Teatro Contemporáneo y Medios audiovisuales : primer acercamiento teórico

La investigación analiza las diferentes escrituras escénicas que se producen cuando el espacio escénico hace uso de los medios audiovisuales. Se centra, esencialmente, en un teatro contemporáneo que fusiona la tecnología con el tiempo-espacio performativo para generar una nueva teatralidad y/o nuevos discursos, impensables sin el vínculo directo entre los dos medios. Este contexto favorece un acercamiento a la creación teatral desde unos parámetros diferentes a la tradición escénica clásica. Un nuevo teatro que replantea la relación entre obra-espectador y obra-proceso de creación.L'investigació analitza les diferents escriptures escèniques que es produeixen quan l'espai escènic utilitza els mitjans audio-visuals. Se centra, essencialment, en un teatre contemporani que fusiona la tecnologia amb l'espai-temps preformatiu, per a generar una nova teatralitat i/o nous discursos impensables sense el vincle directe entre els dos mitjans. Aquest context ofereix un apropament a la creació teatral des d'uns paràmetres diferents a la tradició escènica clàssica. Un nou teatre que replanteja la relació entre obra-espectador i obra-procés de creació

Correction : Monitoring EGFR -T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer

Osimertinib is efficacious in lung cancer patients with epidermal growth factor receptor (EGFR) mutations and acquired resistance (AR) to EGFR tyrosine kinase inhibitors due to EGFR -T790M mutation (T790M). We sought to describe T790M changes in serum/plasma during osimertinib therapy and correlate these changes with treatment outcomes. Serum/plasma from EGFR -mutant lung cancer patients with T790M-AR was collected before and during osimertinib treatment. Changes in T790M were evaluated using a peptide-nucleic acid-PCR assay, and correlated with clinical and radiographic response. Thirteen patients were included. Median time on osimertinib treatment was 10.6 months with a median progression-free survival of 13.6 months. Best response to osimertinib was partial response (PR), stable disease (SD) or progression (PD) in 46.1%, 30.8% and 23.1% of patients, respectively. Most of the patients were paucisymptomatic at baseline. Symptom improvement was reported in 66.6% of responder patients; while symptoms remained stable in 75% of patients with SD, and 66% of patients with PD had clinical deterioration. Three patterns of T790M changes during osimertinib treatment were identified. T790 remained detectable with PD or a short-lasting SD in 15.4% of the patients. T790M disappeared in 69.2% of patients with PR or SD. T790M disappeared, despite clinical and/or radiographic progression in 15.4% of the patients. Changes of T790M in serum/plasma in EGFR -mutant lung cancer patients with T790M-AR might be a useful marker of symptomatic and radiographic outcome to osimertinib. Longer follow-up is needed to establish if subsequent emergence of T790M could be a marker of resistance

Monitoring EGFR -T790M mutation in serum/plasma for prediction of response to third-generation EGFR inhibitors in patients with lung cancer

Osimertinib is efficacious in lung cancer patients with epidermal growth factor receptor (EGFR) mutations and acquired resistance (AR) to EGFR tyrosine kinase inhibitors due to EGFR -T790M mutation (T790M). We sought to describe T790M changes in serum/plasma during osimertinib therapy and correlate these changes with treatment outcomes. Serum/plasma from EGFR -mutant lung cancer patients with T790M-AR was collected before and during osimertinib treatment. Changes in T790M were evaluated using a peptide-nucleic acid-PCR assay, and correlated with clinical and radiographic response. Thirteen patients were included. Median time on osimertinib treatment was 10.6 months with a median progression-free survival of 13.6 months. Best response to osimertinib was partial response (PR), stable disease (SD) or progression (PD) in 46.1%, 30.8% and 23.1% of patients, respectively. Most of the patients were paucisymptomatic at baseline. Symptom improvement was reported in 66.6% of responder patients; while symptoms remained stable in 75% of patients with SD, and 66% of patients with PD had clinical deterioration. Three patterns of T790M changes during osimertinib treatment were identified. T790 remained detectable with PD or a short-lasting SD in 15.4% of the patients. T790M disappeared in 69.2% of patients with PR or SD. T790M disappeared, despite clinical and/or radiographic progression in 15.4% of the patients. Changes of T790M in serum/plasma in EGFR -mutant lung cancer patients with T790M-AR might be a useful marker of symptomatic and radiographic outcome to osimertinib. Longer follow-up is needed to establish if subsequent emergence of T790M could be a marker of resistance

Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Immunohistochemistry (IHC) with mutation-specific antibodies may be an ancillary method of detecting EGFR mutations in lung cancer patients.</p> <p>Methods</p> <p>EGFR mutation status was analyzed by DNA assays, and compared with IHC results in five non-small-cell lung cancer (NSCLC) cell lines and tumor samples from 78 stage IV NSCLC patients.</p> <p>Results</p> <p>IHC correctly identified del 19 in the H1650 and PC9 cell lines, L858R in H1975, and wild-type EGFR in H460 and A549, as well as wild-type EGFR in tumor samples from 22 patients. IHC with the mAb against EGFR with del 19 was highly positive for the protein in all 17 patients with a 15-bp (ELREA) deletion in exon 19, whereas in patients with other deletions, IHC was weakly positive in 3 cases and negative in 9 cases. IHC with the mAb against the L858R mutation showed high positivity for the protein in 25/27 (93%) patients with exon 21 EGFR mutations (all with L858R) but did not identify the L861Q mutation in the remaining two patients.</p> <p>Conclusions</p> <p>IHC with mutation-specific mAbs against EGFR is a promising method for detecting EGFR mutations in NSCLC patients. However these mAbs should be validated with additional studies to clarify their possible role in routine clinical practice for screening EGFR mutations in NSCLC patients.</p

Population-based colorectal cancer screening programmes using a faecal immunochemical test:Should faecal haemoglobin cut-offs differ by age and sex?

Abstract Background The Basque Colorectal Cancer Screening Programme has both high participation rate and high compliance rate of colonoscopy after a positive faecal occult blood test (FIT). Although, colorectal cancer (CRC) screening with biannual (FIT) has shown to reduce CRC mortality, the ultimate effectiveness of the screening programmes depends on the accuracy of FIT and post-FIT colonoscopy, and thus, harms related to false results might not be underestimated. Current CRC screening programmes use a single faecal haemoglobin concentration (f-Hb) cut-off for colonoscopy referral for both sexes and all ages. We aimed to determine optimum f-Hb cut-offs by sex and age without compromising neoplasia detection and interval cancer proportion. Methods Prospective cohort study using a single-sample faecal immunochemical test (FIT) on 444,582 invited average-risk subjects aged 50–69 years. A result was considered positive at ≥20 μg Hb/g faeces. Outcome measures were analysed by sex and age for a wide range of f-Hb cut-offs. Results We analysed 17,387 positive participants in the programme who underwent colonoscopy. Participation rate was 66.5%. Men had a positivity rate for f-Hb of 8.3% and women 4.8% (p < 0.0001). The detection rate for advanced neoplasia (cancer plus advanced adenoma) was 44.0‰ for men and 15.9‰ for women (p < 0.0001). The number of colonoscopies required decreased in both sexes and all age groups through increasing the f-Hb cut-off. However, the loss in CRC detection increased by up to 28.1% in men and 22.9% in women. CRC missed were generally at early stages (Stage I-II: from 70.2% in men to 66.3% in women). Conclusions This study provides detailed outcomes in men and women of different ages at a range of f-Hb cut-offs. We found differences in positivity rates, neoplasia detection rate, number needed to screen, and interval cancers in men and women and in younger and older groups. However, there are factors other than sex and age to consider when consideration is given to setting the f-Hb cut-off

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

LKB1/ AMPK / TSC2 signaling pathway alterations in non-small-cell-lung-carcinoma

El gen supresor tumoral LKB1/STK11b, codifica una serina/treonina quinasa. Las mutaciones de línea germinal en LKB1 están asociadas al síndrome de Peutz-Jeghers (PJS), trastorno dominante autosómico caracterizado por el crecimiento de pólipos en el tracto gastrointestinal, y depósitos de melanina mucocutánea, aumentando el riesgo de ciertos cánceres, incluido el de pulmón. El locus de PJS se encuentra situado en el cromosoma 19p13.3 y el gen responsable fue identificado como LKB1. Las mutaciones del gen LKB1 también están asociadas a los adenocarcinomas de pulmón, ocurren aproximadamente en un tercio de los tumores primarios y en la mitad de las líneas celulares de adenocarcinoma de pulmón, implicando a LKB1 en la patogénesis del cáncer de pulmón. Estudios recientes sugieren que la vía de señalización de LKB1 juega un papel en la protección de las células frente a la apoptosis, en respuesta a niveles de energía o nutrientes bajos, lográndose en parte a través de la supresión de la actividad de mTOR. Hay evidencias en la bibliografía que demuestran que LKB1 activa al complejo heterotrimerico AMPK, formado por tres subunidades, una catalítica (α) y dos reguladoras (β y γ). AMPK es un sensor de energía celular que contribuye a regular el balance energético y la ingesta calórica en la célula. Posteriormente, AMPK fosforila a TSC2. El heterodímero TSC1-TSC2 actúa para inhibir la actividad de mTOR, que es esencial para el control del crecimiento celular y la proliferación. Así, LKB1 funciona como un regulador negativo de mTOR. Está demostrado que LKB1 también regula 11 de las 12 quinasas de la subfamilia de quinasas AMPK in vitro, sugiriendo que una de las funciones del gen supresor LKB1 podría ser la regulación de la vía de señalización de AMPK. Por tanto, LKB1 podría ser un blanco potencial para el tratamiento de cáncer y trastornos metabólicos. Nuestros principales objetivos fueron: ▪ Determinar la frecuencia de alteraciones genéticas y epigenéticas en la vía de señalización LKB1/AMPK/TSC2 en CPCNP, en un panel de 23 líneas celulares (4 líneas celulares epiteliales normales bronquiales inmortalizadas con SV40 y 19 líneas celulares de CPCNP). ▪ Estudiar el estado de metilación de 4 quinasas de la subfamilia de quinasas AMPK: BRSK1, BRSK2, MARK1 MARK4 en 23 líneas celulares. ▪ Examinar la vía LKB1/BRSK2. ▪Analizar el estado de metilación de BRSK2 en 58 FFIP de pacientes con CPCNP. ▪ Determinar el impacto de la pérdida de LKB1 en líneas celulares de CPCNP. Las principales conclusiones fueron: ▪ Las mutaciones de LKB1 no se limitan a los adenocarcinomas, también ocurren en otro subtipo de CPCNP, los carcinomas de células grandes. No se encontró metilación en el promotor de LKB1 en ninguna de las líneas celulares de cáncer pulmón analizadas en este estudio. ▪ No se detectaron mutaciones ni ningún grado de metilación en los distintos componentes estudiados de AMPK y TSC en las 23 líneas celulares analizadas. ▪ De la subfamilia de quinasas de AMPK analizadas, el estado de metilación del promotor BRSK2 representa el de mayor porcentaje: ~ 26% de las líneas celulares y 25,8% del grupo de 58 FFIP de pacientes con CPCNP. ▪ El estado de metilación de BRSK2 se correlaciona significativamente con cuatro parámetros clinicopatológicos: estadio tumoral (P = 0, 025), histología (P = 0, 001), tamaño tumoral (P = 0, 073) y nódulos afectados (P = 0, 04), sugiriendo que el estado de metilación del promotor BRSK2 podría utilizarse como un nuevo biomarcador en la progresión del cáncer de pulmón. ▪ La interrupción de la vía LKB1/BRSK2 podría ser un importante mecanismo molecular, durante el desarrollo del cáncer de pulmón.LKB1, also known as STK11b, is a serine/threonine kinase that functions as a suppressor of tumor growth. Germ line mutations in LKB1 are associated with the Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by benign hemartomas of the gastrointestinal tract and mucocutaneous melanin deposits and an increased risk of certain cancers, including lung. The main PJS locus has been mapped to chromosome 19p13.3, and the gene responsible was identified as LKB1. Mutations in LKB1 gene are also associated with sporadic lung adenocarcinomas and occurs in approximately one-third of primary tumors and half of lung adenocarcinoma cells lines, implicating LKB1 in the pathogenesis of lung cancer. Recent evidence suggests that LKB1 signaling plays a role in protecting cells from apoptosis in response to energy or nutrient deprivation, which is achieved in part through the suppression of mTOR activity. Evidence from the literature supports a protein kinase cascade model in which LKB1 phosphorylates AMPK. AMPK is a heterotrimeric complex comprising a catalytic subunit (α) and two regulatory subunits (β and γ) that act as an intracellular energy sensor maintaining the energy balance within the cell. AMPK subsequently phosphorylates TSC2. Together the TSC1-TSC2 heterodimer acts to suppress the activity of mTOR, which is essential for the control of cell growth and proliferation. Thus, LKB1 functions as a negative regulator of mTOR. Additionally, LKB1 has been shown to regulate 11 of the 12 AMPK family members in vitro, suggesting that one of the tumour suppressor functions of LKB1 may be regulation of AMPK signaling. Therefore, LKB1 could be a potential target for treatment of both cancer and metabolic disorders. In this work we sought to study the signal transduction LKB1/AMPK/TSC2 pathway alterations that contribute to the pathogenesis NSCLC. Our major objectives were: ▪To determine the frequency of genetic and epigenetic alterations in the signal traduction LKB1/AMPK/TSC2 pathway in NSCLC in a panel of 23 cell lines (4 normal bronchial epithelial cell lines immortalized with SV40 and 19 NSCLC cell lines). ▪ To study some components of AMPK-related kinase family that could be activated downstream of LKB1, in particular we analyzed the methylation status of: BRSK1, BRSK2, MARK1, MARK4 in our panel of 23 cell lines. ▪ To examine LKB1/BRSK2 signaling.▪ To make a clinical validation of BRSK2 methylation status, in 58 FFPE of patients with NSCLC. ▪ To determinate the impact of LKB1 depletion on NSCLC cell lines. The major conclusions of this work were: ▪ LKB1 mutations are not confined to adenocarcinomas, they also occur in other NSCLC subtype such as large cell carcinomas. But we found no evidence of LKB1 methylation in any NSCLC cell lines used in this study. ▪ There are not sequence alterations or/and promoter methylation of AMPK and TSC components studied in our 23 panel cell lines. ▪ Of the four AMPK related kinases -BRSK1, BRSK2, MARK1 and MARK4- studied, BRSK2 represents the highest percentage of methylation; ~26 % of NSCLC cell lines and 25.8% in the 58 NSCLC samples. ▪ BRSK2 methylation is significantly correlated with four clinicopatological parameters: tumor stage (P=0,025), histology (P=0,001), tumor size (P=0,073) and nodules affected (P=0,04), suggesting that methylation of BRSK2 could provide a novel biomarker for disease progression in lung cancer. ▪ The disruption of LKB1/BRSK2 signaling could be important in the carcinogenesis of lung, as a molecular mechanism for the development of lung cancer

La Experiencia perceptiva en la Performance Intermedial

A la portada: Institut del Teatre de BarcelonaLa pregunta que impulsa esta investigación, surge desde la posibilidad atribuida a la práctica performativa intermedial para crear nuevos universos perceptivos en relación al espectador. La interrelación entre teatro y medios digitales, desde la perspectiva intermedial, se presenta como un lugar en medio. Se trata de un fenómeno de hibridación capaz de desestabilizar los elementos básicos atribuidos a las artes en vivo: el espacio, el tiempo y el cuerpo. Se trata de una mutación que se origina a través de la convergencia entre lo teatral y lo digital, que abre la posibilidad para que sucedan nuevas situaciones que afecten directamente al modo en que el espectador las percibe. Esta investigación pretende entender el evento intermedial en relación el universo perceptivo del sujeto. Sin embargo, el objetivo de esta investigación, no es únicamente desvelar esos posibles modelos receptivos, sino descubrir que discursos y metodologías nos pueden ayudar a hacerlo. El marco que determina la base teórica de este estudio, toma como referencias principales los discursos contemporáneos generados desde ámbitos diversos: Estudios de comunicación y nuevos medios, Estudios sobre performance y teatro y Estudios sobre estética y filosofía. Marshall McLuhan, Jay David Bolter y Richard Grusin, Chiel Kattenbelt, Erika Fischer-Lichte, Jacques Rancière o Philip Auslander son algunas de la variedad de voces a las que apela esta investigación. Asimismo, se citan creadores, tanto vinculados con la creación new media como a las artes en vivo, internacionales como locales, con el objetivo de entender los diversos paradigmas teóricos que se presentan. Algunos de los cuales son los siguientes: Big Art Group, Station House Opera, Chris Milk, Gob Squad, The Crew Project, Marcel·lí Antúnez Roca, Rimini Protokoll, Blast Theory, Paul Sermon, María Jerez, Roger Bernat, etc. La Tesis se divide en seis capítulos. El Capítulo I opera como una especie de introducción y presenta aquellos conceptos que son más relevantes a la hora de abordar el estudio de la performance intermedial. Los Capítulos II-IV, se presentan como núcleos argumentales que pretenden desmontar el debate en torno a las diferencias ontológicas que tradicionalmente parecen establecerse entre el medio teatral y el medio tecnológico. El Capítulo V presenta, a través del fenómeno de mutación, algunos casos prácticos situados dentro de la práctica intermedial más contemporánea. Estructurado en cuatro subcapítulos, expone las cuatro mutaciones principales que el arte teatral muestra desde la perspectiva intermedial: la mutación espacial, corporal, estructural y temporal. El último y sexto capítulo, se centra en el análisis de la experiencia perceptiva y la figura del espectador dentro de la práctica performativa intermedial.The question that drives this research arises from the possibility attributed to the intermedial performance practice to create new perceptual universes in relation to the spectator. The interrelation between theatre and digital media, from the intermedial perspective, is presented as a place in between. It is a phenomenon of hybridization capable of destabilizing the basic elements attributed to live arts: space, time and body. This is a mutation created through the convergence between live arts and digital medium, that opens up the possibility for new situations affecting directly the way the spectator perceives them. This research aims to understand the intermedial event related to the perceptual universe of the subject. However, the objective of this research is not only to reveal these potential receptive models, but also discover the discourses and the methodologies that can help us do so. The theoretical framework of this research takes as principal references the contemporary discourses generated from several fields: communication and new media studies, theatre and performance studies and studies on aesthetics and philosophy. Marshall McLuhan, Jay David Bolter and Richard Grusin, Chiel Kattenbelt, Erika Fischer-Lichte, Jacques Rancière or Philip Auslander, are some of the different voices introduced in this research. In order to understand the theoretical paradigms presented in this study, both artists linked to new media art and live performance, international and local, are also mentioned. Some of which are: Big Art Group, Station House Opera, Chris Milk, Gob Squad, The Crew Project, Marcel·lí Antunez Roca, Rimini Protokoll, Blast Theory, Paul Sermon, Maria Jerez, Roger Bernat, etc. The thesis is divided into six chapters. Chapter I operates as a kind of introduction and presents concepts that seem more relevant to addressing the study of intermedia performance. Chapters II-IV are presented as core argument seeking to remove the debate on the ontological differences traditionally established between the performance and technology. In Chapter V, through the phenomenon of mutation, some case studies located within the most contemporary intermedial practice are presented. Structured in four chapters, it outlines the four principal mutations that the live arts show from the intermedial perspective: spatial, bodily, structural and temporal mutation. The last and sixth chapter focuses on the analysis of perceptual experience and the figure of the spectator within the intermedial performance practice

LKB1/ AMPK / TSC2 signaling pathway alterations in non-small-cell-lung-carcinoma

El gen supresor tumoral LKB1/STK11b, codifica una serina/treonina quinasa. Las mutaciones de línea germinal en LKB1 están asociadas al síndrome de Peutz-Jeghers (PJS), trastorno dominante autosómico caracterizado por el crecimiento de pólipos en el tracto gastrointestinal, y depósitos de melanina mucocutánea, aumentando el riesgo de ciertos cánceres, incluido el de pulmón. El locus de PJS se encuentra situado en el cromosoma 19p13.3 y el gen responsable fue identificado como LKB1. Las mutaciones del gen LKB1 también están asociadas a los adenocarcinomas de pulmón, ocurren aproximadamente en un tercio de los tumores primarios y en la mitad de las líneas celulares de adenocarcinoma de pulmón, implicando a LKB1 en la patogénesis del cáncer de pulmón. Estudios recientes sugieren que la vía de señalización de LKB1 juega un papel en la protección de las células frente a la apoptosis, en respuesta a niveles de energía o nutrientes bajos, lográndose en parte a través de la supresión de la actividad de mTOR. Hay evidencias en la bibliografía que demuestran que LKB1 activa al complejo heterotrimerico AMPK, formado por tres subunidades, una catalítica (α) y dos reguladoras (β y γ). AMPK es un sensor de energía celular que contribuye a regular el balance energético y la ingesta calórica en la célula. Posteriormente, AMPK fosforila a TSC2. El heterodímero TSC1-TSC2 actúa para inhibir la actividad de mTOR, que es esencial para el control del crecimiento celular y la proliferación. Así, LKB1 funciona como un regulador negativo de mTOR. Está demostrado que LKB1 también regula 11 de las 12 quinasas de la subfamilia de quinasas AMPK in vitro, sugiriendo que una de las funciones del gen supresor LKB1 podría ser la regulación de la vía de señalización de AMPK. Por tanto, LKB1 podría ser un blanco potencial para el tratamiento de cáncer y trastornos metabólicos. Nuestros principales objetivos fueron: ▪ Determinar la frecuencia de alteraciones genéticas y epigenéticas en la vía de señalización LKB1/AMPK/TSC2 en CPCNP, en un panel de 23 líneas celulares (4 líneas celulares epiteliales normales bronquiales inmortalizadas con SV40 y 19 líneas celulares de CPCNP). ▪ Estudiar el estado de metilación de 4 quinasas de la subfamilia de quinasas AMPK: BRSK1, BRSK2, MARK1 MARK4 en 23 líneas celulares. ▪ Examinar la vía LKB1/BRSK2. ▪Analizar el estado de metilación de BRSK2 en 58 FFIP de pacientes con CPCNP. ▪ Determinar el impacto de la pérdida de LKB1 en líneas celulares de CPCNP. Las principales conclusiones fueron: ▪ Las mutaciones de LKB1 no se limitan a los adenocarcinomas, también ocurren en otro subtipo de CPCNP, los carcinomas de células grandes. No se encontró metilación en el promotor de LKB1 en ninguna de las líneas celulares de cáncer pulmón analizadas en este estudio. ▪ No se detectaron mutaciones ni ningún grado de metilación en los distintos componentes estudiados de AMPK y TSC en las 23 líneas celulares analizadas. ▪ De la subfamilia de quinasas de AMPK analizadas, el estado de metilación del promotor BRSK2 representa el de mayor porcentaje: ~ 26% de las líneas celulares y 25,8% del grupo de 58 FFIP de pacientes con CPCNP. ▪ El estado de metilación de BRSK2 se correlaciona significativamente con cuatro parámetros clinicopatológicos: estadio tumoral (P = 0, 025), histología (P = 0, 001), tamaño tumoral (P = 0, 073) y nódulos afectados (P = 0, 04), sugiriendo que el estado de metilación del promotor BRSK2 podría utilizarse como un nuevo biomarcador en la progresión del cáncer de pulmón. ▪ La interrupción de la vía LKB1/BRSK2 podría ser un importante mecanismo molecular, durante el desarrollo del cáncer de pulmón.LKB1, also known as STK11b, is a serine/threonine kinase that functions as a suppressor of tumor growth. Germ line mutations in LKB1 are associated with the Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by benign hemartomas of the gastrointestinal tract and mucocutaneous melanin deposits and an increased risk of certain cancers, including lung. The main PJS locus has been mapped to chromosome 19p13.3, and the gene responsible was identified as LKB1. Mutations in LKB1 gene are also associated with sporadic lung adenocarcinomas and occurs in approximately one-third of primary tumors and half of lung adenocarcinoma cells lines, implicating LKB1 in the pathogenesis of lung cancer. Recent evidence suggests that LKB1 signaling plays a role in protecting cells from apoptosis in response to energy or nutrient deprivation, which is achieved in part through the suppression of mTOR activity. Evidence from the literature supports a protein kinase cascade model in which LKB1 phosphorylates AMPK. AMPK is a heterotrimeric complex comprising a catalytic subunit (α) and two regulatory subunits (β and γ) that act as an intracellular energy sensor maintaining the energy balance within the cell. AMPK subsequently phosphorylates TSC2. Together the TSC1-TSC2 heterodimer acts to suppress the activity of mTOR, which is essential for the control of cell growth and proliferation. Thus, LKB1 functions as a negative regulator of mTOR. Additionally, LKB1 has been shown to regulate 11 of the 12 AMPK family members in vitro, suggesting that one of the tumour suppressor functions of LKB1 may be regulation of AMPK signaling. Therefore, LKB1 could be a potential target for treatment of both cancer and metabolic disorders. In this work we sought to study the signal transduction LKB1/AMPK/TSC2 pathway alterations that contribute to the pathogenesis NSCLC. Our major objectives were: ▪To determine the frequency of genetic and epigenetic alterations in the signal traduction LKB1/AMPK/TSC2 pathway in NSCLC in a panel of 23 cell lines (4 normal bronchial epithelial cell lines immortalized with SV40 and 19 NSCLC cell lines). ▪ To study some components of AMPK-related kinase family that could be activated downstream of LKB1, in particular we analyzed the methylation status of: BRSK1, BRSK2, MARK1, MARK4 in our panel of 23 cell lines. ▪ To examine LKB1/BRSK2 signaling.▪ To make a clinical validation of BRSK2 methylation status, in 58 FFPE of patients with NSCLC. ▪ To determinate the impact of LKB1 depletion on NSCLC cell lines. The major conclusions of this work were: ▪ LKB1 mutations are not confined to adenocarcinomas, they also occur in other NSCLC subtype such as large cell carcinomas. But we found no evidence of LKB1 methylation in any NSCLC cell lines used in this study. ▪ There are not sequence alterations or/and promoter methylation of AMPK and TSC components studied in our 23 panel cell lines. ▪ Of the four AMPK related kinases -BRSK1, BRSK2, MARK1 and MARK4- studied, BRSK2 represents the highest percentage of methylation; ~26 % of NSCLC cell lines and 25.8% in the 58 NSCLC samples. ▪ BRSK2 methylation is significantly correlated with four clinicopatological parameters: tumor stage (P=0,025), histology (P=0,001), tumor size (P=0,073) and nodules affected (P=0,04), suggesting that methylation of BRSK2 could provide a novel biomarker for disease progression in lung cancer. ▪ The disruption of LKB1/BRSK2 signaling could be important in the carcinogenesis of lung, as a molecular mechanism for the development of lung cancer