Cell and Developmental Biology Commons^™

Which Costimulatory Domains In Chimeric Antigen Receptor T Cells Induce Cytokine Responses That Are Linked To A More Toxic Car T Cell Therapy In Acute Lymphocytic Leukemia?, Elisabeth Cohen

Longwood Senior Thesis Proposal

No abstract provided.

Translation Of The Carcinogenic Dna Breakage-Repair Inhibition Mechanism For Hexavalent Chromium To Its Key Targets: Lung Epithelial Cells, Lung Tissue And Impacts On The Genome., Idoia Meaza Isusi

Electronic Theses and Dissertations

Lung cancer is the leading cause of cancer death worldwide. Hexavalent chromium [Cr(VI)] is a human lung carcinogen with widespread occupational and environmental exposure. Despite the known health risks, how Cr(VI) causes lung cancer remains unclear. This dissertation investigates the mechanisms of Cr(VI)-induced carcinogenesis. Cr(VI) causes DNA damage, specifically DNA double strand breaks, and inhibits homologous recombination repair, a high-fidelity repair pathway. Unrepaired DNA double strand breaks or those repaired through error-prone pathways, progress to chromosomal damage, and chromosome instability. The latter is a common characteristic of Cr(VI)-exposed cells, and a hallmark of lung cancer. Although the mechanism of Cr(VI)-induced …

Fc Gamma Receptors Facilitate Antigenic Modulation Of Lilrb4 And Function As Predictive Biomarkers In Acute Monocytic Leukemia, Joshua Morse

Dissertations and Theses (Open Access)

Acute monocytic leukemia (monocytic AML) is a subtype of AML marked by a proliferation of abnormal monoblasts. This subtype represents approximately 10% of AML cases. The prognosis of monocytic AML is poor, with a 5-year survival of ~30%. Most patients are diagnosed at an age when they are unlikely to survive first-line non-targeted cytotoxic chemotherapy as a bridge to hematopoietic stem cell transplant (HSCT). Even patients who achieve remission commonly relapse. This population of patients would greatly benefit from precision-targeted therapies but currently there are none approved for monocytic AML.

Leukocyte immunoglobulin-like receptor B4 (LILRB4) is an immune checkpoint expressed …

Targeting Bard1 Suppresses A Myc-Dependent Transcriptional Program And Tumor Growth In Pancreatic Ductal Adenocarcinoma, Sohum Patel, Eleanor Jenkins, Rutuj P. Kusurkar, Sherry Lee, Wei Jiang, Avinoam Nevler, Matthew Mccoy, Michael J. Pishvaian, Rosalie C. Sears, Jonathan R. Brody, Charles J. Yeo, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin-proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. …

Assessment Of Dose-Dependent Cytotoxicity Of Caffeine On Human Colorectal Adenocarcinoma And Foreskin Fibroblast Cell Lines, Sanjay Srinivasan

Theses/Capstones/Creative Projects

Caffeine is a stimulant well-known for its alertness enhancement and energy functions. Beyond its neurological effects, caffeine also influences cellular qualities, including viability and membrane integrity. This study aimed to investigate the cytotoxic effects of caffeine on two distinct human cell lines: Human Colorectal Adenocarcinoma (HT-29) and Foreskin Fibroblasts (HFF). Cells were exposed to varying concentrations of caffeine to evaluate whether its effects were dose dependent. Cell viability was assessed using the Trypan Blue exclusion and Alamar Blue assays. Results showed that HFF cell death was more evident than the HT-29 Cells, displaying a potential therapeutic for cancer treatment.

Development Of A Behavioral Paradigm To Monitor Seizure Susceptibility And Severity In A Zebrafish Model Of Cblx Syndrome, Claudia Berenice Gil

Open Access Theses & Dissertations

Methylmalonic acidemia and homocysteinemia cblX type (cblX) (MIM#309541) is a rare, X-linked recessive disorder caused by a mutation in the HCFC1 gene. This disorder is characterized by multiple congenital anomalies which include intellectual disability, brain malformations, intractable epilepsy, microcephaly, and facial dysmorphia. The most severe symptom of cblX is intractable epilepsy which is 100% penetrant. Our lab developed a zebrafish model with a mutation in the zebrafish hcfc1a ortholog to study the mechanisms underlying seizure phenotypes in cblX. Our laboratory previously showed that mutation of hcfc1a results in increased number and proliferation of neural precursor cells (NPCs) and an increase …

"Until There Is Nothing Left:" The Environmental And Social Impact Of Extractivist Industries In Grant County, New Mexico 1852-1999, Benjamin Shultz

Open Access Theses & Dissertations

This dissertation research expands and deepens our understanding of the environmental and social impact of the extractivist industries in Grant County, New Mexico, from 1852 to 1999. Much of the scholarship around mining in the historiography tends to focus on Arizona and Northern New Mexico, given the centralization of the mining industry in places like Taos and Santa Fe. The impact of the mining industry on the unique ecosystem and people who resided in Grant County, New Mexico, has not been as thoroughly researched by scholars. Thus, this dissertation extends the literature by revealing how the extractivist industries permanently changed …

Developing A Small Molecule To Inhibit Hsf1 Expression In Cancer And Evaluating Natural Genetic Variation In Small Molecule Toxicity., Michaela Kendal Foley

Theses and Dissertations

Each year cancer affects nearly 20 million people worldwide and genetic differences across populations can impact cancer onset and progression. Specifically, tumors with high levels of HSF1, the master regulator of the cytoprotective heat shock response (HSR), are correlated with poor patient outcomes in multiple cancers such as prostate, breast, and melanoma. Subsequently, the development of pharmacological inhibitors of HSF1 represents a promising strategy for anticancer therapeutics. Using a luciferase-based transcriptional reporter, two small molecule libraries were screened for inhibitors of HSF1 expression in human embryonic kidney cells, yielding ten compounds that decrease HSF1 expression. To identify if cancer lines …

Bang!: Real-Time Measurements And Transcriptomics Of Metabolic Reprogramming In Activated Macrophages At Fever Temperature, Kenneth Howard Taylor

Graduate Theses and Dissertations

We investigated the real-time metabolic rates of activated macrophage cell lines derived from mouse, chicken and rainbow trout. Each species showed a different kinetic signature with metabolic rates accelerating under fever conditions specific to each organism. Upon activation mouse macrophages increased their rate of glycolysis early and then a later reprogramming phase occurred with a dramatic decrease in oxidative phosphorylation (OXPHOS) accompanied by a reciprocal second increase in glycolytic rates. Chicken macrophages showed an initial increase in both glycolytic and OXPHOS rates. The late drop OXPHOS rates also occurred in chicken however there was no reprogramming that occurred as glycolytic …

The Role Of Ucp2 In Pancreatic Cancer Metabolism And Its Potential As A Radiosensitizer, Emily Rieff

Dissertations and Theses (Open Access)

Uncoupling protein 2 (UCP2) is a mitochondrial protein that regulates the flow of protons down the gradient established by the electron transport chain (ETC) without generating ATP, thus uncoupling the proton gradient from ATP generation. In tumors, specifically pancreatic cancer (PDAC), the ETC is highly stimulated to generate the copious ATP needed by the tumor to grow. However, extended ETC use increases reactive oxygen species (ROS), and if left unchecked, results in cell death. To evade this, PDAC employs antioxidant strategies, including upregulating UCP2 in tumor cells. In addition to its uncoupling function, UCP2 indirectly controls ROS levels by maintaining …

An Analysis Of Cellular And Tissue Function Of Lipin In Drosophila Melanogaster, Judah Christian Scott

Graduate Theses and Dissertations

Regulation of energy expenditure and energy storage is a key characteristic of life. Numerous enzymes play a crucial role in regulating energy metabolism. Lipins are a highly conserved family of proteins that function in both lipid synthesis and gene regulation. In the glycerol-3 phosphate pathway, lipins act as a phosphatidate phosphatase (PAP) producing diacylglycerol. In gene regulation, lipins act as transcriptional co-regulators of metabolic genes. The enzymatic PAP activity occurs in the cytoplasm; however, for lipins to function as gene regulators, they must translocate into the nucleus. Nuclear translocation is facilitated by the nuclear localization signal (NLS) within the protein. …

Thymosin Beta-4: A Novel Treatment For Acanthamoeba Keratitis, Victoria A. Murphey

All Theses

Acanthamoeba keratitis (AK) is a severe corneal infection caused by the free-living amoeba, Acanthamoeba. Both stages of its life cycle (trophozoite and cyst) cause infection, primarily in contact lens wearers. It is often misdiagnosed, leading to delayed treatment and poor clinical outcomes. Current treatment options for AK rely on anti-amoebic agents that are toxic to corneal epithelial cells. Further, no single drug can eliminate both forms of the amoeba. Approximately 30% of all AK infections require a corneal transplant.

Thymosin beta-4 (Tβ4) is a G-actin binding protein synthesized in almost all human cells, including corneal epithelial cells. Tβ4 exhibits …

Therapeutic Vulnerabilities Of Venetoclax Resistant Chronic Lymphocytic Leukemia And Novel Treatment Strategies Targeting Bcl2/Bcl-Xl, Daisy Y. Diaz-Rohena

Dissertations and Theses (Open Access)

Despite major advancements in the management of chronic lymphocytic leukemia (CLL), drug resistance remains a major challenge. CLL resistant to venetoclax (VEN) have limited available therapeutic options, especially when the leukemic cells have dysfunctional p53 and have relapsed on Bruton’s tyrosine kinase inhibitors (BTKi). The broad hypothesis of this thesis is that VEN-relapsed CLL exhibits altered dependence on BCL2 family members, which can be exploited for therapeutic benefit. I profiled 28 CLL samples collected from 15 patients either at baseline or at relapse following VEN treatment, which was administered in combination with a BTKi or sequentially as monotherapy after a …

Ascl2 Positive Tumor Cells Modulate The Response Of Metastatic Colorectal Cancer To Mapk-Targeting Therapy, Oscar Eduardo Villarreal

Dissertations and Theses (Open Access)

Colorectal cancer (CRC) is the second leading cause of cancer related deaths with nearly a quarter of patients presenting with metastatic disease at the time of their diagnosis. Therapeutic management of metastatic CRC continues to be a major challenge due to therapy resistance and disease heterogeneity. Due to its central role in tumorigenesis, CRC is commonly treated with MAPK pathway inhibitors (MAPKi). However, clinical trials repeatedly demonstrates that durability of benefit is short-lived in many patients. While genomic mechanisms of acquired resistance have been described, they explain a minority of patients, and further research is needed to determine the underlying …

Identification Of Mitochondrial Defects And Metabolic Consequences In Lynch Syndrome-Related Endometrial Cancer, Mikayla Bowen

Dissertations and Theses (Open Access)

Lynch syndrome (LS), defined by mutations in DNA mismatch repair genes including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Mismatch repair deficiency (MMRd) causes hypermutability, which is assumed to be the main driver of LS-related EC development. However, incomplete penetrance of EC development in women with LS suggests that other modulators are at play. The broad hypothesis of this dissertation is that MMRd causes consequences beyond hypermutability to impact LS-related EC development. Recent studies utilizing our lab’s Msh2-deficient mouse model for LS-EC revealed mitochondrial dysfunction in EC pathogenesis. This new insight led to the …

Developing Novel Therapies Targeting The Tumor Microenvironment Of Aggressive Breast Cancer, Lan T H Phi

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive breast cancer subtypes. The tumor microenvironment (TME) is critical in driving these aggressive breast cancers' clinical phenotype and aggressiveness. Therefore, we explored novel actionable targets and complementary therapies targeting the TME to improve the outcomes of patients with these cancers.

In this thesis, we identified AXL as a potential therapeutic target in IBC due to its role in generating an immunosuppressive TME. Indeed, inhibiting the AXL pathway suppresses IBC tumor growth and reduces M2 macrophage populations in various mouse models. Mechanistically, AXL facilitates the polarization of M2 …

Impact Of Tumor Cell Expressed Cd38 On Metastasis And Immune Evasion In Breast Cancer, Tanvi Visal

Dissertations and Theses (Open Access)

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype. The epithelial-to-mesenchymal transition (EMT) of cancer cells is a key feature of the metastatic cascade and is not a binary process but often generates malignant cells with both epithelial (E) and mesenchymal (M) traits known as hybrid EM cells. Recent studies highlight the enhanced metastatic potential of the hybrid EM cells. However, molecular insights and targetable vulnerabilities within hybrid EM remain elusive. We discovered that hybrid EM murine tumors are enriched in CD38, an immunesuppressive molecule associated with worse clinical outcomes in liquid malignancies but relatively understudied in solid …

Relationship Between Processing Body Formation, Epithelial-To-Mesenchymal Transition, And Invasion In Lung Adenocarcinoma, Amanda Warner

Dissertations and Theses (Open Access)

Lung cancer is the leading cause of cancer-related deaths in the United States, largely due to its ability to metastasize. Epithelial-to-mesenchymal transition (EMT) is a process that enhances the ability of cells to lose their cell-cell contacts, invade, and enter the blood stream which are essential during metastasis. Many transcriptional gene programs are altered during EMT such as activation of mesenchymal transcription factors, like ZEB1, and enhanced response to the TGFβ1 cytokine. In oncogenic contexts, TGFβ1 enhances the formation of processing-bodies (P-bodies) where P-body proteins are required for invasion in multiple cancerous cell lines. P-bodies are a type of ribonucleoprotein …

Rod Photoreceptor Regeneration In A Zebrafish Model With Retinitis Pigmentosa, Eyad Shihabeddin

Dissertations and Theses (Open Access)

A cellular hallmark of inherited retinal degenerative diseases is progressive loss of photoreceptors until one is completely blind. Unlike mammalian models, Zebrafish have the ability to naturally regenerate their neurons after injury or disease is detected. We have generated a zebrafish model with the most common autosomal dominant form of the inherited retinal degenerative disease known as Retinitis Pigmentosa. We utilize immunohistochemistry, single-cell RNA sequencing, several analysis tools, behavioral assays and oligonucleotides to characterize our zebrafish model and identify the transcription factors necessary for rod photoreceptor regeneration. We show that our zebrafish model has continuous degeneration and regeneration of rod …

Overcoming Resistance To Cdk4/6-Targeted Therapy Using Jak2/Stat3 Inhibitor In Triple-Negative Breast Cancer, Chuling Zhuang

Dissertations and Theses (Open Access)

Breast cancer is the most common type of cancer diagnosed in women, with nearly 30% of cases becoming metastatic accounting for over 90% of breast cancer-related deaths. Among different breast cancer subtypes, triple-negative breast cancer (TNBC) has the worst prognosis and the highest propensity to metastasize. However, TNBC patients have limited treatment options due to their lack of actionable drug targets while therapeutic resistances result in high rates of recurrence and metastasis. Cyclin-dependent kinase 4 and 6 (CDK4/6) are major cell cycle regulators that control G1 to S phase transition and aberrant hyperactivation of the CDK4/6 pathway results in uncontrolled …