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Variable Stromal Periductular Expression of CD34 and Smooth Muscle Actin (SMA) in Intraductal Carcinoma of the Breast
Xavier Catteau, Philippe Simon, Michel Vanhaeverbeek, Jean-Christophe No?l
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057773
Abstract: In breast carcinoma, the stromal loss of CD34 expression and acquisition of SMA myofibroblastic features may constitute a prerequisite for tumor invasiveness. However, this hypothesis remains controversial, with some authors describing the loss of CD34 fibrocytes in the absence of SMA myofibroblastic-like cells in the stroma of invasive carcinoma. Others have also described the disappearance of CD34 fibrocytes from in situ carcinoma. To clarify this issue, we compared the distribution of CD34 fibrocytes and SMA reactive myofibroblasts between stromal areas of tumor-free mammary tissue, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). In addition to 28 IDC, 300 normal duct–lobular units and 600 ducts with DCIS (158 low-grade, 266 intermediate, and 176 high-grade) were scored. The relationships between staining patterns and different histological features (grade of DCIS and presence or absence of necrosis) were compared. Loss of CD34 expression and acquisition of SMA expression were more frequent in high-grade in situ lesions than in intermediate and low-grade lesions (p<0.001). When necrosis was found in association with grade 2 or 3 DCIS, the decrease in CD34 expression was higher than in lesions without necrosis and that independently of the grade of DCIS (p<0.05). Necrosis did not appear to play a significant role in the expression of SMA (p = 0.35). In all cases, the stroma of invasive carcinomas showed a complete loss of CD34 fibrocytes. Future research on both CD34 fibrocytes and mechanisms stromal changes are essential in the future and may potentially lead to new treatment approaches.
Plasma fibrinolysis is related to the degree of organ dysfunction but not to the concentration of von Willebrand Factor in critically ill patients
Karim Boudjeltia, Sandra Ollieuz, Michael Piagnerelli, Patrick Biston, Philippe Cauchie, Jean-Louis Vincent, Dany Brohee, Michel Vanhaeverbeek
Thrombosis Journal , 2009, DOI: 10.1186/1477-9560-7-10
Abstract: Forty-nine consecutive patients admitted to an adult medico-surgical intensive care unit (ICU) with (18) or without sepsis (31) were included. C-reactive protein and vWF levels were measured on ICU admission and plasma fibrinolysis was assessed by the Euglobulin Clot Lysis Time (ECLT). The sequential organ failure assessment (SOFA) score and the simplified acute physiology score (SAPS) II were calculated on admission.ECLT was significantly longer in septic than in non-septic patients [1033 min (871–1372) versus 665 min (551–862), p = 0.001]. There were significant correlations between ECLT and C-reactive protein (CRP) concentrations (r = 0.78, p < 0.001) and the Sequential Organ Failure Assessment (SOFA) score (r = 0.39, p = 0.006). The level of vWF was not correlated with the ECLT (r = -0.06, p = 0.65) or the SOFA score (r = -0.02, p = 0.88).ECLT measurement at admission could be a marker of organ dysfunction and a prognostic indicator in critically ill patients.Endothelial cells (ECs) are in tight contact with all organs, so that EC activation and damage has been implicated in the development of multiple organ failure (MOF) [1]. Among the proposed mechanisms, altered fibrinolysis may promote fibrin deposition and thereby contribute to microvascular alterations [2].Fibrinolysis and inflammation may be intertwined. Elevated concentrations of C-reactive protein (CRP), especially when they persist over time, are correlated with the risk of MOF and death [3]. CRP may inhibit fibrinolysis by inducing release of plasminogen activator inhibitor-1 (PAI-1) from human aortic ECs [4]. In addition, the administration of recombinant CRP to volunteers increases circulating PAI-1 levels [5]. We previously showed that hypofibrinolysis assessed by the Euglobulin Clot Lysis Time (ECLT) was strongly correlated with CRP concentrations in critically ill patients [6].ECLT is the test most commonly used to estimate plasma fibrinolytic capacity. The ECLT result represents the balance betw
Increased Basal and Alum-Induced Interleukin-6 Levels in Geriatric Patients Are Associated with Cardiovascular Morbidity
Nathalie Compté, Karim Zouaoui Boudjeltia, Michel Vanhaeverbeek, Sandra De Breucker, Thierry Pepersack, Joel Tassignon, Anne Trelcat, Stanislas Goriely
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081911
Abstract: Background/Aim of the study Low-grade systemic inflammation was suggested to participate to the decline of physiological functions and increased vulnerability encountered in older patients. Geriatric syndromes encompass various features such as functional dependence, polymorbidity, depression and malnutrition. There is a strong prevalence of cardiovascular diseases and related risk factors and chronic cytomegalovirus infections in the geriatric population. As these underlying conditions were proposed to influence the inflammatory state, the aim of this study was to assess their potential contribution to the association of geriatric syndromes with inflammatory parameters. Methodology We recruited 100 subjects in the general population or hospitalized for chronic medical conditions (age, 23-96 years). We collected information on clinical status (medical history, ongoing comorbidities, treatments and geriatric scales), biological parameters (hematological tests, cytomegalovirus serology) and cytokines production (basal and alum-induced interleukin (IL)-1β and IL-6 levels). Using stepwise backward multivariate analyses, we defined which set of clinical and biological variables could be predictive for increased inflammatory markers. Principal Findings We confirmed the age-associated increase of circulating IL-6 levels. In contrast to geriatric scales, we found history of cardiovascular diseases to be strongly associated for this parameter as for high IL-6 production upon ex vivo stimulation with alum. Conclusions Association between low-grade inflammation and geriatric conditions could be linked to underlying cardiovascular diseases.
Frailty in Old Age Is Associated with Decreased Interleukin-12/23 Production in Response to Toll-Like Receptor Ligation
Nathalie Compté, Karim Zouaoui Boudjeltia, Michel Vanhaeverbeek, Sandra De Breucker, Joel Tassignon, Anne Trelcat, Thierry Pepersack, Stanislas Goriely
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065325
Abstract: Aging is associated with progressive alterations of immune functions, leading to higher susceptibility to bacterial and viral infections and reduced vaccine responses. Data concerning cytokine production in response to Toll-like receptor (TLR) ligands are highly variable in old people, reflecting the heterogeneity of the geriatric population. The aim of our study was to define the relative contribution of age and clinical status on TLR-induced interleukin (IL)-12p70 and IL-23 production as these cytokines play an important role in the protection against intracellular and extracellular pathogens, respectively. For this purpose, we recruited 100 subjects (aged 23–96 years) in the general population or hospitalized for chronic diseases. We collected information on clinical status (medical history, ongoing comorbidities, treatments and geriatric scales), biological parameters (biochemical and hematological tests, telomere length determination, cytomegalovirus serology). Whole blood samples were stimulated with a combination of TLR4 and TLR7/8 ligands. We performed univariate and stepwise backward multivariate analyses regression to define which set of clinical variables could be predictive for IL-12p70 and IL-23 production in these conditions. Our results indicated that age was not correlated with TLR-mediated IL-12p70 and IL-23 production. In contrast, poor nutritional status and frailty in subjects >75 years were associated with decreased IL-12p70 and IL-23 production. By intracytoplasmic staining, we confirmed that production of IL-12/23p40 by conventional dendritic cells (DCs) upon TLR ligation was decreased in frail patients. However, proportion of DCs and monocytes subsets, phenotypic maturation and proximal signaling events were found to be comparable in frail and healthy old subjects. These results suggest the importance of age-associated clinical parameters and not age by itself in the alteration of innate immune responses in old individuals and emphasis the importance of innate immune responses in the susceptibility of frail geriatric patients to infections.
Relationship between CRP and hypofibrinolysis: Is this a possible mechanism to explain the association between CRP and outcome in critically ill patients?
Karim Zouaoui Boudjeltia, Michael Piagnerelli, Dany Brohée, Michel Guillaume, Philippe Cauchie, Jean-Louis Vincent, Claude Remacle, Yves Bouckaert, Michel Vanhaeverbeek
Thrombosis Journal , 2004, DOI: 10.1186/1477-9560-2-7
Abstract: In this study, we tested the hypothesis that CRP is associated with hypofibrinolysis in intensive care patients with and without sepsis.We studied the association of inflammation and abnormal fibrinolysis in intensive care unit (ICU) patients with (n = 11) and without (n = 21) sepsis. The inflammatory response was assessed by serum concentration of C-reactive protein (CRP), a marker of the acute phase reaction, which increase rapidly in the inflammatory response, and the plasma fibrinolytic capacity was evaluated by the Euglobulin Clot Lysis Time (ECLT), determined by a new semi-automatic method.ECLT was significantly higher in septic than non-septic patients (1104 ± 439 vs 665 ± 275 min; p = 0.002) and was significantly correlated with CRP concentration (R2 = 0.45; p < 0.001). In a multivariate analysis, CRP was the strongest predictor of ECLT (R2 = 0.51, F = 25.6, p < 0.001). In addition, the overall ICU length of stay was significantly correlated with CRP (R2 = 0.264, p = 0.003) and ECLT (R2 = 0.259, p = 0.003).In critically ill patients a significant correlation thus exists between plasma fibrinolytic capacity and serum CRP levels. Our data were obtained in the first 24 hours of ICU admission or of sepsis, thus, the relation between CRP and hypofibrinolysis appeared very quickly. This finding is compatible with a link between inflammation and abnormal fibrinolysis, and may explain the negative prognostic value of CRP in critically ill patients.Endothelial cells have a key role in the control of vascular permeability and vessel tone, coagulation and fibrinolysis, and inflammatory response [1]. There is an increasing body of evidence supporting the critical role of the vascular endothelium in the pathogenesis of multiple organ failure (MOF) in critically ill patients [2].Endothelial dysfunction/or activation is associated with an imbalance in hemostatic functions. Endothelial cells are responsible for the release of tissue plasminogen activator (t-PA) and contribu
Exposure of Endothelial Cells to Physiological Levels of Myeloperoxidase-Modified LDL Delays Pericellular Fibrinolysis
Karim Zouaoui Boudjeltia, Jalil Daher, Pierre Van Antwerpen, Nicole Moguilevsky, Paul Delree, Jean Ducobu, Martine Raes, Bassam Badran, Michel Vanhaeverbeek, Dany Brohee, Claude Remacle, Luc Vanhamme
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0038810
Abstract: Background Blood fluidity is maintained by a delicate balance between coagulation and fibrinolysis. The endothelial cell surface is a key player in this equilibrium and cell surface disruptions can upset the balance. We investigated the role of pericellular myeloperoxidase oxidized LDLs (Mox-LDLs) in this balance. Methods and Results We designed a technical device that enabled us to monitor fibrinolysis in real-time at the surface of an endothelial cell line (EA.hy926), and showed that Mox-LDL decreased pericellular fibrinolysis. There were no changes in fibrinolysis when EA.hy926 endothelial cells were exposed to native LDL (24 hours) at doses of 10, 50, 100 and up to 1250 μg/ml. However, treatment of EA.hy926 endothelial cells with 10 and 50 μg/ml of Mox-LDL (physiological serum concentrations) increased the lysis time by 15 and 13%, respectively (p<0.001), although this effect was not present at higher concentrations of 100 μg/ml. This effect was not correlated with any changes in PAI-1 or t-PA or PA Receptor (PAR) expression. No effect was observed at the surface of smooth muscle cells used as controls. Conclusion Our data link the current favorite hypothesis that modified LDL has a causal role in atheroma plaque formation with an old suggestion that fibrin may also play a causal role. Our data help complete the paradigm of atherosclerosis: Modified LDL locally enhances fibrin deposition (present work); fibrin deposits enhance endothelial permeability; this effect allows subendothelial accumulation of lipid and foam cells.
Temporal Dissociation between Myeloperoxidase (MPO)-Modified LDL and MPO Elevations during Chronic Sleep Restriction and Recovery in Healthy Young Men
Karim Zouaoui Boudjeltia, Brice Faraut, Maria José Esposito, Patricia Stenuit, Michal Dyzma, Pierre Van Antwerpen, Dany Brohée, Luc Vanhamme, Nicole Moguilevsky, Michel Vanhaeverbeek, Myriam Kerkhofs
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028230
Abstract: Objectives Many studies have evaluated the ways in which sleep disturbances may influence inflammation and the possible links of this effect to cardiovascular risk. Our objective was to investigate the effects of chronic sleep restriction and recovery on several blood cardiovascular biomarkers. Methods and Results Nine healthy male non-smokers, aged 22–29 years, were admitted to the Sleep Laboratory for 11 days and nights under continuous electroencephalogram polysomnography. The study consisted of three baseline nights of 8 hours sleep (from 11 pm to 7 am), five sleep-restricted nights, during which sleep was allowed only between 1 am and 6 am, and three recovery nights of 8 hours sleep (11 pm to 7 am). Myeloperoxidase-modified low-density lipoprotein levels increased during the sleep-restricted period indicating an oxidative stress. A significant increase in the quantity of slow-wave sleep was measured during the first recovery night. After this first recovery night, insulin-like growth factor-1 levels increased and myeloperoxidase concentration peaked. Conclusions We observed for the first time that sleep restriction and the recovery process are associated with differential changes in blood biomarkers of cardiovascular disease.
A New Device to Mimic Intermittent Hypoxia in Mice
Kamil J. Chodzyński, Stephanie Conotte, Luc Vanhamme, Pierre Van Antwerpen, Myriam Kerkhofs, J. L. Legros, Michel Vanhaeverbeek, Alain Van Meerhaeghe, Gregory Coussement, Karim Zouaoui Boudjeltia, Alexandre Legrand
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059973
Abstract: Intermittent hypoxia (hypoxia-reoxygenation) is often associated with cardiovascular morbidity and mortality. We describe a new device which can be used to submit cohorts of mice to controlled and standardised hypoxia-normoxia cycles at an individual level. Mice were placed in individual compartments to which similar gas flow parameters were provided using an open loop strategy. Evaluations made using computational fluid dynamics were confirmed by studying changes in haemoglobin oxygen saturation in vivo. We also modified the parameters of the system and demonstrated its ability to generate different severities of cyclic hypoxemia very precisely, even with very high frequency cycles of hypoxia-reoxygenation. The importance of the parameters on reoxygenation was shown. This device will allow investigators to assess the effects of hypoxia–reoxygenation on different pathological conditions, such as obstructive sleep apnoea or chronic obstructive pulmonary disease.
Myeloperoxidase-Dependent LDL Modifications in Bloodstream Are Mainly Predicted by Angiotensin II, Adiponectin, and Myeloperoxidase Activity: A Cross-Sectional Study in Men
Karim Zouaoui Boudjeltia,Cédric Delporte,Pierre Van Antwerpen,Thierry Franck,Didier Serteyn,Nicole Moguilevsky,Martine Raes,Luc Vanhamme,Michel Vanhaeverbeek,Alain Van Meerhaeghe,Thierry Roumeguère
Mediators of Inflammation , 2013, DOI: 10.1155/2013/750742
Abstract: The present paradigm of atherogenesis proposes that low density lipoproteins (LDLs) are trapped in subendothelial space of the vascular wall where they are oxidized. Previously, we showed that oxidation is not restricted to the subendothelial location. Myeloperoxidase (MPO), an enzyme secreted by neutrophils and macrophages, can modify LDL (Mox-LDL) at the surface of endothelial cells. In addition we observed that the activation of the endothelial cells by angiotensin II amplifies this process. We suggested that induction of the NADPH oxidase complex was a major step in the oxidative process. Based on these data, we asked whether there was an independent association, in 121 patients, between NADPH oxidase modulators, such as angiotensin II, adiponectin, and levels of circulating Mox-LDL. Our observations suggest that the combination of blood angiotensin II, MPO activity, and adiponectin explains, at least partially, serum Mox-LDL levels. 1. Introduction Atherosclerosis is an inflammatory disease involving a crosstalk between vascular cells, monocytes, proinflammatory cytokines, chemokines, and growth factors [1–3]. The current paradigm of early atherosclerosis claims that low-density lipoprotein (LDL) particles are trapped in the subendothelial space of the vascular wall where they can be oxidized. The precise physiological process for LDL oxidation in vivo is still largely unknown and the occurrence of LDL oxidation outside the lesion sites has not definitively been ruled out yet. Evidence accumulated during the last decade has suggested implication of myeloperoxidase (MPO) in inflammation leading to atherogenesis. MPO is produced by macrophages and neutrophils [4] and via its chlorination activity, MPO produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl?). HOCl can oxidize protein-bound amino acid residues among which the formation of 3-chlorotyrosine is considered as specific of the activity of MPO as the latter is the only human enzyme able to produce HOCl. In the context of atherogenesis, MPO, 3-chlorotyrosine, and MPO-dependent modified LDL (Mox-LDL) have all been detected in human atherosclerotic lesions and in the bloodstream [5–8]. We previously demonstrated that Mox-LDL generation could occur in vitro at the surface of the endothelial cells suggesting that it was not restricted to the subendothelial space in vivo [9]. The triad made up by endothelial cell, circulating LDL and MPO, allowed a synergic mechanism for producing Mox-LDL. The starting point of this reaction is the generation of superoxide anion ( )
Ir-LBP, an Ixodes ricinus Tick Salivary LTB4-Binding Lipocalin, Interferes with Host Neutrophil Function
Jér?me Beaufays, Beno?t Adam, Catherine Menten-Dedoyart, Laurence Fievez, Amélie Grosjean, Yves Decrem, Pierre-Paul Prév?t, Sébastien Santini, Robert Brasseur, Michel Brossard, Michel Vanhaeverbeek, Fabrice Bureau, Ernst Heinen, Laurence Lins, Luc Vanhamme, Edmond Godfroid
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003987
Abstract: Background During their blood meal, ticks secrete a wide variety of proteins that can interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. Methodology/Principal Findings We previously identified 14 new lipocalin genes in the tick Ixodes ricinus. One of them codes for a protein that specifically binds leukotriene B4 with a very high affinity (Kd: ±1 nM), similar to that of the neutrophil transmembrane receptor BLT1. By in silico approaches, we modeled the 3D structure of the protein and the binding of LTB4 into the ligand pocket. This protein, called Ir-LBP, inhibits neutrophil chemotaxis in vitro and delays LTB4-induced apoptosis. Ir-LBP also inhibits the host inflammatory response in vivo by decreasing the number and activation of neutrophils located at the tick bite site. Thus, Ir-LBP participates in the tick's ability to interfere with proper neutrophil function in inflammation. Conclusions/Significance These elements suggest that Ir-LBP is a “scavenger” of LTB4, which, in combination with other factors, such as histamine-binding proteins or proteins inhibiting the classical or alternative complement pathways, permits the tick to properly manage its blood meal. Moreover, with regard to its properties, Ir-LBP could possibly be used as a therapeutic tool for illnesses associated with an increased LTB4 production.
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