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1. SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

Author

Hartmann, Jakob, Bajaj, Thomas, Otten, Joy, Klengel, Claudia, Ebert, Tim, Gellner, Anne-Kathrin, Junglas, Ellen, Hafner, Kathrin, Anderzhanova, Elmira A., Tang, Fiona, Missig, Galen, Rexrode, Lindsay, Trussell, Daniel T., Li, Katelyn X., Pöhlmann, Max L., Mackert, Sarah, Geiger, Thomas M., Heinz, Daniel E., Lardenoije, Roy, Dedic, Nina, McCullough, Kenneth M., Próchnicki, Tomasz, Rhomberg, Thomas, Martinelli, Silvia, Payton, Antony, Robinson, Andrew C., Stein, Valentin, Latz, Eicke, Carlezon, Jr, William A., Hausch, Felix, Schmidt, Mathias V., Murgatroyd, Chris, Berretta, Sabina, Klengel, Torsten, Pantazopoulos, Harry, Ressler, Kerry J., and Gassen, Nils C.

Published
2024
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11. Programmed death-ligand 1 expression influenced by tissue sample size. Scoring based on tissue microarrays' and cross-validation with resections, in patients with, stage I–III, non-small cell lung carcinoma of the European Thoracic Oncology Platform Lungscape cohort

Author

Thunnissen, Erik, Kerr, Keith M., Dafni, Urania, Bubendorf, Lukas, Finn, Stephen P., Soltermann, Alex, Biernat, Wojciech, Cheney, Richard, Verbeken, Erik, Warth, Arne, Marchetti, Antonio, Speel, Ernst-Jan M., Pokharel, Saraswati, Quinn, Anne Marie, Monkhorst, Kim, Navarro, Atilio, Madsen, Line Bille, Tsourti, Zoi, Geiger, Thomas, Kammler, Roswitha, Peters, Solange, Stahel, Rolf A., Rosell, Rafael, Blackhall, Fiona, Molina, Miguel Angel, Weder, Walter, Finn, Stephen, Hiltbrunner, Anita, Marti, Nesa, Polydoropoulou, Varvara, Zygoura, Panagiota, Nicolson, Marianne, Stevenson, David A.J, Mathieson, William, Smit, Egbert, Radonic, Teodora, Rulle, Undine, Curioni, Alessandra, Gray, Steven G., Gately, Kathy, Barr, Martin, Meldgaard, Peter, Madsen, Line B., Savic, Spasenija, Lardinois, Didier, Nackaerts, Kristiaan, Dooms, Christophe, Wauters, Els, Van Der Borght, Sara, Wrona, Ania, Rzyman, Witold, Jassem, Jacek, Dienemann, Hendrik, Muley, Thomas, De Luca, Graziano, di Lorito, Alessia, Dingemans, Anne-Marie, Ruland, Andrea, Ferenczy, Philip, Franklin, Lynsey, Baas, Paul, van de Wiel, Bart, Camps, Carlos, and Martorell, Miguel

Published
2020
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13. Curvature of higher direct image sheaves

Author

Geiger, Thomas and Schumacher, Georg

Subjects
Mathematics - Algebraic Geometry, 32L10, 14D20
Abstract

Given a family $(F,h) \to X \times S$ of Hermite-Einstein bundles on a compact K\"ahler manifold $(X,g)$ we consider the higher direct image sheaves $R^q p_* \mathcal{O}(F)$ on $S$, where $p: X \times S \to S$ is the projection. On the complement of an analytic subset these sheaves are locally free and carry a natural metric, induced by the $L_2$ inner product of harmonic forms on the fibers. We compute the curvature of this metric which has a simpler form for families with fixed determinant and families of endomorphism bundles. Furthermore, we discuss the metric for moduli spaces of stable vector bundles., Comment: To appear in Advanced Studies in Pure Mathematics, submitted 13 Nov. 2013

Published
2015

14. Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Author

Geiger, Thomas M., Walz, Michael, Meyners, Christian, Kuehn, Angela, Dreizler, Johannes K., Sugiarto, Wisely O., Maciel, Edvaldo V. S., Zheng, Min, Lermyte, Frederik, Hausch, Felix, Geiger, Thomas M., Walz, Michael, Meyners, Christian, Kuehn, Angela, Dreizler, Johannes K., Sugiarto, Wisely O., Maciel, Edvaldo V. S., Zheng, Min, Lermyte, Frederik, and Hausch, Felix

Abstract

The FK506‐binding protein 51 (FKBP51) is a promising target in a variety of disorders including depression, chronic pain, and obesity. Previous FKBP51‐targeting strategies were restricted to occupation of the FK506‐binding site, which does not affect core functions of FKBP51. Here, we report the discovery of the first FKBP51 proteolysis targeting chimera (PROTAC) that enables degradation of FKBP51 abolishing its scaffolding function. Initial synthesis of 220 FKBP‐focused PROTACs yielded a plethora of active PROTACs for FKBP12, six for FKBP51, and none for FKBP52. Structural analysis of a binary FKBP12:PROTAC complex revealed the molecular basis for negative cooperativity. Linker‐based optimization of first generation FKBP51 PROTACs led to the PROTAC SelDeg51 with improved cellular activity, selectivity, and high cooperativity. The structure of the ternary FKBP51:SelDeg51:VCB complex revealed how SelDeg51 establishes cooperativity by dimerizing FKBP51 and the von Hippel‐Lindau protein (VHL) in a glue‐like fashion. SelDeg51 efficiently depletes FKBP51 and reactivates glucocorticoid receptor (GR)‐signalling, highlighting the enhanced efficacy of full protein degradation compared to classical FKBP51 binding.

Published
2024

15. [4.3.1]Bicyclic FKBP Ligands Inhibit Legionella Pneumophila Infection by LpMip‐Dependent and LpMip‐Independent Mechanisms

Author

Deutscher, Robin C. E., Karagöz, Mustafa Safa, Purder, Patrick L., Kolos, Jürgen M., Meyners, Christian, Oki Sugiarto, Wisely, Krajczy, Patryk, Tebbe, Frederike, Geiger, Thomas M., Ünal, Can, Hellmich, Ute A., Steinert, Michael, Hausch, Felix, Deutscher, Robin C. E., Karagöz, Mustafa Safa, Purder, Patrick L., Kolos, Jürgen M., Meyners, Christian, Oki Sugiarto, Wisely, Krajczy, Patryk, Tebbe, Frederike, Geiger, Thomas M., Ünal, Can, Hellmich, Ute A., Steinert, Michael, and Hausch, Felix

Abstract

Legionella pneumophila is the causative agent of Legionnaires’ disease, a serious form of pneumonia. Its macrophage infectivity potentiator (Mip), a member of a highly conserved family of FK506‐binding proteins (FKBPs), plays a major role in the proliferation of the gram‐negative bacterium in host organisms. In this work, we test our library of >1000 FKBP‐focused ligands for inhibition of LpMip. The [4.3.1]‐bicyclic sulfonamide turned out as a highly preferred scaffold and provided the most potent LpMip inhibitors known so far. Selected compounds were non‐toxic to human cells, displayed antibacterial activity and block bacterial proliferation in cellular infection‐assays as well as infectivity in human lung tissue explants. The results confirm [4.3.1]‐bicyclic sulfonamides as anti‐legionellal agents, although their anti‐infective properties cannot be explained by inhibition of LpMip alone.

Published
2024

16. Can Cellulose Beads Save The Circling of the Planets? Cellulose-Based Consolidating Filler to Stabilise Lifted Brittle Flakes on a Large Painting

Author

Soppa, Karolina, Hoess, Anita, Läuchli, Matthias, Meyer, Silja, Geiger, Thomas, Scherrer, Nadim C., Zumbühl, Stefan, Haupt, Tobias, van den Berg, Klaas Jan, editor, Bonaduce, Ilaria, editor, Burnstock, Aviva, editor, Ormsby, Bronwyn, editor, Scharff, Mikkel, editor, Carlyle, Leslie, editor, Heydenreich, Gunnar, editor, and Keune, Katrien, editor

Published
2019
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17. Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion

Author

Martinelli, Silvia, Anderzhanova, Elmira A., Bajaj, Thomas, Wiechmann, Svenja, Dethloff, Frederik, Weckmann, Katja, Heinz, Daniel E., Ebert, Tim, Hartmann, Jakob, Geiger, Thomas M., Döngi, Michael, Hafner, Kathrin, Pöhlmann, Max L., Jollans, Lee, Philipsen, Alexandra, Schmidt, Susanne V., Schmidt, Ulrike, Maccarrone, Giuseppina, Stein, Valentin, Hausch, Felix, Turck, Christoph W., Schmidt, Mathias V., Gellner, Anne-Kathrin, Kuster, Bernhard, and Gassen, Nils C.

Published
2021
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18. A retrospective cohort study of PD-L1 prevalence, molecular associations and clinical outcomes in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape Project

Author

Kerr, Keith M., Thunnissen, Erik, Dafni, Urania, Finn, Stephen P., Bubendorf, Lukas, Soltermann, Alex, Verbeken, Eric, Biernat, Wojciech, Warth, Arne, Marchetti, Antonio, Speel, Ernst-Jan M., Pokharel, Sarawati, Quinn, Anne Marie, Monkhorst, Kim, Navarro, Atilio, Madsen, Line Bille, Radonic, Teodora, Wilson, Joan, De Luca, Graziano, Gray, Steven G., Cheney, Richard, Savic, Spasenija, Martorell, Miguel, Muley, Thomas, Baas, Paul, Meldgaard, Peter, Blackhall, Fiona, Dingemans, Anne-Marie, Dziadziuszko, Rafal, Vansteenkiste, Johan, Weder, Walter, Polydoropoulou, Varvara, Geiger, Thomas, Kammler, Roswitha, Peters, Solange, and Stahel, Rolf

Published
2019
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19. A multi-megabase copy number gain causes maternal transmission ratio distortion on mouse chromosome 2.

Author

Didion, John, Morgan, Andrew, Clayshulte, Amelia, Mcmullan, Rachel, Yadgary, Liran, Petkov, Petko, Bell, Timothy, Gatti, Daniel, Crowley, James, Hua, Kunjie, Aylor, David, Bai, Ling, Calaway, Mark, Chesler, Elissa, French, John, Geiger, Thomas, Gooch, Terry, Garland, Theodore, Harrill, Alison, Hunter, Kent, McMillan, Leonard, Holt, Matt, Miller, Darla, OBrien, Deborah, Paigen, Kenneth, Pan, Wenqi, Rowe, Lucy, Shaw, Ginger, Simecek, Petr, Sullivan, Patrick, Svenson, Karen, Weinstock, George, Threadgill, David, Pomp, Daniel, Churchill, Gary, and Pardo-Manuel de Villena, Fernando

Subjects
Alleles, Animals, Chromosomes, Crosses, Genetic, DNA Copy Number Variations, Female, Genomics, Genotyping Techniques, Haplotypes, Inheritance Patterns, Male, Meiosis, Mice, Mutation
Abstract

Significant departures from expected Mendelian inheritance ratios (transmission ratio distortion, TRD) are frequently observed in both experimental crosses and natural populations. TRD on mouse Chromosome (Chr) 2 has been reported in multiple experimental crosses, including the Collaborative Cross (CC). Among the eight CC founder inbred strains, we found that Chr 2 TRD was exclusive to females that were heterozygous for the WSB/EiJ allele within a 9.3 Mb region (Chr 2 76.9 - 86.2 Mb). A copy number gain of a 127 kb-long DNA segment (designated as responder to drive, R2d) emerged as the strongest candidate for the causative allele. We mapped R2d sequences to two loci within the candidate interval. R2d1 is located near the proximal boundary, and contains a single copy of R2d in all strains tested. R2d2 maps to a 900 kb interval, and the number of R2d copies varies from zero in classical strains (including the mouse reference genome) to more than 30 in wild-derived strains. Using real-time PCR assays for the copy number, we identified a mutation (R2d2WSBdel1) that eliminates the majority of the R2d2WSB copies without apparent alterations of the surrounding WSB/EiJ haplotype. In a three-generation pedigree segregating for R2d2WSBdel1, the mutation is transmitted to the progeny and Mendelian segregation is restored in females heterozygous for R2d2WSBdel1, thus providing direct evidence that the copy number gain is causal for maternal TRD. We found that transmission ratios in R2d2WSB heterozygous females vary between Mendelian segregation and complete distortion depending on the genetic background, and that TRD is under genetic control of unlinked distorter loci. Although the R2d2WSB transmission ratio was inversely correlated with average litter size, several independent lines of evidence support the contention that female meiotic drive is the cause of the distortion. We discuss the implications and potential applications of this novel meiotic drive system.

Published
2015

22. Use of Poly(vinyl alcohol) in Spray-Dried Dispersions: Enhancing Solubility and Stability of Proteolysis Targeting Chimeras.

Author

Mareczek, Lena, Mueller, Lena K., Halstenberg, Laura, Geiger, Thomas M., Walz, Michael, Zheng, Min, and Hausch, Felix

Subjects
SPRAY drying, AMORPHOUS substances, SPRAY nozzles, BINDING site assay, DISPERSION (Chemistry)
Abstract

PROTACs, proteolysis targeting chimeras, are bifunctional molecules inducing protein degradation through a unique proximity-based mode of action. While offering several advantages unachievable by classical drugs, PROTACs have unfavorable physicochemical properties that pose challenges in application and formulation. In this study, we show the solubility enhancement of two PROTACs, ARV-110 and SelDeg51, using Poly(vinyl alcohol). Hereby, we apply a three-fluid nozzle spray drying set-up to generate an amorphous solid dispersion with a 30% w/w drug loading with the respective PROTACs and the hydrophilic polymer. Dissolution enhancement was achieved and demonstrated for t = 0 and t = 4 weeks at 5 °C using a phosphate buffer with a pH of 6.8. A pH shift study on ARV-110-PVA is shown, covering transfer from simulated gastric fluid (SGF) at pH 2.0 to fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5. Additionally, activity studies and binding assays of the pure SelDeg51 versus the spray-dried SelDeg51-PVA indicate no difference between both samples. Our results show how modern enabling formulation technologies can partially alleviate challenging physicochemical properties, such as the poor solubility of increasingly large 'small' molecules. [ABSTRACT FROM AUTHOR]

Published
2024
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23. Computer-Based Intensity Measurement Assists Pathologists in Scoring Phosphatase and Tensin Homolog Immunohistochemistry — Clinical Associations in NSCLC Patients of the European Thoracic Oncology Platform Lungscape Cohort

Author

Rulle, Undine, Tsourti, Zoi, Casanova, Ruben, Deml, Karl-Friedrich, Verbeken, Eric, Thunnissen, Erik, Warth, Arne, Cheney, Richard, Sejda, Aleksandra, Speel, Ernst Jan, Madsen, Line Bille, Nonaka, Daisuke, Navarro, Atilio, Sansano, Irene, Marchetti, Antonio, Finn, Stephen P., Monkhorst, Kim, Kerr, Keith M., Haberecker, Martina, Wu, Chengguang, Zygoura, Panagiota, Kammler, Roswitha, Geiger, Thomas, Gendreau, Steven, Schulze, Katja, Vrugt, Bart, Wild, Peter, Moch, Holger, Weder, Walter, Ciftlik, Ata Tuna, Dafni, Urania, Peters, Solange, Bubendorf, Lukas, Stahel, Rolf A., and Soltermann, Alex

Published
2018
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25. Evaluation of NGS and RT-PCR Methods for ALK Rearrangement in European NSCLC Patients: Results from the European Thoracic Oncology Platform Lungscape Project

Author

Stahel, Rolf A., Rosell, Rafael, Blackhall, Fiona, Dafni, Urania, Kerr, Keith M., Molina, Miguel Ángel, Bubendorf, Lukas, Weder, Walter, Thunnissen, Erik, Peters, Solange, Finn, Stephen, Hiltbrunner, Anita, Kammler, Roswitha, Geiger, Thomas, Marti, Nesa, Tsourti, Zoi, Polydoropoulou, Varvara, Zygoura, Panagiota, Smyth, Paul, O’Brien, Cathal, Gray, Steven, Soltermann, Alex, Opitz, Isabelle, Curioni, Alessandra, Savic, Spasenija, Lardinois, Didier, Dingemans, Anne-Marie, Speel, Ernst-Jan M., Ruland, Andrea, Marchetti, Antonio, Di Lorito, Alessia, De Luca, Graziano, Malatesta, Sara, Nonaka, Daisuke, Quinn, Anne Marie, Franklin, Lynsey, Biernat, Wojciech, Wrona, Ania, Rzyman, Witold, Jassem, Jacek, Meldgaard, Peter, Hager, Henrik, Madsen, Line B., Camps, Carlos, Martorell, Miguel, Jantus-Lewintre, Eloisa, Guijarro, Ricardo, Nicolson, Marianne, Stevenson, David A.J., Mathieson, William, Baas, Paul, de Jong, Jeroen, Monkhorst, Kim, Smit, Egbert, van Setten, Coralien, de Langen, Joop, Felip, Enriqueta, Hernandez-Losa, Javier, Sansano, Irene, Cheney, Richard, Pine, Mary Beth, Reid, Mary, Taylor, Elizabeth, Nackaerts, Kristiaan, Dooms, Christophe, Wauters, Els, Van Der Borght, Sara, Dienemann, Hendrik, Muley, Thomas, Warth, Arne, Letovanec, Igor, Speel, Ernst-Jan, Sejda, Aleksandra, Verbeken, Eric, Navarro, Atilio, Dziadziuszko, Rafal, Vansteenkiste, Johan, O'Brien, Cathal, Sherlock, Jon, Schageman, Jeoffrey, Kerr, Keith, and Stahel, Rolf

Published
2018
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29. Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project

Author

Bubendorf, Lukas, Dafni, Urania, Schöbel, Martin, Finn, Stephen P., Tischler, Verena, Sejda, Aleksandra, Marchetti, Antonio, Thunnissen, Erik, Verbeken, Eric K., Warth, Arne, Sansano, Irene, Cheney, Richard, Speel, Ernst Jan M., Nonaka, Daisuke, Monkhorst, Kim, Hager, Henrik, Martorell, Miguel, Savic, Spasenija, Kerr, Keith M., Tan, Qiang, Tsourti, Zoi, Geiger, Thomas R., Kammler, Roswitha, Schulze, Katja, Das-Gupta, Ashis, Shames, David, Peters, Solange, and Stahel, Rolf A.

Published
2017
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33. Evaluation of NGS and RT-PCR Methods for ALK Rearrangement in European NSCLC Patients: Results from the European Thoracic Oncology Platform Lungscape Project

Author

Letovanec, Igor, Finn, Stephen, Zygoura, Panagiota, Smyth, Paul, Soltermann, Alex, Bubendorf, Lukas, Speel, Ernst-Jan, Marchetti, Antonio, Nonaka, Daisuke, Monkhorst, Kim, Hager, Henrik, Martorell, Miguel, Sejda, Aleksandra, Cheney, Richard, Hernandez-Losa, Javier, Verbeken, Eric, Weder, Walter, Savic, Spasenija, Di Lorito, Alessia, Navarro, Atilio, Felip, Enriqueta, Warth, Arne, Baas, Paul, Meldgaard, Peter, Blackhall, Fiona, Dingemans, Anne-Marie, Dienemann, Hendrik, Dziadziuszko, Rafal, Vansteenkiste, Johan, OʼBrien, Cathal, Geiger, Thomas, Sherlock, Jon, Schageman, Jeoffrey, Dafni, Urania, Kammler, Roswitha, Kerr, Keith, Thunnissen, Erik, Stahel, Rolf, Peters, Solange, Stahel, Rolf A., Rosell, Rafael, Blackhall, Fiona, Dafni, Urania, Kerr, Keith M., Molina, Miguel Ángel, Bubendorf, Lukas, Weder, Walter, Thunnissen, Erik, Peters, Solange, Finn, Stephen, Hiltbrunner, Anita, Kammler, Roswitha, Geiger, Thomas, Marti, Nesa, Tsourti, Zoi, Polydoropoulou, Varvara, Zygoura, Panagiota, Smyth, Paul, O’Brien, Cathal, Gray, Steven, Soltermann, Alex, Opitz, Isabelle, Curioni, Alessandra, Savic, Spasenija, Lardinois, Didier, Dingemans, Anne-Marie, Speel, Ernst-Jan M., Ruland, Andrea, Marchetti, Antonio, Di Lorito, Alessia, De Luca, Graziano, Malatesta, Sara, Nonaka, Daisuke, Quinn, Anne Marie, Franklin, Lynsey, Biernat, Wojciech, Wrona, Ania, Rzyman, Witold, Jassem, Jacek, Meldgaard, Peter, Hager, Henrik, Madsen, Line B., Camps, Carlos, Martorell, Miguel, Jantus-Lewintre, Eloisa, Guijarro, Ricardo, Nicolson, Marianne, Stevenson, David A.J., Mathieson, William, Baas, Paul, de Jong, Jeroen, Monkhorst, Kim, Smit, Egbert, van Setten, Coralien, de Langen, Joop, Felip, Enriqueta, Hernandez-Losa, Javier, Sansano, Irene, Cheney, Richard, Pine, Mary Beth, Reid, Mary, Taylor, Elizabeth, Nackaerts, Kristiaan, Dooms, Christophe, Wauters, Els, Van Der Borght, Sara, Dienemann, Hendrik, Muley, Thomas, and Warth, Arne

Published
2018
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35. Entdeckung eines potenten PROTAC ermöglicht die gezielte Ausschaltung der Gerüstfunktionen von FKBP51.

Author

Geiger, Thomas M., Walz, Michael, Meyners, Christian, Kuehn, Angela, Dreizler, Johannes K., Sugiarto, Wisely O., Maciel, Edvaldo V. S., Zheng, Min, Lermyte, Frederik, and Hausch, Felix

Subjects
*PROTEOLYSIS, *BLOCKADE, *PROTEINS
Abstract

Das FK506‐bindende Protein 51 (FKBP51) stellt ein vielversprechendes Wirkstoffziel zur Behandlung von verschiedenen Krankheiten dar, darunter Depression, chronischer Schmerz und Fettleibigkeit. Bisherige FKBP51‐gerichtete Wirkstoffe waren auf die Blockade der FK506‐Bindestelle beschränkt, wodurch Kernfunktionen von FKBP51 jedoch nicht beeinträchtigt werden. Hier präsentieren wir die Entwicklung des ersten FKBP51 Proteolysis Targeting Chimeras (PROTAC), der den Abbau von FKBP51 ermöglicht und damit auch die Gerüstfunktion von FKBP51 ausschalten kann. Die initiale Synthese von 220 FKBP‐gerichteten PROTACs ergab eine Vielzahl aktiver PROTACs für FKBP12, sechs für FKBP51 und keinen für FKBP52. Die Strukturanalyse eines binären FKBP12:PROTAC‐Komplexes offenbarte die molekulare Grundlage für negative Kooperativität. Die Linker‐Optimierung eines FKBP51 PROTACs der ersten Generation führte zur Entwicklung von SelDeg51 mit verbesserter zellulärer Aktivität, Selektivität und hoher Kooperativität. Die Struktur des ternären FKBP51:SelDeg51:VCB Komplexes zeigte, wie SelDeg51 durch Dimerisierung von FKBP51 und VHL Kooperativität herstellt, die dem Bindungsmodus von molekularen Klebern ähnelt. SelDeg51 baut FKBP51 auf effiziente Weise in Zellen ab und reaktiviert den GR‐Signalweg, was die erhöhte Wirksamkeit des Proteinabbaus im Vergleich zur klassischen FKBP51‐Besetzung demonstriert. [ABSTRACT FROM AUTHOR]

Published
2024
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37. [4.3.1] Bicyclic FKBP ligands inhibit Legionella pneumophila infection by LpMip-dependent and LpMip independent mechanisms

Author

Deutscher, Robin, primary, Karagöz, Safa, additional, Purder, Patrick, additional, Kolos, Jürgen, additional, Meyners, Christian, additional, Sugiarto, Wisely, additional, Krajczy, Patryk, additional, Tebbe, Frederike, additional, Geiger, Thomas, additional, Ünal, Can, additional, Hellmich, Ute, additional, Steinert, Michael, additional, and Hausch, Felix, additional

Published
2023
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