Immunopathology Commons^™

Comparative Spatial Biology: A Cross-Species Analysis Of Canine Oral Cancers As Models For Human Disease, Ram Pradhyumnan

Honors Undergraduate Theses

Oral squamous cell carcinoma (OSCC), one of the most common malignancies of the oral cavity, remains a clinically challenging disease due to its aggressive behavior, late-stage diagnosis, and limited improvements in therapeutic outcomes over recent decades. A significant barrier to progress in OSCC research and treatment is the lack of suitable preclinical models that recapitulate the complexity and natural progression of the disease. Most current models—including cell lines, xenografts, and genetically engineered mice—fail to capture key features such as the spatial organization of tumor epithelium, interactions with an intact immune system, and the stepwise evolution from normal mucosa to invasive …

Investigating The Ability Of Foxo1 To Maintain Stem Cells, Stella A. Rios, Megan E. Keniry

Research Symposium

Background: Our group discovered that FOXO transcription factors drive stem gene expression in cancer to promote aggressiveness. Work by our group and others demonstrated that FOXO factors universally maintain stem cells including in cancer, embryonic, hematogenic and neuronal contents. Our current efforts are delineating the molecular underpinnings by which FOXO factors halt differentiation to maintain stem cells.

In this project, we are employing myoblasts as a valuable model to examine how Foxo1 maintains stem cells. Foxo1-regulated genes in myoblasts closely parallel its targets in glioblastoma and basal breast cancer stem cells, including targets such as Leukemia Inhibitory Factor, …

Combination Therapy Of Ido1 Inhibition And Anti-Pd1 Mediates Anti-Tumor Immunity By Promoting Memory Immunity Development And Cytotoxicity Of Γδ T And Nk Cells Via Il-2 Signaling And By Overcoming Pro-Tumor Effects Of Tgf-Β Signaling, Hyuk Jee

Dartmouth College Master’s Theses

Cutaneous melanoma is the most aggressive form of skin cancer even though it takes only about 1% of all skin cancers. Even among all cutaneous melanomas, NRAS-mutant melanoma is more aggressive than any other, and about 10-25% of all cutaneous melanoma cases have mutations in NRAS. NRAS is a member of the RAS family of proto-oncogenic GTPase proteins, and it plays a key role in signal transduction pathways responsible for cellular survival, proliferation, and metabolism. Immunotherapy is the first line of defense against NRAS-mutant melanoma because, despite tremendous efforts made for decades, it has not been successful to develop small …

Mucins: Drivers Of Cancer Cell And Microenvironment Crosstalk In Pancreatic Cancer, Xiaoqi Li

Theses & Dissertations

Mucins facilitate the pancreatic cancer (PC) initiation, progression, and metastasis. Among mucins, MUC4 has been reported to inhibit lymphokine-activated cell killing and induce the apoptosis of cytotoxic T-cells. Counterintuitively, MUC4 expression is upregulated by multiple T-cell-secreted cytokines, such as IFN-γ, IL-17, and stroma-secreted factors like retinoic acid. Previously, we have identified that nuclear receptor coactivator 3 (NCOA3) regulates the MUC1 and MUC4 expression by increasing chromatin accessibility and maintaining protein stability. However, the comprehensive crosstalk mediated by MUC4 in cancer cells and T-cells and how its upstream regulator, NCOA3, modifies the cancer cell-intrinsic behavior is still elusive. Here, we show …

Remodeling Anaplastic Thyroid Cancer's Aggressive Profile And Metabolic Signature By Natural Alkaloid Berberine, Tara Elizabeth Jarboe

NYMC Student Theses and Dissertations

Anaplastic thyroid cancer is a rare, fatal cancer with a five-year survival of 4%. Universally diagnosed at stage IV, anaplastic thyroid cancer is characterized by its lack of differentiation, rapid proliferative rate, highly inflammatory tumor microenvironment, and metabolic dysregulation. Refractory to all established therapies, anaplastic thyroid cancer requires a novel therapeutic approach that targets all of these drivers of anaplastic thyroid cancer carcinogenesis. We propose natural alkaloid berberine as a therapeutic with multitarget efficacy to alter mitochondrial metabolism and reprogram anaplastic thyroid cancer’s aggressive phenotype. Our in vitro model uses monocyte cell line U937, anaplastic thyroid cancer cell lines T238 …

The Hepatic Immunological Pattern Shaped By Dominant-Subdominant Cellular Interactions Creates A Collective Function Beyond The Function Of Each Cellular Constituent To Orchestrate Progression Of Hepatocellular Carcinoma, Nicholas J. Koelsch

Theses and Dissertations

Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of taking reductionist approaches and missing the collective function of the hepatic immune system by focusing on specific immune cell types. To this end, we propose that focusing on the dominant-subdominant patterns of the immune cells would allow understanding of the mechanism by which a collective immune function emerges. To identify the collective immune function through a systems immunology perspective, we performed high-throughput analysis of snRNAseq data collected …

A High-Throughput Approach To Characterizing Arv1 On The Regulation Of Lipid Homeostasis Uncovers A Novel Interaction With Epidermal Growth Factor Receptor, Nicholas Anthony Wachowski

Graduate School of Biomedical Sciences Theses and Dissertations

Acyl-CoA cholesterol acyl transferase related enzyme-2 required for viability 1 (ARV1) was first recognized in Saccharomyces cerevisiae in a study done in 2000 by Tinkelenberg et al. In yeast, the deletion of ARV1 results in numerous defects including abnormal sterol trafficking [1], the reduction of sphingolipid metabolism [2], synthesis of glycosylphosphatidylinositol (GPI) anchor [3], ER stress [4], and hypersensitivity of fatty acids leading to lipoapoptosis [5]. Arv1 germline deletion in mice displayed a lean phenotype with increased energy [6]. In humans, ARV1 mutations lead to epileptic encephalopathy [7].

Non-alcoholic fatty liver disease (NAFLD) consists of simple steatosis to non-alcoholic steatohepatitis …

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). …

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 …

Il-17-Cxcr2 Axis Promotes Breast Cancer Metastasis And Therapy Resistance, Lingyun Wu

Theses & Dissertations

Cancer-related fatalities rank as the second leading cause of death in all ages and both genders in the United States. Moreover, breast cancer-related mortality rank as the second leading cause of death in females in the United States in 2019. The main concerns regarding breast cancer management include chemotherapy resistance and metastasis. Thus, the advanced understanding of cancer progression is required to develop improved therapeutic methods for breast cancer patients.

Recent studies demonstrate that neutrophils, as the most abundant leukocytes, play an essential role in breast progression. However, the mechanisms regarding neutrophils recruitment to the tumor sites, and the precise …

A High Throughput Assay For The Detection Of Stimulator Of Interferon Genes (Sting) Agonists, Michael J. Ingling

Graduate School of Biomedical Sciences Theses and Dissertations

The innate immune system includes a menagerie of different cell types, each with a different role in the process of monitoring the body for invaders and presenting gathered debris (antigen) to the adaptive immune system. Somatic cells have intracellular receptors for the same purpose. Cancer cells, however, have avoided these methods of detection despite, in many cases, the tumor’s immunogenic traits. Immuno-oncology is a field dedicated to the immunological traits of tumors, more recently finding ways of instigating an immune response against tumors. In this regard, STING, a receptor of cyclic dinucleotides (CDN), has come to the forefront of immuno-oncology. …

The Cxcr2-Dependent Role Of Cancer-Associated Fibroblasts In Pancreatic Ductal Adenocarcinoma, Mohammad Awaji

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, the fourth leading cause of cancer-related deaths in the USA with over 40,000 deaths per year. Unlike other major cancer types, the progress in dealing with PDAC is plodding, attributed mainly to the asymptomatic nature of the disease, the late diagnosis and the ineffectiveness of current therapies. A better understanding of the biology of the disease could permit the discovery of novel diagnostic and therapeutic tools. With that in mind, we present this dissertation that investigates the tumor-stromal interaction underlined by genetic alterations and inflammation. PDAC develop as …

Evaluating The Effects Of Antibody-Conjugated Multi-Walled Carbon Nanotubes In Combination With Microwave Irradiation, Amy Chall

College of Graduate Studies: Theses & Dissertations

Cancer remains one of the largest public health concerns of our day, particularly in developed countries where technological advances have allowed populations to live well into their eighth decade. In America, those in their 80’s have a 1 in 2 chance of developing cancer in their lifetime. Prostate cancer, specifically is the second leading cause of cancer deaths in males. Traditional cancer therapies cause high levels of toxicity to the patient due to mechanisms of action that often attack cancer cells and healthy cells alike. The holy grail of cancer research is to find a treatment that targets the cancer …

Characterizing Chromosomal Aberrations In Cells Deficient For Both Atm And Msh2, Yeliz Inalman

Dissertations and Theses

Ataxia telangiectasia mutated (ATM) and mutS homologue 2 (MSH2) are important DNA repair proteins that participate in DNA repair pathways to maintain genomic integrity. Mice deficient for ATM and MSH2 mice are viable. However, ATM^-/- mice show growth retardation, neurological defects, and spontaneous lymphomagenesis. MSH2^-/- mice suffer from aggressive lymphoid tumors between two to five months of age and have increased microsatellite instability, which predisposes MSH2^-/- mice to carcinomas. However, mice deficient in both ATM and MSH2 are unable to survive beyond postnatal day 21 (P21). The observed lethality in ATM^-/-MSH2^-/- mice may result …

Regulatory T Cells Promote Breast Cancer Progression Through Inhibiting Classical Activation Of Macrophages, Nicholas M. Clark

Theses and Dissertations

Transient ablation of regulatory T cells has been shown to be effective at hindering tumor growth and metastasis in murine breast cancer model. Based on our lab’s previous work, we have demonstrated that NK cells and CD8+ cytotoxic T cells were not required for the protective effect of Treg cell ablation. However, we also reported that CD4+ helper T cells and IFN-γ were required for the protective effect of Treg cell ablation. Furthermore, we observed that CD11B+ cells responded to Treg ablation therapy by up-regulating target genes of IFN-γ. Therefore, this study aimed to investigate the connection between the myeloid …

Hepatocyte-Specific Deletion Of Tristetraprolin Family Of Rna Binding Proteins Result In The Development Of Hepatocellular Carcinomas, Sonika Patial

Hepatobiliary Cancers: Pathobiology and Translational Advances

No abstract provided.

Development Of Cellular Assays To Monitor Enzymatic And Biological Activity Of Cd73: A Key Modulator Of Anti-Tumor Immune Response, Alexandra Fanuka

Graduate School of Biomedical Sciences Theses and Dissertations

Ecto-5’-nucleotidase, known as CD73, is an extracellular enzyme that converts adenosine monophosphate (AMP) to adenosine and has recently been identified as a potential drug target for cancer immunotherapy. Its immunosuppressive effects, mediated by the activity of adenosine, are associated with higher rates of tumor invasion and metastasis, as well as poorer prognoses overall in many cancer types. CD73 is often co-expressed with ectonucleoside triphosphate diphosphohydrolase-1 (CD39), which catalyzes the conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP), and ADP to AMP on the surface of tumor cells. Dual expression further propagates immunosuppressive effects of adenosine in the tumor microenvironment. …

Novel Role Of Prostate Apoptosis Response-4 Tumor Suppressor In B-Cell Chronic Lymphocytic Leukemia, Mary Kathryn Mckenna

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Chronic Lymphocytic Leukemia (CLL) is defined by the accumulation of clonally expanded CD5+ and CD19+ B lymphocytes in blood and secondary lymphoid organs with impaired apoptotic mechanisms. CLL represents one third of all leukemia cases with an average age of 72 years at diagnosis making it the most common adult leukemia. The Eµ-Tcl1 mouse serves as an excellent model to study the development of CLL as they progress to a CLL like disease by 9-14 months of age, due to overexpression of an oncogene, T cell Leukemia 1(Tcl1), specifically in B cells through the Ig VH promoter and Eµ enhancer …

Defining The Role Of Interferon Regulatory Factor 4 In Chronic Lymphocytic Leukemia., Vipul Shukla

Theses & Dissertations

Chronic Lymphocytic Leukemia (CLL) represents the most common adult leukemia in the Western hemisphere. Despite considerable progress in our current understanding of CLL, this disease remains incurable and the molecular events underlying the complex pathogenesis of CLL are not fully elucidated. Interferon Regulatory Factor 4 (IRF4) belongs to the IRF superfamily of transcription factors that has been shown to play critical roles at multiple stages of B cell development. Interestingly, a Genome Wide Association Study identified Single Nucleotide Polymorphism (SNP) mediated IRF4 down regulation, as a major predisposing genetic event during the development of CLL. However, whether low levels of …

Automated Assessment Of Disease Progression In Acute Myeloid Leukemia By Probabilistic Analysis Of Flow Cytometry Data, Bartek Rajwa, Paul K. Wallace, Elizabeth A. Griffiths, Murat Dundar

Bindley Publications

Objective: Flow cytometry (FC) is a widely acknowledged technology in diagnosis of acute myeloid leukemia (AML) and has been indispensable in determining progression of the disease. Although FC plays a key role as a post-therapy prognosticator and evaluator of therapeutic efficacy, the manual analysis of cytometry data is a barrier to optimization of reproducibility and objectivity. This study investigates the utility of our recently introduced non-parametric Bayesian framework in accurately predicting the direction of change in disease progression in AML patients using FC data. Methods: The highly flexible non-parametric Bayesian model based on the infinite mixture of infinite Gaussian …

Chronic Inflammation As A Result Of Hepatitis C Virus Infection: A Review Of The Literature, Samantha L. Lane

DePaul Discoveries

Approximately 170 million people are infected with Hepatitis C virus (HCV) worldwide^5,6. It is estimated that roughly 80% of those infected suffer from persistent infection with the virus; this persistence of infection is progressive, and over time can lead to fibrosis, cirrhosis, and hepatocellular carcinoma⁷. Chronic inflammation and apoptotic deregulation are both hallmarks of chronic HCV infection, and many molecular pathways are initiated in both the innate and adaptive immune responses during infection with this viral pathogen. The aim of this review was to survey some of the major molecular mechanisms responsible for the induction of …

Phthalates And Phthalate Alternatives: Effects On Proliferative And Estrogenic Target Genes In Ishikawa Cells, Ranjani Sundar '15, Ping Yin, Serdar E. Bulun

Student Publications & Research

Phthalates are used as plasticizers in many of the products found in medical, household, and industrial applications. Much research has not been completed on the effects of these phthalates as potential endocrine disrupting chemicals (EDCs). As these chemicals are ingested, the mechanism by which they affect the reproductive system is largely unknown. The purpose of this study was to observe how 2 phthalates, Di-n-butyl phthalate (DBP) and Diisononyl phthalate (DINP), and 2 phthalate alternatives, Dioctyl terephthalate (DOTP) and BHT (butylated hydroxytoluene)affect uterine cells in comparison to a vehicle treatment and 17β-Estradiol treatment. Changes in expression of mRNA were observed using …

Resistance Of Human Cytomegalovirus To Cyclopropavir Maps To A Base Pair Deletion In The Open Reading Frame Of Ul97, Brian G. Gentry, Laura E. Vollmer, Ellie D. Hall, Katherine Z. Borysko, Jiri Zemlicka, Jeremy P. Kamil, John C. Drach

Oncology Faculty Publications

Human cytomegalovirus (HCMV) is a widespread pathogen in the human population, affecting many immunologically immature and immunocompromised patients, and can result in severe complications, such as interstitial pneumonia and mental retardation. Current chemotherapies for the treatment of HCMV infections include ganciclovir (GCV), foscarnet, and cidofovir. However, the high incidences of adverse effects (neutropenia and nephrotoxicity) limit the use of these drugs. Cyclopropavir (CPV), a guanosine nucleoside analog, is 10-fold more active against HCMV than GCV (50% effective concentrations [EC₅₀s] = 0.46 and 4.1 μM, respectively). We hypothesize that the mechanism of action of CPV is similar to that …

Activation Of Amp-Activated Protein Kinase By 3,39-Diindolylmethane (Dim) Is Associated With Human Prostate Cancer Cell Death In Vitro And In Vivo, Di Chen, Sanjeev Banerjee, Qiuzhi C. Cui, Dejuan Kong, Fazlul H. Sarkar, Q. Ping Dou

Oncology Faculty Publications

There is a large body of scientific evidence suggesting that 3,39-Diindolylmethane (DIM), a compound derived from the digestion of indole-3-carbinol, which is abundant in cruciferous vegetables, harbors anti-tumor activity in vitro and in vivo. Accumulating evidence suggests that AMP-activated protein kinase (AMPK) plays an essential role in cellular energy homeostasis and tumor development and that targeting AMPK may be a promising therapeutic option for cancer treatment in the clinic. We previously reported that a formulated DIM (BR-DIM; hereafter referred as B-DIM) with higher bioavailability was able to induce apoptosis and inhibit cell growth, angiogenesis, and invasion of prostate cancer cells. …