Medicine and Health Sciences Commons^™

Septins Of Platyhelminths: Identification, Phylogeny, Expression And Localization Among Developmental Stages Of Schistosoma Mansoni, Ana E. Zeraik, Gabriel Rinaldi, Victoria H. Mann, Anastas Popratiloff, Ana P.U. Araujo, Ricardo Demarco, Paul J. Brindley

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Septins are a family of eukaryotic GTP binding proteins conserved from yeasts to humans. Originally identified in mutants of budding yeast, septins participate in diverse cellular functions including cytokinesis, organization of actin networks, cell polarity, vesicle trafficking and many others. Septins assemble into heteroligomers to form filaments and rings. Here, four septins of Schistosoma mansoni are described, which appear to be conserved within the phylum Platyhelminthes. These orthologues were related to the SEPT5, SEPT10 and SEPT7 septins of humans, and hence we have termed the schistosome septins SmSEPT5, SmSEPT10, SmSEPT7.1 and SmSEPT7.2. Septin transcripts were detected throughout the developmental cycle …

Metastatic Castration-Resistant Prostate Cancer: Critical Review Of Enzalutamide, Joelle El-Amm, Nihar Patel, Ashley Freeman, Jeanny B. Aragon-Ching

Medicine Faculty Publications

Enzalutamide, previously known as MDV300, is an oral, second-generation androgen receptor (AR) signaling inhibitor or antagonist that was approved by the Food and Drug Administration in 2012 for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) postdocetaxel. Preclinical studies have demonstrated impressive affinity to the AR compared to the first-generation AR inhibitors. The landmark Phase III AFFIRM trial demonstrated improved overall survival benefit compared to placebo in addition to improvement in all tested parameters. Enzalutamide is currently being studied in several trials prechemotherapy and in earlier settings of prostate cancer. This review will discuss the mechanism of action of enzalutamide, …

Spatially Explicit Modeling Of Schistosomiasis Risk In Eastern China Based On A Synthesis Of Epidemiological, Environmental, And Intermediate Host Genetic Data, Matthias Schrader, Torsten Hauffe, Zhijie Zhang, George M. Davis, Fred Jopp, Justin V. Remais, Thomas Wilke

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Schistosomiasis japonica is a major parasitic disease threatening millions of people in China. Though overall prevalence was greatly reduced during the second half of the past century, continued persistence in some areas and cases of re-emergence in others remain major concerns. As many regions in China are approaching disease elimination, obtaining quantitative data on Schistosoma japonicum parasites is increasingly difficult. This study examines the distribution of schistosomiasis in eastern China, taking advantage of the fact that the single intermediate host serves as a major transmission bottleneck. Epidemiological, population-genetic and high-resolution ecological data are combined to construct a predictive model capable …

Microproteinuria During Opisthorchis Viverrini Infection: A Biomarker For Advanced Renal And Hepatobiliary Pathologies From Chronic Opisthorchiasis, Prasert Saichua, Paiboon Sithithaworn, Amar R. Jariwala, David J. Diemert, Jiraporn Sithithaworn, Banchob Sripa, Thewarach Laha, Eimorn Mairiang, Chawalit Pairojkul, Maria V. Periago, Narong Khuntikeo, Jason Mulvenna, Jeffrey M. Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Approximately 680 million people are at risk of infection with Opisthorchis viverrini (OV) andClonorchis sinensis, with an estimated 10 million infected with OV in Southeast Asia alone. While opisthorchiasis is associated with hepatobiliary pathologies, such as advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA), animal models of OV infection show that immune-complex glomerulonephritis is an important renal pathology that develops simultaneously with hepatobiliary pathologies. A cardinal sign of immune-complex glomerulonephritis is the urinary excretion of immunoglobulin G (IgG) (microproteinuria). In community-based studies in OV endemic areas along the Chi River in northeastern Thailand, we observed that over half of …

Conserved Structural Domains In Foxd4l1, A Neural Forkhead Box Transcription Factor, Are Required To Repress Or Activate Target Genes, Steven L. Klein, Karen M. Neilson, John Orban, Sergey Yaklichkin, Jennifer Hoffbauer, Kathy Mood, Ira O. Daar, Sally Ann Moody

Anatomy and Regenerative Biology Faculty Publications

FoxD4L1 is a forkhead transcription factor that expands the neural ectoderm by down-regulating genes that promote the onset of neural differentiation and up-regulating genes that maintain proliferative neural precursors in an immature state. We previously demonstrated that binding of Grg4 to an Eh-1 motif enhances the ability of FoxD4L1 to down-regulate target neural genes but does not account for all of its repressive activity. Herein we analyzed the protein sequence for additional interaction motifs and secondary structure. Eight conserved motifs were identified in the C-terminal region of fish and frog proteins. Extending the analysis to mammals identified a high scoring …

Vaccination Of Balb/C Mice With The Na-Apr-1 M74 Hookworm Vaccine Generates Neutralizing Antibodies And A Potent Immune Response, Amar R. Jariwala, Xi Chen, Mark S. Pearson, Brian Keegan, Jill B. Brelsford, Jordan L. Plieskatt, Bin Zhan, Alex Loukas, Peter Hotez, Jeffrey M. Bethony

GW Research Days 2013

BACKGROUND

Human Hookworm Infection, a neglected tropical disease infects more than 600 million people around the world. Hookworms ingest hemoglobin containing erythrocytes and Necator americanus Aspartic Protease-1 wild type (Na-APR-1wt) a hemoglobinase cleaves hemoglobin to form Heme and Globin. Globin is further digested by other gut enzymes and the nutritional products are absorbed by the hookworm’s gut wall. Also, Heme which is toxic to hookworm is detoxified by the Necator americanus Glutathione Transferase-1 (Na-GST-1); a detoxification enzyme secreted by the gut of the hookworm. Necator americanus Aspartic Protease-1 M74 (Na-APR-1 M74) is a new …

Novel Neutralizing Antibody Assays For Recombinant Human Hookworm Na-Gst-1 Vaccine, Xi Chen, Brian Keegan, Peter J. Hotez, Jeffrey M. Bethony, Amar R. Jariwala

GW Research Days 2013

BACKGROUND

Necator Americanus, a human hookworm causes approximately 85% of the global hookworm infections. Hookworm ingest hemoglobin containing erythrocytes. Hemoglobin is further digested to Heme and Globin by hookworm's gut enzymes. Iron-containing Heme is a potent enzyme inhibitor and generates toxic reactive oxygen species which is toxic to hookworms. Hookworm's gut enzyme Na-GST-1 (Necator Americanus Glutathione S-Transferase-1) has been hypothesized to detoxify Heme. Na-GST-1 adjuvanted with Alhydrogel® is a new vaccine which is currently under clinical development. Na-GST-1 has two active sites, the ligand binding or Heme detoxification site (H-site) and the catalytic active glutathione binding …

Transitioning Veterans Collaborative, Suzanne Arnott, Kiara Baginski, Geoff Ball, Elizabeth Buchanan, Jay Choi, Courtney Gieber, Jackie Lussier, Nigel Madden, Satya Piccioni-Grenna, Nellie Trenga-Schein, Paul Tschudi, Heidi Wolff

ISCOPES Posters and Presentations

No abstract provided.

Break Out: Urogenital Schistosomiasis And Schistosoma Haematobium Infection In The Post-Genomic Era, Paul J. Brindley, Peter J. Hotez

Microbiology, Immunology, and Tropical Medicine Faculty Publications

No abstract provided.

Progress Realized: Trends In Hiv-1 Viral Load And Cd4 Cell Count In A Tertiary-Care Center From 1999 Through 2011, Howard B. Gale, Manuel D. Rodriguez, Heather J. Hoffman, Debra A. Benator, Fred M. Gordin, Ann M. Labriola, Virginia L. Kan

Epidemiology Faculty Publications

Abstract

Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (PSNP-trend) for the association …

Androgen Receptor-Target Genes In African American Prostate Cancer Disparities, Bi-Dar Wang, Qi Yang, Kristin Ceniccola, Fernando Bianco, Ramez Andrawis, Thomas W. Jarrett, Harold A. Frazier, Steven R. Patierno, Norman H. Lee

Pharmacology and Physiology Faculty Publications

The incidence and mortality rates of prostate cancer (PCa) are higher in African American (AA) compared to Caucasian American (CA) men. To elucidate the molecular mechanisms underlying PCa disparities, we employed an integrative approach combining gene expression profiling and pathway and promoter analyses to investigate differential transcriptomes and deregulated signaling pathways in AA versus CA cancers. A comparison of AA and CA PCa specimens identified 1,188 differentially expressed genes. Interestingly, these transcriptional differences were overrepresented in signaling pathways that converged on the androgen receptor (AR), suggesting that the AR may be a unifying oncogenic theme in AA PCa. Gene promoter …

Effects Of Treatment On Ige Responses Against Parasite Allergen-Like Proteins And Immunit To Reinfection In Childhood Schistosome And Hookworm Coinfections, Angela Pinot De Moira, Frances M. Jones, Shona Wilson, Edridah Tukahebwa, Colin M. Fitzsimmons, Joseph K. Mwatha, Jeffrey M. Bethony, Narcis B. Kabatereine, David W. Dunne

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Naturally occurring human immunity to both schistosomiasis and hookworm infection has been associated with IgE responses against parasite allergen-like proteins. Since the two helminths frequently coinfect the same individuals, there is growing advocacy for their concurrent treatment. However, both helminths are known to exert strong immunomodulatory effects; therefore, coinfected individuals could have immune responses different from those characteristically seen in monoinfected individuals. In this study, we measured changes in IgE, IgG1, and IgG4 responses to schistosome and hookworm antigens, including the allergen-like proteins Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1), SmTAL2, and Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2), following concurrent …

Transcriptional Responses Of In Vivo Praziquantel Exposure In Schistosomes Identifies A Functional Role For Calcium Signalling Pathway Member Camkii, Hong You, Donald P. Mcmanus, Wei Hu, Michael J. Smout, Paul J. Brindley, Geoffrey N. Gobert

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Treatment for clinical schistosomiasis has relied centrally on the broad spectrum anthelmintic praziquantel; however, there is limited information on its mode of action or the molecular response of the parasite. This paper presents a transcriptional and functional approach to defining the molecular responses of schistosomes to praziquantel. Differential gene expression in Schistosoma japonicum was investigated by transcriptome-wide microarray analysis of adult worms perfused from infected mice after 0.5 to 24 hours after oral administration of sub-lethal doses of praziquantel. Genes up-regulated initially in male parasites were associated with “Tegument/Muscle Repair” and “Lipid/Ion Regulation” functions and were followed by “Drug Resistance” …

The Expanding Genomic Landscape Of Autism: Discovering The 'Forest' Beyond The 'Trees', Valerie Wailin Hu

Biochemistry and Molecular Medicine Faculty Publications

Autism spectrum disorders (ASDs) are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication, and restricted, repetitive behaviors. Because ASDs are among the most heritable of neuropsychiatric disorders, much of autism research has focused on the search for genetic variants in protein-coding genes (i.e., the "trees"). However, no single gene can account for more than 1% of the cases of ASD. Yet, genome-wide association studies have often identified statistically significant associations of genetic variations in regions of DNA that do not code for proteins (i.e., intergenic regions). There is increasing evidence that such noncoding regions are actively …

The Dn2 Myeloid-T (Dn2mt) Progenitor Is A Target Cell For Leukemic Transformation By The Tlx1 Oncogene, Lynnsey A. Zweier-Renn, Irene Riz, Teresa S. Hawley, Robert G. Hawley

Anatomy and Regenerative Biology Faculty Publications

Introduction: Inappropriate activation of the TLX1 (T-cell leukemia homeobox 1) gene by chromosomal translocation is a recurrent event in human T-cell Acute Lymphoblastic Leukemia (T-ALL). Ectopic expression of TLX1 in murine bone marrow progenitor cells using a conventional retroviral vector efficiently yields immortalized cell lines and induces T-ALL-like tumors in mice after long latency.

Methods: To eliminate a potential contribution of retroviral insertional mutagenesis to TLX1 immortalizing and transforming function, we incorporated the TLX1 gene into an insulated self-inactivating retroviral vector.

Results: Retrovirally transduced TLX1-expressing murine bone marrow progenitor cells had a growth/survival advantage and readily gave rise to immortalized …

Alloreactivity-Based Medical Conditions, Stanislav Vukmanovic, Margaret G. Petroff, Anne M. Stevens, Daniel Rukavina

Pediatrics Faculty Publications

No abstract provided.

Activation Of Human Herpesvirus Replication By Apoptosis, Alka Prasad, Jil Remick, Steven L. Zeichner

Pediatrics Faculty Publications

A central feature of herpesvirus biology is the ability of herpesviruses to remain latent within host cells. Classically, exposure to inducing agents, like activating cytokines or phorbol esters that stimulate host cell signal transduction events, and epigenetic agents (e.g., butyrate) was thought to end latency. We recently showed that Kaposi's sarcoma-associated herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) has another, alternative emergency escape replication pathway that is triggered when KSHV's host cell undergoes apoptosis, characterized by the lack of a requirement for the replication and transcription activator (RTA) protein, accelerated late gene kinetics, and production of virus with decreased infectivity. Caspase-3 …

Bone-Targeted Therapies In Metastatic Castration-Resistant Prostate Cancer: Evolving Paradigms, Joelle El-Amm, Ashley Freeman, Nihar Patel, Jeanny B. Aragon-Ching

Medicine Faculty Publications

Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC …