DOCSLIB.ORG

Clinical, Radiological and Molecular Characterization of Intramedullary

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clinical, Radiological and Molecular Characterization of Intramedullary Lebrun et al. Acta Neuropathologica Communications (2020) 8:128 https://doi.org/10.1186/s40478-020-00962-1 RESEARCH Open Access Clinical, radiological and molecular characterization of intramedullary astrocytomas Laetitia Lebrun1 , Barbara Meléndez1,2, Oriane Blanchard1, Nancy De Nève1, Claude Van Campenhout1, Julie Lelotte3, Danielle Balériaux4, Matteo Riva5, Jacques Brotchi6, Michaël Bruneau6, Olivier De Witte6, Christine Decaestecker7,8, Nicky D’Haene1 and Isabelle Salmon1,7* Abstract Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX.As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Non- canonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas. Keywords: Intramedullary astrocytomas-glial tumor-spinal cord-targeted next-generation sequencing-H3F3A K27M- KIAA1549-BRAF * Correspondence: [email protected] 1Department of Pathology, Erasme University Hospital, Université Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium 7DIAPath, Center for Microscopy and Molecular Imaging, ULB, Gosselies, Belgium Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lebrun et al. Acta Neuropathologica Communications (2020) 8:128 Page 2 of 14 Introduction following inclusion criteria were defined: pathological The recently updated 4th edition of the World Health diagnosis of LG or HG astrocytoma and spine location. Organization (WHO) Classification of Central Nervous We excluded cases with a secondary supratentorial loca- System (CNS) tumors in 2016 (WHO 2016) drastically tion at diagnosis. Pathological diagnosis was reviewed by changed histological diagnosis in neuropathology by in- two neuropathologists (LL and IS) according to the tegrating molecular data into daily diagnostic practice WHO 2016 classification [30]. According to the [30, 51]. The current WHO 2016 classification of CNS cIMPACT-NOW (the Consortium to Inform Molecular tumors is based on clinical criteria, histology and mo- and Practical Approaches to CNS Tumor Taxonomy) lecular characteristics to achieve accurate determination Update 4, the presence of the KIAA1549-BRAF fusion of the prognosis and response to treatment and to im- gene led to grade I pilocytic astrocytoma diagnosis in prove patient management [30]. The WHO 2016 classifi- cases for which a differential diagnosis between grade I cation is applied using the same criteria for supra- pilocytic and grade II diffuse astrocytomas could not be tentorial, infra-tentorial, posterior fossa and intramedul- made [13]. Grade III astrocytoma diagnosis was based lary gliomas, regardless of location. However, the vast on mitotic activity, high cellularity, nuclear atypia with- majority of molecular data on gliomas were obtained out features of glioblastoma (necrosis and microvascular from studies of tumors localized in the brain [5, proliferation). To note, for the three grade III astrocyto- 50].Some studies, however, have shown that particular mas, as surgical resection was not complete according to molecular alterations are related to tumor location. Fu- surgical reports, we could not exclude undersampled sions involving the BRAF and KIAA1549 genes are found glioblastoma. The final cohort consisted of 61 patients in nearly 80% of cerebellar grade I astrocytomas but only with IMAs diagnosed between 1989 and 2019 from 50–55% of non-cerebellar grade I cases [24]. Similarly, Erasme and Saint-Luc University Hospital. Twenty-six of the p.K27M somatic mutation in the H3F3A gene the tumors were grade I pilocytic astrocytomas, 17 were (H3K27M) [41] predominates in high-grade (HG) infil- grade II diffuse astrocytomas, 3 were grade III astrocyto- trative astrocytomas in midline locations, mainly the mas and 12 grade IV astrocytomas. Three cases were brain stem, thalamus and spinal cord [44]. ruled LG astrocytomas because no diagnosis of grade I Only a few studies specifically addressing intramedul- or grade II could be made. To compare the molecular lary gliomas are available. Intramedullary tumors are profile of this cohort of IMAs with their brain counter- rare CNS neoplasms accounting for 2 to 4% of all CNS parts, we used a set of 117 samples obtained from astro- tumors [41, 48]. The majority of these (80%) are gliomas, cytoma patients consecutively diagnosed between 2017 which are ependymomas (60–70%) and astrocytomas and 2019 that were not located in spine and that were (30–40%) [4]. analyzed by next-generation sequencing (NGS) in our The few available studies specific to the molecular alter- daily practical routine diagnosis setting using gene- ations of intramedullary astrocytomas (IMAs) have been targeted “clinical glioma” and “KIAA1549-BRAF fusion” performed and have shown that the most frequent recur- panels (see below). This series included 16 grade I astro- rent molecular alterations are fusions involving cytomas, 13 grade II astrocytomas, 13 grade III astrocy- KIAA1549-BRAF and H3K27M mutations [41]. To date, tomas and 75 grade IV astrocytomas. very few cases with IDH mutations have been described in Magnetic resonance imaging (MRI) exams were IMAs, and these mutations were not classic IDH1 reviewed for available cases (n = 34) by an expert neuro- p.R132H and IDH2 p.R172H mutations [9, 12, 41, 47, 54]. radiologist (DB). For the remaining cases, imaging fea- Nevertheless, while the genetic profiles of brain astro- tures were collected from MRI reports. The imaging cytomas have been largely established, those of uncom- features assessed were location, signal T1 and T2 inten- mon IMAs remain to be defined. The present study sity, contrast enhancement, well-delineated vs. infiltra- aimed to correlate clinical, radiological and molecular tive pattern, cystic component and necrosis. Figure 1 data of IMAs to improve the current knowledge about illustrates representative radiological and pathological the prognosis and molecular profile of these tumors. features of IMAs. Clinical variables were collected based on clinical and Materials and methods surgical reports: age, gender, extent of surgery (biopsy, Patient cohort partial or total resection), adjuvant treatments, follow-up Institutional Review Board approval for a retrospective duration and survival status. Based on MRI reports (con- analysis of archival biobank tissue was obtained from trast enhancement and/or tumor size increase), event-free Biobanque Hôpital Erasme-ULB (BERA), BE_NBWB1, survival (EFS) was assessed as the time until recurrence Biothèque Wallonie Bruxelles (BWB), BBMRI-ERIC) and after gross total resection or disease progression after bi- Biolibrary of Saint-Luc University Hospital, together opsy/partial resection, as defined by Pekmezci et al. [34] with ethical agreement. For
Load more

Recommended publications
  • ACVR1 Antibody Cat
    ACVR1 Antibody Cat. No.: 4791 Western blot analysis of ACVR1 in A549 cell lysate with ACVR1 antibody at 1 μg/mL in (A) the absence and (B) the presence of blocking peptide. Specifications HOST SPECIES: Rabbit SPECIES REACTIVITY: Human, Mouse HOMOLOGY: Predicted species reactivity based on immunogen sequence: Bovine: (100%), Rat: (93%) ACVR1 antibody was raised against a 14 amino acid synthetic peptide near the amino terminus of the human ACVR1. IMMUNOGEN: The immunogen is located within the first 50 amino acids of ACVR1. TESTED APPLICATIONS: ELISA, WB ACVR1 antibody can be used for detection of ACVR1 by Western blot at 1 μg/mL. APPLICATIONS: Antibody validated: Western Blot in human samples. All other applications and species not yet tested. At least four isoforms of ACVR1 are known to exist. This antibody is predicted to have no SPECIFICITY: cross-reactivity to ACVR1B or ACVR1C. POSITIVE CONTROL: 1) Cat. No. 1203 - A549 Cell Lysate Properties October 1, 2021 1 https://www.prosci-inc.com/acvr1-antibody-4791.html PURIFICATION: ACVR1 Antibody is affinity chromatography purified via peptide column. CLONALITY: Polyclonal ISOTYPE: IgG CONJUGATE: Unconjugated PHYSICAL STATE: Liquid BUFFER: ACVR1 Antibody is supplied in PBS containing 0.02% sodium azide. CONCENTRATION: 1 mg/mL ACVR1 antibody can be stored at 4˚C for three months and -20˚C, stable for up to one STORAGE CONDITIONS: year. As with all antibodies care should be taken to avoid repeated freeze thaw cycles. Antibodies should not be exposed to prolonged high temperatures. Additional Info OFFICIAL SYMBOL: ACVR1 ACVR1 Antibody: FOP, ALK2, SKR1, TSRI, ACTRI, ACVR1A, ACVRLK2, Activin receptor type-1, ALTERNATE NAMES: Activin receptor type I, ACTR-I ACCESSION NO.: NP_001096 PROTEIN GI NO.: 4501895 GENE ID: 90 USER NOTE: Optimal dilutions for each application to be determined by the researcher.
    [Show full text]
  • Application of a MYC Degradation
    SCIENCE SIGNALING | RESEARCH ARTICLE CANCER Copyright © 2019 The Authors, some rights reserved; Application of a MYC degradation screen identifies exclusive licensee American Association sensitivity to CDK9 inhibitors in KRAS-mutant for the Advancement of Science. No claim pancreatic cancer to original U.S. Devon R. Blake1, Angelina V. Vaseva2, Richard G. Hodge2, McKenzie P. Kline3, Thomas S. K. Gilbert1,4, Government Works Vikas Tyagi5, Daowei Huang5, Gabrielle C. Whiten5, Jacob E. Larson5, Xiaodong Wang2,5, Kenneth H. Pearce5, Laura E. Herring1,4, Lee M. Graves1,2,4, Stephen V. Frye2,5, Michael J. Emanuele1,2, Adrienne D. Cox1,2,6, Channing J. Der1,2* Stabilization of the MYC oncoprotein by KRAS signaling critically promotes the growth of pancreatic ductal adeno- carcinoma (PDAC). Thus, understanding how MYC protein stability is regulated may lead to effective therapies. Here, we used a previously developed, flow cytometry–based assay that screened a library of >800 protein kinase inhibitors and identified compounds that promoted either the stability or degradation of MYC in a KRAS-mutant PDAC cell line. We validated compounds that stabilized or destabilized MYC and then focused on one compound, Downloaded from UNC10112785, that induced the substantial loss of MYC protein in both two-dimensional (2D) and 3D cell cultures. We determined that this compound is a potent CDK9 inhibitor with a previously uncharacterized scaffold, caused MYC loss through both transcriptional and posttranslational mechanisms, and suppresses PDAC anchorage- dependent and anchorage-independent growth. We discovered that CDK9 enhanced MYC protein stability 62 through a previously unknown, KRAS-independent mechanism involving direct phosphorylation of MYC at Ser .
    [Show full text]
  • ACVR1C Antibody Cat
    ACVR1C Antibody Cat. No.: 4795 ACVR1C Antibody Specifications HOST SPECIES: Rabbit SPECIES REACTIVITY: Human, Mouse, Rat ACVR1C antibody was raised against a 15 amino acid synthetic peptide near the amino terminus of the human ACVR1C. IMMUNOGEN: The immunogen is located within amino acids 130 - 180 of ACVR1C. TESTED APPLICATIONS: ELISA, WB ACVR1C antibody can be used for detection of ACVR1C by Western blot at 1 and 2 μg/mL. APPLICATIONS: Antibody validated: Western Blot in human samples. All other applications and species not yet tested. SPECIFICITY: This antibody is predicted to have no cross-reactivity to ACVR1 or ACVR1B. POSITIVE CONTROL: 1) Cat. No. 1309 - Human Placenta Tissue Lysate Properties PURIFICATION: ACVR1C Antibody is affinity chromatography purified via peptide column. CLONALITY: Polyclonal September 25, 2021 1 https://www.prosci-inc.com/acvr1c-antibody-4795.html ISOTYPE: IgG CONJUGATE: Unconjugated PHYSICAL STATE: Liquid BUFFER: ACVR1C Antibody is supplied in PBS containing 0.02% sodium azide. CONCENTRATION: 1 mg/mL ACVR1C antibody can be stored at 4˚C for three months and -20˚C, stable for up to one STORAGE CONDITIONS: year. As with all antibodies care should be taken to avoid repeated freeze thaw cycles. Antibodies should not be exposed to prolonged high temperatures. Additional Info OFFICIAL SYMBOL: ACVR1 ACVR1C Antibody: FOP, ALK2, SKR1, TSRI, ACTRI, ACVR1A, ACVRLK2, Activin receptor ALTERNATE NAMES: type-1, Activin receptor type I, ACTR-I ACCESSION NO.: Q8NER5 PROTEIN GI NO.: 4501895 GENE ID: 90 USER NOTE: Optimal dilutions for each application to be determined by the researcher. Background and References ACVR1C Antibody: Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins.
    [Show full text]
  • The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome
    Asadi S and Aranian MR, J Hematol Hemother 5: 008 Journal of Hematology & Hemotherapy Review Article The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome Asadi S* and Aranian MR Division of Medical Genetics and Molecular Pathology Research, Harvard University, Boston Children’s Hospital, Iran Abstract *Corresponding author: Shahin Asadi, Division of Medical Genetics and Molecular Pathology Research, Harvard University, Boston Children’s Hospital, Iran, Tel: +98 Fibrodysplasia Ossificans Progressiva (FOP) is a severely dis- 9379923364; E-mail: [email protected] abling heritable disorder of connective tissue characterized by con- genital malformations of the great toes and progressive heterotopic Received Date: February 7, 2020 ossification that forms qualitatively normal bone in characteristic ex- Accepted Date: February 17, 2020 traskeletal sites. Classic FOP is caused by a recurrent activating mu- tation (617G>A; R206H) in the gene ACVR1 (ALK2) encoding Activin Published Date: February 24, 2020 A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor. Atypical FOP patients also have heterozygous Citation: Asadi S, Aranian MR (2020) The Role of Genetics Mutations in Genes ACVR1, BMPR1A, BMPR1B, BMPR2, BMP4 in Stone Man Syndrome. J Hematol ACVR1 missense mutations in conserved amino acids. Hemother 5: 008. Keywords: ACVR1; BMPR1A; BMPR1B; BMPR2; BMP4; Genetics Copyright: © 2020 Asadi S, et al. This is an open-access article distributed under the mutations, Stone man syndrome terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source Overview of Stone Man Syndrome are credited.
    [Show full text]
  • FOP) Can Be Rescued by the Drug Candidate Saracatinib
    Stem Cell Reviews and Reports https://doi.org/10.1007/s12015-020-10103-9 ActivinA Induced SMAD1/5 Signaling in an iPSC Derived EC Model of Fibrodysplasia Ossificans Progressiva (FOP) Can Be Rescued by the Drug Candidate Saracatinib Susanne Hildebrandt1,2,3 & Branka Kampfrath1 & Kristin Fischer3,4 & Laura Hildebrand2,3 & Julia Haupt1 & Harald Stachelscheid3,4 & Petra Knaus 1,2 Accepted: 1 December 2020 # The Author(s) 2021 Abstract Balanced signal transduction is crucial in tissue patterning, particularly in the vasculature. Heterotopic ossification (HO) is tightly linked to vascularization with increased vessel number in hereditary forms of HO, such as Fibrodysplasia ossificans progressiva (FOP). FOP is caused by mutations in the BMP type I receptor ACVR1 leading to aberrant SMAD1/5 signaling in response to ActivinA. Whether observed vascular phenotype in human FOP lesions is connected to aberrant ActivinA signaling is unknown. Blocking of ActivinA prevents HO in FOP mice indicating a central role of the ligand in FOP. Here, we established a new FOP endothelial cell model generated from induced pluripotent stem cells (iECs) to study ActivinA signaling. FOP iECs recapitulate pathogenic ActivinA/SMAD1/5 signaling. Whole transcriptome analysis identified ActivinA mediated activation of the BMP/ NOTCH pathway exclusively in FOP iECs, which was rescued to WT transcriptional levels by the drug candidate Saracatinib. We propose that ActivinA causes transcriptional pre-patterning of the FOP endothelium, which might contribute to differential vascularity in FOP lesions compared to non-hereditary HO. Keywords FOP . BMP-receptor . Activin . iPSCs . Human endothelial cells . HO . Saracatinib Introduction pathological conditions such as cancer and chronic inflamma- tion [2].
    [Show full text]
  • Pharmacological Reactivation of Inactive X-Linked Mecp2 in Cerebral Cortical Neurons of Living Mice
    Pharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice Piotr Przanowskia, Urszula Waskoa, Zeming Zhenga, Jun Yub, Robyn Shermana, Lihua Julie Zhub,c, Michael J. McConnella,d, Jogender Tushir-Singha, Michael R. Greenb,e,1, and Sanchita Bhatnagara,d,1 aDepartment of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908; bDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; cPrograms in Molecular Medicine and Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605; dDepartment of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908; and eHoward Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605 Contributed by Michael R. Green, June 19, 2018 (sent for review March 2, 2018; reviewed by Aseem Z. Ansari and Sukesh R. Bhaumik) Rett syndrome (RTT) is a genetic disorder resulting from a loss-of- Although Xi-linked MECP2 reactivation has implications for function mutation in one copy of the X-linked gene methyl-CpG– the treatment of RTT, the approach has been hampered by a lack binding protein 2 (MECP2). Typical RTT patients are females and, due of complete understanding of the molecular mechanisms of XCI to random X chromosome inactivation (XCI), ∼50% of cells express and the key regulators involved. Recently, however, several large- mutant MECP2 and the other ∼50% express wild-type MECP2. Cells scale screens have identified factors involved in XCI and have expressing mutant MECP2 retain a wild-type copy of MECP2 on the yielded important mechanistic insights (9–11).
    [Show full text]
  • Targeting Myostatin/Activin a Protects Against Skeletal Muscle and Bone Loss During Spaceflight
    Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight Se-Jin Leea,b,1, Adam Lehara, Jessica U. Meirc, Christina Kochc, Andrew Morganc, Lara E. Warrend, Renata Rydzike, Daniel W. Youngstrome, Harshpreet Chandoka, Joshy Georgea, Joseph Gogainf, Michael Michauda, Thomas A. Stoklaseka, Yewei Liua, and Emily L. Germain-Leeg,h aThe Jackson Laboratory for Genomic Medicine, Farmington, CT 06032; bDepartment of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT 06030; cThe National Aeronautics and Space Administration, NASA Johnson Space Center, Houston, TX 77058; dCenter for the Advancement of Science in Space, Houston, TX 77058; eDepartment of Orthopaedic Surgery, University of Connecticut School of Medicine, Farmington, CT 06030; fSomaLogic, Inc., Boulder, CO 80301; gDepartment of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030; and hConnecticut Children’s Center for Rare Bone Disorders, Farmington, CT 06032 Contributed by Se-Jin Lee, August 4, 2020 (sent for review July 14, 2020; reviewed by Shalender Bhasin and Paul Gregorevic) Among the physiological consequences of extended spaceflight signaling and, as a result, can induce significant muscle growth are loss of skeletal muscle and bone mass. One signaling pathway when given systemically to wild type mice (13). Indeed, by that plays an important role in maintaining muscle and bone blocking both ligands, this decoy receptor can induce signifi- homeostasis is that regulated by the secreted signaling proteins, cantly more muscle growth than other MSTN inhibitors, and at myostatin (MSTN) and activin A. Here, we used both genetic and high doses, ACVR2B/Fc can induce over 50% muscle growth in pharmacological approaches to investigate the effect of targeting just 2 wk.
    [Show full text]
  • Activins As Dual Specificity TGF- Family Molecules: SMAD-Activation
    biomolecules Article Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors Oddrun Elise Olsen 1,2, Hanne Hella 1, Samah Elsaadi 1, Carsten Jacobi 3, Erik Martinez-Hackert 4 and Toril Holien 1,2,* 1 Department of Clinical and Molecular Medicine, NTNU – Norwegian University of Science and Technology, 7491 Trondheim, Norway 2 Department of Hematology, St. Olav’s University Hospital, 7030 Trondheim, Norway 3 Novartis Institutes for BioMedical Research Basel, Musculoskeletal Disease Area, Novartis Pharma AG, CH-4056 Basel, Switzerland 4 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA * Correspondence: [email protected]; Tel.: +47-924-21-162 Received: 19 February 2020; Accepted: 27 March 2020; Published: 29 March 2020 Abstract: Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs.
    [Show full text]
  • Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib
    Supplementary Online Content Chen G, McQuade JL, Panka DJ, et al. Clinical, molecular and immune analysis of dabrafenib-trametinib combination treatment for metastatic melanoma that progressed during BRAF inhibitor monotherapy: a phase 2 clinical trial. JAMA Oncology. Published online April 28, 2016. doi:10.1001/jamaoncol.2016.0509. eMethods. eReferences. eTable 1. Clinical efficacy eTable 2. Adverse events eTable 3. Correlation of baseline patient characteristics with treatment outcomes eTable 4. Patient responses and baseline IHC results eFigure 1. Kaplan-Meier analysis of overall survival eFigure 2. Correlation between IHC and RNAseq results eFigure 3. pPRAS40 expression and PFS eFigure 4. Baseline and treatment-induced changes in immune infiltrates eFigure 5. PD-L1 expression eTable 5. Nonsynonymous mutations detected by WES in baseline tumors This supplementary material has been provided by the authors to give readers additional information about their work. © 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 eMethods Whole exome sequencing Whole exome capture libraries for both tumor and normal samples were constructed using 100ng genomic DNA input and following the protocol as described by Fisher et al.,3 with the following adapter modification: Illumina paired end adapters were replaced with palindromic forked adapters with unique 8 base index sequences embedded within the adapter. In-solution hybrid selection was performed using the Illumina Rapid Capture Exome enrichment kit with 38Mb target territory (29Mb baited). The targeted region includes 98.3% of the intervals in the Refseq exome database. Dual-indexed libraries were pooled into groups of up to 96 samples prior to hybridization.
    [Show full text]
  • Signaling Receptors for TGF-B Family Members
    Downloaded from http://cshperspectives.cshlp.org/ on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling Receptors for TGF-b Family Members Carl-Henrik Heldin1 and Aristidis Moustakas1,2 1Ludwig Institute for Cancer Research Ltd., Science for Life Laboratory, Uppsala University, SE-751 24 Uppsala, Sweden 2Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, SE-751 23 Uppsala, Sweden Correspondence: [email protected] Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiq- uitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as tran- scription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 30-kinase, and Rho GTPases. he transforming growth factor b (TGF-b) embryonic development and in the regulation Tfamily of cytokine genes has 33 human of tissue homeostasis, through their abilities to members, encoding TGF-b isoforms, bone regulate cell proliferation, migration, and differ- morphogenetic proteins (BMPs), growth and entiation. Perturbation of signaling by TGF-b differentiation factors (GDFs), activins, inhib- family members is often seen in different dis- ins, nodal, and anti-Mu¨llerian hormone (AMH) eases, including malignancies, inflammatory (Derynck and Miyazono 2008; Moustakas and conditions, and fibrotic conditions.
    [Show full text]
  • ACVR1 Antibody Storage: Store at -20°C
    From Biology to Discovery™ ACVR1 Antibody Storage: Store at -20°C. Minimize freeze-thaw cycles. Product is guaranteed one year from the date of shipment. Subcategory: Rabbit Polyclonal Antibody Cat. No.: 253941 For research use only, not for diagnostic or therapeutic Unit: 0.1 mg procedures. Description: Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I and two type II receptors. Unlike ACVR1B and ACVR1C, ACVR1, also known as activin receptor-like kinase 2 (ALK2), can not transduce activin-mediated signaling, but will transduce BMP and Mullerian inhibiting substance (MIS) group signaling. It is thought that ACVR1 also inhibits activin signaling by blocking the binding of activin to its type II receptor. Recent studies indicate that genetic variation in ACVR1 is associated with polycystic ovary syndrome, suggesting that ACVR1 signaling contributes to disturbed folliculogenesis in these patients. At least four isoforms of ACVR1 are known to exist. This antibody is predicted to have no cross-reactivity to ACVR1B or ACVR1C. Isotype: Rabbit Ig Applications: E, WB Species Reactivity: H, M Format: Each vial contains 0.1 ml IgG in PBS pH 7.4 with 0.02% sodium azide. Antibody was purified by immunogen affinity chromatography. Alternate Names: ACVR1;Activin A receptor type IA; Activin receptor-like kinase 2; Activin receptor type 1A precursor; ACTR-IA; ACVRLK2; ALK2; ALK-2 Accession No.: NP_001096 Antigen: KLH-conjugated synthetic peptide encompassing a sequence within human ACVR1.
    [Show full text]
  • ACVR1C Antibody Catalog # ASC10763
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 ACVR1C Antibody Catalog # ASC10763 Specification ACVR1C Antibody - Product Information Application WB Primary Accession Q04771 Other Accession Q8NER5, 90 Reactivity Human, Mouse, Rat Host Rabbit Clonality Polyclonal Isotype IgG Application Notes ACVR1C antibody can be used for detection of ACVR1C by Western blot at 1 and 2 μg/mL. ACVR1C Antibody - Additional Information Western blot analysis of ACVR1C in human placenta tissue lysate with ACVR1C antibody Gene ID 90 at (A) 1 and (B) 2 µg/mL. Target/Specificity ACVR1C antibody was raised against a 15 amino acid synthetic peptide near the ACVR1C Antibody - Background amino terminus of the human ACVR1C.<br><br>The immunogen is ACVR1C Antibody: Activins are dimeric growth located within amino acids 130 - 180 of and differentiation factors which belong to the ACVR1C. transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling Reconstitution & Storage proteins. Activins signal through a heteromeric ACVR1C antibody can be stored at 4℃ for complex of receptor serine kinases which three months and -20℃, stable for up to include at least two type I and two type II one year. As with all antibodies care should receptors. ACVR1C, also known as ALK7, is a be taken to avoid repeated freeze thaw type I activin receptor and plays a role in cell cycles. Antibodies should not be exposed to differentiation, growth arrest and apoptosis. prolonged high temperatures. ACVR1C can mediate signaling by ligans such as Nodal, GDF-1/3, activin B and activin AB, all Precautions of which can also signal through the ubiquitous ACVR1C Antibody is for research use only activin type I receptor ACVR1B (also known as and not for use in diagnostic or therapeutic ALK4).
    [Show full text]