RESUMO
Salmonellosis, caused by Salmonella enterica serovar Typhimurium, is a significant global threat. Host immunity limits bacterial replication by inducing hepcidin, which degrades ferroportin, reducing iron transfer. However, this boosts macrophage iron storage, aiding intracellular pathogens like Salmonella. Mice lacking ferritin heavy chain (FTH1) in myeloid cells suffer worsened Salmonella infection. Nuclear receptor co-activator 4 (NCOA4) regulates iron release via FTH1 degradation during low iron, but its role in salmonellosis is unclear. Here, we reveal that myeloid NCOA4 deficiency augments spleen iron levels and increases cellular iron accumulation, oxidative stress, and ferroptosis in bone marrow-derived macrophages. This deficiency also increases susceptibility to Salmonella-induced colitis in mice. Mechanistically, NCOA4 suppresses oxidative stress by directly binding to the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (KEAP1) and stabilizing the antioxidant transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2). Activation of NRF2 protects myeloid NCOA4 knockout mice from Salmonella-induced colitis. Antioxidant Tempol and myeloid cell-targeted curcumin offer protection against colitis in myeloid NCOA4-deficient mice. A low iron diet and ferroptosis inhibition also mitigate the heightened colitis in these mice. Overexpression of myeloid cell-specific NCOA4 confers protection against Salmonella-induced colitis via upregulating NRF2 signaling. Serum iron was reduced in myeloid NCOA4-overexpressing mice, but not in NCOA4-deficient mice. Targeted serum metabolomics analysis revealed that many lipids were decreased in myeloid NCOA4-deficient mice, while several of them were increased in myeloid NCOA4-overexpressing mice. Together, this study not only advances our understanding of NCOA4/KEAP1/NRF2/ferroptosis axis but also paves the way for novel myeloid cell-targeted therapies to combat salmonellosis.
RESUMO
OBJECTIVE: The presence of occult nodal metastases in patients with squamous cell carcinoma (SCC) of the oral tongue has implications for treatment. Upwards of 30% of patients will have occult nodal metastases, yet a significant number of patients undergo unnecessary neck dissection to confirm nodal status. This study sought to predict the presence of nodal metastases in patients with SCC of the oral tongue using a convolutional neural network (CNN) that analyzed visual histopathology from the primary tumor alone. METHODS: Cases of SCC of the oral tongue were identified from the records of a single institution. Only patients with complete pathology data were included in the study. The primary tumors were randomized into 2 groups for training and testing, which was performed at 2 different levels of supervision. Board-certified pathologists annotated each slide. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic (ROC) curves and the Youden J statistic were used for primary analysis. RESULTS: Eighty-nine cases of SCC of the oral tongue were included in the study. The best performing algorithm had a high level of supervision and a sensitivity of 65% and specificity of 86% when identifying nodal metastases. The area under the curve (AUC) of the ROC curve for this algorithm was 0.729. CONCLUSION: A CNN can produce an algorithm that is able to predict nodal metastases in patients with squamous cell carcinoma of the oral tongue by analyzing the visual histopathology of the primary tumor alone.