Digital Commons Network^™

Pi3k- And Mtor-Dependent Mechanisms Of Lapatinib Resistance And Resulting Therapeutic Opportunities, Samuel Brady

Dissertations and Theses (Open Access)

Breast cancers with HER2 amplification represent 20-25% of breast cancer cases and are frequently responsive to the HER2 kinase inhibitor lapatinib, but generally for only short duration. We aimed to understand how breast cancers with HER2 amplification become resistant to lapatinib, in order to identify potential therapies that can overcome lapatinib resistance. To establish lapatinib resistance models we treated three HER2+ breast cancer cell lines with lapatinib for several months until they became lapatinib-resistant. We then compared lapatinib-sensitive (parental) cells with their lapatinib-resistant (LapR) counterparts to identify changes conferring lapatinib resistance. We found that activation of PI3K, specifically the p110α …

Nontyphoidal Cardiac Salmonellosis: Two Case Reports And A Review Of The Literature, Daniel Ortiz, Eric M Siegal, Christopher Kramer, Bijoy K Khandheria, Ernesto Brauer

The Texas Heart Institute Journal

Nontyphoidal Salmonella, especially Salmonella enterica, is a rare cause of endocarditis and pericarditis that carries a high mortality rate. Proposed predisposing conditions include immunodeficiency states, congenital heart defects, and cardiac valve diseases. We present 2 cases of cardiovascular salmonellosis. The first case is that of a 73-year-old woman with mechanical mitral and bioprosthetic aortic valves who died from sequelae of nontyphoidal Salmonella mitral valve vegetation, aortic valve abscess, and sepsis. The second case is that of a 62-year-old man with a recent systemic lupus erythematosus exacerbation treated with oral steroids, who presented with obstructive features of tamponade and sepsis secondary …

Role Of Macrophages In Adaptive Resistance To Anti-Vegf Therapy, Heather Dalton

Dissertations and Theses (Open Access)

Background: The clinical implementation of therapies targeting the VEGF pathway in cancer has been limited by acquired resistance; yet, the mechanisms by which this occurs is unclear. We investigated the role of macrophages in the development of acquired resistance to anti-VEGF antibody (AVA) therapy.

Materials and Methods: We first established a murine ovarian cancer model of resistance to anti-VEGF therapy. Using this model we investigated changes in macrophage infiltration during AVA sensitive and resistant phases. We also investigated the in vivo effects of macrophage depletion at the emergence of anti-VEGF resistance and in upfront combination with AVA therapy. In vitro …

Novel Serum Biomarkers For Lung Cancer Early Diagnosis And Clinical Outcome, Fanmao Zhang

Dissertations and Theses (Open Access)

The five-year survival rate for all stages of lung cancer combined is only 17%, which has changed little over the past 40 years. Despite the tremendous efforts made, serum biomarkers with clinical utility for lung cancer early detection and clinical outcome prediction are still lacking. Metabolic alterations have been recognized as an emerging hallmark of cancer. We aimed to investigate the metabolic changes associated with lung cancer and to identify novel clinically applicable serum biomarkers for lung cancer early diagnosis and clinical outcome.

Serum metabolites are potential biomarkers for lung cancer early detection. We first performed global metabolomic profiling followed …

Notch Signaling Inhibited By Ikaros1 In Human T-Cell Acute Lymphoblastic Leukemia, Camille W. Graham

Dissertations and Theses (Open Access)

The highly conserved Notch signaling pathway regulates cell growth, differentiation, survival and apoptosis. In hematopoiesis, Notch signaling drives commitment to the T-cell fate and promotes differentiation, T-cell receptor signaling and immune function. In T-cells, Notch signaling is oncogenic when constitutively active, promoting proliferation and survival while inhibiting differentiation. The majority of patients with T-cell acute lymphoblastic leukemia (TALL) have activating Notch mutations. Similarly, Notch activation is present in more than 75% of murine T-ALL models. In murine T-ALL, loss of Ikaros, a zinc finger transcriptional regulator, leads to disrupted differentiation and also cooperates with activated Notch signaling to promote T-ALL. …

Regulators Of Bacterial Cell Division: Investigations Of Min Oscillation And Ftsa Activity, Jennifer R. Herricks

Dissertations and Theses (Open Access)

Cytokinesis is a fundamental process that is essential for bacterial proliferation. The cytokinetic machinery in bacteria is termed the “divisome”. The divisome is a complex of proteins that forms a ring at midcell over dividing nucleoids. In order for daughter cells to form, the divisome must constrict. As constriction occurs, two new cell poles are formed, one for each daughter cell. The first step in divisome formation is the assembly of FtsZ into a Z ring. The work presented in this dissertation focuses on two proteins that regulate the Z ring: MinD, which is a part of the Min system …

Potential Roles Of Peroxidases In Caenorhabditis Elegans Innate Immunity, George R. Tiller, George R. Tiller

Dissertations and Theses (Open Access)

The production of ROS (reactive oxygen species) in response to pathogen detection is a rapid, nonspecific response that is evolutionarily conserved from nematodes to humans. ROS serve as direct and indirect effectors of innate and adaptive immunity. In Caenorhabditis elegans, a ROS burst is observed during infection and is mediated by the dual oxidase BLI-3, which produces H₂O₂. RNAi (RNA interference) to reduce the amount of BLI-3 results in a significant increase in susceptibility to pathogens, suggesting BLI-3 has a role in the immune response. However, H₂O₂ by itself is not a …

Genetic Predictors Of Metabolic Side Effects Of Diuretic Therapy, Jorge L. Del Aguila

Dissertations and Theses (Open Access)

Thiazide diuretics are a recommended first-line monotherapy for hypertension (i.e.SBP>140 mmHg or DBP>90 mmHg). Even so, diuretics are associated with adverse metabolic side effects, such as hyperlipidemia, hyperglycemia and hypokalemia which increase the risk of developing type II diabetes. This thesis used three analytical strategies to identify and quantify genetic factors that contribute to the development of adverse metabolic effects due to thiazide diuretic treatment. I performed a genome-wide association study (GWAS) and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses …

The Role Of The C5a Receptor In Host Defense Against Listeria Monocytogenes, Daniel Calame

Dissertations and Theses (Open Access)

Listeria monocytogenes (Lm) is a major cause of mortality resulting from food poisoning in the United States. While the complement component C5 is known to be protective in listeriosis, it is unknown how its cleavage fragment C5a participates. Here we show in a model of systemic Lm infection that the C5a receptor is essential for host defense. C5aR-/- mice have reduced survival and increased bacterial burden in the liver and spleen in comparison to WT mice. Surprisingly, C5aR-/- mice also have a dramatic reduction in splenocyte numbers resulting from elevated cell death as indicated by TUNEL staining and caspase 3 …

Egfr Modulates Microrna Maturation In Response To Hypoxia Through Phosphorylation Of Argonaute2, Jia Shen

Dissertations and Theses (Open Access)

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at posttranscriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in regulatory roles to cope with a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumor. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumor cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here, we show that EGFR, …

Mechanisms Of Astrocyte Contribution To Bortezomib-Induced Peripheral Neuropathy, Caleb R. Robinson

Dissertations and Theses (Open Access)

Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma and other non-solid malignancies, alone or in combination with other chemotherapy drugs. Like other chemotherapeutic agents, bortezomib treatment is frequently accompanied by chemotherapy-induced peripheral neuropathy (CIPN) that may be dose-limiting, adversely affecting quality of life and prognosis. The mechanisms behind bortezomib-induced peripheral neuropathy (BIPN) and CIPN overall are largely unknown. Recent findings in other pain models have indicated substantial involvement of glial cells in chronic pain. Although injury models have shown activation of both astrocytes and microglia following insult, research in other CIPN models has shown astrocytic activation …

Utilizing Haplotypes For Sensitive Snp Array-Based Discovery Of Somatic Chromosomal Mutations, Selina M. Vattathil

Dissertations and Theses (Open Access)

Somatic copy-number (CN) gains and losses and copy-neutral loss of heterozygosity (CNLOH) frequently occur in tumors and play a major role in the progression of disease by altering gene dosage and unmasking deleterious recessive variants. Characterizing these mutations in an individual tumor sample is therefore critical for research on the relationship of specific mutations to disease outcome and for clinical decision-making based on mutations with known impact. A pervasive hindrance to sensitive detection of these mutations is genetic heterogeneity and high levels of contaminating normal cells in tumor samples, which limit the fraction of cells carrying informative mutations. The method …

Brit1/Mcph1 Mediates The Dna Damage Response By Inducing P53 Stability And Promoting Atr Signaling, Edward Wang

Dissertations and Theses (Open Access)

The BRCT-repeat inhibitor of hTERT (BRIT1)/MCPH1 protein promotes the process of homologous recombination (HR) to repair DNA double strand breaks (DSBs). In response to DSBs, BRIT1 foci form at damaged sites, and recruits downstream repair proteins including 53BP1, MDC1, NBS1, and the SWI/SNF complex to the DSB region to promote DNA repair. BRIT1 copy number deficiency correlates with increased genomic instability in ovarian cancer specimens and breast cancer cell lines. Here, we propose that additional functions of BRIT1 include a direct interaction with the p53 tumor suppressor protein to promote p53 stability, and binding and recruitment of TopBP1 to sites …

Characterization Of The New Xoft Axxent Electronic Brachytherapy Source Using Presage(Tm), Jennifer Sierra Irwin

Dissertations and Theses (Open Access)

With continuing advances in the burgeoning field of electronic brachytherapy, an accurate method of 3D dosimetry is needed to ensure understanding of dose distributions, which can improve patient care. The aim of this study was to characterize the Xoft Axxent electronic brachytherapy source using PRESAGE^TM dosimeters in order to obtain independent confirmation of TG-43U1 dosimetry values, as well as to further add to the literature of both Xoft and PRESAGE.

PRESAGE is a polyurethane-based solid 3D dosimeter doped with a radiochromic leuco dye which produces a linear change in optical density when exposed to radiation. This optical density change …

Genomic Characterization Of Polyps In Familial Adenomatous Polyposis Patients And Identification Of Candidate Chemopreventive Drugs, Francis A. San Lucas

Dissertations and Theses (Open Access)

Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by APC germline mutations and the development of hundreds to thousands of premalignant adenomas in the gastrointestinal tract at a young age. If left untreated, these patients inevitably develop colon cancer (CRC) and small bowel tumors. We performed exome sequencing of samples from 12 FAP patients to characterize adenomas and to identify candidate genes of adenoma development that may serve as potential targets for chemoprevention drug development. From each patient, a blood and at least one polyp were sequenced with a total of 25 polyps analyzed. In some cases, normal …

Implementation Of Upright Treatments For Lung And Head And Neck Cancers, Ming-Jung Hsieh

Dissertations and Theses (Open Access)

There are numerous benefits to treating patients in the upright position such as better patient comfort and increased total lung volume with reduced lung motion. The purpose of this study was to investigate the feasibility of implementing upright treatments for lung and H&N cancers. Several clinical aspects were examined, including radiation shielding for various fixed beams, collision avoidance, retrospective treatment planning, and an end-to-end test with an anthropomorphic lung phantom.

Results from the shielding study indicated that the primary barrier required an additional 10-26 cm of shielding while the secondary barrier in the beam path required an additional 2-12 cm …

Global Burden Of Disease Study 2010: Interpretation And Implications For The Neglected Tropical Diseases, Peter J. Hotez, Miriam Alvarado, Maria Gloria Basanez, Ian Bolliger, Et Al.

Faculty, Staff and Students Publications

No abstract provided.

Integrating Domain Knowledge To Improve Signal Detection From Electronic Health Records For Pharmacovigilance, Ning Shang

Dissertations and Theses (Open Access)

The intent of this dissertation is to make a contribution to the field of pharmacovigilance. Pharmacovigilance, also known as post-marketing drug surveillance, is the process of continued monitoring for adverse drug reactions (ADRs) after drugs are released into the market. An ADR is a harmful or unpleasant reaction related to the use of a medical product. ADRs were reported to be between the fourth and sixth leading cause of death in the United States in 1994, accounting for 3-7% of medical hospital admissions. On account of the practice of pharmacovigilance, Vioxx (Rofecoxib) and Avandia (Rosiglitazone) are examples of high profile …

Pattern Of Mutation Rates In The Germline Of Drosophila Melanogaster Males From A Large-Scale Mutation Screening Experiment, Jian-Jun Gao, Xue-Rong Pan, Jing Hu, Li Ma, Jian-Min Wu, Ye-Lin Shao, Shi-Meng Ai, Shu-Qun Liu, Sara A Barton, Ronny C Woodruff, Ya-Ping Zhang, Yun-Xin Fu

Faculty, Staff and Student Publications

The sperm or eggs of sexual organisms go through a series of cell divisions from the fertilized egg; mutations can occur at each division. Mutations in the lineage of cells leading to the sperm or eggs are of particular importance because many such mutations may be shared by somatic tissues and also may be inherited, thus having a lasting consequence. For decades, little has been known about the pattern of the mutation rates along the germline development. Recently it was shown from a small portion of data that resulted from a large-scale mutation screening experiment that the rates of recessive …

Outpatient Management Of Heart Failure In The United States, 2006-2008, Kailash Mosalpuria, Sunil K Agarwal, Sirin Yaemsiri, Bredy Pierre-Louis, Samir Saba, Rene Alvarez, Stuart D Russell

The Texas Heart Institute Journal

Better outpatient management of heart failure might improve outcomes and reduce the number of rehospitalizations. This study describes recent outpatient heart-failure management in the United States.

We analyzed data from the National Ambulatory Medical Care Survey of 2006–2008, a multistage random sampling of non-Federal physician offices and hospital outpatient departments.

Annually, 1.7% of all outpatient visits were for heart failure (51% females and 77% non-Hispanic whites; mean age, 73 ± 0.5 yr). Typical comorbidities were hypertension (62%), hyperlipidemia (36%), diabetes mellitus (35%), and ischemic heart disease (29%). Body weight and blood pressure were recorded in about 80% of visits, and …

Who Participates In An Internet-Based Research Program For Mothers Of Infants? A Secondary Prevention Research Study Among Low-Income Families, Edward G. Feil, Kathleen Baggett, Betsy Davis, Craig Leve, Susan H. Landry, Lisa B. Sheeber

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

Objective: The objective of this study was to evaluate the participation rates and factors associated with nonparticipation among mothers living in low-income households who were invited to join a parent-education and -support research program delivered via the Internet with professional support.

Methods: Four hundred and seventy-seven mothers of infants were contacted via a variety of recruitment methods, including presentations at clinics/classes, direct mailings, print advertisement, and Internet posts. Research staff attempted to contact these mothers by phone, to assess their eligibility, and interest in participation. For those who were eligible but declined participation, we assessed reasons for declining and collected …

Youth Voices: Performance Poetry As A Platform For Literacy, Creativity, And Civic Engagement, Emanuelee "Outspoken" Bean, Kate Rybka Brennan

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

The youth slam poetry movement is growing in Houston. Writers in the Schools (WITS) is helping youth explore their truths through performance poetry and the renowned Meta-Four Houston program. Spoken word, slam competitions, and performance poetry bring people together to share stories and listen to our tomorrows. Performance poetry encourages creative self-expression and literacy among youth, while building a literary culture and platform for social change. By teaching youth to own their words, they learn to understand the potential power of their ideas. Performance poetry is a strong vehicle for education, deepening literacy, creativity, and communication skills, while preparing students …

Destination Imagination: Creativity In A World Of Complacency, Joshua Calkin, Megan Karlsen

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

Destination Imagination is a creative problem solving competition for school-aged children that encourages creative growth and long-term problem solving skills. These skills are important for young children as they can be directly related to future success in school, home, and the workplace. This extracurricular activity has impacted 1.5 million people across the globe, and has helped encourage the development of skills that the modern school system leaves untapped.

Strengthening Parental Engagement In Low-Income Latino Communities, Livia Edegger, Jenifer Wagley

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

Avenue Community Development Corporation (Avenue CDC) saw the necessity of increasing parent engagement while fostering leadership development in Houston’s Northside community. The primary goals of Avenue CDC’s Family Leadership Program are to actively engage parents in their children’s education at all grade levels and foster strong relationships between parents, teachers, administrators and the district at large through establishing a dedicated parent leadership team in the community. We aim at providing each school with an opportunity to engage parents through a proven organizing method developed by Local Initiatives Support Corporation (LISC) Houston and Avenue CDC, and parents with a chance to …

Supporting Parents As Teachers: Foundations Of Family Education At The Children’S Museum Of Houston, Shannon Bishop, Cheryl Mccallum

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

This article presents an overview of family learning at the Children’s Museum of Houston. Based on educational theory, and designed to support learning literacy and success in school, Museum programs provide parents with tools to help them nurture children’s intellectual development. The goal of this work is for parents to become better prepared to confidently engage their children in fun and meaningful learning experiences. The long-term benefits include strengthening family relationships and preparing children for success in secondary school and in the workplace.

Evidence-Based Home Visitation Programs Work To Put Children First, Cheryl L. Weise

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

When low-income women become parents for the first time, they often need support, education and encouragement to be the best parent they can be. They truly want to succeed. Desire, unfortunately, is not enough. These women are usually most open to health care assistance, parenting tools, and a therapeutic relationship with a community health worker who provides in-home services. The best partnership for a therapeutic relationship is between a new mother and a nurse. Efficient home visitation programs can save lives and taxpayer dollars. Nurse-Family Partnership pairs an experienced BSN RN with a first-time low-income mother from pregnancy until her …

Impacting Maternal And Prenatal Care Together: A Collaborative Effort To Improve Birth Outcomes, Jamie Freeny, Angela Cummings, Margo Hillard Alford, June Hanke, Linda Lloyd, Deborah Boswell

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

Objectives

To describe the development of a collaborative partnership to improve birth outcomes in Harris County, Texas.

Methods

State and city-level maternal and infant health data were re-analyzed and presented to stakeholders at the zip-code level to generate a renewed response to health issues in these populations, particularly infant mortality. Public and private sector stakeholders convened to form the Impacting Maternal and Prenatal Care Together (IMPACT) Collaborative, identifying four priority areas that required collaborative action.

Results

Priority area action groups are currently working on strategies to improve maternal and infant health outcomes. Collaborative strategies include: raising patient and provider awareness, …

A National Survey Of Parent Support Legislation And Regulations, Nancy P. Correa, Bethanie Van Horne, Bracewell & Giuliani Llp, Christopher Greeley, Angelo P. Giardino

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

Introduction: Parent education has a positive impact on children, parents, families, and the community. CHILDREN AT RISK and Bracewell & Giuliani LLP conducted a policy scan of state statutes regarding parent education.

Methodology: To identify state statutes that address parent education, we conducted a search of statutes in all 50 states using keywords and the online legal research systems. After all state-level policies were ascertained, we selected the most relevant statutes to parent education and identified major themes.

Results: The policy scan identified statutes regarding non-mandated parent education in 40 out of the 50 states. Common themes include: home visitation …

Is It Time To Do More Homework On The Impact Of Childhood Obesity On Academic Achievement?, Shreela V. Sharma

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

Purpose: To provide commentary on the research article “Impact of Pediatric Obesity on Grades in Elementary School,” by Craig A. Johnston, Jennette P. Moreno, Sandra A. Stansberry, and Deborah Woehler .

Findings: In this cross-sectional study the authors examine the association between weight status and math, science and reading grades among 798 2^nd grade children in Texas. The authors show that academic performance, specifically math grades are lower in obese students compared to normal weight students. Finally, the authors propose several physiological and psychological mechanisms including the potential for teacher bias and lower expectations from children who are obese. …

Informing Parent Targeted Interventions To Promote Increased Physical Activity Among Youth, Teresia O'Connor

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

Invited Commentary on "Examining the Disconnect Between Parents' Perceptions and Reality Regarding the Physical Activity Levels of Their Children."