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Ahmadov, Ulvi ; Picard, Daniel ; Bartl, Jasmin ; Silginer, Manuela ; Trajkovic-Arsic, Marija ; Qin, Nan ; Blümel, Lena ; Wolter, Marietta ; Lim, Jonathan K. M. ; Pauck, David ; Winkelkotte, Alina M. ; Melcher, Marlen ; Langini, Maike ; Marquardt, Viktoria ; Sander, Felix ; Stefanski, Anja ; Steltgens, Sascha ; Hassiepen, Christina ; Kaufhold, Anna ; Meyer, Frauke-Dorothee ; Seibt, Annette ; Kleinesudeik, Lara ; Hain, Anika ; Münk, Carsten ; Knobbe-Thomsen, Christiane Brigitte ; Schramm, Alexander ; Fischer, Ute ; Leprivier, Gabriel ; Stühler, Kai ; Fulda, Simone ; Siveke, Jens ; Distelmaier, Felix ; Borkhardt, Arndt ; Weller, Michael ; Roth, Patrick ; Reifenberger, Guido ; Remke, Marc
Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.
Hofbauer, Harald F. ; Gecht, Michael ; Fischer, Sabine C. ; Seybert, Anja ; Frangakis, Achilleas S. ; Stelzer, Ernst H. K. ; Covino, Roberto ; Hummer, Gerhard ; Ernst, Robert
A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important intermediate at the branch point of these pathways and is continuously monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. In this study, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for selective binding of PA over phosphatidylserine (PS). The insertion of the AH into the membrane core renders Opi1 sensitive to the lipid acyl chain composition and provides a means to adjust membrane biogenesis. By rational design of the AH, we tune the membrane-binding properties of Opi1 and control its responsiveness in vivo. Using extensive molecular dynamics simulations, we identify two PA-selective three-finger grips that tightly bind the PA phosphate headgroup while interacting less intimately with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Kleiter, Ingo ; Gahlen, Anna ; Borisow, Nadja ; Fischer, Katrin ; Wernecke, Klaus-Dieter ; Hellwig, Kerstin ; Pache, Florence ; Ruprecht, Klemens ; Havla, Joachim ; Kümpfel, Tania ; Aktas, Orhan ; Hartung, Hans-Peter ; Ringelstein, Marius ; Geis, Christian ; Kleinschnitz, Christoph ; Berthele, Achim ; Hemmer, Bernhard ; Angstwurm, Klemens ; Stellmann, Jan-Patrick ; Schuster, Simon ; Stangel, Martin ; Lauda, Florian ; Tumani, Hayrettin ; Mayer, Christoph ; Krumbholz, Markus ; Zeltner, Lena ; Ziemann, Ulf ; Linker, Ralf ; Schwab, Matthias ; Marziniak, Martin ; Then Bergh, Florian ; Hofstadt-van Oy, Ulrich ; Neuhaus, Oliver ; Zettl, Uwe K. ; Faiss, Jürgen Hartmut ; Wildemann, Brigitte ; Paul, Friedemann ; Jarius, Sven ; Trebst, Corinna
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
Hofbauer, Harald F. ; Gecht, Michael ; Fischer, Sabine C. ; Seybert, Anja ; Frangakis, Achilleas S. ; Stelzer, Ernst H. K. ; Covino, Roberto ; Hummer, Gerhard ; Ernst, Robert
A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS). The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.
The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
Wells, Carrow I. ; Al-Ali, Hassan ; Andrews, David M. ; Asquith, Christopher R. M. ; Axtman, Alison D. ; Chung, Mirra ; Đikić, Ivan ; Ebner, Daniel ; Elkins, Jonathan M. ; Ettmayer, Peter ; Fischer, Christian ; Frederiksen, Mathias ; Gray, Nathanael S. ; Hatch, Stephanie ; Knapp, Stefan ; Lee, Shudong ; Lücking, Ulrich ; Michaelides, Michael ; Mills, Caitlin E. ; Müller, Susanne ; Owen, Dafydd R. ; Picado, Alfredo ; Ramadan, Kristijan ; Saikatendu, Kumar S. ; Schröder, Martin ; Stolz, Alexandra ; Tellechea, Mariana ; Treiber, Daniel K. ; Turunen, Brandon J. ; Vilar, Santiago ; Wang, Jinhua ; Zuercher, William J. ; Willson, Timothy M. ; Drewry, David H.
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Albrecht, Jörg ; Classen, Alice ; Vollstädt, Maximilian ; Mayr, Antonia ; Mollel, Neduvoto Piniel ; Schellenberger Costa, David ; Dulle, Hamadi Iddi ; Fischer, Markus ; Hemp, Andreas ; Howell, Kim M. ; Kleyer, Michael ; Nauss, Thomas ; Peters, Marcell K. ; Tschapka, Marco ; Steffan-Dewenter, Ingolf ; Böhning-Gaese, Katrin ; Schleuning, Matthias
Species’ functional traits set the blueprint for pair-wise interactions in ecological networks. Yet, it is unknown to what extent the functional diversity of plant and animal communities controls network assembly along environmental gradients in real-world ecosystems. Here we address this question with a unique dataset of mutualistic bird–fruit, bird–flower and insect–flower interaction networks and associated functional traits of 200 plant and 282 animal species sampled along broad climate and land-use gradients on Mt. Kilimanjaro. We show that plant functional diversity is mainly limited by precipitation, while animal functional diversity is primarily limited by temperature. Furthermore, shifts in plant and animal functional diversity along the elevational gradient control the niche breadth and partitioning of the respective other trophic level. These findings reveal that climatic constraints on the functional diversity of either plants or animals determine the relative importance of bottom-up and top-down control in plant–animal interaction networks.
Mitrovski, Michael K. ; Alt, Christopher ; Antičić, Tome ; Baatar, B. ; Barna, Daniel ; Bartke, Jerzy ; Behler, Matthias ; Betev, Latchezar ; Białkowska, Helena ; Billmeier, Anja ; Blume, Christoph ; Boimska, Bożena ; Botje, Michiel ; Bracinik, Juraj ; Bramm, Roland ; Brun, René ; Bunčić, Predrag ; Cerny, Vladimír ; Christakoglou, Panagiotis ; Chvala, Ondrej ; Cramer, John G. ; Csató, Péter ; Darmenov, Nikolay ; Dimitrov, Anton ; Dinkelaker, Peter ; Eckardt, Volker ; Filip, Peter ; Fischer, Hans Gerhard ; Flierl, Dominik Bernhard ; Fodor, Zoltán ; Foka, Panagiota ; Freund, Peter ; Friese, Volker ; Gál, József ; Gaździcki, Marek ; Georgopoulos, George ; Gładysz-Dziaduś, Ewa ; Hegyi, Sándor ; Höhne, Claudia ; Kadija, Krešo ; Karev, Alexandre ; Kliemant, Michael ; Kniege, Stefan ; Kolesnikov, Vadim I. ; Kollegger, Thorsten ; Kornaś, Ewelina ; Korus, Robert ; Kowalski, Marek ; Kraus, Ingrid ; Kreps, Michal ; Leeuwen, Marco van ; Lévai, Péter ; Litov, Leandr ; Lungwitz, Benjamin ; Makariev, Martin Vasilev ; Malakhov, Aleksandr I. ; Markert, Christina ; Mateev, Matej D. ; Mayes, Bill W. ; Melkumov, Georgy L. ; Meurer, Christine ; Mischke, André ; Mitrovski, Michael Kosta ; Molnár, József ; Mrówczyński, Stanislaw ; Pálla, Gabriella ; Panagiotou, Apostolos D. ; Panayotov, Dobromir ; Perl, Katarzyna ; Petridis, Athanasios ; Pikna, Miroslav ; Pinsky, Lawrence ; Pühlhofer, Falk ; Reid, Jeffrey G. ; Renfordt, Rainer Arno Ernst ; Retyk, Waldemar ; Richard, Agnes Carol Joanna ; Roland, Christof ; Roland, Gunther ; Rybczyński, Maciej ; Rybicki, Andrzej ; Sandoval, Andres ; Sann, Hans ; Schmitz, Norbert ; Seyboth, Peter ; Siklér, Ferenc ; Sitar, Branislav ; Skrzypczak, Ewa ; Stefanek, Grzegorz ; Stock, Reinhard ; Ströbele, Herbert ; Šuša, Tatjana ; Szentpétery, Imre ; Sziklai, János ; Trainor, Thomas A. ; Varga, Dezsö ; Vassiliou, Maria ; Veres, Gábor I. ; Vesztergombi, György ; Vranić, Danilo ; Wenig, Siegfried ; Wetzler, Alexander Albert ; Włodarczyk, Zbigniew ; Yoo, In-Kwon ; Zaranek, Jacek ; Zimányi, József
A non-monotonic energy dependence of the K + / pi + ratio with a sharp maximum close to 30 A GeV is observed in central Pb+Pb collisions. Within a statistical model of the early stage, this is interpreted as a sign of the phase transition to a QGP, which causes a sharp change in the energy dependence of the strangeness to entropy ratio. This observation naturally motivates us to study the production of multistrange hyperons (Xi, Omega) as a function of the beam energy. Furthermore it was suggested that the kinematic freeze-out of Omega takes place directly at QGP hadronization. If this is indeed the case, the transverse momentum spectra of the Omega directly reflect the transverse expansion velocity of a hadronizing QGP. In this report we show preliminary NA49 results on Omega - and Omega + production in central Pb+Pb collisions at 40 and 158 A GeV and compare them to measurements of Xi - and Xi + production in central Pb+Pb collisions at 30, 40, 80 and 158 A GeV.
Schleuning, Matthias ; Farwig, Nina ; Peters, Marcell K. ; Bergsdorf, Thomas ; Bleher, Bärbel ; Brandl, Roland ; Dalitz, Helmut ; Fischer, Georg ; Freund, Wolfram M. ; Gikungu, Mary Wanjiku ; Hagen, Melanie ; Hita Garcia, Francisco ; Kagezi, Godfrey Hurbby ; Kaib, Manfred ; Kraemer, Manfred ; Lung, Tobias ; Naumann, Clas M. ; Schaab, Gertrud ; Templin, Mathias ; Uster, Dana ; Wägele, Johann Wolfgang ; Böhning-Gaese, Katrin
Forest fragmentation and selective logging are two main drivers of global environmental change and modify biodiversity and environmental conditions in many tropical forests. The consequences of these changes for the functioning of tropical forest ecosystems have rarely been explored in a comprehensive approach. In a Kenyan rainforest, we studied six animal-mediated ecosystem processes and recorded species richness and community composition of all animal taxa involved in these processes. We used linear models and a formal meta-analysis to test whether forest fragmentation and selective logging affected ecosystem processes and biodiversity and used structural equation models to disentangle direct from biodiversity-related indirect effects of human disturbance on multiple ecosystem processes. Fragmentation increased decomposition and reduced antbird predation, while selective logging consistently increased pollination, seed dispersal and army-ant raiding. Fragmentation modified species richness or community composition of five taxa, whereas selective logging did not affect any component of biodiversity. Changes in the abundance of functionally important species were related to lower predation by antbirds and higher decomposition rates in small forest fragments. The positive effects of selective logging on bee pollination, bird seed dispersal and army-ant raiding were direct, i.e. not related to changes in biodiversity, and were probably due to behavioural changes of these highly mobile animal taxa. We conclude that animal-mediated ecosystem processes respond in distinct ways to different types of human disturbance in Kakamega Forest. Our findings suggest that forest fragmentation affects ecosystem processes indirectly by changes in biodiversity, whereas selective logging influences processes directly by modifying local environmental conditions and resource distributions. The positive to neutral effects of selective logging on ecosystem processes show that the functionality of tropical forests can be maintained in moderately disturbed forest fragments. Conservation concepts for tropical forests should thus include not only remaining pristine forests but also functionally viable forest remnants.
Möhler, Markus ; Maderer, Annett ; Schimanski, Carl C. ; Kanzler, Stephan ; Denzer, Ulrike ; Kolligs, Frank Thomas ; Ebert, Matthias P. ; Distelrath, Andrea ; Geißler, Michael ; Trojan, Jörg ; Schütz, Matthias ; Berie, Lisa ; Sauvigny, Christiane ; Lammert, Frank ; Lohse, Ansgar W. ; Dollinger, Matthias ; Lindig, U. ; Duerr, E. M. ; Lubomierski, Nikolaus ; Zimmermann, S. ; Wachtlin, Daniel ; Kaiser, A.-K. ; Schadmand-Fischer, Simin ; Galle, Peter R. ; Wörns, Marcus Alexander
Background: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.
Patients and methods: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).
Results: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.
Conclusion: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.