The A2B adenosine receptor modulates the epithelial- mesenchymal transition through the balance of cAMP/PKA and MAPK/ERK pathway activation in human epithelial lung cells

The epithelial-mesenchymal transition (EMT) is a complex process in which cell phenotype switches from the epithelial to mesenchymal one. The deregulations of this process have been related with the occurrence of different diseases such as lung cancer and fibrosis. In the last decade, several efforts have been devoted in understanding the mechanisms that trigger and sustain this transition process. Adenosine is a purinergic signaling molecule that has been involved in the onset and progression of chronic lung diseases and cancer through the A2Badenosine receptor subtype activation, too. However, the relationship between A2BAR and EMT has not been investigated, yet. Herein, the A2BAR characterization was carried out in human epithelial lung cells. Moreover, the effects of receptor activation on EMT were investigated in the absence and presence of transforming growth factor-beta (TGF-β1), which has been known to promote the transition. The A2BAR activation alone decreased and increased the expression of epithelial markers (E-cadherin) and the mesenchymal one (Vimentin, N-cadherin), respectively, nevertheless a complete EMT was not observed. Surprisingly, the receptor activation counteracted the EMT induced by TGF-β1. Several intracellular pathways regulate the EMT: high levels of cAMP and ERK1/2 phosphorylation has been demonstrated to counteract and promote the transition, respectively. The A2BAR stimulation was able to modulated these two pathways, cAMP/PKA and MAPK/ERK, shifting the fine balance toward activation or inhibition of EMT. In fact, using a selective PKA inhibitor, which blocks the cAMP pathway, the A2BAR-mediated EMT promotion were exacerbated, and conversely the selective inhibition of MAPK/ERK counteracted the receptor-induced transition. These results highlighted the A2BAR as one of the receptors involved in the modulation of EMT process. Nevertheless, its activation is not enough to trigger a complete transition, its ability to affect different intracellular pathways could represent a mechanism at the basis of EMT maintenance/inhibition based on the extracellular microenvironment. Despite further investigations are needed, herein for the first time the A2BAR has been related to the EMT process, and therefore to the different EMT-related pathologies

RET mutated C-cells proliferate more rapidly than non-mutated neoplastic cells

A statistically significant higher prevalence of the RET p.Met918Thr somatic mutation, identified by direct sequencing, was previously reported in MTC >2 cm than in smaller tumors. Aim of this study was to correlate the full RET and RAS mutation profile, identified by a Next Generation Sequencing approach, with the growth rate, proliferation and tumor size of MTC. Data of 149 sporadic MTC patients were correlated with RET mutations and Ki67 positivity. Eighty-one cases had a somatic RET mutation, 40 a RAS mutation and 28 were negative. A statistically significant higher prevalence of RET mutations was found in MTC >2 cm. A higher prevalence of RET more aggressive mutations, higher allelic frequencies and, higher percentage of Ki67 positive cells were found in larger tumors which had also a worse outcome. Our study highlights the predominant role of RET somatic mutations in MTC tumorigenesis. We demonstrate that RET mutation prevalence and allelic frequency (AF) are significantly higher in larger tumors. Based on these results, we can conclude that RET mutated C-cells's growth and proliferation are more rapid than those of non-mutated cells and give origin to bigger and more aggressive MTC

Structured reporting for fibrosing lung disease: a model shared by radiologist and pulmonologist

Objectives: To apply the Delphi exercise with iterative involvement of radiologists and pulmonologists with the aim of defining a structured reporting template for high-resolution computed tomography (HRCT) of patients with fibrosing lung disease (FLD). Methods: The writing committee selected the HRCT criteria\ue2\u80\u94the Delphi items\ue2\u80\u94for rating from both radiology panelists (RP) and pulmonology panelists (PP). The Delphi items were first rated by RPs as \ue2\u80\u9cessential\ue2\u80\u9d, \ue2\u80\u9coptional\ue2\u80\u9d, or \ue2\u80\u9cnot relevant\ue2\u80\u9d. The items rated \ue2\u80\u9cessential\ue2\u80\u9d by < 80% of the RP were selected for the PP rating. The format of reporting was rated by both RP and PP. Results: A total of 42 RPs and 12 PPs participated to the survey. In both Delphi round 1 and 2, 10/27 (37.7%) items were rated \ue2\u80\u9cessential\ue2\u80\u9d by more than 80% of RP. The remaining 17/27 (63.3%) items were rated by the PP in round 3, with 2/17 items (11.7%) rated \ue2\u80\u9cessential\ue2\u80\u9d by the PP. PP proposed additional items for conclusion domain, which were rated by RPs in the fourth round. Poor consensus was observed for the format of reporting. Conclusions: This study provides a template for structured report of FLD that features essential items as agreed by expert thoracic radiologists and pulmonologists

Novel shape parametrization technique applied to the optimization of a supersonic ORC turbine cascade

Shape-optimization techniques are nowadays an essential tool in the design chain of turbomachinery to strike the highperformance targets demanded by modern applications. Although the geometric parametrization may affect significantly the optimization cost and ultimately the optimization outcome, the selection of control points and of the subsequent design space is usually based on heuristic considerations. This paper proposes a cost-efficient parametrization procedure based on the ANOVA analysis of B-Spline control points. To tackle the extremely large computational burden arisen from the use of several control points, a surrogate strategy is implemented, testing four different methods. The optimization relies on surrogate-assisted evolutionary strategies coupled with an experimentally validated CFD solver. The technique is applied to a supersonic Organic Rankine Cycle turbine cascade, which features a converging-diverging bladed channel. It is shown that only the diverging section of the suction side as well as the adjacent region of unguided turning have the major impact on the aerodynamic performance. These findings enable to select an optimal distribution of mobile control points in the optimization block, leading to significant savings in computational cost. Finally, three optimizations are carried out, varying locally the number of control points; results are widely discussed in terms of both optimization outcomes and optimizer robustness

Design and off-design analysis of a highly loaded centrifugal compressor for sCO2 applications operating in near-critical conditions

The closed gas cycle based on supercritical carbon dioxide (sCO2) is a promising solution to realize highly efficient power systems arranged in compact devices. However, the technical feasibility of these so-called sCO2 power systems relies on the development of non-conventional components, whose features are dictated by the peculiar character of the working fluid. The compressor is a key component of the system and its design demands the set-up of novel guidelines, due to the near-critical thermodynamic condition of the fluid, which (i) makes the machine operate with a very low flow function, (ii) experiences steep changes in properties across the machine, and (iii) is prone to phase-change in the intake part of the machine. In this study we revise the entire design workflow of a prototype sCO2 centrifugal compressor, from the preliminary definition of the machine, to the mean-line design, and finally to the detailed definition of the meridional channel and of the blade shape, highlighting the aspects making the machine alternative to conventional ones. The compressor aerodynamics is then analyzed by resorting to a high-fidelity Computational Fluid Dynamics (CFD) model in both design and off-design conditions, considering three speed-lines and low/high flow rate margins. Results show the capabilities and limitations of conventional low-fidelity design procedures for designing sCO2 compressors, especially at off-design conditions, and shed light on the technical implications of the thermodynamic character of the fluid, especially in connection to the onset of phase change in the intake region of the impeller and in the tip clearance

Il paradigma semiotico nelle scienze umane. : Intervista con Paolo Fabbri (Istituto Universitario di Lingue Moderne, Milano).

Corpus "Sémiotique - Sémiologie"In questa intervista Paolo Fabbri intreccia il suo percorso intellettuale con lo sviluppo della semiotica.La necessità di formalizzare il discorso giuridico, l’incontro con Roland Barthes e le istanze di demistificazione dell’ideologia, il lavoro con Algirdas J. Greimas e l’obiettivo di studiare il senso nelle sue articolazioni in un quadro teorico rigoroso e con un metalinguaggio interdefinito.Nell'intervista vengono presentati alcuni dei concetti più rilevanti della semiotica e il suo ruolo rispetto alle altre scienze umane. Infine vengono indicate possibili linee di sviluppo della ricerca. Paolo FABBRI, Professore di Semiotica e Semiotica dell'Arte allo IUAV - Istituto Universitario di Archittettura di Venezia, è uno dei principali esponenti della semiotica di tradizione greimasiana e lo studioso che più l'ha diffusa in Italia.Il suo lavoro, che affronta i problemi del linguaggio, dell'arte, della comunicazione, è sempre volto a sviluppare una teoria semiotica coerente e interdefinita

Assessment of deterministic shape optimizations within a stochastic framework for supersonic organic rankine cycle nozzle cascades

The design of converging-diverging blades for organic Rankine cycle (ORC) applications widely relies on automated shape-optimization processes. As a result, the optimization produces an adapted-nozzle cascade at the design conditions. However, only few works account for the uncertainties in those conditions and their consequences on cascade performance. The proposed solution, i.e., including uncertainties within the optimization routine, demands an overall huge computational cost to estimate the target output statistic at each iteration of the optimization algorithm. With the aim of understanding if this computational cost is avoidable, we study the impact of uncertainties in the design conditions on the robustness of deterministically optimized profiles. Several optimized blades, obtained with different objective functions, constraints, and design variables, are considered in the present numerical analysis, which features a turbulent compressible flow solver and a state-of-the-art uncertainty-quantification (UQ) method. By including measured field variations in the formulation of the UQ problem, we show that a deterministic shape optimization already improves the robustness of the profile with respect to the baseline configuration. Guidelines about objective functions and blade parametrizations for deterministic optimizations are also provided. Finally, a novel methodology to estimate the mass-flow-rate probability density function (PDF) for choked supersonic turbines is proposed, along with a robust reformulation of the constraint problem without increasing the computational cost

High-Fidelity Shape Optimization of Non-Conventional Turbomachinery by Surrogate Evolutionary Strategies

This paper presents a novel tool for the shape optimization of turbomachinery blade profiles operating with fluids in non-ideal thermodynamic conditions and in complex flow configurations. In novel energy conversion systems, such as organic Rankine cycles or supercritical CO2 cycles, the non-conventional turbomachinery layout as well as the complex thermodynamics of the working fluid complicate significantly the blade aerodynamic design. For such applications, the design of turbomachinery may considerably benefit from the use of systematic optimization methods, especially in combination with high-fidelity computational fluid dynamics (CFD), as it is shown in this paper. The proposed technique is implemented in the shape-optimization package FORMA (Fluid-dynamic OptimizeR for turbo-Machinery Aerofoils) developed in-house at the Politecnico di Milano. FORMA is constructed as a combination of a generalized geometrical parametrization technique based on B-splines, a CFD solver featuring turbulence models and arbitrary equations of state, and multiple surrogate-based evolutionary strategies based on either trust-region or training methods. The application to the re-design of a supersonic turbine nozzle shows the capabilities of applying a high-fidelity optimization, consisting of a 50% reduction in the cascade loss coefficient and in an increased flow uniformity at the inlet of the subsequent rotor. Two alternative surrogate-based evolutionary strategies and different fitness functions are tested and discussed, including nonlinear constraints within the design process. The optimization study reveals relevant insights into the design of supersonic turbine nozzles as well on the performance, reliability, and potential of the proposed design technique