bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resveratrol Attenuates Trimethylamine-
N
-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota
Authors: Chen Ming-liang , Yi Long , Zhang Yong , Zhou Xi , Ran Li , Yang Jining , Zhu Jun-dong , Zhang Qian-yong , Mi Man-tian 
Published: April 2016

ABSTRACT

The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-
N
-oxide (TMAO)-induced AS in ApoE
−/−
mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice. Moreover, RSV increased levels of the genera
Lactobacillus
and
Bifidobacterium
, which increased the bile salt hydrolase activity, thereby enhancing bile acid (BA) deconjugation and fecal excretion in C57BL/6J and ApoE
−/−
mice. This was associated with a decrease in ileal BA content, repression of the enterohepatic farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) axis, and increased cholesterol 7a-hydroxylase (CYP7A1) expression and hepatic BA neosynthesis. An FXR antagonist had the same effect on FGF15 and CYP7A1 expression as RSV, while an FXR agonist abolished RSV-induced alterations in FGF15 and CYP7A1 expression. In mice treated with antibiotics, RSV neither decreased TMAO levels nor increased hepatic BA synthesis. Additionally, RSV-induced inhibition of TMAO-caused AS was also markedly abolished by antibiotics. In conclusion, RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling, and the BA neosynthesis was partially mediated through the enterohepatic FXR-FGF15 axis.

IMPORTANCE
Recently, trimethylamine-
N
-oxide (TMAO) has been identified as a novel and independent risk factor for promoting atherosclerosis (AS) partially through inhibiting hepatic bile acid (BA) synthesis. The gut microbiota plays a key role in the pathophysiology of TMAO-induced AS. Resveratrol (RSV) is a natural phytoalexin with prebiotic benefits. A growing body of evidence supports the hypothesis that phenolic phytochemicals with poor bioavailability are possibly acting primarily through remodeling of the gut microbiota. The current study showed that RSV attenuated TMAO-induced AS by decreasing TMAO levels and increasing hepatic BA neosynthesis via gut microbiota remodeling. And RSV-induced hepatic BA neosynthesis was partially mediated through downregulating the enterohepatic farnesoid X receptor-fibroblast growth factor 15 axis. These results offer new insights into the mechanisms responsible for RSV’s anti-AS effects and indicate that the gut microbiota may become an interesting target for pharmacological or dietary interventions to decrease the risk of developing cardiovascular diseases.
Gliotoxin Suppresses Macrophage Immune Function by Subverting Phosphatidylinositol 3,4,5-Trisphosphate Homeostasis
Authors: Schlam Daniel , Canton Johnathan , Carreño Marvin , Kopinski Hannah , Freeman Spencer A. , Grinstein Sergio , Fairn Gregory D. 
Published: April 2016

ABSTRACTAspergillus fumigatus, an opportunistic fungal pathogen, spreads in the environment by releasing numerous conidia that are capable of reaching the small alveolar airways of mammalian hosts. In otherwise healthy individuals, macrophages are responsible for rapidly phagocytosing and eliminating these conidia, effectively curbing their germination and consequent invasion of pulmonary tissue. However, under some circumstances, the fungus evades phagocyte-mediated immunity and persists in the respiratory tree. Here, we report thatA. fumigatusescapes macrophage recognition by strategically targeting phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] metabolism through gliotoxin, a potent immunosuppressive mycotoxin. Time-lapse microscopy revealed that, in response to the toxin, macrophages cease to ruffle, undergo abrupt membrane retraction, and fail to phagocytose large targets effectively. Gliotoxin was found to prevent integrin activation and interfere with actin dynamics, both of which are instrumental for phagocytosis; similar effects were noted in immortalized and primary phagocytes. Detailed studies of the underlying molecular mechanisms of toxicity revealed that inhibition of phagocytosis is attributable to impaired accumulation of PtdIns(3,4,5)P3and the associated dysregulation of downstream effectors, including Rac and/or Cdc42. Strikingly, in response to the diacylglycerol mimetic phorbol 12-myristate 13-acetate, gliotoxin-treated macrophages reactivate beta integrins, reestablish actin dynamics, and regain phagocytic capacity, despite the overt absence of plasmalemmal PtdIns(3,4,5)P3. Together, our findings identify phosphoinositide metabolism as a critical upstream target of gliotoxin and also indicate that increased diacylglycerol levels can bypass the requirement for PtdIns(3,4,5)P3signaling during membrane ruffling and phagocytosis.IMPORTANCEAspergillus fumigatusis the most frequent cause of human infections in theAspergillusgenus. In immunocompromised populations, invasive aspergillosis (IA) is associated with a mortality rate of up to 90%, and current antifungal therapies have failed to prevent or reverse the infection. Therefore, a deeper understanding of the interactions betweenA. fumigatusand its host is required. In healthy humans, alveolar macrophages can ingest and eliminate fungal spores, thus limiting their germination into mycotoxin-producing hyphae. Our studies reveal that gliotoxin—the most abundantAspergillusmycotoxin—undermines the ability of phagocytes to carry out their protective functions. By targeting PtdIns(3,4,5)P3signaling and downregulating phagocytic immune defenses, the toxin could also exacerbate polymicrobial infections. Notably, we were able to reverse gliotoxin toxicity by addition of diacylglycerol analogues, which may provide the basis for therapeutic interventions.
Biologic Treatment Registry Across Canada (BioTRAC): a multicentre, prospective, observational study of patients treated with infliximab for ankylosing spondylitis
Authors: Rahman Proton , Choquette Denis , Bensen William G , Khraishi Majed , Chow Andrew , Zummer Michel , Shaikh Saeed , Sheriff Maqbool , Dixit Sanjay , Sholter Dalton , Psaradellis Eliofotisti , Sampalis John S , Letourneau Vincent , Lehman Allen J , Nantel François , Rampakakis Emmanouil , Otawa Susan , Shawi May 
Published: April 2016

ObjectivesTo describe the profile of patients with ankylosing spondylitis (AS) treated with infliximab in Canadian routine care and to assess the effectiveness and safety of infliximab in real world.Setting46 primary care rheumatology practices across Canada.Participants303 biological-naïve patients with AS or patients previously treated with a biological for <6 months and who were eligible for infliximab treatment as per routine care within the Biologic Treatment Registry Across Canada (BioTRAC).InterventionNot applicable (non-interventional study).Primary and secondary outcomesEffectiveness was assessed with changes in disease parameters (AS Disease Activity Score (ASDAS), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Health Assessment Questionnaire Disease Index (HAQ-DI), physician global assessment of disease activity (MDGA), patient global disease activity (PtGA), back pain, C-reactive protein, erythrocyte sedimentation rate (ESR), morning stiffness). Safety was assessed with the incidence of adverse events (AEs).ResultsOf the 303 patients included, 44.6% were enrolled in 2005–2007 and 55.4% in 2008–2013. Patients enrolled in 2005–2007 had significantly higher MDGA and ESR at baseline while all other disease parameters examined were numerically higher with the exception of PtGA. Treatment with infliximab significantly (p<0.001) improved all disease parameters over time in both groups. At 6 months, 56% and 31% of patients achieved clinically important (change≥1.1) and major (change≥2.0) improvement in ASDAS, respectively; at 48 months, these proportions increased to 75% and 50%, respectively. Among patients unemployed due to disability at baseline, 12.1% returned to work (mean Kaplan-Meier (KM)-based time=38.8 months). The estimated retention rate at 12 and 24 months was 78.3% and 60.1%, respectively. The profile and incidence of AEs were comparable to data previously reported for tumour necrosis factor-α inhibitors.ConclusionsCharacteristics of patients with AS at infliximab initiation changed over time towards lower disease activity and shorter disease duration. Infliximab treatment significantly reduced disease activity independent of treatment initiation year, although patients enrolled in recent years achieved lower disease activity over 48 months.Trial registration numberNCT00741793.
Cancer and non-cancer mortality among French uranium cycle workers: the TRACY cohort
Authors: Samson Eric , Piot Irwin , Zhivin Sergey , Richardson David B , Laroche Pierre , Serond Ana-Paula , Laurier Dominique , Laurent Olivier 
Published: April 2016

ObjectivesThe health effects of internal contamination by radionuclides, and notably by uranium, are poorly characterised. New cohorts of uranium workers are needed to better examine these effects. This paper analyses for the first time the mortality profile of the French cohort of uranium cycle workers. It considers mortality from cancer and non-cancer causes.MethodsThe cohort includes workers employed at least 6 months between 1958 and 2006 in French companies involved in the production of nuclear fuel. Vital status and causes of death were collected from French national registries. Workers were followed-up from 1 January 1968 to 31 December 2008. Standardised mortality ratios (SMRs) were computed based on mortality rates for the French general population.ResultsThe cohort includes 12 649 workers (88% men). The average length of follow-up is 27 years and the mean age at the end of the study is 60 years. Large mortality deficits are observed for non-cancer causes of death such as non-cancer respiratory diseases (SMR=0.51 (0.41 to 0.63)) and circulatory diseases (SMR=0.68 (0.62 to 0.74)). A mortality deficit of lower magnitude is also observed for all cancers combined (SMR (95% CI): 0.76 (0.71 to 0.81)). Pleural mesothelioma is elevated (SMR=2.04 (1.19 to 3.27)).ConclusionsA healthy worker effect is observed in this new cohort of workers involved in the uranium cycle. Collection of individual information on internal uranium exposure as well as other risk factors is underway, to allow for the investigation of uranium-related risks.
Community social capital and tooth loss in Japanese older people: a longitudinal cohort study
Authors: Koyama Shihoko , Aida Jun , Saito Masashige , Kondo Naoki , Sato Yukihiro , Matsuyama Yusuke , Tani Yukako , Sasaki Yuri , Kondo Katsunori , Ojima Toshiyuki , Yamamoto Tatsuo , Tsuboya Toru , Osaka Ken 
Published: April 2016

ObjectiveTo date, no study has prospectively examined the association between social capital (SC) in the community and oral health. The aim of this longitudinal cohort study was to examine the association between both community-level and individual-level SC and tooth loss in older Japanese people.DesignProspective cohort studySettingWe utilised data from the Japan Gerontological Evaluation Study (JAGES) performed in 2010 and 2013 and conducted in 525 districts.ParticipantsThe target population was restricted to non-institutionalised people aged 65 years or older. Participants included 51 280 people who responded to two surveys and who had teeth at baseline.Primary outcome measureThe primary outcome measure was loss of remaining teeth, measured by the downward change of any category of remaining teeth, between baseline and follow-up.ResultsThe mean age of the participants was 72.5 years (SD=5.4). During the study period, 8.2% (n=4180) lost one or more of their remaining teeth. Among three community-level SC variables obtained from factor analysis, an indicator of civic participation significantly reduced the risk of tooth loss (OR 0.93; 95% CI 0.88 to 0.99). The individual-level SC variables ‘hobby activity participation’ and ‘sports group participation’ were also associated with a reduced risk of tooth loss (OR 0.88; 95% CI 0.81 to 0.95 and OR 0.90; 95% CI 0.82 to 0.99, respectively).ConclusionsLiving in a community with rich SC and individuals with good SC is associated with lower incidence of tooth loss among older Japanese people.
Cardiovascular mortality sex differentials in selected East Asian and Western populations
Authors: Zhao Jiaying , Booth Heather , Dear Keith , Tu Edward Jow-Ching 
Published: April 2016

BackgroundExplaining patterns in the sex ratio (male/female) of cardiovascular disease (CVD) mortality would improve understanding of mortality transitions under modernisation. Little research has examined secular trends in this ratio across populations, taking age and cohort into account. We examine cohort effects in the ratios of CVD mortality (including ischaemic heart disease and cerebrovascular disease) among 4 East Asian populations that vary in the timing of their modernisation, and assess the effect of smoking on these patterns in comparison with Western populations.MethodsThe sequential method for log-linear models is applied to analyse age, period and cohort effects for sex ratios. Age and cohort effects are fitted first, with population as offset; period effects are fitted in a second model using the fitted values from the first model as the offset. Lung cancer mortality serves as a proxy for smoking.ResultsIncreases in sex ratios of CVD mortality began in earlier cohorts in Western than in East Asian populations. Once begun, increases were more rapid in East Asia. The cohort effect for the sex ratio of CVD mortality differs from that for lung cancer mortality. Trends in sex ratios of CVD mortality by cohort are similar before and after adjustment for lung cancer mortality in East Asia; the increasing trend across 1900–1945 cohorts is maintained in Western populations after adjustment.ConclusionsThe sex ratio of CVD mortality has increased across successive cohorts living in increasingly modernised environments. There is scant evidence that this increase is attributable to changing sex-specific rates of smoking.
Hemodynamic differences between unstable and stable unruptured aneurysms independent of size and location: a pilot study
Authors: Brinjikji Waleed , Chung Bong Jae , Jimenez Carlos , Putman Christopher , Kallmes David F , Cebral Juan R 
Published: April 2016

BackgroundWhile clinical and angiographic risk factors for intracranial aneurysm instability are well established, it is reasonable to postulate that intra-aneurysmal hemodynamics also have a role in aneurysm instability.ObjectiveTo identify hemodynamic characteristics that differ between radiologically unstable and stable unruptured intracranial aneurysms.Materials and methods12 pairs of unruptured intracranial aneurysms with a 3D rotational angiographic set of images and followed up longitudinally without treatment were studied. Each pair consisted of one stable aneurysm (no change on serial imaging) and one unstable aneurysm (demonstrated growth of at least 1 mm diameter or ruptured during follow-up) of matching size (within 10%) and locations. Patient-specific computational fluid dynamics models were created and run under pulsatile flow conditions. Relevant hemodynamic and geometric variables were calculated and compared between groups using the paired Wilcoxon test.ResultsThe area of the aneurysm under low wall shear stress (low shear stress area (LSA)) was 2.26 times larger in unstable aneurysms than in stable aneurysms (p=0.0499). The mean aneurysm vorticity was smaller by a factor of 0.57 in unstable aneurysms compared with stable aneurysms (p=0.0499). No statistically significant differences in geometric variables or shape indices were found.ConclusionsThis pilot study suggests there may be hemodynamic differences between unstable and stable unruptured cerebral aneurysms. In particular, the area under low wall shear stress was larger in unstable aneurysms. These findings should be considered tentative until confirmed by future larger studies.
Comparison of soil-to-water suspension ratios for determining electrical conductivity of oil-production-water-contaminated soils
Authors: Klaustermeier Aaron , Tomlinson Hannah , Daigh Aaron L.M. , Limb Ryan , DeSutter Thomas , Sedivec Kevin 
Published: April 2016

Soil salinity caused by oil-production-water (brine) contamination is a major issue in regions of oil and gas development. However, rapid site assessment tools such as soil-to-water suspension electrical conductivity (EC) methods and conversion equations have not been previously calibrated and validated for brine-contaminated soils. Our objective was to compare three soil EC methods and derive conversion equations for EC values commonly observed at brine-spill sites. Brine-contaminated soils from western North Dakota were assessed for salinity. Electrical conductivity was determined using 1:1 and 1:5 soil-to-water suspensions (EC1:1, EC1:5) and saturated paste extracts (ECe). Soil EC equilibration times for soil-to-water suspensions were also assessed. Significant relationships (r2 = 0.91 to 0.97, P < 0.0001) existed among all methods for EC values ranging between 0 and 126 dS m−1. Conversion equations were developed based on these relationships and then validated with an independent data set. These new equations reduced ECe prediction errors by 2 to 4.5 times when compare with 14 predictive equations reported in the literature. The conversion equations developed here are recommended for use in remediation efforts when converting EC1:1 and EC1:5 data to ECe on brine-contaminated and noncontaminated soils where ECe is highly correlated to Na concentrations.
Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity
Authors: Pasero Christine , Gravis Gwenaëlle , Guerin Mathilde , Granjeaud Samuel , Thomassin-Piana Jeanne , Rocchi Palma , Paciencia-Gros Maria , Poizat Flora , Bentobji Mélanie , Azario-Cheillan Francine , Walz Jochen , Salem Naji , Brunelle Serge , Moretta Alessandro , Olive Daniel 
Published: April 2016

Abstract
The field of immunotherapy for solid tumors, such as prostate cancer, has been recently focusing on therapies that can counter tumor-mediated immunosuppression. Precise quantification and characterization of the immune infiltrates in tumors is crucial to improve treatment efficacy. Natural killer (NK) cells, major components of the antitumor immune system, have never been isolated from prostate tumors, despite their suspected role in disease progression. Here, we examined the frequency, phenotype, and functions of NK cells infiltrating control and tumor prostate tissues. NK cell infiltrates in prostate tissues were mainly CD56 (NCAM1)-positive and displayed an unexpected immature, but activated, phenotype with low or no cytotoxic potential. Furthermore, we show that TGFβ1 (TGFB1) is highly secreted into the prostate environment and partly mediates the immunosuppressive effects on NK cells. In addition to this basal level of immunotolerance to NK cells, the prostate environment became further resistant to NK cell–mediated immunity upon cancer cell infiltration. Coculture experiments revealed that prostate cancer cells induced the expression of inhibitory receptor (ILT2/LILRB1) and downregulated the expression of activating receptors NKp46 (NCR1), NKG2D (KLRK1), and CD16 (FCGR3) by NK cells, thus preventing their recognition of tumor cells. Notably, blood levels of NKp46 were also decreased in prostate cancer patients and were inversely correlated with levels of prostate-specific antigen, the main prognostic factor in prostate cancer. Our study shows that a strong immunosuppressive environment impairs NK cell function at multiple levels in prostate cancer and provides a rationale for the design of therapies that restore NK cell efficiency in the prostate tumor microenvironment. Cancer Res; 76(8); 2153–65. ©2016 AACR.
c-Myb Enhances Breast Cancer Invasion and Metastasis through the Wnt/β-Catenin/Axin2 Pathway
Authors: Li Yihao , Jin Ke , van Pelt Gabi W. , van Dam Hans , Yu Xiao , Mesker Wilma E. , ten Dijke Peter , Zhou Fangfang , Zhang Long 
Published: April 2016

Abstract
The molecular underpinnings of aggressive breast cancers remain mainly obscure. Here we demonstrate that activation of the transcription factor c-Myb is required for the prometastatic character of basal breast cancers. An analysis of breast cancer patients led us to identify c-Myb as an activator of Wnt/β-catenin signaling. c-Myb interacted with the intracellular Wnt effector β-catenin and coactivated the Wnt/β-catenin target genes Cyclin D1 and Axin2. Moreover, c-Myb controlled metastasis in an Axin2-dependent manner. Expression microarray analyses revealed a positive association between Axin2 and c-Myb, a target of the proinflammatory cytokine IL1β that was found to be required for IL1β-induced breast cancer cell invasion. Overall, our results identified c-Myb as a promoter of breast cancer invasion and metastasis through its ability to activate Wnt/β-catenin/Axin2 signaling. Cancer Res; 76(11); 3364–75. ©2016 AACR.
Plasma Metabolomic Changes following PI3K Inhibition as Pharmacodynamic Biomarkers: Preclinical Discovery to Phase I Trial Evaluation
Authors: Ang Joo Ern , Pandher Rupinder , Ang Joo Chew , Asad Yasmin J. , Henley Alan T. , Valenti Melanie , Box Gary , de Haven Brandon Alexis , Baird Richard D. , Friedman Lori , Derynck Mika , Vanhaesebroeck Bart , Eccles Suzanne A. , Kaye Stan B. , Workman Paul , de Bono Johann S. , Raynaud Florence I. 
Published: April 2016

AbstractPI3K plays a key role in cellular metabolism and cancer. Using a mass spectrometry–based metabolomics platform, we discovered that plasma concentrations of 26 metabolites, including amino acids, acylcarnitines, and phosphatidylcholines, were decreased in mice bearing PTEN-deficient tumors compared with non–tumor-bearing controls and in addition were increased following dosing with class I PI3K inhibitor pictilisib (GDC-0941). These candidate metabolomics biomarkers were evaluated in a phase I dose-escalation clinical trial of pictilisib. Time- and dose-dependent effects were observed in patients for 22 plasma metabolites. The changes exceeded baseline variability, resolved after drug washout, and were recapitulated on continuous dosing. Our study provides a link between modulation of the PI3K pathway and changes in the plasma metabolome and demonstrates that plasma metabolomics is a feasible and promising strategy for biomarker evaluation. Also, our findings provide additional support for an association between insulin resistance, branched-chain amino acids, and related metabolites following PI3K inhibition. Mol Cancer Ther; 15(6); 1412–24. ©2016 AACR.