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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. -
TRAIL and Cardiovascular Disease—A Risk Factor Or Risk Marker: a Systematic Review
Journal of Clinical Medicine Review TRAIL and Cardiovascular Disease—A Risk Factor or Risk Marker: A Systematic Review Katarzyna Kakareko 1,* , Alicja Rydzewska-Rosołowska 1 , Edyta Zbroch 2 and Tomasz Hryszko 1 1 2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University of Białystok, 15-276 Białystok, Poland; [email protected] (A.R.-R.); [email protected] (T.H.) 2 Department of Internal Medicine and Hypertension, Medical University of Białystok, 15-276 Białystok, Poland; [email protected] * Correspondence: [email protected] Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic protein showing broad biological functions. Data from animal studies indicate that TRAIL may possibly contribute to the pathophysiology of cardiomyopathy, atherosclerosis, ischemic stroke and abdomi- nal aortic aneurysm. It has been also suggested that TRAIL might be useful in cardiovascular risk stratification. This systematic review aimed to evaluate whether TRAIL is a risk factor or risk marker in cardiovascular diseases (CVDs) focusing on major adverse cardiovascular events. Two databases (PubMed and Cochrane Library) were searched until December 2020 without a year limit in accor- dance to the PRISMA guidelines. A total of 63 eligible original studies were identified and included in our systematic review. Studies suggest an important role of TRAIL in disorders such as heart failure, myocardial infarction, atrial fibrillation, ischemic stroke, peripheral artery disease, and pul- monary and gestational hypertension. Most evidence associates reduced TRAIL levels and increased TRAIL-R2 concentration with all-cause mortality in patients with CVDs. It is, however, unclear Citation: Kakareko, K.; whether low TRAIL levels should be considered as a risk factor rather than a risk marker of CVDs. -
Dr. Kenneth Kaushansky's Report to the University Senate April 6, 2020
Dr. Kenneth Kaushansky’s report to the University Senate April 6, 2020 Dear Members of the Health Sciences Campus of Stony Brook University, I write today to update members of the Health Sciences Schools and Hospital on our efforts to overcome the COVID-19 pandemic, at least in Suffolk County and perhaps, far beyond. In short, we have mounted an amazing effort as the winds of the pandemic are building up, with ever- increasing numbers of infected individuals being identified. We have prepared for the coming “perfect storm.” And we have begun to model what the campus will look like when the flood waters begin to recede. And while our efforts to buffer the storm have been very well coordinated on many, many fronts, I will summarize our efforts by category. Disclaimer: What follows is a fairly detailed description of the efforts of hundreds of leaders from every corner of Stony Brook Medicine, from clinical to research, from basic to applied, from medical to nursing to technologists, and the spectacular response of several thousand members of the Renaissance School of Medicine (RSOM) and about 7,000 staff members of Stony Brook University Hospital (SBUH). For those who are faint of heart, or overtired (and hence already poised to nod off), please feel free to read as little of this note as you like! And if you are a numbers geek, you might be most interested in section 2, below. With that disclaimer aside, let me begin by explaining the basis for the coordination just mentioned, what I like to call the COVID choreography. -
UW Medicine School of Medicine Science in Medicine Lecturers, 1993-Present
UW Medicine School of Medicine Science in Medicine Lecturers, 1993-Present Presenter Name Lecture Type Year Department/Institution Lecture Title Francis S. Collins, M.D., Ph.D. Annual 1993-94 Center for Human Genome Research/NIH unknown Russell Ross, Ph.D. Distinguished Scientist 1993-94 Pathology unknown David Kimelman, Ph.D. New Investigator 1993-94 Biochemistry unknown Janice S. Blum, Ph.D. New Investigator 1993-94 Immunology unknown Michael W. Schwartz, M.D. New Investigator 1993-94 Medicine unknown Alan Chait, M.D. Science in Medicine 1993-94 Medicine unknown Christopher B. Wilson, M.D. Science in Medicine 1993-94 Immunology and Pediatrics unknown Neil M. Nathanson, Ph.D. Science in Medicine 1993-94 Pharmacology unknown Sheila A. Lukehart, Ph.D. Science in Medicine 1993-94 Medicine, Infectious Diseases unknown Susan Ott Ralph, M.D. Science in Medicine 1993-94 Medicine, Metabolism unknown Susan R. White, Ph.D. WWAMI 1993-94 Washington State University unknown Harold E. Varmus, M.D. Annual 1994-95 Director, NIH unknown Bertil Hille, Ph.D. Distinguished Scientist 1994-95 Physiology and Biophysics unknown Julie Overbaugh, Ph.D. New Investigator 1994-95 Microbiology unknown UW School of Medicine, Office of Research and Graduate Education For more information about the Science in Medicine lecture series contact [email protected] UW Medicine School of Medicine Science in Medicine Lecturers, 1993-Present Presenter Name Lecture Type Year Department/Institution Lecture Title Krzysztof Palczewski, Ph.D. New Investigator 1994-95 Ophthalmology unknown Mark A. Kay, M.D., Ph.D. New Investigator 1994-95 Medicine/Medical Genetics unknown Denise A. Galloway, Ph.D. -
Hunting for Hematopoietic Transcriptional Networks COMMENTARY Kenneth Kaushanskya,1
COMMENTARY Hunting for hematopoietic transcriptional networks COMMENTARY Kenneth Kaushanskya,1 Each day an adult human produces roughly 2.5 × 1011 thousands of platelets) at the site of blood vessel injury erythrocytes, 1 × 1011 leukocytes, and 1 × 1011 plate- and by providing an activated cell surface on which co- lets, numbers that can increase 10- to 20-fold in times agulation proteins (i) assemble and are activated, stabi- of heightened demand. Blood cell production, termed lizing the platelet plug, and (ii) together, initiate vascular hematopoiesis, occurs in the red marrow found mostly in healing. Without platelets, we hemorrhage. Platelets are the skull, spine, and proximal ends of the long bones of also involved in some of the most important diseases of the body. Within the marrow resides a small number of humans: By clotting on ruptured atherosclerotic plaques, hematopoietic stem cells (HSCs), the origin of all blood they cause myocardial infarction, stroke, and arterial in- cells, which undergo a series of proliferative and differ- sufficiency. By binding to circulating tumor cells, platelets entiation steps eventuating in the near half a trillion or promote metastatic spread of cancer. And when more cells produced each day. The molecular “wiring platelets are dysfunctional, they can cause pathological diagram” that regulates the production of mature blood clotting and hemorrhage. Thus, a thorough under- cells from HSCs is both cell intrinsic (gene transcription standing of platelet production—from the HSC to the factors and epigenetic changes) and cell extrinsic CMP, the MEP, the MkP, the megakaryocyte, and finally (growth factors and microenvironmental soluble and cell to circulating platelets—may shed light on a number surface proteins), although whether lineage decisions are physiological and pathological processes, as well as stochastic or directed by external factors remains a con- open doors into novel therapeutic approaches to troversial topic. -
Osteoprotegerin: a Novel Secreted Protein Involved in the Regulation of Bone Density
Cell, Vol. 89, 309±319, April 18, 1997, Copyright 1997 by Cell Press Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density W. S. Simonet,2 D. L. Lacey,7 C. R. Dunstan,7 during normal bone remodeling that occurs throughout M. Kelley,3 M.-S. Chang,4 R. LuÈ thy,4 life. In contrast, osteoclasts differentiate from hemato- H. Q. Nguyen,2 S. Wooden,5 L. Bennett,6 poietic precursors of the monocyte±macrophage lin- T. Boone,10 G. Shimamoto,10 M. DeRose,2 eage and resorb bone matrix. Both these cell types are R. Elliott,1 A. Colombero,1 H.-L. Tan,7 influenced by a wide variety of hormones, inflammatory G. Trail,5 J. Sullivan,8 E. Davy,3 N. Bucay,2 mediators, and growth factors (Suda et al., 1992; Mundy, L. Renshaw-Gegg,5 T. M. Hughes,2 D. Hill,7 1993a, 1993b). An imbalance of osteoblast and osteo- W. Pattison,4 P. Campbell,6 S. Sander,5 clast functions can result in skeletal abnormalities char- G. Van,7 J. Tarpley,7 P. Derby,9 R. Lee,10 acterized by increased (osteopetrosis) or decreased (os- Amgen EST Program, and W. J. Boyle1 teoporosis) bone mass. 1 Department of Cell Biology The study of osteopetrosis in mutant mice has led to 2 Department of Molecular Genetics significant advances in the understanding of the pro- 3 Department of Protein Chemistry cesses that regulate bone mass (Marks, 1989). From 4 Department of Computational Biology these studies we have learned the following: (i) genetic 5 Department of Mammalian Cell Molecular Biology defects in osteoclast development, maturation, and/or 6 Department of Immunology activation lead to decreased bone resorption and uni- 7 Department of Pathology formly result in severe osteopetrosis (Marks, 1989); (ii) 8 Department of Bacterial Expression the stromal microenvironment plays an essential role in osteoclast differentiation (Udagawa et al., 1989); (iii) 9 Department of Protein Structure signal transduction from the cell membrane through Src 10 Department of Process Science tyrosine kinase is necessary for osteoclast-mediated Amgen Inc. -
Belantamab Mafodotin to Treat Multiple Myeloma: a Comprehensive Review of Disease, Drug Efficacy and Side Effects
Review Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects Grace Lassiter 1,*, Cole Bergeron 2, Ryan Guedry 2, Julia Cucarola 2, Adam M. Kaye 3 , Elyse M. Cornett 4, Alan D. Kaye 4 , Giustino Varrassi 5, Omar Viswanath 4,6,7,8 and Ivan Urits 4,9 1 School of Medicine, Georgetown University, Washington, DC 20007, USA 2 School of Medicine, Louisiana State University Shreveport, Shreveport, LA 71103, USA; [email protected] (C.B.); [email protected] (R.G.); [email protected] (J.C.) 3 Department of Pharmacy Practice, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA; akaye@pacific.edu 4 Department of Anesthesiology, Louisiana State University Shreveport, Shreveport, LA 71103, USA; [email protected] (E.M.C.); [email protected] (A.D.K.); [email protected] (O.V.); [email protected] (I.U.) 5 Paolo Procacci Foundation, Via Tacito 7, 00193 Roma, Italy; [email protected] 6 College of Medicine-Phoenix, University of Arizona, Phoenix, AZ 85724, USA 7 Department of Anesthesiology, School of Medicine, Creighton University, Omaha, NE 68124, USA 8 Valley Anesthesiology and Pain Consultants—Envision Physician Services, Phoenix, AZ 85004, USA 9 Southcoast Health, Southcoast Physicians Group Pain Medicine, Wareham, MA 02571, USA * Correspondence: [email protected] Received: 14 December 2020; Accepted: 18 January 2021; Published: 21 January 2021 Abstract: Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. -
TNF Receptor Superfamily Members RANK, RANKL, OPG Pathway As
RESEARCH ARTICLE TNF Receptor Superfamily Members RANK, RANKL, OPG Pathway as Osteoimmunological Biomarker of Bone Healing after Orthognathic Surgery İhsan O Osar1, Yavuz Fındık2, Orhan Akpinar3 ABSTRACT Tumor necrosis factor (TNF) receptor superfamily member receptor activator of nuclear factor-κB (RANK), RANK-ligand (RANKL), and osteoprotegerin (OPG) pathway as osteoimmunological biomarker of bone healing after surgery. These biomarkers play an important role in the bone repair and healing after orthognathic surgery. The aim of our study was to evaluate levels of the RANKL–RANK–OPG cytokine system as osteoimmunological biomarker of bone healing after orthognathic surgery. Receptor activator of nuclear factor-κB, RANKL, and OPG were evaluated in 25 patients who is undergoing orthognathic surgery. Blood samples were collected before the operation, after 1st day, and 10th day of the operation. Differences among OPG, RANK, and RANKL averages were not statistically significant in all time levels and operation types. In this study, we concluded that RANKL/OPG ratio and blood serum RANK levels may show bone remodeling activity and bone remodeling activity after orthognathic surgery, although there is a need for further extensive studies. Keywords: Biomarker, General anesthesia, Orthognathic surgery. International Journal of Experimental Dental Science (2020): 10.5005/jp-journals-10029-1201 INTRODUCTION 1–3Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Orthognathic surgery is the main procedure for the correction Süleyman Demirel University, Isparta, Turkey of jaw function and esthetics of the face. Orthognathic surgery Corresponding Author: Yavuz Fındık, Department of Oral and is performed on the surgeon’s bone, but the processes on the Maxillofacial Surgery, Faculty of Dentistry, Süleyman Demirel University, bone activate the bone formation and destruction events on this Isparta, Turkey, Phone: +902462113251, e-mail: yavuzfindik32@ tissue. -
Trailblazing Strategies for Cancer Treatment
cancers Review TRAILblazing Strategies for Cancer Treatment Anna-Laura Kretz 1, Anna Trauzold 2,3, Andreas Hillenbrand 1, Uwe Knippschild 1, Doris Henne-Bruns 1, Silvia von Karstedt 4,5 and Johannes Lemke 1,* 1 Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; [email protected] (A.-L.K.); [email protected] (A.H.); [email protected] (U.K.); [email protected] (D.H.-B.) 2 Institute for Experimental Cancer Research, University of Kiel, 24105 Kiel, Germany; [email protected] 3 Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, 24105 Kiel, Germany 4 Department of Translational Genomics, University Hospital Cologne, Weyertal 115b, 50931 Cologne, Germany; [email protected] 5 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann Straße 26, 50931 Cologne, Germany * Correspondence: [email protected] Received: 11 March 2019; Accepted: 26 March 2019; Published: 30 March 2019 Abstract: In the late 1990s, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF-family, started receiving much attention for its potential in cancer therapy, due to its capacity to induce apoptosis selectively in tumour cells in vivo. TRAIL binds to its membrane-bound death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) inducing the formation of a death-inducing signalling complex (DISC) thereby activating the apoptotic cascade. The ability of TRAIL to also induce apoptosis independently of p53 makes TRAIL a promising anticancer agent, especially in p53-mutated tumour entities. -
Primary Megakaryocytes Reveal a Role for Transcription Factor NF-E2
Primary Megakaryocytes Reveal a Role for Transcription Factor NF-E2 in Integrin aIIbb3 Signaling Masamichi Shiraga,* Alec Ritchie,* Sallouha Aidoudi,* Veronique Baron,* David Wilcox,‡ Gilbert White,§ Belen Ybarrondo,i George Murphy,¶ Andrew Leavitt,¶ and Sanford Shattil* *Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037; ‡Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; §Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; iPharMingen, Inc., San Diego, California 92139; and ¶Department of Laboratory Medicine, The University of California at San Francisco, San Francisco, California 94143 Abstract. Platelet integrin aIIbb3 responds to intracel- cient in the transcription factor NF-E2 failed to bind lular signals by binding fibrinogen and triggering cy- fibrinogen in response to agonists, despite normal toskeletal reorganization, but the mechanisms of surface expression of aIIbb3. Furthermore, while aIIbb3 signaling remain poorly understood. To better megakaryocytes from wild-type mice spread on immo- understand this process, we established conditions to bilized fibrinogen and exhibited filopodia, lamellipodia study aIIbb3 signaling in primary murine megakaryo- and Rho-dependent focal adhesions and stress fibers, cytes. Unlike platelets, these platelet precursors are NF-E2–deficient megakaryocytes adhered poorly. amenable to genetic manipulation. Cytokine-stimu- These studies establish that agonist-induced activation lated bone marrow cultures produced three arbitrary of aIIbb3 is controlled by NF-E2–regulated signaling populations of aIIbb3-expressing cells with increasing pathways that mature late in megakaryocyte develop- size and DNA ploidy: small progenitors, intermediate- ment and converge at the b3 cytoplasmic tail. Mega- size young megakaryocytes, and large mature mega- karyocytes provide a physiologically relevant and karyocytes. -
Alterations in the Immuno-Skeletal Interface Drive Bone Destruction in HIV-1 Transgenic Rats
Alterations in the immuno-skeletal interface drive bone destruction in HIV-1 transgenic rats Tatyana Vikulinaa,1, Xian Fanb,c,1, Masayoshi Yamaguchia, Susanne Roser-Pagec, Majd Zayzafoond, David M. Guidotb,c, Ighovwerha Ofotokune, and M. Neale Weitzmanna,c,f,2 Divisions of aEndocrinology and Metabolism and Lipids and bPulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, GA 30322; cAtlanta Veterans Affairs Medical Center, Decatur, GA 30033; dDepartment of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; eDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322; and fWinship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322 Edited* by Max D. Cooper, Emory University, Atlanta, GA, and approved June 24, 2010 (received for review March 10, 2010) Osteoporosis and bone fractures are increasingly recognized compli- capable of making RANKL and OPG, B cells are recognized as cations of HIV-1 infection. Although antiretroviral therapy itself has a significant source of RANKL when activated in vitro (13), in complex effects on bone turnover, it is now evident that the majority postmenopausal humans in vivo (3), and in inflammatory con- of HIV-infected individuals already exhibit reduced bone mineral ditions such as periodontitis (14). By contrast, both human (15) density before therapy. The mechanisms responsible are likely multi- and mouse B cells (1) are recognized producers of OPG, which is factorial and have been difficult to delineate in humans. The HIV-1 regulated, in part, by T cells through CD40/CD40 ligand (CD40L) transgenic rat recapitulates many key features of human AIDS. -
Genieplex Quantitative Multiplex Immunoassays
GeniePlex Quantitative Multiplex Immunoassays Quantitatively Measure 1-24 Analytes Per Sample! ELISA Genie: Maximum Support ELISA Genie is а proprietary range of ELISA kits & multiplex assays developed bу Reagent Genie, а global life science reagents company based in London and Dublin. Founded bу Colm Ryan PhD and Seán Mac Fhearraigh PhD, our goal is to provide you with premium quality ELISA kits along with excellent technical and logistics support, so you саn maximise your success. GeniePlex Multiplex Immunoassays GeniePlex: Quantitively Measure 1-24 Analytes Simultaneously! GeniePlex is a bead-based multiplex immunoassay technology. It enables the simultaneous & quantitative detection of up to 24 analytes in as little as 15 μl sample on almost any flow cytometer. It’s like doing 24 different ELISA in every well! Phenomenal Performance Very Sensitive: Measure as low as <10 pg/ml of each analyte Excellent Dynamic Range: Lower limit < 20 pg/mL | Upper limit > 5,000 pg/mL High Precision & Accuracy: Intra-assay CV: < 10% | Inter-assay CV: < 20% | Recovery: 70-130% Low Sample Volumes: Use as little as 15 µl of sample Validated: All assays fully tested for cross-reactivity in our lab Unbeatable Flexibility Comprehensive Choice of Targets: Up to 400 assays & custom formats available for human, mouse, rat, porcine, canine and primates Wide Range of Sample Types: Cell culture supernatants, saliva, plasma, cell/tissue lysates, serum, BALF, pleural and peritoneal fluids & more Multiple Formats: 32-well and 96-well sizes available Convenience Redefined Use Your Own Lab: Assays can be run on most validated flow cytometers (PE & either PE-Cy5 or APC detectors) Free Software: Analyse with commonly available software such as FCAP Software v3.0.