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- Diagnóstico Pré-Natal de Anomalias CromossómicasPublication . Simão, Laurentino; Correia, HildebertoObjetivo: DPN – Diagnóstico, Prognóstico, Prevenção e Tratamento das anomalias cromossómicas fetais.
- Ibuprofen Inhibits Overexpression of Tumor-Related RAC1B through SRSF1Publication . Gonçalves, Vânia; Matos, Paulo; Pereira, Joana; Jordan, PeterThe serrated pathway to colorectal tumor formation involves oncogenic mutations in the BRAF gene, which are sufficient for initiation of hyperplastic growth but not for tumor progression [1]. A previous analysis of colorectal tumors revealed that overexpression of splice variant RAC1B occurs in around 80% of tumors with mutant BRAF and both events proved to cooperate in tumor cell survival [2]. Patients with inflamed human colonic mucosa also have increased expression of RAC1B as well as mice with experimentally induced colitis [3]. The increase of RAC1B in the mouse model was specifically prevented by the nonsteroidal anti-inflammatory drug ibuprofen [3]. The objective of our study is to understand the molecular regulation of RAC1B alternative splicing event and how it contributes to tumorigenesis. HT29 colorectal cell line was used as model to test several signaling pathways after 48h of treatment with ibuprofen. For this we analyzed the proteins of interest by Western Blot and the transcript levels by RT-PCR. Mechanistic studies in cultured HT29 colorectal tumor cells revealed that ibuprofen inhibited RAC1B expression in a cyclooxygenase inhibition–independent manner and targets directly the alternative splicing event [3]. Here, we provide evidence that ibuprofen leads to a protein kinase dependent decrease in expression of SRSF1, a splicing factor that we previously identified to promote RAC1B alternative splicing. Together, our results suggest that stromal cues, namely, inflammation, can trigger changes in RAC1B expression in the colon and identify ibuprofen as a highly specific and efficient inhibitor of RAC1B overexpression in colorectal tumors. Our data identify an additional cyclooxygenase–independent action of ibuprofen and suggest it may be beneficial in the treatment of patients with the subtype of BRAF-mutated serrated colorectal tumors. References [1] Velho S, Moutinho C, Cirnes L, Albuquerque C, Hamelin R, Schmitt F, Carneiro F, Oliveira C, and Seruca R (2008). BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: primary or secondary genetic events in colorectal carcinogenesis? BMC Cancer 8, 255. [2] Matos P, Oliveira C, Velho S, Gonçalves V, da Costa LT, Moyer MP, Seruca R, and Jordan P (2008). B-Raf V600E cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival. Gastroenterology 135, 899–906. [3] Matos P, Kotelevets L, Goncalves V, Henriques AF, Henriques A, Zerbib P, Moyer MP, Chastre E, Jordan P (2013). Ibuprofen inhibits colitis-induced overexpression of tumor-related Rac1b. Neoplasia 15(1):102-11. Acknowledgements Funding Support: grant UID/MULTI/04046/2019, SFRH/BD/109162/2015 and PTDC/BIA-MOL/28386/2017 from FCT
- Measuring the impact of influenza vaccination national strategy among the at risk Portuguese populationPublication . Machado, Ausenda; Nunes, Baltazar; Larrauri, AmparoYearly seasonal influenza vaccine is recommended to individuals with chronic conditions or aged ≥65 years (high-risk group). However, for these high-risk individuals, the vaccine coverage has been lower than targeted, vaccine effectiveness may be altered by age or presence of chronic conditions and the impact of the vaccination strategy is still unknown. With focus in the high-risk group, this thesis aimed contributing to the national influenza strategy by providing information on i) influenza vaccine coverage and associated factors; ii) vaccine effectiveness and iii) impact of influenza vaccination strategy at population level. Results indicate that the proportion of individuals with vaccine uptake for four consecutive seasons was only 27%. Age, having a chronic condition and use of health care were positively associated to vaccine uptake. Vaccine effectiveness was estimated in 52% against medically-attended influenza and 32% against influenza hospital admissions in the ones aged ≥65 years. The tested hypothesis of an effect modification of the vaccine by age or chronic conditions, was inconclusive, probably due to lack of power. The impact of influenza vaccination strategy indicate that on average, during the period 2014/15-2017/18, the strategy averted 715 primary care medically attended influenza; 1833 hospitalizations and 383 intra-hospital. The influenza vaccine strategy had consistent and positive benefit in the high-risk population. To maximize the impact, efforts should be conducted to increase the vaccine coverage and the results of this thesis could be used to design targeted strategies. The continuous monitoring of the vaccine effectiveness and population impact could contribute in this effort. RESUMO - A vacina contra a gripe é recomendada anualmente a indivíduos alto-risco de complicações, nomeadamente aqueles com doenças crónicas ou idade ≥65 anos. Contudo, a cobertura da vacina neste grupo de alto-risco é inferior à meta estabelecida, a efetividade pode ser modificada pela idade e pela doença crónica e o impacto da estratégia de vacinação é desconhecido. Com foco nos individuos de alto-risco, esta tese pretendeu contribuir para a estratégia de vacinação contra a gripe fornecendo informações sobre a i) cobertura vacinal e fatores associados, ii) efetividade da vacina e iii) impacto a nível populacional da estratégia de vacinação. Os resultados indicam que a proporção de indivíduos com toma da vacina nas 4 épocas foi de 27%. A idade, ter doença crónica e utilização de cuidados de saúde estavam positivamente associados à toma de vacina. A hipótese de modificação de efeito da vacina pela idade e comorbilidades foi inconclusiva, decorrente provavelmente da falta de potência do estudo. ). A efetividade da vacina foi estimada em 52% na redução de consultas e em 32% na redução de hospitalizações nos indivíduos com ≥65 anos. Por último, a estratégia de vacinação preveniu em média, durante o período em análise (2014/15-2017/18), 715 consultas, 1833 hospitalizações e 383 óbitos intra-hospitalares. A estratégia de vacinação contra a gripe teve benefícios positivos na população de alto-risco. Para maximizar este impacto devem ser realizados esforços para aumentar a cobertura e os resultados desta tese podem ser importantes no delineamento de intervenções direcionadas. A contínua monitorização da efetividade e do impacto da vacina na população poderiam contribuir para esse objetivo.