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  • 1
    Keywords: CANCER ; CELLS ; SURVIVAL ; carcinoma ; CELL ; LUNG ; INFORMATION ; lung cancer ; LUNG-CANCER ; GENE ; PROTEIN ; TISSUE ; PATIENT ; MACROPHAGES ; MARKER ; prognosis ; CONTRAST ; LYMPH-NODES ; STAGE ; PROGRESSION ; HIGH-RISK ; LOCALIZATION ; HEAD ; HIGH-LEVEL ; non-small cell lung cancer ; CATHEPSIN-B ; STEFIN-A ; TUMOR TISSUE ; LEVEL ; IMMUNOHISTOCHEMICAL ANALYSIS ; NSCLC ; CYSTEINE PROTEASE ; RELEVANCE ; macrophage ; PREDICTOR ; inflammatory cells ; biological markers ; cystatin ; cathepsin ; CYSTEINE PROTEINASE-INHIBITOR ; ENDOGENOUS INHIBITORS ; PROTEASE INHIBITORS ; stefin
    Abstract: Cystatins regulate tumour-associated cysteine proteases, however, their role in tumour progression is not clear yet. To assess their relevance in the progression of nonsmall cell lung cancer (NSCLC) the protein level, cysteine protease activity (CPI) and localization of type I (stefins A and B) and type H (C, E/M and F) cystatins were defined in tumours and control lung counterparts from 165 patients. The medians of CPI activity, stefins A and B were significantly greater in tumour than in lung tissue (2.1-fold, 1.7-fold, 1.2-fold, respectively, all p 〈 0.001). The median levels of cystatin C and cystatin E/M were lower in tumour tissue (0.9-fold, p=0.06; 0.6-fold, p 〈 0.01). In all the samples the levels of cystatin F were below the detection limit. Immunohistochemical analysis revealed the presence of all cystatins in tumour cells and infiltrated inflammatory cells such as macrophages and neutrophils. In univariate survival analysis patients with high levels of stefin A, stefin B and CPI activity exhibited a better survival probability (p=0.05, p=0.05, p 〈 0.01, respectively). In contrast, cystatins C and E/M provided no prognostic information. In multivariate analysis the most powerful predictor of survival was the pTNM stage (p 〈 0.0001; RR 3.5), followed by stefin A, stefin B and CPI activity (all p=0.03; RR 1.5). Our results suggest that only stefins A and B, i.e. type I cystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity. As biological markers they may add independent prognostic information for better assessment of low- and high-risk patients with NSCLC
    Type of Publication: Journal article published
    PubMed ID: 16969475
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  • 2
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; DEATH ; POPULATION ; TISSUE ; MACROPHAGES ; MARKER ; RECOGNITION ; MOUSE ; prevention ; PHAGOCYTOSIS ; MARKERS ; DAMAGE ; NETHERLANDS ; CLEARANCE ; CENTRAL-NERVOUS-SYSTEM ; RECEPTORS ; microglia ; MULTIPLE-SCLEROSIS ; mannose receptor ; SUBPOPULATION ; RE ; BRAIN-TUMORS ; GLIOMA ; GLIOMA-CELLS ; FUNCTIONAL-CHARACTERIZATION ; cell death ; APOPTOTIC CELLS ; immunology ; STRAIN
    Abstract: Microglia phagocytic activity for apoptotic glioma cells is hardly analysed inspite of its relevance to tissue damage prevention. We provide evidence for a phosphatidyl serine-independent clearance of mouse glioma cells at an advanced stage of death, suggesting microglia recognition of late apoptotic markers. Dying cells were immediately cleared or stayed for hours in that stage before engulfment occurred. This phagocytic activity was restricted to a microglia subset representing 30 to 70% of the population according to the used strain. Expression of receptors involved in late apoptotic markers recognition therefore seems confined to a subpopulation of microglia and to be strain-dependent. (C) 2008 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 18495256
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  • 3
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; AGENTS ; CELL ; PATHWAY ; DISEASE ; DISEASES ; PROTEIN ; CULTURED-CELLS ; ACCUMULATION ; RELEASE ; GLYCOPROTEIN ; ISOFORM ; MOUSE ; UP-REGULATION ; PLASMA ; MEMBRANE ; PLASMA-MEMBRANE ; CELL-SURFACE ; protease ; cysteine ; ageing ; CATHEPSIN-B ; CONFORMATIONAL-CHANGES ; CASPASE ; CONFORMATIONAL-CHANGE ; CREUTZFELDT-JAKOB-DISEASE ; INHIBITORS ; PRION PROTEIN ; PRP ACCUMULATION
    Abstract: Prion diseases are characterized by the accumulation of an abnormal, proteinase K-resistant isoform of the prion protein, PrPSc, which is generated by a post-translational conversion of the protease-sensitive normal cell-surface glycoprotein PrPc involving major conformational changes. The conversion is thought to occur at the plasma membrane or along the endocytic pathway towards the lysosome. PrPSc aggregates have been found to accumulate in secondary lysosomes. In our study, the activities of two major lysosomal cysteine proteases, cathepsins B and L, were found to be significantly increased in scrapie-infected Neuro2a cells compared with uninfected cells using biochemical and cytochemical methods. We hypothesize that lysosomal proteases may be involved in a 'second autocatalytic loop' of PrPSc formation, acting in concert with the well-known autocatalytic enhancement of PrP conversion in the presence of PrPSc
    Type of Publication: Journal article published
    PubMed ID: 12867662
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  • 4
    Keywords: RECEPTOR ; CANCER ; CELLS ; INHIBITOR ; SURVIVAL ; carcinoma ; CELL ; Germany ; LUNG ; INFORMATION ; lung cancer ; LUNG-CANCER ; SYSTEM ; SYSTEMS ; COHORT ; POPULATION ; PROTEIN ; TISSUE ; TIME ; PATIENT ; primary ; prognosis ; tumour ; ASSAY ; metastases ; PROGNOSTIC-FACTORS ; PARAMETERS ; MULTIVARIATE ; UROKINASE RECEPTOR ; CARCINOMAS ; PROGNOSTIC FACTORS ; PROTEIN LEVELS ; squamous cell carcinoma ; PARENCHYMA ; RECEPTORS ; POOR-PROGNOSIS ; protease ; PROGNOSTIC FACTOR ; non-small cell lung cancer ; CATHEPSIN-B ; STEFIN-A ; INHIBITORS ; CELL CARCINOMA ; ELISA ; FRACTION ; overall survival ; PH ; CARCINOMA PATIENTS ; carcinoid ; PROGNOSTIC-FACTOR ; ACTIVATOR INHIBITOR ; cathepsin B (cath B) ; CLINICAL-RELEVANCE ; CYSTEINE PROTEASE INHIBITORS ; nonsmall cell lung cancer (NSCLC) ; plasminogenactivator-inhibitor (PAI-1) ; plasminoggenactivator-receptor (uPAR) ; PROTEINASE-INHIBITORS ; PULMONARY ADENOCARCINOMA ; TISSUE-FACTOR ; TUMOR TISSUE
    Abstract: To evaluate the possible role of cysteine proteases and serine proteases.. as well as their respective inhibitors and receptors, as new prognostic factors in NSCLC, we examined, for the first time, 10 biological parameters related to three proteolytic systems within a homogeneous collective of 147 cases of NSCLC. Activities (cath B-AT, cath B-A7.5) and protein levels of cath B-C, cath L-C, uPA, PAI-1, uPAR [measured by three different assays uPAR (ADI), uPAR (HD13), uPAR (IIIF10)] and TF were measured in homogenates of lung tumour tissue and corresponding non-malignant lung parenchyma. Total cath B activity (cath BAT) and enzymatic activity of the fraction of cath B, which is stable and active at pH 7.5 (cath B-A7.5), were determined by a fluorogenic assay using synthetic substrate Z-Arg-Arg-AMC. The concentrations of cath B-C, cath L-C, uPA, PAI-1, uPAR and TF were determined by ELISAs. uPAR was determined using three different ELISA formats. The median levels of cath B-AT (5.1-fold), cath BA7.5 (2.5-fold), cath BC, (8.5-fold), cath L-C (6.6-fold), uPA (6.5-fold), PAI-1 (4.2-fold),x uPAR (ADI) (2.2-fold), uPAR (HD13) (4.0-fold) and uPAR (IIIF10)(2.6-fold) were higher in tumour tissue compared to the lung parenchyma. Cath B-AT, cath B-A7.5 and cath B-C in primary tumours correlated with lymph node metastases. Regarding histologies, the concentration of PAI-1 seems to be associated with the histological cell types of NSCLC. We found the highest values of PAI-1 in large cell carcinoma 〉 SCC, AC 〉 carcinoid and lowest values in metastases of primary tumours of other organs. Only PAI-1 was significantly increased in poorly-differentiated cells (G3) compared to well- and moderately- differentiated cells (G1/G2). PAI-1 significantly correlated with cath B-AT, and cath B-A7.5 with uPAR (ADI), uPAR (HD13), uPAR (IIIF10) with uPA, and only weakly with TF, but not with cath B-C, and cath L-C Significant cot-relations with overall survival in the total population of NSCLC patients were observed in univariate analysis for cath B-AT, cath B-C, PAI-1, uPAR (ADI), uPAR (HD13), and uPAR (IIIF10). Cath L-C was not significantly associated with poor prognosis. Regarding the histological tumour type, only in patients with squamous cell carcinomas did cath B-A7.5 and PAI-1 remain significant prognostic factors. In multivariate survival analysis only two proteolytic factors, PAI-1 and uPAR (III10F), stayed significant. In conclusion, among 10 biological parameters evaluated within the same cohort of patients, only PAI-1, uPAR (ADI), uPAR (HD13), uPAR (IIIF10), cath B-AT and cath B-C are prognostic factors for overall survival of NSCLC patients. Moreover, PAI-1 and uPAR (IIIF10) add independent prognostic information with regard to established clinical and histomorphological factors in NSCLC
    Type of Publication: Journal article published
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