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 'Mai'

Im Mai erhielten Clinician Scientist Julia Sbierski-Kind und ihr Team die Auszeichnung Paper of the Month.

Sbierski-Kind J, Kath J, Brachs S, Streitz M, von Herrath MG, Kühl AA, Schmidt-Bleek K, Mai K, Spranger J, Volk HD. Distinct Housing Conditions Reveal a Major Impact of Adaptive Immunity on the Course of Obesity-Induced Type 2 Diabetes. Front Immunol. 2018; 9: 1069. Published online 2018 May 28. doi:  10.3389/fimmu.2018.01069

Abstract

Obesity is associated with adipose tissue inflammation, insulin resistance, and the development of type 2 diabetes (T2D). However, our knowledge is mostly based on conventional murine models and promising preclinical studies rarely translated into successful therapies. There is a growing awareness of the limitations of studies in laboratory mice, housed in abnormally hygienic specific pathogen-free (SPF) conditions, as relevant aspects of the human immune system remain unappreciated. Here, we assessed the impact of housing conditions on adaptive immunity and metabolic disease processes during high-fat diet (HFD). We therefore compared diet-induced obesity in SPF mice with those housed in non-SPF, so-called “antigen exposed” (AE) conditions. Surprisingly, AE mice fed a HFD maintained increased insulin levels to compensate for insulin resistance, which was reflected in islet hyperplasia and improved glucose tolerance compared to SPF mice. By contrast, we observed higher proportions of effector/memory T cell subsets in blood and liver of HFD AE mice accompanied by the development of non-alcoholic steatohepatitis-like liver pathology. Thus, our data demonstrate the impact of housing conditions on metabolic alterations. Studies in AE mice, in which physiological microbial exposure was restored, could provide a tool for revealing therapeutic targets for immune-based interventions for T2D patients.


BIH Paper of the Month 'April'

Im April erhielten Clinician Scientist Michaela Golić und Ralf Dechend vom TRG Embryonale Programmierung von Herz- und Stoffwechsel-Krankheiten die Auszeichnung Paper of the Month.

Golic, M.; Stojanovska, V.; Bendix, I.; Wehner, A.; Herse, F.; Haase, N.; Kräker, K.; Fischer, C.; Alenina, N.; Bader, M.; Schütte, T.; Schuchardt, M.; van der Giet, M.; Henrich, W.; Muller, D.N.; Felderhoff-Müser, U.; Scherjon, S.; Plösch, T.; Dechend, R. Diabetes mellitus in pregnancy leads to growth restriction and epigenetic modification of the Srebf2 gene in rat fetuses. Hypertension. 2018;71:911-920. https://doi.org/10.1161/HYPERTENSIONAHA.117.10782

Abstract

Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline-induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health.

 


BIH Paper of the Month 'März'

Im März erhält der BIH-Professor für Experimentelle Herz-Kreislaufforschung Holger Gerhardt die Auszeichnung BIH Paper of the Month. Zum Interview

Vion AC, Alt S, Klaus-Bergmann A, Szymborska A, Zheng T, Perovic T, Hammoutene A, Oliveira MB, Bartels-Klein E, Hollfinger I, Rautou PE, Bernabeu MO, Gerhardt H. Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression. J Cell Biol. 201706151. DOI: 10.1083/jcb.201706151

Abstract

Blood flow shapes vascular networks by orchestrating endothelial cell behavior and function. How endothelial cells read and interpret flow-derived signals is poorly understood. Here, we show that endothelial cells in the developing mouse retina form and use luminal primary cilia to stabilize vessel connections selectively in parts of the remodeling vascular plexus experiencing low and intermediate shear stress. Inducible genetic deletion of the essential cilia component intraflagellar transport protein 88 (IFT88) in endothelial cells caused premature and random vessel regression without affecting proliferation, cell cycle progression, or apoptosis. IFT88 mutant cells lacking primary cilia displayed reduced polarization against blood flow, selectively at low and intermediate flow levels, and have a stronger migratory behavior. Molecularly, we identify that primary cilia endow endothelial cells with strongly enhanced sensitivity to bone morphogenic protein 9 (BMP9), selectively under low flow. We propose that BMP9 signaling cooperates with the primary cilia at low flow to keep immature vessels open before high shear stress–mediated remodeling.


BIH Paper of the Month 'Februar'

Im Februar erhielt die BIH-Johanna-Quandt-Professorin Ute Scholl die Auszeichnung Paper of the Month. Zum Interview

Ute I. Scholl, Gabriel Stölting, Julia Schewe, Anne Thiel, Hua Tan, Carol Nelson-Williams, Alfred A. Vichot, Sheng Chih Jin, Erin Loring, Verena Untiet, Taekyeong Yoo, Jungmin Choi, Shengxin Xu, Aihua Wu, Marieluise Kirchner, Philipp Mertins, Lars C. Rump, Ali Mirza Onder, Cory Gamble, Daniel McKenney, Robert W. Lash, Deborah P. Jones, Gary Chune, Priscila Gagliardi, Murim Choi, Richard Gordon, Michael Stowasser, Christoph Fahlke & Richard P. Lifton. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nature Genetics 2018. DOI: 10.1038/s41588-018-0048-5

Abstract

Primary aldosteronism, a common cause of severe hypertension1, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in the proband. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.


BIH Paper of the Month 'Januar'

Im Januar erhielt das Team um Patrick Hundsdörfer und BIH Charité Clinician Scientist Viktor Arnhold die Auszeichnung Paper of the Month. Zum Interview

Viktor Arnhold, Karin Schmelz, Jutta Proba, Annika Winkler, Jasmin Wünschel, Joern Toedling, Hedwig E. Deubzer, Annette Künkele, Angelika Eggert, Johannes H. Schulte1 and Patrick Hundsdoerfer. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. Oncotarget. 2018; 9:2304-2319. https://doi.org/10.18632/oncotarget.23409

Abstract

Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity.


BIH Paper of the Month 'Dezember'

Im Dezemeber wurde die BIH Johanna Quandt-Professorin Il-Kang Na und Martin Szyska mit dem Paper of the Month ausgezeichnet. Zum Interview

Martin Szyska, Stefanie Herda, Stefanie Althoff, Andreas Heimann, Josefine Russ, Daniele D'Abundo, Tra My Dang, Isabell Durieux, Bernd Dörken, Thomas Blankenstein and Il-Kang Na. A Transgenic Dual-Luciferase Reporter Mouse for Longitudinal and Functional Monitoring of T Cells In Vivo. Cancer Immunol Res. 2018 Jan;6(1):110-120. doi: 10.1158/2326-6066.CIR-17-0256. Epub 2017 Dec 19

Abstract

Adoptive T-cell therapy (ATT) efficacy is limited when targeting large solid tumors. The evaluation of ATT outcomes using accessory treatment would greatly benefit from an in vivo monitoring tool, allowing the detection of functional parameters of transferred T cells. Here, we generated transgenic bioluminescence imaging of T cells (BLITC) mice expressing an NFAT-dependent click-beetle luciferase and a constitutive Renilla luciferase, which supports concomitant in vivo analysis of migration and activation of T cells. Rapid transferability of our system to preestablished tumor models was demonstrated in the SV40-large T antigen model via both crossbreeding of BLITC mice into a T-cell receptor (TCR)-transgenic background and TCR transduction of BLITC T cells. We observed rapid tumor infiltration of BLITC CD8+ T cells followed by a burst-like activation that mirrored rejection kinetics. Using the BLITC reporter in the clinically relevant H-Y model, we performed female to male transfers and detected H-Y-specific alloreactivity (graft-versus-host disease) in vivo In an H-Y solid tumor model, we found migration of adoptively transferred H-Y TCR-transgenic CD4+ T cells into the tumor, marked by transient activation. This suggests a rapid inactivation of infiltrating T cells by the tumor microenvironment, as confirmed by their expression of inhibitory receptors. In summary, the BLITC reporter system facilitates analysis of therapeutic parameters for ATT, is rapidly transferable to models of interest not restricted to tumor research, and is suitable for rapid screening of TCR clones for tumor rejection kinetics, as well as off-target effects.


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 Nicola Wilck die Auszeichnung Paper of the Month. Folgender MDC Insights Artikel gibt den Inhalt der Publikation wieder Darmbakterien reagieren empfindlich auf Salz.

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.

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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.

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