Diseases Commons^™

Alternative Splicing Promotes Tumour Aggressiveness And Drug Resistance In African American Prostate Cancer., Bi-Dar Wang, Kristin Ceniccola, Sujin Hwang, Ramez Andrawis, Anelia Horvath, Jennifer A Freedman, Jacqueline Olender, Stefan Knapp, Travers Ching, Lana Garmire, Vyomesh Patel, Mariano A Garcia-Blanco, Steven R Patierno, Norman H Lee

Pharmacology and Physiology Faculty Publications

linical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative …

Honey Bee Gut Dysbiosis: A Novel Context Of Disease Ecology, Kirk E. Anderson, Vincent A. Ricigliano

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

The honey bee microbiota has become a hot-spot of recent research. Highly co-evolved with its host, the hindgut microbiota of a worker honey bee consists of six bacterial species shown to occur reliably in particular proportions. Altered microbiota structure is associated with host deficiencies, and a variety of bacteria found throughout the hive environment can dominate the worker gut suppressing or displacing microbiota function. The synthesis presented here suggests environmental insults alter gut bacterial balance, leading to decreased host function and disease progression. Specific functional groups of native bacteria represent a model system to investigate dysbiosis and the evolution of …

A Study Of Ticks And Tick-Borne Livestock Pathogens In Pakistan, Shahid Karim, Khemraj Budachetri, Nabanita Mukherjee, Jaclyn Williams, Asma Kausar, Muhammad Jawadul Hassan, Steven W. Adamson, Scot E. Dowd, Dmitry Apanskevich, Abdullah Arijo, Zia Uddin Sindhu, Muhammad Azam Kakar, Raja Muhammad Dilpazir Khan, Shafiq Ullah, Muhammad Sohail Sajid, Abid Ali, Zafar Iqbal

Faculty Publications

Background

As obligate blood-feeding arthropods, ticks transmit pathogens to humans and domestic animals more often than other arthropod vectors. Livestock farming plays a vital role in the rural economy of Pakistan, and tick infestation causes serious problems with it. However, research on tick species diversity and tick-borne pathogens has rarely been conducted in Pakistan. In this study, a systematic investigation of the tick species infesting livestock in different ecological regions of Pakistan was conducted to determine the microbiome and pathobiome diversity in the indigenous ticks.

Methodology/Principal findings A total of 3,866 tick specimens were morphologically identified as 19 different tick …

Calcineurin/Nfat Signaling In Activated Astrocytes Drives Network Hyperexcitability In AΒ-Bearing Mice, Pradoldej Sompol, Jennifer L. Furman, Melanie M. Pleiss, Susan D. Kraner, Irina A. Artiushin, Seth R. Batten, Jorge E. Quintero, Linda A. Simmerman, Tina L. Beckett, Mark A. Lovell, M. Paul Murphy, Greg A. Gerhardt, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

Hyperexcitable neuronal networks are mechanistically linked to the pathologic and clinical features of Alzheimer's disease (AD). Astrocytes are a primary defense against hyperexcitability, but their functional phenotype during AD is poorly understood. Here, we found that activated astrocytes in the 5xFAD mouse model were strongly associated with proteolysis of the protein phosphatase calcineurin (CN) and the elevated expression of the CN-dependent transcription factor nuclear factor of activated T cells 4 (NFAT4). Intrahippocampal injections of adeno-associated virus vectors containing the astrocyte-specific promoter Gfa2 and the NFAT inhibitory peptide VIVIT reduced signs of glutamate-mediated hyperexcitability in 5xFAD mice, measured in vivo with …

Validating Candidate Congenital Heart Disease Genes In Drosophila., Jun-Yi Zhu, Yulong Fu, Adam Richman, Zhe Han

Pediatrics Faculty Publications

Genomic sequencing efforts can implicate large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system to validate candidate gene association with pathology is therefore useful. We present such a system employing Drosophila to validate candidate congenital heart disease (CHD) genes. The protocols exploit comprehensive libraries of UAS-GeneX-RNAi fly strains that when crossed into a 4×Hand-Gal4 genetic background afford highly efficient cardiac-specific knockdown of endogenous fly orthologs of human genes. A panel of quantitative assays evaluates phenotypic severity across multiple cardiac parameters. These include developmental lethality, larva and adult heart morphology, …

African-American Esophageal Squamous Cell Carcinoma Expression Profile Reveals Dysregulation Of Stress Response And Detox Networks., Hayriye Verda Erkizan, Kory Johnson, Svetlana Ghimbovschi, Deepa Karkera, Gregory Trachiotis, Houtan Adib, Eric P Hoffman, Robert G Wadleigh

Genomics and Precision Medicine Faculty Publications

BACKGROUND: Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is largely unresponsive to therapy. African-Americans have an increased risk for esophageal squamous cell carcinoma (ESCC), the subtype that shows marked variation in geographic frequency. The molecular architecture of African-American ESCC is still poorly understood. It is unclear why African-American ESCC is more aggressive and the survival rate in these patients is worse than those of other ethnic groups.

METHODS: To begin to define genetic alterations that occur in African-American ESCC we conducted microarray expression profiling in pairs of esophageal squamous cell tumors and matched control tissues.

RESULTS: …

Colonization Density Of The Upper Respiratory Tract As A Predictor Of Pneumonia-Haemophilus Influenzae, Moraxella Catarrhalis, Staphylococcus Aureus, And Pneumocystis Jirovecii., Daniel E Park, Henry C Baggett, Stephen R C Howie, Qiyuan Shi, Nora L Watson, W Abdullah Brooks, Perch Study Group

Epidemiology Faculty Publications

Background.

There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Methods.

In 7 low- and middle-income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or …

Hypersensitivity Of Vagal Pulmonary Afferents Induced By Tumor Necrosis Factor Alpha In Mice, Ruei-Lung Lin, Qihai Gu, Lu-Yuan Lee

Physiology Faculty Publications

Tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine, plays a significant role in the pathogenesis of allergic asthma. Inhalation of TNFα also induces airway hyperresponsiveness in healthy human subjects, and the underlying mechanism is not fully understood. A recent study reported that TNFα caused airway inflammation and a sustained elevation of pulmonary chemoreflex responses in mice, suggesting a possible involvement of heightened sensitivity of vagal pulmonary C-fibers. To investigate this possibility, the present study aimed to investigate the effect of a pretreatment with TNFα on the sensitivity of vagal pulmonary afferents in anesthetized mice. After TNFα (10 μg/ml, 0.03 ml) …

Effects Of Phosphodiesterase 3a Modulation On Murine Cerebral Microhemorrhages, Rachita K. Sumbria, Vitaly Vasilevko, Mher Mahoney Grigoryan, Annlia Paganini-Hill, Ronald Kim, David H. Cribbs, Mark J. Fisher

Pharmacy Faculty Articles and Research

Background: Cerebral microbleeds (CMB) are MRI-demonstrable cerebral microhemorrhages (CMH) which commonly coexist with ischemic stroke. This creates a challenging therapeutic milieu, and a strategy that simultaneously protects the vessel wall and provides anti-thrombotic activity is an attractive potential approach. Phosphodiesterase 3A (PDE3A) inhibition is known to provide cerebral vessel wall protection combined with anti-thrombotic effects. As an initial step in the development of a therapy that simultaneously treats CMB and ischemic stroke, we hypothesized that inhibition of the PDE3A pathway is protective against CMH development.

Methods: The effect of PDE3A pathway inhibition was studied in the inflammation-induced and …

Nfatc2 Modulates Microglial Activation In The Aβpp/Ps1 Mouse Model Of Alzheimer's Disease, Gunjan D. Manocha, Atreyi Ghatak, Kendra L. Puig, Susan D. Kraner, Christopher M. Norris, Colin K. Combs

Pharmacology and Nutritional Sciences Faculty Publications

Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or …

Plasmonic Gold Nanoparticle For Detection Of Fungi And Human Cutaneous Fungal Infections, Tobiloba Sojinrin, Kangze Liu, Joao Conde, Hugh Byrne, James Curtin, Daxiang Cui, Furong Tian

Articles

Fungi, which are common in the environment, can cause a multitude of diseases. Warm, humid conditions allow fungi to grow and infect humans via the respiratory, digestive and reproductive tracts, genital area and other bodily interfaces. Fungi can be detected directly by microscopy, using the potassium hydroxide (KOH) test, which is the gold standard and most popular method for fungal screening. However, this test requires trained personnel operating specialist equipment, including a fluorescent microscope and culture facilities. As most acutely infected patients seek medical attention within the first few days of symptoms, the optimal diagnostic test would be rapid and …

Subsets Of Inflammatory Cytokine Gene Polymorphisms Are Associated With Risk Of Carcinogenic Liver Fluke Opisthorchis Viverrini-Associated Advanced Periductal Fibrosis And Cholangiocarcinoma., Arpa Surapaitoon, Sutas Suttiprapa, Eimorn Mairiang, Narong Khuntikeo, Chawalit Pairojkul, Jeffrey Bethony, Paul J Brindley, Banchob Sripa

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Opisthorchis viverrini infection induces chronic inflammation, and a minor proportion of infected individuals develop advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA). Inflammatory cytokines and/or their gene polymorphisms may link to these biliary pathologies. We therefore investigated associations among cytokine gene polymorphisms and cytokine production in 510 Thai cases infected with O. viverrini who presented with APF+ or APF−, as established by abdominal ultrasonography as well as in patients diagnosed with CCA. Levels of pro-inflammatory and anti-inflammatory cytokines were determined in culture supernatants after stimulation of peripheral blood mononuclear cells (PBMCs) with O. viverrini excretory-secretory (ES) products. Pro-inflammatory cytokines, IL-1β, IL-6, …

A Lipid Binding Structure And Functional Analysis Of Human Arv1, Jessie Lee Cunningham

Graduate School of Biomedical Sciences Theses and Dissertations

Metabolic Syndrome (MetS) is a combination of risk factors that can over time increase the probability of developing diseases, including cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). Acyl-coenzyme-A: cholesterol O-acyl transferase related enzyme required for viability-1, abbreviated as Arv1, is an evolutionarily conserved putative lipid binding protein. Several studies have implicated hArv1 as a critical regulator of lipid transport and trafficking.

Recent work using an Arv1 knock out (KO) mouse model have established a clear link between Arv1 function and the progression of MetS and NAFLD/NASH [unpublished data] [1]. Overall, studies show that …

Immune Checkpoint Inhibition And The Prevalence Of Autoimmune Disorders Among Patients With Lung And Renal Cancer, Sherif M. El-Refai

Pharmaceutical Sciences Faculty Publications

PURPOSE: Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab.

METHODS: An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients …

Molecular Detection Of Tick-Borne Pathogen Diversities In Ticks From Livestock And Reptiles Along The Shores And Adjacent Islands Of Lake Victoria And Lake Baringo, Kenya, David Omondi, Daniel K. Masiga, Burtram C. Fielding, Edward Kariuki, Yvonne Ukamaka Ajamma, Micky M. Mwamuye, Daniel O. Ouso, Jandouwe Villinger

All Peer-Reviewed Publications

Although diverse tick-borne pathogens (TBPs) are endemic to East Africa, with recognized impact on human and livestock health, their diversity and specific interactions with tick and vertebrate host species remain poorly understood in the region. In particular, the role of reptiles in TBP epidemiology remains unknown, despite having been implicated with TBPs of livestock among exported tortoises and lizards. Understanding TBP ecologies, and the potential role of common reptiles, is critical for the development of targeted transmission control strategies for these neglected tropical disease agents. During the wet months (April-May; October-December) of 2012-2013, we surveyed TBP diversity among 4,126 ticks …

Setting Health Research Priorities Using The Chnri Method: Vii. A Review Of The First 50 Applications Of The Chnri Method, Igor Rudan, Sachiyo Yoshida, Kit Yee Chan, Devi Sridhar, Kerri Wazny, Harish Nair, Aziz Sheikh, Mark Tomlinson, Joy E. Lawn, Zulfiqar Ahmed Bhutta

Department of Paediatrics and Child Health

Background: Several recent reviews of the methods used to set research priorities have identified the CHNRI method (acronym derived from the "Child Health and Nutrition Research Initiative") as an approach that clearly became popular and widely used over the past decade. In this paper we review the first 50 examples of application of the CHNRI method, published between 2007 and 2016, and summarize the most important messages that emerged from those experiences.
Methods: We conducted a literature review to identify the first 50 examples of application of the CHNRI method in chronological order. We searched Google Scholar, PubMed and so-called …

Modeling Hiv Dynamics Following 3bnc117 Antibody Infusion, Samantha Erwin

Biology and Medicine Through Mathematics Conference

No abstract provided.

Interaction Of The Tear Film With The Ocular Surface, Richard J. Braun, Amy Janett, Nicholas Gewecke, Spencer Walker

Biology and Medicine Through Mathematics Conference

No abstract provided.

Analyzing Sexual Transmission In The Spread Of The Zika Virus In Colombia, Victoria M. Kelley

Biology and Medicine Through Mathematics Conference

No abstract provided.

Uncertainty Of 1-D Fluid Models In Patients With Pulmonary Hypertension, Mitchel J. Colebank

Biology and Medicine Through Mathematics Conference

No abstract provided.

Control Policies And Sensitivity Analysis In A Cutaneous Leishmaniasis Model: A Case Study In Cusco Region, Peru., Rocio M. Caja-Rivera, Ignacio Barradas

Biology and Medicine Through Mathematics Conference

No abstract provided.

Whole Genome Analysis Of A Schistosomiasis-Transmitting Freshwater Snail., Coen M Adema, Ladeana W Hillier, Catherine S Jones, Eric S Loker, Matty Knight, Patrick Minx, +Several Additional Authors

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Biomphalaria snails are instrumental in transmission of the human blood fluke Schistosoma mansoni. With the World Health Organization's goal to eliminate schistosomiasis as a global health problem by 2025, there is now renewed emphasis on snail control. Here, we characterize the genome of Biomphalaria glabrata, a lophotrochozoan protostome, and provide timely and important information on snail biology. We describe aspects of phero-perception, stress responses, immune function and regulation of gene expression that support the persistence of B. glabrata in the field and may define this species as a suitable snail host for S. mansoni. We identify …

Tumor Necrosis Factor Α Inhibition For Alzheimer's Disease, Rudy Chang, Kei-Lwun Yee, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Tumor necrosis factor α (TNF-α) plays a central role in the pathophysiology of Alzheimer’s disease (AD). Food and Drug Administration–approved biologic TNF-α inhibitors are thus a potential treatment for AD, but they do not cross the blood-brain barrier. In this short review, we discuss the involvement of TNF-α in AD, challenges associated with the development of existing biologic TNF-α inhibitors for AD, and potential therapeutic strategies for targeting TNF-α for AD therapy.

The Regulation Of Rotavirus–Infected Ht29.F8 And Ma104 Cells Treated With Arachidin 1 Or Arachidin 3, Caleb M. Witcher

Electronic Theses and Dissertations

Rotavirus (RV) infections cause severe life threatening diarrhea in young children and immunocompromised individuals. Several effective vaccines have been developed for young children but are not protective against all strains of RV, and there are no anti-RV therapeutics. Our laboratory has discovered a decrease in the number of infectious simian RV particles (SA114f) in human intestinal cell line, HT29.f8 cells with the addition of either of two stilbenoids, arachidin-1 (A1) or arachidin-3 (A3). This suggests effects on the host cell and RV replication. We examined the cellular effects of human RV strain (Wa) on a human intestinal cell line (HT29.f8) …

A Variant Pfcrt Isoform Can Contribute To Plasmodium Falciparum Resistance To The First-Line Partner Drug Piperaquine, Satish K. Dhingra, Devasha Redhi, Jill M. Combrinck, Tomas Yeo, John Okombo, Philipp P. Henrich, Ann N. Cowell, Purva Gupta, Matthew L. Stegman, Jonathan M. Hoke, Roland A. Cooper, Elizabeth Winzeler, Sachel Mok, Timothy J. Egan, David A. Fidock

Collected Faculty Scholarship

Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisininbased combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nucleasebased gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ …

Characterization Of Neuronal Specific Responses To Induced Misfolded Protein Stress In Caenorhabditis Elegans, Claire Gormley

Senior Honors Projects, 2010-2019

Abstract

Misfolded protein stress has been associated with many types of disease,

including neurodegenerative disorders like Alzheimer’s, Parkinson’s and Huntington’s

disease. When a cell accumulates misfolded proteins in the endoplasmic reticulum,

misfolded protein stress occurs and the unfolded protein response (UPR) is triggered to

induce mechanisms that will allow the cell to either survive or undergo cell death. The

nascent polypeptide associated complex (NAC) is a co-translational chaperone and α/β

heterodimer that manages protein folding and localization, and protects against misfolded

protein stress; changes in NAC function have been linked to both neurodegeneration and

cancer. In these studies, I depleted …

Rat Hind Limb Nociceptive Withdrawal Response To Heat And Mechanical Stimuli Depends On Initial Position Of The Paw But Not Stimulus Location, Giavanna Verdi

Senior Honors Projects, 2010-2019

Mammals rapidly withdraw their hind limb in response to noxious stimulation, which is a protective movement known as the nociceptive withdrawal response (NWR). The NWR has been previously studied in spinalized, decerebrated and anesthetized non-human and human mammals; however, there is minimal information on the NWR in intact, unanesthetized non-human mammals.

The first specific aim was to identify the factors that determine the direction and magnitude of the NWR in intact, unanesthetized rats. Based on previous studies, we hypothesized that the location of stimulation and the initial position of the paw preceding the NWR will influence the direction and magnitude …

Effect Of Activity Trackers And Text Messaging On Exercise, Fitness, And Physical Activity Self-Efficacy Of Middle School Students, Alison F. Pittman

Nursing Theses and Dissertations

A decrease in physical activity as children age is a contributing factor to the U.S. obesity epidemic. Middle school children are particularly vulnerable to sedentary activities. Activity trackers show promise as a means to motivate children and adults to increase physical activity (PA). This study examined the effect of a text messaging intervention and use of activity trackers with a companion social website on the body mass index (BMI), body fat percentage, physical fitness, and PA self-efficacy of middle school children. Children aged 11-14 (n=102) were randomly assigned to one of three groups for a 10-week intervention: activity tracker group; …

The Effect Of Staphylococcus Aureus On Stiffness Of Cortical Bone, Ariel N. Kunde

Graduate Theses

Osteomyelitis, a term for bone infection, is a common cause of hospitalization in the United States. Infection leading to osteomyelitis is almost always a product of bacterial origin. Although polymicrobial presence is seen at infection sites of osteomyelitis, Staphylococcus aureus is most commonly isolated and found to be the cause of more than 95% of bone infection in adults. This organism is a common commensal of humans that is carried by an estimated 60% of the US population. S. aureus is transferred by infected asymptomatic individuals, and its ability to proliferate under a variety of environmental conditions contributes to the …

The Impact Of Freedson Bout Vs. Non-Freedson Bout Physical Activity On Metabolic Syndrome Risk In College Students, Valerie Olijar

Masters Theses, 2010-2019

Purpose The aim of this study is to examine moderate to vigorous physical activity in Freedson bouts compared to non-Freedson bouts and their association with Metabolic Syndrome risk factors in college students.

Methods 72 subjects aged 18-26 were recruited from James Madison University. Subjects height, weight, waist circumference, blood pressure, and body composition were assessed on visit 1. Blood pressure, fasted blood glucose, and lipid profile were assessed on visit 2. Subjects wore an Actigraph GT3X+ accelerometer, which measured physical activity and sleep for 7 days and nights. Univariate Pearson correlation analyses were performed to determine the relationship physical activity …