Thrombotic genetic risk factors and warfarin pharmacogenetic variants in São Miguel's healthy population (Azores)

<p>Summary</p> <p>Background</p> <p>The Azorean population presents the highest standardized mortality rate for cardiovascular diseases (CVD) when compared to mainland Portugal and other populations. Since thrombosis is a common cause of CVD, we assessed four polymorphisms in three thrombotic risk genes – <it>F5 </it>(G1691A), <it>F2 </it>(G20210A) and <it>MTHFR </it>(C677T, A1298C), in 469 healthy blood donors from São Miguel Island (Azores). We also analysed the <it>CYP2C9 </it>(C430T, A1075C) and <it>VKORC1 </it>(G1639A) variants in fifty-eight individuals with predisposition to thrombosis (possessing at least one variation in <it>F5 </it>or <it>F2 </it>genes and one in <it>MTHFR</it>) to evaluate their warfarin drug response genetic profiles.</p> <p>Results</p> <p>Among the 469 individuals, the data showed that thrombotic risk allele frequencies – 1691A (4.9%), 20210A (1.8%), 677T (41.7%) and 1298C (24.8%) – were similar to other Caucasians, but significantly different from mainland Portuguese (χ², <it>p </it>< 0.001). The combined analysis of these variants identified twenty-two different genetic profiles (genotype order: <it>F5</it>, <it>F2</it>, <it>MTHFR </it>C677T and A1298C). Complete homozygosity for all wild-type alleles (GG GG CC AA) was present in 11.7%, being GG GG CT AA (22.4%) the most frequent profile. The results also demonstrated that 12.4% (58 out of 469) of São Miguel islanders have increased genetic predisposition to thrombosis. Subsequently, we evaluated these individuals for their warfarin response genetic profiles. The data showed that seven out of fifty-eight individuals are poor metabolizers (two with <it>CYP2C9</it>*2/*2 and five with <it>CYP2C9</it>*2/*3 genotypes). <it>VKORC1 </it>polymorphism analysis identified twelve individuals (20.7%) with AA genotype, who probably will require lower doses of warfarin. The joint analysis of <it>CYP2C9 </it>and <it>VKORC1 </it>revealed that 79.3% (46 out of 58) of the individuals carry at least one polymorphism in these genes. Within these, twenty-five individuals (43.1%) need intermediate and/or low doses of warfarin, if treatment is started.</p> <p>Conclusion</p> <p>The present study demonstrated, for the first time, that São Miguel, and possibly the Azores population, shows significant differences on allele frequencies of thrombotic risk factors when compared to mainland Portugal. This research constitutes a primary approach for future studies on CVD, as well as for the implementation of warfarin dosing protocols using the patient's genotypic information.</p

PubhD UMinho: a investigação científica e a sociedade juntas num bar

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Identificando Características de Organizações Intensivas em Conhecimento em Universidades: Um Estudo de Caso nas Instituições do Sistema ACAFE de Santa Catarina - Brasil

O estudo identifica características de organizações intensivas em conhecimento em universidades. Parte-se do pressuposto de que organizações que desenvolvem atividades na área de educação são, em princípio, organizações intensivas em conhecimento. Para mapear as características que possam confirmar tal pressuposto, estruturou-se o estudo em 4 dimensões: organização e gestão, infra-estrutura, pessoas e tecnologia, através das quais elaborou-se o instrumento de pesquisa. O estudo foi desenvolvido através de um survey utilizando o trabalho de ANGELONI (2002), denominado Modelo Alternativo de Organização do Conhecimento . Os resultados atenderam as expectativas, mesmo apresentando alguns desvios em razão de o assunto tratado ser relativamente novo para as empresas e, mais especificamente para instituições de ensino superior. Conclui-se que as pesquisas acerca da gestão do conhecimento em IES, ainda são incipientes, acreditando-se que os resultados apresentados contribuirão para novas pesquisas e para que as IESs iniciem processos de suas transformações em organizações intensivas em conhecimento

Posttranslational mechanisms associated with reduced NHE3 activity in adult vs. young prehypertensive SHR

Crajoinas RO, Lessa LMA, Carraro-Lacroix LR, Davel APC, Pacheco BPM, Rossoni LV, Malnic G, Girardi ACC. Posttranslational mechanisms associated with reduced NHE3 activity in adult vs. young prehypertensive SHR. Am J Physiol Renal Physiol 299:F872-F881, 2010. First published July 14, 2010; doi:10.1152/ajprenal.00654.2009.-Abnormalities in renal proximal tubular (PT) sodium transport play an important role in the pathophysiology of essential hypertension. the Na(+)/H(+) exchanger isoform 3 (NHE3) represents the major route for sodium entry across the apical membrane of renal PT cells. We therefore aimed to assess in vivo NHE3 transport activity and to define the molecular mechanisms underlying NHE3 regulation before and after development of hypertension in the spontaneously hypertensive rat (SHR). NHE3 function was measured as the rate of bicarbonate reabsorption by means of in vivo stationary microperfusion in PT from young prehypertensive SHR (Y-SHR; 5-wk-old), adult SHR (A-SHR; 14-wk-old), and age-matched Wistar Kyoto (WKY) rats. We found that NHE3-mediated PT bicarbonate reabsorption was reduced with age in the SHR (1.08 +/- 0.10 vs. 0.41 +/- 0.04 nmol/cm(2)xs), while it was increased in the transition from youth to adulthood in the WKY rat (0.59 +/- 0.05 vs. 1.26 +/- 0.11 nmol/cm(2)xs). Higher NHE3 activity in the Y-SHR compared with A-SHR was associated with a predominant microvilli confinement and a lower ratio of phosphorylated NHE3 at serine-552 to total NHE3 (P-NHE3/total). After development of hypertension, P-NHE3/total increased and NHE3 was retracted out of the microvillar microdomain along with the regulator dipeptidyl peptidase IV (DPPIV). Collectively, our data suggest that the PT is playing a role in adapting to the hypertension in the SHR. the molecular mechanisms of this adaptation possibly include an increase of P-NHE3/total and a redistribution of the NHE3-DPPIV complex from the body to the base of the PT microvilli, both predicted to decrease sodium reabsorption.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ São Paulo, Sch Med, Heart Inst InCor, BR-05403900 São Paulo, BrazilUniv São Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05403900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Physiol, São Paulo, BrazilWeb of Scienc

Percepção dos Cuidadores versus Presença de Dificuldades Alimentares Pediátricas: um estudo transversal

Avaliar a percepção de cuidadores de crianças com dificuldades alimentares pediátricas (DAPs) a respeito dos problemas de alimentação de seus filhos. Métodos: Estudo transversal realizado na internação pediátrica com crianças abaixo de 14 anos e seus cuidadores em um hospital público no Sul do Brasil. Coletaram-se dados de prontuário além da aplicação de um questionário. Para avaliar a presença de DAPs foi utilizado o diagnóstico no prontuário. Aprovado pelo comitê de ética da instituição (CAAE nº 65500222300005327). Resultados: Avaliou-se 148 duplas de indivíduos, sendo 54% das crianças menores de 2 anos. As DAPs estavam presentes em 36 (22,8%) dos pacientes avaliados, contrastando aos 40(25,3%) identificados por seus cuidadores. Entre os diagnosticados, 7(19,4%) dos cuidadores negaram a presença de DAP. Desses, 34 (94,4%) já haviam sido internados anteriormente, dos quais 50% tiveram acima de 5 reinternações. Todos os 36(100%) utilizaram sonda para alimentação em algum momento da vida e em 24(66,6%) dos casos foi devido à DAP. Atualmente, 5(13,9%) alimenta-se exclusivamente via oral, 16(44,4%) utiliza via completar (enteral e/ou parenteral) à oral e 15(41,6%) somente via enteral e/ou parenteral. Conclusão: Nota-se discrepância na percepção dos cuidadores em relação ao diagnóstico de DAPs, demonstrando necessidade de investir em educação para identificação e manejo adequado. Fato reforçado pelo alto número de reinternações e uso de vias complementares para alimentação nessas crianças

Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer

© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND)Purpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.info:eu-repo/semantics/publishedVersio