Medicine and Health Sciences Commons^™

Natural Progression Of Low-Gradient Severe Aortic Stenosis With Preserved Ejection Fraction, Antony Leslie Innasimuthu, Sanjay Kumar, Jason Lazar, William E Katz

The Texas Heart Institute Journal

Because the natural progression of low-gradient aortic stenosis (LGAS) has not been well defined, we performed a retrospective study of 116 consecutive patients with aortic stenosis who had undergone follow-up echocardiography at a median interval of 698 days (range, 371–1,020 d). All patients had preserved left ventricular ejection fraction (>0.50) during and after follow-up.

At baseline, patients were classified by aortic valve area (AVA) as having mild stenosis (≥1.5 cm2), moderate stenosis (≥1 to <1.5 cm2), or severe stenosis (<1 cm2). Severe aortic stenosis was further classified by mean gradient (LGAS, mean <40 mmHg; high-gradient aortic stenosis [HGAS], mean ≥40 mmHg). We compared baseline and follow-up values among 4 groups: patients with mild stenosis, moderate stenosis, LGAS, and HGAS.

At baseline, 30 patients had mild stenosis, 54 had moderate stenosis, 24 had LGAS, and 8 had HGAS. Compared with the moderate group, the LGAS …

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 …

Exertional Dyspnea As A Symptom Of Infrarenal Aortic Occlusive Disease, Stacey L Schott, Fernanda Porto Carreiro, James R Harkness, Mahmoud B Malas, Stephen M Sozio, Sammy Zakaria

The Texas Heart Institute Journal

Advanced atherosclerosis of the aorta can cause severe ischemia in the kidneys, refractory hypertension, and claudication. However, no previous reports have clearly associated infrarenal aortic stenosis with shortness of breath. A 77-year-old woman with hypertension and hyperlipidemia presented with exertional dyspnea. Despite extensive testing and observation, no apparent cause for this patient's dyspnea was found. Images revealed severe infrarenal aortic stenosis. After the patient underwent stenting of the aortic occlusion, she had immediate symptomatic improvement and complete resolution of her dyspnea within one month. Twelve months after vascular intervention, the patient remained asymptomatic. In view of the distinct and lasting …

Airway Obstruction In Congenital Central Hypoventilation Syndrome, Alexandra K Reverdin, Ricardo Mosquera, Giuseppe N Colasurdo, Cindy K Jon, Roya M Clements

Faculty, Staff and Student Publications

Congenital central hypoventilation syndrome (CCHS) is the failure of the autonomic system to control adequate ventilation while asleep with preserved ventilatory response while awake. We report a case of a patient with CCHS who presented with intrathoracic and extrathoracic airway obstruction after tracheostomy tube decannulation and phrenic nerve pacer placement. Nocturnal polysomnography (NPSG) revealed hypoxia, hypercapnia and obstructive sleep apnoea, which required bilevel positive airway pressure titration. Airway endoscopy demonstrated tracheomalacia and paretic true vocal cords in the paramedian position during diaphragmatic pacing. Laryngeal electromyography demonstrated muscular electrical impulses that correlated with diaphragmatic pacer settings. Thus, we surmise that the …

Factors Associated With Physical Activity In Kindergarten Children, Carol Hammonds

Dissertations and Theses (Open Access)

Background: Reversing obesity is an urgent public health need for children: worldwide, in 2011 more than 40 million children under the age of five were either overweight or obese. Increasing intensity and duration of physical activity is a strategy to aid in preventing and reducing obesity. A minimum of 60 minutes per day of moderate to vigorous physical activity is recommended for children. School settings, such as full-day kindergarten, where 74% of children in the United States are enrolled, provide opportunities for population-based interventions to increase physical activity, yet little objective data exist on current levels of physical activity in …

How Do Black Nulliparous Women Cognitively Construct Birth?, Marianne F. Moore

Dissertations and Theses (Open Access)

A focused ethnography was conducted to determine the cognitive constructions about birth described by nulliparous Black women in an urban area of the Southwestern US; also, during postpartum, how do these women reconcile expectations with the actual birth? Semi-structured interviews were conducted before birth and after birth.

Women, 16 or older, 17 - 33 weeks carrying a singleton fetus and without anomalies or problems like pre-gestational diabetes, NYHA Cardiac Class III/IV, cancer, renal failure, or sickle cell anemia that eliminated vaginal birth were sequentially recruited and sampled in an affiliated ultrasound clinic. Women scheduled for an anatomy scan were approached. …

Understanding The "Big Picture": End-Of-Life Decisions In The Picu, Amy J. Howells

Dissertations and Theses (Open Access)

Objective: Describe critical care providers' cognitive constructions or their interpretation of the process of decision-making that influences both the technique of conversations and the recommendations given to parents regarding limitation or withdrawal of life sustaining treatments from terminally ill children in the PICU. Design: Qualitative Medical Ethnography. Setting: Tertiary care children's hospital affiliated with a college of medicine. Participants: Eleven critical care providers in the department of pediatrics (attending physicians, critical care fellows, pediatric nurse practitioners, physician assistants). Interventions: In depth, semi-structured interviews designed to explore the experiences of providers in the participation of end-of-life care decision-making. Measurements and Main …

Modulated Functions Of The Fanconi Anemia Core Complex, Yaling Huang

Dissertations and Theses (Open Access)

Cells derived from Fanconi anemia (FA) patients are characterized by hypersensitivity to DNA interstrand crosslinks (ICLs), suggesting that FA genes play a role in ICL repair. Fanconi anemia core complex (including A, B, C, E, F, G, L, FAAP20, and FAAP100) activates the Fanconi pathway by providing the essential E3 ligase activity for FANCD2 mono-ubiquitination. Previous studies suggested the existence of three protein-protein interaction groups. However, the functions of most FA core complex protein are still limited to their presence in the complex. How the spatially-defined FANCD2 ubiquitination is accomplished by the core complex remains unknown.

To elucidate the roles …

Investigating The Role Of Exosomal Communication In The Glioma Microenvironment, Javier Figueroa

Dissertations and Theses (Open Access)

Evidence indicates that human cancers are maintained by a population of cells with stem-like properties called cancer stem cells (CSCs). However, the influence of the surrounding stromal cells on the behavior of the CSCs remains poorly understood. We have recently shown that the micro-environment of human gliomas, the most aggressive human brain tumors, contains both glioma stem cells (GSCs) and cells that resemble human bone marrow-derived mesenchymal stem cells (BM-MSCs), called Glioma Associated-MSCs (GA-MSCs). We have also shown that GA-MSCs generate a cytokine-mediated increase in the growth and self-renewal (clonogenicity) of GSCs. However, other paracrine interactions between GA-MSCs and GSCs …

Targeting Breast Cancer With Bacteriophage Associated Silicon Particles, Srimeenakshi Srinivasan

Dissertations and Theses (Open Access)

Nanoparticle based therapeutics have been successfully used in the treatment of breast cancer. Development of nanovectors targeted to cancer cells or elements in the tumor microenvironment has been pursued to improve their site specific accumulation while reducing the non-specific delivery to normal tissues. However, addition of targeting ligands to the surface of nanovectors while maintaining their payload carrying potential is generally challenging. Therefore, there is a critical need to develop surface decoration strategies that allow for effective combination of targeting and payload delivery to the tumor.

In this study, we propose a novel strategy for covering the surface of mesoporous …

Availability Of Dental Anomaly Phenotype In Individuals With Familial Adenomatous Polyposis, Andrea M. Lewis

Dissertations and Theses (Open Access)

Background: Mutations in the APC gene cause familial adenomatous polyposis (FAP), an autosomal dominant colorectal cancer predisposition associated with the development of hundreds to thousands of adenomatous colorectal polyps beginning in childhood or adolescence. Both malignant and non-malignant extracolonic manifestations are associated with APC gene mutations, including approximately 17% of individuals with various dental anomalies. The availability of dental anomaly information in the medical record remains to be evaluated.

Methods: Medical records were reviewed for documentation of dental anomalies. Dental questionnaires were mailed to 271 individuals with FAP at The University of Texas M. D. Anderson Cancer Center (UTMDACC) to …

Evaluation Of Artifacts In Experimental Cine 4d Ct Acquisition Methods, Sarah Joy

Dissertations and Theses (Open Access)

Four-dimensional computed tomography (4D CT) has increased the accuracy of radiation treatment planning for patients in whom the extent of target motion is large. 4D CT has become a standard of care for radiation treatment simulation, allowing decreased motion artifacts and increased spatiotemporal localization of anatomical structures that move. However, motion artifacts may still remain. These artifacts, or artificial anatomic spatial distributions, add a systematic uncertainty to the treatment process and limit the accuracy of lung function images derived from CT. We proposed to reduce the motion artifacts in cine 4D CT by using three novel investigational 4D CT acquisition …

Tethered Il-15 To Augment The Therapeutic Potential Of T Cells Expressing Chimeric Antigen Receptor: Maintaining Memory Potential, Persistence, And Antitumor Activity, Lenka Hurton

Dissertations and Theses (Open Access)

Tethered IL-15 to augment the therapeutic potential of T cells expressing chimeric antigen receptor: Maintaining memory potential, persistence, and antitumor activity

Adoptive immunotherapy can retarget T cells to CD19, a tumor-associated antigen (TAA) expressed on B-cell malignancies, by the expression of a chimeric antigen receptor (CAR). Infusion of CAR-modified T cells for the treatment B-cell malignancies has demonstrated promise in preclinical and clinical trials. These data highlight the ability of infused CD19-specific T cells to be synchronously activated by large burdens of CD19⁺ leukemia and lymphoma. This can lead to dramatic antitumor effects, but also exposes the recipient to …

Differential Regulation Of Iress In The Aurora A Mrna By Bfgf Through The Mtor Complex To Rc2 Modulates Aurora A Kinase Expression, Roy L. Voice Iii

Dissertations and Theses (Open Access)

Identifying the mechanisms that contribute to tumorigenesis is a major area of focus in our fight against cancer. Epithelial malignant tumors, such as breast, colon, ovarian and pancreatic cancers have been shown to overexpress proteins that control cell mitosis, growth, and proliferation. One of those proteins is the Aurora A kinase. Aurora A kinase is a member of a small family of kinases that contribute to mitotic events such as centrosome duplication, separation, and maturation. Aurora A overexpression leads to genomic instability, which can contribute to tumorigenesis, on the other hand, inhibiting Aurora A expression leads to apoptosis, making it …

Combination Therapy With Aerosol Il-2 And Nk Cells For The Treatment Of Osteosarcoma Lung Metastasis, Sergei R. Guma

Dissertations and Theses (Open Access)

The survival of patients with osteosarcoma lung metastases has not improved in the last 20 years. Novel alternative therapies are needed. The purpose of this investigation was to evaluate the efficacy of combining natural killer [NK] cell therapy with aerosol interleukin-2 [IL-2] for the treatment of osteosarcoma lung metastasis. The expression of NKG2D ligands was analyzed in five different human osteosarcoma cell lines and 103 patient samples (47 from primary tumors and 56 from lung metastases). We discovered that osteosarcoma expresses the ligands for the NKG2D. In vitro studies demonstrated that NK-mediated killing of osteosarcoma cells is dependent on the …

Competition Between Grb2 And Plcγ1 For Binding To Fgfr2 Regulates Phospholipase And Pten Activity, Leading To Cell Invasion And Proliferation, Zahra Timsah

Dissertations and Theses (Open Access)

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Fluctuations in the relative concentrations of proteins in non-stimulated cells can lead to aberrant signaling. In a novel interaction, the SH3 domain of Plcγ1 competes with the SH3 domain of Grb2 for binding to FGFR2 in a concentration-dependent manner. Consequently, reduction of cellular concentrations of Grb2 lead to receptor-dependent recruitment of unphosphorylated Plcγ1. Bringing of the phospholipase to the membrane in this way …

Mechanisms Underlying Distinct Egfr Versus Fgfr-3 And -1 Dependency In Human Bladder Cancer Cells, Tiewei Cheng

Dissertations and Theses (Open Access)

The epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR) are activated by gene amplification, mutation and overexpression in bladder cancer, which drives tumor development and progression. Both EGFR and FGFR inhibitors are currently being tested in clinical trials. However, bladder cancer (BC) cells show remarkably heterogeneous sensitivities to both inhibitors, and the molecular determinants of this heterogeneity are presently unclear. Therefore, in this study, using selective EGFR and FGFR inhibitors in BC cells, we demonstrated that FGFR3 and FGFR1 play largely non-overlapping roles in mediating proliferation and invasion in the distinct “epithelial” and “mesenchymal” subsets of human …

The Association Between The Il-1 Pathway, Isaac C. Wun

Dissertations and Theses (Open Access)

Cutaneous malignant melanoma (CMM) is a potentially lethal malignancy that warrants attention and further research, as it is known to that there is an increasing rate of incidence in theUnited States, and it is also known that exposure to UV light is its most crucial risk factor, and family history of melanoma is also an important risk factor. Melanoma is an aggressive and lethal cancer in humans. There are an estimated new 132,000 melanoma cases annually worldwide, and the trend has doubled in the past 20 years. However, attempts to treat melanoma have encountered considerable resistance and remained ineffective. The …

Development Of A Multi-Purpose Automated Synthesis Module For Production Of Novel Pet Radiopharmaceuticals, I Hong Shih

Dissertations and Theses (Open Access)

Among radiopharmaceuticals of positron emission tomography (PET), ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG) made from commercialized automated synthesis module is the most frequently used in tumor diagnoses. But the false positive findings, such as infectious tissues and post-operative surgical conditions, show strong uptake of ¹⁸F-FDG in PET scans which requires extra clinical procedures to confirm the results. Moreover, the false negative findings, such as low glycolytic activity tumors, reduce the accuracy of PET scans. Therefore, there will be new PET radiopharmaceuticals to redeem the defects of ¹⁸FDG-PET applications.

Current commercialized automated synthesis modules are suitable for clinical use, but …

Systematic Methodology For The Identification Of A Novel Autosomal Dominant Retinitis Pigmentosa Disease-Causing Gene, Jennifer D. Churchill

Dissertations and Theses (Open Access)

Retinitis pigmentosa (RP) is an inherited retinal disease that leads to degeneration of the retina through loss of rod and cone photoreceptor cells and subsequent loss of vision. RP affects approximately 1.5 million people world-wide. Mutations causing autosomal dominant retinitis pigmentosa (adRP) have been identified in 23 different genes. However, these mutations only account for approximately 70% of known adRP cases in Caucasians of Western-European origin and for an even smaller percentage of cases in other ethnicities. My research aims to increase the number of known genes associated with adRP by using an array of advanced genetic techniques to search …

The Novel Upstream Regulator Of Fbxw7, Ji-Hyun Shin

Dissertations and Theses (Open Access)

SCF^FBXW7 is a tumor suppressor E3 ligase protein that targets numerous oncoproteins such as Cyclin E, c-Myc, c-Jun and MCL1. The deregulation of these proteins often leads to the proliferation of cancer cells. Thus, intracellular stability and functional activity of FBXW7 is critical for regulating cancer. However, there is a gap of knowledge about the intracellular signaling pathway or if there is another ubiquitin ligase that regulates FBXW7 stability. Here, I identify a novel mechanism of FBXW7 stability regulation which involves constitutive photomorphogenic 1 (COP1), AKT and CSN6 (i.e. the COP9 signalosome 6).

COP1 is an E3 ubiquitin ligase …

Use Of Positron Emission To Mography For Proton Therapy Verification, Jongmin Cho

Dissertations and Theses (Open Access)

Positron emission tomography (PET), a tool commonly used for cancer staging and response monitoring, has recently been used for proton therapy verification. By imaging tissue activation following proton treatment, attempts have been made to verify proton dose and range. In this dissertation, two novel approaches were developed and tested for the purpose of help improve the proton dose and range estimation as well as verification.

Although there are still some challenges, attempts for proton dose verification using PET has been made by comparing Monte Carlo dose and PET simulations with treatment planned dose and measured PET. In this approach, …

Imbalance Between Neutrophil Elastase And Elafin Promotes Breast Cancer Growth And Progression, Joseph Anthony Caruso

Dissertations and Theses (Open Access)

Elafin, an endogenous serine protease inhibitor, is a critical component of the epithelial barrier against neutrophil elastase (NE) activity. The central hypothesis examined in this dissertation was that elafin has tumor suppressive properties in breast cancer. In support of this hypothesis, immunohistochemical (IHC) analysis revealed that elafin was downregulated in the majority of invasive breast tumors and a subset of pre-invasive ductal carcinoma in situ (DCIS) compared to elafin expression in the normal mammary epithelium. To understand the role of elafin in the mammary epithelium and the impetus for its downregulation during breast tumorigenesis, primary and immortalized human mammary epithelial …

Structure Based Prediction Of Drug-Protein Interactions At Allosteric Sites: To Wards Direct Inhibition Of The Ras Oncogene, Harrison Hocker

Dissertations and Theses (Open Access)

Ras is a monomeric G-protein that mediates multiple signaling pathways. When bound to GTP, Ras binds to and activates effectors and when bound to GDP it does not. Somatic mutations occur in ~15% of all human cancers and cause Ras to be predominantly bound to GTP. Recently, several studies revealed that Ras exists in an ensemble of at least two states when bound to GTP. In the state 1 conformation, Ras is unable to properly bind effectors but holds potential for binding ligands. Conversely, at allosteric sites, state 2 conformations readily bind effectors but not ligands.

To incorporate the flexibility …

Anti-Gd2 Etoposide-Loaded Immunoliposomes For The Treatment Of Gd2 Positive Tumors, Brandon S. Brown

Dissertations and Theses (Open Access)

Systemic chemotherapeutics remain the standard of care for most malignancies even though they frequently suffer from narrow therapeutic index, poor serum solubility, and off-target effects. Monoclonal antibodies that specifically bind antigens overexpressed on many tumors such as the ganglioside, GD2, can be conjugated to drug-loaded liposomes to create a targeted drug delivery system. In this study, we have encapsulated etoposide, a topoisomerase inhibitor effective against a wide range of cancers, in surface modified liposomes decorated with anti-GD2 antibodies. We characterized the properties of the liposomes using a variety of methods including dynamic light scattering, electron microscopy, and Fourier transformed infrared …

Forecasting Longitudinal Changes In Oropharyngeal Tumor Volume, Position, And Morphology During Image-Guided Radiation Therapy, Adam D. Yock

Dissertations and Theses (Open Access)

The purpose of this work was to generate, evaluate, and compare models that predict longitudinal changes in oropharyngeal tumor volume, position, and morphology during radiation therapy.

One volume, one position, and two morphology (size, shape, and position) feature vectors were used to describe 35 oropharyngeal gross tumor volumes (GTVs) during radiation therapy. The two morphology feature vectors comprised the coordinates of the GTV centroids and one of two shape descriptors. One shape descriptor was based on radial distances between the GTV centroid and 614 surface landmarks. The other was based on a spherical harmonic decomposition of these distances. For a …

Image-Guided Proton Therapy For Online Dose-Evaluation And Adaptive Planning, Joey P. Cheung

Dissertations and Theses (Open Access)

The main advantage for using protons in radiotherapy is their finite range in patients, allowing for potential improved sparing of normal tissues. However, this comes at a cost of increased sensitivity to range uncertainties. Density changes along the beam path will affect the proton range and the resultant dose distribution, making it difficult to estimate the impact of visible anatomic changes to the patient dose distribution. In order to better understand the effect of anatomy change on proton dose, some form of treatment-time verification is required and methods to correct for observed changes would be beneficial. Therefore, this project aims …

Activating The 4-1bb Pathway For The Expansion Of Tumor-Infiltrating Lymphocytes For Adoptive T-Cell Therapy For Metastatic Melanoma Patients, Jessica Ann Chacon

Dissertations and Theses (Open Access)

This dissertation project focused on improving the quality of the tumor-infiltrating lymphocytes (TIL) used in Adoptive T-cell therapy by understanding the role of 4-1BB/CD137 co-stimulation during the expansion of the tumor-infiltrating lymphocytes (TIL). Adoptive T-cell therapy using TIL is a promising therapy for late stage melanoma patients, resulting in a 50% response rate and durable long-term survival in over 20% of patients. Current research is aiming at improving the quality of the expanded cells and their persistence in vivo after adoptive transfer to further boost response rates. The specific focus of this dissertation project is the testing of agonistic anti-4-1BB …

Bioactivity And Cell-Mediated Targeting Of Multistage Nanoporous Silicon Particles, Jonathan O. Martinez

Dissertations and Theses (Open Access)

Progress in drug delivery approaches have not adequately translated into clinical advances in the diagnosis or treatment of inflammatory disorders (e.g., cancer). This disconnect is rooted in the inefficient delivery of imaging and therapeutic agents to the inflamed site upon systemic delivery. A multitude of biological barriers pose insurmountable obstacles limiting the ability of the agent to effectively reach and accumulate at the target site. Nanoparticles (NP) surfaced as potential vectors to encapsulate and deliver biological agents. However, even after surface decoration, NP have failed to evade biological barriers (i.e., MPS) and to accumulate at the tumor site at therapeutic …

Methodological Development Of A Multi-Parametric Quantitative Imaging Biomarker Framework For Assessing Treatment Response With Mri, Ryan J. Bosca

Dissertations and Theses (Open Access)

Quantitative imaging biomarkers (QIBs) are increasingly being incorporated into early phase clinical trials as a means of non-invasively assessing the spatially heterogeneous treatment response to anticancer therapies, particularly as indicators for early response. MR QIBs are derived from the analysis of in vivo imaging data, such as that acquired via dynamic contrast enhanced (DCE), dynamic susceptibility enhanced (DSC), and diffusion tensor imaging (DTI). To date, preclinical and clinical applications of such QIBs have provided strong evidence for potential efficacy, but efforts to create meaningful estimates of localized treatment response using multiple QIBs have been stifled by the need for rigorous …