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Targeting Protein Kinase CK2 and CDK4/6 Pathways with a Multi-Kinase Inhibitor ON108110 Suppresses Pro-Survival Signaling and Gr
www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 102), pp: 37753-37765 Research Paper Targeting protein kinase CK2 and CDK4/6 pathways with a multi-kinase inhibitor ON108110 suppresses pro-survival signaling and growth in mantle cell lymphoma and T-acute lymphoblastic leukemia Amol Padgaonkar1,3, Olga Rechkoblit2, Rodgrigo Vasquez-Del Carpio1,4, Venkat Pallela5, Venkata Subbaiah DRC1,6, Stephen C. Cosenza1, Stacey J. Baker1, M.V. Ramana Reddy1, Aneel Aggarwal2 and E. Premkumar Reddy1,2 1Department of Oncological Sciences, Icahn School of Medicine, New York 10029, NY, USA 2Department of Pharmacological Sciences, Icahn School of Medicine, New York 10029, NY, USA 3Present Address: Prescient Healthcare Group, Jersey City 07302, NJ, USA 4Present address: Sandoz, a Novartis Company, Miami 33126, FL, USA 5Present address: Pfizer, Collegeville 19426, PA, USA 6Present address: Carnegie Pharmaceuticals, Monmouth Junction 08852, NJ, USA Correspondence to: E. Premkumar Reddy, email: [email protected] Keywords: mantle cell lumphoma; T-cell acute lymphoblastic leukemia; CDK4; CK2 Received: December 06, 2018 Accepted: December 13, 2018 Published: December 28, 2018 Copyright: Padgaonkar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Overexpression and constitutive activation of CYCLIN D1 and Casein Kinase 2 are common features of many hematologic malignancies, including mantle cell lymphoma (MCL) and leukemias such as T-cell acute lymphoblastic leukemia (T-ALL). Although both CK2 and CDK4 inhibitors have shown promising results against these tumor types, none of these agents have achieved objective responses in the clinic as monotherapies. -
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. -
Evaluation of Chromatin Accessibility in Prefrontal Cortex of Individuals with Schizophrenia
ARTICLE DOI: 10.1038/s41467-018-05379-y OPEN Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia Julien Bryois 1, Melanie E. Garrett2, Lingyun Song3, Alexias Safi3, Paola Giusti-Rodriguez 4, Graham D. Johnson 3, Annie W. Shieh13, Alfonso Buil5, John F. Fullard6, Panos Roussos 6,7,8, Pamela Sklar6, Schahram Akbarian 6, Vahram Haroutunian 6,9, Craig A. Stockmeier 10, Gregory A. Wray3,11, Kevin P. White12, Chunyu Liu13, Timothy E. Reddy 3,14, Allison Ashley-Koch2,15, Patrick F. Sullivan 1,4,16 & Gregory E. Crawford 3,17 1234567890():,; Schizophrenia genome-wide association studies have identified >150 regions of the genome associated with disease risk, yet there is little evidence that coding mutations contribute to this disorder. To explore the mechanism of non-coding regulatory elements in schizophrenia, we performed ATAC-seq on adult prefrontal cortex brain samples from 135 individuals with schizophrenia and 137 controls, and identified 118,152 ATAC-seq peaks. These accessible chromatin regions in the brain are highly enriched for schizophrenia SNP heritability. Accessible chromatin regions that overlap evolutionarily conserved regions exhibit an even higher heritability enrichment, indicating that sequence conservation can further refine functional risk variants. We identify few differences in chromatin accessibility between cases and controls, in contrast to thousands of age-related differential accessible chromatin regions. Altogether, we characterize chromatin accessibility in the human prefrontal cortex, the effect of schizophrenia and age on chromatin accessibility, and provide evidence that our dataset will allow for fine mapping of risk variants. 1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17177 Stockholm, Sweden. -
Tanibirumab (CUI C3490677) Add to Cart
5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor -
WO 2017/173206 Al 5 October 2017 (05.10.2017) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2017/173206 Al 5 October 2017 (05.10.2017) P O P C T (51) International Patent Classification: CA 94121 (US). HUBBARD, Robert; 7684 Marker Road, A61K 31/52 (2006.01) C07D 473/02 (2006.01) San Diego, CA 92087 (US). MIKOLON, David; 6140 A61K 31/505 (2006.01) C07D 473/26 (2006.01) Calle Empinada, San Diego, CA 92120 (US). RAYMON, A61K 31/519 (2006.01) C07D 473/32 (2006.01) Heather; 3520 Vista de la Orilla, San Diego, CA 921 17 (US). SHI, Tao; 4650 Tarantella Lane, San Diego, CA (21) International Application Number: 92130 (US). TRAN, Tam, M.; 8953 Libra Drive, San PCT/US20 17/025252 Diego, CA 92126 (US). TSUJI, Toshiya; 4171 Donald (22) International Filing Date: Court, San Diego, CA 921 17 (US). WONG, Lilly, L.; 871 3 1 March 2017 (3 1.03.2017) Viva Court, Solana Beach, CA 92075 (US). XU, Suichan; 9650 Deer Trail Place, San Diego, CA 92127 (US). ZHU, (25) Filing Language: English Dan; 4432 Calle Mar De Armonia, San Diego, CA 92130 (26) Publication Language: English (US). (30) Priority Data: (74) Agents: BRUNER, Michael, J. et al; Jones Day, 250 Ve- 62/3 17,412 1 April 2016 (01.04.2016) US sey Street, New York, NY 10281-1047 (US). (71) Applicant: SIGNAL PHARMACEUTICALS, LLC (81) Designated States (unless otherwise indicated, for every [US/US]; 10300 Campus Point Drive, Suite 100, San kind of national protection available): AE, AG, AL, AM, Diego, CA 92121 (US). -
The Early Years of Hematology: Gabriel Andral and Giulio Bizzozero’S Solutions to the Blood Enigma
THE EARLY YEARS OF HEMATOLOGY: GABRIEL ANDRAL AND GIULIO BIZZOZERO’S SOLUTIONS TO THE BLOOD ENIGMA Sofia Bruzzese Università Campus Biomedico di Roma Introduction Andral and Bizzozero’s innovations “…the field of hematology, under the guide of Andral, assumed a Both Andral and Bizzozero were two farsighted new fundamental role in the branch of pathology.” scientists. Since the start of haematologic studies Andral Gabriel Andral (1797-1876) is the undisputed father of modern developed more efficient methods for its work, hematology, a position already aknowledged by his contemporaries. introducing his innovative point of view on the Since his early studies in physiopathology, Andral showed his interest use of the microscope. This instrument was not for this field and between 1840 and 1842, he started to center his commonly used during this period, but Andral, research on the composition of blood. In this manner the field of understood the benefit of its practice, especially hematology, under the guide of Andral, assumed a new fundamental role in the study of the blood. For that reason, the in the branch of pathology. His findings laid the foundation stone for the analysis of blood and its alteration were only next generations of doctors. Following in Andral's footsteps, Italian Giulio run following a strict pattern of three phases: all Bizzozero (1846-1901) conducted important studies on the of them needed the use of the microscope. hematopoietic function of the bone marrow and on the platelets. “As for Bizzozero, […] he was considered as the most expert Italian doctor in the use of microscopic techniques.” As for Bizzozero, thanks to the published work between 1862 and 1868, he was considered as the most expert Italian doctor in the use of microscopic techniques. -
Targeting Stat3 and Kinases in Lymphoid Malignancies
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
576065839024.Pdf
Autopsy and Case Reports ISSN: 2236-1960 Hospital Universitário da Universidade de São Paulo Rocha, Luiz Otávio Savassi Luigi Bogliolo: master of a glorious lineage Autopsy and Case Reports, vol. 10, no. 4, 2020 Hospital Universitário da Universidade de São Paulo DOI: 10.4322/acr.2020.234 Available in: http://www.redalyc.org/articulo.oa?id=576065839024 How to cite Complete issue Scientific Information System Redalyc More information about this article Network of Scientific Journals from Latin America and the Caribbean, Spain and Journal's webpage in redalyc.org Portugal Project academic non-profit, developed under the open access initiative Editorial Luigi Bogliolo: master of a glorious lineage Luiz Otávio Savassi Rocha1 How to cite: Rocha LOS. Luigi Bogliolo: master of a glorious lineage. [editorial]. Autops Case Rep [Internet]. 2020;10(4):e2020234. https://doi.org/10.4322/acr.2020.234 Keywords History of Medicine; Pathology; Autopsy LUIGI BOGLIOLO (1908-1981) Of Italian origin but Brazilian by adoption, of Prof. Enrico Emilio Franco, who was a source of Luigi Bogliolo was born on April 18, 1908, on the inspiration for him throughout his life. In the 1931- island of Sardinia, in Sassari, the main commune 1932 biennium, he was a volunteer assistant at the of the province of the same name. He died in Belo Institute of Pathological Anatomy and Histology of Horizonte on September 6, 1981. The firstborn child the University of Sassari, directed by Franco. At the of Enrico Bogliolo, a railroad worker, and Maria end of 1932, he moved, along with his mentor, to Ruju, he graduated with a medical degree from the the Royal Adriatic University Benito Mussolini, based University of Sassari in 1930 as the best student in Bari, where he became a staff assistant in the in his class. -
Whole Exome Sequencing in Families at High Risk for Hodgkin Lymphoma: Identification of a Predisposing Mutation in the KDR Gene
Hodgkin Lymphoma SUPPLEMENTARY APPENDIX Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene Melissa Rotunno, 1 Mary L. McMaster, 1 Joseph Boland, 2 Sara Bass, 2 Xijun Zhang, 2 Laurie Burdett, 2 Belynda Hicks, 2 Sarangan Ravichandran, 3 Brian T. Luke, 3 Meredith Yeager, 2 Laura Fontaine, 4 Paula L. Hyland, 1 Alisa M. Goldstein, 1 NCI DCEG Cancer Sequencing Working Group, NCI DCEG Cancer Genomics Research Laboratory, Stephen J. Chanock, 5 Neil E. Caporaso, 1 Margaret A. Tucker, 6 and Lynn R. Goldin 1 1Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 2Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; 3Ad - vanced Biomedical Computing Center, Leidos Biomedical Research Inc.; Frederick National Laboratory for Cancer Research, Frederick, MD; 4Westat, Inc., Rockville MD; 5Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD; and 6Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA ©2016 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2015.135475 Received: August 19, 2015. Accepted: January 7, 2016. Pre-published: June 13, 2016. Correspondence: [email protected] Supplemental Author Information: NCI DCEG Cancer Sequencing Working Group: Mark H. Greene, Allan Hildesheim, Nan Hu, Maria Theresa Landi, Jennifer Loud, Phuong Mai, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Douglas R. Stewart, Philip R. Taylor, Geoffrey S. Tobias, Xiaohong R. Yang, Guoqin Yu NCI DCEG Cancer Genomics Research Laboratory: Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A. -
Epigenetic Services Citations
Active Motif Epigenetic Services Publications The papers below contain data generated by Active Motif’s Epigenetic Services team. To learn more about our services, please give us a call or visit us at www.activemotif.com/services. Technique Target Journal Year Reference Justin C. Boucher et al. CD28 Costimulatory Domain- ATAC-Seq, Cancer Immunol. Targeted Mutations Enhance Chimeric Antigen Receptor — 2021 RNA-Seq Res. T-cell Function. Cancer Immunol. Res. doi: 10.1158/2326- 6066.CIR-20-0253. Satvik Mareedu et al. Sarcolipin haploinsufficiency Am. J. Physiol. prevents dystrophic cardiomyopathy in mdx mice. RNA-Seq — Heart Circ. 2021 Am J Physiol Heart Circ Physiol. doi: 10.1152/ Physiol. ajpheart.00601.2020. Gabi Schutzius et al. BET bromodomain inhibitors regulate Nature Chemical ChIP-Seq BRD4 2021 keratinocyte plasticity. Nat. Chem. Biol. doi: 10.1038/ Biology s41589-020-00716-z. Siyun Wang et al. cMET promotes metastasis and ChIP-qPCR FOXO3 J. Cell Physiol. 2021 epithelial-mesenchymal transition in colorectal carcinoma by repressing RKIP. J. Cell Physiol. doi: 10.1002/jcp.30142. Sonia Iyer et al. Genetically Defined Syngeneic Mouse Models of Ovarian Cancer as Tools for the Discovery of ATAC-Seq — Cancer Discovery 2021 Combination Immunotherapy. Cancer Discov. doi: doi: 10.1158/2159-8290 Vinod Krishna et al. Integration of the Transcriptome and Genome-Wide Landscape of BRD2 and BRD4 Binding BRD2, BRD4, RNA Motifs Identifies Key Superenhancer Genes and Reveals ChIP-Seq J. Immunol. 2021 Pol II the Mechanism of Bet Inhibitor Action in Rheumatoid Arthritis Synovial Fibroblasts. J. Immunol. doi: doi: 10.4049/ jimmunol.2000286. Daniel Haag et al. -
Platelet Function Disorders
TREATMENT OF HEMOPHILIA APRIL 2008 • NO 19 PLATELET FUNCTION DISORDERS Second Edition Anjali A. Sharathkumar Amy Shapiro Indiana Hemophilia and Thrombosis Center Indianapolis, U.S.A. Published by the World Federation of Hemophilia (WFH), 1999; revised 2008. © World Federation of Hemophilia, 2008 The WFH encourages redistribution of its publications for educational purposes by not-for-profit hemophilia organizations. In order to obtain permission to reprint, redistribute, or translate this publication, please contact the Communications Department at the address below. This publication is accessible from the World Federation of Hemophilia’s website at www.wfh.org. Additional copies are also available from the WFH at: World Federation of Hemophilia 1425 René Lévesque Boulevard West, Suite 1010 Montréal, Québec H3G 1T7 CANADA Tel. : (514) 875-7944 Fax : (514) 875-8916 E-mail: [email protected] Internet: www.wfh.org The Treatment of Hemophilia series is intended to provide general information on the treatment and management of hemophilia. The World Federation of Hemophilia does not engage in the practice of medicine and under no circumstances recommends particular treatment for specific individuals. Dose schedules and other treatment regimes are continually revised and new side effects recognized. WFH makes no representation, express or implied, that drug doses or other treatment recommendations in this publication are correct. For these reasons it is strongly recommended that individuals seek the advice of a medical adviser and/or consult printed instructions provided by the pharmaceutical company before administering any of the drugs referred to in this monograph. Statements and opinions expressed here do not necessarily represent the opinions, policies, or recommendations of the World Federation of Hemophilia, its Executive Committee, or its staff. -
Functional Annotation of Human Long Noncoding Rnas Using Chromatin
bioRxiv preprint doi: https://doi.org/10.1101/2021.01.13.426305; this version posted January 14, 2021. 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. 1 Funconal annotaon of human long noncoding RNAs using chroman conformaon data Saumya Agrawal1, Tanvir Alam2, Masaru Koido1,3, Ivan V. Kulakovskiy4,5, Jessica Severin1, Imad ABugessaisa1, Andrey Buyan5,6, Josee Dos&e7, Masayoshi Itoh1,8, Naoto Kondo9, Yunjing Li10, Mickaël Mendez11, Jordan A. Ramilowski1,12, Ken Yagi1, Kayoko Yasuzawa1, CHi Wai Yip1, Yasushi Okazaki1, MicHael M. Ho9man11,13,14,15, Lisa Strug10, CHung CHau Hon1, CHikashi Terao1, Takeya Kasukawa1, Vsevolod J. Makeev4,16, Jay W. SHin1, Piero Carninci1, MicHiel JL de Hoon1 1RIKEN Center for Integra&ve Medical Sciences, YokoHama, Japan. 2College of Science and Engineering, Hamad Bin KHalifa University, DoHa, Qatar. 3Ins&tute of Medical Science, THe University of Tokyo, Tokyo, Japan. 4Vavilov Ins&tute of General Gene&cs, Russian Academy of Sciences, Moscow, Russia. 5Ins&tute of Protein ResearcH, Russian Academy of Sciences, PusHcHino, Russia. 6Faculty of Bioengineering and Bioinforma&cs, Lomonosov Moscow State University, Moscow, Russia. 7Department of BiocHemistry, Rosalind and Morris Goodman Cancer ResearcH Center, McGill University, Montréal, QuéBec, Canada. 8RIKEN Preven&ve Medicine and Diagnosis Innova&on Program, Wako, Japan. 9RIKEN Center for Life Science TecHnologies, YokoHama, Japan. 10Division of Biosta&s&cs, Dalla Lana ScHool of PuBlic HealtH, University of Toronto, Toronto, Ontario, Canada. 11Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. 12Advanced Medical ResearcH Center, YokoHama City University, YokoHama, Japan.