TY - JOUR A1 - Bernt, Alexander A1 - Rangrez, Ashraf Y. A1 - Eden, Matthias A1 - Jungmann, Andreas A1 - Katz, Sylvia A1 - Rohr, Claudia A1 - Müller, Oliver J. A1 - Katus, Hugo A. A1 - Sossalla, Samuel T. A1 - Williams, Tatjana A1 - Ritter, Oliver A1 - Frank, Derk A1 - Frey, Norbert T1 - Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy JF - Scientific Reports N2 - The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway. KW - Calcineurin-NFATsignaling KW - activation KW - SUMO2 KW - cardiac hypertrophy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167525 VL - 6 IS - 35758 ER - TY - JOUR A1 - Moris, Lisa A1 - Van den Broeck, Thomas A1 - Tosco, Lorenzo A1 - Van Baelen, Anthony A1 - Gontero, Paolo A1 - Karnes, Robert Jeffrey A1 - Everaerts, Wouter A1 - Albersen, Maarten A1 - Bastian, Patrick J. A1 - Chlosta, Piotr A1 - Claessens, Frank A1 - Chun, Felix K. A1 - Graefen, Markus A1 - Gratzke, Christian A1 - Kneitz, Burkhard A1 - Marchioro, Giansilvio A1 - Salas, Rafael Sanchez A1 - Tombal, Bertrand A1 - Van Der Poel, Henk A1 - Walz, Jochen Christoph A1 - De Meerleer, Gert A1 - Bossi, Alberto A1 - Haustermans, Karin A1 - Montorsi, Francesco A1 - Van Poppel, Hendrik A1 - Spahn, Martin A1 - Briganti, Alberto A1 - Joniau, Steven T1 - Impact of lymph node burden on survival of high-risk prostate cancer patients following radical prostatectomy and pelvic lymph node dissection JF - Frontiers in Surgery N2 - Aim To determine the impact of the extent of lymph node invasion (LNI) on long-term oncological outcomes after radical prostatectomy (RP). Material and methods In this retrospective study, we examined the data of 1,249 high-risk, non-metastatic PCa patients treated with RP and pelvic lymph node dissection (PLND) between 1989 and 2011 at eight different tertiary institutions. We fitted univariate and multivariate Cox models to assess independent predictors of cancer-specific survival (CSS) and overall survival (OS). The number of positive lymph node (LN) was dichotomized according to the most informative cutoff predicting CSS. Kaplan–Meier curves assessed CSS and OS rates. Only patients with at least 10 LNs removed at PLND were included. This cutoff was chosen as a surrogate for a well performed PNLD. Results Mean age was 65 years (median: 66, IQR 60–70). Positive surgical margins were present in 53.7% (n = 671). Final Gleason score (GS) was 2–6 in 12.7% (n = 158), 7 in 52% (n = 649), and 8–10 in 35.4% (n = 442). The median number of LNs removed during PLND was 15 (IQR 12–17). Of all patients, 1,128 (90.3%) had 0–3 positive LNs, while 126 (9.7%) had ≥4 positive LNs. Patients with 0–3 positive LNs had significantly better CSS outcome at 10-year follow-up compared to patients with ≥4 positive LNs (87 vs. 50%; p < 0.0001). Similar results were obtained for OS, with a 72 vs. 37% (p < 0.0001) survival at 10 years for patients with 0–3 vs. ≥4 positive LNs, respectively. At multivariate analysis, final GS of 8–10, salvage ADT therapy, and ≥4 (vs. <4) positive LNs were predictors of worse CSS and OS. Pathological stage pT4 was an additional predictor of worse CSS. Conclusion Four or more positive LNs, pathological stage pT4, and final GS of 8–10 represent independent predictors for worse CSS in patients with high-risk PCa. Primary tumor biology remains a strong driver of tumor progression and patients having ≥4 positive LNs could be considered an enriched patient group in which novel treatment strategies should be studied. KW - high-risk prostate cancer KW - lymph node dissection KW - positive lymph node KW - prognosis KW - surgery Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195721 SN - 2296-875X VL - 3 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 - TY - JOUR A1 - Burns, Alan J. A1 - Goldstein, Allan M. A1 - Newgreen, Donald F. A1 - Stamp, Lincon A1 - Schäfer, Karl-Herbert A1 - Metzger, Marco A1 - Hotta, Ryo A1 - Young, Heather M. A1 - Andrews, Peter W. A1 - Thapar, Nikhil A1 - Belkind-Gerson, Jaime A1 - Bondurand, Nadege A1 - Bornstein, Joel C. A1 - Chan, Wood Yee A1 - Cheah, Kathryn A1 - Gershon, Michael D. A1 - Heuckeroth, Robert O. A1 - Hofstra, Robert M.W. A1 - Just, Lothar A1 - Kapur, Raj P. A1 - King, Sebastian K. A1 - McCann, Conor J. A1 - Nagy, Nandor A1 - Ngan, Elly A1 - Obermayr, Florian A1 - Pachnis, Vassilis A1 - Pasricha, Pankaj J. A1 - Sham, Mai Har A1 - Tam, Paul A1 - Vanden Berghe, Pieter T1 - White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies JF - Developmental Biology N2 - Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic. KW - Neural crest cells KW - Rat mynteric plexus KW - Intestinal pseudoobstruction KW - Hypertrophic pyloric-stenosis KW - Hirschsprung disease liability KW - Slow-transit constipation KW - Oxide synthase gene KW - Term follow-up KW - Nitric-oxide KW - In-vivo KW - Enteric nervous system KW - Enteric neuropathies KW - Stem cells KW - Cell replacement therapy KW - Hirschsprung disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187415 VL - 417 IS - 2 ER - TY - JOUR A1 - Ullmann, Andrew J. A1 - Schmidt-Hieber, Martin A1 - Bertz, Hartmut A1 - Heinz, Werner J. A1 - Kiehl, Michael A1 - Krüger, William A1 - Mousset, Sabine A1 - Neuburger, Stefan A1 - Neumann, Silke A1 - Penack, Olaf A1 - Silling, Gerda A1 - Vehreschild, Jörg Janne A1 - Einsele, Hermann A1 - Maschmeyer, Georg T1 - Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016 JF - Annals of Hematology N2 - Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria. KW - Bone-marrow-transplantation KW - Pneumocystis-carinii-pneumonia KW - Influenzae type B KW - Respiratory syncytial virus KW - Infections KW - invasive fungal infections KW - Varicella-Zoster-Virus KW - Hepatitis B virus KW - Herpes simplex virus KW - Human immunodefiency virus KW - Low-dose acyclovir KW - Viral KW - Fungal KW - Bacteria Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187587 VL - 95 IS - 9 ER - TY - JOUR A1 - Walz, Nora A1 - Mühlberger, Andreas A1 - Pauli, Paul T1 - A human open field test reveals thigmotaxis related to agoraphobic fear JF - Biological Psychiatry N2 - BACKGROUND: Thigmotaxis refers to a specific behavior of animals (i.e., to stay close to walls when exploring an open space). Such behavior can be assessed with the open field test (OFT), which is a well-established indicator of animal fear. The detection of similar open field behavior in humans may verify the translational validity of this paradigm. Enhanced thigmotaxis related to anxiety may suggest the relevance of such behavior for anxiety disorders, especially agoraphobia. METHODS: A global positioning system was used to analyze the behavior of 16 patients with agoraphobia and 18 healthy individuals with a risk for agoraphobia (i.e., high anxiety sensitivity) during a human OFT and compare it with appropriate control groups (n = 16 and n = 19). We also tracked 17 patients with agoraphobia and 17 control participants during a city walk that involved walking through an open market square. RESULTS: Our human OFT triggered thigmotaxis in participants; patients with agoraphobia and participants with high anxiety sensitivity exhibited enhanced thigmotaxis. This behavior was evident in increased movement lengths along the wall of the natural open field and fewer entries into the center of the field despite normal movement speed and length. Furthermore, participants avoided passing through the market square during the city walk, indicating again that thigmotaxis is related to agoraphobia. CONCLUSIONS: This study is the first to our knowledge to verify the translational validity of the OFT and to reveal that thigmotaxis, an evolutionarily adaptive behavior shown by most species, is related to agoraphobia, a pathologic fear of open spaces, and anxiety sensitivity, a risk factor for agoraphobia. KW - Agoraphobia KW - Animal models KW - Anxiety sensitivity KW - Avoidance behavior KW - Openfield test KW - Thigmotaxis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187607 VL - 80 IS - 5 ER - TY - JOUR A1 - Müller, Daniel A1 - Schmitz, Patrick W. T1 - Transaction costs and the property rights approach to the theory of the firm JF - European Economic Review N2 - The standard property rights approach is focused on ex ante investment incentives, while there are no transaction costs that might restrain ex post negotiations. We explore the implications of such transaction costs. Prominent conclusions of the property rights theory may be overturned: A party may have stronger investment incentives when a non investing party is the owner, and joint ownership can be the uniquely optimal ownership structure. Intuitively, an ownership structure that is unattractive in the standard model may now be desirable, because it implies large gains from trade, such that the parties are more inclined to incur the transaction costs. KW - Incomplete contracts KW - Property rights approach KW - Vertical integration KW - Joint ownership KW - Transaction costs Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188042 VL - 87 ER - TY - JOUR A1 - Roesch, J. A1 - Panje, C. A1 - Sterzing, F. A1 - Mantel, F. A1 - Nestle, U. A1 - Andratschke, N. A1 - Guckenberger, M. T1 - SBRT for centrally localized NSCLC - What is too central? JF - Radiation Oncology N2 - Purpose Current guidelines recommend stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) in medically inoperable patients. There are excellent outcome and toxicity data for SBRT of peripheral lung tumors. However, the discussion on SBRT for centrally located tumors is controversial. This study evaluated current clinical practice regarding SBRT of centrally located lung tumors, to identify common fractionation schedules and commonly accepted contraindications for SBRT. Methods A questionnaire consisting of two parts was introduced at the annual meeting of the DEGRO working group on stereotactic radiotherapy, representing centers in Germany and Switzerland. The first part of the questionnaire covered general information about the centers, whereas the second part specifically addressed SBRT of centrally located lung tumors, using case examples of nine primary NSCLC patients. Reconstructions of a contrast enhanced CT, as well as PET-Imaging for each case were demonstrated to the participants. Results Twenty-six centers participated in the meeting. The majority was academic (73%), participated in interdisciplinary thoracic oncology tumorboards (88%) and offered SBRT for lung tumors (96%). Two centers questioned the indication of SBRT for central lung tumors because of lack of evidence. The majority of centers had experience in SBRT for central lung tumors (88%) and half of the centers reported more than ten cases treated during a median period of five years. Most fractionation schedules used PTV encompassing doses of 48–60 Gy in eight fractions with maximum doses of 125–150%. A clear indication for SBRT treatment was seen by more than 85% of centers in three of the nine patients in whom tumors were small and not closer than 2 cm to the main bronchus. Prior pneumonectomy or immediate adjacency to hilar/mediastinal structures were not considered as contraindications for SBRT. In cases where the tumor exceeded 4 cm in diameter or was located closer than 4 cm to the carina 50–80% of centers saw an indication for SBRT. One case, with a 7 cm tumor reaching to the carina would have been treated with SBRT only by one center. Conclusion Within DEGRO working group on stereotactic radiotherapy, SBRT for small (<4 cm) early stage NSCLC is a common indication, if the minimal distance to the main bronchi is at least 2 cm. The controversy on the treatment of larger and more central tumors will hopefully be solved by ongoing prospective clinical trials. KW - SBRT KW - SABR KW - NSCLC KW - central lung KW - pulmonary toxicity Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167459 VL - 11 IS - 157 ER - TY - JOUR A1 - Fitchett, David A1 - Zinman, Bernard A1 - Wanner, Christoph A1 - Lachin, John M. A1 - Hantel, Stefan A1 - Salsali, Afshin A1 - Johansen, Odd Erik A1 - Woerle, Hans J. A1 - Broedl, Uli C. A1 - Inzucchi, Silvio E. T1 - Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME (R) trial JF - European Heart Journal N2 - Aims We previously reported that in the EMPA-REG OUTCOME(R) trial, empagliflozin added to standard of care reduced the risk of 3-point major adverse cardiovascular events, cardiovascular and all-cause death, and hospitalization for heart failure in patients with type 2 diabetes and high cardiovascular risk. We have now further investigated heart failure outcomes in all patients and in subgroups, including patients with or without baseline heart failure. Methods and results Patients were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo. Seven thousand and twenty patients were treated; 706 (10.1%) had heart failure at baseline. Heart failure hospitalization or cardiovascular death occurred in a significantly lower percentage of patients treated with empagliflozin 265/4687 patients (5.7%)] than with placebo 198/2333 patients (8.5%)] hazard ratio, HR: 0.66 (95% confidence interval: 0.55-0.79); P < 0.001], corresponding to a number needed to treat to prevent one heart failure hospitalization or cardiovascular death of 35 over 3 years. Consistent effects of empagliflozin were observed across subgroups defined by baseline characteristics, including patients with vs. without heart failure, and across categories of medications to treat diabetes and/or heart failure. Empagliflozin improved other heart failure outcomes, including hospitalization for or death from heart failure 2.8 vs. 4.5%; HR: 0.61 (0.47-0.79); P < 0.001] and was associated with a reduction in all-cause hospitalization 36.8 vs. 39.6%; HR: 0.89 (0.82-0.96); P = 0.003]. Serious adverse events and adverse events leading to discontinuation were reported by a higher proportion of patients with vs. without heart failure at baseline in both treatment groups, but were no more common with empagliflozin than with placebo. Conclusion In patients with type 2 diabetes and high cardiovascular risk, empagliflozin reduced heart failure hospitalization and cardiovascular death, with a consistent benefit in patients with and without baseline heart failure. KW - Cotransporter 2 inhibition KW - Placebo-controlled trial KW - Blood pressure KW - Double-blind KW - Mellitus KW - Weight KW - Collaboration KW - Guidelines KW - Mortality KW - Diseases KW - Cardiovascular disease KW - Hospitalization Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188900 VL - 37 IS - 19 ER - TY - JOUR A1 - Huss, André M. A1 - Halbgebauer, Steffen A1 - Öckl, Patrick A1 - Trebst, Corinna A1 - Spreer, Annette A1 - Borisow, Nadja A1 - Harrer, Andrea A1 - Brecht, Isabel A1 - Balint, Bettina A1 - Stich, Oliver A1 - Schlegel, Sabine A1 - Retzlaff, Nele A1 - Winkelmann, Alexander A1 - Roesler, Romy A1 - Lauda, Florian A1 - Yildiz, Özlem A1 - Voß, Elke A1 - Muche, Rainer A1 - Rauer, Sebastian A1 - Bergh, Florian Then A1 - Otto, Markus A1 - Paul, Friedemann A1 - Wildemann, Brigitte A1 - Kraus, Jörg A1 - Ruprecht, Klemens A1 - Stangel, Martin A1 - Buttmann, Mathias A1 - Zettl, Uwe K. A1 - Tumani, Hayrettin T1 - Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome JF - Journal of Neurology N2 - The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 %) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 %) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 % CI 21-34) compared to 47 months in OCB-negative individuals (95 % CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 % (18/30), whereas it was only 21 % (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria. KW - multiple sklerosis KW - MRI criteria KW - conversion KW - MS KW - CSF KW - biomarker KW - OCB Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186619 VL - 263 IS - 12 ER -