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The combined effects of population growth and aging have led to an increase in the number of cancers.Preventing, diagnosing, treating and curing cancer are therefore, more than ever, imperatives facing medicine - especially to continue the decrease in cancers� mortality rates and to improve the quality of survival.

Background. An influenza A(H1N1) pdm09 infection was diagnosed in a hematopoietic stem cell transplant recipient during conditioning regimen. He was treated with oral oseltamivir, later combined with intravenous zanamivir. The H275Y neuraminidase (NA) mutation was first detected, and an E119D NA mutation was identified during zanamivir therapy. Methods. Recombinant wild-type (WT) E119D and E119D/H275Y A(H1N1) pdm09 NA variants were generated by reverse genetics. Susceptibility to NA inhibitors (NAIs) was evaluated with a fluorometric assay using the 2'-(4-methylumbelliferyli-α-D-N-acetylneuraminic acid (MUNANA) substrate. Susceptibility to favipiravir (T-705) was assessed using plaque reduction assays. The NA affinity and velocity values were determined with NA enzymatic studies. Results. We identified an influenza A(H1N1)pdm09 E119D mutant that exhibited a marked increase in the 50% inhibitory concentrations against all tested NAIs (827-, 25-, 286-, and 702-fold for zanamivir, oseltamivir, peramivir, and laninamivir, respectively). The double E119D/H275Y mutation further increased oseltamivir and peramivir 50% inhibitory concentrations by 790- and >5000-fold, respectively, compared with the WT. The mutant viruses remained susceptible to favipiravir. The NA affinity and velocity values of the E119D variant decreased by 8.1-fold and 4.5-fold, respectively, compared with the WT. Conclusions. The actual emergence of a single NA mutation conferring pan-NAI resistance in the clinical setting reinforces the pressing need to develop new anti-influenza strategies.

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5-5.4 μM), except a higher EC50 value for GluA4 flop (0.7 μM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 μM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 μM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 μM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 μM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer's disease and in Major Depressive Disorder.

Filling the gap for a reference dedicated to the characterization of polymer blends and their micro and nano morphologies, this book provides comprehensive, systematic coverage in a one-stop, two-volume resource for all those working in the field.

Andrade, C.A.; Thomas, Y.F.; Nicolae Lerma, A.; Durand, P., and Anselme, B., 2013. Coastal flooding hazard related to swell events in Cartagena de Indias, Colombia. In the city of Cartagena de Indias, the urban areas of Bocagrande and Castillogrande were built over large sandbars and are extremely sensitive to the risk of coastal flooding during storm surges. However, the risk of flooding is not directly related to local meteorological conditions, but results essentially from hydrodynamic phenomena due to the arrival of heavy swell from far away. A statistical study based on hourly sea-level observations from 1950 to 2000 showed the existence of overflow levels of 0.29, 0.34, and 0.37 m corresponding to return periods of 10, 50, and 100 years. Numerical modeling of overflows was performed from a reanalysis of atmospheric pressure as well as wind and wave data sets produced by the National Oceanic and Atmospheric Administration. The models used were ADCIRC® for the simulation of tides and wind setup, SWAN® for the simulation of wave setup, and pCOULWAVE® for wave run-up estimation. Coastal flooding that affected the city in January 2010 was validated using a HORUS® video monitoring system. Simulations were conducted on expected extreme sea levels during the 21st century. Flooding simulations were performed using both a light detection and ranging high-resolution digital elevation model and a water propagation model based on a recursive algorithm. Results showed the extreme vulnerability of Bocagrande and Castillogrande areas facing the risk of submersion. They raise questions for future risks of flooding taking into account the rates of sea-level rise as well as the effects of wave erosion. La ville de Carthagène des Indes est un pôle industriel et patrimonial important du littoral caribéen de la Colombie. Les quartiers de Bocagrande et Castillogrande édifiés sur un mince cordon littoral sont extrêmement sensibles à l'aléa submersion marine lors des épisodes de Mar de leva. Toutefois, le risque d'inondation n'est pas lié aux conditions météorologiques locales, mais résulte, pour l'essentiel, de phénomènes hydrodynamiques générés par l'arrivée de houles lointaines. L'étude statistique des chroniques horaires du marégraphe entre les années 1950 et 2000 montre l'existence de niveaux de surcote de 0.29, 0.34 et 0.37 m pour des occurrences de 10, 50 et 100 ans. La simulation numérique des surcotes a été conduite par réanalyse d'un certain nombre d'évènements majeurs grâce aux données de pression, vents et houles fournies par la NOAA et l'utilisation conjointe des modèles ADCIRC, pour la simulation de la marée et du set-up lié au vent, SWAN® pour la simulation du set-up lié aux vagues et pCOULWAVE pour le run-up. Les épisodes de submersion ayant affecté la ville en janvier 2010 ont été validés grâce aux caméras vidéo du système HORUS®. Des scenarii de submersion basés sur l'utilisation d'un modèle numérique de terrain haute résolution et d'un modèle de diffusion de crue ont permis de suivre la propagation des flux d'inondation pour les niveaux marins extrêmes attendus pour le 21ème siècle. Les résultats montrent l'extrême vulnérabilité de la ville face à l'aléa submersion. Ils posent la question du risque futur compte tenu des rythmes d'élévation du niveau marin et de l'impact érosif des vagues. La ciudad de Cartagena de Indias es un polo industrial y patrimonial importante del litoral Caribe colombiano. Los barrios de Bocagrande y Castillogrande, construidos sobre un estrecho cordón litoral, son extremadamente sensibles al riesgo de sumersión durante los episodios de Mar de leva. Las inundaciones no son debidas a sobreniveles vinculados a condiciones meteorológicas locales, si no que resultan esencialmente de fenómenos hidrodinámicos generados por la llegada de olas distantes. El estudio estadístico de las crónicas por hora del mareógrafo de Cartagena entre los años 1950 y 2000 muestra la existencia de sobreniveles de 0.29, 0.34 y 0.37 m para períodos de retorno que corresponden a 10, 50 y 100 años. La simulación numérica de los sobreniveles fue conducida por reanálisis de una serie de datos de presión atmosférica y oleaje distribuidos por el NOAA y por el empleo conjunto de los modelos ADCIRC, para la simulación de la marea y del set-up debido al viento, SWAN®, para la simulación del set-up debido a las olas y pCOULWAVE® para el run-up. Los episodios de sumersión que afectaron a la ciudad en enero de 2010 se validaron con cámaras vídeo del sistema HORUS®. Situaciones de sumersión basadas en la utilización conjunta de un modelo numérico de terreno de alta precisión y de un modelo de difusión permitieron seguir la propagación de los flujos de inundación en los niveles del mar extremos establecidos para el siglo XXI. Los resultados muestran la extrema vulnerabilidad del área de Bocagrande ante el riesgo sumersión. Se plantea la cuestión del futuro riesgo de inundación teniendo cuenta tanto los ritmos de subida del nivel marino como del impacto de las olas.

Multiphase polymeric systems include a wide range of materials such as composites, blends, alloys, gels, and interpenetrating polymer networks (IPNs). A one-stop reference on multiphase polymer systems, this book fully covers the preparation, properties, and applications of advanced multiphase systems from macro to nano scales. Edited by well-respected academics in the field of multiphase polymer systems, the book includes contributions from leading international experts. An essential resource for plastic and rubber technologists, filler specialists and researchers in fields studying thermal and electrical properties.

BackgroundThe African Vaccine Regulatory Forum (AVAREF) is a network of African national regulatory authorities (NRAs) and ethics committees (NECs) with an objective of improving access to medicines by reducing and standardizing review and approval times for clinical trial applications, while also optimizing quality of regulatory processes across sub-Saharan Africa (SSA)¹. It utilizes joint reviews and parallel CTA submissions to NRAs, NECs and Institutional Review Boards (IRBs). MethodsNovartis piloted use of the AVAREF procedure for a Phase 2 clinical study in malaria patients involving 7 countries/13 sites in SSA. ResultsA letter of intent for a scientific advice meeting was submitted to AVAREF to trigger the procedure start. The meeting occurred 2 months later with participation of experts from SSA. One NEC identified for inclusion in the procedure did not agree to participate. The timetable was agreed by all parties, which facilitated CTA parallel submissions. However, differences in understanding of the procedure emerged. Despite scheduling of a face to face joint review meeting including all parties to discuss questions on the CTA, two NEC approvals were received prior to the joint review. Validation questions requesting sequential approvals by IRBs/ECs were also received. The procedure is currently ongoing, and the pilot will inform the path for future EC/HA submissions in SSA.ConclusionAVAREF procedure holds promise to reduce lengthy sequential NEC and NRA approval timelines in SSA. It also provides a forum for open discussion of study-related questions and for scientific advice in SSA. Attention is warranted to further clarify the review process and expectations for NECs, in particular.

In Mbyá, target state resultative predicates can only be derived from inchoative verbs. This is in contrast with target state adjectival passives in better studied languages such as English, German and Greek, which can be derived from transitive causatives. I argue that the limited distribution of Mbyá resultatives reveals a point of variation in the association between roots and external-argument introducing Voice heads: while roots of non-agentive transitive causatives need not be lexically associated to agent or causer Voice in English and similar languages, they do in Mbyá. Together with the well documented incompatibility of target state resultatives with agent/causer Voice, this difference explains the restricted distribution of Mbyá resultatives. The proposed analysis stresses the importance of the distinction between target states and resultant states in the structure of adjectival passives and related resultative predicates cross-linguistically.

Tissue engineering involves seeding of cells on bio-mimicked scaffolds providing adhesive surfaces.Researchers though face a range of problems in generating tissue which can be circumvented by employing nanotechnology.