Protective effect of n-acetyl-L-cysteine and rosuvastatin against oxidative stress in fibroblasts from asymptomatic patients with X-ALD: a preliminary study

Introduction: Several studies in the literature have evaluated the role of oxidative stress and adjuvant therapies for X-linked adrenoleukodystrophy (X-ALD). Here, we investigated whether n-acetyl-L-cysteine (NAC) and rosuvastatin (RSV) could influence the generation of reactive species, redox status and nitrative stress in fibroblasts from asymptomatic patients with X-ALD. Methods: Skin biopsy samples were cultured and treated for 2 hours (37 °C) with NAC and RSV.Results: X-ALD fibroblasts generated high levels of reactive oxygen species. These levels were significantly lower in fibroblasts treated with NAC and RSV relative to untreated samples. The X-ALD fibroblasts from asymptomatic patients also had higher catalase activity, and only NAC was able to increase enzyme activity in the samples.Conclusion: Our results indicated that NAC and RSV were able to improve oxidative stress parameters in fibroblasts from asymptomatic patients with X-ALD, showing that adjuvant antioxidant therapy may be a promising treatment strategy for asymptomatic patients with this disease

Antithrombin stabilisation by sulfated carbohydrates correlates with anticoagulant activity

Thermal stabilisation of native antithrombin-III (AT), determined using differential scanning fluorimetry, correlated with the anticoagulant activity of heparin and heparin-related saccharides. Similar conformational changes were induced in native AT by a variety of active and inactive heparin-related sulfated carbohydrates, measured in solution using synchrotron radiation circular dichroism, and their anticoagulant activities. Measurement of native AT stabilisation provides a convenient assay for prospective anticoagulants and represents an additional parameter by which to compare biosimilar heparins.National Science Foundation's National High Magnetic Field Laboratory User Program in the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) Facility (McKnight Brain Institute, University of Florida, USA)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo UNIFESP, Dept Biochem, BR-04044020 São Paulo, BrazilDiamond Light Source Ltd, Beam Line Circular Dichroism 23, Didcot OX11 ODE, Oxon, EnglandUniv Liverpool, Dept Struct & Chem Biol, Liverpool L69 7ZB, Merseyside, EnglandIst Ric Chim & Biochim G Ronzoni, I-20133 Milan, ItalyUniv Fed Rio Grande do Norte, Dept Biochem, BR-59072970 Natal, RN, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Biochem, BR-04044020 São Paulo, BrazilWeb of Scienc

Results from a population-based cohort study

Funding Information: We have read the journal's policy and the authors of this manuscript have the following competing interests: ARF reports travel grants from Roche and advisory board fees from Daiichi Sankyo, Gilead, Merck Sharp & Dohme, Novartis and Roche, outside the submitted work. DMB reports travel grants from LEO Farmacêuticos, Merck Sharp & Dohme, Ipsen, Janssen, Roche, and Novartis, advisory board fees from Janssen, Pfizer, Merck Sharp & Dohme, Angelini, AstraZeneca, and Novartis, and institutional grants from F. Hoffmann-La Roche, outside the submitted work. The other authors have declared that no competing interests exist. Funding Information: The authors acknowledge the RON network that cooperated in providing up-to-date information on cases diagnosed and treated with the drug of interest (participating institutions: Centro Hospitalar Universit?rio de S?o Jo?o, Centro Hospitalar Universit?rio Lisboa Norte, Centro Hospitalar Universit?rio do Algarve, Hospital de Braga, Centro Hospitalar e Universit?rio de Coimbra, Centro Hospitalar de Tr?s-os-Montes e Alto Douro, Hospital Central do Funchal, Centro Hospitalar de Vila Nova de Gaia/Espinho, Centro Hospitalar Lisboa Ocidental, Hospital Garcia de Orta, Centro Hospitalar Universit?rio Lisboa Central, Hospital Distrital de Santar?m, Centro Hospitalar de Entre o Douro e Vouga, Hospital da Senhora da Oliveira Guimar?es, Centro Hospitalar de Set?bal, Centro Hospitalar e Universit?rio do Porto, Centro Hospitalar Tondela Viseu, Hospital do Esp?rito Santo de ?vora, Centro Hospitalar Barreiro Montijo, Hospital Beatriz ?ngelo, Hospital do Santo Esp?rito da Ilha Terceira, Hospital do Divino Esp?rito Santo de Ponta Delgada, Hospital Pedro Hispano ? ULS Matosinhos, Hospital do Litoral Alentejano ? Santiago do Cac?m ? ULS Litoral Alentejano, Centro Hospitalar do Oeste, Centro Hospitalar M?dio Tejo, Hospital Jos? Joaquim Fernandes ? Beja ? ULS Baixo Alentejo, Centro Hospitalar Universit?rio da Cova da Beira, Centro Cl?nico Champalimaud, Hospitais CUF, Hospitais da Luz, Hospitais dos Lus?adas, Hospital Particular do Algarve). Publisher Copyright: © 2022 The AuthorsBackground: Real-world (RW) data may provide valuable information on the effectiveness and safety of medicines, which is particularly relevant for clinicians, patients and third-party payers. Evidence on the effectiveness of palbociclib plus fulvestrant is scarce, which highlights the need of additional studies. The aim of this study was to evaluate the effectiveness of palbociclib plus fulvestrant in advanced breast cancer (ABC). Materials and methods: We conducted a population-based retrospective cohort study and cases of interest were identified through the Portuguese National Cancer Registry database and additional data sources. Patients aged≥18 years, diagnosed with ABC and exposed to palbociclib plus fulvestrant between May 31, 2017 and March 31, 2019 were included. Patients were followed-up until death or cut-off date (February 28, 2021). Primary outcome was rw-progression-free survival (rwPFS). Secondary outcomes were rw-overall survival (rwOS), rw-time to palbociclib failure (rwTPF) and rw-time to next treatment (rwTTNT). Results: A total of 210 patients were included. Median age was 58 years (range 29–83) and 99.05% were female. Median follow-up time was 23.22 months and, at cut-off date, treatment had been discontinued in 189 patients, mainly due to disease progression (n = 152). Median rwPFS was 7.43 months (95% confidence interval [CI] 6.28–9.05) and 2-year rwPFS was 16.65% (95%CI 11.97–22.00). Median rwOS was 24.70 months (95%CI 21.58–29.27), median rwTPF was 7.5 months (95%CI 6.51–9.08) and median rwTTNT was 11.74 months (95%CI 10.33–14.08). Conclusion: Palbociclib plus fulvestrant seems an effective treatment for ABC in real-world context. Compared to registrations studies, rwPFS and rwOS were shorter in real-life setting.publishersversionpublishe

Bacterial and Archaeal Communities Change With Intensity of Vegetation Coverage in Arenized Soils From the Pampa Biome

Arenization occurs in regions that present sandy soils with normal rainfall levels. Predatory use of environmental sources, the dissolution of arenitic rocks and reworking of non-consolidated surface sands intensify this degradation scenario. Thus, this work aimed to evaluate the impact of the arenization process in the Brazilian Pampa Biome and how this phenomenon affects the soil microbial and plant communities. For this purpose, three arenized areas in Southern Brazil (Pampa Biome) were selected and, in each one, three sampling points were studied: arenized (ARA), arenized to grassland transition (AGT), and grassland (GRA) areas. In the three sampling points, soils presented low levels of nutrients, organic matter, mud and pH acidic in all regions but, the presence of vegetation coverage in AGT and GRA areas preserved the topsoil structure. Our study related ARA with bacterial families Alcaligenaceae, Pseudomonadaceae, and Xanthomonadaceae. AGT with bacterial families Bacillaceae and Burkholderiaceae, and plant species Melinis repens (Willd.) Zizka and Paspalum stellatum Humb. and Bonpl. ex Flüggé, and GRA with bacterial families Koribacteraceae, Hyphomicrobiaceae, and Chthoniobacteraceae, and plant species Croton subpannosus Müll.Arg. ex Griseb., Piptochaetium montevidense (Spreng.) Parodi and Elyonurus sp. The three studied areas (as well as sampling points) present soils extremely poor in nutrients with sandy texture, and the bacterial and plant composition well known to be resistant to environmental stresses were dominant. The vulnerability of these areas causes a degradation scenario, which is worsened by agricultural activities. However, in general, this phenomenon is a natural process that occurs mainly due to soil characteristics (poor soils) and climatic variations

FREQUÊNCIA E FATORES ASSOCIADOS À ATIVIDADE FÍSICA NO LAZER ENTRE ADULTOS NO BRASIL E NA AMAZÔNIA LEGAL: ESTUDO DE BASE POPULACIONAL / FREQUENCY AND FACTORS ASSOCIATED WITH LEISURE PHYSICAL ACTIVITY AMONG ADULTS IN BRAZIL AND IN THE AMAZON: POPULATION-BASED STUDY

Introdução: A prática regular de atividade física tem sido recomendada como importante estratégia de promoção em saúde,mas a inatividade física ainda permanece alta em várias regiões. Objetivo: Investigar a frequência e fatores associados à atividadefísica de lazer nas regiões brasileiras e nos estados que compõem a sua Amazônia legal. Métodos: Trata-se de um estudotransversal baseado num inquerido domiciliar de residentes de todas as regiões do Brasil, realizada em 2008 pelo InstitutoBrasileiro de Geografia e Estatística (IBGE). Utilizou-se uma amostra de 186.424 indivíduos com idade entre 20 e 59 anos. Avariável dependente foi atividade física de lazer. Resultados: A frequência da AFL no Brasil foi de 13,8% e entre os estados daAmazônia legal foi de 10,8%. A AFL no Brasil foi maior entre as mulheres na idade entre 20 a 29 anos e na Amazônia legal foientre os homens. Independente da região, quanto maior a renda, escolaridade e autoavaliação de saúde maior a frequência deatividade física de lazer. Conclusão: Atividade física de lazer é menos praticada por pessoas com maior vulnerabilidade socioeconômicae pelos moradores da Amazônia Legal, mesmo que eles tenham os mesmos níveis socioeconômicos dos moradoresdo Brasil.Palavras-chave: Atividade motora. Fatores Socioeconômicos. Estudos Transversais. Desigualdades em Saúde.AbstractIntroduction: Regular physical activity (RPA) has been recommended as an important health promotion strategy, but physicalinactivity remains high in several regions. Objective: To investigate the frequency and factors associated with leisure RPA inBrazilian regions and states that make up its legal Amazon. Methods: This is a cross-sectional study based on a populationbasedsurvey in residents of all regions of Brazil, conducted in 2008 by the Brazilian Institute of Geography and Statistics (IBGE,in Portuguese). We used a sample of 186,424 individuals aged between 20 and 59 years. The dependent variable was leisureRPA. Results: The frequency of leisure RPA in Brazil was 13.8% and among the states of the Amazon region was 10.8%. The leisureRPA in Brazil was higher among women aged between 20 to 29 years and in the Legal Amazon was among men. Regardlessof the region, the higher the income, schooling and health self-assessment the frequency of leisure RPA. Conclusion: Leisure RPAis less practiced by people with higher socioeconomic vulnerability and by the inhabitants of the Amazon, even if they have thesame socioeconomic status of the residents of Brazil.Keywords: Motor Activity. Cross-Sectional Studies. Socioeconomic Factors. Health Inequalitie

Maternal LAMP/p55gagHIV-1 DNA Immunization Induces In Utero Priming and a Long-Lasting Immune Response in Vaccinated Neonates

Infants born to HIV-infected mothers are at high risk of becoming infected during gestation or the breastfeeding period. A search is thus warranted for vaccine formulations that will prevent mother-to-child HIV transmission. The LAMP/gag DNA chimeric vaccine encodes the HIV-1 p55gag fused to the lysosome-associated membrane protein-1 (LAMP-1) and has been shown to enhance anti-Gag antibody (Ab) and cellular immune responses in adult and neonatal mice; such a vaccine represents a new concept in antigen presentation. In this study, we evaluated the effect of LAMP/gag DNA immunization on neonates either before conception or during pregnancy. LAMP/gag immunization of BALB/c mice before conception by the intradermal route led to the transfer of anti-Gag IgG1 Ab through the placenta and via breastfeeding. Furthermore, there were an increased percentage of CD4+CD25+Foxp3+T cells in the spleens of neonates. When offspring were immunized with LAMP/gag DNA, the anti-Gag Ab response and the Gag-specific IFN-γ-secreting cells were decreased. Inhibition of anti-Gag Ab production and cellular responses were not observed six months after immunization, indicating that maternal immunization did not interfere with the long-lasting memory response in offspring. Injection of purified IgG in conjunction with LAMP/gag DNA immunization decreased humoral and cytotoxic T-cell responses. LAMP/gag DNA immunization by intradermal injection prior to conception promoted the transfer of Ab, leading to a diminished response to Gag without interfering with the development of anti-Gag T- and B-cell memory. Finally, we assessed responses after one intravenous injection of LAMP/gag DNA during the last five days of pregnancy. The intravenous injection led to in utero immunization. In conclusion, DNA vaccine enconding LAMP-1 with Gag and other HIV-1 antigens should be considered in the development of a protective vaccine for the maternal/fetal and newborn periods

Metabolic Adaptation of Ralstonia solanacearum during Plant Infection: A Methionine Biosynthesis Case Study

MetE and MetH are two distinct enzymes that catalyze a similar biochemical reaction during the last step of methionine biosynthesis, MetH being a cobalamin-dependent enzyme whereas MetE activity is cobalamin-independent. In this work, we show that the last step of methionine synthesis in the plant pathogen Ralstonia solanacearum is under the transcriptional control of the master pathogenicity regulator HrpG. This control is exerted essentially on metE expression through the intermediate regulator MetR. Expression of metE is strongly and specifically induced in the presence of plant cells in a hrpG- and metR-dependent manner. metE and metR mutants are not auxotrophic for methionine and not affected for growth inside the plant but produce significantly reduced disease symptoms on tomato whereas disruption of metH has no impact on pathogenicity. The finding that the pathogen preferentially induces metE expression rather than metH in the presence of plant cells is indicative of a probable metabolic adaptation to physiological host conditions since this induction of metE occurs in an environment in which cobalamin, the required co-factor for MetH, is absent. It also shows that MetE and MetH are not functionally redundant and are deployed during specific stages of the bacteria lifecycle, the expression of metE and metH being controlled by multiple and distinct signals