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  1. Article: Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS.

    Zivadinov, Robert / Dwyer, Michael G / Carl, Ellen / Poole, Elizabeth M / Cavalier, Steve / Briassouli, Paraskevi / Bergsland, Niels

    Therapeutic advances in neurological disorders

    2020  Volume 13, Page(s) 1756286420970754

    Abstract: Background: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of ... ...

    Abstract Background: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS).
    Methods: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2.
    Results: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy
    Conclusion: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.
    Language English
    Publishing date 2020-11-11
    Publishing country England
    Document type Journal Article
    ZDB-ID 2442245-9
    ISSN 1756-2864 ; 1756-2856
    ISSN (online) 1756-2864
    ISSN 1756-2856
    DOI 10.1177/1756286420970754
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  2. Article ; Online: Binding of anti-SSA antibodies to apoptotic fetal cardiocytes stimulates urokinase plasminogen activator (uPA)/uPA receptor-dependent activation of TGF-β and potentiates fibrosis.

    Briassouli, Paraskevi / Rifkin, Daniel / Clancy, Robert M / Buyon, Jill P

    Journal of immunology (Baltimore, Md. : 1950)

    2011  Volume 187, Issue 10, Page(s) 5392–5401

    Abstract: In congenital heart block (CHB), binding of maternal anti-SSA/Ro Abs to fetal apoptotic cardiocytes impairs their removal by healthy cardiocytes and increases urokinase plasminogen activator (uPA)/uPA receptor (uPAR)-dependent plasmin activation. Because ...

    Abstract In congenital heart block (CHB), binding of maternal anti-SSA/Ro Abs to fetal apoptotic cardiocytes impairs their removal by healthy cardiocytes and increases urokinase plasminogen activator (uPA)/uPA receptor (uPAR)-dependent plasmin activation. Because the uPA/uPAR system plays a role in TGF-β activation, we evaluated whether anti-Ro binding to apoptotic cardiocytes enhances plasmin-mediated activation of TGF-β, thereby promoting a profibrosing phenotype. Supernatants from cocultures of healthy cardiocytes and apoptotic cardiocytes bound by IgG from a mother whose child had CHB (apoptotic-CHB-IgG [apo-CHB-IgG]) exhibited significantly increased levels of active TGF-β compared with supernatants from cocultures of healthy cardiocytes and apoptotic cardiocytes preincubated with IgG from a healthy donor. Treatment of the culture medium with anti-TGF-β Ab or TGF-β inhibitor (SB431542) abrogated the luciferase response, thereby confirming TGF-β dependency. Increased uPA levels and activity were present in supernatants generated from cocultures of healthy cardiocytes and apo-CHB-IgG cardiocytes compared with healthy cardiocytes and apoptotic cardiocytes preincubated with IgG from a healthy donor, respectively. Treatment of apo-CHB-IgG cardiocytes with anti-uPAR or anti-uPA Abs or plasmin inhibitor aprotinin prior to coculturing with healthy cardiocytes attenuated TGF-β activation. Supernatants derived from cocultures of healthy cardiocytes and apo-CHB-IgG cardiocytes promoted Smad2 phosphorylation and fibroblast transdifferentiation, as evidenced by increased smooth muscle actin and collagen expression, which decreased when fibroblasts were treated with supernatants from cocultures pretreated with uPAR Abs. These data suggested that binding of anti-Ro Abs to apoptotic cardiocytes triggers TGF-β activation, by virtue of increasing uPAR-dependent uPA activity, thus initiating and amplifying a cascade of events that promotes myofibroblast transdifferentiation and scar.
    MeSH term(s) Apoptosis/immunology ; Autoantibodies/metabolism ; Binding Sites, Antibody ; Cell Transdifferentiation/immunology ; Cells, Cultured ; Cicatrix/immunology ; Cicatrix/pathology ; Coculture Techniques ; Female ; Fetal Heart/immunology ; Fetal Heart/metabolism ; Fetal Heart/pathology ; Fibrosis ; Humans ; Myocytes, Cardiac/immunology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Receptors, Urokinase Plasminogen Activator/metabolism ; Receptors, Urokinase Plasminogen Activator/physiology ; Ribonucleoproteins/immunology ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/physiology ; Urokinase-Type Plasminogen Activator/metabolism ; Urokinase-Type Plasminogen Activator/physiology
    Chemical Substances Autoantibodies ; Receptors, Urokinase Plasminogen Activator ; Ribonucleoproteins ; SS-A antigen ; Transforming Growth Factor beta ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
    Language English
    Publishing date 2011-10-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1101288
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    Ud II Zs.37: Show issues Location:
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  3. Article ; Online: Role of the urokinase plasminogen activator receptor in mediating impaired efferocytosis of anti-SSA/Ro-bound apoptotic cardiocytes: Implications in the pathogenesis of congenital heart block.

    Briassouli, Paraskevi / Komissarova, Elena V / Clancy, Robert M / Buyon, Jill P

    Circulation research

    2010  Volume 107, Issue 3, Page(s) 374–387

    Abstract: Rationale: Binding of maternal anti-Ro/La antibodies to cognate antigen expressed on apoptotic cardiocytes decreases clearance by healthy cardiocytes, which may contribute to the development of autoimmune associated congenital heart block and fatal ... ...

    Abstract Rationale: Binding of maternal anti-Ro/La antibodies to cognate antigen expressed on apoptotic cardiocytes decreases clearance by healthy cardiocytes, which may contribute to the development of autoimmune associated congenital heart block and fatal cardiomyopathy.
    Objective: Given recent evidence implicating the urokinase plasminogen activator receptor (uPAR) as a "don't eat me" signal during efferocytosis, experiments addressed whether surface bound anti-Ro antibodies inhibit apoptotic cell removal via an effect on the expression/function of the urokinase-type plasminogen activator protease uPA/uPAR system.
    Methods and results: As assessed by flow cytometry and confocal microscopy, uPAR colocalizes and interacts with Ro60 on the surface of apoptotic human fetal cardiocytes. Blocking of uPAR enhances phagocytosis of apoptotic cardiocytes by healthy cardiocytes and reverses the anti-Ro60-dependent impaired clearance of apoptotic cardiocytes. Binding of anti-Ro60 antibodies to apoptotic cardiocytes results in increased uPAR expression, as well as enhanced uPA activity. The binding of anti-Ro60 did not alter other surface molecules involved in cell recognition (calreticulin, CD31, or CD47).
    Conclusions: These data suggest that increased uPAR expression and uPA activity induced by anti-Ro60 binding to the apoptotic fetal cardiocyte provide a molecular basis by which these antibodies inhibit efferocytosis and ultimately lead to scar of the fetal conduction system and working myocardium.
    MeSH term(s) Animals ; Antibodies, Monoclonal ; Apoptosis ; CD47 Antigen/metabolism ; Calreticulin/metabolism ; Cardiomyopathies/immunology ; Chickens/immunology ; Female ; Fetal Diseases/genetics ; Fetus/physiology ; Flow Cytometry ; Heart Block/congenital ; Heart Block/etiology ; Heart Block/genetics ; Heart Conduction System/pathology ; Humans ; Immunoglobulin G ; Mice ; Microscopy, Confocal ; Myocytes, Cardiac/immunology ; Myocytes, Cardiac/pathology ; Myocytes, Cardiac/physiology ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Pregnancy ; Receptors, Urokinase Plasminogen Activator/antagonists & inhibitors ; Receptors, Urokinase Plasminogen Activator/genetics ; Urokinase-Type Plasminogen Activator/metabolism
    Chemical Substances Antibodies, Monoclonal ; CD47 Antigen ; Calreticulin ; Immunoglobulin G ; Platelet Endothelial Cell Adhesion Molecule-1 ; Receptors, Urokinase Plasminogen Activator ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
    Language English
    Publishing date 2010-06-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.109.213629
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  4. Article: The N-terminal domain of the Aurora-A Phe-31 variant encodes an E3 ubiquitin ligase and mediates ubiquitination of IkappaBalpha.

    Briassouli, Paraskevi / Chan, Florence / Linardopoulos, Spiros

    Human molecular genetics

    2006  Volume 15, Issue 22, Page(s) 3343–3350

    Abstract: Aurora-A is an important regulator of mitosis and is frequently amplified in human cancer. Ectopic expression of Aurora-A in mammalian cells induces centrosome amplification, genomic instability and transformation. A common genetic variant in Aurora-A ( ... ...

    Abstract Aurora-A is an important regulator of mitosis and is frequently amplified in human cancer. Ectopic expression of Aurora-A in mammalian cells induces centrosome amplification, genomic instability and transformation. A common genetic variant in Aurora-A (F31I) is preferentially amplified and is associated with the occurrence and the status of colon, oesophageal and breast cancers. Here we demonstrate that the N-terminal domain of Aurora-A Phe-31 variant exhibits an intrinsic ubiquitin ligase activity. Mutation of cysteines 8, 33 and 49 of Aurora-A abolishes the ubiquitin ligase activity of the protein. Aurora-A in a complex with UBE2N/MMS2 catalyses polyubiquitination of IkappaBalpha in vitro and in vivo.
    MeSH term(s) Amino Acid Sequence ; Aurora Kinases ; Conserved Sequence ; Humans ; I-kappa B Kinase/metabolism ; Molecular Sequence Data ; Mutation/genetics ; Phenylalanine/genetics ; Phenylalanine/metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/chemistry ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Sequence Alignment ; Ubiquitin/metabolism ; Ubiquitin-Conjugating Enzymes/genetics ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligases/metabolism
    Chemical Substances Ubiquitin ; Phenylalanine (47E5O17Y3R) ; UBE2N protein, human (EC 2.3.2.23) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Aurora Kinases (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; I-kappa B Kinase (EC 2.7.11.10)
    Language English
    Publishing date 2006-10-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddl410
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    Zs.A 3469: Show issues Location:
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  5. Article: Aurora kinase inhibition downregulates NF-kappaB and sensitises tumour cells to chemotherapeutic agents.

    Sun, Chongbo / Chan, Florence / Briassouli, Paraskevi / Linardopoulos, Spiros

    Biochemical and biophysical research communications

    2006  Volume 352, Issue 1, Page(s) 220–225

    Abstract: We have identified that Aurora-A activates NF-kappaB via IkappaBalpha phosphorylation. Here, we analysed different human tumour cell types for their NF-kappaB activity. We found that there is an association between cell resistance to chemotherapeutic ... ...

    Abstract We have identified that Aurora-A activates NF-kappaB via IkappaBalpha phosphorylation. Here, we analysed different human tumour cell types for their NF-kappaB activity. We found that there is an association between cell resistance to chemotherapeutic agents and NF-kappaB activation. A549 human lung adenocarcinoma cells and SKOV3 human ovarian cancer cells have high levels of NF-kappaB and are resistant to cytotoxic agents such as adriamycin and VP-16 (etoposide). We also found that in A549 and SKOV3 cells treated with a small molecule inhibitor towards Aurora kinases, the NF-kappaB activity was downregulated and the efficacy of cytotoxic drugs was enhanced. In addition, the transcriptional targets Bcl-XL and Bcl-2 were downregulated. This study provides evidence for a potential mechanism of chemoresistance and may be useful for the enhancement of certain chemotherapeutics regimens.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Aurora Kinases ; Cell Line, Tumor ; Down-Regulation/drug effects ; Humans ; NF-kappa B/metabolism ; Piperazines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/metabolism
    Chemical Substances Antineoplastic Agents ; NF-kappa B ; Piperazines ; Protein Kinase Inhibitors ; tozasertib (234335M86K) ; Aurora Kinases (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2006-11-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 205723-2
    ISSN 0006-291X ; 0006-291X
    ISSN (online) 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2006.11.004
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  6. Article ; Online: Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro-Associated Cardiac Neonatal Lupus.

    Saxena, Amit / Izmirly, Peter M / Han, Sung Won / Briassouli, Paraskevi / Rivera, Tania L / Zhong, Hua / Friedman, Deborah M / Clancy, Robert M / Buyon, Jill P

    Journal of the American College of Cardiology

    2015  Volume 66, Issue 8, Page(s) 930–939

    Abstract: Background: Cardiac manifestations of neonatal lupus (cardiac NL) include congenital heart block and cardiomyopathy. Several candidate biomarkers were evaluated in cases at risk for cardiac NL on the basis of potential roles in inflammation, fibrosis, ... ...

    Abstract Background: Cardiac manifestations of neonatal lupus (cardiac NL) include congenital heart block and cardiomyopathy. Several candidate biomarkers were evaluated in cases at risk for cardiac NL on the basis of potential roles in inflammation, fibrosis, and cardiac dysfunction: C-reactive protein (CRP); NT-pro-B-type natriuretic peptide (NT-proBNP); troponin I; matrix metalloproteinase (MMP)-2; urokinase plasminogen activator (uPA); urokinase plasminogen activator receptor (uPAR); plasminogen; and vitamin D.
    Objectives: Identification of maternal and fetal biomarkers associated with development and morbidity of cardiac NL should provide clues to pathogenesis with translational implications for management.
    Methods: Cord (139) and maternal (135) blood samples collected during pregnancies at risk for cardiac NL were available for study. Levels of cord and maternal CRP, cord NT-proBNP, and cord troponin I were evaluated using multiplex assays. Cord and maternal vitamin D were assessed by liquid chromatography-mass spectrometry. MMP-2, uPA, uPAR, and plasminogen were evaluated using ELISA.
    Results: Cord CRP, NT-proBNP, MMP-2, uPA, uPAR, and plasminogen levels were higher in cardiac NL-affected fetuses than in unaffected cases, independent of maternal rheumatic disease, season at highest risk of cardiac NL development, and medications taken during pregnancy. These biomarkers were positively associated with a disease severity score derived from known risk factors for mortality in cardiac NL. Maternal CRP and cord troponin I levels did not differ between the groups. Cord and maternal vitamin D levels were not significantly associated with cardiac NL, but average maternal vitamin D level during pregnancy was positively associated with longer time to postnatal pacemaker placement.
    Conclusions: These data support the association of fetal reactive inflammatory and fibrotic components with development and morbidity of cardiac NL. Following CRP and NT-proBNP levels after birth can potentially monitor severity and progression of cardiac NL. MMP-2 and the uPA/uPAR/plasminogen cascade provide therapeutic targets to decrease fibrosis. Although decreased vitamin D did not confer increased risk, given the positive influence on postnatal outcomes, maternal levels should be optimized.
    MeSH term(s) Antibodies, Antinuclear ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Female ; Heart Diseases/blood ; Heart Diseases/congenital ; Heart Diseases/immunology ; Humans ; Infant, Newborn ; Lupus Erythematosus, Systemic/blood ; Lupus Erythematosus, Systemic/congenital ; Lupus Erythematosus, Systemic/diagnosis ; Lupus Erythematosus, Systemic/immunology ; Male ; Matrix Metalloproteinase 2/blood ; Natriuretic Peptide, Brain/blood ; Peptide Fragments/blood ; Pregnancy ; Receptors, Urokinase Plasminogen Activator/metabolism ; Troponin I/blood ; Vitamin D/blood
    Chemical Substances Antibodies, Antinuclear ; Biomarkers ; Peptide Fragments ; Receptors, Urokinase Plasminogen Activator ; SS-A antibodies ; Troponin I ; pro-brain natriuretic peptide (1-76) ; Natriuretic Peptide, Brain (114471-18-0) ; Vitamin D (1406-16-2) ; C-Reactive Protein (9007-41-4) ; Matrix Metalloproteinase 2 (EC 3.4.24.24)
    Language English
    Publishing date 2015-08-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 605507-2
    ISSN 1558-3597 ; 0735-1097
    ISSN (online) 1558-3597
    ISSN 0735-1097
    DOI 10.1016/j.jacc.2015.06.1088
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    Zs.A 1846: Show issues Location:
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  7. Article: Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha.

    Briassouli, Paraskevi / Chan, Florence / Savage, Kay / Reis-Filho, Jorge S / Linardopoulos, Spiros

    Cancer research

    2007  Volume 67, Issue 4, Page(s) 1689–1695

    Abstract: The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates ... ...

    Abstract The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-kappaB (NF-kappaB) via IkappaBalpha phosphorylation. Inhibition of endogenous Aurora-A reduces tumor necrosis factor alpha (TNFalpha)-induced IkappaBalpha degradation. We analyzed primary human breast cancers, and 13.6% of samples showed Aurora-A gene amplification, all of which exhibited nuclear localization of NF-kappaB. We propose that this subgroup of patients with breast cancer might benefit from inhibiting Aurora-A. We also show that down-regulation of NF-kappaB via Aurora-A depletion can enhance cisplatin-dependent apoptosis. These data define a new role for Aurora-A in regulating IkappaBalpha that is critical for the activation of NF-kappaB-directed gene expression and may be partially responsible for the oncogenic effect of Aurora-A when the gene is amplified and overexpressed in human tumors.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Aurora Kinase A ; Aurora Kinases ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cisplatin/pharmacology ; Down-Regulation ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; HeLa Cells ; Humans ; I-kappa B Proteins/metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/biosynthesis ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Neoplasm Invasiveness ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction
    Chemical Substances Antineoplastic Agents ; I-kappa B Proteins ; NF-kappa B ; NFKBIA protein, human ; NF-KappaB Inhibitor alpha (139874-52-5) ; AURKA protein, human (EC 2.7.11.1) ; Aurora Kinase A (EC 2.7.11.1) ; Aurora Kinases (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2007-02-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-06-2272
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  8. Article ; Online: A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies.

    Briassouli, Paraskevi / Halushka, Marc K / Reed, Joanne H / Molad, Yair / Fox-Talbot, Karen / Buyon, Lucas / Guzman, Edwin / Ludomirsky, Achiau / Clancy, Robert M / Buyon, Jill P

    Rheumatology (Oxford, England)

    2013  Volume 52, Issue 8, Page(s) 1448–1453

    Abstract: Objective: Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) ... ...

    Abstract Objective: Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating β2-glycoprotein I (β2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined.
    Methods: Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies.
    Results: uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 ± 0.1 vs 1.9 ± 0.05 ng/ml (P < 0.0001), 6.6 ± 0.3 vs 2.1 ± 0.2 ng/ml (P < 0.0001) and 435 ± 34 vs 220 ± 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 ± 0.1 vs 1.9 ± 0.05 ng/ml; P = 0.0086, 6.2 ± 1.4 vs 2.2 ± 0.7 ng/ml; P = 0.147 and 412 ± 61 vs 260 ± 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region.
    Conclusion: Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.
    MeSH term(s) Antibodies, Antinuclear/immunology ; Antibodies, Antinuclear/metabolism ; Biomarkers ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Female ; Fetal Blood/immunology ; Fibrinolysin/immunology ; Fibrinolysin/metabolism ; Heart Diseases/immunology ; Heart Diseases/mortality ; Heart Diseases/pathology ; Humans ; Immunohistochemistry ; Infant, Newborn ; Lupus Erythematosus, Systemic/congenital ; Lupus Erythematosus, Systemic/immunology ; Lupus Erythematosus, Systemic/mortality ; Lupus Erythematosus, Systemic/pathology ; Macrophages/immunology ; Myocytes, Cardiac/immunology ; Myocytes, Cardiac/metabolism ; Pregnancy ; Receptors, Urokinase Plasminogen Activator/blood ; Receptors, Urokinase Plasminogen Activator/immunology ; Reference Values ; Ribonucleoproteins/immunology ; Ribonucleoproteins/metabolism ; Survival Rate ; Urokinase-Type Plasminogen Activator/blood ; Urokinase-Type Plasminogen Activator/immunology
    Chemical Substances Antibodies, Antinuclear ; Biomarkers ; Receptors, Urokinase Plasminogen Activator ; Ribonucleoproteins ; SS-A antibodies ; SS-A antigen ; Fibrinolysin (EC 3.4.21.7) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73)
    Language English
    Publishing date 2013-04-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1464822-2
    ISSN 1462-0332 ; 1462-0324
    ISSN (online) 1462-0332
    ISSN 1462-0324
    DOI 10.1093/rheumatology/ket156
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  9. Article ; Online: A novel role of endothelin-1 in linking Toll-like receptor 7-mediated inflammation to fibrosis in congenital heart block.

    Alvarez, David / Briassouli, Paraskevi / Clancy, Robert M / Zavadil, Jiri / Reed, Joanne H / Abellar, Rosanna G / Halushka, Marc / Fox-Talbot, Karen / Barrat, Franck J / Buyon, Jill P

    The Journal of biological chemistry

    2011  Volume 286, Issue 35, Page(s) 30444–30454

    Abstract: Autoimmune associated congenital heart block (CHB) may result from pathogenic cross-talk between inflammatory and profibrosing pathways. Incubation of macrophages with immune complexes (IC) composed of Ro60, a target of the pathologic maternal ... ...

    Abstract Autoimmune associated congenital heart block (CHB) may result from pathogenic cross-talk between inflammatory and profibrosing pathways. Incubation of macrophages with immune complexes (IC) composed of Ro60, a target of the pathologic maternal autoantibodies necessary for CHB, hY3 ssRNA, and affinity-purified anti-Ro60 antibody induces the Toll-like receptor 7 (TLR7)-dependent generation of supernatants that provoke a fibrosing phenotype in human fetal cardiac fibroblasts. We show herein that these cells are a major source of TGFβ and that endothelin-1 (ET-1) is one of the key components responsible for the profibrosing effects generated by stimulated macrophages. Supernatants from macrophages incubated with IC induced the fibroblast secretion of TGFβ, which was inhibited by treating the macrophages with an antagonist of TLR7. Under the same conditions, the induced fibroblast secretion of TGFβ was decreased by inhibitors of the ET-1 receptors ETa or ETb or by an anti-ET-1 antibody but not by an isotype control. Exogenous ET-1 induced a profibrosing phenotype, whereas fibroblasts transfected with either ETa or ETb siRNA were unresponsive to the profibrosing effects of the IC-generated macrophage supernatants. Immunohistochemistry of the hearts from two fetuses dying with CHB revealed the presence of ET-1-producing mononuclear cells in the septal region in areas of calcification and fibrosis. In conclusion, these data support a novel role of ET-1 in linking TLR7 inflammatory signaling to subsequent fibrosis and provide new insight in considering therapeutics for CHB.
    MeSH term(s) Antibodies/chemistry ; Autoimmunity ; Endothelin-1/physiology ; Female ; Fibroblasts/metabolism ; Fibrosis/metabolism ; Flow Cytometry ; Heart Block/congenital ; Heart Block/metabolism ; Humans ; Inflammation ; Leukocytes, Mononuclear/cytology ; Macrophages/cytology ; Macrophages/metabolism ; Ribonucleoproteins/chemistry ; Toll-Like Receptor 7/metabolism ; Transforming Growth Factor beta/metabolism
    Chemical Substances Antibodies ; Endothelin-1 ; Ribonucleoproteins ; SS-A antigen ; Toll-Like Receptor 7 ; Transforming Growth Factor beta
    Language English
    Publishing date 2011-07-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M111.263657
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Ecdysone-inducible expression of oncogenic Ha-Ras in NIH 3T3 cells leads to transient nuclear localization of activated extracellular signal-regulated kinase regulated by mitogen-activated protein kinase phosphatase-1.

    Plows, David / Briassouli, Paraskevi / Owen, Carolyn / Zoumpourlis, Vassilis / Garrett, Michelle D / Pintzas, Alexander

    The Biochemical journal

    2001  Volume 362, Issue Pt 2, Page(s) 305–315

    Abstract: The Ras family of GTP-binding proteins are key transducers of extracellular signals, particularly through the mitogen-activated protein kinase (MAPK) pathway. Constitutively active forms of Ras are found in a variety of tumours, suggesting an important ... ...

    Abstract The Ras family of GTP-binding proteins are key transducers of extracellular signals, particularly through the mitogen-activated protein kinase (MAPK) pathway. Constitutively active forms of Ras are found in a variety of tumours, suggesting an important role for this pathway in cancer. Here we report that initial cellular exposure to oncogenic Ras chronically activated the MAPK pathway in the cytoplasm, but transiently activated the same pathway in the nucleus. Nuclear-activated extracellular signal-regulated kinase (ERK) was rapidly dephosphorylated, with consequent short-term activation of the Elk-1 transcription factor and expression of the c-fos gene. Additional experiments suggested that the regulatory mechanism involved requires the calcium-dependent protein phosphotyrosine phosphatase MAPK phosphatase-1 (MKP-1). This is the first report on the ability of Ras, in the absence of growth factors, to transiently activate the MAPK pathway in the nucleus and show an involvement of MKP-1 in nuclear ERK2 regulation. In addition we show that transient activation of the MAPK pathway is sufficient to drive chronic cell-cycle progression. We conclude that, whereas the MAPK pathway is necessary to initiate cellular proliferation and transformation, the transient nature of the MAPK pathway activation suggests the involvement of additional signalling pathway(s) regulated by Ras.
    MeSH term(s) 3T3 Cells ; Amino Acid Substitution ; Animals ; Cell Cycle ; Cell Cycle Proteins ; Cell Division ; Cell Nucleus/metabolism ; Cell Transformation, Neoplastic/drug effects ; Dual Specificity Phosphatase 1 ; Ecdysone/pharmacology ; Egtazic Acid/analogs & derivatives ; Egtazic Acid/pharmacology ; Enzyme Activation ; Genes, ras ; Immediate-Early Proteins/metabolism ; MAP Kinase Signaling System/physiology ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinases/metabolism ; Okadaic Acid/pharmacology ; Phosphoprotein Phosphatases ; Phosphorylation ; Protein Phosphatase 1 ; Protein Tyrosine Phosphatases/metabolism ; Reproducibility of Results ; Vanadates/pharmacology
    Chemical Substances Cell Cycle Proteins ; Immediate-Early Proteins ; Okadaic Acid (1W21G5Q4N2) ; Ecdysone (3604-87-3) ; Vanadates (3WHH0066W5) ; Egtazic Acid (526U7A2651) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.11.24) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Protein Phosphatase 1 (EC 3.1.3.16) ; Dual Specificity Phosphatase 1 (EC 3.1.3.48) ; Dusp1 protein, mouse (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (K22DDW77C0)
    Language English
    Publishing date 2001-02-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0264-6021 ; 0006-2936 ; 0306-3275
    ISSN (online) 1470-8728
    ISSN 0264-6021 ; 0006-2936 ; 0306-3275
    DOI 10.1042/0264-6021:3620305
    Database MEDical Literature Analysis and Retrieval System OnLINE

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