The morphomolecular features of cholangiocarcinoma in the personalised era

Cholangiocarcinoma is a group of diverse invasive malignancies arising along the biliary tract. The outcomes for patients with cholangiocarcinoma remain poor but an understanding of molecular aberrations and subsequent targeted therapies to these have opened up new treatment prospects. This review describes the clinical and morphological features and classifications of intrahepatic and perihilar cholangiocarcinoma in addition to laying out the related landscape of the molecular pathology within cholangiocarcinoma. The importance of both a high index of suspicion of cholangiocarcinoma and preserving tissue whilst reporting to access molecular testing and personalised treatment pathways is emphasised

A data-driven approach to decode metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), defined by the presence of liver steatosis together with at least one out of five cardiometabolic factors, is the most common cause of chronic liver disease worldwide, affecting around one in three people. Yet the clinical presentation of MASLD and the risk of progression to cirrhosis and adverse clinical outcomes is highly variable. It therefore represents both a global public health threat and a precision medicine challenge. The use of artificial intelligence (AI) is being investigated in MASLD to develop reproducible, quantitative, and automated methods to enhance patient stratification and to discover new biomarkers and therapeutic targets in MASLD. This review details the different applications of AI and machine learning algorithms in MASLD, particularly in the context of analyzing electronic health record, digital pathology, and imaging data. Additionally, it also describes how specific MASLD consortia are leveraging multimodal data sources to spark research breakthroughs in the field. Using a new national level ‘data commons’ (SteatoSITE) as an exemplar, the opportunities as well as the technical challenges of large-scale databases in MASLD research are highlighted

Esterification Prevents Induction of the Mitochondrial Permeability Transition by N-Acetyl Perfluorooctane Sulfonamides

N-Alkyl perfluorooctane sulfonamides have been widely used as surfactants on fabrics and papers, fire retardants, and anticorrosion agents, among many other commercial applications. The broad use, global distribution, and environmental persistence of these compounds has generated considerable interest regarding potentially toxic effects. We have previously reported that perfluorooctanesulfonamidoacetate (FOSAA) and N-ethylperfluorooctanesulfonamidoacetate (N-EtFOSAA) induce the mitochondrial permeability transition (MPT) in vitro, resulting in cytochrome c release, inhibition of respiration, and generation of reactive oxygen species. By synthesizing the corresponding methyl esters of FOSAA and N-EtFOSAA (methyl perlfuorinated sulfonamide acetates), we tested the hypothesis that the N-acetate moiety of FOSAA and N-EtFOSAA is the functional group responsible for induction of the MPT. Swelling of freshly isolated liver mitochondria from Sprague−Dawley rats was monitored spectrophotometrically and membrane potential (ΔΨ) was measured using a tetraphenylphosphonium-selective (TPP+) electrode. In the presence of calcium, 40 μM FOSAA and 7 μM N-EtFOSAA each induced mitochondrial swelling and a biphasic depolarization of membrane potential. Mitochondrial swelling and the second-phase depolarization were inhibited by cyclosporin-A or the catalyst of K+/H+ exchange nigericin, whereas the first-phase depolarization was not affected by either. In contrast, the methyl esters of FOSAA and N-EtFOSAA exhibited no depolarizing or MPT inducing activity. Results of this investigation demonstrate that the carboxylic acid moiety of the N-acetates is the active functional group, which triggers the MPT by perfluorinated sulfonamides

Reliable computational quantification of liver fibrosis is compromised by inherent staining variation

Biopsy remains the gold standard measure for staging liver disease, both to inform prognosis and to assess the response to a given treatment. Semiquantitative scores such as the Ishak fibrosis score are used for evaluation. These scores are utilised in clinical trials, with the US Food and Drug Administration mandating particular scores as inclusion criteria for participants and using the change in score as evidence of treatment efficacy. There is an urgent need for improved, quantitative assessment of liver biopsies to detect small incremental changes in liver architecture over the course of a clinical trial. Artificial intelligence (AI) methods have been proposed as a way to increase the amount of information extracted from a biopsy and to potentially remove bias introduced by manual scoring. We have trained and evaluated an AI tool for measuring the amount of scarring in sections of picrosirius red-stained liver. The AI methodology was compared with both manual scoring and widely available colour space thresholding. Four sequential sections from each case were stained on two separate occasions by two independent clinical laboratories using routine protocols to study the effect of inter- and intra-laboratory staining variation on these tools. Finally, we compared these methods to second harmonic generation (SHG) imaging, a stain-free quantitative measure of collagen. Although AI methods provided a modest improvement over simpler computer-assisted measures, staining variation both within and between labs had a dramatic effect on quantitation, with manual assignment of scar proportion the most consistent. Manual assessment also correlated the most strongly with collagen measured by SHG. In conclusion, results suggest that computational measures of liver scarring from stained sections are compromised by inter- and intra-laboratory staining. Stain-free quantitative measurement using SHG avoids staining-related variation and may prove more accurate in detecting small changes in scarring that may occur in therapeutic trials

Shallow-water benthic habitats of St. John, U.S. Virgin Islands

Coral reef ecosystems of the Virgin Islands Coral Reef National Monument, Virgin Islands National Park and the surrounding waters of St. John, U.S. Virgin Islands are a precious natural resource worthy of special protection and conservation. The mosaic of habitats including coral reefs, seagrasses and mangroves, are home to a diversity of marine organisms. These benthic habitats and their associated inhabitants provide many important ecosystem services to the community of St. John, such as fishing, tourism and shoreline protection. However, coral reef ecosystems throughout the U.S. Caribbean are under increasing pressure from environmental and anthropogenic stressors that threaten to destroy the natural heritage of these marine habitats. Mapping of benthic habitats is an integral component of any effective ecosystem-based management approach. Through the implementation of a multi-year interagency agreement, NOAA’s Center for Coastal Monitoring and Assessment - Biogeography Branch and the U.S. National Park Service (NPS) have completed benthic habitat mapping, field validation and accuracy assessment of maps for the nearshore marine environment of St. John. This work is an expansion of ongoing mapping and monitoring efforts conducted by NOAA and NPS in the U.S. Caribbean and replaces previous NOAA maps generated by Kendall et al. (2001) for the waters around St. John. The use of standardized protocols enables the condition of the coral reef ecosystems around St. John to be evaluated in context to the rest of the Virgin Island Territories and other U.S. coral ecosystems. The products from this effort provide an accurate assessment of the abundance and distribution of marine habitats surrounding St. John to support more effective management and conservation of ocean resources within the National Park system. This report documents the entire process of benthic habitat mapping in St. John. Chapter 1 provides a description of the benthic habitat classification scheme used to categorize the different habitats existing in the nearshore environment. Chapter 2 describes the steps required to create a benthic habitat map from visual interpretation of remotely sensed imagery. Chapter 3 details the process of accuracy assessment and reports on the thematic accuracy of the final maps. Finally, Chapter 4 is a summary of the basic map content and compares the new maps to a previous NOAA effort. Benthic habitat maps of the nearshore marine environment of St. John, U.S. Virgin Islands were created by visual interpretation of remotely sensed imagery. Overhead imagery, including color orthophotography and IKONOS satellite imagery, proved to be an excellent source from which to visually interpret the location, extent and attributes of marine habitats. NOAA scientists were able to accurately and reliably delineate the boundaries of features on digital imagery using a Geographic Information System (GIS) and fi eld investigations. The St. John habitat classification scheme defined benthic communities on the basis of four primary coral reef ecosystem attributes: 1) broad geographic zone, 2) geomorphological structure type, 3) dominant biological cover, and 4) degree of live coral cover. Every feature in the benthic habitat map was assigned a designation at each level of the scheme. The ability to apply any component of this scheme was dependent on being able to identify and delineate a given feature in remotely sensed imagery

Optimal spatial prioritization of control resources for elimination of invasive species under demographic uncertainty

Populations of invasive species often spread heterogeneously across a landscape, consisting of local populations that cluster in space but are connected by dispersal. A fundamental dilemma for invasive species control is how to optimally allocate limited fiscal resources across local populations. Theoretical work based on perfect knowledge of demographic connectivity suggests that targeting local populations from which migrants originate (sources) can be optimal. However, demographic processes such as abundance and dispersal can be highly uncertain, and the relationship between local population density and damage costs (damage function) is rarely known. We used a metapopulation model to understand how budget and uncertainty in abundance, connectivity, and the damage function, together impact return on investment (ROI) for optimal control strategies. Budget, observational uncertainty, and the damage function had strong effects on the optimal resource allocation strategy. Uncertainty in dispersal probability was the least important determinant of ROI. The damage function determined which resource prioritization strategy was optimal when connectivity was symmetric but not when it was asymmetric. When connectivity was asymmetric, prioritizing source populations had a higher ROI than allocating effort equally across local populations, regardless of the damage function, but uncertainty in connectivity structure and abundance reduced ROI of the optimal prioritization strategy by 57% on average depending on the control budget. With low budgets (monthly removal rate of 6.7% of population), there was little advantage to prioritizing resources, especially when connectivity was high or symmetric, and observational uncertainty had only minor effects on ROI. Allotting funding for improved monitoring appeared to be most important when budgets were moderate (monthly removal of 13–20% of the population). Our result showed that multiple sources of observational uncertainty should be considered concurrently for optimizing ROI. Accurate estimates of connectivity direction and abundance were more important than accurate estimates of dispersal rates. Developing cost-effective surveillance methods to reduce observational uncertainties, and quantitative frameworks for determining how resources should be spatially apportioned to multiple monitoring and control activities are important and challenging future directions for optimizing ROI for invasive species control programs

Mineral and vitamin supplementation on sheep farms: 
a survey of practices and farmer knowledge

Mineral and vitamin (MV) supplementation is a routine management practice in many pasture-based systems of prime lamb production. The aim of the current study was to establish the MV supplementation practices on Irish sheep farms and farmer's knowledge and opinions in relation to supplementation strategies and MV deficiencies. A survey, consisting of 22 questions, was administered to all farmers participating in the Teagasc National Farm Survey (NFS) in 2016 which had a sheep enterprise (n = 177). The Teagasc NFS is a stratified random sample of farms with each farm assigned a weighting factor so the results are representative of the national population of farms. Sixty-nine percent of respondents supplemented their flocks with MV in addition to concentrate feed. Twenty-two percent supplemented based on laboratory analysis results (soil, herbage, blood, or tissue analysis). Thirteen percent supplemented based on veterinary advice with only 30% of this advice based on laboratory analysis results. Sixty-five percent supplemented for reasons other than laboratory analysis or veterinary advice; mainly due to tradition and previous experience. The most common stages to supplement ewes were pregnancy (78%), lactation (61%), and pre-mating (50%). Fifty-one percent supplemented lambs post weaning. Mineral buckets (free access solidified molasses-based licks containing MV and in plastic containers) and drenching (oral dosing with MV containing liquid) were the most common methods of supplementing ewes and lambs, respectively. Generic MV products (containing multiple minerals and vitamins) were the most commonly used followed by cobalt only products. Ease of use/labor requirements and cost were the most important factors influencing choice of supplementation method. Forty-six percent rated their level of knowledge on mineral requirements of sheep as "limited or no education/knowledge". Supplementation with MV did not increase (P > 0.05) ewe productivity (number of lambs reared/ewe joined) or gross margin/ewe. It is concluded that most supplementation decisions in sheep production systems are undertaken in the absence of veterinary advice or laboratory results, therefore are not evidence based. Knowledge transfer activities need to be designed to communicate best practice as regards MV supplementation

Role of Hepatocyte Senescence in the Activation of Hepatic Stellate Cells and Liver Fibrosis Progression

Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this 'proof of concept' study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis