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Background Resistance to osimertinib in advanced EGFR- mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. Methods This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR- mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. Results Sixty-five advanced EGFR -mutated NSCLC patients treated with osimertinib in first- ( n  = 56) or in second-line ( n  = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification ( n  = 8), EGFR C797S ( n  = 3), and SCLC transformation ( n  = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. Conclusions Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Background: The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1–3 gene polymorphisms on outcomes of patients was examined. Methods: Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 ( C8092A , C118T ), XPD ( Lys751Gln ), XRCC1 ( Arg399Gln ) and XRCC3 ( Thr241Met ) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay. Results: Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate ( P =0.004), progression-free survival ( P =0.023) and overall survival ( P =0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role ( P =0.036). Conclusion: This study confirms the prognostic role of ERCC1 expression and XRCC1 ( Arg399Gln ) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy.

This paper analyses the evolution of regional inequality in Brazil in the period 1939-1995. Based on a data set organized by the author, indicators of per capita income dispersion among states and regions are presented and their evolution over time is analyzed. The correlation between the regional initial level of per capita income and its growth is considered, testing for Beta convergence. The speed of convergence is calculated in two different forms, the neoclassical model and the coefficient of variation, the later allowing for the analysis of oscillations in inequality over time and its relationship to national economic growth rates. The Kuznetz hypothesis, relating regional income inequality and level of development, is tested. The results indicate the presence of signs of regional income convergence in Brazil, but with important oscillations in the evolution of inequality over time as well as across regions within the country. The association of regional inequality with national income growth produced interesting results, indicating a promising line for future research.[PUBLICATION ABSTRACT]

In this paper we describe about the synthesis of MgMn2O4 thin films by means of off-axis RF magnetron sputtering and their structural and morphological characterisation realised by means of X-ray diffraction (XRD), micro-Raman spectroscopy and Scanning Electron Microscopy (SEM). We explored different synthesis conditions, namely the substrate temperature, Ts, and the sputtering gas composition and we could observe that well-crystallised films are obtained at Ts = 500°C while the effect of the sputtering gas composition is to affect the structural properties of the films deposited. The thin films deposited always present a crystal structure less distorted with respect to the one of the target material. The possibility of synthesising films of low distorted spinels or even cubic ones may be an interesting way of preparing buffering layers for the growth of isostructural materials such as other spinels or pseudocubic perovskites.

Dielectric permittivity ϵ + iϵ′′ (100 Hz – 1 MHz) supplemented by IR (20 – 650 cm−1) reflectivity and Micro-Raman spectra studies were performed on weakly concentrated SrTiO3:Mn (0.1%) crystals and ceramics sintered with deficit of Ti, keeping the ratio (Ti+Mn)/Sr 1. Surprisingly, magnitude of permittivity in SrTiO3:Mn crystals appeared to be depressed at low temperatures as in ceramics, reaching only ∼3000 at T 10 K. At the same time, low temperature IR reflectivity in STO:Mn crystals evidences that TO phonons contribution into low-frequency permittivity is nearly the same as in undoped serial SrTiO3 quantum paraelectric crystals. Together with Micro-Raman data, such features are understood as evidences of STO:Mn(0.1%) crystals inhomogeneity and presence of Mn oxides enriched nano-regions. Currently discussed in literature Mn doping related low-temperature dielectric relaxation is faintly pronounced in dielectric losses of STO:Mn(0.1%) crystals and ceramics and increased in reduced crystals, where at least two relaxation contributions with activation energy ∼40 meV and ∼120 meV can be distinguished displaying at ∼20 – 40 K and 76-114 K temperature regions respectively. The fist relaxation is attributed to reorientation of polaronic defects localized on Mn2+ related centres. Possible nature of the second one is discussed.

Electron paramagnetic resonance (EPR), optical absorption and low-frequency (100 Hz − 1 MHz) dielectric permittivity investigations on Verneuil as-grown and reduced SrTiO3:Mn (0.1% at.) crystals were carried out to establish connection between the structure of Mn doping related centers and the SrTiO3 dielectric properties. At room temperature the EPR spectrum of as-grown crystals evidences isotropic Mn4+ and Mn2+ centers. The Mn2+/Mn4+ ratio increases, according to the EPR spectra, by decreasing the temperature and the signals intensity of both centers strongly decreases approaching T∼120 K. Such behavior is attributed to antiferromagnetic interaction in MnO and MnO2 nano-clusters. Also the dielectric permittivity behavior evidences samples inhomogeneity as well as absence of pronounced dielectric relaxation in as grown crystals. In reduced crystals the Mn2+ concentration increases and the dielectric relaxation emerges evidencing a polaronic-related nature of dipole reorientations.

To assess the role of Notch activation in predicting bevacizumab efficacy in colorectal cancer (CRC). Notch activation was evaluated by immunohistochemistry (IHC) on 65 CRC enrolled within randomized clinical trials assessing first-line bevacizumab-based chemotherapy and on 21 CRC treated with chemotherapy alone. Strong Notch (IHC 3+) activation was negatively associated with response (18 vs 62% in low Notch cases [IHC 0, 1, 2+]; p = 0.016), progression-free survival (4.9 vs 12.1 months; p = 0.002) and overall survival (19.3 vs 30.4 months; p = 0.039). No correlation was found between Notch activation and clinical outcome in CRC treated with chemotherapy alone. A potential role of Notch activation in the antitumor activity of bevacizumab could be hypothesized.