Hemodialysis bilayer bionic blood vessels developed by the mechanical stimulation of hepatitis B viral X(HBX) gene- transfected hepatic stellate cells. / é€šè¿‡æœºæ¢°åŠ›åˆºæ¿€ä¹™åž‹è‚ç‚Žç— æ¯’XåŸºå› (HBX)转染的肝星状细胞制备血液透析用双层仿生血管.

Artificial vascular graft (AVG) fistula is widely used for hemodialysis treatment in patients with renal failure. However, it has poor elasticity and compliance, leading to stenosis and thrombosis. The ideal artificial blood vessel for dialysis should replicate the structure and components of a real artery, which is primarily maintained by collagen in the extracellular matrix (ECM) of arterial cells. Studies have revealed that in hepatitis B virus (HBV)-induced liver fibrosis, hepatic stellate cells (HSCs) become hyperactive and produce excessive ECM fibers. Furthermore, mechanical stimulation can encourage ECM secretion and remodeling of a fiber structure. Based on the above factors, we transfected HSCs with the hepatitis B viral X (HBX) gene for simulating the process of HBV infection. Subsequently, these HBX-HSCs were implanted into a polycaprolactone-polyurethane (PCL-PU) bilayer scaffold in which the inner layer is dense and the outer layer consists of pores, which was mechanically stimulated to promote the secretion of collagen nanofiber from the HBX-HSCs and to facilitate crosslinking with the scaffold. We obtained an ECM-PCL-PU composite bionic blood vessel that could act as access for dialysis after decellularization. Then, the vessel scaffold was implanted into a rabbit's neck arteriovenous fistula model. It exhibited strong tensile strength and smooth blood flow and formed autologous blood vessels in the rabbit's body. Our study demonstrates the use of human cells to create biomimetic dialysis blood vessels, providing a novel approach for creating clinical vascular access for dialysis.

Intelligent Nanoplatform Integrating Macrophage and Cancer Cell Membrane for Synergistic Chemodynamic/Immunotherapy/Photothermal Therapy of Breast Cancer.

Cell membrane-coated nanoplatforms for drug delivery have garnered significant attention due to their inherent cellular properties, such as immune evasion and homing abilities, making them a subject of widespread interest. The coating of mixed membranes from different cell types onto the surface of nanoparticles offers a way to harness natural cell functions, enhancing biocompatibility and improving therapeutic efficacy. In this study, we merged membranes from murine-derived 4T1 breast cancer cells with RAW264.7 (RAW) membranes, creating a hybrid biomimetic coating referred to as TRM. Subsequently, we fabricated hybrid TRM-coated Fe3O4 nanoparticles loaded with indocyanine green (ICG) and imiquimod (R837) for combination therapy in breast cancer. Comprehensive characterization of the RIFe@TRM nanoplatform revealed the inherent properties of both cell types. Compared to bare Fe3O4 nanoparticles, RIFe@TRM nanoparticles exhibited remarkable cell-specific self-recognition for 4T1 cells in vitro, leading to significantly prolonged circulation life span and enhanced in vivo targeting capabilities. Furthermore, the biomimetic RIFe@TRM nanoplatform induced tumor necrosis through the Fenton reaction and photothermal effects, while R837 facilitated enhanced uptake of tumor-associated antigens, further activating CD8+ cytotoxic T cells to strengthen antitumor immunotherapy. Hence, RIFe@TRM nanoplatform demonstrated outstanding synergy in chemodynamic/immunotherapy/photothermal therapies, displaying significant inhibition of breast tumor growth. In summary, this study presents a promising biomimetic nanoplatform for effective treatment of breast cancer.

Identification of potential therapeutic drugs targeting core genes for systemic lupus erythematosus (SLE) and coexisting COVID-19: Insights from bioinformatic analyses.

OBJECTIVE: Systemic lupus erythematosus (SLE) patients are at risk during the COVID-19 pandemic, yet the underlying molecular mechanisms remain incompletely understood. This study sought to analyze the potential molecular connections between COVID-19 and SLE, employing a bioinformatics approach to identify effective drugs for both conditions. METHODS: The data sets GSE100163 and GSE183071 were utilized to determine share differentially expressed genes (DEGs). These DEGs were later analyzed by various bioinformatic methods, including functional enrichment, protein-protein interaction (PPI) network analysis, regulatory network construction, and gene-drug interaction construction. RESULTS: A total of 50 common DEGs were found between COVID-19 and SLE. Gene ontology (GO) functional annotation revealed that "immune response," "innate immune response," "plasma membrane," and "protein binding" were most enriched in. Additionally, the pathways that were enriched include "Th1 and Th2 cell differentiation." The study identified 48 genes/nodes enriched with 292 edges in the PPI network, of which the top 10 hub genes were CD4, IL7R, CD3E, CD5, CD247, KLRB1, CD40LG, CD7, CR2, and GZMK. Furthermore, the study found 48 transcription factors and 8 microRNAs regulating these hub genes. Finally, four drugs namely ibalizumab (targeted to CD4), blinatumomab (targeted to CD3E), muromonab-CD3 (targeted to CD3E), and catumaxomab (targeted to CD3E) were found in gene-drug interaction. CONCLUSION: Four possible drugs that targeted two specific genes, which may be beneficial for COVID-19 patients with SLE.

RNU12 inhibits gastric cancer progression via sponging miR-575 and targeting BLID.

Gastric cancer (GC) is one of the major causes of cancer deaths with 5-year survival ratio of 20%. RNU12 is one of long noncoding RNAs (lncRNAs) regulating the tumor progression. However, how RNU12 affecting GC is not clear. qRT-PCR was utilized for determining the RNU12 expression in cell lines, 113 cases of paired gastric cancer (GC) and their adjacent normal gastric tissues. The biofunction alterations of RNU12 were assessed by its overexpression or knockdown in GC cells. MTT and cloning assay were assayed for the cell proliferation, the flow cytometry for the detection of cell cycle and the wound healing assay (WHA) and transwell invasion assay (TIA) for examining the migration and invasion of cells. The expressions of a set of genes related proliferation and migration were investigated with the Western Blotting (WB). RNA immunoprecipitation (RIP), biotinylated RNA pull-down and dual luciferase reporter tests were used to detect the interactions of RNU12 with miR-575/BLID. The in vivo proliferation and migration ability of RNU12 infected cells were determined in zebrafish system. This study revealed that RNU12 inhibited proliferation, invasion and metastasis by sponging of miR-575 and regulating the downstream BLID and modulated EMT of GC cells. The RNU12/miR-575/BLID axis is likely to be the prognosis biomarkers and drug targets of GC.

Prediction of presurgical metabolic syndrome for gastric cancer-specific mortality is more evident in smokers: The FIESTA study.

BACKGROUNDS: We aimed to test whether the prediction of presurgical metabolic syndrome for postsurgical survival outcomes of gastric cancer hinges upon cigarette smoking status. METHODS: This study is a part of the ongoing Fujian prospective investigation of cancer (FIESTA) study. Patients with gastric cancer received radical resection of primary gastric cancer between January 2000 and December 2010, with the latest follow-up ended in December 2015. The 1:1 propensity score matching analysis was adopted to balance confounders between smokers and never-smokers. Effect-size estimates are expressed as hazard ratio (HR) with 95% confidence interval (CI). Model performance was evaluated using the Hosmer and Lemeshow test and 10-fold cross-validated area under the receiver operating characteristic curve (AUROC). Statistical analyses were completed with SAS software (v9.4). RESULTS: Total 2779 patients with gastric cancer were analyzed, including 2223 smokers and 556 never-smokers. Median follow-up time was 45.6 months. Cigarette smoking was not associated with postsurgical survival differences. Presurgical metabolic syndrome complication was significantly associated with increased gastric cancer-specific mortality in smokers (HR [95% CI]: 2.73 [1.53-4.89], p < 0.001), but not in never-smokers. Relative excess risk due to interaction was estimated to be 2.43 (95% CI: 0.40-4.45). After constructing a risk assessment score, one unit increment was associated with 10% reduced risk of gastric cancer-specific mortality (HR [95% CI]: 0.90 [0.88-0.91], p < 0.001), with 10-fold cross-validated AUROC being 0.82 (95% CI: 0.74-0.92). CONCLUSIONS: Our findings showed that the prediction of presurgical metabolic syndrome for gastric cancer-specific mortality was more evident in smokers. Practically, this study provides evidence base for future personalized prediction and helped risk-stratify gastric cancer patients who might experience serious postsurgical consequences.

An EGFR L858R mutation identified in 1862 Chinese NSCLC patients can be a promising neoantigen vaccine therapeutic strategy.

Background: This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC). Methods: A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different EGFR mutant subtype by using TCGA data. Results: HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th. EGFR L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of EGFR L858R in combination with HLA-A*33:03 were optimal. In a subsequent further analysis on immunological features of EGFR mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with EGFR mutant subtypes suggesting that the process of antigen presentation involved HLA LOH and B2M mechanisms in EGFR L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that EGFR L858R had the lowest TMB compared with other EGFR mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed EGFR L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME). Conclusion: Our study identified that EGFR L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for EGFR L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.

SNHG8 Promotes the Progression of Epstein-Barr Virus-Associated Gastric Cancer via Sponging miR-512-5p and Targeting TRIM28.

SNHG8, a family member of small nucleolar RNA host genes (SNHG), has been reported to act as an oncogene in gastric carcinoma (GC). However, its biological function in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) remains unclear. This study investigated the role of SNHG8 in EBVaGC. Sixty-one cases of EBVaGC, 20 cases of non-EBV-infected gastric cancer (EBVnGC), and relative cell lines were studied for the expression of SNHG8 and BHRF1 (BCL2 homolog reading frame 1) encoded by EBV with Western blot and qRT-PCR assays. The relationship between the expression levels of SNHG8 and the clinical outcome in 61 EBVaGC cases was analyzed. Effects of overexpression or knockdown of BHRF1, SNHG8, or TRIM28 on cell proliferation, migration, invasion, and cell cycle and the related molecules were determined by several assays, including cell proliferation, colony assay, wound healing assay, transwell invasion assay, cell circle with flow cytometry, qRT-PCR, and Western blot for expression levels. The interactions among SNHG8, miR-512-5p, and TRIM28 were determined with Luciferase reporter assay, RNA immunoprecipitation (RIP), pull-down assays, and Western blot assay. The in vivo activity of SNHG8 was assessed with SNHG8 knockdown tumor xenografts in zebrafish. Results demonstrated that the following. (1) BHRF1 and SNHG8 were overexpressed in EBV-encoded RNA 1-positive EBVaGC tissues and cell lines. BHRF1 upregulated the expressions of SNHG8 and TRIM28 in AGS. (2) SNHG8 overexpression had a significant correlation with tumor size and vascular tumor thrombus. Patients with high SNHG8 expression had poorer overall survival (OS) compared to those with low SNHG8 expression. (3) SNHG8 overexpression promoted EBVaGC cell proliferation, migration, and invasion in vitro and in vivo, cell cycle arrested at the G2/M phase via the activation of BCL-2, CCND1, PCNA, PARP1, CDH1, CDH2 VIM, and Snail. (4) Results of dual-luciferase reporter assay, RNA immunoprecipitation, and pull-down assays indicated that SNHG8 sponged miR-512-5p, which targeted on TRIM28 and promoted cancer malignant behaviors of EBVaGC cells. Our data suggest that BHRF1 triggered the expression of SNHG8, which sponged miR-512-5p and upregulated TRIM28 and a set of effectors (such as BCL-2, CCND1, CDH1, CDH2 Snail, and VIM) to promote EBVaGC tumorigenesis and invasion. SNHG8 could be an independent prognostic factor for EBVaGC and sever as target for EBVaGC therapy.

Interaction between fasting blood glucose and tumor embolus in predicting the postoperative prognosis of 4330 Chinese patients with gastrointestinal tract cancer.

Objectives: We aimed to investigate the interaction between fasting blood glucose and tumor embolus, and the potential mediation effect of fasting blood glucose on tumor embolus in predicting gastrointestinal tract cancer-specific mortality risk postoperatively. Methods and Results: 4330 patients were consecutively recruited between January 2000 and December 2010, with annual follow-up ending in December 2015. The median follow-up time was 48.6 months. Two optimal cutoff points for fasting blood glucose (6.11 and 11.69 mmol/L) were identified. Patients with fasting blood glucose <6.11 mmol/L and negative tumor embolus had the best survival, and the worst survival was seen in patients with fasting blood glucose >11.69 mmol/L and positive tumor embolus. The risk was highest for patients with fasting blood glucose >11.69 mmol/L and positive tumor embolus (adjusted HR: 11.91, 95% CI: 9.13 to 15.52). Using the Sobel-Goodman mediation test, the proportion of total effect conferred by tumor embolus that was mediated by fasting blood glucose was estimated to be 45.3%. Conclusions: Our findings indicate a synergistic interaction between fasting blood glucose and tumor embolus in predicting the postoperative prognosis of gastrointestinal tract cancer.

Multiscale network analysis reveals molecular mechanisms and key regulators of the tumor microenvironment in gastric cancer.

Gastric cancer (GC) is the third leading cause of cancer deaths and the fourth most prevalent malignancy worldwide. The high incidence and mortality rates of gastric cancer result from multiple factors such as ineffective screening, diagnosis, and limited treatment options. In our study, we sought to systematically identify predictive molecular networks and key regulators to elucidate complex interacting signaling pathways in GC. We performed an integrative network analysis of the transcriptomic data in The Cancer Genome Atlas (TCGA) gastric cancer cohort and then comprehensively characterized the predictive subnetworks and key regulators by the matched genetic and epigenetic data. We identified 221 gene subnetworks (modules) in GC. The most prognostic subnetworks captured multiple aspects of the tumor microenvironment in GC involving interactions among stromal, epithelial and immune cells. We revealed the genetic and epigenetic underpinnings of those subnetworks and their key transcriptional regulators. We computationally predicted and experimentally validated specific mechanisms of anticancer effects of GKN2 in gastric cancer proliferation and invasion in vitro. The network models and the key regulators of the tumor microenvironment in GC identified here pave a way for developing novel therapeutic strategies for GC.

The risk trajectory between preoperative fasting glucose and common digestive tract cancer-specific mortality in the FIESTA cohort involving 6865 Chinese patients.

Backgrounds: High blood glucose or hyperglycemia is an established risk factor for the development and progression of cancer at many sites, whereas data on the relevance between low blood glucose or hypoglycemia and cancer survival are lacking. Aims: We aimed to assess the shape of risk trajectory between preoperative fasting glucose and postoperative digestive cancer-specific mortality in Chinese. Methods: In total, 6865 patients who underwent radical surgery for esophageal cancer (n=2535), gastric cancer (n=3012) and colorectal cancer (n=1318) during 2000-2010 were followed up as of December 2015. All patients received neither chemotherapy nor radiotherapy before and after the surgery. Optimal cutoff points were determined using survival tree analysis. Results: The median follow-up time was 44.9 months (range: 0.5-188.9 months), with 1065 deaths from esophageal cancer, 1331 from gastric cancer and 412 from colorectal cancer. Using fasting glucose (4.36, 6.09] mmol/L as the reference group, hazard ratios for fasting glucose ≤4.36, (6.09, 8.95], (8.95, 11.5] and >11.5 mmol/L were 1.35 (95% confidence interval: 1.19, 1.54), 2.82 (2.57, 3.11), 3.56 (3.10, 4.08) and 4.27 (3.67, 4.97), respectively (p<0.001). Conclusions: Our findings indicate a U-shaped risk trajectory between preoperative fasting glucose and digestive tract cancer-specific mortality in Chinese. Further external validation is warranted.

Association of Tumor Protein p53 and Ataxia-Telangiectasia Mutated Comutation With Response to Immune Checkpoint Inhibitors and Mortality in Patients With Non-Small Cell Lung Cancer.

Importance: Immune checkpoint inhibitors (ICIs) can elicit durable antitumor responses in patients with non-small cell lung cancer (NSCLC), but only 20% to 25% of patients respond to treatment. As important genes in the DNA damage response pathway, comutation in the tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes may be associated with genomic instability and hypermutation. However, the prevalence of TP53 and ATM comutation and its association with response to ICIs are not fully understood. Objective: To examine the prevalence of the TP53 and ATM comutation, the potential mechanism, and its association with response to ICIs among patients with NSCLC. Design, Setting, and Participants: This multiple-cohort study included patients with NSCLC from the Geneplus Institute, the Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering Cancer Center (MSKCC) databases and from the POPLAR and OAK randomized controlled trials. Samples in the Geneplus cohort were collected and analyzed from April 30, 2015, through February 28, 2019. Data from TCGA, the MSKCC, and the POPLAR and OAK cohorts were obtained on January 1, 2019, and analyzed from January 1 to April 10, 2019. Next-generation sequencing assays were performed on tumor samples by the Geneplus Institute. Genomic, transcriptomic, and clinical data were obtained from TCGA and MSKCC databases. Exposures: Comprehensive genetic profiling was performed to determine the prevalence of TP53 and ATM comutation and its association with prognosis and response to ICIs. Main Outcomes and Measures: The main outcomes were TP53 and ATM comutation frequency, overall survival (OS), progression-free survival, gene set enrichment analysis, and immune profile in NSCLC. Results: Patients with NSCLC analyzed in this study included 2020 patients in the Geneplus cohort (mean [SD] age, 59.5 [10.5] years; 1168 [57.8%] men), 1031 patients in TCGA cohort (mean [SD] age, 66.2 [9.5] years; 579 [56.2%] men), 1527 patients in the MSKCC cohort (662 [43.4%] men), 350 patients in the MSKCC cohort who were treated with ICIs (mean [SD] age, 61.4 [13.8] years; 170 [48.6%] men), and 853 patients in the POPLAR and OAK cohort (mean [SD] age, 63.0 [9.1] years; 527 [61.8%] men). Sites of TP53 and ATM comutation were found scattered throughout the genes, and no significant difference was observed in the frequency of TP53 and ATM comutation within the histologic subtypes and driver genes. In 5 independent cohorts of patients with NSCLC, TP53 and ATM comutation was associated with a significantly higher tumor mutation burden compared with the sole mutation and with no mutation (TCGA, MSKCC, Geneplus, and POPLAR and OAK cohort). Among patients treated with ICIs in the MSKCC cohort, TP53 and ATM comutation was associated with better OS than a single mutation and no mutation among patients with any cancer (median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 14.0 months; ATM mutation alone, 40.0 months; no mutation, 22.0 months; P = .001; NSCLC median OS: TP53 and ATM comutation, not reached; TP53 mutation alone, 11.0 months; ATM mutation alone, 16.0 months; no mutation, 14.0 months; P = .24). Similar results were found in the POPLAR and OAK cohort in which the disease control benefit rate, progression-free survival, and OS were all greater in patients with the TP53 and ATM comutation compared with the other 3 groups (median progression-free survival: TP53 and ATM comutation, 10.4 months; TP53 mutation, 1.6 months; ATM mutation, 3.5 months; no mutation, 2.8 months; P = .01; median OS: TP53 and ATM comutation, 22.1 months; TP53 mutation, 8.3 months; ATM mutation, 15.8 months; no mutation, 15.3 months; P = .002). Conclusions and Relevance: This study's findings suggest that the TP53 and ATM comutation occurs in a subgroup of patients with NSCLC and is associated with an increased tumor mutation burden and response to ICIs. This suggests that TP53 and ATM comutation may have implications as a biomarker for guiding ICI treatment.

Identification of Optimal Baseline Blood Pressure Predicting Postoperative Digestive Tract Cancer-Specific Mortality in the FIESTA Cohort Involving 6865 Patients.

Background and Objectives: Emerging evidence indicates that hypertension is a potential risk and prognostic factor for cancer at many sites. Currently, no data are available on optimal blood pressure target in patients with resectable digestive tract cancer. Here, we did an exploratory analysis in 6865 patients from the FIESTA cohort to identify optimal blood pressure at baseline that can better predict digestive tract cancer-specific mortality risk postoperatively. Methods and Results: Patients were enrolled between January 2000 and December 2010, with follow-up ending in December 2015. All patients received no preoperative and postoperative chemotherapy or radiotherapy. Data were analyzed using Stata software and R language. Optimal cutting points were determined using survival tree analysis. After a median follow-up of 44.9 months, there were 2808 non-survivors and 4057 survivors. Per 10 mm Hg increment, baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure and mean arterial pressure were associated with the significant risk of digestive tract cancer-specific mortality, even after adjusting for confounding factors (adjusted hazard ratio: 1.06, 1.08, 1.06 and 1.09, 95% confidence interval: 1.04-1.08, 1.04-1.12, 1.03-1.09 and 1.05-1.12, P<0.001, <0.001, <0.001 and <0.001, respectively). Patients with baseline SBP of 176 mm Hg or above and DBP of 100 mm Hg or above had poor survival outcomes (median survival time: 39.6 and 37.1 months, respectively). Conclusions: We provide evidence for the use of elevated blood pressure (SBP/DBP ≥176/100 mm Hg) before surgery as a powerful harbinger to predict the survival outcomes of digestive tract cancer patients postoperatively.

Nomogram to Predict Overall Survival for Thoracic Esophageal Squamous Cell Carcinoma Patients After Radical Esophagectomy.

BACKGROUND: Effective tools evaluating the prognosis for patients with esophageal cancer undergoing surgery is lacking. The current study aimed to develop a nomogram to predict overall survival (OS) and provide evidence for adjuvant therapy for patients with esophageal carcinoma after esophagectomy. METHODS: The study retrospectively reviewed patients with pathologic T1N +/T2-4aN0-3, M0 thoracic esophageal squamous cell carcinoma after radical esophagectomy, with or without adjuvant therapy, in one institution as the training cohort (n = 2281). A nomogram was established using Cox proportional hazard regression to identify prognostic factors for OS, which were validated in an independent validation cohort (n = 1437). Area under curve (AUC) values of receiver operating characteristic curves were calculated to evaluate prognostic efficacy. RESULTS: In the training cohort, the median OS was 50.46 months, and the 5-year OS rate was 47.08%. Adjuvant therapy, sex, tumor location, grade, lymphovascular invasion, removed lymph nodes, and T and N categories were identified as predictive factors for OS. The nomogram showed favorable prognostic efficacy in the training and validation cohorts (5-year OS AUC: 0.685 and 0.744, respectively), which was significantly higher than that of the American Joint Committee on Cancer (AJCC) staging system. The nomogram distinguished OS rates among six risk groups, whereas AJCC could not separate the OS of 2A and 1B, 3C and 3B, or 3A and 2B. Patients with a nomogram score of 72 to 227 were predicted to achieve a 5-year OS increase of 10% or more from adjuvant therapy. CONCLUSION: The nomogram could effectively predict OS and aided decision making in adjuvant therapy for patients with thoracic esophageal squamous cell carcinoma after esophagectomy.

Prognostic Value of an Inflammation-Related Index in 6,865 Chinese Patients With Postoperative Digestive Tract Cancers: The FIESTA Study.

Objectives: We sought to determine the optimal cutting points for two inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), to assess their prognostic value in patients with postoperative digestive tract cancers overall and by cancer sites, and further to construct an inflammation-related index based on the two biomarkers and assess its predictive performance. Methods: Total 6,865 assessable patients with digestive tract cancers who underwent tumor resection were consecutively enrolled from Fujian Cancer Hospital between January 2000 and December 2010, including 2535/3012/1318 patients with esophageal/gastric/colorectal cancer. The latest follow-up (median: 44.9 months) ended in December 2015. Optimal cutting points were determined using survival tree analysis overall and by cancer sites. Results: Among all study patients, the optimal cutting points were 2.07 and 168.50 to define high and low NLR and PLR, respectively. High NLR (hazard ratio [HR]: 1.48, 95% confidence interval [CI]: 1.37-1.61) and high PLR (HR: 1.41, 95% CI: 1.29-1.53) were associated with a significantly increased risk for the mortality of digestive tract cancers as a whole. By cancer sites, effect-size estimates were comparable and statistically significant. Elevation over the selected optimal cutting points for both NLR and PLR was associated with 1.69-fold increased risk of cancer-specific mortality compared to patients with simultaneously low NLR and PLR among all study patients, and this association persisted by cancer sites, especially for gastric cancer. Conclusions: Our findings demonstrate that the preoperative integrated NLR and PLR, as an inflammation-related index, is a significant independent predictor for postoperative mortality in Chinese patients with digestive tract cancers both overall and by cancer sites.

Prediction of Metabolic Syndrome for the Survival of Patients With Digestive Tract Cancer: A Meta-Analysis.

Background and Objectives: Growing evidence indicates that metabolic syndrome confers a differential risk for the development and progression of many types of cancer, especially in the digestive tract system. We here synthesized the results of published cohort studies to test whether baseline metabolic syndrome and its components can predict survival in patients with esophageal, gastric, or colorectal cancer. Methods: Literature retrieval, publication selection and data extraction were performed independently by two authors. Analyses were done using STATA software (version 14.1). Results: A total of 15 publications involving 54,656 patients were meta-analyzed. In overall analyses, the presence of metabolic syndrome was associated with a non-significant 19% increased mortality risk for digestive tract cancer (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 1.45 to 2.520.95 to 1.49, P = 0.130; I 2: 94.8%). In stratified analyses, the association between metabolic syndrome and digestive tract cancer survival was statistically significant in prospective studies (HR: 1.64, 95% CI: 1.18 to 2.28), in studies involving postsurgical patients (HR: 1.42, 95% CI: 1.06 to 1.92), and in studies assessing cancer-specific survival (HR: 1.91, 95% CI: 1.45 to 2.52). Further meta-regression analyses indicated that age and smoking were potential sources of between-study heterogeneity (both P < 0.001). The shape of the Begg's funnel plot seemed symmetrical (Begg's test P = 0.945 and Egger's test P = 0.305). Conclusions: Our findings indicate that metabolic syndrome is associated with an increased risk of postsurgical digestive tract cancer-specific mortality. Continued investigations are needed to uncover the precise molecule mechanism linking metabolic syndrome and digestive tract cancer.

PPARG rs3856806 C>T Polymorphism Increased the Risk of Colorectal Cancer: A Case-Control Study in Eastern Chinese Han Population.

Purpose: Functional variants in the peroxisome proliferator-activated receptor gamma (PPARG) and PPARG co-activator 1 (PPARGC1) family (e.g., PPARGC1A and PPARGC1B) genes were predicted to confer susceptibility to colorectal cancer (CRC). The aim of the present study was to explore the relationship between PPARG, PPARGC1A, PPARGC1B polymorphism and the risk of CRC. Patients and methods: We conducted a case-control study with 1,003 CRC cases and 1,303 controls. We selected the PPARG rs3856806 C>T, PPARGC1A rs2970847 C>T, rs8192678 C>T, rs3736265 G>A and PPARGC1B rs7732671 G>C and rs17572019 G>A SNPs to assess the relationship between PPARG, PPARGC1A, PPARGC1B their variants and risk of CRC. Results: We found that the PPARG rs3856806 C>T polymorphism increased the risk of CRC (TT vs. CC: adjusted OR, 1.59, 95% CI 1.08-2.35, P = 0.020; TT/CT vs. CC: adjusted OR, 1.26; 95% CI 1.06-1.49; P = 0.009 and TT vs. CC/CT: adjusted OR, 1.54; 95% CI 1.05-2.26; P = 0.028), even after a Bonferroni correction test. The stratified analysis revealed that the PPARG rs3856806 C>T polymorphism also increased the risk of CRC, especially in male, ≥61 years old, never smoking, never drinking, BMI ≥ 24 kg/m2, colon cancer and rectum cancer subgroups. Conclusion: Our findings highlight that the PPARG rs3856806 C>T polymorphism may increase the risk of CRC. In the future larger sample size case-control studies with a detailed functional assessment are needed to further determine the relationship of the PPARG rs3856806 C>T polymorphism with CRC risk.

Transcriptome­wide piRNA profiling in human gastric cancer.

Piwi­interacting RNAs (piRNAs) comprise the largest class of non­coding RNAs. They represent a molecular feature shared by all non­aging biological systems, including germline and somatic cancer stem cells, which display an indefinite capacity of renewal and proliferation and are potentially immortal. They have been identified in animal stomachs, but their relationship with human gastric cancers remains largely unclear. The present study aimed to identify the piRNAs associated with human gastric cancers across the whole transcriptome. Fresh tumor tissues and adjacent non­tumorous tissues from stomachs were examined using a piRNA microarray (23,677 piRNAs) that was then validated by qPCR. The differential expression of piRNAs between cases and controls was analyzed. The transposable elements (TEs) that are potentially targeted by the risk piRNAs were searched. The expression of the nearest genes that are complementary to the sequences of the piRNAs was examined in the stomach tissue. The regulatory effects of genome­wide significant and replicated cancer­risk DNA variants on the piRNA expression in stomach were tested. Based on the findings, we identified a total of 8,759 piRNAs in human stomachs. Of all, 50 were significantly (P<0.05) and differentially (>2­fold change) expressed between the cases and controls, and 64.7% of the protein­coding genes potentially regulated by the gastric cancer­associated piRNAs were expressed in the human stomach. The expression of many cancer­associated piRNAs was correlated with the genome­wide and replicated cancer­risk SNPs. In conclusion, we conclude that piRNAs are abundant in human stomachs and may play important roles in the etiological processes of gastric cancers.

Association of RAGE gene four single nucleotide polymorphisms with the risk, invasion, metastasis and overall survival of gastric cancer in Chinese.

Objectives: The receptor for advanced glycation end products (RAGE) is an oncogenic trans-membranous receptor expressed in many cells. The aim of this study was to clarify the association between RAGE gene 4 single nucleotide polymorphisms (SNPs) and the risk, invasion, metastasis and overall survival of gastric cancer. Methods and Results: We performed a hospital-based case-control study involving 369 gastric cancer patients and 493 cancer free controls. Four widely-studied SNPs, rs1800625 (T-429C), rs1800624 (T-374A), rs2070600 (Gly82Ser) and rs184003 (G1704T) in RAGE gene, were genotyped by the polymerase chain reaction - ligase detection reaction method. The RAGE gene rs1800625 TT genotype and T allele were significantly associated with a reduced risk of gastric cancer (TT vs. CC: adjusted odds ratio [OR]: 0.72, 95% CI: 0.55-0.95, p=0.021; T vs. C: adjusted OR: 0.67, 95% CI: 0.46-0.97, p=0.032). No hints of significance were detected for the other three SNPs in association with gastric cancer risk. Moreover, rs1800625 and rs184003 were significantly associated with tumor clinical stage (p=0.010 and 0.032, respectively). Survival curves differed significantly between the genotypes of rs1800625. Conclusions: RAGE gene SNP rs1800625 was significantly associated with gastric cancer risk, and rs1800625 and rs184003 were related to tumor clinical stage, indicating that RAGE gene may be a gastric cancer-susceptibility gene.

Expression status of four mismatch repair proteins in patients with colorectal cancer: clinical significance in 1238 cases.

To investigate the expression of mismatch repair proteins (MMR) in colorectal cancer (CRC) and to analyze the correlation between MMR and pathologic features of CRC, immunohistochemistry was used to detect the expression of four MMR proteins (MLHl, PMS2, MSH2 and MSH6). All expression was classified as MMR proficient (pMMR). Absence of one or more of these proteins was classified as MMR deficient (dMMR). Among the 1238 cases of CRC, the four protein expression deletion rates from high to low were: PMS2 5.09% (63/1,238), MLH1 3.47% (43/1,238), MSH6 2.83% (35/1,238), and MSH2 2.10% (26/1,238). The dMMR cases accounted for 8.08% of all CRC cases (100/1,238). The common deletion rates of two or more proteins from high to low were: MLH1/PMS2 41.00% (41/100), MSH2/MSH6 20.00% (20/100), MSH6/PMS 23.00% (3/100), MLH1/MSH2/MSH6/PMS2 1.00% (1/100). dMMR cases were more common than pMMR cases in the ascending colon, T4 stage, stage II group, and poorly-differentiated CRC (P<0.05). MLH1 and PMS2 protein expression deficiency were correlated with tumor site, T stage, and differentiation. The incidence in ileocecum, T4, and poorly differentiated CRC was higher (P<0.05), and these two were positively correlated (P<0.05). The deficiency of MSH2 and MSH6 proteins was correlated with age, tumor site, and TNM stage; it was higher in patients ≤65 years old, in the transverse colon-splenic flexure region, and in stage II CRC (P<0.05), and the two were positively correlated (P<0.05). A co-expression deficiency of MLH1/PMS2 and MSH2/MSH6 was more common. The incidence of dMMR was more common in ascending colon, T4 stage, stage II, and poorly differentiated CRC. This may provide more comparisons and reference data for the molecular mechanism, clinical treatment, and prognosis of CRC.

Interaction Between Prediabetes and the ABO Blood Types in Predicting Postsurgical Esophageal Squamous Cell Carcinoma-Specific Mortality: The FIESTA Study.

Background: We aimed to investigate the interaction between prediabetes and the ABO blood types in predicting esophageal squamous cell carcinoma (ESCC)-specific mortality by analysing data from the FIESTA study on normal/prediabetic patients with ESCC. Methods: Total 1,857 normal/prediabetic patients with ESCC who underwent three-field lymphadenectomy between January 2000 and December 2010 and survived hospitalization were analyzable, with follow-up beginning in 2000 and ending in 2015. Results: At the end of the follow-up, there were 1,161 survivors and 696 non-survivors. The follow-up time ranged from 0.5 to 180 months. The cumulative survival rates in normal patients were obviously better than in prediabetic patients. The cumulative survival rates were significantly higher in normal patients than in prediabetic patients for the blood types O and A (Log-rank test P < 0.05), while no significance was detected for the blood types B and AB. Adjusted risk estimates for ESCC-specific mortality for prediabetic patients relative to normal patients were statistically significant in the blood type B- group (hazard ratio [HR]: 1.71; 95% confidence interval [CI]: 1.33-2.20; P < 0.001), but not in the blood type B+ group (HR: 1.12; 95% CI: 0.77-1.64; P = 0.5544). Conclusions: Our findings indicate that prediabetes can predict the significant risk of ESCC-specific mortality in Chinese Han patients with the blood types O and A.