Upregulation of Apolipoprotein L6 Improves Tumor Immunotherapy by Inducing Immunogenic Cell Death.

In the past few years, immune checkpoint blockade (ICB) therapy has emerged as a breakthrough treatment for cancers and has demonstrated inspiring effects in tumor patients with Epstein-Barr virus (EBV) infection. To allow more patients to benefit from immunotherapy, exploring novel biomarkers based on EBV-related tumors and immunotherapy cohorts was pursued in the present study. The essential biomarkers that may enhance antitumor immunity across EBV-related tumors were identified using the large-scale transcriptomic profiles of EBV-associated tumors and tumor immunotherapy cohorts. The clinical significance of vital genes was evaluated in multiple tumor immunotherapy cohorts. Moreover, the potential function of essential genes in immunotherapy was explored via bioinformatic analyses and verified by qRT-PCR, Western blot analysis, CCK8 assay and flow cytometry. Apolipoprotein L6 (APOL6) was considered the essential biomarker for enhancing antitumor immunity across EBV-positive tumors. The upregulation of APOL6 was correlated with increased response rates and prolonged survival in multiple tumor immunotherapy cohorts. Bioinformatic analyses suggested that APOL6 may enhance tumor immunotherapy by inducing immunogenic cell death. Pancreatic cancer cells transfected with APOL6 overexpression plasmid underwent apoptosis, necroptosis, and pyroptosis with immunogenic features. The biomarker upregulated in EBV-related tumors could further elucidate the drivers of immunotherapy response. The upregulation of APOL6 could improve immunotherapy by triggering immunogenic cell death, thus offering a new target to optimize cancer immunotherapy.

Association between dietary knowledge and overweight and obesity in Chinese children and adolescents: Evidence from the China Health and Nutrition Survey in 2004-2015.

OBJECTIVE: To assess whether dietary knowledge of Chinese children and adolescents and their mothers was associated with childhood and adolescent overweight and obesity. METHODS: This cross-sectional study obtained data from the China Health and Nutrition Survey (CHNS) between 2004 and 2015. Dietary knowledge of children and adolescents and their mothers was assessed by asking questions and statements on diets, and clustered by K-means clustering. Body mass index (BMI) and waist circumference (WC) were used to evaluate overweight and obesity among children and adolescents. The association of dietary knowledge with childhood and adolescent overweight and obesity was evaluated by multivariate regression analysis, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated. RESULTS: A total of 2,338 children and adolescents were included. Children and adolescents with low dietary knowledge were demonstrated to have significantly higher risks of BMI-defined overweight or obesity (OR = 1.66, 95%CI = 1.21-2.28, P = 0.002), and WC-defined obesity (OR = 1.52, 95%CI = 1.12-2.06, P = 0.007) than those with high dietary knowledge. Compared with high dietary knowledge in mothers, low dietary knowledge was associated with significantly elevated risks of BMI-defined overweight or obesity (OR = 1.48, 95%CI = 1.08-2.02, P = 0.014), and WC-defined obesity (OR = 1.59, 95%CI = 1.18-2.16, P = 0.003). Furthermore, significantly increased odds of BMI-defined overweight or obesity and WC-defined non-obesity in children and adolescents were related to low dietary knowledge versus high dietary knowledge of children and adolescents (OR = 1.72, 95%CI = 1.08-2.74, P = 0.023), while there was no association of BMI-defined non-overweight and non-obesity and WC-defined obesity with dietary knowledge among children and adolescents (OR = 1.35, 95%CI = 0.89-2.04, P = 0.161). Additionally, no association was found between dietary knowledge of mothers and BMI-defined overweight or obesity and WC-defined non-obesity among children and adolescents (OR = 1.39, 95%CI = 0.89-2.17, P = 0.155), while low dietary knowledge of mothers was associated with increased odds of BMI-defined non-overweight and non-obesity and WC-defined obesity in children and adolescents (OR = 1.58, 95%CI = 1.03-2.43, P = 0.036). CONCLUSION: Dietary knowledge of children and adolescents and their mothers was associated with childhood and adolescent overweight and obesity. Dietary knowledge of children and adolescents negatively related to the risk of BMI-defined overweight or obesity, and dietary knowledge of mothers to odds of WC-defined obesity.

Molecular Classification of Genes Associated with Hypoxic Lipid Metabolism in Pancreatic Cancer.

Abnormal lipid metabolism often occurs under hypoxic microenvironment, which is an important energy supplement for cancer cell proliferation and metastasis. We aimed to explore the lipid metabolism characteristics and gene expression features of pancreatic ductal adenocarcinoma (PDAC) related to hypoxia and identify biomarkers for molecular classification based on hypoxic lipid metabolism that are evaluable for PDAC prognosis and therapy. The multiple datasets were analyzed integratively, including corresponding clinical information of samples. PDAC possesses a distinct metabolic profile and oxygen level compared with normal pancreatic tissues, according to the bioinformatics methods. In addition, a study on untargeted metabolomics using Ultra Performance Liquid Chromatography Tandem Mass Spectrometry(UPLC-MS) revealed lipid metabolites differences affected by oxygen. Analysis of PDAC gene expression profiling in The Cancer Genome Atlas (TCGA) revealed that the sphingolipid process correlates closely with HIF1α. According to the characters of HIF-1 and sphingolipid, samples can be clustered into three subgroups using non-negative matrix factorization clustering. In cluster2, patients had an increased survival time. Relatively high MUC16 mutation arises in cluster2 and may positively influence the cancer survival rates. This study explored the expression pattern of lipid metabolism under hypoxia microenvironment in PDAC. On the basis of metabolic signatures, we identified the prognosis subtypes linking lipid metabolism to hypoxia. The classifications may be conducive to developing personalized treatment programs targeting metabolic profiles.

Hsa-microRNA-370-3p targeting Snail and Twist1 suppresses IL-8/STAT3-driven hepatocellular carcinoma metastasis.

The pro-inflammatory factor interleukin-8 (IL-8) is related to poor prognosis in hepatocellular carcinoma (HCC) patients. Interleukin-8 enhanced HCC invasion by upregulating Snail and Twist1, whether this modulation relies on microRNAs (miR) is unclear. In this study, hsa-miR-370-3p was screened as candidate miRNA targeting Snail and Twist1, and its expression was downregulated by IL-8. Luciferase assays and RNA electrophoretic mobility shift assays were used to evaluate the interaction between miR-370-3p and targeted mRNAs. Coimmunoprecipitation, luciferase, and ChIP assays were undertaken to investigate the mechanisms underlying IL-8-mediated modification of miR-370-3p. Gain- and loss-of-function studies, Transwell assays, and a xenograft nude mouse model were used to investigate pro- and antitumor activities. Interleukin-8 and miR-370-3p levels were analyzed for clinical relevance in HCC patients. Our results showed that HCC patients with high levels of IL-8 experienced more metastasis and shorter survival. Interleukin-8 induced epithelial-mesenchymal transition and promoted liver cancer cell migration, invasion, and metastasis both in vitro and in vivo. MicroRNA-370-3p interacted with its cognate mRNA within the 3'-UTR regions of Twist1 and Snail mRNA directly and specifically and attenuated IL-8 protumoral effects on liver cancer cells. Interleukin-8 negatively modulated miR-370-3p through signal transducer and activator of transcription 3 (STAT3) activation by recruiting histone deacetylase 1 (HDAC1) to miR-370-3p promoter. The STAT3 and HDAC antagonists inhibited liver cancer cell migration and invasion. Patients with high miR-370-3p and low IL-8 levels had longer overall survival. In conclusion, our study elucidated a novel axis IL-8/STAT3/miR-370-3p/Twist1 and Snail relying on HDAC1 recruitment, which showed both diagnostic and therapeutic potentials of miR-370-3p in HCC metastasis.

A new 7-gene survival score assay for pancreatic cancer patient prognosis prediction.

Gene expression features that are valuable for pancreatic ductal adenocarcinoma (PDAC) prognosis are still largely unknown. We aimed to explore pivotal molecular signatures for PDAC progression and establish an efficient survival score to predict PDAC prognosis. Overall, 163 overlapping genes were identified from three statistical methods, including differentially expressed genes (DEGs), coexpression network analysis (WGCNA), and target genes for miRNAs that were significantly related to PDAC patients' overall survival (OS). Then, according to the optimal value of the cross-validation curve (lambda = 0.031), 7 non-zero coefficients (ARNTL2, DSG3, PTPRR, ANLN, S100A14, ANKRD22, and TSPAN7) were selected to establish a prognostic prediction model of PDAC patients. We further confirmed the expression level of 7 genes using RT-PCR, western blot, and immunohistochemistry staining in PDAC patients' tissues. Our results showed that the ROC curve of the 7-mRNA model indicated good predictive ability for 1- and 2-year OS in three datasets (TCGA: 0.71, 0.69; ICGC: 0.8, 0.74; GEO batch: 0.61, 0.7, respectively). The hazard ratio (HR) of the low-risk group had a similar significant result (TCGA: HR = 0.3723; ICGC: HR = 0.2813; GEO batch: HR = 0.4999; all P < 0.001). Furthermore, Log-rank test results in three cohorts showed that the 7-mRNA assay excellently predicted the prognosis and metastasis, especially in TNM stage I&II subgroups of PDAC. In conclusion, the strong validation of our 7-mRNA signature indicates the promising effectiveness of its clinical application, especially in patients with TNM stages I&II.

Acupoint injection therapy for diabetic retinopathy: A protocol for systematic review and meta-analysis.

BACKGROUND: Diabetic retinopathy (DR) is a common diabetic microvascular complication, and it is also the main cause of blindness in adults. At present, some studies have reported acupoint injection for the treatment of DR. However, the effectiveness and safety are still uncertain. This study aims to evaluate the efficacy and safety of acupoint injection for the treatment of patients with DR. METHODS: The databases of English databases (PubMed, Embase, Cochrane Library, Web of Science) and Chinese databases (China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, and Chinese Biomedical Literatures Database) will be retrieved. Published randomized controlled trials and quasi-randomized controlled trials on the topic will be retrieved by 2 investigators independently. We will apply a fixed-effect model or random effect model basis on the heterogeneity test and employ with RevMan 5.3 software for data synthesis. The total effective rate will be selected as the primary outcome, visual acuity, hemorrhage areas, exudates, capillary nonperfusion areas, hemorheological indicators, mean defect of visual field, glycated hemoglobin, and adverse events as secondary outcomes. RESULTS: This study will comprehensively summarize the high-quality trials to determine the effectiveness and safety of acupoint injection treatment for patients with DR. CONCLUSION: The systematic review of this study will summarize the currently published evidence of acupoint injection treatment for DR to further guide its promotion and application. PROTOCOL REGISTRATION NUMBER: INPLASY2020110026.

S100A16 induces epithelial-mesenchymal transition in human PDAC cells and is a new therapeutic target for pancreatic cancer treatment that synergizes with gemcitabine.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a poor 5-year survival rate of approximately 6%, mostly due to poor treatment response and early progression. The S100 gene family participates in various pathophysiological processes in various malignancies. S100A16 is a member of the S100 family, which is abnormally expressed in PDAC; however, its biological functions and mechanisms of action remain unclear. We analysed the Gene Expression Omnibus (GEO) public database and the gene ChIP data collected in our previous study of human PDAC cell line PANC-1 cocultured with M2 macrophages to identify differentially expressed genes (DEGs). Twenty-three overexpressed genes were identified by screening. Then, the selected genes were analysed using The Cancer Genome Atlas (TCGA) database to assess whether they have significant impact on the overall survival (OS) of PDAC patients. Of the 14 DEGs identified, S100A16 was associated with poor prognosis and was selected for further investigation; the results indicate that S100A16 is positively correlated with epithelial-mesenchymal transition (EMT)-related genes in the TCGA dataset. Subsequent in vitro and in vivo experiments demonstrated that S100A16 induces the EMT to promote the metastasis of human PDAC cells and that the effect is mediated by the enhanced expression of TWIST1 and activation of the STAT3 signalling pathway. The antitumour effect of gemcitabine (GEM) was enhanced in combination with S100A16 downregulation. In conclusion, our findings suggest that S100A16 is a novel potential therapeutic target for human PDAC treatment.