The spear in Anglo-Saxon times

A survey was undertaken to determine the nature and place of the spear during the Anglo-Saxon period, based both on material remains and literary evidence. From their origins to the period of the migrations iron spear-head forms had remained conservative, typically leaf- shaped and often midribbed. Subsequent to the migrations traditional forms survive virtually unmodified throughout Merovingian times on the continent; but in England a divergent series of distinctly insular forms emerge, which are predominantly angular in profile. Separate groups are recognisable, defined by form and significant in chronological and geographical distribution. Smaller numbers of "later” groups are similarly distinguishable by reason of form, but dating is latterly more dependent on the less reliable evidence of comparison with manuscript illustrations .No formal break seems to occur at the Conquest, the later series extending uninterrupted into the earlier medieval period, with the effective break appearing instead during the twelfth century. Simply-made as well as complex, spears are the products of both humble and quality forges so that the critical examination of their composition forms a particularly useful index of the techniques of the Dark Age smith. The wide variety of spear-names are examined, showing something of the nature of different types of the weapon. And in the light of this, and with the aid of manuscript illustrations, it is possible to reconstruct the manner of use of the various kinds of darts and hand-spears mentioned in contemporary texts. Simultaneously the literature indicates a wider symbolic significance for the spear generally in Anglo-Saxon society. An attribute of the god Woden, it has recognisable poetic overtones of war and death. At the same time it is seen as the concrete symbol of the free man's status, and one of the insignia of Germanic kingship

Gambling-related consumer credit use and debt problems: a brief review

People experiencing problems with gambling may use consumer credit to cover expenses and/or continue gambling. This may contribute to debt problems and psychological distress, both of which may have pre-existed (and potentially motivated) their gambling. This review found little empirical investigation of patterns of consumer credit use by gamblers, despite borrowing money being a diagnostic criterion for gambling disorder and financial harms being one of the most commonly reported problems. Research suggests that consumer credit use and debt problems increase with problem gambling severity. Gambling-related debt problems increase the likelihood of experiencing poor psychosocial functioning, including psychological distress, substance use, adverse family impacts, crime, and suicidality. Communities and governments are calling for more socially responsible conduct by financial institutions, which increasingly recognise the potentially harmful impacts of credit provision on the well-being of customers experiencing gambling problems. Policies and interventions are needed relating to consumer credit, debt, and gambling to enhance customers’ financial and psychosocial well-being.This work was partially funded by the Commonwealth Bank of Australia and University of Sydney Industry Seed Funding and an Australian Research Council Discovery Early Career Researcher Award [DE1060100459] awarded to Associate Professor Sally Gainsbury. The funding bodies had no involvement in the research, including but not limited to: the conceptualisation of the manuscript; collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the article for publication

Tumour heterogeneity and immune-modulation.

Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune-modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies

APOBEC3 as a driver of genetic intratumor heterogeneity

Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution

Differential binding affinity of mutated peptides for MHC class I is a predictor of survival in advanced lung cancer and melanoma

Background: Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer. Patients and methods: Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression. Results: In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024). Conclusions: The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted

An agent-based modelling framework to study growth mechanisms in EGFR-L858R mutant alveolar type II cells

Mutations in the epidermal growth factor receptor (EGFR) are common in non-small cell lung cancer (NSCLC), particularly in never-smoker patients. However, these mutations are not always carcinogenic, and have recently been reported in histologically normal lung tissue from patients with and without lung cancer. To investigate the outcome of EGFR mutation in healthy lung stem cells, we grew murine alveolar type-II organoids monoclonally in a 3D Matrigel. Our experiments showed that the \textit{EGFR-L858R} mutation induced a change in organoid structure: mutated organoids displayed more `budding', in comparison to non-mutant controls, which were nearly spherical. We perform on-lattice computational simulations, which suggest that this can be explained by the concentration of division amongst a small number of cells on the surface of the organoid, which may arise from several possible biological mechanisms. These results suggest that the L858R mutation produces structures which expand quickly from surface protrusions. We are currently unable to distinguish the cell-based mechanisms that lead to this spatial heterogeneity in growth, but suggest a number of future experiments which could be used to do so. We suggest that the likelihood of L858R-fuelled tumorigenesis is affected not just by random fluctuations in cell fitness, but by whether the mutation arises in a spatial environment that allows mutant cells to reproduce without being forced to encounter each other. These data may have implications for cancer prevention strategies and for understanding NSCLC progression.Comment: 18 pages, 10 figure

Tracking Cancer Evolution through the Disease Course.

During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field. SIGNIFICANCE: Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non-small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials

Field relations, age, and tectonic setting of metamorphic and plutonic rocks in the Creignish Hills – North Mountain area, southwestern Cape Breton Island, Nova Scotia, Canada

 The Creignish Hills and North Mountain areas of southwestern Cape Breton Island consist mostly of Neoproterozoic rocks typical of the Ganderian Bras d’Or terrane. U-Pb ages presented here for detrital zircon in the Blues Brook Formation of the Creignish Hills confirm a depositional age no greater than about 600 Ma. Although it is possible that some components of the formation are much older, similarities in rock types and field relations suggest that this is not the case. It is likely that the equivalent Malagawatch Formation of the North Mountain area, as well as high-grade metasedimentary rocks of the Melford Formation and Chuggin Road complex in the Creignish Hills and Lime Hill gneiss complex in the North Mountain area, represent the same or stratigraphically equivalent units as the Blues Brook Formation. The minimum ages of all of these units are constrained by cross-cutting syn- and post-tectonic plutons with ages mostly between 565 and 550 Ma, indicating that sediments were deposited, regionally metamorphosed, deformed, and intruded by plutons in less than 40–50 million years. The assemblage of pelitic, psammitic, and carbonate rocks indicates that a passive margin in a tropical climate was quickly changed to an active Andean-type continental margin in which voluminous calcalkaline dioritic to granitic plutons were emplaced. This sedimentary and tectonic history is characteristic of the Bras d’Or terrane and is shared by its likely correlative, the Brookville terrane in southern New Brunswick.