Requirement of CRAMP for mouse macrophages to eliminate phagocytosed E. coli through an autophagy pathway.

Host-derived antimicrobial peptides play an important role in the defense against extracellular bacterial infections. However, the capacity of antimicrobial peptides derived from macrophages as potential antibacterial effectors against intracellular pathogens remains unknown. In this study, we report that normal (wild-type, WT) mouse macrophages increased their expression of cathelin-related antimicrobial peptide (CRAMP, encoded by Camp) after infection by viable E. coli or stimulation with inactivated E. coli and its product lipopolysaccharide (LPS), a process involving activation of NF-κB followed by protease-dependent conversion of CRAMP from an inactive precursor to an active form. The active CRAMP was required by WT macrophages for elimination of phagocytosed E. coli, with participation of autophagy-related proteins ATG5, LC3-II and LAMP-1, as well as for aggregation of the bacteria with p62 (also known as SQSTM1). This process was impaired in CRAMP-/- macrophages, resulting in retention of intracellular bacteria and fragmentation of macrophages. These results indicate that CRAMP is a critical component in autophagy-mediated clearance of intracellular E. coli by mouse macrophages.

Beneficial effects of postoperative radiotherapy for IIIA­N2 non­small cell lung cancer after radical resection analysed using the propensity score­matching method.

The objective of the present study was to investigate the role of postoperative radiotherapy (PORT) after radical resection of stage IIIA-N2 non-small cell lung cancer (NSCLC). Subgroups of patients who benefited from PORT were evaluated. A retrospective review of 288 consecutive patients with resected pIIIA-N2 NSCLC at Beijing Chest Hospital (Beijing, China) was performed. Of these patients, 61 received PORT. The 288 patients were divided into PORT and non-PORT groups according to the treatment received. The baseline characteristics of the two patient groups were balanced using propensity score-matching (PSM; 1:1 matching). In total, 60 patients in the PORT group and 60 patients in the non-PORT group were matched. After PSM, the median survival time of the matched patients was 53 months. The 1-, 3- and 5-year overall survival (OS) rates of the PORT patient group were 95.0, 63.2 and 48.2%, respectively, while those of the non-PORT group were 86.7, 58.3 and 34.5%, respectively, and there was no significant difference between the two groups (P=0.056). The 5-year local recurrence-free survival (LRFS) rate in the PORT group was significantly improved (P=0.001). The effects of PORT on OS and LRFS rates were analysed in patients with different clinicopathological features. For subgroups with multiple N2 stations, N2 positive lymph nodes ≥4 and squamous cell carcinoma, PORT significantly increased the OS and LRFS rates (P<0.05). In conclusion, there was no statistically significant improvement in the 5-year OS rate with PORT overall, but there may be subgroups, such as patients with multiple N2 stations, N2 positive nodes ≥4 and squamous cell carcinoma histology, that could be explored as potentially benefitting from improved 5-year OS and LRFS rates with PORT.

Differential MUC22 expression by epigenetic alterations in human lung squamous cell carcinoma and adenocarcinoma.

Disruption in mucins (MUCs) is involved in cancer development and metastasis and is thus used as a biomarker. Non­small cell lung carcinoma (NSCLC) is characterized by heterogeneous genetic and epigenetic alterations. Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the two primary subtypes of NSCLC that require different therapeutic interventions. Here, we report distinct expression and epigenetic alterations in mucin 22 (MUC22), a new MUC family member, in LUSC vs. LUAD. In lung cancer cell lines and tissues, MUC22 was downregulated in LUSC (MUC22Low) but upregulated in LUAD (MUC22High) with co­expression of MUC21. The aberrant expression of MUC22 was inversely correlated with its promoter hypermethylation in LUSC and hypomethylation in LUAD cells and tissues, respectively. Decreased MUC22 expression in NSCLC cell lines was restored upon treatment with epigenetic modifiers 5­aza­2'­deoxycytidine (5­Aza) or trichostatin A (TSA), accompanied by reduction in global protein level of histone deacetylase 1 (HDAC1) but increased enrichment of histone H3 lysine 9 acetylation (H3K9ac) specifically in the MUC22 promoter in the SK­MES­1 cell line. MUC22 knockdown increased the growth and motility of lung cancer cells and an immortalized human bronchial epithelial BEAS­2B cell line via NF­κB activation. Clinically, MUC22Low in LUSC and MUC22High in LUAD were shown to be indicators of unfavorable overall survival for patients with early cancer stages. Our study reveals that changes in MUC22 expression due to epigenetic alterations in NSCLC may have important biological significance and prognostic potential in LUSC when compared to LUAD. Thus, MUC22 expression and epigenetic alterations may be used for molecular subtyping of NSCLC in precision medicine.

The G-Protein Coupled Formyl Peptide Receptors and Their Role in the Progression of Digestive Tract Cancer.

Chronic inflammation is a causative factor of many cancers, although it originally acts as a protective host response to the loss of tissue homeostasis. Many inflammatory conditions predispose susceptible cells, most of which are of epithelial origin, to neoplastic transformation. There is a close correlation between digestive tract (DT) cancer and chronic inflammation, such as esophageal adenocarcinoma associated with Barrett's esophagus, helicobacter pylori infection as the cause of stomach cancer, hepatitis leading to liver cirrhosis and subsequent cancer, and colon cancer linking to inflammatory bowel diseases and schistosomiasis. A prominent feature of malignant transformation of DT tract epithelial cells is their adoption of somatic gene mutations resulting in abnormal expression of proteins that endow the cells with unlimited proliferation as well as increased motility and invasive capabilities. Many of these events are mediated by Gi-protein coupled chemoattractant receptors (GPCRs) including formyl peptide receptors (FPRs in human, Fprs in mice). In this article, we review the current understanding of FPRs (Fprs) and their function in DT cancer types as well as their potential as therapeutic targets.

Postoperative radiotherapy for patients with completely resected pathological stage IIIA-N2 non-small cell lung cancer: a preferential benefit for squamous cell carcinoma.

BACKGROUND: The beneficial effect of postoperative radiotherapy (PORT) on completely resected pathological IIIA-N2 (pIIIA-N2) non-small cell lung cancer (NSCLC) has been a subject of interest with controversy. The aim of the study was to distinguish the clinical efficacy of PORT on lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC) among pIIIA-N2 NSCLC. PATIENTS AND METHODS: Between October 2010 and September 2016, 288 consecutive patients with completely resected pIIIA-N2 NSCLC at Beijing Chest Hospital were retrospectively analyzed, which consisted of 194 cases of LADC and 85 cases of LSCC. There were 42 (21.6%) patients treated with PORT in LADC cases and 19 (22.3%) patients treated with PORT in LSCC cases. The 5-year overall survival (OS), loco-regional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The prognostic factors were determined using Cox's regression model. RESULTS: Among 194 cases of LADC, the 1-, 3-, and 5-year OS in the PORT group were 95.2%, 61.9% and 40.0%, respectively, while in the non-PORT group were 90.1%, 63.3% and 45.0% (p = 0.948). The use of postoperative chemotherapy (POCT) and smoking index ≥ 400 were both prognostic factors of 5-year rates of OS, LRFS and DMFS. On the other hand, among 85 cases of LSCC, the 1-, 3-, and 5-year OS in the PORT group were 94.7%, 63.2% and 63.2%, respectively, whereas in the non-PORT group were 86.4%, 48.5% and 37.1% (p = 0.026). In this group, only the use of PORT was a favorable prognostic factor for 5-year OS, LRFS and DMFS. CONCLUSIONS: Due to clinicopathological differences among completely resected pIIIA-N2 NSCLC, PORT may not be suitable to all patients. Our study distinguishes pIIIA-N2 LSCC from LADC by their positive responses to PORT.

[Timing of Whole Brain Radiotherapy on Survival of Patients with EGFR-mutated 
Non-small Cell Lung Cancer and Brain Metastases].

BACKGROUND: There is no high-level evidence for the time of whole brain radiotherapy (WBRT) for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) and brain metastases. The aim of this study is to assess the appropriate timing of WBRT for patients with EGFR-mutated NSCLC and brain metastases (BM). METHODS: There were 78 patients diagnosed with EGFR-mutated NSCLC and BM in Beijing Chest Hospital between August 2009 and May 2015. 48 untreated patients who received both WBRT and EGFR-tyrosine kinase inhibitors (TKIs) therapy. Prognostic factors of intracranial progression-free survival (PFS) and overall survival (OS) were identified by Cox proportional hazards modeling. RESULTS: Intracranial objective response rate was 81.3% and disease control rate was 93.8%. Median intracranial PFS was 10 months. Median OS was 18 months. Multivariate analysis of intracranial PFS revealed that Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (HR=30.436, 95%CI: 4.721-196.211, P<0.001) and early WBRT (HR=3.663, 95%CI: 1.657-8.098, P=0.001) had a better intracranial PFS. Multivariate analysis of OS revealed that PS 0-1 (HR=57.607, 95%CI: 6.135-540.953, P<0.001), early WBRT (HR=2.757, 95%CI: 1.140-6.669, P=0.024), and stereotactic radiosurgery (HR=5.964, 95%CI: 1.895-18.767, P=0.002) were independent prognostic factors of OS. CONCLUSIONS: Early WBRT combined with EGFR-TKIs can improve outcomes of patients with EGFR-mutated NSCLC and BM, but it needs to be confirmed by large-sample-size and multicenter prospective clinical trials.