DOCSLIB.ORG

Recombinant Factors for Hemostasis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Recombinant Factors for Hemostasis University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Chemical & Biomolecular Engineering Theses, Chemical and Biomolecular Engineering, Dissertations, & Student Research Department of Summer 2010 Recombinant Factors for Hemostasis Jennifer Calcaterra University of Nebraska at Lincoln, [email protected] Follow this and additional works at: https://digitalcommons.unl.edu/chemengtheses Part of the Biochemical and Biomolecular Engineering Commons Calcaterra, Jennifer, "Recombinant Factors for Hemostasis" (2010). Chemical & Biomolecular Engineering Theses, Dissertations, & Student Research. 5. https://digitalcommons.unl.edu/chemengtheses/5 This Article is brought to you for free and open access by the Chemical and Biomolecular Engineering, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Chemical & Biomolecular Engineering Theses, Dissertations, & Student Research by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Recombinant Factors for Hemostasis by Jennifer Calcaterra A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy Major: Interdepartmental Area of Engineering (Chemical & Biomolecular Engineering) Under the Supervision of Professor William H. Velander Lincoln, Nebraska August, 2010 Recombinant Factors for Hemostasis Jennifer Calcaterra, Ph.D. University of Nebraska, 2010 Adviser: William H. Velander Trauma deaths are a result of hemorrhage in 37% of civilians and 47% military personnel and are the primary cause of death for individuals under 44 years of age. Current techniques used to treat hemorrhage are inadequate for severe bleeding. Preliminary research indicates that fibrin sealants (FS) alone or in combination with a dressing may be more effective; however, it has not been economically feasible for widespread use because of prohibitive costs related to procuring the proteins. To meet future demands for hemostatic therapies, FS will likely include recombinant human fibrinogen (rFI) and recombinant human Factor XIII (rFXIII). The underlying hypothesis of the research presented in this dissertation is that a liquid fibrin sealant (LFS) composed of recombinant FI, FXIII and FIIa in optimized proportions can assist hemostasis in the presence and absence of a bioresorbable bandage while using considerably fewer biologics than commercial products currently available. This dissertation characterized rFI produced in the milk of transgenic cows, plasma-derived thrombin (pdFIIa) activated by sodium citrate and rFXIIIa expressed in genetically engineered Pichia pastoris with respect to their capacity to serve as components in a LFS. The ratios of these factors were optimized to yield a LFS with a rapid clot formation rate and high viscoelastic strength. This optimized LFS was preliminarily tested ex vivo and in vivo. The clotting kinetics and viscoelastic strength of our optimized LFS was equivalent to those of a commercially available LFS; however, it uses approximately 75% less fibrinogen and thrombin. Our optimal LFS successfully achieved hemostasis in a significant number of the wounds that included extensive tissue and vascular damage. LFS applied without the assistance of a dressing was able to stop bleeding of oozing wounds or those with small vessels; however, a scaffold was needed when wounds contained large vasculature. iv Copyright 2010 Jennifer Calcaterra v Dedicated to my parents Kathryn and Robert Calcaterra vi Author’s Acknowledgements I want to thank Dr. Velander for providing me with the opportunity to participate in his groundbreaking research and for his mentorship, guidance and moral support. I appreciate the generous advice of Dr. Anuradha Subramanian. I would also like to thank Mostafa Fatemi for introducing me to the analytical techniques used in blood chemistry. Leonard Akert’s assistance was crucial in overcoming numerous technical hurdles. I will be forever grateful to my family for their support, advice, encouragement, inspiration and proofreading. vii Table of Contents Page List of Tables ……………….………………………………………………………………… ix List of Figures ………………………………………………………………………………… x Chapter 1. Introduction ………………………………………………………………………. 1 Hemostasis ………………………………………………………………………... 2 Fibrinogen …………………………………………………………………………. 4 Hemorrhage treatment ……………………………………………………………... 8 Fibrin sealants ………………………………………………………………………. 9 Recobinant alternatives for fibrin sealants ………………………………………. 10 Hemophilia A ………………………………………………………………………. 11 Dissertation objectives ……………………………………………………………... 12 References …………………………………………………………………………... 14 Chapter 2. Sequence of Activation of Prothrombin by Sodium Citrate ……………………... 20 Abstract ……………………………………………………………………………… 21 Introduction ………………………………………………………………………..... 23 Materials and Methods …………………………………………………………. 29 Results ……………………………………………………………………………….. 36 rFXIIIa characterization ………………………………………………. 36 Prothrombin activation by ecarin, rFIIa, FXa and sodium citrate …………. 36 N-terminal sequencing of activated samples ……………………………… 44 Thrombin activity by chromogenic assay …………………………………. 46 Thrombin activity by SDS-PAGE ………………………………………. 47 Thrombin activity by thromboelastography ………………………………. 48 Discussion ………………………………………………………………………. 49 Acknowledgements ………………………………………………………………….. 57 References …………………………………………………………………………... 58 Chapter 3. Characterization of Recombinant Factor XIII Expressed in Pichia pastoris. ….... 61 Abstract ……………………………………………………………………………… 62 Introduction ………………………………………………………………………… 63 Materials and Methods …………………………………………………………. 69 Results ……………………………………………………………………………….. 78 rFI and pdFIIa characterization …………………………………….. 78 Expression and purification of rFXIII ……………………………………. 78 Comparison of pdFXIII and rFXIII by SDS-PAGE and Western blot ….... 79 Molecular weight estimates of expressed protein ……………………......... 80 Aggregation/molecular weight analysis (SDS-PAGE, DLS, AUC, SEC) .... 81 Activation and inactivation of rFXIII by thrombin ……………………….. 83 Chromogenic activity assay ……………………………………………...... 85 γ-γ crosslinking of fibrin(ogen) by FXIIIa ……………………………...... 86 Clot formation by thromboelastography …………………………………… 88 Discussion ……………………………………………………………………………... 89 Acknowledgements ………………………………………………………………….. 93 References …………………………………………………………………………… 95 Chapter 4. Optimization of a Liquid Fibrin Sealant to Achieve its Maximal Strength and … 103 Activation Speed Abstract ………………………………………………………………………………... 104 Introduction …………………………………………………………………………. 106 Materials and Methods ……………………………………………………………....... 110 Results ……………………………………………………………………………....... 116 rFXIIIa and pdFIIa characterization ……………………………………..... 116 γ-γ crosslinking of FI by FXIIIa ……………………………………………. 116 Thromboelastography analysis of fibrin clot formation …………………... 117 viii Clot lysis by thromboelastography ………………….……………………… 125 Discussion ………………………………………………………………………….… 126 Acknowledgements …………………………………………………………………… 130 References …………………………………………………………………………...… 131 Chapter 5. Ex vivo Evaluation of the Liquid Fibrin Sealant Components ………………… 135 Abstract ………………………………………………………………………………... 136 Introduction ……………………………………………………………………………. 138 Materials and Methods ………………………………………………………………. 139 Results ………………………………………………………………………………… 143 rFXIIIa and pdFIIa characterization …………………………………… 143 Donor data ………………………………………………………………… 144 TEG analysis of haemodilution ………………………………….………. 144 TEG analysis of protein doping into NHB, PRP and PPP ………..………... 149 TEG analysis of time to clot initiation ……………………………...……….. 150 TEG analysis of coagulation time …………………………………………... 153 TEG analysis of maximal clot strength …………………………………….. 155 TEG analysis of lysis ……………………………………………………… 158 Discussion ……………………………………………………………………………. 160 Acknowledgements …………………………………………………………………….. 164 References ……………………………………………………………………………. 165 Chapter 6. Preliminary in vivo Testing of the Optimized Liquid Fibrin Sealant ……………… 167 Abstract ………………………………………………………………………………… 168 Introduction …………………………………………………………………………... 169 Materials and Methods ………………………………………………………………… 172 Results ………………………………………………………………………………… 184 Evaluation of swine clotting factors ……………………………………… 184 LFS on hepatic wedge resections …………………………………………… 186 rLFS on hepatic stelate laceration …………………………………………... 189 rLFS dressing on femoral arteriotomy model ……………………………… 190 rLFS dressing on hepatic resections ………………………………………... 192 Discussion ……………………………………………………………………………. 195 Acknowledgements …………………………………………………………………… 200 References ……………………………………………………………………………. 202 Chapter 7. Biologically Active Single Chain Recombinant Human FVIII:von Willebrand …… 205 Factor Complexes Made Abundantly in Transgenic Milk Abstract ……………………………………………………………………………… 206 Introduction …………………………………………………………………………. 207 Materials and Methods ……………………………………………………………….. 209 Results ………………………………………………………………………………… 214 Identification and expansion of transgenic lineages ……………………….. 214 Coexpression of 226/N6-tg, vWF-tg and AAT-tg in trigenic mouse milk … 217 Presence of FVIII-vWF complexes in trigenic mouse milk ………………… 219 Coexpression of AAT ……………………………………………………….. 221 Quantitative analysis of rFVIII biological activity …………………………. 222 In vivo tail clip assay in the hemophilia A mouse ………………………....... 224 Discussion …………………………………………………………………………… 226 Authorship …………………………………………………………………………… 232 Acknowledgements ………………………………………………………………….
Load more

Recommended publications
  • Geisinger Bloomsburg Hospital Published: July 1, 2019
    Geisinger Bloomsburg Hospital Published: July 1, 2019 DESCRIPTION CHARGE 3D Rendering With Interpretation And Reporting Of Computed Tomography, Magnetic Resonance Imaging, Ultrasound, Or Other Tomographic Modality With Image Postprocessing Under $ 1,230.00 Concurrent Supervision; Requiring Image Postprocessing On An Independent Workstation Abatacept 250 Mg Iv Solr $ 8,383.48 Acarbose 50 Mg Po Tabs $ 9.55 Ace Bandage $ 22.00 Ace Harmnic Crvd Shears Ace36E $ 3,617.00 Acebutolol Hcl 200 Mg Po Caps $ 9.34 Acetaminophen 120 Mg Pr Supp $ 6.70 Acetaminophen 325 Mg Po Tabs $ 6.70 Acetaminophen 325 Mg Pr Supp $ 6.99 Acetaminophen 650 Mg Pr Supp $ 6.70 Acetaminophen 80 Mg Po Chew $ 6.70 Acetaminophen 80 Mg Pr Supp $ 6.99 Acetazolamide 125 Mg Po Tabs $ 15.66 Acetazolamide 250 Mg Po Tabs $ 28.29 Acetazolamide 62.5 Mg (1/2 X 125 Mg) Po Tabs $ 8.81 Acetazolamide Er 500 Mg Po Cp12 $ 28.93 Acetylcholine Chloride 20 Mg Io Solr $ 748.45 Acl Kit Ar-1897S $ 2,819.00 Acute Hepatitis Panel This Panel Must Include The Following: Hepatitis A Antibody (Haab), Igm Antibody (86709) Hepatitis B Core Antibody (Hbcab), Igm Antibody (86705) Hepatitis B Surface $ 672.00 Antigen (Hbsag) (87340) Hepatitis C Antibody (86803) Acyclovir 200 Mg Po Caps $ 11.57 Acyclovir 400 Mg Po Tabs $ 13.81 Adalimumab 40 Mg/0.8Ml Subq Pskt $ 19,539.52 Administration Of Influenza Virus Vaccine $ 35.00 Administration Of Pneumococcal Vaccine $ 35.00 Ado-Trastuzumab Emtansine 100 Mg Iv Solr $ 31,827.85 Ado-Trastuzumab Emtansine 160 Mg Iv Solr $ 50,909.88 Adrenocorticotropic Hormone (Acth) $
    [Show full text]
  • Pharmaceuticals and Medical Devices Safety Information No
    Pharmaceuticals and Medical Devices Safety Information No. 258 June 2009 Table of Contents 1. Selective serotonin reuptake inhibitors (SSRIs) and aggression ······································································································································ 3 2. Important Safety Information ······································································· 10 . .1. Isoflurane ························································································· 10 3. Revision of PRECAUTIONS (No. 206) Olmesartan medoxomil (and 3 others)··························································· 15 4. List of products subject to Early Post-marketing Phase Vigilance.....................................................17 Reference 1. Project for promoting safe use of drugs.............................................20 Reference 2. Manuals for Management of Individual Serious Adverse Drug Reactions..................................................................................21 Reference 3. Extension of cooperating hospitals in the project for “Japan Drug Information Institute in Pregnancy” ..............25 This Pharmaceuticals and Medical Devices Safety Information (PMDSI) is issued based on safety information collected by the Ministry of Health, Labour and Welfare. It is intended to facilitate safer use of pharmaceuticals and medical devices by healthcare providers. PMDSI is available on the Pharmaceuticals and Medical Devices Agency website (http://www.pmda.go.jp/english/index.html) and on the
    [Show full text]
  • PERSONAL INFORMATION Francesco Rodeghiero WORK
    Curriculum Vitae PERSONAL INFORMATION Francesco Rodeghiero WORK EXPERIENCE February 2004- Present Scientific Director Fondazione Progetto Ematologia (Italy) August 2001-October 2015 Director of the Department of Cell Therapy and Hematology Azienda ULSS N.6 (Italy) <p>The Department includes a Unit for Bone Marrow Transplantation, a specialized Center for the diagnosis and treatment of Hemophilia and Thrombosis, and a Research Laboratory</p> 1989- 2016 Professor at the Postgraduate School of Hematology on a contract-basis University of Verona (Italy) February 1993-October 2015 Director of the Hematology Department Azienda ULSS N.6 (Italy) December 1985-October 2015 Director of the Hemostasis and Trombosis Center Azienda ULSS N.6 (Italy) September 2006-November 2016 Member; Chairman from June 2016 to November 2016 Ethics Committee on drugs research and investigational protocol studies of the Vicenza District (Italy) EDUCATION AND TRAINING July 1975- Degree in Medicine University School of Medicine (Italy) December 1984- Postgraduate specialization in Laboratory Medicine University of Padova (Italy) June 1981- Postgraduate specialization in Oncology University of Ferrara (Italy) July 1978- Postgraduate specialization in Hematology University of Ferrara (Italy) ADDITIONAL INFORMATION 15/12/2020 European Medicine Agency Page 1/46 Expertise He has been conducting clinical research in the fields of hematology and hemostasis since the early 1970s. His main interests include thrombocytopenia, hemophilia, von Willebrand disease, thrombophilia, acute promyelocytic leukemia, myeloma, policytemia vera, and the epidemiological aspects of haematological diseases. In the last decades he mainly devoted to clinical research in the field of ITP. Publications 1.T. Barbui, F. Rodeghiero, E. Dini The aspirin tolerance test in von Willebrands disease.
    [Show full text]
  • United States Patent (19) 11 Patent Number: 6,019,993 Bal (45) Date of Patent: Feb
    USOO6O19993A United States Patent (19) 11 Patent Number: 6,019,993 Bal (45) Date of Patent: Feb. 1, 2000 54) VIRUS-INACTIVATED 2-COMPONENT 56) References Cited FIBRIN GLUE FOREIGN PATENT DOCUMENTS 75 Inventor: Frederic Bal, Vienna, Austria O 116 263 1/1986 European Pat. Off.. O 339 607 4/1989 European Pat. Off.. 73 Assignee: Omrix Biopharmaceuticals S.A., O 534 178 3/1993 European Pat. Off.. Brussels, Belgium 2 201993 1/1972 Germany. 2 102 811 2/1983 United Kingdom. 21 Appl. No.: 08/530,167 PCTUS85O1695 9/1985 WIPO. PCTCH920.0036 2/1992 WIPO. 22 PCT Filed: Mar. 27, 1994 PCT/SE92/ 00441 6/1992 WIPO. 86 PCT No.: PCT/EP94/00966 PCTEP9301797 7/1993 WIPO. S371 Date: Nov.30, 1995 Primary Examiner-Carlos Azpuru Attorney, Agent, or Firm-Jacobson, Price, Holman, & S 102(e) Date: Nov.30, 1995 Stern, PLLC 87 PCT Pub. No.: WO94/22503 57 ABSTRACT PCT Pub. Date: Oct. 13, 1994 A two-component fibrin glue for human application includes 30 Foreign Application Priority Data a) a component A containing i) a virus-inactivated and concentrated cryoprecipitate that contains fibrinogen, and ii) Mar. 30, 1993 EP European Pat. Off. .............. 93105298 traneXamic acid or a pharmaceutically acceptable Salt, 51 Int. Cl." A61F 2/06; A61K 35/14 thereof, and b) component B containing a proteolytic 52 U s C - - - - - - - - - - - - - - - - - - - - - - - - - - -424/426. 530,380, 530/381: enzyme that, upon combination with component A, cleaves, O X O -- O - - - s 530(383. 530ass Specifically, fibrinogen present in the cryoprecipitate of 58) Field of Search 424/426,530,380 component A, thereby, effecting a fibrin polymer.
    [Show full text]
  • Comparison of Fibrin Adhesives Prepared by 3 Different Methods
    Original Article Int. Arch. Otorhinolaryngol. 2013;17(1):62-65. DOI: 10.7162/S1809-97772013000100011 Comparison of fibrin adhesives prepared by 3 different methods Juliana Benthien Cavichiolo1, Maurício Buschle2, Bettina Carvalho3. 1) Medical Resident in Otolaryngology, HC-UFPR (Hospital de Clínicas da Universidade Federal do Paraná). 2) MMSc. Physician Assistant, Department of Otolaryngology, Faculty of Medicine, UFPR; Associate Professor of Otolaryngology. 3) Otolaryngologist by ABORLCCF. Institution: Hospital de Clínicas da Universidade Federal do Paraná. Curitiba / PR - Brazil. Mailing address: Juliana Benthien Cavichiolo - Rua General Carneiro, 181 - Alto da XV - Curitiba / PR - Brazil - Zip code: 80060-900 - E-mail: [email protected] Article received on May 1, 2011. Article accepted on October 25, 2012. SUMMARY Introduction: Fibrin tissue adhesive, which has applications in several areas of medicine, can be prepared by different methods. Aim: To compare fibrin tissue adhesives prepared by 3 different methods. Method: In this prospective experimental laboratory study, fibrin tissue adhesives prepared by the use of plasma fibrinogen (group 1), cryoprecipitation (group 2), and precipitation by ammonium sulfate (group 3) were tested on 15 rabbits and 10 fragments of dura mater. The quality of the clots was assessed in terms of the success of the healing process, local toxicity, graft adhesion capacity, and degree of adhesion of 2 fragments of dura mater produced. Results: All methods produced a clot with high adhesion and no toxicity, but tensile strength testing revealed that the glue produced from the ammonium sulfate-precipitated clot (group 3) was the strongest, requiring 39 g/cm ² to separate the fragments as opposed to 23 g/cm ² for group 2 and 13 g/cm ² for group 1.
    [Show full text]
  • Does Tranexamic Acid Stabilised Fibrin Support the Osteogenic Differentiation of Human Periosteum Derived Cells? J
    JEuropean Demol et Cells al. and Materials Vol. 21 2011 (pages 272-285) DOI: 10.22203/eCM.v021a21 Fibrin for osteogenic differentiation ISSN of1473-2262 hPDCs? DOES TRANEXAMIC ACID STABILISED FIBRIN SUPPORT THE OSTEOGENIC DIFFERENTIATION OF HUMAN PERIOSTEUM DERIVED CELLS? J. Demol1,3, J. Eyckmans2,3, S.J. Roberts2,3, F.P. Luyten2,3 and H. Van Oosterwyck1,3,* 1 Division of Biomechanics and Engineering Design, 2 Laboratory for Skeletal Development and Joint Disorders, 3 Prometheus, Division of Skeletal Tissue Engineering Leuven, K.U. Leuven, Leuven, Belgium Abstract Introduction Fibrin sealants have long been used as carrier for osteogenic Fibrin is a natural polymer that is formed during blood cells in bone regeneration. However, it has not been clotting from its precursor protein fibrinogen. The demonstrated whether fibrin’s role is limited to delivering conversion of fibrinogen to fibrin is triggered by thrombin cells to the bone defect or whether fibrin enhances (Blomback, 1996). In fibrin sealants, this coagulation osteogenesis. This study investigated fibrin’s influence on process has been engineered into an adhesive system that the behaviour of human periosteum-derived cells (hPDCs) is widely used in many surgical fields to promote when cultured in vitro under osteogenic conditions in two- haemostasis, sealing and tissue bonding. Commercial dimensional (fibrin substrate) and three-dimensional (fibrin fibrin sealant kits contain highly purified and virally carrier) environments. Tranexamic acid (TEA) was used inactivated human fibrinogen and human thrombin to reduce fibrin degradation after investigating its effect (Jackson, 2001). Fibrin is a non-cytotoxic, fully on hPDCs in monolayer culture on plastic. TEA did not resorbable, bioactive matrix with multiple interaction sites affect proliferation nor calcium deposition of hPDCs under for cells and other proteins (Mosesson et al., 2001).
    [Show full text]
  • WO 2016/133483 Al 25 August 2016 (25.08.2016) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2016/133483 Al 25 August 2016 (25.08.2016) P O P C T (51) International Patent Classification: SHENIA, Iaroslav Viktorovych [UA/UA]; Feodosiyskyy A61L 15/44 (2006.01) A61L 26/00 (2006.01) lane, 14-a, kv. 65, Kyiv, 03028 (UA). A61L 15/54 (2006.01) (74) Agent: BRAGARNYK, Oleksandr Mykolayovych; str. (21) International Application Number: Lomonosova, 60/5-43, Kyiv, 03189 (UA). PCT/UA20 16/0000 19 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 15 February 2016 (15.02.2016) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (30) Priority Data: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, a 2015 01285 16 February 2015 (16.02.2015) UA PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, u 2015 01288 16 February 2015 (16.02.2015) UA SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (72) Inventors; and TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • SAP American Society of Hematology Self-Assessment Program
    ASH®-SAP American Society of Hematology Self-Assessment Program SIXTH EDITION BK-ASH-SAP_6E-150511-FM.indd 1 4/29/2016 3:59:06 PM Disclosures As a provider accredited by the Accreditation Council for Hemostasis Research Society of North America (HTRS); Continuing Medical Education (ACCME), the American member of an advisory board for GlaxoSmithKline. Society of Hematology must ensure balance, independence, objectivity, and scientific rigor in all of the educational ac- Chapter 4, Hematopoietic growth factors tivities it sponsors. All authors are expected to disclose any financial relationships with any proprietary entity producing Aaron T. Gerds declares no competing financial interest. health care goods or services that have occurred within 24 Alan E. Lichtin declares no competing financial interest. months from the start of or during the production of the work and that are relevant to the author’s content. If an au- Chapter 5, Iron metabolism, iron overload, thor has such a financial interest, then she or he must dis- and the porphyrias close the name of the commercial interest and nature of the relationship (eg, consultant, grantee, etc.). An author who Heather A. Leitch has received honoraria, research funding, has no such financial relationship must declare that she or and/or served on advisory boards for Alexion, Apo-Pharma, he has nothing to disclose. The intent of this disclosure is Celgene, and Novartis. She is a member of the Exjade speak- not to prevent an author with a significant financial or other ers’ bureau. Jecko Thachil declares no competing financial relationship from making a presentation, but rather to pro- interest.
    [Show full text]
  • Engineered Technologies to Study the Role of Mechanical Signals in Human Lymphoma Growth and Therapeutic Response
    ENGINEERED TECHNOLOGIES TO STUDY THE ROLE OF MECHANICAL SIGNALS IN HUMAN LYMPHOMA GROWTH AND THERAPEUTIC RESPONSE A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Apoorva May 2018 © 2018 Apoorva ACKNOWLEDGEMENT I am very thankful to my advisor Ankur for his mentorship, support and constant encouragement. His passion and enthusiasm for research are contagious and inspiring. I appreciate his engaging, hands-on and proactive approach to research. I also appreciate Ankur’s patience, and how he went out of his ways to help me on several occasions-- Anything good I do, will be because of him. All this would not have been possible without Marcia Sawyer. Thank you to Marcia for all her unconditional support, encouragement and help. I am glad that when PhD gets tough, Marcia is around to talk to. Last but not least, I appreciate how she kept all the grad students informed and organized. For the phosphorylation studies, Prof. Cosgrove and Alex made significant contribution to the experiments and analysis. I am grateful to Prof. Cosgrove for inspiring discussions, feedback and access to his lab facility. For the computational analysis and microfluidic experiments, I often visited Prof. Kirby. I thank him for his time and ideas. I am also grateful to my other committee members, Prof. Archer and Prof. Shepherd, for their feedback and guidance. When I joined Singh lab, I had absolutely zero knowledge of biomedical engineering. Field and Alberto were the only students in the lab.
    [Show full text]
  • Hemostatic Agents in Hepatobiliary and Pancreas Surgery: a Review of the Literature and Critical Evaluation of a Novel Carrier-Bound Fibrin Sealant (Tachosil)
    International Scholarly Research Network ISRN Surgery Volume 2012, Article ID 729086, 12 pages doi:10.5402/2012/729086 Review Article Hemostatic Agents in Hepatobiliary and Pancreas Surgery: A Review of the Literature and Critical Evaluation of a Novel Carrier-Bound Fibrin Sealant (TachoSil) K. A. Simo,1 E. M. Hanna,1 D. K. Imagawa,2 and D. A. Iannitti1 1 Section of Hepatobiliary and Pancreas Surgery, Department of Surgery, Carolinas Medical Center, 1025 Morehead Medical Drive, Suite 300, Charlotte, NC 28204, USA 2 Division of Hepatobiliary and Pancreas Surgery and Islet Cell Transplantation, Department of Surgery, University of California, Irvine, Orange, CA 92868, USA Correspondence should be addressed to D. A. Iannitti, [email protected] Received 21 May 2012; Accepted 24 July 2012 Academic Editors: J.-M. Catheline, G. Nasso, and B. H. Yong Copyright © 2012 K. A. Simo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Despite progress in surgical techniques applied during hepatobiliary and pancreas (HPB) surgery, bleeding and bile leak remain significant contributors to postoperative mortality and morbidity. Topical hemostatics have been developed and utilized across surgical specialties, but data regarding effectiveness remains inconsistent and sparse in HPB surgery. Methods. A comprehensive search for studies and reviews on hemostatics in HPB surgery was performed via an October 2011 query of Medline, EMBASE, and Cochrane Library. In-depth evaluation of a novel carrier-bound fibrin sealant (TachoSil) was also performed. Results. The literature review illustrates multiple attempts have been made at developing different topical hemostatics and sealants to aid in surgical procedures.
    [Show full text]
  • Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
    MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01
    [Show full text]
  • Hematopoiesis and Hemostasis
    Hematopoiesis and Hemostasis HAP Susan Chabot Hematopoiesis • Blood Cell Formation • Occurs in red bone marrow – Red marrow - found in flat bones and proximal epiphyses of long bones. • Each type of blood cell is produced in response to changing needs of the body. • On average, an ounce of new blood is produced each day with about 100 billion new blood cells/formed elements. Hemocytoblast • Hemo- means blood • Cyto- means cell • -blast means builder • Blood stem cell found in red bone marrow. • Once the precursor cell has committed to become a specific blood type, it cannot be changed. Hemocytoblast Erythropoiesis • Erythrocyte Formation • Because they are anucleated, RBC’s must be regularly replaced. – No info to synthesize proteins, grow or divide. • They begin to fall apart in 100 - 120 days. • Remains of fragmented RBC’s are removed by the spleen and liver. • Entire development , release, and ejection of leftover organelles takes 3-5 days. Normal RBC’s Reticulocytes • The stimulus for RBC production is the amount of OXYGEN in the blood not the NUMBER of RBC’s. • The rate of RBC production is controlled by the hormone ERYTHROPOIETIN. Leuko- and Thrombopoiesis • Leukopoesis = WBC production • Thrombopoesis = platelet production • Controlled by hormones Leukopoesis Thrombopoesis • (CSF) Colony • Thrombopoetin stimulating factor • Little is known • Interleukins about this – Prompts WBC process. production – Boosts other immune processes including inflammation. HEMOSTASIS Hemostasis • Hemo- means blood • -stasis means standing still – Stoppage of bleeding • Fast and localized reaction when a blood vessel breaks. • Involves a series of reactions. • Involves substances normally found in plasma but not activated. • Occurs in 3 main phases Phases of Hemostasis • Step 1: Vascular Spasm – Vasoconstriction, narrowing of blood vessels.
    [Show full text]