@article{MitchellLiWeinholdetal.2016,
  author    = {Mitchell, Jonathan S. and Li, Ni and Weinhold, Niels and F{\"o}rsti, Asta and Ali, Mina and van Duin, Mark and Thorleifsson, Gudmar and Johnson, David C. and Chen, Bowang and Halvarsson, Britt-Marie and Gudbjartsson, Daniel F. and Kuiper, Rowan and Stephens, Owen W. and Bertsch, Uta and Broderick, Peter and Campo, Chiara and Einsele, Hermann and Gregory, Walter A. and Gullberg, Urban and Henrion, Marc and Hillengass, Jens and Hoffmann, Per and Jackson, Graham H. and Johnsson, Ellinor and J{\"o}ud, Magnus and Kristinsson, Sigurdur Y. and Lenhoff, Stig and Lenive, Oleg and Mellqvist, Ulf-Henrik and Migliorini, Gabriele and Nahi, Hareth and Nelander, Sven and Nickel, Jolanta and N{\"o}then, Markus M. and Rafnar, Thorunn and Ross, Fiona M. and da Silva Filho, Miguel Inacio and Swaminathan, Bhairavi and Thomsen, Hauke and Turesson, Ingemar and Vangsted, Annette and Vogel, Ulla and Waage, Anders and Walker, Brian A. and Wihlborg, Anna-Karin and Broyl, Annemiek and Davies, Faith E. and Thorsteinsdottir, Unnur and Langer, Christian and Hansson, Markus and Kaiser, Martin and Sonneveld, Pieter and Stefansson, Kari and Morgan, Gareth J. and Goldschmidt, Hartmut and Hemminki, Kari and Nilsson, Bj{\"o}rn and Houlston, Richard S.},
  title     = {Genome-wide association study identifies multiple susceptibility loci for multiple myeloma},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  doi       = {10.1038/ncomms12050},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165983},
  pages     = {12050},
  year      = {2016},
  abstract  = {Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10-8), 6q21 (rs9372120, P=9.09 × 10-15), 7q36.1 (rs7781265, P=9.71 × 10-9), 8q24.21 (rs1948915, P=4.20 × 10-11), 9p21.3 (rs2811710, P=1.72 × 10-13), 10p12.1 (rs2790457, P=1.77 × 10-8), 16q23.1 (rs7193541, P=5.00 × 10-12) and 20q13.13 (rs6066835, P=1.36 × 10-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.},
  language  = {en}
}
@article{NovakovaSubileauToegeletal.2014,
  author    = {Novakova, Iveta and Subileau, Eva-Anne and Toegel, Stefan and Gruber, Daniela and Lachmann, Bodo and Urban, Ernst and Chesne, Christophe and Noe, Christian R. and Neuhaus, Winfried},
  title     = {Transport Rankings of Non-Steroidal Antiinflammatory Drugs across Blood-Brain Barrier In Vitro Models},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {1},
  doi       = {10.1371/journal.pone.0086806},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119992},
  pages     = {e86806},
  year      = {2014},
  abstract  = {The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB) in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line) for proper data comparison.},
  language  = {en}
}
@phdthesis{Urban2009,
  author    = {Urban, Christian},
  title     = {Design, Synthese und Untersuchung eines Membrantransporters f{\"u}r acetylierte Aminos{\"a}uren},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-38094},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2009},
  abstract  = {Im Rahmen dieser Arbeit wurde ein synthetischer Membrantransporter f{\"u}r acetylierte Aminos{\"a}urecarboxylate entworfen und hergestellt. Als Bindungsstelle f{\"u}r die Carboxylate wurde das Guanidiniocarbonylpyrrol-Motiv von Schmuck verwendet. In den Seitenarm des Pyrrols wurde ein L-Valinamid-Rest eingebracht, um die M{\"o}glichkeit zu zus{\"a}tzlichen Wasserstoffbr{\"u}ckenbindungen zu bieten und gegebenenfalls Substrat- und Enantioselektivit{\"a}t zu erreichen. Zur Herstellung der L{\"o}slichkeit in unpolaren Medien wie dem Inneren der Zellmembran musste eine lipophile Gruppe eingebracht werden. Als l{\"o}slichkeitsvermittelnder Rest wurde Tris-(Dodecyloxy)phenylmethylen ausgew{\"a}hlt, das drei lange unpolare Alkylreste tr{\"a}gt. Zusammengenommen ergab sich so ein Rezeptor f{\"u}r Oxo-Anionen und speziell f{\"u}r Aminos{\"a}urecarboxylate mit erh{\"o}hter L{\"o}slichkeit in organischen Medien. Somit war die F{\"a}higkeit zu Membrantransport gegeben. In Kraftfeldrechnungen erhielt man die vermutliche Struktur des Rezeptor-Substrat-Komplexes, der eine Kombination aus einer Salzbr{\"u}cke, Wasserstoffbr{\"u}ckenbindungen und einer Stapelwechselwirkung von Guanidinum-Kation, Benzylgruppe und ggf. aromatischem Rest des Aminos{\"a}uresubstrates aufweist. Nach erfolgreicher Synthese wurde in Extraktionsexperimenten die F{\"a}higkeit des Rezeptors erprobt, Aminos{\"a}urecarboxylate aus einer w{\"a}ssrigen in eine organische Phase aus zu {\"u}berf{\"u}hren. Man erhielt das beste Extraktionsverm{\"o}gen f{\"u}r Ac-Trp-OH, gefolgt von Ac Phe OH und Ac Tyr OH. Es wurde eine neue Formel aufgestellt, mit der aus den pKS-Werten der Substrate und den Extraktionsdaten mit und ohne Rezeptor die Bindungskonstanten der Rezeptor-Substrat-Komplexe berechnet werden konnten. Die Gr{\"o}ße der Bindungkonstanten entsprach der Reihenfolge Trp > Tyr > Phe ~ Val mit den h{\"o}chsten Bindungskonstanten f{\"u}r das Tryptophanderivat mit 1.5*10E4 1/M. Zur Best{\"a}tigung der Bindungskonstanten wurden ITC-Messungen durchgef{\"u}hrt. Es wurden Messungen des Rezeptors in Chloroform mit den tert-Butylammoniumsalzen der acetylierten Aminos{\"a}uren Phenylalanin, Tyrosin und Valin durchgef{\"u}hrt. F{\"u}r die Werte von Enthalpie und Entropie konnten bei dieser Auswertung konsistente Werte ermittelt werden. Die h{\"o}chsten Werte der Enthalpie erhielt man f{\"u}r das Tyrosinderivat mit 3.7*10E3 cal/mol, gefolgt vom Phenylalaninderivat mit 2.8*10E3 cal/mol und Valinderivat mit 1.3*10E3 cal/mol. Diese Abstufung entspricht dem Einfluss des aromatischen Restes, der durch die Stapelwechselwirkung mit dem Guanidinium-Kation die Bindungsw{\"a}rme erh{\"o}ht und durch den damit verbundenen engeren Komplex den Wert f{\"u}r die Entropie senkt. F{\"u}r die Evaluierung des Transportverm{\"o}gens wurden U-Rohr-Versuche verschiedener Art durchgef{\"u}hrt. Es wurde ein Gradient von pH 6 in der Ausgangsphase auf pH 8 in der Zielphase eingesetzt, wodurch der Rezeptor an der Grenzfl{\"a}che zur Zielphase deprotoniert wurde, was zu gerichtetetem Transport f{\"u}hrte. Es ergaben sich recht starke Unterschiede f{\"u}r die Fluxwerte der einzelnen Substraten, die der Reihenfolge Val > Phe > Ala > Trp > Tyr folgten. Dabei wurde das Valinderivat um den Faktor 17 schneller als das Tyrosinderivat bef{\"o}rdert, mit dem recht hohen Flux von 1.11*10E-6 mol/m2*s, was nahe an den h{\"o}chsten literaturbekannten Wert f{\"u}r acetylierte Aminos{\"a}uren heranreicht. Durch Verwendung gleicher Substratkonzentrationen in Start- und Zielphase konnte aktiver Transport nachgewiesen werden, d.h. Transport gegen das Konzentrationsgef{\"a}lle. Die Triebkraft des Transportes war der Gradient von pH 6 auf pH 8 zwischen Ausgangs- und Zielphase, der durch den Symport von Substrat und einem Proton ausgeglichen wurde. Bei einem kompetitiven Versuch mit einer Mischung der verschiedenen Substrate in der Ausgangsphase wurden ver{\"a}nderte Fluxwerte und Selektivit{\"a}ten festgestellt. Die neue Reihenfolge der Transportgeschwindigkeit war nun Trp > Phe > Val > Tyr > Ala, wobei die Fluxwerte fast durchgehend niedriger waren als im Einzelversuch. Die Ver{\"a}nderung der Werte erschließt sich bei Vergleich mit den thermodynamischen Daten aus den Extraktionsexperimenten. Bei direkter Konkurrenz um den Rezeptor wurden diejenigen Substrate mit den h{\"o}chsten Bindungskonstanten bevorzugt, unabh{\"a}ngig von ihrer Transportgeschwindigkeit. Die schw{\"a}cher bindenden Substrate wurden aus dem Komplex verdr{\"a}ngt und wiesen deswegen niedrigere Transportwerte auf. Der kompetitive Versuch ist somit eine st{\"a}rkere Abbildung der Bindungsst{\"a}rke und entspricht eher der Situation in einer realen Zelle.},
  subject      = {Molekulare Erkennung},
  language  = {de}
}
@article{KarastanevaLanzWaweretal.2015,
  author    = {Karastaneva, Anna and Lanz, Sofia and Wawer, Angela and Behrends, Uta and Schindler, Detlev and Dietrich, Ralf and Burdach, Stefan and Urban, Christian and Benesch, Martin and Seidel, Markus G.},
  title     = {Immune thrombocytopenia in two unrelated Fanconi anemia patients - a mere coincidence?},
  series = {Frontiers in Pediatrics},
  volume    = {3},
  journal   = {Frontiers in Pediatrics},
  number    = {50},
  doi       = {10.3389/fped.2015.00050},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149837},
  year      = {2015},
  abstract  = {Thrombocytopenia and pancytopenia, occurring in patients with Fanconi anemia (FA), are interpreted either as progression to bone marrow failure or as developing myelodysplasia. On the other hand, immune thrombocytopenia (ITP) represents an acquired and often self-limiting benign hematologic disorder, associated with peripheral, immune-mediated, platelet destruction requiring different management modalities than those used in congenital bone marrow failure syndromes, including FA. Here, we describe the clinical course of two independent FA patients with atypical - namely immune - thrombocytopenia. While in one patient belonging to complementation group FA-A, the ITP started at 17 months of age and showed a chronically persisting course with severe purpura, responding well to intravenous immunoglobulins (IVIG) and later also danazol, a synthetic androgen, the other patient (of complementation group FA-D2) had a self-limiting course that resolved after one administration of IVIG. No cytogenetic aberrations or bone marrow abnormalities other than FA-typical mild dysplasia were detected. Our data show that acute and chronic ITP may occur in FA patients and impose individual diagnostic and therapeutic challenges in this rare congenital bone marrow failure/tumor predisposition syndrome. The management and a potential context of immune pathogenesis with the underlying marrow disorder are discussed.},
  language  = {en}
}
@article{GentzschChenSpatzetal.2021,
  author    = {Gentzsch, Christian and Chen, Xinyu and Spatz, Philipp and Košak, Urban and Knez, Damijan and Nose, Naoko and Gobec, Stanislav and Higuchi, Takahiro and Decker, Michael},
  title     = {Synthesis and Initial Characterization of a Reversible, Selective \(^{18}\)F-Labeled Radiotracer for Human Butyrylcholinesterase},
  series = {Molecular Imaging and Biology},
  volume    = {23},
  journal   = {Molecular Imaging and Biology},
  number    = {4},
  issn      = {1860-2002},
  doi       = {10.1007/s11307-021-01584-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269870},
  pages     = {505-515},
  year      = {2021},
  abstract  = {Purpose A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A\(_{β}\) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. Procedures Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[\(^{18}\)F]. IC\(_{50}\) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. Results Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 \%. Identity and > 95.5 \% radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC\(_{50}\) value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K\(_{1}\) = 32.9 nM). Conclusions The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with \(^{18}\)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.},
  language  = {en}
}
@article{UrbanRemmeleDittrichetal.2020,
  author    = {Urban, Lara and Remmele, Christian W. and Dittrich, Marcus and Schwarz, Roland F. and M{\"u}ller, Tobias},
  title     = {covRNA: discovering covariate associations in large-scale gene expression data},
  series = {BMC Reserach Notes},
  volume    = {13},
  journal   = {BMC Reserach Notes},
  doi       = {10.1186/s13104-020-04946-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229258},
  year      = {2020},
  abstract  = {Objective The biological interpretation of gene expression measurements is a challenging task. While ordination methods are routinely used to identify clusters of samples or co-expressed genes, these methods do not take sample or gene annotations into account. We aim to provide a tool that allows users of all backgrounds to assess and visualize the intrinsic correlation structure of complex annotated gene expression data and discover the covariates that jointly affect expression patterns. Results The Bioconductor package covRNA provides a convenient and fast interface for testing and visualizing complex relationships between sample and gene covariates mediated by gene expression data in an entirely unsupervised setting. The relationships between sample and gene covariates are tested by statistical permutation tests and visualized by ordination. The methods are inspired by the fourthcorner and RLQ analyses used in ecological research for the analysis of species abundance data, that we modified to make them suitable for the distributional characteristics of both, RNA-Seq read counts and microarray intensities, and to provide a high-performance parallelized implementation for the analysis of large-scale gene expression data on multi-core computational systems. CovRNA provides additional modules for unsupervised gene filtering and plotting functions to ensure a smooth and coherent analysis workflow.},
  language  = {en}
}
@article{AssfalgSeligTolksdorfetal.2020,
  author    = {Assfalg, Volker and Selig, Katharina and Tolksdorf, Johanna and van Meel, Marieke and de Vries, Erwin and Ramsoebhag, Anne-Marie and Rahmel, Axel and Renders, Lutz and Novotny, Alexander and Matevossian, Edouard and Schneeberger, Stefan and Rosenkranz, Alexander R. and Berlakovich, Gabriela and Ysebaert, Dirk and Knops, No{\"e}l and Kuypers, Dirk and Weekers, Laurent and Muehlfeld, Anja and Rump, Lars-Christian and Hauser, Ingeborg and Pisarski, Przemyslaw and Weimer, Rolf and Fornara, Paolo and Fischer, Lutz and Kliem, Volker and Sester, Urban and Stippel, Dirk and Arns, Wolfgang and Hau, Hans-Michael and Nitschke, Martin and Hoyer, Joachim and Thorban, Stefan and Weinmann-Menke, Julia and Heller, Katharina and Banas, Bernhard and Schwenger, Vedat and Nadalin, Silvio and Lopau, Kai and H{\"u}ser, Norbert and Heemann, Uwe},
  title     = {Repeated kidney re-transplantation—the Eurotransplant experience: a retrospective multicenter outcome analysis},
  series = {Transplant International},
  volume    = {33},
  journal   = {Transplant International},
  number    = {6},
  doi       = {10.1111/tri.13569},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214161},
  pages     = {617 -- 631},
  year      = {2020},
  abstract  = {In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0\% vs. 84.5\%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7\%) than in 1st DDRT (7.1\%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.},
  language  = {en}
}