The Norman conquest: ten centuries of interpretation

The purpose of this study was to investigate the historical accounts of the Norman Conquest and its results. A select group of historians and works, primarily English, were investigated, beginning with the chronicles of medieval writers and continuing chronologically to the works of twentieth century historians. The majority of the texts that were examined pertained to the major problems of the Norman Conquest: the introduction of English feudalism, whether or not the Norman Conquest was an aristocratic revolution, and, how it affected the English church. However, other important areas such as the Conquest's effects on literature, language, economics, and architecture were observed through the "eyes" of past and present historians. A seconday purpose was to assemble for the student of English medieval history, and particularly the Norman Conquest, a variety of primary and secondary sources. Each new generation writes its own histories, seeking to add to the existing cache of material or to reinterpret the existing material in the light of the present. The future study of history will be significantly advanced by historiographic surveys of all major historical events. Professor Wallace K. Ferguson produced an indispensable work for students of the Italian Renaissance, tracing the development of historical thought from the fifteenth to the twentieth century

Budesonide/Glycopyrrolate/Formoterol for the Management of COPD in a UK Primary Care Population : Real-World Use and Early Medication Success

We thank Johann Castaneda for his contribution to protocol development, analysis and interpretation of data. Dr Ruth B Murray (Medscript NZ Ltd) provided medical writing assistance under the direction of the authors, funded by AstraZeneca.Peer reviewe

Feasibility and clinical utility of endoscopic ultrasound guided biopsy of pancreatic cancer for next-generation molecular profiling.

Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in pancreatic cancer (PC). The aim of this study is to investigate the feasibility of genomic profiling using endoscopic ultrasound (EUS) biopsy samples to facilitate personalised therapy for PC. Ninty-five patients underwent additional research biopsies at the time of diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS samples underwent DNA extraction, quantification and targeted gene sequencing. Whole genome (WGS) and RNA sequencing was performed as proof of concept. Only 2 patients (2%) with a diagnosis of PC had insufficient material for targeted sequencing in both FFPE and frozen specimens. Targeted panel sequencing (n=54) revealed mutations in PC genes (KRAS, GNAS, TP53, CDKN2A, SMAD4) in patients with histological evidence of PC, including potentially actionable mutations (BRCA1, BRCA2, ATM, BRAF). WGS (n=5) of EUS samples revealed mutational signatures that are potential biomarkers of therapeutic responsiveness. RNA sequencing (n=35) segregated patients into clinically relevant molecular subtypes based on transcriptome. Integrated multi-omic analysis of PC using standard EUS guided biopsies offers clinical utility to guide personalized therapy and study the molecular pathology in all patients with PC

Professional superheroes: Are changes in higher education stretching hospitality management academics' professionalism to the limit?

The higher education sector in the UK has changed considerably over the last few decades, but particularly in the last ten years. As a result, working practices are such that hospitality management academics are ‘stretching’ their professional orientations in-order to accommodate increased bureaucratic and market-focused requirements, which in-turn impacts upon their professionalism. A typology is introduced in this empirical paper which is used to gain a deeper understanding of professionalism and professional orientations of this vocational academic group in the context of a changed higher education working environment

Digital voices: Posthumanism and the generation of empathy

This chapter investigates digital technologies that variously assist, enable or simulate musical praxis. The first section sets up an opposition between the idea of the digital tool that augments human agency, and the machinic automatism predicated on the idea that reality is fundamentally number (dataism) and ticks along without the need for human consciousness. This gives rise to the idea that mechanical automatism is also intrinsic to human agency, a strand of posthuman thought on which the rest of the chapter turns. Accordingly, the second section shows how posing algorithmic composition as an expression of the posthuman is problematic. The final section focuses on the synthetic voices of digital assistants from online service providers that generate empathy at the price of a surrogate ‘conscience’. Accommodating this within a humanistic model is possible, but a closing case study of Tod Machover’s futurist opera, Death and the Powers (2010), raises the prospect of what might be called a ‘dark ontology’ of the digital

Vaporwave is dead, long live vaporwave!

Popular music subcultures have acknowledged, engaged with, or rejected digital platforms to varying degrees; their relationship to it is often made fraught, ambivalent and ironic by projections of the Internet as inauthentic or impersonal and their inheritance of Romantic-influenced countercultural aesthetics. The genre vaporwave offers a key example of this, especially given that it emerged and exists almost exclusively on digital platforms. Vaporwave addresses its own digital nature and historicity in sound and image, as recent scholarship on it has observed. Its life online represents not an abandonment of traditional formulations of the relationship between culture, technology and authenticity, but a new arena in which to negotiate them

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video Abstract [Figure presented] Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer

Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers.Kathy and Curt Marble Cancer Research FundArthur C. MerrillNational Institutes of Health (U.S.) (Grant CA106416)National Institutes of Health (U.S.) (Grant ROI RR020833)National Institutes of Health (U.S.) (Grant 1F32GM095213-01