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Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Background: Leukocyte progenitors derived from clonal hematopoiesis of undetermined potential (CHIP) are associated with increased cardiovascular events. However, the prevalence and functional relevance of CHIP in coronary artery disease (CAD) are unclear, and cells affected by CHIP have not been detected in human atherosclerotic plaques.
Methods: CHIP mutations in blood and tissues were identified by targeted deep-DNA-sequencing (DNAseq: coverage >3,000) and whole-genome-sequencing (WGS: coverage >35). CHIP-mutated leukocytes were visualized in human atherosclerotic plaques by mutaFISHTM. Functional relevance of CHIP mutations was studied by RNAseq.
Results: DNAseq of whole blood from 540 deceased CAD patients of the Munich cardIovaScular StudIes biObaNk (MISSION) identified 253 (46.9%) CHIP mutation carriers (mean age 78.3 years). DNAseq on myocardium, atherosclerotic coronary and carotid arteries detected identical CHIP mutations in 18 out of 25 mutation carriers in tissue DNA. MutaFISHTM visualized individual macrophages carrying DNMT3A CHIP mutations in human atherosclerotic plaques. Studying monocyte-derived macrophages from Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task (STARNET; n=941) by WGS revealed CHIP mutations in 14.2% (mean age 67.1 years). RNAseq of these macrophages revealed that expression patterns in CHIP mutation carriers differed substantially from those of non-carriers. Moreover, patterns were different depending on the underlying mutations, e.g. those carrying TET2 mutations predominantly displayed upregulated inflammatory signaling whereas ASXL1 mutations showed stronger effects on metabolic pathways.
Conclusions: Deep-DNA-sequencing reveals a high prevalence of CHIP mutations in whole blood of CAD patients. CHIP-affected leukocytes invade plaques in human coronary arteries. RNAseq data obtained from macrophages of CHIP-affected patients suggest that pro-atherosclerotic signaling differs depending on the underlying mutations. Further studies are necessary to understand whether specific pathways affected by CHIP mutations may be targeted for personalized treatment.
The concept of the "comprehensive approach" has become a paradigm for international state engagement in the field of fostering sustainable peace in crisis-ridden countries. This approach stipulates joint actions of different governmental institutions. The ministry of defence, providing interventionist armed forces; the ministry of interior, providing police personal; the ministry of foreign affairs, providing crisis aid and the ministry of economic cooperation and development define the core actors on the highest level, whilst the implementation of this approach is left to the various, highly heterogeneous employees of the ministries and their sub-contractors...
Zur prototypischen Modellierung ausgewählter Völker im Tabletop-Strategiespiel Warhammer Fantasy
(2013)
Der vorliegende Beitrag beschäftigt sich mit der Typisierung einzelner Völker des Tabletop-Strategiespiels 'Warhammer Fantasy'. Unter methodischen Gesichtspunkten kann man für die Ermittlung von Prototypen auf bewährte textlinguistische bzw. lexikalisch-semantische Verfahrensweisen zurückgreifen. Im Folgenden sollen Referenzidentitäten, Isotopieketten, Attribuierungen und Konnotationen betrachtet werden. Die Fülle des vorhandenen Textmaterials (siehe dazu Abschnitt 3) macht eine Fokussierung unumgänglich. Vorliegende Studie beschränkt sich auf die Textgruppe der völkerspezifischen Armeebücher. Besondere Aufmerksamkeit erfahren hierbei einerseits der Text auf dem Rückendeckel (U4), schlichtweg deshalb, weil die Vermutung naheliegt, dass diese Stelle für eine prototypische Verdichtung besonders exponiert ist, und andererseits die Bezeichnungen und Beschreibungen der armeetypischen Einheitentypen, welche die völkerspezifischen Binnenstrukturierungen aufzeigen.