Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration.

Following severe or chronic liver injury, adult ductal cells (cholangiocytes) contribute to regeneration by restoring both hepatocytes and cholangiocytes. We recently showed that ductal cells clonally expand as self-renewing liver organoids that retain their differentiation capacity into both hepatocytes and ductal cells. However, the molecular mechanisms by which adult ductal-committed cells acquire cellular plasticity, initiate organoids and regenerate the damaged tissue remain largely unknown. Here, we describe that ductal cells undergo a transient, genome-wide, remodelling of their transcriptome and epigenome during organoid initiation and in vivo following tissue damage. TET1-mediated hydroxymethylation licences differentiated ductal cells to initiate organoids and activate the regenerative programme through the transcriptional regulation of stem-cell genes and regenerative pathways including the YAP-Hippo signalling. Our results argue in favour of the remodelling of genomic methylome/hydroxymethylome landscapes as a general mechanism by which differentiated cells exit a committed state in response to tissue damage.RCUK Cancer Research UK ERC H2020 Wellcome Trus

Changing pattern of the use of biologic disease modifying antirheumatic drugs in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

Background: During the last 15 years, the comprehensive understanding of the safety, effectiveness, expanding access, and availability of new biologic disease-modifying antirheumatic drugs (bDMARDs) has likely contributed to the pattern of use of these compounds in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Objectives: To assess changes in the baseline characteristics of patients who underwent biological therapy from 2007 to 2018 in a real world setting. Methods: Data were obtained from BIOBADASER, the Spanish registry of biologics. Recorded data is obtained from routine clinical practice. Patients diagnosed with RA, PsA and AS and who started biological treatment from 2007 to 2018 were included. Sociodemographic and clinical variables, as well as first bDMARD used, were stratified by the starting year period (2007-2009; 2010-2012; 2013-2015; 2016-2018) and compared using Anova and Chi-square tests. Results: 6943 patients (2827 RA patients, 1274 PsA and 1261 AS) were included in this analysis (Table 1). Patient age at the beginning of the first biologic was significantly higher during the period 2016-2018 than in 2007-2009 (48.3 vs 50.6). Disease duration until the use of biologics decreased from 8.6 to 8.1 years. In RA patients, disease activity, as assessed by DAS28 at the start of the biological treatment, was significantly higher in the 2007-2009 period than in the last period analyzed (5.1 vs 4.7). The use of TNF inhibitor as a first option also changed significantly (94.6% vs 58.5%). Regarding comorbidities, the number of rheumatic patients treated with biologics and a past history of cancer (1.8% vs 3.7%), ischemic heart disease (1.8% vs 3.1%), hypercholesterolemia (13.6% vs 26.1%), or hypertension (21.7% vs 23.7%) has increased significantly. Conclusion: Our data show that during the last decade the pattern of use of biologics in patients with rheumatic diseases has changed. Nowadays these compounds are used in older patients, with shorter disease duration, with lower disease activity in RA, and with more comorbidities