Circulating anthocyanin metabolites mediate vascular benefits of blueberries:insights from randomized controlled trials, metabolomics, and nutrigenomics

Potential health benefits of blueberries may be due to vascular effects of anthocyanins which predominantly circulate in blood as phenolic acid metabolites. We investigated which role blueberry anthocyanins and circulating metabolites play in mediating improvements in vascular function and explore potential mechanisms using metabolomics and nutrigenomics. Purified anthocyanins exerted a dose-dependent improvement of endothelial function in healthy humans, as measured by flow-mediated dilation (FMD). The effects were similar to those of blueberries containing similar amounts of anthocyanins while control drinks containing fiber, minerals, or vitamins had no significant effect. Daily 1-month blueberry consumption increased FMD and lowered 24h-ambulatory-systolic-blood-pressure. Of the 63 anthocyanin plasma metabolites quantified, 14 and 17 correlated with acute and chronic FMD improvements, respectively. Injection of these metabolites improved FMD in mice. Daily blueberry consumption led to differential expression (>1.2-fold) of 608 genes and 3 microRNAs, with Mir-181c showing a 13-fold increase in peripheral blood mononuclear cells. Patterns of 13 metabolites were independent predictors of gene expression changes and pathway enrichment analysis revealed significantly modulated biological processes involved in cell adhesion, migration, immune response, and cell differentiation. Our results identify anthocyanin metabolites as major mediators of vascular bioactivities of blueberries and changes of cellular gene programs

Risk of developing checkpoint immune pneumonitis and its effect on overall survival in non-small cell lung cancer patients previously treated with radiotherapy

Introduction:Immune checkpoint inhibitor-related pneumonitis (ICIP) is a potentially lifethreatening immune-related adverse event (irAE), especially in non-small cell lung cancer(NSCLC) patients. Currently, the potential for increased irAE in patients who receiveradiotherapy is scarcely known, although a connection between antitumor immuneresponses and irAEs has been suggested. In this study, we evaluated the developmentof ICIP in non-small cell lung cancer patients with prior radiotherapy, treated withimmunotherapy in the second-line.Methods:In this retrospective trial, we included patients treated with second-lineimmunotherapy at the National Cancer Institute in Mexico City from February 2015 toFebruary 2018. Clinical, radiological and treatment variables were evaluated accordingto the presence of ICIP as defined by the Common Terminology Criteria for AdverseEvents (4.0) in patients with or without a previous (≥months) history of radiotherapy.Results:Among 101 NSCLC patients who received treatment with ICIs, 22 patients(21.8%) were diagnosed with ICIP, of which 73% (16/22) had a history of radiotherapy(OR 6.04, 95% CI 2.03−18.0,p<0.001). Median progression free survival and overallsurvival were similar in patients who developed ICIP compared with those who did not,however, patients who presented grade≥2 ICIP had an increased risk of mortality (HR2.54, 95% CI 1.20−5.34,p= 0.014).Conclusion:In this real-world cohort of NSCLC patients treated with ICI, the historyof prior radiotherapy was associated with increased risk for ICIP development. Unlikeother irAEs, grade≥2 ICIP is an independent prognostic factor for decreased survivalin NSCLC patients

Metabolomics profile responses to changing environments in a common bean (Phaseolus vulgaris L.) germplasm collection

Metabolomics is one of the most powerful -omics to assist plant breeding. Despite the recognized genetic diversity in Portuguese common bean germplasm, details on its metabolomics profiles are still missing. Aiming to promote their use and to understand the environment’s effect in bean metabolomics profiles, 107 Portuguese common bean accessions, cropped under contrasting environments, were analyzed using spectrophotometric, untargeted and targeted mass spectrometry approaches. Although genotype was the most relevant factor on bean metabolomics profile, a clear genotype × environment interaction was also detected. Multivariate analysis highlighted, on the heat-stress environment, the existence of higher levels of salicylic acid, and lower levels of triterpene saponins. Three clusters were defined within each environment. White accessions presented the lowest content and the colored ones the highest levels of prenol lipids and flavonoids. Sources of interesting metabolomics profiles are now identified for bean breeding, focusing either on local or on broad adaptation.To FCT, Portugal, in BEGEQA project (PTDC/AGR-TEC/3555/2012), E.M. PhD fellowship (SFRH/BD/89287/2012), as well as to R&D unit, UIDB/04551/2020 (GREEN-IT – Bioresources for sustainability) and COST Action FA1403 (STSM-FA1403-290815-063873) for funding. The authors also acknowledge PORTUGAL 2020 to the Portuguese Mass Spectrometry Network, grant number LISBOA-01-0145-FEDER-402-022125. The project NETDIAMOND (SAICTPAC/0047/2015), financially supported by FEEI (Lisboa 2020 and FCT/POCI-01-0145-FEDER-016385), to the iNOVA4Health (UID/Multi/04462/2013), financially supported by FCT and co-funded by FEDER under the PT2020 Partnership Agreement, as well as to POCI-01-0145-FEDER-029702, funded by FEDER funds through COMPETE2020 – Programa Operacional Competitividade e Internacionalização (POCI) and by national funds (PIDDAC) through FCT/MCTES

Association of a variant in the regulatory region of NADPH oxidase 4 gene and metabolic syndrome in patients with chronic hepatitis C

Abstract\ud \ud Background\ud Given the important contribution of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system to the generation of reactive oxygen species induced by hepatitis C virus (HCV), we investigated two single nucleotide polymorphisms (SNPs) in the putative regulatory region of the genes encoding NADPH oxidase 4 catalytic subunit (NOX4) and its regulatory subunit p22phox (CYBA) and their relation with metabolic and histological variables in patients with HCV.\ud \ud \ud Methods\ud One hundred seventy eight naïve HCV patients (49.3% male; 65% HCV genotype 1) with positive HCV RNA were genotyped using specific primers and fluorescent-labeled probes for SNPs rs3017887 in NOX4 and −675 T → A in CYBA.\ud \ud \ud Results\ud No association was found between the genotype frequencies of NOX4 and CYBA SNPs and inflammation scores or fibrosis stages in the overall population. The presence of the CA + AA genotypes of the NOX4 SNP was nominally associated with a lower alanine aminotransferase (ALT) concentration in the male population (CA + AA = 72.23 ± 6.34 U/L versus CC = 100.22 ± 9.85; mean ± SEM; P = 0.05). The TT genotype of the CYBA SNP was also nominally associated with a lower ALT concentration in the male population (TT = 84.01 ± 6.77 U/L versus TA + AA = 109.67 ± 18.37 U/L; mean ± SEM; P = 0.047). The minor A-allele of the NOX4 SNP was inversely associated with the frequency of metabolic syndrome (MS) in the male population (odds ratio (OR): 0.15; 95% confidence interval (CI): 0.03 to 0.79; P = 0.025).\ud \ud \ud Conclusions\ud The results suggest that the evaluated NOX4 and CYBA SNPs are not direct genetic determinants of fibrosis in HCV patients, but nevertheless NOX4 rs3017887 SNP could indirectly influence fibrosis susceptibility due to its inverse association with MS in male patients

HE-LHC: The High-Energy Large Hadron Collider – Future Circular Collider Conceptual Design Report Volume 4

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1

We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics

HE-LHC: The High-Energy Large Hadron Collider: Future Circular Collider Conceptual Design Report Volume 4

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries

FCC-hh: The Hadron Collider: Future Circular Collider Conceptual Design Report Volume 3

In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100&nbsp;km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100&nbsp;TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries