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Edelény, Hungary

Metzger J.,Mosaiques Diagnostics GmbH | Negm A.A.,Hannover Medical School | Plentz R.R.,University Hospital of Tuebingen | Weismuller T.J.,Hannover Medical School | And 8 more authors.
Gut | Year: 2013

Background: Diagnosis and curative treatment of cholangiocarcinoma (CC) often comes too late due to the lack of reliable tumour markers especially in patients with primary sclerosing cholangitis (PSC). The authors recently introduced bile proteomic analysis for CC diagnosis. Nevertheless, bile collection depends on invasive endoscopic retrograde cholangiography. The authors therefore evaluated urine proteomic analysis for non-invasive CC diagnosis. Methods: Using capillary electrophoresis mass spectrometry the authors established a CC-specific peptide marker model based on the distribution of 42 peptides in 14 CC, 13 PSC and 14 benign biliary disorder (BBD) patients. Results: In cross-sectional validation of 123 patients, the urine peptide marker model correctly classified 35 of 42 CC patients and 64 of 81 PSC and BBD patients with an area under the curve value of 0.87 (95% CI 0.80 to 0.92, p=0.0001, 83% sensitivity, 79% specificity). Evaluation of 101 normal controls resulted in 86% specificity. All 10 patients with CC on top of PSC were correctly classified. The majority of sequence-identified peptides are fragments of interstitial collagens with some of them also detected in blood indicating their extra-renal origin. Immunostaining of liver sections for matrix metallopeptidase 1 indicated increased activity of the interstitial collagenase in liver epithelial cells of CC patients. Conclusion: The urine test differentiates CC from PSC and other BBD and may provide a new diagnostic noninvasive tool for PSC surveillance and CC detection.

Nagel S.,Hospital Martha Maria | Kellner O.,Municipal Hospital | Engel-Riedel W.,Hospital of Lung Diseases | Guetz S.,Robert Koch Hospital | And 3 more authors.
Clinical Lung Cancer | Year: 2011

Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), is used in cancer patients as a supportive care for anemia. For small-cell lung cancer (SCLC), several studies have shown that the administration of ESAs does not affect survival but decreases the need for blood transfusions and improves the quality of life (QOL) of patients receiving chemotherapy. The present randomized phase II study assessed the feasibility, efficacy, and safety of the administration of darbepoetin alfa to patients with SCLC receiving dose-dense (every 2 weeks) standard chemotherapy consisting of carboplatin plus etoposide, pegfilgrastim prophylactically. Seventy-four chemotherapy-naive patients with limited or extensive SCLC received combination chemotherapy for 6 cycles, and half of the patients additionally received darbepoetin to achieve a target hemoglobin concentration of 12-13 g/dL. The primary study outcome, progression-free survival, showed no difference between the 2 arms of the study. Among the secondary endpoints, objective response was similar in the presence and absence of darbepoetin (best response rates = 75.0% vs. 77.8%). Likewise, 1-year survival rates were not different between the 2 treatment arms (40.1% vs. 45.9%). There were no significant differences in grade 3/4 toxicities. As expected, the need for blood transfusions differed significantly: 19.4% of patients in the darbepoetin arm received transfusions versus 38.9% in the control arm. Analysis of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scales at different time points showed that the darbepoetin group's QOL was significantly better for certain readouts and never significantly worse than that of the control group. Thus, the combination of darbepoetin alfa with dose-dense carboplatin plus etoposide was feasible and well tolerated. Addition of darbepoetin alfa to chemotherapy lowered the need for blood transfusions and did not affect measures of survival and objective response.

Mehrtens S.,Robert Koch Hospital | Reboll M.R.,Hannover Medical School
Methods in Molecular Biology | Year: 2014

The dicistronic luciferase reporter gene system is the most common method to isolate and characterize internal ribosome entry sites (IRES). It is based on the expression of a dicistronic RNA comprising two independent reporter genes in 3' and 5'cistrons, and the putative IRES inserted into intercistronic region. The most convenient aspect of using Renilla and firefly luciferase genes is that both gene products can be detected in a single assay using Dual-Luciferase® Reporter Assay System from Promega. The Renilla luciferase coding sequence is often inserted into the 5'cistron and serves as internal control. It is translated cap dependently, as it is close to the cap structure at the 5' end. The 3'cistron located far downstream to the cap structure can only be translated by a cap-independent mechanism when the intercistronic sequence is capable of ribosome binding and re-initiation of translation. Expression level of the 3'cistron is usually normalized to the expression of 5'cistron to estimate the relative IRES activity of intercistronic sequences. © Springer Science+Business Media New York 2014.

Szabo M.,Robert Koch Hospital | Safrany E.,University of Pecs | Pazar B.,National Institute of Rheumatology and Physiotherapy | Malegh B.I.,University of Pecs | And 6 more authors.
Molecular Biology Reports | Year: 2013

Haplotype tagging SNPs of interleukin-23 receptor gene rs1004819, rs7517847, rs7530511, rs2201841, rs1343151 and rs10889677 were determined in 396 patients with rheumatoid arthritis, 190 patients with Crohn's disease, 206 patients with ankylosing spondylitis and 182 controls. Using regression analysis models the rs1004819, rs2201841, and rs10889677 SNPs were found to confer risk for Crohn's disease and ankylosing spondylitis, while rs1343151 had a protective effect in both of these diseases, and the rs2201841 and rs10889677 SNPs showed susceptibility nature for rheumatoid arthritis. Using these SNPs we could study the susceptibility haplotype profiles in these diseases with special attention to the rheumatoid arthritis, first in the literature. Seven different haplotypes could be differentiated. We found that the SNPs exert their susceptibility character in specific haplotype blocks: thus, for rheumatoid arthritis the rs1343151 SNP was risk factor only in a specific haplotype surrounding; this can explain the controversial results published so far about this variant. More importantly, we observed, that while a specific haplotype can confer risk for rheumatoid arthritis, the same haplotype tended to protect against the development of the other two diseases. The data presented here serve evidence for the need of haplotype analysis instead of just single standing SNP analysis when susceptibility to or protection against a certain disease are interpreted. © 2012 Springer Science+Business Media Dordrecht.

Sipeky C.,University of Pecs | Csongei V.,University of Pecs | Jaromi L.,University of Pecs | Safrany E.,University of Pecs | And 5 more authors.
Drug Metabolism and Pharmacokinetics | Year: 2011

The genetic variability, haplotype profile and ethnic differences of MDR1 polymorphisms in healthy Roma and Hungarian populations were analyzed and the results were compared with those of other populations available from the literature. Healthy subjects (465 Roma and 503 Hungarian) were genotyped for C1236T, G2677T/A and C3435T variants of MDR1 by PCR-RFLP assay. Differences were found between the Roma and Hungarian populations in the frequencies of MDR1 1236 CC (20.7 vs. 33.2%) and TT genotypes (30.8 vs. 21.9%), in T allele frequency (0.551 vs. 0.443) (p < 0.002), and in 3435T allele frequency (0.482 vs. 0.527, p < 0.04). Furthermore, the frequency of CGC, CGT and CTT haplotypes was significantly higher in the Hungarian population than in Roma (41.4 vs. 35.3%, 9.04 vs. 6.02% and 2.88 vs. 1.08%, respectively; p < 0.009), whereas the frequency of TGC and TTC haplotypes was higher in the Roma population than in the Hungarian (7.31 vs. 1.68% and 6.67 vs. 2.08%, respectively; p < 0.001). The prevalence of MDR1 polymorphisms in the Hungarian population is similar to that of other European populations; however, some differences were observed in the haplotype structures. In contrast, the Roma population differs from Hungarians, from Caucasians and from populations from India in the incidence of MDR1 common variants and haplotypes. © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX).

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