LPS-induced TNF-α factor mediates pro-inflammatory and pro-fibrogenic pattern in non-alcoholic fatty liver disease

Lipopolysaccharide (LPS) is currently considered one of the major players in non-alcoholic fatty liver disease (NAFLD) pathogenesis and progression. Here, we aim to investigate the possible role of LPS-induced TNF-α factor (LITAF) in inducing a pro-inflammatory and pro-fibrogenic phenotype of non-alcoholic steatohepatitis (NASH).We found that children with NAFLD displayed, in different liver-resident cells, an increased expression of LITAF which correlated with histological traits of hepatic inflammation and fibrosis. Total and nuclear LITAF expression increased in mouse and human hepatic stellate cells (HSCs). Moreover, LPS induced LITAF-dependent transcription of IL-1β, IL-6 and TNF-α in the clonal myofibroblastic HSC LX-2 cell line, and this effect was hampered by LITAF silencing. We showed, for the first time in HSCs, that LITAF recruitment to these cytokine promoters is LPS dependent. However, preventing LITAF nuclear translocation by p38MAPK inhibitor, the expression of IL-6 and TNF-α was significantly reduced with the aid of p65NF-ĸB, while IL-1β transcription exclusively required LITAF expression/activity. Finally, IL-1β levels in plasma mirrored those in the liver and correlated with LPS levels and LITAF-positive HSCs in children with NASH.In conclusion, a more severe histological profile in paediatric NAFLD is associated with LITAF over-expression in HSCs, which in turn correlates with hepatic and circulating IL-1β levels outlining a panel of potential biomarkers of NASH-related liver damage. The in vitro study highlights the role of LITAF as a key regulator of the LPS-induced pro-inflammatory pattern in HSCs and suggests p38MAPK inhibitors as a possible therapeutic approach against hepatic inflammation in NASH

Improved overall survival with Gemtuzumab Ozogamicin (GO) compared with best supportive care (BSC) in elderly patients with untreated acute myeloid leukemia (AML) not considered fit for intensive chemotherapy: final results from the randomized phase III study (AML-19) of the EORTC and gimema leukemia groups

peer reviewe

A Conceptual Design Optimization for a MgB2 DC Transmission Line

This work presents a tool to define an optimized architecture of DC superconducting cables realized with magnesium diboride (MgB2), aimed at minimizing the cable system costs by determining the optimal values of the geometric, physical, and operating parameters. The methodological approach is implemented in the numerical tool OSCaR, previously developed for HTS AC coaxial cables, and adapted here to the analysis of MgB2 conductors. The major updates to the original code are listed in a dedicated section of this manuscript. As an upgrade of the previous version of the model, the fluid-dynamic constraints are evaluated with an accurate modeling of the thermodynamic and thermophysical properties of the cryogenic fluid. Helium gas is selected as the cable cryogen, but the tool allows the user to select also other cryogenic fluids (e.g., liquid hydrogen). As an example of the flexibility of the proposed tool, the results of a parametric analysis are provided. The optimized costs of the cable system, distinguishing between several cost indexes, and some optimized individual design parameters of the MgB2 line are presented as a function of the delivered power

Prioritizing causal disease genes using unbiased genomic features

Background: Cardiovascular disease (CVD) is the leading cause of death in the developed world. Human genetic studies, including genome-wide sequencing and SNP-array approaches, promise to reveal disease genes and mechanisms representing new therapeutic targets. In practice, however, identification of the actual genes contributing to disease pathogenesis has lagged behind identification of associated loci, thus limiting the clinical benefits. Results: To aid in localizing causal genes, we develop a machine learning approach, Objective Prioritization for Enhanced Novelty (OPEN), which quantitatively prioritizes gene-disease associations based on a diverse group of genomic features. This approach uses only unbiased predictive features and thus is not hampered by a preference towards previously well-characterized genes. We demonstrate success in identifying genetic determinants for CVD-related traits, including cholesterol levels, blood pressure, and conduction system and cardiomyopathy phenotypes. Using OPEN, we prioritize genes, including FLNC, for association with increased left ventricular diameter, which is a defining feature of a prevalent cardiovascular disorder, dilated cardiomyopathy or DCM. Using a zebrafish model, we experimentally validate FLNC and identify a novel FLNC splice-site mutation in a patient with severe DCM. Conclusion: Our approach stands to assist interpretation of large-scale genetic studies without compromising their fundamentally unbiased nature. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0534-8) contains supplementary material, which is available to authorized users

The ALICE Zero Degree Calorimeters

In the ALICE experiment at Cern LHC, a set of hadron calorimeters will be used to determine the centrality of the Pb-Pb collision. The spectator protons and neutrons, will be separated from the ion beams, using the separator magnet (D1) of the LHC beam optics and respectively detected by a proton (ZP) and a neutron (ZN) "Zero-degree Calorimeter" (ZDC). The detectors will be placed in front of the separator D2 magnet, 115 meters away from the beam intersection point. The ZDCs are quartz-fiber spaghetti calorimeters that exploit the Cherenkov light produced by the shower particles in silica optical fibers.This technique offers the advantages of high radiation hardness (up to several Grad), fast response and reduced lateral dimension of the detectable shower. In addition, quartz-fiber calorimeters are intrinsically insensitive to radio-activation background, which produces particles below the Cherenkov threshold.The ALICE ZDC should have an energy resolution comparable with the intrinsic energy fluctuations, which range from about 20 0.000000or central events to about 5 0.000000or peripheral ones, according to simulations that use HIJING as event generator. The fiber-to-absorber filling ratio must be chosen as a good compromise between the required energy resolution and the fiber cost.The design of the proposed calorimeter will be discussed, together with the expected performances. Whenever possible, the simulated results will be compared with the experimental ones, obtained with the built prototypes and with the NA50 ZDC, which can be considered as a working prototype for the ALICE neutron calorimeter

Decentralizing Electric Vehicle Supply Chains: Value Proposition and System Design

Distributed ledger technologies are transforming existing business models and business relationships. In particular, blockchain allows non-trusting parties to manage a shared database in a decentralized way and improve the transparency, authenticity, and reliability of the exchanged data. Nonetheless, decentralized paradigms are not yet well established, resulting in only a fraction of blockchain-based applications being successful in the long term.In this paper, we present a blockchain-based solution for the electric vehicle supply chain that we designed in the context of the CONCORDIA project of the European Cybersecurity Competence Network. We describe the goals, the value proposition, the main design choices, and the architecture of our system. Moreover, we discuss the electric vehicle supply chain, analyzing the improvements and limitations introduced by our blockchain-based solution. We analyze our solution from the managerial and technical points of view through a lean business methodology for blockchain solutions. In particular, we developed an economic impact assessment to evaluate the potential costs and revenues of the application of blockchain technology in a supply chain context. Although the blockchain system is inspired by the supply chain of a multinational automotive company, it can be applied to any other multi-actor supply chain

Quartz fiber calorimetry

The fundamentals of a new electromagnetic and hadronic sampling calorimetry based on the detection of Cherenkov light generated in quartz optical fibers are presented. Optical fibers transport light only in a selected angular range which results in a non-obvious and absolutely unique characteristic for this new technique: showers of very narrow visible energy. In addition, the technique is characterized by radiation resistance measured in Gigarads and nanosecond signal duration. Combined, these properties make quartz fiber calorimetry a very promising technique for high intensity heavy ion experiments and for the high pseudorapidity regions of high intensity collider experiments. The results of beam tests and simulations are used to illustrate the basic properties and peculiar characteristics of this recent development

Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation

BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme