Clinical applications of squamous cell carcinoma antigen-immunoglobulins M to monitor chronic hepatitis C

Hepatitis C virus (HCV) is the main cause of chronic liver disease and cirrhosis in Western countries. Over time, the majority of cirrhotic patients develop hepatocellular carcinoma (HCC), one of the most common fatal cancers worldwide - fourth for incidence rate. A high public health priority need is the development of biomarkers to screen for liver disease progression and for early diagnosis of HCC development, particularly in the high risk population represented by HCV-positive patients with cirrhosis. Several studies have shown that serological determination of a novel biomarker, squamous cell carcinoma antigen-immunoglobulins M (SCCA-IgM), might be useful to identify patients with progressive liver disease. In the initial part of this review we summarize the main clinical studies that have investigated this new circulating biomarker on HCV-infected patients, providing evidence that in chronic hepatitis C SCCA-IgM may be used to monitor progression of liver disease, and also to assess the virological response to antiviral treatment. In the last part of this review we address other, not less important, clinical applications of this biomarker in hepatology

role of serpinb3 in hepatocellular carcinoma

SERPINB3 (formerly known as squamous cell carcinoma antigen-1 or SCCA1) is a member of the family of serine-protease inhibitors. SERPINB3 protects cells from oxidative stress conditions, but in chronic liver damage this serpin may lead to hepatocellular carcinoma through different strategies, including inhibition of apoptosis, induction of epithelial to mesenchymal transition and decrease of desmosomal junctions, cell proliferation and invasiveness. SERPINB3 may also contribute to tumor cell resistance to anti-neoplastic drugs through its binding to the respiratory Complex I, protecting cells from the pro-oxidant action of chemotherapeutic agents. Mechanisms of tumor growth promotion induced by SERPINB3 include the inhibition of intratumor infiltration of natural killer cells, up-regulation of Myc oncogene and the recent identification of this serpin as a Ras-responsive factor. In the liver SERPINB3 and SERPINBB4 isoforms (known as squamous cell carcinoma antigen or SCCA) are undetectable in normal hepatocytes, but their expression progressively increases in chronic liver diseases, dysplastic nodules and hepatocellular carcinoma. High SERPINB3 levels have been recently detected in HCC tissue of patients with early tumor recurrence after surgical resection. In serum SERPINB3/4 isoforms (or SCCA) are detectable bound to IgMs (SCCA-IgM) in the majority of HCV infected patients with HCC and in patients with cirrhosis their levels and/or the progressive increase have been found correlated to the risk of HCC development. Preliminary findings in patients with HCC revealed that SCCA-IgM was predictive of HCC prognosis, since low levels of this biomarker were able to identify HCC patients with long overall and progression-free survival

Analysis of distributed multi-periodic systems to achieve consistent data matching

Distributed real-time architecture of an embedded system is often described as a set of communicating components. Such a system is data flow (for its description) and time-triggered (for its execution). This work fits in with these problematics and focuses on the control of the time compatibility of a set of interdependent data used by the system components. The architecture of a component-based system forms a graph of communicating components, where more than one path can link two components. These paths may have different timing characteristics but the flows of information which transit on these paths may need to be adequately matched, so that a component uses inputs which all (directly or indirectly) depend on the same production step. In this paper, we define this temporal data-matching property, we show how to analyze the architecture to detect situations that can cause data matching inconsistencies, and we describe an approach to manage data matching that uses queues to delay too fast paths and timestamps to recognize consistent data

Persistence of extrahepatic hepatitis B virus DNA in the absence of detectable hepatic replication in patients with baboon liver transplants

The presence of hepatitis B virus (HBV) DNA in extrahepatic tissues has been well documented. Whether HBV DNA can persist in extrahepatic tissues for long periods of time in the absence of replication in the liver has not been determined previously. Recently, two patients with end‐stage liver disease secondary to chronic active HBV were treated with baboon liver xenotransplants as these animals are felt to be resistant to HBV infection. Multiple tissues from these two patients were examined for HBV DNA using polymerase chain reaction (PCR). HBV DNA was not detectable in four of five samples of the liver xenografts. A positive signal was observed in a single assay for one sample, but this sample was not positive in subsequent assays. HBV DNA was detected in peripheral blood lymphocytes, spleen, kidney, bone marrow, pancreas, lymph node, heart and small intestine. The level of HBV DNA in these tissues was too low for the detection of HBV DNA replicative intermediates by Southern hybridization; thus, it could not be determined whether the HBV DNA in these tissues represented actively replicating HBV in extrahepatic sites, integrated HBV sequences, HBV in infiltrating lymphocytes, or deposition of HBV immune complexes originating from the plasma. However, it is clear from this study that HBV DNA persisted in multiple tissues for 70 days after replication in the liver had ceased or at least was below the level of detection by PCR. © 1995 Wiley‐Liss, Inc. Copyright © 1995 Wiley‐Liss, Inc., A Wiley Compan

Association cohérente de données dans les systèmes temps réel à base de composants - Application aux logiciels spatiaux

Les architectures distribuées des systèmes embarqués sont souvent décrites sous la forme de composants concurrents communiquant entre eux. De tels systèmes sont à la fois orientés flot de données pour leur description, et dirigés par le temps pour leur exécution. Cette thèse s’inscrit dans cette problématique et se concentre sur le contrôle de la compatibilité temporelle d’un ensemble de données interdépendantes utilisées par les composants du système. L’architecture d’un système modélisé par composants forme un graphe où plusieurs chemins peuvent relier deux composants, avec des caractéristiques temporelles hétérogènes, ce qui induit des temps de parcours disparates. Il est alors important que ces flots d’information soient assemblés de façon cohérente sur le composant destinataire, c’est-à-dire de telle manière que le composant utilise en entrée des données dépendant (directement ou indirectement) du même pas d’exécution du composant à l’origine de ces flots multiples. Dans un premier temps, ce principe d’association cohérente de données est identifié et formalisé. Une méthodologie est proposée afin de détecter, dans un graphe de composants, les configurations pouvant poser des problèmes d’association de données. Dans un deuxième temps, différentes approches sont détaillées afin de gérer l’association cohérente des données dans des systèmes périodiques sans supposer de propriétés strictes sur l’ordonnancement des composants. Dans les systèmes où les composants partagent la même période et où les communications intra-périodiques sont interdites, l’association des données est gérée par un mécanisme de files permettant de rééquilibrer les temps de parcours des données sur les différents chemins. Dans le cas où les composants sont de périodes diverses, un mécanisme d’estampillage des données est utilisé afin de mémoriser les dépendances entre données. Associé à l’utilisation de files, cet estampillage permet aux composants de sélectionner, à chacune de leurs phases d’activation, des ensembles de données cohérents choisis parmi les données à leur disposition. La notion d’association cohérente est ensuite relâchée, permettant une utilisation de données approximativement cohérentes. Des files filtrantes, n’enregistrant qu’une donnée sur un certain nombre de données reçues, permettent de réduire la taille des files nécessaires. Par ailleurs, du fait de la liberté du modèle d’exécution choisi, il existe des situations où il est impossible de garantir la vivacité de l’association cohérente des données. D’autre part, une architecture particulière peut générer des contraintes de cohérence conflictuelles et aboutir à une impossibilité de gestion de la cohérence. Pour terminer, les résultats de ces travaux sont appliqués sur le logiciel applicatif d’un satellite d’observation terrestre détectant des points chauds

Association cohérente de données dans les systèmes temps réel à base de composants - Application aux logiciels spatiaux

Les architectures distribuées des systèmes embarqués sont souvent décrites sous la forme de composants concurrents communiquant entre eux. De tels systèmes sont à la fois orientés flot de données pour leur description, et dirigés par le temps pour leur exécution. Cette thèse s’inscrit dans cette problématique et se concentre sur le contrôle de la compatibilité temporelle d’un ensemble de données interdépendantes utilisées par les composants du système. L’architecture d’un système modélisé par composants forme un graphe où plusieurs chemins peuvent relier deux composants, avec des caractéristiques temporelles hétérogènes, ce qui induit des temps de parcours disparates. Il est alors important que ces flots d’information soient assemblés de façon cohérente sur le composant destinataire, c’est-à-dire de telle manière que le composant utilise en entrée des données dépendant (directement ou indirectement) du même pas d’exécution du composant à l’origine de ces flots multiples. Dans un premier temps, ce principe d’association cohérente de données est identifié et formalisé. Une méthodologie est proposée afin de détecter, dans un graphe de composants, les configurations pouvant poser des problèmes d’association de données. Dans un deuxième temps, différentes approches sont détaillées afin de gérer l’association cohérente des données dans des systèmes périodiques sans supposer de propriétés strictes sur l’ordonnancement des composants. Dans les systèmes où les composants partagent la même période et où les communications intra-périodiques sont interdites, l’association des données est gérée par un mécanisme de files permettant de rééquilibrer les temps de parcours des données sur les différents chemins. Dans le cas où les composants sont de périodes diverses, un mécanisme d’estampillage des données est utilisé afin de mémoriser les dépendances entre données. Associé à l’utilisation de files, cet estampillage permet aux composants de sélectionner, à chacune de leurs phases d’activation, des ensembles de données cohérents choisis parmi les données à leur disposition. La notion d’association cohérente est ensuite relâchée, permettant une utilisation de données approximativement cohérentes. Des files filtrantes, n’enregistrant qu’une donnée sur un certain nombre de données reçues, permettent de réduire la taille des files nécessaires. Par ailleurs, du fait de la liberté du modèle d’exécution choisi, il existe des situations où il est impossible de garantir la vivacité de l’association cohérente des données. D’autre part, une architecture particulière peut générer des contraintes de cohérence conflictuelles et aboutir à une impossibilité de gestion de la cohérence. Pour terminer, les résultats de ces travaux sont appliqués sur le logiciel applicatif d’un satellite d’observation terrestre détectant des points chauds. ABSTRACT : Distributed real time architecture of an embedded system is often described as a set of communicating components. Such a system is both data flow (for its description) and time-triggered (for its execution). This thesis fits in with these problematics and focuses on the control of the time compatibility of a set of interdependent data used by the components of the system. The architecture of a component-based system forms a graph of communicating components, where more than one path can link two components. These paths may have different timing characteristics, so information which transits on these paths takes various time to reach the final component. However, the flows of information need to be adequately matched, so that the final component uses inputs which all (directly or indirectly) depend on the same production step of the initial component. We call this property consistent data matching. The data matching property is defined and formalized. A methodology is proposed to detect, in a component graph, the architecture configurations that have to be analyzed. Several approaches are developed to manage data matching in periodic systems, without considering strict properties on the system scheduling. First, we consider systems composed by components sharing the same period and where intra-periodic communications are forbidden. Data matching is managed using queues that allows to balance the data transit times through the several paths. Then, we study systems where components have independent periods. Queues are also used and data timestamping is added to record data dependencies. Thus, a component is able, for each of its activation steps, to select consistent data sets according to data dependencies among the available input data. Data matching consistency is relaxed to allow the use of approximately consistent data sets. We use filtering queues which record only one data among a given number they receive. Their use allows to reduce the necessary queue size. Due to the loose execution model constraints, some situations exist where data matching liveliness is not guaranteed. Moreover, particular system architectures generate conflictual constraints and lead to an impossible data matching management. The thesis results are applied on the software of an earth observation satellite constellation, Fuego, which detects fires or eruptions

SERPINB3 delays glomerulonephritis and attenuates the lupus-like disease in lupus murine models by inducing a more tolerogenic immune phenotype

Objective: To explore the effects of SERPINB3 administration in murine lupus models with a focus on lupus-like nephritis. Methods: 40 NZB/W F1 mice were subdivided into 4 groups and intraperitoneally injected with recombinant SERPINB3 (7.5 \u3bcg/0.1 mL or 15 \u3bcg/0.1 mL) or PBS (0.1 mL) before (group 1 and 2) or after (group 3 and 4) the development of proteinuria ( 65100 mg/dl). Two additional mice groups were provided by including 20 MRL/lpr mice which were prophylactically injected with SERPINB3 (10 mice, group 5) or PBS (10 mice, group 6). Time of occurrence and levels of anti-dsDNA and anti-C1q antibodies, proteinuria and serum creatinine, overall- and proteinuria-free survival were assessed in mice followed up to natural death. Histological analysis was performed in kidneys of both lupus models. The Th17:Treg cell ratio was assessed by flow-cytometry in splenocytes of treated and untreated MRL/lpr mice. Statistical analysis was performed using non parametric tests and Kaplan-Meier curves, when indicated. Results: Autoantibody levels and proteinuria were significantly decreased and time of occurrence significantly delayed in SERPINB3-treated mice vs. controls. In agreement with these findings, proteinuria-free and overall survival were significantly improved in SERPINB3-treated groups vs. controls. Histological analysis demonstrated a lower prevalence of severe tubular lesions in kidneys of group 5 vs. group 6. SERPINB3-treated mice showed an overall trend toward a reduced prevalence of severe lesions in both strains. Th17:Treg ratio was significantly decreased in splenocytes of MRL/lpr mice treated with SERPINB3, compared to untreated control mice. Conclusions: SERPINB3 significantly improves disease course and delays the onset of severe glomerulonephritis in lupus-prone mice, possibly inducing a more tolerogenic immune phenotype

SERPINB3 (Serpin Peptidase Inhibitor, Clade B (Ovalbumin), Member 3)

Review on SERPINB3 (Serpin Peptidase Inhibitor, Clade B (Ovalbumin), Member 3), with data on DNA, on the protein encoded, and where the gene is implicated

Binding and Uptake into Human Hepatocellular Carcinoma Cells of Peptide-Functionalized Gold Nanoparticles

One of the most daunting challenges of nanomedicine is the finding of appropriate targeting agents to deliver suitable payloads precisely to cells affected by malignancies. Even more complex is to achieve the ability to ensure the nanosystems enter those cells. Here we use 2 nm (metal core) gold nanoparticles to target human hepatocellular carcinoma (HepG2) cells stably transfected with the SERPINB3 (SB3) protein. The nanoparticles were coated with a 85:15 mixture of thiols featuring, respectively, a phosphoryl choline, to ensure water solubility and biocompatibility, and a 28-mer peptide corresponding to the amino acid sequence 21-47 of the hepatitis B virus-PreS1 protein (PreS1(21-47)). Conjugation of the peptide was performed via the maleimide-thiol reaction in methanol allowing the use of a limited amount of the targeting molecule. This is an efficient procedure also in the perspective of selecting libraries of new targeting agents. The rationale behind the selection of the peptide is that SB3, which is undetectable in normal hepatocytes, is over-expressed in hepatocellular carcinoma and in hepatoblastoma and has been proposed as a target of the hepatitis B virus (HBV). For the latter the key recognition element is the PreS1(21-47) peptide, which is a fragment of one of the proteins composing the viral envelope. The ability of the conjugated nanoparticles to bind the target protein SB3, expressed in liver cancer cells, was investigated by surface plasmon resonance analysis and in vitro via cellular uptake analysis followed by atomic absorption analysis of digested samples. The results showed that the PreS1(21-47) peptide is a suitable targeting agent for cells overexpressing the SB3 protein. Even more important is the evidence that the gold nanoparticles are internalized by the cells. The comparison between the surface plasmon resonance analysis and the cellular uptake studies suggests the presentation of the protein on cell surface is critical for efficient recognition

The Brain on Low Power Architectures - Efficient Simulation of Cortical Slow Waves and Asynchronous States

Efficient brain simulation is a scientific grand challenge, a parallel/distributed coding challenge and a source of requirements and suggestions for future computing architectures. Indeed, the human brain includes about 10^15 synapses and 10^11 neurons activated at a mean rate of several Hz. Full brain simulation poses Exascale challenges even if simulated at the highest abstraction level. The WaveScalES experiment in the Human Brain Project (HBP) has the goal of matching experimental measures and simulations of slow waves during deep-sleep and anesthesia and the transition to other brain states. The focus is the development of dedicated large-scale parallel/distributed simulation technologies. The ExaNeSt project designs an ARM-based, low-power HPC architecture scalable to million of cores, developing a dedicated scalable interconnect system, and SWA/AW simulations are included among the driving benchmarks. At the joint between both projects is the INFN proprietary Distributed and Plastic Spiking Neural Networks (DPSNN) simulation engine. DPSNN can be configured to stress either the networking or the computation features available on the execution platforms. The simulation stresses the networking component when the neural net - composed by a relatively low number of neurons, each one projecting thousands of synapses - is distributed over a large number of hardware cores. When growing the number of neurons per core, the computation starts to be the dominating component for short range connections. This paper reports about preliminary performance results obtained on an ARM-based HPC prototype developed in the framework of the ExaNeSt project. Furthermore, a comparison is given of instantaneous power, total energy consumption, execution time and energetic cost per synaptic event of SWA/AW DPSNN simulations when executed on either ARM- or Intel-based server platforms