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Determining early-stage prognostic markers and stratifying patients for effective treatment are two key challenges for improving outcomes for melanoma patients. Previous studies have used tumour transcriptome data to stratify patients into immune subgroups, which were associated with differential melanoma specific survival and potential predictive biomarkers. However, acquiring transcriptome data is a time-consuming and costly process. Moreover, it is not routinely used in the current clinical workflow. Here, we attempt to overcome this by developing deep learning models to classify gigapixel haematoxylin and eosin (H&E) stained pathology slides, which are well established in clinical workflows, into these immune subgroups. We systematically assess six different multiple instance learning (MIL) frameworks, using five different image resolutions and three different feature extraction methods. We show that pathology-specific self-supervised models using 10x resolution patches generate superior representations for the classification of immune subtypes. In addition, in a primary melanoma dataset, we achieve a mean area under the receiver operating characteristic curve (AUC) of 0.80 for classifying histopathology images into 'high' or 'low immune' subgroups and a mean AUC of 0.82 in an independent TCGA melanoma dataset. Furthermore, we show that these models are able to stratify patients into 'high' and 'low immune' subgroups with significantly different melanoma specific survival outcomes (log rank test, P < 0.005). We anticipate that MIL methods will allow us to find new biomarkers of high importance, act as a tool for clinicians to infer the immune landscape of tumours and stratify patients, without needing to carry out additional expensive genetic tests., Funding Agencies|Engineering and Physical Sciences Research Council (EPSRC) , United Kingdom [EP/S024336/1]; Cancer Research UK [C588/A19167, C8216/A6129, C588/A10721]; NIH [CA83115]; Medical Research Council, United Kingdom [MR/S001530/1]; National Pathology Imaging Co-operative, NPIC [104687]; Data to Early Diagnosis and Precision Medicine strand of the government's Industrial Strategy Challenge Fund; N8 research partnership; EPSRC [EP/T022167/1]

Abdominal aortic aneurysm (AAA) is a pathologic enlargement of the infrarenal aorta with an associated risk of rupture. However, the responsible mechanisms are only partially understood. Based on murine and human samples, a heterogeneous distribution of characteristic pathologic features across the aneurysm circumference is expected. Yet, complete histologic workup of the aneurysm sac is scarcely reported. Here, samples from five AAAs covering the complete circumference partially as aortic rings are investigated by histologic means (HE, EvG, immunohistochemistry) and a new method embedding the complete ring. Additionally, two different methods of serial histologic section alignment are applied to create a 3D view. The typical histopathologic features of AAA, elastic fiber degradation, matrix remodeling with collagen deposition, calcification, inflammatory cell infiltration and thrombus coverage were distributed without recognizable pattern across the aneurysm sac in all five patients. Analysis of digitally scanned entire aortic rings facilitates the visualization of these observations. Immunohistochemistry is feasible in such specimen, however, tricky due to tissue disintegration. 3D image stacks were created using open-source and non-generic software correcting for non-rigid warping between consecutive sections. Secondly, 3D image viewers allowed visualization of in-depth changes of the investigated pathologic hallmarks. In conclusion, this exploratory descriptive study demonstrates a heterogeneous histomorphology around the AAA circumference. Warranting an increased sample size, these results might need to be considered in future mechanistic research, especially in reference to intraluminal thrombus coverage. 3D histology of such circular specimen could be a valuable visualization tool for further analysis.

Abdominal aortic aneurysm (AAA) is a pathologic enlargement of the infrarenal aorta with an associated risk of rupture. However, the responsible mechanisms are only partially understood. Based on murine and human samples, a heterogeneous distribution of characteristic pathologic features across the aneurysm circumference is expected. Yet, complete histologic workup of the aneurysm sac is scarcely reported. Here, samples from five AAAs covering the complete circumference partially as aortic rings are investigated by histologic means (HE, EvG, immunohistochemistry) and a new method embedding the complete ring. Additionally, two different methods of serial histologic section alignment are applied to create a 3D view. The typical histopathologic features of AAA, elastic fiber degradation, matrix remodeling with collagen deposition, calcification, inflammatory cell infiltration and thrombus coverage were distributed without recognizable pattern across the aneurysm sac in all five patients. Analysis of digitally scanned entire aortic rings facilitates the visualization of these observations. Immunohistochemistry is feasible in such specimen, however, tricky due to tissue disintegration. 3D image stacks were created using open-source and non-generic software correcting for non-rigid warping between consecutive sections. Secondly, 3D image viewers allowed visualization of in-depth changes of the investigated pathologic hallmarks. In conclusion, this exploratory descriptive study demonstrates a heterogeneous histomorphology around the AAA circumference. Warranting an increased sample size, these results might need to be considered in future mechanistic research, especially in reference to intraluminal thrombus coverage. 3D histology of such circular specimen could be a valuable visualization tool for further analysis.

Regular menstrual shedding and repair of the endometrial functionalis is unique to humans and higher-order primates. The current consensus postulates endometrial glands to have a single-tubular architecture, where multi-potential stem cells reside in the blind-ending glandular-bases. Utilising fixed samples from patients, we have studied the three-dimensional (3D) micro-architecture of the human endometrium. We demonstrate that some non-branching, single, vertical functionalis glands originate from a complex horizontally interconnecting network of basalis glands. The existence of a multipotent endometrial epithelial stem cell capable of regenerating the entire complement of glandular lineages was demonstrated byin vivolineage tracing, using naturally occurring somatic mitochondrial DNA mutations as clonal markers. Vertical tracking of mutated clones showed that at least one stem-cell population resides in the basalis glands. These novel findings provide insight into the efficient and scar-less regenerative potential of the human endometrium. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., Funding Agencies|Wellbeing of Women projectWellbeing of Women (WoW) [RTF510, RG2137]; Cancer Research UKCancer Research UK [A14895]

Human ear reconstruction is recognized as the emblematic enterprise in tissue engineering. Up to now, it has failed to reach human applications requiring appropriate tissue complexity along with an accessible vascular tree. We hereby propose a new method to process human auricles in order to provide a poorly immunogenic, complex and vascularized ear graft scaffold. 12 human ears with their vascular pedicles were procured. Perfusion-decellularization was applied using a SDS/polar solvent protocol. Cell and antigen removal was examined by histology and DNA was quantified. Preservation of the extracellular matrix (ECM) was assessed by conventional and 3D-histology, proteins and cytokines quantifications. Biocompatibility was assessed by implantation in rats for up to 60 days. Adipose-derived stem cells seeding was conducted on scaffold samples and with human aortic endothelial cells whole graft seeding in a perfusion-bioreactor. Histology confirmed cell and antigen clearance. DNA reduction was 97.3%. ECM structure and composition were preserved. Implanted scaffolds were tolerated in vivo, with acceptable inflammation, remodeling, and anti-donor antibody formation. Seeding experiments demonstrated cell engraftment and viability. Vascularized and complex auricular scaffolds can be obtained from human source to provide a platform for further functional auricular tissue engineered constructs, hence providing an ideal road to the vascularized composite tissue engineering approach. The ear is emblematic in the biofabrication of tissues and organs. Current regenerative medicine strategies, with matrix from donor tissues or 3D-printed, didn't reach any application for reconstruction, because critically missing a vascular tree for perfusion and transplantation. We previously described the production of vascularized and cell-compatible scaffolds, from porcine ear grafts. In this study, we ---- applied findings directly to human auricles harvested from postmortem donors, providin

Urban infrastructure assets perform critical functions to the health and well-being of the society. In this paper, we present a prototype decision support system for sustainable subsurface inter-asset management. To the best of the authors’ knowledge, this work is the first on assessing the underground space by considering the inter-asset dependencies using semantic technologies. Based on a family of interlinked city infrastructure asset ontologies describing the ground, roads and buried utilities (e.g. water pipes), various datasets are integrated and logical rules are developed to describe the intra-asset and inter-asset relationships. An inference engine is employed to exploit the knowledge and data for assessing the potential impact of an event. This system can be beneficial to a wide range of stakeholders (e.g. utility incident managers) for quickly gathering of the localised contextual data and identifying potential consequences from what may appear as an insignificant trigger. A video demonstrating the prototype is available at: http://bit.ly/2mdyIY4.

Purpose: The aim of this work was to quantify the extent of lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) in atherosclerotic plaques. Methods: Patients scheduled for carotid endarterectomy underwent four-point Dixon and T1-weighted magnetic resonance imaging (MRI) at 3 Tesla. Fat and R2* maps were generated from the Dixon sequence at the acquired spatial resolution of 0.60 × 0.60 × 0.70 mm voxel size. MRI and three-dimensional (3D) histology volumes of plaques were registered. The registration matrix was applied to segmentations denoting LRNC and IPH in 3D histology to split plaque volumes in regions with and without LRNC and IPH. Results: Five patients were included. Regarding volumes of LRNC identified by 3D histology, the average fat fraction by MRI was significantly higher inside LRNC than outside: 12.64 ± 0.2737% versus 9.294 ± 0.1762% (mean ± standard error of the mean [SEM]; P < 0.001). The same was true for IPH identified by 3D histology, R2* inside versus outside IPH was: 71.81 ± 1.276 s−1 versus 56.94 ± 0.9095 s−1 (mean ± SEM; P < 0.001). There was a strong correlation between the cumulative fat and the volume of LRNC from 3D histology (R2 = 0.92) as well as between cumulative R2* and IPH (R2 = 0.94). Conclusion: Quantitative mapping of fat and R2* from Dixon MRI reliably quantifies the extent of LRNC and IPH.

Assessing the Underworld (ATU) is a large interdisciplinary UK research project, which addresses challenges in integrated inter-asset maintenance. As assets on the surface of the ground (e.g. roads or pavements) and those buried under it (e.g. pipes and cables) are supported by the ground, the properties and processes of soil affect the performance of these assets to a significant degree. In order to make integrated decisions, it is necessary to combine the knowledge and expertise in multiple areas, such as roads, soil, buried assets, sensing, etc. This requires an underpinning knowledge model, in the form of an ontology. Within this context, we present a new ontology for describing soil properties (e.g. soil strength) and processes (e.g. soil compaction), as well as how they affect each other. This ontology can be used to express how the ground affects and is affected by assets buried under the ground or on the ground surface. The ontology is written in OWL 2 and openly available from the University of Leeds data repository: http://​doi.​org/​10.​5518/​54.

Light Microscopes are gradually being replaced by slide scanners in research labs (and even in clinical practice in countries like Sweden). These scanners produce gigapixel images of a single microscope slide (one slide may be 100K x 80K pixels and contain 300K cells). This opens up the opportunity for large scale (whole slide) image analysis at cellular resolution. However, the computational challenges are not insubstantial. In Leeds we have been working on methods for 3D analysis using multiple (hundreds of) serial sections. This presents further challenges in terms of data size, distortion correction, colour variation correction, and correlation with other modalities such as MRI. In my talk I will address our solutions to some of these challenges and look forward at uses of digital pathology in a biomedical engineering and modelling context - addressing some of the problems of analysis data volume (which can be many times the original data volume - itself huge)., A Bioengineering research seminar by Dr Derek Magee, School of Computing, University of Leeds, UK.