ABSTRACT
In this Article, the sentence: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).", should have read: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).". This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations.
ABSTRACT
The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.
Subject(s)
Carcinoma, Hepatocellular/immunology , Immune Tolerance/immunology , Immunoglobulin A/immunology , Inflammation/immunology , Liver Neoplasms/immunology , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/immunology , Animals , B7-H1 Antigen/metabolism , CD8 Antigens/deficiency , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/pathology , Cell Proliferation , Clone Cells/cytology , Clone Cells/immunology , Disease Progression , Female , Gastrointestinal Microbiome , Humans , Immunoglobulin A/metabolism , Inflammation/etiology , Inflammation/pathology , Interleukin-10/metabolism , Liver Cirrhosis/complications , Liver Cirrhosis/immunology , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Neoplasms/etiology , Liver Neoplasms/pathology , Lymphocyte Activation , Male , Mice , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Plasma Cells/immunology , Plasma Cells/metabolism , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
This corrects the article DOI: 10.1038/nature24302.
ABSTRACT
Blood cultures (BC) for bacteria and yeast have traditionally been incubated for 5 days using modern instruments. Many organisms may grow sooner, and the need for the full 5-day incubation period has been questioned. This study evaluated the clinical significance of isolates recovered beyond 96 h. A retrospective chart review was conducted on all positive BC (+BC) performed via BD Bactec FX with >96 h of incubation from 5/2019 to 1/2022 at the UW Health University Hospital clinical microbiology laboratory. A total of 59,958 BC were performed; 6,031 (10%) were +BC. Of +BC, 104 (2%) demonstrated growth >96 h. The 104 cultures were from 89 patients and included 12 (12%) Staphylococcus aureus (1 MRSA), 9 (9%) yeast (8 Candida sp.), 8 (8%) Escherichia coli and 7 (7%) Enterococcus sp. (1 VRE) isolates. Fifty-six percent (n = 50) of the 89 +BC >96 h cases were clinically significant, and 26% (n = 13) resulted in antibiotic adjustments based on the +BC; 4 of these had previous positive cultures. Of the remaining 37 clinically significant +BC >96 h for which no antibiotic changes were made, 32 patients had previous positive cultures. The majority (98%) of BC bottles were positive before 96 h. For isolates that required >96 h, most (56%) were considered clinically significant, including S. aureus and E. coli cultures. Changes to antibiotic therapy were made in a minority (26%) of clinically significant cases. Based on these findings, under routine conditions, laboratories using BD Bactec FX should maintain a 120 h incubation period.
Subject(s)
Bacteremia , Blood Culture , Anti-Bacterial Agents , Bacteremia/diagnosis , Bacteremia/microbiology , Blood Culture/methods , Culture Media , Escherichia coli , Humans , Retrospective Studies , Saccharomyces cerevisiae , Staphylococcus aureusABSTRACT
Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16INK4A permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.