Hydrophobic cis-platinum complexes efficiently incorporated into liposomes

The present invention involves the synthesis and use of new platinum compounds. These new platinum compounds are easy to encapsulate in liposomes at high efficiencies. They are further characterized as platinum (II) four coordinate complex having the formula: ##STR1## wherein R.sub.1 and R.sub.2 are carboxylato monoanions bearing a hydrophobic radical function or a single carboxylato dianion bearing a hydrophobic radical function and R.sub.3 is a vicinal diaminoalkane or vicinal diaminocycloalkane. The complex is substantially soluble in methanol or chloroform and substantially insoluble in water. Said complex may be incorporated into phospholipid liposomes. Such platinum complexes encapsulated in phospholipid liposomes are useful for chemotherapy of platinum complex-sensitive tumors.Board of Regents, University of Texas Syste

Preparation of Dipteran Larvae for Scanning Electron Microscopy with Special Reference to Myiasigen Dipteran Species

Although controversy exists concerning the role of chemical fixatives in scanning electron microscopy (SEM) studies of Dipteran larvae, we have observed that filtered 10% formaldehyde solution gives excellent results as a preservative. After immersing in vivo in formaldehyde, the larvae material is preserved for prolonged periods (up to 8 months), before examination with SEM. As a fixative, formaldehyde preserves the structure of the larval cuticle and produces no visible artifacts. Moreover, postfixation is not necessary. Due to pecularities of the way of life of Wohlfahrtia magnifica (principally the accumulations of necrotic tissue, purulent particles, and other types of substances that often adhere to the numerous spines of larvae), this species must be cleaned before examination by SEM. Manual cleaning with alternating bidistilled water and 0.9% saline solution proved to be a rapid, easy and inexpensive method that gave good results. Both lyophilization drying and critical point drying were used before sputtering the material. While lyophilization drying proved to be the most effective method for instars II and III, critical point drying was the best technique for study of specimens belonging to instar I. The optimum time for drying and conditions for lyophilization and sputter-coating with gold were determined experimentally. Samples were mounted on SEM stubs with double-sided adhesive and silver conductive paint. The method proposed is easy and effective for the SEM study of larvae myiasis-producing diptera

Model-Driven Chatbot Development

Esta versión del artículo ha sido aceptada para su publicación, después de la revisión por pares (cuando corresponda) y está sujeta a los términos de uso de AM de Springer Nature, pero no es la Versión de Registro y no refleja mejoras posteriores a la aceptación, ni ninguna corrección. La versión del registro está disponible en línea en: https://doi.org/10.1007/978-3-030-62522-1_15Chatbots are software services accessed via conversation in natural language. They are increasingly used to help in all kinds of procedures like booking flights, querying visa information or assigning tasks to developers. They can be embedded in webs and social networks, and be used from mobile devices without installing dedicated apps. While many frameworks and platforms have emerged for their development, identifying the most appropriate one for building a particular chatbot requires a high investment of time. Moreover, some of them are closed – resulting in customer lock-in – or require deep technical knowledge. To tackle these issues, we propose a model-driven engineering approach to chatbot development. It comprises a neutral meta-model and a domainspecific language (DSL) for chatbot description; code generators and parsers for several chatbot platforms; and a platform recommender. Our approach supports forward and reverse engineering, and model-based analysis. We demonstrate its feasibility presenting a prototype tool and an evaluation based on migrating third party Dialogflow bots to RasaWork funded by the Spanish Ministry of Science (RTI2018095255-B-I00) and the R&D programme of Madrid (P2018/TCS-4314

Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial.

BackgroundAdjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC.MethodsWe did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805.FindingsBetween June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment.InterpretationAddition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC.FundingNational Cancer Institute of the National Institutes of Health

La erupción submarina de La Restinga en la isla de El Hierro, Canarias: Octubre 2011-Marzo 2012

The first signs of renewed volcanic activity at El Hierro began in July 2011 with the occurrence of abundant, low-magnitude earthquakes. The increasing seismicity culminated on October 10, 2011, with the onset of a submarine eruption about 2 km offshore from La Restinga, the southernmost village on El Hierro. The analysis of seismic and deformation records prior to, and throughout, the eruption allowed the reconstruction of its main phases: 1) ascent of magma and migration of hypocentres from beneath the northern coast (El Golfo) towards the south rift zone, close to La Restinga, probably marking the hydraulic fracturing and the opening of the eruptive conduit; and 2) onset and development of a volcanic eruption indicated by sustained and prolonged harmonic tremor whose intensity varied with time. The features monitored during the eruption include location, depth and morphological evolution of the eruptive source and emission of floating volcanic bombs. These bombs initially showed white, vesiculated cores (originated by partial melting of underlying pre-volcanic sediments upon which the island of El Hierro was constructed) and black basanite rims, and later exclusively hollow basanitic lava balloons. The eruptive products have been matched with a fissural submarine eruption without ever having attained surtseyan explosiveness. The eruption has been active for about five months and ended in March 2012, thus becoming the second longest reported historical eruption in the Canary Islands after the Timanfaya eruption in Lanzarote (1730-1736). This eruption provided the first opportunity in 40 years to manage a volcanic crisis in the Canary Islands and to assess the interpretations and decisions taken, thereby gaining experience for improved management of future volcanic activity. Seismicity and deformation during the eruption were recorded and analysed by the Instituto Geográfico Nacional (IGN). Unfortunately, a lack of systematic sampling of erupted pyroclasts and lavas, as well as the sporadic monitoring of the depth and growth of the submarine vent by deployment of a research vessel, hampered a comprehensive assessment of hazards posed during volcanic activity. Thus, available scientific data and advice were not as high quality as they could have been, thereby limiting the authorities in making the proper decisions at crucial points during the crisis. The response in 2011-12 to the El Hierro eruption has demonstrated that adequate infrastructure and technical means exist in the Canary Islands for the early detection of potential eruptive hazards. However, it also has taught us that having detailed emergency management plans may be of limited value without an accompanying continuous, well-integrated scientific monitoring effort (open to national and international collaboration) during all stages of an eruption.Los primeros indicios de una posible erupción volcánica en El Hierro se percibieron a partir de julio de 2011 en forma de sismos de baja intensidad pero anormalmente numerosos. La intensificación de la sismicidad culminó con el inicio de la erupción submarina el 10 de octubre de 2011 a unos 2 km al sur de La Restinga. La sismicidad y deformación del terreno que precedieron y acompañaron a esta erupción han permitido reconstruir las principales fases de actividad volcánica: 1) generación y ascenso del magma con migración de los hipocentros sísmicos desde el norte, en el Golfo, hasta el rift sur, en La Restinga, marcando la apertura hidráulica del conducto magmático; y 2) inicio y continuidad de la erupción volcánica evidenciada por un tremor armónico continuo de intensidad variable en el tiempo. Las características observadas a lo largo de la erupción, principalmente localización, profundidad y evolución morfológica del foco emisor, así como emisión de materiales volcánicos flotantes, inicialmente con un núcleo blanco poroso (procedentes de la fusión parcial de sedimentos de la capa superior de la corteza oceánica anteriores a la construcción del edificio insular de El Hierro) envuelto por una corteza basanítica y después huecas (lava balloons), se han correspondido con una erupción submarina fisural profunda sin que nunca hayan intervenido mecanismos más explosivos tipo surtseyano. La erupción se mantuvo activa durante unos cinco meses, dándose por finalizada en marzo del 2012, convirtiéndose de este modo en la segunda erupción histórica más longeva de Canarias después de la de Timanfaya (1730-36) en Lanzarote. Esta erupción ha supuesto la primera oportunidad en 40 años de gestionar una crisis volcánica en Canarias y de analizar las observaciones e interpretaciones y las decisiones adoptadas, con objeto de mejorar la gestión de futuras crisis volcánicas. El Instituto Geográfico Nacional (IGN) se encargó de adquirir y analizar la información sísmica y de deformación durante todo el proceso. Sin embargo, no se dispuso inicialmente de un barco oceanográfico que realizara estudios sistemáticos de la profundidad y progresión de la erupción, así como de toma de muestras de los materiales emitidos (piroclastos y lavas), elementos claves para la determinación de la peligrosidad eruptiva. Estas deficiencias en el seguimiento científico del proceso eruptivo dificultaron en algunos momentos la toma de decisiones de protección civil. El análisis de la crisis ha puesto de manifiesto que, aunque se disponga de una infraestructura técnica adecuada para la detección temprana de crisis eruptivas en el archipiélago, de poco valen las medidas administrativas planificadas sin un seguimiento científico continuo e integrador del proceso eruptivo, abierto a la colaboración científica nacional e internacional

Solar science with the Atacama Large Millimeter/submillimeter Array - A new view of our Sun

The Atacama Large Millimeter/submillimeter Array (ALMA) is a new powerful tool for observing the Sun at high spatial, temporal, and spectral resolution. These capabilities can address a broad range of fundamental scientific questions in solar physics. The radiation observed by ALMA originates mostly from the chromosphere - a complex and dynamic region between the photosphere and corona, which plays a crucial role in the transport of energy and matter and, ultimately, the heating of the outer layers of the solar atmosphere. Based on first solar test observations, strategies for regular solar campaigns are currently being developed. State-of-the-art numerical simulations of the solar atmosphere and modeling of instrumental effects can help constrain and optimize future observing modes for ALMA. Here we present a short technical description of ALMA and an overview of past efforts and future possibilities for solar observations at submillimeter and millimeter wavelengths. In addition, selected numerical simulations and observations at other wavelengths demonstrate ALMA's scientific potential for studying the Sun for a large range of science cases.Comment: 73 pages, 21 figures ; Space Science Reviews (accepted December 10th, 2015); accepted versio

Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib

Sudden Cardiac Death and Copy Number Variants: What Do We Know after 10 Years of Genetic Analysis?

Over the last ten years, analysis of copy number variants has increasingly been applied to the study of arrhythmogenic pathologies associated with sudden death, mainly due to significant advances in the field of massive genetic sequencing. Nevertheless, few published reports have focused on the prevalence of copy number variants associated with sudden cardiac death. As a result, the frequency of these genetic alterations in arrhythmogenic diseases as well as their genetic interpretation and clinical translation has not been established. This review summarizes the current available data concerning copy number variants in sudden cardiac death-related diseases