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1. A prognostic neural epigenetic signature in high-grade glioma

Author

Drexler, Richard, Khatri, Robin, Sauvigny, Thomas, Mohme, Malte, Maire, Cecile L., Ryba, Alice, Zghaibeh, Yahya, Dührsen, Lasse, Salviano-Silva, Amanda, Lamszus, Katrin, Westphal, Manfred, Gempt, Jens, Wefers, Annika K., Neumann, Julia E., Bode, Helena, Hausmann, Fabian, Huber, Tobias B., Bonn, Stefan, Jütten, Kerstin, Delev, Daniel, Weber, Katharina J., Harter, Patrick N., Onken, Julia, Vajkoczy, Peter, Capper, David, Wiestler, Benedikt, Weller, Michael, Snijder, Berend, Buck, Alicia, Weiss, Tobias, Göller, Pauline C., Sahm, Felix, Menstel, Joelle Aline, Zimmer, David Niklas, Keough, Michael B., Ni, Lijun, Monje, Michelle, Silverbush, Dana, Hovestadt, Volker, Suvà, Mario L., Krishna, Saritha, Hervey-Jumper, Shawn L., Schüller, Ulrich, Heiland, Dieter H., Hänzelmann, Sonja, and Ricklefs, Franz L.

Published
2024
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2. Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target

Author

Caldi Gomes, Lucas, Hänzelmann, Sonja, Hausmann, Fabian, Khatri, Robin, Oller, Sergio, Parvaz, Mojan, Tzeplaeff, Laura, Pasetto, Laura, Gebelin, Marie, Ebbing, Melanie, Holzapfel, Constantin, Columbro, Stefano Fabrizio, Scozzari, Serena, Knöferle, Johanna, Cordts, Isabell, Demleitner, Antonia F., Deschauer, Marcus, Dufke, Claudia, Sturm, Marc, Zhou, Qihui, Zelina, Pavol, Sudria-Lopez, Emma, Haack, Tobias B., Streb, Sebastian, Kuzma-Kozakiewicz, Magdalena, Edbauer, Dieter, Pasterkamp, R. Jeroen, Laczko, Endre, Rehrauer, Hubert, Schlapbach, Ralph, Carapito, Christine, Bonetto, Valentina, Bonn, Stefan, and Lingor, Paul

Published
2024
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4. Temporal change of DNA methylation subclasses between matched newly diagnosed and recurrent glioblastoma

Author

Drexler, Richard, Khatri, Robin, Schüller, Ulrich, Eckhardt, Alicia, Ryba, Alice, Sauvigny, Thomas, Dührsen, Lasse, Mohme, Malte, Ricklefs, Tammo, Bode, Helena, Hausmann, Fabian, Huber, Tobias B., Bonn, Stefan, Voß, Hannah, Neumann, Julia E., Silverbush, Dana, Hovestadt, Volker, Suvà, Mario L., Lamszus, Katrin, Gempt, Jens, Westphal, Manfred, Heiland, Dieter H., Hänzelmann, Sonja, and Ricklefs, Franz L.

Published
2024
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6. Testosterone affects type I/type II interferon response of neutrophils during hepatic amebiasis

Author

Er-Lukowiak, Marco, primary, Hänzelmann, Sonja, additional, Rothe, Moritz, additional, Moamenpour, David T., additional, Hausmann, Fabian, additional, Khatri, Robin, additional, Hansen, Charlotte, additional, Boldt, Jennifer, additional, Bärreiter, Valentin A., additional, Honecker, Barbara, additional, Bea, Annika, additional, Groneberg, Marie, additional, Fehling, Helena, additional, Marggraff, Claudia, additional, Cadar, Dániel, additional, Bonn, Stefan, additional, Sellau, Julie, additional, and Lotter, Hanna, additional

Published
2023
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7. CNSC-25. NEURAL SIGNATURE OF GBM EXHIBITS SYNAPTOGENIC AND OPC-LIKE FEATURES AND INDEPENDENTLY PREDICTS PATIENT SURVIVAL

Author

Drexler, Richard, primary, Khatri, Robin, additional, Sauvigny, Thomas, additional, Mohme, Malte, additional, Ryba, Alice, additional, Dührsen, Lasse, additional, Maire, Cecile, additional, Salviano-Silva, Amanda, additional, Lamszus, Katrin, additional, Westphal, Manfred, additional, Gempt, Jens, additional, Wefers, Annika, additional, Neumann, Julia, additional, Bode, Helena, additional, Hausmann, Fabian, additional, Huber, Tobias, additional, Bonn, Stefan, additional, Delev, Daniel, additional, Weber, Katharina, additional, Harter, Patrick, additional, Onken, Julia, additional, Vajkoczy, Peter, additional, Capper, David, additional, Wiestler, Benedikt, additional, Monje, Michelle, additional, Silverbush, Dana, additional, Hovestadt, Volker, additional, Suva, Mario, additional, Krishna, Saritha, additional, Hervey-Jumper, Shawn, additional, Schüller, Ulrich, additional, Heiland, Dieter Henrik, additional, Hänzelmann, Sonja, additional, and Ricklefs, Franz L, additional

Published
2023
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8. A universal preservation protocol for multi-omic and histological analysis of kidney tissue

Author

Gies, Sydney E., primary, Hänzelmann, Sonja, additional, Kylies, Dominik, additional, Lagies, Simon, additional, Lassé, Moritz, additional, Hausmann, Fabian, additional, Khatri, Robin, additional, Poets, Manuela, additional, Zhang, Tianran, additional, Lu, Shun, additional, Liu, Shuya, additional, Chilla, Silvia, additional, Edenhofer, Ilka, additional, Czogalla, Jan, additional, Braun, Fabian, additional, Kammerer, Bernd, additional, Rinschen, Markus M., additional, Puelles, Victor G., additional, Bonn, Stefan, additional, Lindenmeyer, Maja, additional, and Huber, Tobias B., additional

Published
2023
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9. Multiomic ALS signatures highlight sex differences and molecular subclusters and identify the MAPK pathway as therapeutic target

Author

Gomes, Lucas Caldi, primary, Hänzelmann, Sonja, additional, Oller, Sergio, additional, Parvaz, Mojan, additional, Hausmann, Fabian, additional, Khatri, Robin, additional, Ebbing, Melanie, additional, Holzapfel, Constantin, additional, Pasetto, Laura, additional, Columbro, Stefano Fabrizio, additional, Scozzari, Serena, additional, Gebelin, Marie, additional, Knöferle, Johanna, additional, Cordts, Isabell, additional, Demleitner, Antonia F., additional, Tzeplaeff, Laura, additional, Deschauer, Marcus, additional, Dufke, Claudia, additional, Sturm, Marc, additional, Zhou, Qihui, additional, Zelina, Pavol, additional, Sudria-Lopez, Emma, additional, Haack, Tobias B., additional, Streb, Sebastian, additional, Kuzma-Kozakiewicz, Magdalena, additional, Edbauer, Dieter, additional, Pasterkamp, R. Jeroen, additional, Laczko, Endre, additional, Rehrauer, Hubert, additional, Schlapbach, Ralph, additional, Carapito, Christine, additional, Bonetto, Valentina, additional, Bonn, Stefan, additional, and Lingor, Paul, additional

Published
2023
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10. Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability

Author

Drexler, Richard, primary, Khatri, Robin, additional, Sauvigny, Thomas, additional, Mohme, Malte, additional, Maire, Cecile L., additional, Ryba, Alice, additional, Zghaibeh, Yahya, additional, Dührsen, Lasse, additional, Salviano-Silva, Amanda, additional, Lamszus, Katrin, additional, Westphal, Manfred, additional, Gempt, Jens, additional, Wefers, Annika K., additional, Neumann, Julia, additional, Bode, Helena, additional, Hausmann, Fabian, additional, Huber, Tobias B., additional, Bonn, Stefan, additional, Jütten, Kerstin, additional, Delev, Daniel, additional, Weber, Katharina J., additional, Harter, Patrick N., additional, Onken, Julia, additional, Vajkoczy, Peter, additional, Capper, David, additional, Wiestler, Benedikt, additional, Weller, Michael, additional, Snijder, Berend, additional, Buck, Alicia, additional, Weiss, Tobias, additional, Keough, Michael B., additional, Ni, Lijun, additional, Monje, Michelle, additional, Silverbush, Dana, additional, Hovestadt, Volker, additional, Suvà, Mario L., additional, Krishna, Saritha, additional, Hervey-Jumper, Shawn L., additional, Schüller, Ulrich, additional, Heiland, Dieter H., additional, Hänzelmann, Sonja, additional, and Ricklefs, Franz L., additional

Published
2023
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11. 2D-interactome of the tumor immune-microenvironment reveals immunosuppressive T cells in primary sclerosing cholangitis-associated cholangiocarcinoma

Author

Krause, Jenny, primary, Casar, Christian, additional, Haenzelmann, Sonja, additional, Hausmann, Fabian, additional, Khatri, Robin, additional, Engblom, Camilla, additional, Das, Srustidhar, additional, Kylies, Dominik, additional, Poch, Tobias, additional, Schwinge, Dorothee, additional, Muscate, Franziska, additional, Cortesi, Filippo, additional, Heumann, Asmus, additional, Ghadban, Tarik, additional, Fischer, Lutz, additional, Clauditz, Till, additional, Krebs, Christian F., additional, Puelles, Victor, additional, Villablanca, Eduardo, additional, Huber, Samuel, additional, Bonn, Stefan, additional, Schramm, Christoph, additional, and Gagliani, Nicola, additional

Published
2023
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12. Epigenetic profiling reveals a strong association between lack of 5-ALA fluorescence and EGFR amplification in IDH-wildtype glioblastoma

Author

Drexler, Richard, primary, Sauvigny, Thomas, additional, Schüller, Ulrich, additional, Eckhardt, Alicia, additional, Maire, Cecile L, additional, Khatri, Robin, additional, Hausmann, Fabian, additional, Hänzelmann, Sonja, additional, Huber, Tobias B, additional, Bonn, Stefan, additional, Bode, Helena, additional, Lamszus, Katrin, additional, Westphal, Manfred, additional, Dührsen, Lasse, additional, and Ricklefs, Franz L, additional

Published
2023
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14. Targeted anticonvulsive treatment of IDH-wildtype glioblastoma based on DNA methylation subclasses

Author

Drexler, Richard, primary, Göttsche, Jennifer, additional, Sauvigny, Thomas, additional, Schüller, Ulrich, additional, Khatri, Robin, additional, Hausmann, Fabian, additional, Hänzelmann, Sonja, additional, Huber, Tobias B, additional, Bonn, Stefan, additional, Heiland, Dieter H, additional, Delev, Daniel, additional, Venkataramani, Varun, additional, Winkler, Frank, additional, Weller, Johannes, additional, Zeyen, Thomas, additional, Herrlinger, Ulrich, additional, Gempt, Jens, additional, Ricklefs, Franz L, additional, and Dührsen, Lasse, additional

Published
2023
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15. BIOM-33. TEMPORAL HETEROGENEITY OF DNA METHYLATION SUBCLASSES BETWEEN MATCHED NEWLY DIAGNOSED AND RECURRENT IDH-WILDTYPE GLIOBLASTOMA

Author

Drexler, Richard, primary, Schüller, Ulrich, additional, Eckhardt, Alicia, additional, Sauvigny, Thomas, additional, Ricklefs, Tammo, additional, Bode, Helena, additional, Khatri, Robin, additional, Hausmann, Fabian, additional, Hänzelmann, Sonja, additional, Huber, Tobias, additional, Bonn, Stefan, additional, Lamszus, Katrin, additional, Westphal, Manfred, additional, Dührsen, Lasse, additional, and Ricklefs, Franz, additional

Published
2022
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18. OS-079-YI - 2D-interactome of the tumor immune-microenvironment reveals immunosuppressive T cells in primary sclerosing cholangitis-associated cholangiocarcinoma

Author

Krause, Jenny, Casar, Christian, Haenzelmann, Sonja, Hausmann, Fabian, Khatri, Robin, Engblom, Camilla, Das, Srustidhar, Kylies, Dominik, Poch, Tobias, Schwinge, Dorothee, Muscate, Franziska, Cortesi, Filippo, Heumann, Asmus, Ghadban, Tarik, Fischer, Lutz, Clauditz, Till, Krebs, Christian F., Puelles, Victor, Villablanca, Eduardo, Huber, Samuel, Bonn, Stefan, Schramm, Christoph, and Gagliani, Nicola

Published
2023
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19. Robust, credible, and interpretable AI-based histopathological prostate cancer grading.

Author

Westhaeusser F, Fuhlert P, Dietrich E, Lennartz M, Khatri R, Kaiser N, Röbeck P, Bülow R, von Stillfried S, Witte A, Ladjevardi S, Drotte A, Severgardh P, Baumbach J, Puelles VG, Häggman M, Brehler M, Boor P, Walhagen P, Dragomir A, Busch C, Graefen M, Bengtsson E, Sauter G, Zimmermann M, and Bonn S

Abstract

Background: Prostate cancer (PCa) is among the most common cancers in men and its diagnosis requires the histopathological evaluation of biopsies by human experts. While several recent artificial intelligence-based (AI) approaches have reached human expert-level PCa grading, they often display significantly reduced performance on external datasets. This reduced performance can be caused by variations in sample preparation, for instance the staining protocol, section thickness, or scanner used. Another limiting factor of contemporary AI-based PCa grading is the prediction of ISUP grades, which leads to the perpetuation of human annotation errors., Methods: We developed the prostate cancer aggressiveness index (PCAI), an AI-based PCa detection and grading framework that is trained on objective patient outcome, rather than subjective ISUP grades. We designed PCAI as a clinical application, containing algorithmic modules that offer robustness to data variation, medical interpretability, and a measure of prediction confidence. To train and evaluate PCAI, we generated a multicentric, retrospective, observational trial consisting of six cohorts with 25,591 patients, 83,864 images, and 5 years of median follow-up from 5 different centers and 3 countries. This includes a high-variance dataset of 8,157 patients and 28,236 images with variations in sample thickness, staining protocol, and scanner, allowing for the systematic evaluation and optimization of model robustness to data variation. The performance of PCAI was assessed on three external test cohorts from two countries, comprising 2,255 patients and 9,437 images., Findings: Using our high-variance datasets, we show how differences in sample processing, particularly slide thickness and staining time, significantly reduce the performance of AI-based PCa grading by up to 6.2 percentage points in the concordance index (C-index). We show how a select set of algorithmic improvements, including domain adversarial training, conferred robustness to data variation, interpretability, and a measure of credibility to PCAI. These changes lead to significant prediction improvement across two biopsy cohorts and one TMA cohort, systematically exceeding expert ISUP grading in C-index and AUROC by up to 22 percentage points., Interpretation: Data variation poses serious risks for AI-based histopathological PCa grading, even when models are trained on large datasets. Algorithmic improvements for model robustness, interpretability, credibility, and training on high-variance data as well as outcome-based severity prediction gives rise to robust models with above ISUP-level PCa grading performance., Competing Interests: Competing interests FW, PF, AD, PS, PW, CB, EB, and SB work part time for Spearpoint Analytics AB, a company developing AI-based digital pathology solutions. The authors declare no other conflicts of interest.

Published
2024
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20. Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability.

Author

Drexler R, Khatri R, Sauvigny T, Mohme M, Maire CL, Ryba A, Zghaibeh Y, Dührsen L, Salviano-Silva A, Lamszus K, Westphal M, Gempt J, Wefers AK, Neumann J, Bode H, Hausmann F, Huber TB, Bonn S, Jütten K, Delev D, Weber KJ, Harter PN, Onken J, Vajkoczy P, Capper D, Wiestler B, Weller M, Snijder B, Buck A, Weiss T, Keough MB, Ni L, Monje M, Silverbush D, Hovestadt V, Suvà ML, Krishna S, Hervey-Jumper SL, Schüller U, Heiland DH, Hänzelmann S, and Ricklefs FL

Abstract

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients' survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant., Competing Interests: Competing Interests M.L.S. is equity holder, scientific co-founder and advisory board member of Immunitas Therapeutics. M.M. holds equity in MapLight Therapeutics.

Published
2023
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