NCoA3 upregulation in breast cancer­associated adipocytes elicits an inflammatory profile.

Nuclear receptor coactivator 3 (NCoA3) is a transcriptional coactivator of NF­κB and other factors, which is expressed at relatively low levels in normal cells and is amplified or overexpressed in several types of cancer, including breast tumors. NCoA3 levels have been shown to be decreased during adipogenesis; however, its role in tumor­surrounding adipose tissue (AT) remains unknown. Therefore, the present study assessed the modulation of NCoA3 in breast cancer­associated adipocytes and evaluated its association with the expression of inflammatory markers. 3T3­L1 adipocytes were stimulated with conditioned medium from human breast cancer cell lines and the expression levels of NCoA3 were evaluated by reverse transcription­quantitative (q)PCR. NF­κB activation was measured by immunofluorescence, and tumor necrosis factor and monocyte chemoattractant protein 1 levels were analyzed by qPCR and dot blot assays. The results obtained from the in vitro model were supported using mammary AT (MAT) from female mice, MAT adjacent to tumors from patients with breast cancer and bioinformatics analysis. The results revealed that adipocytes expressing high levels of NCoA3 were mainly associated with a pro­inflammatory profile. In 3T3­L1 adipocytes, NCoA3 downregulation or NF­κB inhibition reversed the expression of inflammatory molecules. In addition, MAT from patients with a worse prognosis exhibited high levels of this coactivator. Notably, adipocyte NCoA3 levels could be modulated by inflammatory signals from tumors. The modulation of NCoA3 levels in synergy with NF­κB activity in MAT in a tumor context could be factors required to establish breast cancer­associated inflammation. As adipocytes are involved in the development and progression of breast cancer, this signaling network deserves to be further investigated to improve future tumor treatments.

Modelo demostrativo de identificación precoz y atención continua de pacientes con cáncer y necesidad paliativas / Demonstrative model for early identification and continuous care of cancer patients with palliative needs

Los cuidados paliativos (CP) se incorporaron en la salud pública de muchos países con gran variabilidad e inequidad. Argentina posee una incidencia de cáncer media-alta y el Programa Nacional de Cuidados Paliativos no identifica la población diana. El instrumento NECPAL CCOMS-ICO© identifica enfermos con necesidades paliativas. Combina una pregunta (¿Le sorprendería que su paciente falleciera en el próximo año?) con indicadores específicos. El objetivo fue identificar precozmente y mejorar la asistencia integral de pacientes con cáncer y necesidades paliativas. Se reporta la implementación de una intervención sanitaria (Programa Modelo de Atención Paliativa). MÉTODOS: Se incluyó a todos los pacientes oncológicos del hospital universitario (julio de 2014- julio de 2016). Se entrevistó a sus 10 médicos en 69 sesiones individuales con el NECPAL. Se diseñó un programa demostrativo en 4 etapas. RESULTADOS: Hubo 317 pacientes, 57% con necesidades paliativas (NECPAL+). Como resultado de la implementación, el 94% (n=172) de 183 pacientes NECPAL+ fueron derivados a CP (frente a 28% antes del programa); media de seguimiento de 7,4 meses y 183 fallecieron (28 en domicilio). Se superaron estándares de calidad de estructura, proceso y resultado. DISCUSIÓN: Por primera vez en Argentina, esta intervención sanitaria incluyó a casi la totalidad de pacientes con cáncer y necesidades paliativas tempranas en un programa de asistencia continua hasta su fallecimiento en el hospital o domicilio.

RAC3 influences the chemoresistance of colon cancer cells through autophagy and apoptosis inhibition.

BACKGROUND: RAC3 coactivator overexpression has been implicated in tumorigenesis, contributing to inhibition of apoptosis and autophagy. Both mechanisms are involved in resistance to treatment with chemotherapeutic agents. The aim of this study was to investigate its role in chemoresistance of colorectal cancer. METHODS: The sensitivity to 5-fluorouracil and oxaliplatin in colon cancer cells HT-29, HCT 116 and Lovo cell lines, expressing high or low natural levels of RAC3, was investigated using viability assays. RESULTS: In HCT 116 cells, we found that although 5-fluorouracil was a poor inducer of apoptosis, autophagy was strongly induced, while oxaliplatin has shown a similar ability to induce both of them. However, in HCT 116 cells expressing a short hairpin RNA for RAC3, we found an increased sensitivity to both drugs if it is compared with control cells. 5-Fluorouracil and oxaliplatin treatment lead to an enhanced caspase 3-dependent apoptosis and produce an increase of autophagy. In addition, both process have shown to be trigged faster than in control cells, starting earlier after stimulation. CONCLUSIONS: Our results suggest that RAC3 expression levels influence the sensitivity to chemotherapeutic drugs. Therefore, the knowledge of RAC3 expression levels in tumoral samples could be an important contribution to design new improved therapeutic strategies in the future.

El papel de estructura argumental en el procesamiento de los compuestos verbo-nombre del español: Evidencias experimentales / The role of semantic argument structure in spanish verb-noun compound words: Experimental evidence

Los compuestos verbo-nombre del español presentan la particularidad de carecer de un núcleo que aporte los rasgos morfológicos, de categoría o semántico-referenciales. El acceso al significado depende entonces de la relación que mantienen los constituyentes entre sí y no a partir de la identificación de un elemento nuclear, como ocurre en compuestos que poseen un lexema referencial (telaraña, bocacalle). Dentro del compuesto verbo-nombre, la relación semántica que se establece entre los constituyentes no es única. Si bien la estructura semántica prototípica responde al patrón agente-paciente (cortacésped), existen otras posibilidades argumentales, como las relaciones locativas (pasacalle). El estudio realizado tuvo como objetivo determinar hasta qué punto la estructura argumental proyectada por el verbo tiene una influencia en el procesamiento cognitivo de estas unidades. Primeramente, se llevó a cabo un juicio de aceptabilidad para asegurar que los estímulos se correspondieran con la realidad lingüística de los participantes del estudio experimental. A continuación, se administró una prueba de decisión léxica con compuestos que poseían distintos tipos de estructura argumental: (1) agente / paciente (algo que V a N, abrelatas), (2) agente / paciente menos prototípica (procesos metafóricos, chupasangre) y (3) locativos (lugar donde x hace V a N, guardamuebles). Los resultados muestran que los tiempos de decisión (respuesta) ante compuestos locativos fueron significativamente mayores que ante los prototípicos. Este resultado no puede ser explicado por diferencias en longitud o frecuencia de los compuestos o sus constituyentes, por lo que parecen apoyar la hipótesis de que la estructura argumental juega un rol central en el procesamiento de estas palabras.

Research on the processing of compound words offers important insights on how the mental lexicon is organized. It is a current topic in psycholinguistics if compound words are represented and processed as unitary lexical units (full-listing models) or only as individual constituents analyzed via acombinatorial mechanism (full-parsing models). There is enough experimental evidence that both mechanisms are involved (dual-route models). Several characteristics of the stimuli, like length, morphological family size, frequency of compounds and their constituents are important factors to determine how they are processed. Compound words are meaningful units that contain smaller meaningful units. Therefore, in the domain of compounds' studies, several hypotheses have been proposed to explain how only one interpretation is achieved from two independent meanings. Models that describe the construction of lexical semantic features in compound words, like APPLE - Automatic Progressive Parsing and Lexical Excitation (Libben 1994,1998) or CARIN - Competition Among Relations in Nominals (Gagné, 2000), are based on the notion of a morphological head. According to these theories the recognition of the head would trigger an interpretation of the whole word. In noun-noun compounds (pez espada, 'swordfish', telaraña 'spiderweb'), in which the head has the referential features, the identification of this head and the posterior clarification of the relationship with the non-head lexeme is the way to interpret the whole compound (pez 'fish' and tela 'web', respectively). However, not every compound has a head with the referential attributes inside. Verb-noun compounding is an extremely productive word-formation process in Romance languages. Spanish verb-noun compounds have the particularity of being exocentric: these constructions do not present a categorical, morphological or semantic head. Therefore, access to the meaning depends on the relationship between both of their constituent lexemes. For these units, the traditional distinction between semantically transparent and semantically opaque compounds is not suitable, because it doesn't take under consideration the projection of the argument structure by the verbal constituent. The semantic relationship established between the lexemes within a compound is not unique. While the prototypical semantic structure responds to the agent-patient pattern (cortacésped), there are other semantic possibilities, such as locative relationships (pasacalle). The present study addresses the issue of the comprehension of Spanish verb-noun compounds in order to provide evidence about the role of the argument structure projected by the first lexeme in the whole-word meaning. It is proposed that the argument structure of the verbal constituent has a cognitive influence on the processing and comprehension of these units. Firstly, an acceptability judgment test was administrated in order to identify a group of verb-noun compounds that were adequate for the Argentinean Spanish lexicon. Secondly, a lexical decision task was conducted with the stimuli selected as acceptable. Thirty native speakers (20 females), ranged in age from 19 to 34 years old, with at least 12 years of schooling, participated in the experiment. The lexical decision task included three types of compounds according to their argument structure: (1) Agent / patient (abrelatas), (2) Agent / patient with less prototypical features or metaphorical processes (chupasangre), and (3) locatives (guardamuebles). Stimuli were matched according to the whole-word and constituent frequency and length. For the statistical analysis, ANOVAs were calculated for error rates and response times (RTs) for each condition. Results show that reaction times (answers) to locative compounds were significantly higher than to agent-patient compounds. This contrast cannot be explained by differences in frequency or length, of the compounds or their constituents. Consequently, the present results seem to support the hypothesis that argument structure plays a central role in the processing of these words.