Randomized phase II trial of FOLFIRI-panitumumab compared with FOLFIRI alone in patients with RAS wild-type circulating tumor DNA metastatic colorectal cancer beyond progression to first-line FOLFOX-panitumumab: the BEYOND study (GEMCAD 17-01).

PURPOSE: Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). METHODS: In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). RESULTS: Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. CONCLUSIONS: The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.

Desarrollo de la competencia social y prevención de problemas de conducta en el aula infantil / Social Competence Development and Behavior Problems Prevention in Preschool Classrooms / Desenvolvimento da competência social e prevenção de problemas de conduta na sala de aula infantil

Objetivo. El propósito del estudio es analizar el efecto longitudinal del programa de prevención universal Aprender a Convivir sobre la competencia social y los problemas de conducta infantiles. Método. 197 niños de tres años participaron en el programa durante tres años consecutivos y fueron evaluados por sus maestros en distintas variables relacionadas con la competencia social y los problemas de conducta. El análisis de datos se llevó a cabo mediante un ANOVA simple de medidas repetidas, incluyendo como factor intragrupo el momento de evaluación pretest (3 años de edad) y postest (5 años de edad). Resultados. Los resultados mostraron una mejora significativa del grupo experimental, tanto en las variables de competencia social (cooperación social d = 1.55; interacción social d = 1.91; e independencia social d = 1.32) como en las de problemas de conducta (interiorizados d=0.40; y exteriorizados d = 0.48) analizadas. Conclusión. El programa de intervención Aprender a Convivir contribuye al desarrollo de la competencia social del alumnado de Educación Infantil, también tiene un efecto indirecto sobre la reducción de problemas de conducta interiorizados y exteriorizados en niños.

Objective. The purpose of the study is to analyze the longitudinal effect of the universal prevention program, Aprender a Convivir, on children' social competence and behavioral problems. Method. 197 three-year-old children participated in the program for three consecutive school years and were assessed by their teachers in different variables related to social competence and behavior problems variables. Data analysis was carried out through a repeated-measures simple ANOVA including as intra-subject factor assessment time-pretest (3-year-old) and postest (5-year-old). Results. A significant improvement was observed in the experimental group both in the variables of social competence (social cooperation d = 1.55; social interaction d = 1.91; and social independence d = 1.32) as in the variables of behavior problems (internalizing d = 0.40; and externalizing d = 0.48) analyzed. Conclusion. The Aprender a Convivir prevention program contributes to social competence development of preschool students, and also has an indirect effect on the reduction of internalizing and externalizing behavior problems.

Escopo. O propósito do estudo é analisar o efeito longitudinal do programa de prevenção universal Aprender a Conviver sobre a competência social e os problemas de conduta infantis. Metodologia. 197 crianças de tres anos de idade participaram no programa durante três anos consecutivos e foram avaliados por seus professores em distintas variáveis relacionadas com a competência social e os problemas de conduta. A análise de dados foi realizada mediante um ANOVA simples de medidas repetidas, incluindo como fator intragrupo o momento de avaliação pré-teste (3 anos de idade) e post-teste (5 anos de idade). Resultados. Os resultados amostraram uma melhora significativa do grupo experimental tanto nas variáveis de competência social (cooperação social d = 1.55; interação social d = 1.91; e independência social d = 1.32) como nas de problemas de conduta (interiorizados d = 0.40; e exteriorizados d = 0.48) analisadas. Conclusão. O programa de intervenção Aprender a Conviver contribui ao desenvolvimento da competência social do alunado de Educação Infantil, também tem um efeito indireto sobre a redução de problemas de conduta interiorizados e exteriorizados em crianças.

Modulation of mitochondrial activity by S-nitrosoglutathione reductase in Arabidopsis thaliana transgenic cell lines.

The enzyme S-nitrosoglutathione reductase (GSNOR) has an important role in the metabolism of S-nitrosothiols (SNO) and, consequently, in the modulation of nitric oxide (NO)-mediated processes. Although the mitochondrial electron transport chain is an important target of NO, the role of GSNOR in the functionality of plant mitochondria has not been addressed. Here, we measured SNO content and NO emission in Arabidopsis thaliana cell suspension cultures of wild-type (WT) and GSNOR overexpressing (GSNOR(OE)) or antisense (GSNOR(AS)) transgenic lines, grown under optimal conditions and under nutritional stress. Respiratory activity of isolated mitochondria and expression of genes encoding for mitochondrial proteins were also analyzed. Under optimal growth conditions, GSNOR(OE) had the lowest SNO and NO levels and GSNOR(AS) the highest, as expected by the GSNO-consuming activity of GSNOR. Under stress, this pattern was reversed. Analysis of oxygen uptake by isolated mitochondria showed that complex I and external NADH dehydrogenase activities were inhibited in GSNOR(OE) cells grown under nutritional stress. Moreover, GSNOR(OE) could not increase alternative oxidase (AOX) activity under nutritional stress. GSNOR(AS) showed constitutively high activity of external NADH dehydrogenase, and maintained the activity of the uncoupling protein (UCP) under stress. The alterations observed in mitochondrial protein activities were not strictly correlated to changes in gene expression, but instead seemed to be related with the SNO/NO content, suggesting a post-transcriptional regulation. Overall, our results highlight the importance of GSNOR in modulating SNO and NO homeostasis as well mitochondrial functionality, both under normal and adverse conditions in A. thaliana cells.

Galectin-10 is released in the nasal lavage fluid of patients with aspirin-sensitive respiratory disease.

The aim of this work was to determine the presence of galectin-10 in nasal lavage fluid (NLF) of patients with aspirin-sensitive respiratory disease (ASRD) before and after challenge with L-ASA (aspirin) by ELISA. Fifteen ASRD patients, ten aspirin-tolerant asthmatics (ATA), and fifteen healthy controls (HC) were studied. The baseline presence of Galectin-10 in PBMC was determined using real time PCR. Galectin-10 was evaluated in tissue of nasal polyps by western blot. Our results showed a lower expression in PBMC of ASRD patients than in ATA and healthy controls. However, a higher concentration of galectin-10 in NLF was found in ASRD patients before and after L-ASA challenge; western blot confirmed a high expression of galectin-10 in tissue from nasal polyps obtained from ASRD patients. Our results suggest a probable role of galectin-10 in the inflammatory response observed in ASRD patients; however, confirmatory studies are needed.