BIH Paper of the Month

The BIH Paper of the Month is awarded by the BIH Board of Directors to honor a special publication achievement from the joint research space of Charité and MDC. The Paper of the Month is sponsored by the Stiftung Charité as part of its Johanna Quandt Private Excellence Initiative. The prize is awarded at the beginning of each month for a paper published the month before last (i.e. in March a paper will be honored that was published in January). The date of publication that counts here is the date of public accessibility (online and/or print), not an “advanced publication” of an author manuscript that has been accepted for publication. The award is endowed with €500 and goes to the group leader with BIH affiliation.

Publications that can be considered for the award include all those found in a PubMed search in the relevant month for articles with a direct BIH affiliation (affiliation through corporate bodies of the BIH alone is not sufficient).

Publications can also be proposed to the BIH per e-mail at any time.

The criteria for the award are as follows:

  • Mention of BIH affiliation

  • Fit with BIH strategy
    - Contribution to the research/diagnosis/therapy of progressive diseases
    - Transfer between basic and clinical research
    - Transfer between research and commercial application
    - Use of BIH infrastructures
  • Originality of the work

  • Quality assurance measures in the writing and publication of the paper (e.g. open access/open data publications, use of electronic laboratory journals, transparent documentation of study planning and implementation, publication of negative and neutral results, replication studies, etc.)

  • Participation of
    - Young researchers
    - Various research disciplines
    - International authors

  • Gender balance

BIH Paper of the Month 'June'

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.

In June, Josefine Radke receives the Paper of the Month award for the publication on a pathway that plays an important role in the development of malignant gliomas. Read the interview

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.

You can download the publication here.


BIH Paper of the Month 'May'

In May, Nils Blüthgen and his team received the Paper of the Month for their Open Access publication, in which they investigated the ERK signaling path using mathematical modelling. The publication resulted from BIH funding for the the TRG project "Systems Medicine of BRAF-Driven Malignancies". Read the 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.

You can download the publication here.


BIH Paper of the Month 'April'

For their work on the signaling molecule interferon-gamma in cancer development, Thomas Kammertoens and Thomas Blankenstein were awarded with the Paper of the Month 'April'. The work provides evidence for improved T cell therapy against solid cancer deaths. Read the 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.

You can download the publication here.

BIH Paper of the Month 'March'

Ana Pombo and her team present a new method in Nature that allows mapping of the three-dimensional topography of the genome. For this, Pombo receives the Paper of the Month 'March'.

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.

You can download the publication here.


BIH Paper of the Month 'February'

BIH Charité Clinical Scientist Benjamin Strücker and his team were awarded with the BIH Paper of the Month 'February'. In the open access publication Strücker presents a method by which it is possible to engineer an endocrine Neo-Pancreas by repopulation of a decellularized rat pancreas with islets of Langerhans. In further tests, the scientists were able to demonstrate that the Langerhans islands were functional and able to produce insulin.

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.

You can download the publication here


BIH Paper of the Month 'January'

At the beginning of March, Angela M. Kaindl from the Institute of Cell Biology and Neurobiology of the Charité was awarded the BIH Paper of the Month. The publication “CDK5RAP2 Is Required to Maintain the Germ Cell Pool during Embryonic Development” was published in Stem Cell Reports under open access conditions with a total of only five authors and a high proportion of BIH affiliates.

Kaindl has shown in the past that mutations of the CDK5RAP2 gene lead to microcephaly. This paper shows for the first time that the ubiquitously expressed Cdk5rap2 is also required to maintain germ cells during embryonic development. Certain genetic mutations in CDK5RAP2 lead to mitotic delay in germ cells, which is connected to the large-scale death of germ cell derivatives and sterility in male mice. Identifying the mechanisms that cause this death will enhance our understanding of the development of microcephaly and could open up new approaches to the diagnosis of this and other genetic diseases.

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.

Since the publication was published under Open Access conditions, it is freely available. Download here