Dehydroaminophosphonic acids: Synthesis, reactivity and biological applications

Esta tesis doctoral trata sobre la síntesis y estudio de los ácidos α,β-deshidroaminofosfónicos, análogos fosforados de los α,β-deshidroaminoácidos. Estos últimos están presentes en múltiples péptidos, donde afectan de forma decisiva a su reactividad o propiedades conformacionales. Sin embargo, sólo se ha encontrado la estructura de deshidraminofosfonato en un péptido bioactivo: el antibiótico de amplio espectro dehydrophos. Su mecanismo de acción difiere significativamente del descrito tanto para deshidropéptidos y compuestos que contienen un ácido aminofosfónico en su estructura. Así, el dehydrophos es introducido por el microorganismo objetivo, donde libera un acetilfosfonato que resulta tóxico para la célula.Por estos motivos, en el primer capítulo de esta tesis doctoral se describe un método versátil y eficiente para la síntesis del péptido dehydrophos, basado en la generación del resto de dehidroaminofosfonato mediante la reacción de Horner-Wadsworth-Emmons entre formaldehído y un peptidilaminometil bisfosfonato que posee la secuencia peptídica del dehydrophos.Por otro lado, los ácidos acilfosfónicos y sus derivados son generalmente importantes compuestos bioactivos. Por tanto, los análogos del dehydrophos que posean en su estructura distintos sustituyentes podrían llegar a tener interesantes propiedades, ya que serían capaces de liberar en el interior del microorganismo un derivado de ácido acilfosfónico. La versatilidad del procedimiento desarrollado en el capítulo 1 se ha aprovechado para obtener compuestos con el esqueleto del dehydrophos en los que se ha introducido sustituyentes tanto en el grupo ácido fosfónico como en el residuo de vinilo. Por otro lado, dicho método sintético también permite modificar la secuencia peptídica de los compuestos. De este modo, el segundo capítulo de la tesis se ha dedicado al estudio de la síntesis de una serie de derivados del dehydrophos, y a estudiar como las variaciones introducidads en la estructura del dehydrophos afectan a la actividad biológica de los compuestos sintetizados.Además, en comparación con los α,β-deshidroamino ácidos, existen muy pocos estudios sobre la reactividad de los α,β-deshidroaminofosfonatos. Las reacciones estudiadas están limitadas a reacciones de hidrogenación selectiva del doble enlace, adición-1,4 asimétrica de organotrifluoroboratos catalizada por rodio, la cicloadición-1,3 de diazoalcanos y a reacciones de electrociclación. Por tanto, el tercer capítulo de la tesis se ha centrado en estudiar el uso de los deshidroaminofosfonatos como dienófilos en la reacción de Diels-Alder. En dicho estudio se ha analizado la influencia de los grupos protectores de los derivados de ácidos α,β-deshidroaminofosfónicos en el transcurso de la reacción, para así obtener biciclos que contienen un aminofosfonato cuaternario.<br /

Case study on the processing effort of neonyms, neologisms and non-neological units

Aquest article presenta evidències sobre l’esforç de processament d’unitats neològiques que pertanyen a un domini d’expertesa per part de subjectes especialistes en altres dominis. En aquest disseny preexperimental, es van mesurar els temps de reacció (RT) i les taxes de precisió en un grup d’hispanoparlants nadius, amb experiència en camps diferents de la ciència política, d’acord amb el disseny de Suárez et al. (en premsa). Aquest estudi aporta evidència empírica sobre el processament de neònims per part de participants especialistes en altres àmbits, en relació amb els neologismes lingüístics generals i les unitats no neològiques. En aquest sentit, permet contrastar els resultats obtinguts amb els proposats en l’estudi de Suárez et al. (en premsa), aportant evidències per afirmar que l’esforç de processament està relacionat amb l’experiència lingüística dels individus, la qual cosa permet l’ús de diferents mecanismes cognitius segons el grau de proximitat o distància amb el lèxic objecte d’estudi.This article presents evidence on the effort required to process neological units belonging to a specific domain of expertise by subjects who are specialists in other domains. In this pre-experimental design, reaction times (RTs) and accuracy rates were measured on a group of native Spanish speakers with expertise in fields other than political science, in line with the design of Suárez et al. (in press). This study provides empirical evidence regarding the processing of neonyms by participants who are specialists in other domains, in relation to general language neologisms and non-neological units. In this respect, it allows us to contrast the results obtained with those reported in the study by Suárez et al. (in press), providing evidence confirming that the processing effort is related to the individuals’ linguistic experience, allowing the use of different cognitive mechanisms according to the degree of proximity or distance with respect to the lexicon under study

Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel

Metastatic prostate cancer; Chemotherapy; Hormonal therapyCáncer de próstata metastásico; Quimioterapia; Terapia hormonalCàncer de pròstata metastàtic; Quimioteràpia; Teràpia hormonalBackground: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3-0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4-0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2-0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1-3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX

Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer.

The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression

Preliminary analysis of a questionnaire for assessing the social perception of air pollution

ABSTRACT: Objective To analyze the psychometric properties and the structural organization of a questionnaire designed to assess the social perception of air pollution and its health risks in the Valle de Aburrá (Colombia), a geographical area where environmental problems associated with air pollution have been identified. Methods A descriptive study was carried out, in which a questionnaire was designed and validated to determine three dimensions of social perception of air pollution: the socio-territorial dimension, the socio-cognitive dimension and the behavioral dimension. Some socio-demographical variables were also included. After the pilot study, the dimensions of the analysis were organized into 12 categories, made up of 111 items with Likert scales of four or five response options. The instrument was applied to a non-random sample of 318 participants, who were residents of Medellin city and Girardota town. Results After exploratory factor analysis (varimax rotation), the questionnaire was reduced to 68 items assessing seven dimensions of social perception of air pollution and its health risks. The total variance explained is 75 %, and the overall Cronbach's alpha reliability was 0.9. Discussion The dimensions found allow us to develop an approach to the structural organization of the social perception of air pollution in the context of study. Although some socio-cognitive and behavioral dimensions were confirmed, the socio-territorial dimension and the personal involvement variable were not configured as structural components and, conceptually, they need to be reworked. Confirmatory structural analysis of the dimensions of the questionnaire is required.RESUMEN: Objetivo Analizar las propiedades psicométricas y la organización estructural de un cuestionario diseñado para evaluar la percepción social de la contaminación del aire y de sus riesgos para la salud en el Valle de Aburrá, área geográfica donde se ha identificado una problemática ambiental asociada a la polución. Métodos Estudio descriptivo en el que se diseñó y validó un cuestionario que recogía tres dimensiones de la percepción social de la contaminación del aire (socio-territorial, socio-cognitiva y comportamental) y algunas variables sociodemográficas. Tras el estudio piloto, las dimensiones de análisis fueron organizadas en 12 categorías, conformadas por 111 ítems con escalas tipo Likert de cuatro o cinco opciones de respuesta. El instrumento fue aplicado a una muestra no probabilística de 318 participantes, los cuales eran residentes de Medellín y del municipio de Girardota. Resultados Tras el análisis factorial exploratorio (rotación varimax), el cuestionario se redujo a 68 ítems que evalúan siete dimensiones de la percepción social de la contaminación atmosférica y de sus riesgos para la salud. La varianza total explicada es del 75 % y la confiabilidad alpha de Cronbach de la prueba fue 0,9. Discusión Las dimensiones encontradas permiten aproximarse a la organización estructural de la percepción social de la polución y de sus riesgos sanitarios en el contexto de estudio. Aunque algunas dimensiones socio-cognitivas y comportamentales fueron confirmadas, la dimensión socio-territorial y la implicación personal no se configuraron como componentes estructurales y requieren ser reelaboradas conceptualmente. Resulta necesario realizar un análisis estructural confirmatorio de las dimensiones del cuestionario

Healthcare experience and their relationship with demographic, disease and healthcare-related variables: a cross-sectional survey of patients with chronic diseases using the IEXPAC scale.

[Abstract] BACKGROUND: Patient experience is acknowledged as a principal aspect of quality healthcare delivery, and it has implications with regard to outcomes. OBJECTIVES: Our objective was to evaluate the healthcare experience of patients with chronic diseases to identify patient-perceived healthcare gaps and to assess the influence of demographic and healthcare-related variables on patient experiences. METHODS: A cross-sectional survey was delivered to adult patients with chronic diseases: diabetes mellitus (DM), human immunodeficiency virus (HIV) infection, inflammatory bowel disease (IBD) or rheumatic diseases. Patient experiences were assessed with the Instrument for Evaluation of the Experience of Chronic Patients (IEXPAC) questionnaire, with possible scores ranging from 0 (worst) to 10 (best experience). RESULTS: Of the 2474 patients handed the survey, 1618 returned it (response rate 65.4%). Patients identified gaps in healthcare related mainly to access to reliable information and services, interaction with other patients and continuity of healthcare after hospital discharge. The mean ± standard deviation (SD) IEXPAC score was 6.0 ± 1.9 and was higher for patients with HIV (6.6 ± 1.7) than for those with rheumatic disease (5.5 ± 2.0), IBD (5.9 ± 2.0) or DM (5.9 ± 1.9) (p < 0.001). In multivariate models, better overall IEXPAC experience was associated with follow-up by the same physician, follow-up by a nurse, receiving healthcare support from others and treatment with subcutaneous or intravenous drugs. The multivariate model that confirmed patients with HIV or DM had better experience than did those with rheumatic diseases. CONCLUSIONS: Through IEXPAC, patients identified aspects for healthcare quality improvements and circumstances associated with better experience, which may permit greater redirection of healthcare toward patient-centered goals while facilitating improvements in social care and long-term healthcare quality

Tutorial action in the EHEA at the Faculty of Pharmacy of US: 4 years of experience of a student mentoring program

La Facultad de Farmacia de la Universidad de Sevilla (US) tiene en marcha un Programa de Alumnos Tutores desde 2006/07 con el objetivo de que alumnos de cursos superiores (AATT) tutelen a alumnos de nuevo ingreso (1x3). Pretende generar una actitud responsable en los AATT y favorecerles el desarrollo de habilidades sociales, objetivos cualitativos dentro de la educación universitaria que sirven como preparación previa a su inserción en el mundo laboral. La actividad es supervisada por Profesores Tutores (1x3) que analizan la evolución de ambos grupos de alumnos. Es una supervisión activa a través de distintas vías de acción para ayudar a la consecución de objetivos, tales como entrevistas periódicas, revisión de informes, acciones de apoyo como charlas sobre técnicas de estudio, coloquios sobre salidas laborales, exposiciones de las experiencias personales de algunos alumnos recientemente egresados, gestión estratégica de búsqueda de empleo, elaboración de portafolios,… Con respecto a la evolución del programa, el número de profesores ha crecido moderadamente llegando a una situación estable, mientras que el número de alumnos, tanto tutores como tutelados, ha crecido en un ritmo constante acorde a las restricciones indicadas. Los resultados son muy positivos, entendiéndose que el proyecto se enmarca en un contexto más cualitativo que cuantitativo y que el principal objetivo es el robustecimiento de la experiencia y asentar una dinámica de apoyo hacia los alumnos de nuevo ingreso y de planificación de tareas, tutela y responsabilidad en general de los alumnos tutores.The Faculty of Pharmacy of the University of Seville (US) has developed a Student Mentoring Program (from 2006/07 - present). The main objective of this project is that senior students act as Mentor Students for students at their first year in the University (1x3). It aims to generate a responsible attitude in mentor students and to promote the development of social skills, qualitative goals within higher education that serve as preparation prior to their integration into the world of work. This activity is supervised by Mentor Professors (1x3) that analyze the evolution of both groups of students. It is an active monitoring through various actions such as regular interviews, review of reports, support operations such as lectures on study skills, seminars on job opportunities, statements of personal experiences of some recently graduated students, strategic management job search, portfolio development... With regard to the development of the program, the number of Mentor Professors has grown moderately, reaching a stable condition, while the number of students, both tutor and supervised, has grown steadily in line with the restrictions indicated. The results are very positive, considering the more qualitative than quantitative character of the project and that the main objectives are the strengthening of the experience and the establishment of a dynamic support to the new students and scheduling and general responsibility for mentor students

Needs of patients with multi-morbidity and heart failure for the development of a mHealth to improve their self-management: A qualitative analysis

Objective: To provide practical information regarding needs, preferences of content and format of an app to assist the self-management in patients with multi-morbidity and heart failure (HF). Methods: The three-phase study was conducted in Spain. Six integrative reviews, a qualitative methodology based on Van Manen's hermeneutic phenomenology through semi-structured interviews and user stories were used. Data collection continued until data saturation was reached. All data were transcribed verbatim and analysed using a framework approach. Thematic analysis technique following the methods of Braun and Clarke was used for emerging themes. Results: Integrative reviews conducted included practical recommendations to include in the content and format of the App and helped create the interview guide. Interviews revealed 15 subthemes that captured the meaning of narratives offering contextual insights into the development of the App. The main effective mechanisms of multicomponent interventions for patients with HF must contain (a) components that increase the patient's understanding of HF, (b) self-care, (c) self-efficacy and participation of the family/informal caregiver, (4) psychosocial well-being and (5) professional support and use of technology. User stories revealed that patients prioritized improvements in direct contact with health services in case of emergency (90%), nutritional information (70%), type of exercises in order to improve their physical condition (75%) and information about food and drug interaction (60%). The importance of motivation messages (60%) was highlighted by transversal way. Conclusions: The three-phase process integrating theoretical basis, evidence from integrative reviews and research findings from target users has been considered a guide for future app development17 página

Androgen receptor and its splicing variant 7 expression in peripheral blood mononuclear cells and in circulating tumor cells in metastatic castration-resistant prostate cancer

Androgen receptor (AR) signaling remains crucial in castration-resistant prostate cancer (CRPC). Since it is also essential in immune cells, we studied whether the expression of AR full-length (ARFL) and its splicing variant ARV7 in peripheral blood mononuclear cells (PBMC) predicts systemic treatment response in mCRPC in comparison with circulating-tumor cells (CTC). We measured ARFL and ARV7 mRNA in PBMC and CTC from patients prior to receiving abiraterone (AA), enzalutamide (E), or taxanes by a pre-amplification plus quantitative reverse-transcription PCR. They were also tested in LNCaP-ARV7-transfected and in 22RV1 docetaxel-resistant (22RV1DR) cells. We studied 171 PBMC from 136 patients and from 24 non-cancer controls, and 47 CTC from 22 patients. High PBMC ARV7 levels correlated with worse AA/E and better taxane response. In taxane-treated patients high PBMC ARFL also correlated with longer progression-free survival (PFS). High ARV7 and ARFL expression were independently associated with better biochemical-PFS. Conversely, high CTC ARV7 and ARFL correlated with shorter radiological-PFS and overall survival, respectively. High ARV7 in 22RV1DR and LNCaP-ARV7 cells correlated with taxane resistance. In conclusion, ARFL and ARV7 at PBMC or CTC have a different predictive role in the taxane response, suggesting a potential influence of the AR pathway from PBMC in such response modulation