bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzymatically hydrolyzed low-density lipoprotein modulates inflammatory responses in endothelial cells
Authors: Fenske Dominic , Dersch Katrin , Lux Cornelia , Zipse Lisa , Suriyaphol Prapat , Dragneva Yolantha , Han Shan-Rui , Bhakdi Sucharit , Husmann Matthias 
Published: November 2008

SummaryThere is evidence that low-density lipoprotein (LDL) is modified by hydrolytic enzymes,and that the product (E-LDL) induces selective production of interleukin 8 (IL-8) in endothelial cells. Since nuclear factor-kappaB (NF-κB) is a major regulator of IL-8 transcription, we studied its activation in endothelial cells treated with E-LDL. Unexpectedly,the modified lipoprotein not only failed to activate NF-κB, but completely blocked its activation by tumour necrosis factor-alpha (TNF-α) in EA.hy926-cells, as assessed by electrophoretic mobility shift assays and immunofluorescence. Inhibition occurred upstream of NF-κB translocation, as inhibitor of NF-κB- (IκB)-phosphorylation was suppressed by E-LDL. In contrast to NF-κB,transcription factor activator protein-1 (AP-1) proved to be activated. Removal of free fatty acids present in E-LDL obliterated both activation of AP-1 and inhibition of NF-κB. Chromatin immunoprecipitation revealed that phosphorylated c-jun, but not NF-κBp65 bound to the natural IL-8 promoter. Production of endothelial IL-8 and simultaneous modulation of NF-κB in response to hydrolyzed LDL might serve to protect the vessel wall and promote silent removal of the insudated lipoprotein.
Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon
Authors: Brouwers Jacobus R. B. J. , Schalekamp Tom , Wilffert Bob , Beinema Maarten 
Published: November 2008

SummaryCoumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of theVKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 andVKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect ofVKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anti-coagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.
Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system
Authors: Koyanagi Satoru , Kuramoto Yukako , Kimura Masahiko , Oda Masatoshi , Kozako Tomohiro , Hayashida Satoru , Shimeno Hiroshi , Soeda Shinji 
Published: November 2008

SummaryPlasminogen activator inhibitor-1 (PAI-1), a member of the ser-pin gene family, is the primary inhibitor of urokinase-type and tissue-type PA s.PA I-1 plays an important role in the process of peripheral tissue remodeling and fibrinolysis through the regulation of PA activity. This serpin is also produced in brain tissues and may regulate the neural protease sequence in the central nervous system (CNS), as it does in peripheral tissues. In fact, PA I-1 mRNA is up-regulated in mouse brain after stroke.The serpin activity of PA I-1 helps to prevent tissue-type PA -induced neuron death.However, we have previously found that PAI-1 has a novel biological function in the CNS: the contribution to survival of neurites on neurons. In neuronally differentiated rat pheochromocytoma (PC-12) cells, a deficiency of PA I-1 in vitro caused a significant reduction in Bcl-2 and Bcl-XL mRNAs and an increase in Bcl-XS and Bax mRNAs.The change in the balance between mRNA expressions of the anti- and pro-apoptotic Bcl-2 family proteins promoted the apoptotic sequence: cas-pase-3 activation, cytochrome c release from mitochondria and DNA fragmentation. Our results indicate that PA I-1 has an antiapoptotic role in neurons.PAI-1 prevented the disintegration of the formed neuronal networks by maintaining or promoting neuroprotective signaling through the MAPK/ ERK pathway, suggesting that the neuroprotective effect of PAI-1 is independent of its action as a protease inhibitor. This review discusses the neuroprotective effects of PA I-1 in vitro, together with the relevant data from other laboratories. Special emphasis is placed on its action on PC-12 cells.
Regulation of plasminogen activator inhibitor type 1 gene expression by inflammatory mediators and statins
Authors: Kruithof Egbert K. O. 
Published: November 2008

SummaryElevated plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1), also named serpin E1, are encountered in patients with thrombophilia, atherosclerosis, septicemia and the metabolic syndrome and may be associated with an increased risk of complications. Expression of PAI-1 is increased by inflammatory stimuli and decreased by statins, drugs widely used in patients with cardiovascular disease. Increased expression of PAI-1 by inflammatory stimuli is mediated by a large variety of signal transduction pathways, which include the NF-κB and MAP kinase pathways. The downregulating effect of statins on PAI-1 expression is dependent on the inhibition of Rho family proteins and may involve an activation of PI-3 kinase/Akt signaling pathways. In this review we summarize the findings on the effect of inflammation and statins on PAI-1 expression.
Integration of non-SMAD and SMAD signaling in TGF-β1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells
Authors: Samarakoon Rohan , Higgins Paul J. 
Published: November 2008

SummaryOverexpression of plasminogen activator inhibitor-1 (SER-PINE1, PAI-1), the major physiological inhibitor of pericellular plasmin generation, is a significant causative factor in the progression of vascular disorders (e.g. arteriosclerosis, thrombosis, perivascular fibrosis) as well as a biomarker and a predictor of cardiovascular-disease associated mortality. PAI-1 is a temporal/ spatial regulator of pericellular proteolysis and ECM accumulation impacting, thereby, vascular remodeling, smooth muscle cell migration, proliferation and apoptosis. Within the specific context of TGF-β1-initiated vascular fibrosis and neointima formation, PAI-1 is a member of the most prominently expressed subset of TGF-β1-induced transcripts. Recent findings implicate EGFR/pp60c-src
→MEK/ERK1/2 and Rho/ROCK→SMAD2/3 signaling in TGF-β1-stimulated PAI-1 expression in vascular smooth muscle cells. The EGFR is a direct upstream regulator of MEK/ERK1/2 while Rho/ROCK modulate both the duration of SMAD2/3 phosphorylation and nuclear accumulation. E-box motifs (CACGTG) in the PE1/PE2 promoter regions of the human PAI-1 gene, moreover, are platforms for a MAP kinase-directed USF subtype switch (USF-1→USF-2) in response to growth factor addition suggesting that the EGFR→MEK/ERK axis impacts PAI-1 expression, at least partly, through USF-dependent transcriptional controls. This paper reviews recent data suggesting the essential cooperativity among the EGFR→MAP kinase cascade, the Rho/ROCK pathway and SMADs in TGF-β1-initiated PAI-1 expression. The continued clarification of mechanistic controls on PAI-1 transcription may lead to new targeted therapies and clinically-relevant options for the treatment of vascular diseases in which PAI-1 dysregulation is a major underlying pathogenic feature.
Modulation of tissue factor and tissue factor pathway inhibitor-1 by neutrophil proteases
Authors: Steppich Birgit A. , Seitz Isabell , Busch Gabi , Stein Andreas , Ott Ilka 
Published: November 2008

SummaryDuring systemic inflammation, neutrophil activation is accompanied by endothelial cell damage and hypercoagulability. Activated neutrophils release serine proteases that participate in tissue injury.We sought to investigate the effects of neutrophil proteases on proinflammatory and procoagulant changes in endothelial cells.The effects of elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3) on expression of tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI) were examined in human umbilical vein endothelial cells. Flow cytometry demonstrated that these proteases proteolytically degraded endothelial cell-bound TFPI. TFPI mRNA expression was reduced by HNE and CG. PR3, but not HNE or CG, increased surface expression of TF and TF mRNA.Yet, increased TF expression did not enhance TF activity suggesting induction of encrypted TF. Using antibodies and siRNA to inhibit and silence PAR-1 and PAR-2, we observed that PR3 upregulation of TF is at least in part mediated by PAR-1.Although CG and HNE cleaved PAR-1, antibody reactivity to the PAR-1 hirudin-like sequence demonstrated inactivating cleavage, accounting for the selective ability of PR3 to induce PAR-1-mediated procoagulant effects.This was supported by induction of p42/44 MAPK by PR3. In conclusion, PR3 degradation of TFPI increases the procoagulant activity of endothelial cells. Release of PR3 after neutrophil activation may represent an important step in neutrophil-mediated vascular injury.
Transcriptional regulation of the plasminogen activator inhibitor type 1 – with an emphasis on negative regulation
Authors: Nagamine Yoshikuni 
Published: November 2008

SummaryBy inhibiting plasminogen activators uPA and tPA, inducing uPAuPAR internalization and interfering with the interaction between extracellular matrix protein vitronectin and αvβ3 integrin, plasminogen activator inhibitor type 1 (PAI-1) is active in the regulation of various biological processes involving extracellular proteolysis and tissue remodeling. PAI-1 is expressed in many cell types under the control of a variety of signals, depending on cell type. The most prominent and important of these signals are TGFβ, hypoxia and insulin. Although the signaling pathways were largely elucidated, recent investigations have revealed more complicated aspects. The pathways interact at the level of both transcription factors and regulatory elements on the promoter. Furthermore, the engagement of negative factors in these pathways has been shown to be important, adding complexity and versatility to PAI-1 gene regulation.
Heparin-induced thrombocytopenia (HIT): Clinical and economic outcomes
Authors: Piovella Chiara , Fanikos John , Labreche Matthew , Lin Jay , Goldhaber Samuel Z. , Baroletti Steven 
Published: November 2008

SummaryHeparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction that occurs following exposure to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).HIT with thrombosis (HITT) can cause devastating venous thromboembolism or arterial clots, prolonged hospitalization, and increased costs. To explore the economic and clinical implications of HIT and HITT, we initiated a single-center patient registry. In this report, we describe patient characteristics, comorbidities, management strategies, clinical outcomes, and costs. We enrolled 349 hospitalized patients with an enzyme immunoassay-confirmed diagnosis of HIT over a 40-month period. Patients were assessed for the primary outcome of 30-day mortality, as well as baseline characteristics, development of thrombosis, and the economic impact of HIT. The primary outcome measure was 30-day mortality and occurred in 58 (16.6%) patients, 40 (15.3%) in the HIT group versus 18 (20.7%) in the HITT group (p=0.25).The frequency of HIT was greater in patients exposed to UFH than in patients exposed to LMWH (0.8% vs. 0.2%, respectively, p<0.001). Both HIT and HITT patients who were exposed to UFH had higher hospital costs than those exposed to LMWH ($113,100 vs. $56,352, respectively, p<0.001). HIT remains an important clinical problem with a high mortality rate and significant cost, regardless of development of thrombosis. Prospective controlled trials need to be conducted to determine the optimal strategy to reduce the frequency of HIT.
Melanoma cell adhesion can be blocked by heparin in vitro: Suggestion of VLA-4 as a novel target for antimetastatic approaches
Authors: Simonis Dirk , Bendas Gerd , Fritzsche Juliane 
Published: November 2008

SummaryThe clinical benefit of heparin in cancer patients to prolong survival can be attributed to non-anticoagulant mechanisms. Since adhesion molecules are crucially involved in tumour cell metastasis, their inhibition offers an attractive approach for interfering with the metastatic cascade. Heparin is known to attenuate metastasis in a selectin-dependent manner and possessesa variety of additional effects that are thought to influence tumour cell dissemination, proliferation, and angiogenesis. We investigated the adhesion behaviour of B16F10 melanoma cells in vitro regarding selectin- and VLA-4/VCAM-1-mediated binding to get an insight into underlying mechanisms of melanoma cell metastasis. We show that B16F10 cells display binding ability to P- and L-selectin as well as to isolated platelets. In contrast, B16F10 cells did not adhere to immobilized P-selectin under flow. This contributes to recent findings that elucidate a major role of platelet P-selectin for microemboli formation and thus, facilitating metastasis. In contrast, B16F10 cells adhered to endothelial cells under flow, which could partly be inhibited by a function-blocking anti-VCAM-1 mAb. To emphasizeVCAM-1 function, we analyzed cell adhesion at immobilizedVCAM-1 and observed an integrin dependency. Inhibition experiments reveal that heparin influences VLA-4-mediated binding pathways. By a combination of different techniques we prove that the site of heparin action is ratherVLA-4 thanVCAM-1.To our knowledge, this is the first time that heparin is shown to interfere with theVLA-4/VCAM-1 interaction leading to the suggestion of a novel heparin target. Our results may contribute to the understanding of how heparin exerts its anti-metastatic activity.
Thrombotic events in high risk patients are predicted by evaluating different pathways of platelet function
Authors: Marcucci Rossella , Paniccia Rita , Giusti Betti , Fedi Sandra , Antonucci Emilia , Buonamici Piergiovanni , Antoniucci David , Gensini Gian , Abbate Rosanna , Gori Anna 
Published: November 2008

SummaryA higher rate of clinical events in poor clopidogrel and/or aspirin responders was documented by using different methods to measure platelet function, but no conclusive data about the appropriate methodology to explore platelet reactivity are available.A total of 746 patients included in the cohort of the RECLOSE trial who had successful drug-eluting stent implantation were assessed for post-treatment residual platelet reactivity (RPR) in platelet-rich plasma by 10 µM adenosine 5’-diphosphate (ADP),1 mM arachidonic acid (AA) and 2 µg/ml collageninduced platelet aggregation and in whole blood by the PFA-100 system. At six-month follow-up, RPR by two stimuli (ADP and AA or ADP and collagen) and by three stimuli (ADP,AA and collagen) is significantly associated with higher percentage of primary (definite or probable stent thrombosis) and secondary cardiac mortality and stent thrombosis) end-points than RPR by ADP,AA, collagen and PFA-100 system.According to the primary and secondary end points, the specificity values for RPR identified by two (ADP and AA: 94%;ADP and collagen: 97%) and three stimuli were higher with respect to RPR by ADP (88%), or RPR by AA (83%) or RPR by collagen (90%).The positive likelihood ratio values of RPR by three stimuli (9.55) or of RPR by ADP and collagen (8.08) were higher than those of RPR by ADP (2.59), byAA (2.05), by collagen (4.73), or by PFA-100 (2.63).This prospective study documents that the evaluation of platelet reactivity addressed to identify patients at risk of thrombotic events on dual antiplatelet treatment has to be carried out by methods able to explore different pathways.
Biobanks and the search for predictive biomarkers of local and systemic outcome in atherosclerotic disease
Authors: Hurks Rob , Peeters Wouter , Derksen Wouter , Hellings Willem , Hoefer Imo , Moll Frans , de Kleijn Dominique , Pasterkamp Gerard 
Published: November 2008

SummaryMultiple risk factors have been associated with progression of atherosclerosis. To identify the individual patient who is at risk for disruption of a vulnerable plaque, leading to a cardiovascular event, remains a major challenge. Current screening methods, based on traditional risk factors, do not allow risk stratification on an individual level. The discovery of new biomarkers would aid in identifying specific patient groups at risk for adverse cardiovascular events due to atherosclerotic disease progression. The current definition of the vulnerable plaque, e.g. atheromatous inflammatory plaque with a thin fibrous cap, has been based on cross-sectional post-mortem studies. The predictive value of these histological characteristics of the vulnerable plaque is likely to be low, because they are also frequently observed at multiple locations in symptomatic and asymptomatic patients. The Athero-express study follows a new concept to search for the atherosclerotic patient who may suffer from adverse events. In this study, we investigate the predictive value of local plaque composition for adverse events in other vascular territories, regarding the plaque as a concentrated expression of this systemic disease. First results from this longitudinal biobank study show that the local plaque hides strong predictive value for cardiovascular events elsewhere in the vascular tree. Longitudinal biobank studies will facilitate the identification of novel local plaque markers. The search for the plaque protein signature that is predictive for adverse events might enable patient stratification that will allow individualized tailor made medicine and subsequently guide the choice for therapeutic interventions.
Metabolic, hormonal and environmental regulation of plasminogen activator inhibitor-1 (PAI-1) expression: Lessons from the liver
Authors: Dimova Elitsa Y. , Kietzmann Thomas 
Published: November 2008

SummaryPlasminogen activator inhibitor-1 (PAI-1) controls the regulation of the fibrinolytic system in blood by inhibiting both urokinase-type and tissue-type plasminogen activators. Enhanced levels of PAI-1 are found in PAI-1 patients with type 2 diabetes mellitus which is associated with a dysbalance in glucose and lipid homeostasis. Especially a defective insulin response in the liver contributes to the development of hyperglycemia, dyslipidemia and peripheral insulin resistance and may contribute to hepatic overexpression of PAI-1 in diabetes type 2. Furthermore,a substantial upregulation of PAI-1 expression has also been shown in a variety of liver injury models.Thus, the liver appears to be not only a major site of PAI-1 synthesis in response to hormonal changes, but also in response to a variety of other pathological events. PAI-1 expression in liver largely depends on activation of signalling pathways and transcriptional regulators which may be the basis fora new level of cross-talk between different signalling pathways and thus may represent attractive therapeutic candidates.This article will primarily focus on the regulation of PAI-1 expression in liver cells and discuss potential cross-talks between metabolic, hormonal and environmental signals.
Polymorphisms in the protein C gene as risk factor for venous thrombosis
Authors: Doggen Carine , Vos Hans , Reitsma Pieter , Rosendaal Frits , Pomp Elisabeth 
Published: November 2008

SummaryProtein C is an important inhibitor of blood coagulation. We investigated the effect of two polymorphisms within the promoter region of the protein C gene (C/T at position 2405 and A/G at position 2418) on risk of venous thrombosis and on plasma protein C levels. In addition the combined effect of the two polymorphisms with factor V Leiden and oral contraceptive use was investigated. Previous studies on these polymorphisms were small and were not able to investigate synergistic effects. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), protein C levels were determined in 2,043 patients with venous thrombosis and 2,857 control subjects, and the two polymorphisms in 4,285 patients and 4,863 control subjects. The CC/GG genotype was associated with the lowest protein C levels. Compared to carriers of the TT/AA genotype – a genotype associated with higher protein C levels – the risk of venous thrombosis in CC/GG carriers was 1.3-fold increased (95% confidence interval 1.09–1.48). The combination of factor V Leiden with the CC/GG genotype led to a 4.7-fold increased risk, compared to non-carriers with the TT/AA genotype. Oral contraceptive use together with the CC/ GG genotype resulted in a 5.2-fold increased risk. In conclusion, the CC/GG genotype is associated with lower levels of protein C and an elevated risk of venous thrombosis compared to the TT/AA genotype. There is no clear synergistic effect of the CC/ GG genotype with factor V Leiden or oral contraceptive use on thrombotic risk.
The ‘PAI-1 paradox’ in vascular remodelling
Authors: Bonello Steve , Diebold Isabel , Kraicun Damir , Görlach Agnes 
Published: November 2008

SummaryVascular remodelling isa complex phenomenon associated with restructuring of the vessel wall as a consequence of disruption of vascular homeostasis. Alterations of the vascular wall have been linked to a variety of cardiovascular disorders including atherosclerosis, vascular injury and pulmonary hypertension. Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin (serine proteinase inhibitor) family and acts as an important inhibitor of fibrinolysis by interfering with the plasminogen system. In addition to its anti-fibrinolytic effects, PAI-1 appears to modulate cellular responses linked to vascular remodelling. Since PAI-1 levels have been shown to be altered in various disorders associated with vascular remodelling of the systemic and pulmonary vascular bed, this serpin may playa pivotal role in the pathogenesis of these diseases.
Competing Jurisdictions Between MERCOSUR and WTO
Authors: Lavranos Nikolaos , Vielliard Nicolas 
Published: November 2008

AbstractThe wider issues raised by the Brazilian Tyres case are discussed in this contribution. Regarding the institutional aspects, this case examines the difficulties between regional dispute settlement systems and the global WTO dispute settlement system. In particular, the WTO Appellate Body showed no deference towards the prior report of the MERCOSUR Arbitral Tribunal. Indeed, the WTO Appellate Body is espousing a supremacy of WTO law – not only vis-à-vis regional dispute settlement bodies, but also regarding WTO panels. It is argued that this attitude is not sustainable in the light of the increasing proliferation of international courts and tribunals, which inevitably results into disputes being adjudicated by different courts and tribunals at different levels. Regarding the substantive aspects, this case is a prime example of the difficulties of balancing non-trade interests and trade interests. At the end, trade interests superseded the nontrade interests. It is argued that the way Article XX GATT has been interpreted and applied by the WTO Appellate Body leaves states insufficient room to address urgent environmental and health problems by restricting trade. It is argued that in this case Brazil's non-trade interests should have been given preference over the trade interests of the EC and Uruguay.