Search PubMed⌕ Search

Biomedical subjects

Stefan Meuer

Publications and source records attributed to Stefan Meuer.

9 recordsLinked to original sources
PubMed2006

Pharmacodynamic monitoring of cyclosporine a in renal allograft recipients shows a quantitative relationship between immunosuppression and the occurrence of recurrent infections and malignancies.

BACKGROUND: At present it is unclear which dose and consecutive blood levels of cyclosporine A (CsA) are optimal with respect to immunosuppressive efficacy and drug specific side effects at the level of individual patients. Several pharmacodynamic measures of CsA effects have been proposed, but have not become clinical routine yet. Besides the lack of practicability, the biological relevance of these assays has not been determined so far. METHODS: Residual expression of nuclear factor of activated T-cells (NFAT)-regulated genes two hours after drug intake was used as molecular pharmacodynamic marker to assess CsA effects on lymphocytes and correlated with the frequency of recurrent infections and malignancies in patients with five or more years of follow-up posttransplantation. RESULTS: Recurrent infectious complications were observed in 44% and malignancies in 20% of the 133 patients studied. Patients with a strong suppression of NFAT-regulated genes by CsA--as judged by a residual level of transcription of less than 15% after drug intake--develop more frequent infections (53% vs. 29%; P = 0.005) and malignancies (22% vs. 4%; P = 0.002). The lack of correlation between the incidence of these complications and CsA blood concentration might point to the interindividual differences in the sensitivity towards calcineurin inhibition. CONCLUSION: The data presented here reveal a clear relation between the frequency of infectious and malignant complications and the degree of suppression of NFAT-regulated genes by CsA in transplanted patients. Therefore, pharmacodynamic monitoring of CsA efficacy in transplanted patients might be a useful tool to adjust immunosuppressive therapy in individual patients.

Adult↗
PubMed2006

Differentially expressed genes in postperfusion biopsies predict early graft dysfunction after liver transplantation.

BACKGROUND: Preservation induced injury is a major contributing factor to early graft dysfunction in liver allograft recipients. We hypothesized that changes in gene expression represent the earliest indicator of ischemia/reperfusion-related injuries measurable in the graft and could be used as prognostic marker for the occurrence of graft-related complications. METHODS: We studied the expression of 67 genes, known to play a role in acute inflammatory processes by real-time polymerase chain reaction in 59 postperfusion biopsies. The level of expression was correlated with the occurrence of graft-related complications. RESULTS: We identified six genes that were significantly correlated with the occurrence of early graft dysfunction (Spearman test, two-tailed; P<0.05). High C-reactive protein (CRP) gene expression levels correlated significantly with the need of therapeutic interventions due to graft-related complications (P=0,011). Furthermore, five genes related to vascular endothelial cell physiology (CTGF, WWP2, CD274, VEGF. and its receptor FLT1) showed significantly reduced expression in the postperfusion biopsies of patients with need of therapeutic interventions due to graft-related complications in the first month (P<0.05). Using a risk score based on the expression of these five genes, complications could be predicted with 96% sensitivity (ROC analysis, specificity: 74%, positive predictive value: 72%, negative predictive value: 96%). CONCLUSION: Quantitative gene expression analysis in postperfusion biopsies may be a valuable tool to prospectively identify patients at risk for early clinical allograft dysfunction after liver transplantation.

Acute Disease↗
PubMed2005

Aberrant gata-3 expression in human pancreatic cancer.

Gata-3 has been shown to specifically alter its expression patterns in different types of cancers. Recent evidence suggests that an interference of Gata-3 exists in the TGF-beta signaling pathway. To determine the role of Gata-3 in pancreatic cancer, pancreatic cancer samples were analyzed in comparison to normal pancreatic tissues. Furthermore, four different pancreatic cancer cell lines with different alterations of the TGF-beta pathway were studied. To evaluate if a potential relationship with TGF-beta signaling pathway exists, we correlated mRNA expression levels with the expression of TGF-betas, TGF-beta receptors, and Smad-3. Finally, we analyzed the influence of TGF-beta on Gata-3 expression in vitro. All pancreatic cancer samples demonstrated a marked overexpression of Gata-3 mRNA and protein. Immunohistochemical staining revealed strong and persistent cytoplasmic Gata-3 immunoreactivity in cancer cells. In an electrophoretic mobility shift assay, a disturbed nuclear translocation was confirmed. The expression of Gata-3 showed a significant correlation with the expression of TGF-betas, TGF-beta receptors, and Smad-3. TGF-beta responsive cell lines showed a downregulation of Gata-3 mRNA upon TGF-beta exposure, whereas in TGF-beta-unresponsive cell lines, Gata-3 mRNA expression persisted at high levels. Furthermore, strong specific upregulation of Gata-3 impaired nuclear translocation and its cooperative action with the TGF-beta pathway, suggesting that Gata-3 plays a central role in human pancreatic cancer.

Adult↗
PubMed2004

Monitoring of NFAT-regulated gene expression in the peripheral blood of allograft recipients: a novel perspective toward individually optimized drug doses of cyclosporine A.

BACKGROUND: With the introduction of cyclosporine A (CsA), long-term allograft function has significantly improved. Problems related to limited therapeutic margins and CsA toxicity remain unsolved. Until now there have been no reliable, practical markers to measure the biologic activity of CsA in vivo. METHODS: Expression of NFAT (nuclear factor of activated T cells)-regulated genes (interleukin 2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor) in phorbol myristate acetate/ionomycin-stimulated peripheral blood from healthy volunteers (n=34) and from stable renal (n=25), cardiac (n=26), and liver (n=14) transplant recipients receiving CsA therapy was measured by quantitative real-time reverse transcriptase-polymerase chain reaction before and 2 hr after drug intake. Gene expression and CsA plasma levels were correlated. RESULTS: Two hours after oral CsA ingestion, the mean suppression of induced interleukin 2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor gene expression was 85%. The individual decline of NFAT-regulated gene expression and the total drug exposure at this time point were closely related. Six hours after oral CsA uptake, gene expression levels reached predose values and subsequently increased further in some patients (rebound effect). CONCLUSION: Quantitative measurement of the inhibition of NFAT-regulated gene expression 2 hr after CsA intake represents a novel approach to assess the biologic effectiveness of CsA therapy and has the potential to enable individualized immunosuppressive regimens.

Adult↗
PubMed2004

Analysis of NFAT-regulated gene expression in vivo: a novel perspective for optimal individualized doses of calcineurin inhibitors.

BACKGROUND: With the introduction of cyclosporine A (CsA) long-term allograft function has been significantly improved. Problems regarding limited therapeutic margins and CsA toxicity remain unsolved. Up to now there are no reliable, practical markers to measure the biological activity of CsA in vivo. METHODS: Expression of nuclear factor of activated T lymphocytes (NFAT)-regulated genes in PMA/ionomycin-stimulated peripheral blood from stable renal-transplant (n = 25) recipients under CsA therapy were measured by quantitative real-time RT-PCR before and 2 h after drug intake. The relative expression of three NFAT-regulated genes was scored, averaged and presented as the multi-gene expression score ranging from 0 to 12 points. Gene expression data and CsA plasma levels were correlated. RESULTS: A reliable and precise method to measure functional consequences of calcineurin inhibition in the individual patient was established. The individual decline in NFAT-regulated gene expression and the total drug exposure were in close relation (rho = 0.602). CONCLUSION: Quantitative measurement of NFAT-regulated gene expression in CsA-treated patients represents a potent new approach to assess the biological effectiveness of CsA therapy and has the potential to enable individualized immunosuppressive regimens.

Adult↗
PubMed2002

CD antigens 2002.

Explore the source record for details and available documents.

Antibodies, Monoclonal↗