An ontology-based secure design framework for graph-based databases

Graph-based databases are concerned with performance and flexibility. Most of the existing approaches used to design secure NoSQL databases are limited to the final implementation stage, and do not involve the design of security and access control issues at higher abstraction levels. Ensuring security and access control for Graph-based databases is difficult, as each approach differs significantly depending on the technology employed. In this paper, we propose the first technology-ascetic framework with which to design secure Graph-based databases. Our proposal raises the abstraction level by using ontologies to simultaneously model database and security requirements together. This is supported by the TITAN framework, which facilitates the way in which both aspects are dealt with. The great advantages of our approach are, therefore, that it: allows database designers to focus on the simultaneous protection of security and data while ignoring the implementation details; facilitates the secure design and rapid migration of security rules by deriving specific security measures for each underlying technology, and enables database designers to employ ontology reasoning in order to verify whether the security rules are consistent. We show the applicability of our proposal by applying it to a case study based on a hospital data access control.This work has been developed within the AETHER-UA (PID2020-112540RB-C43), AETHER-UMA (PID2020-112540RB-C41) and AETHER-UCLM (PID2020-112540RB-C42), ALBA (TED2021-130355B-C31, TED2021-130355B-C33), PRESECREL (PID2021-124502OB-C42) projects funded by the “Ministerio de Ciencia e Innovación”, Andalusian PAIDI program with grant (P18-RT-2799) and the BALLADER Project (PROMETEO/2021/088) funded by the “Consellería de Innovación, Universidades, Ciencia Sociedad Digital”, Generalitat Valenciana

Trombocitopenia inducida por tamoxifeno y letrozol

Medicin

Optimizing cryopreservation conditions for use of fucosylated human mesenchymal stromal cells in anti-inflammatory/immunomodulatory therapeutics

Mesenchymal stem/stromal cells (MSCs) are being increasingly used in cell-based therapies due to their broad anti-inflammatory and immunomodulatory properties. Intravascularly-administered MSCs do not efficiently migrate to sites of inflammation/immunopathology, but this shortfall has been overcome by cell surface enzymatic fucosylation to engender expression of the potent E-selectin ligand HCELL. In applications of cell-based therapies, cryopreservation enables stability in both storage and transport of the produced cells from the manufacturing facility to the point of care. However, it has been reported that cryopreservation and thawing dampens their immunomodulatory/anti-inflammatory activity even after a reactivation/reconditioning step. To address this issue, we employed a variety of methods to cryopreserve and thaw fucosylated human MSCs derived from either bone marrow or adipose tissue sources. We then evaluated their immunosuppressive properties, cell viability, morphology, proliferation kinetics, immunophenotype, senescence, and osteogenic and adipogenic differentiation. Our studies provide new insights into the immunobiology of cryopreserved and thawed MSCs and offer a readily applicable approach to optimize the use of fucosylated human allogeneic MSCs as immunomodulatory/anti-inflammatory therapeutics

Systematic Minigene-Based Splicing Analysis and Tentative Clinical Classification of 52 CHEK2 Splice-Site Variants

[Background]: Disrupted pre-mRNA splicing is a frequent deleterious mechanism in hereditary cancer. We aimed to functionally analyze candidate spliceogenic variants of the breast cancer susceptibility gene CHEK2 by splicing reporter minigenes.[Methods]: A total of 128 CHEK2 splice-site variants identified in the Breast Cancer After Diagnostic Gene Sequencing (BRIDGES) project (https://cordis.europa.eu/project/id/634935) were analyzed with MaxEntScan and subsetted to 52 variants predicted to impact splicing. Three CHEK2 minigenes, which span all 15 exons, were constructed and validated. The 52 selected variants were then genetically engineered into the minigenes and assayed in MCF-7 (human breast adenocarcinoma) cells.[Results]. Of 52 variants, 46 (88.5%) impaired splicing. Some of them led to complex splicing patterns with up to 11 different transcripts. Thirty-four variants induced splicing anomalies without any trace or negligible amounts of the full-length transcript. A total of 89 different transcripts were annotated, which derived from different events: single- or multi-exon skipping, alternative site-usage, mutually exclusive exon inclusion, intron retention or combinations of the abovementioned events. Fifty-nine transcripts were predicted to introduce premature termination codons, 7 kept the original open-reading frame, 5 removed the translation start codon, 6 affected the 5′UTR (Untranslated Region), and 2 included missense variations. Analysis of variant c.684-2A > G revealed the activation of a non-canonical TG-acceptor site and exon 6 sequences critical for its recognition.[Conclusions]: Incorporation of minigene read-outs into an ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology)-based classification scheme allowed us to classify 32 CHEK2 variants (27 pathogenic/likely pathogenic and 5 likely benign). However, 20 variants (38%) remained of uncertain significance, reflecting in part the complex splicing patterns of this gene.P. Devilee, M.P.G. Vreeswijk, D.F. Easton, M. de la Hoya, and E.A. Velasco-Sampedro have received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 634935. E.A. Velasco-Sampedro’s lab is supported by grants from the Spanish Ministry of Science and Innovation, Plan Nacional de I + D + I 2013–2016, ISCIII (PI20/00225) co-funded by FEDER from Regional Development European Funds (European Union) and from the Consejería de Educación, Junta de Castilla y León, ref. CSI242P18 (actuación cofinanciada P.O. FEDER 2014–2020 de Castilla y León), Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Escalera de Excelencia, Junta de Castilla y Leon (Ref. CLU-2019–2002). M. de la Hoya lab is supported by a grant from the Spanish Ministry of Science and Innovation, Plan Nacional de I + D + I 2013–2016, ISCIII (PI20/00110) co-funded by FEDER from Regional Development European Funds (European Union). D.F. Easton is supported by Government of Canada through Genome Canada and the Canadian Institutes of Health Research, The Ministère de l’Économie et de l’Innovation du Québec through Genome Québec, and by the Wellcome Trust [grant no: v203477/Z/16/Z]; E. Bueno-Martínez is a postdoctoral researcher funded by the University of Valladolid (POSTDOC-UVA05, 2022–2025). L. Sanoguera-Miralles is supported by a predoctoral fellowship from the AECC-Scientific Foundation, Sede Provincial de Valladolid (2019–2023). I. Llinares-Burguet is supported by predoctoral fellowships from the Consejería de Educación, Junta de Castilla y León (2022–2025). A. Esteban-Sánchez is supported through the Operational Program for Youth Employment and Youth Employment Initiative (YEI) of the Community of Madrid in 2020, and co-financed by the European Social Fund.Peer reviewe

Cystic Echinococcosis in Spain: Current Situation and Relevance for Other Endemic Areas in Europe

Cystic echinococcosis (CE) remains an important health problem in many regions of the world, both where no control measures have been implemented, and where control programs have been incompletely successful with ensuing re-emergence of the disease. In Spain, official data on CE show an increase in the proportion of intermediate hosts with CE during the last few years, and autochthonous pediatric patients have been reported, a sign of active local transmission of disease. A similar picture emerges from data reported to the European Food Safety Authority by other European countries. Nevertheless, several crucial aspects related to CE that would help better understand and control the disease have not been tackled appropriately, in particular the emergence of infection in specific geographical areas. In this respect, while some data are missing, other data are conflicting because they come from different databases. We review the current situation of CE in Spain compared with areas in which similar problems in the CE field exist, and offer recommendations on how to overcome those limitations. Specifically, we believe that the introduction of national registries for CE with online data entry, following the example set by the European Registry for Alveolar Echinococcosis, would help streamline data collection on CE by eliminating the need for evaluating and integrating data from multiple regions, by avoiding duplication of data from patients who access several different health facilities over time, and by providing much needed clinical and epidemiological data that are currently accessible only to clinicians

The importance of being warm (during inflation)

The amplitude of primordial curvature perturbations is enhanced when a radiation bath at a temperature T>H is sustained during inflation by dissipative particle production, which is particularly significant when a non-trivial statistical ensemble of inflaton fluctuations is also maintained. Since gravitational modes are oblivious to dissipative dynamics, this generically lowers the tensor-to-scalar ratio and yields a modified consistency relation for warm inflation, as well as changing the tilt of the scalar spectrum. We show that this alters the landscape of observationally allowed inflationary models, with for example the quartic chaotic potential being in very good agreement with the Planck results for nearly-thermal inflaton fluctuations, whilst essentially ruled out for an underlying vacuum state. We also discuss other simple models that are in agreement with the Planck data within a renormalizable model of warm inflation.Comment: 7 pages, 1 figure; added discussion and references; matches published version in Phys. Lett.

Warm baryogenesis

AbstractWe show that a baryon asymmetry can be generated by dissipative effects during warm inflation via a supersymmetric two-stage mechanism, where the inflaton is coupled to heavy mediator fields that then decay into light species through B- and CP-violating interactions. In contrast with thermal GUT baryogenesis models, the temperature during inflation is always below the heavy mass threshold, simultaneously suppressing thermal and quantum corrections to the inflaton potential and the production of dangerous GUT relics. This naturally gives a small baryon asymmetry close to the observed value, although parametrically larger values may be diluted after inflation along with any gravitino overabundance. Furthermore, this process yields baryon isocurvature perturbations within the range of future experiments, making this an attractive and testable model of GUT baryogenesis

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1