TY  - JOUR
A1  - Gerecke, Christian
A1  - Scholtka, Bettina
A1  - Loewenstein, Yvonne
A1  - Fait, Isabel
A1  - Gottschalk, Uwe
A1  - Rogoll, Dorothee
A1  - Melcher, Ralph
A1  - Kleuser, Burkhard
T1  - Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer
JF  - Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft
N2  - Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer.
 Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9).
 A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD).
 The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.
KW  - Epigenetic
KW  - DNA methylation
KW  - Colon cancer
KW  - Colitis
KW  - Gastrointestinal tract
KW  - Biomarker
Y1  - 2015
U6  - https://doi.org/10.1007/s00432-015-1972-8
SN  - 0171-5216
SN  - 1432-1335
VL  - 141
IS  - 12
SP  - 2097
EP  - 2107
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Schraplau, Anne
A1  - Schewe, Bettina
A1  - Neuschäfer-Rube, Frank
A1  - Ringel, Sebastian
A1  - Neuber, Corinna
A1  - Kleuser, Burkhard
A1  - Püschel, Gerhard Paul
T1  - Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital
JF  - Toxicology
N2  - Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
KW  - Endocrine disruption
KW  - Xenobesity
KW  - Aryl-hydrocarbon receptor
KW  - Cyp2b1
KW  - Thyroid hormone
KW  - UDP-glucuronosyltransferase
Y1  - 2015
U6  - https://doi.org/10.1016/j.tox.2014.12.004
SN  - 0300-483X
VL  - 328
SP  - 21
EP  - 28
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Prüfer, Nicole
A1  - Kleuser, Burkhard
A1  - van der Giet, Markus
T1  - The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality
JF  - Biological chemistry
N2  - The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL's anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL's protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL's biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function.
KW  - atherosclerosis
KW  - high-density lipoprotein (HDL)
KW  - inflammation
KW  - serum amyloid A (SAA)
KW  - sphingosine-1-phosphate (S1P)
Y1  - 2015
U6  - https://doi.org/10.1515/hsz-2014-0192
SN  - 1431-6730
SN  - 1437-4315
VL  - 396
IS  - 6-7
SP  - 573
EP  - 583
PB  - De Gruyter
CY  - Berlin
ER  - 
TY  - CHAP
A1  - Frombach, Janna
A1  - Rancan, Fiorenza
A1  - Fleige, Emanuel
A1  - Haag, Rainer
A1  - Schumacher, Frank
A1  - Kleuser, Burkhard
A1  - Yamamoto, Kenji
A1  - Rühl, Eckart
A1  - Blume-Peytavi, Ulrike
A1  - Vogt, Annika
T1  - Skin penetration and dexamethasone release from polymer nanoparticles in ex vivo human skin
T2  - The journal of investigative dermatology
Y1  - 2015
SN  - 0022-202X
SN  - 1523-1747
VL  - 135
SP  - S52
EP  - S52
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Reichel, Martin
A1  - Hoenig, Stefanie
A1  - Liebisch, Gerhard
A1  - Lüth, Anja
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Schmitz, Gerd
A1  - Kornhuber, Johannes
T1  - Alterations of plasma glycerophospholipid and sphingolipid species in male alcohol-dependent patients
JF  - Biochimica et biophysica acta : Molecular and cell biology of lipids
N2  - Background: Alcohol abuse is a major risk factor for somatic and neuropsychiatric diseases. Despite their potential clinical importance, little is known about the alterations of plasma glycerophospholipid (GPL) and sphingolipid (SPL) species associated with alcohol abuse.
 Methods: Plasma GPL and SPL species were quantified using electrospray ionization tandem mass spectrometry in samples from 23 male alcohol-dependent patients before and after detoxification, as well as from 20 healthy male controls.
 Results: A comparison of alcohol-dependent patients with controls revealed higher phosphatidylcholine (PC; P-value = 0.008) and phosphatidylinositol (PI; P-value = 0.001) concentrations in patients before detoxification, and higher PI (P-value = 0.001) and phosphatidylethanolamine (PE)-based plasmalogen (PEP; P-value = 0.003) concentrations after detoxification. Lysophosphatidylcholines (LPC) were increased by acute intoxication (P-value = 0.002). Sphingomyelin (SM) concentration increased during detoxification (P-value = 0.011). The concentration of SM 23:0 was lower in patients (P-value = 2.79 x 10(-5)), and the concentrations of ceramide Cer d18:1/16:0 and Cer d18:1/18:0 were higher in patients (P-value = 2.45 x 10(-5) and 3.73 x 10(-5)). Activity of lysosomal acid sphingomyelinase (ASM) in patients correlated positively with the concentrations of eight LPC species, while activity of secreted ASM was inversely correlated with several PE, PI and PC species, and positively correlated with the molar ratio of PC to SM (Pearson's r = 0.432; P-value = 0.039).
 Conclusion: Plasma concentrations of numerous GPL and SPL species were altered in alcohol-dependent patients. These molecules might serve as potential biomarkers to improve the diagnosis of patients and to indicate health risks associated with alcohol abuse. Our study further indicates that there are strong interactions between plasma GPL concentrations and SPL metabolism. (C) 2015 Elsevier B.V. All rights reserved.
KW  - Acid sphingomyelinase
KW  - Alcohol dependence
KW  - Anxiety
KW  - Cardiovascular
KW  - Case-control study
KW  - Ceramide
KW  - Clinical
KW  - Depression
KW  - Diagnostic
KW  - Disease
KW  - Glycerophospholipids
KW  - Lysophosphatidylcholines
KW  - Mass spectrometry
KW  - Phosphatidylcholines
KW  - Phosphatidylinositols
KW  - Plasma
KW  - Plasmalogens
KW  - Sphingolipids
KW  - Sphingomyelin
KW  - Tandem mass spectrometry
Y1  - 2015
U6  - https://doi.org/10.1016/j.bbalip.2015.08.005
SN  - 1388-1981
SN  - 0006-3002
VL  - 1851
IS  - 11
SP  - 1501
EP  - 1510
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Henry, Brian D.
A1  - Neill, Daniel R.
A1  - Becker, Katrin Anne
A1  - Gore, Suzanna
A1  - Bricio-Moreno, Laura
A1  - Ziobro, Regan
A1  - Edwards, Michael J.
A1  - Muehlemann, Kathrin
A1  - Steinmann, Joerg
A1  - Kleuser, Burkhard
A1  - Japtok, Lukasz
A1  - Luginbuehl, Miriam
A1  - Wolfmeier, Heidi
A1  - Scherag, Andre
A1  - Gulbins, Erich
A1  - Kadioglu, Aras
A1  - Draeger, Annette
A1  - Babiychuk, Eduard B.
T1  - Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice
JF  - Nature biotechnology : the science and business of biotechnology
N2  - Gram-positive bacterial pathogens that secrete cytotoxic pore-forming toxins, such as Staphylococcus aureus and Streptococcus pneumoniae, cause a substantial burden of disease. Inspired by the principles that govern natural toxin-host interactions, we have engineered artificial liposomes that are tailored to effectively compete with host cells for toxin binding. Liposome-bound toxins are unable to lyse mammalian cells in vitro. We use these artificial liposomes as decoy targets to sequester bacterial toxins that are produced during active infection in vivo. Administration of artificial liposomes within 10 h after infection rescues mice from septicemia caused by S. aureus and S. pneumoniae, whereas untreated mice die within 24-33 h. Furthermore, liposomes protect mice against invasive pneumococcal pneumonia. Composed exclusively of naturally occurring lipids, tailored liposomes are not bactericidal and could be used therapeutically either alone or in conjunction with antibiotics to combat bacterial infections and to minimize toxin-induced tissue damage that occurs during bacterial clearance.
Y1  - 2015
U6  - https://doi.org/10.1038/nbt.3037
SN  - 1087-0156
SN  - 1546-1696
VL  - 33
IS  - 1
SP  - 81
EP  - U295
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Japtok, Lukasz
A1  - Schmitz, Elisabeth I.
A1  - Fayyaz, Susann
A1  - Krämer, Stephanie
A1  - Hsu, Leigh J.
A1  - Kleuser, Burkhard
T1  - Sphingosine 1-phosphate counteracts insulin signaling in pancreatic beta-cells via the sphingosine 1-phosphate receptor subtype 2
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - Glucolipotoxic stress has been identified as a key player in the progression of pancreatic beta-cell dysfunction contributing to insulin resistance and the development of type 2 diabetes mellitus (T2D). It has been suggested that bioactive lipid intermediates, formed under lipotoxic conditions, are involved in these processes. Here, we show that sphingosine 1-phosphate (S1P) levels are not only increased in palmitate-stimulated pancreatic beta-cells but also regulate beta-cell homeostasis in a divergent manner. Although S1P possesses a prosurvival effect in beta-cells, an enhanced level of the sphingolipid antagonizes insulin-mediated cell growth and survival via the sphingosine 1-phosphate receptor subtype 2 (S1P(2)) followed by an inhibition of Akt-signaling. In an attempt to investigate the role of the S1P/S1P(2) axis in vivo, the New Zealand obese (NZO) diabetic mouse model, characterized by beta-cell loss under high-fat diet (HFD) conditions, was used. The occurrence of T2D was accompanied by an increase of plasma S1P levels. To examine whether S1P contributes to the morphologic changes of islets via S1P(2), the receptor antagonist JTE-013 was administered. Most interestingly, JTE-013 rescued beta-cell damage clearly indicating an important role of the S1P(2) in beta-cell homeostasis. Therefore, the present study provides a new therapeutic strategy to diminish beta-cell dysfunction and the development of T2D.
KW  - type 2 diabetes mellitus
KW  - sphingolipids
KW  - survival
KW  - proliferation
KW  - Akt signaling
Y1  - 2015
U6  - https://doi.org/10.1096/fj.14-263194
SN  - 0892-6638
SN  - 1530-6860
VL  - 29
IS  - 8
SP  - 3357
EP  - 3369
PB  - Federation of American Societies for Experimental Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Michels, Meta
A1  - Japtok, Lukasz
A1  - Alisjahbana, Bachti
A1  - Wisaksana, Rudi
A1  - Sumardi, Uun
A1  - Puspita, Mita
A1  - Kleuser, Burkhard
A1  - de Mast, Quirijn
A1  - van der Ven, Andre J. A. M.
T1  - Decreased plasma levels of the endothelial protective sphingosine-1-phosphate are associated with dengue-induced plasma leakage
JF  - Journal of infection
N2  - Background: A transient endothelial hyperpermeability is a hallmark of severe dengue infections. Sphingosine-1-phosphate (S1P) maintains vascular integrity and protects against plasma leakage. We related plasma S1P levels to dengue-induced plasma leakage and studied mechanisms that may underlie the decrease in S1P levels in dengue.
 Methods: We determined circulating levels of S1P in 44 Indonesian adults with acute dengue and related levels to plasma leakage, as determined by daily ultrasonography, and to levels of its chaperone apolipoprotein M, other lipoproteins and platelets.
 Results: Plasma S1P levels were decreased during dengue and patients with plasma leakage had lower median levels compared to those without (638 vs. 745 nM; p < 0.01). ApoM and other lipoprotein levels were also decreased during dengue, but did not correlate to S1P levels. Platelet counts correlated positively with S1P levels, but S1P levels were not higher in frozen-thawed platelet rich plasma, arguing against platelets as an important cellular source of S1P in dengue.
 Conclusions: Decreased plasma S1P levels during dengue are associated with plasma leakage. We speculate that decreased levels of ApoM underlies the lower S1P levels. Modulation of S1P levels and its receptors may be a novel therapeutic intervention to prevent plasma leakage in dengue. (C) 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
KW  - Sphingosine 1phosphate
KW  - Dengue
KW  - APOM protein
KW  - Human
KW  - Blood platelets
Y1  - 2015
U6  - https://doi.org/10.1016/j.jinf.2015.06.014
SN  - 0163-4453
SN  - 1532-2742
VL  - 71
IS  - 4
SP  - 480
EP  - 487
PB  - Elsevier
CY  - London
ER  - 
TY  - JOUR
A1  - Carpinteiro, Alexander
A1  - Becker, Katrin Anne
A1  - Japtok, Lukasz
A1  - Hessler, Gabriele
A1  - Keitsch, Simone
A1  - Pozgajova, Miroslava
A1  - Schmid, Kurt W.
A1  - Adams, Constantin
A1  - Müller, Stefan
A1  - Kleuser, Burkhard
A1  - Edwards, Michael J.
A1  - Grassme, Heike
A1  - Helfrich, Iris
A1  - Gulbins, Erich
T1  - Regulation of hematogenous tumor metastasis by acid sphingomyelinase
JF  - EMBO molecular medicine
N2  - Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1(-/-) mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of 51 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C-16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing 1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis.
KW  - acid sphingomyelinase
KW  - ceramide
KW  - integrins
KW  - platelets
KW  - tumor-metastasis
Y1  - 2015
SN  - 1757-4676
SN  - 1757-4684
VL  - 7
IS  - 6
SP  - 714
EP  - 734
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Chakraborty, Sudipta
A1  - Chen, Pan
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Bowman, Aaron B.
A1  - Aschner, Michael A.
T1  - Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C-elegans
JF  - Metallomics : integrated biometal science
Y1  - 2015
U6  - https://doi.org/10.1039/c5mt00052a
SN  - 1756-5901
SN  - 1756-591X
VL  - 7
IS  - 5
SP  - 847
EP  - 856
PB  - Royal Society of Chemistry
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Schumacher, Fabian
A1  - Chakraborty, Sudipta
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Schwerdtle, Tanja
A1  - Aschner, Michael A.
A1  - Bornhorst, Julia
T1  - Highly sensitive isotope-dilution liquid-chromatography-electrospray ionization-tandem-mass spectrometry approach to study the drug-mediated modulation of dopamine and serotonin levels in Caenorhabditis elegans
JF  - Talanta : the international journal of pure and applied analytical chemistry
N2  - Dopamine (DA) and serotonin (SRT) are monoamine neurotransmitters that play a key role in regulating the central and peripheral nervous system. Their impaired metabolism has been implicated in several neurological disorders, such as Parkinson's disease and depression. Consequently, it is imperative to monitor changes in levels of these low-abundant neurotransmitters and their role in mediating disease. For the first time, a rapid, specific and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DA and SRT in the nematode Caenorhabditis elegans (C. elegans). This model organism offers a unique approach for studying the effect of various drugs and environmental conditions on neurotransmitter levels, given by the conserved DA and SRT biology, including synaptic release, trafficking and formation. We introduce a novel sample preparation protocol incorporating the usage of sodium thiosulfate in perchloric acid as extraction medium that assures high recovery of the relatively unstable neurotransmitters monitored. Moreover, the use of both deuterated internal standards and the multiple reaction monitoring (MRM) technique allows for unequivocal quantification. Thereby, to the best of our knowledge, we achieve a detection sensitivity that clearly exceeds those of published DA and SRT quantification methods in various matrices. We are the first to show that exposure of C elegans to the monoamine oxidase B (MAOB) inhibitor selegiline or the catechol-O-methyltransferase (COMT) inhibitor tolcapone, in order to block DA and SRT degradation, resulted in accumulation of the respective neurotransmitter. Assessment of a behavioral output of the dopaminergic system (basal slowing response) corroborated the analytical LC-MS/MS data. Thus, utilization of the C elegans model system in conjunction with our analytical method is well-suited to investigate drug-mediated modulation of the DA and SRT system in order to identify compounds with neuroprotective or regenerative properties. (C) 2015 Elsevier B.V. All rights reserved.
KW  - Caenorhabditis elegans
KW  - Dopamine
KW  - Serotonin
KW  - Liquid chromatography-tandem mass spectrometry
KW  - Isotope-dilution analysis
Y1  - 2015
U6  - https://doi.org/10.1016/j.talanta.2015.05.057
SN  - 0039-9140
SN  - 1873-3573
VL  - 144
SP  - 71
EP  - 79
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - GEN
A1  - Chakraborty, Sudipta
A1  - Chen, Pan
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Bowman, Aaron B.
A1  - Aschner, Michael A.
T1  - Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans
N2  - Overexposure to the essential metal manganese (Mn) can result in an irreversible condition known as manganism that shares similar pathophysiology with Parkinson's disease (PD), including dopaminergic (DAergic) cell loss that leads to motor and cognitive impairments. However, the mechanisms behind this neurotoxicity and its relationship with PD remain unclear. Many genes confer risk for autosomal recessive, early-onset PD, including the parkin/PARK2 gene that encodes for the E3 ubiquitin ligase Parkin. Using Caenorhabditis elegans (C. elegans) as an invertebrate model that conserves the DAergic system, we previously reported significantly increased Mn accumulation in pdr-1/parkin mutants compared to wildtype (WT) animals. For the current study, we hypothesize that this enhanced accumulation is due to alterations in Mn transport in the pdr-1 mutants. While no change in mRNA expression of the major Mn importer proteins (smf-1-3) was found in pdr-1 mutants, significant downregulation in mRNA levels of the putative Mn exporter ferroportin (fpn-1.1) was observed. Using a strain overexpressing fpn-1.1 in worms lacking pdr-1, we show evidence for attenuation of several endpoints of Mn-induced toxicity, including survival, metal accumulation, mitochondrial copy number and DAergic integrity, compared to pdr-1 mutants alone. These changes suggest a novel role of pdr-1 in modulating Mn export through altered transporter expression, and provides further support of metal dyshomeostasis as a component of Parkinsonism pathophysiology.
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 290 
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-99508
ER  -