Biological Phenomena, Cell Phenomena, and Immunity Commons^™

Small-Molecule Inhibitor Of Af9/Enl-Dot1l/Af4/Aff4 Interactions Suppresses Malignant Gene Expression And Tumor Grow, Fangrui Wu, Shenyou Nie, Yuan Yao, Tong Huo, Xin Li, Xiaowei Wu, Jidong Zhao, Yi-Lun Lin, Yinjie Zhang, Qianxing Mo, Yongcheng Song

Faculty, Staff and Students Publications

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target.

Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological …

A Role For Endothelial Tissue-Nonspecific Alkaline Phosphatase In Blood-Tissue Barrier Health And Disease, Allison L. Brichacek

Graduate Theses, Dissertations, and Problem Reports (ETD)

Sepsis is a disorder that targets the microcirculation with significant effects at blood-tissue barriers such as the blood-brain barrier (BBB) and gut-vascular barrier (GVB). Intestinal barrier dysfunction is thought to be one of the most important contributors to multi-organ dysfunction in sepsis. As a common site of infection, the impaired gut allows the dissemination of bacteria, which exacerbates the disease pathophysiology, and can lead to long-term morbidity and mortality. The mechanisms that influence altered barrier permeability in the GVB in sepsis and other inflammatory disorders are not well understood. Tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity, which has been shown to …

Rapid Induction Of The Unfolded Protein Response And Apoptosis By Estrogen Mimic Ttc-352 For The Treatment Of Endocrine-Resistant Breast Cancer, Balkees Abderrahman, Philipp Y Maximov, Ramona F Curpan, Sean W Fanning, Jay S Hanspal, Ping Fan, Charles E Foulds, Yue Chen, Anna Malovannaya, Antrix Jain, Rui Xiong, Geoffrey L Greene, Debra A Tonetti, Gregory R J Thatcher, V Craig Jordan

Faculty, Staff and Students Publications

Patients with long-term estrogen-deprived breast cancer (BC), after resistance to tamoxifen or aromatase inhibitors develops, can experience tumor regression when treated with estrogens. Estrogen’s anti-tumor effect is attributed to apoptosis via the estrogen receptor (ER). Estrogen treatment can have unpleasant gynecological and non-gynecological adverse events thus the development of safer estrogenic agents remains a clinical priority. Here, we study synthetic selective estrogen mimics (SEMs) BMI-135 and TTC-352, and the naturally-occurring estrogen estetrol (E4), which are proposed as safer estrogenic agents compared to 17β-estradiol (E2), for the treatment of endocrine-resistant BC. TTC-352 and E4 are being evaluated in BC clinical trials. …

The Role Of Anti-Inflammatory Cytokine Interleukin-10 (Il-10) In Tauopathies, Lea L. Weston

Biomedical Sciences ETDs

Tauopathies are neurodegenerative diseases, including Alzheimer’s disease, that are associated with pathological accumulation of the microtubule associated protein tau (MAPT, or tau) (Lee et al., 2001). Abnormal hyperphosphorylated tau (pTau) strongly correlate with cognitive impairment (Nelson et al., 2012). Neuroinflammation is also associated with tauopathies (Gerhard et al., 2006b; Edison et al., 2008) and is implicated in driving tau pathology (Yoshiyama et al., 2007, Maphis et al., 2015b). Therefore, it is compelling to understand the role of anti-inflammatory cytokines in limiting neuroinflammation and tau pathology. Interleukin-10 (IL-10) is a well-established anti-inflammatory cytokine with roles in limiting inflammation in the central …

Trypanosoma Cruzi Modulates Piwi-Interacting Rna Expression In Primary Human Cardiac Myocytes During The Early Phase Of Infection, Kayla J. Rayford, Ayorinde Cooley, Ashutosh Arun, Girish Rachakonda, Yulia Kleschenko, Fernando Villalta, Siddharth Pratap, Maria F. Lima, Pius N. Nde

Publications and Research

Trypanosoma cruzi dysregulates the gene expression profile of primary human cardiomyocytes (PHCM) during the early phase of infection through a mechanism which remains to be elucidated. The role that small non-coding RNAs (sncRNA) including PIWI-interacting RNA (piRNA) play in regulating gene expression during the early phase of infection is unknown. To understand how T. cruzi dysregulate gene expression in the heart, we challenged PHCM with T. cruzi trypomastigotes and analyzed sncRNA, especially piRNA, by RNA-sequencing. The parasite induced significant differential expression of host piRNAs, which can target and regulate the genes which are important during the early infection phase. An …

The Effects Of Moderate-Severe Plaque Psoriasis On Patient Well-Being And Prevention Of Flares, Glenn Devera

Nursing | Senior Theses

Psoriasis is a chronic skin condition that is indicated by red, patchy and scaly skin that can be painful when irritated. Patients with psoriasis have an increased risk for a number of chronic diseases. Despite the expansion of treatments for moderate-to-severe psoriasis over the last decade, patients may still find that treatment strategies are not as successful, leaving them dissatisfied with their treatments. A relationship built upon trust between the nurse and the patient diagnosed with psoriasis may serve to help ensure optimal care. A comprehensive literature review was performed and found that best practices for patient management need to …

The Role Of Liver Sinusoidal Endothelial Cells In Liver Malady Homeostasis, Fatima Cabral

Department of Biochemistry: Dissertations, Theses, and Student Research

Current literature described techniques for the purification of liver cell types through text alone. The techniques described for the isolation of liver sinusoidal endothelial cells as well as hepatocytes described here are modified from a published article in the Journal of Visualized experiments. The video protocol allows for the user to successfully isolate cells as the most difficult parts of the procedure are demonstrated visually. The detection of liver maladies such as the non-alcoholic fatty liver disease, the stage if this disease and differentiation between non-alcoholic and alcoholic fatty liver disease is demonstrated in the development of a unique panel …

Loss Of Class Iii Phosphoinositide 3-Kinase Vps34 Results In Cone Degeneration, Ammaji Rajala, Feng He, Robert E Anderson, Theodore G Wensel, Raju V S Rajala

Faculty, Staff and Students Publications

The major pathway for the production of the low-abundance membrane lipid phosphatidylinositol 3-phosphate (PI(3)P) synthesis is catalyzed by class III phosphoinositide 3-kinase (PI3K) Vps34. The absence of Vps34 was previously found to disrupt autophagy and other membrane-trafficking pathways in some sensory neurons, but the roles of phosphatidylinositol 3-phosphate and Vps34 in cone photoreceptor cells have not previously been explored. We found that the deletion of Vps34 in neighboring rods in mouse retina did not disrupt cone function up to 8 weeks after birth, despite diminished rod function. Immunoblotting and lipid analysis of cones isolated from the cone-dominant retinas of the …

Allogeneic Mesenchymal Cell Therapy In Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The Cctrn Seneca Trial, Roberto Bolli, Emerson C Perin, James T Willerson, Phillip C Yang, Jay H Traverse, Timothy D Henry, Carl J Pepine, Raul D Mitrani, Joshua M Hare, Michael P Murphy, Keith L March, Sohail Ikram, David P Lee, Connor O'Brien, Jean-Bernard Durand, Kathy Miller, Joao A Lima, Mohammad R Ostovaneh, Bharath Ambale-Venkatesh, Adrian P Gee, Sara Richman, Doris A Taylor, Shelly L Sayre, Judy Bettencourt, Rachel W Vojvodic, Michelle L Cohen, Lara M Simpson, Dejian Lai, David Aguilar, Catalin Loghin, Lem Moyé, Ray F Ebert, Barry R Davis, Robert D Simari

Faculty, Staff and Student Publications

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment.

OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC.

METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 10

RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the …

Plasmodium Impairs Antibacterial Innate Immunity To Systemic Infections In Part Through Hemozoin-Bound Bioactive Molecules., Christopher Lynn Harding

Electronic Theses and Dissertations

Despite efforts to decrease the global health burden of malaria, infections with Plasmodium species continue to cause over 200 million episodes of malaria each year which resulted in 405,000 deaths in 2018 [1]. One complication of malaria is increased susceptibility to invasive bacterial infections. Plasmodium infections impair host immunity to non-Typhoid Salmonella (NTS) through activities of heme oxygenase I (HO-I) )-induced release of immature granulocytes and myeloid cell-derived IL-10. Yet, it is not known if these mechanisms are specific to NTS. We show here, that Plasmodium yoelii 17XNL (Py) infected mice had impaired clearance of systemic Listeria monocytogenes (Lm) during …

Development, Expansion And Role Of Myeloid-Derived Suppressor Cells In Post-Sepsis Immune Suppression, Tuqa Alkhateeb

Electronic Theses and Dissertations

Myeloid-derived suppressor cells (MDSCs) numbers increase significantly in sepsis and are associated with high mortality rates. These myeloid cell precursors promote immunosuppression, especially in the late (post sepsis) stage. However, the mechanisms that underlie MDSC expansion and programming are not completely understood. To investigate these mechanisms, we used a cecal-ligation and puncture (CLP) mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive phase. Previous studies in our laboratory showed that microRNA (miR)-21 and miR-181b elevate levels of the transcription factor nuclear factor 1 (NFI-A) that promotes MDSC expansion. We report here that miR-21 …

Thrombospondin-1 Plays An Essential Role In Yes-Associated Protein Nuclear Translocation During The Early Phase Of Trypanosoma Cruzi Infection In Heart Endothelial Cells, Ashutosh Arun, Kayla J. Rayford, Ayorinde Cooley, Girish Rachakonda, Fernando Villalta, Siddharth Pratap, Maria F. Lima, Nader Sheibani, Pius N. Nde

Publications and Research

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease. This neglected tropical disease causes severe morbidity and mortality in endemic regions. About 30% of T. cruzi infected individuals will present with cardiac complications. Invasive trypomastigotes released from infected cells can be carried in the vascular endothelial system to infect neighboring and distant cells. During the process of cellular infection, the parasite induces host cells, to increase the levels of host thrombospondin-1 (TSP-1), to facilitate the process of infection. TSP-1 plays important roles in the functioning of vascular cells, including vascular endothelial cells with important implications in cardiovascular …

Burden-Of-Illness Associated With Bleeding-Related Hospitalizations In Atrial Fibrillation Patients: Findings From The Nationwide Readmission Database, Benjamin Miao, Monique Miller, Belinda Lovelace, Anne Beaubrun, Kelly Mcneil-Posey, Mark J Alberts, William Frank Peacock, Olivia S Costa, Charles Michael White, Craig I Coleman

Faculty, Staff and Students Publications

Introduction  A paucity of contemporary data examining bleeding-related hospitalization outcomes in atrial fibrillation (AF) patients exists.

Methods  Adults in the Nationwide Readmissions Database (January 2016–November 2016) with AF and hospitalized for intracranial hemorrhage (ICH), gastrointestinal, genitourinary, or other bleeding were identified. Association between bleed types and outcomes were assessed using multivariable regression (gastrointestinal defined as referent) and reported as crude incidences and adjusted odds ratios (ORs) or mean differences with 95% confidence intervals (CIs).

Results  In total, 196,878 index bleeding-related hospitalizations were identified in this AF cohort (CHA2DS2VASc score ≥2 in 95.1%), with 70.8% classified as gastrointestinal. The overall incidences …

Ipledge Must Abstain From Abstinence, Kami Lowery, Theodore Rosen, Janet Malek

Faculty, Staff and Students Publications

Isotretinoin has unmatched efficacy in the treatment of acne. However, because isotretinoin is a teratogen that can cause profound birth defects, the iPLEDGE program regulates the drug's distribution in the United States. To minimize fetal exposure to isotretinoin, the program requires that female patients capable of becoming pregnant use two forms of contraception or commit to abstinence while using this therapy. This manuscript argues that iPLEDGE should be revised to remove abstinence as an acceptable contraceptive option in the face of evidence that disputes its efficacy. All patients, regardless of reported sexual activity, should be required to use data-proven contraception. …

How Can We Stop Cancer?, Joseph R. Current

The Review: A Journal of Undergraduate Student Research

Cancer is a disease that humans have been struggling to combat for centuries. It originates from the accumulation of several mutations over the life of a cell that causes it to evade cell death and multiply rapidly. It can affect any tissue in the body and can spread to other parts of the body through metastasis. Cancer comes in numerous shapes and sizes with different levels of aggression, growth speeds, and health risks. Many treatments for cancer exist today, three of the most popular being surgery, chemotherapy, and radiation therapy, which can be used in combinations with other treatments to …

Investigating The Interactions Between Individual Calmodulin And Hiv-1 Protein Domains, Riley K. Kendall, Jerry Larue

Student Scholar Symposium Abstracts and Posters

The World Health Organization found that 37.9 million people were living with HIV by the end of 2018. HIV is a virus that weakens the immune system through viral replication and the destruction of CD4⁺ T-cells, which are white blood cells that detect infection and make antibodies. A cure for HIV has not yet been discovered. HIV-1 contains a Gag polyprotein which regulates the stages of viral replication. Previous studies suggest that the myristoyl group of a matrix protein peptide found on the Gag polyprotein, MA, forms a complex with a calcium-binding, multifunctional regulatory protein called Calmodulin (CaM). CaM …

How Immune T-Cell Augmentation Can Help Prevent Covid-19: A Possible Nutritional Solution Using Ketogenic Lifestyle, Ravi K. Kamepalli Md,Fidsa,Cwsp

The University of Louisville Journal of Respiratory Infections

No abstract provided.

Vaccines In Current Culture: The Hpv Vaccine Controversy, Alyssa Johnston

Senior Honors Theses

The use of vaccinations has drastically decreased mortality and morbidity rates related to infectious disease and has become an intrinsic part of modern health care. However, the fear of risks related to vaccines has been partially responsible for the decisions of many parents to delay or avoid vaccinating their children. The human papilloma virus (HPV) vaccine specifically is one of the most controversial vaccines in current culture due to reports of new onset or exacerbation of autoimmune diseases, infertility, and even death following its administration. This review synthesizes information regarding the relevance and safety of the HPV vaccine, as well …

Evidence That Brain-Reactive Autoantibodies Contribute To Chronic Neuronal Internalization Of Exogenous Amyloid-Β1-42 And Key Cell Surface Proteins During Alzheimer's Disease Pathogenesis, Eric L Goldwaser, Nimish K Acharya, Hao Wu, George A Godsey, Abhirup Sarkar, Cassandra A Demarshall, Mary C Kosciuk, Robert G Nagele

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-β1-42 (Aβ42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aβ42, IgG, GluR2/3, and α7nAChR as well as lysosomal compartment expansion in these …

The Role Of Interleukin-18 In Myocardial Ischemia/Reperfusion, Yogesh Dhakal

Theses and Dissertations

Acute Myocardial Infarction (AMI) is one of the leading causes of morbidity for cardiovascular diseases (CVDs) in the western world. While mortality rates for AMI has reduced in the last 20 years due to advancements in clinical interventions, patients who have an AMI are significantly more likely to develop heart failure (HF) in the following years. Reperfusion of the ischemic tissue is a necessary procedure to restore blood delivery to cardiomyocytes, minimize myocardial dysfunction, and reduce infarct size. Still, the step of reperfusion itself induces myocardial damage in a phenomenon known as reperfusion injury. Considering that the degree of myocardial …

Oral Contraceptives As Possible Acl Injury Prevention Method, Haley Schweizer

Capstone Showcase

ABSTRACT

Introduction: Anterior Cruciate Ligament (ACL) injuries are an upsetting setback for many athletes that require a long and costly recovery process. The injury rates are four times greater in women than men. Preventative measures that help to prevent ACL injuries are limited to stretching and strengthening. Therefore, this review aims to investigate if oral contraceptive [I] usage provides a possible new avenue for prevention of ACL injury [O] in young female athletes (ages 18-30) [P] compared to those that do not take oral contraceptives [C].

Methods: A literature review was performed though PubMed, Google Scholar, SCOPUS Database, and ClinicalKey …

Assessing Morphology Of Iprgcs After Traumatic Brain Injury, Brian Foresi, Matt Smith

Williams Honors College, Honors Research Projects

ipRGCs are retinal ganglion cells that project to visual processing centers of the brain for nonimage forming visual functions. The relation of ipRGCs to tramatic brain injury (TBI) is emerging as data has been published describing ipRGC functional changes in TBI affected military veterans. Major symptomologies of concussions, a mild form of TBI, also overlap with the function governed by sites in the brain with major ipRGC projection percentages. Assesing if a morphological change is occuring in the ipRGCs after a TBI could support the idea of a pathological mechanism of the injury. This study could also indicate further relevance …

It's A Hard Nacht Life: Understanding How Nlrp12 Ticks, Abbigale Julia Brown

Graduate Theses/Dissertations

The protein NOD- like receptor pyrin domain containing 12 (NLRP12) comes from a family of protein receptors with a wide range of functions including fertility as well as anti-inflammatory properties. The biological role of NLRP12 is poorly understood: research on the mechanisms behind its function and/or activation remains contradictory between different cell models. Current research suggests its involvement in a multi-protein complex named the inflammasome. The alternative hypothesis that has also been proposed is that NLRP12 is not a part of the inflammasome, rather it negatively regulates a transcription factor known as NF-��B down stream of Toll-like receptors. NLRP12 is …

Natural Autoantibodies: Origin, Function And Utility For Diagnosis Of Disease, Abhirup Sarkar

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and …

Caspases And Cancer: Connections Through Circular Dichroism Spectroscopy, Sarah M. Hethcox

Honors College Theses

While excessive cell death inevitably leads to negative effects, the endurance of damaged cells in the presence of death signals can be equally detrimental to health. Apoptosis, or programmed cell death, is a highly regulated process in which cues from within or from outside a cell can trigger an irreversible sequence of signals that carry out cell destruction known as the apoptotic cascade. A group of enzymes called caspases play a vital role in this cascade with some participating as initiators and others acting as effectors of protein cleavage and intracellular breakdown. Although it is normal for the activity of …

Large Scale Dynamical Model Of Macrophage/Hiv Interactions, Sean T. Bresnahan, Matthew M. Froid

UNO Student Research and Creative Activity Fair

Properties emerge from the dynamics of large-scale molecular networks that are not discernible at the individual gene or protein level. Mathematical models - such as probabilistic Boolean networks - of molecular systems offer a deeper insight into how these emergent properties arise. Here, we introduce a non-linear, deterministic Boolean model of protein, gene, and chemical interactions in human macrophage cells during HIV infection. Our model is composed of 713 nodes with 1583 interactions between nodes and is responsive to 38 different inputs including signaling molecules, bacteria, viruses, and HIV viral particles. Additionally, the model accurately simulates the dynamics of over …

Understanding Pseudomonas Aeruginosa Alginate Regulation And Its Link To Chronic Lung Infections In Cystic Fibrosis Patients, Roy Al Ahmar

Theses, Dissertations and Capstones

Cystic Fibrosis (CF) is a genetic disorder caused by mutations in the gene encoding Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This disorder results in thick lung secretions which compromise the patient’s immune system. Chronic lung infections with Pseudomonas aeruginosa biofilms is a major factor that contributes to poor outcome for clinical treatment. The overall hypothesis of this dissertation is that small colony variant and pyrimidine biosynthesis are linked with biofilm formation, alginate production is dependent on MucA proteolysis, rifaximin can be repurposed to treat biofilm infection and multiplex PCR can be used to rapidly measure the bacterial cell density in …

Correcting Glucose-6-Phosphate Dehydrogenase Deficiency With A Small-Molecule Activator, Sunhee Hwang, Karen Mruk, Simin Rahighi, Andrew G. Raub, Che-Hong Chen, Lisa E. Dorn, Naoki Horikoshi, Soichi Wakatsuki, James K. Chen, Daria Mochly-Rosen

Pharmacy Faculty Articles and Research

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the …

Inhibition Of Ribosome Biogenesis Through Genetic And Chemical Approaches, Leonid Anikin

Graduate School of Biomedical Sciences Theses and Dissertations

In order to maintain the ability to generate proteins, proliferating cells must continuously generate ribosomes, designating up to 80% of their energy to ribosome biogenesis (RBG). RBG involves transcription of rDNA by RNA polymerases I (Pol I) and III (Pol III), expression of approximately 80 ribosomal proteins, and assembly of these components in a process referred to as ribosome maturation. During maturation, the Pol I transcribed 47S pre-rRNA undergoes a number of processing events, while simultaneously interacting with processing factors and ribosomal proteins that drive pre-ribosome assembly. Inhibition of RBG has become one of the pursued targets for cancer therapy …

Evaluation Of Endothelial Cell Responses To Elevated Glucose, Gabriella Sugerman

Master's Theses

Developing a tissue-engineered Blood Vessel Mimic (BVM) to represent diabetic macrovascular disease could expedite design of new vascular devices specifically tailored to diabetic patients. In contribution toward this model, this thesis assessed Human Umbilical Vein Endothelial Cell (HUVEC) responses to high glucose conditions. Interleukin 6 (IL-6) and Cluster of Differentiation 36 (CD36) were selected to signify oxidative stress activity, a hallmark of diabetic macrovascular disease. Next, activity of potential reference genes B2M, HPRT1, and ACTB was assessed. All genes were found to exceed acceptable variability, so the E-ΔC T method of data analysis was selected. Next, cellular responses to high …