Medicine and Health Sciences Commons^™

Targeting Strategies To Optimize The Therapeutic Potential Of Gold Compounds Against Her2-Positive Breast Cancers, Afruja Ahad

Dissertations, Theses, and Capstone Projects

The overexpression of HER2 accounts for 20-30% of breast cancer tumors and not only serves as a marker for poor predictive clinical outcomes but also as a target for treatment. Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutic drugs to provide targeted treatment without toxicity to normal tissue. Most of the ADCs currently in the clinic for cancer chemotherapy are based on complex organic molecules. In contrast, the conjugation of metallodrugs to mAbs has been overlooked when there is enormous potential in this area with the resurgence of metal-based drugs as prospective cancer …

Dna Methylation-Based Epigenetic Biomarkers In Cell-Type Deconvolution And Tumor Tissue Of Origin Identification, Ze Zhang

Dartmouth College Ph.D Dissertations

DNA methylation is an epigenetic modification that regulates gene expression and is essential to establishing and preserving cellular identity. Genome-wide DNA methylation arrays provide a standardized and cost-effective approach to measuring DNA methylation. When combined with a cell-type reference library, DNA methylation measures allow the assessment of underlying cell-type proportions in heterogeneous mixtures. This approach, known as DNA methylation deconvolution or methylation cytometry, offers a standardized and cost-effective method for evaluating cell-type proportions. While this approach has succeeded in discerning cell types in various human tissues like blood, brain, tumors, skin, breast, and buccal swabs, the existing methods have major …

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation And Progression, Janine M. Deblasi

USF Tampa Graduate Theses and Dissertations

NRF2 is a redox-responsive transcription factor the directs the antioxidant program and several critical metabolic processes. Mutations in NRF2 or its negative regulator KEAP1 occur in up to one third of non-small cell lung cancers (NSCLCs) and are often associated with resistance to therapy and poor outcomes. In the present studies, murine alleles of the Keap1 and Nrf2 mutations found in human NSCLC were developed and I comprehensively investigated their impact on tumor initiation and progression. I observed that chronic Nrf2 stabilization by Keap1 loss-of-function or Nrf2 activating mutation was not sufficient to cause lung tumor initiation, even when p53 …

Early Stage Or Curable Cancer Diagnoses In Minorities: A Journey Of Survivors, Lora Asberry

Master of Science in Integrative Biology Theses

Patients diagnosed with early-staged or curable forms of cancer experience physical, as well as, mental challenges associated with disease progression and treatment. Previous studies have demonstrated that minorities and underrepresented communities did not receive the same level of care in comparison to their non-minority counterparts. Previous studies have also demonstrated that health disparities among minorities affected their cancer journey. This study addressed: how medical disparities varied between minorities and non-minorities, the overall effects of the cancer diagnoses in minorities compared to non-minorities, whether these perspectives differed in male vs. female participants, and whether there were any possible communication barriers between …

Synthesis, Characterization And Biological Evaluation Of Polyarginine Derived Bone-Targeting Peptides, Gina L. Antuono

Seton Hall University Dissertations and Theses (ETDs)

Osteoblast-targeting peptides in the treatment of bone disease is a new and novel approach to offering effective treatment of various cancers and can be used in bio-medical, medicinal chemistry and biotechnology applications. By targeting adhesion proteins produced by osteoblast cells, certain cancers which migrate and metastasize to the bone may be more effectively treated. An osteoblast-targeting peptide composed of Ser-Asp-Ser-Ser-Asp (SDSSD) which selectively binds to osteoblast cells via periostin has recently been identified. This peptide was functionalized with polyurethane, generating nanomicelles which encapsulated RNA for the therapeutic treatment of osteoporosis. This study has served as the basis for the research …

Development Of A Computational Model To Investigate Pathways And The Effects Of Treatment In Fanconi Anemia, Sabrina Kellett

Biological Sciences Undergraduate Honors Theses

Fanconi Anemia (FA) is a rare type of anemia that is not easily studied and can have very detrimental effects. This disease compromises the bone marrow, resulting in decreased hemopoiesis. Symptoms of FA also include abnormalities in the brain and spinal cord, incorrect formation of the kidneys, abnormal formation of the heart and lungs, and a dramatically increased risk of developing cancer. FA can be caused by various mutations in any of the 22 genes that encode for proteins involved in what is called the FA DNA repair pathway. In healthy individuals, this pathway specifically repairs interstrand cross-links (ICLs) recognized …

Sit Less, Move More: A National Study Of Physical-Activity Behavior And Cancer, Stella O. Nwogugu

Dissertations, Theses, and Capstone Projects

Background: Physical activity is associated with lower risks of cancer, the second leading cause of death among Americans. Yet, sedentary behavior is the prevailing lifestyle for about 80% of American adults. Additionally, cancer survivors remain significantly inactive, even though physical activity has been shown to decrease risk of cancer and cancer recurrence, improve tolerance of cancer therapy, and reduce mortality. This research explores the relative impact of personal agency, social support, and key demographic variables on physical-activity behavior for a national sample of adults as well as how these relationships differ for cancer survivors and their counterparts.

Methods: Using the …

Protacs – A Novel And Rapidly Developing Field Of Targeted Protein Degradation, Hannah R. Gatley

Theses and Dissertations

There is a continued need for new technology and strategies for tackling cancer and other diseases, and within the current century a novel therapeutic strategy has emerged in the realm of targeted protein degradation called Proteolysis-Targeting Chimeras (PROTACs). This technology specifically targets and degrades disease-causing proteins via the ubiquitin-proteasome system, and has seen an explosion of research and intrigue in both academia and industry over the past two decades. The diversity of PROTAC classes based on the E3 ligase recruiting ligand and the target protein allows for a universal molecular structure that can be customized for a specific target and …

Movement As Medicine: Dance/Movement Therapy For Individuals With Autism, Parkinson’S Disease, And Cancer, Alessia Zanobini

CMC Senior Theses

Dance/movement therapy (D/MT) is the psychotherapeutic use of expressive, creative movement to support holistic well-being. D/MT views the human being as a single body-mind unit and movement as a manifestation of life experiences. While typically practiced as a mental health intervention, D/MT can be adapted for a variety of populations. This thesis evaluates scientific data for the non-traditional use of D/MT for three conditions: autism, Parkinson’s disease, and cancer. For individuals on the autism spectrum, D/MT can strengthen attunement skills, provide creative communication outlets, and relieve harmful physical manifestations of autism. For individuals with Parkinson’s disease, D/MT can simultaneously ease …

Promoting Healthier Treatment Outcomes In Obese Cancer Patients Taking High Dose Methotrexate, Carly Dell'ova

Walden Dissertations and Doctoral Studies

Cancer and obesity rates continue to rise, creating enormous public heath burdens to the individual and at the national and global levels, reducing quality of life, and increasing spending. Moreover, the relationships between cancer and obesity are not well understood. A commonly used chemotherapy for several types of cancer is high dose methotrexate (HDMTX). Along with chemotherapy, especially at high doses, comes toxicity to specific organs and the entire body. However, limited research has been conducted on obese cancer patients as they are often excluded from clinical studies. Practitioners need to better understand how to dose these patients to provide …

Identification Of Novel Biosynthetic Gene Clusters Encoding For Polyketide/Nrps-Producing Chemotherapeutic Compounds From Marine-Derived Streptomyces Hygroscopicus From A Marine Sanctuary, Hannah Ruth Flaherty

Honors Theses and Capstones

Nearly one out of six deaths in 2020, around ten million people, were caused by cancer, making it a leading cause of death worldwide (WHO, 2022). This major public health issue, in addition to the rise of multidrug-resistant (MDR) pathogens, provides a high demand for the discovery of new pharmaceutical drugs to be used clinically to treat these conditions. The Streptomyces genus accounts to produce 39% of all microbial metabolites currently approved for human health, indicating its potential as an important species to study for antimicrobial and anticancer agents. The long linear genome of Streptomyces contains specialized sequences known as …

Visualization And Characterization Of The Immunological Synapse Between Chlorotoxin Chimeric Antigen (Cltx-Car) Redirected T Cells And Targeted Glioblastoma Tumors, Arianna Livi

CMC Senior Theses

Chimeric Antigen Receptor T (CAR-T) cells have demonstrated anti-tumor activity against aggressive and invasive cancers such as glioblastoma (GBM); however, clinical response rates remain low in clinical trial studies. Tumor heterogeneity and tumor microenvironment conditions pose significant challenges for treatment of GBM, thus continuous optimization of CAR-T cell therapies and identification of novel, widely expressed, and highly specific GBM antigens are vital to better patient outcomes. A newly developed CAR-T cell construct incorporating chlorotoxin (CLTX) as the targeting domain exhibited broad GBM-targeting capabilities and elicited potent cytotoxic effects during preclinical studies and is currently being tested in a phase I …

Nanoparticle Conjugated Photosensitizer For Targeted Photodynamic Inactivation Of Cancer Cells, Symone D. Crowder

Honors College Theses

Photodynamic therapy (PDT) is considered to be a potential replacement for traditional methods of chemotherapy. It includes the administration of photosensitizing agents (PS), which generate reactive oxygen species (ROS) upon excitation at a specific wavelength. With new outlooks and techniques, cancer research is advancing each day. It has allowed the progress of several theranostic drug delivery systems (DDS) exploring the area of nanomedicine.2 In the present work, a Rhodamine derivative, Rhodamine 6G (R6G) was used as the PS. In general, rhodamine compounds undergo cytotoxic reactions on photoexcitation by electron transfer reactions with folic acid within cells, making them a favorable …

A Microfluidics-Based Approach For Isolation Of Antigen-Specific Cd8+ T Cells, Meredith Frank

Dissertations & Theses (Open Access)

Cancer is a global epidemic: there are predicted to be 200 million new cases this year alone. Almost a quarter of all cancer-related deaths are caused by lung cancer, for which 5-year survival rates are just above 20%. 85% of lung cancer diagnoses are classified as non-small cell lung cancer (NSCLC) for which 5-year survival rates in metastatic disease are less than 10%. Early detection and targeted therapies have improved prognoses, yet relapse is still common among patients.

Immunotherapies that leverage tumor-specific CD8⁺ cytotoxic T cells have shown great promise for the treatment of NSCLC. However, although highly promising, …

The Role Of Reactive Oxygen Species In The Accumulation Of Driver Mutations In B Cell Acute Lymphoblastic Leukemia, Mia P. Sams

Electronic Thesis and Dissertation Repository

B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with recurrent mutations and high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine was tested for its ability to prolong lifespan of a mouse model of B-ALL and reduce frequency of mutations. Mice treated with 1g/L of N-acetylcysteine in drinking water were found to have delayed onset of B-ALL at 11 weeks of age and changes in gene expression relating to B cell development, calcium-apoptosis signaling, and pathways in cancer, although no differences in lifespan were observed. Tumours from treated …

Developing Novel Water-Soluble Porphyrins For Potential Use As Photosensitizers In Photodynamic Therapy, Kayla R. Whittington

Honors Theses

Photodynamic therapy (PDT) is a treatment modality for various illnesses, including some types of cancer. Lung cancer is the leading cause of cancer death in the United States. The prevalence of lung cancer in certain gender, racial, ethnic, and socioeconomic groups add to existing health disparities in the United States. For this reason, it is necessary to address the social determinants underlying lung cancer disparities, as well as improve treatment options. These treatment options should be cost effective, convenient, and increase survival rates. This research focused on synthesizing novel water-soluble porphyrin compounds for use as photosensitive agents in PDT for …

Human Papillomavirus 16 E2 Regulates Host Cell Pathways Important For Cancer Progression And Treatment Sensitivity Which May Contribute To Cancer Outcomes, Christian Fontan

Theses and Dissertations

Human papillomaviruses (HPVs) are causative agents in around 5% of all cancers, including cervical and oropharyngeal. A feature of HPV cancers is their better clinical outcome compared with non-HPV anatomical counterparts. In turn, the presence of E2 predicts a better clinical outcome in HPV-positive cancers; the reason(s) for the better outcome of E2-positive patients is not fully understood.

Previously, we demonstrated that HPV16 E2 regulates host gene transcription that is relevant to the HPV16 lifecycle in N/Tert-1 cells. One of the genes repressed by E2 and the entire HPV16 genome in N/Tert-1 cells is TWIST1. In these studies, we demonstrate …

Changes In Physical Activity And Relationships To Submaximal Exercise Capacity And Cardiac Function During Breast Cancer Therapy, Moriah P. Bellissimo

Theses and Dissertations

Background: Breast cancer (BC) survivors are at high risk for heart failure due to curative cancer therapies. In non-cancer populations, physical activity is a first line treatment for preventing cardiovascular disease. This study examined whether more physical activity was associated with better submaximal exercise capacity and cardiac function during the first three months of cancer therapy.

Methods: Participants included 223 women with stage I-III BC before therapy and after three months of undergoing treatment and 126 controls. Leisure time physical activity was reported using the Godin Sheppard leisure time exercise questionnaire. Cardiac function was assessed by cardiac magnetic resonance, and …

Differentiating The Mechanistic Role And Chemotherapeutic Potential Of Src And Podoplanin In Oncogenic Transformation, Edward P. Retzbach

Graduate School of Biomedical Sciences Theses and Dissertations

There were an estimated 20 million new cancer cases worldwide in 2020, resulting in nearly 1000 deaths per hour [1]. Oral cancer exemplifies the difficulties of treating cancer patients. The first line for oral cancer treatment is surgery and radiation that can lead to patient disfigurement and decreased quality of life in cancer survivors [2-4]. Though there have been many developments in chemotherapy in the last 30 years, the 50% mortality rate associated with oral cancer has not changed [4, 5]. Longitudinal studies that track survival rates in oral cancer patients demonstrate a 3-fold reduction in patient deaths when patients …

The Investigations Of Nps Modulated Immunity And Immunometabolism, Brittney Leigh Ruedlinger

Biomedical Sciences Theses & Dissertations

Cancers remain in the top noncommunicable diseases responsible for premature mortality. The heterogeneity among cancers and within tumors makes treating them ever more challenging. Our misfortune for developing cures is mocked by cancer, with the lowest probability of success (PoS) through clinical trials and FDA approval. At the basic level, there are generally two broad gaps impeding cancer eradication: the unidentified shared mechanism(s) exploited by all cancers and the therapeutic approach to intervene. Nanosecond pulse stimulation (NPS) offers a unique approach since its broad impacts intersect those often hijacked by oncogenesis. Metabolic pathways, known for dysfunctions among cancers, share a …

Uncovering A Myc-Driven Tumor-Suppressive Program In Proliferating Lymphocytes, Elena Tonc

Arts & Sciences Electronic Theses and Dissertations

Rapid cell proliferation is a hallmark feature of adaptive immune cells lymphocytes. It is essential for the establishment of diverse antigen receptor repertoires and amplification of antigen-specific immune responses. While such proliferation is beneficial for host protection from infections and cancers, it inevitably elevates the risk of oncogenic transformation. In developing and germinal center B lymphocytes, the risk is further increased by endogenous, genomic insults due to antigen receptor rearrangements and somatic mutations, with which expression of the proto-oncogene c-MYC is closely associated. Nonetheless, frequencies of cancers originated from B lymphocytes are relatively low, suggesting that they are protected from …

Understanding The Pathogenesis Of Renal Medullary Carcinoma, Melinda Soeung

Dissertations & Theses (Open Access)

Renal medullary carcinoma (RMC) is a lethal cancer that predominantly affects young individuals with sickle cell trait (SCT). It is not currently understood why RMC only affects certain individuals with SCT. We found that patients with RMC more frequently participated in high-intensity exercise than matched controls. Using mouse models of SCT, we demonstrated the significant increase of renal hypoxia in the right kidney following high- but not moderate-intensity exercise. We also demonstrated in cell culture studies that SMARCB1 is ubiquitinated for proteasome-mediated degradation in hypoxia, and the re-expression of SMARCB1 leads to compromised proliferation in renal cells specifically in the …

Unveiling Global Roles Of G-Quadruplexes And G4-22 In Human Genetics, Ruth Barros De Paula

Dissertations & Theses (Open Access)

G-quadruplexes are non-B DNA structures formed by four or more runs of repeated guanines that confer unique features to living organism’s genomes. These sequences are enriched in regulatory regions, such as promoters and 5’ UTRs, and have distinct regulatory roles in both health and disease states. Even though previous studies showed the impact of G4 in gene expression, none of them summarized the location-specific effect of G4. Also, there is no broad understanding about the most common G4 repeat in the human genome, named here as G4-22, and how it links to the evolution of mammals and their biology. In …

Targeting Plasma Membrane Phosphatidylserine Content To Inhibit Oncogenic Kras Function, Walaa E. Kattan

Dissertations & Theses (Open Access)

The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We therefore investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidylinositol-4-phosphate (PI4P) synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion …

A Time-Course Characterization Of Muscle Function And Mitochondrial Markers During Colorectal Cancer-Induced Cachexia In Tumor-Bearing Male Mice, Ana Cabrera Ayuso

Graduate Theses and Dissertations

Cachexia is a multisystemic and multifactorial syndrome prevalent in cancer patients. It is clinically defined by involuntary loss of >5% weight in a six-month window, despite nutritional interventions. A negative energy balance characterizes cancer cachexia (CC), it is associated with weakness and fatigue in skeletal muscle. Impaired muscle function is associated with lower quality of life in cancer patients. Defects in mitochondrial function are strongly associated with muscle wasting. This study explored muscular contractile function and mitochondrial quality control (MQC) markers in soleus, gastrocnemius, and tibialis anterior (TA) muscles of C26-induced male tumor-bearing mice during a 25-day time course. It …

A Comparative Study On Cannabidiol In Melanoma Migration And Invasion: Charlotte's Web Vs. Purified Cbd, 2020–2021, Ruby Thamert

Theses

Over the last decade, much attention has been focused on compounds from Cannabis sativa in treating a variety of diseases including cancer. This study examines the abilities of two different cannabidiol oils to decrease the migration and invasion of melanoma cells in vitro. Skin cancers are the most common cancers in the world. While malignant melanoma is the least common type of skin cancer, it is the deadliest. Patients diagnosed with stage IV disease have only a 15-20% five-year survival rate even with aggressive multimodal treatment, demonstrating the need for additional therapeutic options. Because melanoma is often fatal when …

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 …

Assessing Genetic Counselors' Clinical Approach And Practices Regarding Pathogenic/Likely Pathogenic Variant Downgrades, Grant Bonesteele

Dissertations & Theses (Open Access)

Although rare, variant downgrades from a pathogenic/likely pathogenic (P/LP) variant to a variant of uncertain significance can have a significant impact on patients and their families in the clinical cancer setting. However, there is a lack of literature about how to approach these potentially challenging cases as a genetic counselor. Therefore, we aimed to characterize genetic counselors’ experiences, approach, and practices to variant downgrade cases using an online survey. The survey asked participants how they would approach variant downgrade scenarios involving the CDH1 or ATM genes with variable family histories. Genetic counselors appear to be united in whether they would …

Understanding The Role Of Ano1 In Oral Cancer, Mallary Forrest

UNLV Theses, Dissertations, Professional Papers, and Capstones

In 2008, the gene ANO1 was discovered to encode a calcium activated chloride channel. This gene is located on the 11q13 locus, a locus that is commonly amplified in many cancers including cancer of the head and neck. ANO1 is situated in close proximity to genes associated with growth and apoptosis. As rapid proliferation and lack of apoptosis are hallmark characteristics of cancer, growth factors and apoptosis mediators are expected to be altered in cancer. But what does a calcium activated chloride channel have to contribute to cancer’s pathogenesis? Is it an active gene in cancer progression or is it …

Unraveling Host-Gut Microbiota Dialogue And Its Impact On Response To Immune Checkpoint Blockade, Alexandria Cogdill

Dissertations & Theses (Open Access)

Cancer is a disease with only one degree of separation, affecting one in two men and one in three women in their lifetimes; accounting for 1 of every 6 deaths. While cancer mortality rates continue to improve, incidence rates are expected to rise and shift through 2050 due to epidemiological and demographic transitions worldwide. As such, it is imperative to continue to investigate and improve our understanding of both disease etiology and hallmarks of response to treatment. Currently, conventional therapies include, but are not limited to, surgery, chemotherapy, and radiotherapy. However, within the past decade, major advances have been made …