Is existing legislation fit-for-purpose to achieve Good Environmental Status in European seas?

Recent additions to marine environmental legislation are usually designed to fill gaps in protection and management, build on existing practices or correct deficiencies in previous instruments. Article 13 of the European Marine Strategy Framework Directive (MSFD) requires Member States to develop a Programme of Measures (PoM) by 2015, to meet the objective of Good Environmental Status (GES) for their waters by 2020. This review explores key maritime-related policies with the aim to identify the opportunities and threats that they pose for the achievement of GES. It specifically examines how Member States have relied on and will integrate existing legislation and policies to implement their PoM and the potential opportunities and difficulties associated with this. Using case studies of three Member States, other external impediments to achieving GES are discussed including uses and users of the marine environment who are not governed by the MSFD, and gives recommendations for overcoming barriers

Parallel computation of the reachability graph of petri net models with semantic information

Formal verification plays a crucial role when dealing with correctness of systems. In a previous work, the authors proposed a class of models, the Unary Resource Description Framework Petri Nets (U-RDF-PN), which integrated Petri nets and (RDF-based) semantic information. The work also proposed a model checking approach for the analysis of system behavioural properties that made use of the net reachability graph. Computing such a graph, specially when dealing with high-level structures as RDF graphs, is a very expensive task that must be considered. This paper describes the development of a parallel solution for the computation of the reachability graph of U-RDF-PN models. Besides that, the paper presents some experimental results when the tool was deployed in cluster and cloud frameworks. The results not only show the improvement in the total time required for computing the graph, but also the high scalability of the solution, which make it very useful thanks to the current (and future) availability of cloud infrastructures

Análisis de workflows científicos mediante el paradigma de las U-RDF-PN

La computación científica ha ganado un creciente interés en los últimos años en áreas afines a las ciencias de la vida. Los workflows científicos son un tipo especial de workflow utilizados en escenarios de grandes dimensiones y gran complejidad computacional, como modelos climáticos, estructuras biológicas, química, cirugía o simulación de desastres, por ejemplo. La computación científica ha mejorado progresivamente a través de la introducción de nuevos paradigmas y tecnologías para poder abordar desafíos cada vez más complejos. Esta línea de investigación se centra en la adición de aspectos semánticos al área de la computación científica, aportando un método de model checking basado en la introducción de aspectos y anotaciones semánticas tanto en los modelos como en las fórmulas que deben verificarse. La adición de aspectos semánticos flexibiliza la especificación y facilita la integración de servicios remotos y heterogéneos. Como punto de partida, el desarrollo del toolkit COMBAS (COmprobador de Modelos Basado en Semántica) proporciona un entorno que integra herramientas para la verificación de modelos que incluyen información semántica y la navegación por las estructuras resultante del proceso. Para la descripción de modelos de workflows científicos se utiliza una clase de Redes de Petri de alto nivel anotadas con información semántica, las U-RDF-PN, en las que el Grupo de Integración de Sistemas Distribuidos y Heterogéneos (GIDHE), donde el autor desarrolla su línea de investigación, tiene una amplia y demostrada experiencia. Finalmente, el enfoque propuesto se aplicará a una serie de problemas reales de relevancia en el mundo científico para demostrar su utilidad y viabilidad

New Gravity Map of the Western Galicia Margin:The Spanish Exclusive Economic Zone Project

Since 1995, the most intensive mapping of the seafloor off the Spanish coast has been carried out in the framework of the Spanish Exclusive Economic Zone Project (ZEEE).The main objectives of this project are to obtain improved multibeam bathymetric cartography of the areas off Spanish coastlines, and to perform a geophysical survey,well-suited with a 10-knot navigation velocity (some techniques requires lower navigation velocity). The geophysical survey includes gravity, geomagnetism, and low-penetration seismic techniques in order to infer the geological structure of the seafloor. Other oceanographic variables such as current, surface salinity, and temperature profiles, can be recorded without compromising this systematic survey effort. The ZEEE Project has carried out its survey activities for one month every year.Data acquisition is achieved aboard the Spanish R/V Hesperides. Until 1997, surveying efforts concentrated on the Balearic Sea and Valencia Gulf, both in the western Mediterranean Sea. Between 1998 and 2000, the ZEEE Project investigations were conducted offshore the Canary Archipelago. Since 2001, the third phase of the program has been focused on the West Galicia Margin in the northeastern Atlantic Ocean. Survey results on the West Galicia Margin area are of interest for two key reasons. First, there is great scientific interest in the improvement of the knowledge of this non-volcanic rifting margin, since this margin offers good conditions for the study of the processes that take place in this type of geological context,because it is sediment-starved. Second, the obtained results also have major socioeconomic repercussions because they can prove significant to defining the expansion of the Spanish shelf,beyond Spain’s Economic Exclusive Zone distance of 200 nautical miles. All of the gravity data acquired to date on this area have been stored as a database, with the aim of preparing gravity anomaly maps on a scale 1:200,000.The database and gravity anomaly charts from the ZEEE Project will provide the most coherent and complete gravity perspective available for this area. This article describes the efforts and accomplishments of the project to date

Circulating HPV DNA as a Biomarker for Pre-Invasive and Early Invasive Cervical Cancer: A Feasibility Study

BACKGROUND: High-risk HPV infection is responsible for >99% of cervix cancers (CC). In persistent infections that lead to cancer, the tumour breaches the basement membrane, releasing HPV-DNA into the bloodstream (cHPV-DNA). A next-generation sequencing assay (NGS) for detection of plasma HPV circulating DNA (cHPV-DNA) has demonstrated high sensitivity and specificity in patients with locally advanced cervix cancers. We hypothesised that cHPV-DNA is detectable in early invasive cervical cancers but not in pre-invasive lesions (CIN). METHODS: Blood samples were collected from patients with CIN (n = 52) and FIGO stage 1A-1B CC (n = 12) prior to treatment and at follow-up. DNA extraction from plasma, followed by NGS, was used for the detection of cHPV-DNA. RESULTS: None of the patients with pre-invasive lesions were positive for CHPV-DNA. In invasive tumours, plasma from one patient (10%) reached the threshold of positivity for cHPV-DNA in plasma. CONCLUSION: Low detection of cHPV-DNA in early CC may be explained by small tumour size, poorer access to lymphatics and circulation, and therefore little shedding of cHPV-DNA in plasma at detectable levels. The detection rate of cHPV-DNA in patients with early invasive cervix cancer using even the most sensitive of currently available technologies lacks adequate sensitivity for clinical utility

Efficient Genotyping of KRAS Mutant Non-Small Cell Lung Cancer Using a Multiplexed Droplet Digital PCR Approach

© 2015 Pender et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Droplet digital PCR (ddPCR) can be used to detect low frequency mutations in oncogenedriven lung cancer. The range of KRAS point mutations observed in NSCLC necessitates a multiplex approach to efficient mutation detection in circulating DNA. Here we report the design and optimisation of three discriminatory ddPCR multiplex assays investigating nine different KRAS mutations using PrimePCRddPCRMutation Assays and the Bio-Rad QX100 system. Together these mutations account for 95% of the nucleotide changes found in KRAS in human cancer. Multiplex reactions were optimised on genomic DNA extracted from KRAS mutant cell lines and tested on DNA extracted from fixed tumour tissue from a cohort of lung cancer patients without prior knowledge of the specific KRAS genotype. The multiplex ddPCR assays had a limit of detection of better than 1 mutant KRAS molecule in 2,000 wild-type KRAS molecules, which compared favourably with a limit of detection of 1 in 50 for next generation sequencing and 1 in 10 for Sanger sequencing. Multiplex ddPCR assays thus provide a highly efficient methodology to identify KRAS mutations in lung adenocarcinoma

Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study

Introduction Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC + pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. Methods This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. Results From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). Conclusions Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC + PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet

Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: A randomized clinical trial

This article has been accepted for publication in Clinical Infectious Diseases ©2014 The Authors .Published by Oxford University Press on Clinical Infectious Disease 60.5. DOI: 10.1093/cid/ciu898Background. It is unclear whether metabolic or body composition effects may differ between protease inhibitor-based regimens recommended for initial treatment of HIV infection. Methods. ATADAR is a phase IV, open-label, multicenter randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Pre-defined end-points were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. Results. At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95%CI -0.6 to 21.6); and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95%CI -0.5 to 17.6). Seven vs. five patients discontinued atazanavir/ritonavir or darunavir/ritonavir due to adverse effects. Total and HDL cholesterol similarly increased in both arms, but triglycerides increased more in atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95%CI 726.7 to 4997.7; P=0.0090), limb fat (estimated difference 1403.3 gr; 95%CI 388.4 to 2418.2; P=0.0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm2; 95%CI 1.9 to 55.0; P=0.0362) increased more in atazanavir/ritonavir than in darunavir/ritonavir arm. Body fat changes in atazanavir/ritonavir arm were associated with higher insulin resistance. Conclusions. We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically-relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and total and subcutaneous fat than darunavir/ritonavir and fat gains with atazanavir/ritonavir were associated with insulin resistanceThis is an Investigator Sponsored Research study. It was supported in part by research grants from Bristol‐Myers Squibb and Janssen‐Cilag; Instituto de Salud Carlos III (PI12/01217) and Red Temática Cooperativa de Investigación en SIDA G03/173 (RIS‐EST11), Ministerio de Ciencia e Innovación, Spain. (Registration number: NCT01274780; registry name: ATADAR; EUDRACT; 2010‐021002‐38)

Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES

Background: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane. Patients and methods: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated. Results: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29–23.70) for a change from 1st quartile (Q1) to Q1–Q3 and HR of 15.54 (95% CI 3.70–65.24) for a change from Q1 to Q4. Conclusion: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2–3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2–3 years and who remain disease-free after 2–3 years

Genomic profile of advanced breast cancer in circulating tumour DNA.

The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities