TY - JOUR A1 - Ludwig, Nicole A1 - Werner, Tamara V. A1 - Backes, Christina A1 - Trampert, Patrick A1 - Gessler, Manfred A1 - Keller, Andreas A1 - Lenhof, Hans-Peter A1 - Graf, Norbert A1 - Meese, Eckart T1 - Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes JF - International Journal of Mokecular Sciences N2 - Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT KW - miRNA KW - Wilms tumor KW - blastemal KW - regressive Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165430 VL - 17 IS - 4 ER - TY - JOUR A1 - Schmitt, Jana A1 - Backes, Christina A1 - Nourkami-Tutdibi, Nasenien A1 - Leidinger, Petra A1 - Deutscher, Stephanie A1 - Beier, Markus A1 - Gessler, Manfred A1 - Graf, Norbert A1 - Lenhof, Hans-Peter A1 - Keller, Andreas A1 - Meese, Eckart T1 - Treatment-independent miRNA signature in blood of wilms tumor patients JF - BMC Genomics N2 - Background Blood-born miRNA signatures have recently been reported for various tumor diseases. Here, we compared the miRNA signature in Wilms tumor patients prior and after preoperative chemotherapy according to SIOP protocol 2001. Results We did not find a significant difference between miRNA signature of both groups. However both, Wilms tumor patients prior and after chemotherapy showed a miRNA signature different from healthy controls. The signature of Wilms tumor patients prior to chemotherapy showed an accuracy of 97.5% and of patients after chemotherapy an accuracy of 97.0%, each as compared to healthy controls. Conclusion Our results provide evidence for a blood-born Wilms tumor miRNA signature largely independent of four weeks preoperative chemotherapy treatment. KW - miRNA Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124034 VL - 13 IS - 379 ER - TY - JOUR A1 - Schmitt, Jana A1 - Keller, Andreas A1 - Nourkami-Tutdibi, Nasenien A1 - Heisel, Sabrina A1 - Habel, Nunja A1 - Leidinger, Petra A1 - Ludwig, Nicole A1 - Gessler, Manfred A1 - Graf, Norbert A1 - Berthold, Frank A1 - Lenhof, Hans-Peter A1 - Meese, Eckart T1 - Autoantibody Signature Differentiates Wilms Tumor Patients from Neuroblastoma Patients JF - PLoS ONE N2 - Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor. KW - Heparan-sulfate KW - N-Myc KW - Serum autoantibodies KW - Suppressors EXT1 KW - Neuro-blastoma KW - Allelic loss KW - Lung-cancer KW - Children KW - Amplification KW - Therapy Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133794 VL - 6 IS - 12 ER - TY - JOUR A1 - Keller, Andreas A1 - Leidinger, Petra A1 - Vogel, Britta A1 - Backes, Christina A1 - ElSharawy, Abdou A1 - Galata, Valentina A1 - Mueller, Sabine C. A1 - Marquart, Sabine A1 - Schrauder, Michael G. A1 - Strick, Reiner A1 - Bauer, Andrea A1 - Wischhusen, Jörg A1 - Beier, Markus A1 - Kohlhaas, Jochen A1 - Katus, Hugo A. A1 - Hoheisel, Jörg A1 - Franke, Andre A1 - Meder, Benjamin A1 - Meese, Eckart T1 - miRNAs can be generally associated with human pathologies as exemplified for miR-144* JF - BMC MEDICINE N2 - Background: miRNA profiles are promising biomarker candidates for a manifold of human pathologies, opening new avenues for diagnosis and prognosis. Beyond studies that describe miRNAs frequently as markers for specific traits, we asked whether a general pattern for miRNAs across many diseases exists. Methods: We evaluated genome-wide circulating profiles of 1,049 patients suffering from 19 different cancer and non-cancer diseases as well as unaffected controls. The results were validated on 319 individuals using qRT-PCR. Results: We discovered 34 miRNAs with strong disease association. Among those, we found substantially decreased levels of hsa-miR-144* and hsa-miR-20b with AUC of 0.751 ( 95% CI: 0.703-0.799), respectively. We also discovered a set of miRNAs, including hsa-miR-155*, as rather stable markers, offering reasonable control miRNAs for future studies. The strong downregulation of hsa-miR-144* and the less variable pattern of hsa-miR-155* has been validated in a cohort of 319 samples in three different centers. Here, breast cancer as an additional disease phenotype not included in the screening phase has been included as the 20th trait. Conclusions: Our study on 1,368 patients including 1,049 genome-wide miRNA profiles and 319 qRT-PCR validations further underscores the high potential of specific blood-borne miRNA patterns as molecular biomarkers. Importantly, we highlight 34 miRNAs that are generally dysregulated in human pathologies. Although these markers are not specific to certain diseases they may add to the diagnosis in combination with other markers, building a specific signature. Besides these dysregulated miRNAs, we propose a set of constant miRNAs that may be used as control markers. KW - peripheral blood KW - microna profiles KW - disease KW - signature KW - expression KW - miRNA KW - microarray KW - biomarker KW - bioinformatics KW - lung-cancer KW - multiple sclerosis KW - gene KW - serum Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114349 SN - 1741-7015 VL - 12 ER - TY - THES A1 - Keller, Andreas T1 - Genetic Intervention in Sensory Systems of a Fly T1 - Genetische Intervention in sensorischen Systemen einer Fliege N2 - Die vorliegende Arbeit vergleicht Transgene, die in Drosophila Neuronen exprimiert wurden, um diese abzutöten oder zu blockieren. Tetanus Neurotoxin erwies sich als sehr effizient, um chemische Synapsen zu blockieren. Synapsen, die aus einer chemischen und einer elektrischen Komponente bestehen, ließen sich dagegen mit einem ektopisch exprimierten humanen Kalium-Kanal zuverlässiger ausschalten. Es wurden drei Möglichkeiten verglichen, eine zeitliche Kontrolle über die Funktion von Neuronen zu erlangen. Keines der getesteten Systeme erwies sich als universell anwendbar, aber die durch Rekombination induzierte Tetanus Neurotoxin Expression ist ein vielversprechender Ansatz. Die aus dieser vergleichenden methodischen Studie gewonnenen Ergebnisse wurden angewendet, um die Rolle von Neuronen in sensorischen Systemen bei der Verarbeitung verschiedener sensorischer Informationen zu untersuchen. Chemische und mechanische Rezeptorneuronen konnten den olfaktorisch gesteuerten Verhaltensweisen beziehungsweise den lokomotorischen Leistungen, denen sie zu Grunde liegen, zugeordnet werden. Hauptthema der Arbeit ist die Suche nach Neuronen, die an der Bewegungsdetektion im visuellen System beteiligt sind. Dabei zeigte sich, daß weder L2 noch L4 Neuronen im ersten visuellen Neuropil essentiell für die Detektion von Bewegung sind. Vielmehr deuten die Ergebnisse darauf hin, daß die Bewegungsdetektion über das Netzwerk der amacrinen Zellen (a) erfolgt. Die für vertikale Bewegung sensitiven VS Zellen in der Lobula Platte erwiesen sich als nicht notwendig für die Verhaltensreaktionen auf vertikale Bewegungsreize. Daraus folgt auch, daß in der Strukturmutante optomotor blind das Fehlen der VS Zellen nicht ursächlich für die stark eingeschränkten Reaktionen auf vertikale Bewegung ist. Ein anderer Defekt in optomotor blind muß dafür verantwortlich sein. Die Arbeit zeigt das große Potential der beschriebenen Methoden zur Untersuchung der Informationsverarbeitung im Nervensystem von Drosophila. Einzelne Neuronengruppen konnten komplexen Verhaltensweisen zugeordnet werden und Theorien über die Informationsverarbeitung konnten in Verhaltensexperimenten mit transgenen Fliegen getestet werden. Eine weitere Verfeinerung der Methodik zur genetischen Intervention wird das Drosophila Gehirn zu einem noch besseren Modell für die Informationsverarbeitung in Nervensystemen machen. N2 - Different transgenes that can be expressed in neurons to kill or block them were compared. Tetanus neurotoxin blocked chemical synapses very efficiently. Synapses consisting of a chemical and an electrical component were blocked more reliably by expressing a human inwardly rectifying potassium channel. To gain temporal control over neuronal function, three genetic tools have been investigated. None of the systems is without drawbacks, however, the recombination induced tetanus neurotoxin expression is a promising approach. The knowledge gained from the comparative methodological study was used to investigate the role of neurons in sensory systems in processing different sensory informations. Receptor neurons sensitive for chemical or mechanical stimuli were correlated to specific olfactory behaviors or locomotor tasks. The main topic of this thesis is the much discussed question of which neurons are involved in motion processing in the visual system of flies. Neither L2 nor L4 neurons in the first visual neuropil are essential for motion-detection. The results indicate that maybe motion is detected by the network of amacrine cells (a). The vertical motion-sensitive VS cells in the lobula plate are not necessary for behavioral responses to vertical motion. This finding implies that the lack of VS cells in the structural mutant optomotor blind is not causally related to the altered responses to motion stimuli. Other abnormalities in optomotor blind are responsible for this behavioral phenotype. This work shows the potential of the described methods in studying information processing in the Drosophila brain. Groups of neurons were correlated to complex behavioral responses and theories about information processing were tested by behavioral experiments with transgenic flies. The refinement of the genetic tools to interfere with neuronal function will make the Drosophila brain an even better model to study information processing in nervous systems. KW - Taufliege KW - Bewegungssehen KW - Neurophysiologie KW - Nervengift KW - Drosophila KW - Tetanus Neurotoxin KW - Bewegungsdetektion KW - Visuelles System KW - Lamina KW - Lobula Platte KW - Drosophila KW - Tetanus Neurotoxin KW - Motion detection KW - visual system KW - lamina KW - lobula plate Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-680 ER - TY - JOUR A1 - Abu-Halima, Masood A1 - Häusler, Sebastian A1 - Backes, Christina A1 - Fehlmann, Tobias A1 - Staib, Claudia A1 - Nestel, Sigrun A1 - Nazarenko, Irina A1 - Meese, Eckart A1 - Keller, Andreas T1 - Micro-ribonucleic acids and extracellular vesicles repertoire in the spent culture media is altered in women undergoing \(In\) \(Vitro\) Fertilization JF - Scientific Reports N2 - MicroRNAs (miRNAs) are class of small RNA molecules with major impact on gene regulation. We analyzed the potential of miRNAs secreted from pre-implantation embryos into the embryonic culture media as biomarkers to predict successful pregnancy. Using microarray analysis, we profiled the miRNome of the 56 spent culture media (SCM) after embryos transfer and found a total of 621 miRNAs in the SCM. On average, we detected 163 miRNAs in SCM of samples with failed pregnancies, but only 149 SCM miRNAs of embryos leading to pregnancies. MiR-634 predicted an embryo transfer leading to a positive pregnancy with an accuracy of 71% and a sensitivity of 85%. Among the 621 miRNAs, 102 (16.4%) showed a differential expression between positive and negative outcome of pregnancy with miR-29c-3p as the most significantly differentially expressed miRNA. The number of extracellular vehicles was lower in SCM with positive outcomes (3.8 × 10\(^9\)/mL EVs), as compared to a negative outcome (7.35 × 10\(^9\)/mL EVs) possibly explaining the reduced number of miRNAs in the SCM associated with failed pregnancies. The analysis of the miRNome in the SCM of couples undergoing fertility treatment lays the ground towards development of biomarkers to predict successful pregnancy and towards understanding the role of embryonic miRNAs found in the SCM. KW - Medicine KW - miRNAs KW - Molecular biology KW - Non-coding RNAs Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173632 VL - 7 ER -