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Bründl, Johannes ; Wallinger, Sabine ; Breyer, Johannes ; Weber, Florian ; Evert, Matthias ; Georgopoulos, Nikolaos Theodoros ; Rosenhammer, Bernd ; Burger, Maximilian ; Otto, Wolfgang ; Rubenwolf, Peter
Background: To study the expression pattern, localisation and potential clinical significance of aquaporin water channels (AQP) both in prostate cancer (PC) cell lines and in benign and malignant human prostate tissue.
Methods: The AQP transcript and protein expression of HPrEC, LNCaP, DU-145 and PC3 cell lines was investigated using reverse transcriptase polymerase chain reaction (RT-PCR) and immunofluorescence (IF) microscopy labelling. Immunohistochemistry (IHC) was performed to assess AQP protein expression in surgical specimens of benign prostatic hyperplasia as well as in PC. Tissue mRNA expression of AQPs was quantified by single-step reverse transcriptase quantitative polymerase chain reaction (qPCR). Relative gene expression was determined using the 40-ΔCT method and correlated to clinicopathological parameters.
Results: Transcripts of AQP 1, 3, 4, 7, 8, 10 and 11 were expressed in all four cell lines, while AQP 9 transcripts were not detected in malignant cell lines. IF microscopy confirmed AQP 3, 4, 5, 7 and 9 protein expression. IHC revealed highly heterogeneous AQP 3 protein expression in PC specimens, with a marked decrease in expression in tumours of increasing malignancy. Loss of AQP 9 was shown in PC specimens. mRNA expression of AQP3 was found to be negatively correlated to PSA levels (ρ = − 0.354; p = 0.013), D’Amico risk stratification (ρ = − 0.336; p = 0.012), ISUP grade (ρ = − 0.321; p = 0.017) and Gleason score (ρ = − 0.342; p = 0.011).
Conclusions: This is the first study to systematically characterize human prostate cell lines, benign prostatic hyperplasia and PC in relation to all 13 members of the AQP family. Our results indicate the differential expression of several AQPs in benign and malignant prostate tissue. A significant correlation was observed between AQP 3 expression and tumour grade, with progressive loss in more malignant tumours. Taken together, AQPs may play a role in the progression of PC and AQP expression patterns may serve as a prognostic marker.
Langheinrich, Melanie ; Wirtz, Stefan ; Kneis, Barbara ; Gittler, Matthias M. ; Tyc, Olaf ; Schierwagen, Robert ; Brunner, Maximilian ; Krautz, Christian ; Weber, Georg F. ; Pilarsky, Christian ; Trebicka, Jonel ; Agaimy, Abbas ; Grützmann, Robert ; Kersting, Stephan
Postoperative complications after pancreatic surgery are still a significant problem in clinical practice. The aim of this study was to characterize and compare the microbiomes of different body compartments (bile duct, duodenal mucosa, pancreatic tumor lesion, postoperative drainage fluid, and stool samples; preoperative and postoperative) in patients undergoing pancreatic surgery for suspected pancreatic cancer, and their association with relevant clinical factors (stent placement, pancreatic fistula, and gland texture). For this, solid (duodenal mucosa, pancreatic tumor tissue, stool) and liquid (bile, drainage fluid) biopsy samples of 10 patients were analyzed using 16s rRNA gene next-generation sequencing. Our analysis revealed: (i) a distinct microbiome in the different compartments, (ii) markedly higher abundance of Enterococcus in patients undergoing preoperative stent placement in the common bile duct, (iii) significant differences in the beta diversity between patients who developed a postoperative pancreatic fistula (POPF B/C), (iv) patients with POPF B/C were more likely to have bacteria belonging to the genus Enterococcus, and (v) differences in microbiome composition with regard to the pancreatic gland texture. The structure of the microbiome is distinctive in different compartments, and can be associated with the development of a postoperative pancreatic fistula.
Buitelaar, Paul ; Eigner, Thomas ; Gulrajani, Greg ; Schutz, Alexander ; Siegel, Melanie ; Weber, Nicolas ; Cimiano, Philipp ; Ladwig, Günter ; Mantel, Matthias ; Zhu, Honggang
This demo abstract describes the SmartWeb Ontology-based Information Extraction System (SOBIE). A key feature of SOBIE is that all information is extracted and stored with respect to the SmartWeb ontology. In this way, other components of the systems, which use the same ontology, can access this information in a straightforward way. We will show how information extracted by SOBIE is visualized within its original context, thus enhancing the browsing experience of the end user.
Böhmert, Stephanie ; Kübel, Sarah ; Müller, Markus Matthias ; Weber, Christian Friedrich ; Adam, Elisabeth ; Dröse, Stefan ; Zacharowski, Kai ; Fischer, Dania
Background: Conditions during blood product storage and transportation should maintain quality. The aim of this in vitro study was to investigate the effect of interruption of agitation, temporary cooling (TC), and pneumatic tube system transportation (PTST) on the aggregation ability (AA) and mitochondrial function (MF) of platelet concentrates (PC).
Study Design and Methods: A PC was divided equally into four subunits and then allocated to four test groups. The control group (I) was stored as recommended (continuous agitation, 22 ± 2°C) for 4 days. The test groups were stored without agitation (II), stored as recommended, albeit 4°C for 60 minutes on day (d)2 (III) and PTST (IV). Aggregometry was measured using Multiplate (RocheAG; ADPtest, ASPItest, TRAPtest, COLtest) and MF using Oxygraph‐2k (Oroboros Instruments). The basal and maximum mitochondrial respiratory rate (MMRR) were determined. AA and MF were measured daily in I and II and AA in III and IV on d2 after TC/PTST. Statistical analysis was performed using tests for matched observations.
Results: Eleven PCs were used. TRAP‐6 induced AA was significantly lower in II when compared to I on d4 (P = 0.015*). In III the ASPItest was significantly lower (P = 0.032*). IV showed no significant differences. The basal and MMRR were significantly reduced over 4 days in I and II (for both rates in both groups: P = <0.0001*). No significant differences occurred on d4 (P = 0.495).
Conclusion: Our results indicate that ex vivo AA and MF of PCs are unaffected, even in no‐ideal storage and transport circumstances with respect to agitation, temperature, and force.
Altınçekiç, Nadide ; Korn, Sophie Marianne ; Qureshi, Nusrat Shahin ; Dujardin, Marie ; Ninot-Pedrosa, Martí ; Abele, Rupert ; Abi Saad, Marie Jose ; Alfano, Caterina ; Almeida, Fabio C. L. ; Alshamleh, Islam ; Amorim, Gisele Cardoso de ; Anderson, Thomas K. ; Anobom, Cristiane D. ; Anorma, Chelsea ; Bains, Jasleen Kaur ; Bax, Adriaan ; Blackledge, Martin ; Blechar, Julius ; Böckmann, Anja ; Brigandat, Louis ; Bula, Anna ; Bütikofer, Matthias ; Camacho-Zarco, Aldo R. ; Carlomagno, Teresa ; Caruso, Icaro Putinhon ; Ceylan, Betül ; Chaikuad, Apirat ; Chu, Feixia ; Cole, Laura ; Crosby, Marquise G. ; De Jesus, Vanessa ; Dhamotharan, Karthikeyan ; Felli, Isabella C. ; Ferner, Jan ; Fleischmann, Yanick ; Fogeron, Marie-Laure ; Fourkiotis, Nikolaos K. ; Fuks, Christin ; Fürtig, Boris ; Gallo, Angelo ; Gande, Santosh L. ; Gerez, Juan Atilio ; Ghosh, Dhiman ; Gomes-Neto, Francisco ; Gorbatyuk, Oksana ; Guseva, Serafima ; Hacker, Carolin ; Häfner, Sabine ; Hao, Bing ; Hargittay, Bruno ; Henzler-Wildman, Katherine ; Hoch, Jeffrey C. ; Hohmann, Katharina Felicitas ; Hutchison, Marie T. ; Jaudzems, Kristaps ; Jović, Katarina ; Kaderli, Janina ; Kalnins, Gints ; Kanepe, Iveta ; Kirchdoerfer, Robert N. ; Kirkpatrick, John ; Knapp, Stefan ; Krishnathas, Robin ; Kutz, Felicitas ; Zur Lage, Susanne ; Lambertz, Roderick ; Lang, Andras ; Laurents, Douglas ; Lecoq, Lauriane ; Linhard, Verena ; Löhr, Frank ; Malki, Anas ; Bessa, Luiza Mamigonian ; Martin, Rachel W. ; Matzel, Tobias ; Maurin, Damien ; McNutt, Seth W. ; Mebus-Antunes, Nathane Cunha ; Meier, Beat H. ; Meiser, Nathalie ; Mompeán, Miguel ; Monaca, Elisa ; Montserret, Roland ; Perez, Laura Mariño ; Moser, Celine ; Muhle-Goll, Claudia ; Neves-Martins, Thais Cristtina ; Ni, Xiamonin ; Norton-Baker, Brenna ; Pierattelli, Roberta ; Pontoriero, Letizia ; Pustovalova, Yulia ; Ohlenschläger, Oliver ; Orts, Julien ; Poian, Andrea T. da ; Pyper, Dennis Joshua ; Richter, Christian ; Riek, Roland ; Rienstra, Chad M. ; Robertson, Angus ; Pinheiro, Anderson S. ; Sabbatella, Raffaele ; Salvi, Nicola ; Saxena, Krishna ; Schulte, Linda ; Schiavina, Marco ; Schwalbe, Harald ; Silber, Mara ; Almeida, Marcius da Silva ; Sprague-Piercy, Marc A. ; Spyroulias, Georgios A. ; Sreeramulu, Sridhar ; Tants, Jan-Niklas ; Tars, Kaspars ; Torres, Felix ; Töws, Sabrina ; Trevino, Miguel A. ; Trucks, Sven ; Tsika, Aikaterini C. ; Varga, Krisztina ; Wang, Ying ; Weber, Marco E. ; Weigand, Julia E. ; Wiedemann, Christoph ; Wirmer-Bartoschek, Julia ; Wirtz Martin, Maria Alexandra ; Zehnder, Johannes ; Hengesbach, Martin ; Schlundt, Andreas
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
Wolking, Stefan ; Schulz, Herbert ; Nies, Anne T ; McCormack, Mark ; Schäffeler, Elke ; Auce, Pauls ; Avbersek, Andreja ; Becker, Felicitas ; Klein, Karl Martin ; Krenn, Martin ; Møller, Rikke S. ; Nikanorova, Marina ; Weckhuysen, Sarah ; Cavalleri, Gianpiero L. ; Delanty, Norman ; Depondt, Chantal ; Johnson, Michael R. ; Koeleman, Bobby P. C. ; Kunz, Wolfram S. ; Marson, Anthony G. ; Sander, Josemir W. ; Sills, Graeme J. ; Striano, Pasquale ; Zara, Federico J. ; Zimprich, Fritz ; Weber, Yvonne G. ; Krause, Roland ; Sisodiya, Sanjay M. ; Schwab, Matthias ; Sander, Thomas ; Lerche, Holger
Aim: Pharmacoresistance is a major burden in epilepsy treatment. We aimed to identify genetic biomarkers in response to specific antiepileptic drugs (AEDs) in genetic generalized epilepsies (GGE). Materials & methods: We conducted a genome-wide association study (GWAS) of 3.3 million autosomal SNPs in 893 European subjects with GGE – responsive or nonresponsive to lamotrigine, levetiracetam and valproic acid. Results: Our GWAS of AED response revealed suggestive evidence for association at 29 genomic loci (p <10-5) but no significant association reflecting its limited power. The suggestive associations highlight candidate genes that are implicated in epileptogenesis and neurodevelopment. Conclusion: This first GWAS of AED response in GGE provides a comprehensive reference of SNP associations for hypothesis-driven candidate gene analyses in upcoming pharmacogenetic studies.
Haenisch, Frieder ; Cooper, Jason D. ; Reif, Andreas ; Kittel-Schneider, Sarah ; Steiner, Johann ; Leweke, F. Markus ; Rothermundt, Matthias ; Beveren, Nico J. M. van ; Crespo-Facorro, Benedicto ; Niebuhr, David W. ; Cowan, David N. ; Weber, Natalya S. ; Yolken, Robert H. ; Penninx, Brenda W. J. H. ; Bahn, Sabine
Highlights
• A panel of 20 biomarkers was identified capable of differentiating BD patients from controls.
• Excellent discrimination between established BD patients and controls.
• Good to excellent discrimination between misdiagnosed BD patients and first onset MDD patients.
• Fair to good discrimination between pre-diagnostic BD patients and controls.
• Study demonstrates the potential utility of a protein biomarker panel as a diagnostic test for BD.
Abstract
Background: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD.
Methods and findings: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten-fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies.
We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC) ⩾ 0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel.
Conclusions: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD.
Gabler, Matthias ; Kramer, Jan ; Schmidt, Jurema ; Pollinger, Julius Carl ; Weber, Julia ; Kaiser, Astrid ; Löhr, Frank ; Proschak, Ewgenij ; Schubert-Zsilavecz, Manfred ; Merk, Daniel
The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
Ablikim, Medina ; Achasov, Mikhail N. ; Ahmed, Samer ; Albrecht, Malte ; Amoroso, Antonio ; An, Fenfen ; An, Qi ; Bai, Jingzhi ; Bai, Y. ; Bakina, Olga ; Baldini Ferroli, Rinaldo ; Ban, Yong ; Bennett, D.W. ; Bennett, Jake V. ; Berger, Niklaus ; Bertani, Monica ; Bettoni, Diego ; Bian, J.M. ; Bianchi, Fabrizio ; Boger, E. ; Boyko, Igor R. ; Briere, Roy A. ; Cai, H. ; Cai, Xiao ; Cakir, O. ; Calcaterra, Alessandro ; Cao, G.F. ; Çetin, Serkant Ali ; Chai, J. ; Chang, Jinfan ; Chelkov, Gueorgui A. ; Chen, G. ; Chen, Hesheng ; Chen, J.C. ; Chen, M.L. ; Chen, P.L. ; Chen, S.J. ; Chen, X.R. ; Chen, Yuanbo ; Chu, X.K. ; Cibinetto, Gianluigi ; Dai, Hongliang ; Dai, J.P. ; Dbeyssi, Alaa ; Dedovich, Dmitri V. ; Deng, Ziyan ; Denig, Achim ; Denysenko, Igor ; Destefanis, Marco Giovanni Maria ; De Mori, Francesca ; Ding, Y. ; Dong, C. ; Dong, J. ; Dong, Liaoyuan ; Dong, Mingyi ; Dou, Z.L. ; Du, Shuxian ; Duan, P.F. ; Fang, J. ; Fang, Shuangshi ; Fang, Y. ; Farinelli, Riccardo ; Fava, Luciano ; Fegan, S. ; Feldbauer, Florian ; Felici, Giulietto ; Feng, C.Q. ; Fioravanti, Elisa ; Fritsch, Miriam ; Fu, Chengdong ; Gao, Q. ; Gao, X.L. ; Gao, Y. ; Gao, Y.G. ; Gao, Z. ; Garillon, B. ; Garzia, I. ; Goetzen, Klaus ; Gong, L. ; Gong, Wenxuan ; Gradl, Wolfgang ; Greco, M. ; Gu, Minhao ; Gu, Y.T. ; Guo, Aiqiang ; Guo, R.P. ; Guo, Yuping ; Haddadi, Z. ; Han, S. ; Hao, Xiqing ; Harris, F.A. ; He, K.L. ; He, X.Q. ; Heinsius, Fritz-Herbert ; Held, T. ; Heng, Yuekun ; Holtmann, Tobias ; Hou, Zhilong ; Hu, Haiming ; Hu, T. ; Hu, Y. ; Huang, G.S. ; Huang, J.S. ; Huang, Xingtao ; Huang, X.Z. ; Huang, Z.L. ; Hussain, Tahir ; Ikegami Andersson, Walter ; Ji, Quan ; Ji, Qingping ; Ji, X.B. ; Ji, X.L. ; Jiang, Xiaoshan ; Jiang, X.Y. ; Jiao, J.B. ; Jiao, Z. ; Jin, D.P. ; Jin, Shan ; Jin, Y. ; Johansson, Tord ; Julin, A. ; Kalantar-Nayestanaki, Nasser ; Kang, Xiaolin ; Kang, X.S. ; Kavatsyuk, Myroslav O. ; Ke, Bai-Cian ; Khan, T. ; Khoukaz, Alfons ; Kiese, P. ; Kliemt, Ralf ; Koch, Leonard ; Kolcu, Onur Bugra ; Kopf, Bertram ; Kornicer, M. ; Kuemmel, M. ; Küßner, Meike ; Kuhlmann, M. ; Kupsc, Andrzej ; Kühn, Wolfgang ; Lange, Jens Sören ; Lara, M. ; Larin, Paul ; Lavezzi, Lia ; Leithoff, H. ; Leng, C. ; Li, C. ; Li, Cheng ; Li, D.M. ; Li, F. ; Li, F.Y. ; Li, G. ; Li, Haibo ; Li, H.J. ; Li, J.C. ; Li, Jin ; Li, K.J. ; Li, Kang ; Li, Ke ; Li, Lei ; Li, P.L. ; Li, P.R. ; Li, Q.Y. ; Li, Weidong ; Li, Weiguo ; Li, X.L. ; Li, X.N. ; Li, X.Q. ; Li, Z.B. ; Liang, H. ; Liang, Y.F. ; Liang, Y.T. ; Liao, G.R. ; Lin, D.X. ; Liu, B. ; Liu, B.J. ; Liu, C.X. ; Liu, D. ; Liu, F.H. ; Liu, Fang ; Liu, Feng ; Liu, H.B. ; Liu, H.M. ; Liu, Huanhuan ; Liu, Huihui ; Liu, J.B. ; Liu, J.Y. ; Liu, K. ; Liu, K.Y. ; Liu, Ke ; Liu, L.D. ; Liu, P.L. ; Liu, Q. ; Liu, S.B. ; Liu, X. ; Liu, Y.B. ; Liu, Zhen-An ; Liu, Zhiqing ; Long, Y.F. ; Lou, Xinchou ; Lu, H.J. ; Lu, Junguang ; Lu, Y. ; Lu, Yunpeng ; Luo, Chenglin ; Luo, M.X. ; Luo, X.L. ; Lyu, Xiao-Rui ; Ma, Fengcai ; Ma, H.L. ; Ma, Lianliang ; Ma, M.M. ; Ma, Qiumei ; Ma, T. ; Ma, X.N. ; Ma, Xiaoyan ; Ma, Y.M. ; Maas, Frank E. ; Maggiora, Marco ; Malik, Qadeer Afzal ; Mao, Yajun ; Mao, Zepu ; Marcello, Simonetta ; Meng, Z.X. ; Messchendorp, Johannes Gerhardus ; Mezzadri, Giulio ; Min, J. ; Min, T.J. ; Mitchell, Ryan Edward ; Mo, Xiaohu ; Mo, Y.J. ; Morales Morales, C. ; Muchnoi, Nikolai Yu. ; Muramatsu, H. ; Mustafa, A. ; Nefedov, Yury ; Nerling, Frank ; Nikolaev, Ivan Borisovich ; Ning, Z. ; Nisar, Shabana ; Niu, S.L. ; Niu, X.Y. ; Olsen, Stephen L. ; Ouyang, Qun ; Pacetti, Simone ; Pan, Y. ; Papenbrock, Michael ; Patteri, P. ; Pelizäus, Marc ; Pellegrino, Jacopo ; Peng, H.P. ; Peters, Klaus ; Pettersson, J. ; Ping, J.L. ; Ping, R.G. ; Pitka, A. ; Poling, Ronald ; Prasad, Vindhyawasini ; Qi, H.R. ; Qi, Ming ; Qian, S. ; Qiao, Congfeng ; Qin, N. ; Qin, X.S. ; Qin, Zhonghua ; Qiu, Jinfa ; Rashid, K.H. ; Redmer, Christoph Florian ; Richter, Matthias ; Ripka, M. ; Da Rocha Rolo, Manuel Dionisio ; Rong, Gang ; Rosner, Christoph ; Sarantsev, Andrei V. ; Savrié, M. ; 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Zhu, Y.S. ; Zhu, Zian ; Zhuang, J. ; Zou, B.S. ; Zou, Jiaheng
Using a data sample of e+e− collision data corresponding to an integrated luminosity of 2.93 fb−1 collected with the BESIII detector at a center-of-mass energy of s=3.773GeV, we search for the singly Cabibbo-suppressed decays D0→π0π0π0, π0π0η, π0ηη and ηηη using the double tag method. The absolute branching fractions are measured to be B(D0→π0π0π0)=(2.0±0.4±0.3)×10−4, B(D0→π0π0η)=(3.8±1.1±0.7)×10−4 and B(D0→π0ηη)=(7.3±1.6±1.5)×10−4 with the statistical significances of 4.8σ, 3.8σ and 5.5σ, respectively, where the first uncertainties are statistical and the second ones systematic. No significant signal of D0→ηηη is found, and the upper limit on its decay branching fraction is set to be B(D0→ηηη)<1.3×10−4 at the 90% confidence level.