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Background: The interaction between gut microbiota and innate immunity plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Myeloid differentiation factor 88 (MyD88) is the core adaptor for Toll-like receptors (TLRs) defending against microbial invasion and initiating downstream immune response during microbiota-host interaction. However, the role of MyD88 in the pathogenesis of IBD is controversial. This study aims to investigate the impact of MyD88 on intestinal inflammation and the underlying mechanism. Methods: MyD88 inhibitor (TJ-M2010-5, TJ5) were used to investigate the effect of MyD88 suppression on acute DSS-induced colitis. Disease activity index, colon length, histological score and inflammatory cytokines were examined to evaluate the colitis severity. The RNA transcriptome analysis and 16S rDNA sequencing were used to detect the potential mechanism. Results: In the acute DSS-colitis model, the colitis severity was not alleviated in TJ5-treated mice, though the significantly lower of MyD88 expression and NF-κB activation were exhibited compared with control mice. Meanwhile, the 16S rDNA sequencing and RNA transcriptome analysis showed a higher abundance of intestinal Proteobacteria and an up-regulation of NOD-like receptors (NLRs) signaling pathway in colitis mice after MyD88 suppression. Further blockade of the NLR signaling pathway or elimination of gut microbiota with broad-spectrum antibiotics in DSS-induced colitis mice treated with TJ5 ameliorated the disease severity that was not improved by solely MyD88 inhibition. The downregulated NLR signaling pathway after broad-spectrum antibiotics treatment suggested that the MyD88 suppressionassociated dysbiosis may stimulate intestinal inflammation via NLR signaling pathway. Conclusion: Our study revealed that the suppression of MyD88 may be associated with unfavorable changes in the gut microbiota composition and lead to immune activation mediated by NLRs, which may play an important role in modulating intestinal inflammation.

Background Neoadjuvant immunotherapy is promising for locally-advanced non-small cell lung cancer (NSCLC). The in situ immune patterns, as predictor of PD-1/PD-L1 blockade outcomes, of the primary tumor (PT) and metastatic lymph nodes (mLNs) is unknown. Methods Multiplex immunofluorescence staining and multispectral imaging were used to evaluate the in situ immune patterns of T cells (CD3+) and cytotoxic T cells (CD8+) in terms of density, location (center of tumor [CT] and invasive margin [IM]), and the PD-L1 expression status of tumor cells and stromal T cells of paired PTs and mLNs in 38 stage-III NSCLCs.Results The densities of T cells and cytotoxic T cells were correlated between PTs and mLNs at both CT and IM. Higher densities of stromal T cells (S-CD3+) at CT and both S-CD3+ and cytotoxic T cells (S-CD8+) at IM were observed in mLNs compared to PTs, while in tumor compartment, there were no differences in the densities of T cells (T-CD3+) or cytotoxic T cells (T-CD8+). Only the density of stromal PD-L1-positive T cells (S-PD-L1+CD3+) at CT was correlated between PTs and mLNs, while the densities and frequencies of S-PD-L1+CD3+ at CT and IM of mLNs were higher than PTs. Combine positive score discordance of PD-L1 between PTs and mLNs was greater than tumor proportion score.Conclusions In situ immune patterns of T cells and cytotoxic T cells were different between PTs and mLNs in NSCLC. Higher densities of S-CD3+ and S-PD-L1+CD3+ in mLNs may result in better immune-mediated response to neoadjuvant immunotherapy.

Background To ascertain if concurrent chemotherapy (CCT) benefits people with stage II nasopharyngeal carcinoma (NPC) treated with two‐dimensional radiotherapy (2DRT) or intensity‐modulated radiotherapy (IMRT). Methods A total of 4157 patients diagnosed with stage II NPC were evaluated. Patients received radiotherapy (RT) with/without CCT. Patients were divided into 2DRT and IMRT subgroups. After propensity score matching, the role of CCT was explored in these two subgroups. Overall survival (OS) was the primary endpoint and progression‐free survival (PFS), locoregional relapse‐free survival (LRFS) and distant metastasis‐free survival (DMFS) were secondary endpoints. Results In the 2DRT subgroup, CCT addition to RT benefited cases with T1N1/T2N1 in OS, PFS and LRFS (P, In this study, we explored if concurrent chemotherapy (CCT) benefits people with stage II nasopharyngeal carcinoma (NPC) treated with two‐dimensional radiotherapy (2DRT) or intensity‐modulated radiotherapy (IMRT).

Purpose We combined conventional clinical and pathological characteristics and pathological architectural grading scores to develop a prognostic model to identify a specific group of patients with stage I lung adenocarcinomas with poor survival following surgery. Methods This retrospective study included 198 patients with stage I lung adenocarcinomas recruited from 2004 to 2013. Multivariate analyses were used to confirm independent risk factors, which were checked for internal validity using the bootstrapping method. The prognostic scores, derived from β-coefficients using the Cox regression model, classified patients into high- and low-risk groups. The predictive performance and discriminative ability of the model were assessed by the area under the receiver operating characteristic curve (AUC), concordance index (C-index) and Kaplan–Meier survival analyses. Results Three risk factors were identified: T2 (rounding of β-coefficients = 81), necrosis (rounding of β-coefficients = 67), and pathological architectural score of 5–6 (rounding of β-coefficients = 58). The final prognostic score was the sum of points. The derived prognostic scores stratified patients into low- (score ≤ 103) and high- (score > 103) risk groups, with significant differences in 5-year overall survival (high vs. low risk: 49.3% vs. 88.0%, respectively; hazard ratio: 4.55; p Conclusion An integrated prognostic model was developed to discriminate resected stage I adenocarcinoma patients into low- and high-risk groups, which will help clinicians select individual treatment strategies.

The impact of specific co-mutations in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is unclear. Tissues from 147 consecutive patients with resected EGFR-mutated lung adenocarcinomas treated at Sun Yat-Sen University Cancer Center were analyzed by next-generation sequencing (NGS). Associations between mutation status, patient baseline characteristics, and survival outcomes (disease-free survival [DFS] and overall survival [OS]) after surgical resection were analyzed. TP53 and protein kinase D (PKD) mutations were the two most frequently observed co-mutations in this cohort. Dual PKD/EGFR and TP53/EGFR mutations were found in 39 (27%) and 72 patients (49%), respectively, with dual TP53/EGFR mutations more commonly observed in male patients (P = 0.021). Both TP53 (hazard ratio [HR] 2.08, 95% confidence interval [CI] 1.23–3.54, P = 0.007) and PKD co-mutations (HR 1.72, 95% CI 1.01–2.93, P = 0.044) were associated with shorter DFS, but not OS, in univariate analysis. In multivariate analysis, patients harboring PKD/TP53 co-mutations had shorter DFS compared with PKD−/TP53− cases (HR 2.49, 95% CI 1.15–5.37, P = 0.02). In a subgroup of never-smokers, TP53 co-mutations were associated with significantly worse OS (HR 50.11, 95% CI 2.39–1049.83, P = 0.012). TP53 and PKD mutations were the two most frequently observed co-mutations in resected EGFR-mutated lung adenocarcinoma. Both mutations were associated with poorer prognoses in affected patients.