The role of actin cytoskeleton downstream of the Src oncogene in the earlier events of breast tumour progression

Tumorigenesis is a multistep process, by which cells acquire genetic and epigenetic alterations in oncogenes and tumour suppressor genes, which provide growth and/or survival advantage. Subsequent alterations may condemn these pre-malignant cells into malignant ones with invasive and metastatic abilities. Proto-oncogenes of the Src-family kinases have been linked to tumorigenesis and their over-expression and activation described in breast cancer. Increased Src activity has been associated with increased cell proliferation, survival, epithelialmesenchymal transition (EMT), migration, invasion and metastasis. Although Src is well-known to trigger cancer cell mobility, migration and invasion, through regulation of filamentous actin (F-actin), whether it also uses F-actin to promote proliferation and survival of tumour cells at pre-malignant stages remains unknown. Our lab has demonstrated that Src promotes apical F-actin accumulation in Drosophila epithelia. In turn, F-actin limits Src-induced apoptosis or tissue overgrowth.(...)Fundação Calouste GulbenkianLiga Portuguesa Contra o Cancro/Pfize

Identificação de biomarcadores terapêuticos em melanoma

Mestrado em Biomedicina MolecularO melanoma deriva da transformação maligna de melanócitos e é frequentemente encontrado na pele e na região ocular. A identificação de marcadores moleculares que inequivocamente indiquem a agressividade do tumor ou que possam prever a resposta/resistência a uma terapia é uma prioridade da comunidade científica que estuda esta patologia. Mutações do gene do BRAF, maioritariamente V600E e mutações do gene do NRAS têm sido implicadas no desenvolvimento de melanoma cutâneo. Enquanto, mutações nos genes do GNAQ e GNA11 são encontradas com elevada frequência em melanomas uveais. Todas estas mutações podem levar à activação da via de sinalização das MAP cínases, conduzindo ao aumento da proliferação celular O objectivo deste estudo foi a identificação de mutações genéticas frequentes como indicadores de prognósticos ou de previsão de resposta a uma terapia de inibição da via do mTOR e avaliar o potencial de efectores desta via como biomarcadores terapêuticos em melanomas cutâneos e oculares. A existência de alterações genéticas nos genes do BRAF e NRAS foi determinada em 13 casos de melanoma cutâneo. O estado mutacional dos genes GNAQ e GNA11 foi avaliado em 34 casos de melanoma ocular. A análise mutacional foi realizada com recurso a PCR e sequenciação. A associação entre o estado mutacional e as características clínico-patológicas foi também estudada. Um conjunto de linhas celulares de melanoma com diferentes perfis genéticos foi tratado com um fármaco inibidor do mTOR, RAD001. A proliferação celular e apoptose foram avaliadas com os ensaios SRB e TUNEL, respectivamente, a expressão de efectores da via do mTOR foi detectada por immunoblotting. G361, uma linha celular derivada de melanoma cutâneo com mutação BRAFV600E, apresentou a maior inibição de crescimento após tratamento com RAD001. RAD001 não induziu um aumento de apoptose em nenhuma das linhas celulares utilizadas neste estudo, sugerindo que o RAD001 não induz alterações no processo de apoptose. Este estudo apresenta a mutação BRAFV600E como um possível marcador terapêutico do fármaco, RAD001, para pacientes com melanoma cutâneo mas não para pacientes com melanoma ocular, podendo no futuro ser uma ferramenta útil na selecção de pacientes para uma terapia baseada na inibição do mTOR.Melanoma results from the malignant transformation of melanocytes and is frequently found in the skin and ocular region. The identification of molecular biomarkers, which unequivocally indicate the aggressiveness of the tumour or predict the response/resistance to a therapy, is of high priority in the field of melanoma research. BRAF gene mutations, predominantly V600E, and mutations in the NRAS gene have been implicated in the development of cutaneous melanoma. Mutations in the GNAQ and GNA11 genes are found frequently in ocular melanoma, particularly in the uveal subtype. These mutations can lead to the activation of the MAPK pathway, which can lead to growth-promoting activities. The aim of this study was to identify frequent mutations that can be used as prognosis or predictive markers for mTOR pathway inhibition. In addition, the potential of mTOR pathway effectors as therapeutic biomarkers in cutaneous and ocular melanoma was also addressed. Genetic alterations in the BRAF and NRAS genes were determined in 13 cutaneous melanoma tumour samples and GNAQ and GNA11 genes mutational status were evaluated in a series of 34 tumour samples of ocular melanoma. Mutational analysis was done by PCR/Sequencing. The mutational status and its correlation to clinical-pathologial features was then assessed. A panel of melanoma cell lines with different BRAF, GNAQ and GNA11 mutational status were treated with RAD001, an mTOR pathway inhibitor. Cell viability and apoptosis were assessed by SRB assay and TUNEL assay, respectively, mTOR pathway effectors expression levels were detected by immunoblotting. G361, a cutaneous melanoma-derived cell line, which harbours BRAFV600E, showed the highest level of cell growth inhibition after treatment with RAD001. RAD001 did not induce increased levels of apoptosis in any of the cell lines treated, suggesting that RAD001 does not induce alterations in the apoptosis process. This study supports BRAF mutational status as a possible predictive biomarker to RAD001 treatment in cutaneous melanoma but not in ocular melanoma patients and as a promising tool to select patients to mTOR inhibition therapy

Educomunicação e suas áreas de intervenção: Novos paradigmas para o diálogo intercultural

oai:omp.abpeducom.org.br:publicationFormat/1O material aqui divulgado representa, em essência, a contribuição do VII Encontro Brasileiro de Educomunicação ao V Global MIL Week, da UNESCO, ocorrido na ECA/USP, entre 3 e 5 de novembro de 2016. Estamos diante de um conjunto de 104 papers executivos, com uma média de entre 7 e 10 páginas, cada um. Com este rico e abundante material, chegamos ao sétimo e-book publicado pela ABPEducom, em seus seis primeiros anos de existência. A especificidade desta obra é a de trazer as “Áreas de Intervenção” do campo da Educomunicação, colocando-as a serviço de uma meta essencial ao agir educomunicativo: o diálogo intercultural, trabalhado na linha do tema geral do evento internacional: Media and Information Literacy: New Paradigms for Intercultural Dialogue

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

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

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat