WO2009039542A3 - Methods of screening for compounds having anti- inflammatory activity and/or prevent / treat vascular leak - Google Patents

Methods of screening for compounds having anti- inflammatory activity and/or prevent / treat vascular leak Download PDF

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Publication number
WO2009039542A3
WO2009039542A3 PCT/AT2008/000337 AT2008000337W WO2009039542A3 WO 2009039542 A3 WO2009039542 A3 WO 2009039542A3 AT 2008000337 W AT2008000337 W AT 2008000337W WO 2009039542 A3 WO2009039542 A3 WO 2009039542A3
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WO
WIPO (PCT)
Prior art keywords
screening
methods
compounds
prevent
vascular leak
Prior art date
Application number
PCT/AT2008/000337
Other languages
French (fr)
Other versions
WO2009039542A9 (en
WO2009039542A2 (en
Inventor
Peter Petzelbauer
Rainer Henning
Sonja Reingruber
Waltraud Pasteiner
Marion Groeger
Original Assignee
Fibrex Medical Res & Dev Gmbh
Peter Petzelbauer
Rainer Henning
Sonja Reingruber
Waltraud Pasteiner
Marion Groeger
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/860,488 external-priority patent/US20090081192A1/en
Priority claimed from AT19392007A external-priority patent/AT506121A1/en
Application filed by Fibrex Medical Res & Dev Gmbh, Peter Petzelbauer, Rainer Henning, Sonja Reingruber, Waltraud Pasteiner, Marion Groeger filed Critical Fibrex Medical Res & Dev Gmbh
Priority to JP2010525162A priority Critical patent/JP2010540892A/en
Priority to EP08799926A priority patent/EP2193370A2/en
Publication of WO2009039542A2 publication Critical patent/WO2009039542A2/en
Publication of WO2009039542A9 publication Critical patent/WO2009039542A9/en
Publication of WO2009039542A3 publication Critical patent/WO2009039542A3/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5064—Endothelial cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/42—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving phosphatase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/585—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with a particulate label, e.g. coloured latex
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases
    • G01N2800/065—Bowel diseases, e.g. Crohn, ulcerative colitis, IBS
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/06—Gastro-intestinal diseases
    • G01N2800/067—Pancreatitis or colitis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/08—Hepato-biliairy disorders other than hepatitis
    • G01N2800/085—Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G01N2800/122—Chronic or obstructive airway disorders, e.g. asthma COPD
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G01N2800/125—Adult respiratory distress syndrome
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/16—Ophthalmology
    • G01N2800/164—Retinal disorders, e.g. retinopathy
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/20—Dermatological disorders
    • G01N2800/202—Dermatitis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/20—Dermatological disorders
    • G01N2800/205—Scaling palpular diseases, e.g. psoriasis, pytiriasis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/22—Haematology
    • G01N2800/224—Haemostasis or coagulation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders
    • G01N2800/245—Transplantation related diseases, e.g. graft versus host disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/324—Coronary artery diseases, e.g. angina pectoris, myocardial infarction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/32—Cardiovascular disorders
    • G01N2800/328—Vasculitis, i.e. inflammation of blood vessels
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/34—Genitourinary disorders
    • G01N2800/347—Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Food Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)

Abstract

Methods of screening for modulators of Racl, RhoA or focal adhesion kinase (FAK) in endothelial cells are disclosed. The effect is determined by- measuring endothelial permeability, Racl or RhoA activity and phosphorylation of FAK. Vascular permeability may be stimulated by thrombin. Method of screening for compounds that prevent vascular leak in a warm-blooded animal undergoing systematic inflammatory response triggered by LPS, using fluorescence labelled micro-beads. A method of screening comprising a combination of all said methods is also disclosed. Compounds and pharmaceutical preparations being identified by said methods.
PCT/AT2008/000337 2007-09-24 2008-09-22 Methods of screening for compounds having anti- inflammatory activity and/or prevent / treat vascular leak WO2009039542A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2010525162A JP2010540892A (en) 2007-09-24 2008-09-22 Method for screening compound having anti-inflammatory activity
EP08799926A EP2193370A2 (en) 2007-09-24 2008-09-22 Methods of screening for compounds having anti-inflammatory activity

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US11/860,488 US20090081192A1 (en) 2007-09-24 2007-09-24 Methods of screening for compounds having anti-inflammatory activity
US11/860,488 2007-09-24
AT19392007A AT506121A1 (en) 2007-11-28 2007-11-28 Screening for compounds, e.g. proteins or peptides, that increase the activity of the protein Rac1 comprises contacting cultured endothelial cells with a test compound and measuring endothelial permeability
ATA1939/2007 2007-11-28

Publications (3)

Publication Number Publication Date
WO2009039542A2 WO2009039542A2 (en) 2009-04-02
WO2009039542A9 WO2009039542A9 (en) 2009-05-14
WO2009039542A3 true WO2009039542A3 (en) 2009-07-02

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PCT/AT2008/000337 WO2009039542A2 (en) 2007-09-24 2008-09-22 Methods of screening for compounds having anti- inflammatory activity and/or prevent / treat vascular leak

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EP (1) EP2193370A2 (en)
JP (1) JP2010540892A (en)
WO (1) WO2009039542A2 (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286725A1 (en) * 2008-05-15 2009-11-19 Fibrex Medical Research & Development Gmbh Peptides and derivatives thereof, the manufacturing thereof as well as their use for preparing a therapeutically and/or preventively active pharmaceutical composition
WO2010043444A2 (en) * 2008-10-15 2010-04-22 Fibrex Medical Research & Development Gmbh Pharmaceutical preparation for the treatment and/or prevention of ischemia/reperfusion injury and the sequels thereof
KR101127225B1 (en) 2010-01-07 2012-03-29 건국대학교 산학협력단 Biomarker of Urothelial Cancer and the Diagnostic Method of the Same
CA2840883C (en) 2011-07-07 2019-07-16 Merck Patent Gmbh Substituted azaheterocycles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405315A2 (en) * 1989-06-30 1991-01-02 American Cyanamid Company Use of a phagocyte-activating agent : LPS or IL-2 for the manufacture of a medicament for treating staphylococcus aureus infection in cows
WO2006000007A1 (en) * 2004-06-25 2006-01-05 Fibrex Medical Research & Development Gesmbh Use of peptides derived from the a alpha or b beta chain of human fibrinogen for the treatment of shock
WO2007070899A2 (en) * 2005-12-23 2007-06-28 Fibrex Medical Research & Development Gmbh Pharmaceutical composition for treating haemorrhagic shock and its consecutive symptoms

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003226349B2 (en) * 2002-04-11 2008-01-31 Children's Medical Center Corporation Methods for inhibiting vascular hyperpermeability
JP2006101755A (en) * 2004-10-05 2006-04-20 Tokyoto Igaku Kenkyu Kiko Allergic mouse

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405315A2 (en) * 1989-06-30 1991-01-02 American Cyanamid Company Use of a phagocyte-activating agent : LPS or IL-2 for the manufacture of a medicament for treating staphylococcus aureus infection in cows
WO2006000007A1 (en) * 2004-06-25 2006-01-05 Fibrex Medical Research & Development Gesmbh Use of peptides derived from the a alpha or b beta chain of human fibrinogen for the treatment of shock
WO2007070899A2 (en) * 2005-12-23 2007-06-28 Fibrex Medical Research & Development Gmbh Pharmaceutical composition for treating haemorrhagic shock and its consecutive symptoms

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
HINSBERGH VAN V W M ET AL: "Intracellular signalling involved in modulating human endothelial barrier function", JOURNAL OF ANATOMY, CAMBRIDGE UNIVERSITY PRESS, CAMBRIDGE, GB, vol. 200, 1 January 2002 (2002-01-01), pages 549 - 560, XP002261213, ISSN: 0021-8782 *
HOLINSTAT MICHAEL ET AL: "Suppression of RhoA activity by focal adhesion kinase-induced activation of p190RhoGAP: role in regulation of endothelial permeability.", THE JOURNAL OF BIOLOGICAL CHEMISTRY 27 JAN 2006, vol. 281, no. 4, 27 January 2006 (2006-01-27), pages 2296 - 2305, XP002512837, ISSN: 0021-9258 *
KLINGER ET AL: "Natriuretic peptides differentially attenuate thrombin-induced barrier dysfunction in pulmonary microvascular endothelial cells", EXPERIMENTAL CELL RESEARCH, ACADEMIC PRESS, US, vol. 312, no. 4, 15 February 2006 (2006-02-15), pages 401 - 410, XP005207531, ISSN: 0014-4827 *
KNEZEVIC NEBOJSA ET AL: "GDI-1 phosphorylation switch at serine 96 induces RhoA activation and increased endothelial permeability.", MOLECULAR AND CELLULAR BIOLOGY SEP 2007, vol. 27, no. 18, 1 September 2007 (2007-09-01), pages 6323 - 6333, XP002512836, ISSN: 0270-7306 *
MARCUS ET AL: "Measurement of Endothelial Permeability", ANNALS OF VASCULAR SURGERY, QUALITY MEDICAL PUBLISHING, ST. LOUIS, MO, US, vol. 12, no. 4, 1 July 1998 (1998-07-01), pages 384 - 390, XP005940431, ISSN: 0890-5096 *
SAENZ-MORALES ET AL: "Requirements for proximal tubule epithelial cell detachment in response to ischemia: Role of oxidative stress", EXPERIMENTAL CELL RESEARCH, ACADEMIC PRESS, US, vol. 312, no. 19, 15 November 2006 (2006-11-15), pages 3711 - 3727, XP005716783, ISSN: 0014-4827 *
TORIUMI Y ET AL: "Pioglitazone reduces monocyte adhesion to vascular endothelium under flow by modulating RhoA GTPase and focal adhesion kinase", FEBS LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 553, no. 3, 23 October 2003 (2003-10-23), pages 419 - 422, XP004468259, ISSN: 0014-5793 *
VAN NIEUW AMERONGEN GEERTEN P ET AL: "GIT1 mediates thrombin signaling in endothelial cells: role in turnover of RhoA-type focal adhesions.", CIRCULATION RESEARCH 30 APR 2004, vol. 94, no. 8, 30 April 2004 (2004-04-30), pages 1041 - 1049, XP002512838, ISSN: 1524-4571 *
WOJCIAK-STOTHARD BEATA ET AL: "Rac and Rho play opposing roles in the regulation of hypoxia/reoxygenation-induced permeability changes in pulmonary artery endothelial cells.", AMERICAN JOURNAL OF PHYSIOLOGY. LUNG CELLULAR AND MOLECULAR PHYSIOLOGY APR 2005, vol. 288, no. 4, April 2005 (2005-04-01), pages L749 - L760, XP002512834, ISSN: 1040-0605 *
WOJCIAK-STOTHARD BEATA ET AL: "Rac1 and RhoA as regulators of endothelial phenotype and barrier function in hypoxia-induced neonatal pulmonary hypertension.", AMERICAN JOURNAL OF PHYSIOLOGY. LUNG CELLULAR AND MOLECULAR PHYSIOLOGY JUN 2006, vol. 290, no. 6, June 2006 (2006-06-01), pages L1173 - L1182, XP002512835, ISSN: 1040-0605 *
WOJCIAK-STOTHARD BEATA ET AL: "Rho GTPases and the regulation of endothelial permeability.", VASCULAR PHARMACOLOGY NOV 2002, vol. 39, no. 4-5, November 2002 (2002-11-01), pages 187 - 199, XP002512833, ISSN: 1537-1891 *

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Publication number Publication date
WO2009039542A9 (en) 2009-05-14
WO2009039542A2 (en) 2009-04-02
EP2193370A2 (en) 2010-06-09
JP2010540892A (en) 2010-12-24

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