[A multicenter epidemiological investigation of brain injury in hospitalized preterm infants in Anhui, China].

OBJECTIVE: To investigate the risk factors for brain injury in preterm infants by a multicenter epidemiological investigation of brain injury in hospitalized preterm infants in Anhui, China. METHODS: Preterm infants who were hospitalized in the department of neonatology in 9 hospitals of Anhui Neonatal Collaboration Network between January 2016 and January 2017 were enrolled as subjects. The data of maternal pregnancy and clinical data of preterm infants were collected, and the logistic regression model was used to analyze the risk factors for brain injury in preterm infants. RESULTS: A total of 3 378 preterm infants were enrolled. Of the 3 378 preterm infants, 798 (23.56%) had periventricular-intraventricular hemorrhage (PVH-IVH), and 88 (2.60%) had periventricular leukomalacia (PVL). Intrauterine distress, anemia, hypoglycemia and necrotizing enterocolitis (NEC) were risk factors for PVH-IVH (OR=1.310, 1.591, 1.835, and 3.310 respectively; P<0.05), while a higher gestational age was a protective factor against PVH-IVH (OR=0.671, P<0.05). PVH-IVH, NEC and mechanical ventilation were risk factors for PVL (OR=4.017, 3.018, and 2.166 respectively; P<0.05), and female sex and use of pulmonary surfactant were protective factors against PVL (OR=0.514 and 0.418 respectively; P<0.05). CONCLUSIONS: Asphyxia/anoxia, infection/inflammation, mechanical ventilation, anemia and hypoglycemia may increase the risk of brain injury in preterm infants.

Respiratory syncytial virus infection up-regulates TLR7 expression by inducing oxidative stress via the Nrf2/ARE pathway in A549 cells.

In order to better understand the early pathways of the pathogenesis of, and immune response to, RSV, herein, we explored the relationship between TLR7 expression and oxidative stress induction following RSV infection in A549 cells. We studied the intervening effects of the Nrf2/ARE pathway agonist butylated hydroxyanisole (BHA) and inhibitor trigonelline (TRI) on TLR7 modulation or oxidative stress induction. For comparison purposes, we set up seven treatment groups in this study, including RSV-treated cells, BHA + RSV-treated cells, TRI + RSV-treated cells, normal cell controls, inactivated RSV controls, BHA controls and TRI controls. We measured changes in TLR7, IL-6, TNF-α mRNA using RT-PCR and IL-6, TNF-α and IL-1ß protein using ELISA as well as TLR7, Nrf2 and HO-1 protein using Western blot in A549 cells from the different treatment groups. We also assessed changes in cell proliferation and measured changes in ·OH and NO in A549 cells from the different treatment groups. The results indicate that TLR7 up-regulation is related to RSV infection and the induction of oxidative stress and that TLR7 expression was mediated by the anti-inflammatory effects of Nrf2/ARE pathway inhibitors or agonists. Our experiments may help elucidate the underlying pathology of RSV infection and suggest potential therapeutic targets for drug development and the prevention of RSV-induced human diseases.

Independent predictive value of blood inflammatory composite markers in ovarian cancer: recent clinical evidence and perspective focusing on NLR and PLR.

Ovarian cancer (OC) is one of the deadliest malignant tumors affecting women worldwide. The predictive value of some blood inflammatory composite markers in OC has been extensively reported. They can be used for early detection and differential diagnosis of OC and can be used for predicting survival, treatment response, and recurrence in the affected patients. Here, we reviewed the predictive values of composite inflammatory markers based on complete blood count, namely neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio, and systemic inflammation index and markers based on blood protein, namely C-reactive protein-to-albumin ratio and prognostic nutritional index in OC, with a focus on NLR and PLR. We referred to the clinical studies on these six markers, reviewed the patient population, and summarized the marker cut-off values, significance, and limitations of these studies. All these studies were retrospective and most of them were single-center clinical studies with small sample sizes. We found that the cut-off values of these markers have not been unified, and methods used to determine these values varied among studies. The predictive value of these markers on survival was mainly reflected in the postoperative patients of multiple subtypes of ovarian cancer including epithelial OC, high-grade serous ovarian carcinoma, and ovarian clear cell carcinoma. We focused on NLR and PLR and calculated their pooled hazard ratios. NLR and PLR were reliable in predicting overall and progression-free survivals in patients with OC. Therefore, it is necessary to adjust important confounding factors and conduct a long-term follow-up prospective cohort study to further clarify the cut-off values of NLR and PLR and their clinical applications.

Research progress and value of albumin-related inflammatory markers in the prognosis of non-small cell lung cancer: a review of clinical evidence.

Inflammatory markers have a wide range of predictive values in the prognosis of non-small lung cancer (NSCLC). Poor nutritional status usually means a poor prognosis in patients with NSCLC, which is widely recognized by oncologists and nutritionists. Serum albumin has a certain value in evaluating the prognosis of patients. Several inflammatory albumin-related markers have been proposed, but they have not been widely used in predicting the prognosis of NSCLC in clinical practice. We aim to systematically review the published clinical evidence of albumin-related inflammatory markers in predicting the prognosis of NSCLC and to describe their progress and value. The results showed that the markers included in the review could be prognostic indicators in patients with NSCLC. However, we found that the cut-off value of albumin-related inflammatory markers with quantitative nature was very chaotic and needed to be defined by recognized standards. We summarized and compared the advantages and disadvantages of these markers, but a prospective cohort study with long-term follow-up after adjustment for important confounders is still necessary. Whether the results and conclusions could be directly applied in clinical practice needs to be identified and evaluated. There is an urgent need to classify and standardize the albumin-related inflammatory markers that play an important role in the prognosis of NSCLC, which is the key to ensuring the transformation from clinical study to clinical application.

Albumin-related inflammatory markers could be prognostic indicators in non-small cell lung cancer.The classification and standardization of albumin-related inflammatory markers guarantee the transformation from clinical study to clinical application.Future prospective studies of albumin-related inflammatory markers excluding confounding factors are very necessary.

SDC1 and ITGA2 as novel prognostic biomarkers for PDAC related to IPMN.

The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package 'limma.' A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable survival prognosis was demonstrated by SDC1 and ITGA2, which were highly expressed during in vitro PDAC cell proliferation, apoptosis, and migration. SDC1high was enriched in interferon alpha (IFN-α) response and ITGA2high was primarily detected in epithelial-mesenchymal transition (EMT), which was verified using western blotting. We concluded that SDC1 and ITGA2 are potential prognostic biomarkers for PDAC associated with IPMN. Downregulation of SDC1 and ITGA2 expression in PDAC occurs via a mechanism involving possible regulation of IFN-α response, EMT, and immunity, which may act as new targets for PDAC therapy.

Prognostic Value of Glasgow Prognostic Score in Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Background: Systemic inflammation is a key factor in tumor growth. The Glasgow Prognostic Score (GPS) has a certain value in predicting the prognosis of lung cancer. However, these results still do not have a unified direction. Methods: A systematic review and meta-analysis were performed to investigate the relationship between GPS and the prognosis of patients with non-small cell lung cancer (NSCLC). We set patients as follows: GPS = 0 vs. GPS = 1 or 2, GPS = 0 vs. GPS = 1, GPS = 0 vs. GPS = 2. We collected the hazard ratio (HR) and the 95% confidence interval (CI). Results: A total of 21 studies were included, involving 7333 patients. We observed a significant correlation with GPS and poor OS in NSCLC patients (HRGPS=0 vs. GPS=1 or 2 = 1.62, 95% CI: 1.27-2.07, p ≤ .001; HRGPS=0 vs GPS=1 = 2.14, 95% CI:1.31-3.49, p ≤ .001; HRGPS=0 vs. GPS=2 = 2.64, 95% CI: 1.45-4.82, p ≤ .001). Moreover, we made a subgroup analysis of surgery and stage. The results showed that when divided into GPS = 0 group and GPS = 1 or 2 group, the effect of high GPS on OS was more obvious in surgery (HR = 1.79, 95% CI: 1.08-2.97, p = .024). When GPS was divided into two groups (GPS = 0 and GPS = 1 or 2), the III-IV stage, higher GPS is associated with poor OS (HR = 1.73, 95% CI: 1.43-2.09, p ≤ .001). In the comparison of GPS = 0 and GPS = 1 group (HR = 1.56, 95% CI: 1.05-2.31, p = .026) and the grouping of GPS = 0 and GPS = 2(HR = 2.23, 95% CI: 1.17-4.26, p = .015), we came to the same conclusion. Conclusion: For patients with NSCLC, higher GPS is associated with poor prognosis, and GPS may be a reliable prognostic indicator. The decrease of GPS after pretreatment may be an effective way to improve the prognosis of NSCLC.

Analysis of the correlation between Zeste enhancer homolog 2 (EZH2) mRNA expression and the prognosis of mesothelioma patients and immune infiltration.

Mesothelioma lies one of the most malignant tumors, in which the identification of the corresponding biomarkers is extremely critical. This study aims to investigate the prognostic value of enhancer homolog 2 (EZH2) mRNA expression in mesothelioma patients accompanied with its immune infiltration analysis. Gene expression, clinical information and enrichment analysis were obtained based on the Cancer Genome Atlas (TCGA), the immune infiltration analysis and bioinformatics analysis were performed. Clinical information and gene expression were obtained from 86 patients with mesothelioma based on TCGA database. Survival analysis, GSEA enrichment analysis, and immune infiltration analysis of EZH2 expression were carried out using R (version 3.6.3) (statistical analysis and visualization). The correlation of EZH2 expression with immune cell infiltration in mesothelioma was analyzed according to the TIMER database (Fig. https://cistrome.shinyapps.io/timer/ ). A univariate and multivariate analysis of general data obtained from the TCGA database was performed, involving age, gender, stage, pathological type, and whether they had received radiotherapy, the results indicated the association of high expression of EZH2 with poor prognosis in mesothelioma patients, with the worse prognosis in the High group (HR = 2.75, 95% CI 1.68-4.52, P < 0.010). Moreover, ROC curves showed that EZH2 expression predicted 1-year survival with an AUC of 0.740, 2-year survival with an AUC of 0.756, and 3-year survival with an AUC of 0.692, suggesting a robust predictive effect of EZH2 expression on prognosis. KEGG pathway analysis indicated five pathways showing the strongest positive correlation with EZH2 expression: cell cycle, DNA replication, Cell adhesion molecules cams, Primary immuno deficiency, Tsate transduction, and five pathways showing the strongest negative correlation with EZH2 expression: Glycolysis gluconeogenesis, Drug metabolism, cytochrome P450, retinol metabolism, fatty acid metabolism ribosome. We investigated the correlation between EZH2 expression and the level of immune infiltration in mesothelioma tissues. The results indicated that EZH2 expression played a critical role in immune infiltration, of which the high expression was correlated with the reduced number of NK cells, Mast cells, and Th17 cells. Moreover, mesothelioma patients with high EZH2 expression differ from those with low EZH2 expression in their tumor immune microenvironment. EZH2, as a new prognostic biomarker for mesothelioma, contributes to elucidating how changes in the immune environment promote the development of mesothelioma. Further analysis, EZH2 may serve as a biological test to predict the prognosis of mesothelioma.

Prognostic Value of EZH2 in Non-Small-Cell Lung Cancers: A Meta-Analysis and Bioinformatics Analysis.

BACKGROUND: The prognosis of non-small-cell lung cancer (NSCLC) has not been significantly improved. In the past several years, research on epigenetics is in full swing. There is a focus on the gene EZH2; however, its role as a predictor of the prognosis of NSCLC is in the debate. OBJECTIVE: To clarify if the expression level of EZH2 can influence the prognosis of NSCLC and explain its prognostic value. METHODS: We have systematically searched PubMed, Web of Science, and Cochrane library, screened relevant articles, and conducted a meta-analysis on the expression level of EZH2 in NSCLC. We collected the hazard ratio (HR) and the 95% confidence interval (CI) and used STATA 12.0 to calculate the combined result of EZH2 overall survival. In addition, we conducted subgroup analyses, a sensitivity analysis, and a funnel plot to test the reliability of the results. We further validated these meta-analysis results using the Kaplan-Meier plotter database and The Cancer Genome Atlas (TCGA) database. In addition, we have investigated the correlation between EZH2 expression and EGFR expression, KRAS expression, BRAF expression, and smoking in TCGA database to further explore the mechanism behind the influence of high EZH2 expression on lung cancer prognosis. RESULTS: 13 studies including 2180 participants were included in the meta-analysis. We found that high expression of EZH2 indicates a poor prognosis of NSCLC (HR = 1.65 and 95% CI 1.16-2.35; p ≤ 0.001). Subgroup analyses showed high heterogeneity in stages I-IV (I 2 = 85.1% and p ≤ 0.001) and stages I-III (I 2 = 66.9% and p = 0.029) but not in stage I (I 2 = 0.00% and p = 0.589). In the Kaplan-Meier plotter database, there was a high expression in 963 cases and low expression in 964 cases (HR = 1.31 and 95% CI 1.15-1.48; p < 0.05). Further analysis found that the high expression of EZH2 was statistically significant in lung adenocarcinoma (HR = 1.27and 95% CI 1.01-1.6; p = 0.045), but not in lung squamous cell carcinoma (HR = 1.03 and 95% CI 0.81-1.3; p = 0.820). The results of the TCGA database showed that the expression of EZH2 in normal tissues was lower than that in lung cancer tissues (p < 0.05). Smoking was associated with high expression of EZH2 (p < 0.001). EZH2 was also highly expressed in lung cancers with positive KRAS expression, and the correlation was positive in lung adenocarcinoma (r = 0.3129 and p < 0.001). The correlation was also positive in lung squamous cell carcinoma (r = 0.3567 and p < 0.001). EZH2 expression was positively correlated with BRAF expression (r = 0.2397 and p < 0.001), especially in lung squamous cell carcinoma (r = 0.3662 and p < 0.001). In lung squamous cell carcinoma, a positive yet weak correlation was observed between EZH2 expression and EGFR expression (r = 0.1122 and p < 0.001). CONCLUSIONS: The high expression of EZH2 indicates a poor prognosis of NSCLC, which may be related to tumor stage or cancer type. EZH2 may be an independent prognostic factor for NSCLC. EZH2 high expression or its synergistic action with KRAS and BRAF mutations affects the prognosis of non-small-cell lung cancer.

LncRNA KLF3-AS1 in human mesenchymal stem cell-derived exosomes ameliorates pyroptosis of cardiomyocytes and myocardial infarction through miR-138-5p/Sirt1 axis.

AIM: Myocardial infarction (MI) is a severe disease with increased mortality and disability rates, posing heavy economic burden for society. Exosomes were uncovered to mediate intercellular communication after MI. This study aims to explore the effect and mechanism of lncRNA KLF3-AS1 in exosomes secreted by human mesenchymal stem cells (hMSCs) on pyroptosis of cardiomyocytes and MI. METHODS: Exosomes from hMSCs were isolated and identified. Exosomes from hMSCs with transfection of KLF3-AS1 for overexpression were injected into MI rat model or incubated with hypoxia cardiomyocytes. Effect of KLF3-AS1 on MI area, cell viability, apoptosis, and pyroptosis was determined. The relationship among miR-138-5p, KLF3-AS1, and Sirt1 was verified by dual-luciferase reporter assay. Normal cardiomyocytes were transfected with miR-138-5p inhibitor or sh-Sirt1 to clarify whether alteration of miR-138-5p or sh-Sirt1 can regulate the effect of KLF3-AS1 on cardiomyocytes. RESULTS: Exosomes from hMSCs were successfully extracted. Transfection of KLF3-AS1 exosome in rats and incubation with KLF3-AS1 exosome in hypoxia cardiomyocytes both verified that overexpression of KLF3-AS1 in exosomes leads to reduced MI area, decreased cell apoptosis and pyroptosis, and attenuated MI progression. KLF3-AS1 can sponge miR-138-5p to regulate Sirt1 expression. miR-138-5p inhibitor transfection and KLF3-AS1 exosome incubation contribute to attenuated pyroptosis and MI both in vivo and in vitro, while transfection of sh-Sirt1 could reverse the protective effect of exosomal KLF3-AS1 on hypoxia cardiomyocytes. CONCLUSION: LncRNA KLF3-AS1 in exosomes secreted from hMSCs by acting as a ceRNA to sponge miR-138-5p can regulate Sirt1 so as to inhibit cell pyroptosis and attenuate MI progression.

Oxidative stress modulates the expression of toll­like receptor 3 during respiratory syncytial virus infection in human lung epithelial A549 cells.

Toll­like receptor 3 (TLR3) can react with double stranded RNA and is involved in the inflammatory response to respiratory syncytial virus (RSV) infection. Also, oxidative stress has been reported to be involved in RSV infection. However, the correlation between oxidative stress and TLR3 activation during RSV infection is unclear. Therefore, the present study investigated the association between TLR3 expression and oxidative stress modulation during RSV infection in A549 cells. For comparison, seven treatment groups were established, including RSV­treated cells, N­acetyl­L­cysteine (NAC)+RSV­treated cells, oxidant hydrogen peroxide (H2O2)+RSV­treated cells, normal cell control, inactivated RSV control, NAC control and H2O2 control. The mRNA expression changes of TLR3, interferon regulatory factor­3 (IRF3), nuclear factor­κB (NF­κB) and superoxide dismutase 1 (SOD1) were measured using semi­quantitative reverse transcription­polymerase chain reaction, and the protein changes of TLR3 and phospho­NF­κB p65 were determined using western blot in A549 cells from the different treatment groups. The present study also evaluated the differences in hydroxyl free radical (·OH), nitric oxide (NO) and total SOD activity in the different treatment groups. The results demonstrated that RSV infection of A549 cells increased the levels of ·OH and NO, while decreasing the activity of total SOD. Pretreatment of A549 cells with H2O2 prior to RSV infection upregulated the mRNA and protein expression of TLR3 and NF­κB, and downregulated the mRNA expression of IRF3 and SOD1, as well as the total SOD activity. When the infected cells were pretreated with NAC, the mRNA and protein expression of these genes were reversed. These variations in the TLR3­mediated signaling pathway molecules suggested that oxidative stress may be a key regulator for TLR3 activation during RSV infection. RSV­induced oxidative stress may potentially activate TLR3 and enhance TLR3­mediated inflammation. These results may provide better understanding of the RSV­induced inflammatory and immune pathways, and may also contribute to the drug development and prevention of human RSV diseases.

Protective effects of Radix Pseudostellariae polysaccharides against exercise-induced oxidative stress in male rats.

The main purpose of this study was to examine the effect of Radix Pseudostellariae polysaccharides (RPPs) against swimming exercise-induced oxidative stress in male rats. A total of 40 male Wistar rats were randomized into four groups: the control (C), low-dose RPP supplementation (LRS), medium-dose RPP supplementation (MRS) and high-dose RPP supplementation (HRS) groups. The control group received saline solution and the supplementation groups received different doses of RPPs (100, 200 and 400 mg/kg body weight, respectively). The animals were medicated orally and daily for 28 days. On day 28, the rats were made to swim until exhausted. The exhaustive swimming time and various biochemical parameters, including blood lactate, hemoglobin, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA), were measured. The results showed that RPP supplementation elevates the exercise tolerance and decreases the blood lactate level of rats following exhaustive swimming exercise. RPP supplementation augments the levels of hemoglobin and anti-oxidant enzymes (CAT, SOD and GSH-Px), and effectively decreases the MDA content of the skeletal muscle of rats, which suggests that RPP supplementation has a protective effect against exercise-induced oxidative stress.