List of requirements on formalisms and selection of appropriate tools

This deliverable reports on the activities for the set-up of the modelling environments for the evaluation activities of WP5. To this objective, it reports on the identified modelling peculiarities of the electric power infrastructure and the information infrastructures and of their interdependencies, recalls the tools that have been considered and concentrates on the tools that are, and will be, used in the project: DrawNET, DEEM and EPSys which have been developed before and during the project by the partners, and M\uf6bius and PRISM, developed respectively at the University of Illinois at Urbana Champaign and at the University of Birmingham (and recently at the University of Oxford)

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis

We previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention

Methodologies synthesis

This deliverable deals with the modelling and analysis of interdependencies between critical infrastructures, focussing attention on two interdependent infrastructures studied in the context of CRUTIAL: the electric power infrastructure and the information infrastructures supporting management, control and maintenance functionality. The main objectives are: 1) investigate the main challenges to be addressed for the analysis and modelling of interdependencies, 2) review the modelling methodologies and tools that can be used to address these challenges and support the evaluation of the impact of interdependencies on the dependability and resilience of the service delivered to the users, and 3) present the preliminary directions investigated so far by the CRUTIAL consortium for describing and modelling interdependencies

Mirror system of the RICH detector of the NA62 experiment

A large RICH detector is used in NA62 to suppress the muon contamination in the charged pion selection by a factor 100 in the momentum range between 15 and 35 GeV/c. The detector consists of a 17 m long tank (vessel), filled with neon gas at atmospheric pressure. Cherenkov light is reflected by a mosaic of 20 spherical mirrors with 17 m focal length, placed at the downstream end, and collected by 1952 photomultipliers (PMTs) placed at the upstream end. In this paper the characterization of the mirrors before installation and the mirror support system are described. The mirror installation procedure and the laser alignment are also illustrated

The Improvement of Durability of Reinforced Concretes for Sustainable Structures: A Review on Different Approaches

The topic of sustainability of reinforced concrete structures is strictly related with their durability in aggressive environments. In particular, at equal environmental impact, the higher the durability of construction materials, the higher the sustainability. The present review deals with the possible strategies aimed at producing sustainable and durable reinforced concrete structures in different environments. It focuses on the design methodologies as well as the use of unconventional corrosion-resistant reinforcements, alternative binders to Portland cement, and innovative or traditional solutions for reinforced concrete protection and prevention against rebars corrosion such as corrosion inhibitors, coatings, self-healing techniques, and waterproofing aggregates. Analysis of the scientific literature highlights that there is no preferential way for the production of “green” concrete but that the sustainability of the building materials can only be achieved by implementing simulta-neous multiple strategies aimed at reducing environmental impact and improving both durability and performances

Advances in preclinical therapeutics development using small animal imaging and molecular analyses: the gastrointestinal stromal tumors model

The large use of target therapies in the treatment of gastrointestinal stromal tumors (GISTs) highlighted the urgency to integrate new molecular imaging technologies, to develop new criteria for tumor response evaluation and to reach a more comprehensive definition of the molecular target. These aspects, which come from clinical experiences, are not considered enough in preclinical research studies which aim to evaluate the efficacy of new drugs or new combination of drugs with molecular target. We developed a xenograft animal model GIST882 using nude mice. We evaluated both the molecular and functional characterization of the tumor mass. The mutational analysis of KIT receptor of the GIST882 cell lines and tumor mass showed a mutation on exon 13 that was still present after in vivo cell growth. The glucose metabolism and cell proliferation was evaluated with a small animal PET using both FDG and FLT. The experimental development of new therapies for GIST treatment requires sophisticated animal models in order to represent the tumor molecular heterogeneity already demonstrated in the clinical setting and in order to evaluate the efficacy of the treatment also considering the inhibition of tumor metabolism, and not only considering the change in size of tumors. This approach of cancer research on GISTs is crucial and essential for innovative perspectives that could cross over to other types of cancer

Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor

In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents

Vaccination with human anti-trastuzumab anti-idiotype scFv reverses HER2 immunological tolerance and induces tumor immunity in MMTV.f.huHER2(Fo5) mice

International audienceINTRODUCTION: Novel adjuvant therapies are needed to prevent metastatic relapses in HER2-expressing breast cancer. Here, we tested whether trastuzumab-selected single-chain Fv (scFv) could be used to develop an anti-idiotype-based vaccine to inhibit growth of HER2-positive tumor cells in vitro and in vivo through induction of long-lasting HER-specific immunity. METHODS: BALB/c mice were immunized with anti-trastuzumab anti-idiotype (anti-Id) scFv (scFv40 and scFv69), which mimic human HER2. Their sera were assessed for the presence of HER2-specific Ab1' antibodies and for their ability to reduce viability of SK-OV-3 cells, a HER2-positive cancer cell line, in nude mice. MMTV.f.huHER2(Fo5) transgenic mice were immunized with scFv40 and scFv69 and, then, growth inhibition of spontaneous HER2-positive mammary tumors, humoral response, antibody isotype as well as splenocyte secretion of IL2 and IFN-γ were evaluated. RESULTS: Adoptively-transferred sera from BALB/c mice immunized with scFv40 and scFv69 contain anti-HER2 Ab1' antibodies that can efficiently inhibit growth of SK-OV-3 cell tumors in nude mice. Similarly, prophylactic vaccination with anti-Id scFv69 fully protects virgin or primiparous FVB-MMTV.f.huHER2(Fo5) females from developing spontaneous mammary tumors. Moreover, such vaccination elicits an anti-HER2 Ab1' immune response together with a scFv69-specific Th1 response with IL2 and IFN-γ cytokine secretion. CONCLUSIONS: Anti-trastuzumab anti-Id scFv69, used as a therapeutic or prophylactic vaccine, protects mice from developing HER2-positive mammary tumors by inducing both anti-HER2 Ab1' antibody production and an anti-HER2 Th2-dependent immune response. These results suggest that scFv69 could be used as an anti-Id-based vaccine for adjuvant therapy of patients with HER2-positive tumors to reverse immunological tolerance to HER2