BIH Paper of the Month

Mit dem BIH Paper of the Month würdigt der Vorstand des BIH monatlich eine besondere Publikationsleistung aus dem gemeinsamen Forschungsraum von Charité und MDC. Das Paper of the Month wird von der Stiftung Charité im Rahmen ihrer Privaten Exzellenzinitiative Johanna Quandt gefördert. Der Preis wird zu Beginn jedes Monats für eine Publikation vergeben, die im vorletzten Monat veröffentlicht wurde (so wird im März eine Publikation aus dem Monat Januar prämiert). Als Datum der Veröffentlichung gilt die öffentliche Verfügbarkeit (online und/oder Druck) des Artikels, nicht jedoch eine “advanced publication“ von zur Veröffentlichung angenommenen Autorenmanuskripten. Das Preisgeld von 500 Euro erhält die Gruppenleiterin oder der Gruppenleiter, für die die Autorin oder der Autor mit BIH-Affiliation arbeitet.

Berücksichtigt werden Publikationen, die bei einer PubMed-Suche nach Veröffentlichungen mit direkter BIH-Affiliation (alleinige Affiliation über die Gliedkörperschaften reicht nicht aus) im entsprechenden Monat gefunden werden.

Zusätzlich können dem BIH per E-Mail jederzeit Publikationen vorgeschlagen werden.

Die Kriterien für die Preisvergabe sind:

  • Nennung der BIH-Affiliation

  • Passfähigkeit zur BIH-Strategie
    - Beitrag zu Erforschung/Diagnose/Therapie progredienter Krankheiten
    - Transfer zwischen Grundlagen- und klinischer Forschung
    - Transfer zwischen Forschung und kommerzieller Anwendung
    - Nutzung von BIH-Infrastrukturen
  • Originalität der Arbeit

  • Maßnahmen zur Qualitätssicherung bei der Erarbeitung und Veröffentlichung des Papers (z. B. Open-Access / Open-Data-Publikation, Verwendung von elektronischen Laborbüchern, transparente Dokumentation von Studienplanung und -durchführung, Publikation von negativen oder neutralen Ergebnissen, Replikationsstudien etc.)

  • Beteiligung von
    - Nachwuchswissenschaftlern
    - unterschiedlichen Forschungsdisziplinen
    - Internationalen Autoren

  • Gender Balance

BIH Paper of the Month 'November (2)'

Im Oktober gab es keine Auszeichnung, dafür wurden im November zwei Paper ausgezeichnet.

Im November erhielten Dominik N. Müller und sein Team die Auszeichnung Paper of the Month.

Nicola Wilck, Mariana G. Matus, Sean M. Kearney, Scott W. Olesen, Kristoffer Forslund, Hendrik Bartolomaeus, Stefanie Haase, Anja Mähler, András Balogh, Lajos Markó, Olga Vvedenskaya, Friedrich H. Kleiner, Dmitry Tsvetkov, Lars Klug, Paul I. Costea, Shinichi Sunagawa, Lisa Maier, Natalia Rakova, Valentin Schatz, Patrick Neubert, Christian Frätzer, Alexander Krannich, Maik Gollasch, Diana A. Grohme, Beatriz F. Côrte-Real, Roman G. Gerlach, Marijana Basic, Athanasios Typas, Chuan Wu, Jens M. Titze, Jonathan Jantsch, Michael Boschmann, Ralf Dechend, Markus Kleinewietfeld, Stefan Kempa, Peer Bork, Ralf A. Linker, Eric J. Alm & Dominik N. Müller. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589. 30. November 2017.
doi:10.1038/nature24628

Abstract

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut–immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

Die Publikation steht hier zum Download zur Verfügung.


BIH Paper of the Month 'November (1)'

Im Oktober gab es keine Auszeichnung, dafür wurden im November zwei Paper ausgezeichnet.

Im November erhielt der BIH Charité Clinician Scientist Programm-Teilnehmer Anton G. Henssen und sein Team die Auszeichnung Paper of the Month. Zum Interview

Anton G. Henssen, Casie Reed, Eileen Jiang1, Heathcliff Dorado Garcia, Jennifer von Stebut, Ian C. MacArthur, Patrick Hundsdoerfer, Jun Hyun Kim, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Neil J. Ganem, Filemon Dela Cruz, Andrew L. Kung, Johannes H. Schulte, John H. Petrini and Alex Kentsis. Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. Science Translational Medicine. 01 Nov 2017. Vol. 9, Issue 414. DOI: 10.1126/scitranslmed.aam9078

Abstract

Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, PGBD5, that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity–deficient mutant, was sufficient to induce sensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment and underwent apoptosis in both dividing and G1-phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against most neuroblastoma, medulloblastoma, Ewing sarcoma, and rhabdoid tumor cells tested while sparing nontransformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including substantial antitumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.

Die Publikation steht hier zum Download zur Verfügung.


BIH Paper of the Month 'September'

Im September erhielten Wolfgang Uckert, Felix Lorenz und ihr Team die Auszeichnung Paper of the Month. Zum Interview

Lorenz FKM, Ellinger C, Kieback E, Wilde S, Lietz M, Schendel DJ, Uckert W. Unbiased identification of T cell receptors targeting immunodominant peptide-MHC complexes for T cell receptor immunotherapy. Hum Gene Ther. 2017 Sep 26. doi: 10.1089/hum.2017.122.

Abstract

T cell receptor (TCR) immunotherapy uses T cells engineered with new TCRs to enable detection and killing of cancer cells. Efficacy of TCR immunotherapy depends on targeting antigenic peptides that are efficiently presented by the best suited major histocompatibility complex (MHC) molecules of cancer cells. However, efficient strategies are lacking to easily identify TCRs recognizing immunodominant peptide-MHC (pMHC) combinations utilizing any of the six possible MHC class I alleles of a cancer cell. We generated an MHC cell library and developed a platform approach to detect, isolate and re-express TCRs specific for immunodominant pMHCs. The platform approach was applied to identify a human papillomavirus (HPV16) oncogene E5-specific TCR, recognizing a novel, naturally processed pMHC (HLA-B*15:01), and a cytomegalovirus-specific TCR targeting an immunodominant pMHC (HLA-B*07:02). The platform provides a useful tool to isolate in an unbiased manner TCRs specific for novel and immunodominant pMHC targets for use in TCR immunotherapy.

Die Publikation steht hier zum Download zur Verfügung.


BIH Paper of the Month 'August'

Im August erhielten Wolfgang Böhmerle, Matthias Endres und Petra Hühnchen die Auszeichnung Paper of the Month. Zum Interview

Huehnchen P, Boehmerle W, Springer A, Freyer D, Endres M. A novel preventive therapy for paclitaxel-induced cognitive deficits: preclinical evidence from C57BL/6 mice. Transl Psychiatry. 2017 Aug 1;7(8):e1185. doi: 10.1038/tp.2017.149.

Abstract

Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg-1 paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230 nm l-1, which was sevenfold higher compared with the neocortex. Histologic analysis revealed a reduced hippocampal cell proliferation. In vitro, we observed severe toxicity in slowly proliferating neural stem cells (NSC) as well as human neuronal progenitor cells after 2 h exposure to low nanomolar concentrations of PTX. In comparison, mature post-mitotic hippocampal neurons and cell lines of malignant cells were less vulnerable. In PTX-treated NSC, we observed an increase of intracellular calcium levels, as well as an increased activity of calpain- and caspase 3/7, suggesting a calcium-dependent mechanism. This cell death pathway could be specifically inhibited with lithium, but not glycogen synthase kinase 3 inhibitors, which protected NSC in vitro. In vivo, preemptive treatment of mice with lithium prevented PTX-induced memory deficits and abnormal adult hippocampal neurogenesis. In summary, we identified a molecular pathomechanism, which invokes PTX-induced cytotoxicity in NSC independent of cell cycle status. This pathway could be pharmacologically inhibited with lithium without impairing paclitaxel's tubulin-dependent cytostatic mode of action, enabling a potential translational clinical approach.

Die Publikation steht hier zum Download zur Verfügung.


BIH Paper of the Month 'Juni'

Im Juni erhielten Josefine Radke, Julia Onken und das Team die Auszeichnung Paper of the Month für die Publikation über einen Signalweg, der bei der Entstehung von malignen Gliomen eine wichtige Rolle spielt. Zum Interview

Onken J, Vajkoczy P, Torka R, Hempt C, Patsouris V, Heppner FL, Radke J. Phospho-AXL is widely expressed in glioblastoma and associated with significant shorter overall survival. Oncotarget. 2017 Jun 13. doi: 10.18632/oncotarget.18468.

Abstract

Receptor tyrosine kinase AXL (RTK-AXL) is regarded as a suitable target in glioblastoma (GBM) therapy. Since AXL kinase inhibitors are about to get approval for clinical use, patients with a potential benefit from therapy targeting AXL need to be identified. We therefore assessed the expression pattern of Phospho-AXL (P-AXL), the biologically active form of AXL, in 90 patients with newly diagnosed GBM, which was found to be detectable in 67 patients (corresponding to 74%). We identified three main P-AXL expression patterns: i) exclusively in the tumor vasculature (13%), ii) in areas of hypercellularity (35%), or iii) both, in the tumor vasculature and in hypercellular areas of the tumor tissue (52%). Pattern iii) is associated with significant decrease in overall survival (Hazard ratio 2.349, 95% confidence interval 1.069 to 5.162, *p=0.03). Our data suggest that P-AXL may serve as a therapeutic target in the majority of GBM patients.

Die Publikation steht hier zum Download zur Verfügung.


BIH Paper of the Month 'Mai'

Im Mai erhielt Nils Blüthgen und sein Team das Paper of the Month für ihre Open Access Publikation, in der sie mittels mathematischen Modellierungen den ERK Signalweg untersuchen. Die Publikation ist aus dem TRG Projekt "Systems Medicine of BRAF-driven Malignancies" hervorgegangen. Zum Interview

Uhlitz F, Sieber A, Wyler E, Fritsche-Guenther R, Meisig J, Landthaler M, Klinger B, Blüthgen N. An immediate-late gene expression module decodes ERK signal duration. Mol Syst Biol. 2017 May 3;13(5):928. doi: 10.15252/msb.20177554.

Abstract

The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF By mathematical modelling, we identified a new gene expression module of immediate-late genes (ILGs) distinct in gene expression dynamics and function. We find that mRNA longevity enables these ILGs to respond late and thus translate ERK signal duration into response amplitude. Despite their late response, their GC-rich promoter structure suggested and metabolic labelling with 4SU confirmed that transcription of ILGs is induced immediately. A comparative analysis shows that the principle of duration decoding is conserved in PC12 cells and MCF7 cells, two paradigm cell systems for ERK signal duration. Altogether, our findings suggest that ILGs function as a gene expression module to decode ERK signal duration.

Die Publikation steht hier zum Download zur Verfügung.


BIH Paper of the Month 'April'

Für ihre Arbeit über die Wirkungsweise des Botenstoff Interferon-Gamma bei der Krebsentstehung erhielten Thomas Blankenstein und Thomas Kammertöns die Auszeichnung Paper of the Month 'April'. Die Arbeit liefert Anhaltspunkte für eine verbesserte T-Zell-Therapie gegen solide Krebstumore. Zum Interview

Thomas Kammertoens, Christian Friese, Ainhoa Arina, Christian Idel, Dana Briesemeister, Michael Rothe, Andranik Ivanov, Anna Szymborska, Giannino Patone, Severine Kunz, Daniel Sommermeyer, Boris Engels, Matthias Leisegang, Ana Textor, Hans Joerg Fehling, Marcus Fruttiger, Michael Lohoff, Andreas Herrmann, Hua Yu, Ralph Weichselbaum, Wolfgang Uckert, Norbert Hübner, Holger Gerhardt, Dieter Beule, Hans Schreiber, Thomas Blankenstein. Tumour ischaemia by interferon-γ resembles physiological blood vessel regression. Nature 545, 98–102 (04 May 2017). doi: 10.1038/nature22311

Abstract

The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models. Although IFNγ can impede tumour growth by acting directly on cancer cells, it must also act on the tumour stroma for effective rejection of large, established tumours. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ–GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.

Die Publikation steht hier zum Download zur Verfügung


BIH Paper of the Month 'März'

Ana Pombo und ihr Team stellen in Nature eine neue Methode vor, mit der sich die dreidimensionale Topographie des gesamten Genoms kartieren lässt. Dafür erhält Pombo das Paper of the Month 'März'.

Beagrie RA, Scialdone A, Schueler M, Kraemer DC, Chotalia M, Xie SQ, Barbieri M, de Santiago I, Lavitas LM, Branco MR, Fraser J, Dostie J, Game L, Dillon N, Edwards PA, Nicodemi M, Pombo A. Complex multi-enhancer contacts captured by genome architecture mapping. Nature. 2017 Mar 23;543(7646):519-524. doi: 10.1038/nature21411. Epub 2017 Mar 8.

Abstract

The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.

Die Publikation steht hier zum Download zur Verfügung.


BIH Paper of the Month 'Februar'

Die Auszeichnung BIH Paper of the Month ‘Februar’ ging an den BIH Charité Clinican Scientist Benjamin Strücker und sein Team. In der Open Access Publikation Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans stellt Strücker eine Methode vor, mit der es möglich ist, nach Entfernung aller zellulären Bestandteile der Bauchspeicheldrüse der Ratte, die extrazelluläre Matrix mit Langerhansschen Inseln wieder zu besiedeln. In weiteren Tests konnten die Wissenschaftlerinnen und Wissenschaftler nachweisen, dass die Langerhansschen Inseln funktionsfähig waren und Insulin produzieren konnten.

H. Napierala, K.-H. Hillebrandt, N. Haep, P. Tang, M. Tintemann, J. Gassner, M. Noesser, H. Everwien, N. Seiffert, M. Kluge, E. Teegen, D. Polenz, S. Lippert, D. Geisel, A. Reutzel Selke, N. Raschzok, A. Andreou, J. Pratschke, I. M. Sauer & B. Struecker. Engineering an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans. Scientific Reports 7. Article number: 41777 (2017) doi:10.1038/srep41777

Abstract

Decellularization of pancreata and repopulation of these non-immunogenic matrices with islets and endothelial cells could provide transplantable, endocrine Neo- Pancreata. In this study, rat pancreata were perfusion decellularized and repopulated with intact islets, comparing three perfusion routes (Artery, Portal Vein, Pancreatic Duct). Decellularization effectively removed all cellular components but conserved the pancreas specific extracellular matrix. Digital subtraction angiography of the matrices showed a conserved integrity of the decellularized vascular system but a contrast emersion into the parenchyma via the decellularized pancreatic duct. Islets infused via the pancreatic duct leaked from the ductular system into the peri-ductular decellularized space despite their magnitude. TUNEL staining and Glucose stimulated insulin secretion revealed that islets were viable and functional after the process. We present the first available protocol for perfusion decellularization of rat pancreata via three different perfusion routes. Furthermore, we provide first proof-of-concept for the repopulation of the decellularized rat pancreata with functional islets of Langerhans. The presented technique can serve as a bioengineering platform to generate implantable and functional endocrine Neo-Pancreata.

Die Publikation steht hier zum Download zur Verfügung


BIH Paper of the Month 'Januar'

Anfang März wurde Angela M. Kaindl vom Institute of Cell Biology and Neurobiology der Charité mit dem BIH Paper of the Month ausgezeichnet. Die Veröffentlichung “CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development” wurde in Stem Cell Reports unter Open Access Bedingungen publiziert und hat insgesamt nur fünf Autorinnen und Autoren und einen hohen Anteil an BIH-Affiliierten.

Kaindl hat in der Vergangenheit gezeigt, dass Mutationen im Gen CDK5RAP2 zu Mikrozephalie führen. Diese Arbeit zeigt zum ersten Mal, dass das ubiquitär exprimierte Cdk5rap2 auch für die Erhaltung der Keimzellen während der Embryoentwicklung erforderlich ist. So verlängern bestimmte Genveränderungen in CDK5RAP2 die Mitose der Keimzellen. Die verlängerte Mitose ist mit einem massiven Absterben der Keimzellabkömmlinge verbunden und führt bei männlichen Mäusen zur Sterilität. Die Klärung der Mechanismen, die dieses Absterben bewirken wird unser Verständnis für die Entstehung der Mikrozephalie erweitern und könnte neue Ansätze bei der Diagnose dieser und anderer Erbkrankheiten eröffnen.

Zaqout S, Bessa P, Krämer N, Stoltenburg-Didinger G, Kaindl AM. CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development. Stem Cell Reports. 2017 Jan 31. pii: S2213-6711(17)30017-6. doi: 10.1016/j.stemcr.2017.01.002.

Abstract

Gene products linked to microcephaly have been studied foremost for their role in brain development, while their function in the development of other organs has been largely neglected. Here, we report the critical role of Cdk5rap2 in maintaining the germ cell pool during embryonic development. We highlight that infertility in Cdk5rap2 mutant mice is secondary to a lack of spermatogenic cells in adult mice as a result of an early developmental defect in the germ cells through mitotic delay, prolonged cell cycle, and apoptosis.

Da die Veröffentlichung unter Open Access Bedingungen publiziert wurde, ist sie frei verfügbar. Zum Download