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Kristin Reiche

Professor of Digital Molecular Medicine

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Publications

TitleYear
Anti-CD4 Antibody–modulated Transplants for GvHD Prevention in Haematopoietic Cell Transplantation
2026
Kristina Roth, Dennis Loeffler, Conny Blumert, Alexander Scholz, Kristin Reiche, Marcus…
Blood
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Authors:Kristina Roth, Dennis Loeffler, Conny Blumert, Alexander Scholz, Kristin Reiche, Marcus Bauer, Claudia Wickenhauser, Denise Schiefer, Nadja Hilger, André-René Blaudszun, Jenifer Thees, Jasmin Walter, Sandy U Tretbar, Ulrike Koehl, Stephan Fricke, Ulrich Blache
Publication date:01/29/2026
Journal:Blood
Publisher:Content Repository Only!
Description:Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic haematopoietic cell transplantation. Currently, immunosuppressants are used for GvHD prophylaxis and treatment in the majority of transplant recipients. Due to their systemic, non-specific mode of action, this treatment regimen is frequently associated with severe toxic side effects, opportunistic infections as well as cancer relapse when treating haematologic malignancies. By using short-term ex vivo modulation of haematopoietic cell transplants with the anti-human CD4 antibody MAX.16H5, we have developed a novel immune tolerance-inducing strategy enabling potent GvHD prevention. Functional in vitro assays and transcriptome profiling data suggest impaired TCR signalling and a shift towards an IL-10-dependent regulatory phenotype as the primary mechanism of action of anti-human CD4 antibody treatment …
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Deep learning-aided inter-species-comparison reveals shared and distinct molecular patterns in cynomolgus monkey and humans following non-specific T cell activation
2025
Vincent D Friedrich, Kari Neier, Kristina Müller, Birgit Fogal, Zuzana Loncova, Michael…
Frontiers in Immunology 16, 1603716
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Authors:Vincent D Friedrich, Kari Neier, Kristina Müller, Birgit Fogal, Zuzana Loncova, Michael Rade, Muhammad Shoaib, Ulrike Köhl, Kathleen Hoyt, Parimal Pande, Lily Blanchard, Ernest Raymond, Markus Scholz, Kristin Reiche, Holger Kirsten
Publication date:12/12/2025
Journal:Frontiers in Immunology
Volume:16
Pages:1603716
Publisher:Frontiers Media SA
Description:The early phase of drug development relies on the examination of the efficacy and safety of therapeutic agents in animal models. Due to their close genetic and physiological relation to humans, cynomolgus monkeys (Macaca fascicularis) are a promising animal model in preclinical studies investigating the immune system. However, the shared and divergent characteristics of the immune response at the molecular level are not yet fully understood, which makes transferring findings from these studies to human conditions challenging. Here, we demonstrate a cross-species analysis pipeline using single-cell transcriptomics (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs), investigating the transcriptomic response in cynomolgus monkeys and healthy humans following anti-CD3/anti-CD28 T cell activation. For this, PBMCs were collected at baseline, stimulated in vitro, and measured at 0 hours, at 6 hours and at 24 hours post-stimulation, with two biological replicates per species. The analysis integrates Variational Autoencoder (VAE)-based deep learning, cell-cell communication, differential gene expression, and pathway enrichment for an in-depth data exploration. We observed shared molecular patterns across species in the transition from innate to adaptive immune response, such as the increase of CD4+ T cell proportion and the reduction of CD14+CD16- and CD14lowCD16+ monocytes. Specific transcriptional clusters related to metabolic reprogramming emerged in CD8+ T cells and related to inflammatory and antiviral programs in NK cells at 24 hours post-stimulation in both species, with stronger regulation of pathways …
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CAR T-cell therapy induces remission in multiorgan IgG4-related disease with hepatobiliary involvement
2025
Verena Keitel, Michael C Kreissl, Tobias Goetze, Carola Dröge, Christina Katharina Kuhn…
Journal of hepatology
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Authors:Verena Keitel, Michael C Kreissl, Tobias Goetze, Carola Dröge, Christina Katharina Kuhn, Nhu-Nguyen Pham, Dennis Löffler, Dominique Borie, Jens Schreiber, Martin Boettcher, Katrin Hippe, Maciej Pech, Martin Mikusko, Ulrike Köhl, Denise Walther, Kristin Reiche, Dimitrios Mougiakakos
Publication date:12/08/2025
Journal:Journal of hepatology
Publisher:Elsevier
Description:IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder in which IgG4+ B cells and T cells interact to drive chronic organ inflammation. Patients with multiorgan involvement may become refractory to standard therapy, resulting in progressive organ damage and risk of organ failure. Here, we report a patient with treatment-refractory multiorgan IgG4-RD treated with CD19-directed CAR T cells and describe the clinical and immunologic effects over more than 12 months of follow-up. A 60-year-old man with IgG4-RD involving the pancreas, hepatobiliary tract, and lungs refractory to long-term immunosuppression received autologous CD19-directed CAR T cells. Disease course was monitored longitudinally, and peripheral blood underwent multimodal immune profiling. CAR T cell therapy was well tolerated, with only grade 1 cytokine release syndrome, no neurotoxicity, and transient cytopenias without infections …
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Endothelial dysfunction and proinflammatory state determine severe hematotoxicity and inferior outcome of CAR‐T therapy
2025
Lukas Scheller, Xiang Zhou, Henry Loeffler‐Wirth, Markus Kreuz, Sofie‐Katrin Kadel, Sve…
HemaSphere 9 (12), e70267
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Authors:Lukas Scheller, Xiang Zhou, Henry Loeffler‐Wirth, Markus Kreuz, Sofie‐Katrin Kadel, Sven Schimanski, Hannah Schulze, Anna Ruckdeschel, Florian Eisele, Verena Konetzki, Maria Jornet Culubret, Maximilian Merz, Julia Mersi, Johannes Waldschmidt, Sophia Danhof, Ulrike Köhl, K Martin Kortüm, Leo Rasche, Hermann Einsele, Johannes Düll, Max S Topp, Michael Hudecek, Kristin Reiche, Miriam Alb
Publication date:12/01/2025
Journal:HemaSphere
Volume:9
Issue:12
Pages:e70267
Description:Hematotoxicity and infections are the main drivers of non‐relapse mortality after chimeric antigen receptor (CAR)‐T therapy. Consequently, reliable predictive biomarkers are highly needed to improve risk assessment and optimize patient management. In this study, we applied the immune‐related adverse outcome pathway concept to delineate key events and risk factors of CAR‐T‐associated hematotoxicity. To identify predictive biomarkers, we performed flow cytometry and multiplex assays before and early after CAR‐T infusion on 78 patients (ide‐cel n = 31; axi‐cel n = 24; and cilta‐cel n = 23) undergoing CAR‐T therapy. Severe hematotoxicity was linked to endothelial dysfunction, as evidenced by reduced levels of ANG1, soluble selectins, and increased soluble VCAM‐1 (sVCAM‐1) early after CAR‐T infusion. Increased sVCAM‐1, reflecting endothelial dysfunction, elevated soluble IL‐2R (sIL‐2R …
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Endothelial dysfunction and proinflammatory state determine severe hematotoxicity and adverse outcome of CAR-T therapy
2025
Lukas Scheller, Xiang Zhou, Markus Kreuz, Henry Loeffler-Wirth, Sofie-Katrin Kadel, Sve…
Blood 146, 809
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Authors:Lukas Scheller, Xiang Zhou, Markus Kreuz, Henry Loeffler-Wirth, Sofie-Katrin Kadel, Sven Schimanski, Hannah Schulze, Anna Marie Ruckdeschel, Florian Eisele, Verena Konetzki, Maria Jornet Culubret, Julia Mersi, Johannes Waldschmidt, Sophia Danhof, Maximilian Merz, Ulrike Koehl, K Martin Kortüm, Leo Rasche, Hermann Einsele, Johannes Duell, Max S Topp, Michael Hudecek, Kristin Reiche, Miriam Alb
Publication date:11/03/2025
Journal:Blood
Volume:146
Pages:809
Publisher:Content Repository Only!
Description:Hematotoxicity with prolonged cytopenia is the most relevant high-grade toxicity after chimeric antigen receptor (CAR)-T therapy. It is associated with higher risk for infections, impaired quality of life, increased healthcare burden, and contributes substantially to mortality. Despite its clinical relevance, predictive biomarkers, particularly those reflecting underlying mechanisms, remain scarce. In this study, we employed the immune-related adverse outcome pathway framework to delineate hematotoxicity into defined, measurable key events and to identify mechanistically informed biomarkers to enhance risk stratification and guide patient management.This European initiative between four CAR-T cell centers included 78 patients with relapsed/refractory multiple myeloma (MM) or diffuse large B-cell lymphoma treated with ide-cel (n=31), cilta-cel (n=23), or axi-cel (n=24). Peripheral blood was collected before apheresis …
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Spatiotemporal and genetic tracking of long-term persisting CAR-T cells following ciltacabtagene autoleucel treatment for multiple myeloma reveals molecular insights into late …
2025
David Fandrei, Sabine Seiffert, Christina Kuhn, Michael Rade, Esmée van Vliet, Vera von…
Blood 146 (Supplement 1), 690-690
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Authors:David Fandrei, Sabine Seiffert, Christina Kuhn, Michael Rade, Esmée van Vliet, Vera von Landenberg-Roberg, Manja Meggendorfer, Luise Fischer, Markus Kreuz, Dennis Löffler, Conny Blumert, Anja Grahnert, Maik Friedrich, Patrick Born, Thomas Wiemers, Emilie-Charlot Skerbek, Kathrin Jäger, Sebastian Greiser, Ronny Baber, Song-Yau Wang, Simone Heyn, Georg-Nikolaus Franke, Andreas Boldt, Dominik Schmiedel, Sebastian Böttcher, Marco Herling, Jurgen Kuball, Marietta Truger, Torsten Haferlach, Jan Krönke, Uwe Platzbecker, Klaus Metzeler, Ulrike Koehl, Vladan Vucinic, Zsolt Sebestyen, Kristin Reiche, Maximillian Merz
Publication date:11/03/2025
Journal:Blood
Volume:146
Issue:Supplement 1
Pages:690-690
Publisher:American Society of Hematology
Description: Introduction Ciltacabtagene autoleucel (cilta-cel) is an anti-BCMA CAR-T cell therapy which led to >70% complete response (CR) rates in relapsed/refractory multiple myeloma (MM) patients. Long-term (LT) persisting CAR-T cells may influence both remission durability and adverse events (AE), yet cellular kinetics are heterogeneous across patients. Here, we investigated the impact of LT persisting CAR-T cells in MM patients following cilta-cel treatment. Methods Flow cytometry-based immune monitoring in peripheral blood (PB) comprising CAR-T cell quantification was performed at days 0 (D0), 4, 7, 14, and 30, and months 3 (M3), 6, 12, 18, and 24 following cilta-cel infusion. In total, 36 patients with maximum expansion (cmax) >101 CAR-T cells/µL and ≥1 immune monitoring ≥M6 (median: 7 time points, range: 5-10) were included. Single-cell RNA/TCR-seq of PB …
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Sarcopenia and body composition predict survival and reveal immunometabolic dysfunction via single-cell profiling in anti-BCMA CAR T-treated myeloma
2025
Thomas Wiemers, Michael Rade, Nora Grieb, Maximilian Ferle, Tihomir Dermendzhiev, David…
Blood 146, 7676
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Authors:Thomas Wiemers, Michael Rade, Nora Grieb, Maximilian Ferle, Tihomir Dermendzhiev, David Fandrei, Patrick Born, Sabine Seiffert, Anja Grahnert, Maik Friedrich, Ronny Baber, Markus Kreuz, Klaus Metzeler, Marco Herling, Carmen Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Andreas Boldt, Ulrike Koehl, Kristin Reiche, Timm Denecke, Urvi Shah, Uwe Platzbecker, Vladan Vucinic, Hans-Jonas Meyer, Maximilian Merz
Publication date:11/03/2025
Journal:Blood
Volume:146
Pages:7676
Publisher:Content Repository Only!
Description:Introduction:Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), achieving unprecedented responses even in heavily pretreated patients. However, outcomes remain highly variable, shaped by a multifactorial interplay of patient characteristics and disease biology. While these determinants are increasingly well-defined, the role of body composition - particularly adipose tissue and skeletal muscle distribution - has not been systematically evaluated in RRMM.Methods:We retrospectively evaluated 108 RRMM patients treated with Idecabtagene vicleucel (ide-cel) or Ciltacabtagene autoleucel (cilta-cel) between 2021 and 2025. BMI was calculated before CAR T-cell infusion and pre-treatment CT scans were used to quantify total (TAT), subcutaneous (SAT), and visceral adipose tissue (VAT) as well as skeletal muscle (SM) area. For survival …
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CERTOMICS: Trusted Single-Cell Multiomics Pipeline for High-Resolution Profiling of Adoptive Cellular Immunotherapies
2025
Christina Katharina Kuhn, David Schmidt, Michael Rade, Josephine Selke, U Sandy Tretbar…
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Authors:Christina Katharina Kuhn, David Schmidt, Michael Rade, Josephine Selke, U Sandy Tretbar, Maximilian Merz, Jan Grau, Kristin Reiche
Publication date:10/23/2025
Description:Adoptive cellular immunontherapies, such as chimeric antigen receptor (CAR) T cell therapy, have transformed cancer treatment, yet challenges such as resistance, relapse, and high costs limit their efficacy and accessibility. A comprehensive understanding of cellular heterogeneity and molecular profiles is essential to improve these therapies. Advanced single-cell multiomics technologies have the power to analyze the complex interactions between CAR-engineered cells, immune cells, and tumor cells. However, standardized single-cell multiomics computational pipelines specifically tailored to CAR-engineered cell products are lacking. Due to the synthetic nature of CAR transgenes, additional steps are required for the identification and characterization of CAR-positive cells within single-cell multiomics data, which are not included in standard pipelines. To address this, we present CERTOMICS, a Nextflow-based pipeline offering enhanced CERTainty in immunophenotyping and data interpretation, tailored for single-cell multi OMICS profiling of adoptive cellular immunotherapies. The pipeline standardizes processing 10x Genomics single-cell multiomics data and integrates CAR-specific identification and quality control. Additionally, a curated repository of CAR construct sequences and annotation data is provided, serving as a resource to support the analysis and development of CAR T cell therapies.
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ROR2-specific CAR T cells are effective against hematologic and solid tumors and well tolerated in mice
2025
Justus Weber, Michael Rade, Josefine Michael, Liz Therese Tony, Fabian Freitag, Peter S…
Cell Reports Medicine 6 (10)
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Authors:Justus Weber, Michael Rade, Josefine Michael, Liz Therese Tony, Fabian Freitag, Peter Spieler, Claudia Müller, Charis Kalogirou, Laura Mainz, Jörg Lehmann, Robert Klopfleisch, Mathias T Rosenfeldt, Sophia Danhof, K Martin Kortüm, Ulrike Köhl, Hermann Einsele, Christoph Rader, Kristin Reiche, Thomas Nerreter, Michael Hudecek
Publication date:10/21/2025
Journal:Cell Reports Medicine
Volume:6
Issue:10
Publisher:Elsevier
Description:Receptor tyrosine kinase (RTK)-like orphan receptor 2 (ROR2) has been nominated as a target for kinase inhibitors due to its role in oncogenic signaling. Here, we show that ROR2 is a target for chimeric antigen receptor (CAR) T cells in hematologic and solid tumors. We show consistent ROR2 expression in multiple myeloma (MM) and developed ROR2-CAR T cells that confer potent activity against human MM xenografts in vivo. We analyzed public gene expression data and reveal an inverse correlation between ROR2 expression and patient survival for six types of cancer, i.e., lower-grade glioma, thyroid carcinoma, stomach adenocarcinoma, bladder cancer, and papillary and clear cell renal cell cancer (ccRCC). We confirm potent activity of ROR2-CAR T cells against ccRCC in vitro and in vivo. Treatment with ROR2-CAR T cells was well tolerated, without signs of on-target off-tumor toxicity in mice, supporting …
Cited by:1
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Call for preserving specialized knowledge and contributions of the CAT to advancing ATMPs in Europe
2025
Delphine Ammar, Carmen Sanges, David Henderson, Inga Schapitz, Michael Hudecek, Maik Lu…
Cytotherapy
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Authors:Delphine Ammar, Carmen Sanges, David Henderson, Inga Schapitz, Michael Hudecek, Maik Luu, Martina Schüssler-Lenz, Christian Buchholz, Paul Franz, Kristin Reiche, Ulrike Köhl, Norbert Ifrah, Bruno Quesnel, Maria Thermeli, Marie Jose Kersten, Franco Locatelli, Maria Luisa d'Amore, Chiara Bonini, Monica Casucci, Ulrike Philippar, Robin Doeswijk, Frederick Thielen, Carin Uyl-de Groot, Judith Theelen, Bernd Schröder, Andreas Kremer, Maria Quaranta, Felipe Prosper, Jan Van den Brulle, Ulf Grawunder, Emmanuel Donnadieu, Anne Galy, Christophe Ferrand, Nina Worel, Dirk Busch, Javier Briones, Leopold Sellner, Jurgen Kuball, Anna Sureda, Jacquelyn Awigena-Cook
Publication date:09/23/2025
Journal:Cytotherapy
Publisher:Elsevier
Description:With the proposal for major reform of the pharmaceutical legislation (Regulation (EU) 2023/0131, Directive (EU) 2023/0132) in April 2023, the foundations of Europe’s regulatory architecture are being reshaped. The revised legislation proposes the removal of specialized committee functions (e.g., Committee for Advanced Therapies - CAT) by integrating their remit into other regulatory bodies, such as the Pharmacovigilance Risk Assessment Committee (PRAC) and Committee for Medicinal Products for Human Use (CHMP) and expert working groups. This decision may further challenge innovation in Europe, particularly in the field of advanced therapy medicinal products (ATMPs), which has already experienced a notable decline in global clinical trial activity over the past decade. This article emphasizes the importance of involving multi-stakeholder consortia such as T2EVOLVE in shaping pharmaceutical …
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Building immune digital twins: An international and transdisciplinary community effort
2025
Anna Niarakis, Gary An, Luiz Ladeira, Noriko F Hiroi, Athina Papadopoulou, Francis P Cr…
ImmunoInformatics, 100060
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Authors:Anna Niarakis, Gary An, Luiz Ladeira, Noriko F Hiroi, Athina Papadopoulou, Francis P Crawley, Niloofar Nikaein, Laurence Calzone, Eirini Tsirvouli, Hasan Balci, Marina Esteban Medina, Lorenzo Veschini, Ozan Ozisik, Francesco Messina, Malvina Marku, Van Du T Tran, Arnau Montagud, Nikola Schlosserova, Yashwanth Subbannayya, Martina Kutmon, Michael L Blinov, Rahuman S Malik Sheriff, Robert Phair, Peter Hunter, Kristin Reiche, Jasmin Fisher, Liesbet Geris, Yaron Ilan, James A Glazier, Philippe Moingeon, Reinhard Laubenbacher
Publication date:09/16/2025
Journal:ImmunoInformatics
Pages:100060
Publisher:Elsevier
Description:Digital twins, initially developed for industrial applications, are set to make significant advancements in medicine and healthcare. They have demonstrated promising potential for drug development and personalised care, especially in cardiovascular diagnostics and insulin-dependent diabetes management. A particularly compelling application lies in immune responses and immune-mediated diseases, given the immune system’s essential role in preserving human health, from fighting infections to managing autoimmune diseases. Creating Immune Digital Twins (IDTs) holds great promise for medicine and healthcare. At the same time, the development of a reliable and robust IDT presents significant challenges due to the inherent complexity and polymorphism of the human immune system, the difficulties in measuring patients’ immune state in vivo, and the intrinsic difficulties associated with modelling complex …
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Single-cell and high-definition spatial sequencing of melanoma reveal new candidates for targeted cell-based therapies
2025
A Stubenvoll, FP Grosse, MA Chango, M Schmidt, A Paschen, C Kaempf, CT Schoeder, F Wein…
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT 23 (S 6), 13-13
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Authors:A Stubenvoll, FP Grosse, MA Chango, M Schmidt, A Paschen, C Kaempf, CT Schoeder, F Weinberg, C Arndt, A Feldmann, D Loeffler, C Blumert, K Reiche, M Kunz
Publication date:09/15/2025
Journal:JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
Volume:23
Issue:S 6
Pages:13-13
Publisher:WILEY
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Splenomegaly is Associated with High-Tumor Burden, Prolonged Cytopenia and Adverse Outcome after BCMA-directed CAR T-Cell Therapy
2025
Thomas Wiemers, Maximilian Ferle, Jonas Ader, Veronika Sotikova, David Fandrei, Nora Gr…
Clinical Lymphoma Myeloma and Leukemia 25, S106-S107
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Authors:Thomas Wiemers, Maximilian Ferle, Jonas Ader, Veronika Sotikova, David Fandrei, Nora Grieb, Luise Fischer, Patrick Born, Heike Weidnder, Song Yau Wang, Madlen Jentzsch, Georg-Nikolaus Franke, Carmen Herling, Klaus Metzeler, Marco Herling, Simone Heyn, Timm Denecke, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Thomas Neumuth, Hans-Jonas Meyer, Maximilian Merz
Publication date:09/01/2025
Journal:Clinical Lymphoma Myeloma and Leukemia
Volume:25
Pages:S106-S107
Publisher:Elsevier
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Body composition predicts poor outcomes and reveals immunometabolic dysfunction via single-cell profiling in anti-BCMA CAR T-treated myeloma
2025
Thomas C Wiemers, Michael Rade, Nora Grieb, Maximilian Ferle, Tihomir Dermendzhiev, Dav…
medRxiv, 2025.08. 23.25334251
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Authors:Thomas C Wiemers, Michael Rade, Nora Grieb, Maximilian Ferle, Tihomir Dermendzhiev, David Fandrei, Patrick Born, Luise Fischer, Sabine Seiffert, Anja Grahnert, Maik Friedrich, Ronny Baber, Markus Kreuz, Klaus H Metzeler, Marco Herling, Carmen D Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Andreas Boldt, Thomas Neumuth, Urvi A Shah, Ulrike Köhl, Kristin Reiche, Timm Denecke, Uwe Platzbecker, Vladan Vucinic, Hans-Jonas Meyer, Maximilian Merz
Publication date:08/28/2025
Journal:medRxiv
Pages:2025.08. 23.25334251
Publisher:Cold Spring Harbor Laboratory Press
Description:Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of relapsed or refractory multiple myeloma (RRMM), yet outcomes remain heterogenous. The prognostic role of body composition in this context is unknown. We retrospectively analyzed 108 RRMM patients treated with anti-B-cell maturation antigen (BCMA) CAR T-cell therapy. Pre-treatment Computed tomography imaging was utilized to quantify total adipose tissue (TAT), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle area to assess sarcopenia. Longitudinal flow cytometric and single-cell multi-omic analyses were conducted to characterize the quantitative and qualitative influences of body composition on the immune microenvironment. Patients with BMI <25 kg/m2 experienced significantly worse overall survival (OS) compared to high-BMI patients. Reduced TAT, primarily driven by low SAT, was associated with inferior OS, diminished response and elevated soluble BCMA. Sarcopenia independently predicted poorer OS, while progression-free survival was unaffected by the respective parameters. Low SAT and sarcopenia correlated with lower bystander T-cell counts at leukapheresis. Longitudinal T-cell receptor sequencing and single-cell transcriptomics revealed diminished cytotoxic and interferon signaling, reduced T-cell clonality, and increased oxidative phosphorylation activity following CAR T-cell infusion. Our findings identify low SAT and sarcopenia as prognostic biomarkers that influence survival, therapeutic response, and immunometabolic profiles. Their quantification through standard imaging techniques offers a …
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Immune cells play a critical role in cytokine-and endotoxin-mediated endothelial permeability
2025
Patricia Gogesch, Samira Ortega Iannazzo, Nicole Rupp, Joachim Rom, Markus Kreuz, Krist…
Plos one 20 (8), e0329700
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Authors:Patricia Gogesch, Samira Ortega Iannazzo, Nicole Rupp, Joachim Rom, Markus Kreuz, Kristin Reiche, Martina Anzaghe, Zoe Waibler, imSAVAR Consortium
Publication date:08/14/2025
Journal:Plos one
Volume:20
Issue:8
Pages:e0329700
Publisher:Public Library of Science
Description:Vascular leakage (VL) is a severe pathology occurring in a broad range of scenarios, e.g., during sepsis, cytokine storms, or as side effect of immunotherapies. Its severity is underlined by the high lethality rate of 20−30% for the systemic capillary leakage syndrome. While many compounds are reported to affect endothelial cell (EC)-activation, exact mechanisms behind VL remain unclear. We analyzed activation, viability, cytokine secretion, and relative permeability of human umbilical vein endothelial cells (HUVECs) upon treatment with 16 different stimuli. Relative HUVEC-permeability was assessed in a trans-well-based leakage assay in presence or absence of human peripheral blood mononuclear cells (PBMCs). HUVEC-activation is characterized by correlating upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin, as well as production of interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, and IL-6. Strong HUVEC-activation and reduced viability was observed upon treatment with IL-1β, tumor necrosis factor (TNF)-α, a TGN1412-induced cytokine cocktail (SNTGN1412), thrombin, and lipopolysaccharide (LPS). Only thrombin, SNTGN1412, and vascular endothelial growth factor (VEGF) led to increased relative permeability, while other compounds associated with vascular leakage, including TNF-α, IL-1β, or LPS, had no direct effect on relative HUVEC-permeability. Interestingly, co-cultures with PBMCs mediated IL-1β- and LPS- but not TNF-α-induced relative HUVEC-permeability. In our study, we show that HUVEC activation upon direct stimulation does not necessarily …
Cited by:1
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An explorable model of an adverse outcome pathway of cytokine release syndrome related to the administration of immunomodulatory biotherapeutics and cellular therapies
2025
Alexander Mazein, Oxana Lopata, Kristin Reiche, Katherina Sewald, Miriam Alb, Christina…
Frontiers in immunology 16, 1601670
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Authors:Alexander Mazein, Oxana Lopata, Kristin Reiche, Katherina Sewald, Miriam Alb, Christina Sakellariou, Patricia Gogesch, Hannah Morgan, Vanessa Neuhaus, Nhu-Nguyen Pham, Charline Sommer, Ethan Perkins, Birgit Fogal, Muhammad Shoaib, Reinhard Schneider, Venkata Satagopam, Marek Ostaszewski
Publication date:08/08/2025
Journal:Frontiers in immunology
Volume:16
Pages:1601670
Publisher:Frontiers Media SA
Description:Introduction Cytokine release syndrome (CRS) is a potentially severe systemic inflammatory condition triggered by various immunomodulatory therapies, making understanding its pathogenesis critical for improving patient outcomes. Results/Methods By combining immunotoxicology and systems biology approaches, we offer a novel and integrative conceptual model of CRS as an adverse outcome (AO), induced by five different immunomodulatory biotherapies: 1) chimeric antigen receptor (CAR) T cells, 2) checkpoint inhibitors, 3) T cell engaging bispecific modalities, 4) monoclonal antibodies targeting and activating T cell receptors, and 5) FcγR activating monoclonal antibodies. This model uniquely integrates multiple CRS-inducing therapies into a unified framework, offering a comprehensive mechanistic representation of CRS pathophysiology. For that, we built an adverse outcome pathway (AOP) CRS network for these therapies and then developed a systems biology map of molecular mechanisms relevant to the AOP network. The map of mechanisms is made available via a dedicated online platform for exploration and data visualisation. It includes 24 cell types, 425 entities and 430 interactions. Discussion Beyond a static representation, the CRS Map serves as a dynamic tool for clinical and research applications, allowing researchers and clinicians to explore CRS progression in detail, identify biomarkers, and discover potential therapeutic targets. The map demonstrates stages of CRS progression and shows molecules that can be measured in relevant immunotoxicological assays, as well as potential drug targets for therapeutic …
Cited by:4
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Design specifications for biomedical virtual twins in engineered adoptive cellular immunotherapies
2025
Ulrike Weirauch, Markus Kreuz, Colin Birkenbihl, Miriam Alb, Maria Quaranta, Laurence C…
NPJ Digital Medicine 8 (1), 493
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Authors:Ulrike Weirauch, Markus Kreuz, Colin Birkenbihl, Miriam Alb, Maria Quaranta, Laurence Calzone, Sophia Orozco-Ruiz, Stefanie Binder, Luise Fischer, Solène Clavreul, Morine Maguri, Maximilian Ferle, Michael Rade, Guillaume Azarias, Jay R Hydren, Jakub Jamarik, Daniel Schwarz, Zsolt Sebestyen, Jurgen Kuball, Georg Popp, Chloé Antoine, Manon Knockaert, Clara T Schoeder, David Fandrei, Carmen Sanges, Vaclovas Radvilas, Nico Gagelmann, Markus Rückert, Olaf Penack, Stephan Fricke, Andreas Schmidt, Carol Ward, Carl Steinbeisser, Jean-Marc Van Gyseghem, Anna Niarakis, Laurent Garderet, Michael Hudecek, Thomas Neumuth, Uwe Platzbecker, Ulrike Köhl, Regina Demlova, Andreas Kremer, Stefan Franke, Holger Fröhlich, Maximilian Merz, Kristin Reiche, CERTAINTY Consortium Ferle Maximilian 1 10 11 On behalf of the CERTAINTY Consortium Van Gyseghem Jean-Marc 17 On behalf of the CERTAINTY Consortium Köhl Ulrike 1 7 11 On behalf of the CERTAINTY Consortium
Publication date:08/01/2025
Journal:NPJ Digital Medicine
Volume:8
Issue:1
Pages:493
Publisher:Nature Publishing Group UK
Description:In (immune)oncology, virtual twins (VTs) offer patient-individual decision support. Nevertheless, current VTs do not incorporate the unique properties of engineered adoptive cellular immunotherapies (eACIs). Here, we outline the minimal design specifications for VTs for engineered ACIs (eACI-VTs) to model the complex interplay between cell product and patient physiology. We motivate utilizing VTs in eACIs to provide decision support and reflect on how eACI-VTs can support the widespread use of eACIs.
Cited by:4
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Virtual twins for personalised CAR T-cell therapy in myeloma
2025
Kristin Reiche, Ulrike Weirauch, Markus Kreuz, Luise Fischer, Luuk Gras, Thomas Neumuth…
The Lancet. Haematology 12 (7), e490-e491
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Authors:Kristin Reiche, Ulrike Weirauch, Markus Kreuz, Luise Fischer, Luuk Gras, Thomas Neumuth, Uwe Platzbecker, Ulrike Köhl, Regina Demlova, Andreas Kremer, Holger Fröhlich, Stefan Franke, Maximilian Merz, CERTAINTY Consortium
Publication date:07/01/2025
Journal:The Lancet. Haematology
Volume:12
Issue:7
Pages:e490-e491
Description:Virtual twins for personalised CAR T-cell therapy in myeloma Virtual twins for personalised CAR T-cell therapy in myeloma Lancet Haematol. 2025 Jul;12(7):e490-e491. doi: 10.1016/S2352-3026(25)00170-X. Authors Kristin Reiche 1 , Ulrike Weirauch 2 , Markus Kreuz 2 , Luise Fischer 3 , Luuk Gras 4 , Thomas Neumuth 5 , Uwe Platzbecker 3 , Ulrike Köhl 6 , Regina Demlova 7 , Andreas Kremer 8 , Holger Fröhlich 9 , Stefan Franke 5 , Maximilian Merz 3 ; CERTAINTY Consortium Collaborators CERTAINTY Consortium: Colin Birkenbihl, Miriam Alb, Maria Quaranta, Laurence Calzone, Sophia Orozco-Ruiz, Stefanie Binder, Solène Clavreul, Morine Maguri, Maximilian Ferle, Michael Rade, Guillaume Azarias, Jay R Hydren, Jakub Jamarik, Daniel Schwarz, Zsolt Sebastyen, Jurgen Kuball, Georg Popp, Chloé Antoine, Manon Knockaert, Clara T Schoeder, David Fandrei, Carmen Sanges, Vaclovas Radvilas, Nico …
Cited by:2
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Unsupervised risk factor identification across cancer types and data modalities via explainable artificial intelligence
2025
Maximilian Ferle, Jonas Ader, Thomas Wiemers, Nora Grieb, Adrian Lindenmeyer, Hans-Jona…
arXiv preprint arXiv:2506.12944
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Authors:Maximilian Ferle, Jonas Ader, Thomas Wiemers, Nora Grieb, Adrian Lindenmeyer, Hans-Jonas Meyer, Thomas Neumuth, Markus Kreuz, Kristin Reiche, Maximilian Merz
Publication date:06/15/2025
Journal:arXiv preprint arXiv:2506.12944
Description:Risk stratification is a key tool in clinical decision-making, yet current approaches often fail to translate sophisticated survival analysis into actionable clinical criteria. We present a novel method for unsupervised machine learning that directly optimizes for survival heterogeneity across patient clusters through a differentiable adaptation of the multivariate logrank statistic. Unlike most existing methods that rely on proxy metrics, our approach represents novel methodology for training any neural network architecture on any data modality to identify prognostically distinct patient groups. We thoroughly evaluate the method in simulation experiments and demonstrate its utility in practice by applying it to two distinct cancer types: analyzing laboratory parameters from multiple myeloma patients and computed tomography images from non-small cell lung cancer patients, identifying prognostically distinct patient subgroups with significantly different survival outcomes in both cases. Post-hoc explainability analyses uncover clinically meaningful features determining the group assignments which align well with established risk factors and thus lend strong weight to the methods utility. This pan-cancer, model-agnostic approach represents a valuable advancement in clinical risk stratification, enabling the discovery of novel prognostic signatures across diverse data types while providing interpretable results that promise to complement treatment personalization and clinical decision-making in oncology and beyond.
Resources:[PDF] from arxiv.org
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Was wäre, wenn…: Szenarien der Zelltherapie digital durchgespielt.
2025
Ulrike Weirauch, Christoph Kämpf, Kristin Reiche
IM+ io (2)
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Authors:Ulrike Weirauch, Christoph Kämpf, Kristin Reiche
Publication date:06/01/2025
Journal:IM+ io
Issue:2
Description:Tumorzelle, werden dadurch aktiviert und zerstören die Tumorzelle. Derzeit sind sechs autologe CAR-T-Zelltherapien in der EU zugelassen. Die CAR-T-Zelltherapie ermöglicht Patient: innen langanhaltende Remissionen. Allerdings sprechen nicht alle Patient: innen gleich gut auf die Behandlung an [2]. Virtuelle Zwillinge (VTs) könnten helfen, das individuell passende CAR-T-Zellprodukt auszuwählen und so die Wirkung zu verbessern und Nebenwirkungen zu verringern. Dies kann Therapiekosten senken und knappe Herstellungskapazitäten für CAR-T-Zellen optimieren. Wir definieren Virtuelle Zwillinge im Gesundheitswesen als eine Kombination mehrerer patient: innenindividueller Digitaler Zwillinge (DTs). Ein DT für ein einzelnes Organ ist dessen digitales Abbild, welches kontinuierlich mit patient: innenindividuellen Daten über den Zustand des Organs aktualisiert wird [3]. So können zum Beispiel vor einem …
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Predicting progression events in multiple myeloma from routine blood work
2025
Maximilian Ferle, Nora Grieb, Markus Kreuz, Jonas Ader, Hartmut Goldschmidt, Elias K Ma…
NPJ digital medicine 8 (1), 231
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Authors:Maximilian Ferle, Nora Grieb, Markus Kreuz, Jonas Ader, Hartmut Goldschmidt, Elias K Mai, Uta Bertsch, Uwe Platzbecker, Thomas Neumuth, Kristin Reiche, Alexander Oeser, Maximilian Merz
Publication date:04/30/2025
Journal:NPJ digital medicine
Volume:8
Issue:1
Pages:231
Publisher:Nature Publishing Group UK
Description:This study introduces a system for predicting disease progression events in multiple myeloma patients from the CoMMpass study (N = 1186). Utilizing a hybrid neural network architecture, our model predicts future blood work from historical lab results with high accuracy, significantly outperforming baseline estimators for key disease parameters. Disease progression events are annotated in the forecasted data, predicting these events with significant reliability. We externally validated our model using the GMMG-MM5 study dataset (N = 504), and could reproduce the main results of our study. Our approach enables early detection and personalized monitoring of patients at risk of impeding progression. Designed modularly, our system enhances interpretability, facilitates integration of additional modules, and uses routine blood work measurements to ensure accessibility in clinical settings. With this, we contribute …
Cited by:6
Resources:[HTML] from nature.com
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Emerging T-cell lymphomas after CAR T-cell therapy
2025
Till Braun, Florian Kuschel, Kristin Reiche, Maximilian Merz, Marco Herling
Leukemia 39 (6), 1337
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Authors:Till Braun, Florian Kuschel, Kristin Reiche, Maximilian Merz, Marco Herling
Publication date:04/07/2025
Journal:Leukemia
Volume:39
Issue:6
Pages:1337
Description:Emerging T-cell lymphomas after CAR T-cell therapy - PMC Skip to main content Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. NCBI home page Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Close Search Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Search Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC …
Cited by:9
Resources:[HTML] from nih.gov
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A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma
2025
Michael Rade, David Fandrei, Markus Kreuz, Sabine Seiffert, Anja Grahnert, Maik Friedri…
Cancer cell
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Authors:Michael Rade, David Fandrei, Markus Kreuz, Sabine Seiffert, Anja Grahnert, Maik Friedrich, Thomas Wiemers, Patrick Born, Luise Fischer, Heike Weidner, Lorenz C Hofbauer, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jonathan Scolnick, Mirco Friedrich, Farid Keramati, Peter Brazda, Zsolt Sebestyen, Jürgen Kuball, Miriam Alb, Lukas Scheller, Michael Hudecek, Hermann Einsele, Klaus H Metzeler, Marco Herling, Carmen Diana Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Andreas Boldt, Ulrike Köhl, Uwe Platzbecker, Vladan Vucinic, Kristin Reiche, Maximilian Merz
Publication date:03/18/2025
Journal:Cancer cell
Publisher:Elsevier
Description:Chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) are transforming treatment for relapsed or refractory multiple myeloma (RRMM). We analyze 61 RRMM patients receiving idecabtagene vicleucel (Ide-cel; n = 34) or ciltacabtagene autoleucel (Cilta-cel; n = 27) and find that Cilta-cel achieves higher complete response (CR) rates (78% vs. 38%) and longer progression-free survival. Using a longitudinal single-cell multi-omics atlas of 135 blood samples, we show that Cilta-cel induces expansion of CD4+ cytotoxic T cells associated with CR and immune-related toxicities, whereas non-CR CD8+ T cells display impaired effector programs. Among non-B cells, plasmacytoid dendritic cells (pDCs) show the highest BCMA expression and BCMA-targeted agents eradicate a blastic plasmacytoid dendritic cell neoplasm line, suggesting a novel therapeutic avenue for this disease …
Cited by:1
Resources:[HTML] from cell.com
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INNOVATIVE APPROACHES TO IMPROVE SAFETY EVALUATION IN THE NONCLINICAL DEVELOPMENT OF CAR T CELLS AND IMMUNOMODULATORY BIOTHERAPEUTICS: THE IMSAVAR PROJECT
2025
Miriam Alb, Lukas Scheller, Tengku Ibrahim Maulana, Claudia Teufel, Peter Loskill, Huub…
HUMAN GENE THERAPY 36 (5-6), E701-E701
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Authors:Miriam Alb, Lukas Scheller, Tengku Ibrahim Maulana, Claudia Teufel, Peter Loskill, Huub J Weener, Andries D Van der Meer, Katherina Sewald, Ulrike Weirauch, Kristin Reiche, Ulrike Koehl, Michael Hudecek
Publication date:03/01/2025
Journal:HUMAN GENE THERAPY
Volume:36
Issue:5-6
Pages:E701-E701
Publisher:MARY ANN LIEBERT, INC
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TARGETING RECEPTOR TYROSINE KINASE ROR2 WITH CAR T CELLS IS EFFECTIVE AGAINST HEMATOLOGIC AND SOLID TUMORS, AND WELL TOLERATED IN MICE
2025
Justus Weber, Michael Rade, Peter Spieler, Charis Kalogirou, Sophia Danhof, Hermann Ein…
HUMAN GENE THERAPY 36 (5-6), E711-E711
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Authors:Justus Weber, Michael Rade, Peter Spieler, Charis Kalogirou, Sophia Danhof, Hermann Einsele, Kristin Reiche, Thomas Nerreter, Michael Hudecek, Marc Philipp Schauer
Publication date:03/01/2025
Journal:HUMAN GENE THERAPY
Volume:36
Issue:5-6
Pages:E711-E711
Publisher:MARY ANN LIEBERT, INC
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Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody
2025
Till Braun, Michael Rade, Maximilian Merz, Hanna Klepzig, Florian Große, David Fandrei,…
Nature Medicine, 1-9
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Authors:Till Braun, Michael Rade, Maximilian Merz, Hanna Klepzig, Florian Große, David Fandrei, Nhu-Nguyen Pham, Markus Kreuz, Christina Katharina Kuhn, Florian Kuschel, Dennis Löffler, Jörn Meinel, Eva Heger, Viola Schweinsberg, Natali Pflug, Uwe Platzbecker, Michael Hallek, Udo Holtick, Ulrike Köhl, Christof Scheid, Kristin Reiche, Marco Herling, Tim Richardson
Publication date:02/21/2025
Journal:Nature Medicine
Pages:1-9
Publisher:Nature Publishing Group US
Description:Chimeric antigen receptor (CAR) T cells and bispecific T cell engagers have become integral components in the treatment of relapsed/refractory multiple myeloma. We report a 63-year-old male who received ciltacabtagene autoleucel CAR T cells and the GPRC5D × CD3 bispecific talquetamab for early relapse of his multiple myeloma. Nine months after CAR T therapy, he developed a symptomatic leukemic peripheral T cell lymphoma with cutaneous and intestinal involvement. Longitudinal single-cell RNA and T cell receptor sequencing of peripheral blood and bone marrow revealed two hyperexpanded CAR-carrying T cell clones. These expanded clones exhibited an exhausted effector-memory T cell transcriptional signature, and the neoplasm itself was sensitive to dexamethasone treatment. The immunophenotypic and transcriptional alterations of these abnormal T cells resembled those of T-large granular …
Cited by:20
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Prognostic implications of splenomegaly in BCMA-directed CAR T-Cell therapy for relapsed myeloma
2025
Thomas Wiemers, Maximilian Ferle, Jonas Ader, Veronika Sotikova, David Fandrei, Nora Gr…
medRxiv, 2025.01. 31.25321490
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Authors:Thomas Wiemers, Maximilian Ferle, Jonas Ader, Veronika Sotikova, David Fandrei, Nora Grieb, Luise Fischer, Patrick Born, Heike Weidner, Song Yau Wang, Madlen Jentzsch, Georg-Nikolaus Franke, Carmen Herling, Klaus Metzeler, Marco Herling, Simone Heyn, Timm Denecke, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Hans-Jonas Meyer, Thomas Neumuth, Maximilian Merz
Publication date:02/02/2025
Journal:medRxiv
Pages:2025.01. 31.25321490
Publisher:Cold Spring Harbor Laboratory Press
Description:B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has shown promise for patients with relapsed or refractory multiple myeloma (RRMM), yet its use is often complicated by adverse events such as cytokine release syndrome and hematologic toxicities. This study evaluates the prognostic significance of spleen size, measured via computed tomography (CT), in predicting clinical outcomes for RRMM patients undergoing CAR T-cell therapy. We retrospectively analyzed data from patients treated with Idecabtagene vicleucel or Ciltacabtagen autoleucel (N=73) and show that enlarged spleen size is associated with severe and prolonged thrombocytopenia, higher metabolic tumor volumes, and elevated soluble BCMA (sBCMA) levels. Our findings indicate that splenomegaly (>340 cm³) is an independent prognostic marker for both progression-free and overall survival, outperforming markers such as sBCMA levels, EASIX, and CAR- Hematotox scores. These results suggest that spleen size could enhance risk stratification in CAR T-cell therapy for RRMM patients, offering a readily accessible tool for guiding monitoring strategies and healthcare resource management.
Cited by:1
Resources:[PDF] from medrxiv.org
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Bispecific antibodies as bridging to BCMA CAR-T cell therapy for relapsed/refractory multiple myeloma
2025
David Fandrei, Sabine Seiffert, Michael Rade, Susanne Rieprecht, Nico Gagelmann, Patric…
Blood cancer discovery 6 (1), 38-54
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Authors:David Fandrei, Sabine Seiffert, Michael Rade, Susanne Rieprecht, Nico Gagelmann, Patrick Born, Thomas Wiemers, Heike Weidner, Markus Kreuz, Tamara Schassberger, Jannik Koßmann, Marlene Mangold, Daniel Fürst, Luise Fischer, Ronny Baber, Simone Heyn, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrike Köhl, Maik Friedrich, Andreas Boldt, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz
Publication date:01/08/2025
Journal:Blood cancer discovery
Volume:6
Issue:1
Pages:38-54
Publisher:American Association for Cancer Research
Description:Establishing a strategy for sequencing of T cell–redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunologic impact of bispecific T cell–engaging antibodies (BsAb) as bridging therapy (BT) to subsequent B-cell maturation antigen–directed chimeric antigen receptor T (CAR-T) cell therapies in 52 patients with RRMM. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared with chemotherapy, anti-CD38, or anti-SLAMF7 antibody–based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T-cell expansion in patients receiving BsAbs as BT. In vitro cytotoxicity of CAR-T cells was comparable among BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T-cell compartments in patients with previous exposure to …
Cited by:29
Resources:[HTML] from nih.gov
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Igor Age Kos, Universitätsklinikum des Saarlandes, Germany
2025
Ravi K Patel, Anna Ossami Saidy, Marek Ostaszewski, A Mazein, O Lopata, K Reiche, K Sew…
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Authors:Ravi K Patel, Anna Ossami Saidy, Marek Ostaszewski, A Mazein, O Lopata, K Reiche, K Sewald, M Alb, C Sakellariou, P Gogesch, H Morgan, V Neuhaus, NN Pham, C Sommer, E Perkins, B Fogal, M Shoaib, R Schneider, V Satagopam, Gogesch Sakellariou, Neuhaus Morgan, Sommer Pham, Fogal Perkins, Schneider Shoaib
Publication date:01/01/2025
Description:Results/Methods: By combining immunotoxicology and systems biology approaches, we offer a novel and integrative conceptual model of CRS as an adverse outcome (AO), induced by five different immunomodulatory biotherapies: 1) chimeric antigen receptor (CAR) T cells, 2) checkpoint inhibitors, 3) T cell engaging bispecific modalities, 4) monoclonal antibodies
Resources:[PDF] from fraunhofer.de
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Immune digital twins for complex human pathologies: applications, limitations, and challenges
2024
Anna Niarakis, Reinhard Laubenbacher, Gary An, Yaron Ilan, Jasmin Fisher, Åsmund Flobak…
NPJ systems biology and applications 10 (1), 141
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Authors:Anna Niarakis, Reinhard Laubenbacher, Gary An, Yaron Ilan, Jasmin Fisher, Åsmund Flobak, Kristin Reiche, María Rodríguez Martínez, Liesbet Geris, Luiz Ladeira, Lorenzo Veschini, Michael L Blinov, Francesco Messina, Luis L Fonseca, Sandra Ferreira, Arnau Montagud, Vincent Noël, Malvina Marku, Eirini Tsirvouli, Marcella M Torres, Leonard A Harris, TJ Sego, Chase Cockrell, Amanda E Shick, Hasan Balci, Albin Salazar, Kinza Rian, Ahmed Abdelmonem Hemedan, Marina Esteban-Medina, Bernard Staumont, Esteban Hernandez-Vargas, Shiny Martis B, Alejandro Madrid-Valiente, Panagiotis Karampelesis, Luis Sordo Vieira, Pradyumna Harlapur, Alexander Kulesza, Niloofar Nikaein, Winston Garira, Rahuman S Malik Sheriff, Juilee Thakar, Van Du T Tran, Jose Carbonell-Caballero, Soroush Safaei, Alfonso Valencia, Andrei Zinovyev, James A Glazier
Publication date:11/30/2024
Journal:NPJ systems biology and applications
Volume:10
Issue:1
Pages:141
Publisher:Nature Publishing Group UK
Description:Digital twins represent a key technology for precision health. Medical digital twins consist of computational models that represent the health state of individual patients over time, enabling optimal therapeutics and forecasting patient prognosis. Many health conditions involve the immune system, so it is crucial to include its key features when designing medical digital twins. The immune response is complex and varies across diseases and patients, and its modelling requires the collective expertise of the clinical, immunology, and computational modelling communities. This review outlines the initial progress on immune digital twins and the various initiatives to facilitate communication between interdisciplinary communities. We also outline the crucial aspects of an immune digital twin design and the prerequisites for its implementation in the clinic. We propose some initial use cases that could serve as “proof of concept …
Cited by:49
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Persistent Thrombocytopenia and Neutropenia Are Associated with Increased Mortality in Patients Treated with Anti-BCMA CAR T Cells for Relapsed/Refractory Multiple Myeloma
2024
Thomas C Wiemers, David Fandrei, Sabine Seiffert, Michael Rade, Susanne Rieprecht, Patr…
Blood 144, 7095
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Authors:Thomas C Wiemers, David Fandrei, Sabine Seiffert, Michael Rade, Susanne Rieprecht, Patrick Born, Markus Kreuz, Luise Fischer, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrike Köhl, Maik Friedrich, Andreas Boldt, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz
Publication date:11/05/2024
Journal:Blood
Volume:144
Pages:7095
Publisher:Content Repository Only!
Description:Background:CAR T cell therapy has transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM). However, some patients experience significant hematologic toxicities, potentially restricting their wider use. In this study, we investigated the occurrence of thrombocytopenia and neutropenia in patients receiving anti-BCMA CAR T cell therapy and examined their associations with in vivo CAR T cell expansion and clinical outcomes.Methods:We conducted a retrospective analysis of 61 patients treated with anti-BCMA CAR T cell therapies. All patients received bridging therapy (BT), and type of BT was classified as bispecific antibodies, anti-CD38-based, anti-SLAMF7-based or conventional chemotherapy. Responders were defined as patients achieving PR or better according to IMWG criteria by month 6 after CAR T cell infusion. Flow cytometry was utilized to monitor CAR+ and non …
Cited by:4
Resources:[HTML] from sciencedirect.com
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The Differences between Ide-Cel and Cilta-Cel in Relapsed Myeloma at Single Cell Resolution
2024
David Fandrei, Michael Rade, Markus Kreuz, Luise Fischer, Patrick Born, Sabine Seiffert…
Blood 144, 1877
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Authors:David Fandrei, Michael Rade, Markus Kreuz, Luise Fischer, Patrick Born, Sabine Seiffert, Andreas Boldt, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrike Köhl, Uwe Platzbecker, Vladan Vucinic, Kristin Reiche, Maximilian Merz
Publication date:11/05/2024
Journal:Blood
Volume:144
Pages:1877
Publisher:Content Repository Only!
Description:Introduction: The two commercially available BCMA-directed CAR T cell therapies idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). Results from clinical trials suggest superior outcome with cilta-cel compared to ide-cel. We conducted a comprehensive longitudinal single-cell multi-omics study in a large real-world cohort of RRMM patients to identify markers associated with response, resistance or side effects after ide-cel or cilta-cel.Methods: Peripheral blood mononuclear cells (PBMCs) were isolated on the day of leukapheresis (LP), and on days 30 and 100 post infusion. PBMCs were subjected to single cell RNA, TCR, BCR and surface protein analysis. Additionally, peripheral blood samples collected at the day of LP, after lymphodepletion and on days 7, 14, 30 and 100 following CAR T cell therapy were …
Cited by:2
Resources:[HTML] from sciencedirect.com
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Immune cells play a critical role in cytokine-and endotoxin-mediated endothelial permeability
2024
Samira Ortega Iannazzo, Patricia Gogesch, Nicole Rupp, Joachim Rom, Markus Kreuz, Krist…
EUROPEAN JOURNAL OF IMMUNOLOGY 54, 199-199
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Authors:Samira Ortega Iannazzo, Patricia Gogesch, Nicole Rupp, Joachim Rom, Markus Kreuz, Kristin Reiche, Martina Anzaghe, Zoe Waibler
Publication date:09/01/2024
Journal:EUROPEAN JOURNAL OF IMMUNOLOGY
Volume:54
Pages:199-199
Publisher:WILEY
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Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma
2024
Michael Rade, Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas…
Nature cancer 5 (9), 1318-1333
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Authors:Michael Rade, Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Birthe Schetschorke, Saskia Hell, Sebastian Schwind, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Ulrike Köhl, Uwe Platzbecker, Kristin Reiche, Vladan Vucinic, Maximilian Merz
Publication date:09/01/2024
Journal:Nature cancer
Volume:5
Issue:9
Pages:1318-1333
Publisher:Nature Publishing Group US
Description:Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential …
Cited by:44
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A spatial transcriptomics browser for discovering gene expression landscapes across microscopic tissue sections
2024
Maria Schmidt, Susanna Avagyan, Kristin Reiche, Hans Binder, Henry Loeffler-Wirth
Current issues in molecular biology 46 (5), 4701-4720
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Authors:Maria Schmidt, Susanna Avagyan, Kristin Reiche, Hans Binder, Henry Loeffler-Wirth
Publication date:05/13/2024
Journal:Current issues in molecular biology
Volume:46
Issue:5
Pages:4701-4720
Publisher:MDPI
Description:A crucial feature of life is its spatial organization and compartmentalization on the molecular, cellular, and tissue levels. Spatial transcriptomics (ST) technology has opened a new chapter of the sequencing revolution, emerging rapidly with transformative effects across biology. This technique produces extensive and complex sequencing data, raising the need for computational methods for their comprehensive analysis and interpretation. We developed the ST browser web tool for the interactive discovery of ST images, focusing on different functional aspects such as single gene expression, the expression of functional gene sets, as well as the inspection of the spatial patterns of cell–cell interactions. As a unique feature, our tool applies self-organizing map (SOM) machine learning to the ST data. Our SOM data portrayal method generates individual gene expression landscapes for each spot in the ST image, enabling its downstream analysis with high resolution. The performance of the spatial browser is demonstrated by disentangling the intra-tumoral heterogeneity of melanoma and the microarchitecture of the mouse brain. The integration of machine-learning-based SOM portrayal into an interactive ST analysis environment opens novel perspectives for the comprehensive knowledge mining of the organization and interactions of cellular ecosystems.
Cited by:6
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A reliable transcriptomic risk-score applicable to formalin-fixed paraffin-embedded biopsies improves outcome prediction in localized prostate cancer
2024
Michael Rade, Markus Kreuz, Angelika Borkowetz, Ulrich Sommer, Conny Blumert, Susanne F…
Molecular Medicine 30 (1), 19
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Authors:Michael Rade, Markus Kreuz, Angelika Borkowetz, Ulrich Sommer, Conny Blumert, Susanne Füssel, Catharina Bertram, Dennis Löffler, Dominik J Otto, Livia A Wöller, Carolin Schimmelpfennig, Ulrike Köhl, Ann-Cathrin Gottschling, Pia Hönscheid, Gustavo B Baretton, Manfred Wirth, Christian Thomas, Friedemann Horn, Kristin Reiche
Publication date:02/01/2024
Journal:Molecular Medicine
Volume:30
Issue:1
Pages:19
Publisher:BioMed Central
Description:Background Clinical manifestation of prostate cancer (PCa) is highly variable. Aggressive tumors require radical treatment while clinically non-significant ones may be suitable for active surveillance. We previously developed the prognostic ProstaTrend RNA signature based on transcriptome‐wide microarray and RNA-sequencing (RNA-Seq) analyses, primarily of prostatectomy specimens. An RNA-Seq study of formalin-fixed paraffin-embedded (FFPE) tumor biopsies has now allowed us to use this test as a basis for the development of a novel test that is applicable to FFPE biopsies as a tool for early routine PCa diagnostics. Methods All patients of the FFPE biopsy cohort were treated by radical prostatectomy and median follow-up for biochemical recurrence (BCR) was 9 years. Based on the transcriptome data of 176 FFPE biopsies, we filtered ProstaTrend for genes susceptible to FFPE-associated degradation via …
Cited by:7
Resources:[HTML] from springer.com
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Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma
2024
Luise Fischer, Nora Grieb, Patrick Born, Ronald Weiss, Sabine Seiffert, Andreas Boldt, …
Leukemia 38 (2), 372-382
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Authors:Luise Fischer, Nora Grieb, Patrick Born, Ronald Weiss, Sabine Seiffert, Andreas Boldt, Stephan Fricke, Paul Franz, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Heike Weidner, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Janine Kirchberg, Saskia Hell, Sebastian Schwind, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Kristin Reiche, Ulrike Köhl, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz
Publication date:02/01/2024
Journal:Leukemia
Volume:38
Issue:2
Pages:372-382
Publisher:Nature Publishing Group UK
Description:B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8+ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8+ T cells at day of …
Cited by:56
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New regulatory thinking is needed for AI-based personalised drug and cell therapies in precision oncology
2024
Bouchra Derraz, Gabriele Breda, Christoph Kaempf, Franziska Baenke, Fabienne Cotte, Kri…
NPJ Precision Oncology 8 (1), 23
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Authors:Bouchra Derraz, Gabriele Breda, Christoph Kaempf, Franziska Baenke, Fabienne Cotte, Kristin Reiche, Ulrike Köhl, Jakob Nikolas Kather, Deborah Eskenazy, Stephen Gilbert
Publication date:01/30/2024
Journal:NPJ Precision Oncology
Volume:8
Issue:1
Pages:23
Publisher:Nature Publishing Group UK
Description:Until recently the application of artificial intelligence (AI) in precision oncology was confined to activities in drug development and had limited impact on the personalisation of therapy. Now, a number of approaches have been proposed for the personalisation of drug and cell therapies with AI applied to therapy design, planning and delivery at the patient’s bedside. Some drug and cell-based therapies are already tuneable to the individual to optimise efficacy, to reduce toxicity, to adapt the dosing regime, to design combination therapy approaches and, preclinically, even to personalise the receptor design of cell therapies. Developments in AI-based healthcare are accelerating through the adoption of foundation models, and generalist medical AI models have been proposed. The application of these approaches in therapy design is already being explored and realistic short-term advances include the application to …
Cited by:85
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Using interactive platforms to encode, manage and explore immune-related adverse outcome pathways
2024
Alexander Mazein, Muhammad Shoaib, Miriam Alb, Christina Sakellariou, Charline Sommer, …
Journal of immunotoxicology 21 (sup1), S5-S12
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Authors:Alexander Mazein, Muhammad Shoaib, Miriam Alb, Christina Sakellariou, Charline Sommer, Katherina Sewald, Kristin Reiche, Patricia Gogesch, Luise A Roser, Samira Ortega Iannazzo, Sapna Sheth, Susanne Schiffmann, Zoe Waibler, Vanessa Neuhaus, Susann Dehmel, Venkata Satagopam, Reinhard Schneider, Marek Ostaszewski, Wei Gu
Publication date:01/26/2024
Journal:Journal of immunotoxicology
Volume:21
Issue:sup1
Pages:S5-S12
Publisher:Taylor & Francis
Description:This work focuses on the need for modeling and predicting adverse outcomes in immunotoxicology to improve nonclinical assessments of the safety of immunomodulatory therapies. The integrated approach includes, first, the adverse outcome pathway concept established in the toxicology field, and, second, the systems medicine disease map approach for describing molecular mechanisms involved in a particular pathology. The proposed systems immunotoxicology workflow is illustrated with chimeric antigen receptor (CAR) T cell treatment as a use case. To this end, the linear adverse outcome pathway (AOP) is expanded into a molecular interaction model in standard systems biology formats. Then it is shown how knowledge related to immunotoxic events can be integrated, encoded, managed, and explored to benefit the research community. The map is accessible online at https://imsavar.elixir-luxembourg.org …
Cited by:13
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Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept
2024
Miriam Alb, Kristin Reiche, Michael Rade, Katherina Sewald, Peter Loskill, Madalena Cip…
Journal of immunotoxicology 21 (sup1), S13-S28
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Authors:Miriam Alb, Kristin Reiche, Michael Rade, Katherina Sewald, Peter Loskill, Madalena Cipriano, Tengku Ibrahim Maulana, Andries D van der Meer, Huub J Weener, Laure-Alix Clerbaux, Birgit Fogal, Nirav Patel, Karissa Adkins, Emma Lund, Ethan Perkins, Christopher Cooper, Jan van den Brulle, Hannah Morgan, Tina Rubic-Schneider, Hui Ling, Keith DiPetrillo, Jonathan Moggs, Ulrike Köhl, Michael Hudecek
Publication date:01/26/2024
Journal:Journal of immunotoxicology
Volume:21
Issue:sup1
Pages:S13-S28
Publisher:Taylor & Francis
Description:The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable in vitro and in vivo models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy. The IMI2/EU project imSAVAR (immune safety avatar: non-clinical mimicking of the immune system effects of immunomodulatory therapies) aims at creating a platform for novel tools and models …
Cited by:11
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OS02-03 Using a systems biology approach to construct adverse outcome pathway networks aligned with the FAIR principles
2024
L Ladeira, A Mazein, M Ostaszewski, A Verhoeven, E Kuchovská, J Sanz-Serrano, A Drees, …
Toxicology letters 399
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Authors:L Ladeira, A Mazein, M Ostaszewski, A Verhoeven, E Kuchovská, J Sanz-Serrano, A Drees, Kristin Reiche, K Sewald, E Fritsche, B Staumont, Liesbet Geris, M Vinken
Publication date:01/01/2024
Journal:Toxicology letters
Volume:399
Description:Adverse Outcome Pathways (AOPs) serve as frameworks connecting molecular initiating events to adverse outcomes through key events (KE), which are essential for understanding the link between chemical exposure and adverse health effects. Current graphical representations of AOPs are being adapted for machine-readability, aligning with FAIR principles (Findability, Accessibility, Interoperability, and Reuse of digital assets). The Systems Biology Graphical Notation (SBGN) elements enhance AOPs with standardized graphical notation, improving visualization and interpretability, as introduced by Mazein and collaborators (2023). In addition, artificial intelligence (AI)-based systematic review, data screening and curation have been performed by van Ertvelde and collaborators (2023) to accelerate the building of large AOP networks. The KE descriptor concept overlaps with the biology enrichment present in …
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Survivorship data in prostate cancer: where are we and where do we need to be?
2024
Beth Russell, Katharina Beyer, Ailbhe Lawlor, Monique J Roobol, Lionne DF Venderbos, Se…
European Urology Open Science 59, 27-29
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Authors:Beth Russell, Katharina Beyer, Ailbhe Lawlor, Monique J Roobol, Lionne DF Venderbos, Sebastiaan Remmers, Erik Briers, Sara J MacLennan, Steven MacLennan, Muhammad Imran Omar, Mieke Van Hemelrijck, Emma Smith, James N'Dow, Karin Plass, Maria Ribal, Nicolas Mottet, Robert Shepherd, Tom Abbott, Ken Mastris, Lisa Moris, Michael Lardas, Thomas Van den Broeck, Peter-Paul Willemse, Nicola Fossati, Karl Pang, Riccardo Campi, Isabella Greco, Mauro Gacci, Sergio Serni, Anders Bjartell, Ragnar Lonnerbro, Alberto Briganti, Daniele Crosti, Roberto Garzonio, Giorgio Gandaglia, Martina Faticoni, Chris Bangma, Maria Jongerden, Derya Tilki, Anssi Auvinen, Teemu Murtola, Tapio Visakorpi, Kirsi Talala, Teuvo Tammela, Aino Siltari, Stephane Lejeune, Laurence Colette, Simona Caputova, Delielena Poli, Sophie Byrne, Luz Fialho, Ashley Rowland, Neo Tapela, Nicola Di Flora, Kathi Apostolidis, Valerie Lemair, Bertrand De Meulder, Charles Auffray, Nesrine Taibi, Ayman Hijazy, Albert Saporta, Kai Sun, Shaun Power, Nazanin Zounemat Kermani, Kees van Bochove, Azadeh Tafreshiha, Chiara Bernini, Denis Horgan, Louise Fullwood, Marc Holtorf, Doron Lancet, Gabi Bernstein, Sheela Tripathee, Manfred Wirth, Michael Froehner, Beate Brenner, Angelika Borkowetz, Christian Thomas, Friedemann Horn, Kristin Reiche, Markus Kreuz, Andreas Josefsson, Delila Gasi Tandefelt, Jonas Hugosson, Jack Schalken, Henkjan Huisman, Thomas Hofmarcher, Peter Lindgren, Emelie Andersson, Adam Fridhammar, Monica Tames Grijalva, Susan Evans-Axelsson, Frank Verholen, Jihong Zong, John-Edward Butler-Ransohoff, Todd Williamson, Reg Waldeck, Amanda Bruno, Ekaterina Nevedomskaya, Samuel Fatoba, Niculae Constantinovici, Carl Steinbeisser, Monika Maass, Patrizia Torremante, Emmanuelle Dochy, Federica Pisa, Marc Dietrich Voss, Kishore Papineni, Jing Wang-silvanto, Robert Snijder, Xuewei Wang, Mark Lambrecht, Russ Wolfinger, Sherinne Eid, Soundarya Palanisamy, Samiul Haque, Laurent Antoni, Angela Servan, Katie Pascoe, Paul Robinson, Joana Lencart, Bertrand Jaton, Heidi Turunen, Olavi Kilkku, Pasi Pohjanjousi, Olli Voima, Liina Nevalaita, Keijo Punakivi, Sarah Seager, Shilpa Ratwani, Katarzyna Grzeslak, James Brash, Elaine Longden-Chapman, Danny Burke, Muriel Licour, Sarah Payne, Alan Yong, Flavia Lujan, Sophia Le Mare, Jan Hendrich, Michael Bussmann, Christian Reich
Publication date:01/01/2024
Journal:European Urology Open Science
Volume:59
Pages:27-29
Publisher:Elsevier
Description:Cancer survivorship was recently identified as a prostate cancer (PCa) research priority by PIONEER, a European network of excellence for big data in PCa. Despite being a research priority, cancer survivorship lacks a clear and agreed definition, and there is a distinct paucity of patient-reported outcome (PRO) data available on the subject. Data collection on cancer survivorship depends on the availability and implementation of (validated) routinely collected patient-reported outcome measures (PROMs). There have been recent advances in the availability of such PROMs. For instance, the European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) is developing survivorship questionnaires. This provides an excellent first step in improving the data available on cancer survivorship. However, we propose that an agreed, standardised definition of (prostate) cancer survivorship …
Cited by:3
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Biomarker discovery and confirmation using statistical and machine learning approaches in transcriptomics
2024
Michael Rade
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Authors:Michael Rade
Publication date:01/01/2024
Description:A biomarker is an indicator of (ab) normal molecular or cellular processes found in tissues, blood or other body fluids. It can also serve as an indicator of the response to an intervention, such as a drug response, toxic exposure, or disease. As a measurable and evaluable characteristic that indicative underlying biological processes, biomarkers can be used in immunology, toxicology, cancer research, and in a variety of application scenarios. These applications include the use of biomarkers as diagnostic tools, predictors of disease prognosis, monitoring clinical response to an intervention, or as tools for staging a disease. Another example is the early safety assessment of biomarkers for immunotherapies, which benefits from non-clinical models that provide an objective assessment of human immunological processes. Biomarkers accompanying non-clinical safety models enable the evaluation of models and risk prediction of immune-related adverse events. Biomarkers can be, for example, histological, radiological, physiological, or molecular in origin. At the molecular level, biomarkers have biophysical properties, which allow their measurements in biological samples (eg, plasma, serum, tissue). A gene-based biomarker could be, for example, a single nucleotide polymorphism associated with a particular disease or represent the expression level of a single gene or gene set. Biomarker analyses can be performed using various screening technologies such as mass spectrometry, proteomic approaches, high-throughput screening, or cell-and tissue-based DNA microarrays. Here, we aimed to discover gene-based biomarkers using transcriptome …
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A time-resolved meta-analysis of consensus gene expression profiles during human T-cell activation
2023
Michael Rade, Sebastian Böhlen, Vanessa Neuhaus, Dennis Löffler, Conny Blumert, Maximil…
Genome biology 24 (1), 287
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Authors:Michael Rade, Sebastian Böhlen, Vanessa Neuhaus, Dennis Löffler, Conny Blumert, Maximilian Merz, Ulrike Köhl, Susann Dehmel, Katherina Sewald, Kristin Reiche
Publication date:12/14/2023
Journal:Genome biology
Volume:24
Issue:1
Pages:287
Publisher:BioMed Central
Description:Background The coordinated transcriptional regulation of activated T-cells is based on a complex dynamic behavior of signaling networks. Given an external stimulus, T-cell gene expression is characterized by impulse and sustained patterns over the course. Here, we analyze the temporal pattern of activation across different T-cell populations to develop consensus gene signatures for T-cell activation. Results Here, we identify and verify general biomarker signatures robustly evaluating T-cell activation in a time-resolved manner. We identify time-resolved gene expression profiles comprising 521 genes of up to 10 disjunct time points during activation and different polarization conditions. The gene signatures include central transcriptional regulators of T-cell activation, representing successive waves as well as sustained patterns of induction. They cover sustained repressed, intermediate, and late response …
Cited by:19
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Microglia and neuron derived extracellular vesicles show distinct small RNA patterns in Alzheimer’s disease
2023
Skaiste Arbaciauskaite, Susann Allelein, Alexander Scholz, Dennis Loeffler, Kristin Rei…
Alzheimer's & Dementia 19, e075361
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Authors:Skaiste Arbaciauskaite, Susann Allelein, Alexander Scholz, Dennis Loeffler, Kristin Reiche, Conny Blumert, Dirk Kuhlmeier
Publication date:12/01/2023
Journal:Alzheimer's & Dementia
Volume:19
Pages:e075361
Description:Background Extracellular vesicles (EVs) are nano‐sized membranous particles that are released by almost all cells in the human body. EVs carry different cargo (e.g. protein, lipid, nucleic acids) that differs based on the EVs biogenesis and state of the cell during the release. Therefore, EVs are excellent for identifying disease patterns and biomarkers. The need to understand the pathogenetic patterns and biomarkers in neurodegenerative diseases is crucial for early diagnosis as well as potential therapeutic intervention. Studies show that small RNA, especially miRNA participate in pathologic processes connected to neurodegeneration, therefore we have specifically looked into microglia and neuron derived EVs small RNA content of patients with Alzheimer’s disease (AD) and control patients. The aim of the study was to find AD patterns coded in small RNA. Method EVs were isolated specifically from microglia …
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Cellular Dynamics Following CAR T Cell Therapy Are Associated with Response, Resistance and Cytokine Release Syndrome in Relapsed/Refractory Multiple Myeloma
2023
Luise Fischer, Patrick Born, Ronald Weiss, Nora Grieb, Sabine Seiffert, Andreas Boldt, …
Blood 142, 1008
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Authors:Luise Fischer, Patrick Born, Ronald Weiss, Nora Grieb, Sabine Seiffert, Andreas Boldt, Stephan Fricke, Paul Franz, Christina Kloetzer, Simone Heyn, Ronny Baber, Song-Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Janine Kirchberg, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Kristin Reiche, Ulrike Koehl, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz
Publication date:11/02/2023
Journal:Blood
Volume:142
Pages:1008
Publisher:Content Repository Only!
Description:IntroductionThe introduction of B cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). While long-term follow-up of CD19 CAR T cells demonstrated a connection between CAR T cell expansion and persistence with outcome, very little is known about persistence and effects on bystander cells of BCMA-targeting CAR T cells.MethodsWe analyzed 27 RRMM patients (pts) treated with Idecabtagene vicleucel (Ide-cel) at our center. Pts were grouped based on their remission evaluated 100 days after infusion into responders (partial response or better, n=16) or non-responders (progressive disease, n=11). Peripheral blood (pb) was drawn at day of leukapheresis, at day of infusion/after lymphodepletion (LD, d0) and at several time points following Ide-cel infusion (d7, d14, d30 and d100). In order to reflect a …
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Single cell multi-omic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma
2023
Maximilian Merz, Luise Fischer, Jaren Sia, Patrick Born, Ronald Weiss, Nora Grieb, Mich…
Blood 142, 453
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Authors:Maximilian Merz, Luise Fischer, Jaren Sia, Patrick Born, Ronald Weiss, Nora Grieb, Michael Rade, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Klaus H Metzeler, Marco Herling, Carmen Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Ulrike Koehl, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic
Publication date:11/02/2023
Journal:Blood
Volume:142
Pages:453
Publisher:Content Repository Only!
Description:Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment of relapsed/refractory multiple myeloma (RRMM). Robust variables that predict long-term response are currently missing. Limited data are especially available on the impact of bridging therapies on manufacturing and outcome. We conducted a longitudinal single-cell multi-omics study to identify factors that predict response to BCMA-directed CAR T cells. Changes in the immune microenvironment associated with response were analyzed as well as the impact of prior bridging therapy with bispecific antibodies on subsequent CAR T cell manufacturing and outcome.Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 29 consecutive MM patients treated with commercially available anti-BCMA CAR T cells on the day of leukapheresis as well as days 30 and 100 after CAR T cell infusion. PBMCs were …
Cited by:4
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IN-DEPTH CHARACTERIZATION OF THE IMMUNE MICROENVIRONMENT OF PATIENTS UNDERGOING CAR T CELL THERAPY
2023
M Alb, U Weirauch, R Weiss, D Loeffler, V Kopfnagel, C Blumert, J Duell, L Scheller, A …
HUMAN GENE THERAPY 34 (21-22), A37-A37
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Authors:M Alb, U Weirauch, R Weiss, D Loeffler, V Kopfnagel, C Blumert, J Duell, L Scheller, A Boldt, V Vucinic, U Platzbecker, U Koehl, M Hudecek, K Reiche
Publication date:11/01/2023
Journal:HUMAN GENE THERAPY
Volume:34
Issue:21-22
Pages:A37-A37
Publisher:MARY ANN LIEBERT, INC
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Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma
2023
Maximilian Merz, Luise Fischer, Nora Grieb, Patrick Born, Ronald Weiss, Sabine Seiffert…
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Authors:Maximilian Merz, Luise Fischer, Nora Grieb, Patrick Born, Ronald Weiss, Sabine Seiffert, Andreas Boldt, Stephan Fricke, Paul Franz, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song-Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Janine Kirchberg, Saskia Hell, Sebastian Schwind, Klaus Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Kristin Reiche, Ulrike Koehl, Uwe Platzbecker, Vladan Vucinic
Publication date:10/06/2023
Description:B cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T cells revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM). However, data on cellular (CAR) T cell dynamics and the association with response, resistance or the occurrence of cytokine release syndrome (CRS) are limited. Therefore, we performed a comprehensive flow cytometry analysis of 27 RRMM patients treated with Idecabtagene vicleucel (Ide-cel) to assess the expansion capacity, persistence and effects on bystander cells of BCMA-targeting CAR T cells. Additionally, we addressed side effects, like cytokine release syndrome (CRS) and cytopenia. Our results show that in vivo expansion of CD8+ CAR T cells is correlated to response, however persistence is not essential for durable remission in RRMM patients. In addition, our data provide evidence, that an increased fraction of CD8+ T cells at day of leukapheresis in combination with successful lymphodepletion positively influence the outcome. We show that patients at risk for higher-grade CRS can be identified already prior to lymphodepletion. Our extensive characterization contributes to a better understanding of the dynamics and effects of BCMA-targeting CAR T cells, in order to predict the response of individual patients as well as side effects, which can be counteracted at an early stage or even prevented.
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Nonclinical mimicking of the immune system effects of immunomodulatory therapies: The imSAVAR project: P1111
2023
M Alb, L Scheller, H Einsele, K Sewald, U Weirauch, K Reiche, U Köhl, M Hudecek
Oncology Research and Treatment 46, 317-318
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Authors:M Alb, L Scheller, H Einsele, K Sewald, U Weirauch, K Reiche, U Köhl, M Hudecek
Publication date:10/01/2023
Journal:Oncology Research and Treatment
Volume:46
Pages:317-318
Description:Methods: In MAIA, pts with NDMM ineligible for high-dose chemotherapy and ASCT were randomized 1: 1 to receive D-Rd or Rd. All pts received 28-day cycles of oral Rd (R: 25mg on Days 1-21; d: 40mg on Days 1, 8, 15, 22). Pts in the D-Rd arm received intravenous daratumumab (16mg/kg QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter). Pts in both arms were treated until disease progression or unacceptable toxicity. e primary endpoint was PFS, and key secondary endpoints included ORR and MRD–negativity rate (10–5 sensitivity). Results: Pts were randomized (D-Rd, n= 368; Rd, n= 369) and most subgroups had a similar number of pts per treatment arm. After a 64.5-month median follow-up, PFS and ORR generally favored D-Rd versus Rd across subgroups. MRD-negativity rates were higher with D-Rd versus Rd for pts aged≥ 75 years (26.9% vs 9.9%; P< 0.0001), pts with ISS stage III disease …
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In depth characterization of patients undergoing CAR-T therapy reveals new potential predictors for CRS/ICANS and prolonged cytopenias: P384
2023
L Scheller, K Reiche, S Schimanski, H Hornburger, S-K Kadel, A Ruckdeschel, F Eisele, H…
Oncology Research and Treatment 46, 198-199
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Authors:L Scheller, K Reiche, S Schimanski, H Hornburger, S-K Kadel, A Ruckdeschel, F Eisele, H Einsele, U Köhl, J Düll, MS Topp, M Hudecek, M Alb
Publication date:10/01/2023
Journal:Oncology Research and Treatment
Volume:46
Pages:198-199
Description:Methods: Target antigen expression was analyzed in cell lines and a broad GBM patient collective via IHC, qPCR and flow cytometry. 2nd generation CAR-T cells were manufactured by fusing the respective scFvs to an IgG spacer, transmembrane domain and a signaling module comprising CD3z and 4-1BB. CARs were expressed in T cells by lentiviral transduction and their anti-tumoral capacities were investigated in vitro, in vivo (orthotopic mouse models) and ex vivo (PDOs). In this course, cytokine production (ELISA), proliferation (CFSE assay, Ki67 staining) and cytotoxicity (luciferase-based assay, CC3 apoptosis staining, BLI imaging) was analyzed. Results: Given the results of our screenings, we focused on GD2 and two novel undisclosed antigen candidates. In in vitro co-culture assays including seven different GBM cell lines (GCL) expressing either one or more of the three antigens to varying levels, we …
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OA-04 Single cell multi-omic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma
2023
Nora Grieb, Ronald Weiss, Jaren Sia, Michael Rade, Luise Fischer, Patrick Born, Stephan…
Clinical Lymphoma Myeloma and Leukemia 23, S3
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Authors:Nora Grieb, Ronald Weiss, Jaren Sia, Michael Rade, Luise Fischer, Patrick Born, Stephan Fricke, Paul Franz, Jonathan Scolnick, Stacy Xu, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Sandra Hoffmann, Enrica Bach, Klaus Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Kristin Reiche, Ulrike Köhl, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz
Publication date:09/01/2023
Journal:Clinical Lymphoma Myeloma and Leukemia
Volume:23
Pages:S3
Publisher:Elsevier
Description:20th International Myeloma Society Annual Meeting September 2023 S3 Abstracts OA-04 Single cell multi‑omic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma Nora Grieb1, Ronald Weiss1, Jaren Sia1, Michael Rade1, Luise Fischer1, Patrick Born1, Stephan Fricke2, Paul Franz2, Jonathan Scolnick3, Stacy Xu3, Anne Sophie Kubasch1, Ronny Baber1, Song Yau Wang1, Sandra Hoffmann1, Enrica Bach1, Klaus Metzeler1, Marco Herling1, Madlen Jentzsch1, Georg‑Nikolaus Franke1, Ulrich Sack1, Kristin Reiche2, Ulrike Kö hl2, Uwe Platzbecker1, Vladan Vucinic1, Maximilian Merz1 1University Hospital of Leipzig; 2Fraunhofer IZI; 3Singleron Biotechnologies Introduction: Robust biomarkers of response and resistance to chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma (RRMM) are …
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P-009 Cellular dynamics following CAR T cell therapy are associated with response, resistance and cytokine release syndrome in relapsed/refractory myeloma
2023
Luise Fischer, Ronald Weiss, Nora Grieb, Michael Rade, Patrick Born, Andreas Boldt, Ste…
Clinical Lymphoma Myeloma and Leukemia 23, S37-S38
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Authors:Luise Fischer, Ronald Weiss, Nora Grieb, Michael Rade, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz, Ulrike Köhl
Publication date:09/01/2023
Journal:Clinical Lymphoma Myeloma and Leukemia
Volume:23
Pages:S37-S38
Publisher:Elsevier
Description:20th International Myeloma Society Annual Meeting September 2023 S37 Abstracts P-008 Idecabtagene vicleucel (ide‑cel) vs standard regimens in triple‑class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM): KarMMa‑3 subgroup analysis in patients receiving bridging therapy Hermann Einsele1, Paula RodrÃguez‑Otero2, Bertrand Arnulf3, Krina Patel4, Salomon Manier5, Luciano Costa6, Nizar Bahlis7, Annemiek Broijl8, Christine Chen9, Ingerid Weum Abrahamsen10, Michel Delforge11, Usama Gergis12, Marc Raab13, Seema Singhal14, Rafat Abonour15, Anna Truppel‑Hartmann16, Rashmi Bhatnagar17, Jasper Felten18, Andrea Caia18, Fan Wu18, Julia Piasecki18, Mark Cook19, Sikander Ailawadhi20 1Universitä tsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany; 2ClÃnica Universidad de Navarra, CIMA, CIBERONC, IDISNA, Pamplona …
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Multi-gene expression assay for prostate carcinoma
2023

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Publication date:08/24/2023
Description:YMZPQKXPKZZSFV-CPWYAANMSA-N 2-[3-[(1r)-1-[(2s)-1-[(2s)-2-[(1r)-cyclohex-2-en-1-yl]-2-(3, 4, 5-trimethoxyphenyl) acetyl] piperidine-2-carbonyl] oxy-3-(3, 4-dimethoxyphenyl) propyl] phenoxy] acetic acid Chemical compound C1= C (OC) C (OC)= CC= C1CC [C@ H](C= 1C= C (OCC (O)= O) C= CC= 1) OC (= O)[C@ H] 1N (C (= O)[C@@ H]([C@ H] 2C= CCCC2) C= 2C= C (OC) C (OC)= C (OC) C= 2) CCCC1 YMZPQKXPKZZSFV-CPWYAANMSA-N 0.000 description 1 KIAPWMKFHIKQOZ-UHFFFAOYSA-N 2-[[(4-fluorophenyl)-oxomethyl] amino] benzoic acid methyl ester Chemical compound COC (= O) C1= CC= CC= C1NC (= O) C1= CC= C (F) C= C1 KIAPWMKFHIKQOZ-UHFFFAOYSA-N 0.000 description 1
Cited by:1
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Teclistamab impairs detection of BCMA CAR-T cells
2023
Bettina Glatte, Kerstin Wenk, Anja Grahnert, Maik Friedrich, Maximilian Merz, Vladan Vu…
Blood advances 7 (15), 3842-3845
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Authors:Bettina Glatte, Kerstin Wenk, Anja Grahnert, Maik Friedrich, Maximilian Merz, Vladan Vucinic, Luise Fischer, Kristin Reiche, Miriam Alb, Michael Hudecek, Paul Franz, Stephan Fricke, Uwe Platzbecker, Ulrike Koehl, Ulrich Sack, Andreas Boldt, Sunna Hauschildt, Ronald Weiss
Publication date:08/08/2023
Journal:Blood advances
Volume:7
Issue:15
Pages:3842-3845
Publisher:American Society of Hematology
Description:COI notes: MM, VV and UP receive honoraria from Janssen and BMS. MM is also supported by Janssen Research. SF was a consultant for Janssen-Cilag. SF, PF, RW and AG are involved in collaborations with Novartis and Miltenyi Biotec regarding the production of CAR T cells. MH receive speaker honoraria from Novartis, Janssen, Celgene/BMS, and has participated in scientific advisory boards for Janssen and Celgene/BMS. MH is listed as an inventor on patent applications and granted patents related to CAR technologies and CAR T-cell therapy that have been filed by the Fred Hutchinson Cancer Research Center and the University of Wuerzburg, and that have been, in part, licensed to industry. MH is a cofounder and equity owner of T-CURX GmbH, Wuerzburg, Germany. UK is a consultant in immunooncology for AstraZeneca, Affimed, Glycostem, GammaDelta and Zelluna, and has collaborations with …
Cited by:6
Resources:[HTML] from sciencedirect.com
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Characterization and evaluation of gene fusions as a measure of genetic instability and disease prognosis in prostate cancer
2023
Carolin Schimmelpfennig, Michael Rade, Susanne Füssel, Dennis Löffler, Conny Blumert, C…
BMC cancer 23 (1), 575
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Authors:Carolin Schimmelpfennig, Michael Rade, Susanne Füssel, Dennis Löffler, Conny Blumert, Catharina Bertram, Angelika Borkowetz, Dominik J Otto, Sven-Holger Puppel, Pia Hönscheid, Ulrich Sommer, Gustavo B Baretton, Ulrike Köhl, Manfred Wirth, Christian Thomas, Friedemann Horn, Markus Kreuz, Kristin Reiche
Publication date:06/22/2023
Journal:BMC cancer
Volume:23
Issue:1
Pages:575
Publisher:BioMed Central
Description:Background Prostate cancer (PCa) is one of the most prevalent cancers worldwide. The clinical manifestations and molecular characteristics of PCa are highly variable. Aggressive types require radical treatment, whereas indolent ones may be suitable for active surveillance or organ-preserving focal therapies. Patient stratification by clinical or pathological risk categories still lacks sufficient precision. Incorporating molecular biomarkers, such as transcriptome-wide expression signatures, improves patient stratification but so far excludes chromosomal rearrangements. In this study, we investigated gene fusions in PCa, characterized potential novel candidates, and explored their role as prognostic markers for PCa progression. Methods We analyzed 630 patients in four cohorts with varying traits regarding sequencing protocols, sample conservation, and PCa risk group. The datasets included transcriptome-wide …
Cited by:5
Resources:[HTML] from springer.com
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Transcriptomic signatures reveal a shift towards an anti-inflammatory gene expression profile but also the induction of type I and type II interferon signaling networks through …
2023
Johannes R Schmidt, Janine Haupt, Sina Riemschneider, Christoph Kämpf, Dennis Löffler, …
Frontiers in Immunology 14, 1156493
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Authors:Johannes R Schmidt, Janine Haupt, Sina Riemschneider, Christoph Kämpf, Dennis Löffler, Conny Blumert, Kristin Reiche, Ulrike Koehl, Stefan Kalkhof, Jörg Lehmann
Publication date:05/23/2023
Journal:Frontiers in Immunology
Volume:14
Pages:1156493
Publisher:Frontiers Media SA
Description:Introduction The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a broad range of target genes involved in the xenobiotic response, cell cycle control and circadian rhythm. AhR is constitutively expressed in macrophages (Mϕ), acting as key regulator of cytokine production. While proinflammatory cytokines, i.e., IL-1β, IL-6, IL-12, are suppressed through AhR activation, anti-inflammatory IL-10 is induced. However, the underlying mechanisms of those effects and the importance of the specific ligand structure are not yet completely understood. Methods Therefore, we have compared the global gene expression pattern in activated murine bone marrow-derived macrophages (BMMs) subsequently to exposure with either benzo[a]pyrene (BaP) or indole-3-carbinol (I3C), representing high-affinity vs. low-affinity AhR ligands, respectively, by means of mRNA sequencing. AhR dependency of observed effects was proved using BMMs from AhR-knockout (Ahr-/- ) mice. Results and discussion In total, more than 1,000 differentially expressed genes (DEGs) could be mapped, covering a plethora of AhR-modulated effects on basal cellular processes, i.e., transcription and translation, but also immune functions, i.e., antigen presentation, cytokine production, and phagocytosis. Among DEGs were genes that are already known to be regulated by AhR, i.e., Irf1, Ido2, and Cd84. However, we identified DEGs not yet described to be AhR-regulated in Mϕ so far, i.e., Slpi, Il12rb1, and Il21r. All six genes likely contribute to shifting the Mϕ phenotype from proinflammatory to anti-inflammatory. The majority of DEGs induced through …
Cited by:15
Resources:[HTML] from frontiersin.org
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Immunotherapy: IN-DEPTH CHARACTERIZATION OF THE IMMUNE MICROENVIRONMENT OF PATIENTS UNDERGOING CAR T CELL THERAPY
2023
U Weirauch, M Alb, R Weiß, D Löffler, V Kopfnagel, C Blumert, J Düll, L Scheller, A Bol…
Cytotherapy 25 (6), S255-S256
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Authors:U Weirauch, M Alb, R Weiß, D Löffler, V Kopfnagel, C Blumert, J Düll, L Scheller, A Boldt, V Vucinic, U Platzbecker, U Köhl, M Hudecek, K Reiche
Publication date:05/01/2023
Journal:Cytotherapy
Volume:25
Issue:6
Pages:S255-S256
Publisher:Elsevier
Description:JCYT 25060502 S1465-3249 (23) 00633-3 10.1016/S1465-3249 (23) 00633-3 International Society for Cell & Gene Therapy Copyright &# x00A9; 2023 International Society for Cell & Gene Therapy POSTER ABSTRACTS: Immunotherapy 1088 Immunotherapy: IN-DEPTH CHARACTERIZATION OF THE IMMUNE MICROENVIRONMENT OF PATIENTS UNDERGOING CAR T CELL THERAPY U. Weirauch M. Alb R. Wei&# x00DF; D. L&# x00F6; ffler V. Kopfnagel C. Blumert J. D&# x00FC; ll L. Scheller A. Boldt V. Vucinic U. Platzbecker U. K&# x00F6; hl M. Hudecek K. Reiche
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Atypisches Fibroxanthom und pleomorphes dermales Sarkom–Genexpressionsanalyse im Vergleich zum entdifferenzierten Plattenepithelkarzinom der Haut
2023
Iris Marie Anders, Carolin Schimmelpfennig, Karolin Wiedemann, Dennis Löffler, Christop…
JDDG: Journal der Deutschen Dermatologischen Gesellschaft 21 (5), 482-492
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Authors:Iris Marie Anders, Carolin Schimmelpfennig, Karolin Wiedemann, Dennis Löffler, Christoph Kämpf, Conny Blumert, Kristin Reiche, Manfred Kunz, Ulf Anderegg, Jan‐Christoph Simon, Mirjana Ziemer
Publication date:05/01/2023
Journal:JDDG: Journal der Deutschen Dermatologischen Gesellschaft
Volume:21
Issue:5
Pages:482-492
Description:Hintergrund Der histogenetische Ursprung des atypischen Fibroxanthoms (AFX) und pleomorphen dermalen Sarkoms (PDS) ist nicht abschließend geklärt. Neben einem fibroblastären Ursprung wird aufgrund starker klinischer, histomorphologischer und molekulargenetischer Ähnlichkeiten zum entdifferenzierten Plattenepithelkarzinom der Haut (cutaneous squamous cell carcinoma, cSCC) eine keratinozytäre Differenzierung diskutiert. Patienten und Methodik 56 Fälle (36 AFX, 8 PDS, 12 entdifferenzierte cSCC) wurden hinsichtlich ihrer klinischen, histomorphologischen und immunhistochemischen Charakteristika untersucht. An 18 Fällen (6 AFX/PDS, 6 entdifferenzierte cSCC, 6 differenzierte cSCC) wurde eine RNA‐Transkriptomanalyse durchgeführt. Ergebnisse Klinisch bestätigten sich starke Gemeinsamkeiten hinsichtlich Alter, Geschlecht und Lokalisation der Tumoren. Histomorphologisch ist es häufig …
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Atypical fibroxanthoma and pleomorphic dermal sarcoma–gene expression analysis compared with undifferentiated cutaneous squamous cell carcinoma
2023
Iris Marie Anders, Carolin Schimmelpfennig, Karolin Wiedemann, Dennis Löffler, Christop…
JDDG: Journal der Deutschen Dermatologischen Gesellschaft 21 (5), 482-491
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Authors:Iris Marie Anders, Carolin Schimmelpfennig, Karolin Wiedemann, Dennis Löffler, Christoph Kämpf, Conny Blumert, Kristin Reiche, Manfred Kunz, Ulf Anderegg, Jan‐Christoph Simon, Mirjana Ziemer
Publication date:05/01/2023
Journal:JDDG: Journal der Deutschen Dermatologischen Gesellschaft
Volume:21
Issue:5
Pages:482-491
Description:Background The histogenetic origin of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) has not been definitively elucidated. In addition to a fibroblastic origin, a keratinocytic differentiation is discussed due to strong clinical, histomorphological and molecular genetic similarities with undifferentiated cutaneous squamous cell carcinoma (cSCC). Patients and Methods 56 cases (36 AFXs, 8 PDSs, 12 undifferentiated cSCCs) were evaluated for their clinical, histomorphological, and immunohistochemical characteristics. RNA transcriptome analysis was performed on 18 cases (6 AFXs/PDSs, 6 undifferentiated cSCCs, 6 differentiated cSCCs). Results Clinically, the strong similarities in age, gender and tumor location were confirmed. Without further immunohistochemical staining, histomorphological differentiation between AFX/PDS and undifferentiated cSCC is often impossible. Principal …
Cited by:7
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Detection of Immune Cell Interactions in malignant Melanoma by spatial RNA Sequencing
2023
Florian Grosse, Dennis Loeffler, Michael Rade, Hans Binder, Maria Schmidt, Markus Kreuz…
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT 21, 14-15
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Authors:Florian Grosse, Dennis Loeffler, Michael Rade, Hans Binder, Maria Schmidt, Markus Kreuz, Sebastian Greiser, Conny Blumert, Kristin Reiche, Manfred Kunz
Publication date:04/01/2023
Journal:JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
Volume:21
Pages:14-15
Publisher:WILEY
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How well do polygenic risk scores identify men at high risk for prostate cancer? Systematic review and meta-analysis
2023
Aino Siltari, Ragnar Lönnerbro, Karl Pang, Kirill Shiranov, Alex Asiimwe, Susan Evans-A…
Clinical genitourinary cancer 21 (2), 316. e1-316. e11
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Authors:Aino Siltari, Ragnar Lönnerbro, Karl Pang, Kirill Shiranov, Alex Asiimwe, Susan Evans-Axelsson, Billy Franks, Amit Kiran, Teemu J Murtola, Jack Schalken, Carl Steinbeisser, Anders Bjartell, Anssi Auvinen, J N’Dow, EJ Smith, R Shepherd, M Ribal, N Mottet, L Moris, M Lardas, PP Willemse, G Gandaglia, R Campi, Rossella Nicoletti, M Gacci, A Briganti, MM Ratti, E Alleva, L Leardini, ES Sisca, R Bangma, M Roobol, S Remmers, D Tilki, T Visakorpi, K Talala, T Tammela, M van Hemelrijck, K Bayer, S Lejeune, S Byrne, L Fialho, P Palaiologou B De Meulder, C Auffray, A Hijazy, S Power, N Zounemat Kermani, K van Bochove, M Kalafati, M Moinat, E Voss, D Horgan, L Fullwood, M Holtorf, D Lancet, G Bernstein, I Omar, S MacLennan, S Maclennan, S Tripathee, M Wirth, M Froehner, B Brenner, A Borkowetz, C Thomas, F Horn, K Reiche, M Kreux, A Josefsson, D Gasi Tandefekt, J Hugosson, H Huisman, J Schalken, T Hofmacher, P Lindgren, E Andersson, A Fridhammar, J Zong, JE Butler-Ransohoff, R Herrera, M Maass, P Torremante, MD Voss, Z Devecseri, T Abbott, C Dau, K Papineni, R Snijder, M Lambrecht, R Wolfinger, S Rogiers, A Servan, L Antoni, K Pacoe, P Robinson, B Jaton, D Bakkard, H Turunen, O Kilkku, P Pohjanjousi, O Voima, L Nevalaita, C Reich, S Araujo, E Longden-Chapman, D Burke, P Agapow, S Derkits, M Licour, C McCrea, S Payne, A Yong, L Thompson, S Le Mare, M Bussmann, D Kotik
Publication date:04/01/2023
Journal:Clinical genitourinary cancer
Volume:21
Issue:2
Pages:316. e1-316. e11
Publisher:Elsevier
Description:Objectives Patients and methods
Cited by:18
Resources:[HTML] from sciencedirect.com
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Single cell multi-omic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma
2023
Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stepha…
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Authors:Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Kubasch, Ronny Baber, Song Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Birthe Schetschorke, Saskia Hell, Sebastian Schwind, Klaus Metzeler, Marco Herling, Madlen Jentzsch, Georg Franke, Ulrich Sack, Kristin Reiche, Ulrike Koehl, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz
Publication date:02/28/2023
Description:Markers predicting response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected cells isolated from peripheral blood and bone marrow before and after the application of CAR T cells directed against B cell maturation antigen to single cell multi-omic analyses to identify markers associated with resistance and early relapse. Differences between responders and non-responders were already identified at time of leukapheresis. Non-responders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressing CD8+ and NK cell function. The analyses of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded compared to low/intermediate expanded clones. We identified potential immunotherapeutic targets on …
Cited by:1
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From Research to Regulated Software
2023
Christoph Kämpf, Alexander Scholz, Markus Kreuz, Kristin Reiche
Conference for research software developers in Germany 2023
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Authors:Christoph Kämpf, Alexander Scholz, Markus Kreuz, Kristin Reiche
Publication date:01/01/2023
Journal:Conference for research software developers in Germany 2023
Description:We develop computational and omic-wide methods to identify and validate new biomarkers for personalised diagnosis and prognosis of diseases. Before these methods can be used in patient care they have to be implemented as regulated software. Regulated software is software that has to conform to some legislation. Legislation requires software development to be conform to IEC/ISO standards. We have a software that is intended to be used as a in-vitro diagnostic. So we had to establish an IEC 62304 conform software development process. Here we share some insights about: our tool stack, our processes, handling a lot of documents and how it all links to software engineering best practices and reproducible science.
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Transcriptional states of CAR-T infusion relate to neurotoxicity–lessons from high-resolution single-cell SOM expression portraying
2022
Henry Loeffler-Wirth, Michael Rade, Arsen Arakelyan, Markus Kreuz, Markus Loeffler, Ulr…
Frontiers in immunology 13, 994885
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Authors:Henry Loeffler-Wirth, Michael Rade, Arsen Arakelyan, Markus Kreuz, Markus Loeffler, Ulrike Koehl, Kristin Reiche, Hans Binder
Publication date:09/28/2022
Journal:Frontiers in immunology
Volume:13
Pages:994885
Publisher:Frontiers Media SA
Description:Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for patients with B cell lymphomas, however it copes with partly severe adverse effects like neurotoxicity. Single-cell resolved molecular data sets in combination with clinical parametrization allow for comprehensive characterization of cellular subpopulations, their transcriptomic states, and their relation to the adverse effects. We here present a re-analysis of single-cell RNA sequencing data of 24 patients comprising more than 130,000 cells with focus on cellular states and their association to immune cell related neurotoxicity. For this, we developed a single-cell data portraying workflow to disentangle the transcriptional state space with single-cell resolution and its analysis in terms of modularly-composed cellular programs. We demonstrated capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses. Our analysis revealed that the T cell composition of the patient’s infusion product as well as the spectrum of their transcriptional states of cells derived from patients with low ICANS grade do not markedly differ from those of cells from high ICANS patients, while the relative abundancies, particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR positive cells, vary. Our study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity.
Cited by:5
Resources:[HTML] from frontiersin.org
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New Strategies to improve the Safety of CAR-T Cell Immunotherapy: the imSAVAR Project
2022
M Alb, H Einsele, P Loskill, A Van der Meer, K Sewald, K Reiche, U Koehl, M Hudecek
ONCOLOGY RESEARCH AND TREATMENT 45 (SUPPL 2), 70-71
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Authors:M Alb, H Einsele, P Loskill, A Van der Meer, K Sewald, K Reiche, U Koehl, M Hudecek
Publication date:09/01/2022
Journal:ONCOLOGY RESEARCH AND TREATMENT
Volume:45
Issue:SUPPL 2
Pages:70-71
Publisher:KARGER
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Time 2EVOLVE: predicting efficacy of engineered T-cells–how far is the bench from the bedside?
2022
Sonia Guedan, Maik Luu, Delphine Ammar, Paula Barbao, Chiara Bonini, Philippe Bousso, C…
Journal for Immunotherapy of Cancer 10 (5), e003487
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Authors:Sonia Guedan, Maik Luu, Delphine Ammar, Paula Barbao, Chiara Bonini, Philippe Bousso, Christian J Buchholz, Monica Casucci, Biagio De Angelis, Emmanuel Donnadieu, David Espie, Beatrice Greco, Richard Groen, Johannes B Huppa, Chahrazade Kantari-Mimoun, Bruno Laugel, Mary Mantock, Janet L Markman, Emma Morris, Concetta Quintarelli, Michael Rade, Kristin Reiche, Alba Rodriguez-Garcia, Juan Roberto Rodriguez-Madoz, Eliana Ruggiero, Maria Themeli, Michael Hudecek, Ibtissam Marchiq
Publication date:05/16/2022
Journal:Journal for Immunotherapy of Cancer
Volume:10
Issue:5
Pages:e003487
Description:Immunotherapy with gene engineered CAR and TCR transgenic T-cells is a transformative treatment in cancer medicine. There is a rich pipeline with target antigens and sophisticated technologies that will enable establishing this novel treatment not only in rare hematological malignancies, but also in common solid tumors. The T2EVOLVE consortium is a public private partnership directed at accelerating the preclinical development of and increasing access to engineered T-cell immunotherapies for cancer patients. A key ambition in T2EVOLVE is to assess the currently available preclinical models for evaluating safety and efficacy of engineered T cell therapy and developing new models and test parameters with higher predictive value for clinical safety and efficacy in order to improve and accelerate the selection of lead T-cell products for clinical translation. Here, we review existing and emerging preclinical …
Cited by:31
Resources:[HTML] from nih.gov
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Time to evolve: predicting engineered T cell-associated toxicity with next-generation models
2022
Emmanuel Donnadieu, Maik Luu, Miriam Alb, Brigitte Anliker, Silvia Arcangeli, Chiara Bo…
Journal for immunotherapy of cancer 10 (5), e003486
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Authors:Emmanuel Donnadieu, Maik Luu, Miriam Alb, Brigitte Anliker, Silvia Arcangeli, Chiara Bonini, Biagio De Angelis, Rashmi Choudhary, David Espie, Anne Galy, Cam Holland, Zoltán Ivics, Chahrazade Kantari-Mimoun, Marie Jose Kersten, Ulrike Köhl, Chantal Kuhn, Bruno Laugel, Franco Locatelli, Ibtissam Marchiq, Janet Markman, Marta Angiola Moresco, Emma Morris, Helene Negre, Concetta Quintarelli, Michael Rade, Kristin Reiche, Matthias Renner, Eliana Ruggiero, Carmen Sanges, Hans Stauss, Maria Themeli, Jan Van den Brulle, Michael Hudecek, Monica Casucci
Publication date:05/16/2022
Journal:Journal for immunotherapy of cancer
Volume:10
Issue:5
Pages:e003486
Description:Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public–private partnership directed at accelerating the preclinical development and increasing access to …
Cited by:62
Resources:[HTML] from nih.gov
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Immunotherapy: NOVEL STRATEGIES TO ENHANCE THE SAFETY OF CAR T CELL IMMUNOTHERAPY: THE IMSAVAR PROJECT
2022
M Alb, H Einsele, P Loskill, A Van der Meer, K Sewald, K Reiche, U Koehl, M Hudecek
Cytotherapy 24 (5), S122
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Authors:M Alb, H Einsele, P Loskill, A Van der Meer, K Sewald, K Reiche, U Koehl, M Hudecek
Publication date:05/01/2022
Journal:Cytotherapy
Volume:24
Issue:5
Pages:S122
Publisher:Elsevier
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Spatial transcriptomics of primary melanoma lesions
2022
M Rade, D Loeffler, FP Grosse, A Scholz, C Blumert, K Reiche, M Kunz
EXPERIMENTAL DERMATOLOGY 31 (2), E90-E91
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Authors:M Rade, D Loeffler, FP Grosse, A Scholz, C Blumert, K Reiche, M Kunz
Publication date:02/01/2022
Journal:EXPERIMENTAL DERMATOLOGY
Volume:31
Issue:2
Pages:E90-E91
Publisher:WILEY
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RNA sequencing of glioblastoma tissue slice cultures reveals the effects of treatment at the transcriptional level
2022
Susann Haehnel, Michael Rade, Nicole Kaiser, Kristin Reiche, Andreas Horn, Dennis Loeff…
FEBS Open bio 12 (2), 480-493
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Authors:Susann Haehnel, Michael Rade, Nicole Kaiser, Kristin Reiche, Andreas Horn, Dennis Loeffler, Conny Blumert, Felicitas Rapp, Friedemann Horn, Juergen Meixensberger, Christof Renner, Wolf Mueller, Frank Gaunitz, Ingo Bechmann, Karsten Winter
Publication date:02/01/2022
Journal:FEBS Open bio
Volume:12
Issue:2
Pages:480-493
Description:One of the major challenges in cancer research is finding models that closely resemble tumors within patients. Human tissue slice cultures are a promising approach to provide a model of the patient's tumor biology ex vivo. Recently, it was shown that these slices can be successfully analyzed by whole transcriptome sequencing as well as automated histochemistry, increasing their usability as preclinical model. Glioblastoma multiforme (GBM) is a highly malignant brain tumor with poor prognosis and little is known about its genetic background and heterogeneity regarding therapy success. In this study, tissue from the tumors of 25 patients with primary GBM was processed into slice cultures and treated with standard therapy (irradiation and temozolomide). Total RNA sequencing and automated histochemistry were performed to enable analysis of treatment effects at a transcriptional and histological level. Slice …
Cited by:5
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Transcriptional states of CAR-T infusion relate to neurotoxicity
2022
Henry Loeffler-Wirth, Michael Rade, Arsen Arakelyan, Markus Kreuz, Markus Loeffler, Ulr…
:read more
Authors:Henry Loeffler-Wirth, Michael Rade, Arsen Arakelyan, Markus Kreuz, Markus Loeffler, Ulrike Koehl, Kristin Reiche, Hans Binder
Publication date:01/01/2022
Description:Abstract (EN) Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for patients with B cell lymphomas, however it copes with partly severe adverse effects like neurotoxicity. Single-cell resolved molecular data sets in combination with clinical parametrization allow for comprehensive characterization of cellular subpopulations, their transcriptomic states, and their relation to the adverse effects. We here present a re-analysis of single-cell RNA sequencing data of 24 patients comprising more than 130,000 cells with focus on cellular states and their association to immune cell related neurotoxicity. For this, we developed a single-cell data portraying workflow to disentangle the transcriptional state space with single-cell resolution and its analysis in terms of modularly-composed cellular programs. We demonstrated capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses. Our analysis revealed that the T cell composition of the patient’s infusion product as well as the spectrum of their transcriptional states of cells derived from patients with low ICANS grade do not markedly differ from those of cells from high ICANS patients, while the relative abundancies, particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR positive cells, vary. Our study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity.
:view less
Time 2EVOLVE: Predicting efficacy of engineered T-cells-how far is the bench from the bedside?
2022
Sonia Guedan Carrio, Maik Luu, Delphine Ammar, Paula Barbao, Chiara Bonini, Philippe Bo…
:read more
Authors:Sonia Guedan Carrio, Maik Luu, Delphine Ammar, Paula Barbao, Chiara Bonini, Philippe Bousso, Christian J Buchholz, Monica Casucci, Biagio de Angelis, Emmanuel Donnadieu, David Espie, Beatrice Greco, Richard Groen, Johannes B Huppa, Chahrazade Kantari-Mimoun, Bruno Laugel, Mary Mantock, Janet Markman, Emma Morris, Concetta Quintarelli, Michael Rade, Kristin Reiche, Alba Rodriguez-Garcia, Juan Roberto Rodriguez-Madoz, Eliana Ruggiero, Maria Themeli, Michael Hudecek, Ibtissam Marchiq
Publication date:01/01/2022
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Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19
2021
Benjamin Krämer, Rainer Knoll, Lorenzo Bonaguro, Michael ToVinh, Jan Raabe, Rosario Ast…
Immunity 54 (11), 2650-2669. e14
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Authors:Benjamin Krämer, Rainer Knoll, Lorenzo Bonaguro, Michael ToVinh, Jan Raabe, Rosario Astaburuaga-García, Jonas Schulte-Schrepping, Kim Melanie Kaiser, Gereon J Rieke, Jenny Bischoff, Malte B Monin, Christoph Hoffmeister, Stefan Schlabe, Elena De Domenico, Nico Reusch, Kristian Händler, Gary Reynolds, Nils Blüthgen, Gudrun Hack, Claudia Finnemann, Hans D Nischalke, Christian P Strassburg, Emily Stephenson, Yapeng Su, Louis Gardner, Dan Yuan, Daniel Chen, Jason Goldman, Philipp Rosenstiel, Susanne V Schmidt, Eicke Latz, Kevin Hrusovsky, Andrew J Ball, Joe M Johnson, Paul-Albert Koenig, Florian I Schmidt, Muzlifah Haniffa, James R Heath, Beate M Kümmerer, Verena Keitel, Björn Jensen, Paula Stubbemann, Florian Kurth, Leif E Sander, Birgit Sawitzki, Janine Altmüller, Angel Angelov, Anna C Aschenbrenner, Robert Bals, Alexander Bartholomäus, Anke Becker, Matthias Becker, Daniela Bezdan, Michael Bitzer, Conny Blumert, Ezio Bonifacio, Peer Bork, Bunk Boyke, Helmut Blum, Nicolas Casadei, Thomas Clavel, Maria Colome-Tatche, Markus Cornberg, Inti Alberto De La Rosa Velázquez, Andreas Diefenbach, Alexander Dilthey, Nicole Fischer, Konrad Förstner, Sören Franzenburg, Julia-Stefanie Frick, Gisela Gabernet, Julien Gagneur, Tina Ganzenmueller, Marie Gauder, Janina Geißert, Alexander Goesmann, Siri Göpel, Adam Grundhoff, Hajo Grundmann, Torsten Hain, Frank Hanses, Ute Hehr, André Heimbach, Marius Hoeper, Friedemann Horn, Daniel Hübschmann, Michael Hummel, Thomas Iftner, Angelika Iftner, Thomas Illig, Stefan Janssen, Jörn Kalinowski, René Kallies, Birte Kehr, Andreas Keller, Oliver T Keppler, Sarah Kim-Hellmuth, Christoph Klein, Michael Knop, Oliver Kohlbacher, Karl Köhrer, Jan Korbel, Peter G Kremsner, Denise Kühnert, Ingo Kurth, Markus Landthaler, Yang Li, Kerstin U Ludwig, Oliwia Makarewicz, Federico Marini, Manja Marz, Alice C McHardy, Christian Mertes, Maximilian Münchhoff, Sven Nahnsen, Markus Nöthen, Francine Ntoumi, Peter Nürnberg, Stephan Ossowski, Jörg Overmann, Silke Peter, Klaus Pfeffer, Isabell Pink, Anna R Poetsch, Ulrike Protzer, Alfred Pühler, Nikolaus Rajewsky, Markus Ralser, Kristin Reiche, Olaf Rieß, Stephan Ripke, Ulisses Nunes da Rocha, Philip Rosenstiel, Antoine-Emmanuel Saliba, Leif Erik Sander, Simone Scheithauer, Philipp Schiffer, Jonathan Schmid-Burgk, Wulf Schneider, Eva-Christina Schulte, Joachim L Schultze, Alexander Sczyrba, Mariam L Sharaf, Yogesh Singh, Michael Sonnabend, Oliver Stegle, Jens Stoye, Fabian Theis, Thomas Ulas, Janne Vehreschild
Publication date:11/09/2021
Journal:Immunity
Volume:54
Issue:11
Pages:2650-2669. e14
Publisher:Elsevier
Description:Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant …
Cited by:254
Resources:[HTML] from cell.com
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Alzheimer-related genes show accelerated evolution
2021
Anne Nitsche, Christian Arnold, Uwe Ueberham, Kristin Reiche, Jörg Fallmann, Jörg Hacke…
Molecular psychiatry 26 (10), 5790-5796
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Authors:Anne Nitsche, Christian Arnold, Uwe Ueberham, Kristin Reiche, Jörg Fallmann, Jörg Hackermüller, Friedemann Horn, Peter F Stadler, Thomas Arendt
Publication date:10/01/2021
Journal:Molecular psychiatry
Volume:26
Issue:10
Pages:5790-5796
Publisher:Nature Publishing Group UK
Description:Alzheimerʼs disease (AD) is a neurodegenerative disorder of unknown cause with complex genetic and environmental traits. While AD is extremely prevalent in human elderly, it hardly occurs in non-primate mammals and even non-human-primates develop only an incomplete form of the disease. This specificity of AD to human clearly implies a phylogenetic aspect. Still, the evolutionary dimension of AD pathomechanism remains difficult to prove and has not been established so far. To analyze the evolutionary age and dynamics of AD-associated-genes, we established the AD-associated genome-wide RNA-profile comprising both protein-coding and non-protein-coding transcripts. We than applied a systematic analysis on the conservation of splice-sites as a measure of gene-structure based on multiple alignments across vertebrates of homologs of AD-associated-genes. Here, we show that nearly all AD …
Cited by:29
Resources:[HTML] from nature.com
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The noncoding RNA LINC00152 conveys contradicting effects in different glioblastoma cells
2021
Stefanie Binder, Ivonne Zipfel, Claudia Müller, Karolin Wiedemann, Carolin Schimmelpfen…
Scientific Reports 11 (1), 18499
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Authors:Stefanie Binder, Ivonne Zipfel, Claudia Müller, Karolin Wiedemann, Carolin Schimmelpfennig, Gabriele Pfeifer, Kristin Reiche, Sunna Hauschildt, Jörg Lehmann, Ulrike Köhl, Friedemann Horn, Maik Friedrich
Publication date:09/16/2021
Journal:Scientific Reports
Volume:11
Issue:1
Pages:18499
Publisher:Nature Publishing Group UK
Description:Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor, characterized by its high genetic heterogeneity. In search of novel putative therapeutic RNA targets we investigated the role of the oncogenic long noncoding RNA LINC00152 (CYTOR, and STAiR18) in A172 glioblastoma cells. Here, we are the first to describe, that LINC00152 unexpectedly acts in a tumor suppressive manner in this cell line. SiRNA-based knockdown of LINC00152 enhanced malignant tumor behaviors including proliferation, cell cycle entry, migration, and invasion, contradicting previous studies using U87-MG and LN229 glioblastoma cells. Furthermore, LINC00152 knockdown had no influence on survival of A172 glioblastoma cells. In a genome wide transcription analysis of A172 and U87-MG glioblastoma cells, we identified 70 LINC00152 target genes involved in locomotion, cell migration, and motility in A172 cells …
Cited by:9
Resources:[HTML] from nature.com
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The key role of patient involvement in the development of core outcome sets in prostate cancer
2021
Katharina Beyer, Sara J MacLennan, Lisa Moris, Michael Lardas, Ken Mastris, Gary Hooker…
European Urology Focus 7 (5), 943-946
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Authors:Katharina Beyer, Sara J MacLennan, Lisa Moris, Michael Lardas, Ken Mastris, Gary Hooker, Robert Greene, Erik Briers, Muhammad Imran Omar, Jemma Healey, Sheela Tripathee, Giorgio Gandaglia, Lionne DF Venderbos, Emma J Smith, Josefine Bjorkqvist, Alex Asiimwe, Johannes Huber, Monique J Roobol, Jihong Zong, Anders Bjartell, James N’Dow, Alberto Briganti, Steven MacLennan, Mieke Van Hemelrijck, Emma Jane Smith, James N'Dow, Karin Plass, Maria Ribal, Nicolas Mottet, Robert Shepherd, Thomas Van den Broeck, Peter-Paul Willemse, Riccardo Campi, Mauro Gacci, LU Susan Evans-Axelsson, Daniele Crosti, Massimiliano Meoni, Roberto Garzonio, Chris Bangma, Monique Roobol, Sebastiaan Remmers, Derya Tilki, Anssi Auvinen, Teemu Murtola, Tapio Visakorpi, Kirsi Talala, Teuvo Tammela, Aino Siltari, Stephane Lejeune, Femke van Diggelen, Sophie Byrne, Luz Fialho, Antonella Cardone, Paulina Gono, Bertrand De Meulder, Charles Auffray, Irina-Afrodita Balaur, Nesrine Taibi, Shaun Power, Nazanin Zounemat Kermani, Kees van Bochove, Elisa Cirillo, Maxim Moinat, Emma Voss, Denis Horgan, Louise Fullwood, Marc Holtorf, Doron Lancet, Gabi Bernstein, Imran Omar, Sara MacLennan, Manfred Wirth, Michael Froehner, Beate Brenner, Angelika Borkowetz, Christian Thomas, Friedemann Horn, Kristin Reiche, Markus Kreuz, Andreas Josefsson, Delila Gasi Tandefelt, Jonas Hugosson, Jack Schalken, Henkjan Huisman, Thomas Hofmarcher, Peter Lindgren, Emelie Andersson, Adam Fridhammar, Frank Verholen, John-Edward Butler-Ransohoff, Todd Williamson, Kumari Chandrawansa, Reg Waldeck, Megan Molnar, Amanda Bruno, Ronald Herrera, Ekaterina Nevedomskaya, Samuel Fatoba, Niculae Constantinovici, Ateesha Mohamed, Carl Steinbeißer, Siddhanth Kedhagae, Monika Maass, Patrizia Torremante, Marc Dietrich Voss, Zsuzsanna Devecseri, Tom Abbott, Amit Kiran, Chad Dau, Kishore Papineni, Jing Wang-silvanto, Steve Hass, Robert Snijder, Verena Doyé, Xuewei Wang, Andy Garnham, Mark Lambrecht, Russ Wolfinger, Stijn Rogiers, Angela Servan, Joaquin Casariego, Mohamed Samir, Katie Pascoe, Paul Robinson, Christian Reich, Shilpa Ratwani, Elaine Longden-Chapman, Danny Burke, Paul Agapow, Sahra Derkits, Muriel Licour, Michelle Ang, Sarah Payne, Alan Yong, Lucy Thompson, Sophia Le Mare, Michael Bussmann, Inken Köhler, Guido Juckeland, Daniel Kotik, PIONEER Consortium
Publication date:09/01/2021
Journal:European Urology Focus
Volume:7
Issue:5
Pages:943-946
Publisher:Elsevier
Description:Patients are the stewards of their own care and hence their voice is important when designing and implementing research. Patients should be involved not only as participants in research that impacts their care, as the recipients of that care and any associated harms, but also as research collaborators in prioritising important questions from the patient perspective and designing the research and the ways in which is it most appropriate to involve patients. The PIONEER Consortium, an international multistakeholder collaboration lead by the European Association of Urology, has developed a core outcome set (COS) for localised and metastatic prostate cancer relevant to all stakeholders in particular patients. Throughout the work of PIONEER, patient representatives were involved as collaborators in setting the research agenda, and a wider group of patients was involved as participants in developing COSs, for …
Cited by:9
Resources:[HTML] from sciencedirect.com
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Distinct immune signatures indicative of treatment response and immune-related adverse events in melanoma patients under immune checkpoint inhibitor therapy
2021
Robin Reschke, Philipp Gussek, Andreas Boldt, Ulrich Sack, Ulrike Köhl, Florian Lordick…
International journal of molecular sciences 22 (15), 8017
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Authors:Robin Reschke, Philipp Gussek, Andreas Boldt, Ulrich Sack, Ulrike Köhl, Florian Lordick, Thomas Gora, Markus Kreuz, Kristin Reiche, Jan-Christoph Simon, Mirjana Ziemer, Manfred Kunz
Publication date:07/27/2021
Journal:International journal of molecular sciences
Volume:22
Issue:15
Pages:8017
Publisher:MDPI
Description:To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA−CD45RO+CCR7−) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.
Cited by:38
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Low energy electron irradiation is a potent alternative to gamma irradiation for the inactivation of (CAR-) NK-92 cells in ATMP manufacturing
2021
Lia Walcher, Ann-Kathrin Kistenmacher, Charline Sommer, Sebastian Böhlen, Christina Zie…
Frontiers in immunology 12, 684052
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Authors:Lia Walcher, Ann-Kathrin Kistenmacher, Charline Sommer, Sebastian Böhlen, Christina Ziemann, Susann Dehmel, Armin Braun, Uta Sandy Tretbar, Stephan Klöß, Axel Schambach, Michael Morgan, Dennis Löffler, Christoph Kaempf, Conny Blumert, Kristin Reiche, Jana Beckmann, Ulla König, Bastian Standfest, Martin Thoma, Gustavo R Makert, Sebastian Ulbert, Uta Kossatz-Boehlert, Ulrike Köhl, Anna Duenkel, Stephan Fricke
Publication date:06/04/2021
Journal:Frontiers in immunology
Volume:12
Pages:684052
Publisher:Frontiers Media SA
Description:Background With increasing clinical use of NK-92 cells and their CAR-modified derivatives in cancer immunotherapy, there is a growing demand for efficient production processes of these “off-the-shelf” therapeutics. In order to ensure safety and prevent the occurrence of secondary tumors, (CAR-)NK-92 cell proliferation has to be inactivated before transfusion. This is commonly achieved by gamma irradiation. Recently, we showed proof of concept that low energy electron irradiation (LEEI) is a new method for NK-92 inactivation. LEEI has several advantages over gamma irradiation, including a faster reaction time, a more reproducible dose rate and much less requirements on radiation shielding. Here, LEEI was further evaluated as a promising alternative to gamma irradiation yielding cells with highly maintained cytotoxic effector function. Methods Effectiveness and efficiency of LEEI and gamma irradiation were analyzed using NK-92 and CD123-directed CAR-NK-92 cells. LEE-irradiated cells were extensively characterized and compared to gamma-irradiated cells via flow cytometry, cytotoxicity assays, and comet assays, amongst others. Results Our results show that both irradiation methods caused a progressive decrease in cell viability and are, therefore, suitable for inhibition of cell proliferation. Notably, the NK-mediated specific lysis of tumor cells was maintained at stable levels for three days post-irradiation, with a trend towards higher activities after LEEI treatment as compared to gamma irradiation. Both gamma irradiation as well as LEEI led to substantial DNA damage and an accumulation of irradiated cells in the G2/M cell cycle …
Cited by:21
Resources:[HTML] from frontiersin.org
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Immune signatures of treatment response and immune-related adverse events in melanoma patients under checkpoint inhibitor therapy
2021
R Reschke, P Gussek, A Boldt, U Sack, U Koehl, F Lordick, M Kreuz, K Reiche, JC Simon, …
EXPERIMENTAL DERMATOLOGY 30 (3), E57-E57
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Authors:R Reschke, P Gussek, A Boldt, U Sack, U Koehl, F Lordick, M Kreuz, K Reiche, JC Simon, M Ziemer, M Kunz
Publication date:03/01/2021
Journal:EXPERIMENTAL DERMATOLOGY
Volume:30
Issue:3
Pages:E57-E57
Publisher:WILEY
Description:Background Summary Acknowledgments Aim Percentage of CD8+ effector memory T cells Absolute number of CD8+ effector memory T cell
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Immune Signatures for the Response and Occurrence of immune-mediated Side Effects under Immune Checkpoint Inhibitor Therapy in Stage IV Melanoma Patients
2021
R Reschke, P Gussek, A Boldt, U Sack, U Koehl, F Lordick, M Kreuz, K Reiche, JC Simon, …
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT 19, 7-8
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Authors:R Reschke, P Gussek, A Boldt, U Sack, U Koehl, F Lordick, M Kreuz, K Reiche, JC Simon, M Ziemer, M Kunz
Publication date:02/01/2021
Journal:JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
Volume:19
Pages:7-8
Publisher:WILEY
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ProstaTrend—a multivariable prognostic RNA expression score for aggressive prostate cancer
2020
Markus Kreuz, Dominik J Otto, Susanne Fuessel, Conny Blumert, Catharina Bertram, Sophie…
European urology 78 (3), 452-459
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Authors:Markus Kreuz, Dominik J Otto, Susanne Fuessel, Conny Blumert, Catharina Bertram, Sophie Bartsch, Dennis Loeffler, Sven-Holger Puppel, Michael Rade, Tilo Buschmann, Sabina Christ, Kati Erdmann, Maik Friedrich, Michael Froehner, Michael H Muders, Stephan Schreiber, Michael Specht, Marieta I Toma, Fabio Benigni, Massimo Freschi, Giorgio Gandaglia, Alberto Briganti, Gustavo B Baretton, Markus Loeffler, Jörg Hackermüller, Kristin Reiche, Manfred Wirth, Friedemann Horn
Publication date:09/01/2020
Journal:European urology
Volume:78
Issue:3
Pages:452-459
Publisher:Elsevier
Description:Background Objective Design, setting, and participants Outcome measurements and statistical analysis
Cited by:24
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Introducing PIONEER: a project to harness big data in prostate cancer research (vol 41, pg 513, 2020)
2020
Muhammad Imran Omar, Monique J Roobol, Maria J Ribal, Thomas Abbott, Paul-Michael Agapo…
NATURE REVIEWS UROLOGY 17 (8), 482-482
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Authors:Muhammad Imran Omar, Monique J Roobol, Maria J Ribal, Thomas Abbott, Paul-Michael Agapow, Sonia Araujo, Alex Asiimwe, Charles Auffray, Irina Balaur, Katharina Beyer, Chiara Bernini, Anders Bjartell, Alberto Briganti, John-Edward Butler-Ransohoff, Riccardo Campi, Marinel Cavelaars, Bertrand De Meulder, Zsuzsanna Devecseri, Marc Dietrich Voss, Konstantinos Dimitropoulos, Susan Evans-Axelsson, Billy Franks, Louise Fullwood, Denis Horgan, Emma Jane Smith, Amit Kiran, Kati Kivinummi, Mark Lambrecht, Doron Lancet, Peter Lindgren, Sara MacLennan, Steven MacLennan, Maria Manuela Nogueira, Fredrik Moen, Maxim Moinat, Kishore Papineni, Christian Reich, Kristin Reiche, Stijn Rogiers, Claudio Sartini, Kees van Bochove, Femke van Diggelen, Mieke Van Hemelrijck, Hein Van Poppel, Jihong Zong, James N'Dow
Publication date:08/01/2020
Journal:NATURE REVIEWS UROLOGY
Volume:17
Issue:8
Pages:482-482
Publisher:NATURE PUBLISHING GROUP
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Introducing PIONEER: a project to harness big data in prostate cancer research
2020
Muhammad Imran Omar, Monique J Roobol, Maria J Ribal, Thomas Abbott, Paul-Michael Agapo…
Nature Reviews Urology 17 (6), 351-362
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Authors:Muhammad Imran Omar, Monique J Roobol, Maria J Ribal, Thomas Abbott, Paul-Michael Agapow, Sonia Araujo, Alex Asiimwe, Charles Auffray, Irina Balaur, Katharina Beyer, Chiara Bernini, Anders Bjartell, Alberto Briganti, John-Edward Butler-Ransohoff, Riccardo Campi, Marinel Cavelaars, Bertrand De Meulder, Zsuzsanna Devecseri, Marc Dietrich Voss, Konstantinos Dimitropoulos, Susan Evans-Axelsson, Billy Franks, Louise Fullwood, Denis Horgan, Emma Jane Smith, Amit Kiran, Kati Kivinummi, Mark Lambrecht, Doron Lancet, Peter Lindgren, Sara MacLennan, Steven MacLennan, Maria Manuela Nogueira, Fredrik Moen, Maxim Moinat, Kishore Papineni, Christian Reich, Kristin Reiche, Stijn Rogiers, Claudio Sartini, Kees van Bochove, Femke van Diggelen, Mieke Van Hemelrijck, Hein Van Poppel, Jihong Zong, James N’Dow
Publication date:06/15/2020
Journal:Nature Reviews Urology
Volume:17
Issue:6
Pages:351-362
Publisher:Nature Publishing Group UK
Description:Prostate Cancer Diagnosis and Treatment Enhancement Through the Power of Big Data in Europe (PIONEER) is a European network of excellence for big data in prostate cancer, consisting of 32 private and public stakeholders from 9 countries across Europe. Launched by the Innovative Medicines Initiative 2 and part of the Big Data for Better Outcomes Programme (BD4BO), the overarching goal of PIONEER is to provide high-quality evidence on prostate cancer management by unlocking the potential of big data. The project has identified critical evidence gaps in prostate cancer care, via a detailed prioritization exercise including all key stakeholders. By standardizing and integrating existing high-quality and multidisciplinary data sources from patients with prostate cancer across different stages of the disease, the resulting big data will be assembled into a single innovative data platform for research. Based on a …
Cited by:45
Resources:[PDF] from universiteitleiden.nl
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The role of lncRNAs TAPIR-1 and-2 as diagnostic markers and potential therapeutic targets in prostate cancer
2020
Maik Friedrich, Karolin Wiedemann, Kristin Reiche, Sven-Holger Puppel, Gabriele Pfeifer…
Cancers 12 (5), 1122
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Authors:Maik Friedrich, Karolin Wiedemann, Kristin Reiche, Sven-Holger Puppel, Gabriele Pfeifer, Ivonne Zipfel, Stefanie Binder, Ulrike Koehl, Gerd A Mueller, Kurt Engeland, Achim Aigner, Susanne Fuessel, Michael Froehner, Claudia Peitzsch, Anna Dubrovska, Michael Rade, Sabina Christ, Stephan Schreiber, Joerg Hackermueller, Joerg Lehmann, Marieta I Toma, Michael H Muders, Ulrich Sommer, Gustavo B Baretton, Manfred Wirth, Friedemann Horn
Publication date:04/30/2020
Journal:Cancers
Volume:12
Issue:5
Pages:1122
Publisher:MDPI
Description:In search of new biomarkers suitable for the diagnosis and treatment of prostate cancer, genome-wide transcriptome sequencing was carried out with tissue specimens from 40 prostate cancer (PCa) and 8 benign prostate hyperplasia patients. We identified two intergenic long non-coding transcripts, located in close genomic proximity, which are highly expressed in PCa. Microarray studies on a larger cohort comprising 155 patients showed a profound diagnostic potential of these transcripts (AUC~0.94), which we designated as tumor associated prostate cancer increased lncRNA (TAPIR-1 and -2). To test their therapeutic potential, knockdown experiments with siRNA were carried out. The knockdown caused an increase in the p53/TP53 tumor suppressor protein level followed by downregulation of a large number of cell cycle- and DNA-damage repair key regulators. Furthermore, in radiation therapy resistant tumor cells, the knockdown leads to a renewed sensitization of these cells to radiation treatment. Accordingly, in a preclinical PCa xenograft model in mice, the systemic application of nanoparticles loaded with siRNA targeting TAPIR-1 significantly reduced tumor growth. These findings point to a crucial role of TAPIR-1 and -2 in PCa.
Cited by:24
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Master and servant: LINC00152–a STAT3-induced long noncoding RNA regulates STAT3 in a positive feedback in human multiple myeloma
2020
Stefanie Binder, Ivonne Zipfel, Maik Friedrich, Diana Riedel, Stefanie Ende, Christoph …
BMC medical genomics 13 (1), 22
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Authors:Stefanie Binder, Ivonne Zipfel, Maik Friedrich, Diana Riedel, Stefanie Ende, Christoph Kämpf, Karolin Wiedemann, Tilo Buschmann, Sven-Holger Puppel, Kristin Reiche, Peter F Stadler, Friedemann Horn
Publication date:02/10/2020
Journal:BMC medical genomics
Volume:13
Issue:1
Pages:22
Publisher:BioMed Central
Description:Background The survival of INA-6 human multiple myeloma cells is strictly dependent upon the Interleukin-6-activated transcription factor STAT3. Although transcriptional analyses have revealed many genes regulated by STAT3, to date no protein-coding STAT3 target gene is known to mediate survival in INA-6 cells. Therefore, the aim here was to identify and analyze non-protein-coding STAT3 target genes. In addition to the oncogenic microRNA-21, we previously described five long noncoding RNAs (lncRNAs) induced by STAT3, named STAiRs. Here, we focus on STAT3-induced RNA 18 (STAiR18), an mRNA-like, long ncRNA that is duplicated in the human lineage. One STAiR18 locus is annotated as the already well described LINC00152/CYTOR, however, the other harbors the MIR4435-2HG gene and is, up to now, barely described. Methods CAPTURE-RNA-sequencing was used to analyze STAiR18 …
Cited by:15
Resources:[HTML] from springer.com
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Necessity for next-generation quality assessment of CAR T cell manufacturing and advanced therapy guidance
2020
Barbara Seliger, Kristin Reiche, Chiara Massa, Stephan Fricke, Gerno Schmiedeknecht, Fr…
Cell Gene Ther Insights 1, 163-8
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Authors:Barbara Seliger, Kristin Reiche, Chiara Massa, Stephan Fricke, Gerno Schmiedeknecht, Friedemann Horn, Conny Blumert, Miriam Alb, M l Hudecek, Ulrike Koehl
Publication date:01/01/2020
Journal:Cell Gene Ther Insights
Volume:1
Pages:163-8
Description:Despite encouraging clinical results in B-cell malignancies, redirected chimeric antigen receptor (CAR) T cells bear several medical and economic challenges. On the one hand, increasing numbers of patients require reproducible and automatic manufacturing of high quality, clinical-grade CAR T cells retaining the expression of the CAR gene and their catalytic function as well as respective biomarkers to predict processing failure, which is lacking so far. On the other hand, there is an increasing interest in advanced biomarkers for therapy guidance and especially, for preclinical testing to assess side effects such as CRS and CRES.
Cited by:1
Resources:[PDF] from imsavar.eu
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Deep sequencing and automated histochemistry of human tissue slice cultures improve their usability as preclinical model for cancer research
2019
Susann Haehnel, Kristin Reiche, Dennis Loeffler, Andreas Horn, Conny Blumert, Sven-Holg…
Scientific Reports 9 (1), 19961
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Authors:Susann Haehnel, Kristin Reiche, Dennis Loeffler, Andreas Horn, Conny Blumert, Sven-Holger Puppel, Nicole Kaiser, Felicitas Rapp, Michael Rade, Friedemann Horn, Juergen Meixensberger, Ingo Bechmann, Frank Gaunitz, Karsten Winter
Publication date:12/27/2019
Journal:Scientific Reports
Volume:9
Issue:1
Pages:19961
Publisher:Nature Publishing Group UK
Description:Cancer research requires models closely resembling the tumor in the patient. Human tissue cultures can overcome interspecies limitations of animal models or the loss of tissue architecture in in vitro models. However, analysis of tissue slices is often limited to histology. Here, we demonstrate that slices are also suitable for whole transcriptome sequencing and present a method for automated histochemistry of whole slices. Tumor and peritumoral tissue from a patient with glioblastoma was processed to slice cultures, which were treated with standard therapy including temozolomide and X-irradiation. Then, RNA sequencing and automated histochemistry were performed. RNA sequencing was successfully accomplished with a sequencing depth of 243 to 368 x 106 reads per sample. Comparing tumor and peritumoral tissue, we identified 1888 genes significantly downregulated and 2382 genes upregulated in tumor …
Cited by:15
Resources:[HTML] from nature.com
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uap: reproducible and robust HTS data analysis
2019
Christoph Kämpf, Michael Specht, Alexander Scholz, Sven-Holger Puppel, Gero Doose, Kris…
BMC bioinformatics 20 (1), 664
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Authors:Christoph Kämpf, Michael Specht, Alexander Scholz, Sven-Holger Puppel, Gero Doose, Kristin Reiche, Jana Schor, Jörg Hackermüller
Publication date:12/12/2019
Journal:BMC bioinformatics
Volume:20
Issue:1
Pages:664
Publisher:BioMed Central
Description:Background A lack of reproducibility has been repeatedly criticized in computational research. High throughput sequencing (HTS) data analysis is a complex multi-step process. For most of the steps a range of bioinformatic tools is available and for most tools manifold parameters need to be set. Due to this complexity, HTS data analysis is particularly prone to reproducibility and consistency issues. We have defined four criteria that in our opinion ensure a minimal degree of reproducible research for HTS data analysis. A series of workflow management systems is available for assisting complex multi-step data analyses. However, to the best of our knowledge, none of the currently available work flow management systems satisfies all four criteria for reproducible HTS analysis. Results Here we present uap, a workflow management system dedicated to robust, consistent, and reproducible HTS data analysis. uap is …
Cited by:22
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Master and servant-The complex interplay of a long non-coding RNA and its transcription factor STAT3 in human Multiple Myeloma
2019
S Binder, I Zipfel, D Riedel, N Hoesler, M Friedrich, T Buschmann, K Reiche, F Horn
EUROPEAN JOURNAL OF IMMUNOLOGY 49, 79-79
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Authors:S Binder, I Zipfel, D Riedel, N Hoesler, M Friedrich, T Buschmann, K Reiche, F Horn
Publication date:09/01/2019
Journal:EUROPEAN JOURNAL OF IMMUNOLOGY
Volume:49
Pages:79-79
Publisher:WILEY
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Map and model—moving from observation to prediction in toxicogenomics
2019
Andreas Schüttler, Rolf Altenburger, Madeleine Ammar, Marcella Bader-Blukott, Gianina J…
Gigascience 8 (6), giz057
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Authors:Andreas Schüttler, Rolf Altenburger, Madeleine Ammar, Marcella Bader-Blukott, Gianina Jakobs, Johanna Knapp, Janet Krüger, Kristin Reiche, Gi-Mick Wu, Wibke Busch
Publication date:06/01/2019
Journal:Gigascience
Volume:8
Issue:6
Pages:giz057
Publisher:Oxford University Press
Description:Background Chemicals induce compound-specific changes in the transcriptome of an organism (toxicogenomic fingerprints). This provides potential insights about the cellular or physiological responses to chemical exposure and adverse effects, which is needed in assessment of chemical-related hazards or environmental health. In this regard, comparison or connection of different experiments becomes important when interpreting toxicogenomic experiments. Owing to lack of capturing response dynamics, comparability is often limited. In this study, we aim to overcome these constraints. Results We developed an experimental design and bioinformatic analysis strategy to infer time- and concentration-resolved toxicogenomic fingerprints. We projected the fingerprints to a universal coordinate system (toxicogenomic universe) based on a self-organizing map of toxicogenomic …
Cited by:25
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RNA-biomarkers for diagnosis of prostate cancer
2019

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Publication date:05/28/2019
Description:The invention relates to the identification and selection of differentially expressed transcripts (biomarker) in tumor cells. Specific determination of the level of these biomarkers can be used for screening and diagnosis of prostate cancer. Clinical application of assays based on these biomarker help reduce the high number of false positives of current standard screening assays.
Cited by:3
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RNA-biomarkers for diagnosing prostate cancer
2019

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Publication date:05/14/2019
Description:the invention is in the field of molecular biology. More particularly, the invention relates to the analysis of RNA transcripts. Most particularly, the invention is in the field of diagnosing prostate cancer. Prostate cancer is the most frequently diagnosed cancer in men. In 2012, the annual number of newly diagnosed prostate cancer cases was reported as approximately 240,000 cases in the United States and approximately 360,000 in the European Union, 68,000 of which in Germany. In the United States, lifetime risks for prostate cancer diagnosis and for dying of prostate cancer are currently estimated at 15.9% and 2.8%, respectively. Despite widespread screening for prostate cancer and major advances in the treatment of metastatic disease, prostate cancer remains the second most common cause of cancer death for men with over 250,000 deaths each year in the Western world.
Cited by:3
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RNA-biomarkers for diagnosis of prostate cancer
2019

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Publication date:02/05/2019
Description:The invention relates to the identification and selection of differentially expressed transcripts (biomarker) in tumour cells. Specific determination of the level of these biomarkers can be used for screening and diagnosis of prostate cancer. Clinical application of assays based on these biomarker help reduce the high number of false positives of current standard screening assays. 2005/0118625 A1
Cited by:4
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RNA-biomarkers for diagnosis of prostate cancer
2019

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Publication date:02/05/2019
Description:The invention relates to the identification and selection of differentially expressed transcripts (biomarker) in tumour cells. Specific determination of the level of these biomarkers can be used for screening and diagnosis of prostate cancer.
Cited by:3
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Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA
2018
Nina Rehage, Elena Davydova, Christine Conrad, Gesine Behrens, Andreas Maiser, Jenny E …
Nature communications 9 (1), 299
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Authors:Nina Rehage, Elena Davydova, Christine Conrad, Gesine Behrens, Andreas Maiser, Jenny E Stehklein, Sven Brenner, Juliane Klein, Aicha Jeridi, Anne Hoffmann, Eunhae Lee, Umberto Dianzani, Rob Willemsen, Regina Feederle, Kristin Reiche, Jörg Hackermüller, Heinrich Leonhardt, Sonia Sharma, Dierk Niessing, Vigo Heissmeyer
Publication date:01/19/2018
Journal:Nature communications
Volume:9
Issue:1
Pages:299
Publisher:Nature Publishing Group UK
Description:The ubiquitously expressed RNA-binding proteins Roquin-1 and Roquin-2 are essential for appropriate immune cell function and postnatal survival of mice. Roquin proteins repress target mRNAs by recognizing secondary structures in their 3′-UTRs and by inducing mRNA decay. However, it is unknown if other cellular proteins contribute to target control. To identify cofactors of Roquin, we used RNA interference to screen ~1500 genes involved in RNA-binding or mRNA degradation, and identified NUFIP2 as a cofactor of Roquin-induced mRNA decay. NUFIP2 binds directly and with high affinity to Roquin, which stabilizes NUFIP2 in cells. Post-transcriptional repression of human ICOS by endogenous Roquin proteins requires two neighboring non-canonical stem-loops in the ICOS 3′-UTR. This unconventional cis-element as well as another tandem loop known to confer Roquin-mediated regulation of the Ox40 …
Cited by:41
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Finding the needle in the Haystack-prostate cancer diagnostics by liquid biopsy
2018
Stefanie Monika Ende, Stefanie Binder, Michael Reuter, Dennis Löffler, Sven-Holger Pupp…
Journal of Extracellular Vesicles 7, 88-88
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Authors:Stefanie Monika Ende, Stefanie Binder, Michael Reuter, Dennis Löffler, Sven-Holger Puppel, Conny Blumert, Kristin Reiche, Friedemann Horn
Publication date:01/01/2018
Journal:Journal of Extracellular Vesicles
Volume:7
Pages:88-88
Publisher:John Wiley & Sons, Inc.
Description:Background Extracellular vesicles (EVs) harbour great potential when applied in innovative liquid biopsy approaches for the diagnosis of various diseases. They could outperform conventional procedures by avoiding risks and disadvantages of regular biopsies eg pain, fever, bleeding, infection and various lasting damages. Their immense diagnostic value in discriminating between healthy and cancer patients was already shown in several studies but the use of vesicle-based tests in clinical settings is still very limited. This is at least partially due to the fact that vesicles relevant for diagnosis are massively outnumbered by vesicles produced by multiple, divergent other sources, and hence the informative biomarker patterns are often concealed by irrelevant ones. We aim at developing a specific and sensitive diagnostic test for prostate cancer (PCa) based on plasma vesicles that can be identified by tissue specific … Background
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Roquin targets mRNAs in a 3′-UTR-specific manner by different modes of regulation
2018
Heissmeyer V. Essig K, Kronbeck N, Guimaraes JC, Lohs C, Schlundt A, Hoffmann A, Behren…
Nature Communications
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Authors:Heissmeyer V. Essig K, Kronbeck N, Guimaraes JC, Lohs C, Schlundt A, Hoffmann A, Behrens G, Brenner S, Kowalska J, Lopez-Rodriguez C, Jemielity J, Holtmann H, Reiche K, Hackermüller J, Sattler M, Zavolan M
Publication date:01/01/2018
Journal:Nature Communications
Description:The RNA-binding proteins Roquin-1 and Roquin-2 redundantly control gene expression and cell-fate decisions. Here, we show that Roquin not only interacts with stem–loop structures, but also with a linear sequence element present in about half of its targets. Comprehensive analysis of a minimal response element of the Nfkbid 3′-UTR shows that six stem–loop structures cooperate to exert robust and profound post-transcriptional regulation. Only binding of multiple Roquin proteins to several stem–loops exerts full repression, which redundantly involved deadenylation and decapping, but also translational inhibition. Globally, most Roquin targets are regulated by mRNA decay, whereas a small subset, including the Nfat5 mRNA, with more binding sites in their 3′-UTRs, are also subject to translational inhibition. These findings provide insights into how the robustness and magnitude of Roquin-mediated …
Cited by:73
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STAT3-induced long noncoding RNAs in multiple myeloma cells display different properties in cancer
2017
Stefanie Binder, Nadine Hösler, Diana Riedel, Ivonne Zipfel, Tilo Buschmann, Christoph …
Scientific reports 7 (1), 7976
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Authors:Stefanie Binder, Nadine Hösler, Diana Riedel, Ivonne Zipfel, Tilo Buschmann, Christoph Kämpf, Kristin Reiche, Renate Burger, Martin Gramatzki, Jörg Hackermüller, Peter F Stadler, Friedemann Horn
Publication date:08/11/2017
Journal:Scientific reports
Volume:7
Issue:1
Pages:7976
Publisher:Nature Publishing Group UK
Description:Interleukin-6 (IL-6)-activated Signal Transducer and Activator of Transcription 3 (STAT3) facilitates survival in the multiple myeloma cell line INA-6 and therefore represents an oncogenic key player. However, the biological mechanisms are still not fully understood. In previous studies we identified microRNA-21 as a STAT3 target gene with strong anti-apoptotic potential, suggesting that noncoding RNAs have an impact on the pathogenesis of human multiple myeloma. Here, we describe five long noncoding RNAs (lncRNAs) induced by IL-6-activated STAT3, which we named STAiRs. While STAiRs 1, 2 and 6 remain unprocessed in the nucleus and show myeloma-specific expression, STAiRs 15 and 18 are spliced and broadly expressed. Especially STAiR2 and STAiR18 are promising candidates. STAiR2 originates from the first intron of a tumor suppressor gene. Our data support a mutually exclusive expression of …
Cited by:30
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The transcriptome of the zebrafish embryo after chemical exposure: a meta-analysis
2017
Andreas Schüttler, Kristin Reiche, Rolf Altenburger, Wibke Busch
Toxicological Sciences 157 (2), 291-304
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Authors:Andreas Schüttler, Kristin Reiche, Rolf Altenburger, Wibke Busch
Publication date:06/01/2017
Journal:Toxicological Sciences
Volume:157
Issue:2
Pages:291-304
Publisher:Oxford University Press
Description:Numerous studies have been published in the past years investigating the transcriptome of the zebrafish embryo (ZFE) upon being subjected to chemical stress. Aiming at a more mechanistic understanding of the results of such studies, knowledge about commonalities of transcript regulation in response to chemical stress is needed. Thus, our goal in this study was to identify and interpret genes and gene sets constituting a general response to chemical exposure. Therefore, we aggregated and reanalyzed published toxicogenomics data obtained with the ZFE. We found that overlap of differentially transcribed genes in response to chemical stress across independent studies is generally low and the most commonly differentially transcribed genes appear in less than 50% of all treatments across studies. However, effect size analysis revealed several genes showing a common trend of differential expression, among …
Cited by:52
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Discovery and validation of immunological biomarkers in milk for health monitoring of dairy cows-results from a multiomics approach
2017
K Zoldan, J Schneider, T Moellmer, C Fueldner, J Knauer, M Fuerll, A Starke, M Specht, …
J. Adv. Dairy Res 5 (2)
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Authors:K Zoldan, J Schneider, T Moellmer, C Fueldner, J Knauer, M Fuerll, A Starke, M Specht, K Reiche, J Hackermueller, S Kalkhof, M Von Bergen, U Bergfeld, R Fischer, S Pache, J Lehmann
Publication date:01/01/2017
Journal:J. Adv. Dairy Res
Volume:5
Issue:2
Description:At onset of milk production and in early lactation highly producing dairy cows are most susceptible for inflammatory diseases due to functional suppression of immune cells. Intensive supervision of the animals is essential and implementation of new technologies to on-farm routines will be the next step to provide automation and improvement of herd health monitoring programs. Objective of our study was to identify and validate immunological biomarkers in milk that indicate extra-mammary inflammatory diseases to characterize the general health status of highly-producing dairy cows. In total 89 healthy and 75 diseased animals (German Holstein cows) were included. Diseases were distinguished by either systemic (extra-mammary) occurrence or those affecting the mammary gland (mastitis) and further classified by their severity. For protein biomarker discovery we used a top-down approach to narrow down a broad range of secreted gene products of the milk cell transcriptome (microarray) and proteome to a few promising candidates which were validated using real-time PCR and ELISA. The most promising biomarker candidates were statistically evaluated. Receiver operating characteristic analysis revealed haptoglobin, secretory component, lactoferrin and vascular endothelial growth factor showing the highest discriminatory capability for diseased vs. healthy cows. Values for sensitivity at a specificity of 94% were 82% for haptoglobin, 59% for secretory component, 55% for lactoferrin and 67% for vascular endothelial growth factor. Statistical evaluation by multinomial logistic regression and k-nearest neighbor method confirmed haptoglobin as …
Cited by:14
Resources:[PDF] from researchgate.net
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Novel rna-biomarkers for diagnosis of prostate cancer
2016

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Publication date:10/13/2016
Description:BACKGROUND 0002 Prostate cancer is the most frequently diagnosed cancer in men. In 2012, the annual number of newly diagnosed prostate cancer cases was reported as approxi mately 240,000 cases in the United States and approxi mately 360,000 in the European Union, 68,000 of which in Germany. In the United States, lifetime risks for prostate cancer diagnosis and for dying of prostate cancer are cur rently estimated at 15.9% and 2.8%, respectively. Despite widespread screening for prostate cancer and major advances in the treatment of metastatic disease, prostate cancer remains the second most common cause of cancer death for men with over 250,000 deaths each year in the
Cited by:4
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NEXT-GENERATION SEQUENCING REVEALS TRANSCRIPT CLUSTERS WITH PROGNOSTIC POTENTIAL FOR PROSTATE CANCER: MP02-03
2016
Friedemann Horn, Sabina Christ-Breulmann, Sven-Holger Puppel, Tilo Buschmann, Kristin R…
Journal of Urology 195 (4), e10
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Authors:Friedemann Horn, Sabina Christ-Breulmann, Sven-Holger Puppel, Tilo Buschmann, Kristin Reiche, Michael Specht, Catharina Bertram, Maik Friedrich, Stefanie Binder, Conny Blumert, Jörg Hackermüller, Markus Kreuz, Markus Löffler, Marieta I Toma, Michael Muders, Gustavo B Baretton, Michael Fröhner, Susanne Füssel, Manfred Wirth
Publication date:04/01/2016
Journal:Journal of Urology
Volume:195
Issue:4
Pages:e10
Publisher:LWW
Description:METHODS Using strand-specific, paired-end long-RNA next-generation sequencing (NGS) and microarray studies, we analysed the transcriptomes of prostate tumor and tumor-free samples. Fresh frozen tissues were obtained from radical prostatectomies of PCa patients with a follow-up of at least 7 years. The cohort was stratified to contain distinct risk groups with respect to Gleason score, lymph node metastases, and survival. RNA was isolated from cryosections, quality-controlled for tumor cell contents. 64 samples were subjected to NGS at a depth of 200 million reads per sample. Subsequently, 256 prostate samples were studied using customized microarrays covering transcripts differentially expressed in the sequencing cohort as well as all RNAs annotated in public databases. To retrieve prognostic biomarker signatures, the data obtained were analysed using a correlational clustering and self organizing …
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728 Transcriptome-wide expression study reveals biomarker signature with prognostic potential for prostate cancer
2016
F Horn, S Christ-Breulmann, SH Puppel, T Buschmann, K Reiche, M Specht, C Bertram, M Fr…
European Urology Supplements 3 (15), e728
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Authors:F Horn, S Christ-Breulmann, SH Puppel, T Buschmann, K Reiche, M Specht, C Bertram, M Friedrich, S Binder, C Blumert, J Hackermüller, M Kreuz, M Löffler, MI Toma, M Muders, GB Baretton, M Fröhner, S Füssel, M Wirth
Publication date:01/01/2016
Journal:European Urology Supplements
Volume:3
Issue:15
Pages:e728
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380 Novel long non-protein coding RNAs as biomarkers and potential therapeutic targets for prostate cancer
2016
S Christ-Breulmann, F Horn, SH Puppel, T Buschmann, K Reiche, M Specht, C Bertram, M Fr…
European Urology Supplements 3 (15), e380
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Authors:S Christ-Breulmann, F Horn, SH Puppel, T Buschmann, K Reiche, M Specht, C Bertram, M Friedrich, C Blumert, S Binder, J Hackermüller, M Kreuz, M Löffler, MI Toma, M Muders, GB Baretton, M Fröhner, S Füssel, M Wirth
Publication date:01/01/2016
Journal:European Urology Supplements
Volume:3
Issue:15
Pages:e380
Cited by:1
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Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci
2015
Holger Kirsten, Hoor Al-Hasani, Lesca Holdt, Arnd Gross, Frank Beutner, Knut Krohn, Kat…
Human molecular genetics 24 (16), 4746-4763
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Authors:Holger Kirsten, Hoor Al-Hasani, Lesca Holdt, Arnd Gross, Frank Beutner, Knut Krohn, Katrin Horn, Peter Ahnert, Ralph Burkhardt, Kristin Reiche, Jörg Hackermüller, Markus Löffler, Daniel Teupser, Joachim Thiery, Markus Scholz
Publication date:08/15/2015
Journal:Human molecular genetics
Volume:24
Issue:16
Pages:4746-4763
Publisher:Oxford University Press
Description:Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs …
Cited by:126
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Comparison of splice sites reveals that long noncoding RNAs are evolutionarily well conserved
2015
Anne Nitsche, Dominic Rose, Mario Fasold, Kristin Reiche, Peter F Stadler
Rna 21 (5), 801-812
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Authors:Anne Nitsche, Dominic Rose, Mario Fasold, Kristin Reiche, Peter F Stadler
Publication date:05/01/2015
Journal:Rna
Volume:21
Issue:5
Pages:801-812
Publisher:Cold Spring Harbor Lab
Description:Large-scale RNA sequencing has revealed a large number of long mRNA-like transcripts (lncRNAs) that do not code for proteins. The evolutionary history of these lncRNAs has been notoriously hard to study systematically due to their low level of sequence conservation that precludes comprehensive homology-based surveys and makes them nearly impossible to align. An increasing number of special cases, however, has been shown to be at least as old as the vertebrate lineage. Here we use the conservation of splice sites to trace the evolution of lncRNAs. We show that >85% of the human GENCODE lncRNAs were already present at the divergence of placental mammals and many hundreds of these RNAs date back even further. Nevertheless, we observe a fast turnover of intron/exon structures. We conclude that lncRNA genes are evolutionary ancient components of vertebrate genomes that show an …
Cited by:120
Resources:[PDF] from cshlp.org
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Applications of Statistical Learning Methods to Biological Data
2015
Kristin Reiche
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Authors:Kristin Reiche
Publication date:01/27/2015
Description:► But the true total RNA output Si is unknown.► Si varies drastically between different samples i.► Hence, if a transcript is highly expressed in sample i but not in another, the remaining transcripts in sample i are undersampled.► Without adjustment, the remaining transcripts will be seen to be down-regulated in i.
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Novel RNA-biomarkers for diagnosis and prognosis of prostate carcinoma
2015
Friedemann Horn, Jörg Hackermüller, Sabina Christ-Breulmann, Kristin Reiche, Manfred Wi…
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Authors:Friedemann Horn, Jörg Hackermüller, Sabina Christ-Breulmann, Kristin Reiche, Manfred Wirth, Michael Fröhner, Susanne Füssel
Publication date:01/01/2015
Description:WO15082420A1 [EN] The invention relates to the identification and selection of differentially expressed transcripts (biomarker) in tumour cells. Specific determination of the level of these biomarkers can be used for screening and diagnosis of prostate cancer. Clinical application of assays based on these biomarker help reduce the high number of false positives of current standard screening assays.
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CEM-Designer: Design of custom expression microarrays in the post-ENCODE Era
2014
Christian Arnold, Fabian Externbrink, Jörg Hackermüller, Kristin Reiche
Journal of biotechnology 189, 154-156
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Authors:Christian Arnold, Fabian Externbrink, Jörg Hackermüller, Kristin Reiche
Publication date:11/10/2014
Journal:Journal of biotechnology
Volume:189
Pages:154-156
Publisher:Elsevier
Description:Microarrays are widely used in gene expression studies, and custom expression microarrays are popular to monitor expression changes of a customer-defined set of genes. However, the complexity of transcriptomes uncovered recently make custom expression microarray design a non-trivial task. Pervasive transcription and alternative processing of transcripts generate a wealth of interweaved transcripts that requires well-considered probe design strategies and is largely neglected in existing approaches.We developed the web server CEM-Designer that facilitates microarray platform independent design of custom expression microarrays for complex transcriptomes. CEM-Designer covers (i) the collection and generation of a set of unique target sequences from different sources and (ii) the selection of a set of sensitive and specific probes that optimally represents the target sequences. Probe design itself is left to …
Cited by:6
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Long non-coding RNAs differentially expressed between normal versus primary breast tumor tissues disclose converse changes to breast cancer-related protein-coding genes
2014
Kristin Reiche, Katharina Kasack, Stephan Schreiber, Torben Lüders, Eldri U Due, Bjørn …
PloS one 9 (9), e106076
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Authors:Kristin Reiche, Katharina Kasack, Stephan Schreiber, Torben Lüders, Eldri U Due, Bjørn Naume, Margit Riis, Vessela N Kristensen, Friedemann Horn, Anne-Lise Børresen-Dale, Jörg Hackermüller, Lars O Baumbusch
Publication date:09/29/2014
Journal:PloS one
Volume:9
Issue:9
Pages:e106076
Publisher:Public Library of Science
Description:Breast cancer, the second leading cause of cancer death in women, is a highly heterogeneous disease, characterized by distinct genomic and transcriptomic profiles. Transcriptome analyses prevalently assessed protein-coding genes; however, the majority of the mammalian genome is expressed in numerous non-coding transcripts. Emerging evidence supports that many of these non-coding RNAs are specifically expressed during development, tumorigenesis, and metastasis. The focus of this study was to investigate the expression features and molecular characteristics of long non-coding RNAs (lncRNAs) in breast cancer. We investigated 26 breast tumor and 5 normal tissue samples utilizing a custom expression microarray enclosing probes for mRNAs as well as novel and previously identified lncRNAs. We identified more than 19,000 unique regions significantly differentially expressed between normal versus breast tumor tissue, half of these regions were non-coding without any evidence for functional open reading frames or sequence similarity to known proteins. The identified non-coding regions were primarily located in introns (53%) or in the intergenic space (33%), frequently orientated in antisense-direction of protein-coding genes (14%), and commonly distributed at promoter-, transcription factor binding-, or enhancer-sites. Analyzing the most diverse mRNA breast cancer subtypes Basal-like versus Luminal A and B resulted in 3,025 significantly differentially expressed unique loci, including 682 (23%) for non-coding transcripts. A notable number of differentially expressed protein-coding genes displayed non-synonymous expression …
Cited by:50
Resources:[HTML] from plos.org
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Cell cycle, oncogenic and tumor suppressor pathways regulate numerous long and macro non-protein-coding RNAs
2014
Jörg Hackermüller, Kristin Reiche, Christian Otto, Nadine Hösler, Conny Blumert, Katja …
Genome biology 15 (3), R48
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Authors:Jörg Hackermüller, Kristin Reiche, Christian Otto, Nadine Hösler, Conny Blumert, Katja Brocke-Heidrich, Levin Böhlig, Anne Nitsche, Katharina Kasack, Peter Ahnert, Wolfgang Krupp, Kurt Engeland, Peter F Stadler, Friedemann Horn
Publication date:03/04/2014
Journal:Genome biology
Volume:15
Issue:3
Pages:R48
Publisher:BioMed Central
Description:Background The genome is pervasively transcribed but most transcripts do not code for proteins, constituting non-protein-coding RNAs. Despite increasing numbers of functional reports of individual long non-coding RNAs (lncRNAs), assessing the extent of functionality among the non-coding transcriptional output of mammalian cells remains intricate. In the protein-coding world, transcripts differentially expressed in the context of processes essential for the survival of multicellular organisms have been instrumental in the discovery of functionally relevant proteins and their deregulation is frequently associated with diseases. We therefore systematically identified lncRNAs expressed differentially in response to oncologically relevant processes and cell-cycle, p53 and STAT3 pathways, using tiling arrays. Results We found that up to 80% of the pathway-triggered transcriptional responses are non-coding. Among these …
Cited by:55
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Assessment Of Long Noncoding Rna Expression Using Whole Transcriptome Sequencing Of COPD Blood Samples From The Eclipse Cohort
2013
Jorg Hackermuller, Peter Ahnert, Sabina Christ, Jens M Hohlfeld, Friedemann Horn, Norbe…
D33. CHRONIC OBSTRUCTIVE PULMONARY DISEASE: GENETICS, A5513-A5513
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Authors:Jorg Hackermuller, Peter Ahnert, Sabina Christ, Jens M Hohlfeld, Friedemann Horn, Norbert Krug, Elena Lindemann, Markus Loffler, Stefan Lorenz, Kristin Reiche, Kai Sohn, Michael Specht, Bruce Miller, Nicholas W Locantore, Ruth Tal-Singer
Publication date:05/01/2013
Journal:D33. CHRONIC OBSTRUCTIVE PULMONARY DISEASE: GENETICS
Pages:A5513-A5513
Publisher:American Thoracic Society
Description:Rationale: For COPD, there is a high clinical need for reliable biomarkers that predict disease progression, which is characterized by decline of lung function as measured by FEV1. Non-protein-coding RNAs are a large class of transcripts that have recently been recognized to be highly specifically regulated and disease-associated, some of which are already used as biomarkers for oncological diseases. The Fraunhofer R&D consortium RIBOLUTION aims at identifying and validating novel RNA-based biomarkers for various diseases. Methods: Assuming that COPD has a significant systemic component, and because markers for standard diagnostic applications need to be easily accessible, we chose to search for predictive markers for COPD progression in whole blood samples. From the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) COPD cohort, we selected 80 …
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LocARNAscan: Incorporating thermodynamic stability in sequence and structure-based RNA homology search
2013
Sebastian Will, Michael F Siebauer, Steffen Heyne, Jan Engelhardt, Peter F Stadler, Kri…
Algorithms for Molecular Biology 8 (1), 14
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Authors:Sebastian Will, Michael F Siebauer, Steffen Heyne, Jan Engelhardt, Peter F Stadler, Kristin Reiche, Rolf Backofen
Publication date:04/20/2013
Journal:Algorithms for Molecular Biology
Volume:8
Issue:1
Pages:14
Publisher:BioMed Central
Description:Background The search for distant homologs has become an import issue in genome annotation. A particular difficulty is posed by divergent homologs that have lost recognizable sequence similarity. This same problem also arises in the recognition of novel members of large classes of RNAs such as snoRNAs or microRNAs that consist of families unrelated by common descent. Current homology search tools for structured RNAs are either based entirely on sequence similarity (such as blast or hmmer) or combine sequence and secondary structure. The most prominent example of the latter class of tools is Infernal. Alternatives are descriptor-based methods. In most practical applications published to-date, however, the information contained in covariance models or manually prescribed search patterns is dominated by sequence information. Here we ask two related questions: (1) Is secondary structure alone …
Cited by:21
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MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma
2013
Kerstin Boll, Kristin Reiche, Katharina Kasack, N Mörbt, Antje K Kretzschmar, JM Tomm, …
Oncogene 32 (3), 277-285
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Authors:Kerstin Boll, Kristin Reiche, Katharina Kasack, N Mörbt, Antje K Kretzschmar, JM Tomm, G Verhaegh, J Schalken, Martin von Bergen, Friedemann Horn, Jörg Hackermüller
Publication date:01/01/2013
Journal:Oncogene
Volume:32
Issue:3
Pages:277-285
Publisher:Nature Publishing Group
Description:With∼ 30 000 deaths annually in the United States, prostate cancer (PCa) is a major oncologic disease. Here we show that the microRNAs miR-130a, miR-203 and miR-205 jointly interfere with the two major oncogenic pathways in prostate carcinoma and are downregulated in cancer tissue. Using transcriptomics we show that the microRNAs repress several gene products known to be overexpressed in this cancer. Argonaute 2 (AGO2) co-immunoprecipitation, reporter assays and western blot analysis demonstrate that the microRNAs directly target several components of the mitogen-activated protein kinase (MAPK) and androgen receptor (AR) signaling pathways, among those several AR coregulators and HRAS (Harvey rat sarcoma viral oncogene homolog), and repress signaling activity. Both pathways are central for the development of the primary tumor and in particular the progression to its incurable …
Cited by:251
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Detection of differentially expressed segments in tiling array data
2012
Christian Otto, Kristin Reiche, Jörg Hackermüller
Bioinformatics 28 (11), 1471-1479
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Authors:Christian Otto, Kristin Reiche, Jörg Hackermüller
Publication date:06/01/2012
Journal:Bioinformatics
Volume:28
Issue:11
Pages:1471-1479
Publisher:Oxford University Press
Description: Motivation: Tiling arrays have been a mainstay of unbiased genome-wide transcriptomics over the last decade. Currently available approaches to identify expressed or differentially expressed segments in tiling array data are limited in the recovery of the underlying gene structures and require several parameters that are intensity-related or partly dataset-specific. Results: We have developed TileShuffle, a statistical approach that identifies transcribed and differentially expressed segments as significant differences from the background distribution while considering sequence-specific affinity biases and cross-hybridization. It avoids dataset-specific parameters in order to provide better comparability of different tiling array datasets, based on different technologies or array designs. TileShuffle detects highly and differentially expressed segments in biological data with significantly lower false …
Cited by:17
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LocARNA-alignment & folding
2012
Sebastian Will, Tejal Joshi, Ivo L Hofacker, Peter F Stadler, Rolf Backofen, Kristin Re…
RNA 18 (5), 900-14
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Authors:Sebastian Will, Tejal Joshi, Ivo L Hofacker, Peter F Stadler, Rolf Backofen, Kristin Reiche, Martin Raden, Syed M Ali, Omer S Alkhnbashi, Anke Busch, Fabrizio Costa, Jason A Davis, Florian Eggenhofer, Rick Gelhausen, Jens Georg, Steffen Heyne, Michael Hiller, Kousik Kundu, Robert Kleinkauf, Steffen C Lott, Mostafa M Mohamed, Alexander Mattheis, Milad Miladi, Andreas S Richter, Joachim Wolff, Patrick R Wright, Rolf Backofen
Publication date:01/01/2012
Journal:RNA
Volume:18
Issue:5
Pages:900-14
Description:LocARNA is a tool for multiple alignment of RNA molecules. LocARNA requires only RNA sequences as input and will simultaneously fold and align the input sequences. Specifications of additional constraints or fixed input structures are possible. LocARNA outputs a multiple alignment together with a consensus structure. For the folding it makes use of a very realistic energy model for RNAs as it is by RNAfold of the Vienna RNA package (or Zuker's mfold). For the alignment it features RIBOSUM-like similarity scoring and realistic gap cost. The LocARNA software is available for download as part of the LocARNA package (GPL 3).
Cited by:2
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Deletion analysis of the 3′ long terminal repeat sequence of plant retrotransposon Tto1 identifies 125 base pairs redundancy as sufficient for first strand transfer
2011
Andrea Tramontano, Alexander Donath, Stephan H Bernhart, Kristin Reiche, Gudrun Böhmdor…
Virology 412 (1), 75-82
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Authors:Andrea Tramontano, Alexander Donath, Stephan H Bernhart, Kristin Reiche, Gudrun Böhmdorfer, Peter F Stadler, Andreas Bachmair
Publication date:03/30/2011
Journal:Virology
Volume:412
Issue:1
Pages:75-82
Publisher:Academic Press
Description:Retroviruses and many retrotransposons are flanked by sequence repeats called long terminal repeats (LTRs). These sequences contain a promoter region, which is active in the 5′ LTR, and transcription termination signals, which are active in the LTR copy present at the 3′ end. A section in the middle of the LTR, called Redundancy region, occurs at both ends of the mRNA. Here we show that in the copia type retrotransposon Tto1, the promoter and terminator functions of the LTR can be supplied by heterologous sequences, thereby converting the LTR into a significantly shorter sub-terminal repeat. An engineered Tto1 element with 125 instead of the usual 574 base pairs repeated in the 5′ and 3′ region can still promote strand transfer during cDNA synthesis, defining a minimal Redundancy region for this element. Based on this finding, we propose a model for first strand transfer of Tto1.
Cited by:5
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Bioinformatics for RNomics
2011
Kristin Reiche, Katharina Schutt, Kerstin Boll, Friedemann Horn, Jörg Hackermüller
Bioinformatics for Omics Data: Methods and Protocols, 299-330
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Authors:Kristin Reiche, Katharina Schutt, Kerstin Boll, Friedemann Horn, Jörg Hackermüller
Publication date:01/29/2011
Journal:Bioinformatics for Omics Data: Methods and Protocols
Pages:299-330
Publisher:Humana Press
Description:Rapid improvements in high-throughput experimental technologies make it nowadays possible to study the expression, as well as changes in expression, of whole transcriptomes under different environmental conditions in a detailed view. We describe current approaches to identify genome-wide functional RNA transcripts (experimentally as well as computationally), and focus on computational methods that may be utilized to disclose their function. While genome databases offer a wealth of information about known and putative functions for protein-coding genes, functional information for novel non-coding RNA genes is almost nonexistent. This is mainly explained by the lack of established software tools to efficiently reveal the function and evolutionary origin of non-coding RNA genes. Here, we describe in detail computational approaches one may follow to annotate and classify an RNA transcript.
Cited by:5
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Identification of ncRNAs regulating differencoation and function of CD4+ T cells
2011
N Hösler, NHJ Hackermüller, K Reiche, F Horn
Cytokine
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Authors:N Hösler, NHJ Hackermüller, K Reiche, F Horn
Publication date:01/01/2011
Journal:Cytokine
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Differential expression of non-coding transcripts in breast cancer cells
2011
K Kasack, K Reiche, F Horn, J Hackermüller
Research Festival for Life Sciences 2011
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Authors:K Kasack, K Reiche, F Horn, J Hackermüller
Publication date:01/01/2011
Journal:Research Festival for Life Sciences 2011
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LNCaP xenograft mouse model for investigating the therapeutic potential of three microRNAs downregulated in prostate cancer
2011
R Ascherl, K Boll, K Reiche, K Kasack, AK Kretzschmar, J Tomm, F Horn, J Hackermüller, …
Research Festival for Life Sciences 2011
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Authors:R Ascherl, K Boll, K Reiche, K Kasack, AK Kretzschmar, J Tomm, F Horn, J Hackermüller, N Mörbt, G Verhaegh, J Schalken, M von Bergen
Publication date:01/01/2011
Journal:Research Festival for Life Sciences 2011
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The primary transcriptome of the major human pathogen Helicobacter pylori
2010
Cynthia M Sharma, Steve Hoffmann, Fabien Darfeuille, Jérémy Reignier, Sven Findeiß, Ale…
Nature 464 (7286), 250-255
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Authors:Cynthia M Sharma, Steve Hoffmann, Fabien Darfeuille, Jérémy Reignier, Sven Findeiß, Alexandra Sittka, Sandrine Chabas, Kristin Reiche, Jörg Hackermüller, Richard Reinhardt, Peter F Stadler, Jörg Vogel
Publication date:03/11/2010
Journal:Nature
Volume:464
Issue:7286
Pages:250-255
Publisher:Nature Publishing Group UK
Description:Genome sequencing of Helicobacter pylori has revealed the potential proteins and genetic diversity of this prevalent human pathogen, yet little is known about its transcriptional organization and noncoding RNA output. Massively parallel cDNA sequencing (RNA-seq) has been revolutionizing global transcriptomic analysis. Here, using a novel differential approach (dRNA-seq) selective for the 5′ end of primary transcripts, we present a genome-wide map of H. pylori transcriptional start sites and operons. We discovered hundreds of transcriptional start sites within operons, and opposite to annotated genes, indicating that complexity of gene expression from the small H. pylori genome is increased by uncoupling of polycistrons and by genome-wide antisense transcription. We also discovered an unexpected number of ∼60 small RNAs including the ε-subdivision counterpart of the regulatory 6S RNA and associated …
Cited by:1392
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Molecular signatures of long non-coding RNAs in breast cancer patients
2010
LO Baumbusch, K Reiche, K Schutt, S Schreiber, EU Due, T Lüders, VN Kristensen, F Horn,…
European Association for Cancer Research (Meeting) 2010
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Authors:LO Baumbusch, K Reiche, K Schutt, S Schreiber, EU Due, T Lüders, VN Kristensen, F Horn, J Hackermüller, AL Borresen-Dale
Publication date:01/01/2010
Journal:European Association for Cancer Research (Meeting) 2010
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Non-protein coding RNAs in breast cancer initiating cells
2010
K Schutt, K Reiche, K Boll, F Horn, J Hackermüller
Research Festival for Life Sciences 2010
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Authors:K Schutt, K Reiche, K Boll, F Horn, J Hackermüller
Publication date:01/01/2010
Journal:Research Festival for Life Sciences 2010
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Identification and annotation of non-protein coding RNAs.
2009
Kristin Reiche, Katharina Schutt, Kerstin Ullmann, Friedemann Horn, Jörg Hackermüller
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Authors:Kristin Reiche, Katharina Schutt, Kerstin Ullmann, Friedemann Horn, Jörg Hackermüller
Publication date:12/14/2009
Description:Of the 3.3 billion bases of the human genome, only about 2% code for proteins. Since very recently, the remaining 98% have been considered to be’junk’and functionless. However, large transcriptomic studies like ENCODE (ENCyclopedia Of DNA Elements)(1) or FANTOM (The Functional Annotation Of the Mammalian Genome)(2) have shown that around 90% of the genome is actively transcribed into RNA. The pilot phase of the ENCODE Project was focused on 1% of the human genome sequence and was organized as an international consortium of computational and laboratory-based scientists working to develop and apply high-throughput approaches for detecting all sequence elements that confer biological function. The studies advanced the collective knowledge about human genome function in several major areas. The ENCODE project provided convincing evidence that the genome is pervasively transcribed and the systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Beside this, the studies offered a more sophisticated view on chromatin structure and interand intra-species sequence comparison with respect to mammalian evolution has yielded new mechanistic and evolutionary insights concerning the functional landscape of the hu-
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Long non-protein coding RNAs in oncogenic pathways
2009
Jörg Hackermüller, Katja Brocke-Heidrich, Kristin Reiche, Antje Kretzschmar, K Schutt, …
JOURNAL OF NEUROCHEMISTRY 110, 99-100
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Authors:Jörg Hackermüller, Katja Brocke-Heidrich, Kristin Reiche, Antje Kretzschmar, K Schutt, Peter Ahnert, L Boehlig, Peter F Stadler, Kurt Engeland, Friedemann Horn
Publication date:07/01/2009
Journal:JOURNAL OF NEUROCHEMISTRY
Volume:110
Pages:99-100
Publisher:WILEY-BLACKWELL PUBLISHING, INC
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Structural profiles of human miRNA families from pairwise clustering
2009
Bogumił Kaczkowski, Elfar Torarinsson, Kristin Reiche, Jakob Hull Havgaard, Peter F Sta…
Bioinformatics 25 (3), 291-294
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Authors:Bogumił Kaczkowski, Elfar Torarinsson, Kristin Reiche, Jakob Hull Havgaard, Peter F Stadler, Jan Gorodkin
Publication date:02/01/2009
Journal:Bioinformatics
Volume:25
Issue:3
Pages:291-294
Publisher:Oxford University Press
Description:MicroRNAs (miRNAs) are a group of small, ∼21 nt long, riboreg-ulators inhibiting gene expression at a post-transcriptional level. Their most distinctive structural feature is the foldback hairpin of their precursor pre-miRNAs. Even though each pre-miRNA deposited in miRBase has its secondary structure already predicted, little is known about the patterns of structural conservation among pre-miRNAs. We address this issue by clustering the human pre-miRNA sequences based on pairwise, sequence and secondary structure alignment using FOLDALIGN, followed by global multiple alignment of obtained clusters by WAR. As a result, the common secondary structure was successfully determined for four FOLDALIGN clusters: the RF00027 structural family of the Rfam database and three clusters with previously undescribed consensus structures. Availability:  http://genome.ku.dk/resources/mirclust …
Cited by:82
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Transcriptome profiling reveals many novel p53-regulated human non-coding RNAs
2009
L Böhlig, Jörg Hackermüller, Dominic Rose, Kristin Reiche, Antje Kretzschmar, Peter F S…
Conference on Advances in Molecular Mechanisms of Neurological Disorders 2009
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Authors:L Böhlig, Jörg Hackermüller, Dominic Rose, Kristin Reiche, Antje Kretzschmar, Peter F Stadler, Friedemann Horn, Kurt Engeland
Publication date:01/01/2009
Journal:Conference on Advances in Molecular Mechanisms of Neurological Disorders 2009
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Duplicated RNA genes in teleost fish genomes
2008
Dominic Rose, Julian Jöris, Jörg Hackermüller, Kristin Reiche, Qiang Li, Peter F Stadle…
Journal of bioinformatics and computational biology 6 (06), 1157-1175
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Authors:Dominic Rose, Julian Jöris, Jörg Hackermüller, Kristin Reiche, Qiang Li, Peter F Stadler
Publication date:12/01/2008
Journal:Journal of bioinformatics and computational biology
Volume:6
Issue:06
Pages:1157-1175
Publisher:Imperial College Press
Description:Teleost fishes share a duplication of their entire genomes. We report here on a computational survey of structured non-coding RNAs (ncRNAs) in teleost genomes, focusing on the fate of fish-specific duplicates. As in other metazoan groups, we find evidence of a large number (11,543) of structured RNAs, most of which (~86%) are clade-specific or evolve so fast that their tetrapod homologs cannot be detected. In surprising contrast to protein-coding genes, the fish-specific genome duplication did not lead to a large number of paralogous ncRNAs: only 188 candidates, mostly microRNAs, appear in a larger copy number in teleosts than in tetrapods, suggesting that large-scale gene duplications do not play a major role in the expansion of the vertebrate ncRNA inventory.
Cited by:18
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NcDNAlign: plausible multiple alignments of non-protein-coding genomic sequences
2008
Dominic Rose, Jana Hertel, Kristin Reiche, Peter F Stadler, Jörg Hackermüller
Genomics 92 (1), 65-74
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Authors:Dominic Rose, Jana Hertel, Kristin Reiche, Peter F Stadler, Jörg Hackermüller
Publication date:07/01/2008
Journal:Genomics
Volume:92
Issue:1
Pages:65-74
Publisher:Academic Press
Description:Genome-wide multiple sequence alignments (MSAs) are a necessary prerequisite for an increasingly diverse collection of comparative genomic approaches. Here we present a versatile method that generates high-quality MSAs for non-protein-coding sequences. The NcDNAlign pipeline combines pairwise BLAST alignments to create initial MSAs, which are then locally improved and trimmed. The program is optimized for speed and hence is particulary well-suited to pilot studies. We demonstrate the practical use of NcDNAlign in three case studies: the search for ncRNAs in gammaproteobacteria and the analysis of conserved noncoding DNA in nematodes and teleost fish, in the latter case focusing on the fate of duplicated ultra-conserved regions. Compared to the currently widely used genome-wide alignment program TBA, our program results in a 20- to 30-fold reduction of CPU time necessary to generate …
Cited by:22
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Computational Identification and Annotation of non-coding RNAs
2008
Kristin Reiche
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Authors:Kristin Reiche
Publication date:01/01/2008
Cited by:1
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NcDNAlign
2008
Dominic Rose, Jana Hertel, Kristin Reiche, Peter F Stadler, Jörg Hackermüller
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Authors:Dominic Rose, Jana Hertel, Kristin Reiche, Peter F Stadler, Jörg Hackermüller
Publication date:01/01/2008
Description:Abstract (EN) Genome-wide multiple sequence alignments (MSAs) are a necessary prerequisite for an increasingly diverse collection of comparative genomic approaches. Here we present a versatile method that generates high-quality MSAs for non-protein-coding sequences. The NcDNAlign pipeline combines pairwise BLAST alignments to create initial MSAs, which are then locally improved and trimmed. The program is optimized for speed and hence is particulary well-suited to pilot studies. We demonstrate the practical use of NcDNAlign in three case studies: the search for ncRNAs in gammaproteobacteria and the analysis of conserved noncoding DNA in nematodes and teleost fish, in the latter case focusing on the fate of duplicated ultra-conserved regions. Compared to the currently widely used genome-wide alignment program TBA, our program results in a 20-to 30-fold reduction of CPU time necessary to generate gammaproteobacterial alignments. A showcase application of bacterial ncRNA prediction based on alignments of both algorithms results in similar sensitivity, false discovery rates, and up to 100 putatively novel ncRNA structures. Similar findings hold for our application of NcDNAlign to the identification of ultra-conserved regions in nematodes and teleosts. Both approaches yield conserved sequences of unknown function, result in novel evolutionary insights into conservation patterns among these genomes, and manifest the benefits of an efficient and reliable genome-wide alignment package. The software is available under the GNU Public License at http://www. bioinf. uni-leipzig. de/Software/NcDNAlign/.
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Computational RNomics of drosophilids
2007
Dominic Rose, Jörg Hackermüller, Stefan Washietl, Kristin Reiche, Jana Hertel, Sven Fin…
BMC genomics 8 (1), 406
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Authors:Dominic Rose, Jörg Hackermüller, Stefan Washietl, Kristin Reiche, Jana Hertel, Sven Findeiß, Peter F Stadler, Sonja J Prohaska
Publication date:11/08/2007
Journal:BMC genomics
Volume:8
Issue:1
Pages:406
Publisher:BioMed Central
Description:Background Recent experimental and computational studies have provided overwhelming evidence for a plethora of diverse transcripts that are unrelated to protein-coding genes. One subclass consists of those RNAs that require distinctive secondary structure motifs to exert their biological function and hence exhibit distinctive patterns of sequence conservation characteristic for positive selection on RNA secondary structure. The deep-sequencing of 12 drosophilid species coordinated by the NHGRI provides an ideal data set of comparative computational approaches to determine those genomic loci that code for evolutionarily conserved RNA motifs. This class of loci includes the majority of the known small ncRNAs as well as structured RNA motifs in mRNAs. We report here on a genome-wide survey using RNAz. Results We obtain 16 000 high quality predictions among which we recover the majority of the known …
Cited by:61
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
2007
Management Group Liefer Laura A. 51 Wetterstrand Kris A. 51 Good Peter J. 51 Feingold E…
nature 447 (7146), 799-816
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Authors:Management Group Liefer Laura A. 51 Wetterstrand Kris A. 51 Good Peter J. 51 Feingold Elise A. 51 Guyer Mark S. 51 Collins Francis S. 52, Baylor College of Medicine Human Genome Sequencing Center*, Washington University Genome Sequencing Center*, Broad Institute*, Children’s Hospital Oakland Research Institute*, Mark Gerstein, Stylianos E Antonarakis, Serafim Batzoglou, Nick Goldman, Ross C Hardison, David Haussler, Webb Miller, Lior Pachter, Eric D Green, Arend Sidow, Zhiping Weng, Nathan D Trinklein, Yutao Fu, Zhengdong D Zhang, Ulaş Karaöz, Leah Barrera, Rhona Stuart, Deyou Zheng, Srinka Ghosh, Paul Flicek, David C King, James Taylor, Adam Ameur, Stefan Enroth, Mark C Bieda, Christoph M Koch, Heather A Hirsch, Chia-Lin Wei, Jill Cheng, Jonghwan Kim, Akshay A Bhinge, Paul G Giresi, Nan Jiang, Jun Liu, Fei Yao, Wing-Kin Sung, Kuo Ping Chiu, Vinsensius B Vega, Charlie WH Lee, Patrick Ng, Atif Shahab, Edward A Sekinger, Annie Yang, Zarmik Moqtaderi, Zhou Zhu, Xiaoqin Xu, Sharon Squazzo, Matthew J Oberley, David Inman, Michael A Singer, Todd A Richmond, Kyle J Munn, Alvaro Rada-Iglesias, Ola Wallerman, Jan Komorowski, Gayle K Clelland, Sarah Wilcox, Shane C Dillon, Robert M Andrews, Joanna C Fowler, Phillippe Couttet, Keith D James, Gregory C Lefebvre, Alexander W Bruce, Oliver M Dovey, Peter D Ellis, Pawandeep Dhami, Cordelia F Langford, Nigel P Carter, David Vetrie, Philipp Kapranov, David A Nix, Ian Bell, Sandeep Patel, Joel Rozowsky, Ghia Euskirchen, Stephen Hartman, Jin Lian, Jiaqian Wu, Alexander E Urban, Peter Kraus, Sara Van Calcar, Nate Heintzman, Tae Hoon Kim, Kun Wang, Chunxu Qu, Gary Hon, Rosa Luna, Christopher K Glass, M Geoff Rosenfeld, Shelley Force Aldred, Sara J Cooper, Anason Halees, Jane M Lin, Hennady P Shulha, Xiaoling Zhang, Mousheng Xu, Jaafar NS Haidar, Yong Yu, Ewan Birney*, Sherman Weissman, Yijun Ruan, Jason D Lieb, Vishwanath R Iyer, Roland D Green, Thomas R Gingeras, Claes Wadelius, Ian Dunham, Kevin Struhl, Ross C Hardison, Mark Gerstein, Peggy J Farnham, Richard M Myers, Bing Ren, Michael Snyder, Daryl J Thomas, Kate Rosenbloom, Rachel A Harte, Angie S Hinrichs, Heather Trumbower, Hiram Clawson, Jennifer Hillman-Jackson, Ann S Zweig, Kayla Smith, Archana Thakkapallayil, Galt Barber, Robert M Kuhn, Donna Karolchik, David Haussler, W James Kent, Emmanouil T Dermitzakis, Lluis Armengol, Christine P Bird, Taane G Clark, Gregory M Cooper, Paul IW de Bakker, Andrew D Kern, Nuria Lopez-Bigas, Joel D Martin, Barbara E Stranger
Publication date:06/14/2007
Journal:nature
Volume:447
Issue:7146
Pages:799-816
Publisher:Nature Publishing Group UK
Description:We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a …
Cited by:6279
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Structured RNAs in the ENCODE selected regions of the human genome
2007
Stefan Washietl, Jakob S Pedersen, Jan O Korbel, Claudia Stocsits, Andreas R Gruber, Jö…
Genome research 17 (6), 852-864
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Authors:Stefan Washietl, Jakob S Pedersen, Jan O Korbel, Claudia Stocsits, Andreas R Gruber, Jörg Hackermüller, Jana Hertel, Manja Lindemeyer, Kristin Reiche, Andrea Tanzer, Catherine Ucla, Carine Wyss, Stylianos E Antonarakis, France Denoeud, Julien Lagarde, Jorg Drenkow, Philipp Kapranov, Thomas R Gingeras, Roderic Guigo, Michael Snyder, Mark B Gerstein, Alexandre Reymond, Ivo L Hofacker, Peter F Stadler
Publication date:06/01/2007
Journal:Genome research
Volume:17
Issue:6
Pages:852-864
Publisher:Cold Spring Harbor Lab
Description:Functional RNA structures play an important role both in the context of noncoding RNA transcripts as well as regulatory elements in mRNAs. Here we present a computational study to detect functional RNA structures within the ENCODE regions of the human genome. Since structural RNAs in general lack characteristic signals in primary sequence, comparative approaches evaluating evolutionary conservation of structures are most promising. We have used three recently introduced programs based on either phylogenetic–stochastic context-free grammar (EvoFold) or energy directed folding (RNAz and AlifoldZ), yielding several thousand candidate structures (corresponding to ∼2.7% of the ENCODE regions). EvoFold has its highest sensitivity in highly conserved and relatively AU-rich regions, while RNAz favors slightly GC-rich regions, resulting in a relatively small overlap between methods. Comparison with the …
Cited by:228
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RNAstrand: reading direction of structured RNAs in multiple sequence alignments
2007
Kristin Reiche, Peter F Stadler
Algorithms for Molecular Biology 2 (1), 6
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Authors:Kristin Reiche, Peter F Stadler
Publication date:05/31/2007
Journal:Algorithms for Molecular Biology
Volume:2
Issue:1
Pages:6
Publisher:BioMed Central
Description:Motivation Genome-wide screens for structured ncRNA genes in mammals, urochordates, and nematodes have predicted thousands of putative ncRNA genes and other structured RNA motifs. A prerequisite for their functional annotation is to determine the reading direction with high precision. Results While folding energies of an RNA and its reverse complement are similar, the differences are sufficient at least in conjunction with substitution patterns to discriminate between structured RNAs and their complements. We present here a support vector machine that reliably classifies the reading direction of a structured RNA from a multiple sequence alignment and provides a considerable improvement in classification accuracy over previous approaches. Software RNAstrand is freely available as a stand-alone tool from http://www.bioinf.uni-leipzig.de/Software/RNAstrand and is also included in the latest release of RNAz …
Cited by:38
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Inferring noncoding RNA families and classes by means of genome-scale structure-based clustering
2007
Sebastian Will, Kristin Reiche, Ivo L Hofacker, Peter F Stadler, Rolf Backofen
PLoS computational biology 3 (4), e65
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Authors:Sebastian Will, Kristin Reiche, Ivo L Hofacker, Peter F Stadler, Rolf Backofen
Publication date:04/01/2007
Journal:PLoS computational biology
Volume:3
Issue:4
Pages:e65
Publisher:Public Library of Science
Description:The RFAM database defines families of ncRNAs by means of sequence similarities that are sufficient to establish homology. In some cases, such as microRNAs and box H/ACA snoRNAs, functional commonalities define classes of RNAs that are characterized by structural similarities, and typically consist of multiple RNA families. Recent advances in high-throughput transcriptomics and comparative genomics have produced very large sets of putative noncoding RNAs and regulatory RNA signals. For many of them, evidence for stabilizing selection acting on their secondary structures has been derived, and at least approximate models of their structures have been computed. The overwhelming majority of these hypothetical RNAs cannot be assigned to established families or classes. We present here a structure-based clustering approach that is capable of extracting putative RNA classes from genome-wide surveys for structured RNAs. The LocARNA (local alignment of RNA) tool implements a novel variant of the Sankoff algorithm that is sufficiently fast to deal with several thousand candidate sequences. The method is also robust against false positive predictions, i.e., a contamination of the input data with unstructured or nonconserved sequences. We have successfully tested the LocARNA-based clustering approach on the sequences of the RFAM-seed alignments. Furthermore, we have applied it to a previously published set of 3,332 predicted structured elements in the Ciona intestinalis genome (Missal K, Rose D, Stadler PF (2005) Noncoding RNAs in Ciona intestinalis. Bioinformatics 21 (Supplement 2): i77–i78). In addition to recovering, e.g …
Cited by:619
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RNAs everywhere: Genome‐wide annotation of structured RNAs
2007
Rolf Backofen, Stephan H Bernhart, Christoph Flamm, Claudia Fried, Guido Fritzsch, Jörg…
Journal of Experimental Zoology Part B: Molecular and Developmental Evolution 308 (1), …
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Authors:Rolf Backofen, Stephan H Bernhart, Christoph Flamm, Claudia Fried, Guido Fritzsch, Jörg Hackermüller, Jana Hertel, Ivo L Hofacker, Kristin Missal, Axel Mosig, Sonja J Prohaska, Dominic Rose, Peter F Stadler, Andrea Tanzer, Stefan Washietl, Sebastian Will
Publication date:01/15/2007
Journal:Journal of Experimental Zoology Part B: Molecular and Developmental Evolution
Volume:308
Issue:1
Pages:1-25
Publisher:Wiley Subscription Services, Inc., A Wiley Company
Description:Starting with the discovery of microRNAs and the advent of genome‐wide transcriptomics, non‐protein‐coding transcripts have moved from a fringe topic to a central field research in molecular biology. In this contribution we review the state of the art of “computational RNomics”, i.e., the bioinformatics approaches to genome‐wide RNA annotation. Instead of rehashing results from recently published surveys in detail, we focus here on the open problem in the field, namely (functional) annotation of the plethora of putative RNAs. A series of exploratory studies are used to provide non‐trivial examples for the discussion of some of the difficulties. J. Exp. Zool. (Mol. Dev. Evol.) 308B, 2007. © 2006 Wiley‐Liss, Inc.
Cited by:94
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Structured RNAs in the ENCODE selected regions of the human
2007
Roderic Guigó, Michael Snyder, Mark B Gerstein, Alexandre Reymond, Ivo L Hofacker, Pete…
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Authors:Roderic Guigó, Michael Snyder, Mark B Gerstein, Alexandre Reymond, Ivo L Hofacker, Peter F Stadler, France Denoeud Antonarakis, Julien Lagarde, Jorg Drenkow, Philipp Kapranov, Thomas R Gingeras, Jana Hertel, Manja Lindemeyer, Kristin Reiche, Andrea Tanzer, Catherine Ucla, Carine Wyss, Stylianos E Stefan Washietl, Jakob S Pedersen, Jan O Korbel, Claudia Stocsits, Andreas R Gruber, Jörg Hackermüller
Publication date:01/01/2007
Description:Functional RNA structures play an important role both in the context of noncoding RNA transcripts as well as regulatory elements in mRNAs. Here we present a computational study to detect functional RNA structures within the ENCODE regions of the human genome. Since structural RNAs in general lack characteristic signals in primary sequence, comparative approaches evaluating evolutionary conservation of structures are most promising. We have used three recently introduced programs based on either phylogenetic–stochastic context-free grammar (EvoFold) or energy directed folding (RNAz and AlifoldZ), yielding several thousand candidate structures (corresponding to∼ 2.7% of the ENCODE regions). EvoFold has its highest sensitivity in highly conserved and relatively AU-rich regions, while RNAz favors slightly GC-rich regions, resulting in a relatively small overlap between methods. Comparison with the GENCODE annotation points to functional RNAs in all genomic contexts, with a slightly increased density in 3-UTRs. While we estimate a significant false discovery rate of∼ 50%–70% many of the predictions can be further substantiated by additional criteria: 248 loci are predicted by both RNAz and EvoFold, and an additional 239 RNAz or EvoFold predictions are supported by the (more stringent) AlifoldZ algorithm. Five hundred seventy RNAz structure predictions fall into regions that show signs of selection pressure also on the sequence level (ie, conserved elements). More than 700 predictions overlap with noncoding transcripts detected by oligonucleotide tiling arrays. One hundred seventy-five selected candidates were tested by …
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Prediction of structured non‐coding RNAs in the genomes of the nematodes Caenorhabditis elegans and Caenorhabditis briggsae
2006
Kristin Missal, Xiaopeng Zhu, Dominic Rose, Wei Deng, Geir Skogerbø, Runsheng Chen, Pet…
Journal of Experimental Zoology Part B: Molecular and Developmental Evolution 306 (4), …
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Authors:Kristin Missal, Xiaopeng Zhu, Dominic Rose, Wei Deng, Geir Skogerbø, Runsheng Chen, Peter F Stadler
Publication date:07/15/2006
Journal:Journal of Experimental Zoology Part B: Molecular and Developmental Evolution
Volume:306
Issue:4
Pages:379-392
Publisher:Wiley Subscription Services, Inc., A Wiley Company
Description:We present a survey for non‐coding RNAs and other structured RNA motifs in the genomes of Caenorhabditis elegans and Caenorhabditis briggsae using the RNAz program. This approach explicitly evaluates comparative sequence information to detect stabilizing selection acting on RNA secondary structure. We detect 3,672 structured RNA motifs, of which only 678 are known non‐translated RNAs (ncRNAs) or clear homologs of known C. elegans ncRNAs. Most of these signals are located in introns or at a distance from known protein‐coding genes. With an estimated false positive rate of about 50% and a sensitivity on the order of 50%, we estimate that the nematode genomes contain between 3,000 and 4,000 RNAs with evolutionary conserved secondary structures. Only a small fraction of these belongs to the known RNA classes, including tRNAs, snoRNAs, snRNAs, or microRNAs. A relatively small class of …
Cited by:61
Resources:[PDF] from academia.edu
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Gene network inference from incomplete expression data: transcriptional control of hematopoietic commitment
2006
Kristin Missal, Michael A Cross, Dirk Drasdo
Bioinformatics 22 (6), 731-738
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Authors:Kristin Missal, Michael A Cross, Dirk Drasdo
Publication date:03/15/2006
Journal:Bioinformatics
Volume:22
Issue:6
Pages:731-738
Publisher:Oxford University Press
Description: Motivation: The topology and function of gene regulation networks are commonly inferred from time series of gene expression levels in cell populations. This strategy is usually invalid if the gene expression in different cells of the population is not synchronous. A promising, though technically more demanding alternative is therefore to measure the gene expression levels in single cells individually. The inference of a gene regulation network requires knowledge of the gene expression levels at successive time points, at least before and after a network transition. However, owing to experimental limitations a complete determination of the precursor state is not possible. Results: We investigate a strategy for the inference of gene regulatory networks from incomplete expression data based on dynamic Bayesian networks. This permits prediction of the number of experiments necessary for network …
Cited by:27
Resources:[HTML] from oup.com
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The expansion of the metazoan microRNA repertoire
2006
Jana Hertel, Manuela Lindemeyer, Kristin Missal, Claudia Fried, Andrea Tanzer, Christop…
BMC genomics 7 (1), 25
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Authors:Jana Hertel, Manuela Lindemeyer, Kristin Missal, Claudia Fried, Andrea Tanzer, Christoph Flamm, Ivo L Hofacker, Peter F Stadler, Students of Bioinformatics Computer Labs 2004 and 2005 studla@ bioinf. uni-leipzig. de
Publication date:02/15/2006
Journal:BMC genomics
Volume:7
Issue:1
Pages:25
Publisher:BioMed Central
Description:Background MicroRNAs have been identified as crucial regulators in both animals and plants. Here we report on a comprehensive comparative study of all known miRNA families in animals. We expand the MicroRNA Registry 6.0 by more than 1000 new homologs of miRNA precursors whose expression has been verified in at least one species. Using this uniform data basis we analyze their evolutionary history in terms of individual gene phylogenies and in terms of preservation of genomic nearness across species. This allows us to reliably identify microRNA clusters that are derived from a common transcript. Results We identify three episodes of microRNA innovation that correspond to major developmental innovations: A class of about 20 miRNAs is common to protostomes and deuterostomes and might be related to the advent of bilaterians. A second large wave of innovations maps to the branch leading to the …
Cited by:393
Resources:[HTML] from springer.com
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Non-coding RNAs in Ciona intestinalis
2005
Kristin Missal, Dominic Rose, Peter F Stadler
Bioinformatics 21 (suppl_2), ii77-ii78
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Authors:Kristin Missal, Dominic Rose, Peter F Stadler
Publication date:09/01/2005
Journal:Bioinformatics
Volume:21
Issue:suppl_2
Pages:ii77-ii78
Publisher:Oxford University Press
Description: Motivation: The analysis of animal genomes showed that only a minute part of their DNA codes for proteins. Recent experimental results agree, however, that a large fraction of these genomes are transcribed and hence are probably functional at the RNA level. A computational survey of vertebrate genomes has predicted thousands of previously unknown ncRNAs with evolutionarily conserved secondary structures. Extending these comparative studies beyond vertebrates is difficult, however, since most ncRNAs evolve quickly at the sequence level while conserving their characteristic secondarystructures. Results: We report on a computational screen of structured ncRNAs in the urochordate lineage based on a comparison of the genomic data from Ciona intestinalis, Ciona savignyi and Oikopleura dioica. We predict >1000 ncRNAs with an evolutionarily conserved RNA secondary structure. Of …
Cited by:63
Resources:[PDF] from oup.com
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Evolutionary patterns of non-coding RNAs
2005
Athanasius F Bompfünewerer, Christoph Flamm, Claudia Fried, Guido Fritzsch, Ivo L Hofac…
Theory in Biosciences 123 (4), 301-369
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Authors:Athanasius F Bompfünewerer, Christoph Flamm, Claudia Fried, Guido Fritzsch, Ivo L Hofacker, Jörg Lehmann, Kristin Missal, Axel Mosig, Bettina Müller, Sonja J Prohaska, Bärbel MR Stadler, Peter F Stadler, Andrea Tanzer, Stefan Washietl, Christina Witwer
Publication date:04/15/2005
Journal:Theory in Biosciences
Volume:123
Issue:4
Pages:301-369
Publisher:No longer published by Elsevier
Description:A plethora of new functions of non-coding RNAs (ncRNAs) have been discovered in past few years. In fact, RNA is emerging as the central player in cellular regulation, taking on active roles in multiple regulatory layers from transcription, RNA maturation, and RNA modification to translational regulation. Nevertheless, very little is known about the evolution of this “Modern RNA World” and its components. In this contribution, we attempt to provide at least a cursory overview of the diversity of ncRNAs and functional RNA motifs in non-translated regions of regular messenger RNAs (mRNAs) with an emphasis on evolutionary questions. This survey is complemented by an in-depth analysis of examples from different classes of RNAs focusing mostly on their evolution in the vertebrate lineage. We present a survey of Y RNA genes in vertebrates and study the molecular evolution of the U7 snRNA, the snoRNAs E1/U17, E2 …
Cited by:100
Resources:[PDF] from univie.ac.at
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Predicting progression events in multiple myeloma from routine blood work
Elias K Mai, Uta Bertsch, Uwe Platzbecker, Thomas Neumuth, Kristin Reiche
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Authors:Elias K Mai, Uta Bertsch, Uwe Platzbecker, Thomas Neumuth, Kristin Reiche
Description:This study introduces a system for predicting disease progression events in multiple myeloma patients from the CoMMpass study (N= 1186). Utilizing a hybrid neural network architecture, our model predicts future blood work from historical lab results with high accuracy, significantly outperforming baseline estimators for key disease parameters. Disease progression events are annotated in the forecasted data, predicting these events with significant reliability. We externally validated our model using the GMMG-MM5 study dataset (N= 504), and could reproduce the main results of our study. Our approach enables early detection and personalized monitoring of patients at risk of impeding progression. Designed modularly, our system enhances interpretability, facilitates integration of additional modules, and uses routine blood work measurements to ensure accessibility in clinical settings. With this, we contribute to the …
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SoupViewer—efficient analysis of large cluster trees
Jan Engelhardt, Peter F Stadler, Kristin Reiche
German Conference on Bioinformatics 2009, 147
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Authors:Jan Engelhardt, Peter F Stadler, Kristin Reiche
Journal:German Conference on Bioinformatics 2009
Pages:147
Description:Genome-wide computational and experimental screens for structured noncoding RNA (ncRNA) genes in different taxa resulted in an extensive list of putative structured ncRNAs. Only a minority of them could be assigned to already known ncRNAs by sequence similarity. We presented a clustering method which detects homologous secondary structure motifs in a set of sequences by pairwise sequence-structure alignments [Wil+ 07]. The clustering procedure results in a hierarchical cluster-tree which reflects structural similarities. NcRNAs sharing similar secondary structures are found in the same group, divergent ncRNAs are separated. We provided a method which extracts reasonable subtrees of high-similar structure motifs automatically [Rei08]. However, such full-automatic clustering is not free of misclassifications. This is the reason why the cluster tree may still to be examined by a human expert to check if the partitions are reasonable. The graphical cluster-tree viewer SoupViewer which reports for each subtree sequence and structural conservation as well as a significance measure that the subtree consists of ncRNA candidates sharing the same structural motif, provides a user-friendly framework for semi-automatic detection of high-interesting groups. The most important advantage compared to already existing tree viewers is that for each internal node the secondary consensus structure and the alignment of the sequences belonging to this node can be displayed easily. The structure-based clustering pipeline is a very useful approach for annotating ncRNAs. The new developed SoupViewer makes the analyses of large cluster trees much …
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Efficient ncRNA gene finding: Scanning whole genomes using a fast variant of the Sankoff algorithm
Michael Siebauer, Kristin Reiche, Sebastian Will, Peter F Stadler, Rolf Backofen
German Conference on Bioinformatics 2009, 186
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Authors:Michael Siebauer, Kristin Reiche, Sebastian Will, Peter F Stadler, Rolf Backofen
Journal:German Conference on Bioinformatics 2009
Pages:186
Description:Genome-wide transcriptomic studies demonstrated that mammalian genomes are almost completely transcribed into transcripts that are not translated into protein [The07]. Evidences emerged that the majority of such non-coding RNA (ncRNA) genes are likely to be functional and participate in a wide range of molecular processes [Mer+ 09]. Most known functions of ncRNAs require specific structural motifs inducing conserved secondary structures; while less evolutionary pressure is observed for their primary sequences. While efficient methods exist to scan whole genomes for homologous genes, that are conserved on sequence level, nothing comparable is currently available for functional transcripts that are just conserved in secondary structure. We present here a true scanning variant of LocARNA [Wil+ 07], an efficient variant of the Sankoff algorithm [San85]. It is suitable for genome-wide ncRNA gene finding, in case the ncRNA exhibits a conserved secondary structure. It computes semi-global alignments based on the assumption that for small ncRNAs the entire transcript should be conserved. For the query ncRNA the full ensemble of secondary structures is required as input and provided as a probability distribution (McCaskills algorithm [McC90]). A map of secondary structure predictions of a certain length must be provided for the target genome which is time-consuming but needs to be computed just once for different queries of similar length.
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