Harmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance.

Therapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.This work was supported by the FUNDAÇÃO PARA A CIÊNCIA E TECNOLOGIA (FCT) Research Center Grant UID/BIM/04773/2013, Centre for Biomedical Research (CBMR), and by the Spanish Ministry of Science, Innovation and Universities through Grant RTI2018-094629-B-I00 to WL. B.I.F. was supported by FCT-SFRH/BPD/100434/2014 and the Marie Curie Individual Fellowship project TRIBBLES (#748585). This work was also supported by two LPCC-NRS/Terry Fox grants (2016/2017; 2017/2018). S. Machado is the recipient of a ProRegeM grant PD/BD/114258/2016. I. Duarte was supported by a scholarship from FCT Grant PTDC/BEX-BID/5410/2014S

Acesso a Tratamento Endovascular para Acidente Vascular Cerebral Isquémico em Portugal

Introduction: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. Material and Methods: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. Results: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. Conclusion: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.Introdução: A aprovação do tratamento endovascular para o acidente vascular cerebral isquémico obrigou à reorganização dos cuidados de saúde em Portugal. Os nove centros que realizam tratamento endovascular não estão distribuídos equitativamente pelo território, o que poderá causar acesso diferencial a tratamento. O principal objetivo deste estudo é realizar uma análise descritiva da frequência e métricas temporais do tratamento endovascular em Portugal continental e seus distritos. Material e Métodos: Estudo de coorte nacional multicêntrico, incluindo todos os doentes com acidente vascular cerebral isquémico submetidos a tratamento endovascular em Portugal continental durante um período de dois anos (julho 2015 a junho 2017). Foram colhidos dados demográficos, relacionados com o acidente vascular cerebral e variáveis do procedimento. Taxas de tratamento endovascular brutas e ajustadas (ajuste indireto a idade e sexo) foram calculadas por 100 000 habitantes/ano para Portugal continental e cada distrito. Métricas de procedimento como tempo entre instalação, primeira porta e punção foram também analisadas. Resultados: Foram registados 1625 tratamentos endovasculares, indicando uma taxa bruta nacional de tratamento endovascular de 8,27/100 000 habitantes/ano. As taxas de tratamento endovascular entre distritos variaram entre 1,58 e 16,53/100 000/ano, com taxas mais elevadas nos distritos próximos a hospitais com tratamento endovascular. O tempo entre sintomas e punção femural entre distritos variou entre 212 e 432 minutos. Conclusão: Portugal continental apresenta uma taxa nacional de tratamento endovascular elevada, apresentando, contudo, assimetrias regionais no acesso. As métricas temporais foram comparáveis com as observadas nos ensaios clínicos piloto