissertations and Theses (Open Access)

Melanoma is the most malignant form of skin cancer. The five-year survival rate for metastatic melanoma is 19.9%. Although targeted therapy of BRAF and MEK inhibitors were developed for melanoma, resistance to therapy is inevitable. Immune checkpoint blockade, which reverses the suppression of the immune system, on the other hand, has shown a durable response in 20-30% of patients with metastatic melanoma. However, more predictive and robust biomarkers of response to this therapy are still needed, and resistance mechanisms remain incompletely understood. To address this, we examined a cohort of metastatic melanoma patients treated with sequential checkpoint blockade against cytotoxic …

Memory Potential, Molecular Characterization, And Translational Applications Of The Novel Theo/Tceo T Cell Phenotype, Todd Bartkowiak, Todd Bartkowiak

Dissertations and Theses (Open Access)

T cells comprise a substantial arm of the immune system and are exquisitely adapted to combat pathogens and tumors. The inflammatory environment largely dictates the nature of T cell response. A hallmark of T cell-mediated immunity is formation of immunological memory; the ability to respond more potently to re-encounter with pathogens. The immune system is also capable of recognizing tumors as foreign, much like viral or bacterial pathogens. Tumors have evolved, though, to generate an immunosuppressive environment to avoid destruction. The field of immunotherapy seeks to overcome immune suppression, in part by targeting T cell co-receptors on the cell surface …

Impact Of Kras/Nras Mutational Heterogeneity On Clinical Outcomes In Colorectal Cancer, Jonathan M. Loree

Dissertations and Theses (Open Access)

Introduction: Mutations in KRAS/NRAS (RAS) predict a lack of benefit from anti-EGFR agents in metastatic colorectal cancer (mCRC). As next generation sequencing (NGS) has advanced, we are discovering atypical and low allele frequency mutations. We aimed to evaluate how NGS can optimally define RAS mutant CRC and the role of relative mutant allele frequency (rMAF) as a biomarker.

Methods: Using institutional and public cohorts of mCRC patients with NGS results, we described the prevalence and clinical impact of atypical (not in current guidelines) and low rMAF RAS mutations (RAS MAF by the MAF of the mutated gene with …

Quality Of Life: Socio-Demographic And Genetic Determinants As Well As Links With Cancer Outcomes, Jeanne Pierzynski

Dissertations and Theses (Open Access)

Quality of life (QOL) is an independent prognostic factor for cancer. Lung cancer is the leading cause of cancer death. Breast cancer is the most diagnosed. Bladder cancer is the most expensive cancer to treat because of its high recurrence rate. We set to perform comprehensive analyses of predictors of QOL in these cancer sites with the future goal of improving QOL and outcomes.

In 6,456 newly diagnosed lung cancer patients, we investigated the relationship between baseline patient characteristics and QOL to identify determinants of QOL. A QOL questionnaire (SF-12v1) measured patients’ physical component summary (PCS) and mental component summary …

Dynamic Assessment Of Nk Cell Interactions With Pediatric Tumor Cells To Predict Response To Immunotherapy, Arianexys Aquino Lopez

Dissertations and Theses (Open Access)

Due to Natural Killer (NK) cells’ capacity to target tumor cells without prior sensitization, adoptive NK cell therapy represents a promising immunotherapy approach for pediatric cancer patients. Our laboratory has developed an NK cell expansion protocol that generates large quantities of NK cells for therapeutic infusion. Given that NK cells are heterogeneous, with variable receptor expression and potential to target tumor cells, the purpose of my study was to determine whether subpopulations of NK cells with enhanced anti-tumor potential could be identified for increased potency of the NK cell infusion product. In addition, we previously showed that our expanded NK …

The Functions Of Setd5 And Mir-221 In Embryonic Stem Cell Differentiation, Tsai-Yu Chen

Dissertations and Theses (Open Access)

Embryonic stem cells (ESCs) are a widely used model system to study cellular differentiation because of their pluripotent characteristics, and ESC differentiation is an epigenetic process. In an effort to identify a new epigenetic factor that is required for ESC differentiation, the function of SETD5 in ESCs was studied for this thesis. Results show that SETD5 is essential for retinoic acid (RA)-induced differentiation of mouse ESCs and for RA-induced expression of critical developmental genes (e.g., Hoxa1 and Hoxa2) and neuron-related genes (e.g., Nestin and Pax6). SETD5 was upregulated during ESC differentiation. Additional results demonstrated that SETD5 bound to …

Circulating Autoantibodies In Human Traumatic Spinal Cord Injury Subjects And Their Relationship To The Development Of Neuropathic Pain, Georgene Hergenroeder

Dissertations and Theses (Open Access)

Background:

Approximately 17,500 spinal cord injuries (SCI) occur yearly in the U.S. causing considerable morbidity and mortality. Neuropathic pain (NP) ensues in 40-70% of SCI. An autoimmune response resulting from disruption of the blood-spinal cord-barrier may be a contributor to NP. However, the relationship between autoantibodies and NP after SCI in humans has not been thoroughly characterized nor have autoantigens been identified. Glial fibrillary acidic protein (GFAP) and collapsin response mediator protein2 (CRMP2) were identified as candidate autoantigens. The hypothesis is that proteins from the injured spinal cord released by SCI trigger autoantibody production which can lead to the development …

Modeling Post Stroke Respiratory Dysfunction, Apneas And Cognitive Decline, Anthony Patrizz

Dissertations and Theses (Open Access)

Modeling Post Stroke Respiratory Dysfunction,

Apneas and Cognitive Decline

Anthony Patrizz, B.A.

Advisory Professor: Louise McCullough M.D., Ph.D.

Stroke is a major cause of mortality and the leading cause of long-term disability in the US. More than 60% of individuals suffering a first time stroke develop respiratory dysfunction, prolonging recovery and increasing mortality. Post-stroke cognitive decline is a major contributor to disability and nursing home placement, therefore the cognitive consequences of Stroke Induced Respiratory Dysfunction (SIRD) need to be explored if we hope to enhance functional recovery. The first step towards treatment of the negative consequences of SIRD is the …

Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon

Dissertations and Theses (Open Access)

Salt inducible kinase 1 (SIK1) has been considered a stress-inducible kinase since it was first cloned in 1999. Continued efforts since this time have been dedicated to characterizing the structure and function of SIK1. Such research has laid the ground work for our understanding of SIK1 action and regulation in tissue and stimuli dependent manners. The fundamental findings of this dissertation continue in this tradition and include investigations of SIK1 regulatory mechanisms in skeletal muscle cells, the cellular and physiological effects of SIK1 loss of function in vitro and in vivo, and intracellular metabolic and mitochondrial regulation by this …

Endocytic Trafficking Of The Amyloid Precursor Protein In Rat Cortical Neurons, Sahily Reyes

Dissertations and Theses (Open Access)

Amyloid-beta (Aβ) aggregation and deposition into extracellular plaques is a hallmark of the most common forms of dementia, including Alzheimer’s disease. The Aβ-containing plaques result from pathogenic cleavage of amyloid precursor protein (APP) by secretases resulting in intracellular production of Aβ peptides that are secreted and accumulate extracellularly. Despite considerable progress towards understanding APP processing and Aβ aggregation, the mechanisms underlying endosomal production of Aβ peptides and their secretion remain unclear. Using endosomes isolated from cultured primary neurons, we determined that the trafficking of APP from the endosomal membrane into internal vesicles of late endosome/multivesicular bodies (MVB) is dependent on …

Membrane Bound Il21 Promotes Natural Killer Cell Expansion Through Mir 124-3p Mediated Regulation, Anitha Somanchi

Dissertations and Theses (Open Access)

Natural Killer (NK) cells are cells of the innate immune system that act as first line of defense against viral infections and participate in tumor immune surveillance. NK cells do not cause graft versus host disease (GvHD), or require prior antigen exposure to exert anti-tumor activity, hence are an attractive choice for immunotherapy applications. Owing to small numbers of NK cells in peripheral blood (1-32%, with a 6% median), ex vivo expansion of NK cells is critical for NK cell adoptive immunotherapy, various expansion platforms have been explored over the decades. We developed a robust platform for ex vivo expansion …

Bioresorbable Scaffolds In Spontaneous Coronary Artery Dissection: Long-Term Follow-Up In 4 Patients, Santiago Jesús Camacho Freire, Antonio Enrique Gómez Menchero, Jessica Roa Garrido, Javier León Jiménez, Rosa Cardenal Piris, José Francisco Díaz Fernández

The Texas Heart Institute Journal

Spontaneous coronary artery dissection is a rare condition, and diagnosis and treatment are challenging among patients who present with acute coronary syndrome. Typically, the condition affects young females who have no underlying atherosclerotic disease. To date, few cases of bioresorbable scaffold implantation for the treatment of spontaneous coronary artery dissection have been reported. Therefore, we describe the cases of 4 patients whom we treated with scaffolds. We evaluated the long-term results by using intravascular ultrasound and optical coherence tomographic scanning.

Recurrent Biatrial Myxoma In A 41-Year-Old Woman After Left Atrial Myxoma Resection, Xiaoming Jia, Anjali Kohli, Jane Jarjour, Chung-Jiah Justin Chen, Brendan Gilmore, Rashed Tabbaa, Edward Lee Poythress

The Texas Heart Institute Journal

Bilateral recurrence of atrial myxoma has been reported only a few times. We describe the case of a 41-year-old woman who had undergone left atrial myxoma resection and presented 9 years later with myxomas in both atria. The patient underwent successful resection of both masses with resolution of symptoms. We discuss the phenomenon of recurrent biatrial myxoma.

Multimodal Imaging Of Anomalous Left Coronary Artery From The Pulmonary Artery In A 75-Year-Old Woman, Margaret M Fuchs, Rachel J Le, Michael W Cullen, Joseph J Maleszewski, Naser M Ammash

The Texas Heart Institute Journal

Anomalous origin of the left coronary artery from the pulmonary artery is rare and typically results in mitral regurgitation, ventricular arrhythmias, heart failure, and sudden death. The condition most often manifests itself in early childhood, but some individuals are diagnosed much later. We describe the case of a 75-year-old woman with heart failure in whom stepwise multimodal imaging revealed anomalous origin of the left coronary artery from the pulmonary artery.

Col4a2 Is Associated With Lacunar Ischemic Stroke And Deep Ich: Meta-Analyses Among 21,500 Cases And 40,600 Controls, Kristiina Rannikmäe, Vhinoth Sivakumaran, Henry Millar, Rainer Malik, Christopher D Anderson, Mike Chong, Tushar Dave, Guido J Falcone, Israel Fernandez-Cadenas, Jordi Jimenez-Conde, Arne Lindgren, Joan Montaner, Martin O'Donnell, Guillaume Paré, Farid Radmanesh, Natalia S Rost, Agnieszka Slowik, Martin Söderholm, Matthew Traylor, Sara L Pulit, Sudha Seshadri, Brad B Worrall, Daniel Woo, Hugh S Markus, Braxton D Mitchell, Martin Dichgans, Jonathan Rosand, Cathie L M Sudlow

Faculty, Staff and Student Publications

OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.

METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (

RESULTS: A locus in

CONCLUSIONS: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

Predictors Of High-Sensitivity Cardiac Troponin T Elevation In Patients With Acute Paroxysmal Supraventricular Tachycardia And Ischemic Heart Disease, Mehdi Sayadnik, Akbar Shafiee, Yaser Jenab, Arash Jalali, Saeed Sadeghian

The Texas Heart Institute Journal

We studied the predictors and patterns of high-sensitivity cardiac troponin T (hs-cTnT) elevation in patients with paroxysmal supraventricular tachycardia (PSVT) in the presence and absence of ischemic heart disease.

During calendar year 2013, we enrolled 70 of 72 consecutive adult patients with PSVT who presented at our center within 4 hours after the onset of tachycardia. On the basis of increased hs-cTnT at either of 2 initial measurements, we divided patients into groups (hs-cTnT–positive and hs-cTnT–negative), to study the predictors of enzyme elevation. We then divided the hs-cTnT–positive patients into 2 groups—those with and those without ischemic heart disease—and compared …

Left Circumflex Coronary Artery As The Culprit Vessel In St-Segment-Elevation Myocardial Infarction, Diab Ghanim, Fabio Kusniec, Wadi Kinany, Dahud Qarawani, David Meerkin, Khaled Taha, Offer Amir, Shemy Carasso

The Texas Heart Institute Journal

The prevalence of the left circumflex coronary artery (LCx) as the culprit vessel in ST-segment-elevation myocardial infarction (STEMI) is reportedly lowest among that of the 3 main epicardial arteries, and has not been described for non-STEMI (NSTEMI) and stable angina pectoris. We sought to define the distribution of culprit arteries in these clinical presentations and suggest mechanisms for the differences.

We reviewed 189 coronary angiograms of patients with STEMI, 203 with NSTEMI, and 548 with stable angina (n=940), and compared distributions of stenotic and culprit coronary arteries (lesions prompting intervention).

Obstructive coronary lesions (≥50% narrowing) were more prevalent in the …

The Rise And Fall Of Estrogen Therapy: Is Testosterone For "Manopause" Next?, Briana T Costello, Keri Sprung, Stephanie A Coulter

The Texas Heart Institute Journal

No abstract provided.

Management Of Chronic Venous Disease, Michael Mcardle, Eduardo A Hernandez-Vila

The Texas Heart Institute Journal

No abstract provided.

A Blessing, Jeremy A Ross

The Texas Heart Institute Journal

No abstract provided.

Project Echo: A Telementoring Program For Cervical Cancer Prevention And Treatment In Low-Resource Settings, Melissa S Lopez, Ellen S Baker, Andrea M Milbourne, Rose M Gowen, Ana M Rodriguez, Cesaltina Lorenzoni, Catherine Mwaba, Susan Citonje Msadabwe, José Humberto Tavares, Georgia Fontes-Cintra, Gustavo Zucca-Matthes, Donato Callegaro-Filho, Danielle Ramos-Martin, Icaro Thiago De Carvalho, Robson Coelho, Renato Moretti Marques, Thiago Chulam, Mila Pontremoli-Salcedo, Fernanda Nozar, Veronica Fiol, Mauricio Maza, Sanjeev Arora, Ernest T Hawk, Kathleen M Schmeler

Faculty, Staff and Student Publications

Cervical cancer incidence and mortality rates are significantly higher in low- and middle-income countries compared with the United States and other developed countries. This disparity is caused by decreased access to screening, often coupled with low numbers of trained providers offering cancer prevention and treatment services. However, similar disparities are also found in underserved areas of the United States, such as the Texas-Mexico border, where cervical cancer mortality rates are 30% higher than in the rest of Texas. To address these issues, we have adopted the Project ECHO (Extension for Community Healthcare Outcomes) program, a low-cost telementoring model previously proven …

Genetic Moderation Of Cocaine Subjective Effects By Variation In The Tph1, Tph2, And Slc6a4 Serotonin Genes, Michelle A Patriquin, Sara C Hamon, Mark J Harding, Ellen M Nielsen, Thomas F Newton, Richard De La Garza, David A Nielsen

Staff and Researcher Publications

Objective: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine.

Methods: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used …

Increased Habenular Connectivity In Opioid Users Is Associated With An Α5 Subunit Nicotinic Receptor Genetic Variant, Kaylah Curtis, Humsini Viswanath, Kenia M Velasquez, David L Molfese, Mark J Harding, Eduardo Aramayo, Philip R Baldwin, Elisa Ambrosi, Alok Madan, Michelle Patriquin, B Christopher Frueh, J Christopher Fowler, Thomas R Kosten, David A Nielsen, Ramiro Salas

Staff and Researcher Publications

Background and objectives: Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive …

Effects Of Once-Weekly Exenatide On Cardiovascular Outcomes In Type 2 Diabetes, Rury R Holman, M Angelyn Bethel, Robert J Mentz, Vivian P Thompson, Yuliya Lokhnygina, John B Buse, Juliana C Chan, Jasmine Choi, Stephanie M Gustavson, Nayyar Iqbal, Aldo P Maggioni, Steven P Marso, Peter Öhman, Neha J Pagidipati, Neil Poulter, Ambady Ramachandran, Bernard Zinman, Adrian F Hernandez

Faculty, Staff and Student Publications

BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.

METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.

RESULTS: …