Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs.

Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre-malignant immortalised cells, we ectopically expressed telomerase in telomere-compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period-aggravated by p53 deficiency-and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy.

Video gamers of League of Legends: The role of passion in abusive use and in performance.

There is growing concern about the addictive potential of Massively Multiplayer Online Role Playing Games (MMORPG). The Multiplayer Online Battle Arena (MOBA) is a new genre, poorly studied but very popular, in which performance holds priority over immersion. The aim of the current study was to explore the influence of passion both on abuse and performance, using the dualistic model of passion. A total of 369 participants completed an online questionnaire that included problematic use and the Passion Scale. From players' nicknames, performance statistics were obtained. The results show that harmonious passion is a protector from negative consequences. On the other hand, obsessive passion predicts negative consequences and use of videogames for evasion. Obsessive passion also predicts better performance. These results suggest that distinguishing the two kinds of passion is important because they influence vulnerability to developing maladaptive behaviors and also players' performance.

Los juegos Massively Multiplayer Online Role Playing Games (MMORPG) han suscitado preocupación por su potencial adictivo. Los  Multiplayer Online Battle Arena (MOBA) son un nuevo género poco estudiado, pero que goza de gran popularidad, en el que prima el rendimiento por encima de la inmersión. El objetivo del presente estudio era explorar qué influencia tenía la pasión tanto en el rendimiento como en el uso abusivo a partir del Modelo Dual de la Pasión. Un total de 369 participantes completaron un cuestionario en línea que incluía usos abusivos y la Escala de la Pasión. A partir del alías del jugador se obtuvieron estadísticas de rendimiento. Los resultados muestran que la pasión armónica es un protector de sufrir consecuencias negativas de jugar. Por otro lado, la pasión obsesiva predice consecuencias negativas  y el uso para la evasión. La pasión obsesiva también predice mejores resultados de rendimiento. Estos resultados sugieren que el tipo de pasión de los videojugadores es importante, ya que influye en la vulnerabilidad de sufrir conductas desadaptativas y en el rendimiento del jugador.

Optical security verification by synthesizing thin films with unique polarimetric signatures.

This Letter reports the production and optical polarimetric verification of codes based on thin-film technology for security applications. Because thin-film structures display distinctive polarization signatures, this data is used to authenticate the message encoded. Samples are analyzed using an imaging ellipsometer able to measure the 16 components of the Mueller matrix. As a result, the behavior of the thin film under polarized light becomes completely characterized. This information is utilized to distinguish among true and false codes by means of correlation. Without the imaging optics the components of the Mueller matrix become noise-like distributions and, consequently, the message encoded is no longer available. Then, a set of Stokes vectors are generated numerically for any polarization state of the illuminating beam and thus, machine learning techniques can be used to perform classification. We show that successful authentication is possible using the k-nearest neighbors algorithm in thin-films codes that have been anisotropically phase-encoded with pseudorandom phase code.

Mueller matrix microscope with a dual continuous rotating compensator setup and digital demodulation.

In this paper we describe a new Mueller matrix (MM) microscope that generalizes and makes quantitative the polarized light microscopy technique. In this instrument all the elements of the MU are simultaneously determined from the analysis in the frequency domain of the time-dependent intensity of the light beam at every pixel of the camera. The variations in intensity are created by the two compensators continuously rotating at different angular frequencies. A typical measurement is completed in a little over one minute and it can be applied to any visible wavelength. Some examples are presented to demonstrate the capabilities of the instrument.

Water plasma functionalized CNTs/MnO2 composites for supercapacitors.

A water plasma treatment applied to vertically-aligned multiwall carbon nanotubes (CNTs) synthesized by plasma enhanced chemical vapour deposition gives rise to surface functionalization and purification of the CNTs, along with an improvement of their electrochemical properties. Additional increase of their charge storage capability is achieved by anodic deposition of manganese dioxide lining the surface of plasma-treated nanotubes. The morphology (nanoflower, layer, or needle-like structure) and oxidation state of manganese oxide depend on the voltage window applied during charge-discharge measurements and are found to be key points for improved efficiency of capacitor devices. MnO2/CNTs nanocomposites exhibit an increase in their specific capacitance from 678 Fg(-1), for untreated CNTs, up to 750 Fg(-1), for water plasma-treated CNTs.

Vertically aligned carbon nanotubes for microelectrode arrays applications.

In this work a methodology to fabricate carbon nanotube based electrodes using plasma enhanced chemical vapour deposition has been explored and defined. The final integrated microelectrode based devices should present specific properties that make them suitable for microelectrode arrays applications. The methodology studied has been focused on the preparation of highly regular and dense vertically aligned carbon nanotube (VACNT) mat compatible with the standard lithography used for microelectrode arrays technology.

Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the Steady-State Pharmacokinetics of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAFV600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.

Absolute Bioavailability of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAFV600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14 C-labeled vemurafenib in patients with BRAFV600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14 C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14 C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUCτ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC0-inf ) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment-emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade-4 anaphylactic reaction occurring during infusion of 14 C-labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Malignancies.

This phase 1 open-label, multicenter, 3-period, fixed-sequence study evaluated the effect of multiple doses of vemurafenib on the pharmacokinetics of 1 dose of tizanidine, a probe CYP1A2 substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Patients received 1 dose of tizanidine 2 mg on day 1 (period A), vemurafenib 960 mg twice daily on days 2-21 (period B), and 1 dose of tizanidine 2 mg and vemurafenib 960 mg twice daily on day 22 (period C). Log-transformed area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) values for tizanidine in 16 patients were compared between periods A (tizanidine alone) and C (tizanidine plus vemurafenib) using an analysis of variance model. Multiple doses of vemurafenib increased plasma exposure of 1 dose of tizanidine, with geometric mean ratios (period C/period A) for Cmax , AUCinf , and AUClast of 2.15 (90%CI, 1.71-2.71), 4.22 (90%CI, 3.37-5.28), and 4.74 (90%CI, 3.55-6.33), respectively; 90%CIs were all outside predefined limits for lack of drug-drug interaction (0.82-1.22). This study confirmed vemurafenib as a moderate inhibitor of CYP1A2 in vivo, with a statistically significant drug-drug interaction with tizanidine. Caution should be exercised when dosing vemurafenib concurrently with CYP1A2 substrates.

Effect of Rifampicin on the Pharmacokinetics of a Single Dose of Vemurafenib in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

Vemurafenib prolongs survival in patients with BRAFV600 -mutated advanced melanoma. In vitro studies show cytochrome P450 (CYP) 3A4 is involved in vemurafenib metabolism, but the effect of strong inducers or inhibitors of CYP3A4 on vemurafenib exposure in vivo is unknown. This phase 1, open-label, multicenter study evaluated the effect of rifampicin, a CYP3A4 inducer, on the pharmacokinetics of single-dose vemurafenib in 27 patients with BRAFV600 mutation-positive metastatic malignancy. Patients received a single oral dose of vemurafenib 960 mg on day 1, oral rifampicin 600 mg daily on days 8-16 (period B), and a single oral dose of vemurafenib 960 mg on day 17 and rifampicin 600 mg daily for days 17-23 (period C), with plasma samples obtained up to 168 hours after vemurafenib dosing. The geometric mean ratio (period C/period A) of area under the concentration-time curve from time zero to last measurable concentration time point and area under the concentration-time curve from time zero to infinity for vemurafenib (n = 23 for the pharmacokinetic analysis) was 0.61 (90% confidence interval, 0.48-0.78) and 0.60 (90% confidence interval, 0.47-0.76), respectively, indicating rifampicin significantly decreased vemurafenib plasma exposure by approximately 40%. The geometric mean ratio of the maximum concentration for vemurafenib was 1.1; this slight increase is likely owing to one outlier in period C. Adverse events were consistent with those previously seen for rifampicin and for vemurafenib monotherapy. Caution is advised when dosing vemurafenib concurrently with CYP3A4 inducers.

Evaluation of Graphene/WO3 and Graphene/CeO x Structures as Electrodes for Supercapacitor Applications.

The combination of graphene with transition metal oxides can result in very promising hybrid materials for use in energy storage applications thanks to its intriguing properties, i.e., highly tunable surface area, outstanding electrical conductivity, good chemical stability, and excellent mechanical behavior. In the present work, we evaluate the performance of graphene/metal oxide (WO3 and CeO x ) layered structures as potential electrodes in supercapacitor applications. Graphene layers were grown by chemical vapor deposition (CVD) on copper substrates. Single and layer-by-layer graphene stacks were fabricated combining graphene transfer techniques and metal oxides grown by magnetron sputtering. The electrochemical properties of the samples were analyzed and the results suggest an improvement in the performance of the device with the increase in the number of graphene layers. Furthermore, deposition of transition metal oxides within the stack of graphene layers further improves the areal capacitance of the device up to 4.55 mF/cm2, for the case of a three-layer stack. Such high values are interpreted as a result of the copper oxide grown between the copper substrate and the graphene layer. The electrodes present good stability for the first 850 cycles before degradation.

Ocular bioanalysis: challenges and advancements in recent years for these rare matrices.

There are many ocular diseases still presenting unmet medical needs. Therefore, new ophthalmologic drugs are being developed. Bioanalysis of eye compartments (along with plasma and other tissues) is important to determine exposure of the target organ to the drug and to help interpret local pharmacological or toxic effects. This review article identifies several challenges that occur within ocular bioanalysis. They include sample collection and preparation, analytical issues, sourcing control matrix, data interpretation and regulatory requirements. It summarizes how these challenges have been recently addressed, how research has advanced and which questions remain unanswered. Recommendations are made based on the literature and our practical experience within ocular bioanalysis and future perspectives are discussed.

New Three-Dimensional Porous Electrode Concept: Vertically-Aligned Carbon Nanotubes Directly Grown on Embroidered Copper Structures.

New three-dimensional (3D) porous electrode concepts are required to overcome limitations in Li-ion batteries in terms of morphology (e.g., shapes, dimensions), mechanical stability (e.g., flexibility, high electroactive mass loadings), and electrochemical performance (e.g., low volumetric energy densities and rate capabilities). Here a new electrode concept is introduced based on the direct growth of vertically-aligned carbon nanotubes (VA-CNTs) on embroidered Cu current collectors. The direct growth of VA-CNTs was achieved by plasma-enhanced chemical vapor deposition (PECVD), and there was no application of any post-treatment or cleaning procedure. The electrochemical behavior of the as-grown VA-CNTs was analyzed by charge/discharge cycles at different specific currents and with electrochemical impedance spectroscopy (EIS) measurements. The results were compared with values found in the literature. The as-grown VA-CNTs exhibit higher specific capacities than graphite and pristine VA-CNTs found in the literature. This together with the possibilities that the Cu embroidered structures offer in terms of specific surface area, total surface area, and designs provide a breakthrough in new 3D electrode concepts.

Aqueous stabilisation of carbon-encapsulated superparamagnetic α-iron nanoparticles for biomedical applications.

Carbon-based nanomaterials, such as carbon-encapsulated magnetic nanoparticles (CEMNP, core@shell), show a wide range of desirable properties for applications in the biomedical field (clinical MRI, hyperthermia), for energy production and storage (hydrogen storage), for the improvement of electronic components and for environmental applications (water-treatment). However, this kind of nanoparticle tends to aggregate in water suspensions. This often hampers the processability of the suspensions and presents an obstacle to their application in many fields. Here the stabilisation of core-shell Fe-C nanoparticles by surface adsorbed polyvinyl-alcohol (PVA) is presented. Different PVA/CEMNP mass ratios (9, 36, 144 and 576 w/w) were studied. Several characterisation techniques were used in order to determine the size distribution of the particles and to optimize the PVA/CEMNP ratio. A good colloidal stability was obtained for spherical nanoparticles about 50 nm in diameter containing several superparamagnetic Fe cores. The nanoparticles were found to be isolated and well dispersed in solution. The use of PVA for coating carbon-encapsulated Fe nanoparticles does not only result in a good colloidal stability in aqueous suspensions, but the resulting particles also show low cytotoxicity and an interesting cell internalization behaviour. The simple stabilization method developed here can likely be extended to other core@shell nanoparticle systems as well as other carbon-based nanomaterials in the future.