The Arf tumor suppressor protein inhibits Miz1 to suppress cell adhesion and induce apoptosis

Arf assembles a complex containing Miz1, heterochromatin, and histone H3K3 to block expression of genes involved in cell adhesion and signal transduction. The resulting blockade of cell–cell and cell–matrix interactions facilitates elimination of cells carrying oncogenic mutations

Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib

Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR. Objective: to investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib. In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA. A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR. Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients

Urinary Metabolome Analysis Reveals Potential Microbiota Alteration and Electrophilic Burden Induced by High Red Meat Diet: Results from the French NutriNet‐Santé Cohort and an in vivo Intervention Study in Rats

International audienceScope: High red and processed meat consumption is associated with several adverse outcomes such as colorectal cancer and overall global mortality. However, the underlying mechanisms remain debated and need to be elucidated.Methods and results: Urinary untargeted LC-MS metabolomics data from 240 subjects from the French cohort NutriNet-Santé were analysed. Individuals were matched and divided into 3 groups according to their consumption of red and processed meat: high red and processed meat consumers, non-red and processed meat consumers and an at random group. Results were supported by a preclinical experiment where rats were fed either a high red meat or a control diet. Microbiota derived metabolites, in particular indoxyl sulfate and cinnamoylglycine, were found impacted by the high red meat diet in both studies, suggesting a modification of microbiota by the high red/processed meat diet. Rat microbiota sequencing analysis strengthened this observation. Although not evidenced in the human study, rat mercapturic acid profile concomitantly revealed an increased lipid peroxidation induced by high red meat diet.Conclusion: Novel microbiota metabolites were identified as red meat consumption potential biomarkers, suggesting a deleterious effect, which could partly explain the adverse effects associated with high red and processed meat consumption

Urinary Metabolome Analysis Reveals Potential Microbiota Alteration and Electrophilic Burden Induced by High Red Meat Diet: Results from the French NutriNet‐Santé Cohort and an in vivo Intervention Study in Rats

International audienceScope: High red and processed meat consumption is associated with several adverse outcomes such as colorectal cancer and overall global mortality. However, the underlying mechanisms remain debated and need to be elucidated.Methods and results: Urinary untargeted LC-MS metabolomics data from 240 subjects from the French cohort NutriNet-Santé were analysed. Individuals were matched and divided into 3 groups according to their consumption of red and processed meat: high red and processed meat consumers, non-red and processed meat consumers and an at random group. Results were supported by a preclinical experiment where rats were fed either a high red meat or a control diet. Microbiota derived metabolites, in particular indoxyl sulfate and cinnamoylglycine, were found impacted by the high red meat diet in both studies, suggesting a modification of microbiota by the high red/processed meat diet. Rat microbiota sequencing analysis strengthened this observation. Although not evidenced in the human study, rat mercapturic acid profile concomitantly revealed an increased lipid peroxidation induced by high red meat diet.Conclusion: Novel microbiota metabolites were identified as red meat consumption potential biomarkers, suggesting a deleterious effect, which could partly explain the adverse effects associated with high red and processed meat consumption

Reduced Hepatic Synthesis of Calcidiol in Uremia

Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D3 C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P < 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D3 or 1α-hydroxyvitamin D3, respectively, suggesting impaired C-25-hydroxylation of vitamin D3. Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms

Cognitive barriers to calling a smoking quitline

INTRODUCTION: This study examined cognitive barriers that might prevent cigarette smokers who are interested in quitting from calling a smoking quitline. METHODS: Using qualitative and quantitative methods, we developed a 53-item inventory of possible cognitive barriers to quitline access. A total of 641 daily smokers who reported high intentions to stop smoking in the next 30 days completed this inventory and were then prompted to call a toll-free smoking quitline (800-QUIT NOW) on 3 occasions. Two months later, they completed a follow-up phone interview to assess use of the quitline, quit attempts, and smoking status. RESULTS: Exploratory and confirmatory factor analysis of the barrier items revealed a 5-factor solution: stigma, low appraisal of the service, no need for assistance, poor fit with the service, and privacy concerns. Endorsements of barrier factors were generally low. Although several barrier factor scores predicted concurrent intentions to call a quitline in the near future, none prospectively predicted calling the quitline by 2-month follow-up. DISCUSSION: Cognitive barriers to use of quitlines remain elusive

A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation

Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.

ObjectivesAmong patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant.DesignSecondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722).SettingOne hundred-fifty-three ICUs in 13 countries.PatientsAltogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ).InterventionsNone.Measurements and main resultsTotal mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p p p p p p p p = 0.007).ConclusionsAmong STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions