Medicine and Health Sciences Commons^™

Managing Variant Discrepancy In Hereditary Cancer: Clinical Practice, Barriers, And Desired Resources, Ellen Zirkelbach

Dissertations and Theses (Open Access)

Variants are changes in the DNA whose phenotypic effects may or may not be definitively understood. Because variant interpretation is a complex process, sources sometimes disagree on the classification of a variant, which is called a variant discrepancy. This study aimed to determine the practice of genetic counselors regarding variant discrepancies and to identify the barriers to counseling a variant discrepancy in hereditary cancer genetic testing. This investigation was unique because it was the first to address variant discrepancies from a clinical point of view. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. …

Evaluating The Impact Of Post-Translational Modifications By The Secreted Zinc Metalloprotease, Gele, On The Major Autolysin Of E. Faecalis, Atla, And A Stress-Induced Protein, Salb, Emily K. Stinemetz

Dissertations and Theses (Open Access)

AtlA is the major peptidoglycan hydrolase of E. faecalis involved in cell separation of dividing cells. SalB is a secreted stress-induced protein regulated by the CroRS system. In addition, these two proteins also appear to be affected by the virulence factor, gelatinase (GelE). GelE is a secreted zinc metalloprotease known to impact various cellular functions by post- translational modification of protein substrates. The overall objective of this work was to understand how GelE cleavage of secreted proteins, specifically AtlA and SalB, changes their function. Herein, I discovered that GelE modifies both AtlA and SalB. As visualized by Western blot analysis …

Genesurance Counseling: Patient Perspectives, Chelsea Wagner

Dissertations and Theses (Open Access)

Genetic counselors (GCs) have recently reported an increase in the discussion of insurance-related, or “genesurance,” topics during genetic counseling sessions. Despite increasing frequency, little knowledge exists about genesurance conversations and patient expectations. This study aimed to assess patient expectations of GCs in genesurance discussions and evaluate if health insurance literacy impacted these expectations. A 38-item survey, including a validated tool to assess health insurance literacy (HIL) was administered prior to patients receiving prenatal or cancer genetic counseling at three participating institutions. A total of 360 responses were analyzed. Key variables were compared using chi-square analysis and multivariable logistic regression was …

Mathematical Modeling Reveals That G2/M Checkpoint Override, Hui Ju Hsieh

Dissertations and Theses (Open Access)

Cell cycle checkpoints determine whether cells meet requirements to progress through the next stage. In response to DNA damage, how cells activate checkpoints have been well studied, but little is known about checkpoint deactivation (recovery), which directly impacts on cell fate. In tumor cells, the signaling network has been rewired due to epigenetic and genetic alterations, which result in resistance to the cell cycle control, and thus resistance to chemotherapy or radiation therapy. Therefore, it is critical to identify molecules required for checkpoint recovery or adaptation after DNA damage.

To achieve this goal, we performed a multidisciplinary study combining reverse …

On The Origin Of Sensory Errors, Jonathan R. Flynn

Dissertations and Theses (Open Access)

Estimation of perceptual variables is imprecise and prone to errors. Although the properties of these perceptual errors are well characterized, the physiological basis for these errors is unknown. One previously proposed explanation for these errors is the trial-by-trial variability of the responses of sensory neurons that encode the percept. Initially, it would seem that a complicated electrophysiological experiment would need to be performed to test this hypothesis. However, using a strong theoretical framework, I demonstrate that it is possible to determine statistical characteristics of the physiological mechanism responsible for perceptual errors solely from a behavioral experiment. The basis for this …

Attitudes To Ward And Uptake Of Prenatal Genetic Screening And Testing In Twin Pregnancies, Kathryn M. Reese

Dissertations and Theses (Open Access)

The rate of twinning is rising and is associated with delayed age at childbirth and increased infertility treatments. Since the introduction of non-invasive prenatal testing, interest in and uptake of genetic screening and testing in twin pregnancies has not been investigated. Therefore, this study aimed to describe the attitudes toward and uptake of current prenatal genetic screening and testing options in twin pregnancies. Forty-two women with twin gestations were recruited from UTHealth and Baylor College of Medicine sites between August 2016 and January 2017 for participation in a descriptive study consisting of a questionnaire (n=42) and semi-structured phone interview (n=15). …

Investigation Of The Roles Of Asf1 And Caf-1-Mediated Chromatin Assembly In The Human Dna Damage Response, Ting-Hsiang Huang

Dissertations and Theses (Open Access)

The access-repair-restore model for the role of chromatin in DNA repair infers that chromatin is a mere obstacle to DNA repair. However, here we show that blocking chromatin assembly of newly-synthesized histones, via knockdown of the histone chaperones ASF1A, CAF-1 or a mutation that specifically prevents ASF1 binding to histones, hinders loading of Rad51 onto ssDNA during homologous recombination, as a consequence of reduced recruitment of the Rad51 loader MMS22L/TONSL to ssDNA, resulting in persistent RPA foci, extensive DNA end-resection, and persistent activation of the ATR-Chk1 pathway. By contrast, ASF1 and CAF-1 render the rapid inactivation of ATM Chk2 pathway …

Developing Novel Approaches To Improve Response To T Cell Based Cancer Immunotherapy, Rina M. Mbofung

Dissertations and Theses (Open Access)

Recently, T cell based immunotherapies have moved to the forefront of cancer immunotherapy with the success of Adoptive T cell therapy (ACT) and Immune checkpoint blockade.ACT, where patients are treated with tumour infiltrating T cells (TILs), conferred a clinical response rate of ~50%. Treatment with anti-CTLA4 and anti –PD1 therapy, conferred response rates of up to 50%, greatly improving the overall survival of patients with advanced melanoma amongst other cancer types. Despite the encouraging outcomes, there are relatively low response rates coupled with the delay of weeks to months before tumour shrinkage can be appreciated. Thus, understanding what tumour intrinsic …

The Utilization Of Prenatal Microarray: A Survey Of Current Genetic Counseling Practices And Barriers, Leslie N. Durham, Leslie Durham

Dissertations and Theses (Open Access)

Chromosomal microarray (CMA) assesses chromosome copy number variants (CNVs) missed by standard karyotyping. The American College of Obstetricians and Gynecologists (ACOG) recommends CMA for all patients with fetuses with an ultrasound anomaly and suggests that it be made available to all women undergoing invasive testing. In order to assess prenatal genetic counselors’ (GCs) practices regarding the utilization of CMA we conducted a survey of their current practices, attitudes, and perceived barriers. Of the 192 respondents, 183 (95%) have incorporated CMA into clinical practice with the majority (64%) believing that the benefits of CMA outweigh the harms. However, only half (52%) …

Statistical Methods For Assessing Structural Change In Human & Microbial Genomes, Xuan Zhu

Dissertations and Theses (Open Access)

Genetic sequencing has been recognized as an effective approach to accurately address biological problems, such as clinical detection of disease, mutation discovery, and targeting specific biomarkers associated with complex diseases. Compared with conventional Sanger sequencing, next-generation sequencing costs much less due to massively parallel high-throughput sequencing. However, due to large numbers of short read sequences, the accuracy of high-throughput sequencing data remains a challenge in that the data obtained from next-generation sequencing often has higher error rates, which may impact downstream genomic analysis. Even if the downstream genomic analysis performs well, the quality of the result will still be impacted …

Characterizing The Source Of Neutrophil Elastase And Proteinase 3 Cross-Presentation In B-Cell Acute Lymphoblastic Leukemia, Selena Carmona

Dissertations and Theses (Open Access)

Discovery of tumor-associated antigens is an important step in designing effective antigen-targeting immunotherapies. PR1 is a nonameric human leukocyte antigen (HLA)-A2 restricted leukemia-associated antigen derived from serine proteases neutrophil elastase (NE) and proteinase 3 (P3). NE and P3 are primarily expressed in cells of myeloid lineage including granulocytes, bone marrow progenitors and myeloid leukemia. Our lab reported that NE and P3 are cross-presented by antigen presenting cells (APCs) and solid tumors, a mechanism whereby exogenous antigens are endocytosed and presented on HLA class I molecules, inducing a cytotoxic T lymphocyte (CTL)-mediated immune response. Therefore, identifying non-myeloid tumors capable of PR1 …

Undergraduate Student Perceptions And Awareness Of Genetic Counseling, Amanda Gerard

Dissertations and Theses (Open Access)

Genetic counseling (GC) is a rapidly expanding field, and the supply of certified genetic counselors is currently unable to keep up with job demand. Research is fairly limited regarding the awareness and perceptions potential genetic counseling program applicants have of the field and what factors most influence their interest in the field. This study aimed to examine some of these topics. The current study includes data collected from 1,389 undergraduate students in the sciences at 23 universities across the United States who were surveyed regarding information related to their awareness, perceptions, knowledge, and interest in GC. Data analysis was performed …

Attitudes Of Clinicians To Wards Cardiac Surgery And Trisomy 18, Meagan Kaulfus

Dissertations and Theses (Open Access)

Trisomy 18 is an autosomal trisomy characterized by minor to major birth defects, severe disabilities, and high rates of pre- and neonatal mortality. Interventions for these infants have traditionally been withheld with focus instead on palliative support. The issues and attitudes surrounding surgical treatment of congenital heart defects, which occur in approximately 90% of infants with trisomy 18, is of our study’s interest as recent literature has indicated that cardiac surgery is being performed and may lead to improved survival compared to palliative care. In this study, the attitudes of clinicians of multiple specialties towards cardiac surgery for infants with …

Peptide Vaccine Formulation Controls The Duration Of Antigen Presentation And Magnitude Of Tumor‐Specific Cd8+ T Cell Response, Hiep Khong

Dissertations and Theses (Open Access)

Despite remarkable progresses in vaccinology, therapeutic cancer vaccines have not achieved their full potential. We previously showed that the duration of antigen presentation critically affected the quantity and quality of T cell response and subsequent anti‐tumor efficacy. Here we describe L‐tyrosine amino acid‐based microparticles as a novel peptide vaccine adjuvant for the induction of tumor‐specific T cells. L‐tyrosine microparticles did not induce inflammasome activation, but instead extended antigen presentation time. The consequent prolongation in antigen presentation translated into prolonged T cell proliferation and superior numbers and anti‐tumor function of vaccination‐induced CD8+ T cells. Indeed, prolonging antigen presentation by repeated injection …

Analysis Of The Biochemical And Cellular Activities Of Substrate Binding By The Molecular Chaperone Hsp110/Sse1, Veronica M. Garcia

Dissertations and Theses (Open Access)

Molecular chaperones ensure protein quality during protein synthesis, delivery, damage repair, and degradation. The ubiquitous and highly conserved molecular chaperone 70-kDa heat-shock proteins (Hsp70s) are essential in maintaining protein homeostasis by cycling through high and low affinity binding of unfolded protein clients to facilitate folding. The Hsp110 class of chaperones are divergent relatives of Hsp70 that are extremely effective in preventing protein aggregation but lack the hallmark folding activity seen in Hsp70s. Hsp110s serve as Hsp70 nucleotide exchange factors (NEF) that facilitate the Hsp70 folding cycle by inducing release of protein substrate from Hsp70, thus recycling the chaperone for a …

Mathematical Modeling Reveals That G2/M Checkpoint Override Creates A Therapeutic Vulnerability In Tsc2-Null Tumors, Hui Ju Hsieh

Dissertations and Theses (Open Access)

Cell cycle checkpoints determine whether cells meet requirements to progress through the next stage. In response to DNA damage, how cells activate checkpoints have been well studied, but little is known about checkpoint deactivation (recovery), which directly impacts on cell fate. In tumor cells, the signaling network has been rewired due to epigenetic and genetic alterations, which result in resistance to the cell cycle control, and thus resistance to chemotherapy or radiation therapy. Therefore, it is critical to identify molecules required for checkpoint recovery or adaptation after DNA damage.

To achieve this goal, we performed a multidisciplinary study combining reverse …

Mathematical Modeling Reveals That G2/M Checkpoint Override Creates A Therapeutic Vulnerability In Tsc2-Null Tumors, Hui-Ju Hsieh

Dissertations and Theses (Open Access)

Cell cycle checkpoints determine whether cells meet requirements to progress through the next stage. In response to DNA damage, how cells activate checkpoints have been well studied, but little is known about checkpoint deactivation (recovery), which directly impacts on cell fate. In tumor cells, the signaling network has been rewired due to epigenetic and genetic alterations, which result in resistance to the cell cycle control, and thus resistance to chemotherapy or radiation therapy. Therefore, it is critical to identify molecules required for checkpoint recovery or adaptation after DNA damage.

To achieve this goal, we performed a multidisciplinary study combining reverse …

The Role Of Adenosine Signaling In Mature Erythrocytes And Erythroid Progenitors, Hong Liu

Dissertations and Theses (Open Access)

Adenosine is a ubiquitous nucleoside in almost all the cells throughout our bodies. It is highly induced particularly under hypoxia or energy depletion conditions. Adenosine functions as a critical ligand, after binding to membrane-associated adenosine receptors, adenosine initiates a downstream signaling cascade and subsequently contributes to functions of nervous system, immune response, vascular function and even metabolism.

Hypoxia is a condition with limited O₂ availability in the whole body or a region of the body. It is a major consequence of many respiratory and cardiovascular diseases, as well as for people living and working at high altitudes or other …

Cd47+ Exosomes Facilitate Effective Targeting Of Oncogenic Kras In Pancreatic Cancer, Sushrut Kamerkar

Dissertations and Theses (Open Access)

Despite the current standard of care, the prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains dismal. Genetic analyses of PDAC show that mutations in the GTPase KRAS are encountered in the majority of patients that present with the disease, and are key drivers of cancer initiation, progression and metastasis. However, while it is recognized that the Ras mediated signaling pathway is a key mediator of PDAC progression, a direct and specific targeting of Ras has been elusive. Therefore, due to the indisputable evidence for the causal functional role of RAS in the biology of PDAC, new approaches to specifically …

Targeting Autophagy To Improve Efficacy Of Cdk4/6 Inhibition In Breast Cancer, Smruthi Vijayaraghavan

Dissertations and Theses (Open Access)

Deregulation of the cell cycle machinery is a hallmark of cancer, leading to aberrant proliferation and tumorigenesis. The crucial role of the CDK4/6-Cyclin D pathway has led to the development and FDA approval (palbociclib, ribociclib) of CDK4/6 inhibitors for the treatment of advanced estrogen receptor positive breast cancer. However, three major clinical challenges remain: i) adverse events leading to discontinuation of therapy and ii) lack of reliable biomarkers to identify responsive patients and iii) acquired resistance to CDK4/6 inhibitors. Previous in vitro studies have shown that palbociclib mediated CDK4/6 inhibition induces G1 arrest and senescence in ER+ breast cancer cells, …

Characterization Of The Role Of The Pkm101-Encoded T4ss Outer Membrane Core Complex In Substrate Transfer, Pilus Biogenesis, And Recipient Cell Contact, Jay E. Gordon

Dissertations and Theses (Open Access)

The bacterial type IV secretion systems (T4SS) encoded on the Escherichia coli pKM101 and R388 conjugative plasmids and the Agrobacterium tumefaciens virB operon are composed of 12 subunits arranged in an architecturally similar fashion. Structural studies of the T4SS from R388 (Trw_R388) highlighted the presence of a distinct outer membrane core complex (OMCC) and inner membrane complex (IMC) joined together by a central stalk. This thesis is focused on the development of the pKM101 model system and the role of an OMCC cap region formed by alpha helical antenna projections (AP) found in VirB10 and TraF_pKM101. …

Detecting And Evaluating Therapy Induced Changes In Radiomics Features Measured From Non-Small Cell Lung Cancer To Predict Patient Outcomes, Xenia J. Fave

Dissertations and Theses (Open Access)

The purpose of this study was to investigate whether radiomics features measured from weekly 4-dimensional computed tomography (4DCT) images of non-small cell lung cancers (NSCLC) change during treatment and if those changes are prognostic for patient outcomes or dependent on treatment modality. Radiomics features are quantitative metrics designed to evaluate tumor heterogeneity from routine medical imaging. Features that are prognostic for patient outcome could be used to monitor tumor response and identify high-risk patients for adaptive treatment. This would be especially valuable for NSCLC due to the high prevalence and mortality of this disease.

A novel process was designed to …

Understanding Patient Safety Reports Via Multi-Label Text Classification And Semantic Representation, Chen Liang

Dissertations and Theses (Open Access)

Medical errors are the results of problems in health care delivery. One of the key steps to eliminate errors and improve patient safety is through patient safety event reporting. A patient safety report may record a number of critical factors that are involved in the health care when incidents, near misses, and unsafe conditions occur. Therefore, clinicians and risk management can generate actionable knowledge by harnessing useful information from reports. To date, efforts have been made to establish a nationwide reporting and error analysis mechanism. The increasing volume of reports has been driving improvement in quantity measures of patient safety. …

Further Advances For The Sequential Multiple Assignment Randomized Trial (Smart), Tianjiao Dai

Dissertations and Theses (Open Access)

ABSTRACT

FURTHER ADVANCES FOR THE SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMIZED TRIAL (SMART)

Tianjiao Dai, M.S.

Advisory Professor: Sanjay Shete, Ph.D.

Sequential multiple assignment randomized trial (SMART) designs have been developed these years for studying adaptive interventions. In my Ph.D. study, I mainly investigate how to further improve SMART designs and optimize the interventions for each individual in the trial. My dissertation has focused on two topics of SMART designs.

1) Developing a novel SMART design that can reduce the cost and side effects associated with the interventions and proposing the corresponding analytic methods. I have developed a time-varying SMART design in …

A Life Cycle Approach To The Development And Validation Of An Ontology Of The U.S. Common Rule (45 C.F.R. § 46), Francis Manion

Dissertations and Theses (Open Access)

Requirements for the protection of human research subjects stem from directly from federal regulation by the Department of Health and Human Services in Title 45 of the Code of Federal Regulations (C.F.R.) part 46. 15 other federal agencies include subpart A of part 46 verbatim in their own body of regulation. Hence 45 C.F.R. part 46 subpart A has come to be called colloquially the ‘Common Rule.’

Overall motivation for this study began as a desire to facilitate the ethical sharing of biospecimen samples from large biospecimen collections by using ontologies. Previous work demonstrated that in general the informed consent …

Integrating Behavioral Trigger Messages Into A Mhealth System Design For Chronic Disease Management, Scott Sittig

Dissertations and Theses (Open Access)

Recent changes in health information technology have dramatically altered the face, delivery, and management of healthcare particularly as it relates to mHealth. With increases in smart phone ownership, mHealth potentially has the ability to provide far-reaching transformation of chronic disease management particularly when aligned with behavioral change theories and persuasive technology. MHealth applications have an advantage over computers and various print communications as the consumer can engage with the application at any time and at any location. The Interactive Health Communication Application (IHCA) states that by combining support mechanisms such as behavior change theories into electronic devices as a method …

Understanding Pubmed Search Results Using Topic Models And Interactive Information Visualization, Zhiguo Yu

Dissertations and Theses (Open Access)

With data increasing exponentially, extracting and understanding information, themes and relationships from larger collections of documents is becoming more and more important to researchers in many areas. PubMed, which comprises more than 25 million citations, uses Medical Subject Headings (MeSH) to index articles to better facilitate their management, searching and indexing. However, researchers are still challenged to find and then get a meaningful overview of a set of documents in a specific area of interest. This is due in part to several limitations of MeSH terms, including: the need to monitor and expand the vocabulary; the lack of concept coverage …

Improving Syntactic Parsing Of Clinical Text Using Domain Knowledge, Min Jiang

Dissertations and Theses (Open Access)

Syntactic parsing is one of the fundamental tasks of Natural Language Processing (NLP). However, few studies have explored syntactic parsing in the medical domain. This dissertation systematically investigated different methods to improve the performance of syntactic parsing of clinical text, including (1) Constructing two clinical treebanks of discharge summaries and progress notes by developing annotation guidelines that handle missing elements in clinical sentences; (2) Retraining four state-of-the-art parsers, including the Stanford parser, Berkeley parser, Charniak parser, and Bikel parser, using clinical treebanks, and comparing their performance to identify better parsing approaches; and (3) Developing new methods to reduce syntactic ambiguity …

Targeting Apoptotic Pathways To Overcome Drug Resistance In Acute Myeloid Leukemia, Rongqing Pan

Dissertations and Theses (Open Access)

Evasion of apoptosis is integral to tumorigenesis and drug resistance. BCL-2 and p53 proteins represent two focal nodes in convergent apoptosis signaling. Upregulation of anti-apoptotic BCL-2 family members and inactivation of p53 functions are two canonical approaches exploited by cancer cells to escape apoptosis. In the current study, we find that BCL-2 protein is highly expressed in acute myeloid leukemia (AML) cells. BCL-2–specific inhibitor ABT-199 potently induces mitochondrial apoptosis in AML cells and effectively kills AML stem/progenitor cells. Our biomarker studies demonstrate that both BH3 profiling and the expression profiling of BCL-2 proteins may serve as predictive biomarkers for the …

The Role Of Two Homologous E3 Ligases In Muscle Physiology, Gabrielle F. Gloston

Dissertations and Theses (Open Access)

Ubiquitin-mediated proteasomal degradation is an essential cellular function that is coordinated by three key components: E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligases. There are an estimated 600 E3 ligases, some of which share high sequence homology; however, the functional significance often remains unknown. FBXL3 and FBXL21 are two homologous E3 ligases that have previously been reported to dictate circadian periodicity, with FBXL3 being the dominant E3 ligase and FBXL21 playing a regulatory role. A recent Yeast Two-Hybrid screen revealed a new shared target of FBXL3 and FBXL21: Telethonin (also known as TCAP). TCAP is a …