Medicine and Health Sciences Commons^™

Cancer Associated Fibroblast Derived Angiogenic Factor Mfap5 In Ovarian Cancer Progression, Sze Lee Cecilia Leung

Dissertations and Theses (Open Access)

Advanced stage ovarian cancer is the most lethal gynecologic malignancy. No major improvement on patient survival has been achieved in the past decade. Therefore, identification of predictive or prognostic markers and further understanding of the molecular mechanisms in ovarian cancer progression are of paramount importance.

While cancer cells have always been the targets for the identification of prognostic and predictive markers, the potential for developing new diagnosis and treatments based on the tumor supporting stromal microenvironment is relatively unexplored. Using transcriptome profiling analysis on microdissected stromal and epithelial components of normal and malignant ovarian tissues, we identified a gene signature …

Synthetic Lethality Of Cdk Inhibition And Doxorubicin In Triple-Negative Breast Cancer Requires P53 Inactivation, Natalie A. Jabbour-Leung

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) is an aggressive malignancy in which the tumors lack expression of estrogen receptor, progesterone receptor and HER2. As such, TNBC patients cannot benefit from clinically available targeted therapies and must rely on chemotherapy and surgery for treatment. While initially responding well to chemotherapy, TNBC patients are at increased risk of developing distant metastasis and have decreased overall survival compared to non-TNBC patients. A majority of TNBC tumors carry p53 mutations, enabling them to bypass the G1 checkpoint and complete the cell cycle even in the presence of DNA damage. Therefore, we hypothesized that TNBC cells are …

Sunitinib-Induced Cardiotoxicity Exposes Microvascular And Metabolic Derangements In The Failing Heart, Meredith R. Rodriguez

Dissertations and Theses (Open Access)

Cardiac dysfunction is one of the largest obstacles to effective cancer treatment. Not only do a growing number of cancer patients have significant cardiovascular risk factors at the time of diagnosis, but a number of targeted therapies can themselves cause cardiac dysfunction. These newer treatment options are also increasingly effective, placing a growing emphasis on post-cancer quality of life. In some instances, a patient may outlive his or her cancer only to succumb to heart failure in as little as five years. One such targeted therapy is the small molecular receptor tyrosine kinase sunitinib. Sunitinib was developed in the early …

Influx And Efflux Of Adenine Nucleotides From Erythrocytes Regulate Oxygen Transport And Systemic Metabolism, William G. O'Brien Iii

Dissertations and Theses (Open Access)

Erythrocytes are responsible for ensuring a sufficient supply of oxygen to meet activity demands. The mammalian erythrocytes primarily modulate their oxygen-carrying capacity by varying the levels of organic phosphates, such as 2,3-BPG. In other organisms, such as fish, ATP instead of 2,3-BPG is used to modulate their erythrocyte’s oxygen binding ability. Here, using a series of genetically modified mice, we investigated a previously unrecognized pathway of adenine nucleotide influx and efflux that modulates erythrocyte’s oxygen binding ability and controls systemic metabolism. Our studies show that the loss of AMPD3 and CD73, two important enzymes in regulating AMP levels intra- and …

Oxidative Protein Folding Pathways In Gram-Positive Actinobacteria, Melissa E. Robinson

Dissertations and Theses (Open Access)

Disulfide bonds are important for the stability of many secreted proteins. These covalent linkages, which result from the oxidation of neighboring cysteine (Cys) residues, are often rate-limiting steps for protein folding and maturation. Disulfide bond formation is restricted to extracellular oxidizing compartments like the eukaryotic endoplasmic reticulum and Gram-negative bacterial periplasm. Protein oxidation has been well-studied in these organisms, but largely ignored in Gram-positive bacteria. Due to the absence of an outer membrane, these organisms are thought to lack compartments in which to catalyze oxidative protein folding.

This thesis reveals that Gram-positive Actinobacteria use disulfide bond formation to help fold …

Knowledge And Self-Esteem In Individuals With Neurofibromatosis Type 1 (Nf1), Kayla Vaughn

Dissertations and Theses (Open Access)

Neurofibromatosis Type 1 (NF1) is a progressive genetic disorder characterized mainly by café-au-lait macules, Lisch nodules, as well as cutaneous and subcutaneous neurofibromas among other traits. Due to the physical manifestations of the condition, it has been observed that individuals with NF1 have lower self-esteem (SE) when compared to the general population. Additionally, a study published over 20 years ago found that overall knowledge of NF1 was poor in individuals affected with the condition. The goal of our study was to reassess knowledge in this population and investigate whether it is related to SE. A survey comprised of knowledge-based questions …

Characterization Of Low Density Intracranial Lesions Using Dual-Energy Computed To Mography, Jessica L. Nute

Dissertations and Theses (Open Access)

Calcific and hemorrhagic foci of susceptibility are frequently encountered on routine brain MR studies. Both etiologies cause variations in local magnetic field strength, leading to dark regions on the MR images that cannot be classified. Single-energy CT (SECT) can be used to identify lesions with attenuation over 100 HU as calcific, however lesions with lower attenuation cannot be reliably identified. While calcific lesions are unlikely to cause harm, hemorrhagic lesions carry a risk of subsequent intracranial bleeding; as such, identification of hemorrhage is vital in preventing the inappropriate use of anticoagulant medications in patients with hemorrhagic lesions.

Given there currently …

Developmental Origins Of Renal Connecting Tubule And Collecting Duct: Role Of Aqp2+ Progenitor Cells, Lihe Chen

Dissertations and Theses (Open Access)

The connecting tubule interconnects the nephron and collecting duct, which arise from kidney mesenchyme and the ureteric bud, respectively, to generate the functional tubular networks. The collecting duct is comprised of principal cells and intercalated cells, which bear different molecular signatures and regulate sodium/water and acid/base balance, respectively. The progenitor cells of the connecting tubule and the collecting duct remain virtually unknown.

We generated two Aqp2 lineage tracing mouse models. In these models, Aqp2Cre transgene drives Cre expression by the Aqp2 promoter to exclusively either inactivate histone H3 K79 methyltransferase Dot1l (Dot1l^f/f Aqp2Cre) or activate RFP in …

Targeted Inhibition Of Pi3k, Mtor, And Igf1r For The Treatment Of Undifferentiated Pleomorphic Sarcoma, Caitlin Denise May

Dissertations and Theses (Open Access)

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal malignancy largely devoid of indicators for its originating tissue. Surgery remains the standard of care, as radiation therapy and systemic chemotherapy have limited efficacy in UPS patients with localized and metastatic disease, respectively. Therefore, it is imperative to identify and evaluate novel therapeutic targets in UPS in order to provide more efficacious treatment options for patients. Previous studies have revealed that members of the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathway can be used to predict patient outcome in cohorts containing patients with various subtypes of soft tissue sarcoma. Furthermore, we have …

Texas Physicians' Awareness And Utilization Of Genetic Services, Callie L. Jenevein

Dissertations and Theses (Open Access)

The number of disorders for which genetic testing is available has increased nearly 500% in the past 15 years. Access to the majority of genetic tests and services hinges on physicians’ ability to identify patients at risk for genetic disease and provide appropriate testing and counseling or refer to genetic specialists. Recent research demonstrates the need for referrals to genetic specialists by showing that many physicians lack skills required to perform appropriate genetic services, such as making proper risk assessments, providing genetic counseling, ordering genetic testing and interpreting results. However, little research exists on physicians’ awareness and utilization of genetic …

Spiritual Exploration In The Prenatal Genetic Counseling Session, Katelynn G. Sagaser

Dissertations and Theses (Open Access)

Religion and spirituality are important components of many individuals’ lives, and spiritual needs may present among persons receiving medical care. Spirituality has been demonstrated to be significant in the coping of women experiencing pregnancy complications (Breen et al. 2006; Price et al. 2007). To characterize the manner in which prenatal genetic counselors might address spiritual issues with their patients, we surveyed 283 patients receiving prenatal genetic counseling using the Brief RCope and a series of questions that examined interest in spiritual exploration. Counselors were concurrently surveyed to identify the spiritual language used within the session and the counselor’s perceived importance …

Selection Methods For Genetically-Modified T Cells: In Support Of Translational Therapy, David Rushworth

Dissertations and Theses (Open Access)

T cells are blood cells which organize the immune system of the host. These cells are necessary for the host to respond appropriately to threats from foreign organisms and cancerous growth. However, in the case of certain infections and cancer, T cells are unable to respond appropriately to a threat and establish immunity. This leads to disease when the infection or cancer is not sufficiently eliminated. On the other hand, T cells can lack tolerance for healthy tissue and perceive healthy tissue as infected. The ensuing over-reactive immune response also leads to disease. A delicate balance must exist between immunity …

Evaluation Of Current Knowledge Of Genetics Among Dental Students, Residents And Dental Hygiene Students, Carla Mcgruder

Dissertations and Theses (Open Access)

Genetic testing is increasingly available in clinical settings. To provide personalized patient care, dental health professionals must have a greater understanding of genetics. The Commission on Dental Accreditation (CODA) credentials all dental schools in the United States and currently does not mandate genetics training for official approval of programs. There is little information about dental genetics education and no known studies that have evaluated dental students, residents and dental hygiene students’ knowledge of human genetics. It is crucial to assess genetics knowledge of this population to ascertain if dental schools are preparing students for the future of personalized dentistry. This …

Social-Demographics, Health Behaviors, Telomere Length In Mexican-American Cohort And Circulating Dna Methylation In Bladder Cancer, Lixia Han

Dissertations and Theses (Open Access)

I. SOCIAL-DEMOGRAPHICS, HEALTH BEHAVIORS, AND TELOMERE LENGTH IN MEXICAN AMERICANS: A COHORT STUDY

Recent studies using a prospective cohort design have suggested that telomere length in peripheral blood leukocytes is not only a potential indicator of cellular aging that has been linked to stressful life experience and health behaviors, but also a prognostic marker for major chronic diseases; however, such study has never been done among adult Mexican Americans. In this current study, we examined cross-sectional associations among social-demographics, lifestyle behaviors, and relative telomere length (RTL) in peripheral blood leukocytes, as well as longitudinal relationships among major chronic diseases, weight …

Rest Regulatory Circuit Controls Distinct Oncogenic Properties Of Glioblastoma Stem Cells Through Specific Micrornas, Anantha L Marisetty

Dissertations and Theses (Open Access)

Glioblastoma Multiforme (GBM) is the most common and aggressive primary malignant brain tumor in adults. With an average survival of only 12-16 months the prognosis for GBM patients remains dismal, with less than 5% of patients surviving 5 years. New mechanism-based approaches are necessary for the management of patients with GBM. Many GBM tumors are believed to be caused by self-renewing, glioblastoma-derived stem-like cells (GSCs). These GSCs are resistant to chemo- and radiation therapies, and are believed to be responsible for tumor recurrence. In a recent paper from our lab we have shown that REST, RE1-silencing transcription factor, regulates oncogenic …

Actions Of Pi3k-Delta Inhibitor, Idelalisib, And Its Combination With Bendamustine In Chronic Lymphocytic Leukemia, Prexy Modi

Dissertations and Theses (Open Access)

Class I phosphatidylinositol 3-kinase isoforms (α, β, δ, and γ) play a major role in cancer cell growth and survival. PI3K α and β are most studied. PI3K pathway is highly dysregulated in many cancers and aberrant PI3K signaling is associated with oncogene mutations and disease progression in solid tumors and in hematologic malignancies.

Chronic lymphocytic leukemia (CLL) is driven by B-cell receptor (BCR) signaling that promotes B-cell proliferation and survival. PI3K is a critical node in BCR pathway and PI3Kδ has a pivotal role in B-cell development and maintenance and this isoform is over-expressed in many B-cell malignancies, including …

Functional In Vivo Screen Identifies Pygo2 As A Putative Gene To Promote Prostate Cancer, Xiaolu Pan

Dissertations and Theses (Open Access)

Poor prognosis of prostate cancer is correlated with rampant chromosomal copy number alterations, highlighting the potential function of genes with copy number gains and losses in driving prostate cancer progression. To identify putative genes promoting prostate cancer, an in vivo tumorigenesis screen was performed for 286 genes that are recurrently amplified and overexpressed in human prostate cancer. The transcription co-activator protein PYGO2 was identified as a major hit for further in vivo functional and clinical validation. Overexpression of PYGO2 could enhance primary tumor growth as well as local invasion to lymph nodes using AR-positive prostate cancer cell line LNCaP. PYGO2 …

Investigating The Roles Of P63 And P73 Isoforms To Therapeutically Treat P53-Altered Cancers, Avinashnarayan Venkatanarayan

Dissertations and Theses (Open Access)

Investigating the roles of p63 & p73 isoforms to therapeutically treat

p53-altered cancers

Avinashnarayan Venkatanarayan, M.S.

Supervisory Professor: Elsa R. Flores, Ph.D.

The TP53 tumor suppressor is mutated in approximately 50% of human cancers rendering cancer therapies ineffective. p53 reactivation suppresses tumor formation in mice. However, this strategy has proven difficult to implement therapeutically. An alternate approach to overcome p53 loss is to manipulate the p53-family members, p63 and p73, which interact and share structural similarities to p53. p63 and p73, unlike p53 are less frequently mutated and have two major isoforms with distinct functions …

Evaluating The Nccn Clinical Criteria For Hereditary Breast And Ovarian Cancer Syndrome Genetic Testing, Caiqian Wu

Dissertations and Theses (Open Access)

Hereditary Breast and Ovarian Cancer (HBOC) syndrome predisposes females with a BRCA1 or BRCA2 mutation to an up to 85% lifetime risk for breast cancer and an up to 40% lifetime risk for ovarian cancer. It is crucial for individuals with HBOC to be identified to allow for proper screening, management, and identification of at-risk family members in order to reduce mortality. The National Comprehensive Cancer Network (NCCN) has established clinical guidelines for when to recommend BRCA1/2 testing. A retrospective chart review of 1123 M.D. Anderson Cancer Center breast cancer patients was performed in order to evaluate the positive predictive …

Gene Set Analysis Of Post-Lactational Mammary Gland Involution Gene Signatures In Inflammatory And Triple Negative Breast Cancer, Arvind Bambhroliya

Dissertations and Theses (Open Access)

With each cycle of pregnancy and lactation, the mammary gland undergoes dramatic changes. Clarkson et al. (2004) and Stein et al. (2004) conducted a detailed analysis of these changes in the mouse mammary gland. Their results showed that tissue remodeling during post-lactational involution period mimics wound healing and tumorigenesis like pathological conditions. This indicates that post-lactational involution may create the microenvironment that initiates the development of precancerous mammary cells and promotes the progression of precancerous cells into cancer cells. Moreover, epidemiological studies have found that triple-negative (TN) breast cancer (BC) is associated with lower frequency and duration of breastfeeding compared …

Thermal Ablation Alters The Tumor Microenvironment Activating A Robust Immune Response., Matthew T. Campbell M.D.

Dissertations and Theses (Open Access)

THERMAL ABLATION ALTERS THE TUMOR MICROENVIRONMENT ACTIVATING A ROBUST IMMUNE RESPONSE.

Matthew T Campbell, M.D.

Advisor Professor: Padmanee Sharma, M.D Ph.D

Ablation techniques including radiofrequency ablation (RFA) and cryoablation have been shown to influence the immune system in animal models. Rare abscopal events, a distant metastatic response to a local procedure, have been observed in humans following both RFA and cryoablation. These rare observations have led to interest in further defining the impact of ablation procedures on the immune signature in the tumor microenvironment and in the systemic circulation.

Retrospectively 9 patients with nephrectomy alone (control) were compared to 16 …

Post-Translational Regulation Of Zeb1 Contributes To Tgfβ-Mediated Emt, Roxsan Manshouri

Dissertations and Theses (Open Access)

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States due in part to the affinity of tumors to metastasize. Understanding the process which contributes to metastasis provides promise for the discovery of novel therapeutic targets. Epithelial-to-mesenchymal transition (EMT) is a proposed model for the initiation of metastasis. During EMT epithelial cells lose their cell adhesion properties and acquire a mesenchymal-like phenotype, allowing tumor cells to migrate from their epithelial cell community and invade remote locations. EMT is mediated by several signaling pathways, with transforming growth factor-beta (TGF-β) receiving attention for its up-regulation in …

Correlation Matrix Analysis Identifies Gene Signatures Of Immune Cell Subsets And Their Interactions In Follicular Lymphoma, Jason R. Westin

Dissertations and Theses (Open Access)

There are important but ill-defined interactions between benign immune cell subsets and neoplastic B cells within follicular lymphoma (FL). Using the novel technique of correlation matrix analysis (CMA) of publicly available FL whole-tumor gene expression profiling (GEP) data, we have identified signatures of immune cell subsets. Overall survival correlated most highly with a model using signatures of macrophages, T cells, and stroma, which was able to add significantly to existing clinical prognostic tools. From our own data of a cohort of 43 FL tumors sorted into B-cell and non-B cell (NB) fractions for GEP, CMA of the tumor infiltrating NB …

Isoform Selective Regulation Of Adenylyl Cyclase By Small Molecule Inhibitors And Gbetagamma Protein, Cameron S. Brand

Dissertations and Theses (Open Access)

The nine membrane-bound isoforms of adenylyl cyclase (AC), via synthesis of the signaling molecule cyclic AMP (cAMP), are involved in many isoform specific physiological functions. All nine isoforms share a similar structural organization; thus, AC isoform differences in physiological function are due to different regulatory profiles. A physiological example is Gβγ, which can conditionally enhance stimulation of ACs 2, 4, 5, 6, and 7, but inhibit ACs 1, 3, and 8. There is also pharmacological control of AC isoforms through small molecule inhibitors.

Isoform specific AC functions could be explained by regulatory differences as subtle as single amino acid changes. …

Measuring Single Cell Responses To Lapatinib In A Heterogeneous Population, Preety Priya

Dissertations and Theses (Open Access)

Cancer is notonedisease butasaga of diseases and is the outcome of disturbed homeostasis in the normal cells due to the deregulation of its genetic makeup. With advent of technologies thatallowdetailed molecular characterizationoftumors, targeted therapies have emerged as a more promising and specific mode of treatment. However, a major challenge with targeted therapy is the acquired resistance in the cancer cells to these therapies, quite often very rapidly in the course of a few months. One of the major targets in cancer has been the EGFR/ErbB2 network in breast and other cancer types. Prior work from our lab and others have …

Regulation Of Cell Adhesion By The Ferm Proteins, Ptpn14 And Merlin, Patty Dimarco Hewitt

Dissertations and Theses (Open Access)

Cell-cell adhesion is critical for the control of tissue organization and homeostasis. A family of proteins that regulate cell-cell adhesions is the FERM (4.1 protein, Ezrin, Radixin, Moesin) domain-containing proteins.One FERM domain protein, the non-receptor tyrosine phosphatase PTPN14, is mutated or deleted in several human cancers suggesting that it may be involved in tumor development and/or progression. Additionally, the loss of the FERM domain protein Merlin is associated with tumor development and metastasis.Both PTPN14 and Merlin have been shown to localize and possibly regulate adherens junction (AJ) functions. This work sought to determine if …

Estimated Exposure To Arsenic In Breastfed And Formula-Fed Infants In A United States Cohort, Courtney C. Carignan, Kathryn L. Cottingham, Brian P. Jackson, Shohreh F. Farzan, A Jay Gandolfi, Tracy Punshon, Carol L. Folt, Margaret R. Karagas

Dartmouth Scholarship

Background: Previous studies indicate that concentrations of arsenic in breast milk are relatively low even in areas with high drinking-water arsenic. However, it is uncertain whether breastfeeding leads to reduced infant exposure to arsenic in regions with lower arsenic concentrations.

Objective: We estimated the relative contributions of breast milk and formula to arsenic exposure during early infancy in a U.S. population.

Methods: We measured arsenic in home tap water (n = 874), urine from 6-week-old infants (n = 72), and breast milk from mothers (n = 9) enrolled in the New Hampshire Birth Cohort Study (NHBCS) using …

Health Care In The Community: Developing Academic/Practice Partnerships For Care Coordination And Managing Transitions, Mary E. Fortier, Edd, Rn, Cnl, Donna M. Fountain, Phd(C), Aprn, Phcns-Bc, Maryelena Vargas, Phd, Rn, Lisa Heelan-Fancher, Phd, Fnp-Bc, Anp-Bc, Tracy Perron, Phd, Rn, Katherine Hinic, Phd, Rn, Anp-Bc, Beth Ann Swan, Phd, Crnp, Faan

College of Nursing Faculty Papers & Presentations

Executive Summary

The delivery of health care is quickly changing from an acute care to a community-based setting.

Faculty development and mastery in the use of new technologies, such as high-definition simulation and virtual communities are crucial for effective student learning outcomes.

Students' benefit include opportunities for hands-on experience in various patient care scenarios, real-time faculty feedback regarding their critical reasoning and clinical performance, interdisciplinary collaboration, and access to a nonthreatening learning environment.

The results of this study provide some evidence of the benefits of developing faculty and nursing curricula that addresses the shift from an illness-based, acute hospital model, …

Central Line-Associated Blood Stream Infections In Pediatric Intensive Care Units: Longitudinal Trends And Compliance With Bundle Strategies., Jeffrey D. Edwards, Carolyn T. Herzig, Hangsheng Liu, Monika Pogorzelska-Maziarz, Philip Zachariah, Andrew W. Dick, Lisa Saiman, Patricia W. Stone, E. Yoko Furuya

College of Nursing Faculty Papers & Presentations

BACKGROUND: Knowing the temporal trend central line-associated bloodstream infection (CLABSI) rates among U.S. pediatric intensive care units (PICUs), the current extent of central line bundle compliance, and the impact of compliance on rates is necessary to understand what has been accomplished and can be improved in CLABSI prevention.

METHODS: This is a longitudinal study of PICUs in National Healthcare Safety Network hospitals and a cross-sectional survey of directors and managers of infection prevention and control departments regarding PICU CLABSI prevention practices, including self-reported compliance with elements of central line bundles. Associations between 2011-2012 PICU CLABSI rates and infection prevention practices …

Mechanisms Of Low Dose Arsenic Lymphoid Stem Cell Immunotoxicity And Potential Interactions With Dibenzo[Def, P]Chrysene (Dbc), Peace Chinyere Ezeh

Biomedical Sciences ETDs

In vivo assessment of the effects of inorganic arsenic, arsenite (As+3), on the bone marrow (BM) immune progenitor cells in mice showed that 300 parts per billion (ppb) As+3 given over 30 days in drinking water, produced a decrease in total BM cells recovered and suppressed the lymphoid (pre-B) but not the myeloid (GM) progenitor cells colony forming units (CFUs). 75 and 300 ppb As+3 also suppressed spleen T-dependent antibody responses. There was no shift in the general markers of early hematopoietic stem cells, CD34 and CD38, or the mesenchymal stem cells, CD105, in the BM. Splenic CD45+ B cells …