Identification of key methylation differentially expressed genes in posterior fossa ependymoma based on epigenomic and transcriptome analysis.

BACKGROUND: Posterior fossa ependymoma (EPN-PF) can be classified into Group A posterior fossa ependymoma (EPN-PFA) and Group B posterior fossa ependymoma (EPN-PFB) according to DNA CpG island methylation profile status and gene expression. EPN-PFA usually occurs in children younger than 5 years and has a poor prognosis. METHODS: Using epigenome and transcriptome microarray data, a multi-component weighted gene co-expression network analysis (WGCNA) was used to systematically identify the hub genes of EPN-PF. We downloaded two microarray datasets (GSE66354 and GSE114523) from the Gene Expression Omnibus (GEO) database. The Limma R package was used to identify differentially expressed genes (DEGs), and ChAMP R was used to analyze the differential methylation genes (DMGs) between EPN-PFA and EPN-PFB. GO and KEGG enrichment analyses were performed using the Metascape database. RESULTS: GO analysis showed that enriched genes were significantly enriched in the extracellular matrix organization, adaptive immune response, membrane raft, focal adhesion, NF-kappa B pathway, and axon guidance, as suggested by KEGG analysis. Through WGCNA, we found that MEblue had a significant correlation with EPN-PF (R = 0.69, P = 1 × 10-08) and selected the 180 hub genes in the blue module. By comparing the DEGs, DMGs, and hub genes in the co-expression network, we identified five hypermethylated, lower expressed genes in EPN-PFA (ATP4B, CCDC151, DMKN, SCN4B, and TUBA4B), and three of them were confirmed by IHC. CONCLUSION: ssGSEA and GSVA analysis indicated that these five hub genes could lead to poor prognosis by inducing hypoxia, PI3K-Akt-mTOR, and TNFα-NFKB pathways. Further study of these dysmethylated hub genes in EPN-PF and the pathways they participate in may provides new ideas for EPN-PF treatment.

Comparison of Definitive Chemoradiotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND: This retrospective study was designed to estimate the efficacy and toxicity of definitive radiotherapy with concurrent or sequential docetaxel/S-1 for patients with locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Of the 62 eligible patients enrolled in this study during January 1, 2010 to December 31, 2014 from Qilu Hospital, Shandong University, Shandong Province, 39 patients received 3 cycles of docetaxel/S-1 during and after radiotherapy (concurrent chemoradiotherapy, CCRT), and 23 patients had radiotherapy followed by 3 cycles of docetaxel and S-1 (sequential chemoradiotherapy, SCRT). RESULTS: The CR of CCRT and SCRT groups were 48.72 and 21.74 %, respectively (p = 0.035). The median progress-free survival (PFS) of CCRT group (23.5 months) was significantly higher than SCRT group (11.7 months; p = 0.004). The median overall survival (OS) of CCRT group (33.5 months) also was significantly higher than SCRT group (24.0 months; p = 0.004). At 2 years, in this patient population, the rate of PFS of CCRT group was (44.2 ± 8.2 %), significantly higher than SCRT group (11.9 ± 9.6 %; p = 0.002). The 2-year OS rate of CCRT (68.6 ± 7.5 %) was significantly higher than SCRT group as well (42.0 ± 14.0 %; p = 0.002). The incidence of adverse events was higher in CCRT than SCRT group. No grade 4 or grade 5 adverse events occurred in our study. CONCLUSIONS: Definitive radiotherapy with concurrent or sequential docetaxel and S-1 for inoperable locally advanced ESCC was very well tolerated and remarkably active. In both CCRT and SCRT groups, acute toxicities were manageable. This regimen holds promises for treatment of esophageal carcinoma and warrants further investigation.

The clinical significance of systemic inflammation score in esophageal squamous cell carcinoma.

The objective of this study was to investigate the clinical significance of systemic inflammation score (SIS) and prognostic nutritional index (PNI) in esophageal squamous cell carcinoma (ESCC) patients who underwent esophagectomy. Records from 206 patients with histologically diagnosed ESCC who underwent esophagectomy at Qilu Hospital of Shandong University from January 2007 to December 2008 were retrospectively reviewed. The median disease-free survival (DFS) of this cohort was 32.3 months and 5-year DFS was 34.5 %. The median overall survival (OS) was 39.5 months and 5-year OS was 40.8 %. We found that high SIS was significantly associated with increased tumor length (p = 0.021), increased depth of invasion (p = 0.001), lymph node metastasis (p = 0.038), and advanced pathological stage (p = 0.004). Kaplan-Meier survival analysis revealed that both high SIS and low PNI were significantly associated with inferior DFS (for the SIS, p = 0.005; for the PNI, p = 0.003) and OS (for the SIS, p = 0.007; for the PNI, p = 0.002). In multivariate analysis, SIS was an independent prognostic indicator for both DFS and OS. However, PNI was not an independent prognosticator in multivariate analysis. SIS was a novel and promising inflammation-based prognostic score than PNI in ESCC patients who underwent esophagectomy.

Methylation of tissue factor pathway inhibitor 2 as a prognostic biomarker for hepatocellular carcinoma after hepatectomy.

BACKGROUND AND AIM: Methylation of tissue factor pathway inhibitor 2 (TFPI2) gene has been detected in hepatocellular carcinoma (HCC). However, the clinicopathologcial significance and prognostic value of TFPI2 methylation in HCC remains largely unknown. This study aimed to investigate the prognostic value of TFPI2 methylation in HCC after hepatectomy. METHODS: Methylation status of TFPI2 gene was examined in 178 surgical specimens of HCC and 20 normal liver samples using methylation-specific polymerase chain reaction. RESULTS: Methylation of TFPI2 gene was detected in 44.9% (80 of 178) of primary HCC samples, 10.7% (19 of 178) of the corresponding non-tumorous liver samples, and 5.0% (1/20) of the normal liver samples. The mRNA concentrations of TFPI2 in primary HCC tissues were significantly lower than those in corresponding non-tumorous liver tissues and those in normal liver tissues. TFPI2 methylation was significantly associated with higher TNM stage. Patients with TFPI2 methylation demonstrated a significantly poorer prognosis than those without TFPI2 methylation for both overall survival and disease-free survival (P < 0.001, respectively). Multivariate analyses confirmed that TFPI2 methylation was an independent prognostic factor for both overall survival (P = 0.002) and disease-free survival (P = 0.000) in HCC after hepatectomy. Moreover, TFPI2 methylation was found to be the only independent predictor for early tumor recurrence of HCC after resection based on multivariate analysis (P = 0.002). CONCLUSIONS: Methylation of TFPI2 predicts high risk of advanced tumor stage, early tumor recurrence, and poor prognosis, and it could be a potential prognostic biomarker in patients with HCC after hepatectomy.

Irradiated fibroblasts promote epithelial-mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma.

Recent evidence suggested that nonirradiated cancer-associated fibroblasts (CAFs) promoted aggressive phenotypes of cancer cells through epithelial-mesenchymal transition (EMT). Hepatoma-derived growth factor (HDGF) is a radiosensitive gene of esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the effect of irradiated fibroblasts on EMT and HDGF expression of ESCC. Our study demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of ESCC cells and the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. Scattering of ESCC cells was also accelerated by the supernatant from irradiated fibroblasts. Exposure of ESCC cells to supernatant from irradiated fibroblasts resulted in decreased E-cadherin, increased vimentin in vitro and ß-catenin was demonstrated to localize to the nucleus in tumor cells with irradiated fibroblasts in vivo models. The expression of HDGF and ß-catenin were increased in both fibroblasts and ESCC cells of irradiated group in vitro and in vivo models. Interestingly, the tumor cells adjoining the stromal fibroblasts displayed strong nuclear HDGF immunoreactivity, which suggested the occurrence of a paracrine effect of fibroblasts on HDGF expression. These data suggested that irradiated fibroblasts promoted invasion, growth, EMT and HDGF expression of ESCC.

The effect of socioeconomic status on health-care delay and treatment of esophageal cancer.

BACKGROUND: Socioeconomic status (SES) has been focused on as a key determinant of the incidence of cancer, cancer stage at diagnosis as well as treatment choices in western countries. However, to the authors' knowledge, little work has been done concerning the relationship of SES and esophageal cancer in China. METHODS: Patients diagnosed with primary esophageal cancer from January to December 2007 in Qilu hospital were included. Socioeconomic status was determined by a questionnaire including religion, years of schooling and high education, place of residence, occupation, annual household income, and insurance. RESULTS: A total of 238 cases were collected in this study. Linear-by-linear association testing revealed that health-care delay was significantly associated with SES (P = 0.009). Multivariable logistic regression analysis revealed that increased health-care delay (>2 months) was more frequently observed in patients with lower SES (OR 2.271; 95% CI 1.069-4.853). Patients diagnosed at TNM I and II were more frequently in higher SES groups (P = 0.017). The association test was statistically significant for undergoing surgical resection only (P = 0.015) and chemotherapy (P = 0.015). Multivariable logistic regression analysis revealed that surgical resection only was less performed in higher SES group compared with lower SES group (OR 0.372; 95% CI 0.188-0.734). For chemotherapy, higher SES patients had a three-fold higher likelihood compared with lower SES group (OR 3.042; 95% CI 1.335-6.928). CONCLUSION: Socioeconomic status was found to be associated with health-care delay, tumor stage and treatment modalities in esophageal cancer.

Prognostic significance of lymph node ratio in esophageal cancer.

N staging predicting esophageal cancer patient prognosis has been studied. Lymph node ratio, which is considered to show metastatic lymph node status more accurately, is found to have prognostic significance in several tumors. We investigated whether lymph node ratio (LNR) was associated with the prognosis of esophageal cancer in this study. Esophageal cancer patients who underwent esophagectomy at Qilu Hospital of Shandong University from January 2007 to December 2008 were studied. A total of 209 cases were evaluated in this study. The median disease-free survival (DFS) of this cohort was 35.2 months, and 5-year DFS rate was 32.1%. The median overall survival (OS) was 46.4 months, and 5-year OS rate was 40.0%. Kaplan-Meier survival analysis revealed that patients with LNR higher than 0.2 had significantly poorer DFS (p < 0.001) and OS (p < 0.001) than those with LNR less than 0.2. In a multivariate analysis, LNR was found to be an independent prognostic factor for DFS (p = 0.008, HR 1.863, 95% CI 1.180-2.942) and OS (p = 0.025, HR 1.708, 95% CI 1.068-2.731). N stage (p = 0.028, HR 1.626, 95% CI 1.055-2.506) was also found to be an independent prognostic factors for OS. Subgroups analysis revealed significant difference in OS and DFS rates between different LNR categories within the same N stages (p < 0.05) but not between different N stages within the same LNR category (p > 0.05). LNR was recognized as an independent factor in both OS and DFS in esophageal cancer. Besides, LNR showed a better prognostic value than N stage for esophageal cancer.

The clinical significance of preoperative plasma fibrinogen level and platelet count in resectable esophageal squamous cell carcinoma.

BACKGROUND: Patients with malignant disease frequently present with activated coagulation pathways, which are potentially associated with tumor progression and prognosis. The aims of the study were to investigate the clinical significance of preoperative plasma fibrinogen level and platelet count in esophageal squamous cell carcinoma (ESCC) treated by curative surgery. METHODS: A total of 119 patients with ESCC treated by curative surgery in Qilu Hospital of Shandong University were included in the study. RESULTS: The preoperative plasma fibrinogen levels in the patients with ESCC ranged from 2.2 to 6.91 g/L (mean ± SD, 3.85 ± 0.95 g/L). The incidence of hyperfibrinogenemia was 43.7% (52/119, cut-off value 4.0 g/L). Hyperfibrinogenemia was found to be positively correlated with increased tumor length (P = 0.027), increased depth of invasion (P = 0.013), advanced pathological stages (P = 0.011), and disease recurrence (P = 0.026). The platelet counts ranged from 78 × 10(9)/L to 936 × 10(9)/L (mean ± SD, 254.51 ± 89.26 × 10(9)/L). The incidence of thrombocytosis was 20.2% (24/119, cut-off value 300 × 10(9)/L). Thrombocytosis was more frequently seen in male gender (P = 0.029) and non-smokers (P = 0.008). Plasma fibrinogen levels were significantly correlated with platelet counts (r = 0.018, P = 0.048). Hyperfibrinogenemia was significantly associated with poor disease-free (P = 0.009, hazard ratio (HR) = 1.784, 95% confidence interval (CI) = 1.153 to 2.761) and overall (P = 0.003, HR = 1.992, 95% CI = 1.259 to 3.152) survivals in univariate analysis, but not an independent prognostic indicator in multivariate analysis. Thrombocytosis was not significantly associated with disease-free (P = 0.765, HR = 0.918, 95% CI = 0.524 to 1.608) or overall (P = 0.809, HR = 1.072, 95% CI = 0.618 to 1.891) survivals in univariate analysis. CONCLUSIONS: The study suggested that hyperfibrinogenemia is a valuable predictor for disease progression in ESCC. Anticoagulation therapy might be considered to control cancer progression in future studies.

BIIB021, a novel Hsp90 inhibitor, sensitizes esophageal squamous cell carcinoma to radiation.

BIIB021 is a novel, orally available inhibitor of heat shock protein 90 (Hsp90) that is currently in phase I/II clinical trials. BIIB021 induces the apoptosis of various types of tumor cells in vitro and in vivo. The aim of this study is to investigate the effect of BIIB021 on the radiosensitivity of esophageal squamous cell carcinoma (ESCC). The results indicated that BIIB021 exhibited strong antitumor activity in ESCC cell lines, either as a single agent or in combination with radiation. BIIB021 significantly downregulated radioresistant proteins including EGFR, Akt, Raf-1 of ESCC cell lines, increased apoptotic cells and enhanced G2 arrest that is more radiosensitive cell cycle phase. These results suggest that this synthetic Hsp90 inhibitor simultaneously affects multiple pathways involved in tumor development and progression in the ESCC setting and may represent a better strategy for the treatment of ESCC patients, either as a monotherapy or a radiosensitizer.

The clinical significance of tumor-infiltrating neutrophils and neutrophil-to-CD8+ lymphocyte ratio in patients with resectable esophageal squamous cell carcinoma.

BACKGROUND: The interaction between tumor cells and inflammatory cells has not been systematically investigated in esophageal squamous cell carcinoma (ESCC). The main aims of the study were to investigate the clinical significance of tumor-infiltrating neutrophils and neturophil-to-CD8+ lymphocyte ratio (NLR), and to analyze the distribution of tumor-infiltrating neutrophils and CD8+ lymphocytes in ESCC treated by curative resection. METHODS: The expressions of CD66b and CD8 were assessed with double staining immunohistochemistry in the surgical specimens from 90 patients with ESCC treated by curative surgery. RESULTS: We showed that increased intratumoral neutrophils were significantly associated with lymph node metastasis (P = 0.016), and advanced pathological stages (P = 0.013). Decreased peritumoral CD8+ lymphocyte density was more frequently observed in patients with single positive lymph node (p = 0.045). Peritumoral NLR was significantly associated with advanced T stages (p < 0.001), lymph node metastasis (p = 0.041) and a trend towards advanced pathological stages (p = 0.053). Increased intratumoral neutrophils were significantly associated with decreased disease-free survival (p < 0.001) and overall survival (p < 0.001) in univariate analysis and were identified as an independent prognostic factor for disease-free survival (p = 0.006) and overall survival (p = 0.037) in multivariate analysis. Neither the density nor the distribution of tumor-infiltrating neutrophils was significantly correlated with that of CD8+ lymphocytes. The density of intratumoral CD8+ lymphocytes was significantly lower than (P < 0.001) and moderately correlated with (r = 0.434, p < 0.001) that in peritumoral area. CONCLUSIONS: Increased intratumoral neutrophils were an independent poor prognostic factor and peritumoral NLR was significantly associated with disease progression in ESCC treated by curative surgery, suggesting the possible effect of immune misbalance of tumor microenvironment in facilitating ESCC progression. Immunotherapy targeted to the above predictors should be considered in the future.

Down-regulation of stromal caveolin-1 expression in esophageal squamous cell carcinoma: a potent predictor of lymph node metastases, early tumor recurrence, and poor prognosis.

BACKGROUND: Recent studies have identified loss of stromal caveolin-1 (Cav-1) expression as a new prognostic histological characteristic in various types of human cancers. However, the clinical and pathological significance of stromal Cav-1 expression in esophageal squamous cell carcinoma (ESCC) remains largely unknown. We examined Cav-1 expression in both tumor and stromal cells in ESCC tissue by immunohistochemical analysis to evaluate its clinicopathological significance and prognostic value. METHODS: A total of 110 patients with ESCC who underwent surgical resection were included in this study. The expression of Cav-1 in both tumor and stromal cells in esophageal tumor tissues was examined immunohistochemically. RESULTS: Cav-1 expression was found in the cytoplasm of both tumor and stromal cells. Tumor Cav-1 overexpression was observed in 37.3 % tumors, which correlated to deeper tumor invasion (p = 0.038). Down-regulation of stromal Cav-1 expression was observed in 40.9 % tumors. The stromal Cav-1 down-regulation group had more lymph node metastases and more locoregional recurrences than those with higher expression (p = 0.020 and p = 0.002, respectively). In addition, down-regulation of stromal Cav-1 expression was associated with shorter disease-free survival (p < 0.001) and overall survival (p < 0.001). Multivariate analysis revealed that down-regulation of stromal Cav-1 expression was an independent prognostic factor for both disease-free survival (p = 0.028) and overall survival (p = 0.007). CONCLUSIONS: Down-regulation of stromal Cav-1 expression in ESCC had high malignant potential. It predicts high-risk of lymph node metastases and locoregional recurrence, and it could be a powerful prognostic marker for patients with ESCC.

Shorter dinner-to-bed time is associated with gastric cardia adenocarcinoma risk partly in a reflux-dependent manner.

BACKGROUND: Gastric cancer remains the second cause of cancer-related death worldwide. The aim of this study was to investigate the effects of shorter dinner-to-bed time, post-dinner walk, and obesity on gastric cardia adenocarcinoma (GCA) risk. METHODS: The study subjects consisted of 146 GCA patients and 166 healthy controls roughly matched by gender and age. Conditional logistic regression was used to calculated odds ratio (OR) and 95 % confidence intervals (CIs). RESULTS: The adjusted ORs of GCA for subjects with shorter dinner-to-bed time were 4.18 (95 % CI 2.10-8.33) compared with those with longer dinner-to-bed time. What is more, when reflux symptom was added into the multivariate models, risk estimate for shorter dinner-to-bed time decreased greatly, but still remained statistically significant (p = 0.007). Post-dinner walk was associated with a significantly decreased GCA risk (adjusted OR 0.54; 95 % CI 0.31-0.94). When subjects were analyzed according to post-dinner walk, the adjusted OR of GCA for shorter dinner-to-bed time relative to longer dinner-to-bed time was much higher for non-walking subjects (adjusted OR 20.21) than walking subjects (adjusted OR 1.39). We further found a significant interaction between shorter dinner-to-bed time and post-dinner walk regarding the risk of GCA (adjusted OR 0.07; p = 0.001). CONCLUSIONS: We found that shorter dinner-to-bed time was associated with significantly increased GCA risk, partly depending on reflux symptoms, while post-dinner walk was related to a significantly decreased GCA risk and could greatly attenuate the GCA risk attributable to shorter dinner-to-bed time.

Prognostic value of body mass index for patients undergoing esophagectomy for esophageal squamous cell carcinoma.

OBJECTIVE: The correlation between high body mass index and outcomes after esophagectomy has not been systematically addressed. Some studies have shown that patients with a high body mass index had better overall survival and disease-free survival compared with those with a normal/low body mass index, whereas others have shown that the body mass index was not of prognostic value. METHODS: Ninety-nine patients with esophageal squamous cell carcinoma were retrospectively reviewed in this study. Patients' postoperative overall and disease-free survivals were compared between the two groups (body mass index <24.00 kg/m(2) and body mass index ≥24.00 kg/m(2)). RESULTS: There were 66 patients in the low/normal body mass index group (body mass index <24.00 kg/m(2)) and 28 patients in the high body mass index group (body mass index ≥24.00 kg/m(2)). Although disease recurrence were more frequent in the high body mass index group vs. the low/normal body mass index group, there was no significant difference noted (60.7%, 40.9%, P = 0.078). The 3-year overall survival rates were 60.6% in the low/normal body mass index group and 57.1% in the high body mass index group (P = 0.392). The 3-year disease-free survival rates were higher in the low/normal body mass index group vs. the high body mass index group (56.1%, 39.3%, P = 0.048). On multivariate analysis, the number of lymph node metastases (hazard ratio: 1.192, 95% confidence interval: 1.076-1.320, P = 0.001) was recognized as an independent prognostic factor for overall survival. Both body weight loss (hazard ratio: 2.153, 95% confidence interval: 1.027-4.511, P = 0.042) and the number of lymph node metastases (hazard ratio: 1.669, 95% confidence interval: 1.297-2.146, P < 0.001) were significantly and independently associated with disease-free survival. CONCLUSIONS: Our results suggest that high body mass index appears to shorten disease-free survival in esophageal squamous cell carcinoma patients and further studies are needed to detect the mechanism.

The association of miR-146a rs2910164 and miR-196a2 rs11614913 polymorphisms with cancer risk: a meta-analysis of 32 studies.

MicroRNAs (miRNAs) are small non-coding RNA molecules, which act as post-transcriptional regulators of gene expression and have been implicated in initiation, progression and treatment outcome of diverse cancers. Single nucleotide polymorphisms (SNPs), as the most common type of genetic variation, also exist in miRNA genes and can lead to alteration in miRNA expression resulting in diverse functional consequences. Emerging studies have evaluated the association of miRNA SNPs with cancer risk, but the results remain inconclusive. To assess the relationship between miRNA SNPs and cancer risk, we performed a meta-analysis of 18 studies involving 20660 subjects for miR-146a rs2910164 polymorphism and 21 studies involving 26,018 subjects for miR-196a2 rs11614913 polymorphism. As for rs2910164, no significant association of cancer risk was found in the overall analysis. In subgroup analysis by cancer type, ethnicity, source of controls and sample size, significant association of cancer risk was mainly found in papillary thyroid carcinoma, primary liver cancer, cervical cancer, Caucasian population and small sample size studies. For rs11614913, significant results were found in all the tested genetic models and T allele or its carriers were associated with decreased cancer risk in overall analysis (T vs. C: OR = 0.888, 95% CI 0.84-0.938; TT+TC vs. CC: OR = 0.897, 95% CI 0.828-0.971). In stratified analysis by cancer type and ethnicity, significant association of cancer risk was observed in breast cancer, lung cancer, colorectal cancer and Asian population, but not in Caucasian population. During further stratified analysis by source of controls and sample size, results similar to those of overall analysis were found in all of the subgroups. Taken together, our results indicated that miR-196a2 rs11614913 T variant probably contribute to decreased susceptibility to cancer. However, limited evidence was found for association of miR-146a rs2910164 with cancer risk, and further well-designed studies with large sample size will be necessary to validate the effect of miR-146a rs2910164 on cancer susceptibility.

[Bioinformatic analysis of immune correlation and prognostic value of SERPINs in glioma].

Objective To investigate the expression of serine protease inhibitors (SERPINs) and immune infiltration in gliomas and identify their relationship with the prognosis. Methods By using R and several bioinformatics analysis databases, the expression of 35 genes of Serpins in glioma tissues from TCGA were collected and analyzed; In GEPIA, genes with significant differences were selected for survival analysis and genes with the most prognostic value were chosen for further analysis. To probe the correlation between SERPIN and tumor immunity, gene expression in pan-cancer, cells cluster enrichment in tumor tissue, and the correlation between macrophage infiltration and SERPIN expression were analyzed, via TIMER and TISCH. Results The expression of SERPIN in glioma changed, showing a significant correlation with glioma grade and prognosis. SERPINE2 and SERPINH1 were significantly correlated with the prognosis of patients with high-grade glioma, and may involve in the immune regulation within the tumor immune microenvironment through different pathways with immune cells. Conclusion The expression of SERPINs are closely related to the clinical prognosis and immunity in glioma, among which SERPINE2 and SERPINH1 are the key genes with significant effect.

Clinical and Epidemiological Study of Intracranial Tumors in Children and Identification of Diagnostic Biomarkers for the Most Common Tumor Subtype and Their Relationship with the Immune Microenvironment Through Bioinformatics Analysis.

Brain tumors are the second most common pediatric malignancy and have poor prognosis. Understanding the pathogenesis of tumors at the molecular level is essential for clinical treatment. We conducted a retrospective study on the epidemiology of brain tumors in children based on clinical data obtained from a neurosurgical center. After identifying the most prevalent tumor subtype, we identified new potential diagnostic biomarkers through bioinformatics analysis of the public database. All children (0-15 years) with brain tumors diagnosed histopathologically between 2010 and 2020 at the Department of Neurosurgery, Xijing Hospital, were reviewed retrospectively for age distribution, sex predilection, native location, tumor location, symptoms, and histological grade, and identified the most common tumor subtypes. Two datasets (GSE44971 and GSE44684) were downloaded from the Gene Expression Omnibus database, whereas the GSE44971 dataset was used to screen the differentially expressed genes between normal and tumor samples. Gene ontology, disease ontology, and gene set enrichment analysis enrichment analyses were performed to investigate the underlying mechanisms of differentially expressed genes in the tumor. Combined with methylation data in the GSE44684 dataset, we further analyzed the correlation between methylation and gene expression levels. Two algorithms, LASSO and SVM-RFE, were used to select the hub genes of the tumor. The diagnostic value of the hub genes was assessed using the receiver operating characteristic (ROC) curve. Finally, we further evaluated the relationship between the hub gene and the tumor microenvironment and immune gene sets. Overall, 650 children from 18 provinces in China were included in this study. The male-to-female ratio was 1.41:1, and the number of patients reached a peak in the 10-15-year-old group (41.4%).The most common symptoms we encountered in our institute were headache and dizziness 250 (28.2%), and nausea and vomiting 228 (25.7%). The predominant location is supratentorial, with a supratentorial to infratentorial ratio of 1.74:1. Low-grade tumors (WHO I/II) constituted 60.9% of all cases and were predominant in every age group. According to basic classification, the most common tumor subtype is pilocytic astrocytoma (PA). A total of 3264 differentially expressed genes were identified in the GSE44971 dataset, which are mainly involved in the process of neural signal transduction, immunity, and some diseases. Correlation analysis indicated that the expression of 45 differentially expressed genes was negatively correlated with promoter DNA methylation. Next, we acquired five hub genes (NCKAP1L, GPR37L1, CSPG4, PPFIA4, and C8orf46) from the 45 differentially expressed genes by intersecting the LASSO and SVM-RFE models. The ROC analysis revealed that the five hub genes had good diagnostic value for patients with PA (AUC > 0.99). Furthermore, the expression of NCKAP1L was negatively correlated with immune, stromal, and estimated scores, and positively correlated with immune gene sets. This study, based on the data analysis of intracranial tumors in children in a single center over the past 10 years, reflected the clinical and epidemiological characteristics of intracranial tumors in children in Northwest China to a certain extent. PA is considered the most common subtype of intracranial tumors in children. Through bioinformatics analysis, we suggested that NCKAP1L, GPR37L1, CSPG4, PPFIA4, and C8orf46 are potential biomarkers for the diagnosis of PA.

Development and validation of an eight-gene signature based predictive model to evaluate the prognosis of hepatocellular carcinoma patients: a bioinformatic study.

Background: Hepatocellular carcinoma (HCC) is a malignant tumor with a poor prognosis, however, biomarkers for the prognostic assessment of HCC remain suboptimal. Consequently, we aimed to develop a reliable tool for prognostic estimation of HCC. Methods: Differentially expressed genes (DEGs) between HCC and adjacent normal tissues in 3 Gene Expression Omnibus (GEO) datasets were identified, followed by hub gene selection and least absolute shrinkage and selection operator (LASSO) Cox regression to develop a prognostic gene signature. Kaplan-Meier survival analysis, univariate and multivariate Cox regression, time-dependent area under the curve (AUC), and integrated value of time-dependent AUC (iAUC) were used to assess the relationship between predictors and clinical outcomes in the training and validation datasets. Then we built nomograms including gene signature and clinicopathological factors to forecast the probability of death. Moreover, we performed quantitative real-time PCR (qPCR) to compare the expression of prognostic genes between HCC and adjacent normal tissues. Finally, the relationship between prognostic genes and tumor microenvironment (TME) was investigated using immune cell infiltration algorithms and single cell transcriptomic database. Results: Eight prognostic genes (CDC20, PTTG1, TOP2A, CXCL2, CXCL14, CYP2C9, MT1F, and GHR) were finally identified to construct the gene signature. Each patient's risk score was calculated according to the gene signature. Patients with high-risk scores showed worse outcomes in the training set [hazard ratio (HR) =3.404, P<0.001]. Risk score, age, body mass index (BMI), and TNM stage were identified as independent prognostic factors for overall survival (OS) in the training set. The nomogram including risk score and other independent prognostic factors showed better performance as opposed to the clinicopathological model. In the validation dataset, we obtained the similar results as well. Moreover, we found a close relationship between risk score and immune cell infiltration. Patients with high-risk scores had elevated expression of immune checkpoint genes, indicating that these patients may be more suitable for immunotherapy. Conclusions: We have established and validated an eight-gene based prognostic model, which could be an effective tool for the prognostic evaluation of HCC patients.

The efficacy and safety of Apatinib in the treatment of advanced non-small cell lung cancer: A retrospective trial.

Background: As a potent inhibitor of the vascular endothelial growth factor (VEGF) signaling pathway, Apatinib has been used in antitumor treatment for some time. The study aimed to research the therapeutic effects and toxicity of Apatinib in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: We retrospectively analyzed 128 NSCLC patients treated with Apatinib in Qilu Hospital of Shandong University. Response Evaluation Criteria in Solid Tumors (RECIST) criteria was adopted to evaluate the treatment effect, and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 was conducted to determine the Adverse Events (AEs). Cox proportional hazard model and Kaplan-Meier function were applied to evaluate the progression-free survival (PFS) and overall survival (OS). Results: Among 128 NSCLC patients, partial response (PR) were observed in 15 patients, stable disease (SD) in 66 patients and progressive disease (PD) in 47 patients. The objective response rate (ORR) and disease control rate (DCR) accounted for 11.7% and 63.3% respectively. The median PFS (mPFS) and median OS (mOS) were 4.4 months and 17.2 months. Common side effects of Apatinib were hypertension (n=48), proteinuria (n=35), and hand-foot syndrome (HFS) (n=30), all of the side effects were controllable. No significant difference was observed in efficacy and AEs between the higher dose group (Apatinib>500mg/d) and the lower dose group (Apatinib=500mg/d). Conclusions: The study suggested that Apatinib with a lower dose (=500mg/d) has good efficacy and safety in the treatment of advanced NSCLC after first-line chemotherapy.

HBO Alleviates Neural Stem Cell Pyroptosis via lncRNA-H19/miR-423-5p/NLRP3 Axis and Improves Neurogenesis after Oxygen Glucose Deprivation.

Due to the limited neurogenesis capacity, there has been a big challenge in better recovery from neurological dysfunction caused by stroke for a long time. Neural stem cell (NSC) programmed death is one of the unfavorable factors for neural regeneration after stroke. The types of death such as apoptosis and necroptosis have been deeply investigated while the pyroptosis of NSCs is not quite understood. Although it is well accepted that hyperbaric oxygen (HBO) alleviates the oxygen-glucose deprivation (OGD) injury after stroke and reduces programmed death of NSCs, whether NSC pyroptosis is involved in this process is still unknown. Therefore, this study is aimed at studying the potential effect of HBO treatment on NSC pyroptosis following OGD exposure, as well as its influence on NSC proliferation and differentiation in vitro. The results revealed that OGD increased NOD-like receptor protein 3 (NLRP3) expression to induce the pyroptotic death of NSCs, which was rescued by HBO treatment. And the upregulated lncRNA-H19 functioned as a molecular sponge of miR-423-5p to target NLRP3 for NSC pyroptosis following OGD. Most importantly, it was confirmed that HBO exerted protection of NSCs against pyroptosis by inhibiting lncRNA-H19/miR-423-5p/NLRP3 axis. Moreover, HBO restraint of lncRNA-H19-associated pyroptosis benefited the proliferation and neuronal differentiation of NSCs. It was concluded that HBO attenuated NSC pyroptosis via lncRNA-H19/miR-423-5p/NLRP3 axis and enhanced neurogenesis following OGD. The findings provide new insight into NSC programmed death and enlighten therapeutic strategy after stroke.

Downregulation of microRNA-124-3p promotes subventricular zone neural stem cell activation by enhancing the function of BDNF downstream pathways after traumatic brain injury in adult rats.

AIMS: In this study, the effect of intracerebral ventricle injection with a miR-124-3p agomir or antagomir on prognosis and on subventricular zone (SVZ) neural stem cells (NSCs) in adult rats with moderate traumatic brain injury (TBI) was investigated. METHODS: Model rats with moderate controlled cortical impact (CCI) were established and verified as described previously. The dynamic changes in miR-124-3p and the status of NSCs in the SVZ were analyzed. To evaluate the effect of lateral ventricle injection with miR-124-3p analogs and inhibitors after TBI, modified neurological severity scores (mNSSs) and rotarod tests were used to assess motor function prognosis. The variation in SVZ NSC marker expression was also explored. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of predicted miR-124-3p targets was performed to infer miR-124-3p functions, and miR-124-3p effects on pivotal predicted targets were further explored. RESULTS: Administration of miR-124 inhibitors enhanced SVZ NSC proliferation and improved the motor function of TBI rats. Functional analysis of miR-124 targets revealed high correlations between miR-124 and neurotrophin signaling pathways, especially the TrkB downstream pathway. PI3K, Akt3, and Ras were found to be crucial miR-124 targets and to be involved in most predicted functional pathways. Interference with miR-124 expression in the lateral ventricle affected the PI3K/Akt3 and Ras pathways in the SVZ, and miR-124 inhibitors intensified the potency of brain-derived neurotrophic factor (BDNF) in SVZ NSC proliferation after TBI. CONCLUSION: Disrupting miR-124 expression through lateral ventricle injection has beneficial effects on neuroregeneration and TBI prognosis. Moreover, the combined use of BDNF and miR-124 inhibitors might lead to better outcomes in TBI than BDNF treatment alone.