@article{HaarmannDeissProchaskaetal.2010, author = {Haarmann, Axel and Deiss, Annika and Prochaska, Juergen and Foerch, Christian and Weksler, Babette and Romero, Ignacio and Couraud, Pierre-Olivier and Stoll, Guido and Rieckmann, Peter and Buttmann, Mathias}, title = {Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68468}, year = {2010}, abstract = {Background: An inducible release of soluble junctional adhesion molecule-A (sJAM-A) under pro-inflammatory conditions was described in cultured non-CNS endothelial cells (EC) and increased sJAM-A serum levels were found to indicate inflammation in non-CNS vascular beds. Here we studied the regulation of JAM-A expression in cultured brain EC and evaluated sJAM-A as a serum biomarker of blood-brain barrier (BBB) function. Methodology/Principal Findings: As previously reported in non-CNS EC types, pro-inflammatory stimulation of primary or immortalized (hCMEC/D3) human brain microvascular EC (HBMEC) induced a redistribution of cell-bound JAM-A on the cell surface away from tight junctions, along with a dissociation from the cytoskeleton. This was paralleled by reduced immunocytochemical staining of occludin and zonula occludens-1 as well as by increased paracellular permeability for dextran 3000. Both a self-developed ELISA test and Western blot analysis detected a constitutive sJAM-A release by HBMEC into culture supernatants, which importantly was unaffected by pro-inflammatory or hypoxia/reoxygenation challenge. Accordingly, serum levels of sJAM-A were unaltered in 14 patients with clinically active multiple sclerosis compared to 45 stable patients and remained unchanged in 13 patients with acute ischemic non-small vessel stroke over time. Conclusion: Soluble JAM-A was not suited as a biomarker of BBB breakdown in our hands. The unexpected non-inducibility of sJAM-A release at the human BBB might contribute to a particular resistance of brain EC to inflammatory stimuli, protecting the CNS compartment.}, subject = {Biomarker}, language = {en} } @article{VerghoKneitzRosenwaldetal.2014, author = {Vergho, Daniel and Kneitz, Susanne and Rosenwald, Andreas and Scherer, Charlotte and Spahn, Martin and Burger, Maximilian and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma}, doi = {10.1186/1471-2407-14-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110061}, year = {2014}, abstract = {Background Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs. Methods Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC). Results RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease. Conclusions A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.}, language = {en} } @article{RinaldettiPfirrmannManzetal.2018, author = {Rinaldetti, S{\´e}bastien and Pfirrmann, Markus and Manz, Kirsi and Guilhot, Joelle and Dietz, Christian and Panagiotidis, Panayiotidis and Spiess, Birgit and Seifarth, Wolfgang and Fabarius, Alice and M{\"u}ller, Martin and Pagoni, Maria and Dimou, Maria and Dengler, Jolanta and Waller, Cornelius F. and Br{\"u}mmendorf, Tim H. and Herbst, Regina and Burchert, Andreas and Janßen, Carsten and Goebeler, Maria Elisabeth and Jost, Philipp J. and Hanzel, Stefan and Schafhausen, Philippe and Prange-Krex, Gabriele and Illmer, Thomas and Janzen, Viktor and Klausmann, Martine and Eckert, Robert and B{\"u}schel, Gerd and Kiani, Alexander and Hofmann, Wolf-Karsten and Mahon, Fran{\c{c}}ois-Xavier and Saussele, Susanne}, title = {Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial}, series = {Clinical Lymphoma, Myeloma \& Leukemia}, volume = {18}, journal = {Clinical Lymphoma, Myeloma \& Leukemia}, number = {4}, doi = {10.1016/j.clml.2018.02.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226281}, pages = {266-271}, year = {2018}, abstract = {Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54\% (95\% confidence interval [CI], 46\%-62\%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95\% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47\% (95\% CI, 37\%-57\%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72\% (95\% CI, 55\%-82\%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc.}, language = {en} }