DOCSLIB.ORG

Effects of Targeting the Transcription Factors Ikaros and Aiolos on B Cell Activation and Differentiation in Systemic Lupus Erythematosus

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Effects of Targeting the Transcription Factors Ikaros and Aiolos on B Cell Activation and Differentiation in Systemic Lupus Erythematosus Immunology and inflammation Lupus Sci Med: first published as 10.1136/lupus-2020-000445 on 16 March 2021. Downloaded from Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus Felice Rivellese ,1 Sotiria Manou- Stathopoulou,1 Daniele Mauro,1 Katriona Goldmann,1 Debasish Pyne,2 Ravindra Rajakariar,3 Patrick Gordon,4 Peter Schafer,5 Michele Bombardieri,1 Costantino Pitzalis,1 Myles J Lewis 1 To cite: Rivellese F, ABSTRACT Manou- Stathopoulou S, Objective To evaluate the effects of targeting Ikaros and Key messages Mauro D, et al. Effects of Aiolos by cereblon modulator iberdomide on the activation What is already known about this subject? targeting the transcription and differentiation of B- cells from patients with systemic factors Ikaros and Aiolos The transcription factors Ikaros and Aiolos, which lupus erythematosus (SLE). ► on B cell activation and are critical for B cell differentiation, are implicated in Methods CD19+ B- cells isolated from the peripheral differentiation in systemic systemic lupus erythematosus (SLE) pathogenesis. blood of patients with SLE (n=41) were cultured with lupus erythematosus. Targeting Ikaros and Aiolos using the cereblon mod- TLR7 ligand resiquimod ±IFNα together with iberdomide ► Lupus Science & Medicine ulator iberdomide has been proposed as a promising 2021;8:e000445. doi:10.1136/ or control from day 0 (n=16). Additionally, in vitro B- cell therapeutic agent. lupus-2020-000445 differentiation was induced by stimulation with IL-2/IL-10/ IL-15/CD40L/resiquimod with iberdomide or control, given What does this study add? at day 0 or at day 4. At day 5, immunoglobulins were ► Additional material is ► Targeting Ikaros and Aiolos with iberdomide inhibits published online only. To view, measured by ELISA and cells analysed by flow cytometry. the TLR7- mediated differentiation of plasmablasts in please visit the journal online RNA- Seq was performed on fluorescence- activated cell- human SLE. - + low + + (http:// dx. doi. org/ 10. 1136/ sorted CD27 IgD naïve- B- cells and CD20 CD27 CD38 ► Iberdomide inhibits TLR7 and interferon driven au- lupus- 2020- 000445). plasmablasts to investigate the transcriptional toantibody production by SLE autoreactive B cells. consequences of iberdomide. ► RNA- sequencing was used to detect differentially Results Iberdomide significantly inhibited theTLR7 and expressed genes in iberdomide- treated differentiat- http://lupus.bmj.com/ FR, SM- S and DM contributed IFNα-mediated production of immunoglobulins from SLE ed SLE plasmablasts, thus identifying genes which equally. B- cells and the production of antinuclear antibodies as are most directly under the control of Ikaros and well as significantly reducing the number of CD27+CD38+ Received 16 September 2020 Aiolos. plasmablasts (0.3±0.18, vehicle 1.01±0.56, p=0.011) Revised 22 December 2020 + How might this impact on clinical practice or future Accepted 28 January 2021 and CD138 plasma cells (0.12±0.06, vehicle 0.28±0.02, p=0.03). Additionally, treatment with iberdomide from developments? day 0 significantly inhibited the differentiation of SLE B- ► This study provides strong evidence that therapeu- cells into plasmablasts (6.4±13.5 vs vehicle 34.9±20.1, tic targeting of Ikaros and Aiolos can ameliorate key on September 25, 2021 by guest. Protected copyright. p=0.013) and antibody production. When given at later pathogenic processes in human SLE. stages of differentiation, iberdomide did not affect the numbers of plasmablasts or the production of antibodies; however, it induced a significant modulation of gene cell lineages and their maturation into effector expression involving IKZF1 and IKZF3 transcriptional cells.1 IKZF1 (Ikaros) is an essential regulator programmes in both naïve B-cells and plasmablasts (400 of common lymphoid progenitor (CLP) stem and 461 differentially modulated genes, respectively, false cells. Ikzf1- deficient mice lack CLP and fail to discovery rate<0.05). generate mature B/T lymphocytes, natural Conclusion These results demonstrate the relevance of 2 3 Ikaros and Aiolos as therapeutic targets in SLE due to their killer and dendritic cells. IKZF1 also acts ability to modulate B cell activation and differentiation as a checkpoint at the pro- B cell to pre- B cell © Author(s) (or their 4 5 employer(s)) 2021. Re- use downstream of TLR7. transition stage. In contrast, IKZF3 (Aiolos) permitted under CC BY. is necessary for memory B cell and plasma cell Published by BMJ. formation and Ikzf3 deficient mice lack both For numbered affiliations see of these mature B cell populations.6 7 end of article. INTRODUCTION IKZF1, IKZF3 and more recently IKZF2 Correspondence to The Ikaros family of zinc- fingers (IKZF) (Helios) have been identified as suscepti- Dr Myles J Lewis; myles. lewis@ proteins are transcription factors critical for bility loci in systemic lupus erythematosus qmul. ac. uk the development of key haemopoietic stem (SLE) in large- scale genome- wide associated Rivellese F, et al. Lupus Science & Medicine 2021;8:e000445. doi:10.1136/lupus-2020-000445 1 Lupus Science & Medicine Lupus Sci Med: first published as 10.1136/lupus-2020-000445 on 16 March 2021. Downloaded from Table 1 Summary of patient characteristics (n=41) peripheral blood B cells from patients with SLE, specifi- cally on (i) TLR7 and IFN mediated B cell activation and Age, years mean (SD), range 47 (13) 21–72 differentiation, (ii) plasmablast/plasma cell differentia- Gender (female) 81% tion and (iii) transcriptional programmes underlying B ANA+ 86% cell differentiation. dsDNA+ 62% APS+ 19% MATERIALS AND METHODS Sm+ 14% Patient recruitment Skin involvement* 60% Peripheral blood and clinical demographics were collected from patients with a diagnosis of SLE from Barts Arthritis 60% Health NHS Trust and Kings College Hospital NHS Trust. Serositis 15% All study participants provided written informed consent Renal disease 10% at time of sample collection and fulfilled the 2012 updated Leucopaenia 25% American College of Rheumatology classification criteria 29 Thrombocytopaenia 5% ACR criteria for SLE. Patient characteristics are summa- rised in table 1. Sample collection from patients and Hydroxychloroquine 86% subsequent analysis were approved by UK local ethical Steroids 37.5% committee (REC reference 17/WS/0172). Patients or the *Including malar rash, photosensitivity and discoid lupus. public were not involved in the design, conduct, reporting or dissemination plans of the research. studies.8–13 IKZF1 polymorphism rs4917014 was identi- Blood processing and B cell isolation fied as a trans- expression quantitative trait locus, driving Peripheral blood mononuclear cells were isolated from upregulation of type 1 IFN genes and downregulation of peripheral blood using gradient separation with Lymph- complement genes.14 Ikaros has also been shown to influ- oprep (Alere), with RBC lysis via incubation in ammo- ence TLR7 signalling,15 representing another link with nium chloride (RBC-lysis buffer, Stemcell) for 5 min on SLE pathogenesis.16 ice. CD19+ cells were isolated via negative magnetic selec- Ikaros and Aiolos have emerged as the therapeutic tion with EasySep Human B Cell Isolation Kit (Stemcell). targets of the immunomodulatory drugs thalidomide and Purity (>95%) of isolated B cells was verified by flow cytom- analogues such as lenalidomide, which act as agonists for etry. For selected experiments, 1–2×105 B cells at baseline the ubiquitination E3 ligase complex cereblon,17 thus were stored in RNAprotect Cell Reagent (QIAGEN) and inducing ubiquitination and proteasomal degradation frozen at −80°C for subsequent RNA extraction. 18–20 of Ikaros and Aiolos. Thalidomide and its analogues http://lupus.bmj.com/ are well established as treatment options for multiple B cell culture and TLR7/IFN stimulation 21 Human B cells freshly isolated from patients with SLE myeloma. Lenalidomide inhibits plasma cells differen- 6 tiation from healthy donors in vitro22 and has been found were resuspended at concentration 0.5×10 cells/mL in to be effective in cases of treatment-refractor y cutaneous Iscove’s modified Dulbecco’s medium (IMDM) with 10% manifestations of SLE.23–25 More recently, a novel cereblon fetal calf serum (FCS), 1% antibiotic- antimycotic (Gibco) ligand has been developed, iberdomide, which binds with and 3 µM synthetic TLR7 agonist Resiquimod (R848, Invi- vogen) with/without 1000 IU IFNα (Enzo), together with higher affinity than thalidomide and other analogues, on September 25, 2021 by guest. Protected copyright. resulting in greater Ikaros/Aiolos degradation.26 iberdomide 1, 10 or 100 nM or vehicle control. At 5 days, In preliminary studies, iberdomide reduced Ikaros and cells were harvested for fluorescence- activated cell sorting Aiolos expression in SLE B cells, while inhibiting antibody (FACS) analysis, and supernatants stored for ELISA. production and differentiation of B cells into plasmab- 27 B cell culture and plasmablast differentiation lasts. Iberdomide has undergone a phase I study, which Human B cells freshly isolated from SLE patients were explored the effects of oral administration in healthy resuspended and cultured using a modified plasmablast volunteers and confirmed the reduction of Ikaros and 30 28 differentiation protocol with HA- sCD40L (R&D) at 50 Aiolos at protein level in B cells, T cells and monocytes. ng/mL cross-linked with 1 µg/mL anti- HA IgG (R&D), Iberdomide also inhibited anti-dsDNA and antiphospho- IL-2 at 20 U/mL, IL-10 at 50 ng/mL (Peprotech), IL-15 lipid antibody production ex vivo from SLE mononu- at 10 ng/mL (Peprotech) and TLR7 ligand R848 at 3 µM clear cells. Iberdomide reduced absolute B cell counts, (Invivogen). Iberdomide (10 nM) or control vehicle was augmented IL-2 production from T cells and inhibited added at two timepoints, at either day 0 or 18 hours prior IL-1β production in response to proinflammatory stimuli, to harvest on day 4. After 5 days, cells were harvested for underpinning its further development for the treatment FACS, and supernatants stored for ELISA. of SLE, with an ongoing phase II trial ( Clinical-­​Trials.
Load more

Recommended publications
  • Cyclin D1 Is a Direct Transcriptional Target of GATA3 in Neuroblastoma Tumor Cells
    Oncogene (2010) 29, 2739–2745 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc SHORT COMMUNICATION Cyclin D1 is a direct transcriptional target of GATA3 in neuroblastoma tumor cells JJ Molenaar1,2, ME Ebus1, J Koster1, E Santo1, D Geerts1, R Versteeg1 and HN Caron2 1Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands and 2Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Almost all neuroblastoma tumors express excess levels of 2000). Several checkpoints normally prevent premature Cyclin D1 (CCND1) compared to normal tissues and cell-cycle progression and cell division. The crucial G1 other tumor types. Only a small percentage of these entry point is controlled by the D-type Cyclins that can neuroblastoma tumors have high-level amplification of the activate CDK4/6 that in turn phosphorylate the pRb Cyclin D1 gene. The other neuroblastoma tumors have protein. This results in a release of the E2F transcription equally high Cyclin D1 expression without amplification. factor that causes transcriptional upregulation of Silencing of Cyclin D1 expression was previously found to numerous genes involved in further progression of the trigger differentiation of neuroblastoma cells. Over- cell cycle (Sherr, 1996). expression of Cyclin D1 is therefore one of the most Neuroblastomas are embryonal tumors that originate frequent mechanisms with a postulated function in neuro- from precursor cells of the sympathetic nervous system. blastoma pathogenesis. The cause for the Cyclin D1 This tumor has a very poor prognosis and despite the overexpression is unknown.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • A Clinicopathological and Molecular Genetic Analysis of Low-Grade Glioma in Adults
    A CLINICOPATHOLOGICAL AND MOLECULAR GENETIC ANALYSIS OF LOW-GRADE GLIOMA IN ADULTS Presented by ANUSHREE SINGH MSc A thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy Brain Tumour Research Centre Research Institute in Healthcare Sciences Faculty of Science and Engineering University of Wolverhampton November 2014 i DECLARATION This work or any part thereof has not previously been presented in any form to the University or to any other body whether for the purposes of assessment, publication or for any other purpose (unless otherwise indicated). Save for any express acknowledgments, references and/or bibliographies cited in the work, I confirm that the intellectual content of the work is the result of my own efforts and of no other person. The right of Anushree Singh to be identified as author of this work is asserted in accordance with ss.77 and 78 of the Copyright, Designs and Patents Act 1988. At this date copyright is owned by the author. Signature: Anushree Date: 30th November 2014 ii ABSTRACT The aim of the study was to identify molecular markers that can determine progression of low grade glioma. This was done using various approaches such as IDH1 and IDH2 mutation analysis, MGMT methylation analysis, copy number analysis using array comparative genomic hybridisation and identification of differentially expressed miRNAs using miRNA microarray analysis. IDH1 mutation was present at a frequency of 71% in low grade glioma and was identified as an independent marker for improved OS in a multivariate analysis, which confirms the previous findings in low grade glioma studies.
    [Show full text]
  • Aiolos Overexpression in Systemic Lupus Erythematosus B Cell
    Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 This information is current as Modulation of Cereblon Activity of September 27, 2021. Yumi Nakayama, Jolanta Kosek, Lori Capone, Eun Mi Hur, Peter H. Schafer and Garth E. Ringheim J Immunol 2017; 199:2388-2407; Prepublished online 28 August 2017; Downloaded from doi: 10.4049/jimmunol.1601725 http://www.jimmunol.org/content/199/7/2388 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2017/08/26/jimmunol.160172 Material 5.DCSupplemental References This article cites 131 articles, 45 of which you can access for free at: http://www.jimmunol.org/content/199/7/2388.full#ref-list-1 Why The JI? Submit online. by guest on September 27, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
    [Show full text]
  • Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell
    cancers Article Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 Weiqiang Zhao 1,*, Ying Li 2 , Chenjiao Yao 2 , Guojuan Zhang 1, Kevin Y. Zhao 1, Wei Chen 1, Peng Ru 1, Xiaokang Pan 1, Huolin Tu 1 and Daniel Jones 1 1 The James Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA; [email protected] (G.Z.); [email protected] (K.Y.Z.); [email protected] (W.C.); [email protected] (P.R.); [email protected] (X.P.); [email protected] (H.T.); [email protected] (D.J.) 2 The Department of Pediatrics and Department of Hematology, Xiang-Ya Third Hospital, Changsha 410013, China; [email protected] (Y.L.); [email protected] (C.Y.) * Correspondence: [email protected]; Tel.: +1-6142934210 Received: 27 August 2020; Accepted: 22 October 2020; Published: 28 October 2020 Simple Summary: Abnormal RNA splicing plays a fundamental role in leukemogenesis in acute lymphoblastic leukemia (ALL). Many cases of high-risk B-cell ALL cases, including BCR-ABL1+ and BCR-ABL1-like ALL, share a common molecular mechanism of aberrant fusion transcripts involving tyrosine kinase genes combined with dysregulation of the transcription factor and lymphocyte differentiation factor IKZF1. Dysfunction of IKZF1 in ALL is caused by mutation and gene deletion but also alternative splicing resulting in exon skipping with production of aberrant IKZF1 proteins. We report here an assay to detect aberrantly spliced isoforms of IKZF1 in ALL to assist in diagnosis, outcome prediction, and therapy selection in ALL and the identification of a novel altered IKZF1 product in a model ALL cell line.
    [Show full text]
  • CDC2 Mediates Progestin Initiated Endometrial Stromal Cell Proliferation: a PR Signaling to Gene Expression Independently of Its Binding to Chromatin
    CDC2 Mediates Progestin Initiated Endometrial Stromal Cell Proliferation: A PR Signaling to Gene Expression Independently of Its Binding to Chromatin Griselda Vallejo1, Alejandro D. La Greca1., Inti C. Tarifa-Reischle1., Ana C. Mestre-Citrinovitz1, Cecilia Ballare´ 2, Miguel Beato2,3, Patricia Saragu¨ eta1* 1 Instituto de Biologı´a y Medicina Experimental, IByME-Conicet, Buenos Aires, Argentina, 2 Centre de Regulacio´ Geno`mica, (CRG), Barcelona, Spain, 3 University Pompeu Fabra (UPF), Barcelona, Spain Abstract Although non-genomic steroid receptor pathways have been studied over the past decade, little is known about the direct gene expression changes that take place as a consequence of their activation. Progesterone controls proliferation of rat endometrial stromal cells during the peri-implantation phase of pregnancy. We showed that picomolar concentration of progestin R5020 mimics this control in UIII endometrial stromal cells via ERK1-2 and AKT activation mediated by interaction of Progesterone Receptor (PR) with Estrogen Receptor beta (ERb) and without transcriptional activity of endogenous PR and ER. Here we identify early downstream targets of cytoplasmic PR signaling and their possible role in endometrial stromal cell proliferation. Microarray analysis of global gene expression changes in UIII cells treated for 45 min with progestin identified 97 up- and 341 down-regulated genes. The most over-represented molecular functions were transcription factors and regulatory factors associated with cell proliferation and cell cycle, a large fraction of which were repressors down-regulated by hormone. Further analysis verified that progestins regulate Ccnd1, JunD, Usf1, Gfi1, Cyr61, and Cdkn1b through PR- mediated activation of ligand-free ER, ERK1-2 or AKT, in the absence of genomic PR binding.
    [Show full text]
  • CRISPR Activation Screening of Circulating Tumor Cells Identifies Enhancers of Blood-Based Metastasis
    CRISPR Activation Screening of Circulating Tumor Cells Identifies Enhancers of Blood-Based Metastasis The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Ebright, Richard Yon. 2020. CRISPR Activation Screening of Circulating Tumor Cells Identifies Enhancers of Blood-Based Metastasis. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365157 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA CRISPR activation screening of circulating tumor cells identifies enhancers of blood-based metastasis A dissertation presented by Richard Yon Ebright to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts September 2019 © 2019 Richard Yon Ebright All rights reserved. Dissertation Advisors: Daniel A. Haber & Shyamala Maheswaran Richard Yon Ebright CRISPR activation screening of circulating tumor cells identifies enhancers of blood-based metastasis Abstract Over ninety percent of cancer mortality is attributable to metastasis, most commonly due to the blood-borne dissemination of cancer cells from a primary tumor to secondary tissues. However, the vast majority of these cancer cells in the circulation, known as circulating tumor cells (CTCs), never go on to form clinically relevant metastases, instead dying or senescing in the circulation or at distant sites.
    [Show full text]
  • Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes.
    [Show full text]
  • B-Cell Malignancies in Microrna Eμ-Mir-17∼92 Transgenic Mice
    B-cell malignancies in microRNA Eμ-miR-17∼92 transgenic mice Sukhinder K. Sandhua, Matteo Fassana,b, Stefano Voliniaa,c, Francesca Lovata, Veronica Balattia, Yuri Pekarskya, and Carlo M. Crocea,1 aDepartment of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH 43210; bARC-NET Research Centre, University of Verona, VR 37134, Verona, Italy; cDepartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, FE 44121 Ferrara, Italy Contributed by Carlo M. Croce, September 22, 2013 (sent for review July 12, 2013) miR-17∼92 is a polycistronic microRNA (miR) cluster (consisting of cluster, but not of its paralogs, has shown that miR-17∼92 plays miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) which an important role in B-cell development, and the KO mice die frequently is overexpressed in several solid and lymphoid malig- shortly after birth from lung hypoplasia and ventricular septal nancies. Loss- and gain-of-function studies have revealed the role defects (8). Further examination of the role of individual miRs in of miR-17∼92 in heart, lung, and B-cell development and in Myc- B-cell lymphomas showed that miR-19a and miR19b are required induced B-cell lymphomas, respectively. Recent studies indicate and sufficient for the proliferative activities of the cluster (9). that overexpression of this locus leads to lymphoproliferation, To understand better the role of the miR-17∼92 cluster in but no experimental proof that dysregulation of this cluster causes B-cell neoplastic progression, we generated miR-17∼92 B-cell– B-cell lymphomas or leukemias is available.
    [Show full text]
  • Per2 Antibody
    Product Datasheet Per2 Antibody Catalog No: #SAB436 Orders: [email protected] Description Support: [email protected] Product Name Per2 Antibody Host Species Rabbit Clonality Polyclonal Purification Antibodies were produced by immunizing rabbits with synthetic peptide and KLH conjugates. Antibodies were purified by affinity-chromatography using epitope-specific peptide. Applications Custom antibody Species Reactivity Ms Immunogen Type Peptide-KLH Target Name Per2 Other Names Period circadian protein homolog 2 Accession No. uniprot:O54943 Calculated MW 136kDa Formulation Supplied at 1.0mg/mL in phosphate buffered saline (without Mg2+ and Ca2+), pH 7.4, 150mM NaCl, 0.02% sodium azide and 85% glycerol. Storage Store at -20°C for long term preservation (recommended). Store at 4°C for short term use. Application Details Western blotting: 1:500~1:1000 Background Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers').
    [Show full text]
  • Coactivation of NF-Kb and Notch Signaling Is Sufficient to Induce B
    Regular Article LYMPHOID NEOPLASIA Coactivation of NF-kB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion Downloaded from https://ashpublications.org/blood/article-pdf/135/2/108/1550992/bloodbld2019001438.pdf by UNIV OF IOWA LIBRARIES user on 20 February 2020 Yan Xiu,1,* Qianze Dong,1,2,* Lin Fu,1,2 Aaron Bossler,1 Xiaobing Tang,1,2 Brendan Boyce,3 Nicholas Borcherding,1 Mariah Leidinger,1 Jose´ Luis Sardina,4,5 Hai-hui Xue,6 Qingchang Li,2 Andrew Feldman,7 Iannis Aifantis,8 Francesco Boccalatte,8 Lili Wang,9 Meiling Jin,9 Joseph Khoury,10 Wei Wang,10 Shimin Hu,10 Youzhong Yuan,11 Endi Wang,12 Ji Yuan,13 Siegfried Janz,14 John Colgan,15 Hasem Habelhah,1 Thomas Waldschmidt,1 Markus Muschen,¨ 9 Adam Bagg,16 Benjamin Darbro,17 and Chen Zhao1,18 1Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA; 2Department of Pathology, China Medical University, Shenyang, China; 3Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY; 4Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain; 5Josep Carreras Leukaemia Research Institute, Campus ICO-Germans Trias i Pujol, Barcelona, Spain; 6Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA; 7Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN; 8Department of Pathology, NYU School of Medicine,
    [Show full text]
  • Mir-376C Promotes Carcinogenesis and Serves As a Plasma Marker for Gastric Carcinoma
    RESEARCH ARTICLE miR-376c promotes carcinogenesis and serves as a plasma marker for gastric carcinoma Pei-Shih Hung1, Chin-Yau Chen2, Wei-Ting Chen2, Chen-Yu Kuo3, Wen-Liang Fang4,5, Kuo-Hung Huang4,5, Peng-Chih Chiu5, Su-Shun Lo2,6* 1 Department of Education and Medical Research, National Yang-Ming University Hospital, Yilan, Taiwan, 2 Department of Surgery, National Yang-Ming University Hospital, Yilan, Taiwan, 3 Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan, 4 Division of General Surgery, Veterans General Hospital±Taipei, Taipei, Taiwan, 5 Department of Dentistry, National Yang-Ming University Hospital, Yilan, Taiwan, 6 School of Medicine, National Yang-Ming University, Taipei, Taiwan a1111111111 [email protected] a1111111111 * a1111111111 a1111111111 a1111111111 Abstract Gastric carcinoma is highly prevalent throughout the world. Understanding the pathogenesis of this disease will benefit diagnosis and resolution. Studies show that miRNAs are involved in the tumorigenesis of gastric carcinoma. An initial screening followed by subsequent vali- OPEN ACCESS dation identified that miR-376c is up-regulated in gastric carcinoma tissue and the plasma Citation: Hung P-S, Chen C-Y, Chen W-T, Kuo C-Y, of patients with the disease. In addition, the urinary level of miR-376c is also significantly Fang W-L, Huang K-H, et al. (2017) miR-376c increased in gastric carcinoma patients. The plasma miR-376c level was validated as a bio- promotes carcinogenesis and serves as a plasma marker for gastric carcinoma. PLoS ONE 12(5): marker for gastric carcinoma, including early stage tumors. The induction of miR-376c was e0177346.
    [Show full text]