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The use of artificial intelligence will transform clinical practice over the next decade and the early impact of this will likely be the integration of image analysis and machine learning into routine histopathology. In the UK and around the world, a digital revolution is transforming the reporting practice of diagnostic histopathology and this has sparked a proliferation of image analysis software tools. While this is an exciting development that could discover novel predictive clinical information and potentially address international pathology workforce shortages, there is a clear need for a robust and evidence‐based framework in which to develop these new tools in a collaborative manner that meets regulatory approval. With these issues in mind, the NCRI Cellular Molecular Pathology (CM‐Path) initiative and the British In Vitro Diagnostics Association (BIVDA) have set out a roadmap to help academia, industry, and clinicians develop new software tools to the point of approved clinical use. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Oesophageal exposure to duodenogastroesophageal refluxate is implicated in the development of Barrett's metaplasia ( BM), with increased risk of progression to oesophageal adenocarcinoma. The literature proposes that reflux exposure activates NF-κ B, driving the aberrant expression of intestine-specific caudal-related homeobox ( CDX) genes. However, early events in the pathogenesis of BM from normal epithelium are poorly understood. To investigate this, our study subjected a 3 D model of the normal human oesophageal mucosa to repeated, pulsatile exposure to specific bile components and examined changes in gene expression. Initial 2 D experiments with a range of bile salts observed that taurochenodeoxycholate ( TCDC) impacted upon NF-κ B activation without causing cell death. Informed by this, the 3 D oesophageal model was repeatedly exposed to TCDC in the presence and absence of acid, and the epithelial cells underwent gene expression profiling. We identified ~300 differentially expressed genes following each treatment, with a large and significant overlap between treatments. Enrichment analysis (Broad GSEA, DAVID and Metacore™; GeneGo Inc) identified multiple gene sets related to cell signalling, inflammation, proliferation, differentiation and cell adhesion. Specifically NF-κB activation, Wnt signalling, cell adhesion and targets for the transcription factors PTF1A and HNF4α were highlighted. Our data suggest that HNF4α isoform switching may be an early event in Barrett's pathogenesis. CDX1/2 targets were, however, not enriched, suggesting that although CDX1/2 activation reportedly plays a role in BM development, it may not be an initial event. Our findings highlight new areas for investigation in the earliest stages of BM pathogenesis of oesophageal diseases and new potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Summary Oesophageal exposure to duodenogastro-oesophageal refluxate leads to reflux oesophagitis and is implicated in the development of Barrett's metaplasia (BM). NF-κB signalling in epithelial cells is associated with the activation of transcription factors believed to be central to BM development, whilst NF-κB activation in fibroblasts plays a critical role in matrix remodelling. Our aim was to study the effects of acid exposure on NF-κB activation in primary human oesophageal fibroblasts (HOFs) and primary and immortalized oesophageal squames and to investigate any epithelial/stromal interactions in the response of these cells to acid. Primary HOFs and primary and immortalized oesophageal epithelial cells were exposed to acid (pH 7 - pH 4 ≤ 120 min) in single or pulsed treatments. Conditioned medium from epithelial cells following acid exposure was also applied to fibroblasts. Cell viability was determined by MTT-ESTA. NF-κB activation was determined by cellular localization of NF-κB/p65 visualized by immunofluorescence. Conditioned medium from oesophageal epithelial cells, subjected to pH 5 pulsatile exposure, activated NF-κB in fibroblasts, with some inter-patient variability, but these conditions did not directly activate NF-κB in the epithelial cells themselves. Significant NF-κB activation was seen in the epithelial cells but only with greater acidity and exposure times (pH 4, 60-120 min). Our findings show that acid exposure can cause indirect activation of stromal cells by epithelial-stromal interactions. This may contribute to the pathogenesis of oesophageal diseases, and the inter-patient variability may go some way to explain why some patients with reflux oesophagitis develop BM and others do not. [ABSTRACT FROM AUTHOR]

Parberry-Clark C, Bury J P, Cross S S & Winder S J (2011) Histopathology 59, 180-187 Loss of dystroglycan function in oesophageal cancer Aims: Oesophageal cancer is an increasingly common human malignancy, with its incidence in the West rapidly rising. It is associated with a very poor prognosis, and its exact pathogenesis is uncertain. Dystroglycan and E-cadherin are cell adhesion molecules, the loss of which is often related to tumour differentiation, aggressiveness and invasiveness. The aim was therefore to evaluate their roles in oesophageal carcinogenesis. Methods and results: mRNA and protein levels of dystroglycan and E-cadherin were examined in oesophageal normal and tumour tissue samples, and in FLO-1 oesophageal adenocarcinoma cells, using immunohistochemistry, western blotting and reverse transcription polymerase chain reaction. E-cadherin,α-dystroglycan and β-dystroglycan levels were decreased in the oesophageal primary tumour samples, despite the presence of normal levels of dystroglycan mRNA. In FLO-1 cells, increasing cell density caused a decrease in protein levels of β-dystroglycan over time, despite the persistent presence of dystroglycan mRNA. Re-expression of dystroglycan in FLO-1 cells reduced the numbers and size of colonies formed in soft agar, indicative of a role for dystroglycan in suppressing the tumour phenotype. Conclusions: The adenocarcinoma cells mirrored the in vivo situation with respect to dystroglycan function, making this a useful model of oesophageal carcinogenesis; moreover, loss of dystroglycan protein, despite the presence of dystroglycan mRNA, points to a post-translational mechanism of dystroglycan loss. [ABSTRACT FROM AUTHOR]

Rare inherited mutations in the mutL homolog 1 ( MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (−93G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 −93A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG = 3.30, 95% CI 1.46-7.47, n = 1392, p = 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG=1.68, 95% confidence interval (CI) 1.00-2.83, n = 1,518, p = 0.05, proximal vs distal CRC). These findings suggest that the MLH1 −93G>A polymorphism defines a low penetrance risk allele for CRC. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Continuation chemotherapy is a key component of the treatment of childhood acute lymphoblastic leukaemia. During this treatment phase, weekly dose adjustments are carried out based on current and historical full blood counts (FBCs). The dose decision pathway is complex and suboptimal therapy may result if information on FBC results is not readily available and/or the prescriber is inexperienced. A web-based decision-support system (Leukaemia Intervention Scheduling and Advice,‘LISA’) was designed to facilitate access to FBC information across geographical locations and to assist with dosage adjustments. A balanced-block crossover analysis was performed to evaluate the system. Thirty-six clinicians with varying degrees of experience were each asked to decide on appropriate oral chemotherapy dosages for eight simulated cases: four using LISA and four without. LISA significantly reduced the number of erroneous prescriptions (zero of 144 with LISA vs. 54 of 144 without; P < 0·0001) without affecting the number of times subjects deliberately overrode the protocol (seven of 144 times using LISA and six of 144 without). Using LISA reduced the time taken by novices to reach a decision for each case but increased the time taken by experts. Thirty-five of 36 subjects said they would be likely to use the system if it were available. A system like LISA is likely to be acceptable to clinicians, and has the potential to increase protocol compliance and decrease prescribing errors while allowing clinicians to override the protocol in specific cases where sound reasons exist for doing so. [ABSTRACT FROM AUTHOR]

We present the current status of RADDOSE-3D, a software tool allowing the estimation of the dose absorbed in a macromolecular crystallography diffraction experiment. The code allows a temporal and spatial dose contour map to be calculated for a crystal of any geometry and size as it is rotated in an X-ray beam, and gives several summary dose values: among them diffraction weighted dose. This allows experimenters to plan data collections which will minimize radiation damage effects by spreading the absorbed dose more homogeneously, and thus to optimize the use of their crystals. It also allows quantitative comparisons between different radiation damage studies, giving a universal ' x-axis' against which to plot various metrics. [ABSTRACT FROM AUTHOR]