The Thrombopoietin Receptor : Revisiting the Master Regulator of Platelet Production
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Platelet-Derived Growth Factor Receptor Expression and Amplification in Choroid Plexus Carcinomas
Modern Pathology (2008) 21, 265–270 & 2008 USCAP, Inc All rights reserved 0893-3952/08 $30.00 www.modernpathology.org Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas Nina N Nupponen1,*, Janna Paulsson2,*, Astrid Jeibmann3, Brigitte Wrede4, Minna Tanner5, Johannes EA Wolff 6, Werner Paulus3, Arne O¨ stman2 and Martin Hasselblatt3 1Molecular Cancer Biology Program, University of Helsinki, Helsinki, Finland; 2Department of Oncology–Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden; 3Institute of Neuropathology, University Hospital Mu¨nster, Mu¨nster, Germany; 4Department of Pediatric Oncology, University of Regensburg, Regensburg, Germany; 5Department of Oncology, Tampere University Hospital, Tampere, Finland and 6Children’s Cancer Hospital, MD Anderson Cancer Center, Houston, TX, USA Platelet-derived growth factor (PDGF) receptor signaling has been implicated in the development of glial tumors, but not yet been examined in choroid plexus carcinomas, pediatric tumors with dismal prognosis for which novel treatment options would be desirable. Therefore, protein expression of PDGF receptors a and b as well as amplification status of the respective genes, PDGFRA and PDGFRB, were examined in a series of 22 patients harboring choroid plexus carcinoma using immunohistochemistry and chromogenic in situ hybridization (CISH). The majority of choroid plexus carcinomas expressed PDGF receptors with 6 cases (27%) displaying high staining scores for PDGF receptor a and 13 cases (59%) showing high staining scores for PDGF receptor b. Correspondingly, copy-number gains of PDGFRA were observed in 8 cases out of 12 cases available for CISH and 1 case displayed amplification (six or more signals per nucleus). The proportion of choroid plexus carcinomas with amplification of PDGFRB was even higher (5/12 cases). -
Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only. -
How I Treat Myelofibrosis
From www.bloodjournal.org by guest on October 7, 2014. For personal use only. Prepublished online September 16, 2014; doi:10.1182/blood-2014-07-575373 How I treat myelofibrosis Francisco Cervantes Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Advance online articles have been peer reviewed and accepted for publication but have not yet appeared in the paper journal (edited, typeset versions may be posted when available prior to final publication). Advance online articles are citable and establish publication priority; they are indexed by PubMed from initial publication. Citations to Advance online articles must include digital object identifier (DOIs) and date of initial publication. Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved. From www.bloodjournal.org by guest on October 7, 2014. For personal use only. Blood First Edition Paper, prepublished online September 16, 2014; DOI 10.1182/blood-2014-07-575373 How I treat myelofibrosis By Francisco Cervantes, MD, PhD, Hematology Department, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain Correspondence: Francisco Cervantes, MD, Hematology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. Phone: +34 932275428. -
Thrombopoietin Supports the Continuous Growth of Cytokine-Dependent Human Leukemia Cell Lines HG Drexler, M Zaborski and H Quentmeier
Leukemia (1997) 11, 541–551 1997 Stockton Press All rights reserved 0887-6924/97 $12.00 Thrombopoietin supports the continuous growth of cytokine-dependent human leukemia cell lines HG Drexler, M Zaborski and H Quentmeier DSMZ-German Collection of Microorganisms and Cell Cultures, Department of Human and Animal Cell Cultures, Mascheroder Weg 1 B, D-38124 Braunschweig, Germany Hematopoiesis is a complex process of regulated cellular pro- nate membrane receptor. This binding triggers a series of intra- liferation and differentiation from the primitive stem cells to the cellular mediators involved in the growth factor’s signaling final fully differentiated cell. The long and extensive search for a factor specifically regulating megakaryocytopoiesis led to the pathways. Recently, a novel hematopoietic growth factor, cloning of a hormone, here called thrombopoietin (TPO), that termed thrombopoietin (TPO), was cloned and shown to be a specifically promotes proliferation and differentiation of the megakaryocytic lineage-associated growth and differentiation megakaryocytic lineage. The availability of recombinant TPO factor. Binding of TPO to its receptor, c-MPL, mediates plei- and its imminent clinical use has made a more detailed under- otropic effects on megakaryocyte development in vitro and in standing of its effects on hematopoietic cells more urgent. Nor- vivo. TPO is clearly the primary regulator of this cell lineage mal megakaryocyto- and thrombopoiesis occurs predomi- nantly in the bone marrow, a difficult organ to study in situ, acting at all levels of megakaryocytopoiesis and thrombopo- particularly in humans, due to the low numbers of megakary- iesis (reviewed in Ref. 1). ocytic progenitors and the consequent difficult isolation as The availability of TPO will be of considerable clinical pure populations. -
The Receptor Tyrosine Kinase Trka Is Increased and Targetable in HER2-Positive Breast Cancer
biomolecules Article The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer Nathan Griffin 1,2, Mark Marsland 1,2, Severine Roselli 1,2, Christopher Oldmeadow 2,3, 2,4 2,4 1,2, , 1,2, John Attia , Marjorie M. Walker , Hubert Hondermarck * y and Sam Faulkner y 1 School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; nathan.griffi[email protected] (N.G.); [email protected] (M.M.); [email protected] (S.R.); [email protected] (S.F.) 2 Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, NSW 2305, Australia; [email protected] (C.O.); [email protected] (J.A.); [email protected] (M.M.W.) 3 School of Mathematical and Physical Sciences, Faculty of Science and Information Technology, University of Newcastle, Callaghan, NSW 2308, Australia 4 School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia * Correspondence: [email protected]; Tel.: +61-2492-18830; Fax: +61-2492-16903 Contributed equally to the study. y Received: 19 August 2020; Accepted: 15 September 2020; Published: 17 September 2020 Abstract: The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). -
CD137 Microbead Kit CD137 Microbead + Cells
CD137 MicroBead Kit human Order no. 130-093-476 Contents 1.2 Background information 1. Description The activation-induced antigen CD137 (4-1BB) is a 30 kDa glycoprotein of the tumor necrosis factor (TNF) receptor 1.1 Principle of the MACS® Separation + + superfamily. It is mainly expressed on activated CD4 and CD8 1.2 Background information T cells, activated B cells, and natural killer cells, but can also be 1.3 Applications found on resting monocytes and dendritic cells. As a costimulatory molecule, CD137 is involved in the activation 1.4 Reagent and instrument requirements and survival of CD4, CD8, and NK cells. Its engagement enhances 2. Protocol expansion of T cells and activates them to secrete cytokines. CD137 has been described to be a suitable marker for antigen- 2.1 Sample preparation specific activation of human CD8+ T cells, as CD137 is not expressed 2.2 Magnetic labeling on resting CD8+ T cells and its expression is reliably induced after 2.3 Magnetic separation 24 hours of stimulation.¹,² 3. Example of a separation using the CD137 MicroBead Kit 1.3 Applications 4. References ● Enrichment of CD137+ T cells for phenotypical and functional 5. Appendix characterization. ● Enrichment of activated antigen-specific T cells after antigen- Warnings specific stimulation. Reagents contain sodium azide. Under acidic conditions sodium 1.4 Reagent and instrument requirements azide yields hydrazoic acid, which is extremely toxic. Azide ● compounds should be diluted with running water before discarding. Buffer: Prepare a solution containing phosphate-buffered These precautions are recommended to avoid deposits in plumbing saline (PBS), pH 7.2, 0.5% bovine serum albumin (BSA), where explosive conditions may develop. -
Side Effects of Molecular-Targeted Therapies in Solid Cancers : a New Challenge in Cancer Therapy Management
Side effects of molecular-targeted therapies in solid cancers : a new challenge in cancer therapy management Ahmad Awada, MD, PhD Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) Brussels, Belgium PLAN OF THE LECTURE 1. Concept 2. Achievements on the management of side effects 3. Remaining challenges 4. New challenges with the development of molecular-targeted therapies 5. Conclusions Reducing the cancer- related problems and the side effects of the SUPPORTIVE CARE = medicine administered to treat the disease SIDE EFFECTS OF CANCER THERAPY: ACHIEVEMENTS Side effect Preventive & Therapeutic intervention • Febrile neutropenia • G-CSF, Anti-infectives • Anemia • Epoetine •Mucositis •Laser therapy, Palifermin • Nausea & Vomiting • 5-HT3 and neurokin-1-receptor antagonists •Thromboembolic •LMW Heparin events • Cardiomyopathy • Liposomal formulations, Dexrazonane (anthracyclines) MANAGEMENT OF SIDE EFFECTS : REMAINING CHALLENGES • Alopecia • Thrombocytopenia ( ! Promising Thrombopoietin- mimetics are under investigation) • Asthenia MOLECULAR TARGETS AND THERAPIES (1) Drug Class Mechanism of action Main tumor indication Gefitinib* Small molecule TK inhibitor of EGFR NSCLC (Iressa) Erlotinib* Small molecule TK inhibitor of EGFR NSCLC (Tarceva) Cetuximab* Monoclonal Antibody Blocks EGFR Colorectal, Head & (Erbitux) Neck, NSCLC Monoclonal Panitumumab* Antibody Blocks EGFR Colorectal (Vectibix) * Investigational in BC TK : tyrosine kinase; EGFR : epidermal growth factor receptor MOLECULAR TARGETS AND THERAPIES -
DOPTELET (Avatrombopag) RATIONALE for INCLUSION IN
DOPTELET (avatrombopag) RATIONALE FOR INCLUSION IN PA PROGRAM Background Doptelet is a thrombopoietin (TPO) receptor agonist used to increase platelet counts. Doptelet (avatrombopag) is an orally bioavailable, small molecule TPO receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. Doptelet does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production (1). Regulatory Status FDA approved indication: Doptelet is a thrombopoietin receptor agonist indicated for the treatment of: (1) 1. Thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. 2. Thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment. Doptelet should not be administered to patients with chronic liver disease in an attempt to normalize platelet counts (1). Doptelet is a thrombopoietin (TPO) receptor agonist and TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with chronic liver disease. A Doppler ultrasound is a noninvasive test that can be used to estimate the blood flow through blood vessels by bouncing high-frequency sound waves (ultrasound) off circulating red blood cells. A Doppler ultrasound may help determine if Doptelet therapy is appropriate for a patient (1-2). The safety and effectiveness of Doptelet in pediatric patients have not been established (1). Summary Doptelet is a thrombopoietin (TPO) receptor agonist used to increase platelet counts. Doptelet (avatrombopag) is an orally bioavailable, small molecule TPO receptor agonist that stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells resulting in an increased production of platelets. -
Insights Into the Cellular Mechanisms of Erythropoietin-Thrombopoietin Synergy
Papayannopoulou et al.: Epo and Tpo Synergy Experimental Hematology 24:660-669 (19961 661 @ 1996 International Society for Experimental Hematology Rapid Communication ulation with fluorescence microscopy. Purified subsets were grown in plasma clot and methylcellulose clonal cultures and in suspension cultures using the combinations of cytokines Insights into the cellular mechanisms cadaveric bone marrow cells obtained from Northwest described in the text. Single cells from the different subsets Center, Puget Sound Blood Bank (Seattle, WA), were were. also deposited (by FACS) on 96-well plates containing of erythropoietin-thrombopoietin synergy washed, and incubated overnight in IMDM with 10% medmm and cytokines. Clonal growth from single-cell wells calf serum on tissue culture plates to remove adherent were double-labeled with antiglycophorin A-PE and anti Thalia Papayannopoulou, Martha Brice, Denise Farrer, Kenneth Kaushansky From the nonadherent cells, CD34+ cells were isolated CD41- FITC between days 10 and 19. direct immunoadherence on anti-CD34 monoclonal anti University of Washington, Department of Medicine, Seattle, WA (mAb)-coated plates, as previously described [15]. Purity Immunocytochemistry Offprint requests to: Thalia Papayannopoulou, MD, DrSci, University of Washington, isolated CD34+ cells ranged from 80 to 96% by this For immunocytochemistry, either plasma clot or cytospin cell Division of Hematology, Box 357710, Seattle, WA 98195-7710 od. Peripheral blood CD34 + cells from granulocyte preparations were used. These were fixed at days 6-7 and (Received 24 January 1996; revised 14 February 1996; accepted 16 February 1996) ulating factor (G-CSF)-mobilized normal donors 12-13 with pH 6.5 Histochoice (Amresco, Solon, OH) and provided by Dr. -
The Molecular Mechanisms That Control Thrombopoiesis
The molecular mechanisms that control thrombopoiesis Kenneth Kaushansky J Clin Invest. 2005;115(12):3339-3347. https://doi.org/10.1172/JCI26674. Review Series Our understanding of thrombopoiesis — the formation of blood platelets — has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-producing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances. Find the latest version: https://jci.me/26674/pdf Review series The molecular mechanisms that control thrombopoiesis Kenneth Kaushansky Department of Medicine, Division of Hematology/Oncology, University of California, San Diego, San Diego, California, USA. Our understanding of thrombopoiesis — the formation of blood platelets — has improved greatly in the last decade, with the cloning and characterization of thrombopoietin, the primary regulator of this process. Thrombopoietin affects nearly all aspects of platelet production, from self-renewal and expansion of HSCs, through stimulation of the proliferation of megakaryocyte progenitor cells, to support of the maturation of these cells into platelet-pro- ducing cells. The molecular and cellular mechanisms through which thrombopoietin affects platelet production provide new insights into the interplay between intrinsic and extrinsic influences on hematopoiesis and highlight new opportunities to translate basic biology into clinical advances. -
N-Glycosylation As Determinant of Epidermal Growth Factor Receptor Conformation in Membranes
N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes Karol Kaszubaa,1, Michał Grzybekb,c,1, Adam Orłowskia, Reinis Dannea, Tomasz Róga, Kai Simonsd,2, Ünal Coskunb,c,2, and Ilpo Vattulainena,e,2 aDepartment of Physics, Tampere University of Technology, FI-33101 Tampere, Finland; bPaul Langerhans Institute Dresden of the Helmholtz Centre Munich at the University Clinic Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; cGerman Center for Diabetes Research (DZD e.V.), 85764 Neuherberg, Germany; dMax Planck Institute for Molecular Cell Biology and Genetics, 01307 Dresden, Germany; and eCenter for Biomembrane Physics (MEMPHYS), University of Southern Denmark, 5230 Odense, Denmark Contributed by Kai Simons, February 24, 2015 (sent for review April 10, 2014; reviewed by Helmut Grubmüller and Paul M. P. Van Bergen en Henegouwen) The epidermal growth factor receptor (EGFR) regulates several data at the single-molecule level stipulate a greater distance critical cellular processes and is an important target for cancer between the ECD of the receptor and the membrane in the therapy. In lieu of a crystallographic structure of the complete absence of ligand (9, 10). receptor, atomistic molecular dynamics (MD) simulations have To resolve this discrepancy, the present study considers two recently shown that they can excel in studies of the full-length key parameters that were not included in previous simulations of receptor. Here we present atomistic MD simulations of the mono- the monomeric EGFR: N-glycosylation of the ectodomain of meric N-glycosylated human EGFR in biomimetic lipid bilayers that EGFR that contributes up to 50 kDa of the total molecular are, in parallel, also used for the reconstitution of full-length recep- weight of ∼178 kDa (11, 12), and a lipid environment that pre- tors. -
Induction of Erythropoietin Increases the Cell Proliferation Rate in a Hypoxia‑Inducible Factor‑1‑Dependent and ‑Independent Manner in Renal Cell Carcinoma Cell Lines
ONCOLOGY LETTERS 5: 1765-1770, 2013 Induction of erythropoietin increases the cell proliferation rate in a hypoxia‑inducible factor‑1‑dependent and ‑independent manner in renal cell carcinoma cell lines YUTAKA FUJISUE1, TAKATOSHI NAKAGAWA2, KIYOSHI TAKAHARA1, TERUO INAMOTO1, SATOSHI KIYAMA1, HARUHITO AZUMA1 and MICHIO ASAHI2 Departments of 1Urology and 2Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan Received November 28, 2012; Accepted February 25, 2013 DOI: 10.3892/ol.2013.1283 Abstract. Erythropoietin (Epo) is a potent inducer of erythro- Introduction poiesis that is mainly produced in the kidney. Epo is expressed not only in the normal kidney, but also in renal cell carcinomas Erythropoietin (Epo) is a 30-kDa glycoprotein that functions (RCCs). The aim of the present study was to gain insights as an important cytokine in erythrocytes. Epo is usually into the roles of Epo and its receptor (EpoR) in RCC cells. produced by stromal cells of the adult kidney cortex or fetal The study used two RCC cell lines, Caki-1 and SKRC44, in liver and then released into the blood, with its production which Epo and EpoR are known to be highly expressed. The initially induced by hypoxia or hypotension (1-5). In the bone proliferation rate and expression level of hypoxia-inducible marrow, Epo binds to the erythropoietin receptor (EpoR) factor-1α (HIF-1α) were measured prior to and following expressed in erythroid progenitor cells or undifferentiated Epo treatment and under normoxic and hypoxic conditions. erythroblasts, which induces signal transduction mechanisms To examine whether HIF-1α or Epo were involved in cellular that protect the undifferentiated erythrocytes from apoptosis proliferation during hypoxia, these proteins were knocked and promote their proliferation and differentiation.