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Background: Lung adenocarcinoma (LUAD) accounts for 40% of all lung cancer cases. Although driver mutations in the K-RAS oncogene occurs in 25% of all LUAD cases, to date, there are no available targeted therapies. Infiltrating neutrophils in LUAD are indicative of the worst survival outcomes. The C-X-C motif chemokine receptor 2 (CXCR2) mediates their recruitment to the tumour microenvironment where they promote a pro-tumorigenic environment. CXCR2 ligand expression is higher in KRAS-driven LUAD compared to the other most frequently mutated oncogenes. Therefore, we hypothesize that K-RASdriven LUAD may be the best candidate for a CXCR2 targeted treatment strategy. Method: The PREdiction of Clinical Outcomes from Genomic Profiles (PRECOG) is a dataset of gene expression and survival outcome. The dataset includes data from approximately 18 000 human patients with 39 different malignancies. The dataset was used to determine whether high neutrophil infiltration, CXCR2 expression and CXCR2 ligand expression were associated with poor survival outcomes in LUAD. A 100 patient LUAD tissue microarray was built and stained for neutrophil elastase and CXCR2 by immunohistochemistry. Kaplan-Meier curves were used determine the effect of high neutrophil or CXCR2+ cell infiltration in the LUAD tumour microenvironment on survival outcome. The Cancer Cell Line Encyclopedia (CCLE) is an online dataset that provides gene expression and genotype data from 947 human cancer cell lines (36 cancer types). Expression data of all LUAD cell lines (n¼70) from CCLE was obtained for all known CXCR2 ligands. The expression of CXCR2 ligands in K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines was compared. Microfluidics devices were used to compare the neutrophil recruitment to K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines. The neutrophil recruitment to each of the cell lines was compared in the presence and absence of CXCR2 inhibition. Result: Using the PRECOG dataset, we found that CXCR2 expression in neutrophils is at least 18-fold greater than its expression in other immune cell types. Using all the LUAD cell lines (n¼70) available on the CCLE, we found that K-RAS-driven LUAD is the highest CXCR2 ligand expresser as compared to EGFR, ALK and ROS1-driven LUAD. Moreover, using PRECOG, we found that poorer survival outcome is associated with high expression of eight out of nine known CXCR2 ligands (p <0.05). In addition, high neutrophil infiltration in LUAD is associated with the worst survival outcome compared to other immune cell infiltrates (p <0.001). In accordance with the PRECOG data, the presence of infiltrating neutrophils in a 100 patient LUAD tissue microarray is associated with poorer survival outcome when compared to patients with no infiltrating neutrophils (p <0.05). Neutrophil migration to K-RAS, EGFR, ALK and ROS1-driven LUAD cell lines was examined in microfluidics devices and found to be highest in K-RAS-driven LUAD. CXCR2 inhibition reduced neutrophil migration only in K-RAS-driven lung adenocarcinoma (p <0.05). Conclusi...

Background: Lung cancer is the deadliest cancer in the world. Several oncogenic drivers are observed in non-small cell lung cancer (NSCLC) and they have been used as therapeutic targets. The frequency of the major driver genes in lung adenocarcinoma varies based on ethnicity and the impact in the Brazilian admixture population has not been explored. Thus, we aimed to investigate the presence gene mutations of EGFR, KRAS, and BRAF, and ALK, RET and ROS1 rearrangements in Brazilian lung adenocarcinoma and to associate the presence of these alterations with clinicopathological characteristics and genetic ancestry. Method: We evaluated 444 patients diagnosed with lung adenocarcinoma at Barretos Cancer Hospital. The presence of EGFR, KRAS and BRAF mutations in hotspot regions were evaluated by direct sequencing. For EGFR/KRAS/BRAF wild-type samples, we investigated the presence of ALK, RET and ROS1 rearrangements by the NanoString platform. Genetic ancestry was assessed by a multiplexed 46-ancestry informative markers panel. Stats: X 2 test and Cox regression model. Result: Overall, 232 were male (52%) and 212 female (48%) and the average mean at diagnosis was 61 years. The majority of the patients were self-reported as white (77%), smokers (68%) and most patients were diagnosed at stage IV (74%). The median overall survival in patients at stage IV was 8.8 months. The frequency of EGFR mutations was 22.7% (n¼101) and they were independently associated with never-smokers and Asian ancestry. KRAS mutations were found in 20.4% (n¼91) of cases and were independently associated with smoking. The frequency BRAF mutations was of 1% (n¼4), being all of them non-V600 BRAF. The frequency of ALK rearrangements was 2.25% (n¼10) and was associated with younger age, the presence of metastases and advanced disease stage at diagnosis. RET and ROS1 rearrangements were only observed in 0.2% each (n¼1/each) of cases. All the alterations identified in the oncogenic drivers were mutually exclusive. Conclusion: The evaluation of the major driver genes for NSCLC, EGFR, KRAS, BRAF, ALK, RET and ROS1 can guide better clinical strategies for Brazilian lung adenocarcinoma, and the frequencies observed of these genes are in line with reported in other populations.

La formación permanente es un derecho y un deber profesional del profesorado de enseñanzas no universitarias. Se sustenta por el Ministerio de Educación y Formación Profesional en colaboración con las consejerías y departamentos de educación de cada comunidad autónoma, centros educativos y centros de formación de profesores. Dado que la competencia matemática se considera clave e instrumental y la necesidad de adaptar la docencia a los nuevos tiempos, este estudio pretende analizar la adecuación de los programas de formación permanente del profesorado de matemáticas de educación primaria. El estudio realiza un análisis descriptivo-comparativo de la oferta matemática anunciada desde los portales web nacionales y regionales centrada en los recursos, soportes digitales, competencia digital en primaria. Hay muchas iniciativas nacionales y regionales relacionadas con la formación de redes de profesorado, de alumnado, de recursos educativos abiertos libres y de distintos cursos. Sin embargo, la oferta educativa publicada por las comunidades autónomas es muy desigual, estando, casi todas, muy centradas en el desarrollo de la competencia digital relegando al resto de competencias. Con las fortalezas y singularidades de cada comunidad autónoma, se propone la página web ideal de formación permanente de profesorado en matemáticas.

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