miR-218 targets survivin and regulates resistance to chemotherapeutics in breast cancer

Multidrug resistance (MDR) remains one of the most significant obstacles in breast cancer treatment, and this process often involves dysregulation of a great number of microRNAs (miRNAs). Some miRNAs are indicators of drug resistance and confer resistance to chemotherapeutic drugs, although our understanding of this complex process is still incomplete. We have used a combination of miRNA profiling and real-time PCR in two drug-resistant derivatives of MCF-7 and Cal51 cells. Experimental modulation of miR expression has been obtained by retroviral transfection. Taxol and doxorubicin IC50 values were obtained by short-term drug sensitivity assays. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays and the levels of apoptosis-related proteins bcl-2 and bax by real-time PCR and Western blot. miR target was studied using transient transfection of luciferase constructs with the 3 untranslated regions (UTR) of target mRNAs. Small interfering RNA-mediated genetic knock-down was performed in MDR cells and its modulatory effect on apoptosis examined. The effect of miRNA on tumorigenicity and tumor drug response was studied in mouse xenografts. miRNA profiling of two drug-resistant breast cancer cell models indicated that miR-218 was down-regulated in both MCF-7/A02 and CALDOX cells. Ectopic expression of miR-218 resensitized both drug-resistant cell lines to doxorubicin and taxol due to an increase in apoptosis. miR-218 binds survivin (BIRC5) mRNA 3-UTR and down-regulated reporter luciferase activity. Experimental down-regulation of survivin by RNA interference in drug-resistant cells did mimic the sensitization observed when miRNA-218 was up-regulated. In addition, resensitization to taxol was also observed in mouse tumor xenografts from cells over-expressing miR-218. miR-218 is involved in the development of MDR in breast cancer cells via targeting survivin and leading to evasion of apoptosis. Targeting miR-218 and survivin may thus provide a potential strategy for reversing drug resistance in breast cancer

Tendencias cognitivas y procesos de abstracción en el aprendizaje del Álgebra y de la Geometría

In the present paper we discuss eleven kinds of phenomena which make themselves manifest at the time students are learning new mathematical concepts and operations. These phenomena can be observed both in the classroom and during clinical interviews. When learning mathematics, new rules are constantly being formed, due to the fact that new ways are found to extend conceptual networks previously developed. A central aspect in this point of view is the idea of sense, as opposed to meaning, when speaking about an MSS. In all the cornments, we have tried to distinguish between these two notions: meaning and sense

East Wind, West Wind: Toward the modernization of traditional Chinese medicine.

Traditional Chinese medicine (TCM) has used herbal remedies for more than 2,000 years. The use of complimentary therapies has increased dramatically during the last years, especially in the West, and the incorporation and modernization of TCM in current medical practice is gaining momentum. We reflect on the main bottlenecks in the modernization of arcane Chinese herbal medicine: lack of standardization, safety concerns and poor quality of clinical trials, as well as the ways these are being overcome. Progress in these areas will facilitate the implementation of an efficacy approach, in which only successful clinical trials lead to the molecular characterization of active compounds and their mechanism of action. Traditional pharmacological methodologies will produce novel leads and drugs, and we describe TCM successes such as the discovery of artemisinin as well as many others still in the pipeline. Neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, cancer and cardiovascular disease are the main cause of mortality in the Western world and, with an increasing old population in South East Asia, this trend will also increase in the Far East. TCM has been used for long time for treating these diseases in China and other East Asian countries. However, the holistic nature of TCM requires a paradigm shift. By changing our way of thinking, from "one-target, one-drug" to "network-target, multiple-component-therapeutics," network pharmacology, together with other system biology methodologies, will pave the way toward TCM modernization

Características del emplazamiento, Petrología y Geoquímica de Espessartitas en el Plutón de la Maladeta: estudio preliminar

[Resumen] Los diques de lamprófidos espessartíticos son frecuentes en el plutón circunscrito de La Maladeta (Pirineos Centrales, Huesca-Lérida). Su emplazamiento, se produjo bajo unas condiciones confinadas y con un control estructural, afectando a todos los litotipos plutónicos (Cuarzo-Gabros, Granodioritas, Tonalitas y Sienogranitos) y, también a las etapas filonianas ácidas (Aplita y Pegmatitas). La composición mineral (con destacado contenido en anfíboles de composición hornblenda pargasítica) y la Geoquímica, definen una afinidad calco-alcalina cuya signatura en elementos mayores y trazas, es bastante análoga a la óbtenida en lamprófidos similares, emplazados en macizos granodioríticos. Esta afinidad presenta una relación genética con la granodiorita, como término volumétricamente más representativo del Macizo.[Abstract] Lamprophyric dykes (Spessartites) are frequent in the Maladeta circumscribe plutonic massif (Central Pyrenees, Huesca-Lérida). The setting of these dykes, under confinant strains and with a structural control, affected to á1l the plutonic rocktypes (Quanz-Gabbros, Granodiorites, Tonalites and Syenogranites) and to the acid dykes (Aplites and Pegmatites) too. The mineral (with high contents in Pargasitic-Hornblende amphiboles) and geochemical compositions, define a calc-alkaline affinity, very similar (Major and trace elements) to that of analogue lan prophyres, set in Granodioritic massifs. This affinity shows a genetic relation with the Granodiorite, as volumetrically most representative rock-type in the massif

Adaptive resistance is not responsible for long-term drug resistance in a cellular model of triple negative breast cancer

Resistance to cancer therapeutics represents a leading cause of mortality and is particularly important in cancers, such as triple negative breast cancer, for which no targeted therapy is available, as these are only treated with traditional chemotherapeutics. Cancer, as well as bacterial, drug resistance can be intrinsic, acquired or adaptive. Adaptive cancer drug resistance is gaining attention as a mechanism for the generation of long-term drug resistance as is the case with bacterial antibiotic resistance. We have used a cellular model of triple negative breast cancer (CAL51) and its drug resistance derivative (CALDOX) to gain insight into genome-wide expression changes associated with long-term doxorubicin (a widely used anthracycline for cancer treatment) resistance and doxorubicin-induced stress. Previous work indicates that both naïve and resistance cells have a functional p53-p21 axis controlling cell cycle at G1, although this is not a driver for drug resistance, but down-regulation of TOP2A (topoisomerase IIα). As expected, CALDOX cells have a signature characterized, in addition to down-regulation of TOP2A, by genes and pathways associated with drug resistance, metastasis and stemness. Both CAL51 and CALDOX stress signatures share 12 common genes (TRIM22, FAS, SPATA18, SULF2, CDKN1A, GDF15, MYO6, CXCL5, CROT, EPPK1, ZMAT3 and CD44), with roles in the above-mentioned pathways, indicating that these cells have similar functional responses to doxorubicin relaying on the p53 control of apoptosis. Eight genes are shared by both drug stress signatures (in CAL51 and CALDOX cells) and CALDOX resistant cells (FAS, SULF2, CDKN1A, CXCL5, CD44, SPATA18, TRIM22 and CROT), many of them targets of p53. This corroborates experimental data indicating that CALDOX cells, even in the absence of drug, have activated, at least partially, the p53-p21 axis and DNA damage response. Although this eight-gene signature might be an indicator of adaptive resistance, as this transient phenomenon due to short-term stress may not revert to its original state upon withdrawal of the stressor, previous experimental data indicates that the p53-p21 axis is not responsible for doxorubicin resistance. Importantly, TOP2A is not responsive to doxorubicin treatment and thus absent in both drug stress signatures. This indicates that during the generation of doxorubicin resistance, cells acquire genetic changes likely to be random, leading to down regulation of TOP2A, but selected during the generation of cells due to the presence of drug in the culture medium. This poses a considerable constraint for the development of strategies aimed at avoiding the emergence of drug resistance in the clinic

Petrology of the Maladeta granitoids ln the Tahüll-Lago Negro sector (Lérida)

[Resumen] El Macizo plutónico de La Maladeta (Huesca-Lérida) corresponde, en su sector central (Tahül1-lago Negro), a un plutón circunscrito, cuyo carácter polifásico, está representado por los cuatro pulsos siguientes: a) los Cuarzo-Gabros, ubicados en su extremo sur, b) las Granodioritas que, con contenidos variables en anfíbol y biotita, comprenden, en conjunto, el volumen dominante y el pulso más representativo, c) las tonalitas con alto contenido en biotita y, por último, d) los sienogranitos (de dos micas) situados en su zona más central. La composición modal y, en especial, el análisis químico de las fases minerales principales (piroxeno, anfíbol, plagioclasa, biotita, moscovita y feldespato) corroboran una evolución magmática gradual, desde las composiciones más indiferenciadas (Cuarzo-Gabros) hasta las más tardías (Sienogranitos). Se observa una buena correspondencia entre la evolución petrologica (a nivel espacia!) y la de composición mineral, obtenidas por nosotros, con la secuencia de edades radiométicas (Rb/ Sr y U/Pb) determinadas por MICHARD-VITRAC, A. el al, (1980). Esta zonación tiene, a su vez, una muy buena correspondencia con las pautas de evolución geoquímica (elementos mayores y trazas) obtenidas en estudios preliminares (ARRANZ, E., 1991; ARRANZ, E. el al., 1991 a, by c).[Abstract] The Maladeta plutonic Massif (Huesca-Lérida) corresponds, in its central area (Tahül1-Lago Negro), to a circumscribed pluton wich, with multiepisodic character, is represented by the fol1owing four pulses: a) the Quartz-Gabbros, located in its southern extreme brim, b) the Granodiorites that, with variable amount in amphibole and biotite, consist, as a whole, the dominant volume and the most representative pulse, c) the biotite-rich Tonalites and, lastly, d) the syenogranites (with two micas), located in its centermost point. The modal composition and, special1y, the chemical analysis in main mineral phases (pyroxene, amphibole, plagioclase, biotite, muscovite, and feldspar), confirm a gradual magmatic evolution, from' a more indifferentiate composition (Quartz-Gabbross) to the latest (Syenogranites). There exists a good correspondence between the petrological and mineralogical composition, obtained by us, with the sequence of radiometric dates (Rb/Sr and U/Pb) analysed by MICHARD-VITRAC el al., (1980). The petrological zonation has, in turn, a very good correspondence with the pattern of magmatic evolution (major and trace elements) obtained in preliminary studies (ARRANZ, E., 1991; ARRANZ, E. el al., 1991 a, b y c)

Composition and barometric implications of the amphiboles from the Maladeta plutonic complex (Central Pyrenees, Huesca-Lérida)

[Abstract] The composition of the amphiboles in basic rocks (gabbros and diorites), granodiorites, monzogranites with minor amphibole and mafic microgranular enclaves from the Maladetta massif, corresponds to calcic terms (magnesioHornblende, actinolitic hornblende and actinolite), with reduced values ofAl tot• The main substitutional types are edenite, pargasite and Ti-Tschermakite, with other minor types, generating compositions with an AIIV excess. The application of three of the proposed calibrations for the Altot in Horblende geobarometer, gives anomalously low pressure values for the cristallyzation of the plutonic rock-types, suggesting that the amphibole crystals were formed below 2 Kbar of pressure, and in a continous way to subsolidus conditions,probably at the same time as AI-saturating phases formed

Modeling the Temporal Nature of Human Behavior for Demographics Prediction

Mobile phone metadata is increasingly used for humanitarian purposes in developing countries as traditional data is scarce. Basic demographic information is however often absent from mobile phone datasets, limiting the operational impact of the datasets. For these reasons, there has been a growing interest in predicting demographic information from mobile phone metadata. Previous work focused on creating increasingly advanced features to be modeled with standard machine learning algorithms. We here instead model the raw mobile phone metadata directly using deep learning, exploiting the temporal nature of the patterns in the data. From high-level assumptions we design a data representation and convolutional network architecture for modeling patterns within a week. We then examine three strategies for aggregating patterns across weeks and show that our method reaches state-of-the-art accuracy on both age and gender prediction using only the temporal modality in mobile metadata. We finally validate our method on low activity users and evaluate the modeling assumptions.Comment: Accepted at ECML 2017. A previous version of this paper was titled 'Using Deep Learning to Predict Demographics from Mobile Phone Metadata' and was accepted at the ICLR 2016 worksho

Las doleritas toleiticas triasicas del sector SE de la Cordillera Ibérica : Petrología y Geoquímica

Las doleritas toleíticas aflorantes en diapiros triásicos del SE de la Cordillera Ibérica (Alfarp, Quesa y Lugar Nuevo de Fenollet, SE de Valencia) representan líquidos diferenciados (valores bajos en Ni, Cr y mg*) emplazados como sills, de escaso espesor, por debajo de sedimentos (arcillas, margas y yesos), poco consolidados, del límite Triásico superior-Hettangiense. Su composición mineral y geoquímica, con afinidad toleítica continental y similitud a MORB, evidencia el carácter menos diferenciado de las doleritas de Alfarp, respecto a las de Quesa, siendo las doleritas aflorantes en Fenollet las que presentan una composición más evolucionada. Estas doleritas son la expresión de un magmatismo poco profundo, asociado al inicio del rifting mesozoico, desarrollado en la zona de intersección del rift celtibérico y el borde NE del surco bético. Este magmatismo presenta claras diferencias respecto a las doleritas toleíticas, menos diferenciadas, de los dominios pirenaico y bético.The tholeiitic dolerites that crop out in three diapirs of the SE of the Iberian Chain (Alfarp, Quesa and Lugar Nuevo de Fenollet, Valencia), are the expression of evolved (iow Ni, Cr and mg* values) basic magmas, injected into poorly lithified sediments (iutites, marls and gypsum) which represent the Upper Triassic (Keuper facies)-Hettangian boundary, developing sills with reduced thickness. Their mineral and whole-rock geochemical compositions indicate a continental tholeiitic affinity and certain similarities to a MORB composition and, on the other hand, show that the Alfarp dolerites represent the less evolved compositions, whereas the Fenollet dolerites show a significantly greater differentiation. These rocks are the expression of a shallow magmatism, related to the initial stages of the mesozoic rifting that affected the intersection of the Celtiberian Rift with the Betic Graben. This magmatism is clearly different of the isochronous tholeiitic magmatism (dolerites) which crops out at the Pyrenees and [email protected]

Injuries in Physical Education of High School. A Problem?

El control de la incidencia de lesiones en la clase de Educación Física debe ser un factor prioritario para la salud pública. El objetivo de este estudio es analizar la incidencia de lesiones en las clases de Educación Física (EF) y cómo se relacionan con la falta de participación de los estudiantes. Estudio de cohortes prospectivo. Conglomerado de muestreo bi-etapa para un total de 637 estudiantes. Las ausencias y las lesiones se registraron durante el curso escolar. De 1.463 sesiones, solo el 4,58% registró ausencias causadas por lesión (0,33% de la participación total esperada). La tasa de lesiones producidas en las clases de Educación Física fue de 1,90 por cada 1.000 horas de participación. La frecuencia de ausencia en las clases de Educación Física debido a una lesión es muy baja en comparación con la participación general esperada; por lo tanto, no es un factor que influya significativamente en la tasa de participación de los estudiantesThe incidence of injuries in physical education class should be a priority factor for public health. The aim of this study is to analyze the incidence of injuries in Physical Education (PE) lessons and how they relate to lack of full student participation. Prospective cohort study. Conglomerate bi-stage sampling for a total of 637 students. Absence and injuries were recorded for the school year. Of 1463 lessons, only 4.58% were documented with identification of the causal incident (0.33% of the total participation expected). The rate of injuries produced in PE lessons was of 1.90 for every 1000 hours of participation. The frequency of absence of in PE lessons due to injury is very low compared to the overall expected participation; therefore it is not a factor that influences the rate of student participation significantl