Highlights d Deletion of MyD88 in myofibroblasts leads to reduced intestinal tumorigenesis d Deletion of MyD88 in myofibroblasts attenuates IEC proliferation in colitis d Deletion of MyD88 in myofibroblasts inhibits macrophage M2 polarization d OPN secreted by myofibroblasts activates the STAT3/PPARg pathway in macrophages

During liver fibrosis, quiescent HSCs (qHSCs) are activated to become activated HSCs (aHSCs)/myofibroblasts. The signal adapter MyD88, an essential component of TLR signaling, plays an important role in liver fibrosis. However, far less is known about the specific effects of MyD88 signaling in both qHSCs and aHSCs in the progress of liver fibrosis. Here, we used a CCl4-induced mouse fibrosis model in which MyD88 was selectively depleted in qHSCs (GFAPMyD88−/− mice) or aHSCs (α-SMAMyD88−/− mice). MyD88 deficiency in qHSCs or aHSCs attenuated liver fibrosis in mice and inhibited α-SMA-positive cell activation. Inhibition of MyD88 in HSCs decreased α-SMA and collagen I levels, inflammatory cell infiltration, and pro-inflammatory gene expression. Furthermore, MyD88 signaling in HSCs increased the secretion of CXCL10, which promoted macrophage M1 polarization through CXCR3, leading to activation of the JAK/STAT1 pathway. Inhibition of CXCL10 attenuated macrophage M1 polarization and reduced liver fibrosis. Thus, MyD88 signaling in HSCs crucially contributes to liver fibrosis and provides a promising therapeutic target for the prevention and treatment of liver fibrosis.

Aberrantly expressed microRNAs (miRNAs) are essential for the tumorigenesis of gastric carcinoma (GC). Nevertheless, an effect of miR-383 on GC cells apoptosis has not been acknowledged previously. Here, we investigated the miR-383 level and anti-apoptotic protein Bcl-2 level in specimens of GC. Bioinformatics analyses was performed, and assay of luciferase-reporter was used for analyzing the relationship between Bcl-2 and miR-383. We analyzed survival of GC cells upon Fluorouracil treatment in an assay of CCK, and measured apoptosis of cells using flow cytometric FITC Annexin V apoptosis detection assay. The level of miR-383 was found extremely lower while the level of Bcl-2 levels was found extremely higher in GC specimens, in comparison with tissue from the adjacent non-tumor region. Additionally, the miR-383 level and Bcl-2 level inversely correlated in specimens of GC. In comparison with miR-383-high subjects, MiR-383-low subjects showed overall lower survival. Bioinformatics analyses revealed that miR-383 targeted the 3’-UTR of Bcl-2 mRNA to restrain its translation, demonstrated in a luciferase reporter assay. MiR-383 overexpression inhibited the Bcl-2-mediated survival of cell against apoptosis induced by Fluorouracil, while miR-383 depletion enhanced the cell survival. Together, these data indicate that suppression of miR-383 in GC improves the Bcl-2-mediated cell survival of GC against the chemotherapy-induced cell death. MiR-383 re-expression in cells of GC might augment apoptosis of GC cells during chemotherapy.

checkpoint inhibitors (ICI) remains unclear. We sought to investigate differential outcomes to ICI among KRAS subtypes.Methods: Patients with KRAS mt mNSCLC receiving ICI at two institutions from 2013-2021 were included. Outcomes studied were overall response rate (ORR) and median progression-free survival (mPFS). Patients with KRAS G12C mutations were compared to non-G12C.Results: We identified 123 patients, 42 (37%) KRAS G12C and 73 (63%) non-G12C. The G12C group were older (median 67 vs 65; p¼0.05) and had a greater proportion of PD-L1 high (>50%) expression (63 vs 39%, p¼0.02). There were no differences in other characteristics including smoking history: (86% vs 76%; p¼0.2). Most patients received ICI monotherapy (81% vs 73%). ORR was significantly higher in G12C vs. non-G12C (49% vs 25%, p¼0.031). In a multivariate logistic regression, G12C (OR 2.7, p¼0.04), PD-L150% (OR 4.6, p¼0.002), TP53 (OR 3.0, p¼0.02), but not smoking (p¼0.4), were independent predictors of response. mPFS was longer in the G12C vs. non-G12C group (11.7m vs. 3.8m, p¼0.1). In a multivariate analysis adjusting for smoking, TP53 and line of treatment, G12C (HR 0.6, p¼0.05) and PD-L150% (HR 0.5, p¼0.01) remained predictive of PFS. Further subdivision by KRAS subtype and PD-L1 status (Table ) revealed that patients in the G12C group with high PD-L1 expression had significant benefit from ICI over other subtypes: ORR 65%, mPFS 23.5m.Legal entity responsible for the study: The authors.