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To tackle the cloud-provider lock-in, the open grid forum is developing the open cloud computing interface (OCCI), a standardized interface for managing any kind of cloud resources. Besides the OCCI Core model, which defines the basic modeling elements for cloud resources, further standardized extensions exist that reflect the requirements of different cloud service levels, such as infrastructure and platform elements. However, so far the OCCI platform extension is very coarse-grained and lacks supporting use cases and implementations. Especially, it does not define how the components of the application itself can be managed. In this paper, we discuss the features of MoDMaCAO, a model-driven framework that extends the OCCI platform extension. The users of the framework are able to design and validate cloud application topologies and subsequently deploy them on OCCI compliant clouds by using configuration management tools. [ABSTRACT FROM AUTHOR]

Background and objective: Transarterial chemoembolization (TACE) is the gold standard treatment in intermediate hepatocellular carcinoma (HCC), but long-term disease control rates remain low. Herein, we compared results of TACE followed by hypofractionated radiotherapy (TACE-hRT) to surgical resection (SR) in early single or paucinodular intrahepatic HCC. Methods: Between June 2004 and November 2016, data on 160 consecutive patients with Barcelona Clinic Liver Cancer (BCLC) stage A Child–Pugh A HCC treated with SR or TACE-hRT in our expert center were retrospectively reviewed. Time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were evaluated. Clinical outcomes were compared using the stabilized-weights inverse probability of treatment weighting propensity score. Results: Ninety-eight patients underwent SR and 62 were treated by TACE-hRT. Median total dose of RT was 54 Gy (interquartile range [IQR] 54–54) in 3‑Gy fractions. Median OS follow-up was 93 months. TTP did not significantly differ between patients following SR and TACE-hRT, with 1‑year rates of 68.2% and 82.6% (p = 0.17), respectively. In contrast, PFS and OS were lower in the TACE-hRT group (p = 0.015 and p = 0.006), with a median OS of 37 vs. 63 months for patients with surgery and TACE-hRT, respectively. In multivariate analysis, a significant negative impact on PFS and OS was seen for age at diagnosis, on TTP for alcohol-related liver disease, and on OS for total number of HCC nodules. Symptomatic grade ≥ 3 adverse events were presented by 42 (42.9%) SR and 19 (30.6%) TACE-hRT patients (p = 0.17). Conclusion: In patients presenting Child–Pugh A BCLC‑A HCC with high risk for surgical complications, TACE-hRT can be an effective and safe treatment. However, surgical management remains the standard of care whenever possible. [ABSTRACT FROM AUTHOR]

With the advent of cloud computing, different cloud providers with heterogeneous cloud services (compute, storage, network, applications, etc.) and their related Application Programming Interfaces (APIs) have emerged. This heterogeneity complicates the implementation of an interoperable cloud system. Several standards have been proposed to address this challenge and provide a unified interface to cloud resources. The Open Cloud Computing Interface (OCCI) thereby focuses on the standardization of a common API for Infrastructure-as-a-Service (IaaS) providers, while the Topology and Orchestration Specification for Cloud Applications (TOSCA) focuses on the standardization of a template language to enable the proper definition of the topology of cloud applications and their orchestrations on top of a cloud system. TOSCA thereby does not define how the application topologies are created on the cloud. Therefore, we analyze the conceptual similarities between the two approaches and we study how we can integrate them to obtain a complete standard-based approach to manage both Cloud Infrastructure and Cloud application layers. We propose an automated extensive mapping between the concepts of the two standards, and we provide TOSCA Studio, a model-driven tool chain for TOSCA that conforms to OCCI. TOSCA Studio allows to graphically design cloud applications as well as to deploy and manage them at runtime using a fully model-driven cloud orchestrator based on the two standards. Our contribution is validated by successfully transforming and deploying three cloud applications: WordPress, Node Cellar and Multi-Tier. [ABSTRACT FROM AUTHOR]

Background: This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenib pretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.Methods: Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b ('3 + 3' design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).Results: In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5-74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).Conclusions: Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit-risk balance in sorafenib pretreated aHCC with MET overexpression.Trial Registration: ClinicalTrials.gov: NCT02115373. [ABSTRACT FROM AUTHOR]

Hepatitis Delta virus (HDV) is a satellite of Hepatitis B virus with a single-stranded circular RNA genome. HDV RNA genome synthesis is carried out in infected cells by cellular RNA polymerases with the assistance of the small hepatitis delta antigen (S-HDAg). Here we show that S-HDAg binds the bromodomain (BRD) adjacent to zinc finger domain 2B (BAZ2B) protein, a regulatory subunit of BAZ2B-associated remodeling factor (BRF) ISWI chromatin remodeling complexes. shRNA-mediated silencing of BAZ2B or its inactivation with the BAZ2B BRD inhibitor GSK2801 impairs HDV replication in HDV-infected human hepatocytes. S-HDAg contains a short linear interacting motif (SLiM) KacXXR, similar to the one recognized by BAZ2B BRD in histone H3. We found that the integrity of the S-HDAg SLiM sequence is required for S-HDAg interaction with BAZ2B BRD and for HDV RNA replication. Our results suggest that S-HDAg uses a histone mimicry strategy to co-activate the RNA polymerase II-dependent synthesis of HDV RNA and sustain HDV replication. Histone mimicry of viral components is a strategy to subvert host factors for virus replication. Here, the authors show that an acetylated histone-like motif of the small Hepatitis Delta Antigen (S-HDAg) interacts with the chromatin remodeler BAZ2B to recruit the DNA-dependent RNA polymerase II for HDV RNA replication. [ABSTRACT FROM AUTHOR]

Purpose: Trans-acting splicing factors (SF) shape the eukaryotic transcriptome by regulating alternative splicing (AS). This process is recurrently modulated in liver cancer suggesting its direct contribution to the course of liver disease. The aim of our study was to investigate the relationship between the regulation of SFs expression and liver damage. Methods: The expression profile of 10 liver-specific SF and the AS events of 7 genes associated with liver disorders was assessed by western-blotting in 6 murine models representing different stages of liver damage, from inflammation to hepatocellular carcinoma (HCC). Relevant SFs (PSF, SRSF3, and SRSF6) and target genes (INSR, SRSF3, and SLK) modulated in mice were investigated in a cohort of 179 HCC patients. Results: Each murine model of liver disease was characterized by a unique SF expression profile. Changes in the SF profile did not affect AS events of the selected genes despite the presence of corresponding splicing sites. In human HCC expression of SFs, including the tumor-suppressor SRSF3, and AS regulation of genes studied were frequently upregulated in tumor versus non-tumor tissues. Risk of tumor recurrence positively correlated with AS isoform of the INSR gene. In contrast, increased levels of SFs expression correlated with an extended overall survival of patients. Conclusions: Dysregulation of SF expression is an early event occurring during liver injury and not just at the stage of HCC. Besides impacting on AS regulation, overexpression of SF may contribute to preserving hepatocyte homeostasis during liver pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Sorafenib remains one major first-line therapeutic options for advanced hepatocellular carcinoma (aHCC), with modest efficacy. We investigated the addition of gemcitabine and oxaliplatin (GEMOX) to sorafenib in aHCC patients. Methods: Our multicentre phase II trial randomised aHCC first-line patients to sorafenib (400 mg BID) or sorafenib-GEMOX every 2 weeks (1000 mg/m2 gemcitabine; 100 mg/m2 oxaliplatin). Primary endpoint was the 4-month progression-free survival (PFS) rate. Results: Ninety-four patients were randomised (sorafenib-GEMOX: n = 48; sorafenib: n = 46). Median age was 64 years, PS 0 (69%) or 1 (31%), 63% patients had cirrhosis, 29% portal vein thrombosis and 70% extra-hepatic disease. Median duration of sorafenib treatment was 4 months (1–51); median number of GEMOX cycles was 7 (1–16). The 4-month PFS rates were 64% and 61% in the sorafenib-GEMOX and sorafenib arms, respectively; median PFS and OS were 6.2 (95% CI: 3.8–6.8) and 13.5 (7.5–16.2) months, and 4.6 (3.9–6.2) months and 14.8 (12.2–22.2), respectively. The ORR/DCR were 9%/70% and 15%/77% in the sorafenib-GEMOX and sorafenib alone arms, respectively. Main toxicities were (sorafenib-GEMOX/sorafenib) neutropenia (23%/0), thrombocytopenia (33%/0), diarrhoea (18%/9), peripheral neuropathy (5%/0) and hand–foot syndrome (5%/18). Conclusions: Addition of GEMOX had an inpact on ORR and was well-tolerated as frontline systemic therapy. The benefit on PFS seems moderate; no subsequent study was planned. [ABSTRACT FROM AUTHOR]

Multi-cloud computing is a promising paradigm to support very large scale world wide distributed applications. Multi-cloud computing is the usage of multiple, independent cloud environments, which assumed no priori agreement between cloud providers or third party. However, multi-cloud computing has to face several key challenges such as portability, provisioning, elasticity, and high availability. Developers will not only have to deploy applications to a specific cloud, but will also have to consider application portability from one cloud to another, and to deploy distributed applications spanning multiple clouds. This article presents soCloud a service-oriented component-based Platform as a Service for managing portability, elasticity, provisioning, and high availability across multiple clouds. soCloud is based on the OASIS Service Component Architecture standard in order to address portability. soCloud provides services for managing provisioning, elasticity, and high availability across multiple clouds. soCloud has been deployed and evaluated on top of ten existing cloud providers: Windows Azure, DELL KACE, Amazon EC2, CloudBees, OpenShift, dotCloud, Jelastic, Heroku, Appfog, and an Eucalyptus private cloud. [ABSTRACT FROM AUTHOR]

Variability management is a key issue when building and evolving software-intensive systems, making it possible to extend, configure, customize and adapt such systems to customers' needs and specific deployment contexts. A wide form of variability can be found in extensible software systems, typically built on top of plugin-based architectures that offer a (large) number of configuration options through plugins. In an ideal world, a software architect should be able to generate a system variant on-demand, corresponding to a particular assembly of plugins. To this end, the variation points and constraints between architectural elements should be properly modeled and maintained over time (i.e., for each version of an architecture). A crucial, yet error-prone and time-consuming, task for a software architect is to build an accurate representation of the variability of an architecture, in order to prevent unsafe architectural variants and reach the highest possible level of flexibility. In this article, we propose a reverse engineering process for producing a variability model (i.e., a feature model) of a plugin-based architecture. We develop automated techniques to extract and combine different variability descriptions, including a hierarchical software architecture model, a plugin dependency model and the software architect knowledge. By computing and reasoning about differences between versions of architectural feature models, software architect can control both the variability extraction and evolution processes. The proposed approach has been applied to a representative, large-scale plugin-based system (FraSCAti), considering different versions of its architecture. We report on our experience in this context. [ABSTRACT FROM AUTHOR]

Component-based software engineering has achieved wide acceptance in the domain of software engineering by improving productivity, reusability and composition. This success has also encouraged the emergence of a plethora of component models. Nevertheless, even if the abstract models of most of lightweight component models are quite similar, their programming models can still differ a lot. This drawback limits the reuse and composition of components implemented using different programming models. The contribution of this article is to introduce Fraclet as a programming model common to several lightweight component models. This programming model is presented as an annotation framework, which allows the developer to annotate the program code with the elements of the abstract component model. Then, using a generative approach, the annotated program code is completed according to the programming model of the component model to be supported by the component runtime environment. This article shows that this annotation framework provides a significant simplification of the program code by removing all dependencies on the component model interfaces. These benefits are illustrated with the F ractal and O penCOM component models. [ABSTRACT FROM AUTHOR]

The role of interferon-a (IFN-a) remains unclear in prevention of virus-induced hepatocellular carcinoma in humans. We have investigated it herewith in the X/myc transgenic mouse model of Hepadnavirus-related hepatocarcinogenesis because of upregulation of c-myc oncogene in the liver. We have demonstrated that IFN-a can downregulate dose-dependently hepatocyte proliferation and c-myc overexpression at early premalignant stages, while it does not affect either hepatocyte apoptosis or telomerase activity at these steps. However, continuous and long-term administration of IFN-a dose-dependently delays tumor onset in dysplastic livers and increases overall survival of animals, more efficiently whether started before the onset of dysplasia. The present study therefore highlights that early preventive administration of IFN-a can slow down evolution towards hepatocellular carcinoma via repression of c-myc and hepatocyte proliferation at premalignant steps in experimental c-myc-induced hepatocarcinogenesis. However, the transient effect observed in this study emphasizes a need to clarify the possible mechanisms of acquired resistance and subsequent therapeutic escape. Our experimental model may be a pertinent tool to explore antioncogenic properties of IFN-a in human cirrhotic livers showing c-myc upregulation.Oncogene (2003) 22, 2762-2771. doi:10.1038/sj.onc.1206375 [ABSTRACT FROM AUTHOR]