A runaway PRH/HHEX-Notch3 positive feedback loop drives cholangiocarcinoma and determines response to CDK4/6 inhibition

This is the author accepted manuscript. The final version is available from the American Association for Cancer Research via the DOI in this recordAberrant Notch and Wnt signalling are known drivers of cholangiocarcinoma (CCA) but the underlying factors that initiate and maintain these pathways are not known. Here we show that the PRH/HHEX transcription factor forms a positive transcriptional feedback loop with Notch3 that is critical in CCA. PRH/HHEX expression was elevated in CCA and depletion of PRH reduced CCA tumour growth in a xenograft model. Overexpression of PRH in primary human biliary epithelial cells was sufficient to increase cell proliferation and produce an invasive phenotype. Interrogation of the gene networks regulated by PRH and Notch3 revealed that unlike Notch3, PRH directly activated canonical Wnt signalling. These data indicate that hyperactivation of Notch and Wnt signalling is independent of the underlying mutational landscape and has a common origin in dysregulation of PRH. Moreover, they suggest new therapeutic options based on the dependence of specific Wnt, Notch, and CDK4/6 inhibitors on PRH activity.Medical Research Council (MRC)Thailand Research Fund (TRF

One Health drivers of antibacterial resistance: Quantifying the relative impacts of human, animal and environmental use and transmission

This is the final version. Available on open access from Elsevier via the DOI in this recordData accessibility statement: All model code is open source and available for download on GitHub https://github.com/rdbooton/OHDARTmodelObjectives Antibacterial resistance (ABR) is a major global health security threat, with a disproportionate burden on lower-and middle-income countries (LMICs). It is not understood how ‘One Health’, where human health is co-dependent on animal health and the environment, might impact the burden of ABR in LMICs. Thailand's 2017 “National Strategic Plan on Antimicrobial Resistance” (NSP-AMR) aims to reduce AMR morbidity by 50% through 20% reductions in human and 30% in animal antibacterial use (ABU). There is a need to understand the implications of such a plan within a One Health perspective. Methods A model of ABU, gut colonisation with extended-spectrum beta-lactamase (ESBL)-producing bacteria and transmission was calibrated using estimates of the prevalence of ESBL-producing bacteria in Thailand. This model was used to project the reduction in human ABR over 20 years (2020–2040) for each One Health driver, including individual transmission rates between humans, animals and the environment, and to estimate the long-term impact of the NSP-AMR intervention. Results The model predicts that human ABU was the most important factor in reducing the colonisation of humans with resistant bacteria (maximum 65.7–99.7% reduction). The NSP-AMR is projected to reduce human colonisation by 6.0–18.8%, with more ambitious targets (30% reductions in human ABU) increasing this to 8.5–24.9%. Conclusions Our model provides a simple framework to explain the mechanisms underpinning ABR, suggesting that future interventions targeting the simultaneous reduction of transmission and ABU would help to control ABR more effectively in Thailand.Antimicrobial Resistance Cross Council Initiativ