TMAO and Gut Microbial-Derived Metabolites TML and γBB Are Not Associated with Thrombotic Risk in Patients with Venous Thromboembolism

Background: The present work evaluates the association between circulating concentrations of Trimethylamine-N-oxide (TMAO), gamma butyrobetaine (gamma BB), and trimetyllisine (TML) in controls and patients with venous thromboembolism (VTE) with coagulation parameters. Methods: The study involved 54 VTE patients and 57 controls. Platelet function, platelet hyperreactivity, platelet adhesiveness, thrombosis-associated parameters, and thrombin generation parameters were studied. Plasma TMAO, gamma BB, and TML determination was performed using an ultra-high-performance liquid chromatography system coupled with mass spectrometry. Results: No differences were found for TMAO, gamma BB, or TML concentrations between controls and VTE patients. In thrombin generation tests, TMAO, gamma BB, and TML showed a positive correlation with lag time and time to peak. TMAO, gamma BB, and TML negatively correlated with peak height. No significant differences were observed regarding TMAO, gamma BB, and TML concentrations between the two blood withdrawals, nor when the control and VTE patients were analyzed separately. No correlation was observed between these gut metabolites and platelet function parameters. Conclusions: No differences were found regarding TMAO, gamma BB, and TML concentrations between the control and VTE groups. Some correlations were found; however, they were mild or went in the opposite direction of what would be expected if TMAO and its derivatives were related to VTE risk

SEOM clinical guidelines for the treatment of head and neck cancer (2017)

Head and neck cancer (HNC) is defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2013 publication, Spanish Society of Medical Oncology (SEOM) presents an update of HNC diagnosis and treatment guideline. The eighth edition of TNM classification, published in January 2017, introduces important changes for p16-positive oropharyngeal tumours, for lip and oral cavity cancer and for N3 category. In addition, there are new data about induction chemotherapy and the role of immunotherapy in HNC

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122–treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30–1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03–1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population

The capacity of apob-depleted plasma in inducing atp-binding cassette a1/g1-mediated macrophage cholesterol efflux-but not gut microbial-derived metabolites-is independently associated with mortality in patients with st-segment elevation myocardial infarction

Altres ajuts: Fundació per a la Bioquímica Clínica i Patologia MolecularImpaired HDL-mediated macrophage cholesterol efflux and higher circulating concentrations of trimethylamine N-oxide (TMAO) levels are independent risk factors for cardiovascular mortality. The TMAO precursors, γ-butyrobetaine (γBB) and Trimethyllysine (TML), have also been recently associated with cardiovascular death, but their interactions with HDL-mediated cholesterol efflux remain unclear. We aimed to determine the associations between APOB depleted plasma-mediated macrophage cholesterol efflux and plasma TMAO, γBB, and TML concentrations and explore their association with two-year follow-up mortality in patients with acute ST-elevation myocardial infarction (STEMI) and unstable angina (UA). Baseline and ATP-binding cassette transporter ABCA1 and ABCG1 (ABCA1/G1)-mediated macrophage cholesterol efflux to APOB-depleted plasma was decreased in patients with STEMI, and the latter was further impaired in those who died during follow-up. Moreover, the circulating concentrations of TMAO, γBB, and TML were higher in the deceased STEMI patients when compared with the STEMI survivors or UA patients. However, after statistical adjustment, only ABCA1/G1-mediated macrophage cholesterol efflux remained significantly associated with mortality. Furthermore, neither the TMAO, γBB, nor TML levels altered the HDL-mediated macrophage cholesterol efflux in vitro. We conclude that impaired ABCA1/G1-mediated macrophage cholesterol efflux is independently associated with mortality at follow-up in STEMI patients

Challenges for Sustained Observing and Forecasting Systems in the Mediterranean Sea

The Mediterranean community represented in this paper is the result of more than 30 years of EU and nationally funded coordination, which has led to key contributions in science concepts and operational initiatives. Together with the establishment of operational services, the community has coordinated with universities, research centers, research infrastructures and private companies to implement advanced multi-platform and integrated observing and forecasting systems that facilitate the advancement of operational services, scientific achievements and mission-oriented innovation. Thus, the community can respond to societal challenges and stakeholders needs, developing a variety of fit-for-purpose services such as the Copernicus Marine Service. The combination of state-of-the-art observations and forecasting provides new opportunities for downstream services in response to the needs of the heavily populated Mediterranean coastal areas and to climate change. The challenge over the next decade is to sustain ocean observations within the research community, to monitor the variability at small scales, e.g., the mesoscale/submesoscale, to resolve the sub-basin/seasonal and inter-annual variability in the circulation, and thus establish the decadal variability, understand and correct the model-associated biases and to enhance model-data integration and ensemble forecasting for uncertainty estimation. Better knowledge and understanding of the level of Mediterranean variability will enable a subsequent evaluation of the impacts and mitigation of the effect of human activities and climate change on the biodiversity and the ecosystem, which will support environmental assessments and decisions. Further challenges include extending the science-based added-value products into societal relevant downstream services and engaging with communities to build initiatives that will contribute to the 2030 Agenda and more specifically to SDG14 and the UN's Decade of Ocean Science for sustainable development, by this contributing to bridge the science-policy gap. The Mediterranean observing and forecasting capacity was built on the basis of community best practices in monitoring and modeling, and can serve as a basis for the development of an integrated global ocean observing system

Challenges for Sustained Observing and Forecasting Systems in the Mediterranean Sea

The Mediterranean community represented in this paper is the result of more than 30 years of EU and nationally funded coordination, which has led to key contributions in science concepts and operational initiatives. Together with the establishment of operational services, the community has coordinated with universities, research centers, research infrastructures and private companies to implement advanced multi-platform and integrated observing and forecasting systems that facilitate the advancement of operational services, scientific achievements and mission-oriented innovation. Thus, the community can respond to societal challenges and stakeholders needs, developing a variety of fit-for-purpose services such as the Copernicus Marine Service. The combination of state-of-the-art observations and forecasting provides new opportunities for downstream services in response to the needs of the heavily populated Mediterranean coastal areas and to climate change. The challenge over the next decade is to sustain ocean observations within the research community, to monitor the variability at small scales, e.g., the mesoscale/submesoscale, to resolve the sub-basin/seasonal and inter-annual variability in the circulation, and thus establish the decadal variability, understand and correct the model-associated biases and to enhance model-data integration and ensemble forecasting for uncertainty estimation. Better knowledge and understanding of the level of Mediterranean variability will enable a subsequent evaluation of the impacts and mitigation of the effect of human activities and climate change on the biodiversity and the ecosystem, which will support environmental assessments and decisions. Further challenges include extending the science-based added-value products into societal relevant downstream services and engaging with communities to build initiatives that will contribute to the 2030 Agenda and more specifically to SDG14 and the UN's Decade of Ocean Science for sustainable development, by this contributing to bridge the science-policy gap. The Mediterranean observing and forecasting capacity was built on the basis of community best practices in monitoring and modeling, and can serve as a basis for the development of an integrated global ocean observing system

Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages.

HMG-CoA reductase inhibitors (statins) decrease atherosclerosis by lowering low-density-lipoprotein cholesterol. Statins are also thought to have additional anti-atherogenic properties, yet defining these non-conventional modes of statin action remains incomplete. We have previously developed a novel mouse transplant model of atherosclerosis regression in which aortic segments from diseased donors are placed into normolipidemic recipients. With this model, we demonstrated the rapid loss of CD68+ cells (mainly macrophages) in plaques through the induction of a chemokine receptor CCR7-dependent emigration process. Because the human and mouse CCR7 promoter contain Sterol Response Elements (SREs), we hypothesized that Sterol Regulatory Element Binding Proteins (SREBPs) are involved in increasing CCR7 expression and through this mechanism, statins would promote CD68+ cell emigration from plaques. We examined whether statin activation of the SREBP pathway in vivo would induce CCR7 expression and promote macrophage emigration from plaques. We found that western diet-fed apoE(-/-) mice treated with either atorvastatin or rosuvastatin led to a substantial reduction in the CD68+ cell content in the plaques despite continued hyperlipidemia. We also observed a significant increase in CCR7 mRNA in CD68+ cells from both the atorvastatin and rosuvastatin treated mice associated with emigration of CD68+ cells from plaques. Importantly, CCR7(-/-)/apoE(-/-) double knockout mice failed to display a reduction in CD68+ cell content upon statin treatment. Statins also affected the recruitment of transcriptional regulatory proteins and the organization of the chromatin at the CCR7 promoter to increase the transcriptional activity. Statins promote the beneficial remodeling of plaques in diseased mouse arteries through the stimulation of the CCR7 emigration pathway in macrophages. Therefore, statins may exhibit some of their clinical benefits by not only retarding the progression of atherosclerosis, but also accelerating its regression

Disodium ascorbyl phytostanol phosphate (FM-VP4), a modified phytostanol, is a highly active hypocholesterolaemic agent that affects the enterohepatic circulation of both cholesterol and bile acids in mice

Disodium ascorbyl phytostanol phosphate (FM-VP4) is a synthetic compound derived from sitostanol and campestanol that has proved to be efficient as a cholesterol-lowering therapy in mice and human subjects. However, the mechanism of action of FM-VP4 remains unknown. The present study tests the ability of FM-VP4 to alter intestinal and liver cholesterol homeostasis in mice. Female C57BL/6J mice were fed either a control chow or a 2 % FM-VP4-enriched diet for 4 weeks. FM-VP4 reduced the in vivo net intestinal cholesterol absorption and plasma and liver cholesterol concentrations by 2.2-, 1.5- and 1.6-fold, respectively, compared with control mice. Furthermore, FM-VP4 also showed an impact on bile acid homeostasis. In FM-VP4 mice, liver and intestinal bile acid content was increased by 1.3- and 2.3-fold, respectively, whereas faecal bile acid output was 3.3-fold lower. FM-VP4 also increased the intestinal absorption of orally administered [H-3]taurocholic acid to small intestine in vivo. Inhibition of intestinal cholesterol absorption by FM-VP4 was not mediated via transcriptional increases in intestine liver X receptor (LXR)-alpha, adenosine triphosphate-binding cassette transporter (ABC)-A1, ABCG5/G8 nor to decreases in intestinal Niemann-Pick Cl-like 1 (NPC1L1) expression. In contrast, FM-VP4 up-regulated liver LXR alpha, ABCA1, ABCG5, scavenger receptor class BI (SR-BI) and hydroxymethylglutaryl coenzyme A reductase (HMGCoA-R) gene expression, whereas it down-regulated several farnesoid X receptor (FXR)-target genes such as cytochrome P450 family 7 subfamily A polypeptide I (CYP7AI) and Na+/taurocholate co-transporter polypeptide (NTCP). In conclusion, FM-VP4 reduced intestinal cholesterol absorption, plasma and liver cholesterol and affected bile acid homeostasis by inducing bile acid intestinal reabsorption and changed the liver expression of genes that play an essential role in cholesterol homeostasis. This is the first phytosterol or stanol that affects bile acid metabolism and lowers plasma cholesterol levels in normocholesterolaemic mice