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Novel Imaging-Based Techniques Reveal A Role For Pd-1/Pd-L1 In Tumor Immune Surveillance In The Lung, Todd Bartkowiak

Dissertations and Theses (Open Access)

The binding of immune inhibitory receptor Programmed Death 1 (PD-1) on T cells to its ligand PD-L1 has been implicated as a major contributor to tumor induced immune suppression. Clinical trials of PD-L1 blockade have proven effective in unleashing therapeutic anti-tumor immune responses in a subset of patients with advanced melanoma, yet current response rates are low for reasons that remain unclear. Hypothesizing that the PD-1/PD-L1 pathway regulates T cell surveillance within the tumor microenvironment, we employed intravital microscopy to investigate the in vivo impact of PD-L1 blocking antibody upon tumor-associated immune cell migration. However, current analytical methods of intravital …

Trpv1 Channels Contribute To Behavioral Hypersensitivity And Spontaneous Activity In Nociceptors After Spinal Cord Injury, Zizhen Wu

Dissertations and Theses (Open Access)

A majority of persons who have sustained spinal cord injury (SCI) develop chronic pain. While most investigators have assumed that the critical mechanisms underlying neuropathic pain after SCI are restricted to the central nervous system (CNS), recent studies showed that contusive SCI results in a large increase in spontaneous activity in primary nociceptors, which is correlated significantly with mechanical allodynia and thermal hyperalgesia. Upregulation of ion channel transient receptor vanilloid 1 (TRPV1) has been observed in the dorsal horn of the spinal cord after SCI, and reduction of SCI-induced hyperalgesia by a TRPV1 antagonist has been claimed. However, the possibility …

Acceleration Of The Panin Development In Mice Expressing Oncogenic K-Ras Due To A High Fat Diet, Bincy Philip

Dissertations and Theses (Open Access)

Obesity is postulated to be one of the major risk factors for pancreatic cancer, and recently it was indicated that an elevated body mass index (BMI correlates strongly with a decrease in patient survival. Despite the evident relationship, the molecular mechanisms involved are unclear. Oncogenic mutation of K-Ras is found early and is universal in pancreatic cancer. Extensive evidence indicates oncogenic K-Ras is not entirely active and it requires a triggering event to surpass the activity of Ras beyond the threshold necessary for a Ras-inflammation feed-forward loop. We hypothesize that high fat intake induces a persistent low level inflammatory response …

A Novel Mechanism Of Skin Tumor Promotion Involving Interferon-Gamma (Ifnγ)/Signal Transducer And Activator Of Transcription-1 (Stat1) Signaling In Epidermis, Ronald Bozeman

Dissertations and Theses (Open Access)

The JAK-STAT pathway is a major signaling pathway involved in many biological processes including proliferation, apoptosis, and differentiation. Aberrant expression of STATs has been reported in multiple human cancers and murine mouse models of tumorigenesis. Previous studies from our lab and others have established a critical role for Stat3 in epithelial tumorigenesis, but the role of Stat1 is largely unknown. The current study was designed to explore the role of Stat1 during multistage skin carcinogenesis. Topical treatment with both TPA and the anthrone derivative chrysarobin (CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Tyr701) and serine (Ser727) residues …

Stimulation Through Tlr4 Increases Fviii Inhibitor Formation In A Mouse Model Of Hemophilia A, Claire K. Holley

Dissertations and Theses (Open Access)

Hemophilia A is a clotting disorder caused by functional factor VIII (FVIII) deficiency. About 25% of patients treated with therapeutic recombinant FVIII develop antibodies (inhibitors) that render subsequent FVIII treatments ineffective. The immune mechanisms of inhibitor formation are not entirely understood, but circumstantial evidence indicates a role for increased inflammatory response, possibly via stimulation of Toll-like receptors (TLRs), at the time of FVIII immunization. I hypothesized that stimulation through TLR4 in conjunction with FVIII treatments would increase the formation of FVIII inhibitors. To test this hypothesis, FVIII K.O. mice were injected with recombinant human FVIII with or without concomitant doses …

Delayed Thrombus Resolution And Fibroproliferative Vascular Wound Healing From Deficiency Of Type Iii Collagen: A Paradoxical Mechanism For Tissue Fragility, Amy J. Reid

Dissertations and Theses (Open Access)

Vascular Ehlers-Danlos syndrome is a heritable disease of connective tissue caused by mutations in COL3A1, conferring a tissue deficiency of type III collagen. Cutaneous wounds heal poorly in these patients, and they are susceptible to spontaneous and catastrophic rupture of expansible hollow organs like the gut, uterus, and medium-sized to large arteries, which leads to premature death. Although the predisposition for organ rupture is often attributed to inherent tissue fragility, investigation of arteries from a haploinsufficient Col3a1 mouse model (Col3a1^+/-) demonstrates that mutant arteries withstand even supraphysiologic pressures comparably to wild-type vessels. We hypothesize that injury …

Investigating The Roles Of The P63 Isoforms In The Microrna Biogenesis Pathway, Deepavali Chakravarti

Dissertations and Theses (Open Access)

MicroRNAs play roles in various biological processes like development, tumorigenesis, metastasis and pluripotency. My thesis work has demonstrated roles for p63, a p53 family member, in the upstream regulation of microRNA biogenesis. The p63 gene has a complex gene structure and has multiple isoforms. The TAp63 isoforms contain an acidic transcription activation domain. The ΔNp63 isoforms, lack the TA domain, but have a proline rich region critical for gene transactivation. To understand the functions of these isoforms, the Flores lab generated TAp63 and ΔNp63 conditional knock out mice. Using these mice and tissues and cells from these mice we have …

The Role Of Type I Insulin-Like Growth Factor Receptor Signaling In Breast Cancer Brain Metastasis, Sandra M. Saldana

Dissertations and Theses (Open Access)

Brain metastasis is a common cause of mortality in cancer patients. Approximately 20-30% of breast cancer patients acquire brain metastasis, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF- IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that the IGF-IR signaling axis is constitutively active in brain-seeking sublines of breast cancer cells, driving an increase in in vitro metastatic properties. We demonstrate that IGF-IR signaling is activated in an autocrine manner …

Ms 015 Guide To Joseph Melnick, Phd Papers (1943-1989), Joseph Melnick (1914-2001)

Manuscript Finding Aids

Joseph Melnick, PhD papers contains correspondence and reprints that document the career of Dr. Melnick, who was a leading epidemiologist, best known for his research on polio. See more at MS 015.

Examining The Relationship Between Media Use And Aggression, Sexuality, And Body Image, Temple Northup

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

Objectives: The primary purpose of this research is to understand the media's impact on individual attitudes and behaviors related to aggression, sexuality, and body image. This research is of particular importance because it uses up-to-date data reflecting effects based on the current media environment. Additionally, it includes a racially diverse sample.

Methods: A survey of 407 students at a large, public university was conducted. The survey instrument contained general measures related to media consumption, including overall television, video game, and internet use, as well as more specific questions related to particular types of media, such as pornography. For the dependent …

Ms171: Interview With Julie Knobil, Julie Knobil M.A., Ph.D., Houston Academy Of Medicine-Texas Medical Center Library

Texas Medical Center - Women's History Project

An oral interview with Juile (Hotchkiss) Knobil, research professor of physiology and then integrative biology at the Medical School, where she lectured on mammalian physiology and perinatal endocrinology. See more at Texas Medical Center-Women's History Project and its finding aid.

Biomarkers Of Maternal And Fetal Exposure To Organochlorine Pesticides Measured In Pregnant Hispanic Women From Brownsville, Texas, Ken Sexton, Jennifer J Salinas, Thomas J Mcdonald, Rose M Z Gowen, Rebecca P Miller, Joseph B Mccormick, Susan P Fisher-Hoch

Faculty, Staff and Student Publications

Biomarkers of organochlorine pesticides were measured in both venous and umbilical cord blood from 35 pregnant Hispanic women living in Brownsville, Texas, USA. Gas chromatography with an electron capture detector was used to analyze specimens for 30 individual pesticides or their metabolites. Results indicate that blood concentrations were relatively low for most individual compounds, but that high-end (upper 10th percentile) values for total DDT were comparatively high. Although health effects associated with measured blood concentrations are uncertain, there is concern that fetal exposure to low levels of these OC compounds, either individually or in combination, might contribute to subsequent health …

Induction Of Early Biomarkers In A Thrombus-Induced Sheep Model Of Ischemic Heart Failure, Aluganti N Chandrakala, Pawel Kwiatkowski, Chittoor B Sai-Sudhakar, Benjamin Sun, Angela Phillips, Sampath Parthasarathy

The Texas Heart Institute Journal

The levels of brain natriuretic peptide (BNP) and monocyte chemoattractant protein-1 (MCP-1) are known to be increased in the sera of subjects with heart failure. Existing models do not account for the biomass of thrombus that occurs in patients undergoing myocardial infarction. In this study, we compared the expressions of sheep-derived genes for BNP, MCP-1, and atrial natriuretic peptide in a new large-animal model of thrombus-induced heart failure. Thrombus of autologous platelets was injected directly into the left circumflex coronary arteries of sheep. Cardiac ischemic injury was evaluated by troponin I levels, and heart failure progression was monitored with the …

Preventing Sudden Cardiac Death In Athletes: In Search Of Evidence-Based, Cost-Effective Screening, Paolo Angelini, Mladen I Vidovich, Christine E Lawless, Macarthur A Elayda, J Alberto Lopez, Dwayne Wolf, James T Willerson

The Texas Heart Institute Journal

Sudden cardiac death in athletes is a recurrent phenomenon at sporting events and during training. Recent studies have associated sudden cardiac death with such cardiovascular conditions as coronary artery anomalies, cardiomyopathies, and electrocardiographic abnormalities, most of which are screenable with modern imaging techniques. We recently inaugurated the Center for Coronary Artery Anomalies at the Texas Heart Institute, which is dedicated to preventing sudden cardiac death in the young and investigating coronary artery anomalies. There, we are conducting 2 cross-sectional studies intended to firmly establish and quantify, in a large group of individuals from a general population, risk factors for sudden …

Early Hemodynamic And Biochemical Changes In Overloaded Swine Ventricleearly Hemodynamic And Biochemical Changes In Overloaded Swine Ventricle, Sandro Gelsomino, Fabiana Lucà, Chiara Nediani, Sandra Zecchi Orlandini, Daniele Bani, Antonio S Rubino, Attilio Renzulli, Roberto Lorusso, Andrea Consolo, Antonino Lo Cascio, Jos Maessen, Gian Franco Gensini

The Texas Heart Institute Journal

The present study was undertaken to investigate, in an animal model, the relationship between sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity, phospholamban phosphorylation, acylphosphatase activity, and hemodynamic changes that occur in the early phase of pressure overload. In 54 study-group pigs, weighing 40±5 kg each, an aortic stenosis was created with a band of umbilical tape tied around the aorta; 18 sham-operated pigs formed our control group. Eight animals (6 study and 2 control) were randomly assigned to each experimental time (0.5, 3, 6, 12, 24, 48, 72, 96, and 168 hr). All indices of left ventricular function declined significantly, with a …

Some Thoughts About The Historic Events That Led To The First Clinical Implantation Of A Total Artificial Heart, Denton A Cooley

The Texas Heart Institute Journal

No abstract provided.

The Pathobiology Of Acute Coronary Syndromes: Clinical Implications And Central Role Of The Mitochondria, L Maximilian Buja

The Texas Heart Institute Journal

Ongoing investigation has provided new insights into the pathobiology of myocardial ischemic injury. These include an improved understanding of the roles of the major modes of cell injury and death, including oncosis, apoptosis, and unregulated autophagy, as well as the central role of the mitochondria in the progression of myocardial ischemic injury, reperfusion injury, and myocardial conditioning. This understanding is providing insights for developing new pathophysiologic, pharmacologic, and cell-based therapies, alone or in combination with percutaneous coronary interventions, for better preservation of myocardium and reduction of morbidity and mortality rates from ischemic heart disease.

Mitochondrial Cardiomyopathy: Pathophysiology, Diagnosis, And Management, Deborah E Meyers, Haseeb Ilias Basha, Mary Kay Koenig

The Texas Heart Institute Journal

Mitochondrial disease is a heterogeneous group of multisystemic diseases that develop consequent to mutations in nuclear or mitochondrial DNA. The prevalence of inherited mitochondrial disease has been estimated to be greater than 1 in 5,000 births; however, the diagnosis and treatment of this disease are not taught in most adult-cardiology curricula. Because mitochondrial diseases often occur as a syndrome with resultant multiorgan dysfunction, they might not immediately appear to be specific to the cardiovascular system. Mitochondrial cardiomyopathy can be described as a myocardial condition characterized by abnormal heart-muscle structure, function, or both, secondary to genetic defects involving the mitochondrial respiratory …

Low Serum Triglyceride Levels As Predictors Of Cardiac Death In Heart Failure Patients, Guliz Kozdag, Gokhan Ertas, Ender Emre, Yasar Akay, Umut Celikyurt, Tayfun Sahin, Gozde Gorur, Kurtulus Karauzum, Irem Yilmaz, Dilek Ural, Mira Sarsekeyeva

The Texas Heart Institute Journal

Understanding the influence of sex differences on predictors of cardiac mortality rates in chronic heart failure might enable us to lengthen lifetimes and to improve lives. This study describes the influence of sex on cardiovascular mortality rates among chronic heart failure patients.

From January 2003 through December 2009, we evaluated 637 consecutive patients (409 men and 228 women) with chronic heart failure, who ranged in age from 18 through 94 years (mean age, 64 ± 13 yr) and ranged in New York Heart Association (NYHA) functional class from II through IV. The mean follow-up period was 38 ± 15 months, …

Preventing Deep Wound Infection After Coronary Artery Bypass Grafting: A Review, Charles S Bryan, William M Yarbrough

The Texas Heart Institute Journal

The consequences of deep wound infections before, during, and after coronary artery bypass grafting have prompted research to clarify risk factors and explore preventive measures to keep infection rates at an irreducible minimum. An analysis of 42 studies in which investigators used multivariate logistic regression analysis revealed that diabetes mellitus and obesity are by far the chief preoperative risk factors. A 4-point preoperative scoring system based on a patient's body mass index and the presence or absence of diabetes is one practical way to determine the risk of mediastinitis, and other risk-estimate methods are being refined. Intraoperative risk factors include …

Stab Wound Of The Heart With Unusual Sequelae, Peter I Praeger, Jonathan Praeger, Ahmed M Abdel-Razek, Elie M Elmann

The Texas Heart Institute Journal

A 31-year-old woman was admitted to the emergency department with a stab wound to the heart. She was initially stable but rapidly developed hypotension. While the operating room and staff were in preparation, she underwent pericardiocentesis. She was then rushed to the operating room by the general surgical trauma team, who performed a bilateral anterior thoracotomy to control the bleeding. In the recovery room, the patient was still hypotensive, so cardiothoracic surgery was consulted.

An echocardiogram revealed severe hypokinesis of both ventricles. The cardiothoracic surgeons returned her to the operating room and discovered that the anterior pericardium had been completely …

Biochemical Characterization Of Binding Partners Of Two Hsp70 Co-Chaperones In Saccharomyces Cerevisiae, Jacob Verghese

Dissertations and Theses (Open Access)

Cells are exposed to a variety of environmental and physiological changes including temperature, pH and nutrient availability. These changes cause stress to cells, which results in protein misfolding and altered cellular protein homeostasis. How proteins fold into their three-dimensional functional structure is a fundamental biological process with important relevance to human health. Misfolded and aggregated proteins are linked to multiple neurodegenerative diseases, cardiovascular disease and cystic fibrosis. To combat proteotoxic stress, cells deploy an array of molecular chaperones that assist in the repair or removal of misfolded proteins.

Hsp70, an evolutionarily conserved molecular chaperone, promotes protein folding and helps maintain …

A Study On The Function Of 14-3-3sigma In Regulating Cancer Energy Metabolism, Liem M. Phan, Liem M. Phan

Dissertations and Theses (Open Access)

Metabolic reprogramming has been shown to be a major cancer hallmark providing tumor cells with significant advantages for survival, proliferation, growth, metastasis and resistance against anti-cancer therapies. Glycolysis, glutaminolysis and mitochondrial biogenesis are among the most essential cancer metabolic alterations because these pathways provide cancer cells with not only energy but also crucial metabolites to support large-scale biosynthesis, rapid proliferation and tumorigenesis. In this study, we find that 14-3-3σ suppresses all these three metabolic processes by promoting the degradation of their main driver, c-Myc. In fact, 14-3-3s significantly enhances c-Myc poly-ubiquitination and subsequent degradation, reduces c-Myc transcriptional activity, and down-regulates …

Identifying Genetic Variants And Characterizing Their Role In Clubfoot, Katelyn S. Weymouth

Dissertations and Theses (Open Access)

Clubfoot is a common, complex birth defect affecting 4,000 newborns in the United States and 135,000 world-wide each year. The clubfoot deformity is characterized by inward and rigid downward displacement of one or both feet, along with persistent calf muscle hypoplasia. Despite strong evidence for a genetic liability, there is a limited understanding of the genetic and environmental factors contributing to the etiology of clubfoot. The studies described in this dissertation were performed to identify variants and/or genes associated with clubfoot. Genome-wide linkage scan performed on ten multiplex clubfoot families identified seven new chromosomal regions that provide new areas to …

Genetic Analysis Of The Hippo Pathway In Mouse Liver, Li Lu

Dissertations and Theses (Open Access)

Cancer therapy and tumor treatment remain unsolved puzzles. Genetic screening for tumor suppressor genes in Drosophila revealed the Hippo-signaling pathway as a kinase cascade consisting of five core components. Disrupting the pathway by deleting the main component genes breaks the balance of cell proliferation and apoptosis and results in epithelial tissue tumorigenesis. The pathway is therefore believed to be a tumor suppressor pathway. However, a corresponding role in mammals is yet to be determined. Our lab began to investigate the tumor suppression function of the potent mammalian Hippo pathway by putting floxed alleles into the mouse genome flanking the functional-domain-expressing …

Fibulin-2 Stabilizes Tumor Extracellular Matrix And Drives Malignant Progression Of Lung Adenocarcinoma, Brandi N. Baird

Dissertations and Theses (Open Access)

The ECM of epithelial carcinomas undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How tumors maintain ECM integrity in the face of dynamic biophysical forces is still largely unclear. This study addresses these deficiencies using mouse models of human lung adenocarcinoma. Spontaneous lung tumors were marked by disorganized basement membranes, dense collagen networks, and increased tissue stiffness. Metastasis-prone lung adenocarcinoma cells secreted fibulin-2 (Fbln2), a matrix glycoprotein involved in ECM supra-molecular assembly. Fibulin-2 depletion in tumor cells decreased the intra-tumoral abundance of matrix metalloproteinases and reduced collagen cross-linking and tumor compressive properties resulting in …

Simultaneous Induction Of Nkg2d And Nkg2d Ligand For Promoting Immune Surveillance By Il-12 Plus Doxorubicin Treatment, Jiemiao Hu

Dissertations and Theses (Open Access)

NKG2D (natural killer group 2, member D) and its ligands interaction in tumor microenvironment directs tumor infiltrating immune cells to recognize tumor cells, stimulate cytotoxic effector immune cells, and therefore eradicate tumor cells. IL-12, a cytokine produced by antigen presenting cells, has remarkable antitumor effect by activating innate and adaptive immunity. Doxorubicin, a commonly used chemotherapeutic agent also boosts the host antitumor immune response to cause tumor cell death. Our previous publication suggests that IL-12 plus doxorubicin enhances NKG2D function-dependent inhibition of tumor progression and promotes CD8⁺T cells infiltrating into tumors. The purpose of this study is to …

Post-Transcriptional Regulation Of Mammalian Gene Expression In Non-Coding Region Of Target Rna, Jing Lin

Dissertations and Theses (Open Access)

Tumor Suppressor Candidate 2 (TUSC2) is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. TUSC2 mRNA transcripts could be detected on Northern blots in both normal lung and some lung cancer cell lines, but no endogenous TUSC2 protein could be detected in a majority of lung cancer cell lines. Mechanisms regulating TUSC2 protein expression and its inactivation in primary lung cancer cells are largely unknown. We investigated the role of the 5’- and 3’-untranslated regions (UTRs) of the TUSC2 gene in the regulation of TUSC2 protein expression. We found that two small upstream open-reading frames (uORFs) …

Prostate Cancer Stem Cells: Drug To Lerance, Experimental Reconstitution And Castration Resistance, Xin Chen

Dissertations and Theses (Open Access)

Prostate cancer (PCa) is one of the leading malignancies affecting men in the Western world. Although tremendous effort has been made towards understanding PCa development and developing clinical treatments in the past decades, the exact mechanisms of PCa are still not clearly understood. Emerging evidence has postulated that a population of stem cell-like cells inside a tumor, termed ‘cancer stem cells (CSCs)’, may be the cells responsible for tumor initiation, progression, recurrence, metastasis and therapy resistance. Like CSC studies in other cancer types, it has been reported that PCa also contains CSCs. However, there remain several unresolved questions that need …

Induction Of Stronger And Long Lasting Vaccine Immunity To Tuberculosis, Pearl Bakhru

Dissertations and Theses (Open Access)

Tuberculosis is a major cause of death due to an infection in mankind. BCG vaccine protects against childhood tuberculosis although, it fails to protect against adult tuberculosis. BCG vaccine localizes to immature phagosomes of macrophages, and avoids lysosomal fusion, which decreases peptide antigen production. Peptides are essential for macrophage-mediated priming of CD4 and CD8 T cells respectively through MHC-II and MHC-I pathways. Furthermore, BCG reduces the expression of MHC-II in macrophages of mice after infection, through Toll-like receptor-1/2 (TLR-1/2) mediated signaling. In my first aim, I hypothesized that BCG-induced reduction of MHC-II levels in macrophages can decrease CD4 T cell …