Novel Bayesian Adaptive Clinical Trial Designs In Early Phases, Haitao Pan

Dissertations and Theses (Open Access)

Early phase, or phase I and phase II, trials are the first step in testing new medicines that have been developed in the lab. The main goal of phase I clinical trials is to establish the recommended dose of new drugs for phase II trials. For the cytotoxic drugs, the goal is to find maximum tolerated dose (MTD). The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Therefore, dose escalation methods, especially Bayesian designs, are recommended to be used in phase I …

Improving Nk Cell Therapy For Osteosarcoma, Jennifer Foltz

Dissertations and Theses (Open Access)

Osteosarcoma (OS) is the most common primary bone tumor. Despite new treatment options, 5-year survival for metastatic OS has remained at only 30% for the last 30 years. Adoptive transfer of Natural Killer (NK) cells holds promise for a new, non-toxic therapy for OS. NK cells are part of the innate immune system and readily kill metastatic and chemotherapy-resistant OS in vitro and in murine models. However, there is little data regarding their efficacy in animal models with an intact immune system. In addition, the OS tumor microenvironment is highly suppressive, producing TGFβ which impedes NK cell killing of solid …

Image Registration To Map Endoscopic Video To Computed To Mography For Head And Neck Radiotherapy Patients, William S. Ingram

Dissertations and Theses (Open Access)

The purpose of this work was to explore the feasibility of registering endoscopic video to radiotherapy treatment plans for patients with head and neck cancer without physical tracking of the endoscope during the examination. Endoscopy-CT registration would provide a clinical tool that could be used to enhance the treatment planning process and would allow for new methods to study the incidence of radiation-related toxicity.

Endoscopic video frames were registered to CT by optimizing virtual endoscope placement to maximize the similarity between the frame and the virtual image. Virtual endoscopic images were rendered using a polygonal mesh created by segmenting the …

Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno

Dissertations and Theses (Open Access)

Triple-negative (TNBC) and inflammatory (IBC) breast cancer are the most aggressive forms of breast cancer, accounting for 20% and 10% of cancer-related deaths, respectively. Among IBC cases, 30% are additionally classified with TNBC molecular pathology, a diagnosis that significantly worsens patient’s prognosis. The current lack of TNBC and IBC molecular understanding prevents the development of effective therapeutic strategies. To identify effective treatments, we explored aberrant apoptosis pathways and cell membrane fluidity as novel therapeutic targets.

We first identified an effective therapeutic strategy against TNBC and IBC by pro-apoptotic protein NOXA-mediated inhibition of the anti-apoptotic protein MCL1 following inhibition of histone …

Investigating The Role Of Prmt1 And Arginine Methylation Of Hsp70 In Human Pancreatic Cancer, Liang Wang

Dissertations and Theses (Open Access)

Protein arginine methyltransferase 1 (PRMT1) is the major arginine methyltransferase, which catalyzes the addition of one or two methyl groups to the arginine residues of its substrate proteins. The best-known substrate for PRMT1 is histone, while more and more non-histone proteins are now found to be methylated by PRMT1. Dysregulation of PRMT1 is reported in several human cancer types. However, its biological roles in human pancreatic cancer initiation and development are still unclear. In the first part of this study, I found that the expression level of PRMT1 was elevated in both human and mouse pancreatic cancer tissues in immunohistochemistry …

Structural And Functional Effect Of Phosphorylation On Ampa Receptors, Caitlin E. Nurik

Dissertations and Theses (Open Access)

Structural and Functional Effect of Phosphorylation on AMPA Receptors

Cailtin Edmunds show you, BA

Advisory Professor: Vasanthi Jayaraman, Ph. D.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is the primary contributor to neuronal fast excitatory transmission, and plays a key role in learning and memory. Previous studies have established that residues S818, S831, and T840 in the C-terminal segment of GluA1 homomeric AMPA receptor are phosphorylated by PKC, and phosphorylation at these sites leads to an increase in receptor conductance. We show that the domain inclusive of those sites alters its secondary structure due to phosphorylation (using glutamate substitution as a mimic) …

Improvements In Four-Dimensional And Dual Energy Computed To Mography, Rachael M. Martin

Dissertations and Theses (Open Access)

Dual energy and 4D computed tomography (CT) seek to address some of the limitations in traditional CT imaging. Dual energy CT, among other purposes, allows for the quantification and improved visualization of contrast materials, and 4D CT is often used in radiation therapy applications as it allows for the visualization and quantification of object motion. While much research has been done with these technologies, areas remain for potential improvement, both in preclinical and clinical settings, which will be explored in this dissertation. Preclinical dual energy cone-beam CT (CBCT) can benefit from wider separation between the peak energy of the two …

Hsp27 And Chemotherapy-Induced Autophagy As Biomarkers In Osteosarcoma, John Andrew Livingston

Dissertations and Theses (Open Access)

Survival for patients with osteosarcoma has not improved for > 30 years. Despite aggressive multi-agent chemotherapy combined with surgical resection, a significant fraction of patients with localized disease relapse after optimal treatment. We evaluated the occurrence of cytoplasmic LC3B (light chain 3B)-positive puncta (a marker of autophagy) and presence of HSP27 (heat shock protein 27) in cancer cells within pre-treatment biopsy, post-treatment surgical resection, and metastatic osteosarcoma specimens by immunohistochemistry in 260 patients. LCB3+ puncta expression was seen in 34% of pre-treatment. 50% of resection, and 67% of metastasis samples. Sixty-six percent of all specimens were scored positive for HSP27 (85% …

Mechanisms Underlying The Sensitivity And Resistance Of Gastric Cancer Cells To Met Inhibitors, Rebecca Schroeder

Dissertations and Theses (Open Access)

MET amplification has been clinically credentialed as a therapeutic target in gastric cancer, but the molecular mechanisms underlying sensitivity and resistance to MET inhibitors are still not well understood. Using whole-genome mRNA expression profiling, we identified autophagy as a top molecular pathway that was activated by the MET inhibitor crizotinib in drug-sensitive human gastric cancer cells, and functional studies confirmed that crizotinib increased autophagy levels in the drug sensitive cells in a concentration-dependent manner. We then used chemical and molecular approaches to inhibit autophagy in order to define its role in cell death. The clinically available inhibitor of autophagy, chloroquine, …

Pharmacologic And Genetic Manipulations Of Angiotensin Signaling In Thoracic Aortic Disease Models, Andrew M. Peters

Dissertations and Theses (Open Access)

Thoracic aortic aneurysms and dissections (TAAD) are a major cause of morbidity and mortality in patients. Many different risk factors have been associated TAAD, but hypertension is the largest risk factor. Subsets of TAAD patients have identifiable syndromic genetic diseases, yet a number of genetic non-syndromic patients have been identified. Infusion of angiotensin II into mouse models causes aortic disease through inflammation and fibrosis. An angiotensin type I receptor (AT1R) blocker (ARB) or an angiotensin converting enzyme (ACE) inhibitor (ACEi) can reverse aortic pathology in some mouse models. I set out to better understand the relationship between angiotensin and TAAD …

Factors Influencing Attendance, Postpartum Follow-Up, And Contraceptive Usage Among Teenage Centeringpregnancy® Participants, Latia Hickerson

Dissertations and Theses (Open Access)

Background: Teenage mothers are less likely to obtain postpartum examinations and contraception, increasing risks for negative social and health outcomes. The CenteringPregnancy® prenatal care model has been found to improve outcomes. However, little is known about factors influencing CenteringPregnancy® attendance or how this attendance impacts future pregnancy rates among teenagers.

Aim: The purpose of this study was to explore the association between CenteringPregnancy® attendance, postpartum return, contraception initiation and method selection. Additionally, the Group Care and Perinatal Behaviors Framework was used to assess the association between food insecurity, housing insecurity, intimate partner violence relationship status, partner group attendance and total …

Associations Among Meaning Of Illness, Quality Of Life, Symptom Burden And Depression In Patients With Leptomeningeal Metastasis, Julie Walker

Dissertations and Theses (Open Access)

Background Patients with leptomeningeal metastasis (LM) have symptoms related to disease within the neuroaxis, cancer sites outside the neuroaxis and treatment toxicities. Furthermore, the meaning ascribed to advanced cancer, such as LM, may impact the perceived severity, frequency and distress of symptoms as well as quality of life (QoL) and depression. Our aim was to explore and describe relationships among meaning of illness (MoI), depression, QoL and symptom burden in LM patients and to explore whether adding spine-related items from the MD Anderson Symptom Inventory-Spine (MDASI-SP) to the MDASI-Brain Tumor (BT) enhanced understanding of symptom burden in this population.

Methods …

Cyclin B1 Mediates The Effect Of Uchl1 In Promoting Cell Cycle Progression In Uterine Papillary Serous Carcinoma, Suet Ying Kwan

Dissertations and Theses (Open Access)

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue.

We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1 …

Barriers To Expansion Of Supervision Networks At Genetic Counseling Training Programs, Jordan E. Berg

Dissertations and Theses (Open Access)

Job openings outpace new graduates due to exponential growth in genetic counseling, leading to a workforce shortage. Expanding training slots to meet this demand presumably is linked to the number of supervisors. Thus, there is a need to systematically review barriers to supervision. This study aimed to determine and compare barriers to expansion of supervision networks at genetic counseling training programs as perceived by current supervisors, non-supervisors, and Program Directors. Certified genetic counselors were recruited via National Society of Genetic Counselors e-blast with an invitation to complete an online survey; Program Directors were emailed personal letters of invitation. Twenty-three Program …

Clinical Applicability Of Proposed Algorithm For Identifying Individuals At Risk For Hereditary Hematologic Malignancies, Maggie Clifford

Dissertations and Theses (Open Access)

Over the past decade, more than 12 genes have been identified to cause hereditary predispositions to hematologic malignancies. These syndromes are characterized by an increased risk to develop myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or aplastic anemia (AA) at young ages, with various phenotypic features including peripheral cytopenias, immune dysfunction and skeletal defects. In 2013, Churpek et al. proposed a referral algorithm which consists of certain criteria for identifying leukemia patients who may benefit from genetic assessment for these hereditary syndromes. These criteria assess personal history of cytopenias, skin or nail abnormalities, immune deficiencies/atypical infections, and other associated clinical …

Molecular Determinants Of Residual Disease In Ovarian Cancer, Kshipra M. Gharpure

Dissertations and Theses (Open Access)

The standard treatment for high grade serous ovarian cancer is primary cytoreductive surgery followed by adjuvant chemotherapy. Residual disease followed by surgery is associated with adverse overall and progression-free survival as well as poor response to adjuvant chemotherapy. Accurate identification of patients at high risk of residual disease will help avoid unnecessary surgeries and help in triaging these patients to neoadjuvant chemotherapy prior to interval surgical debulking. In this study, we address this clinical issue by identifying and validating molecular biomarkers that can predict the likelihood of residual disease in ovarian cancer patients. Using publically available databases and microarray datasets, …

The External Globus Pallidus: Bidirectional Control Over Anxiety-Related Behavior Mediated By Crfr1, Albert J. Hunt Jr

Dissertations and Theses (Open Access)

Abstract

THE EXTERNAL GLOBUS PALLIDUS: BIDIRECTIONAL CONTROL OVER ANXIETY-RELATED BEHAVIOR MEDIATED BY CRFR1

Albert Lee Joseph Hunt, Jr., B.S.

Advisory Professor: Shane Cunha, Ph.D.

Corticotropin-releasing factor receptor 1 (CRFR1), the principle receptor responsible for the anxiogenic activity of the stress peptide CRF, is abundantly expressed in the external globus pallidus (GPe) raising the question whether activity in the GPe is altered in response to stress. I show that CRFR1 expressing neurons are of the “prototypic” subtype of GPe neurons. I provide evidence of novel circuits from CRF neurons in stress-responsive nuclei, including the paraventricular nucleus of the hypothalamus (PVN) and …

Visualizing The Dynamics Of Immune Surveillance In Brain Tumors By Intravital Multiphoton Microscopy, Felix Nwajei

Dissertations and Theses (Open Access)

Visualizing the dynamics of immune surveillance in brain tumors by intravital multiphoton microscopy

By

Felix I. Nwajei, MD

Supervisory Professor: Tomasz Zal, Ph.D.

Brain tumors (BTs) generally have a bad prognosis despite conventional treatment strategies. Immunotherapy is a relatively novel treatment approach that has shown benefit for durable treatment of melanoma, and is a promising candidate for different tumor types including BTs. Immunotherapeutic strategies work by exploiting and/or enhancing natural anti-tumor immune response, a process that is critically dependent on adaptive immunity, T cell infiltration and surveillance of tumor. However, little is known about the dynamics and regulation of T …

Parp Inhibitor Upregulates Pd-L1 Expression And Enhances Cancer-Associated Immunosuppression, Shiping Jiao

Dissertations and Theses (Open Access)

With recent approvals for therapeutic antibodies that block CTLA4, PD-1 and PD-L1, immune checkpoints have emerged as new targets in cancer therapy. In addition, there is accumulating evidence highlighting the role of cancer-associated immunity in patient response to cytotoxic anticancer agents. Inhibitors of poly (ADP-ribose) polymerase (PARP) have shown substantial cytotoxic effects against tumors with defects in DNA damage responses. However, whether a crosstalk between PARP inhibition and immune checkpoints exists remains unclear. Here, it has been shown that PARP inhibitors (PARPis) upregulate PD-L1 expression in multiple cancer cell lines, human xenograft tumors, and syngeneic mouse tumors. Mechanistically, PARPi inactivates …

Effect Of Entinostat On Nk Cell-Mediated Cytotoxicity Against Os Cells And Os Lung Metastsis, Simin Kiany

Dissertations and Theses (Open Access)

The purpose of this study was to investigate the effect of the HDAC inhibitor entinostat on the efficacy of NK cell therapy for OS lung metastasis. The Lung is the most common site of OS metastatic spread in OS and pulmonary metastasis is the main cause of mortality. We have previously demonstrated that NK cell therapy has minimal efficacy against OS metastasis. We wished to determine whether we could augment the killing of OS cells in vitro and improve the efficacy of NK cell therapy in vivo by adding oral administration of entinostat. We elected to use our nude mouse …

The Hypoxic Adenosine Response Modulates Macrophage Differentiation And Contributes To Lung Disease, Kemly Mary Philip

Dissertations and Theses (Open Access)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease which affects 5 - 8 million individuals worldwide and 200,000 individuals in the United States alone. Although prevalent, we do not know what causes IPF and no effective curative treatment exists for this disease. Our laboratory has shown that extracellular accumulation of adenosine and subsequent activation of the adenosine 2B (ADORA2B) receptor promotes immune cell invasion, airspace destruction, and fibrosis in chronic lung disease. Additionally, alternatively activated alveolar macrophages (AAMs) expressing ADORA2B, have been implicated in mediating adenosine’s pro-fibrotic effects in IPF. However, the exact role of AAMs in the hypoxic …

Role And Regulation Of Sphingosine 1-Phosphate In Erythrocyte, Kaiqi Sun

Dissertations and Theses (Open Access)

Sphingosine 1-phosphate (S1P) is a bioactive signaling sphingolipid produced in every mammalian cell. It plays a variety of important roles both in and outside of cells. S1P is highly enriched in mature erythrocytes because of the high enzymatic activity of the S1P-generating enzyme Sphingosine Kinase 1 (Sphk1) and the absence of S1P degrading enzymes. Erythrocytes are considered only a major reservoir for S1P because they supply S1P to the circulation for the regulation of various physiological processes which include but are not limited to immune cell trafficking, endothelial integrity and hematopoietic stem cell mobilization. However, if S1P plays a role …

Integrative Analysis Of Omics Data In Adult Glioma And Other Tcga Cancers To Guide Precision Medicine, Xin Hu, Xin Hu

Dissertations and Theses (Open Access)

Transcriptomic profiling and gene expression signatures have been widely applied as effective approaches for enhancing the molecular classification, diagnosis, prognosis or prediction of therapeutic response towards personalized therapy for cancer patients. Thanks to modern genome-wide profiling technology, scientists are able to build engines leveraging massive genomic variations and integrating with clinical data to identify “at risk” individuals for the sake of prevention, diagnosis and therapeutic interventions. In my graduate work for my Ph.D. thesis, I have investigated genomic sequencing data mining to comprehensively characterise molecular classifications and aberrant genomic events associated with clinical prognosis and treatment response, through applying high-dimensional …

Tumor-Cell Derived Inhibin, Beta A Is Essential For Adrenergic Effects On Fibroblast Activation, Archana Sidalaghatta Nagaraja

Dissertations and Theses (Open Access)

Objectives: Catecholamine-mediated effects driven by elevated adrenergic signaling are known to increase tumor growth and metastasis by direct effects on tumor cells. However, knowledge of effects of adrenergic signaling on other cells such as cancer-associated fibroblasts (CAFs) within the tumor microenvironment is limited. We hypothesize that adrenergic signaling and norepinephrine can accelerate the induction of CAF-phenotype to promote inflammation and metastasis.

Methods: Ingenuity Pathway Analysis and NetWalker were used to assess gene expression data from patients with known CESD (Center for Epidemiological Studies-Depression)-score alongside microdissected CAFs from primary ovarian cancer. Tumor samples from mice exposed to daily restraint-stress or non-stressed …

Statistical Methods For Two Problems In Cancer Research: Analysis Of Rna-Seq Data From Archival Samples And Characterization Of Onset Of Multiple Primary Cancers, Jialu Li

Dissertations and Theses (Open Access)

My dissertation is focused on quantitative methodology development and application for two important topics in translational and clinical cancer research.

The first topic was motivated by the challenge of applying transcriptome sequencing (RNA-seq) to formalin-fixation and paraffin-embedding (FFPE) tumor samples for reliable diagnostic development. We designed a biospecimen study to directly compare gene expression results from different protocols to prepare libraries for RNA-seq from human breast cancer tissues, with randomization to fresh-frozen (FF) or FFPE conditions. To comprehensively evaluate the FFPE RNA-seq data quality for expression profiling, we developed multiple computational methods for assessment, such as the uniformity and continuity …

The Role Of The Diras Family Members In Regulating Ras Function, Cancer Growth And Autophagy, Margie Nicole Sutton

Dissertations and Theses (Open Access)

DIRAS3 is a maternally imprinted tumor suppressor gene that is downregulated by multiple mechanisms across several tumor types. When re-expressed, DIRAS3 decreases proliferation, inhibits motility, and induces autophagy and tumor dormancy. DIRAS3 encodes a 26 kDa small GTPase with 60% homology to Ras and Rap, differing from oncogenic Ras family members by a 34-amino acid N-terminal extension that is required for its tumor suppressive function in ovarian cancer. By assessing the structure-function relationship, I found that DIRAS3 inhibits Ras-induced transformation and is a natural antagonist of Ras/MAPK signaling. DIRAS3 binds directly to Ras and disrupts cluster formation inhibiting the activation …

Androgen Receptor And Prostate Cancer Cell Heterogeneity, Qu Deng

Dissertations and Theses (Open Access)

Androgen receptor (AR) plays an important role in prostate cancer (PCa) development and has been the main therapeutic target in advanced PCa. AR expression is heterogeneous in both primary PCa and castration resistant prostate cancer (CRPC). However, the functional significance of AR heterogeneity in regulating PCa biology and response to androgen/AR-targeted therapies remains unclear. The overarching hypothesis for my Ph.D is that AR heterogeneity contributes to PCa development, progression, and therapy resistance. A more specific postulate is that PCa cells expressing AR (i.e, AR⁺) and PCa cells expressing little AR (i.e, AR^-/lo) possess intrinsically distinct …

Proteomic Identification Of Histone Post-Translational Modifications Induced By Dna Double-Strand Breaks And Novel Proteins Involved In The Dna Damage Response, Pingping Wang

Dissertations and Theses (Open Access)

Inaccurate repair of DNA double-strand breaks (DSBs) can lead to DNA mutation and chromosome rearrangements, causing human diseases such as cancer. Although we know the basic mechanisms of DSB repair, the added complexities in the chromatin context are unclear. This is partially due to the lack of unbiased systems for identifying proteins and post-translational modifications (PTMs) involved in DSB repair. In this work, we established a novel method, termed DSB-ChAP-MS (Double Strand Break-Chromatin Affinity Purification with Mass Spectrometry), for the affinity purification of a sequence-specific single copy endogenous chromosomal locus containing a DSB, followed by the proteomic identification of enriched …

Fret-Based Investigations Of The Structure-Function Relationships In The Nmda Receptor, Drew M. Dolino

Dissertations and Theses (Open Access)

The N-methyl-D-aspartate (NMDA) receptor is one member of a class of proteins known as the ionotropic glutamate receptors. Ionotropic glutamate receptors mediate the majority of excitatory neurotransmission in the central nervous system, with the NMDA receptor standing out among these receptors for its requirement of a co-agonist, its magnesium-block-based coincidence detection, its slow kinetics, its calcium permeability, its allosteric modulation, and its especially important functional roles in synaptic plasticity, excitotoxicity, and more. In recent years, a wealth of structural information has come about describing endpoint structures to high resolution, but such structures are unable to fully resolve the movements …

Characterization And Reversal Of Doxorubicin-Mediated Changes In Sensory Neurons, Brittany L. Coughlin

Dissertations and Theses (Open Access)

Chemotherapeutic agents impair memory in humans as well as in animal models. Such memory impairments can be persistent, lasting years after exposure to chemotherapy. Doxorubicin (DOX), a common chemotherapeutic agent, has been associated with memory impairments in humans and induces memory deficits in rodent models. DOX also impairs serotonin (5-HT)-induced long-term synaptic facilitation (LTF) in Aplysia sensorimotor co-cultures, a cellular analog of long-term memory formation. In addition, DOX leads to dynamic activation of extracellular signal-regulated kinase (ERK), consisting of an immediate and a delayed phase of activation, and to transient activation of p38 mitogen-activated protein kinase (p38 MAPK) in Aplysia …