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ObjectiveNeutrophils are prominent components of solid tumours and exhibit distinct phenotypes in different tumour microenvironments. However, the nature, regulation, function and clinical relevance of neutrophils in human gastric cancer (GC) are presently unknown.DesignFlow cytometry analyses were performed to examine levels and phenotype of neutrophils in samples from 105 patients with GC. Kaplan-Meier plots for overall survival were performed using the log-rank test. Neutrophils and T cells were isolated, stimulated and/or cultured for in vitro and in vivo regulation and function assays.ResultsPatients with GC showed a significantly higher neutrophil infiltration in tumours. These tumour-infiltrating neutrophils showed an activated CD54+ phenotype and expressed high level immunosuppressive molecule programmed death-ligand 1 (PD-L1). Neutrophils activated by tumours prolonged their lifespan and strongly expressed PD-L1 proteins with similar phenotype to their status in GC, and significant correlations were found between the levels of PD-L1 and CD54 on tumour-infiltrating neutrophils. Moreover, these PD-L1+ neutrophils in tumours were associated with disease progression and reduced GC patient survival. Tumour-derived GM-CSF activated neutrophils and induced neutrophil PD-L1 expression via Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signalling pathway. The activated PD-L1+ neutrophils effectively suppressed normal T-cell immunity in vitro and contributed to the growth and progression of human GC in vivo; the effect could be reversed by blocking PD-L1 on these neutrophils.ConclusionsOur results illuminate a novel mechanism of PD-L1 expression on tumour-activated neutrophils in GC, and also provide functional evidence for these novel GM-CSF-PD-L1 pathways to prevent, and to treat this immune tolerance feature of GC.

Insulin resistance (IR) and the consequences of compensatory hyperinsulinemia are pathogenic factors for a set of metabolic abnormalities, which contribute to the development of diabetes mellitus and cardiovascular diseases. We compared traditional lipid levels and ratios and combined them with fasting plasma glucose (FPG) levels or adiposity status for determining their efficiency as independent risk factors for IR. We enrolled 511 Taiwanese individuals for the analysis. The clinical usefulness of various parameters--such as traditional lipid levels and ratios; visceral adiposity indicators, visceral adiposity index (VAI), and lipid accumulation product (LAP); the product of triglyceride (TG) and FPG (the TyG index); TyG with adiposity status (TyG-body mass index [BMI]) and TyG-waist circumference index [WC]); and adipokine levels and ratios--was analyzed to identify IR. For all lipid ratios, the TG/high-density lipoprotein cholesterol (HDL-C) ratio had the highest additional percentage of variation in the homeostasis model assessment of insulin resistance (HOMA-IR; 7.0% in total); for all variables of interest, TyG-BMI and leptin-adiponectin ratio (LAR) were strongly associated with HOMA-IR, with 16.6% and 23.2% of variability, respectively. A logistic regression analysis revealed similar patterns. A receiver operating characteristic (ROC) curve analysis indicated that TG/HDL-C was a more efficient IR discriminator than other lipid variables or ratios. The area under the ROC curve (AUC) for VAI (0.734) and TyG (0.708) was larger than that for TG/HDL-C (0.707). TyG-BMI and LAR had the largest AUC (0.801 and 0.801, respectively). TyG-BMI is a simple, powerful, and clinically useful surrogate marker for early identification of IR.

This study aims to investigate the wound-healing effectiveness of the phenolic compound, naringin, both in vitro and in vivo. Male mice were shaved on their dorsal skin under isoflurane, a biopsy punch was made in four symmetrical circular resection windows (6 mm) to induce a wound. These excision wounds were used to study the topical effects of naringin in terms of various biochemical, molecular, and histological parameters. We observed a significant recovery in the wound area. Increased levels of MMP-2, 9, 14, TIMP-2, VEGF-A, and VEGF-R1 were induced by naringin in the HaCaT cells. The time course experiments further revealed that levels of VEGF-A and B increased within 36 h; whereas levels of VEGF-C decreased. In line with this, VEGF-R3 levels, but not VEGF-R1 and 2 levels, increased soon after stimulation; although the increase subsided after 36 h. Additionally, naringin cream upregulated wound healing in vitro. The blockage of VEGF by Bevacizumab abolished the function of naringin cream on cell migration. Histological alterations in the wounded skin were restored by naringin cream, which accelerated wound healing via upregulated expression of growth factors (VEGF-A, B, and C and VEGF-R3), and thus increased MMP-2, 9, 14 expressions.

Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163 + CD206 + M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163 + CD206 + M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10 high TGF-β high IL-12 p35 low ) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.

Natural killer (NK) cell activity is influenced by a complex integration of signaling pathways activated downstream of both activating and inhibitory surface receptors. The tumor microenvironment can suppress NK cell activity, and there is a great clinical interest in understanding whether modulating tumor-mediated NK cell suppression and/or boosting preexisting NK cell numbers in cancer patients is therapeutically viable. To this light, we characterized the surface receptor phenotypes of peripheral blood NK cells and examined their clinical relevance to human gastric cancer (GC). We found that the proportion of peripheral blood NK cells which expressed the activating receptors NKp30, NKp46, NKG2D, and DNAM-1 was significantly decreased in GC patients compared to healthy donors, and that this decrease was positively associated with tumor progression. At the same time, plasma TGF-β1 concentrations were significantly increased in GC patients and negatively correlated with the proportion of NKp30, NKp46, NKG2D, and DNAM-1 expressing NK cells. Furthermore, TGF-β1 significantly downregulated the expression of NKp30, NKp46, NKG2D, and DNAM-1 on NK cells in vitro, and the addition of galunisertib, an inhibitor of the TGF-β receptor subunit I, reversed this downregulation. Altogether, our data suggest that the decreased expression of activating receptors NKp30, NKp46, NKG2D, and DNAM-1 on peripheral blood NK cells is positively associated with GC progression, and that TGF-β1-mediated NK cell suppression may be a therapeutically targetable characteristic of GC.

Chinese herbal medicine (CHM) is frequently applied in conjunction with western pharmacotherapy to relieve symptoms in patients with CKD. However, evidence-based research into the effectiveness of CHM use as applied to treat CKD is limited and warrants further investigation. The aim of this study is to assess whether adjunctive treatment with CHM affected survival rate of CKD patients undergoing conventional western medical management. A total of 14,718 CKD patients, including 6,958 CHM users and 7,760 non-CHM users, were recruited from the Longitudinal Health Insurance Database 2000, a sub-dataset of the National Health Insurance Research Database, to conduct this study. Demographic characteristics, including sex, age, job type, residential area, and comorbidity were considered as covariates to adjust the analysis. A network analysis of treatments, including with herbal formulas and single herbs, was performed to investigate the core patterns of CHM use for the treatment of CKD patients. The Kaplan-Meier method was used to determine the survival rate between CHM and non-CHM groups. After matching for sex and age, there were 550 subjects in both the CHM and non-CHM cohorts. Other than presence of diabetes (adjusted = 0.57, < 0.001) and urinary tract infection (adjusted OR = 0.69, < 0.05), sex, age, job type, area of residence, and other comorbidities indicated no special preference for CHM use among subjects. Bunge (SM) and Ji-Sheng-Shen-Qi-Wan (JSSQW) were the most frequent single herb and formula, respectively, prescribed for patients with CKD. The most frequent CHM combination between herbs and formulas was JSSQW, associated with Baill. (RO), SM and (Fisch.) Bunge (AM). The long-term survival rate demonstrated significant benefits for CHM users within a 12-year follow-up period ( < 0.004). This nationwide retrospective cohort study provides valuable insight into the characteristics and prescription patterns of CHM usage in CKD patients. JSSQW associated with RO, SM, and AM is the most common CHM prescription. CHM improves long-term survival in patients with CKD, suggesting that CHM is an effective adjuvant therapy for CKD.

The indica and japonica rice ( Oryza sativa ) subspecies differ in nitrate (NO 3 − ) assimilation capacity and nitrogen (N) use efficiency (NUE). Here, we show that a major component of this difference is conferred by allelic variation at OsNR2 , a gene encoding a NADH/NADPH-dependent NO 3 − reductase (NR). Selection-driven allelic divergence has resulted in variant indica and japonica OsNR2 alleles encoding structurally distinct OsNR2 proteins, with indica OsNR2 exhibiting greater NR activity. Indica OsNR2 also promotes NO 3 − uptake via feed-forward interaction with OsNRT1.1B , a gene encoding a NO 3 − uptake transporter. These properties enable indica OsNR2 to confer increased effective tiller number, grain yield and NUE on japonica rice, effects enhanced by interaction with an additionally introgressed indica OsNRT1.1B allele. In consequence, indica OsNR2 provides an important breeding resource for the sustainable increases in japonica rice yields necessary for future global food security. Indica rice has higher nitrate assimilation and nitrogen use efficiency (NUE) than japonica rice, but the mechanism is unclear. Here, the authors reveal that the difference is partly due to allelic variation of a nitrate reductase encoding gene and this indica allele can increase yield potential and NUE.

Increasing studies indicate that circular RNAs (circRNAs) play critical roles in tumor metabolism of multiple cancers. However, the contribution of circRNAs in glutamine metabolism of esophageal squamous cell carcinoma (ESCC) remains elusive. The objective of this research was to investigate the role and mechanism of circRNA hsa_circ_0001093 (circ_0001093) in the glutamine metabolism and tumorigenesis of ESCC. Circ_0001093, microRNA-579-3p (miR-579-3p) and glutaminase (GLS) expressions in ESCC tissues and cell lines were measured by qRT-PCR, tissue array or Western blot. Cell proliferation, invasion and migration were assessed by CCK-8 or transwell assays. Glutamine consumption, glutamate and ATP production were detected by indicated assay kits. The relationships between circ_0001093 and miR-579-3p or GLS mRNA were investigated by bioinformatics analysis, RNA pull-down, luciferase reporter and RNA immunoprecipitation (RIP) assays. Here, we found that circ_0001093 expression was up-regulated in ESCC tissues and cell lines. Increased circ_0001093 expression predicted an unfavourable prognosis, and was associated with the lymph node metastasis, TNM staging and tumor size in ESCC tissues. Circ_0001093 knockdown suppressed cell proliferation, invasion, migration and glutamine metabolism of ESCC cells, while circ_0001093 over-expression showed the opposite effects. Mechanistically, circ_0001093 acted as a competing endogenous RNA (ceRNA) by sponging miR-579-3p, thereby increasing GLS expression. Furthermore, the inhibitory effects of circ_0001093 knockdown on the invasion, migration and glutamine metabolism were partly rescued by miR-579-3p inhibition or GLS over-expression in ESCC cells. Additionally, miR-579-3p expression was down-regulated in ESCC tissues, while GLS expression was up-regulated. In conclusion, this study first provides evidence that the circ_0001093/miR-579-3p/GLS regulatory network can affect glutamine metabolism and malignant phenotype of ESCC, which can further impact ESCC progression.

Background DNA methylation is a major epigenetic modification involved in regulating gene expression. The effects of DNA methylation on gene expression differ by genomic location and vary across kingdoms, species and environmental conditions. To identify the functional regulatory roles of DNA methylation, the correlation between DNA methylation changes and alterations in gene expression is crucial. With the advance of next-generation sequencing, genome-wide methylation and gene expression profiling have become feasible. Current bioinformatics tools for investigating such correlation are designed to the assessment of DNA methylation at CG sites. The correlation of non-CG methylation and gene expression is very limited. Some bioinformatics databases allow correlation analysis, but they are limited to specific genomes such as that of humans and do not allow user-provided data. Results Here, we developed a bioinformatics web tool, MethGET (Methylation and Gene Expression Teller), that is specialized to analyse the association between genome-wide DNA methylation and gene expression. MethGET is the first web tool to which users can supply their own data from any genome. It is also the tool that correlates gene expression with CG, CHG, and CHH methylation based on whole-genome bisulfite sequencing data. MethGET not only reveals the correlation within an individual sample (single-methylome) but also performs comparisons between two groups of samples (multiple-methylomes). For single-methylome analyses, MethGET provides Pearson correlations and ordinal associations to investigate the relationship between DNA methylation and gene expression. It also groups genes with different gene expression levels to view the methylation distribution at specific genomic regions. Multiple-methylome analyses include comparative analyses and heatmap representations between two groups. These functions enable the detailed investigation of the role of DNA methylation in gene regulation. Additionally, we applied MethGET to rice regeneration data and discovered that CHH methylation in the gene body region may play a role in the tissue culture process, which demonstrates the capability of MethGET for use in epigenomic research. Conclusions MethGET is a Python software that correlates DNA methylation and gene expression. Its web interface is publicly available at https://paoyang.ipmb.sinica.edu.tw/Software.html . The stand-alone version and source codes are available on GitHub at https://github.com/Jason-Teng/MethGET .

Social networks allow people to connect to one another. Over time, these accounts become an essential part of one's online identity. The account stores various personal data and contains one's network of acquaintances. Attackers seek to compromise user accounts for various malicious purposes, such as distributing spam, phishing, and much more. Timely detection of compromises becomes crucial for protecting users and social networks. This article proposes a novel system for detecting compromises of a social network account by considering both post behavior and textual content. A deep multi-layer perceptron-based autoencoder is leveraged to consolidate diverse features and extract underlying relationships. Experiments show that the proposed system outperforms previous techniques that considered only behavioral information. The authors believe that this work is well-timed, significant especially in the world that has been largely locked down by the COVID-19 pandemic and thus depends much more on reliable social networks to stay connected.