Overlapping cytokines in H. pylori infection and gastric cancer: A tandem meta-analysis.

Background: Previous evidence indicated that Helicobacter pylori-induced inflammation is the first step towards gastric carcinogenesis. However, investigations of the immunological factors driving this process have shown inconsistencies. We aimed to present a thorough summary of all researched cytokines in relation to H. pylori infection and GC and relate these to global GC risk. Methods: We performed a systematic review and tandem meta-analysis identifying all published studies reporting on serum cytokine levels in H. pylori-infected cases vs. non-infected controls and gastric cancer cases vs. non-gastric cancer controls, with sub-analyses performed to identify global regional differences in cytokine induction and their correlation with GC incidence. Results: Only levels of systemic IL-6 (standardized mean difference [SMD]:0.95, 95%CI [0.45;1.45]) and TNF-α (SMD:0.88, 95%CI [0.46; 1.29]) were significantly increased upon H. pylori infection. Sub-analysis showed that of IL-6 levels were increased upon H. pylori infection in East Asian, Middle Eastern and Southeast Asian cohorts, but not in North America, Europe, Russia and Africa. Serum levels of IL-6, IL-7, IL-10, IL-12, and TNF-α were significantly raised in GC. Exploration of the relationship between serum cytokines changes upon H. pylori infection and regional differences in risk of GC development indicated that the SMD of IL-6 serum levels presents a significant correlation with the relative incidence of GC (r=0.81, p=0.00014). Conclusion: This study shows that H. pylori infection and GC are associated with increased IL-6 and TNF-α levels. Particularly, IL-6 shows region-specific increases that correlate with GC incidence, making it a key contender for the cause of this disease.

A Potential Biomarker of Combination of Tumor Mutation Burden and Copy Number Alteration for Efficacy of Immunotherapy in KRAS-Mutant Advanced Lung Adenocarcinoma.

OBJECTIVES: The Kirsten Rat Sarcoma (KRAS) mutation is the commonest oncogenic drive mutation in lung adenocarcinoma (LUAD) and immunotherapy may be quite promising for KRAS-mutant LUAD. While the effects of tumor mutation burden (TMB) and copy number alteration (CNA) are poorly understood in this illness, our study aimed to explore the roles TMB and CNA play in the prediction of response to immune checkpoint inhibitor (ICI) therapy in advanced KRAS-mutant LUAD. METHODS: Mutation and clinical data were downloaded from cBioPortal. We evaluated KRAS mutation status and divided patients into different subgroups based on TMB and CNA cutoffs to investigate the predictive value of these biomarkers on ICI response. RESULTS: KRAS mutation with concurrent TP53 or STK11 mutations had higher TMB and CNA compared to KRAS mutation alone. The KRAS G12C and G > T mutation subgroups, with TP53 or STK11 co-mutation, also had higher TMB and CNA. We found that TMB and CNA were independently associated with progression-free survival (PFS) and durable clinical benefits (DCB); TMB was positively correlated with PFS (P = 0.0074) and DCB (P = 0.0008) while low CNA was associated with prolonged PFS (P = 0.0060) and DCB (P = 0.0018). However, TMB alone did not distinguish benefits among KRAS-mutant patients. Notably, when combining TMB and CNA, low TMB and high CNA revealed worse outcomes of ICI therapy (mPFS: 2.20m, P = 0.0023; proportion of DCB: 24%, P = 0.0001). CONCLUSION: The combination of TMB and CNA provides more sensible and accurate prediction of ICI response than individual factors in KRAS-mutant LUAD. Moreover, low TMB and high CNA can be utilized as a potential biomarker to predict adverse outcome in KRAS-mutant LUAD.

Circ_0000218 plays a carcinogenic role in laryngeal cancer through regulating microRNA-139-3p/Smad3 axis.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) accounts for about 85%-90% of all cases of laryngeal cancer. So far, the role and molecular mechanism of circular RNA 0,000,218 (circ_0000218)/microRNA (miR)-139-3p in laryngeal cancer are not clear. The present study aimed to investigate the role and regulatory mechanism of circ_0000218/miR-139-3p in laryngeal cancerin vitro and in vivo. METHODS: quantitative real time polymerase chain reaction (qRT-PCR) was used to detect the expression of circ_0000218/miR-139-3p in LSCC cells. Dual luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm binding sites between miR-139-3p and smad family member 3 (Smad3), and circ_0000218 and miR-139-3p. Cell Counting Kit-8 (CCK-8) and cell apoptosis analysis were used to detect cell viability and apoptosis. Xenograft experiment was performed to show in vivo effect of circ_0000218/miR-139-3p on the growth of LSCC. RESULTS: Circ_0000218 was highly expressed in LSCC cells. miR-139-3p, lower expressed in LSCC cells, was negatively regulated by circ_0000218 in LSCC cells. Besides, the findings suggested that circ_0000218 silencing inhibited the LSCC cell viability and promoted apoptosis by negatively regulating miR-139-3p expression. Furthermore, the data indicated that miR-139-3p inhibited the viability of LSCC cells and promoted apoptosis, and these effects were reversed by Smad3 over-expression. In addition, the in vivo effects of circ_0000218/miR-139-3p on LSCC were consistent with the in vitro study. CONCLUSIONS: circ_0000218 inhibition inhibited the growth of LSCC by targeting miR-139-3p/Smad3 axis. Our present study provided a new target for laryngeal cancer treatment.

Tumor-infiltrating immune cells in hepatocellular carcinoma: Tregs is correlated with poor overall survival.

Systematic interrogation of tumor-infiltrating immune cells (TIICs) is key to the prediction of clinical outcome and development of immunotherapies. However, little is known about the TIICs of hepatocellular carcinoma (HCC) and its impact on the prognosis of patients and potential for immunotherapy. We applied CIBERSORT of 1090 tumors to infer the infiltration of 22 subsets of TIICs using gene expression data. Unsupervised clustering analysis by 22 TIICs revealed 4 clusters of tumors, mainly defined by macrophages and T cells, with distinct prognosis and associations with immune checkpoint molecules, including PD-1, CD274, CTLA-4, LAG-3 and IFNG. We found tumors with decreased number of M1 macrophages or increased regulatory T cells were associated with poor prognosis. Based on the multivariate Cox analysis, a nomogram was also established for clinical application. In conclusion, composition of the TIICs in HCC was quite different, which is an important determinant of prognosis with great potential to identify candidates for immunotherapy.

PD-L1 Predicts Poor Prognosis in Surgically Resected Limited Stage Small-Cell Lung Cancer.

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive high-grade neuroendocrine tumor with limited treatment strategies. Programmed death 1 (PD-1) and its ligand (PD-L1), delta-like ligand-3 (DLL-3), and poly ADP-ribose polymerase (PARP) inhibitors have shed light on the treatment of extensive stage-SCLC. However, the expression and prognostic role of PD-L1, DLL-3, and PARP are barely explored in surgically resected limited stage-SCLC (LS-SCLC). METHODS: We retrospectively reviewed 404 SCLC patients from 2011 to 2018 in the First Affiliated Hospital of Xi'an Jiaotong University and collected 43 surgically resected LS-SCLC samples with adequate materials and histological specimens containing abundant tumor cells. Immunohistochemistry staining of PD-L1, DLL-3, and PAPR1 was performed by anti-PD-L1 (22C3/Dako), anti-DLL-3, and anti-PAPR1 antibodies, respectively. Positive expression of PD-L1 was characterized as >5% tumor cells and/or tumor-infiltrating immune cells expressing PD-L1. The correlation between PD-L1, DLL-3, PARP1, and clinicopathological characteristics of surgically resected LS-SCLC patients was performed by χ2 test. The survival curves were calculated by the Kaplan-Meier method and analyzed by the Log rank test and Cox proportional hazards model. RESULTS AND CONCLUSION: 63.04% patients were positive for PD-L1, 65.12% were positive for DLL-3, and 20.93% were positive for PARP1. DLL-3 was significantly overexpressed in SCLC tissues, compared with matched para-noncancerous tissues. Male, elder than 60 years old, advanced TNM stage, smoking, and positive PD-L1 expression predicted shorter DFS, while patients received adjuvant therapy performed better DFS. Further multivariate analysis revealed that TNM stage (HR=2.51, 95% CI=1.31-4.78, P=0.005) was an individual prognostic factor for DFS in LS-SCLC. Moreover, advanced TNM stage and positive PD-L1 expression also indicated worse OS, but adjuvant therapy improved OS in LS-SCLC. Multivariate analysis demonstrated that PD-L1 and TNM stage were independent and significant negative predictive factors for OS (HR=2.89, 95% CI=1.21-6.93, P=0.017; HR=2.49, 95% CI=1.25-4.94, P=0.009 for PD-L1 and TNM stage, respectively), while adjuvant treatment was an independent positive prognostic factor for OS (HR=0.37, 95% CI=0.17-0.81, P=0.012).