Digital Commons Network^™

Aav-Crispr Gene Editing Is Negated By Pre-Existing Immunity To Cas9, Ang Li, Mark R Tanner, Ciaran M Lee, Ayrea E Hurley, Marco De Giorgi, Kelsey E Jarrett, Timothy H Davis, Alexandria M Doerfler, Gang Bao, Christine Beeton, William R Lagor

Faculty, Staff and Students Publications

Adeno-associated viral (AAV) vectors are a leading candidate for the delivery of CRISPR-Cas9 for therapeutic genome editing in vivo. However, AAV-based delivery involves persistent expression of the Cas9 nuclease, a bacterial protein. Recent studies indicate a high prevalence of neutralizing antibodies and T cells specific to the commonly used Cas9 orthologs from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in humans. We tested in a mouse model whether pre-existing immunity to SaCas9 would pose a barrier to liver genome editing with AAV packaging CRISPR-Cas9. Although efficient genome editing occurred in mouse liver with pre-existing SaCas9 immunity, this was accompanied by …

Wolff-Parkinson-White Syndrome: De Novo Variants And Evidence For Mutational Burden In Genes Associated With Atrial Fibrillation, Zeynep H Coban-Akdemir, Wu-Lin Charng, Mahshid Azamian, Ingrid S Paine, Jaya Punetha, Christopher M Grochowski, Tomasz Gambin, Santiago O Valdes, Bryan Cannon, Gladys Zapata, Patricia P Hernandez, Shalini Jhangiani, Harsha Doddapaneni, Jianhong Hu, Fatima Boricha, Donna M Muzny, Eric Boerwinkle, Yaping Yang, Richard A Gibbs, Jennifer E Posey, Xander H T Wehrens, John W Belmont, Jeffrey J Kim, Christina Y Miyake, James R Lupski, Seema R Lalani

Faculty, Staff and Student Publications

BACKGROUND: Wolff-Parkinson-White (WPW) syndrome is a relatively common arrhythmia affecting ~1-3/1,000 individuals. Mutations in PRKAG2 have been described in rare patients in association with cardiomyopathy. However, the genetic basis of WPW in individuals with a structurally normal heart remains poorly understood. Sudden death due to atrial fibrillation (AF) can also occur in these individuals. Several studies have indicated that despite ablation of an accessory pathway, the risk of AF remains high in patients compared to general population.

METHODS: We applied exome sequencing in 305 subjects, including 65 trios, 80 singletons, and 6 multiple affected families. We used de novo analysis, …

Functional Heterogeneity And Metabolic Adaptation Of Fibroblasts In Cancer, Lisa Becker

Dissertations and Theses (Open Access)

The tumor microenvironment is comprised of a multitude of cell types producing a milieu of cytokines, growth factors an extracellular matrix. Together, this intricate network of cells plays highly critical roles in determining a tumor’s potential to progress and metastasize. As the predominant cell types in the tumor microenvironment, cancer-associated fibroblasts (CAFs) are a key component in the regulation of tumor development and progression, but their exact functions in tumorigenesis remain poorly understood. This is partly due to the considerable heterogeneity amongst these cells, which confounds the characterization of their roles within the tumor microenvironment. Nevertheless, recent studies have provided …

Role Of Micro-Rna For Pain After Surgery: Narrative Review Of Animal And Human Studies, Juan P Cata, Aysegul Gorur, Xiaoyi Yuan, Nathaniel K Berg, Anil K Sood, Holger K Eltzschig

Faculty, Staff and Student Publications

One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate …

Hypoxia-Inducible Factor (Hif)-2Α Reprograms Liver Macrophages To Protect Against Acute Liver Injury Via The Production Of Interleukin-6, Rachel Y Gao, Meng Wang, Qihui Liu, Dechun Feng, Yankai Wen, Yang Xia, Sean P Colgan, Holger K Eltzschig, Cynthia Ju

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Acetaminophen (APAP) overdose represents the most frequent cause of acute liver failure, resulting in death or liver transplantation in more than one third of patients in the United States. The effectiveness of the only antidote, N-acetylcysteine, declines rapidly after APAP ingestion, long before patients are admitted to the clinic with symptoms of severe liver injury. The direct hepatotoxicity of APAP triggers a cascade of innate immune responses that may exacerbate or limit the progression of tissue damage. A better understanding of this complex mechanism will help uncover targets for therapeutic interventions.

APPROACH AND RESULTS: We observed that …

Discovery Of A Selective Inhibitor Of Doublecortin Like Kinase 1, Fleur M Ferguson, Behnam Nabet, Srivatsan Raghavan, Yan Liu, Alan L Leggett, Miljan Kuljanin, Radha L Kalekar, Annan Yang, Shuning He, Jinhua Wang, Raymond W S Ng, Rita Sulahian, Lianbo Li, Emily J Poulin, Ling Huang, Jost Koren, Nora Dieguez-Martinez, Sergio Espinosa, Zhiyang Zeng, Cesear R Corona, James D Vasta, Ryoma Ohi, Taebo Sim, Nam Doo Kim, Wayne Harshbarger, Jose M Lizcano, Matthew B Robers, Senthil Muthaswamy, Charles Y Lin, A Thomas Look, Kevin M Haigis, Joseph D Mancias, Brian M Wolpin, Andrew J Aguirre, William C Hahn, Kenneth D Westover, Nathanael S Gray

Faculty, Staff and Students Publications

Doublecortin like kinase 1 (DCLK1) is an understudied kinase that is upregulated in a wide range of cancers, including pancreatic ductal adenocarcinoma (PDAC). However, little is known about its potential as a therapeutic target. We used chemoproteomic profiling and structure-based design to develop a selective, in vivo-compatible chemical probe of the DCLK1 kinase domain, DCLK1-IN-1. We demonstrate activity of DCLK1-IN-1 against clinically relevant patient-derived PDAC organoid models and use a combination of RNA-sequencing, proteomics and phosphoproteomics analysis to reveal that DCLK1 inhibition modulates proteins and pathways associated with cell motility in this context. DCLK1-IN-1 will serve as a versatile tool …

Myeloma Cells Shift Osteoblastogenesis To Adipogenesis By Inhibiting The Ubiquitin Ligase Murf1 In Mesenchymal Stem Cells, Zhiqiang Liu, Huan Liu, Jin He, Pei Lin, Qiang Tong, Jing Yang

Faculty, Staff and Students Publications

The suppression of bone formation is a hallmark of multiple myeloma. Myeloma cells inhibit osteoblastogenesis from mesenchymal stem cells (MSCs), which can also differentiate into adipocytes. We investigated myeloma-MSC interactions and the effects of such interactions on the differentiation of MSCs into adipocytes or osteoblasts using single-cell RNA sequencing, in vitro co-culture, and subcutaneous injection of MSCs and myeloma cells into mice. Our results revealed that the α4 subunit of integrin on myeloma cells stimulated vascular cell adhesion molecule 1 (VCAM1) on MSCs, leading to the activation of protein kinase C β1 (PKCβ1) signaling and repression of the muscle ring-finger …

Age-Dependent Involvement Of Gut Mast Cells And Histamine In Post-Stroke Inflammation, Maria Pilar Blasco, Anjali Chauhan, Pedram Honarpisheh, Hilda Ahnstedt, John D'Aigle, Arunkumar Ganesan, Sriram Ayyaswamy, Frank Blixt, Susan Venable, Angela Major, David Durgan, Anthony Haag, Julia Kofler, Robert Bryan, Louise D Mccullough, Bhanu Priya Ganesh

Faculty, Staff and Students Publications

BACKGROUND: Risk of stroke-related morbidity and mortality increases significantly with age. Aging is associated with chronic, low-grade inflammation, which is thought to contribute to the poorer outcomes after stroke seen in the elderly. Histamine (HA) is a major molecular mediator of inflammation, and mast cells residing in the gut are a primary source of histamine.

METHODS: Stroke was induced in male C57BL/6 J mice at 3 months (young) and 20 months (aged) of age. Role of histamine after stroke was examined using young (Yg) and aged (Ag) mice; mice underwent MCAO surgery and were euthanized at 6 h, 24 h, …

Tfeb Regulates Murine Liver Cell Fate During Development And Regeneration, Nunzia Pastore, Tuong Huynh, Niculin J Herz, Alessia Calcagni', Tiemo J Klisch, Lorenzo Brunetti, Kangho Ho Kim, Marco De Giorgi, Ayrea Hurley, Annamaria Carissimo, Margherita Mutarelli, Niya Aleksieva, Luca D'Orsi, William R Lagor, David D Moore, Carmine Settembre, Milton J Finegold, Stuart J Forbes, Andrea Ballabio

Faculty, Staff and Students Publications

It is well established that pluripotent stem cells in fetal and postnatal liver (LPCs) can differentiate into both hepatocytes and cholangiocytes. However, the signaling pathways implicated in the differentiation of LPCs are still incompletely understood. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is known to be involved in osteoblast and myeloid differentiation, but its role in lineage commitment in the liver has not been investigated. Here we show that during development and upon regeneration TFEB drives the differentiation status of murine LPCs into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation. Genetic interaction studies show that …

Proteolysis-Targeting Chimera (Protac) For Targeted Protein Degradation And Cancer Therapy, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several …

Physician Hospital Arrangement Influence On Nonprofit Hospital Quality,Financial Performance And Community Benefit Expenditures, Andrea Cervin

Dissertations and Theses (Open Access)

Federal policy has encouraged hospitals to provide certain quality outcomes and cost containment. Hospitals have responded by forming physician hospital organizations in attempts to achieve quality outcomes and capture reimbursements. At the same time, federal policy has awarded hospitals with nonprofit status with the requirement to provide community benefits in exchange for the tax exemption they receive. With the formation of physician hospital organizations, there remains the question of whether hospitals are achieving desired quality metrics and whether hospitals are financially viable. There is also public and media interest recently regarding whether nonprofit hospitals fulfill their obligations for community benefit …

Determining The Drivers Of Quality Of Life In Hiv Patints Treated With Antiretroviral Therapy In Subsaharan Africa, Oubote Sangbana

Dissertations and Theses (Open Access)

During the last decade, HIV in sub-Saharan Africa has shifted from a fatal disease to a chronic condition thanks to the expansion of antiretroviral therapy (ART). As a result, the focus of care has transitioned from survival to quality of life (QoL), and the latter has become a significant outcome measure during patient follow up. Yet, the determinants of QoL among HIV patients in western and central Africa are not well known. The objective of this dissertation was to determine the main factors associated with QoL among ART-treated HIV adult patients in western and central Africa to ensure healthcare providers …

Effects Of Penfluridol On Integrin-Fak Signaling And Tumor Cell Killing In Combination With Oncolytic Hsv In Glioblastoma, Mitra Nair

Dissertations and Theses (Open Access)

Integrins are known to play an important role in activating multiple intracellular pathways, one of which is focal adhesion kinase (FAK). Phosphorylation of FAK can lead to the activation of various downstream signaling pathways that can increase tumor cell growth and proliferation, making it an ideal target for cancer therapeutics. Due to the fact that many FAK inhibitors are limited in their penetration of the blood brain barrier, we investigated the use of Penfluridol, an antipsychotic drug known to attenuate integrin expression at a transcriptional level, in combination with oncolytic herpes simplex I virus (oHSV) in a glioblastoma model. We …

Economic Evaluation Of Implementing Hpv Vaccine Promotion Interventions For Cervical Cancer In The United States, Chi-Fang Wu

Dissertations and Theses (Open Access)

The HPV vaccine has been proven as a safe and effective method for preventing cervical cancer. However, the HPV vaccine coverage rate in the U.S. is suboptimal. Various interventions have been implemented to improve HPV vaccine coverage. However, evidence of the cost-effectiveness of HPV vaccine promotion interventions is lacking. We conducted an economic evaluation to assess HPV vaccine promotion interventions of cervical cancer in the U.S. Firstly, a systematic review was conducted to review evidence on interventions aimed at increasing HPV vaccine coverage and to summarize the cost and effectiveness of these interventions. We included 56 HPV vaccine promotion studies …

Comparison Of Interactive Electronic Versus Standard Document Method For Obtaining Patient Informed Consent, Jermaine Mcmillan

Dissertations and Theses (Open Access)

The primary objective of this study was to determine whether participants who received an interactive electronic consent (EC) had a better understanding of a medical procedure (apheresis) compared to those who received the standard document (SD) consent. The study was conducted with apheresis donors whose responses were used to determine if the EC facilitated better comprehension and retention of consent information by the study participants than by SD consenting methods. By comprehension, the goal was to have participants who can understand, summarize, or make judgments based on the content presented in the informed consent. By retention, the goal was to …

The Intersection Of Diet, Health And The Environment: Plant Based Diets And Public Health, Christine E. Jovanovic

Dissertations and Theses (Open Access)

Both globally and within the United States, chronic disease has become a major driver of mortality and morbidity. In the United States in 2017, the top ten causes of mortality accounted for 74% of all deaths [2]; of these causes, half are closely linked to diet (heart disease, cancer, stroke, Alzheimer’s and diabetes). [3] In 2013, Ioannidis estimated that 26% of deaths and 14% of disability adjusted life years (DALYs) in the United States may be attributable to dietary risk factors, controlling for obesity. [4] At the same time, diet also has an important impact on the environment. Direct emissions …

Personalized Estimation And Causal Inference Via Deep Learning Algorithms, Yuanyuan Liu

Dissertations and Theses (Open Access)

Personalized approaches have shown great potential to transform modern medicine. As challenging as it may sound, we are making tremendous progress with the help of data sciences and machine learning. Two fundamental tasks in data sciences are prediction and inference. In this dissertation, I proposed to address these two tasks using deep learning approaches in the setting of personalized medicine. First, I developed a novel framework to estimate individualized treatment effects (ITE), which quantified the variation in response to the same treatment among patients with heterogeneous profiles. The ITE estimation has the potential to replace the one-size-fits-all average treatment effects …

The Role Of Dna Methylation In White Matter Hyperintensity Burden: An Integrative Approach, Yunju Yang

Dissertations and Theses (Open Access)

Cerebral white matter hyperintensities (WMH) on MRI are an indicator of cerebral small vessel disease, a major risk factor for vascular dementia and stroke. DNA methylation may contribute to the molecular underpinnings of WMH, which are highly heritable. We performed a meta-analysis of 11 epigenome-wide association studies in 6,019 middle-aged to elderly subjects, who were free of dementia and stroke and were of African (AA) or European (EA) descent. In each study, association between WMH volume and each CpG was tested within ancestry using a linear mixed model, adjusted for age, sex, total intracranial volume, white blood cell count, technical …

The Influence Of Sodium And Potassium On Blood Pressure Genetics In The Population Architecture Using Genomics And Epidemiology Study, Cynthia S. Bell

Dissertations and Theses (Open Access)

Multiple polymorphisms have shown associations with blood pressure (BP) levels and hypertension status, but the overall genetic effect on BP has been small and accounts for only a small fraction of the variation in population-wide BP characteristics. These weak associations of BP with genotype may not be attributable to the examining the “wrong” single nucleotide polymorphism (SNP) but may instead be the result of noisy BP phenotypes based on mmHg alone. Adding information from the underlying mechanisms of nutritional intake, reuptake, and excretion on BP may produce more informative BP phenotypes to study. To explore this complex relationship between diet, …

Estimating Children’S Health Risks From Recreational Beach Play Following An Oil Spill, Tanu K. Altomare

Dissertations and Theses (Open Access)

Environmental contamination from marine oil spills can have damaging impacts on ecosystems and human health. In 2010, an explosion of the Deepwater Horizon (DWH) oil drilling platform resulted in approximately 1,728 km of shoreline oiling. Existing research characterizes health risk from exposure to oil spill chemicals (OSCs) for adults; however, data on impacts to child health are limited. One objective of the Beach Exposure And Child HEalth Study (BEACHES), funded by the Gulf of Mexico Research Initiative, is to estimate health risks to children between walking and six years of age from exposure to OSCs in a post-oil spill scenario …

Using S-Predixcan To Identify Associations Of Genetically Determined Gene Expression Levels With Carotid Intima Media Thickness, Andy Bryan A Castaneda

Dissertations and Theses (Open Access)

The aim of the study was to identify associations between predicted gene expression levels using S-PrediXcan and carotid intima media thickness (cIMT) in order to elucidate the etiology of atherosclerosis. Further, we wanted to compare our results to those from a transcriptome wide association study (TWAS) that used actual gene expression levels in whole blood. For our analysis we used summary statistics from a GWAS of cIMT from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, tissue-specific gene expression profiles from the GTEx project, and S-PrediXcan prediction models. The TWAS of cIMT that we compared our …

Alternative Carbon Utilization As A Virulence Determinant For Candida Albicans, Robert Williams

Dissertations and Theses (Open Access)

Candida albicans is a polymorphic unicellular fungus that has evolved to proficiently colonize and infect mammals. A common constituent of the microbiome in the GI tract, mouth, vagina, and skin, C. albicans is also an opportunistic pathogen capable of causing a variety of mucosal infections and the life-threatening disseminated candidiasis. Systemic C. albicans infections are a serious and growing issue; the fungus is the fourth most common cause of nosocomial bloodstream infections which has a mortality rate reaching 50%. As antifungal resistance continues to rise, it is critical that I understand the molecular basis of disseminated fungal infections.

The phagocytes …

Estrogen Receptor-Α Expressing Neurons In The Ventrolateral Vmh Regulate Glucose Balance, Yanlin He, Pingwen Xu, Chunmei Wang, Yan Xia, Meng Yu, Yongjie Yang, Kaifan Yu, Xing Cai, Na Qu, Kenji Saito, Julia Wang, Ilirjana Hyseni, Matthew Robertson, Badrajee Piyarathna, Min Gao, Sohaib A Khan, Feng Liu, Rui Chen, Cristian Coarfa, Zhongming Zhao, Qingchun Tong, Zheng Sun, Yong Xu

Children’s Nutrition Research Center Staff Publications

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH …

Alternative Polyadenylation Modulates Expression Of Pro-Fibrotic Proteins And Contributes To Lung Fibrosis, Junsuk Ko

Dissertations and Theses (Open Access)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease which affects about 5 to 8 million individuals in the world. Despite the high prevalence, there is currently no cure for IPF, and the cause of this disease is still unclear. Our laboratory and collaborators have shown that nudix hydrolase 21 (NUDT21, which is also known as cleavage factor 25, CFIm25) is a key regulator of alternative polyadenylation (APA). NUDT21 depletion causes 3’UTR shortening via APA leading to enhanced mRNA stability and protein translation. This NUDT21 reduction promotes tumor growth in glioblastoma by enhancing expression of oncogenes. Cancer and IPF share …

Preclinical Studies Of A Novel Idh1 Inhibitor In Acute Myeloid Leukemia (Aml), Vivian Salama

Dissertations and Theses (Open Access)

LY3410738, a novel covalent Isocitrate Dehydrogenase 1 (IDH1) inhibitor in Acute Myeloid Leukemia, it is more effective than Ivosidenib (AG120) and has a potent anti-leukemic effect against IDH1 mutant acute myeloid leukemia in combination with Venetoclax (ABT-199).

Acute myeloid Leukemia (AML) is an aggressive neoplastic blood disorder characterized by proliferation of poorly differentiated cells of myeloid lineage. IDH1 is a cytoplasmic enzyme that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the citric acid cycle. Somatic gain-of-function mutations in IDH1 occur in ~10% of the newly diagnosed AML patients. The neo-enzymatic activity of mutant IDH1 results in accumulation …

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). …

Modulation Of Pi3k-Akt Pathway In Colorectal Cancer, Maliha Nusrat

Dissertations and Theses (Open Access)

The phosphatidylinositol-3-kinase (PI3K) signaling pathway is activated in 20-40% colorectal cancers (CRC) through PTEN loss (PTEN^loss) and PIK3CA mutations (PIK3CA^mut). Allosteric AKT inhibition with MK2206 monotherapy has been ineffective in CRC patients. We investigated the impact of MK2206 on pharmacodynamic (PD) markers and signaling pathways using reverse phase protein array (RPPA) on (1) paired tumor biopsies from a clinical trial of MK2206 in PI3K-altered metastatic CRC, (2) PTEN^lossCRC patient derived xenografts (PDX) treated with MK2206 or carrier, and (3) MK2206-treated cell lines. PD inhibition was deep in cell lines, less but significant in …

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 …