Cell and Developmental Biology Commons^™

Chemotherapy-Induced Modulation Of Tumor Antigen Presentation, Alaina C. Larson

Theses & Dissertations

Pancreatic cancer is a lethal malignancy, with a five-year overall survival rate of just 13%. Current treatment approaches thus require modification and attention has shifted towards improving immunotherapy efficacy. Select chemotherapy drugs possess inherent immunomodulatory activity and could be used to initiate immunotherapeutic success, thereby restoring anti-tumor immunity in pancreatic cancer. In this work, I evaluated the impact of the chemotherapy drug gemcitabine on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine regulated HLA-I expression on multiple levels, increasing pancreatic cancer cells’ HLA-I mRNA transcripts, total protein and surface expression, as well as surface stability. Temperature-dependent assay …

Targeting Ksr1 To Inhibit Stemness And Therapy Resistance, Heidi M. Vieira

Theses & Dissertations

Tumor heterogeneity is an important contributor to therapy resistance and relapse. Within the tumor, there are subpopulations of tumorigenic, self-renewing cells with enhanced clonogenicity and chemoresistance, termed tumor-initiating cells (TICs). Despite their importance in treatment response, there are no effective therapies to target TICs in solid tumors.

This study identifies a novel role for Kinase Suppressor of Ras 1 (KSR1) in regulating TICs and therapy resistance in Ras-driven cancers. KSR1 is a molecular scaffold in the Raf/MEK/ERK kinase cascade downstream of Ras. KSR1 is necessary for Ras-mediated transformation, but dispensable for normal cell growth; further, ksr1^-/- mice are phenotypically …

Exploring The Role Of Rb1 In Cellular Differentiation Using Patient-Derived Stem Cells, Ambily Vincent

Theses and Dissertations

The Retinoblastoma (RB1) gene, predominantly recognized as a tumour suppressor, plays a crucial role in early growth and development. Mice lacking the retinoblastoma gene do not survive and exhibit defects in the differentiation of various tissues, underscoring its involvement in cellular differentiation. This suggests that the functions of the RB1 gene extend beyond its role as a tumour suppressor, encompassing cell cycle regulation, maintenance of genomic stability, cellular senescence, and cellular differentiation.

While the tumour suppressor function of the RB1 has been extensively studied, its role in cellular differentiation remains incompletely understood. Existing literature, primarily based on animal models, has …

Stanniocalcin 2 Governs Cancer Cell Adaptation To Nutrient Insufficiency Through Alleviation Of Oxidative Stress, Shuo Qie, Haijuan Xiong, Yaqi Liu, Chenhui Yan, Yalei Wang, Lifeng Tian, Chenguang Wang, Nianli Sang

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by …

Assessment Of Tripeptides Self-Assembly & Er Stress On Cell Viability And Exosome Secretion In Mda-Mb231, Azmat Parveen

Theses and Dissertations

This study delves into the effects of tripeptides KYpF and WYpK(NBD) on MDA-MB-231 cells, uncovering KYpF's ability to reduce cell proliferation and exosome secretion in peptide treated cells. Conversely, WYpK(NBD) demonstrated significant toxicity at 10 μM. These insights pave the way for optimizing peptide-based cellular treatments for exosome secretion purposes.

Elucidation Of Molecular Mechanisms Underlying Tumor Necrosis Factor (Tnf) Release From Mast Cells, Tolulope Eunice Ayo

Dissertations

Mast cells are one of the major producers of tumor necrosis factor-alpha (TNF), and mast cell-derived TNF (MC-TNF) is associated with pathological conditions such as rheumatoid arthritis, inflammatory bowel diseases, and allergic asthma. However, the molecular machinery underlying TNF release from mast cells has been unclear, despite the conserved nature of exocytosis. To delineate the exocytic machinery required for TNF release from mast cells, we systematically dissected the exocytic fusion machinery (e.g., Munc13, Munc18, and VAMP families) expressed in mast cells, using a combination of CRISPR-dependent knockout, RNA interference, confocal microscopy, lentiviral rescue experiments, and cell-based assays. Out of the …

Identification Of Bacterial Transcriptomic Signatures In Breast Cancer Tissues Using Publicly Available Datasets, Rasaq Awosemo

Master's Theses

Breast cancer remains a significant global health concern, with increasing evidence suggesting a link between bacterial infections and cancer progression. This study aims to identify bacterial transcriptomic signatures within breast cancer tissues using publicly available datasets. While previous work in our lab has extensively explored the role of Borrelia burgdorferi in cancer, this research broadens the focus to investigate the presence of various bacterial species across different breast cancer samples.

Employing advanced bioinformatics methodologies, including the STAR aligner and MetaPhlAn for metatranscriptomics analysis, we analyzed RNA-sequencing data from the Gene Expression Omnibus (GEO). Our findings reveal diverse bacterial communities within …

Manipulation Of Cellular Proliferating Cell Nuclear Antigen (Pcna) During Herpes Simplex Virus Type 1 Infection, Jessica Packard, Jill A. Dembowski

Electronic Theses and Dissertations

Herpes simplex virus type 1 (HSV-1) is a double stranded DNA virus that replicates within the nucleus of host cells. Using accelerated native isolation of proteins on nascent DNA (aniPOND), cellular proteins were found to associate with HSV-1 replication forks. One host factor of interest is proliferating cell nuclear antigen (PCNA), the DNA sliding clamp that tethers DNA polymerases and DNA damage response proteins to replicating cellular DNA. Although HSV-1 encodes its own DNA polymerase processivity factor (UL42), PCNA plays a key role in HSV-1 infection. We used commercially available PCNA inhibitors and short hairpin RNAs (shRNA) to investigate how …

Elucidating The Roles Of Septin Proteins In Thermotolerance And Cell Wall Integrity In Cryptococcus Neoformans, Stephani S. Martinez Barrera

All Dissertations

Cryptococcus neoformans is a globally distributed fungal pathogen responsible for causing cryptococcal meningitis in immunocompromised individuals. This pathogenic yeast must adapt to changes in temperature upon entering the human host. Septin proteins are conserved filament-forming GTPases that assemble as higher-order complexes at the cell cortex to support cytokinesis and morphogenesis in fungal and animal cells. In C. neoformans, four septin homologs (Cdc3, Cdc10, Cdc11, and Cdc12) assemble at the mother-bud neck, contributing to cytokinesis through poorly understood mechanisms. C. neoformans strains lacking the septins Cdc3 or Cdc12 are viable at 25°C, but fail to proliferate at 37°C, and are …

Functional Contribution Of Epithelial To Mesenchymal Transition Program On Krasg12d Targeting Efficacy In Pancreatic Cancer, Ana S. Maldonado

Dissertations and Theses (Open Access)

Functional contribution of epithelial to mesenchymal transition program on KRAS^G12D targeting efficacy in pancreatic cancer

Ana S. Maldonado, BS

Advisory Professor: Raghu Kalluri, M.D., Ph.D.

Pancreatic Ductal Adenocarcinoma (PDAC), a highly aggressive, metastatic, and therapeutically resistant form of pancreatic cancer has been projected to become the second-leading cause of cancer related mortality in the United States. This is driven by its detection difficulty, treatment efficacy, and asymptomatic nature, among other factors. PDAC is driven predominantly by KRAS^G12D mutations, which are responsible for the initial development of pancreatic intraepithelial neoplasia (Pan-IN) lesions, that are further maintained and progressed until …

Expression Of The Αvβ3 Integrin Affects Prostate Cancer Sev Cargo And Density And Promotes Sev Pro-Tumorigenic Activity In Vivo Through A Gpi-Anchored Receptor, Ngr2, Cecilia Verrillo, Fabio Quaglia, Christopher Shields, Stephen Lin, Andrew Kossenkov, Hsin-Yao Tang, David Speicher, Nicole Naranjo, Anna Testa, William Kelly, Qin Liu, Benjamin Leiby, Luca Musante, Khalid Sossey-Alaoui, Navneet Dogra, Tzu-Yi Chen, Dario Altieri, Lucia Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved …

Early Onset Alzheimer’S Disease Markers In Mouse Hippocampus Unveiled By Single-Cell Transcriptomic Analysis Following Cranial Radiotherapy, Tuba Aksoy

Dissertations and Theses (Open Access)

Cranial radiation therapy plays an integral role in the treatment of brain tumors but can lead to progressive cognitive deficits in survivors by mechanisms that are poorly understood. To develop preventive or mitigative strategies, it is crucial to better understand the underlying pathogenesis of radiation-induced cognitive impairments. The study investigated single-cell transcriptomics and DNA methylation changes as potential drivers of persistent cellular dysfunction after radiation exposure, specifically concentrating on the CA1-3 regions of the hippocampus and the prefrontal cortex due to their role in cognitive functions. Thirteen-week-old mice underwent whole-brain radiation at clinically relevant doses. Following whole-brain radiation, an assessment …

Placental Co-Transcriptional Activator Vestigial-Like 1 (Vgll1) Drives Tumorigenesis Via Increasing Transcription Of Proliferation And Invasion Genes, Heather Sonnemann

Dissertations and Theses (Open Access)

Vestigial-like 1 (VGLL1) is a co-transcriptional activator that binds to TEA domain containing transcription factors (TEADs). Its expression is upregulated in a variety of aggressive cancer types, including pancreatic and basal-like breast cancer, and increased transcription of VGLL1 is strongly correlated with poor prognosis and decreased overall patient survival. In normal tissues, VGLL1 is most highly expressed within placental trophoblast cells, which share the common attributes of rapid cellular proliferation and invasion with tumor cells. The impact of VGLL1 in cancer has not been fully elucidated and no VGLL1-targeted therapy currently exists. The aim of this study was to evaluate …

Vesicle-Associated Membrane Proteins In Airway Mucin Secretion, Boxuan Yang

Dissertations and Theses (Open Access)

Mucus plays a vital role in shielding the lungs against harmful substances such as particles, pathogens, and chemicals inhaled from the environment. It captures these harmful elements, and ciliary action helps to expel them from the lungs. Paradoxically, malfunctioning of mucus induces the development of various respiratory illnesses, including asthma, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases. Despite extensive research on controlling mucin production and hydration, the process of secretion is not yet fully comprehended.

Mucin undergoes regulated secretion at two rates: a low baseline rate and a high stimulated rate. Over the past 25 years, …

Nutrient Intake And Nutritional Status Of Blood Cancer Patients At A Tertiary Hospital In India: A Cross-Sectional Descriptive Analysis Of Leukemia, Lymphoma And Multiple Myeloma, Enock Topisia, Loise Wamahiga Wang’Ondu

Haematology and Oncology, East Africa

In 2018, there were an estimated 18 million cancer cases worldwide, with lymphoma, multiple myeloma, and leukemia contributing to a significant portion of these cases. Lymphoma accounted for 79,990 cases, multiple myeloma for 159,985 cases, and leukemia for 437,033 cases globally (AICR, 2018). In the United States alone, approximately 30,770 people are diagnosed with multiple myeloma each year. Multiple myeloma comprises about 1.8% of all cancers and around 10% of all “blood cancers,” which includes leukemia (Penn Medicine, 2020). India ranks third in the highest reported cases of blood cancer, following the United States and China, affecting more than 70,000 …

Differential Effect Of An Evolving Amyloid And Tau Pathology On Brain Phospholipids And Bioactive Lipid Mediators In Rat Models Of Alzheimer-Like Pathology, Sonia Do Carmo, Marie Audrey I. Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T. Emmerson, Janice C. Malcolm, Quentin Bonomo, Nicolas G. Bazan, A. Claudio Cuello

School of Graduate Studies Faculty Publications

Background: Brain inflammation contributes significantly to the pathophysiology of Alzheimer’s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved. Methods: In this study, we examined the cortical levels of DHA- and AA-derived bioactive …

Diesel Exhaust Particles Alter Mitochondrial Bioenergetics And Camp Producing Capacity In Human Bronchial Epithelial Cells, Isabella Cattani-Cavalieri, Marina Trombetta-Lima, Hong Yan, Ana L. Manzano-Covarrubias, Hoeke A. Baarsma, Asmaa Oun, Melissa Mol Van Der Veen, Emily Oosterhout, Amalia M. Dolga, Rennolds S. Ostrom, Samuel Santos Valenca, Martina Schmidt

Pharmacy Faculty Articles and Research

Introduction: Air pollution from diesel combustion is linked in part to the generation of diesel exhaust particles (DEP). DEP exposure induces various processes, including inflammation and oxidative stress, which ultimately contribute to a decline in lung function. Cyclic AMP (cAMP) signaling is critical for lung homeostasis. The impact of DEP on cAMP signaling is largely unknown.

Methods: We exposed human bronchial epithelial (BEAS-2B) cells to DEP for 24–72 h and evaluated mitochondrial bioenergetics, markers of oxidative stress and inflammation and the components of cAMP signaling. Mitochondrial bioenergetics was measured at 72 h to capture the potential and accumulative effects of …

Genetics Of Mdh In Humans, Adam Haberman, Celeste N. Peterson

Biology: Faculty Scholarship

Malate dehydrogenase (MDH) performs key roles in metabolism, but little is known about its function specifically in human health and disease. In this minireview, we describe the incomplete state of our knowledge of human MDH genetics. Humans have three MDH genes with a total of four validated isoforms. MDH1 and MDH2 are widely expressed, while MDH1B is only expressed in a small subset of tissues. Many mutations in MDH1 and MDH2 have been identified in patients, but only a few have been studied to determine what symptoms they cause. MDH1 has been associated with cancer and a neurodevelopmental disorder. MDH2 …

Functional And Structural Analysis Of The Neimann-Pick Disease Type C Pathway To Include Caveolin-1, Anthony Michael Seat

Chemistry and Chemical Biology ETDs

Human disease is often thought of as an all or nothing prospect, either one has the disease or one does not. This does not bear out in clinical or personal experiences, instead demonstrating that disease occurs within a spectrum ranging from presumed unaffected to demonstrably and detrimentally affected.Neimann-Pick disease is one example of this spectrum look into diseased states, with multiple named versions of a phenotypically similar disease. We focus on Neimann-Picktype C (NPC), which is the result of a disruption in the efflux of cholesterol and sphingolipids from the endocytic pathway. NPC demonstrates this concept of a spectrum of …

Role Of Sds-22/Pp1 Phosphatase In Polarizing The Germplasm Of Caenorhabditis Elegans Embryo, Aparna Nurni Ravi

Dartmouth College Ph.D Dissertations

During asymmetric cell division, cell polarity and cell cycle are tightly coupled to ensure robust segregation of cell fate determinants and generation of cellular diversity. In the one-cell C. elegans embryo, multiple cell cycle kinases regulate cell polarization and posterior segregation of germline fate determinants (germplasm). For example, PLK-1 kinase inhibits the retention of its germplasm substrate POS-1 in the anterior, driving POS-1 segregation to the posterior (Han et al., 2018). Additionally, MBK-2 kinase disassembles P granules in the anterior through phosphorylation of the P granule scaffold MEG-3, helping to drive P granule segregation to the posterior (Wang et al., …