Methodological framework for an integrated multi-scale vulnerability and resilience assessment

The deliverable illustrates the methodological framework to assess vulnerability and resilience across different temporal and spatial scales, acknowledging the different domains where the latter may manifest, and in particular in the natural and the built environment, allocating a large importance to the so called “critical infrastructures”, in social and economic systems. A set of four matrices has been developed to identify what aspects should be looked at before the impact, that is to say what shows the potential ability or inability to cope with an extreme; at the impact, addressing in particular the capacity (or incapacity) to sustain various types of stresses (in the form of acceleration, pressure, heat…); in the time immediately after the impact, as the ability (or inability) to suffer losses and still continue functioning; and in the longer term of recovery, as the capacity to find a new state of equilibrium in which the fragilities manifested during and after the impact are addressed. Developing the framework, a particular attention has been paid to the relationships among systems within the same matrix and among matrices, across spatial and temporal scales. A set of matrices has been developed for different natural hazards, including in particular landslides and floods, trying to include as much as possible what past cases, the international literature and prior experience of involved partners have indicated as relevant parameters and factors to look at. In this regard, the project builds on the state of the art, embedding what has been learned until now in terms of response capacity to a variety of stresses and in the meantime identifying gaps to be addressed by future research

Elevated levels of plasma homocysteine in postmenopausal women

Abstract Background: Low levels of plasma homocysteine have been found in children and adult populations living in Burkina Faso in association with a low prevalence of coronary heart disease. Methods: Based on this finding, the levels of plasma homocysteine and other thiols (cysteine, cysteinylglycine, glutathione) in postmenopausal women living in Burkina Faso were evaluated with the aim of investigating whether age and life conditions influence plasma homocysteine and other thiol levels. Results: It was found that in older postmenopausal women the mean level o

A Novel GCK Large Genomic Rearrangement in a Patient with MODY-2 Detected by Clinical Exome Sequencing

Maturity-onset diabetes of the young (MODY) is a rare form of non-autoimmune diabetes with an autosomal dominant inheritance. To date, 14 genes have been reported as genetic basis of MODY. GCK gene, encoding the glucokinase enzyme, was the first MODY gene to be identified. GCK heterozygous inactivating variants cause the GCK-MODY or MODY2 subtype. However, partial or whole gene deletions have been rarely identified, showing it to be a rare cause of GCK-MODY. We reported the molecular evaluation of a Ukrainian patient with clinical diagnosis of MODY2. We performed the Next generation sequencing of the clinical exome using the Clinical Exome Solution® kit (SOPHiA Genetics), followed by the design of a 14 genes virtual panel related to the suggestive diagnosis of MODY. Bioinformatics analysis was performed using the SOPHiA DDM platform (SOPHiA Genetics). The SALSA MLPA kit for MODY (MRC-Holland) was used for relative quantification of GCK exons. From the molecular evaluation, no pathogenic sequence variants were detected in the investigated genes. Copy Number Variation analysis was able to identify a large deletion involving the last three exons of the GCK gene. This result was confirmed by MLPA. To the best of our knowledge, the identified rearrangement has never been reported in the literature

Entinostat for the treatment of breast cancer

Introduction: Breast cancer accounts for 29% of malignant tumors. It is an heterogenous disease covering a spectrum of different molecular subtypes. Epigenetic aberrations may affect gene expression through DNA and histone proteins modifications thus promoting tumor progression and resistance to anti- tumor treatment. Area covered: This article explores the potential role of entinostat in the treatment of breast cancer. The clinical trials evaluating entinostat are discussed, highlighting preclinical data and early-phase clinical studies results. The emerging activity of entinostat in several clinical settings is evaluated by focusing on endocrine-resistant, HER2 positive and triple-negative breast cancer with promising activity in boosting the immune-system. Expert opinion: Entinostat, a synthetic benzamide derivative class I histone deacetylases (HDACs) inhibitor, inhibits cell proliferation and promotes apoptosis in breast cancer. Several results from clinical trials demonstrate that the addition of an epigenetic therapy to antiestrogen therapy may be an effective approach to targeting resistance pathways in breast cancer, particularly in hormone-positive disease. Agents such as entinostat may have a role in immunogenic modulation. Genetic and pharmacological inhibition studies identified HDAC as a key determinant in the reversal of carcinoma immune escape. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines

Status and challenges for the concept design development of the EU DEMO Plant Electrical System

The EU DEMO Plant Electrical System (PES) main scopes are to supply all the plant electrical loads and to deliver to the Power Transmission Grid (PTG) the net electrical power generated. The studies on the PES during the Pre-Concept Design (PCD) Phase were mainly addressed to understand the possible issues, related to the special features both of the power generated, with respect to a power plant of the same size, and of the power to be supplied to the electrical loads. For this purpose, the approach was to start the design of the different PES components adopting technologies already utilized in fusion experiments and in Nuclear Power Plants (NPP) to verify their applicability and identify possible limits when scaled to the DEMO size and applied to the specific pulsed operating conditions. This work is not completed, however several issues have been already identified related to the pulsed operation of the turbine generator, the large amount of recirculation power, the very high peaks of active power required for the plasma formation and control, the huge reactive power demand, if thyristor converter technology was adopted to supply the superconducting coils, etc.. The paper gives an overview on the features and scope of the PES and its subsystems, on the main achievements during the Pre-Concept Design (PCD) Phase, on the challenges for the development of the conceptual design in the next framework program and on the plan to face them

Tumour-derived PGD2 and NKp30-B7H6 engagement drives an immunosuppressive ILC2-MDSC axis.

Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 and NKp30 with elevated tumour-derived PGD2 and B7H6, respectively. ILC2s, in turn, activate monocytic myeloid-derived suppressor cells (M-MDSCs) via IL-13 secretion. Upon treating APL with all-trans retinoic acid and achieving complete remission, the levels of PGD2, NKp30, ILC2s, IL-13 and M-MDSCs are restored. Similarly, disruption of this tumour immunosuppressive axis by specifically blocking PGD2, IL-13 and NKp30 partially restores ILC2 and M-MDSC levels and results in increased survival. Thus, using APL as a model, we uncover a tolerogenic pathway that may represent a relevant immunosuppressive, therapeutic targetable, mechanism operating in various human tumour types, as supported by our observations in prostate cancer.Group 2 innate lymphoid cells (ILC2s) modulate inflammatory and allergic responses, but their function in cancer immunity is still unclear. Here the authors show that, in acute promyelocytic leukaemia, tumour-activated ILC2s secrete IL-13 to induce myeloid-derived suppressor cells and support tumour growth

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Long non‐coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation

Transition from proliferative-to-invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down-regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR-depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re-expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor-initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient-rich conditions by repressing translation of selected ISR RNAs

A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form

Background: More than 90% of Congenital Adrenal Hyperplasia (CAH) cases are associated with mutations in the 21-hydroxylase gene (CYP21A2) in the HLA class III area on the short arm of chromosome 6p21.3. In this region, a 30 kb deletion produces a non functional chimeric gene with its 5′ and 3′ ends corresponding to CYP21A1P pseudogene and CYP21A2, respectively. To date, five different CYP21A1P/CYP21A2 chimeric genes have been found and characterized in recent studies. In this paper, we describe a new CYP21A1P/CYP21A2 chimera (CH-6) found in an Italian CAH patient. Methods Southern blot analysis and CYP21A2 sequencing were performed on the patient. In addition, in order to isolate the new CH-6 chimeric gene, two different strategies were used. Results: The CYP21A2 sequencing analysis showed that the patient was homozygote for the g.655C/A<G mutation and heterozygote for the p.P30L missense mutation. In addition, the promoter sequence revealed the presence, in heterozygosis, of 13 SNPs generally produced by microconversion events between gene and pseudogene. Southern blot analysis showed that the woman was heterozygote for the classic 30-kb deletion producing a new CYP21A1P/CYP21A2 chimeric gene (CH-6). The hybrid junction site was located between the end of intron 2 pseudogene, after the g.656C/A<G mutation, and the beginning of exon 3, before the 8 bp deletion. Consequently, CH-6 carries three mutations: the weak pseudogene promoter region, the p.P30L and the g.655C/A<G splice mutation. Conclusion: We describe a new CYP21A1P/CYP21A2 chimera (CH-6), associated with the HLA-B15, DR13 haplotype, in a young Italian CAH patient. © 2009 Concolino et al; licensee BioMed Central Ltd