TY - JOUR A1 - Babski, Julia A1 - Haas, Karina A. A1 - Näther-Schindler, Daniela A1 - Pfeiffer, Friedhelm A1 - Förstner, Konrad U. A1 - Hammelmann, Matthias A1 - Hilker, Rolf A1 - Becker, Anke A1 - Sharma, Cynthia M. A1 - Marchfelder, Anita A1 - Soppa, Jörg T1 - Genome-wide identification of transcriptional start sites in the haloarchaeon Haloferax volcanii based on differential RNA-Seq (dRNA-Seq) JF - BMC Genomics N2 - Background Differential RNA-Seq (dRNA-Seq) is a recently developed method of performing primary transcriptome analyses that allows for the genome-wide mapping of transcriptional start sites (TSSs) and the identification of novel transcripts. Although the transcriptomes of diverse bacterial species have been characterized by dRNA-Seq, the transcriptome analysis of archaeal species is still rather limited. Therefore, we used dRNA-Seq to characterize the primary transcriptome of the model archaeon Haloferax volcanii. Results Three independent cultures of Hfx. volcanii grown under optimal conditions to the mid-exponential growth phase were used to determine the primary transcriptome and map the 5′-ends of the transcripts. In total, 4749 potential TSSs were detected. A position weight matrix (PWM) was derived for the promoter predictions, and the results showed that 64 % of the TSSs were preceded by stringent or relaxed basal promoters. Of the identified TSSs, 1851 belonged to protein-coding genes. Thus, fewer than half (46 %) of the 4040 protein-coding genes were expressed under optimal growth conditions. Seventy-two percent of all protein-coding transcripts were leaderless, which emphasized that this pathway is the major pathway for translation initiation in haloarchaea. A total of 2898 of the TSSs belonged to potential non-coding RNAs, which accounted for an unexpectedly high fraction (61 %) of all transcripts. Most of the non-coding TSSs had not been previously described (2792) and represented novel sequences (59 % of all TSSs). A large fraction of the potential novel non-coding transcripts were cis-antisense RNAs (1244 aTSSs). A strong negative correlation between the levels of antisense transcripts and cognate sense mRNAs was found, which suggested that the negative regulation of gene expression via antisense RNAs may play an important role in haloarchaea. The other types of novel non-coding transcripts corresponded to internal transcripts overlapping with mRNAs (1153 iTSSs) and intergenic small RNA (sRNA) candidates (395 TSSs). Conclusion This study provides a comprehensive map of the primary transcriptome of Hfx. volcanii grown under optimal conditions. Fewer than half of all protein-coding genes have been transcribed under these conditions. Unexpectedly, more than half of the detected TSSs belonged to several classes of non-coding RNAs. Thus, RNA-based regulation appears to play a more important role in haloarchaea than previously anticipated. KW - Archaea KW - dRNA-Seq KW - Promoter KW - Non-coding RNAs KW - sRNA KW - Haloferax volcanii KW - Transcriptome KW - Leaderless transcript KW - Antisense RNA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164553 VL - 17 IS - 629 ER - TY - JOUR A1 - Schoffer, Olaf A1 - Schülein, Stefanie A1 - Arand, Gerlinde A1 - Arnholdt, Hans A1 - Baaske, Dieter A1 - Bargou, Ralf C. A1 - Becker, Nikolaus A1 - Beckmann, Matthias W. A1 - Bodack, Yves A1 - Böhme, Beatrix A1 - Bozkurt, Tayfun A1 - Breitsprecher, Regine A1 - Buchali, Andre A1 - Burger, Elke A1 - Burger, Ulrike A1 - Dommisch, Klaus A1 - Elsner, Gudrun A1 - Fernschild, Karin A1 - Flintzer, Ulrike A1 - Funke, Uwe A1 - Gerken, Michael A1 - Göbel, Hubert A1 - Grobe, Norbert A1 - Gumpp, Vera A1 - Heinzerling, Lucie A1 - Kempfer, Lana Raffaela A1 - Kiani, Alexander A1 - Klinkhammer-Schalke, Monika A1 - Klöcking, Sabine A1 - Kreibich, Ute A1 - Knabner, Katrin A1 - Kuhn, Peter A1 - Lutze, Stine A1 - Mäder, Uwe A1 - Maisel, Tanja A1 - Maschke, Jan A1 - Middeke, Martin A1 - Neubauer, Andreas A1 - Niedostatek, Antje A1 - Opazo-Saez, Anabelle A1 - Peters, Christoph A1 - Schell, Beatrice A1 - Schenkirsch, Gerhard A1 - Schmalenberg, Harald A1 - Schmidt, Peter A1 - Schneider, Constanze A1 - Schubotz, Birgit A1 - Seide, Anika A1 - Strecker, Paul A1 - Taubenheim, Sabine A1 - Wackes, Matthias A1 - Weiß, Steffen A1 - Welke, Claudia A1 - Werner, Carmen A1 - Wittekind, Christian A1 - Wulff, Jörg A1 - Zettl, Heike A1 - Klug, Stefanie J. T1 - Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011 JF - BMC Cancer N2 - Background Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. Methods Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. Results The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97–0.97), sex (OR 1.18, 95% CI 1.11–1.25), date of diagnosis (OR 1.05, 95% CI 1.04–1.06), ‘diagnosis during screening’ (OR 3.24, 95% CI 2.50–4.19) and place of residence (OR 1.23, 95% CI 1.16–1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8–83.9%). Conclusions No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008. " KW - Malignant melanoma KW - TNM staging KW - Survival analysis KW - Skin cancer screening KW - Stage distribution Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164544 VL - 16 IS - 936 ER - TY - JOUR A1 - Stölzel, F. A1 - Mohr, B. A1 - Kramer, M. A1 - Oelschlägel, U. A1 - Bochtler, T. A1 - Berdel, W. E. A1 - Kaufmann, M. A1 - Baldus, C. D. A1 - Schäfer-Eckart, K. A1 - Stuhlmann, R. A1 - Einsele, H. A1 - Krause, S. W. A1 - Serve, H. A1 - Hänel, M. A1 - Herbst, R. A1 - Neubauer, A. A1 - Sohlbach, K. A1 - Mayer, J. A1 - Middeke, J. M. A1 - Platzbecker, U. A1 - Schaich, M. A1 - Krämer, A. A1 - Röllig, C. A1 - Schetelig, J. A1 - Bornhäuser, M. A1 - Ehninger, G. T1 - Karyotype complexity and prognosis in acute myeloid leukemia JF - Blood Cancer Journal N2 - A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21∼22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with 4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21∼22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype. KW - Cancer genetics KW - Genetics research Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164530 VL - 6 ER - TY - JOUR A1 - Wilhelm, M. A1 - Smetak, M. A1 - Reimer, P. A1 - Geissinger, E. A1 - Ruediger, T. A1 - Metzner, B. A1 - Schmitz, N. A1 - Engert, A. A1 - Schaefer-Eckart, K. A1 - Birkmann, J. T1 - First-line therapy of peripheral T-cell lymphoma: extension and long-term follow-up of a study investigating the role of autologous stem cell transplantation JF - Blood Cancer Journal N2 - Current guidelines recommend consolidation with autologous stem cell transplantation (autoSCT) after induction chemotherapy for most patients with peripheral T-cell lymphoma (PTCL). This assumption is based on five prospective phase II studies, three of which included <50 patients with limited follow-up. Here we present the final analysis of the prospective German study. The treatment regimen consisted of four to six cycles of CHOP chemotherapy followed by mobilizing therapy and stem cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemo(radio)therapy and autoSCT. From January 2001 to July 2010, 111 patients were enrolled in the study. The main subgroups were PTCL not specified (n=42) and angioimmunoblastic T-cell lymphoma (n=37). Seventy-five (68%) of the 111 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the complete response rate after myeloablative therapy was 59%. The estimated 5-year overall survival, disease-free survival and progression-free survival rates were 44%, 54% and 39%, respectively. The results of this study confirm that upfront autoSCT can result in long-term remissions in patients with all major subtypes of PTCL and therefore should be part of first-line therapy whenever possible. KW - Chemotherapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164506 VL - 6 ER - TY - JOUR A1 - Gökbuget, N. A1 - Kelsh, M. A1 - Chia, V. A1 - Advani, A. A1 - Bassan, R. A1 - Dombret, H. A1 - Doubek, M. A1 - Fielding, A. K. A1 - Giebel, S. A1 - Haddad, V. A1 - Hoelzer, D. A1 - Holland, C. A1 - Ifrah, N. A1 - Katz, A. A1 - Maniar, T. A1 - Martinelli, G. A1 - Morgades, M. A1 - O'Brien, S. A1 - Ribera, J.-M. A1 - Rowe, J. M. A1 - Stein, A. A1 - Topp, M. A1 - Wadleigh, M. A1 - Kantarjian, H. T1 - Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia JF - Blood Cancer Journal N2 - We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data. KW - Acute lymphocytic leukaemia KW - Drug development Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164495 VL - 6 ER - TY - JOUR A1 - Fornari, C. I. A1 - Rappl, P. H. O. A1 - Morelhao, S. L. A1 - Peixoto, T. R. F. A1 - Bentmann, H. A1 - Reinert, F. A1 - Abramof, E. T1 - Preservation of pristine Bi\(_2\)Te\(_3\) thin film topological insulator surface after ex situ mechanical removal of Te capping layer JF - APL Materials N2 - Ex situ analyses on topological insulator films require protection against surface contamination during air exposure. This work reports on a technique that combines deposition of protective capping just after epitaxial growth and its mechanical removal inside ultra-high vacuum systems. This method was applied to Bi2Te3 films with thickness varying from 8 to 170 nm. Contrarily to other methods, this technique does not require any sputtering or thermal annealing setups installed inside the analyzing system and preserves both film thickness and surface characteristics. These results suggest that the technique presented here can be expanded to other topological insulator materials. KW - Insulator surfaces KW - Atomic force microscopy KW - Insulating thin films KW - Molecular beam epitaxy KW - Surface states KW - Vacuum chambers KW - Thin film growth KW - Sputter deposition KW - Epitaxy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164468 VL - 4 ER - TY - JOUR A1 - Trudzinski, Franziska C. A1 - Minko, Peter A1 - Rapp, Daniel A1 - Fähndrich, Sebastian A1 - Haake, Hendrik A1 - Haab, Myriam A1 - Bohle, Rainer M. A1 - Flaig, Monika A1 - Kaestner, Franziska A1 - Bals, Robert A1 - Wilkens, Heinrike A1 - Muellenbach, Ralf M. A1 - Link, Andreas A1 - Groesdonk, Heinrich V. A1 - Lensch, Christian A1 - Langer, Frank A1 - Lepper, Philipp M. T1 - Runtime and aPTT predict venous thrombosis and thromboembolism in patients on extracorporeal membrane oxygenation: a retrospective analysis JF - Annals of Intensive Care N2 - Background Even though bleeding and thromboembolic events are major complications of extracorporeal membrane oxygenation (ECMO), data on the incidence of venous thrombosis (VT) and thromboembolism (VTE) under ECMO are scarce. This study analyzes the incidence and predictors of VTE in patients treated with ECMO due to respiratory failure. Methods Retrospective analysis of patients treated on ECMO in our center from 04/2010 to 11/2015. Patients with thromboembolic events prior to admission were excluded. Diagnosis was made by imaging in survivors and postmortem examination in deceased patients. Results Out of 102 screened cases, 42 survivors and 21 autopsy cases [mean age 46.0 ± 14.4 years; 37 (58.7 %) males] fulfilling the above-mentioned criteria were included. Thirty-four patients (54.0 %) underwent ECMO therapy due to ARDS, and 29 patients (46.0 %) with chronic organ failure were bridged to lung transplantation. Despite systemic anticoagulation at a mean PTT of 50.6 ± 12.8 s, [VT/VTE 47.0 ± 12.3 s and no VT/VTE 53.63 ± 12.51 s (p = 0.037)], VT and/or VTE was observed in 29 cases (46.1 %). The rate of V. cava thrombosis was 15/29 (51.7 %). Diagnosis of pulmonary embolism prevailed in deceased patients [5/21 (23.8 %) vs. 2/42 (4.8 %) (p = 0.036)]. In a multivariable analysis, only aPTT and time on ECMO predicted VT/VTE. There was no difference in the incidence of clinically diagnosed VT in ECMO survivors and autopsy findings. Conclusions Venous thrombosis and thromboembolism following ECMO therapy are frequent. Quality of anticoagulation and ECMO runtime predicted thromboembolic events. " KW - Pulmonary Embolism KW - Inferior Vena Cava KW - Venous Thrombosis KW - Fresh Freeze Plasma KW - Extracorporeal Membrane Oxygenation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164455 VL - 6 ER - TY - JOUR A1 - Lotz, Christian A1 - Schmid, Freia F. A1 - Rossi, Angela A1 - Kurdyn, Szymon A1 - Kampik, Daniel A1 - De Wever, Bart A1 - Walles, Heike A1 - Groeber, Florian K. T1 - Alternative Methods for the Replacement of Eye Irritation Testing JF - ALTEX - Alternatives to Animal Experimentation N2 - In the last decades significant regulatory attempts were made to replace, refine and reduce animal testing to assess the risk of consumer products for the human eye. As the original in vivo Draize eye test is criticized for limited predictivity, costs and ethical issues, several animal-free test methods have been developed to categorize substances according to the global harmonized system (GHS) for eye irritation. This review summarizes the progress of alternative test methods for the assessment of eye irritation. Based on the corneal anatomy and current knowledge of the mechanisms causing eye irritation, different ex vivo and in vitro methods will be presented and discussed with regard to possible limitations and status of regulatory acceptance. In addition to established in vitro models, this review will also highlight emerging, full thickness cornea models that might be suited to predict all GHS categories. KW - eye irritation testing KW - alternatives KW - Draize eye test KW - OECD guideline KW - corneal equivalent Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164444 VL - 33 IS - 1 ER - TY - JOUR A1 - Groeber, Florian A1 - Engelhardt, Lisa A1 - Lange, Julia A1 - Kurdyn, Szymon A1 - Schmid, Freia F. A1 - Rücker, Christoph A1 - Mielke, Stephan A1 - Walles, Heike A1 - Hansmann, Jan T1 - A First Vascularized Skin Equivalent as an Alternative to Animal Experimentation JF - ALTEX - Alternatives to Animal Experimentation N2 - Tissue-engineered skin equivalents mimic key aspects of the human skin, and can thus be employed as wound coverage for large skin defects or as in vitro test systems as an alternative to animal models. However, current skin equivalents lack a functional vasculature limiting clinical and research applications. This study demonstrates the generation of a vascularized skin equivalent with a perfused vascular network by combining a biological vascularized scaffold (BioVaSc) based on a decellularized segment of a porcine jejunum and a tailored bioreactor system. Briefly, the BioVaSc was seeded with human fibroblasts, keratinocytes, and human microvascular endothelial cells. After 14 days at the air-liquid interface, hematoxylin & eosin and immunohistological staining revealed a specific histological architecture representative of the human dermis and epidermis including a papillary-like architecture at the dermal-epidermal-junction. The formation of the skin barrier was measured non-destructively using impedance spectroscopy. Additionally, endothelial cells lined the walls of the formed vessels that could be perfused with a physiological volume flow. Due to the presence of a complex in-vivo-like vasculature, the here shown skin equivalent has the potential for skin grafting and represents a sophisticated in vitro model for dermatological research. KW - alternative to animal testing KW - skin equivalents KW - tissue engineering KW - vascularization Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164438 VL - 33 IS - 4 ER - TY - JOUR A1 - De Palma, Adriana A1 - Abrahamczyk, Stefan A1 - Aizen, Marcelo A. A1 - Albrecht, Matthias A1 - Basset, Yves A1 - Bates, Adam A1 - Blake, Robin J. A1 - Boutin, Céline A1 - Bugter, Rob A1 - Connop, Stuart A1 - Cruz-López, Leopoldo A1 - Cunningham, Saul A. A1 - Darvill, Ben A1 - Diekötter, Tim A1 - Dorn, Silvia A1 - Downing, Nicola A1 - Entling, Martin H. A1 - Farwig, Nina A1 - Felicioli, Antonio A1 - Fonte, Steven J. A1 - Fowler, Robert A1 - Franzen, Markus Franzén A1 - Goulson, Dave A1 - Grass, Ingo A1 - Hanley, Mick E. A1 - Hendrix, Stephen D. A1 - Herrmann, Farina A1 - Herzog, Felix A1 - Holzschuh, Andrea A1 - Jauker, Birgit A1 - Kessler, Michael A1 - Knight, M. E. A1 - Kruess, Andreas A1 - Lavelle, Patrick A1 - Le Féon, Violette A1 - Lentini, Pia A1 - Malone, Louise A. A1 - Marshall, Jon A1 - Martínez Pachón, Eliana A1 - McFrederick, Quinn S. A1 - Morales, Carolina L. A1 - Mudri-Stojnic, Sonja A1 - Nates-Parra, Guiomar A1 - Nilsson, Sven G. A1 - Öckinger, Erik A1 - Osgathorpe, Lynne A1 - Parra-H, Alejandro A1 - Peres, Carlos A. A1 - Persson, Anna S. A1 - Petanidou, Theodora A1 - Poveda, Katja A1 - Power, Eileen F. A1 - Quaranta, Marino A1 - Quintero, Carolina A1 - Rader, Romina A1 - Richards, Miriam H. A1 - Roulston, T’ai A1 - Rousseau, Laurent A1 - Sadler, Jonathan P. A1 - Samnegård, Ulrika A1 - Schellhorn, Nancy A. A1 - Schüepp, Christof A1 - Schweiger, Oliver A1 - Smith-Pardo, Allan H. A1 - Steffan-Dewenter, Ingolf A1 - Stout, Jane C. A1 - Tonietto, Rebecca K. A1 - Tscharntke, Teja A1 - Tylianakis, Jason M. A1 - Verboven, Hans A. F. A1 - Vergara, Carlos H. A1 - Verhulst, Jort A1 - Westphal, Catrin A1 - Yoon, Hyung Joo A1 - Purvis, Andy T1 - Predicting bee community responses to land-use changes: Effects of geographic and taxonomic biases JF - Scientific Reports N2 - Land-use change and intensification threaten bee populations worldwide, imperilling pollination services. Global models are needed to better characterise, project, and mitigate bees' responses to these human impacts. The available data are, however, geographically and taxonomically unrepresentative; most data are from North America and Western Europe, overrepresenting bumblebees and raising concerns that model results may not be generalizable to other regions and taxa. To assess whether the geographic and taxonomic biases of data could undermine effectiveness of models for conservation policy, we have collated from the published literature a global dataset of bee diversity at sites facing land-use change and intensification, and assess whether bee responses to these pressures vary across 11 regions (Western, Northern, Eastern and Southern Europe; North, Central and South America; Australia and New Zealand; South East Asia; Middle and Southern Africa) and between bumblebees and other bees. Our analyses highlight strong regionally-based responses of total abundance, species richness and Simpson's diversity to land use, caused by variation in the sensitivity of species and potentially in the nature of threats. These results suggest that global extrapolation of models based on geographically and taxonomically restricted data may underestimate the true uncertainty, increasing the risk of ecological surprises. KW - bee community KW - land-use change KW - intensification KW - geographic biases KW - taxonomic biases KW - global dataset Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167642 VL - 6 ER -