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Background In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed–platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed–platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed–platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab. Patients and methods Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators’ choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed–platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS. Results After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed–platinum continued to improve OS [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69] and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed–platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed–platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed–platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed–platinum and 66.8% of patients receiving placebo plus pemetrexed–platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off. Conclusions Pembrolizumab plus pemetrexed–platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed–platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed–platinum in patients with previously untreated metastatic nonsquamous NSCLC.

In this paper the seismic response of a multi-storey reinforced concrete (RC) building base isolated by lead rubber bearings (LRBs) is compared with the seismic response of the same structure base isolated by an innovative seismic isolator which we called high damping hybrid seismic isolator (HDHSI). The study is performed in the context of passive structural control and seismic base isolation technique for the earthquake resistance of RC buildings. This novel high damping hybrid seismic isolator (HDHSI) is obtained by the assembly in series of a lead rubber bearing (LRB) and a friction slider (FS) characterized by a high friction coefficient. The base isolation system is realized by elastomeric materials and steel-teflon bearings. The nonlinear behavior of the composite devices is investigated by reporting a detailed analysis of the hysteretic cycles of the isolators. The purpose of the analysis is to highlight the features offered by the proposed HDHSI base isolation system compared to the traditional LRB base isolation system in the seismic protection of structures. Nonlinear dynamic analyses are performed for base isolated multi-storey RC structures. In the analysis the inputs of different seismic events are adopted which can be considered as extreme events in terms of peak ground acceleration and in terms of frequency content. The seismic records are related to seismic events obtained by suitably amplifying the El Centro earthquake. They are characterized by their high values of the peak ground acceleration. Another seismic event considered in the analysis is the Erzincan earthquake which is characterized by high energetic content at low frequencies. Accordingly, the seismic events adopted in the analysis are characterized by anomalous values of intensity and frequency content. A nonlinear dynamic analysis is illustrated for a multi-storey RC building base isolated by the proposed HDHSI system compared with the traditional LRB base isolation system. The time history of the base shear and the time history of the base displacement of the superstructure are illustrated for the different analyzed seismic events. The benefits of the presented composite HDHSI base isolation system are shown to be appropriate in conferring a suitable seismic protection to multi-storey RC buildings even under extreme seismic events.

Titanium dioxide (TiO2) is a well-known biocompatible material with important applications in many fields of biomedicine. Here we show our results on the development of a new TiO2 based sol-gel system that can act as negative tone resist for both ultraviolet (UV) and electron beam (EB) lithographies. The system allows the direct patterning of high resolution structures (down to 40nm). Moreover, it allows the preparation of nanopatterned nanoporous TiO2 simply by changing the conditions of resist development. The presented system can be used as functional tool for the systematic investigation of cell behavior with respect to a complex topographic texture of the substrate (cell guidance). TiO2 structures of different dimensions, geometries and nanoporosity, whose size ranges from a few hundred to a few tens nanometer, are obtained after UV and/or EB lithography. The adhesion of different cell lines, i.e., human osteosarcoma (HOS) and neuroblastoma (N2A), on the patterns is assessed and our results show that cells have a preference for TiO2 patterns with respect to glass. Display Omitted A new formula directly patternable nanoporous TiO2 resist is presented.The gel is sensitive to both UV and electron beam exposure.The system can be prepared with smooth and porous morphology.Complex structures with different geometries and morphologies can be achieved.The system can be used in cell guidance experiments.

Droplets with colloidal biological suspensions evaporating on substrates with defined wetting properties generate confined environments for initiating aggregation and self-assembly processes. We describe smart micro- and nanostructured surfaces, optimized for probing single droplets and residues by synchrotron radiation micro- and nanobeam diffraction techniques. Applications are presented for Ac-IVD and β-amyloid (1–42) peptides capable of forming cross-β sheet structures. Complementary synchrotron radiation FTIR microspectroscopy addresses secondary structure formation. The high synchrotron radiation source brilliance enables fast raster-scan experiments.

The excitation of plasmonic Fano resonances leads to a dual advantage in nano-photonics, in terms of local field enhancement and far-field spectral selectivity. Nevertheless, a remarkable challenge related to the hybridization between bright and dark plasmonic modes, i.e. between the two elements cooperating to the Fano resonance generation, consists in the sub-wavelength activation of dark modes via near-field channel. In this regard, strongly coupled plasmonic nano-assemblies are ideal systems providing a highly efficient way towards their excitation. Here, we analyze two trimer nano-architectures supporting respectively electric and magnetic Fano resonances. The different approaches employed for describing the two systems highlighted the role that the near-field coupling and the LSPs de-phasing separately play in the Fano hybridization phenomena.

Resume Introduction Determiner des facteurs predictifs de bonne reponse au crosslinking (CXL) dans la prise en charge du keratocone evolutif. Patients et methodes Cinquante-quatre yeux de 41 patients ont beneficie d’un CXL entre juin 2011 et decembre 2012 pour keratocone evolutif. Un examen clinique ophtalmologique avec une topographie corneenne (Orbscan ® ) est realise a 1, 3, 6 mois, 1 an en postoperatoire et compare a l’examen preoperatoire. Resultats A un an, le CXL permet une amelioration significative de la meilleure acuite visuelle corrigee (MAVC) (0,16 ± 0,21 LogMar en preoperatoire versus 0,09 ± 0,16 LogMar a 1 an, p = 0,007), une stabilite de l’astigmatisme refractif (AR) ( p = 0,69), une amelioration significative de l’astigmatisme irregulier topographique des 3 mm centraux ( p = 0,04), et une stabilite du Kmax (48,4 D ± 4,1 en preoperatoire versus 48,5 D ± 4,1 a 1 an, p = 0,46). Les facteurs predictifs d’amelioration postoperatoire de MAVC sont, en preoperatoire, une MAVC faible, un AR eleve et un keratocone evolue. Les facteurs predictifs de stabilite du Kmax postoperatoire sont un keratocone preoperatoire peu evolue, et principalement localise dans les 3 mm centraux. Conclusion Cette etude retrospective confirme l’interet et l’efficacite du CXL dans la prise en charge therapeutique d’un keratocone evolutif, tant sur le plan refractif que topographique. La localisation du cone ou son excentricite semble etre un facteur expliquant la variabilite des resultats bibliographiques d’efficacite du CXL. La severite du cone apparait dans cette etude comme etant un facteur predictif de mauvaise reponse topographique au CXL, mais devant etre pondere par la localisation preferentielle du cone (3 ou 5 mm centraux).

Display Omitted An approach for the fabrication of hybrid nanostructures has been proposed.ZnO flowers have been grown selectively on the top of gold nanopillars.Raman analysis have shown that ZnO presents a wurtzite structure.Such systems could find application in photocatalysis or energy harvesting. We fabricated flower-like shaped ZnO nanorods on the apexes of hollow gold nanopillars by Focused Ion Beam lithography and hydrothermal growth. The hollow nanopillar geometry was defined on a photoresist by ion-beam induced inversion and subsequently metalized. Then the bottom section of the pillars was protected by a second resist coating, exposing only the nanopillar tips for hydrothermal growth of ZnO. The wurtzite crystalline structure of the ZnO nanorods that composes the flowers was confirmed by Raman spectroscopy. Such novel 3D hybrid metal semiconductor nanostructures are promising materials for catalysis and energy harvesting.

Graphical abstractDisplay Omitted Highlights? We use a microfluidic chamber to investigate the cell rolling. ? We examine changes of cell behavior according to the hydrodynamic parameters. ? We schematize the cell behavior from firm adhesion to free rolling regime with the shear stress. ? We model the cell rolling accounting the adhesion force represented by a linear spring. ? The good fitting between numerical and experimental describes the cell behavior. Here we present a model and an experimental investigation to study cell bound to the floor of a microfluidic system and the flow induced detachment. The experimental investigation has been performed by a microfluidic assay biofunctionalized with specific antibodies. The upregulation of the cell membrane density of specific antigens has been exploited to detect and concentrate cells using hydrodynamic forces. The numerical model explored the role that the hydrodynamic forces have on adhesion-detachment of cell to the biofunctionalized substrate. To account the adhesion force, the cell receptor-surface ligand interaction has been represented by a linear spring exerting adhesive force on the target cell. The experimental investigation with the W6/32, an antibody that binds specifically to MHC class I molecule and which has an important role in the recognition of the tumor cells from the immune system, has been simulated by the numerical model with a constant spring Ks=7.5i?10-8N/s. The velocity of cells and of the fluid and the experimental capture yield have been compared. The existence of three different regimes of cell behavior has been shown, moving from firm adhesion to free rolling. Up to 30µl/s the cells experience the adherent rolling, whilst at higher flow rate the cells start to move with the fluid in a regime of free rolling. The model provides physical insight, explaining apparently counterintuitive features of the prototype assay data.

Silver nanoparticles (NPs) aggregates with an overall size in the nano meter range were fabricated employing non conventional electroless techniques. The structure of the aggregates was analyzed through direct SEM and AFM imaging; space-frequency based variables, including fractal dimension, were extracted in order to yield a quantitative measurement of the topography of the systems at study. These observations were explained within the framework of diffusion limited aggregation (DLA). DLA theory founds upon the paradigm that, in the limit of very fast chemical reactions, diffusion is the sole driving force that regulates the dynamics of aggregation of NPs. The mathematical model confirmed the experimental findings whereby the fractal dimension of the clusters is size dependent, that is, larger systems are more discontinuous than smaller. The model would also predict that, under certain conditions, a characteristic length exists beyond which the fractal dimension is constant. DLA theory is consistent and predictive in nature, and may be of valuable help in designing devices that utilize rough metal surfaces and the derived effects thereof, including SERS substrates.

In this paper we present numerical FDTD calculations, optimizing experimental setup conditions for surface plasmon polariton (SPP) generation. The simulation considers a silver nanocone placed on a Si"3N"4 membrane, and studies the effects on the apex for a linearly polarized Gaussian light beam impinging from below or from the side of the cone. Radially polarized focused beams already proved to generate efficiently SPPs; in this work, we show that also linear polarization leads to an efficient generation of SPPs on the cone surface, as long as tilt angle and numeric aperture are optimized. In particular, we show that our setup conditions and proposed device, designed for a @l=633nm linearly polarized He-Ne laser, can enhance the incoming electric field up to 150 times at the apex of the cone.

Superhydrophobic surfaces were fabricated comprising cylindrical micro-pillars arranged in a regular hexagonal lattice. These structures are hierarchical in that the pillars incorporate, on the top, nanoporous silicon films. In sight of the superhydrophobicity of the system, the devices retain the ability of manipulating and concentrating diluted biological solutions, while, on account of the nanoporous films, they would efficiently filter the biological content of such solutions. The major advance, here, is the simultaneous use of the properties above, and thus important applications are envisioned where extremely small quantities of bio-markers are efficiently extracted from serum and analyzed employing conventional and well assessed spectroscopy techniques. Ultra low concentrated small Rhodamine molecules were here efficiently analyzed using FTIR spectroscopy techniques, thus demonstrating that these devices are effective.

In this work we report, for the first time to our knowledge, the possibility to fabricate various structures, with good optical proprieties, on the top of optical fibers, using the two-photon lithography (TPL) technique. We show the convenience of this approach to quickly create generic 3D shapes using a single set-up by contrast to past shape-dependent methods. A set of different structures are fabricated and characterized to demonstrate the versatility of this approach and their high optical quality.

We present the first results of microstructure replica with re-usable masters in poly vinyl alcohol (PVA). Microneedles of heights ranging from 500 to 1100@mm were fabricated through double-exposure deep X-ray lithography (DXRL) process and successfully replicated. A single PVA master was used as a template to successfully replicate up to 10 PMMA microneedle arrays, suggesting that this method might be a possible alternative to PDMS processes. A preliminary characterization of the relationship between the surface roughness of the substrates and the force required for demoulding was also performed.

Although the degradation of Pentacene-based thin-film-transistors upon exposure to air has been widely observed, the degradation mechanism is not completely understood. We report a straightforward mass spectrometry investigation of Pentacene thin film oxidation upon exposure to air, mimicking the degradation of the transistor in its operational environment. We found that only a concomitant presence of humidity, oxygen, and light can produce a significant oxidation. Several oxidation products, including impurities of the starting material, are clearly identified and their percentage roughly estimated. The collected data cannot be fully explained with through conventional reaction mechanisms, suggesting that a more complicated scenario involving water, oxygen, and light should be studied.

We report on the interactions between spin-coated pentacene films and molecules present in air (nitrogen, oxygen, and moisture) studied by means of micro-Raman spectroscopy. We found that while oxygen does not interact with pentacene, water molecules diffuse in the film proportionally to the relative humidity of the ambient, giving rise to an interaction that affects pentacene’s optical properties. These findings are fully reversible when dry ambient is restored, and they could be ascribed to the formation of a reversible water–pentacene complex theoretically calculated. This interaction affects a specific pentacene vibration mode that could lead to reversible formation of electron traps involved in the degradation of the electrical performance of pentacene.

Polymer pyrolysis to nanoceramics is employed for the production of photo-luminescent thin film samples, consisting of Si-nanocrystals dispersed in silica matrix. Thin films were deposited on Si wafer by spin-coating technique from a triethoxysilane-derived sol–gel solution. This is a fast process and a low cost technique. Samples were annealed at different temperatures between 600 °C and 1300 °C, under N 2 gas atmosphere. Structural evolution and luminescence from Si-ncs vs. temperature were investigated by FT-IR absorption spectroscopy and photo-luminescence. Absorption spectrum of As-Prep sample shows several vibrational bands due to Si–H, C–H x , and Si–O–Si structural units, without any appreciable luminescence. Silica phase segregation and intense PL (790 nm) due to Si-ncs were observed on annealing at T > 1000 °C.

The purpose of this article is to show that it is possible to make efficient optical tweezers using a properly modified single mode fiber. By using a micro-lens, fabricated directly on the cleaved end of an optical fiber, by a focused ion beam milling process, efficient optical tweezers can be obtained. A 30 keV focused Ga+ ion beam is used to mill a continuous profile microstructure. An axicon with 10 mu m diameters and 5 pm high is fabricated, which permits the transformation of a Gaussian mode in a Bessel mode beam. This particular mode was used to form an optical trap. Measures of the propagation profile and of the trapping effect will be discussed. (c) 2006 Elsevier B.V. All rights reserved.

We report on the correlation between structural and electrical properties of pentacene thin film transistors fabricated by the novel supersonic molecular beam epitaxy (SuMBE) technique. We exploited the ability of SuMBE that, through the control on the molecular precursors in the beam, allows improving the quality in terms of structure and morphology of the semi-conducting thin films compared to the more standard OMBE growth. Different growth conditions were explored to find the better range of beam parameters improving the performance of the TFT device whereas the quality of the films grown was studied by atomic force microscopy. We show that the initial kinetic energy of the pentacene molecule strongly affects both the morphology of the films and the electrical properties of the devices that result to be strongly correlated. With our FET devices prepared, on SiO 2 /Si and top Au contact, we achieved the very promising field effect mobility larger than 0.5 cm 2 V −1 s −1 for films grown at room temperature at a pentacene kinetic energy of about 5.5 eV that are characterized by large crystalline grains (>2 μm).

Nowadays the relevance of silicon chemistry is spreading due to the applications of Si, in particular in semiconductors, in order to obtain an increasing number of performing materials. A theoretical investigation based on the Density Functional Theory has been done on the reaction paths implied in the Pt-catalysed alkene hydrosilylation, a process through which the selective grafting of organic molecules to silicon can be obtained. We studied the Si-H oxidative addition of SiH 4 to a diphosphine molecule, the C 2 H 4 insertion on Pt-H and Pt-SiH 3 bonds, the isomerisation of the product of the C 2 H 4 insertion, and the two following Si-C and C-H reductive eliminations. The set of these processes are known as the Chalk-Harrod mechanism and the modified Chalk-Harrod mechanism, respectively. The main goal of this work has been to identify the rate determining step of both mechanisms. Moreover, by employing dynamics simulations, we have reached a possible alternative product in the oxidative addition step.

Modern medicine and biology search for new powerful tool for biomarkers discovery, appears one of the most promising approaches for early cancer diagnosis. Nowadays, the low molecular weight fraction of human serum is the most informative source of biomarkers, but their study and identification are very difficult due to the incredible complexity of the raw human serum. In this work we describe a novel tool for the filtration of crude human serum or other bio-fluid based on water soluble nanoparticles. Nanoparticles with a pore size of about 2–3 nm, and diameters of 200 nm were obtained by ultrasonication of nanoporous silicon. The porous nanoparticles act as a nanosieve able to exclusively harvest the low molecular weight fraction of the fluid thanks to a controllable pore size. After a short incubation, the infiltrated nanosieves can be extracted from the starting fluid by means of centrifugation, and dissolved in water in a few minutes to give the captured molecules back in their native state, without degradation and contamination. The raw fluid is so split in two components of high and low molecular weight, that are both available for further analyses with any other investigation technique. Here, fluorescence spectroscopy, 2D-gel electrophoresis, and mass spectrometry are exploited to show the split of different bio-fluids under physiological condition. A cut-off (or split level) of 13 kDa is demonstrated also for human serum.

In this paper we report the fabrication and characterization of a plasmonic device for label-free detection of few molecules in sub-wavelength regime by means of Raman scattering. The device is based on the coupling between a gold nanocone and a photonic crystal cavity, that is able to excite surface plasmon polaritons (SPPs) at the base on the cone. During the propagation toward the tip of the cone, the SPPs experiment and adiabatic compression that allow the accumulation of a very high electric field at the tip end. Raman enhancement factor of more than five order of magnitude is reported for a tip with a radius of curvature of about 10nm. The present results open up future perspective on single molecule detection even in combination with AFM measurements.

We have implemented the polarizable continuum model for solute–solvent interactions into a plane-wave (PW) Car–Parrinello code. A comparison between PW and Gaussian-type orbitals (GTO) basis sets implementations, concerning solvation energies and dipole moments of a number of small systems, is reported. All the computations have been performed using the BPW91 exchange-correlation functional. GTO calculation has been performed using the 6-311G(d,p) basis set for geometry optimizations, and the aug-cc-pVTZ basis for energies and dipole moments. PW calculations were carried out on the Gaussian optimized geometries, up to an energy cutoff of 30 Ry. Excellent agreement between PW and GTO calculations is obtained, with average deviations of solute–solvent interaction energies lower than 0.5 kcal/mol.

This paper reports on the fabrication and characterization of a novel device for surface enhanced Raman scattering, fabricated using focused ion beam milling and electron beam induced deposition. The device exploits a photonic crystal cavity as an optical source to couple the incident laser with a metallic tapered nanolenses. The collected Raman measurements show that exploiting such approach is possible to overcome the difficulties related to scattering and diffraction phenomena occurring when visible laser illuminates nano-structures. A clear Raman scattering enhancement has been demonstrated for label-free detection of molecule in sub-wavelength regime.

The boson characteristic function is computed in the entire region of momenta. A comparison with the BCS kernel is discussed.

The positive- and negative-ion fast atom bombardment mass spectra of an octapeptide from sawfly larvae, acting as a liver toxin, have been obtained. The spectra showed abundant pseudo-molecular ions, and significant sequence ions. The peptide structure has been so determined as C 6 H 5 COAlaPheValIleAspAspGluGln (or iso-Gln). The toxin was also found to comprise four amino acids, Ala, Phe, one Asp and one Glu residue with the D-absolute configuration.

We derive relations among the coefficients of the renormalization group equations by using the renormalized set of equations of motion obtained in the framework of analytic regularization for a scalar theory with gφ 4 interactions.