Low-velocity impacts (LVI) on composite laminates pose significant safety issues since they are able to generate extended damage within the structure, mostly delaminations and matrix cracking, while ...being hardly detectable in visual inspections. The role of LVI tests at the coupon level is to evaluate quantities that can be useful both in the design process, such as the delamination threshold load, and in dealing with safety issues, that is correlating the internal damage with the indentation depth.
This paper aims at providing a benchmark of LVIs on quasi-isotropic carbon/epoxy laminates; 2 laminates are tested, 16 and 24 plies and a total of 8 impact energies have been selected ranging from very low energy impacts up to around 30 J. Delamination threshold loads, shape and extension of delaminations as well as post-impact 3D measurements of the impacted surface have been carried out in order to characterize the behavior of the considered material system in LVIs.
The analysis of test results relevant to the lowest energies pointed out that large contact force fluctuations, typically associated to delamination onset, occurred but ultrasonic scans did not reveal any significant internal damage. Due to these unexpected results, such tests were further investigated through a detailed FE model. The results of this investigation highlights the detrimental effects of the dissipative mechanisms of the impactor. A combined numerical–experimental approach is thus proposed to evaluate the effective impact energies.
In this work, the Huber-Hencky-Von Mises criterion for isotropic materials is integrated into a special density-based algorithm for topology optimization (TO). The algorithm makes use of (a) ...Non-Uniform Rational Basis Spline (NURBS) hyper-surfaces to represent the pseudo-density field describing the topology of the continuum and (b) the well-known Solid Isotropic Material with Penalization approach. The local behavior and the singularity of stresses are efficiently handled thanks to the NURBS blending functions properties and a suitable aggregation function. To this end, a dedicated strategy is proposed to properly update the parameters governing the behavior of the aggregation function during the iterations of the optimization process. Moreover, the gradient of the criterion is derived in closed form (in the most general case when both displacements and forces are applied as boundary conditions) by exploiting the local support property of NURBS entities. A sensitivity analysis of the optimized topology to the integer parameters of the NURBS hyper-surface is carried out. Furthermore, a manufacturing requirement related to the minimum allowable size is also integrated into the problem formulation. The effectiveness of the approach is proven on 2 D and 3 D benchmark problems taken from the literature.
The treatment of some cancer patients has shifted from traditional, non-specific cytotoxic chemotherapy to chronic treatment with molecular targeted therapies. Imatinib mesylate, a selective ...inhibitor of tyrosine kinases (TKIs) is the most prominent example of this new era and has opened the way to the development of several additional TKIs, including sunitinib, nilotinib, dasatinib, sorafenib and lapatinib, in the treatment of various hematological malignancies and solid tumors. All these agents are characterized by an important inter-individual pharmacokinetic variability, are at risk for drug interactions, and are not devoid of toxicity. Additionally, they are administered for prolonged periods, anticipating the careful monitoring of their plasma exposure via Therapeutic Drug Monitoring (TDM) to be an important component of patients’ follow-up. We have developed a liquid chromatography–tandem mass spectrometry method (LC–MS/MS) requiring 100μL of plasma for the simultaneous determination of the six major TKIs currently in use. Plasma is purified by protein precipitation and the supernatant is diluted in ammonium formate 20mM (pH 4.0) 1:2. Reverse-phase chromatographic separation of TKIs is obtained using a gradient elution of 20mM ammonium formate pH 2.2 and acetonitrile containing 1% formic acid, followed by rinsing and re-equilibration to the initial solvent composition up to 20min. Analyte quantification, using matrix-matched calibration samples, is performed by electro-spray ionization–triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<9.6%), overall process efficiency (87.1–104.2%), as well as TKIs short- and long-term stability in plasma. The method is precise (inter-day CV%: 1.3–9.4%), accurate (−9.2 to +9.9%) and sensitive (lower limits of quantification comprised between 1 and 10ng/mL). This is the first broad-range LC–MS/MS assay covering the major currently in-use TKIs. It is an improvement over previous methods in terms of convenience (a single extraction procedure for six major TKIs, reducing significantly the analytical time), sensitivity, selectivity and throughput. It may contribute to filling the current knowledge gaps in the pharmacokinetics/pharmacodynamics relationships of the latest TKIs developed after imatinib and better define their therapeutic ranges in different patient populations in order to evaluate whether a systematic TDM-guided dose adjustment of these anticancer drugs could contribute to minimize the risk of major adverse reactions and to increase the probability of efficient, long lasting, therapeutic response.
An increasing consumer demand for pomegranate has been globally observed, mainly thanks to the scientific evidence related to its functional and health-promoting features. Pomegranate fruits from ...twenty accessions identified in Southeastern Italy were characterized according to morphological and chemical features. Juices extracted from pomegranate fruits were fermented with selected
PU1 and the antioxidant activity investigated. Whey was added to juices to promote the microbial growth. Fermentation led to the increase of the radical scavenging activity (up to 40%) and significant inhibition of the linoleic acid peroxidation. The three fermented juices showing the highest antioxidant activity, and the corresponding unfermented controls, were further characterized. In detail, the cytotoxicity and the protective role toward artificially induced oxidative stress were determined on murine fibroblasts Balb 3T3 through the determination of the viability and the intracellular ROS (reactive oxygen species) scavenging activity (RSA). RSA reached values of
70% in fermented juices, being
40% higher than the unfermented and control samples. Phenols compounds of the pomegranate juices obtained from accessions "Bitonto Piscina," "Sanrà nero," and "Wonderful (reference cultivar) were analyzed through ultrahigh pressure liquid chromatography coupled with mass spectrometry, showing that a marked increase (up to 60%) of the ellagitannins derivatives occurred during fermentation. Sensory analysis showed suitability of the fermented juices to be used as beverage and food ingredient.
In this paper, a multi-scale modeling approach is proposed to determine the undamped natural frequencies of lattice structures (LSs) and the related mode shapes. At the macroscopic scale, the LS is ...modeled as an equivalent homogenized medium whose elastic properties are determined through the strain energy-based homogenization technique. The accuracy of the finite element (FE) model of the homogenized continuum (denoted as low-fidelity FE model) in predicting the undamped natural frequencies and the associated modes is assessed by comparing them to those provided by a high-fidelity FE model of the real architecture of the LS (wherein all the geometrical features of the LS are explicitly modeled). In this context, the influence of the number of representative volume elements (RVEs) to be considered at the macroscopic scale on the relative error on the natural frequencies, resulting from both FE models of the LS, is investigated. Moreover, the influence of the geometrical imperfections induced by the additive manufacturing technology on the accuracy of the low-fidelity FE model is also investigated. These analyses are carried out for different topologies of LS taken from the literature. Results highlight that the accuracy of the low-fidelity FE model in predicting the undamped natural frequencies and their related mode shapes mainly depends upon the LS RVE topology and on the number of RVEs considered at the macroscopic scale.
This open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.
Patients were ...randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary end point was progression-free survival (PFS).
In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years 95% confidence interval (CI), 2.0 to not reached with cetuximab and 2.0 years (95% CI, 1.5–2.8) with control hazard ratio (HR), 0.79; 95% CI, 0.58–1.07; P = 0.13. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2–4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52–1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31–0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64–1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.
Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.
NCT01107639
•A novel global/local finite element approach is developed.•The method makes use of the Carrera unified formulation to enhance the solution in critical areas.•Global analyses are performed with ...available finite element tools, such as Nastran and Abaqus.•By using higher-order models in critical areas, it is possible to recover accurate stress/strain fields.•The method is demonstrated to be very effective for both metallic and composite structures.
The design and analysis of aerospace structures requires a detailed evaluation of stresses. Nevertheless, the complexity of large structures and the use of composite materials can significantly increase the computational costs of the models. The computational burden of such analyses can be reduced by a suitable global/local approach developed in a very general Finite Element framework. Generally, a global/local modelling approach aims at using a finer mesh in the “local” zones where a detailed evaluation of stress/strain field is required, whereas a coarse mesh is used in the rest of the structure. This work proposes a global/local methodology to set up a high-order beam model in the Carrera Unified Formulation framework only for a reduced region of the global model. The methodology makes use of two steps. In the first step, a static analysis of the global structure is done by means of a commercial software in order to identify the critical regions deserving more accurate investigations. In the second step, thus, a high-order beam model is employed for the local region based on the information from the previous global analysis. Linear elastic static analysis are considered in this work, and the attention is mainly focussed on the capability of the method to provide stable solutions and accurate 3D stress fields in the local region, even in the case of laminated composite structures. Hence, the effectiveness of the proposed approach is proven through some meaningful benchmarks.
The estimation of the information carried by spike times is crucial for a quantitative understanding of brain function, but it is difficult because of an upward bias due to limited experimental ...sampling. We present new progress, based on two basic insights, on reducing the bias problem. First, we show that by means of a careful application of data-shuffling techniques, it is possible to cancel almost entirely the bias of the noise entropy, the most biased part of information. This procedure provides a new information estimator that is much less biased than the standard direct one and has similar variance. Second, we use a nonparametric test to determine whether all the information encoded by the spike train can be decoded assuming a low-dimensional response model. If this is the case, the complexity of response space can be fully captured by a small number of easily sampled parameters. Combining these two different procedures, we obtain a new class of precise estimators of information quantities, which can provide data-robust upper and lower bounds to the mutual information. These bounds are tight even when the number of trials per stimulus available is one order of magnitude smaller than the number of possible responses. The effectiveness and the usefulness of the methods are tested through applications to simulated data and recordings from somatosensory cortex. This application shows that even in the presence of strong correlations, our methods constrain precisely the amount of information encoded by real spike trains recorded in vivo.
Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of ...mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S.
Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments.
A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% 95% confidence interval (CI) 54–83 and 68% (95% CI 53–81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E.
No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted.
NCT01005199.
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