Cell and Developmental Biology Commons^™

Receptor Tyrosine Kinases-Mediated Acquired Parp Inhibitor Resistance In Breast Cancer, Mei-Kuang Chen

Dissertations and Theses (Open Access)

Leveraging compromised DNA damage repair (DDR) pathways commonly found in tumor cells, a classic strategy in cancer therapy is inducing excessive DNA damage to cause cancer cell death. Small molecule poly(ADP-ribose) polymerase (PARP) inhibitors (PARP-is) have been approved for clinical use in treating breast cancer and ovarian cancer patients bearing DDR-deficient tumors with mutations in breast cancer susceptibility genes (BRCA^m). However, accumulating evidences show that both intrinsic and acquired resistances to PARP-is exist in clinic and pre-clinical animal models. Therefore, I developed panels of cells with acquired PARP-is resistance from PARP-is-sensitive triple negative breast cancer (TNBC) cell …

Heterogeneous Nuclear Ribonucleoprotein K (Hnrnp K) Overexpression And Its Interaction With Runx1 Rna In Acute Myeloid Leukemia, Marisa Aitken

Dissertations and Theses (Open Access)

Acute myeloid leukemia (AML) is an often devastating hematologic malignancy with 5-year overall survival lingering near 20%. Acquiring a deeper understanding of molecular underpinnings of leukemogenesis will provide a basis for developing more effective therapeutic strategies for patients with AML.

Here, we identified overexpression of hnRNP K as a recurrent abnormality in a subset (~20%) of AML patients. High levels of this RNA-binding protein associated with inferior clinical outcomes in de novo AML. Thus, to evaluate its putative oncogenic capacity in myeloid disease, we overexpressed hnRNP K in murine hematopoietic stem and progenitor cells isolated from fetal liver cells (FLCs). …

Effect Of Sympathetic Nervous System Mediators On The Tumor Microenvironment Via Small Extracellular Vesicles In Ovarian Cancer, Sujanitha Umamaheswaran, Sujanitha Umamaheswaran

Dissertations and Theses (Open Access)

Effect of sympathetic nervous system mediators on the tumor microenvironment via small extracellular vesicles in ovarian cancer

Sujanitha Umamaheswaran, BTech

Advisor: Anil K. Sood, MD

Background:Psychological stress can promote progression of gynecological malignancies by increasing secretion of sympathetic nervous system (SNS) mediators, namely catecholamines. However, the mechanisms underlying these effects are poorly explored. Here, we examined the effect of stress hormones on small extracellular vesicles (EVs) release in gynecological malignancies and the biological impact of these stress-conditioned EVs on the tumor microenvironment.

Methods:Supernatants were collected from epithelial ovarian cancer cell lines treated with norepinephrine, epinephrine or hydrocortisone. Small EVs were …

Impact Of Epa And Dha Supplementation And 15-Lox-1 Expression On Colitis And Colitis-Associated Colorectal Cancer, Jonathan Jaoude

Dissertations and Theses (Open Access)

Inflammatory bowel disease (IBD) patients not only suffer from colitis but also from increased morbidity and mortality of colitis-associated colorectal cancer (CAC). The enzyme 15-lipoxygenase-1 (15-LOX-1) is crucial to converting omega-3 fatty acid derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to resolvins, potent anti-inflammatory products. 15-LOX-1 effects on the conversion of EPA and DHA to resolvins that subsequently exert anti-inflammatory and anti-tumorigenic effects have received little attention. To address this knowledge gap, we hypothesize that 15-LOX-1 expression in colonic epithelial cells is essential for resolvin biosynthesis from EPA and DHA to modulate immunophenotype, limit inflammation, promote resolution, and help …

Exosomal Communication By Metastatic Osteosarcoma Cells Modulates Alveolar Macrophages To An M2 Tumor-Promoting Phenotype And Inhibits Tumoricidal Functions, Kerri Wolf

Dissertations and Theses (Open Access)

Osteosarcoma metastasizes to the lung, and there is a link between the predominance of tumor promoting immunosuppressive M2 macrophages in the metastases and poor patient survival. By contrast, M1macrophage predominance correlates with longer survival. M2 macrophages can be induced by various stimuli in the tumor microenvironment, including exosomes, which are 40- to 150-nm vesicles that are involved in intercellular communication and contribute to tumor progression and immune evasion. Recognizing that tumor cells can influence the tumor microenvironment to make it more permissive and because of the link between M2 dominance and curtailed patient survival, we evaluated the effect of …

Understanding Intercellular Signaling During Lung Injury-Repair, Margo Patricia Cain

Dissertations and Theses (Open Access)

The mammalian lung is a complex system of specialized cell types with precise spatial organization designed to cooperate to perform gas exchange. These cell types together coordinate organ development, homeostasis, and repair after injury through signals either presented or secreted, known as ligands, to be received by receptors on the surface of another, or in some cases, the same cell. The alveolar region of the lung, the primary region of gas exchange, responds to various types of injuries with different lung repair mechanisms. In order to explore how the various cell types in the lung communicate to drive tissue repair …

A Novel Uv Resistance In Rad23-Depleted Tetrahymena Thermophila, Emily M. Schmoll

Graduate Theses/Dissertations

Rad23 is a highly conserved cellular scaffold protein which participates in the nucleotide excision repair pathway and ubiquitin proteasome system. It is hypothesized that the contradictory roles of Rad23 within these two systems, acting to enhance stability or facilitate degradation respectively, could be regulated via post-translational modification of the ubiquitin-like domain of the protein. To this end, a Rad23 somatic knockout cell line was established in Tetrahymena thermophila, with the eventual goal of knocking in a mutant Rad23 protein lacking potential for UbL ubiquitylation. In contrast to the UV-sensitive phenotype observed in similar models, Rad23-depleted Tetrahymena cell lines displayed significantly …

Size-Dependent Inhibitory Effects Of Antibiotic Nanocarriers On Filamentation Of E. Coli, Preeyaporn Songkiatisak, Feng Ding, Pavan Kumar Cherukuri, Xiao-Hong Nancy Xu

Chemistry & Biochemistry Faculty Publications

Multidrug membrane transporters exist in both prokaryotic and eukaryotic cells and cause multidrug resistance (MDR), which results in an urgent need for new and more effective therapeutic agents. In this study, we used three different sized antibiotic nanocarriers to study their mode of action and their size-dependent inhibitory effects against Escherichia coli (E. coli). Antibiotic nanocarriers (AgMUNH–Oflx NPs) with 8.6 × 10², 9.4 × 10³ and 6.5 × 10⁵ Oflx molecules per nanoparticle (NP) were prepared by functionalizing Ag NPs (2.4 ± 0.7, 13.0 ± 3.1 and 92.6 ± 4.4 nm) with a monolayer …

Efficient Conditional Inactivation Of Rdh10 Reveals Important Role Of Retinoic Acid During Lung Branching Morphogenesis., Nhut Quang Huy Tran

Electronic Theses and Dissertations

Birth defects are complicated pathological processes. Many birth defects can be traced back to disrupted regulation of molecular signaling pathways during embryogenesis. One of the most important gene regulatory factors during embryo development is retinoic acid (RA). However, studying the specific roles of RA in each organ during embryogenesis in vivo is challenging. The Sandell laboratory has a conditional mutant mouse model that can potentially be used for studying the role of RA during embryogenesis by inducing stage-specific RA deficiency. This model allows retinol dehydrogenase 10 (Rdh10), a gene required for RA production, to be inactivated at a …

Mouse Embryonic Stem Cells Are Sensitive To The Cytotoxicity Of Nitric Oxide: Biological Implications For Early Embryogenesis, Mckenzie C. Hargis

Honors Theses

The early embryo, before implantation, is at a very vulnerable stage in development where it faces various inflammatory cytokines throughout the implantation process. In this stage, the cells in the blastocyst, the preimplantation stage embryo, must proliferate rapidly for tissue formation. However, it is known that inflammatory cytokines can inhibit cell proliferation. Previous studies have shown that embryonic stem cells (mESCs), the major cell component in the blastocyst, are unresponsive to treatments of tumor necrosis factor ⍺ (TNF⍺) and interferon 𝛾 (IFN𝛾), two inflammatory cytokines involved in the implantation process. Treatment of mESC-differentiated fibroblasts (mESC-FBs) with TNF⍺ and IFN𝛾 in …

Motor Neuron Connections And Innervation Of Muscles In Drosophila Melanogaster, Sharon Tang

Student Theses and Dissertations

Drosophila melanogaster have two sets of muscle systems: larval muscles and adult muscles. The larval somatic muscle system is established during embryogenesis and is necessary for hatching, feeding, and crawling of the larvae. Like humans, Drosophila muscles have individual characteristics, like unique sizes, shapes, orientations, attachment sites, and innervation patterns by motor neurons. These properties are encoded by a group of transcriptional regulators that are expressed in specific muscle subsets. Currently, there are over twenty known transcription factors required for the development of the 30 distinct larval somatic muscles and specification of those muscle properties. We have examined how muscle-specific …

Development Of In Vitro Models To Study The Rapid Extraintestinal Dissemination Of Salmonella., Adarsh Gopinath

Electronic Theses and Dissertations

Salmonella appears in the bloodstream of mice in as little as 15 minutes after oral inoculation and establishes persistent colonies in the spleen and liver. While its pathway to blood is undetermined, this phenomenon is dependent on the activity of Salmonella pathogenicity island 2 (SPI-2) coded type III secretion system (T3SS) and CD18+ phagocytes. We hypothesize that dendritic cells associated with the basal face of the gut epithelium, that are naturally migratory and known to sample for luminal antigens directly transport Salmonella to the bloodstream. This process comprises of at least two phases, dissociation and reverse transmigration. We define dissociation …

Preliminary Study: Leucine Supplementation Exacerbates Muscle Wasting Independent Of The Ubiquitin-Proteasome System, Katarina Bejarano

Graduate Theses and Dissertations

Cancer cachexia is the rapid, drastic loss of muscle mass associated with cancer and is not reversible by conventional nutritional means (Brown et al., 2018; Brown et al., 2017). It occurs in ~80% of cancer patients and is responsible for 20-40% of cancer-related deaths (Brown et al., 2018; Brown et al., 2017). This condition leaves patients with fatigue, functional impairment, reduced quality of life, and a decrease in survival rates. Cachexia occurs through an imbalance between protein degradation and protein synthesis (Brown et al., 2018), which is associated with inflammation and altered metabolic processes.

Several studies have investigated the effects …

Elucidating The Developmental Defects In Zebrafish Associated With The Cardiac Drug Verapamil, Blake Stephan Justis

Graduate Theses/Dissertations

Birth defects are abnormalities in a developing organism that lead to a malformation in structure or function. Over half of birth defects have no determined cause; however, known causes occur by genetic anomalies, exposure to environmental agents (a.k.a. teratogens), or multifactorial reasons. To explain the unknown causes of birth defects, an area of focus in this study is to identify potential teratogens. Identifying these teratogens, is key to preventing future birth defects. An obvious source of teratogens in pregnant women would be that of pharmaceuticals. Thus, a main goal of this study is to identify drugs that cause birth defects. …

Myosin V-Mediated Cargo Traffic Toward The Trans-Golgi Network And Myosin V Implications In Snc1 Exocytosis, Vy Ngoc Khanh Nguyen

Graduate Theses/Dissertations

Retrieval of cargo proteins from the endosome towards the trans-Golgi network (TGN) is a crucial intracellular process for cellular homeostasis. Its dysfunction is associated with pathogenesis of Alzheimer and Parkinson's diseases. Myosin family proteins are cellular motors walking along actin filaments by utilizing the chemical energy from ATP hydrolysis, known to involve in pleiotropic cellular trafficking pathways. However, the question of whether myosins play a role in the trafficking of Snc1 and Vps10 has not been addressed yet. The present study assesses the potential roles of all five yeast myosins in the recycling of two membrane cargo, Snc1 and …

Characterizing Erad And Antioxidant Response In Ixodes Scapularis Ise6 Cells During Borrelia Infection, Latoyia Downs

Master's Theses

Ticks are hematophagous ectoparasites that transmit a multitude of diseases to humans. Borrelia burgdorferi (BB) and Borrelia miyamotoi (BM) are both tick-borne pathogens that cause disease in humans and are transmitted by the black-legged tick (Ixodes scapularis). A byproduct of blood digestion generates reactive oxygen species that are toxic and cause oxidative stress which promotes cellular damage and dysfunction. The endoplasmic reticulum (ER) is especially affected by oxidative stress, resulting in a buildup of improperly folded proteins in the ER lumen called ER stress. To prevent cellular damage, the tick utilizes an antioxidant system to neutralize ROS and mechanisms …

Inhibition Of The Spectraplakin Protein Microtubule Actin Crosslinking Factor 1 Sensitizes Glioblastomas To Radiation, Kala Bonner, Danielle Borlay, Orica Kutten, Quincy A. Quick

Biology Faculty Research

Background

Microtubule actin crosslinking factor 1 (MACF1) is a spectraplakin cytoskeletal crosslinking protein whose function and role in cancer biology has lacked investigation. Recent studies have identified MACF1 as a novel target in glioblastomas expressed in tissue from tumor patient explants but not normal brain tissue and when silenced has an antitumorigenic impact on these tumors. Radiation as a single agent therapy to treat glioblastomas has been used for decades and has done little to improve survival of individuals diagnosed with this disease. However, contemporary clinical radiotherapy protocols have provided evidence that combinatorial radiotherapy approaches confer a therapeutic benefit in …

An Analysis Of Crispr-Cas Gene Editing In Agriculture, Ashley Laliberte

Honors Scholar Theses

The CRISPR-Cas system is a promising form of gene editing, especially for the agriculture industry. The ability to make single-nucleotide edits within a gene of interest, without the need to introduce foreign DNA, is a powerful tool for designing healthier and more efficient crops and food animals. This system provides opportunity for increased nutritional value, decreased food waste, and more economically and environmentally sustainable food production. Though this biotechnology is facing mechanistic limitations due to off-target effects and inefficient homology-directed repair, vast improvements have already been made to improve its efficacy. The CRISPR-Cas system is already the most advanced form …

Otx2 Represses Sister Cell Fate Choices In The Developing Retina To Promote Photoreceptor Specification, Miruna Georgiana Ghinia Tegla, Diego F. Buenaventura, Diana Y. Kim, Cassandra Thakurdin, Kevin C. Gonzalez, Mark M. Emerson

Publications and Research

During vertebrate retinal development, subsets of progenitor cells generate progeny in a non-stochastic manner, suggesting that these decisions are tightly regulated. However, the gene-regulatory network components that are functionally important in these progenitor cells are largely unknown. Here we identify a functional role for the OTX2 transcription factor in this process. CRISPR/Cas9 gene editing was used to produce somatic mutations of OTX2 in the chick retina and identified similar phenotypes to those observed in human patients. Single cell RNA sequencing was used to determine the functional consequences OTX2 gene editing on the population of cells derived from OTX2-expressing retinal progenitor …

Cd11b+ Depletion Of Bone Marrow Derived Macrophages Negatively Affects Bone Fracture Healing, Sarah Hozain

Seton Hall University Dissertations and Theses (ETDs)

Hematoma formation and inflammation occurs during the beginning stages of fracture repair, which require the presence of innate cells such as macrophages. Macrophages are subdivided into proinflammatory, M1, or anti-inflammatory, M2, phenotypes with different functions, cytokine profiles, and surface markers. In this study, in vitro and in vivo models were used to deplete M1 macrophages, using Mac-1 Sap conjugated antibody (Mac1SAP), to determine the effects on fracture healing. In vitro study, primary macrophages isolated from mice femoral bone marrow were harvested and differentiated into M1 macrophages (+LPS), M2 macrophages (+IL-4), or undifferentiated then treated with either vehicle or 10pM Mac1SAP. …