Translational Medical Research Commons^™

Gender Differences In Virologic Response After Antiretroviral Therapy In Treatment-Naïve Hiv-Infected Individuals: Results From The 550 Clinic Hiv Cohort Study., Andrea Reyes-Vega, Alejandra Loban, Kavitha Srinivasan, Stephen P. Furmanek, Conner English, Mary Bishop, Cathy Spencer, Daniel Truelove, Julio A. Ramirez, Anupama Raghuram, Paula Peyrani

Faculty and Staff Scholarship

Background

Controversy still exists regarding gender differences in virologic response between treatment-na•ve HIV-infected individuals. The objective of this study was to evaluate gender difference in virologic and immunologic response to antiretroviral therapy in treatment-na•ve HIV-infected individuals. Methods

This was a retrospective, observational study of treatment-na•ve HIV-infected individuals managed at the 550 clinic who started antiretroviral therapy (ART) between January 1st, 2010 and December 31, 2015. Patients with available viral load and CD4 counts before and one year after initiating ART were included in this study. Virologic suppression was defined as < 48 HIV-1 RNA copies/mL, and mmunologic recovery was defined as a CD4 count increase of at least 150 cells/mm3. Dichotomous variables were reported in number and percentages and analyzed using Chi-squared tests and Fisher’s exact (whichever was appropriate). Continuous variables were reported as median and interquartile range (IQR) and analyzed using Wilcox rank-sum tests. Multivariate analyses performed were logistic regressions with adjustment for other covariates. P value <0.05 was considered statistically significant. R version 3.3.2 was used for the statistical analysis. Results

A total of 70 women and 90 men were included …

Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno

Dissertations and Theses (Open Access)

Triple-negative (TNBC) and inflammatory (IBC) breast cancer are the most aggressive forms of breast cancer, accounting for 20% and 10% of cancer-related deaths, respectively. Among IBC cases, 30% are additionally classified with TNBC molecular pathology, a diagnosis that significantly worsens patient’s prognosis. The current lack of TNBC and IBC molecular understanding prevents the development of effective therapeutic strategies. To identify effective treatments, we explored aberrant apoptosis pathways and cell membrane fluidity as novel therapeutic targets.

We first identified an effective therapeutic strategy against TNBC and IBC by pro-apoptotic protein NOXA-mediated inhibition of the anti-apoptotic protein MCL1 following inhibition of histone …

Cyclin B1 Mediates The Effect Of Uchl1 In Promoting Cell Cycle Progression In Uterine Papillary Serous Carcinoma, Suet Ying Kwan

Dissertations and Theses (Open Access)

Uterine papillary serous carcinoma (UPSC) is an aggressive form of endometrial cancer with poor survival rates and a high risk of recurrence. The rarity of UPSC poses challenges to the discovery of novel targeted therapies. Therefore, the purpose of this dissertation was to identify novel therapeutic targets that could aid in the management of UPSC. To do so, we began with the relatively large cohort of UPSC cases in the TCGA data set, which was used to identify differentially expressed genes between UPSC and low-grade endometrioid endometrial carcinoma (EEC) and normal tissue.

We identified Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1 …

Developing Novel Approaches To Improve Response To T Cell Based Cancer Immunotherapy, Rina M. Mbofung

Dissertations and Theses (Open Access)

Recently, T cell based immunotherapies have moved to the forefront of cancer immunotherapy with the success of Adoptive T cell therapy (ACT) and Immune checkpoint blockade.ACT, where patients are treated with tumour infiltrating T cells (TILs), conferred a clinical response rate of ~50%. Treatment with anti-CTLA4 and anti –PD1 therapy, conferred response rates of up to 50%, greatly improving the overall survival of patients with advanced melanoma amongst other cancer types. Despite the encouraging outcomes, there are relatively low response rates coupled with the delay of weeks to months before tumour shrinkage can be appreciated. Thus, understanding what tumour intrinsic …

Targeting Autophagy To Improve Efficacy Of Cdk4/6 Inhibition In Breast Cancer, Smruthi Vijayaraghavan

Dissertations and Theses (Open Access)

Deregulation of the cell cycle machinery is a hallmark of cancer, leading to aberrant proliferation and tumorigenesis. The crucial role of the CDK4/6-Cyclin D pathway has led to the development and FDA approval (palbociclib, ribociclib) of CDK4/6 inhibitors for the treatment of advanced estrogen receptor positive breast cancer. However, three major clinical challenges remain: i) adverse events leading to discontinuation of therapy and ii) lack of reliable biomarkers to identify responsive patients and iii) acquired resistance to CDK4/6 inhibitors. Previous in vitro studies have shown that palbociclib mediated CDK4/6 inhibition induces G1 arrest and senescence in ER+ breast cancer cells, …

Chemogenetic Stimulation Of The Hypoglossal Neurons Improves Upper Airway Patency, Thomas Curado, Kenneth Fishbein, Huy Pho, Michael Brennick, Olga Dergacheva, David Mendelowitz, +Several Additional Authors

Pharmacology and Physiology Faculty Publications

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6–8 weeks genioglossus EMG and dynamic MRI …

Correcting The Trajectory Of Stroke Therapeutic Research, Keith R. Pennypacker, Gregory J. Bix, Justin F. Fraser

Neurology Faculty Publications

No abstract provided.

Translational Models For Vascular Cognitive Impairment: A Review Including Larger Species, Atticus H. Hainsworth, Stuart M. Allan, Johannes Boltze, Catriona Cunningham, Chad Farris, Elizabeth Head, Masafumi Ihara, Jeremy D. Isaacs, Raj N. Kalaria, Saskia A. M. J. Lesnik Oberstein, Mark B. Moss, Björn Nitzsche, Gary A. Rosenberg, Julie W. Rutten, Melita Salkovic-Petrisic, Aron M. Troen

Pharmacology and Nutritional Sciences Faculty Publications

Background: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited.

Methods: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, …

Lysosomal Storage Diseases, Carlos Ferreira, William Gahl

Pediatrics Faculty Publications

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency …

Bladder Antimuscarinics And Cognitive Decline In Elderly Patients, Daniela Claudia Moga, Erin L. Abner, Qishan Wu, Gregory A. Jicha

Pharmacy Practice and Science Faculty Publications

Introduction: The evidence on the impact of bladder antimuscarinics initiation on cognitive function in older adults is inconsistent.

Methods: A retrospective analysis of data from the National Alzheimer's Coordinating Center (NACC) on enrollees 65 years and older evaluated the association between antimuscarinic initiation and cognitive decline. We defined decline from baseline (yes/no) for cognitive assessments included in the NACC Uniform Data Set 2.0 battery. New users were matched on year of enrollment and time in the cohort to randomly selected nonusers. Analyses were conducted using inverse probability of treatment weights based on baseline propensity scores.

Results: Our analyses included 698 …

The Mechanical Properties Of Non-Failing And Failing Human Myocardium, Cheavar A. Blair

Theses and Dissertations--Physiology

Heart failure is a clinical syndrome that manifests when there are structural and functional impairments to the heart that reduces the ability of the ventricles to fill or eject blood. The syndrome affects ~6 million Americans and is responsible for nearly 300,000 deaths annually. At the core of the syndrome are dysfunctional sarcomeres, the machinery that drives cardiac contraction and relaxation. By assessing the mechanical properties of human cardiac tissue, the information provided in this dissertation will provide data that demonstrates how sarcomeric dysfunction contributes to heart failure in the left and right ventricles. Additionally, these data will supply information …

Efficacy Of Nutritional Interventions To Lower Circulating Ceramides In Young Adults: Fruvedomic Pilot Study, Alice T. Matthews, Oluremi A. Famodu, Melissa D. Olfert, Pamela J. Murray, Christopher F. Cuff, Marianne T. Downes, Norman J. Haughey, Sarah E. Colby, Paul D. Chantler, I. Mark Olfert, Joseph W. Mcfadden

Faculty & Staff Scholarship

The 2010 USDA Dietary Guidelines for Americans (DGA) recommends a diet largely composed of fruit and vegetables. Consuming a diet high in fruit and vegetables and low in refined carbohydrates and saturated fat may reduce an individual’s risk for type 2 diabetes, nonalcoholic fatty liver disease, low-grade chronic inflammation, and metabolic syndrome (MetS). Several recent studies have implicated the bioactive sphingolipid ceramide as an associative and causative biomarker for the development of these conditions. Considering that the intake of fruit and vegetables is frequently inadequate in young adults, we performed a pilot investigation to assess the efficacy of a free-living …

Effect Of Arginine On Oligomerization And Stability Of N-Acetylglutamate Synthase., N Haskins, A Mumo, P H Brown, Mendel Tuchman, Hiroki Morizono, L Caldovic

Genomics and Precision Medicine Faculty Publications

N-acetylglutamate synthase (NAGS; E.C.2.3.1.1) catalyzes the formation of N-acetylglutamate (NAG) from acetyl coenzyme A and glutamate. In microorganisms and plants, NAG is the first intermediate of the L-arginine biosynthesis; in animals, NAG is an allosteric activator of carbamylphosphate synthetase I and III. In some bacteria bifunctional N-acetylglutamate synthase-kinase (NAGS-K) catalyzes the first two steps of L-arginine biosynthesis. L-arginine inhibits NAGS in bacteria, fungi, and plants and activates NAGS in mammals. L-arginine increased thermal stability of the NAGS-K from Maricaulis maris (MmNAGS-K) while it destabilized the NAGS-K from Xanthomonas campestris (XcNAGS-K). Analytical gel chromatography and ultracentrifugation indicated tetrameric structure of the …

Inflammatory Gene Expression In Women Diagnosed With Polycystic Ovarian Syndrome, Myles K. Taylor

Electronic Theses & Dissertations

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The pathophysiology of PCOS has conventionally thought to originate from androgen excess. However, recent evidence suggests that androgen excess is a downstream consequence to inflammatory dysregulation and subsequent metabolic abnormalities. Inflammatory mRNA gene expression of TNFa and IL-1ß in mononuclear cells isolated from women diagnosed with PCOS was explored using qPCR. Additionally, the correlations between body mass index (BMI) and fasting glucose on mRNA expression of TNFa and IL-1ß were explored. mRNA expression of both TNFa and IL-1ß were found to be significantly higher in PCOS …

Network Inference Driven Drug Discovery, Gergely Zahoránszky-Kőhalmi, Tudor I. Oprea, Cristian G. Bologa, Subramani Mani, Oleg Ursu

Biomedical Sciences ETDs

The application of rational drug design principles in the era of network-pharmacology requires the investigation of drug-target and target-target interactions in order to design new drugs. The presented research was aimed at developing novel computational methods that enable the efficient analysis of complex biomedical data and to promote the hypothesis generation in the context of translational research. The three chapters of the Dissertation relate to various segments of drug discovery and development process.

The first chapter introduces the integrated predictive drug discovery platform „SmartGraph”. The novel collaborative-filtering based algorithm „Target Based Recommender (TBR)” was developed in the framework of this …

Blood-Tissue Barriers And Autoantibodies In Neurodegenerative Disease Pathogenesis: An Approach To Diagnostics And Disease Mechanism, Eric Luria Goldwaser

Graduate School of Biomedical Sciences Theses and Dissertations

Brain homeostasis can be affected in a number of ways that lead to gross anatomical, cellular, and molecular disturbances giving rise to diseases like Alzheimer’s disease (AD) and related dementias. Unfortunately, the mechanistic pathoetiology of AD’s hallmark features of cerebral amyloid plaque buildup and neuronal death are still disputed. Using human brain AD sections, immunohistochemistry experiments revealed internalized surface proteins, co-localized to an expanded lysosomal compartment. Other stains for amyloid-β1-42 (Aβ42) and various immunoglobulin (Ig) species displayed them leaking out of the cerebrovasculature through a dysfunctional blood-brain barrier (BBB), binding to neurons in the vicinity, and localizing to intracellular vesicles …

Viruses, Vaccines And The Public, Judy Diamond, Julia Mcquillan, Amy Spiegel, Patricia Wonch Hill, Rebecca Smith, John T. West, Charles Wood

World of Viruses

Current research in virology is changing public conceptions about vaccines and infectious disease. The University of Nebraska State Museum collaborated with research virologists, science writers, artists and learning researchers to create public outreach materials about viruses and infectious disease. The project, funded by the National Institute of Health’s SEPA program, developed comics, a book with Carl Zimmer, and other materials and programs. The project launched three kinds of learning research: 1) a survey of Nebraska adults on their opinions about vaccines and infectious disease; 2) a study comparing the mental models of viruses, vaccines and infection from virologists, teachers, and …

Molecular Analyses Of Circadian Gene Variants Reveal Sex-Dependent Links Between Depression And Clocks, S-Q Shi, M. J. White, H. M. Borsetti, Julie S. Pendergast, A. Hida, C. M. Ciarleglio, P. A. De Verteuil, A. G. Cadar, C. Cala, D. G. Mcmahon, R. C. Shelton, S. M. Williams, C. H. Johnson

Biology Faculty Publications

An extensive literature links circadian irregularities and/or sleep abnormalities to mood disorders. Despite the strong genetic component underlying many mood disorders, however, previous genetic associations between circadian clock gene variants and major depressive disorder (MDD) have been weak. We applied a combined molecular/functional and genetic association approach to circadian gene polymorphisms in sex-stratified populations of control subjects and case subjects suffering from MDD. This approach identified significant sex-dependent associations of common variants of the circadian clock genes hClock, hPer3 and hNpas2 with major depression and demonstrated functional effects of these polymorphisms on the expression or activity of the hCLOCK …

Privatization Of Biomedical Research: A Short Term Answer With Long Term Consequences, Frederick Azalekor

Nebraska College Preparatory Academy: Senior Capstone Projects

Biomedical research owned by the government is now available to be owned by private institutions. This results in stagnant innovations because researchers have trouble with all the restrictions that are placed by private institutions. Privatization of biomedical research has short term positive effects but its negative effects are overarching and disastrous. One way to combat this, is for licenses to be deployed slowly with future consequences in mind.

• Privatization has short term benefits but long term disadvantages are disastrous. • To reduce damaging effect, privatization must be deployed slowly and carefully. • Patents or proprietary ownership must be given …

Characterizing The Oncogenic Properties Of C-Terminal Binding Protein, Evan T. Sumner

Theses and Dissertations

The paralogous C-terminal binding proteins (CtBP) 1 and 2 are evolutionarily conserved transcriptional coregulators that target and disrupt the expression of several genes essential for multiple cellular processes critical to regulating tumor formation. CtBP’s ability to govern the transcription of genes necessary for apoptosis, tumor suppression, invasion/migration and EMT gives rise to its oncogenic activities. Both isoforms of CtBP are found to be overexpressed in cancers including colorectal, pancreatic, ovarian, and breast, with higher levels correlating to lower overall median survival. Although multiple lines of evidence suggest CtBP plays a role in tumorigenesis, it has never been formally characterized as …

Overcoming Treatment Resistance In Heterogeneous Tumors, Nikhil Hebbar

Theses and Dissertations--Toxicology and Cancer Biology

Most primary tumors are heterogeneous and are often composed of therapy-sensitive and emerging therapy-resistant cancer cells. Rather unexpectedly, treatment of therapy-sensitive tumor cells in heterogeneous tumor microenvironments resulted in apoptosis of the therapy-resistant cancer cells. We identified a novel Par-4 amino-terminal fragment (PAF, which includes amino acids 1-131 of Par-4) that is produced and released by therapy-sensitive cancer cells following therapy-induced caspase-dependent cleavage of the tumor suppressor Par-4. PAF caused paracrine apoptosis in therapy-resistant cancer cells. Unlike Par-4-inducible apoptosis, which is dependent on the cell surface GRP78 receptor, PAF produced cancer-selective apoptosis independent of cell surface GRP78 function. Par-4 contains …

Introducing Novel Combinatorial Targeted Therapies In Multiple Types Of Cancer, Mehrad Tavallai

Theses and Dissertations

The cancers of liver, colon and breast are amongst the top five most prevalent and most fatal worldwide. As the Raf/MEK/ERK pathway is frequently deregulated in hepatocellular carcinoma (HCC), sorafenib, a Raf kinase inhibitor, became the first systemic therapy approved for the treatment of patients with HCC. However, sorafenib only produced modest effects with low response rates in the clinic. Similarly, regorafenib, which was approved for the treatment of metastatic colorectal cancer (CRC), has had a poor response rate in the clinic. Since phosphodiesterase type 5 has been reported to be overexpressed in HCC and CRC, we hypothesized that sildenafil, …

Mechanisms And Intervention Strategies For Alcohol And Hiv-Antiretroviral Therapy-Induced Liver Injury., Hridgandh Donde

Electronic Theses and Dissertations

Chronic alcohol consumption is a leading cause of liver disease and liver-related death worldwide. Alcoholic liver disease includes, hepatic steatosis, steatohepatitis and ultimately fibrosis and cirrhosis. Emerging evidence has established the important role of the “gut-liver” axis in the development of alcoholic liver disease (ALD). Our recent work indicated that chronic alcohol induced perturbations in the gut microbiome and consequent changes in fatty acids have a major impact on the development of intestinal barrier dysfunction and ALD. The aim of this study was to investigate whether treatment with tributyrin - a butyrate prodrug results in protection against ALD in terms …

Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer, Daniel L. Smith

Dissertations and Theses (Open Access)

Prophylactic cranial irradiation (PCI) is a preventative whole-brain irradiation technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with small cell lung cancer and acute lymphoblastic leukemia. A population of breast cancer patients – stage IV, HER2+ or triple-negative – has emerged as having a high risk of developing brain metastases. Because only 10-20% of breast cancer patients diagnosed with brain metastases survive longer than one year, in this high-risk population the benefit of PCI – potential for reduced incidence of brain metastasis and improved overall survival – may outweigh the risks – …

Pertinacity Volume 1 Issue 1, Yuri Hosokawa

Pertinacity

No abstract provided.

Actions Of Pi3k-Delta Inhibitor, Idelalisib, And Its Combination With Bendamustine In Chronic Lymphocytic Leukemia, Prexy Modi

Dissertations and Theses (Open Access)

Class I phosphatidylinositol 3-kinase isoforms (α, β, δ, and γ) play a major role in cancer cell growth and survival. PI3K α and β are most studied. PI3K pathway is highly dysregulated in many cancers and aberrant PI3K signaling is associated with oncogene mutations and disease progression in solid tumors and in hematologic malignancies.

Chronic lymphocytic leukemia (CLL) is driven by B-cell receptor (BCR) signaling that promotes B-cell proliferation and survival. PI3K is a critical node in BCR pathway and PI3Kδ has a pivotal role in B-cell development and maintenance and this isoform is over-expressed in many B-cell malignancies, including …

Investigating The Roles Of P63 And P73 Isoforms To Therapeutically Treat P53-Altered Cancers, Avinashnarayan Venkatanarayan

Dissertations and Theses (Open Access)

Investigating the roles of p63 & p73 isoforms to therapeutically treat

p53-altered cancers

Avinashnarayan Venkatanarayan, M.S.

Supervisory Professor: Elsa R. Flores, Ph.D.

The TP53 tumor suppressor is mutated in approximately 50% of human cancers rendering cancer therapies ineffective. p53 reactivation suppresses tumor formation in mice. However, this strategy has proven difficult to implement therapeutically. An alternate approach to overcome p53 loss is to manipulate the p53-family members, p63 and p73, which interact and share structural similarities to p53. p63 and p73, unlike p53 are less frequently mutated and have two major isoforms with distinct functions …

Vestibular Dysfunction, Altered Macular Structure And Trait Localization In A/J Inbred Mice, Sarath Vijayakumar, Teresa E. Lever, Jessica Pierce, Xing Zhao, David Bergstrom, Yunxia Wang Lundberg, Timothy A. Jones, Sherri M. Jones

Department of Special Education and Communication Disorders: Faculty Publications

A/J mice develop progressive hearing loss that begins before one month of age and is attributed to cochlear hair cell degeneration. Screening tests indicated this strain also develops early onset vestibular dysfunction and has otoconial deficits. The purpose of this study was to characterize the vestibular dysfunction and macular structural pathology over the lifespan of A/J mice. Vestibular function was measured using linear vestibular evoked potentials (VsEPs). Macular structural pathology was evaluated using light microscopy, SEM, TEM, confocal microscopy and Western blotting. Individually, vestibular functional deficits in mice ranged from mild to profound. On average, A/J mice had significantly reduced …

Brain Blast 2015 Speakers Poster, Annie Leslie

Brain Blast

Poster from UNE's Brain Blast 2015 listing the expected presenters at this event.*

Female Breakfast Skippers Display A Disrupted Cortisol Rhythm And Levated Blood Pressure, Megan Witbracht, Nancy L. Keim, Shavawn Forester, Adrianne Widaman, Kevin D. Laugero

United States Department of Agriculture-Agricultural Research Service / University of Nebraska-Lincoln: Faculty Publications

Chronic stress and over-activity in the hypothalamic–pituitary–adrenal (HPA) axis may link breakfast skipping and poor cardiometabolic health. Missing the first major meal of the day in rodents prolongs elevated circulating corticosterone at a time when it's normally decreasing. To extend these findings to humans, we hypothesized that habitual breakfast skippers would display a similar pattern of circulating cortisol and alterations in meal and stress-induced cortisol reactions. Normal weight to obese women aged 18–45 years old who were strictly defined as either breakfast skippers (n = 30) or breakfast eaters (n = 35) were invited to participate in our …