Medical Sciences Commons^™

Anxiety Associated Increased Cpg Methylation In The Promoter Of Asb1: A Translational Approach Evidenced By Epidemiological And Clinical Studies And A Murine Model, Rebecca T. Emeny, Jens Baumert, Anthony S. Zannas, Sonja Kunze, Simone Wahl, Stella Iurato

Dartmouth Scholarship

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n= 1522, age 32–72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited …

The Effects Of Early Mobilization On Length Of Stay For Patients Undergoing Total Joint Replacement Surgery., Megan Howard Pt, Mpt, Kimberly Fritts Pt, Mpt

Department of Medicine

No abstract provided.

The Motor Cortical Representation Of A Muscle Is Not Homogeneous In Brain Connectivity, Jo Armour Smith, Alaa Albishi, Sarine Babikian, Skulpan Asavasopon, Beth E. Fisher, Jason Kutch

Physical Therapy Faculty Articles and Research

Functional connectivity patterns of the motor cortical representational area of single muscles have not been extensively mapped in humans, particularly for the axial musculature. Functional connectivity may provide a neural substrate for adaptation of muscle activity in axial muscles that have both voluntary and postural functions. The purpose of this study was to combine brain stimulation and neuroimaging to both map the cortical representation of the external oblique (EO) in primary motor cortex (M1) and supplementary motor area (SMA), and to establish the resting-state functional connectivity associated with this representation. Motor evoked potentials were elicited from the EO muscle in …

H2s And Homocysteine Control A Novel Feedback Regulation Of Cystathionine Beta Synthase And Cystathionine Gamma Lyase In Cardiomyocytes., Shyam Sundar Nandi, Paras K. Mishra

Journal Articles: Cellular & Integrative Physiology

Hydrogen sulfide (H2S), a cardioprotective gas, is endogenously produced from homocysteine by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE) enzymes. However, effect of H2S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesize that homocysteine and H2S regulate CBS and CSE expressions in a dose dependent manner in cardiomyocytes, and CBS deficiency induces cardiac CSE expression. To test the hypothesis, we treated murine atrial HL1 cardiomyocytes with increasing doses of homocysteine or Na2S/GYY4137, a H2S donor, and measured the levels of CBS and CSE. We found that homocysteine upregulates CSE …

Multi-Scale Spatial Cognition Models And Bio-Inspired Robot Navigation, Martin I. Llofriu Alonso

USF Tampa Graduate Theses and Dissertations

The rodent navigation system has been the focus of study for over a century. Discoveries made lately have provided insight on the inner workings of this system. Since then, computational approaches have been used to test hypothesis, as well as to improve robotics navigation and learning by taking inspiration on the rodent navigation system.

This dissertation focuses on the study of the multi-scale representation of the rat’s current location found in the rat hippocampus. It first introduces a model that uses these different scales in the Morris maze task to show their advantages. The generalization power of larger scales of …

A Role For Ankyring In Maturation And Maintenance Of The Nodes Of Ranvier., Benjamin Yang, Bridget M. Curran, Stephen R. Tymanskyj

Department of Neuroscience Faculty Papers

No abstract provided.

A Delayed H3k27me3 Accumulation After Dna Replication Of Embryonic Stem Cells Opens Chromatin For Lineage Specific Transcription Factors To Bind And Initiate Differentiation, Jingli Cai, Svetlana Petruk, Robyn Sussman, Sina K. Kovermann, Samantha Mariani, Bruno Calabretta, Steven B Mcmahon, Hugh W. Brock, Lorraine Iacovitti, Alexander Mazo

Department of Neuroscience Faculty Papers

Introduction

Pluripotent stem cells (PSCs) have been useful to generate differentiated progenies for cell replacement therapy, and disease models. The Parkinson’s Disease (PD) field was arguably one of the first to have embraced the promise of stem cells. However, regardless of the differentiation protocols used, cultures and grafts continue to contain multiple cell types with midbrain dopamine (mDA) neural progenitors (NPs) and neurons representing only a fraction of total cells in the dish or graft. During cell differentiation, recruitment of transcription factors (TFs) to repressed genes in euchromatin is essential to activate new transcriptional programs, which is impeded by condensed …

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) …

Presynaptic Lrp4 Promotes Synapse Number And Function Of Excitatory Cns Neurons., Timothy J. Mosca, David J. Luginbuhl, Irving E. Wang, Liqun Luo

Department of Neuroscience Faculty Papers

Precise coordination of synaptic connections ensures proper information flow within circuits. The activity of presynaptic organizing molecules signaling to downstream pathways is essential for such coordination, though such entities remain incompletely known. We show that LRP4, a conserved transmembrane protein known for its postsynaptic roles, functions presynaptically as an organizing molecule. In the Drosophila brain, LRP4 localizes to the nerve terminals at or near active zones. Loss of presynaptic LRP4 reduces excitatory (not inhibitory) synapse number, impairs active zone architecture, and abolishes olfactory attraction - the latter of which can be suppressed by reducing presynaptic GABAB receptors. LRP4 overexpression increases …

Week Of June 12, 2017, New York Medical College

InTouch

• New York Medical College Marks its 158th Commencement Ceremony, Bestowing Degrees on 395 Graduates
• NYMC Unveils the Center of Excellence in Precision Medicine and Responses to Bioterrorism and Disasters
• Office of Medical Education Hosts Preceptor Appreciation Banquet
• SHSP Applauds New Honor Society Inductees
• TCDM Makes Progress on Dental Clinic

Selective Inhibition Of Small-Diameter Axons Using Infrared Light, Emilie H. Lothet, Kendrick M. Shaw, Hui Lu, Junqi Zhuo, Yves T. Wang, Shi Gu, Hillel J. Chiel, Michael W. Jenkins

Faculty Scholarship

Novel clinical treatments to target peripheral nerves are being developed which primarily use electrical current. Recently, infrared (IR) light was shown to inhibit peripheral nerves with high spatial and temporal specificity. Here, for the first time, we demonstrate that IR can selectively and reversibly inhibit small-diameter axons at lower radiant exposures than large-diameter axons. We provide a mathematical rationale, and then demonstrate it experimentally in individual axons of identified neurons in the marine mollusk Aplysia californica, and in axons within the vagus nerve of a mammal, the musk shrew Suncus murinus. The ability to selectively, rapidly, and reversibly control small-diameter …

Integration Of Metabolomics, Transcriptomics, And Microrna Expression Profiling Reveals A Mir-143-Hk2-Glucose Network Underlying Zinc-Deficiency-Associated Esophageal Neoplasia, Louise Y. Fong, Ruiyan Jing, Karl Smalley, Cristian Taccioli, Johannes Fahrmann, Dinesh K. Barupal, Hansjuerg Alder, John L. Farber, Oliver Fiehn, Carlo M. Croce

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Esophageal squamous cell carcinoma (ESCC) in humans is a deadly disease associated with dietary zinc (Zn)-deficiency. In the rat esophagus, Zn-deficiency induces cell proliferation, alters mRNA and microRNA gene expression, and promotes ESCC. We investigated whether Zn-deficiency alters cell metabolism by evaluating metabolomic profiles of esophageal epithelia from Zn-deficient and replenished rats vs sufficient rats, using untargeted gas chromatography time-of-flight mass spectrometry (n = 8/group). The Zn-deficient proliferative esophagus exhibits a distinct metabolic profile with glucose down 153-fold and lactic acid up 1.7-fold (P < 0.0001), indicating aerobic glycolysis (the "Warburg effect"), a hallmark of cancer cells. Zn-replenishment rapidly increases glucose content, restores deregulated metabolites to control levels, and reverses the hyperplastic phenotype. Integration of metabolomics and our reported transcriptomic data for this tissue unveils a link between glucose down-regulation and overexpression of HK2, an enzyme that catalyzes the first step of glycolysis and is overexpressed in cancer cells. Searching our published microRNA profile, we find that the tumor-suppressor miR-143, a negative regulator of HK2, is down-regulated in Zn-deficient esophagus. Using in situ hybridization and immunohistochemical analysis, the inverse correlation between miR-143 down-regulation and HK2 overexpression is documented in hyperplastic Zndeficient esophagus, archived ESCC-bearing Zn-deficient esophagus, and human ESCC tissues. Thus, to sustain uncontrolled cell proliferation, Zn-deficiency reprograms glucose metabolism by modulating expression of miR-143 and its target HK2. Our work provides new insight into critical roles of Zn in ESCC development and prevention. © Fong et al.

The Intra-Rater Reliability Of The Clavicular Jump Test (Cjt), Thomas Koc

Seton Hall University Dissertations and Theses (ETDs)

Background: Shoulder pain is the third most common musculoskeletal complaint in today’s society. Approximately 50% of patients with shoulder pain seek medical attention, which includes physical therapy. A thorough understanding of the anatomy of the shoulder, including its fascial attachments, its biomechanics, and functional relationship to nearby spinal regions is crucial for successful rehabilitation diagnostics and treatment interventions. Purpose: The purpose of this study is to determine the intra-rater reliability of the Clavicular Jump Test (CJT). Methods: This study is a quasi-experimental, one-group pretest-posttest (repeated measures), and correlation design. A total of 96 subjects (47 males and 49 females) volunteered …

Obesity, Metabolic Factors And Risk Of Different Histological Types Of Lung Cancer: A Mendelian Randomization Study, Robert Carreras-Torres, Mattias Johansson, Philip C. Haycock, Kaitlin H. Wade, Caroline L. Relton, Richard M. Martin, George Davey Smith, Demetrius Albanes, Melinda C. Aldrich, Angeline Andrew, Susanne M. Arnold, Heike Bickeböller, Stig E. Bojesen, Hans Brunnström, Jonas Manjer, Irene Brüske, Neil E. Caporaso, Chu Chen, David C. Christiani, Warren Jay Christian, Jennifer A. Doherty, Eric J. Duell, John K. Field, Michael P. A. Davies, Michael W. Marcus, Gary E. Goodman, Kjell Grankvist, Aage Haugen, Yun-Chul Hong, Lambertus A. Kiemeney

Markey Cancer Center Faculty Publications

Background

Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.

Methods and findings

We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of …

Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), Ronald C. Bruntz, Andrew N. Lane, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.

Mixed-Mode Oscillations In Pyramidal Neurons Under Antiepileptic Drug Conditions, Babak V-Ghaffari, M. Kouhnavard, Sherif M. Elbasiouny

Neuroscience, Cell Biology, & Physiology Faculty Publications

Subthreshold oscillations in combination with large-amplitude oscillations generate mixedmode oscillations (MMOs), which mediate various spatial and temporal cognition and memory processes and behavioral motor tasks. Although many studies have shown that canard theory is a reliable method to investigate the properties underlying the MMOs phenomena, the relationship between the results obtained by applying canard theory and conductancebased models of neurons and their electrophysiological mechanisms are still not well understood. The goal of this study was to apply canard theory to the conductance-based model of pyramidal neurons in layer V of the Entorhinal Cortex to investigate the properties of MMOs under …

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, …

Signalling Via The Osteopontin And High Mobility Group Box-1 Axis Drives The Fibrogenic Response To Liver Injury, Elena Arriazu, Xiaodong Ge, Tung-Ming Leung, Fernando Magdaleno, Aritz Lopategi, Yongke Lu, Naoto Kitamura, Raquel Urtasun, Neil Theise, Daniel J. Antoine, Natalia Nieto

Pharmacology, Physiology and Toxicology

Objective: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression. Design and results: Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas …

A Whole Lot Of Shakin' Going On: Movement Disorders Caused By Brain Trauma, Jack E. Hubbard, Samuel D. Hodge, Jr.

Cleveland State Law Review

There has been a lot of publicity directed to the consequence of brain trauma, such as headaches forgetfulness, irritability, and depression. That is only part of the sequelae. A little-known but challenging result of brain trauma is the development of or aggravation of a movement disorder such as a tremor, dystonia, a tic, or Parkinson’s Disease.

A movement disorder is an all-encompassing term that refers to a constellation of neurological issues that cause involuntary or voluntary movements or abnormal positioning of a body part. Various regions of the brain interact with each other to control movements of the body. If …

The Trial Lawyer And The Reptilian Brain: A Critique, Louis J. Sirico, Jr.

Cleveland State Law Review

This Article brings together neuroscience, cultural symbolism, and the strategies of practicing lawyers to critique the reptile strategy, now popular among trial lawyers. The strategy directs the lawyer to trigger the reptilian brains of jurors so that they react instinctively to threats to themselves and their communities. When humans feel threatened, the reptilian brain, the most primitive part of the brain, takes charge and instinctively controls human conduct. Therefore, if a lawyer can make a juror feel threatened, the lawyer makes an appeal to the juror’s reptilian brain and virtually assures a victory. Thus, a lawyer’s argument should intensify the …

Genome- And Cd4+ T-Cell Methylome-Wide Association Study Of Circulating Trimethylamine-N-Oxide In The Genetics Of Lipid Lowering Drugs And Diet Network (Goldn), Stella Aslibekyan, Marguerite R. Irvin, Bertha A. Hidalgo, Rodney T. Perry, Elias J. Jeyarajah, Erwin Garcia, Irina Shalaurova, Paul N. Hopkins, Michael A. Province, Hemant K. Tiwari, Jose M. Ordovas, Devin M. Absher, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels.

Methods and results: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, …

Comparative Effectiveness Research Of Disease-Modifying Therapies For The Management Of Multiple Sclerosis: Analysis Of A Large Health Insurance Claims Database., Aaron Boster, Jacqueline Nicholas, Ning Wu, Wei-Shi Yeh, Monica Fay, Michael Edwards, Ming-Yi Huang, Andrew Lee

Neuroscience Articles

INTRODUCTION: Limited data are available on the real-world effectiveness of newer oral disease-modifying therapies (DMTs) in multiple sclerosis. The purpose of this study was to retrospectively compare the real-world effectiveness of dimethyl fumarate (DMF), fingolimod, teriflunomide, and injectable DMTs in routine clinical practice based on US claims data.

METHODS: Patients newly-initiating DMF, interferon beta (IFNβ), glatiramer acetate (GA), teriflunomide, or fingolimod in 2013 were identified in the Truven MarketScan Commercial Claims Databases (N = 6372). Relapse episodes were identified based on a published claim-based algorithm and used to determine the annualized relapse rate (ARR) for the year before and after …

Zinc Transporters Ybtx And Znuabc Are Required For The Virulence Of Yersinia Pestis In Bubonic And Pneumonic Plague In Mice, Alexander G. Bobrov, Olga Kirillina, Marina Y. Fosso, Jacqueline D. Fetherston, M. Clarke Miller, Tiva T. Vancleave, Joseph A. Burlison, William K. Arnold, Matthew B. Lawrenz, Sylvie Garneau-Tsodikova, Robert D. Perry

Microbiology, Immunology, and Molecular Genetics Faculty Publications

A number of bacterial pathogens require the ZnuABC Zinc (Zn²⁺) transporter and/or a second Zn²⁺ transport system to overcome Zn²⁺ sequestration by mammalian hosts. Previously we have shown that in addition to ZnuABC, Yersinia pestis possesses a second Zn²⁺ transporter that involves components of the yersiniabactin (Ybt), siderophore-dependent iron transport system. Synthesis of the Ybt siderophore and YbtX, a member of the major facilitator superfamily, are both critical components of the second Zn²⁺ transport system. Here we demonstrate that a ybtX znu double mutant is essentially avirulent in mouse models of bubonic and pneumonic …

Risk Of Incident Clinical Diagnosis Of Alzheimer's Disease-Type Dementia Attributable To Pathology-Confirmed Vascular Disease, Hiroko H. Dodge, Jian Zhu, Randy Woltjer, Peter T. Nelson, David A. Bennett, Nigel J. Cairns, David W. Fardo, Jeffrey A. Kaye, Deniz-Erten Lyons, Nora Mattek, Julie A. Schneider, Lisa C. Silbert, Chengjie Xiong, Lei Yu, Frederick A. Schmitt, Richard J. Kryscio, Erin L. Abner, Smart Data Consortium

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD).

METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with …

Lack Of Effect Of Vitamin D3 Supplementation In Autism: A 20-Week, Placebo-Controlled Rct, Conor Kerley, Clare Power, Louise Gallagher, David Coghlan

Articles

No abstract provided.

Bioactivity Of Oral Linaclotide In Human Colorectum For Cancer Chemoprevention., David S. Weinberg, Jieru E. Lin, Nathan R. Foster, Gary Della'zanna, Asad Umar, Drew Seisler, Walter K. Kraft, David M. Kastenberg, Leo C. Katz, Paul J. Limburg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 mg of oral linaclotide daily for 7 days to healthy …

The Role Of Tgf-Β In Ctb-Insulin Regulated Human Dendritic Cell Tolerance, Grace Edosewe Esebanmen

Loma Linda University Electronic Theses, Dissertations & Projects

Cholera toxin B subunit fusion to autoantigen vaccines such as proinsulin (CTB-INS) down regulates dendritic cell (DC) activation and induces the synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased IDO1 biosynthesis may play an important role in CTB-INS vaccine inhibition of DC activation. Previous studies suggest transforming growth factor beta (TGF-β) may play a role in the stimulation of IDO1 biosynthesis for induction of immunological tolerance in murine DCs. To elucidate the mechanisms by which CTB-INS may stimulate IDO1 biosynthesis and mediate tolerance in human DCs, we investigated the …