CERVANTES: A Model-Based Approach for Service-Oriented Systems Development

Context: The benefits of the Model-Driven Software Engineering application for Service-Oriented Computing. Objective: This paper proposes a Model-Based approach for Service-Oriented Systems Development. Method: Following the Model-Driven Reverse Engineering process, from the models discovery, to the generation of the current Model-Based Approach for Service-Oriented Systems Development. Results: The CERVANTES metamodel is presented and compared to other initiatives. Conclusions: This study shows how Model-Driven Engineering can be used to develop Service Oriented Systems in practice

Studying sporadic and familial Alzheimer's disease on iPSC-derived hippocampal and cortical neurons: effect of APOE and Presenilin1

Alzheimer's disease (AD) is pathologically characterised by the presence of amyloid-beta plaques, neurofibrillary tangles containing hyperphosphorylated Tau protein, neuroinflammation and neuronal death leading to progressive cognitive impairment. The ¿4 allele of the gene encoding apolipoprotein E (APOE), which is mainly expressed in glial cells, is the strongest genetic risk factor for sporadic AD. Increasing evidence has shown that APOE4 may disrupt normal astrocyte activity, potentially contributing to AD pathology, but the impact of different APOE alleles on astrocyte differentiation, maturation and function is not yet fully understood. To go in depth on these questions, we obtained induced pluripotent stem cells (iPSCs) from fibroblasts of AD patients carrying ¿3 and ¿4 alleles (in homozygosis) and from healthy patients. We also used gene-edited iPSC lines homozygous for the main APOE variants and an APOE knock-out line. iPSC-derived human astrocytes were generated by establishing a differentiation protocol through the consecutive addition of small molecules and growth factors, and the expression of typical markers (GFAP, GLT1, AQP4 and S100beta) and APOE was analysed. In addition, astrocytes exhibited functional features like glutamate uptake capacity and calcium waves production. They also responded to an inflammatory stimulus (IL-1beta and TNF-alpha) or to the presence of amyloid-beta 1-42 peptide by changing their morphology and increasing the expression levels of pro-inflammatory factors and cytokines. Our results shed light on the potential dual role of APOE polymorphism and the individual¿s genetic background in favouring or perhaps preventing AD pathology

Emerging risk factors and the dose-response relationship between physical activity and lone atrial fibrillation: a prospective case-control study

A history of a parts per thousand yen2000 h of vigorous endurance training, tall stature, abdominal obesity, and OSA are frequently encountered as risk factors in patients with Ln-AF. Fewer than 2000 total hours of high-intensity endurance training associates with reduced Ln-AF risk

Galician consensus on management of cardiotoxicity in breast cancer: risk factors, prevention, and early intervention

This Galician consensus statement is a joint oncologists/cardiologists initiative indented to establish basic recommendations on how to prevent and to manage the cardiotoxicity in breast cancer with the aim of ensuring an optimal cardiovascular care of these patients. A clinical screening of the patients before treatment is recommended to stratify them into a determined risk group based on their intrinsic cardiovascular risk factors and those extrinsic arose from breast cancer therapy, thereby providing individualized preventive and monitoring measures. Suitable initial and ongoing assessments for patients with low and moderate/high risk and planned treatment with anthracyclines and trastuzumab are given; also, measures aimed at preventing and correcting any modifiable risk factor are pointed out .TEVA Farma Españ

Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma

The NADPH oxidase NOX4 has been proposed as necessary for the apoptosis induced by the Transforming Growth Factor-beta (TGF-I3) in hepatocytes and hepatocellular carcinoma (HCC) cells. However, whether NOX4 is required for TGF-I3-induced canonical (SMADs) or non-canonical signals is not fully understood yet, neither its potential involvement in other parallel actions induced by TGF-I3. In this work we have used CRISPR Cas9 technology to stable attenuate NOX4 expression in HCC cells. Results have indicated that NOX4 is required for an efficient SMAD2/3 phosphorylation in response to TGF-I3, whereas non-canonical signals, such as the phos-phorylation of the Epidermal Growth Receptor or AKT, are higher in NOX4 silenced cells. TGF-I3-mediated in-hibition of cell proliferation and viability is attenuated in NOX4 silenced cells, correlating with decreased response in terms of apoptosis, and maintenance of high expression of MYC and CYCLIN D1. These results would indicate that NOX4 is required for all the tumor suppressor actions of TGF-I3 in HCC. However, analysis in human HCC tumors has revealed a worse prognosis for patients showing high expression of TGF-I31-related genes concomitant with high expression of NOX4. Deepening into other tumorigenic actions of TGF-I3 that may contribute to tumor progression, we found that NOX4 is also required for TGF-I3-induced migratory effects. The Epithelial-Mesenchymal transition (EMT) program does not appear to be affected by attenuation of NOX4 levels. However, TGF-I3-mediated regulation of cytoskeleton dynamics and focal adhesions require NOX4, which is necessary for TGF-I3-induced increase in the chaperone Hsp27 and correct subcellular localization of Hic-5 within focal adhesions, as well for upregulation of the metalloprotease MMP9. All these results together point to NOX4 as a key element in the whole TGF-I3 signaling in HCC cells, revealing an unknown role for NOX4 as tumor promoter in HCC patients presenting activation of the TGF-I3 pathway

Health-related quality of life with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor–positive metastatic breast cancer: Patient-reported outcomes in the PEARL study

Background: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes. Patients and methods: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively. Results: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4–8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55–0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale. Conclusion: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated. Trial registration number: NCT02028507 (ClinTrials.gov). EudraCT study number: 2013-003170-27. © 2021 The Author(s

Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients

In order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis

«Derecho, poder y libertad» a propósito de las batallas por la autonomía jurisdiccional entre las Audiencias del Cusco y Charcas (1820-1825)

As of 1820 and after the invasion of San Martin, the Peruvian judicial system had to adapt to the de facto disappearance of the High Court of Lima, as well as to the model that had been designed by the Constitution of 1812 and the Magistrate and High Court Code of 9 October, 1812. This paper analyzes said process and the ensuing tension resulting from the High Courts of Cusco and Charcas having to solve procedural problems, but paying special attention to the debates and actors, especially lawyers, that constituted the Hispanic judicial culture during the Three-Year Liberal Period in the viceroyship of Peru, supposing that said reality extended to the national construction of Peru and Bolivia.A partir de 1820 y tras la invasión de San Martín, el sistema judicial peruano tuvo que adecuarse a la desaparición de facto de la Audiencia de Lima y al modelo diseñado por la Constitución de 1812 y el Reglamento de las Audiencias y Juzgados de primera instancia del 9 de octubre de 1812. El artículo analiza tal proceso y las tensiones generadas cuando las Audiencias Nacionales de Cusco y Charcas hubieron de resolver problemas de procedimiento, pero sobre todo se ahonda en los debates y actores, abogados fundamentalmente, que conformaron la cultura jurídica hispana durante el Trienio Liberal en el virreinato del Perú, asumiendo que tal realidad trascendió en la construcción nacional del Perú y Bolivia

Precise measurement of the W-boson mass with the CDF II detector

We have measured the W-boson mass MW using data corresponding to 2.2/fb of integrated luminosity collected in proton-antiproton collisions at 1.96 TeV with the CDF II detector at the Fermilab Tevatron collider. Samples consisting of 470126 W->enu candidates and 624708 W->munu candidates yield the measurement MW = 80387 +- 12 (stat) +- 15 (syst) = 80387 +- 19 MeV. This is the most precise measurement of the W-boson mass to date and significantly exceeds the precision of all previous measurements combined

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO