Therapeutic benefit of selective inhibition of p110α PI3-kinase in pancreatic neuroendocrine tumors

Purpose: mutations in the PI3K pathway occur in 16% of patients with pancreatic neuroendocrine tumors (PanNETs), which suggests that these tumors are an exciting setting for PI3K/AKT/mTOR pharmacologic intervention. Everolimus, an mTOR inhibitor, is being used to treat patients with advanced PanNETs. However, resistance tomTOR-targeted therapy is emerging partially due to the loss of mTOR-dependent feedback inhibition of AKT. In contrast, the response to PI3K inhibitors in PanNETs is unknown. Experimental Design: in the current study, we assessed the frequency of PI3K pathway activation in human PanNETs and in RIP1-Tag2 mice, a preclinical tumor model of PanNETs, and we investigated the therapeutic efficacy of inhibiting PI3K in RIP1-Tag2 mice using a combination of pan (GDC-0941) and p110 alpha-selective (GDC-0326) inhibitors and isoform-specific PI3K kinase-dead-mutant mice. Results: human and mouse PanNETs showed enhanced pAKT, pPRAS40, and pS6 positivity compared with normal tissue. Although treatment of RIP1-Tag2 mice with GDC-0941 led to reduced tumor growth with no impact on tumor vessels, the selective inactivation of the p110 alpha PI3K isoform, either genetically or pharmacologically, reduced tumor growth as well as vascular area. Furthermore, GDC-0326 reduced the incidence of liver and lymph node metastasis compared with vehicle-treated mice. We also demonstrated that tumor and stromal cells are implicated in the antitumor activity of GDC-0326 in RIP1-Tag2 tumors. Conclusions: our data provide a rationale for p110a-selective intervention in PanNETs and unravel a new function of this kinase in cancer biology through its role in promoting metastasis

Population genomics of Bombus terrestris reveals high but unstructured genetic diversity in a potential glacial refugium

Ongoing climate change is expected to cause an increase in temperature and a reduction of precipitation levels in the Mediterranean region, which might cause changes in many species distributions. These effects negatively influence species gene pools, decreasing genetic variability and adaptive potential. Here, we use mitochondrial DNA and RADseq to analyse population genetic structure and genetic diversity of the bumblebee species Bombus terrestris (subspecies Bombus terrestris lusitanicus), in the Iberian Peninsula. Although this subspecies shows a panmictic pattern of population structure across Iberia and beyond, we found differentiation between subspecies B. t. lusitanicus and B. t. africanus, probably caused by the existence of barriers to gene flow between Iberia and North Africa. Furthermore, the results revealed that the Iberian Peninsula harbours a large fraction of B. terrestris intraspecific genetic variation, with the highest number of mitochondrial haplotypes found when compared with any other region in Europe studied so far, suggesting a potential role for the Iberian Peninsula as a glacial refugium. Our findings strengthen the idea that Iberia is a very important source of diversity for the global genetic pool of this species, because rare alleles might play a role in population resilience against human- or climate-mediated changes.info:eu-repo/semantics/publishedVersio

SARS-CoV-2 introductions and early dynamics of the epidemic in Portugal

Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. Methods By applying recent phylodynamic models that allow integration of individual-based travel history, we reconstructed and characterized the spatio-temporal dynamics of SARSCoV-2 introductions and early dissemination in Portugal. Results We detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy, and Switzerland), which were consistent with the countries with the highest connectivity with Portugal. Although most introductions were estimated to have occurred during early March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal throughout February, before the first cases were confirmed. Conclusions Here we conclude that the earlier implementation of measures could have minimized the number of introductions and subsequent virus expansion in Portugal. This study lays the foundation for genomic epidemiology of SARS-CoV-2 in Portugal, and highlights the need for systematic and geographically-representative genomic surveillance.We gratefully acknowledge to Sara Hill and Nuno Faria (University of Oxford) and Joshua Quick and Nick Loman (University of Birmingham) for kindly providing us with the initial sets of Artic Network primers for NGS; Rafael Mamede (MRamirez team, IMM, Lisbon) for developing and sharing a bioinformatics script for sequence curation (https://github.com/rfm-targa/BioinfUtils); Philippe Lemey (KU Leuven) for providing guidance on the implementation of the phylodynamic models; Joshua L. Cherry (National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health) for providing guidance with the subsampling strategies; and all authors, originating and submitting laboratories who have contributed genome data on GISAID (https://www.gisaid.org/) on which part of this research is based. The opinions expressed in this article are those of the authors and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. This study is co-funded by Fundação para a Ciência e Tecnologia and Agência de Investigação Clínica e Inovação Biomédica (234_596874175) on behalf of the Research 4 COVID-19 call. Some infrastructural resources used in this study come from the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT).info:eu-repo/semantics/publishedVersio

COOPEDU IV — Cooperação e Educação de Qualidade

O quarto Congresso Internacional de Cooperação e Educação-IV COOPEDU, organizado pelo Centro de Estudos Internacionais (CEI) do Instituto Universitário de Lisboa e pela Escola Superior de Educação e Ciências Sociais do Instituto Politécnico de Leiria decorreu nos dias 8 e 9 de novembro de 2018, subordinado à temática Cooperação e Educação de Qualidade. Este congresso insere-se numa linha de continuidade de intervenção por parte das duas instituições organizadoras e dos elementos coordenadores e este ano beneficiou do financiamento do Instituto Camões, obtido através de um procedimento concursal, que nos permitiu contar com a participação presencial de elementos dos Países Africanos de Língua Portuguesa, fortemente implicados nas problemáticas da Educação e da Formação. Contou também com a participação do Instituto Camões e da Fundação Calouste Gulbenkian, entidades que sistematizaram a sua intervenção nos domínios da cooperação na área da educação nos últimos anos. A opção pela temática da qualidade pareceu aos organizadores pertinente e actual. Com efeito os sistemas educativos dos países que constituem a Comunidade de países de língua portuguesa têm implementado várias reformas mas em vários domínios mantem-se a insatisfação de responsáveis políticos, pedagogos, técnicos sociais face aos resultados obtidos. Aliás o caminho de procura da Qualidade é interminável porque vai a par da aposta na exigência e na promoção da cidadania e responsabilidade social. As comunicações que agora se publicam estão organizadas em dois eixos: o das Políticas da Educação e Formação e o das dimensões em que se traduzem essas políticas. Neste último eixo encontramos fios condutores para agregarmos as comunicações apresentadas

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt