5,894 research outputs found
Letter to the editor concerning “Liver transplantation for metastatic wild-type gastrointestinal stromal tumor in the era of molecular targeted therapies: Report of a first case"
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SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update
Loss of function of the succinate dehydrogenase complex characterizes 20-40% of all KIT/PDGFRA-negative GIST. Approximately half of SDH-deficient GIST patients lack SDHx mutations and are caused by a hypermethylation of the SDHC promoter, which causes the repression of SDHC transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and SDHA mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically. SDHB, SDHC, and SDHD mutations in GIST occur in only 20-30% of cases and most of these SDH mutations are germline. More recently, germline mutations in SDHA have also been described in several patients with loss of function of the SDH complex. SDHA-mutant patients usually carry two mutational events at the SDHA locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding SDHA-mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor SDHA somatic mutations, and offers a view towards understanding the importance of genetic counselling for SDHA-variant carriers and relatives
Numerical simulation and experimental validation of fatigue behavior of wood-glass fiber composite T joint
In this paper, a numerical FE model is developed with ANSYS and validated by experimental tests to identify possible
damage locations and fatigue breakage in different wood-glass fiber composite T-joints for marine applications. Both
static and fatigue tests in three-point bending configuration have been performe
Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases
The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer
Preclinical Models of Visceral Sarcomas
Visceral sarcomas are a rare malignant subgroup of soft tissue sarcomas (STSs). STSs, accounting for 1% of all adult tumors, are derived from mesenchymal tissues and exhibit a wide heterogeneity. Their rarity and the high number of histotypes hinder the understanding of tumor development mechanisms and negatively influence clinical outcomes and treatment approaches. Although some STSs (~20%) have identifiable genetic markers, as specific mutations or translocations, most are characterized by complex genomic profiles. Thus, identification of new therapeutic targets and development of personalized therapies are urgent clinical needs. Although cell lines are useful for preclinical investigations, more reliable preclinical models are required to develop and test new potential therapies. Here, we provide an overview of the available in vitro and in vivo models of visceral sarcomas, whose gene signatures are still not well characterized, to highlight current challenges and provide insights for future studies
Modelling of national and local interactions between heat and electricity networks in low-carbon energy systems
Decarbonisation of the heating and cooling sector is critical for achieving long-term energy and climate change objectives. Closer integration between heating/cooling and electricity systems can provide additional flexibility required to support the integration of variable renewables and other low-carbon energy sources. This paper proposes a framework for identifying cost-efficient solutions for supplying district heating systems within both operation and investment timescales, while considering local and national-level interactions between heat and electricity infrastructures. The proposed optimisation model minimises the levelised cost of a portfolio of heating technologies, and in particular Combined Heat and Power (CHP) and polygeneration systems, centralised heat pumps (HPs), centralised boilers and thermal energy storage (TES). A number of illustrative case studies are presented, quantifying the impact of renewable penetration, electricity price volatility, local grid constraints and local emission targets on optimal planning and operation of heat production assets. The sensitivity analysis demonstrates that the cost-optimal TES capacity could increase by 41–134% in order to manage a constraint in the local electricity grid, while in systems with higher RES penetration reflected in higher electricity price volatility it may be optimal to increase the TES capacity by 50–66% compared to constant prices, allowing centralised electric HP technologies to divert excess electricity produced by intermittent renewable generators to the heating sector. This confirms the importance of reflecting the whole-system value of heating technologies in the underlying cost-benefit analysis of heat networks
Thermo-economic assessment of flexible nuclear power plants in the UK’s future low-carbon electricity system: role of thermal energy storage
Nuclear power plants are commonly operated as baseload units due to their low variable costs, high investment costs and limited ability to modulate their output. The increasing penetration of intermittent renewable power will require additional flexibility from conventional generation units, in order to follow the fluctuating renewable output while guaranteeing security of energy supply. In this context, coupling nuclear reactors with thermal energy storage could ensure a more continuous and efficient operation of nuclear power plants, while at other times allowing their operation to become more flexible and cost-effective. This study considers options for upgrading a 1610-MWel nuclear power plant with the addition of a thermal energy storage system and secondary power generators. The analysed configuration allows the plant to generate up to 2130 MWel during peak load, representing an increase of 32% in nominal rated power. The gross whole-system benefits of operating the proposed configuration are quantified over several scenarios for the UK’s low-carbon electricity system. Replacing conventional with flexible nuclear plant configuration is found to generate system cost savings that are between £24.3m/yr and £88.9m/yr, with the highest benefit achieved when stored heat is fully discharged in 0.5 hours (the default case is 1 hour). At an estimated cost of added flexibility of £42.7m/yr, the proposed flexibility upgrade to a nuclear power plant appears to be economically justified for a wide range of low-carbon scenarios, provided that the number of flexible nuclear units in the system is small
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Computer-aided working-fluid design, thermodynamic optimisation and technoeconomic assessment of ORC systems for waste-heat recovery
The wider adoption of organic Rankine cycle (ORC) technology can be facilitated by improved thermodynamic performance and reduced costs. In this context the power system should be evaluated based on a thermeconomic assessment with the aim of improving economic viability. This paper couples the computer- aided molecular design (CAMD) of the working-fluid with thermodynamic modelling and optimisation, in addition to heat-exchanger sizing models, component cost correlations, and a thermoeconomic assessment. The proposed CAMD-ORC framework, based on the SAFT-γ Mie equation of state, allows the thermodynamic optimisation of the cycle and working-fluid in a single stage, thus removing subjective and pre-emptive screening criteria that would otherwise exist in conventional studies. Following validation, the framework is used to identify optimal working-fluids for three different heat sources (150, 250 and 350 °C), corresponding to small- to medium-scale applications. In each case, the optimal combination of working-fluid and ORC system is identified, and investment costs are evaluated. It is observed that fluids with low specific-investment costs (SIC) are different to those that maximise power output. The fluids with the lowest SIC are isoheptane, 2-pentene and 2-heptene, with SICs of 5,620, 2,760 and 2,070 £/kW respectively, and corresponding power outputs of 32.9, 136.6 and 213.9 kW
Signaling response to transient redox stress in human isolated T cells: Molecular sensor role of syk kinase and functional involvement of IL2 receptor and L-selectine
Reactive oxygen species (ROS) are central effectors of inflammation and play a key role in cell signaling. Previous reports have described an association between oxidative events and the modulation of innate immunity. However, the role of redox signaling in adaptive immunity is still not well understood. This work is based on a novel investigation of diamide, a specific oxidant of sulfhydryl groups, and it is the first performed in purified T cell tyrosine phosphorylation signaling. Our data show that ex vivo T cells respond to –SH group oxidation with a distinctive tyrosine phosphorylation response and that these events elicit specific cellular responses. The expression of two essential T-cell receptors, CD25 and CD62L, and T-cell cytokine release is also affected in a specific way. Experiments with Syk inhibitors indicate a major contribution of this kinase in these phenomena. This pilot work confirms the presence of crosstalk between oxidation of cysteine residues and tyrosine phosphorylation changes, resulting in a series of functional events in freshly isolated T cells. Our experiments show a novel role of Syk inhibitors in applying their anti-inflammatory action through the inhibition of a ROS-generated reaction
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