A 3D Heterotypic Breast Cancer Model Demonstrates a Role for Mesenchymal Stem Cells in Driving a Proliferative and Invasive Phenotype

Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote breast cancer (BC) progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D co-culture model, spheroids incorporating breast cancer cells (BCCs), both cell lines and primary BCCs expanded as patient-derived xenografts, and MSCs were established. MSCs in co-cultures were shown to enhance proliferation of estrogen receptor (ER)/progesterone receptor (PR)-positive BCCs. In addition, co-culture resulted in downregulation of E-cadherin in parallel with upregulation of the epithelial-mesenchymal transition (EMT)-relation transcription factor, SNAIL. Cytoplasmic relocalization of ski-related novel protein N (SnON), a negative regulator of transforming growth factor-beta (TGF-β) signalling, and of β-catenin, involved in a number of pathways including Wnt signalling, was also observed in BCCs in co-cultures in contrast to monocultures. In addition, the β-catenin inhibitor, 3-[[(4-methylphenyl)sulfonyl]amino]-benzoic acid methyl ester (MSAB), mediated reduced growth and invasion in the co-cultures. This study highlights the potential role for SnON as a biomarker for BC invasiveness, and the importance of interactions between TGF-β and Wnt signalling, involving SnON. Such pathways may contribute towards identifying possible targets for therapeutic intervention in BC patients

Assessing the economic impact of vaccine availability when controlling foot and mouth disease outbreaks

Predictive models have been used extensively to assess the likely effectiveness of vaccination policies as part of control measures in the event of a foot and mouth disease (FMD) outbreak. However, the availability of vaccine stocks and the impact of vaccine availability on disease control strategies represent a key uncertainty when assessing potential control strategies. Using an epidemiological, spatially explicit, simulation model in combination with a direct cost calculator, we assessed how vaccine availability constraints may affect the economic benefit of a “vaccination-to-live” strategy during a FMD outbreak in Scotland, when implemented alongside culling of infected premises and dangerous contacts. We investigated the impact of vaccine stock size and restocking delays on epidemiological and economic outcomes. We also assessed delays in the initial decision to vaccinate, maximum daily vaccination capacity, and vaccine efficacy. For scenarios with conditions conducive to large outbreaks, all vaccination strategies perform better than the strategy where only culling is implemented. A stock of 200,000 doses, enough to vaccinate 12% of the Scottish cattle population, would be sufficient to maximize the relative benefits of vaccination, both epidemiologically and economically. However, this generates a wider variation in economic cost than if vaccination is not implemented, making outcomes harder to predict. The probability of direct costs exceeding £500 million is reduced when vaccination is used and is steadily reduced further as the size of initial vaccine stock increases. If only a suboptimal quantity of vaccine doses is initially available (100,000 doses), restocking delays of more than 2 weeks rapidly increase the cost of controlling outbreaks. Impacts of low vaccine availability or restocking delays are particularly aggravated by delays in the initial decision to vaccinate, or low vaccine efficacy. Our findings confirm that implementing an emergency vaccination-to-live strategy in addition to the conventional stamping out strategy is economically beneficial in scenarios with conditions conducive to large FMD outbreaks in Scotland. However, the size of the initial vaccine stock available at the start of the outbreak and the interplay with other factors, such as vaccine efficacy and delays in restocking or implementing vaccination, should be considered in making decisions about optimal control strategies for FMD outbreaks

Active adaptive conservation of threatened species in the face of uncertainty

Adaptive management has a long history in the natural resource management literature, but despite this, few practitioners have developed adaptive strategies to conserve threatened species. Active adaptive management provides a framework for valuing learning by measuring the degree to which it improves long-run management outcomes. The challenge of an active adaptive approach is to find the correct balance between gaining knowledge to improve management in the future and achieving the best short-term outcome based on current knowledge. We develop and analyze a framework for active adaptive management of a threatened species. Our case study concerns a novel facial tumor disease affecting the Australian threatened species Sarcophilus harrisii: the Tasmanian devil. We use stochastic dynamic programming with Bayesian updating to identify the management strategy that maximizes the Tasmanian devil population growth rate, taking into account improvements to management through learning to better understand disease latency and the relative effectiveness of three competing management options. Exactly which management action we choose each year is driven by the credibility of competing hypotheses about disease latency and by the population growth rate predicted by each hypothesis under the competing management actions. We discover that the optimal combination of management actions depends on the number of sites available and the time remaining to implement management. Our approach to active adaptive management provides a framework to identify the optimal amount of effort to invest in learning to achieve long-run conservation objectives

Population gene introgression and high genome plasticity for the zoonotic pathogen Streptococcus agalactiae

The influence that bacterial adaptation (or niche partitioning) within species has on gene spillover and transmission among bacteria populations occupying different niches is not well understood. Streptococcus agalactiae is an important bacterial pathogen that has a taxonomically diverse host range making it an excellent model system to study these processes. Here we analyze a global set of 901 genome sequences from nine diverse host species to advance our understanding of these processes. Bayesian clustering analysis delineated twelve major populations that closely aligned with niches. Comparative genomics revealed extensive gene gain/loss among populations and a large pan-genome of 9,527 genes, which remained open and was strongly partitioned among niches. As a result, the biochemical characteristics of eleven populations were highly distinctive (significantly enriched). Positive selection was detected and biochemical characteristics of the dispensable genes under selection were enriched in ten populations. Despite the strong gene partitioning, phylogenomics detected gene spillover. In particular, tetracycline resistance (which likely evolved in the human-associated population) from humans to bovine, canines, seals, and fish, demonstrating how a gene selected in one host can ultimately be transmitted into another, and biased transmission from humans to bovines was confirmed with a Bayesian migration analysis. Our findings show high bacterial genome plasticity acting in balance with selection pressure from distinct functional requirements of niches that is associated with an extensive and highly partitioned dispensable genome, likely facilitating continued and expansive adaptation

Application of a 3D hydrogel-based model to replace use of animals for passaging patient-derived xenografts

PurposeThis 3D in vitro cancer model for propagation of patient-derived cells, using a synthetic self-assembling peptide gel, allows the formation of a fully characterised, tailorable tumour microenvironment. Unlike many existing 3D cancer models, the peptide gel is inert, apart from molecules and motifs deliberately added or produced by cells within the model.MethodsBreast cancer patient-derived xenografts (PDXs) were disaggregated and embedded in a peptide hydrogel. Growth was monitored by microscopic examination and at intervals, cells were extracted from the gels and passaged on into fresh gels. Passaged cells were assessed by qPCR and immunostaining techniques for the retention of characteristic markers.ResultsBreast cancer PDXs were shown to be capable of expansion over four or more passages in the peptide gel. Contaminating mouse cells were found to be rapidly removed by successive passages. The resulting human cells were shown to be compatible with a range of common assays useful for assessing survival, growth and maintenance of heterogeneity.ConclusionsBased on these findings, the hydrogel has the potential to provide an effective and practical breast cancer model for the passage of PDXs which will have the added benefits of being relatively cheap, fully-defined and free from the use of animals or animal products. Encapsulated cells will require further validation to confirm the maintenance of cell heterogeneity, genotypes and phenotypes across passage, but with further development, including the addition of bespoke cell and matrix components of the tumour microenvironment, there is clear potential to model other cancer types

The toxicity of the methylimidazolium ionic liquids, with a focus on M8OI and hepatic effects

Ionic liquids are a diverse range of charged chemicals with low volatility and often liquids at ambient temperatures. This characteristic has in part lead to them being considered environmentally-friendly replacements for existing volatile solvents. However, methylimidazolium ionic liquids are slow to break down in the environment and a recent study at Newcastle detected 1 octyl 3 methylimidazolium (M8OI) – an 8 carbon variant methylimidazolium ionic liquid - in soils in close proximity to a landfill site. The current M8OI toxicity database in cultured mammalian cells, in experimental animal studies and in model indicators of environmental impact are reviewed. Selected analytical data from the Newcastle study suggest the soils in close proximity to the landfill site, an urban soil lacking overt contamination, had variable levels of M8OI. The potential for M8OI - or a structurally related ionic liquid – to trigger primary biliary cholangitis (PBC), an autoimmune liver disease thought to be triggered by an unknown agent(s) in the environment, is reviewed

Inflammatory bowel disease in young patients : challenges faced by black and minority ethnic communities in the UK

This document is the peer reviewed version of the following article: Christopher Alexakis, Avril Nash, Michele Lloyd, Fiona Brooks, James O. Lindsay, and Andrew Poullis, ‘Inflammatory bowel disease in young patients: challenges faced by blank and minority ethnic communities in the UK’, Health and Social Care in the Community, Vol. 23 (6): 665-672, first published 9 February 2015, which has been published in final form at doi: 10.1111/hsc.12188. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.There is strong evidence indicating that inflammatory bowel disease (IBD) is increasing among black and minority ethnic (BME) communities. Despite this rise in prevalence, there is a paucity of research relating to ethnicity and IBD outside the USA. Furthermore, the symptoms of IBD are reported to start during childhood or adolescence in 20–25% of people with the condition. It is therefore important that young people's experiences of diagnosis, treatment and living with IBD are fully understood to ensure effective services and information provision. The study reported on in this paper was commissioned by a UK charity (Crohn's and Colitis UK) with the aim of increasing understanding of the specific issues and service needs of young people with IBD from BME communities. Empirical research entailed in-depth semi-structured interviews with 20 young people from BME groups accessed through gastroenterology departments at three collaborating NHS hospitals in England serving ethnically diverse populations. Interviews were carried out from June to December 2010 and sought to capture young people's views with IBD. A thematic analysis of their experiences identified many commonalities with other young people with IBD, such as the problematic route to formal diagnosis and the impact of IBD on education. The young people also experienced tensions between effective self-management strategies and cultural norms and practices relating to food. Moreover, the ability of parents to provide support was hampered for some young people by the absence of culturally competent services that were responsive to the families’ communication needs. The findings highlight the need for more culturally appropriate information concerning IBD, and improved responsiveness to young people with IBD within primary care and the education system, as well as culturally competent messaging relating to the specific nature of the condition among the wider South Asian and black communitiesPeer reviewedFinal Accepted Versio

A sea of Lilliputians

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Palaeogeography, Palaeoclimatology, Palaeoecology 284 (2009): 88-113, doi:10.1016/j.palaeo.2009.08.020.Smaller size is generally seen as a negative response of organisms to stressful environmental conditions, associated with low diversity and species dominance. The mean size of the coccolithophorids decreased through the Neogene, leading to the prediction that their extant representatives are characterized by poor diversification and low specialization. The study of the (exo)coccospheres of selected taxa in the order Syracosphaerales negates this prediction, revealing that on the contrary some extant lineages are highly diversified and remarkably specialized. Whereas the general role of coccoliths remains indeterminate, this analysis suggests that some highly derived coccoliths may be modified for the collection of food particles, including picoplankton, thus implying that mixotrophy may characterize these lineages. In the extant coccolithophorids, species richness of genera is inversely correlated with the size of cells, definitive evidence that small size is part of a morphologic strategy rather than a sign of evolutionary failure. Because of their extreme minuteness, the extant nannoplankton can be well compared to Lilliputians, but the trend toward size decrease in Neogene lineages is not attributable to the Lilliput effect described by Urbanek (1993)