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

Dissertations and Theses (Open Access)

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

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

Dissertations and Theses (Open Access)

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

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

Dissertations and Theses (Open Access)

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

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

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

Dissertations and Theses (Open Access)

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

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

Dissertations and Theses (Open Access)

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

Ionic Mechanism Of Lysosomal Function And Cell Metabolism, Jian Xiong

Dissertations and Theses (Open Access)

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

Glutamine …

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

Dissertations and Theses (Open Access)

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

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

Dissertations and Theses (Open Access)

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

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

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

Estimates Of Throughput And Utilization At Freestanding Compared To Low-Volume Hospital-Based Emergency Departments, Nick Jouriles, Erin L Simon

Faculty, Staff and Students Publications

OBJECTIVE: Our investigation compared throughput metrics and utilization measures for freestanding emergency departments (FSEDs) versus hospital-based emergency departments (HBEDs) of similar volumes in the United States.

METHODS: This study is a cross sectional survey of 183 FSEDs and 317 HBEDs located across the United States using the Emergency Department Benchmarking Alliance (EDBA) Database. We measured common emergency department (ED) throughput metrics. Primary outcomes included overall length of stay, length of stay for admitted, and length of stay for treated and released patients. Outcomes were weighted based on the proportion of ED volume per facility as per a prior pilot study. …

Spinal Cord Injury Provider Knowledge And Attitudes Toward Bacteriuria Management And Antibiotic Stewardship, Ivy Poon, Sally Ann Holmes, Lindsey Martin, Barbara W Trautner

Faculty, Staff and Students Publications

INTRODUCTION: Bacteriuria, either asymptomatic or urinary tract infection, is common in persons with spinal cord injury or disorder (SCI/D). In the Veterans Health Administration (VHA), conflicting clinical practice guidelines make appropriate bacteriuria management and antibiotic stewardship challenging.

OBJECTIVE: To explore SCI/D provider knowledge, attitudes, and teamwork around bacteriuria management during the VHA SCI/D annual examination.

DESIGN: Mixed methods.

SETTING: VHA SCI/D centers.

PARTICIPANTS: SCI/D staff providers and physical medicine and rehabilitation resident physicians.

MAIN OUTCOME MEASUREMENTS: Knowledge, safety, and teamwork scores on bacteriuria management using a validated questionnaire. Themes on barriers and facilitators to bacteriuria management during the SCI/D annual …

Mouse Models To Study The Pathophysiology Of Combined Methylmalonic Acidemia And Homocystinuria, Cblc Type, Chih-Wei Hsu, Leeyean Wong, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria, cblC type, is the most common inherited disorder of cobalamin metabolism and is characterized by severe fetal developmental defects primarily impacting the central nervous system, hematopoietic system, and heart. CblC was previously shown to be due to mutations in the MMACHC gene, which encodes a protein thought to function in intracellular cobalamin trafficking and biosynthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are required for the production of succinyl-CoA and methionine, respectively. However, it is currently unclear whether additional roles for MMACHC exist outside of cobalamin metabolism. Furthermore, due to a lack of sufficient …

Postacute Covid-19: An Overview And Approach To Classification, Hana M El Sahly, Robert L Atmar, Prathit A Kulkarni

Faculty, Staff and Students Publications

As the coronavirus disease 2019 (COVID-19) pandemic has progressed, a large volume of literature has developed delineating the clinical manifestations of acute infection. Recent reports have also started to describe persistent symptoms extending beyond the period of initial illness or hospitalization. Anecdotes of different signs and symptoms occurring after acute infection have also arisen in the lay press. Here we describe the current existing medical literature on the emerging concept of postacute COVID-19 and suggest an approach to classifying different manifestations of the syndrome. We also review long-term clinical manifestations observed in patients who recovered from infection due to other …

The Cancer Patient And Cardiology, Dan Atar, Lina Badimon, Jeroen J Bax, Daniela Cardinale, Antonella Cardone, Elizabeth A M Feijen, Péter Ferdinandy, Teresa López-Fernández, Chris P Gale, John H Maduro, Javid Moslehi, Torbjørn Omland, Juan Carlos Plana Gomez, Jessica Scott, Thomas M Suter, Giorgio Minotti

Faculty, Staff and Students Publications

Advances in cancer treatments have improved clinical outcomes, leading to an increasing population of cancer survivors. However, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach that includes expertise in oncology, cardiology and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and …

Survival Analysis Of Colorectal Cancer Patients With Liver Metastasis, Brandon O’Grady

Dissertations and Theses (Open Access)

Background- Colorectal cancer is the third most common cancer in the world. I investigated the survival rates among colorectal cancer patients diagnosed with hepatic metastasis to see if any variables are associated colorectal risk and survival. Methods- Patients were diagnosed from 2000-2019 and collected through MD Anderson’s database. A descriptive analysis, univariate analysis, Kaplan-Meier with Mantel log-rank test, Cox proportion hazard regression and a Stratified Cox Model was performed to investigate death. A competing risk regression was implemented to investigate liver recurrence. Results- There was a clear difference in the survival outcome between liver surgery patients and non-liver surgery patients …

The Cortico-Limbo-Thalamo-Cortical Circuits: An Update To The Original Papez Circuit Of The Human Limbic System, Eric J Thomas, J Bryan Sexton

Faculty, Staff and Student Publications

OBJECTIVES: Key validated clinical metrics are being used individually and in aggregate (Baby-MONITOR) to monitor the performance of neonatal intensive care units (NICUs). The degree to which perceptions of key components of safety culture, safety climate, and teamwork are related to aspects of NICU quality of care is poorly understood. The objective of this study was to test whether NICU performance on key clinical metrics correlates with caregiver perceptions of safety culture.

STUDY DESIGN: Cross-sectional study of 6253 very low-birth-weight infants in 44 NICUs. We measured clinical quality via the Baby-MONITOR and its nine risk-adjusted and standardized subcomponents (antenatal corticosteroids, …

Tracheostomy While On Extracorporeal Membrane Oxygenation: A Comparison Of Percutaneous And Open Procedures, Reshma Hussain, Mehmet H Akay, Rahat Hussain, Jayeshkumar Patel, Chandni Patel, Yafen Liang, John Zaki, Biswajit Kar, Igor D Gregoric

Faculty, Staff and Student Publications

Although the ideal timing of tracheostomy for critically ill patients is controversial, transitioning from an endotracheal tube can be beneficial. Concerns arise for patients under extracorporeal membrane oxygenation (ECMO) support. Studies have described percutaneous and open tracheostomy approaches for critically ill patients but, to our knowledge, have not compared the two specifically in ECMO patients. This study analyzed safety and aimed to identify if there was a difference in major bleeding or other tracheostomy-associated complications. A single-center retrospective cohort study of all patients who received tracheostomy while on ECMO from July 2013 to May 2019 was completed. The primary endpoint …

Model For End-Stage Liver Disease-Sodium Underestimates 90-Day Mortality Risk In Patients With Acute-On-Chronic Liver Failure, Abbas Rana, Hashem B El-Serag, Fasiha Kanwal

Faculty, Staff and Students Publications

BACKGROUND & AIMS: It is unclear whether the model for end-stage liver disease-sodium (MELD-Na) score captures the clinical severity of acute-on-chronic liver failure (ACLF). We compared observed 90-day mortality in patients with ACLF with expected mortality based on the calculated MELD-Na and examined the consequences of underestimating clinical severity.

METHODS: We identified patients with ACLF during hospitalization for cirrhosis in 127 VA hospitals between 01/01/2004 and 12/31/2014. We examined MELD-Na scores by ACLF presence and grade. We used actual and observed 90-day mortality to estimate a standardized mortality ratio (SMR) by ACLF presence and grade. We used transplant center-specific median …

Epilepsy Risk Prediction Model For Patients With Tuberous Sclerosis Complex, Darcy A Krueger, Hope Northrup, Tacern Study Group

Faculty, Staff and Student Publications

BACKGROUND: Individuals with tuberous sclerosis complex are at increased risk of epilepsy. Early seizure control improves developmental outcomes, making identifying at-risk patients critically important. Despite several identified risk factors, it remains difficult to predict. The purpose of the study was to evaluate the combined risk prediction of previously identified risk factors for epilepsy in individuals with tuberous sclerosis complex.

METHODS: The study group (n = 333) consisted of individuals with tuberous sclerosis complex who were enrolled in the Tuberous Sclerosis Complex Autism Center of Excellence Research Network and UT TSC Biobank. The outcome was defined as having an epilepsy diagnosis. …

Evaluation Of Outpatient Anticoagulation Bridging After Left Ventricular Assist Device Implantation, Rebecca A. Rainess, Lauren Alderman, Teresa Cicci, Monty Yoder, Barbara Pisani, Thomas O’Neill, Diego Malaver

The VAD Journal

Objective: The aim of this study is to evaluate the safety of outpatient anticoagulation bridging following left ventricular assist device (LVAD) implantation.

Methods: This study is a retrospective, single-center cohort of adult patients who underwent LVAD implantation (HeartMate II™ or HeartMate 3™) and received warfarin and at least one dose of therapeutic enoxaparin or fondaparinux for outpatient anticoagulation bridging. The primary endpoint was the incidence of bleeding complications within one week of completing the bridging episode. Secondary endpoints included the incidence of new hemolysis or thrombosis within 30 days, INR at the time of bridge initiation, duration of anticoagulation bridge, …

Security And Privacy When Applying Fair Principles To Genomic Information, Jaime Delgado, Silvia Llorente

Faculty, Staff and Student Publications

Making data Findable, Accessible, Interoperable and Reusable (FAIR) is a good approach when data needs to be shared. However, security and privacy are still critical aspects. In the FAIRification process, there is a need both for de-identification of data and for license attribution. The paper analyses some of the issues related to this process when the objective is sharing genomic information. The main results are the identification of the already existing standards that could be used for this purpose and how to combine them. Nevertheless, the area is quickly evolving and more specific standards could be specified.

Role For Carbohydrate Response Element-Binding Protein (Chrebp) In High Glucose-Mediated Repression Of Long Noncoding Rna Tug1, Yashpal S Kanwar, Li Li, Naravat Poungavrin, Paul A Overbeek, Benny H Chang, Farhad R Danesh

Faculty, Staff and Students Publications

Long noncoding RNAs (lncRNAs) have been shown to play key roles in a variety of biological activities of the cell. However, less is known about how lncRNAs respond to environmental cues and what transcriptional mechanisms regulate their expression. Studies from our laboratory have shown that the lncRNA Tug1 (taurine upregulated gene 1) is crucial for the progression of diabetic kidney disease, a major microvascular complication of diabetes. Using a combination of proximity labeling with the engineered soybean ascorbate peroxidase (APEX2), ChIP-qPCR, biotin-labeled oligonucleotide pulldown, and classical promoter luciferase assays in kidney podocytes, we extend our initial observations in the current …

Social And Leisure Activities Predict Transitions In Cognitive Functioning In Older Mexican Adults: A Latent Transition Analysis Of The Mexican Health And Aging Study, Lee A Niswander

Faculty, Staff and Student Publications

Disruptions in neural tube (NT) closure result in neural tube defects (NTDs). To understand the molecular processes required for mammalian NT closure, we investigated the role of Snx3, a sorting nexin gene. Snx3−/− mutant mouse embryos display a fully-penetrant cranial NTD. In vivo, we observed decreased canonical WNT target gene expression in the cranial neural epithelium of the Snx3−/− embryos and a defect in convergent extension of the neural epithelium. Snx3−/− cells show decreased WNT secretion, and live cell imaging reveals aberrant recycling of the WNT ligand-binding protein WLS and mis-trafficking to the lysosome for degradation. The importance …

Extended Cable For Left Ventricular Assist Devices For Monitoring Isolated Patients During The Covid-19 Pandemic, Neal A. Waxali, James M. Kenward, Laurie P. Loza, Yasser Varona, Arvind Bhimaraj

The VAD Journal

We present a method to create an extended cable for patients who are supported by left ventricular assist devices (LVADs) while infected with SARS-CoV-2. The arrangement described facilitates the LVAD monitor console’s positioning outside of the patient’s room to minimize exposure of the mechanical circulatory support team to the novel coronavirus.

Myosight-Semi-Automated Image Analysis Of Skeletal Muscle Cross Sections, Susan L Hamilton

Faculty, Staff and Students Publications

BACKGROUND: Manual analysis of cross-sectional area, fiber-type distribution, and total and centralized nuclei in skeletal muscle cross sections is tedious and time consuming, necessitating an accurate, automated method of analysis. While several excellent programs are available, our analyses of skeletal muscle disease models suggest the need for additional features and flexibility to adequately describe disease pathology. We introduce a new semi-automated analysis program, MyoSight, which is designed to facilitate image analysis of skeletal muscle cross sections and provide additional flexibility in the analyses.

RESULTS: We describe staining and imaging methods that generate high-quality images of immunofluorescent-labelled cross sections from mouse …

Ryanodine Receptor 1-Related Disorders: An Historical Perspective And Proposal For A Unified Nomenclature, Carsten G Bönnemann, James J Dowling, Susan L Hamilton, Katherine G Meilleur, Robert T Dirksen

Faculty, Staff and Students Publications

The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.Historically, RYR1-RM-affected individuals were …

Impact Of Diabetes On The Gut And Salivary Iga Microbiomes, Sarah M Gunter, Goo Jun, David Aguilar, William B Perkison, Craig L Hanis, Herbert L Dupont

Faculty, Staff and Student Publications

Mucosal surfaces like those present in the lung, gut, and mouth interface with distinct external environments. These mucosal gateways are not only portals of entry for potential pathogens but also homes to microbial communities that impact host health. Secretory immunoglobulin A (SIgA) is the single most abundant acquired immune component secreted onto mucosal surfaces and, via the process of immune exclusion, shapes the architecture of these microbiomes. Not all microorganisms at mucosal surfaces are targeted by SIgA; therefore, a better understanding of the SIgA-coated fraction may identify the microbial constituents that stimulate host immune responses in the context of health …

Increasing Hpv Vaccination In A Network Of Pediatric Clinics Using A Multi-Component Approach, Sally W. Vernon, Lara S. Savas, Ross Shegog, C. Mary Healy, Erica L. Frost, Sharon P. Coan, Efrat K. Gabay, Sharice M. Preston, Claire A. Crawford, Stanley W. Spinner, Matthew A. Wilber

Journal of Applied Research on Children: Informing Policy for Children at Risk

Background: Despite continued public health efforts to increase human papillomavirus (HPV) vaccination among adolescents, initiation remains below the level needed to reach the Healthy People 2020 goal of 80% series completion by age 13.

Methods: We developed, implemented, and evaluated a multi-component program that used evidence-based strategies to increase HPV vaccine initiation in a network of 51 pediatric clinics in Houston, Texas. Our target populations were the clinic network, healthcare providers, male and female patients ages 11-17, and their parents. The program, called the Adolescent Vaccination Program (AVP), was conducted from March 2016 through March 2019 and contained strategies to …

Cost – Benefit Analysis Of Austin Public Health’S Peer To Peer Adolescent Sexual Health Education Program, Kim Wilson, Ujas Patel, Shannon Sandrea, Fernanda Santos, Henry Shelton Brown Iii

Journal of Family Strengths

Background

Despite the rapid decline in teen pregnancy rates in recent years, teen pregnancies and STIs remain a significant concern, especially for minority youth. As a result, numerous sexual health programs have been introduced, with some success. In Austin, Texas, an implementation of “Making Proud Choices” entitled Peer-to-Peer (P2P) was introduced in 2015 and serves between 750 and 800 students of largely Hispanic origin annually.

Methods

In this study, we assessed whether P2P was cost-beneficial. We used a Bernoulli model to estimate averted cases of pregnancies, key STIs and their sequelae: HIV, chlamydia, gonorrhea, genital herpes, human papillomavirus and pelvic …

Structural Basis Of Ion Transport And Inhibition In Ferroportin, Jiemin Shen, Lie Wang, Zhichun Xu, Ye Yu, Preetham Bachina, Hanzhi Zhang, Xiao Fan, Arthur Laganowsky, Nieng Yan, Ming Zhou

Faculty, Staff and Students Publications

Ferroportin is an iron exporter essential for releasing cellular iron into circulation. Ferroportin is inhibited by a peptide hormone, hepcidin. In humans, mutations in ferroportin lead to ferroportin diseases that are often associated with accumulation of iron in macrophages and symptoms of iron deficiency anemia. Here we present the structures of the ferroportin from the primate Philippine tarsier (TsFpn) in the presence and absence of hepcidin solved by cryo-electron microscopy. TsFpn is composed of two domains resembling a clamshell and the structure defines two metal ion binding sites, one in each domain. Both structures are in an outward-facing conformation, and …

Retail Access Is Associated With Multiple Tobacco Product Use Among Adolescent, Dale S. Mantey, Onyema G. Chido-Amajuoyi, Cristina S. Barroso

Journal of Family Strengths

Background: Enforcement of retail access laws is essential to preventing adolescent tobacco use. A growing proportion of adolescent tobacco users report using two or more products. However, research has yet to explore the relationship between retail access and multiple tobacco product use.

Methods: Data were obtained from the 2018 National Youth Tobacco Survey. Participants were 2,199 middle and high school tobacco users. Multivariate, multinomial logistic regression models were used to examine the relationship between tobacco retail access and past 30-day single, dual, and poly (three or more) tobacco product use. Covariates included sex, race/ethnicity, grade level, and tobacco marketing exposure. …