The development of IBD is known to involve early immunological alterations, but our understanding of the changes in antibody epitope repertoires moving from the prediagnostic phase towards disease onset remains incomplete. In this study, we comprehensively characterised systemic antibody responses in patients with IBD before and after disease onset, aiming to identify prediagnostic disease biomarkers. Within Lifelines, a population-based cohort study collecting and storing longitudinal samples from 167 000 individuals over∼15 years, we identified 178 individuals with blood samples taken both before and after IBD-onset. In these prediagnosis and postdiagnosis serum samples (median time span 3.9 years), we profiled antibody epitope repertoires against 344 000 rationally selected microbial, food and immune antigens using phage-display immunoprecipitation sequencing. Postdiagnosis, we observe reduced antibody frequencies against herpesviruses, particularly for Epstein-Barr virus and varicella zoster virus, and elevated antibody frequencies against specific enteroviruses, including adenovirus C and enterovirus types B and C. Even before diagnosis, individuals who ultimately developed Crohn's disease (CD) displayed elevated antibody reactivity against flagellins of both commensal and pathogenic bacteria. This CD-specific profile became even more pronounced postdiagnosis, suggesting the formation of IBD-specific antibody responses years before disease onset. This study is the first comprehensive high-resolution analysis of the exact antigenic nature of systemic antibody responses during the transition from prediagnostic to established IBD. The antibody signatures we found may represent a route to developing biomarkers that identify individuals at high risk of developing disease.

Non-variceal upper gastrointestinal bleeding (NVUGIB) remains a major cause of morbidity and mortality. Rebleeding rates following endoscopic treatment can reach up to 25% within 72 hours in patients with high-risk lesions. To evaluate the efficacy of a haemostatic powder (Nexpowder) in reducing rebleeding rates after conventional endoscopic treatment in patients with NVUGIB. This was a prospective, multicentre, randomised controlled trial involving patients with acute NVUGIB from high-risk lesions who achieved initial endoscopic haemostasis. Participants were randomised 1:1 to receive either the haemostatic powder or no further therapy (control group). The primary outcome was the rebleeding rate within 72 hours post-treatment. Secondary outcomes included the 30-day rebleeding rate and the safety profile. A total of 341 patients (72.1% male; mean age 64.8 years) were included, with 173 in the powder group and 168 in the control group. Baseline characteristics were similar between groups. Ulcer bleeding was the predominant aetiology (n=317), with Forrest type I bleeding observed in two-thirds of cases. The 72-hour rebleeding rate was significantly lower in the powder group (2.9%, 95% CI 0.9 to 6.6%) compared with the control group (11.3%, 95% CI 6.9 to 17.1%; p =0.005). A significant reduction was also observed in the 30-day cumulative rebleeding rate (7.0% vs 18.8%), with similar findings in the ulcer subgroup for the 3-day rebleeding rate (3.0% vs 12.0%; p =0.004). No adverse events related to the powder application were reported. The application of Nexpowder following endoscopic haemostasis significantly reduced both early (3 days) and late (30 days) rebleeding rates in patients with NVUGIB, particularly in cases of ulcer-related bleeding. NCT04124588.

RAS mutations are frequently observed in human cholangiocarcinoma (CCA), while they are relatively rare in hepatocellular carcinoma (HCC). The role of RAS-dependent signalling pathways in CCA development is currently not well understood. The objective of this study was to investigate RAS-dependent signalling pathways in CCA and their role in tumour development and differentiation. We used genetically engineered mouse models with liver-specific deletion of tumour suppressors Rb and p53 together with activation of oncogenic Kras to investigate the cell of origin in intrahepatic CCA and to elucidate the role of RAS-dependent signalling pathways in CCA development. In mice, Kras-mutant intrahepatic CCA develops primarily from hepatocytes and shows activation of PI3K/AKT and MEK/ERK signalling downstream of KRAS. Targeted genetic inactivation of each of these pathways leads to delayed tumour growth and profound alterations in tumour differentiation. Specifically, reduced PI3K/AKT signalling promotes more well-differentiated tumours, whereas the inactivation of MEK/ERK signalling induces a differentiation switch towards a more hepatocyte-like phenotype. This switch is accompanied by activation of WNT/β-catenin signalling, a pathway commonly activated in human HCC. These findings provide insights into the role of RAS-dependent pathways in liver cancer differentiation and offer a compelling explanation for the high prevalence of RAS mutations in human CCA compared with HCC.