Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro

Aims: Products of lipid oxidation, such as 4-hydroxynonenal (4-HNE), are key activators of hepatic stellate cells (HSC) to a pro-fibrogenic phenotype. Isolevuglandins (IsoLG) are a family of acyclic γ-ketoaldehydes formed through oxidation of arachidonic acid or as by-products of the cyclooxygenase pathway. IsoLGs are highly reactive aldehydes which are efficient at forming protein adducts and cross-links at concentrations 100-fold lower than 4-hydroxynonenal. Since the contribution of IsoLGs to liver injury has not been studied, we synthesized 15-E2-IsoLG and used it to investigate whether IsoLG could induce activation of HSC. / Results: Primary human HSC were exposed to 15-E2-IsoLG for up to 48 hours. Exposure to 5 μM 15-E2-IsoLG in HSCs promoted cytotoxicity and apoptosis. At non-cytotoxic doses (50 pM-500 nM) 15-E2-IsoLG promoted HSC activation, indicated by increased expression of α-SMA, sustained activation of ERK and JNK signaling pathways, and increased mRNA and/or protein expression of cytokines and chemokines, which was blocked by inhibitors of JNK and NF-kB. In addition, IsoLG promoted formation of reactive oxygen species, and induced an early activation of ER stress, followed by autophagy. Inhibition of autophagy partially reduced the pro-inflammatory effects of IsoLG, suggesting that it might serve as a cytoprotective response. / Innovation: This study is the first to describe the biological effects of IsoLG in primary HSC, the main drivers of hepatic fibrosis. / Conclusions: IsoLGs represent a newly identified class of activators of HSC in vitro, which are biologically active at concentrations as low as 500 pM, and are particularly effective at promoting a pro-inflammatory response and autophagy

Technical Note - On Matrix Exponential Differentiation with Application to Weighted Sum Distributions

In this note, we revisit the innovative transform approach introduced by Cai et al. [Cai, N., Song, Y., Kou, S., 2015. A general framework for pricing Asian options under Markov processes] for accurately approximating the probability distribution of a weighted stochastic sum or time integral under general one-dimensional Markov processes. Since then, Song et al. [Song, Y., Cai, N., Kou, S., 2018. Computable error bounds of Laplace inversion for pricing Asian options] and Cui et al. [Cui, Z., Lee, C., Liu, Y., 2018. Single-transform formulas for pricing Asian options in a general approximation framework under Markov processes] have achieved an efficient reduction of the original double to a single transform approach. We move one step further by approaching the problem from a new angle and, by dealing with the main obstacle relating to the differentiation of the exponential of a matrix, we bypass the transform inversion. We highlight the benefit from the new result by means of some numerical examples

General optimized lower and upper bounds for discrete and continuous arithmetic Asian options

We propose an accurate method for pricing arithmetic Asian options on the discrete or continuous average in a general model setting by means of a lower bound approximation. In particular, we derive analytical expressions for the lower bound in the Fourier domain. This is then recovered by a single univariate inversion and sharpened using an optimization technique. In addition, we derive an upper bound to the error from the lower bound price approximation. Our proposed method can be applied to computing the prices and price sensitivities of Asian options with fixed or floating strike price, discrete or continuous averaging, under a wide range of stochastic dynamic models, including exponential Lévy models, stochastic volatility models, and the constant elasticity of variance diffusion. Our extensive numerical experiments highlight the notable performance and robustness of our optimized lower bound for different test cases

TRAIL regulatory receptors constrain human hepatic stellate cell apoptosis

This work was funded by UCLH NIHR BRC (sample collection), Wellcome Trust Investigator award (MKM) and Clinical Research Training Fellowship (USG); Medical Research Council grant (MKM) and Clinician Scientist Fellowship (DP); EASL fellowship (IO); National Health and Medical Research Council Australia (KPS)

Fractal Profit Landscape of the Stock Market

We investigate the structure of the profit landscape obtained from the most basic, fluctuation based, trading strategy applied for the daily stock price data. The strategy is parameterized by only two variables, p and q. Stocks are sold and bought if the log return is bigger than p and less than -q, respectively. Repetition of this simple strategy for a long time gives the profit defined in the underlying two-dimensional parameter space of p and q. It is revealed that the local maxima in the profit landscape are spread in the form of a fractal structure. The fractal structure implies that successful strategies are not localized to any region of the profit landscape and are neither spaced evenly throughout the profit landscape, which makes the optimization notoriously hard and hypersensitive for partial or limited information. The concrete implication of this property is demonstrated by showing that optimization of one stock for future values or other stocks renders worse profit than a strategy that ignores fluctuations, i.e., a long-term buy-and-hold strategy.Comment: 12 pages, 4 figure

Treatment challenges in and outside a specialist network setting: Pancreatic neuroendocrine tumours

Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network

Outcomes and risk score for distal pancreatectomy with celiac axis resection (DP-CAR) : an international multicenter analysis

Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is a treatment option for selected patients with pancreatic cancer involving the celiac axis. A recent multicenter European study reported a 90-day mortality rate of 16%, highlighting the importance of patient selection. The authors constructed a risk score to predict 90-day mortality and assessed oncologic outcomes. Methods: This multicenter retrospective cohort study investigated patients undergoing DP-CAR at 20 European centers from 12 countries (model design 2000-2016) and three very-high-volume international centers in the United States and Japan (model validation 2004-2017). The area under receiver operator curve (AUC) and calibration plots were used for validation of the 90-day mortality risk model. Secondary outcomes included resection margin status, adjuvant therapy, and survival. Results: For 191 DP-CAR patients, the 90-day mortality rate was 5.5% (95 confidence interval [CI], 2.2-11%) at 5 high-volume (1 DP-CAR/year) and 18% (95 CI, 9-30%) at 18 low-volume DP-CAR centers (P=0.015). A risk score with age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, multivisceral resection, open versus minimally invasive surgery, and low- versus high-volume center performed well in both the design and validation cohorts (AUC, 0.79 vs 0.74; P=0.642). For 174 patients with pancreatic ductal adenocarcinoma, the R0 resection rate was 60%, neoadjuvant and adjuvant therapies were applied for respectively 69% and 67% of the patients, and the median overall survival period was 19months (95 CI, 15-25months). Conclusions: When performed for selected patients at high-volume centers, DP-CAR is associated with acceptable 90-day mortality and overall survival. The authors propose a 90-day mortality risk score to improve patient selection and outcomes, with DP-CAR volume as the dominant predictor

Histopathologic predictors of survival and recurrence in resected ampullary adenocarcinoma

Objective: The aim of the study was to define histopathologic characteristics that independently predict overall survival (OS) and disease-free survival (DFS), in patients who underwent resection of an ampullary adenocarcinoma with curative intent. Summary Background Data: A broad range of survival rates have been described for adenocarcinoma of the ampulla of Vater, presumably due to morphological heterogeneity which is a result of the different epitheliums ampullary adenocarcinoma can arise from (intestinal or pancreaticobiliary). Large series with homogenous patient selection are scarce. Methods: A retrospective multicenter cohort analysis of patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma in 9 European tertiary referral centers between February 2006 and December 2017 was performed. Collected data included demographics, histopathologic details, survival, and recurrence. OS and DFS analyses were performed using Kaplan–Meier curves and Cox proportional hazard models. Results: Overall, 887 patients were included, with a mean age of 66 ± 10 years. The median OS was 64 months with 1-, 3-, 5-, and 10-year OS rates of 89%, 63%, 52%, and 37%, respectively. Histopathologic subtype, differentiation grade, lymphovascular invasion, perineural invasion, T-stage, N-stage, resection margin, and adjuvant chemotherapy were correlated with OS and DFS. N-stage (HR = 3.30 [2.09–5.21]), perineural invasion (HR = 1.50 [1.01–2.23]), and adjuvant chemotherapy (HR = 0.69 [0.48–0.97]) were independent predictors of OS in multivariable analysis, whereas DFS was only adversely predicted by N-stage (HR = 2.65 [1.65–4.27]). Conclusions: Independent predictors of OS in resected ampullary cancer were N-stage, perineural invasion, and adjuvant chemotherapy. N-stage was the only predictor of DFS. These findings improve predicting survival and recurrence after resection of ampullary adenocarcinoma

Liver Volumetry Plug and Play: Do It Yourself with ImageJ

AB - BACKGROUND: A small remnant liver volume is an important risk factor for posthepatectomy liver failure and can be predicted accurately by computed tomography (CT) volumetry using radiologic image analysis software. Unfortunately, this software is expensive and usually requires support by a radiologist. ImageJ is a freely downloadable image analysis software package developed by the National Institute of Health (NIH) and brings liver volumetry to the surgeon's desktop. We aimed to assess the accuracy of ImageJ for hepatic CT volumetry. METHODS: ImageJ was downloaded from http://www.rsb.info.nih.gov/ij/ . Preoperative CT scans of 15 patients who underwent liver resection for colorectal cancer liver metastases were retrospectively analyzed. Scans were opened in ImageJ; and the liver, all metastases, and the intended parenchymal transection line were manually outlined on each slice. The area of each selected region, metastasis, resection specimen, and remnant liver was multiplied by the slice thickness to calculate volume. Volumes of virtual liver resection specimens measured with ImageJ were compared with specimen weights and calculated volumes obtained during pathology examination after resection. RESULTS: There was an excellent correlation between the volumes calculated with ImageJ and the actual measured weights of the resection specimens (r(2) = 0.98, p < 0.0001). The weight/volume ratio amounted to 0.88 +/- 0.04 (standard error) and was in agreement with our earlier findings using CT-linked radiologic software. CONCLUSION: ImageJ can be used for accurate hepatic CT volumetry on a personal computer. This application brings CT volumetry to the surgeon's desktop at no expense and is particularly useful in cases of tertiary referred patients, who already have a proper CT scan on CD-ROM from the referring institution. Most likely the discrepancy between volume and weight results from exsanguination of the liver after resectio

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty