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Murine Kupffer cells (KCs) comprise CD11bhi and F4/80hi subsets. Tissue-resident macrophages are known to express the tyrosine kinase receptors colony-stimulating factor 1 receptor (Csf1r) and Mer. However, the expression of Csf1r and Mer on KC subsets and the importance of these tyrosine kinases during liver regeneration (LR) are unknown. KCs from wild-type and Csf1r-GFP mice were characterized by flow cytometry. Partial hepatectomy (PH) was performed in mice treated with clodronate liposomes, a Csf1r small molecule inhibitor or depleting antibody, or a small molecule Mer inhibitor. Sera and livers were analyzed. The function of sorted KC subsets was tested in vitro. Mer was specifically expressed on tissue-resident F4/80hi KCs, 55% of which also expressed Csf1r. Mer+Csf1r+ and Mer+Csf1r- KCs had distinct expression of macrophage markers. Csf1r inhibition in mice reduced F4/80hi KCs by approximately 50%, but did not affect CD11bhi KCs. Clodronate liposomes depleted F4/80hi KCs, but also altered levels of other intrahepatic leukocytes. Csf1r inhibition delayed LR, as demonstrated by a 20% reduction in liver-to-body weight ratios 7 days after PH. At 36h after PH, Csf1r inhibition increased serum ALT and histological liver injury, and decreased liver cell proliferation. A small molecule inhibitor of Mer did not alter the percentage of KCs or their proliferation and just modestly delayed LR. In vitro, Csf1r or Mer inhibition did not decrease KC viability, but did attenuate their cytokine response to stimulation. F4/80hi KCs are Mer+ and can be subdivided based on Csf1r expression. Csf1r or Mer inhibition each reduces KC cytokine production and delays LR.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.

Australia is a sink for low pathogenicity avian influenza viruses, with isolated circulation occurring on the continent. We report the incursion of a Eurasian low pathogenicity avian influenza H5 virus into Australia. This report benefits surveillance and diagnostic work because of the risk and current absence of highly pathogenic avian influenza A(H5N1).

Patient and Public Involvement and Engagement (PPIE) is an essential element of any clinical trial, to ensure that the research design and resources are acceptable and the trial produces findings that are relevant to research participants and service-users. The WILL (When to Induce Labour to Limit risk in pregnancy hypertension) Trial Management Team involved a group of patient and public members to develop an infographic, for service-users and -providers, to communicate the risks of chronic and gestational hypertension at term gestational age. Based on national resources in the UK for PPIE, including those from the National Institute for Health and Care Research (NIHR) and Health Research Authority, active trial sites (all in the UK) were approached to invite women with pregnancy hypertension to the PPIE group, and advertisements were placed on the Action on Pre-Eclampsia Charity (APEC) and NIHR People in Research websites. PPIE resources were established by the Trial Management Team and virtual meetings with the PPIE members held to co-design and develop the infographic from existing trial materials, using Microsoft Publisher. Seven diverse PPIE members were involved, six from NIHR People in Research and one from APEC. No members were engaged from active sites. From initial set-up to REC approval of the infographic took 9 months, and a considerable time commitment from the Trial Manager and Senior Research Midwives, to navigate practicalities (e.g. team consensus-building). Four meetings were held and 15 iterations of the infographic were developed with the group. The infographic incorporated requests from PPIE members for a design that was inclusive of all races, cultures, abilities and genders. Discussions with PPIE group members improved our understanding of the acceptability of the trial intervention to some cultures. The Research Ethics Committee (REC) requested revisions to PPIE-approved wording about the risk of stillbirth, from '1 in 1000' to 'small increased risk' prior to issuing approval for use. More practical support would be useful for researchers seeking to establish PPIE groups, and RECs reviewing resources that are co-produced. Our case study provides a practical, step-by-step account of establishing a PPIE group without a funded co-lead, highlighting strengths such as the diversity of members, the incorporation of cultural perspectives, and the development of inclusive patient-facing materials. These findings add to PPIE practice by offering operational guidance, lessons learned and a summary checklist as an additional resource that can complement existing high-level frameworks.