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Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells
Leukemia (2010) 24, 756–764 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells A Pellagatti1, M Cazzola2, A Giagounidis3, J Perry1, L Malcovati2, MG Della Porta2,MJa¨dersten4, S Killick5, A Verma6, CJ Norbury7, E Hellstro¨m-Lindberg4, JS Wainscoat1 and J Boultwood1 1LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK; 2Department of Hematology Oncology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany; 4Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK; 6Albert Einstein College of Medicine, Bronx, NY, USA and 7Sir William Dunn School of Pathology, University of Oxford, Oxford, UK To gain insight into the molecular pathogenesis of the the World Health Organization.6,7 Patients with refractory myelodysplastic syndromes (MDS), we performed global gene anemia (RA) with or without ringed sideroblasts, according to expression profiling and pathway analysis on the hemato- poietic stem cells (HSC) of 183 MDS patients as compared with the the French–American–British classification, were subdivided HSC of 17 healthy controls. The most significantly deregulated based on the presence or absence of multilineage dysplasia. In pathways in MDS include interferon signaling, thrombopoietin addition, patients with RA with excess blasts (RAEB) were signaling and the Wnt pathways. Among the most signifi- subdivided into two categories, RAEB1 and RAEB2, based on the cantly deregulated gene pathways in early MDS are immuno- percentage of bone marrow blasts. -
GSK3 Is a Negative Regulator of the Thermogenic Program in Brown Adipocytes
GSK3 is a negative regulator of the thermogenic program in brown adipocytes Markussen, Lasse K.; Winther, Sally; Wicksteed, Barton; Hansen, Jacob B. Published in: Scientific Reports DOI: 10.1038/s41598-018-21795-y Publication date: 2018 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Markussen, L. K., Winther, S., Wicksteed, B., & Hansen, J. B. (2018). GSK3 is a negative regulator of the thermogenic program in brown adipocytes. Scientific Reports, 8, 1-12. [3469]. https://doi.org/10.1038/s41598- 018-21795-y Download date: 01. okt.. 2021 www.nature.com/scientificreports OPEN GSK3 is a negative regulator of the thermogenic program in brown adipocytes Received: 16 January 2017 Lasse K. Markussen1, Sally Winther1, Barton Wicksteed2 & Jacob B. Hansen 1 Accepted: 9 February 2018 Brown adipose tissue is a promising therapeutic target in metabolic disorders due to its ability to Published: xx xx xxxx dissipate energy and improve systemic insulin sensitivity and glucose homeostasis. β-Adrenergic stimulation of brown adipocytes leads to an increase in oxygen consumption and induction of a thermogenic gene program that includes uncoupling protein 1 (Ucp1) and fbroblast growth factor 21 (Fgf21). In kinase inhibitor screens, we have identifed glycogen synthase kinase 3 (GSK3) as a negative regulator of basal and β-adrenergically stimulated Fgf21 expression in cultured brown adipocytes. In addition, inhibition of GSK3 also caused increased Ucp1 expression and oxygen consumption. β-Adrenergic stimulation triggered an inhibitory phosphorylation of GSK3 in a protein kinase A (PKA)- dependent manner. Mechanistically, inhibition of GSK3 activated the mitogen activated protein kinase (MAPK) kinase 3/6-p38 MAPK-activating transcription factor 2 signaling module. -
Mouse Rras2 Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Rras2 Knockout Project (CRISPR/Cas9) Objective: To create a Rras2 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Rras2 gene (NCBI Reference Sequence: NM_025846 ; Ensembl: ENSMUSG00000055723 ) is located on Mouse chromosome 7. 6 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 6 (Transcript: ENSMUST00000069449). Exon 3~5 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Homozygote and heterozygote null mice are lymphopenic, resulting from diminished homeostatic proliferation and impaired T cell and B cell survival. Mice homozygous for a gene trap insertion exhibit retinal degeneration, and increased total body mass and total body fat. Exon 3 starts from about 32.19% of the coding region. Exon 3~5 covers 54.08% of the coding region. The size of effective KO region: ~8729 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 3 4 5 6 Legends Exon of mouse Rras2 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 1302 bp section upstream of Exon 3 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. -
The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid
The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome Annette K. Brenner, Elise Aasebø, Maria Hernandez-Valladares, Frode Selheim, Frode Berven, Ida-Sofie Grønningsæter, Sushma Bartaula-Brevik and Øystein Bruserud Supplementary Material S2 of S31 Table S1. Detailed information about the 68 AML patients included in the study. # of blasts Viability Proliferation Cytokine Viable cells Change in ID Gender Age Etiology FAB Cytogenetics Mutations CD34 Colonies (109/L) (%) 48 h (cpm) secretion (106) 5 weeks phenotype 1 M 42 de novo 241 M2 normal Flt3 pos 31.0 3848 low 0.24 7 yes 2 M 82 MF 12.4 M2 t(9;22) wt pos 81.6 74,686 low 1.43 969 yes 3 F 49 CML/relapse 149 M2 complex n.d. pos 26.2 3472 low 0.08 n.d. no 4 M 33 de novo 62.0 M2 normal wt pos 67.5 6206 low 0.08 6.5 no 5 M 71 relapse 91.0 M4 normal NPM1 pos 63.5 21,331 low 0.17 n.d. yes 6 M 83 de novo 109 M1 n.d. wt pos 19.1 8764 low 1.65 693 no 7 F 77 MDS 26.4 M1 normal wt pos 89.4 53,799 high 3.43 2746 no 8 M 46 de novo 26.9 M1 normal NPM1 n.d. n.d. 3472 low 1.56 n.d. no 9 M 68 MF 50.8 M4 normal D835 pos 69.4 1640 low 0.08 n.d. -
MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells
Cell Stem Cell Article MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells Amy N. Abell,1,2,7,* Nicole Vincent Jordan,1,2,7 Weichun Huang,6 Aleix Prat,2,4 Alicia A. Midland,5 Nancy L. Johnson,1,2 Deborah A. Granger,1,2 Piotr A. Mieczkowski,2,3 Charles M. Perou,2,4 Shawn M. Gomez,5 Leping Li,6 and Gary L. Johnson1,2,* 1Department of Pharmacology 2Lineberger Comprehensive Cancer Center 3Department of Genetics and Carolina Center for Genome Sciences 4Department of Genetics 5Department of Biomedical Engineering and Curriculum in Bioinformatics and Computational Biology University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA 6Biostatistics Branch, National Institute of Environmental Health Sciences RTP, NC 27709, USA 7These authors contributed equally to this work *Correspondence: [email protected] (A.N.A.), [email protected] (G.L.J.) DOI 10.1016/j.stem.2011.03.008 SUMMARY berg, 2008). During development, EMT is responsible for proper formation of the body plan and for differentiation of many tissues Epithelial stem cells self-renew while maintaining and organs. Examples of EMT in mammalian development multipotency, but the dependence of stem cell prop- include implantation, gastrulation, and neural crest formation erties on maintenance of the epithelial phenotype is (Thiery et al., 2009). Initiation of placenta formation regulated unclear. We previously showed that trophoblast by trophoectoderm differentiation is the first, and yet most poorly stem (TS) cells lacking the protein kinase MAP3K4 defined, developmental EMT. maintain properties of both stemness and epithelial- The commitment of stem cells to specialized cell types requires extensive reprogramming of gene expression, involving, in part, mesenchymal transition (EMT). -
Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K
Published OnlineFirst August 9, 2018; DOI: 10.1158/1078-0432.CCR-18-0717 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Targeting the CDK4/6-Rb Pathway Enhances Response to PI3K Inhibition in PIK3CA-Mutant Lung Squamous Cell Carcinoma Ruoshi Shi1,2, Ming Li1, Vibha Raghavan1, Shirley Tam1, Michael Cabanero1, Nhu-An Pham1, Frances A. Shepherd1,3, Nadeem Moghal1,2, and Ming-Sound Tsao1,2,4 Abstract Purpose: Lung squamous cell carcinoma (LUSC) is a major of LUSC PDX models identified PI3K pathway alterations in subtype of non–small cell lung cancer characterized by mul- over 50% of the models. In vivo screening using PI3K tiple genetic alterations, particularly PI3K pathway alterations inhibitors in 12 of these models identified PIK3CA mutation which have been identified in over 50% of LUSC cases. Despite as a predictive biomarker of response (<20% tumor growth being an attractive target, single-agent PI3K inhibitors have compared with baseline/vehicle). Combined inhibition of demonstrated modest response in LUSC. Thus, novel combi- PI3K and CDK4/6 in models with PIK3CA mutation resulted nation therapies targeting LUSC are needed. in greater antitumor effects compared with either mono- Experimental Design: PI3K inhibitors alone and in com- therapy alone. In addition, the combination of the two bination with CDK4/6 inhibitors were evaluated in previously drugs achieved targeted inhibition of the PI3K and cell-cycle established LUSC patient-derived xenografts (PDX) using an pathways. in vivo screening method. Screening results were validated with Conclusions: PIK3CA mutations predict response to PI3K in vivo expansion to 5 to 8 mice per arm. -
RRAS2 Rabbit Polyclonal Antibody – TA308124 | Origene
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for TA308124 RRAS2 Rabbit Polyclonal Antibody Product data: Product Type: Primary Antibodies Applications: IHC, WB Recommended Dilution: IHC:1:100-1:1000; WB:1:1000-1:10000 Reactivity: Human, Mouse (Predicted: Bovine, Rhesus Monkey, Rat) Host: Rabbit Isotype: IgG Clonality: Polyclonal Immunogen: Recombinant fragment corresponding to a region within amino acids 1 and 204 of TC21 (Uniprot ID#P62070) Formulation: 0.1M Tris, 0.1M Glycine, 10% Glycerol (pH7). 0.01% Thimerosal was added as a preservative. Concentration: lot specific Purification: Purified by antigen-affinity chromatography. Conjugation: Unconjugated Storage: Store at -20°C as received. Stability: Stable for 12 months from date of receipt. Predicted Protein Size: 23 kDa Gene Name: related RAS viral (r-ras) oncogene homolog 2 Database Link: NP_001096139 Entrez Gene 66922 MouseEntrez Gene 365355 RatEntrez Gene 22800 Human P62070 Synonyms: TC21 Note: Seq homology of immunogen across species: Rat (100%), Rhesus Monkey (100%), Bovine (100%) Protein Families: Druggable Genome Protein Pathways: MAPK signaling pathway, Regulation of actin cytoskeleton, Tight junction This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online » ©2021 OriGene Technologies, Inc., 9620 Medical Center Drive, Ste 200, Rockville, MD 20850, US 1 / 3 RRAS2 Rabbit Polyclonal Antibody – TA308124 Product images: Sample (50 ug of whole cell lysate). A: mouse brain. 12% SDS PAGE. TA308124 diluted at 1:5000. Sample (30 ug of whole cell lysate). -
Macrophage Activation JUNB Is a Key Transcriptional Modulator Of
JUNB Is a Key Transcriptional Modulator of Macrophage Activation Mary F. Fontana, Alyssa Baccarella, Nidhi Pancholi, Miles A. Pufall, De'Broski R. Herbert and Charles C. Kim This information is current as of October 2, 2021. J Immunol 2015; 194:177-186; Prepublished online 3 December 2014; doi: 10.4049/jimmunol.1401595 http://www.jimmunol.org/content/194/1/177 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/12/03/jimmunol.140159 Material 5.DCSupplemental References This article cites 40 articles, 7 of which you can access for free at: http://www.jimmunol.org/content/194/1/177.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • 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 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology JUNB Is a Key Transcriptional Modulator of Macrophage Activation Mary F. Fontana,* Alyssa Baccarella,* Nidhi Pancholi,* Miles A. -
Role and Regulation of the P53-Homolog P73 in the Transformation of Normal Human Fibroblasts
Role and regulation of the p53-homolog p73 in the transformation of normal human fibroblasts Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Bayerischen Julius-Maximilians-Universität Würzburg vorgelegt von Lars Hofmann aus Aschaffenburg Würzburg 2007 Eingereicht am Mitglieder der Promotionskommission: Vorsitzender: Prof. Dr. Dr. Martin J. Müller Gutachter: Prof. Dr. Michael P. Schön Gutachter : Prof. Dr. Georg Krohne Tag des Promotionskolloquiums: Doktorurkunde ausgehändigt am Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbständig angefertigt und keine anderen als die angegebenen Hilfsmittel und Quellen verwendet habe. Diese Arbeit wurde weder in gleicher noch in ähnlicher Form in einem anderen Prüfungsverfahren vorgelegt. Ich habe früher, außer den mit dem Zulassungsgesuch urkundlichen Graden, keine weiteren akademischen Grade erworben und zu erwerben gesucht. Würzburg, Lars Hofmann Content SUMMARY ................................................................................................................ IV ZUSAMMENFASSUNG ............................................................................................. V 1. INTRODUCTION ................................................................................................. 1 1.1. Molecular basics of cancer .......................................................................................... 1 1.2. Early research on tumorigenesis ................................................................................. 3 1.3. Developing -
Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in Vitro and in Vivo
TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Genetik Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in vitro and in vivo - Towards Response Prediction in Cancer Therapy with Kinase Inhibitors Michaela Bairlein Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ. -Prof. Dr. K. Schneitz Prüfer der Dissertation: 1. Univ.-Prof. Dr. A. Gierl 2. Hon.-Prof. Dr. h.c. A. Ullrich (Eberhard-Karls-Universität Tübingen) 3. Univ.-Prof. A. Schnieke, Ph.D. Die Dissertation wurde am 07.01.2010 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 19.04.2010 angenommen. FOR MY PARENTS 1 Contents 2 Summary ................................................................................................................................................................... 5 3 Zusammenfassung .................................................................................................................................................... 6 4 Introduction .............................................................................................................................................................. 8 4.1 Cancer .............................................................................................................................................................. -
Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight. -
Molecular Signatures Differentiate Immune States in Type 1 Diabetes Families
Page 1 of 65 Diabetes Molecular signatures differentiate immune states in Type 1 diabetes families Yi-Guang Chen1, Susanne M. Cabrera1, Shuang Jia1, Mary L. Kaldunski1, Joanna Kramer1, Sami Cheong2, Rhonda Geoffrey1, Mark F. Roethle1, Jeffrey E. Woodliff3, Carla J. Greenbaum4, Xujing Wang5, and Martin J. Hessner1 1The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin Milwaukee, WI 53226, USA. 2The Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. 3Flow Cytometry & Cell Separation Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA. 4Diabetes Research Program, Benaroya Research Institute, Seattle, WA, 98101, USA. 5Systems Biology Center, the National Heart, Lung, and Blood Institute, the National Institutes of Health, Bethesda, MD 20824, USA. Corresponding author: Martin J. Hessner, Ph.D., The Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, WI 53226, USA Tel: 011-1-414-955-4496; Fax: 011-1-414-955-6663; E-mail: [email protected]. Running title: Innate Inflammation in T1D Families Word count: 3999 Number of Tables: 1 Number of Figures: 7 1 For Peer Review Only Diabetes Publish Ahead of Print, published online April 23, 2014 Diabetes Page 2 of 65 ABSTRACT Mechanisms associated with Type 1 diabetes (T1D) development remain incompletely defined. Employing a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially IL-1 dependent, signatures associated with pre and recent onset (RO) T1D relative to unrelated healthy controls (uHC).