Medicine and Health Sciences Commons^™

Withaferin A And Immune Checkpoint Blocker Therapy For The Treatment Of Non-Small Cell Lung Cancer, Roukiah Khalil

USF Tampa Graduate Theses and Dissertations

Lung cancer is the first cause of cancer-related deaths in both men and women with an overall five-year survival rate of 28%. Although immune checkpoint blockers (ICBs) are currently FDA-approved for the treatment of non-small cell lung cancer (NSCLC), only 17-20% of patients achieve durable responses by the induction of immunologic memory. The lack of response in most patients can be attributed to the tumor-intrinsic or tumor-extrinsic immune resistance mechanisms. A biomarker of importance is the Programmed Death Ligand-1 (PD-L1), as higher PD-L1 expression is usually associated with a better response to ICBs. Although studies have attempted to combine ICBs …

Apkcs Role In Neuroblastoma Cell Signaling Cascades And Implications Of Apkcs Inhibitors As Potential Therapeutics, Sloan Breedy

USF Tampa Graduate Theses and Dissertations

Neuroblastoma (NB) is a cancer that develops in the neuroblasts. It is the most common cancer in children under the age of 1 year, accounting for approximately 6% of all cancers. The prognosis of NB is linked to both age and degree of cell differentiation. This results in a range of survival rates for patients, with outcomes ranging from recurrence and mortality to high survival rates and tumor regression. Our previous work indicated that PKC-ι promotes cell proliferation in NB cells through the PKC-ι/Cdk7/Cdk2 cascade. We report on two atypical protein kinase inhibitors as potential therapeutic candidates against BE(2)-C and …

Role Of Bmi1 In Acute Lung Injury, María Helena Hernández-Cuervo

USF Tampa Graduate Theses and Dissertations

Acute Lung Injury (ALI) is a set of signs and symptoms that lead to acute hypoxemic respiratory failure characterized by bilateral pulmonary infiltrates not attributed to cardiogenic origin. It is caused by a massive innate immune response, with the migration of white blood cells (neutrophils and macrophages principally) and a cytokine storm, followed by alterations in mitochondrial function, increase in reactive oxygen species production, and oxidative stress that in turn induces more mitochondrial damage. Several studies have shown that mitochondrial alterations are key events in the mechanism of ALI and reducing mitochondrial dysfunction could be a possible target in the …

Evolution Of Targeted Therapy Resistance In Eml4-Alk Positive Non-Small Cell Lung Cancer, Robert Vander Velde

USF Tampa Graduate Theses and Dissertations

Targeted therapies have emerged as potent treatments that lead to the remission of many tumors. However, they rarely cure cancers in advanced, metastatic settings. This is due to the evolution of resistance, which in turn can be ascribed to the survival of small subpopulations of tolerant and/or resistant cells. Here we investigated the evolution of resistance to EML4-ALK inhibitors in non-small cell lung cancer (NSCLC) and demonstrated that resistance evolves gradually, from unique pre-treatment sub-populations, as multiple resistance mechanisms accumulate in a Darwinian fashion. Despite accumulating multiple changes, cells evolved, in parallel, toward similar inhibitor specific phenotypes. Evolving cells have …

Bone Microenvironmental Control Of Skeletal Malignancy, Chen Hao Lo

USF Tampa Graduate Theses and Dissertations

Bone is a common site of metastasis for many solid malignancies. Bone-metastatic cancers pose a significant clinical problem worldwide and is among the main causes for cancer patient morbidity and mortality. Patients with advanced bone-metastatic diseases often present with either osteolytic or osteogenic bone diseases as their cancers progress. These bone pathologies are products of the cancer co-opting the local bone remodeling stroma to yield important growth nutrients and factors. Unfortunately, skeletal metastases remain incurable and are fatal. Identifying and understanding the causal multicellular and molecular interactions underlying skeletal malignancies can yield crucial ideas for targeting and inhibiting disease progression. …

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 …

Structure Based Inhibitor Discovery Targeting Multiple Β-Lactamases Involved In Antibiotic Resistance, Afroza Akhtar

USF Tampa Graduate Theses and Dissertations

Emergence of antibiotic resistance severely threatens the existing medication and prevention facilities against an over increasing range of infections caused by a wide range of microbes. Specifically, treatment of Gram-negative bacterial infection is getting more problematic due to their resilience against β-lactam antibiotics: the most commonly prescribed antibiotics in clinical settings. Production of β-lactamases is the most prevalent mechanism utilized by various Gram-negative pathogens to become resistant to the β-lactam antibiotics e.g, penicillins, cephalosporins, carbapenems and monobactams. These enzymes mediate their function through hydrolyzing the core β-lactam ring present in all β-lactam antibiotics which causes opening of the ring and …

The Role Of Atypical Protein Kinase C In Colorectal Cancer Cells Carcinogenesis, S M Anisul Islam

USF Tampa Graduate Theses and Dissertations

Colorectal cancer (CRC) is the third most common malignancy and the fourth most common cause of cancer-related death worldwide. CRC is a life-threatening disease due to therapy-resistant cancerous cells. The exact mechanisms of cell growth, survival, metastasis and inter & intracellular signaling pathways involved in CRC are still a significant challenge. Moreover, the treatment of metastatic CRC considered palliative for many years aimed for an improved life, with little hope of a cure, highlighting the need for developing novel targeted therapy for CRC. Hence, investigating new molecular mechanism(s) that lead to colorectal carcinogenesis may give insight into the therapeutic target. …

Hybrid Fusion Protein For Inhibition Of Multiple Proteases For Chronic Wound Healing, Graham L. Strauss

USF Tampa Graduate Theses and Dissertations

Many diseases display a multitude of relevant factors that contribute to the persistence of the disease and difficulty treating it. The multifactorial characteristics of some diseases lead to the requirement of combination of treatments in order to restore health. The latter may necessitate the mixing of treatments, medications, and therapeutics to first halt the disease, then assist the human body in returning itself to a state of normality. For example, chronic wounds exhibit this multifactor characteristic in which there exist many factors that lead to the body’s inability to properly heal in a timely manner. This presents a further threat …

Targeting Pten For Therapy In Cancer And Ptenopathies, Emily Palumbo

USF Tampa Graduate Theses and Dissertations

PTEN, a dual protein and lipid phosphatase, regulates a myriad of cellular functions including PI3K pathway signaling, cell migration, proliferation, invasion and apoptosis. PTEN mutations often lead to multiple malignancies, including prostate, breast, endometrial, skin and brain cancers, associated with hyperactive PI3K signaling. PTEN mutations have also been associated with a variety of other diseases, classified as PTEN Hamartoma Tumor Syndromes (PHTS). In addition, compromised function or reduced expression of PTEN due to non-genomic mechanisms are associated with many types of hyperproliferative diseases, such as restenosis and neoplastic diseases, including melanoma, lung, breast, prostate and colon cancers. Although PI3K pathway …

Roux-En-Y Gastric Bypass Attenuates Obesity-Related Liver Injury, Drew Alan Rideout

USF Tampa Graduate Theses and Dissertations

Obesity is a growing epidemic in the United States with significant co-morbidities. Non-Alcoholic Fatty Liver Disease (NAFLD) is a prevalent manifestation of obesity that can lead to cirrhosis. Roux-en-Y gastric bypass (RYGB) results in substantial long-term weight loss and resolution of obesity-related metabolic diseases. There appears to be a weight-independent molecular mechanism for the improvement of diabetes mellitus and NAFLD after RYGB, which is poorly understood. Obesity is associated with chronic inflammation that accompanies the hepatic steatosis. Through unknown mechanisms, RYGB in humans increases serum levels of the fat-derived adipocytokine, adiponectin. Adiponectin (an anti-inflammatory cytokine) is known to have a …

Cyclophilin 40 As A Novel Disaggregase, Jeremy Dustin Baker

USF Tampa Graduate Theses and Dissertations

The negative health and economic impacts of neurodegenerative diseases on Americans is astounding and accelerating with an aging population. The Alzheimer’s Association reports that 5.7 million Americans suffer from Alzheimer’s disease (AD), a number which is expected to increase to 14 million by 2050. In economic terms, AD and other neurodegenerative disorders will cost the US over $275 billion in 2018, rising to over $1 trillion annually by 2050. AD causes gross brain atrophy and is most damaging throughout the cortex and the hippocampus, regions required for higher cognitive function and memory. AD presents as tangles within neurons composed of …

Actinomycin D And Telmisartan Combination Therapy Targets Lung Cancer Stem Cells, Ryan Green

USF Tampa Graduate Theses and Dissertations

The failure of lung cancer treatments has been attributed partly to the development of drug resistance, however the underlying cellular and molecular mechanisms are poorly understood. It has been suggested that a very small group of specific cells within the heterogeneous tumors, cancer initiating stem cells (CSC), develop resistance to treatment, survive and later initiate the growth of new tumors. Due to their pivotal role in maintenance and relapse of tumors following the acquisition of drug resistance, we reasoned that novel drugs targeting cancer cells and CSC might provide the most effective treatments, if not a cure. To this end, …

Role Of Heat Shock Transcription Factor 1 In Ovarian Cancer Epithelial-Mesenchymal Transition And Drug Sensitivity, Chase David Powell

USF Tampa Graduate Theses and Dissertations

The heat shock response (HSR) is a robust cellular reaction to mitigate protein damage from heat and other challenges to the proteome. This protective molecular program in humans is controlled by heat shock transcription factor 1 (HSF1). Activation of HSF1 leads to the induction of an array of cytoprotective genes, many of which code for chaperones. These chaperones, known as heat shock proteins (HSPs), are responsible for maintaining the functional integrity of the proteome. HSPs achieve this by promoting proper folding and assembly of nascent proteins, refolding denatured proteins, and processing for degradation proteins and aggregates which cannot be returned …

18f-Fdg Pet/Ctct-Based Radiomics For The Prediction Of Radiochemotherapy Treatment Outcomes Of Cervical Cancer, Badereldeen Abdulmajeed Altazi

USF Tampa Graduate Theses and Dissertations

Cervical cancer remains the third most commonly diagnosed gynecological malignancy in the United States and throughout the world despite being potentially preventable. Patients diagnosed with cervical cancer may develop local recurrence in the cervix and surrounding structures (vaginal apex, parametrial, or paracervical), regional recurrence in pelvic lymph nodes, distant metastasis, or a combination of all. The management of such treatment outcomes has not been subject to rigorous investigation. Therefore, there is a need for studies and clinical trials that focus on decision making to support the choice of the best treatment modality that leads to the minimal number of adverse …

Microfluidic Biopsy Trapping Device For The Real-Time Monitoring Of The Tumor Microenvironment, Angela Holton

USF Tampa Graduate Theses and Dissertations

The tumor microenvironment is composed of cellular and stromal components such as tumor cells, mesenchymal cells, immune cells, cancer associated fibroblasts and the supporting extracellular matrix. The tumor microenvironment provides crucial support for growth and progression of tumor cells and affects tumor response to therapeutic interventions. To better understand tumor biology and to develop effective cancer therapeutic agents it is important to develop preclinical platforms that can faithfully recapitulate the tumor microenvironment and the complex interaction between the tumor and its surrounding stromal elements. Drug studies performed in vitro with conventional two-dimensional cancer cell line models do not optimally represent …

Functional Roles Of Matrix Metalloproteinases In Bone Metastatic Prostate Cancer, Jeremy S. Frieling

USF Tampa Graduate Theses and Dissertations

Skeletal metastasis is a lethal component of many advanced cancers including prostate, the second most common cancer among men. Patients whose prostate cancer is localized and detected early benefit from multiple treatment options ranging from active surveillance to radiation and surgery, resulting in a 5-year survival rate of nearly 100%. Unfortunately, the prognosis and survival for patients with advanced metastatic disease is much worse due to the highly aggressive nature of the disease and a paucity of treatment options. Understanding the mechanisms and interactions that occur between metastatic cancer cells and the bone will enable the future treatment landscape for …

Mass-Spectrometry Based Proteomics Of Age-Related Changes In Murine Microglia, Antwoine Flowers

USF Tampa Graduate Theses and Dissertations

The last century has seen a steady increase in the extension of the average lifespan. This has concomitantly produced higher incidences of age-related chronic degenerative diseases like Alzheimer’s and Parkinson’s diseases. Age is the single greatest risk factor for the development of not just these degenerative conditions but cancer as well. The aged niche undergoes a number of maladaptive changes that allow underlying conditions to present and progress. Exactly which changes, contribute to the progression of which disease is currently an area of intense study. However, these answers often present therapeutic targets for disease prevention. Age is characterized by a …

Development Of Tools For Stable Transfection In The Human Filarial Parasite Brugia Malayi Via The Piggybac Transposon System, Johan Chabanon

USF Tampa Graduate Theses and Dissertations

Brugia malayi is one of three species of nematode known to cause lymphatic filariasis (LF) in humans. LF infects over 120 million people, causing debilitating disease. Various global programs have been launched in the past 20 years to eliminate LF. These programs have greatly scaled up the resources and efforts allocated to halting the transmission and reducing disease burden. Only a few drugs are used to treat LF, and resistance is thus a devastating possibility. Research aimed at identifying new drug targets could therefore prove essential in elimination of LF.

Genetic manipulation of B. malayi has been limited to transient …

A Novel Abi-Domain Protein Controls Virulence Determinant Production In Staphylococcus Aureus, Stephanie Michelle Marroquin

USF Tampa Graduate Theses and Dissertations

A major factor in the success of Staphylococcus aureus as a pathogen is its vast arsenal of virulence determinants and, more importantly, the tight and precisely- timed regulation of these factors. Here we investigate the product of the S. aureus gene, SAUSA300_1984, encoding a putative transmembrane protein. This as yet uncharacterized protein belongs to the Abi (abortive infection) family, which are commonly annotated as CAAX-proteases, and are significantly understudied in prokaryotes. In S. aureus the disruption of SAUSA300_1984 results in a drastic reduction of proteolytic and hemolytic activity, as well as diminished pigmentation. This phenotype appears to be mediated through …

Gene Expression Profiling And The Role Of Hsf1 In Ovarian Cancer In 3d Spheroid Models, Trillitye Paullin

USF Tampa Graduate Theses and Dissertations

Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. These poor statistics are related to a lack of early symptoms and inadequate screening techniques. This results in the cancer going undetected until later stages when the tumor has metastasized through a process that requires the epithelial to mesenchymal transition (EMT). In lieu of traditional monolayer cell culture, EMT and cancer progression in general is best characterized through the use of 3D spheroid models. In this study, we examine gene expression changes through microarray analysis in …

Regulation Of Palmitoylation Enzymes And Substrates By Intrinsically Disordered Regions, Krishna D. Reddy

USF Tampa Graduate Theses and Dissertations

Protein palmitoylation refers to the process of adding a 16-carbon saturated fatty acid to the cysteine of a substrate protein, and this can in turn affect the substrate’s localization, stability, folding, and several other processes. This process is catalyzed by a family of 23 mammalian protein acyltransferases (PATs), a family of transmembrane enzymes that modify an estimated 10% of the proteome. At this point in time, no structure of a protein in this family has been solved, and therefore there is poor understanding about the regulation of the enzymes and their substrates. Most proteins, including palmitoylation enzymes and substrates, have …

Contribution Of Epithelial Hypoxia Signaling To Pulmonary Fibrosis: Role Of Fak1 And Galectin-1 As Driver Molecules, Jaymin J. Kathiriya

USF Tampa Graduate Theses and Dissertations

Idiopathic Pulmonary Fibrosis (IPF) is a deadly disease of unknown origin, which causes 80,000 deaths every year in the US and Europe combined. Unknown etiology and late diagnosis, combined with limited treatment options, contribute to a dismal survival rate of 3-5 years post diagnosis. Although molecular mechanisms underlying IPF pathogenesis and progression have been studied for over two decades, lack of in vivo models that recapitulate chronic, progressive, and irreversible nature of IPF have contributed to limited therapeutic success in clinical trials. Currently, only two drugs, Pirfenidone and Nintedanib, are approved for IPF treatment in the US, with their efficacy …

Regulation Of Nachrs And Stemness By Nicotine And E-Cigarettes In Nsclc, Courtney Schaal

USF Tampa Graduate Theses and Dissertations

Lung cancer is the leading cause of cancer-related death in both men and women, nationally and internationally and kills more people each year than breast, prostate, and colon cancers combined. Non-small cell lung carcinoma (NSCLC) is the most common histological subtype of lung cancer, and accounts for 85% of all cases. Cigarette smoking is the single greatest risk factor for lung cancer, and is correlated with 80-90% of all lung cancer deaths. Nicotine, the addictive component of tobacco smoke, is not a carcinogen and cannot initiate tumors itself; however, it is known to act as a tumor promoter, by enhancing …

A Caenorhabditis Elegans Model To Detect Developmental Teratogens With Adverse Reproductive And Metabolic Effects, Alexis Ann Killeen

USF Tampa Graduate Theses and Dissertations

Obesity is a current epidemic in the United States. Greater than one third of adults and nearly one fifth of children are classified as obese (Ogden, 2014). Increased awareness of this problem has triggered interest into the potentially causal agents in our environment. These agents, termed obesogens, are a type of teratogen hypothesized to work during embryonic development by programming offspring to store excess fat. A type of teratogen, obesogens are also typically reprotoxic, affecting germline development and embryonic viability. These noxious teratogens span a variety of different chemical classes including estrogen mimics, metals and metalloids, biocides, and even voluntary …

Cell Cycle Arrest By Tgfß1 Is Dependent On The Inhibition Of Cmg Helicase Assembly And Activation, Brook Samuel Nepon-Sixt

USF Tampa Graduate Theses and Dissertations

Tumorigenesis is a multifaceted set of events consisting of the deregulation of several cell-autonomous and tissue microenvironmental processes that ultimately leads to the acquisition of malignant disease. Transforming growth factor beta (TGFß) and its family members are regulatory cytokines that function to ensure proper organismal development and the maintenance of homeostasis by controlling cellular differentiation, proliferation, adhesion, and survival, as well as by modulating components of the cellular microenvironment and immune system. The pleiotropic control by TGFß of these cell intrinsic and extrinsic factors is intimately linked to the prevention of tumor formation, the specifics of which are dependent on …

Intrinsic Disorder Where You Least Expect It: The Incidence And Functional Relevance Of Intrinsic Disorder In Enzymes And The Protein Data Bank, Shelly Deforte

USF Tampa Graduate Theses and Dissertations

Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) exist as interconverting conformational ensembles, without a single fixed three-dimensional structure in vivo. The focus in the literature up to this point has been primarily on IDPs that are mostly or entirely disordered. Therefore, we have an incomplete understanding of the incidence and functional relevance of IDPRs in proteins that have regions of both order and disorder. This work explores these populations, by examining IDPRs in the Protein Data Bank (PDB) and in enzymes. By applying disorder prediction methods combined with an analysis of missing regions in crystal structure data, …

Inhibiting The Interaction Between Grp94 And Myocilin To Treat Primary Open-Angle Glaucoma, Andrew Stothert

USF Tampa Graduate Theses and Dissertations

Glaucoma is a neurodegenerative protein misfolding disorder classified by increases in IOP, damage to retinal ganglion cells (RGCs), optic nerve (ON) head damage, and progressive irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form of glaucoma, constituting over 90% of clinical cases. POAG is observed in patients where normal outflow channels, mainly the trabecular meshwork (TM), are exposed at the angle formed by the iris and cornea. However, due to TM cellular dysfunction, aqueous outflow resistance is increased preventing normal circulation of aqueous humor. Recent studies have shown that in 2-4% of POAG cases, increased intracellular levels of …

Targeting Tau Degradation By Small Molecule Inhibitors For Treatment Of Tauopathies, Mackenzie Martin

USF Tampa Graduate Theses and Dissertations

Tauopathies are neurodegenerative diseases that affect millions of people around the world. Tauopathies include more than 20 neurodegenerative diseases. Some of the most common tauopathies are Alzheimer’s disease (AD), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), Pick’s disease, corticobasal degeneration, progressive supranuclear palsy (PSP), agyrophillic grain disease, and amyotrophic lateral sclerosis (ALS). These diseases can cause significant memory loss, behavioral changes, motor deficits and speech impairments. Tauopathies stem from accumulation of the microtubule associated protein tau (MAPT). Tau stabilizes microtubules and helps with axonal transport. In a disease state tau becomes hyperphosphorylated and truncated leading to its aggregation. More recently …

Cell Permeability Studies Of Aapeptides And Novel Molecular Probes For Ad, Ge Bai

USF Tampa Graduate Theses and Dissertations

Alzheimer's diseases(AD) has been discovered and under research for more than 70 years, However there is no cure for these progressive and devastating diseases. Based on the following hypothsis: Aß metabolite problem/over production result in the accumulation, and lead to aggregation is the cause of Alzheimer’s disease. AApeptide and Melatonin derivatives can bind to Aß and block the aggregation of β amyloid monomers, decrease the toxicity of Aß to neurons and slow the progressive of Alzheimer’s diseases. In addition, AApeptide which mimic transmembrane peptide Tat will have similar transmembrane function. We have set up our goals as follows: 1) Using …