University of Cologne

About: University of Cologne is a education organization based out in Cologne, Germany. It is known for research contribution in the topics: Population & Transplantation. The organization has 32050 authors who have published 66350 publications receiving 2210092 citations. The organization is also known as: Universität zu Köln & Universitatis Coloniensis.

Paraoxonase-1 is a major determinant of clopidogrel efficacy

Abstract: Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

Telomerase activation by genomic rearrangements in high-risk neuroblastoma

Abstract: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

Treatment of Older Patients with Mantle-Cell Lymphoma

Abstract: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of ritux imab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to main tenance therapy with rituximab or interferon alfa, each given until progression. RESULTS Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P = 0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P = 0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects oc curred more frequently in the R-FC group than in the R-CHOP group, but the fre quency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% con fidence interval, 0.36 to 0.87; P = 0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall sur vival (4-year survival rate, 87%, vs. 63% with interferon alfa; P = 0.005). CONCLUSIONS R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.)

CBOL Protist Working Group: Barcoding Eukaryotic Richness beyond the Animal, Plant, and Fungal Kingdoms

Abstract: Animals, plants, and fungi—the three traditional kingdoms of multicellular eukaryotic life—make up almost all of the visible biosphere, and they account for the majority of catalogued species on Earth [1]. The remaining eukaryotes have been assembled for convenience into the protists, a group composed of many diverse lineages, single-celled for the most part, that diverged after Archaea and Bacteria evolved but before plants, animals, or fungi appeared on Earth. Given their single-celled nature, discovering and describing new species has been difficult, and many protistan lineages contain a relatively small number of formally described species (Figure 1A), despite the critical importance of several groups as pathogens, environmental quality indicators, and markers of past environmental changes. It would seem natural to apply molecular techniques such as DNA barcoding to the taxonomy of protists to compensate for the lack of diagnostic morphological features, but this has been hampered by the extreme diversity within the group. The genetic divergence observed between and within major protistan groups greatly exceeds that found in each of the three multicellular kingdoms. No single set of molecular markers has been identified that will work in all lineages, but an international working group is now close to a solution. A universal DNA barcode for protists coupled with group-specific barcodes will enable an explosion of taxonomic research that will catalyze diverse applications.