Sirt1 protects from K-Ras-driven lung carcinogenesis.

The NAD+-dependent deacetylase SIRT1 can be oncogenic or tumor suppressive depending on the tissue. Little is known about the role of SIRT1 in non-small cell lung carcinoma (NSCLC), one of the deadliest cancers, that is frequently associated with mutated K-RAS Therefore, we investigated the effect of SIRT1 on K-RAS-driven lung carcinogenesis. We report that SIRT1 protein levels are downregulated by oncogenic K-RAS in a MEK and PI3K-dependent manner in mouse embryo fibroblasts (MEFs), and in human lung adenocarcinoma cell lines. Furthermore, Sirt1 overexpression in mice delays the appearance of K-RasG12V-driven lung adenocarcinomas, reducing the number and size of carcinomas at the time of death and extending survival. Consistently, lower levels of SIRT1 are associated with worse prognosis in human NSCLCs. Mechanistically, analysis of mouse Sirt1-Tg pneumocytes, isolated shortly after K-RasG12V activation, reveals that Sirt1 overexpression alters pathways involved in tumor development: proliferation, apoptosis, or extracellular matrix organization. Our work demonstrates a tumor suppressive role of SIRT1 in the development of K-RAS-driven lung adenocarcinomas in mice and humans, suggesting that the SIRT1-K-RAS axis could be a therapeutic target for NSCLCs.We thank Jesus Herranz for his biostatistical advice; and Alba de Martino, Patricia Gonzalez, Maria Gomez, and Zaira Vega, from the Histopathology Unit at the CNIO, for their work in mouse histopathology. Work in the laboratory of P.J.F.-M. was funded by the IMDEA Food, the Spanish Association against Cancer (aecc) and the Ramon Areces (CIVP18A3891) Foundation. Work in the laboratory of M.S. was funded by the CNIO and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (SAF project), the European Research Council (ERC Advanced Grant), the European Union (RISK-IR project), and the Botin Foundation and Banco Santander (Santander Universities Global Division). Work in the laboratory of DH was funded by Rutgers Cancer Institute of New Jersey, the Alex's Lemonade Stand Foundation Shark Tank Award and by the National Institutes of Health Grant K99/R00 CA197869. Work in the laboratory of M.S.C. was supported by a grant (SAF2012-40026) from the Spanish Ministry of Science and Innovation. L.F.C-M. was supported by a PhD Fellowship from the Portuguese Foundation for Science and Technology (FCT-MCTES, SFRH/BD/124022/2016).S

Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity.

Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.General: We thank Prof. Jose Maria. Ordovas for his kind suggestions; nutritionists Helena Marcos-Pasero, Elena Aguilar-Aguilar and Isabel Espinosa-Salinas for their help with volunteers management; Rosa Serrano for her help with animal experiments; Susana Molina for her advice with PBMC isolation; Luisa Mariscal, Domingo Fernandez, Lola Martinez, Diego Megias, Patricia Gonzalez, Fernando Pelaez, Anabel Sanz, Carolina Pola, Celia de la Calle, Ana Ortega, Ana Sagrera, Jose Miguel Frade, Elena Lopez-Guadamillas, Maribel Munoz, Susana Llanos, Andres Fernandez, Aranzazu Sierra, Andres Lopez, Noemi Haro and Ildefonso Rodriguez for their excellent technical and scientific support. Work at the laboratory of P.J.F.M. is funded by the Ramon Areces Foundation, (CIVP18A3891), Asociacion Espanola contra el Cancer-AECC (SIRTBIO-LABAE18008FERN), a Ramon y Cajal Award from the Spanish Ministry of Science, Innovation and Universities (MICINN) (RYC-2017-22335), RETOS projects Program of MICINN (SAF2017-85766-R) and the Portuguese Foundation for Science and Technology (FCT-MCTES, SFRH/BD/124022/2016). Work at the laboratory of ARM was funded by the MICINN (PID2019-110183RB-C21), Regional Government of Community of Madrid (P2018/BAA-4343-ALIBIRD2020-CM) and the Ramon Areces Foundation. Work at the laboratory of A.D.R. Funded by the Comunidad de Madrid-Talento Grant 2018-T1/BMD-11966 and the MICINN PID-2019-106893RA-100. Work at the laboratory of L.D. is funded by projects from the Health Research Fund (ISCIII FIS PI14/01374 and FISPI17/00508) and from a Manuel de Oya research fellowship from the Beer and Health Foundation. Work at the laboratory of A.E. is funded by a Ramon y Cajal Award from MICINN (RYC-2013-13546) and RETOS projects Program of the MICINN, co-funded by the European Regional Development Fund (ERDF) (SAF2015-67538-R). Work in the laboratory of M.S. was funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and the "laCaixa" Foundation.S

Observation of Higgs boson production in association with a top quark pair at the LHC with the ATLAS detector

The observation of Higgs boson production in association with a top quark pair ( tt¯H ), based on the analysis of proton–proton collision data at a centre-of-mass energy of 13 TeV recorded with the ATLAS detector at the Large Hadron Collider, is presented. Using data corresponding to integrated luminosities of up to 79.8 fb −1 , and considering Higgs boson decays into bb¯ , WW⁎ , τ+τ− , γγ , and ZZ⁎ , the observed significance is 5.8 standard deviations, compared to an expectation of 4.9 standard deviations. Combined with the tt¯H searches using a dataset corresponding to integrated luminosities of 4.5 fb −1 at 7 TeV and 20.3 fb −1 at 8 TeV, the observed (expected) significance is 6.3 (5.1) standard deviations. Assuming Standard Model branching fractions, the total tt¯H production cross section at 13 TeV is measured to be 670 ± 90 (stat.) −100+110 (syst.) fb, in agreement with the Standard Model prediction.Peer Reviewe

Measurement of photon–jet transverse momentum correlations in 5.02 TeV Pb + Pb and pppp collisions with ATLAS

Jets created in association with a photon can be used as a calibrated probe to study energy loss in the medium created in nuclear collisions. Measurements of the transverse momentum balance between isolated photons and inclusive jets are presented using integrated luminosities of 0.49 nb$^{-1}$ of Pb+Pb collision data at $\sqrt{s_\mathrm{NN}}=5.02$ TeV and 25 pb$^{-1}$ of $pp$ collision data at $\sqrt{s}=5.02$ TeV recorded with the ATLAS detector at the LHC. Photons with transverse momentum $63.1 31.6$ GeV and pseudorapidity $\left|\eta^\mathrm{jet}\right| 7\pi/8$. Distributions of the per-photon jet yield as a function of $x_\mathrm{J\gamma}$, $(1/N_\gamma)(\mathrm{d}N/\mathrm{d}x_\mathrm{J\gamma})$, are corrected for detector effects via a two-dimensional unfolding procedure and reported at the particle level. In $pp$ collisions, the distributions are well described by Monte Carlo event generators. In Pb+Pb collisions, the $x_\mathrm{J\gamma}$ distribution is modified from that observed in $pp$ collisions with increasing centrality, consistent with the picture of parton energy loss in the hot nuclear medium. The data are compared with a suite of energy-loss models and calculations.Peer Reviewe

Manejo da hanseníase na atenção primária: diagnóstico e tratamento / Leprosy management in primary care: diagnosis and treatment

A Hanseníase é uma patologia de evolução alongada, e seu agente causador é o Mycobacterium leprae. Seus sinais e sintomas são no nível dermatoneurológico. Nesse contexto, esse estudo tem por objetivo geral analisar por meio da pesquisa baseada em evidências - PBE- achados da literatura, sobre estigmas que envolvem pacientes com hanseníase e praticas da educação em saude durante o tratamento na atenção básica. Pesquisa baseada em evidências, utilizando os indexadores Pubmed, Scielo e Cohcrane com os seguintes filtros: resumo abstract, textos open access, idioma português e inglês, período 2016 a 2021. Também foram utilizados manuais e boletins epidemiológicos disponíveis na página do Ministério da Saúde. O material foi selecionado de modo a buscar responder os objetivos dessa pesquisa e portanto utilizou os descritores em saúde: hanseníase, atenção básica, diagnóstico, tratamento. Foram abordadas práticas de educação em saude que envolvem orientações e estigmas em saude. Entende-se que o manejo da hanseníase envolve sensibilidade, consciência e sobretudo conhecimento embasado para consubstanciar a prática clínica

Amiloidose cardíaca: Cardiac amyloidosis

Introdução: A amiloidose cardíaca é uma doença rara e multissistêmica, causada por depósito amiloide de proteínas solúveis, que precipitam nos tecidos na forma de agregados fibrilares amiloides. Esses depósitos amiloides podem causar vários distúrbios cardíacos, e seus portadores são divididos em quatro grupos. Apresentação do caso: paciente com 73 anos, apresentou-se à urgência e emergência devido dispneia aos médios e pequenos esforços, com piora progressiva dos últimos meses. Hipertenso crônico, sem outras comorbidades. Apresentava-se lúcido, orientado em tempo e espaço, acianótico, anictérico, hipocorado, dispneico, com ritmo cardíaco irregular, bulhas normofonéticas, e presença de terceira bulha. Presença de estertores crepitantes bilateralmente, com redução discreta do murmúrio vesicular em terço inferior pulmonar esquerdo e direto. Edema de membros inferiores bilateral em região perimaleolar e tibial (++/++++), panturrilhas livres. Discussão: Por apresentar achados inespecíficos, seu diagnóstico é limitado, suspeitado diante de casos de insuficiência cardíaca encontrada em ecocardiograma e alterações de condução em eletrocardiogramas. Durante investigação, é comum a presença de depósito amiloide em rins, fígado, baço e outros órgãos, dentre eles o coração, causando alterações em seus tecidos. Conclusão: O diagnóstico precoce é necessário para evitar a progressão da doença. O tratamento é baseado na estabilização dos depósitos e drogas para alívio sintomático, além de controle das anormalidades clínicas e hemodinâmicas

Histoplasmose Pulmonar: Pulmonary Histoplasmosis

Introdução: A histoplasmose pulmonar é uma micose causada pelo fungo dimórfico Histoplasma capsulatum, sendo uma das infecções respiratórias fúngicas mais comum no mundo. Apresentação do caso: paciente do sexo feminino, 49 anos de idade, foi admitida no hospital, queixando-se de dor torácica predominante em hemitórax direito, com piora progressiva nos últimos 5 meses. Afirmou que a dor tem intensidade 5 de 10 com duração intermitente. Negou febre, tosse, dispneia e emagrecimento. Apresenta alterações clínicas e radiográficas típicas de tuberculose ou neoplasia, mas que teve essas hipóteses descartadas, confirmando a histoplasmose pulmonar. Discussão: Essa doenca é prevalente no continente americano e acomete mais o sexo masculino. A gravidade do quadro varia de acordo com o grau de exposição ao fator causador, podendo variar da ausência de sintomas à falência respiratória ou morte. O diagnóstico é feito por exames complementares e laboratoriais e, tendo em vista a semelhança radiológica entre lesões malignas e a histoplasmose pulmonar, é de suma importância a exclusão desse diagnóstico diferencial a fim de evitar iatrogenias. Conclusão: Ao achado radiológico de um nódulo pulmonar solitário, a principal hipótese diagnóstica é de uma neoplasia maligna, entretanto a histoplasmose pulmonar deve ser considerada por também apresentar infiltrados reticulonodulares à radiografia,  principalmente em pacientes residentes em áreas endêmicas

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

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio