Historical Frisians in an archaeological light 5 Egge Knol and Nelleke IJssennagger 2. The Anglo-Frisian Question 25 John Hines 3. Frisian between the Roman and the Early Medieval Periods: Language contact, Celts and Romans 43 Peter Schrijver 4. 'All quiet on the Western Front?' The Western Netherlands and the 'North Sea Culture' in the Migration Period 53 Menno Dijkstra and Jan de Koning 5. Power and Identity in the Southern North Sea Area: The Migration and Merovingian Periods 75 Johan Nicolay 6. How 'English' is the Early Frisian Runic Corpus? The evidence of sounds and forms 93 Gaby Waxenberger 7. The Geography and Dialects of Old Saxon: River-basin communication networks and the distributional patterns of North Sea Germanic features in Old Saxon 125 Arjen Versloot and Elżbieta Adamczyk 8. Between Sievern and Gudendorf: Enclosed sites in the northwestern Elbe-Weser triangle and their significance in respect of society, communication and migration during the Roman Iron Age and Migration Period 149 Iris Aufderhaar 9. Cultural Convergence in a Maritime Context: Language and material culture as parallel phenomena in the early-medieval southern North Sea region 173 Pieterjan Deckers vi 10. The Kingdom of East Anglia, Frisia and Continental Connections, c. ad 600-900 Tim Pestell 11. A Comparison of the Injury Tariffs in the Early Kentish and the Frisian Law Codes Han Nijdam 12. Cultural Contacts between the Western Baltic, the North Sea Region and Scandinavia: Attributing runic finds to runic traditions and corpora of the Early Viking Age Christiane Zimmermann and Hauke Jöns Index vii figures Palaeography and People, Egge Knol and Nelleke IJssennagger 1.1 Palaeogeographical map of the northern Netherlands, c. 500 bc. 1.2 Palaeogeographical map of the northern Netherlands, c. ad 800. 1.3 The Frisian coastal area in the 8th century ad and the dates of conversion to Christianity. 1.4 The distribution of Frisian regions around ad 1300. 1.5 The 8th-century weapon grave of Antum. The Anglo-Frisian Question, John Hines 2.1 Rune-forms representing a, ae, o and oe in the Anglo-Saxon fuþorc. 2.2 The reverse of the Schweindorf solidus. 2.3 Copper-alloy brooches found in England and the Netherlands. 'All quiet on the Western Front', Menno Dijkstra and Jan de Koning 4.1 Palaeogeographical reconstruction of the Netherlands in the early Middle Ages. 4.2 Palaeogeographical reconstruction with the distribution of water-and place-names that derive from prehistoric or Roman times in the western Netherlands. 4.3 Handmade plain and decorated 'Anglo-Saxon' style pottery from the early-medieval cemetery of Rijnsburg-De Horn. 4.4 The cruciform brooch from Katwijk. 4.5 The perifical geographical position of the western Dutch coastal area in the Migration Period. Power and Identity in the Southern North Sea Area, Johan Nicolay 5.1 Equal-armed brooch from Dösemoor (Lkr. Stade). 5.2 Geographical distribution of 5th-century 'Saxon-style' equal-armed brooches. 5.3 Type-C bracteates from the coastal areas of the northern Netherlands and northern Germany...
Breast cancer (BC) is a complex and heterogenous disease, and various approaches have been used to classify BC into several subtypes to improve diagnostic and therapeutic outcomes. One of the features of BC is deregulated transcription, which allows for classification of the disease based on gene expression signature into four basic types: Luminal A, Luminal B, HER2-enriched, and triple negative (TNBC)/basal-like. Novel therapeutic approaches targeting oncogenic transcriptional programs may represent a promising strategy, in particular for TNBC, where the lack of common genetic alterations has so far limited the development of targeted therapies. The CDK8 module of the mediator complex represents an effective therapeutic target across multiple hematologic malignancies and solid tumors. CDK8 module of mediator functions as a master coordinator of transcription, bridging enhancers and core promoters. Meta-analysis of transcriptomic data revealed that higher CDK8 expression and its paralog CDK19 is associated with shorter relapse-free survival (RFS) in all molecular subtypes of BC. Our analysis of curated TCGA data revealed that >15% of all BC have alterations in either CDK8 or CDK19. Increased expression of CDK8 in BC can be partially attributed to copy number gains and amplifications. High CDK8 expression was inversely correlated with the expression of estrogen receptor (ER) and positively correlated with occurrence of TP53 mutations. In order to identify whether increased expression of CDK8/19 in BC could be associated with increased sensitivity to pharmacological inhibition of both kinases, we have interrogated a panel of BC cell lines representing various subtypes with RVU120 - a specific, selective inhibitor of CDK8/CDK19, currently being tested in a first-in-human Phase Ib clinical trial. The highest sensitivity to RVU120 in clonogenic assays has been observed for TNBC and ER-/PR-/HER2+ cells with high STAT3 phosphorylation levels. In contrast, neither RVU120 nor other CDK8 inhibitors were able to inhibit mitogenic effect of estrogen, confirming differential efficacy in hormone - independent BC. Detailed transcriptional profiling of responder cells revealed high enrichment of TNF/NFKB and STAT target genes (signatures associated with inflammatory phenotypes) and SOX4 target genes (signatures associated with invasiveness and stemness). Non-responder cells were characterized by enrichment of transcriptional signatures of ER activity. Efficacy of RVU120 in TNBC cells has been corroborated in a three-dimensional (3D) spheroid viability assay that could predict in vivo efficacy of RVU120 in tested xenograft models and recapitulated using other chemically non-related CDK8 inhibitors, indicating a class effect. Single agent efficacy of RVU120 has been confirmed in subcutaneous TNBC xenograft models in vivo at well tolerated doses. These studies provide rationale for further development of RVU120 in TNBC patients. Citation Format: Tomasz Rzymski, Aniela Gołas, Milena Mazan, Urszula Pakulska, Magdalena Masiejczyk, Agata Stachowicz, Justyna Martyka, Michał Combik, Katarzyna Wiklik, Kristina Goller, Marta Obacz, Elżbieta Adamczyk, Krzysztof Brzózka. Selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-13.
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