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Sievers, Philipp ; Henneken, Sophie C. ; Blume, Christina ; Sill, Martin ; Schrimpf, Daniel ; Stichel, Damian ; Okonechnikov, Konstantin ; Reuss, David ; Benzel, Julia ; Maaß, Kendra K. ; Kool, Marcel ; Sturm, Dominik ; Zheng, Tuyu ; Ghasemi, David R. ; Kohlhof-Meinecke, Patricia ; Cruz, Ofelia ; Suñol, Mariona ; Lavarino, Cinzia ; Ruf, Viktoria ; Boldt, Henning B. ; Pagès, Mélanie ; Pouget, Celso ; Schweizer, Leonille ; Kranendonk, Mariëtte E. G. ; Akhtar, Noreen ; Bunkowski, Stephanie ; Stadelmann, Christine ; Schüller, Ulrich ; Müller, Wolf C. ; Dohmen, Hildegard ; Acker, Till ; Harter, Patrick Nikolaus ; Mawrin, Christian ; Beschorner, Rudi ; Brandner, Sebastian ; Snuderl, Matija ; Abdullaev, Zied ; Aldape, Kenneth ; Gilbert, Mark R. ; Armstrong, Terri S. ; Ellison, David W. ; Capper, David ; Ichimura, Koichi ; Reifenberger, Guido ; Grundy, Richard G. ; Jabado, Nada ; Krskova, Lenka ; Zapotocky, Michal ; Vicha, Ales ; Varlet, Pascale ; Wesseling, Pieter ; Rutkowski, Stefan ; Korshunov, Andrey ; Wick, Wolfgang ; Pfister, Stefan ; Jones, David T. W. ; Deimling, Andreas von ; Pajtler, Kristian Wilfried ; Sahm, Felix
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
Eckardt, Jan-Niklas ; Stasik, Sebastian ; Kramer, Michael ; Röllig, Christoph ; Krämer, Alwin ; Scholl, Sebastian ; Hochhaus, Andreas ; Crysandt, Martina ; Brümmendorf, Tim Henrik ; Naumann, Ralph ; Steffen, Björn ; Kunzmann, Volker ; Einsele, Hermann ; Schaich, Markus ; Burchert, Andreas ; Neubauer, Andreas ; Schäfer-Eckart, Kerstin ; Schliemann, Christoph ; Krause, Stefan W. ; Herbst, Regina ; Hänel, Mathias ; Frickhofen, Norbert ; Noppeney, Richard ; Kaiser, Ulrich ; Baldus, Claudia ; Kaufmann, Martin ; Rácil, Zdenek ; Platzbecker, Uwe ; Berdel, Wolfgang E. ; Mayer, Jiří ; Serve, Hubert ; Müller-Tidow, Carsten ; Ehninger, Gerhard ; Stölzel, Friedrich ; Kroschinsky, Frank ; Schetelig, Johannes ; Bornhäuser, Martin ; Thiede, Christian ; Middeke, Jan Moritz
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Bock, Jens-Oliver ; Luppa, Melanie ; Brettschneider, Christian ; Riedel-Heller, Steffi Gerlinde ; Bickel, Horst ; Fuchs, Angela ; Gensichen, Jochen ; Maier, Wolfgang ; Mergenthal, Karola ; Schäfer, Ingmar ; Schön, Gerhard ; Weyerer, Siegfried ; Wiese, Birgitt ; Bussche, Hendrik van den ; Scherer, Martin ; König, Hans-Helmut
Objective: The objective of this study was to describe and analyze the effects of depression on health care utilization and costs in a sample of multimorbid elderly patients.
Method: This cross-sectional analysis used data of a prospective cohort study, consisting of 1,050 randomly selected multimorbid primary care patients aged 65 to 85 years. Depression was defined as a score of six points or more on the Geriatric Depression Scale (GDS-15). Subjects passed a geriatric assessment, including a questionnaire for health care utilization. The impact of depression on health care costs was analyzed using multiple linear regression models. A societal perspective was adopted.
Results: Prevalence of depression was 10.7%. Mean total costs per six-month period were €8,144 (95% CI: €6,199-€10,090) in patients with depression as compared to €3,137 (95% CI: €2,735-€3,538; p<0.001) in patients without depression. The positive association between depression and total costs persisted after controlling for socio-economic variables, functional status and level of multimorbidity. In particular, multiple regression analyses showed a significant positive association between depression and pharmaceutical costs.
Conclusion: Among multimorbid elderly patients, depression was associated with significantly higher health care utilization and costs. The effect of depression on costs was even greater than reported by previous studies conducted in less morbid patients.
Kanz, Birgit ; Brackel, Wolfgang von ; Cezanne, Rainer ; Eichler, Marion ; Hohmann, Marie-Luise ; Teuber, Dietmar ; Printzen, Christian
Die Flechte Cladonia stygia (Fr.) Ruoss wurde anlässlich einer Bestandsaufnahme der Rentierflechten 2009 erstmals aus Hessen gemeldet. Da die Unterscheidung von der ähnlichen C. rangiferina (L.) F. H. Wigg. anhand morphologischer Merkmale oft unsicher ist, wurden molekulargenetische Daten zur Identifizierung der hessischen Belege der Art herangezogen. Phylogenetische Stammbäume auf der Grundlage von sechs mitochondrialen und nuklearen Genloci untermauern die Abgrenzung beider Arten. Nur zwei von sieben gemeldeten hessischen Vorkommen gehören nach diesen Ergebnissen zu C. stygia, die übrigen zu C. rangiferina. Eine gezielte Suche nach C. stygia und eine durch molekulargenetische Daten untermauerte Bestimmung der Belege erscheint notwendig, um den Status der Art in Hessen zuverlässig beurteilen zu können.
Barucca, Gianni ; Davì, F. ; Lancioni, G. ; Mengucci, P. ; Montalto, L. ; Natali, P. P. ; Paone, N. ; Rinaldi, D. ; Scalise, L. ; Erni, W. ; Krusche, B. ; Steinacher, M. ; Walford, N. ; Cao, N. ; Liu, Z. ; Liu, C. ; Liu, B. ; Shen, X. ; Sun, S. ; Tao, J. ; Xiong, X. A. ; Zhao, G. ; Zhao, J. ; Albrecht, Malte ; Alkakhi, W. ; Bökelmann, S. ; Coen, S. ; Feldbauer, Florian ; Fink, M. ; Frech, J. ; Freudenreich, V. ; Fritsch, Miriam ; Grochowski, J. ; Hagdorn, R. ; Heinsius, Fritz-Herbert ; Held, T. ; Holtmann, Tobias ; Keshk, Iman ; Koch, H. ; Kopf, Bertram ; Kuhlmann, M. ; Kümmel, M. ; Küßner, M. ; Li, J. ; Linzen, L. ; Maldaner, Stephan ; Oppotsch, J. ; Pankonin, S. ; Pelizäus, Marc ; Pflüger, S. ; Pitka, A. ; Reher, J. ; Reicherz, G. ; Schnier, Claudius ; Steinke, M. ; Triffterer, T. ; Wenzel, C. ; Wiedner, Ulrich ; Denizli, H. ; Er, N. ; Keskin, U. ; Olgun, A. T. ; Yerlikaya, S. ; Yilmaz, A. ; Beck, R. ; Hammann, C. ; Hartmann, J. ; Ketzer, Bernhard ; Müllers, J. ; Rossbach, M. ; Salisbury, B. ; Schmidt, Christian Joachim ; Thoma, U. ; Urban, M. ; Bianconi, A. ; Bragadireanu, Mario ; Pantea, D. ; Domagala, M. ; Filo, G. ; Lisowski, E. ; Lisowski, F. ; Michałek, M. ; Poznański, P. ; Płażek, J. ; Korcyl, K. ; Kozela, A. ; Lebiedowicz, P. ; Pysz, K. ; Schäfer, W. ; Szczurek, A. ; Firlej, M. ; Fiutowski, T. ; Idzik, M. ; Moron, J. ; Swientek, K. ; Terlecki, P. ; Korcyl, G. ; Lalik, R. ; Malige, A. ; Moskal, P. ; Nowakowski, K. ; Przygoda, W. ; Rathod, N. ; Rudy, Z. ; Salabura, P. ; Smyrski, J. ; Augustin, I. ; Böhm, R. ; Lehmann, I. ; Schmitt, L. ; Varentsov, V. ; Al-Turany, Mohammad ; Belias, A. ; Deppe, H. ; Dzhygadlo, R. ; Flemming, H. ; Gerhardt, A. ; Götzen, Klaus ; Heinz, Andreas ; Jiang, P. ; Karabowicz, R. ; Koch, S. ; Kurilla, U. ; Lehmann, D. ; Lühning, J. ; Lynen, U. ; Orth, H. ; Peters, Klaus ; Saito, T. ; Schepers, G. ; Schmidt, C. J. ; Schwarz, C. ; Schwiening, J. ; Täschner, Alexander ; Traxler, M. ; Voss, B. ; Wieczorek, P. ; Abazov, V. ; Alexeev, G. ; Arefiev, V. A. ; Astakhov, V. ; Barabanov, M. Yu. ; Batyunya, B. V. ; Dodokhov, V. Kh. ; Efremov, A. ; Fechtchenko, A. ; Galoyan, A. ; Golovanov, G. ; Koshurnikov, E. K. ; Lobanov, Y. Yu. ; Olshevskiy, A. G. ; Piskun, A. A. ; Samartsev, A. ; Shimanski, S. ; Skachkov, N. B. ; Skachkova, A. N. ; Strokovsky, E. A. ; Tokmenin, V. ; Uzhinsky, V. ; Verkheev, A. ; Vodopianov, A. ; Zhuravlev, N. I. ; Branford, D. ; Watts, D. ; Böhm, M. ; Eyrich, W. ; Lehmann, A. ; Miehling, D. ; Pfaffinger, M. ; Quin, N. ; Robison, L. ; Seth, K. ; Xiao, T. ; Bettoni, Diego ; Ali, A. ; Hamdi, A. ; Himmelreich, Mathilde ; Krebs, M. ; Nakhoul, S. ; Nerling, Frank ; Belousov, A. ; Kisel, Ivan ; Kozlov, Grigory ; Pugach, M. ; Zyzak, Maksym ; Bianchi, Nicola ; Gianotti, Paola ; Lucherini, V. ; Bracco, G. ; Bettner, Y. ; Bodenschatz, S. ; Brinkmann, K. T. ; Brück, L. ; Diehl, S. ; Dormenev, V. ; Düren, M. ; Erlen, T. ; Föhl, K. ; Hahn, C. ; Hayrapetyan, A. ; Hofmann, J. ; Kegel, S. ; Kesselkaul, M. ; Köseoglu, I. ; Kripko, A. ; Kühn, Wolfgang ; Lange, Jens Sören ; Metag, V. ; Moritz, M. ; Nanova, M. ; Novotny, R. ; Orsich, P. ; Pereira-de-Lira, J. ; Peter, M. ; Sachs, M. ; Schmidt, M. ; Schubert, R. ; Stenzel, H. ; Straube, M. ; Strickert, M. ; Thöring, U. ; Wasem, T. ; Wohlfahrt, B. ; Zaunick, H. G. ; Tomasi-Gustafsson, E. ; Glazier, D. ; Ireland, D. ; Seitz, B. ; Deepak, P. N. ; Kulkarni, A. ; Kappert, R. ; Kavatsyuk, Myroslav O. ; Loehner, H. ; Messchendorp, Johannes Gerhardus ; Rodin, Viktor ; Schakel, P. ; Vejdani, S. ; Dutta, K. ; Kalita, K. ; Huang, G. ; Liu, D. ; Peng, H. ; Qi, H. ; Sun, Y. ; Zhou, X. ; Kunze, M. ; Azizi, K. ; Tavukoglu, Z. ; Derichs, A. ; Dosdall, R. ; Esmail, W. ; Gillitzer, A. ; Goldenbaum, F. ; Grunwald, D. ; Jokhovets, L. ; Kannika, J. ; Kulessa, P. ; Orfanitski, S. ; Pérez Andrade, G. ; Prasuhn, D. ; Prencipe, E. ; Pütz, J. ; Ritman, J. ; Rosenthal, E. ; Schadmand, S. ; Schmitz, R. ; Scholl, A. ; Sefzick, T. ; Serdyuk, V. ; Stockmanns, T. ; Veretennikov, D. ; Wintz, P. ; Wüstner, P. ; Xu, H. ; Zhou, Y. ; Cao, X. ; Hu, Q. ; Li, Z. ; Li, H. ; Liang, Y. ; Ma, X. ; Rigato, V. ; Isaksson, L. ; Achenbach, P. ; Corell, O. ; Denig, Achim ; Distler, M. ; Hoek, M. ; Lauth, W. ; Leithoff, H. H. ; Liu, Z. ; Merkel, H. ; Müller, U. ; Pochodzalla, J. ; Schlimme, S. ; Sfienti, C. ; Thiel, M. ; Zambrana, M. ; Ahmed, Samer ; Bleser, S. ; Bölting, M. ; Capozza, L. ; Dbeyssi, A. ; Ehret, A. ; Klasen, R. ; Kliemt, Ralf ; Maas, F. ; Motzko, C. ; Noll, O. ; Piñeiro, D. Rodríguez ; Schupp, F. ; Steinen, M. ; Wolff, S. ; Zimmermann, I. ; Fedorov, A. ; Kazlou, D. ; Korzhik, M. ; Missevitch, O. ; Balanutsa, P. ; Chernetsky, V. ; Demekhin, A. ; Dolgolenko, A. ; Fedorets, P. ; Gerasimov, A. ; Golubev, A. ; Goryachev, V. ; Kantsyrev, Alexey V. ; Kirin, D. Y. ; Kristi, N. ; Ladygina, E. ; Luschevskaya, E. ; Matveev, V. A. ; Panjushkin, V. ; Stavinskiy, A. V. ; Balashoff, A. ; Boukharov, A. ; Malyshev, O. ; Basant, K. N. ; Kumawat, H. ; Roy, B. ; Saxena, Alok ; Yogesh, S. ; Bonaventura, D. ; Brand, P. ; Fritzsch, C. ; Grieser, S. ; Hargens, C. ; Hergemöller, A. K. ; Hetz, B. ; Hüsken, Nils ; Kellers, J. ; Khoukaz, Alfons ; Mannweiler, C. ; Vestrick, S. ; Bumrungkoh, D. ; Herold, Christoph ; Khosonthongkee, K. ; Kobdaj, Chinorat ; Limphirat, A. ; Manasatitpong, K. ; Nasawad, T. ; Pongampai, S. ; Simantathammakul, T. ; Srisawad, P. ; Wongprachanukul, N. ; Yan, Y. ; Yu, C. ; Zhang, X. ; Zhu, W. ; Blinov, A. E. ; Kononov, S. ; Kravchenko, E. A. ; Antokhin, E. ; Barnyakov, A. Yu. ; Beloborodov, K. ; Blinov, V. E. ; Kuyanov, I. A. ; Pivovarov, S. ; Pyata, E. ; Tikhonov, Y. ; Hunter, G. ; Lattery, M. ; Pace, H. ; Boca, Gianluigi ; Duda, D. ; Finger, M. ; Finger, M. ; Kveton, A. ; Pesek, M. ; Peskova, M. ; Prochazka, I. ; Slunecka, M. ; Volf, M. ; Gallus, P. ; Jary, V. ; Korchak, O. ; Marcisovsky, M. ; Neue, G. ; Novy, J. ; Tomasek, L. ; Tomasek, M. ; Virius, M. ; Vrba, V. ; Abramov, V. ; Bukreeva, S. ; Chernichenko, S. ; Derevschikov, A. ; Ferapontov, V. ; Goncharenko, Y. ; Levin, A. ; Maslova, E. ; Melnik, Y. ; Meščanin, Aleksei P. ; Minaev, N. ; Mochalov, V. ; Moiseev, V. ; Morozov, D. ; Nogach, L. ; Poslavskiy, S. ; Ryazantsev, A. ; Ryzhikov, S. ; Semenov, P. ; Shein, I. ; Uzunian, A. ; Vasiliev, Andrey ; Yakutin, A. ; Roy, U. ; Yabsley, B. ; Belostotski, S. ; Fedotov, G. ; Gavrilov, G. ; Izotov, A. ; Manaenkov, S. ; Miklukho, O. ; Zhdanov, A. ; Atac, A. ; Bäck, T. ; Cederwall, B. ; Makonyi, K. ; Preston, M. ; Tegner, P. E. ; Wölbing, D. ; Gandhi, K. ; Rai, A. K. ; Godre, S. ; Crede, V. ; Dobbs, S. ; Eugenio, P. ; Lersch, D. ; Calvo, D. ; De Remigis, P. ; Filippi, A. ; Mazza, G. ; Rivetti, Angelo ; Wheadon, R. ; Bussa, M. P. ; Spataro, Stefano ; Iazzi, F. ; Lavagno, A. ; Martin, A. ; Akram, A. ; Calen, H. ; Ikegami Andersson, Walter ; Johansson, Tord ; Kupsc, Andrzej ; Marciniewski, P. ; Papenbrock, Michael ; Regina, J. ; Rieger, J. ; Schönning, K. ; Wolke, M. ; Pothodi Chackara, V. ; Chlopik, A. ; Kesik, G. ; Melnychuk, D. ; Tarasiuk, J. ; Wojciechowski, M. ; Wronka, S. ; Zwieglinski, B. ; Amsler, C. ; Bühler, Paul ; Marton, J. ; Nalti, W. ; Steinschaden, D. ; Widmann, Eberhard ; Zimmermann, S. ; Zmeskal, Johann
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.
Assfalg, Volker ; Selig, Katharina ; Tolksdorf, Johanna ; Meel, Marieke van ; Vries, Erwin de ; Ramsoebhag, Anne‐Marie ; Rahmel, Axel ; Renders, Lutz ; Novotny, Alexander ; Matevossian, Edouard ; Schneeberger, Stefan ; Rosenkranz, Alexander ; Berlakovich, Gabriela ; Ysebaert, Dirk ; Knops, Noël ; Kuypers, Dirk ; Weekers, Laurent ; Muehlfeld, Anja ; Rump, Lars‐Christian ; Hauser, Ingeborg A. ; Pisarski, Przemyslaw ; Weimer, Rolf ; Fornara, Paolo ; Fischer, Lutz ; Kliem, Volker ; Sester, Urban ; Stippel, Dirk ; Arns, Wolfgang ; Hau, Hans‐Michael ; Nitschke, Martin ; Hoyer, Joachim ; Thorban, Stefan ; Weinmann‐Menke, Julia ; Heller, Katharina ; Banas, Bernhard ; Schwenger, Vedat ; Nadalin, Silvio ; Lopau, Kai ; Hüser, Norbert ; Heemann, Uwe
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.
Öztürk, Fatma Cagla ; Akkuş, Baki ; Atanasov, Dinko ; Beyer, Heinrich F. ; Bosch, Fritz ; Boutin, David ; Brandau, Carsten ; Bühler, Paul ; Çakirli Mutlu, Rabia Burcu ; Chen, Ruijiu ; Chen, Weidong ; Chen, Xiangcheng ; Dillmann, Iris ; Dimopoulou, Christina ; Enders, Wolfgang ; Essel, Hans G. ; Faestermann, Thomas ; Forstner, Oliver ; Gao, Bing-Shui ; Geissel, Hans ; Gernhäuser, Roman ; Grisenti, Robert Evaristo ; Gumberidze, Alexandre ; Hagmann, Siegbert ; Heftrich, Tanja ; Heil, Michael ; Herdrich, Marc Oliver ; Hillenbrand, Pierre-Michel ; Izumikawa, Takuji ; Kienle, Paul ; Klaushofer, Christoph ; Kleffner, Carl-Michael ; Kozhuharov, Christophor ; Knöbel, Ronja ; Kovalenko, Oleksandr ; Kreim, Susanne ; Kühl, Thomas ; Lederer-Woods, Claudia ; Lestinsky, Michael ; Litvinov, Sergey A. ; Litvinov, Yuri A. ; Liu, Zhong ; Ma, Xinwen ; Maier, Ludwig W. ; Mei, Bo ; Miura, Hiroshi ; Mukha, Ivan ; Najafi, Mohammad Ali ; Nagae, Daisuke ; Nishimura, Takuro ; Nociforo, Chiara ; Nolden, Fritz ; Ohtsubo, Takashi ; Öktem, Yeşim ; Omika, Shunichiro ; Ozawa, Akira ; Petridis, Nikolaos ; Piotrowski, Jeremi ; Reifarth, René ; Roßbach, Jörg ; Sánchez Alarcón, Rodolfo Marcelo ; Sanjari, Mohammad Shahab ; Scheidenberger, Christoph ; Sidhu, Ragandeep Singh ; Simon, Haik ; Spillmann, Uwe ; Steck, Markus ; Stöhlker, Thomas ; Sun, Baohua ; Susam, Lidya Amon ; Suzaki, Fumi ; Suzuki, Takeshi ; Torilov, Sergey Yu. ; Trageser, Christian ; Trassinelli, Martino ; Trotsenko, Sergiy ; Tu, Xiaolin ; Walker, Philip M. ; Wang, M. ; Weber, Günter ; Weick, Helmut ; Winckler, Nicolas ; Winters, Danyal Ferdinant Alexander ; Woods, Philip John ; Yamaguchi, Takayuki ; Xu, X.D. ; Yan, X.L. ; Yang, Jiancheng ; Yuan, You-Jin ; Zhang, Yuhu ; Zhou, Xiaohong
An experiment addressing electron capture (EC) decay of hydrogen-like 142Pm60+ions has been conducted at the experimental storage ring (ESR) at GSI. The decay appears to be purely exponential and no modulations were observed. Decay times for about 9000 individual EC decays have been measured by applying the single-ion decay spectroscopy method. Both visually and automatically analysed data can be described by a single exponential decay with decay constants of 0.0126(7)s−1 for automatic analysis and 0.0141(7)s−1 for manual analysis. If a modulation superimposed on the exponential decay curve is assumed, the best fit gives a modulation amplitude of merely 0.019(15), which is compatible with zero and by 4.9 standard deviations smaller than in the original observation which had an amplitude of 0.23(4).
Medema, Marnix H. ; Kottmann, Renzo ; Yilmaz, Pelin ; Cummings, Matthew ; Biggins, John B. ; Kai, Blin ; de Bruijn, Irene ; Chooi, Yit Heng ; Claesen, Jan ; Coates, R. Cameron ; Cruz-Morales, Pablo ; Duddela, Srikanth ; Düsterhus, Stephanie ; Edwards, Daniel J. ; Fewer, David P. ; Garg, Neha ; Geiger, Christoph ; Gomez-Escribano, Juan Pablo ; Greule, Anja ; Hadjithomas, Michalis ; Haines, Anthony S. ; Helfrich, Eric J. N. ; Hillwig, Matthew L. ; Ishida, Keishi ; Jones, Adam C. ; Jones, Carla S. ; Jungmann, Katrin ; Kegler, Carsten ; Kim, Hyun Uk ; Kötter, Peter ; Krug, Daniel ; Masschelein, Joleen ; Melnik, Alexey V. ; Mantovan, Simone M. ; Monroe, Emily A. ; Moore, Marcus ; Moss, Nathan ; Nützmann, Hans-Wilhelm ; Pan, Guohui ; Pati, Amrita ; Petras, Daniel ; Reen, F. Jerry ; Rosconi, Federico ; Rui, Zhe ; Tian, Zhenhua ; Tobias, Nicholas J. ; Tsunematsu, Yuta ; Wiemann, Philipp ; Wyckoff, Elizabeth ; Yan, Xiaohui ; Yim, Grace ; Yu, Fengan ; Xie, Yunchang ; Aigle, Bertrand ; Apel, Alexander K. ; Balibar, Carl J. ; Balskus, Emily P. ; Barona-Gómez, Francisco ; Bechthold, Andreas ; Bode, Helge Björn ; Borriss, Rainer ; Brady, Sean F. ; Brakhage, Axel A. ; Caffrey, Patrick ; Cheng, Yi-Qiang ; Clardy, Jon ; Cox, Russell J. ; De Mot, René ; Donadio, Stefano ; Donia, Mohamed S. ; van der Donk, Wilfred A. ; Dorrestein, Pieter C. ; Doyle, Sean ; Driessen, Arnold J. M. ; Ehling-Schulz, Monika ; Entian, Karl-Dieter ; Fischbach, Michael A. ; Gerwick, Lena ; Gerwick, William H. ; Gross, Harald ; Gust, Bertolt ; Hertweck, Christian ; Höfte, Monica ; Jensen, Susan E. ; Ju, Jianhua ; Katz, Leonard ; Kaysser, Leonard ; Klassen, Jonathan L. ; Keller, Nancy P. ; Kormanec, Jan ; Kuipers, Oscar P. ; Kuzuyama, Tomohisa ; Kyrpides, Nikos C. ; Kwon, Hyung-Jin ; Lautru, Sylvie ; Lavigne, Rob ; Lee, Chia Y. ; Linquan, Bai ; Liu, Xinyu ; Liu, Wen ; Luzhetskyy, Andriy ; Mahmud, Taifo ; Mast, Yvonne ; Méndez, Carmen ; Metsä-Ketelä, Mikko ; Micklefield, Jason ; Mitchell, Douglas A. ; Moore, Bradley S. ; Moreira, Leonilde M. ; Müller, Rolf ; Neilan, Brett A. ; Nett, Markus ; Nielsen, Jens ; O’Gara, Fergal ; Oikawa, Hideaki ; Osbourn, Anne ; Osburne, Marcia S. ; Ostash, Bohdan ; Payne, Shelley M. ; Pernodet, Jean-Luc ; Petricek, Miroslav ; Piel, Jörn ; Ploux, Olivier ; Raaijmakers, Jos M. ; Salas, José A. ; Schmitt, Esther K. ; Scott, Barry ; Seipke, Ryan F. ; Shen, Ben ; Sherman, David H. ; Sivonen, Kaarina ; Smanski, Michael J. ; Sosio, Margherita ; Stegmann, Evi ; Süssmuth, Roderich D. ; Tahlan, Kapil ; Thomas, Christopher M. ; Tang, Yi ; Truman, Andrew W. ; Viaud, Muriel ; Walton, Jonathan D. ; Walsh, Christopher T. ; Weber, Tilmann ; van Wezel, Gilles P. ; Wilkinson, Barrie ; Willey, Joanne M. ; Wohlleben, Wolfgang ; Wright, Gerard D. ; Ziemert, Nadine ; Zhang, Changsheng ; Zotchev, Sergey B. ; Breitling, Rainer ; Takano, Eriko ; Glöckner, Frank Oliver
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.
Teichtmeister, Tobias A. ; Paulsen, Christian ; Ambach, Sebastian J. ; Wurst, Klaus ; Bayarjargal, Lkhamsuren ; Schnick, Wolfgang ; Huppertz, Hubert
Herein, the high-pressure/high-temperature synthesis (11 GPa, 650 °C) of Tb3B10O17(OH)5 in a modified Walker-type multianvil device is presented. The structure of this rare-earth borate was determined by single-crystal X-ray diffraction methods and was found to crystallize orthorhombically in the space group Pmn21 (no. 31) with the unit cell parameters a = 16.2527(4), b = 4.4373(1), and c = 8.8174(2) Å. The new compound was further characterized using infrared spectroscopy, energy-dispersive X-ray spectroscopy, second harmonic generation (SHG) measurements, and temperature-dependent X-ray powder diffraction. Tb3B10O17(OH)5 decomposes to β-Tb(BO2)3 at temperatures higher than 460 °C. With increasing temperatures, the formation of μ-TbBO3 was observed, which transforms to π-TbBO3 upon cooling.
Muth, Daniel Rudolf ; Priglinger, Siegfried Georg ; Shajari, Mehdi ; Kreutzer, Thomas Christian ; Mayer, Wolfgang Johann
Purpose: To describe a novel surgical technique of a combined implantation of an artificial iris and a scleral fixated intraocular lens (IOL) using flanged IOL haptics (“Yamane” technique).
Observations: The suturelessly implanted artificial iris-IOL-sandwich was stable with good functional as well as aesthetic results. However, our case showed a postoperative intraocular pressure rise.
Conclusions: The presented case demonstrates that a visual as well as cosmetical rehabilitation seems to be possible even after severe, penetrating ocular trauma with profound iris defects.
Importance: The sutureless IOL scleral fixation technique can also be used in combination with a sutureless artificial iris implantation. Further studies are needed to evaluate the long-term safety profile and rates of postoperative complications.
Hornung, Claudia ; Poehlein, Anja ; Haack, Frederike Svenja ; Schmidt, Martina ; Dierking, Katja ; Pohlen, Andrea ; Schulenburg, Hinrich ; Blokesch, Melanie ; Plener, Laure ; Jung, Kirsten ; Bonge, Andreas ; Krohn-Molt, Ines ; Utpatel, Christian ; Timmermann, Gabriele ; Spieck, Eva ; Pommerening-Röser, Andreas ; Bode, Edna ; Bode, Helge Björn ; Daniel, Rolf ; Schmeißer, Christel ; Streit, Wolfgang R.
Janthinobacteria commonly form biofilms on eukaryotic hosts and are known to synthesize antibacterial and antifungal compounds. Janthinobacterium sp. HH01 was recently isolated from an aquatic environment and its genome sequence was established. The genome consists of a single chromosome and reveals a size of 7.10 Mb, being the largest janthinobacterial genome so far known. Approximately 80% of the 5,980 coding sequences (CDSs) present in the HH01 genome could be assigned putative functions. The genome encodes a wealth of secretory functions and several large clusters for polyketide biosynthesis. HH01 also encodes a remarkable number of proteins involved in resistance to drugs or heavy metals. Interestingly, the genome of HH01 apparently lacks the N-acylhomoserine lactone (AHL)-dependent signaling system and the AI-2-dependent quorum sensing regulatory circuit. Instead it encodes a homologue of the Legionella- and Vibrio-like autoinducer (lqsA/cqsA) synthase gene which we designated jqsA. The jqsA gene is linked to a cognate sensor kinase (jqsS) which is flanked by the response regulator jqsR. Here we show that a jqsA deletion has strong impact on the violacein biosynthesis in Janthinobacterium sp. HH01 and that a jqsA deletion mutant can be functionally complemented with the V. cholerae cqsA and the L. pneumophila lqsA genes.
Ziereis, Helmut ; Hoor, Peter ; Grooß, Jens-Uwe ; Zahn, Andreas ; Stratmann, Greta Annabell ; Stock, Paul ; Lichtenstern, Michael ; Krause, Jens ; Bense, Vera ; Afchine, Armin ; Rolf, Christian ; Woiwode, Wolfgang ; Braun, Marleen ; Ungermann, Jörn ; Marsing, Andreas ; Voigt, Christiane ; Engel, Andreas ; Sinnhuber, Björn-Martin ; Oelhaf, Hermann
During winter 2015/2016, the Arctic stratosphere was characterized by extraordinarily low temperatures in connection with a very strong polar vortex and with the occurrence of extensive polar stratospheric clouds. From mid-December 2015 until mid-March 2016, the German research aircraft HALO (High Altitude and Long-Range Research Aircraft) was deployed to probe the lowermost stratosphere in the Arctic region within the POLSTRACC (Polar Stratosphere in a Changing Climate) mission. More than 20 flights have been conducted out of Kiruna, Sweden, and Oberpfaffenhofen, Germany, covering the whole winter period. Besides total reactive nitrogen (NOy), observations of nitrous oxide, nitric acid, ozone, and water were used for this study. Total reactive nitrogen and its partitioning between the gas and particle phases are key parameters for understanding processes controlling the ozone budget in the polar winter stratosphere. The vertical redistribution of total reactive nitrogen was evaluated by using tracer–tracer correlations (NOy–N2O and NOy–O3). The trace gases are well correlated as long as the NOy distribution is controlled by its gas-phase production from N2O. Deviations of the observed NOy from this correlation indicate the influence of heterogeneous processes. In early winter no such deviations have been observed. In January, however, air masses with extensive nitrification were encountered at altitudes between 12 and 15 km. The excess NOy amounted to about 6 ppb. During several flights, along with gas-phase nitrification, indications for extensive occurrence of nitric acid containing particles at flight altitude were found. These observations support the assumption of sedimentation and subsequent evaporation of nitric acid-containing particles, leading to redistribution of total reactive nitrogen at lower altitudes. Remnants of nitrified air masses have been observed until mid-March. Between the end of February and mid-March, denitrified air masses have also been observed in connection with high potential temperatures. This indicates the downward transport of air masses that have been denitrified during the earlier winter phase. Using tracer–tracer correlations, missing total reactive nitrogen was estimated to amount to 6 ppb. Further, indications of transport and mixing of these processed air masses outside the vortex have been found, contributing to the chemical budget of the winter lowermost stratosphere. Observations within POLSTRACC, at the bottom of the vortex, reflect heterogeneous processes from the overlying Arctic winter stratosphere. The comparison of the observations with CLaMS model simulations confirm and complete the picture arising from the present measurements. The simulations confirm that the ensemble of all observations is representative of the vortex-wide vertical NOy redistribution.
Das erstmals Ende 2002 im Süden Chinas aufgetretene schwere akute respiratorische Syndrom (SARS) führte bis zum August 2003 zu insgesamt über 8000 Erkrankungen und über 700 Todesfällen. Eine von der Weltgesundheitsorganisation (WHO) ins Leben gerufene Kooperation verschiedener Laboratorien weltweit ermöglichte innerhalb von nur vier Wochen die Identifizierung des kausalen Agens, eines bislang unbekannten Coronavirus (vorläufig bezeichnet als SARS-assoziiertes Coronavirus oder SARS-CoV), welches die Koch’schen Postulate erfüllt. Der Erreger lässt sich (unter Hochsicherheitsbedingungen) gut in Zellkulturen vermehren, was weitere Studien zur Stabilität sowie die Entwicklung von antiviral wirksamen Substanzen und Impfstoffen erleichtert.
Obwohl schon rasch diagnostische Labortests, insbesondere zum Nachweis der viralen Nukleinsäure und virusspezifischer Antikörper, zur Verfügung standen, basiert die Falldefinition von SARS weiterhin auf klinisch-epidemiologischen Kriterien. In Hinblick auf die Gefahr eines (saisonalen) Wiederauftretens der Infektion müssen die verfügbaren Labormethoden dringend überprüft und weiter verbessert werden.
SARS ist ein gutes Beispiel dafür, wie schnell sich eine Infektionskrankheit über den internationalen Reiseverkehr ausbreiten kann, aber auch dafür, wie wichtig in einem solchen Falle eine gut koordinierte internationale Kooperation ist; durch Einsatz neuester, aber auch bewährter konventioneller Labormethoden und ständigen Austausch aktueller (Zwischen-)Ergebnisse sowie von Patientenproben und Reagenzien führte eine bisher einmalige Zusammenarbeit schnell zu einem Durchbruch. Dies lässt auf ähnliche Fortschritte beim Kampf gegen weitere neuartige Infektionserreger hoffen.
Schaller-Paule, Martin A. ; Yalachkov, Yavor Vasilev ; Steinmetz, Helmuth ; Friedauer, Lucie ; Hattingen, Elke ; Miesbach, Wolfgang ; Weber, Frank ; Kirchmayr, Konstantin ; Schäfer, Jan Hendrik ; Förch, Christian
Background and Objectives: Proteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.
Methods: Patients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.
Results: Of 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.
Discussion: D-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.
Classification of Evidence: This study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.
Ring, Klaus ; Gerhardt, Wolfgang ; Hauf, Volker ; Schroeder-Hohenwarth, Hanns Christian ; Deusinger, Ingrid ; Riesenhuber, Heinz
Thill, Marc ; Friedrich, Michael ; Kolberg-Liedtke, Cornelia ; Albert, Ute-Susann ; Banys-Paluchowski, Maggie ; Bauerfeind, Ingo ; Blohmer, Jens-Uwe ; Budach, Wilfried ; Dall, Peter ; Fallenberg, Eva Maria ; Fasching, Peter Andreas ; Fehm, Tanja ; Gerber, Bernd ; Gluz, Oleg ; Harbeck, Nadia ; Heil, Jörg ; Huober, Jens ; Jackisch, Christian ; Kreipe, Hans-H. ; Krug, David ; Kühn, Thorsten ; Kümmel, Sherko ; Loibl, Sibylle ; Lüftner, Diana ; Lux, Michael Patrick ; Maass, Nicolai ; Mundhenke, Christoph ; Nitz, Ulrike ; Park-Simon, Tjoung-Won ; Reimer, Toralf ; Rhiem, Kerstin ; Rody, Achim ; Schmidt, Marcus ; Schneeweiss, Andreas ; Schütz, Florian ; Sinn, Peter ; Solbach, Christine ; Solomayer, Erich-Franz ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Witzel, Isabell ; Wöckel, Achim ; Müller, Volkmar ; Janni, Wolfgang ; Ditsch, Nina
Settelmeier, Stephan ; Kessler, Lukas ; Varasteh, Zohreh ; Mahabadi, Amir Abbas ; Michel, Christian Lars ; Papathanasiou, Maria ; Laschinsky, Christina ; Rischpler, Christoph ; Fendler, Wolfgang P. ; Schlosser, Thomas Wilfried ; Umutlu, Lale ; Herrmann, Ken ; Rassaf, Tienush ; Kersting, David
Happel, Christian ; Kranert, Wolfgang Tilman ; Gröner, Daniel ; Baumgarten, Justus ; Halstenberg, Jörg ; Bockisch, Benjamin ; Sabet, Amir ; Grünwald, Frank
Aim: Radioiodine therapy (RIT) may trigger the development of Graves’ ophthalmopathy (GO) or exacerbate pre-existing subclinical GO. Therefore, glucocorticoid administration is recommended for patients with pre-existing GO. Aim of this study was to analyze the influence of glucocorticoid therapy with methylprednisolone on intratherapeutic effective half-life (EHL) of radioiodine-131 in patients with Graves’ disease (GD) as recent studies showed an effect for prednisolone.
Methods: In a retrospective study, 264 patients with GD who underwent RIT without any additional antithyroid medication were evaluated. Intrathyroidal EHL was determined pre- and intratherapeutically. Patients with co-existing GO (n = 43) received methylprednisolone according to a fixed scheme starting 1 day prior to RIT, patients without GO (n = 221) did not receive any protective glucocorticoid medication. The ratios of EHL during RIT and during radioiodine uptake test (RIUT) were compared.
Results: Patients receiving methylprednisolone showed a slight decrease of the mean EHL from 5.63 d (RIUT) to 5.39 d (RIT) (p > 0.05). A comparable result was obtained in patients without glucocorticoids (5.71 d (RIUT) to 5.47 d (RIT); p > 0.05). The ratios of the EHL between RIT and RIUT failed to show a significant difference between the two groups. EHL is therefore not significantly influenced by an additional protective treatment with methylprednisolone.
Conclusions: In the present study a decreased intrathyroidal EHL under glucocorticoid medication with methylprednisolone could not be detected. Therefore, co-medication with methylprednisolone in patients with GO may be preferred to avoid an intratherapeutic decrease of EHL by accompanying protective glucocorticoides.