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2. Organ manifestations of COVID-19: what have we learned so far (not only) from autopsies?

Author

Jonigk, Danny, Werlein, Christopher, Acker, Till, Aepfelbacher, Martin, Amann, Kerstin U., Baretton, Gustavo, Barth, Peter, Bohle, Rainer M., Büttner, Andreas, Büttner, Reinhard, Dettmeyer, Reinhard, Eichhorn, Philip, Elezkurtaj, Sefer, Esposito, Irene, Evert, Katja, Evert, Matthias, Fend, Falko, Gaßler, Nikolaus, Gattenlöhner, Stefan, Glatzel, Markus, Göbel, Heike, Gradhand, Elise, Hansen, Torsten, Hartmann, Arndt, Heinemann, Axel, Heppner, Frank L., Hilsenbeck, Julia, Horst, David, Kamp, Jan C., Mall, Gita, Märkl, Bruno, Ondruschka, Benjamin, Pablik, Jessica, Pfefferle, Susanne, Quaas, Alexander, Radbruch, Helena, Röcken, Christoph, Rosenwald, Andreas, Roth, Wilfried, Rudelius, Martina, Schirmacher, Peter, Slotta-Huspenina, Julia, Smith, Kevin, Sommer, Linna, Stock, Konrad, Ströbel, Philipp, Strobl, Stephanie, Titze, Ulf, Weirich, Gregor, Weis, Joachim, Werner, Martin, Wickenhauser, Claudia, Wiech, Thorsten, Wild, Peter, Welte, Tobias, von Stillfried, Saskia, and Boor, Peter

Published
2022
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3. Oligosarcomas, IDH-mutant are distinct and aggressive

Author

Suwala, Abigail K., Felix, Marius, Friedel, Dennis, Stichel, Damian, Schrimpf, Daniel, Hinz, Felix, Hewer, Ekkehard, Schweizer, Leonille, Dohmen, Hildegard, Pohl, Ute, Staszewski, Ori, Korshunov, Andrey, Stein, Marco, Wongsurawat, Thidathip, Cheunsuacchon, Pornsuk, Sathornsumetee, Sith, Koelsche, Christian, Turner, Clinton, Le Rhun, Emilie, Mühlebner, Angelika, Schucht, Philippe, Özduman, Koray, Ono, Takahiro, Shimizu, Hiroaki, Prinz, Marco, Acker, Till, Herold-Mende, Christel, Kessler, Tobias, Wick, Wolfgang, Capper, David, Wesseling, Pieter, Sahm, Felix, von Deimling, Andreas, Hartmann, Christian, and Reuss, David E.

Published
2022
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4. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

Author

Alhalabi, Karam T., Stichel, Damian, Sievers, Philipp, Peterziel, Heike, Sommerkamp, Alexander C., Sturm, Dominik, Wittmann, Andrea, Sill, Martin, Jäger, Natalie, Beck, Pengbo, Pajtler, Kristian W., Snuderl, Matija, Jour, George, Delorenzo, Michael, Martin, Allison M., Levy, Adam, Dalvi, Nagma, Hansford, Jordan R., Gottardo, Nicholas G., Uro-Coste, Emmanuelle, Maurage, Claude-Alain, Godfraind, Catherine, Vandenbos, Fanny, Pietsch, Torsten, Kramm, Christof, Filippidou, Maria, Kattamis, Antonis, Jones, Chris, Øra, Ingrid, Mikkelsen, Torben Stamm, Zapotocky, Michal, Sumerauer, David, Scheie, David, McCabe, Martin, Wesseling, Pieter, Tops, Bastiaan B. J., Kranendonk, Mariëtte E. G., Karajannis, Matthias A., Bouvier, Nancy, Papaemmanuil, Elli, Dohmen, Hildegard, Acker, Till, von Hoff, Katja, Schmid, Simone, Miele, Evelina, Filipski, Katharina, Kitanovski, Lidija, Krskova, Lenka, Gojo, Johannes, Haberler, Christine, Alvaro, Frank, Ecker, Jonas, Selt, Florian, Milde, Till, Witt, Olaf, Oehme, Ina, Kool, Marcel, von Deimling, Andreas, Korshunov, Andrey, Pfister, Stefan M., Sahm, Felix, and Jones, David T. W.

Published
2021
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6. DistSNE: Distributed computing and online visualization of DNA methylation‐based central nervous system tumor classification.

Author

Schmid, Kai, Sehring, Jannik, Németh, Attila, Harter, Patrick N., Weber, Katharina J., Vengadeswaran, Abishaa, Storf, Holger, Seidemann, Christian, Karki, Kapil, Fischer, Patrick, Dohmen, Hildegard, Selignow, Carmen, von Deimling, Andreas, Grau, Stefan, Schröder, Uwe, Plate, Karl H., Stein, Marco, Uhl, Eberhard, Acker, Till, and Amsel, Daniel

Subjects
CENTRAL nervous system tumors, TUMOR classification, DATA visualization, DNA methylation, CENTRAL nervous system
Abstract

The current state‐of‐the‐art analysis of central nervous system (CNS) tumors through DNA methylation profiling relies on the tumor classifier developed by Capper and colleagues, which centrally harnesses DNA methylation data provided by users. Here, we present a distributed‐computing‐based approach for CNS tumor classification that achieves a comparable performance to centralized systems while safeguarding privacy. We utilize the t‐distributed neighborhood embedding (t‐SNE) model for dimensionality reduction and visualization of tumor classification results in two‐dimensional graphs in a distributed approach across multiple sites (DistSNE). DistSNE provides an intuitive web interface (https://gin-tsne.med.uni-giessen.de) for user‐friendly local data management and federated methylome‐based tumor classification calculations for multiple collaborators in a DataSHIELD environment. The freely accessible web interface supports convenient data upload, result review, and summary report generation. Importantly, increasing sample size as achieved through distributed access to additional datasets allows DistSNE to improve cluster analysis and enhance predictive power. Collectively, DistSNE enables a simple and fast classification of CNS tumors using large‐scale methylation data from distributed sources, while maintaining the privacy and allowing easy and flexible network expansion to other institutes. This approach holds great potential for advancing human brain tumor classification and fostering collaborative precision medicine in neuro‐oncology. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1

Author

Suwala, Abigail K., Stichel, Damian, Schrimpf, Daniel, Maas, Sybren L. N., Sill, Martin, Dohmen, Hildegard, Banan, Rouzbeh, Reinhardt, Annekathrin, Sievers, Philipp, Hinz, Felix, Blattner-Johnson, Mirjam, Hartmann, Christian, Schweizer, Leonille, Boldt, Henning B., Kristensen, Bjarne Winther, Schittenhelm, Jens, Wood, Matthew D., Chotard, Guillaume, Bjergvig, Rolf, Das, Anirban, Tabori, Uri, Hasselblatt, Martin, Korshunov, Andrey, Abdullaev, Zied, Quezado, Martha, Aldape, Kenneth, Harter, Patrick N., Snuderl, Matija, Hench, Jürgen, Frank, Stephan, Acker, Till, Brandner, Sebastian, Winkler, Frank, Wesseling, Pieter, Pfister, Stefan M., Reuss, David E., Wick, Wolfgang, von Deimling, Andreas, Jones, David T. W., and Sahm, Felix

Published
2021
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9. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction

Author

Tombor, Lukas S., John, David, Glaser, Simone F., Luxán, Guillermo, Forte, Elvira, Furtado, Milena, Rosenthal, Nadia, Baumgarten, Nina, Schulz, Marcel H., Wittig, Janina, Rogg, Eva-Maria, Manavski, Yosif, Fischer, Ariane, Muhly-Reinholz, Marion, Klee, Kathrin, Looso, Mario, Selignow, Carmen, Acker, Till, Bibli, Sofia-Iris, Fleming, Ingrid, Patrick, Ralph, Harvey, Richard P., Abplanalp, Wesley T., and Dimmeler, Stefanie

Published
2021
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10. Infratentorial IDH-mutant astrocytoma is a distinct subtype

Author

Banan, Rouzbeh, Stichel, Damian, Bleck, Anja, Hong, Bujung, Lehmann, Ulrich, Suwala, Abigail, Reinhardt, Annekathrin, Schrimpf, Daniel, Buslei, Rolf, Stadelmann, Christine, Ehlert, Karoline, Prinz, Marco, Acker, Till, Schittenhelm, Jens, Kaul, David, Schweizer, Leonille, Capper, David, Harter, Patrick N., Etminan, Nima, Jones, David T. W., Pfister, Stefan M., Herold-Mende, Christel, Wick, Wolfgang, Sahm, Felix, von Deimling, Andreas, Hartmann, Christian, and Reuss, David E.

Published
2020
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13. Distribution of ferritin complex in the adult brain and altered composition in neuroferritinopathy due to a novel variant in the ferritin heavy chain gene FTH1 (c.409_410del; p.H137Lfs*4).

Author

Umathum, Vincent, Weber, Axel, Amsel, Daniel, Alexopoulos, Ioannis, Becker, Christina, Roth, Angela, Günther, Andreas, Selignow, Carmen, Ritschel, Nadja, Nishimura, Anna, Schaiter, Alexander, Németh, Attila, van der Ven, Peter F. M., Acker, Till, and Schänzer, Anne

Subjects
FERRITIN, LIBRARY users, IRON, ADULTS, LIBRARY resources, RESEARCH personnel
Abstract

This article explores the distribution and composition of the ferritin complex in the adult brain and its connection to neuroferritinopathy (NF), a type of neurodegeneration with brain iron accumulation (NBIA). NF is characterized by symptoms like movement disturbances and tremors. The study identifies a novel variant in the ferritin heavy chain gene (FTH1) that is associated with NF and provides insights into the role of ferritin in both healthy and diseased brains. The authors, a diverse group of researchers, present their findings in a respectful and culturally sensitive manner, making this report a valuable resource for library patrons researching this topic. [Extracted from the article]

Published
2024
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14. Beyond ribosome biogenesis: noncoding nucleolar RNAs in physiology and tumor biology.

Author

Böğürcü-Seidel, Nuray, Ritschel, Nadja, Acker, Till, and Németh, Attila

Subjects
ORGANELLE formation, NON-coding RNA, RIBOSOMES, PHYSIOLOGY, RNA metabolism, BIOLOGY, LINCRNA, NUCLEOLUS
Abstract

The nucleolus, the largest subcompartment of the nucleus, stands out from the nucleoplasm due to its exceptionally high local RNA and low DNA concentrations. Within this central hub of nuclear RNA metabolism, ribosome biogenesis is the most prominent ribonucleoprotein (RNP) biogenesis process, critically determining the structure and function of the nucleolus. However, recent studies have shed light on other roles of the nucleolus, exploring the interplay with various noncoding RNAs that are not directly involved in ribosome synthesis. This review focuses on this intriguing topic and summarizes the techniques to study and the latest findings on nucleolar long noncoding RNAs (lncRNAs) as well as microRNAs (miRNAs) in the context of nucleolus biology beyond ribosome biogenesis. We particularly focus on the multifaceted roles of the nucleolus and noncoding RNAs in physiology and tumor biology. [ABSTRACT FROM AUTHOR]

Published
2023
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15. Leveraging Attention-Based Convolutional Neural Networks for Meningioma Classification in Computational Histopathology.

Author

Sehring, Jannik, Dohmen, Hildegard, Selignow, Carmen, Schmid, Kai, Grau, Stefan, Stein, Marco, Uhl, Eberhard, Mukhopadhyay, Anirban, Németh, Attila, Amsel, Daniel, and Acker, Till

Subjects
INDIVIDUALIZED medicine, ARTIFICIAL intelligence, CANCER, DNA methylation, MENINGIOMA, MENINGES, BENZOPYRANS, RESEARCH funding, ARTIFICIAL neural networks, DECISION making in clinical medicine, ALGORITHMS, LONGITUDINAL method
Abstract

Simple Summary: Meningioma is the most common primary intracranial tumor. DNA methylation-based subtyping, while highly useful for diagnosis and treatment planning, is costly and not widely available. Therefore, the identification of methylation classes based on histological sections would be highly beneficial as it could greatly support and accelerate diagnostic and treatment decisions. We developed and systematically evaluated an AI framework to perform the classification of the most prevalent methylation subtypes based on histological sections. The model achieved a balanced accuracy of 0.870 for benign-1 vs benign-2 and 0.749 for benign-1 vs. intermediate-A in a narrow validation set. Combined with the network's assessed focus on key tumor regions these results provide a promising proof-of-concept of such an AI-driven classification approach in precision medicine. Convolutional neural networks (CNNs) are becoming increasingly valuable tools for advanced computational histopathology, promoting precision medicine through exceptional visual decoding abilities. Meningiomas, the most prevalent primary intracranial tumors, necessitate accurate grading and classification for informed clinical decision-making. Recently, DNA methylation-based molecular classification of meningiomas has proven to be more effective in predicting tumor recurrence than traditional histopathological methods. However, DNA methylation profiling is expensive, labor-intensive, and not widely accessible. Consequently, a digital histology-based prediction of DNA methylation classes would be advantageous, complementing molecular classification. In this study, we developed and rigorously assessed an attention-based multiple-instance deep neural network for predicting meningioma methylation classes using tumor methylome data from 142 (+51) patients and corresponding hematoxylin-eosin-stained histological sections. Pairwise analysis of sample cohorts from three meningioma methylation classes demonstrated high accuracy in two combinations. The performance of our approach was validated using an independent set of 51 meningioma patient samples. Importantly, attention map visualization revealed that the algorithm primarily focuses on tumor regions deemed significant by neuropathologists, offering insights into the decision-making process of the CNN. Our findings highlight the capacity of CNNs to effectively harness phenotypic information from histological sections through computerized images for precision medicine. Notably, this study is the first demonstration of predicting clinically relevant DNA methylome information using computer vision applied to standard histopathology. The introduced AI framework holds great potential in supporting, augmenting, and expediting meningioma classification in the future. [ABSTRACT FROM AUTHOR]

Published
2023
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17. KLF4K409Q–mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

Author

von Spreckelsen, Niklas, Waldt, Natalie, Poetschke, Rebecca, Kesseler, Christoph, Dohmen, Hildegard, Jiao, Hui-Ke, Nemeth, Attila, Schob, Stefan, Scherlach, Cordula, Sandalcioglu, Ibrahim Erol, Deckert, Martina, Angenstein, Frank, Krischek, Boris, Stavrinou, Pantelis, Timmer, Marco, Remke, Marc, Kirches, Elmar, Goldbrunner, Roland, Chiocca, E. Antonio, Huettelmaier, Stefan, Acker, Till, and Mawrin, Christian

Published
2020
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18. Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities

Author

Reinhardt, Annekathrin, Stichel, Damian, Schrimpf, Daniel, Koelsche, Christian, Wefers, Annika K., Ebrahimi, Azadeh, Sievers, Philipp, Huang, Kristin, Casalini, M. Belén, Fernández-Klett, Francisco, Suwala, Abigail, Weller, Michael, Gramatzki, Dorothee, Felsberg, Joerg, Reifenberger, Guido, Becker, Albert, Hans, Volkmar H., Prinz, Marco, Staszewski, Ori, Acker, Till, Dohmen, Hildegard, Hartmann, Christian, Paulus, Werner, Heß, Katharina, Brokinkel, Benjamin, Schittenhelm, Jens, Buslei, Rolf, Deckert, Martina, Mawrin, Christian, Hewer, Ekkehard, Pohl, Ute, Jaunmuktane, Zane, Brandner, Sebastian, Unterberg, Andreas, Hänggi, Daniel, Platten, Michael, Pfister, Stefan M., Wick, Wolfgang, Herold-Mende, Christel, Korshunov, Andrey, Reuss, David E., Sahm, Felix, Jones, David T. W., Capper, David, and von Deimling, Andreas

Published
2019
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19. DNA methylation-based classification of central nervous system tumours

Author

Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hölsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jürgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brück, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hänggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mühleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Hernáiz, Kramm, Christof M., Müller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Frühwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blümcke, Ingmar, Bendszus, Martin, Debus, Jürgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schüller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, and Pfister, Stefan M.

Published
2018
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22. Intracranial hemorrhage in COVID-19 patients during extracorporeal membrane oxygenation for acute respiratory failure : a nationwide register study report

Author

von Stillfried, Saskia, Bülow, Roman David, Wienströer, Jan, Pfefferle, Susanne, Glatzel, Markus, Krasemann, Susanne, Matschke, Jakob, Jonigk, Danny, Werlein, Christopher, Schirmacher, Peter, Domke, Lisa Maria, Hartmann, Laura, Klein, Isabel Madeleine, Weis, Joachim, Schwab, Constantin, Röcken, Christoph, Friemann, Johannes, Langer, Dorothea, Roth, Wilfried, Strobl, Stephanie, Rudelius, Martina, Stock, Konrad Friedrich, Weichert, Wilko, Delbridge, Claire, Bremer, Juliane, Kasajima, Atsuko, Kuhn, Peer-Hendrik, Slotta-Huspenina, Julia, Weirich, Gregor, Barth, Peter, Wardelmann, Eva, Schnepper, Alexander, Evert, Katja, Büttner, Andreas, Manhart, Johannes, Knüchel, R., Nigbur, Stefan, Bittmann, Iris, Fend, Falko, Bösmüller, Hans, Granai, Massimo, Klingel, Karin, Warm, Verena, Steinestel, Konrad, Umathum, Vincent Gottfried, Rosenwald, Andreas, Breitbach, Anna, Kurz, Florian, Vogt, Niklas, Cacchi, Claudio, Freeborn, Benita, Wucherpfennig, Sophie, Spring, Oliver, Braun, Georg, Röhrig, Rainer, Römmele, Christoph, Märkl, Bruno, Claus, Rainer, Dhillon, Christine, Schaller, Tina, Sipos, Eva, Hirschbühl, Klaus, Wittmann, Michael, Kling, Elisabeth, Kröncke, Thomas, Meybohm, Patrick, Heppner, Frank L., Meinhardt, Jenny, Radbruch, Helena, Streit, Simon, Horst, David, Elezkurtaj, Sefer, Quaas, Alexander, Göbel, Heike, Hansen, Torsten, Titze, Ulf, Boor, Peter, Lorenzen, Johann, Reuter, Thomas, Woloszyn, Jaroslaw, Baretton, Gustavo, Hilsenbeck, Julia, Meinhardt, Matthias, Pablik, Jessica, Sommer, Linna, Holotiuk, Olaf, Meinel, Meike, DeRegCOVID Collaborators, Mahlke, Nina, Esposito, Irene, Crudele, Graziano, Seidl, Maximilian, Amann, Kerstin U., Coras, Roland, Hartmann, Arndt, Eichhorn, Philip, Haller, Florian, Lange, Fabienne, Böcker, Jana, Schmid, Kurt Werner, Ingenwerth, Marc, Rawitzer, Josefine, Theegarten, Dirk, Birngruber, Christoph G., Wild, Peter, Gradhand, Elise, Smith, Kevin, Werner, Martin, Schilling, Oliver, Schmidt, Jens, Acker, Till, Gattenlöhner, Stefan, Stadelmann, Christine, Metz, Imke, Franz, Jonas, Stork, Lidia, Thomas, Carolina, Zechel, Sabrina, Ströbel, Philipp, Wickenhauser, Claudia, Tholen, Pauline, Fathke, Christine, Harder, Anja, Ondruschka, Benjamin, Dietz, Eric, Edler, Carolin, Fitzek, Antonia, Fröb, Daniela, Heinemann, Axel, Heinrich, Fabian, Klein, Anke, Majeed, Raphael, Kniep, Inga, Lohner, Larissa, Möbius, Dustin, Püschel, Klaus, Schädler, Julia, Schröder, Ann-Sophie, Sperhake, Jan-Peter, Aepfelbacher, Martin, Fischer, Nicole, and Lütgehetmann, Marc

Subjects
ddc:610
Published
2022

24. KLF4 K409Q –mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment

Author

von Spreckelsen, Niklas, Waldt, Natalie, Poetschke, Rebecca, Kesseler, Christoph, Dohmen, Hildegard, Jiao, Hui-Ke, Nemeth, Attila, Schob, Stefan, Scherlach, Cordula, Sandalcioglu, Ibrahim Erol, Deckert, Martina, Angenstein, Frank, Krischek, Boris, Stavrinou, Pantelis, Timmer, Marco, Remke, Marc, Kirches, Elmar, Goldbrunner, Roland, Chiocca, E. Antonio, Huettelmaier, Stefan, Acker, Till, and Mawrin, Christian

Subjects
pharmacology [Protein Kinase Inhibitors], drug effects [Gene Expression Regulation, Neoplastic], analogs & derivatives [Sirolimus], genetics [Gene Expression Regulation, Neoplastic], lcsh:RC346-429, drug effects [Kruppel-Like Transcription Factors], Mice, Meningeal Neoplasms, Edema, RNA-Seq, Hypoxia, antagonists & inhibitors [Mechanistic Target of Rapamycin Complex 1], genetics [Meningeal Neoplasms], Reverse Transcriptase Polymerase Chain Reaction, genetics [Meningioma], KLF4, genetics [Tumor Hypoxia], Up-Regulation, Gene Expression Regulation, Neoplastic, K409Q, Meningioma, Signal Transduction, Kruppel-Like Transcription Factors, pharmacology [Sirolimus], Mice, Nude, Mechanistic Target of Rapamycin Complex 1, genetics [Hypoxia], Skull Base Neoplasms, Prolyl Hydroxylases, Kruppel-Like Factor 4, metabolism [Meningeal Neoplasms], Cell Line, Tumor, genetics [Hypoxia-Inducible Factor 1, alpha Subunit], otorhinolaryngologic diseases, Animals, Humans, HIF, ddc:610, neoplasms, Protein Kinase Inhibitors, lcsh:Neurology. Diseases of the nervous system, Cell Proliferation, Sirolimus, Research, metabolism [Hypoxia-Inducible Factor 1, alpha Subunit], genetics [Kruppel-Like Transcription Factors], Hypoxia-Inducible Factor 1, alpha Subunit, metabolism [Hypoxia], nervous system diseases, metabolism [Meningioma], Mutation, Tumor Hypoxia, drug effects [Hypoxia-Inducible Factor 1, alpha Subunit], Neoplasm Transplantation
Abstract

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

Published
2020

25. Biomarker selection in a federated setting with data protection constraints

Author

Zöller, Daniela, Amsel, Daniel, Lenz, Stefan, Fischer, Patrick, Schneider, Henning, Dohmen, Hildegard, Acker, Till, and Binder, Harald

Subjects
data protection constraints, ddc: 610, boosting, DataSHIELD, 610 Medical sciences, Medicine, federated analysis, multivariable prognostic score
Abstract

Background: Genetic biomarkers become increasingly more important for clinical management of patients, but the discovery of new ones requires large cohorts. In many countries, data protection constraints forbid exchange of individual-level data between different research institutes, but researchers [for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

Published
2021

27. Mutations in HID1 Cause Syndromic Infantile Encephalopathy and Hypopituitarism

Author

Schänzer, Anne, Achleitner, Melanie T., Trümbach, Dietrich, Hubert, Laurence, Munnich, Arnold, Ahlemeyer, Barbara, AlAbdulrahim, Maha M., Greif, Philipp A., Vosberg, Sebastian, Hummer, Blake, Feichtinger, René G., Mayr, Johannes A., Wortmann, Saskia B., Aichner, Heidi, Rudnik-Schöneborn, Sabine, Ruiz, Anna, Gabau, Elisabeth, Sánchez, Jacobo Pérez, Ellard, Sian, Homfray, Tessa, Stals, Karen L., Wurst, Wolfgang, Neubauer, Bernd A., Acker, Till, Bohlander, Stefan K., Asensio, Cédric, Besmond, Claude, Alkuraya, Fowzan S., AlSayed, Moenaldeen D., Hahn, Andreas, Weber, Axel, and Justus Liebig University Giessen

Subjects
0301 basic medicine, Male, Pituitary gland, Pathology, medicine.medical_specialty, Central nervous system, genetics [Epilepsy], Hypopituitarism, Peptide hormone, Article, pathology [Epilepsy], 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Atrophy, Exome Sequencing, Medicine, Humans, ddc:610, genetics [Hypopituitarism], Exome sequencing, Alleles, Cerebral atrophy, Brain Diseases, business.industry, genetics [Brain Diseases], pathology [Brain Diseases], Infant, medicine.disease, pathology [Pituitary Gland], ddc, 030104 developmental biology, medicine.anatomical_structure, Neurology, Pituitary Gland, Child, Preschool, Female, Neurology (clinical), pathology [Hypopituitarism], business, General Economics, Econometrics and Finance, 030217 neurology & neurosurgery
Abstract

Objective Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. Methods Whole exome sequencing (WES) was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. Results Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Post mortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate (ECAR) upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. Interpretation Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. This article is protected by copyright. All rights reserved.

Published
2021

28. Association of Clonal Hematopoiesis of Indeterminate Potential with Inflammatory Gene Expression in Patients with COPD.

Author

Kuhnert, Stefan, Mansouri, Siavash, Rieger, Michael A., Savai, Rajkumar, Avci, Edibe, Díaz-Piña, Gabriela, Padmasekar, Manju, Looso, Mario, Hadzic, Stefan, Acker, Till, Klatt, Stephan, Wilhelm, Jochen, Fleming, Ingrid, Sommer, Natascha, Weissmann, Norbert, Vogelmeier, Claus, Bals, Robert, Zeiher, Andreas, Dimmeler, Stefanie, and Seeger, Werner

Subjects
CHOLINE, HEMATOPOIESIS, GENE expression, CHRONIC obstructive pulmonary disease, PHOSPHOLIPASE D, IMMUNOSENESCENCE, SOMATIC mutation
Abstract

Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (~20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function. [ABSTRACT FROM AUTHOR]

Published
2022
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32. Angiopoietin 1 and 2 gene and protein expression is differentially regulated in acute anti-Thy 1.1 glomerulonephritis

Author

Campean, Valentina, Karpe, Britta, Haas, Christian, Atalla, Akram, Peters, Harm, Rupprecht, Harald, Liebner, Stefan, Acker, Till, Plate, Karl, and Amann, Kerstin

Subjects
Glomerulonephritis -- Physiological aspects, Gene expression -- Research, Vascular endothelial growth factor -- Properties, Protein microarrays -- Properties, Physiological research, Biological sciences
Abstract

Capillary neoformation is important in repair of glomerular injury of various origins. VEGF was shown to be crucial for glomerular capillary repair in glomerulonephritis (GN). We reasoned that other angiogenic factors are likewise involved in glomerular capillary remodeling and found angiopoietin 1 and -2 (ANG1 and ANG2) mRNA to be upregulated in cDNA microarrays of microdissected glomeruli of anti-Thy 1.1 GN of the rat. We then studied glomerular in situ gene and protein expression of ANG1 and ANG2 and their receptor Tie-2 in the course of antianti-Thy 1.1 GN, which was induced by injection of OX-7 antibody. Animals were perfusion fixed at days 6 and 12 after GN induction and compared with nonnephritic controls receiving PBS. Capillary damage and repair were quantitatively analyzed using stereological techniques. Gene and protein expression of ANG1 and ANG2 and their receptor Tie-2 was analyzed using real-time quantitative PCR from microdissected glomeruli, nonradioactive in situ hybridization, double immunofluorescence, and Western blot analysis. Glomerular capillarization assessed as length density was significantly lower at day 6 of anti-Thy 1.1 GN than in controls; it was back to normal values at day 12. ANG1 and ANG2 gene expression was markedly upregulated at day 6 of the disease compared with controls. Protein expression of ANG1 and ANG2 was confined to podocytes and that of Tie-2 to endothelial cells. At day 12 of anti-Thy 1.1 GN when capillary restoration was nearly completed, ANG1 and ANG2 gene expression returned to basal levels, whereas Tie-2 expression was still high. With the use of a combined molecular and in situ approach, the spatial and temporal gene and protein expression of the angiopoietins and their receptor was analyzed in anti-Thy 1.1 GN. The results indicate that glomerular expression of ANG1 and ANG2 and Tie-2 is differentially regulated and may contribute to healing and endothelial cell stabilization in experimental GN. vascular endothelial growth factor; microarrays; glomerular injury; repair

Published
2008

34. Case Report of Complete Radiological Response of a Thalamic Glioblastoma After Treatment With Proton Therapy Followed by Temozolomide and Tumor-Treating Fields

Author

Stein, Marco, Dohmen, Hildegard, Wölk, Bernhard, Eberle, Fabian, Kolodziej, Malgorzata, Acker, Till, Uhl, Eberhard, and Jensen, Alexandra

Subjects
Cancer Research, Oncology, glioblastoma, proton therapy, radiological response, Case Report, biopsy, TTFields
Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. We present a case of a 42-year-old male patient presenting with headache and vomiting. Imaging demonstrated obstructive hydrocephalus and a ring-enhancing lesion in the right posterior thalamus. After endoscopic third ventriculostomy and stereotactic biopsy, the histopathologic diagnosis of a malignant glioma was confirmed by DNA methylation array as GBM isocitrate dehydrogenase wild type. The patient was treated with combined treatment of chemoradiation with temozolomide (TMZ) including proton boost, TMZ maintenance, and tumor-treating fields. In this case report, complete radiological response was observed 1 year after the end of radiation therapy.

Published
2020
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35. MIRACUM: Medical Informatics in Research and Care in University Medicine

Author

Prokosch, Hans-Ulrich, Acker, Till, Bernarding, Johannes, Binder, Harald, Boeker, Martin, Boerries, Melanie, Daumke, Philipp, Ganslandt, Thomas, Hesser, Jürgen, Höning, Gunther, Neumaier, Michael, Marquardt, Kurt, Renz, Harald, Rothkötter, Hermann-Josef, Schade-Brittinger, Carmen, Schmücker, Paul, Schüttler, Jürgen, Sedlmayr, Martin, Serve, Hubert, Sohrabi, Keywan, and Storf, Holger

Subjects
Health Knowledge, Attitudes, Practice, MIRACUM, Biomedical Research, Information Dissemination, data sharing, Patient Selection, Data reuse, Focus Theme – Original Articles, Medical Informatics Initiative, data integration centres, Hospitals, University, Search Engine, Policy, Humans, Clinical Governance, Delivery of Health Care, Medical Informatics
Abstract

Summary Introduction: This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. Similar to other large international data sharing networks (e.g. OHDSI, PCORnet, eMerge, RD-Connect) MIRACUM is a consortium of academic and hospital partners as well as one industrial partner in eight German cities which have joined forces to create interoperable data integration centres (DIC) and make data within those DIC available for innovative new IT solutions in patient care and medical research. Objectives: Sharing data shall be supported by common interoperable tools and services, in order to leverage the power of such data for biomedical discovery and moving towards a learning health system. This paper aims at illustrating the major building blocks and concepts which MIRACUM will apply to achieve this goal. Governance and Policies: Besides establishing an efficient governance structure within the MIRACUM consortium (based on the steering board, a central administrative office, the general MIRACUM assembly, six working groups and the international scientific advisory board), defining DIC governance rules and data sharing policies, as well as establishing (at each MIRACUM DIC site, but also for MIRACUM in total) use and access committees are major building blocks for the success of such an endeavor. Architectural Framework and Methodology: The MIRACUM DIC architecture builds on a comprehensive ecosystem of reusable open source tools (MIRACOLIX), which are linkable and interoperable amongst each other, but also with the existing software environment of the MIRACUM hospitals. Efficient data protection measures, considering patient consent, data harmonization and a MIRACUM metadata repository as well as a common data model are major pillars of this framework. The methodological approach for shared data usage relies on a federated querying and analysis concept. Use Cases: MIRACUM aims at proving the value of their DIC with three use cases: IT support for patient recruitment into clinical trials, the development and routine care implementation of a clinico-molecular predictive knowledge tool, and molecular-guided therapy recommendations in molecular tumor boards. Results: Based on the MIRACUM DIC release in the nine months conceptual phase first large scale analysis for stroke and colorectal cancer cohorts have been pursued. Discussion: Beyond all technological challenges successfully applying the MIRACUM tools for the enrichment of our knowledge about diagnostic and therapeutic concepts, thus supporting the concept of a Learning Health System will be crucial for the acceptance and sustainability in the medical community and the MIRACUM university hospitals.

Published
2018

41. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions

Author

Carmeliet, Peter, Moons, Lieve, Luttun, Aernout, Vincenti, Valeria, Compernolle, Veerle, De Mol, Maria, Wu, Yan, Bono, Francoise, Devy, Laetitia, Beck, Heike, Scholz, Dimitri, Acker, Till, DiPalma, Tina, Dewerchin, Mieke, Noel, Agnes, Stalmans, Ingeborg, Barra, Adriano, Blacher, Sylvia, Vandendriessche, Thierry, Ponten, Annica, Eriksson, Ulf, Plate, Karl H., Foidart, Jean-Michel, Schaper, Wolfgang, Charnock-Jones, D. Stephen, Hicklin, Daniel J., Herbert, Jean-Marc, Collen, Desire, and Persico, M. Graziella

Abstract

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PlGF), remains unknown. Both VEGF and PlGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VEGFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PlGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PlGF (Pgf[sup.-/-]). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf[sup.-/-] mice. However, loss of PlGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf[sup.-/-] mice, indicating that PlGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PlGF and VEGF was specific, as PlGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VEGFR-1 was activated by PlGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PlGF or VEGF/PlGF. By upregulating PlGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders., Author(s): Peter Carmeliet (corresponding author) [1]; Lieve Moons [1]; Aernout Luttun [1]; Valeria Vincenti [2]; Veerle Compernolle [1]; Maria De Mol [1]; Yan Wu [3]; Francoise Bono [4]; Laetitia Devy [...]

Published
2001
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45. Genetic evidence for a tumor suppressor role of HIF-2α

Author

Acker, Till, Diez-Juan, Antonio, Aragones, Julian, Tjwa, Marc, Brusselmans, Koen, Moons, Lieve, Fukumura, Dai, Moreno-Murciano, Maria Paz, Herbert, Jean-Marc, Burger, Angelika, Riedel, Johanna, Elvert, Gerd, Flamme, Ingo, Maxwell, Patrick H., Collen, Désiré, Dewerchin, Mieke, Jain, Rakesh K., Plate, Karl H., and Carmeliet, Peter

Published
2005
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46. Childhood supratentorial ependymomas with fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features

Author

Andreiuolo, Felipe, Varlet, Pascale, Tauziède-Espariat, Arnault, Jünger, Stephanie T., Dörner, Evelyn, Dreschmann, Verena, Kuchelmeister, Klaus, Waha, Andreas, Haberler, Christine, Slavc, Irene, Corbacioglu, Selim, Riemenschneider, Markus J., Leipold, Alfred, Rüdiger, Thomas, Körholz, Dieter, Acker, Till, Russo, Alexandra, Faber, Jörg, Sommer, Clemens, Armbrust, Sven, Rose, Martina, Erdlenbruch, Bernhard, Hans, Volkmar H., Bernbeck, Benedikt, Schneider, Dominik, Lorenzen, Johann, Ebinger, Martin, Handgretinger, Rupert, Neumann, Manuela, van Buiren, Miriam, Prinz, Marco, Roganovic, Jelena, Jakovcevic, Antonia, Park, Sung-Hye, Grill, Jacques, Puget, Stéphanie, Messing-Jünger, Martina, Reinhard, Harald, Bergmann, Markus, Hattingen, Elke, and Pietsch, Torsten

Subjects
BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Oncology, childhood, ependymoma, supratentorial, YAP1‐MAMLD1 fusion, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Onkologija, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Pediatrics, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Pedijatrija
Abstract

Ependymoma with YAP1‐MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1‐MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1‐MAMLD1 fusion was documented by RT‐PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo‐rosettes, small to medium‐sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot‐like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1‐MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1–11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow‐up, 4.84 years). In this to date, largest series of ependymomas with YAP1‐MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

Published
2019

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