Model Driven Engineering and Dependability Analyses: The Topcased Approach

International audienceModel Driven Engineering approaches are widely promoted to overcome difficulties to design, validate and maintain large complex systems. They present interesting dependability characteristics especially in terms of prevention of design faults and validation of design correctness. However industrial needs, practices and applicable standards impose constraints on the dependability activities to perform and justify. Therefore it is necessary to analyze how a complete dependability and safety process can be integrated with model-driven approaches within a seamless global process: which dependability activities are naturally covered or facilitated by model-driven approaches, and which additional activities are needed with which support. This paper presents the results of a study aiming at the establishment of requirements to model-driven engineering methods and tools, to support dependability analyses

Spin Read-out of the Motion of Levitated Electrically Rotated Diamonds

Recent advancements with trapped nano- and micro-particles have enabled the exploration of motional states on unprecedented scales. Rotational degrees of freedom stand out due to their intrinsic non-linearity and their coupling with internal spin degrees of freedom, opening up possibilities for gyroscopy and magnetometry applications and the creation of macroscopic quantum superpositions. However, current techniques for fast and reliable rotation of particles with internal spins face challenges, such as optical absorption and heating issues. Here, to address this gap, we demonstrate electrically driven rotation of micro-particles levitating in Paul traps. We show that micro-particles can be set to rotate stably at 150,000 rpm by operating in a hitherto unexplored parametrically driven regime using the particle electric quadrupolar moment. Moreover, the spin states of nitrogen-vacancy centers in diamonds undergoing full rotation were successfully controlled, allowing accurate angular trajectory reconstruction and demonstrating high rotational stability over extended periods. These achievements mark progress toward interfacing full rotation with internal magnetic degrees of freedom in micron-scale objects. In particular, it extends significantly the type of particles that can be rotated, such as ferromagnets, which offers direct implications for the study of large gyromagnetic effects at the micro-scale

keynote 412 phase iii study of pembrolizumab plus chemoradiation vs chemoradiation alone for locally advanced head and neck squamous cell carcinoma hnscc

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Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3 , with a selective decrease of C36:2 PI-3,4,5-P3 . Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution

A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors

Phosphatidylinositol 3-kinase (PI3K) pathway activation is associated with resistance to paclitaxel in solid tumors. We assessed the safety and activity of alpelisib, an oral, selective PI3K p110\u3b1 inhibitor, plus paclitaxel in patients with advanced solid tumors. This Phase Ib, multicenter, open-label, dose-finding study, with a planned dose-expansion phase of alpelisib once daily (QD) plus fixed-dose paclitaxel, recruited patients with advanced solid tumors. For the dose-finding phase, the primary objective was determination of maximum tolerated and/or recommended Phase II dose of alpelisib plus paclitaxel, and the secondary objectives included the assessment of safety for this combination. From March 2014 to August 2016, 19 patients with advanced solid tumors were treated with alpelisib QD (300 mg, n=6; 250 mg, n=4; 150 mg, n=9) plus paclitaxel (80 mg/m2, per standard of care). During dose finding, five of 12 (41.7%) evaluable patients for MTD determination experienced dose-limiting toxicities: alpelisib 300 mg, Grade 2 hyperglycemia (n=1); alpelisib 250 mg, Grade 2 hyperglycemia (n=1), Grade 4 hyperglycemia and Grade 3 acute kidney injury (n=1); and alpelisib 150 mg, Grade 2 hyperglycemia (n=1) and Grade 4 leukopenia (n=1). The MTD of alpelisib when administered with paclitaxel was 150 mg QD. Most frequent all-grade AEs were diarrhea (73.7%; Grade 3/4 10.5%) and hyperglycemia (57.9%; Grade 3/4 31.6%). The planned dose-expansion phase was not initiated. Alpelisib plus paclitaxel has a challenging safety profile in patients with advanced solid tumors. This study was closed following the completion of the dosefinding phase. Clinical trial registration: ClinicalTrials.gov NCT02051751