The p53 Family of Transcription Factors Represses the Alpha- fetoprotein Gene Expression in Hepatocellular Carcinoma

Background: p53 deletion and mutation as well as upregulation of alpha-fetoprotein (AFP) are hallmarks of hepatocarcinogenesis. p63 and p73 belong to the family of p53-related transcription factors expressing a variety of isoforms. The expression of dominant negative (ΔN) p73 is related to the reduced survival of patients with hepatocellular carcinoma (HCC). In this study, we characterized the interaction between p53 family-dependent signaling pathways and the regulation of AFP at the gene and protein levels as essential determinants of therapeutic response and prognosis in HCC. Methods: Putative p53-, p63- and p73-binding sites within the AFP gene were identified in silico. Hep3B cells were transfected with plasmids encoding for p53, p63 and p73 to analyze the interplay of the p53 family with AFP. AFP transcription was determined by RT-qPCR. Protein levels of AFP, p53, p63 and p73 were analyzed by Western blot. Results: Underlining the importance of the crosstalk between the p53 family-dependent pathways and AFP regulation we identified eight novel putative binding sites for the members of the p53 family within the introns 1, 2, 3, 4, 7, 8, 11, and 12 of the AFP gene. Accordingly, full-length isoforms of p53, p63 and p73 efficiently downregulated AFP both on mRNA and protein level. Thus, the p53 family members were identified to be major regulators of AFP repression. Of note, p63 was characterized as a novel and p73 as the most efficient repressor of AFP. Conclusion: p53 mutation and upregulation of AFP are essential oncogenic events in the development of HCC. Here we show that AFP gene regulation occurs via a combined action of the p53 family members p53, p63 and p73. All three tumor suppressors reduce AFP gene and protein expression. Thus, our findings reveal a novel interaction of p53 family-dependent signaling pathways and AFP regulation at the gene and protein levels in HCC

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Performance of simple noninvasive scoring systems for the prediction of advanced fibrosis in patients with chronic hepatitis B

Background and aim The aim of the study was to analyze the diagnostic performance and clinical utility of simple noninvasive tests for the detection of advanced fibrosis in patients with chronic hepatitis B (CHB) infection seen at a tertiary referral center in Germany. Patients and methods We retrospectively analyzed 239 adult CHB patients with available liver biopsies. Patient demographics, hepatitis B markers, antiviral treatment, laboratory parameters, results from liver imaging, and histology were recorded. The sensitivity, specificity, and positive and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas and cut-off values for fibrosis index based on the four factors, aspartate aminotransferase-alanine aminotransferase ratio index (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and age-platelet index. Results The median documented duration of CHB infection was 31 months (range: 6-340 months); 86% of the patients were Caucasian and 71% were men. The AUROCs for the detection of advanced fibrosis were 0.75 [ 95% confidence interval (CI): 0.67-0.82], 0.72 (95% CI: 0.64-0.80), 0.48 (95% CI: 0.39-0.56), and 0.73 (95% CI: 0.66-0.81) for fibrosis index the four factors, APRI, AAR, and age-platelet index, respectively. Patients with advanced fibrosis on biopsy were misclassified as having mild fibrosis in 35% (APRI) to 82% (AAR) of cases. Conclusion Because of their moderate test performance (AUROCs: 0.48-0.75) and their high misclassification rate, we could not confirm a reliable clinical utility for the analyzed noninvasive fibrosis scoring systems for the prediction of advanced fibrosis in mostly Caucasian CHB patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

Recommandations d'un collectif franco-suisse d'experts pour une meilleure évaluation de la qualité écotoxicologique des sédiments par l'étude des communautés benthiques

National audienceLes sédiments ont un rôle écologique essentiel pour de nombreuses espèces aquatiques. Toutefois, leur capacité à capter les polluants persistants peut participer à long terme à la contamination des milieux aquatiques. Aussi, afin de mieux prendre en compte les impacts écotoxicologiques de la contamination des sédiments et appréhender le risque écologique qui en découle, il est important de disposer de méthodes d'évaluation robustes. Cet article présente la contribution d'un groupe franco-suisse réunissant chercheurs, gestionnaires et représentants de bureaux d'études qui ont travaillé ensemble afin de dresser un état des lieux et formuler des recommandations pour mieux caractériser la contamination des sédiments, les niveaux d'exposition des communautés benthiques et les effets possibles sur ces espèces

Recommendations from a French-Swiss expert panel for improving the ecotoxicological quality assessment of sediments through the study of benthic communities

International audienceLes sédiments ont un rôle écologique essentiel pour de nombreuses espèces aquatiques.Toutefois, leur capacité à capter les polluants persistants peut participer à long termeà la contamination des milieux aquatiques. Aussi, afin de mieux prendre en compte les impactsécotoxicologiques de la contamination des sédiments et appréhender le risque écologiquequi en découle, il est important de disposer de méthodes d'évaluation robustes. Cet article présentela contribution d'un groupe franco-suisse réunissant chercheurs, gestionnaires et représentantsde bureaux d’études qui ont travaillé ensemble afin de dresser un état des lieux et formulerdes recommandations pour mieux caractériser la contamination des sédiments, les niveauxd’exposition des communautés benthiques et les effets possibles sur ces espèce

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

International audienceAbstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 )