Medicine and Health Sciences Commons^™

Sctiger: A Deep-Learning Method For Inferring Gene Regulatory Networks From Single-Cell Gene Expression Data, Madison Dautle

Theses and Dissertations

Inferring gene regulatory networks (GRNs) from single-cell RNA-sequencing (scRNA-seq) data is an important computational question to reveal fundamental regulatory mechanisms. Although many computational methods have been designed to predict GRNs, none work on condition specific GRNs by directly using paired datasets of case versus control experiments, common in diverse biological research projects. We present a novel deep-learning based method, scTIGER, for GRN detection by using the co-dynamics of gene expression. scTIGER also employs cell type-based pseudotiming, an attention-based convolutional neural network method, and permutation-based significance testing to infer GRNs from gene modules. We first applied scTIGER to scRNA-seq datasets of …

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

Frailty And Neurocognition In Prostate Cancer, Lindsey Hanson

Theses & Dissertations

Prostate cancer (PCa) treatment often leads to distressing side effects ranging from muscle loss, physical inactivity, and fatigue to cancer associated cognitive decline (CACD). Evidence suggests that men treated with androgen deprivation therapy (ADT) may have a specifically high risk of CACD, partially due to increased frailty. However, the current literature on cognitive effects of ADT is equivocal. Therefore, the primary objectives of this study were to (1) compare cognitive function, physical activity (PA), and fitness in men receiving ADT, men scheduled to receive radiation, and men under active surveillance for PCa; (2) examine changes in cognitive performance and PA …

Tissue-Specific Matrix Control Of Cell Cohesion And Migration Signaling Complexes, Tristen Tellman

Dissertations & Theses (Open Access)

The extracellular matrix (ECM) is a complex, interconnected network of three major constituents: collagens, glycoproteins, and proteoglycans, along with their enzyme modifiers. Within this network and beyond the structural role, each ECM molecule contributes a context-specific signal that influences cellular fate and behavior. Among these behaviors, cellular migration provides an essential function in developing tissues, wound healing, and cancer cell metastasis. Using two glandular organs, the normal salivary gland and the cancerous prostate, this dissertation describes the tissue-specific composition of two ECM signaling complexes (type I hemidesmosomes and the perlecan-semaphorin 3A-plexin A1-neuropilin-1 (PSPN) complex) and translates this knowledge into viable …

Design, Synthesis And Evaluation Of Novel Inhibitors Of Type 5 And 10 17Β-Hydroxysteroid Dehydrogenases, Ahmed Morsy

Theses & Dissertations

17β-Hydroxysteroid dehydrogenases (17β-HSDs) are essential enzymes in steroid metabolism. More and more evidence points to the pivotal contributions of these enzymes in various other metabolic pathways. Therefore, the latest research results give new insights into the complex metabolic interconnectivity of the 17β-HSDs with human diseases. This dissertation focuses on the metabolic activities of type 5 and 10 17β-HSDs. More specifically, regarding 17β-HSD5 contributions to the progression of prostate cancer (PCa) and 17β-HSD10 aggravation of amyloid-beta (Aβ)-induced toxicity in Alzheimer's disease (AD).

The second leading cause of cancer-related death in males is PCa, with the highest incidence rate of all cancers …

Mechanistic And Translational Studies On Skeletal Malignancies, Jeremy Mcguire

USF Tampa Graduate Theses and Dissertations

New treatment strategies are desperately needed for treating skeletal malignancy. Skeletal malignancies can be either primary cancer that originated in the bone, such as osteosarcoma, or metastatic cancer that spread from another organ to the skeleton, as in the case of breast or prostate cancer. In this thesis, I will detail two projects that focus on the discovery of new treatment strategies for both primary skeletal malignancy and metastatic skeletal malignancy.

The first project focuses on the primary skeletal malignancy, osteosarcoma, a rare cancer that is commonly diagnosed in children and young adults and metastasizes to the lungs. The survival …

P53r245w Mutation Elicits Metastatic Phenotype In Pten Deficient Prostate Cancer, Ky Pham

Dissertations & Theses (Open Access)

Trp53 mutations are the most frequent genetic alterations in prostate cancer and are associated with more aggressive disease and worse overall survival. The majority of Trp53 mutations in prostate cancer are missense mutations, resulting in amino acid substitutions with profound effect. In addition to the loss of wild type function, missense mutations in Trp53 result in a gain-of-function (GOF) phenotype. This GOF phenotype confers biologic advantages to the tumor cells, enabling them to metastasize and invade distant organs. In this study, we generated mice carrying a conditional prostate-specific p53R245W mutant and Pten deletion to access the role of this common …

Development Of Mithramycin Analogues With Improved Efficacy And Reduced Toxicity For Treatment Of Ets-Dependent Tumors In Ewing Sarcoma And Prostate Cancer, Joseph Michael Eckenrode

Theses and Dissertations--Pharmacy

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor …

Fluorescently Labeled Sirnas And Their Theranostic Applications In Cancer Gene Therapy, Stephen David Kozuch

Seton Hall University Dissertations and Theses (ETDs)

Gene therapy has emerged as a promising precision nano-medicine strategy in the treatment of numerous diseases including cancer. At the forefront of its utility are the applications of short-interfering RNA (siRNA), that silence oncogenic mRNA expression leading to cancer cell death through the RNA interference (RNAi) pathway. Despite the therapeutic potential, siRNAs are limited by poor pharmacological properties, which has hindered their translation into the clinic. Recent studies, however, have highlighted the applications of modified siRNAs, including the use of fluorescent probes and siRNA nanostructures in cancer detection and treatment. The siRNAs reported in this thesis are designed to target …

Elucidation Of The Functions Of Neuropilin 2 In Osteoclasts In Promoting Prostate Cancer Bone Metastasis., Navatha S. Polavaram

Theses & Dissertations

Bone metastasis is one of the major clinical concerns that causes skeletal related malignancies and increased mortality. Bone is one of the preferred sites for metastatic prostate cancer. The metastatic prostate cancer cells interact with bone cells (osteoblasts and osteoclasts) resulting in an imbalance in the bone homeostasis leading to increased activation of osteoblasts over osteoclasts. Our preliminary data indicated a non-tyrosine kinase receptor Neuropilin 2 (NRP2) is expressed in osteoclasts induced by metastatic prostate cancer cells and acts as a negative regulator of osteoclast differentiation and function. We hypothesize that prostate cancer -induced NRP2 expression in osteoclasts is necessary …

Outcomes Of Genetic Testing In A Genitourinary Genetics Clinic, Annelise Pace

Dissertations & Theses (Open Access)

Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU-related hereditary cancer syndromes but there is limited research on the clinical picture of these patients, including their cancerous and non-cancerous features, the genetic testing strategy for this population, and the probability of having a positive germline mutation if testing is performed. The purpose of this study is to determine the most common indications for ordering genetic testing in a GU Genetics Clinic and evaluate whether there is a relationship between the indication for genetic testing …

Paclitaxel Enhances Oncolytic Potential Of Herpes Simplex Virus Type-1 In Cancer Cells, Misagh Naderi

LSU Master's Theses

Taxanes are spindle poisons that bind to and stabilize microtubules resulting in mitotic arrest. Herpes simplex Typ-1 (HSV-1) virions utilize the microtubular network for intracellular transport during both virus entry and virus egress from infected cells. It has been reported previously that taxanes may synergize with oncolytic herpes simplex viruses in the treatment of experimental prostate and breast tumors in mice. Other reports have indicated that taxanes may inhibit viral replication in infected cells. In this study the previously characterized Oncolytic Herpes Simplex Virus type 1 (OSVP), which was constructed in Kousoulas lab was used in conjugation with paclitaxel (taxol) …

Androgen Receptor And Prostate Cancer Cell Heterogeneity, Qu Deng

Dissertations & 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 …

Microrna-186 And Metastatic Prostate Cancer., Dominique Zilpha Jones

Electronic Theses and Dissertations

MicroRNA (miR) dysregulation alters cancer-associated gene expression, which contributes to cancer pathogenesis. For example, miR-186 over expression lead to enhanced proliferation and migration in pancreatic cancer cell models. However, the role of miR-186 in prostate cancer (PCa) remains controversial. Previously, miR-186-5p was up-regulated in PCa patient serum (stage III/IV) compared to controls. Furthermore, miR-186-5p was up-regulated in metastatic PCa (PC-3, MDA PCa 2b, LNCaP) relative to normal prostate epithelial cells (RWPE1). We hypothesized miR-186 inhibition will reduce aggressive PCa using metastatic cell models. To test this, we evaluated whether miR-186-5p inhibition would reduce aggressive PCa behavior and overexpression induce malignant …

Rna Nanotechnology For Next Generation Targeted Drug Delivery, Fengmei Pi

Theses and Dissertations--Pharmacy

The emerging field of RNA nanotechnology is developing into a promising platform for therapeutically application. Utilizing the state-of-art RNA nanotechnology, RNA nanoparticles can be designed and constructed with controllable shape, size for both RNA therapeutics and chemical drug delivery. The high homogeneity in particle size and ease for RNA therapeutic module conjugation, made it feasible to explore versatile RNA nanoparticle designs for preclinical studies.

One vital module for therapeutic RNA nanoparticle design is RNA aptamer, which can enable the RNA nanoparticles find its specific target for targeted drug delivery. A system of screening divalent RNA aptamers for cancer cell targeting …

Role Of Talin1 Phosphorylation In Beta1 Integrin Activation And Prostate Cancer Metastasis, Jung-Kang Jin

Dissertations & Theses (Open Access)

Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind and activate integrins but the mechanism by which this occurs is unknown. As integrin activation and overexpression of talins promote prostate cancer metastasis, understanding the mechanism by which talins activate integrins will better elucidate their roles in Prostate cancer metastasis. Phosphorylation of talins on serine 425 has been associated with β1 integrin functions. Work in this dissertation tested the hypothesis that increased talin1 S425 phosphorylation was required for β1 integrin activation and promotion of prostate cancer metastasis.

I first used shRNA to …

The Effect Of Exercise Intensity On Physiological And Psychological Outcomes In Breast And Prostate Cancer Survivors: A Controlled Study, Eric Martin

Theses

Introduction

Research has identified a need to explore the components of exercise prescription for cancer survivors, particularly the most effective exercise intensity. The main purpose of this research was to examine whether exercise intensity modulates a range of physiological and psychological outcomes for breast and prostate cancer survivors. The primary outcomes were related to peak oxygen consumption (VO2peak) and quality of life (QOL). VO2peak is a highly sensitive measure that indicates overall health. QOL references the general wellbeing of individuals, and is an outcome of great importance in cancer rehabilitation research.

Pilot Study

A pilot study involving breast cancer survivors …

Microrna Regulation Of Prostate Cancer Stem/Progenitor Cells And Prostate Cancer Development, Can Liu

Dissertations & Theses (Open Access)

Most human tumors contain a population of cells with stem cell properties, called cancer stem cells (CSCs), which are believed to be responsible for tumor establishment, metastasis, and resistance to clinical therapy. It’s crucial to understand the regulatory mechanisms unique to CSCs, so that we may design CSC-specific therapeutics. Recent discoveries of microRNA (miRNA) have provided a new avenue in understanding the regulatory mechanisms of cancer. However, how miRNAs may regulate CSCs is still poorly understood. Here, we present miRNA expression profiling in six populations of prostate cancer (PCa) stem/progenitor cells that possess distinct tumorigenic properties. Six miRNAs were identified …

A New Tumor Suppressor Gene Candidate Regulated By The Non-Coding Rna Pca3 In Human Prostate Cancer, Alessandro K. Lee

Dissertations & Theses (Open Access)

Prostate cancer is the second leading cause of cancer-related death and the most common non-skin cancer in men in the USA. Considerable advancements in the practice of medicine have allowed a significant improvement in the diagnosis and treatment of this disease and, in recent years, both incidence and mortality rates have been slightly declining. However, it is still estimated that 1 man in 6 will be diagnosed with prostate cancer during his lifetime, and 1 man in 35 will die of the disease.

In order to identify novel strategies and effective therapeutic approaches in the fight against prostate cancer, it …

Gene Therapy Using Tet-Repressor System To Modulate Prostate Tumor Microenvironment, Nazita Yousefieh

Theses and Dissertations in Biomedical Sciences

Prostate cancer is the most commonly diagnosed malignancy in men in the United States and is projected to be the third most frequent cause of male cancer-related deaths in 2007 after lung and skin cancers. The initial treatment for prostate cancer at early stages is prostatectomy or radiation, which usually is curative. However, approximately 20% of patients are not cured by such treatments and their cancer recurs, sometimes with long latencies. In other patients prostate cancer is diagnosed only after the cancer has metastasized and there are no effective therapies at this stage. Therefore immunotherapy seems to be a promising …

Maldi Mass Spectrometry Imaging For The Discovery Of Prostate Carcinoma Biomarkers, Lisa Harris Cazares

Theses and Dissertations in Biomedical Sciences

The elucidation of new biological markers of prostate cancer (PCa) should aid in the detection, and prognosis of this disease. Diagnostic decision making by pathologists in prostate cancer is highly dependent on tissue morphology. The ability to localize disease-specific molecular changes in tissue would help improve this critical pathology decision making process. Direct profiling of proteins in tissue sections using MALDI imaging mass spectrometry (MALDI-IMS) has the power to link molecular detail to morphological and pathological changes, enhancing the ability to identify candidates for new specific biomarkers. However, critical questions remain regarding the integration of this technique with clinical decision …

The Use Of Proteomic Technologies To Identify Serum Glycoproteins For The Early Detection Of Liver And Prostate Cancers, Elizabeth Ellen Schwegler

Theses and Dissertations in Biomedical Sciences

The application of proteomic technologies to identify serum glycoproteins is an emerging technique to identify new biomarkers indicative of disease severity. Many of these newly evolving protein-profiling methodologies have evolved from previous global protein expression profiling studies such as those involving SELDI-TOF-MS technologies. Though the SELDI approach could distinguish disease from normal by utilizing protein patterns as shown herein with the HCC study of chapter II, it was unable to offer sequence information on the selected peaks, and did not have the ability to analyze the entire dynamic range of the serum/plasma proteome. To address these deficiencies, new strategies that …

Prostate Specific Membrane Antigen (Psma): Immunoassay Development And Characterization Of Transcriptional Regulation, Zhen Xiao

Theses and Dissertations in Biomedical Sciences

Prostate cancer (PCA) is the most common cancer and the second leading cause of death among American men. The high mortality is greatly attributed to the lack of early detection tools and effective treatment for metastasis and relapses. Biomarkers that can discriminate benign from malignant tumor and signal the development of androgen independent and metastatic tumor are needed. A biomarker designated prostate specific membrane antigen (PSMA) has the potential to fulfill this need. The objective of this study is to develop a clinically useful immunoassay for quantitation of serum PSMA and to study the molecular mechanism underlying the upregulation of …