Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorptionionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycinruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycinruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycinruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycinruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

UPLC-TOF-MS for plant metabolomics: a sequential approach for wound marker analysis in Arabidopsis thaliana.

The model plant Arabidopsis thaliana was studied for the search of new metabolites involved in wound signalling. Diverse LC approaches were considered in terms of efficiency and analysis time and a 7-min gradient on a UPLC-TOF-MS system with a short column was chosen for metabolite fingerprinting. This screening step was designed to allow the comparison of a high number of samples over a wide range of time points after stress induction in positive and negative ionisation modes. Thanks to data treatment, clear discrimination was obtained, providing lists of potential stress-induced ions. In a second step, the fingerprinting conditions were transferred to longer column, providing a higher peak capacity able to demonstrate the presence of isomers among the highlighted compounds.

El cervell bilingüe pren decisions més depressa

Diferents estudis mostren que les persones que parlen dues llengües són més àgils a l"hora de resoldre conflictes en què cal valorar diferents informacions de manera simultània

El cervell bilingüe pren decisions més depressa

Diferents estudis mostren que les persones que parlen dues llengües són més àgils a l"hora de resoldre conflictes en què cal valorar diferents informacions de manera simultània

La generatividad en la vejez y su relación con el bienestar: ¿Quién más contribuye es quien más se beneficia?

El objetivo de la investigación fue la adaptación al español de las escalas de interés y comportamientos generativos de McAdams, así co-mo el estudio de la generatividad en la vejez y su relación con el bienestar. La muestra estuvo compuesta por 165 voluntarios mayores de 65 años que, además de las versiones españolas de las escalas de generatividad, completa-ron instrumentos para evaluar satisfacción con la vida y orientación al futu-ro. Los resultados indicaron que la fiabilidad de las versiones españolas de las escalas de generatividad fue aceptable y similar a las originales en inglés. Mientras el interés generativo se relacionó con la satisfacción con la vida, los comportamientos generativos no lo hicieron. Sin embargo, ambas esca-las sí se relacionaron con la orientación al futuro, aunque esta relación no se confirmó en un análisis multivariable. Los resultados resaltan la importancia de la generatividad en la vejez y de distinguir entre interés y acción generati-va, ya que sus beneficios podrían ser muy diferentes.

Análisis de las estrategias de comunicación transmedia de los clubes de fútbol más relevantes de Europa: FC Barcelona, Real Madrid CF,Chelsea FC y Manchester United FC

El presente documento propone una investigación en Narrativas Transmedia (NT)que centre el análisis en dos objetivos generales: 1) desarrollar un estudio comparativo de la producción transmedia dentro de la estrategia de comunicación de cuatro clubes de fútbol relevantes de Europa: FC Barcelona, Real Madrid CF, Chelsea FC y Manchester United FC, y 2) analizar un caso específico de producción transmedia del FCBarcelona. Para este fin, la investigación propone un análisis de los elementos narratológicos y semióticos de la estrategia de comunicación y a través de la técnica metodológica del análisis narrativo busca encontrar resultados que permitan describir el fenómeno de las NT dentro de una estrategia de comunicación institucional o corporativa. Esta propuesta de investigación es el trabajo final para obtener el título de Máster en Estudios Avanzados en Comunicación Social y es el anteproyecto de investigación de la futura tesis doctoral en Comunicación.

Rapid LC-MS/MS quantification of the major benzodiazepines and their metabolites on dried blood spots using a simple and cost-effective sample pretreatment.

BACKGROUND: Dried blood spots (DBS) sampling has gained popularity in the bioanalytical community as an alternative to conventional plasma sampling, as it provides numerous benefits in terms of sample collection and logistics. The aim of this work was to show that these advantages can be coupled with a simple and cost-effective sample pretreatment, with subsequent rapid LC-MS/MS analysis for quantitation of 15 benzodiazepines, six metabolites and three Z-drugs. For this purpose, a simplified offline procedure was developed that consisted of letting a 5-µl DBS infuse directly into 100 µl of MeOH, in a conventional LC vial. RESULTS: The parameters related to the DBS pretreatment, such as extraction time or internal standard addition, were investigated and optimized, demonstrating that passive infusion in a regular LC vial was sufficient to quantitatively extract the analytes of interest. The method was validated according to international criteria in the therapeutic concentration ranges of the selected compounds. CONCLUSION: The presented strategy proved to be efficient for the rapid analysis of the selected drugs. Indeed, the offline sample preparation was reduced to a minimum, using a small amount of organic solvent and consumables, without affecting the accuracy of the method. Thus, this approach enables simple and rapid DBS analysis, even when using a non-DBS-dedicated autosampler, while lowering the costs and environmental impact.

Determination of 241Pu in nuclear waste slurries: a comparative study using LSC and ICP-MS.

(241)Pu was determined in slurry samples from a nuclear reactor decommissioning project at the Paul Scherrer Institute (Switzerland). To validate the results, the (241)Pu activities of five samples were determined by LSC (TriCarb and Quantulus) and ICP-MS, with each instrument at a different laboratory. In lack of certified reference materials for (241)Pu, the methods were further validated using the (241)Pu information values of two reference sediments (IAEA-300 and IAEA-384). Excellent agreement with the results was found between LSC and ICP-MS in the nuclear waste slurries and the reference sediments.

Jóvenes y prácticas comunicativas: más allá de los datos estadísticos

La forma en que adolescentes y jóvenes utilizan las tecnologías de la información y la comunicación es diferente a la de la población adulta. Las prácticas son más intensivas y extensivas entre l@s más jóvenes, tal y como muestran las estadísticas disponibles. Este resultado, ampliamente conocido, nos lleva a preguntarnos ¿qué implicaciones tienen estas prácticas comunicativas de las generaciones más jóvenes?Tomando como punto de partida algunos estudios que analizan la situación, tanto en España como en otros países, revisaremos los cambios que ya se están produciendo en ámbitos que van desde el aprendizaje a la socialización. Revisaremos, asimismo, algunas propuestas que intentan dar una explicación teórica global de las prácticas y las actitudes comunicativas de jóvenes y adolescentes. En el análisis tendremos en cuenta el creciente proceso de individualización de nuestras sociedades y la presencia habitual de comunidades de práctica permanentemente conectadas que caracterizan a estas generaciones.

Les monedes en els contextos funeraris del suburbi oriental de Tàrraco: més enllà de Caront

La deposició de moneda a les tombes és un fenomen conegut i àmpliament debatut entre els especialistes. Comunament interpretada com a oferta votiva i enquadrada dins la genètica definició d'"òbol de Caront", la moneda ha estat un element d'aixovar poc estudiat i analitzat superficialment. A través de l'article es pretén examinar des d'una posició crítica aquest fest a partir de la documentació de les monedes trobades en contextos funeraris en el suburbi oriental de la ciutat de Tàrraco. A través del reexàmen de les monedes és possible una aproximació més realista i sensible a la gran variabilitat formal dels rituals funeraris d'època romana.

El trastorn específic del llenguatge : més enllà del perfil psicololingüistic

El Trastorn Específic del Llenguatge (TEL) és un dètficit lingüístic que afecta el desenvolupament normal del llenguatge, en qui es poden veure implicades tant la comprensió com l'expressió, i en què es mostra un rendiment cognitiu superior al linguístic. L'objectiu d'aquest treball és estudiar el perfil psicolingüístic de nens amb TEL. S'hi estudien setze nens, vuit amb TEL i vuit que segueixen la pauta estàndard de desenvolupament del llenguatge (NP); tots els nens tenen entre 5 i 9;4 anys d'edat. Les diferències són notables entre els dos grups de nens estudiats, tant quantitativament com qualitativament. En l'estudi es pot observar que la comprensió es relaciona directament amb els errors gramaticals i sintàctics en el nens amb TEL. També es destaquen les relacions existents entre errors de formulació i errors gramaticals i sintàctics, d'una banda, i entre aquests dos últims, de ['altra. Les característiques que mostren els nens amb TEL comprometen el seu procés d'escolarització i la seva integració social.

Ultra-performance liquid chromatography mass spectrometry and sensitive bioassay methods for quantification of posaconazole plasma concentrations after oral dosing.

Posaconazole (POS) is a new antifungal agent for prevention and therapy of mycoses in immunocompromised patients. Variable POS pharmacokinetics after oral dosing may influence efficacy: a trough threshold of 0.5 ?g/ml has been recently proposed. Measurement of POS plasma concentrations by complex chromatographic techniques may thus contribute to optimize prevention and management of life-threatening infections. No microbiological analytical method is available. The objective of this study was to develop and validate a new simplified ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method and a sensitive bioassay for quantification of POS over the clinical plasma concentration range. The UPLC-MS/MS equipment consisted of a triple quadrupole mass spectrometer, an electrospray ionization (ESI) source, and a C(18) analytical column. The Candida albicans POS-hypersusceptible mutant (MIC of 0.002 ?g/ml) ?cdr1 ?cdr2 ?flu ?mdr1 ?can constructed by targeted deletion of multidrug efflux transporters and calcineurin genes was used for the bioassay. POS was extracted from plasma by protein precipitation with acetonitrile-methanol (75%/25%, vol/vol). Reproducible standard curves were obtained over the range 0.014 to 12 (UPLC-MS/MS) and 0.028 to 12 ?g/ml (bioassay). Intra- and interrun accuracy levels were 106% ± 2% and 103% ± 4% for UPLC-MS/MS and 102% ± 8% and 104% ± 1% for bioassay, respectively. The intra- and interrun coefficients of variation were 7% ± 4% and 7% ± 3% for UPLC-MS/MS and 5% ± 3% and 4% ± 2% for bioassay, respectively. An excellent correlation between POS plasma concentrations measured by UPLC-MS/MS and bioassay was found (concordance, 0.96). In 26 hemato-oncological patients receiving oral POS, 27/69 (39%) trough plasma concentrations were lower than 0.5 ?g/ml. The UPLC-MS/MS method and sensitive bioassay offer alternative tools for accurate and precise quantification of the plasma concentrations in patients receiving oral posaconazole.