Photothermal Ferrotherapy - Induced Immunogenic Cell Death via Iron-Based Ternary Chalcogenide Nanoparticles Against Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is highly malignant and prone to recurrence and metastasis. Patients with TNBC have limited therapeutic options, often resulting in poor prognosis. Some new treatments for TNBC have been considered in the past decade, such as immunotherapy, photothermal therapy (PTT), and ferroptosis therapy, that allow the rapid and minimally invasive ablation of cancer. However, a multifunctional nanodrug system with more potent efficacy for TNBC is still needed. The use of iron-based ternary chalcogenide nanoparticles (NPs), namely AgFeS2 , is reported, which synergistically combines photothermal therapy, ferrotherapy, and immunotherapy in one system for the treatment of TNBC. AgFeS2 possesses excellent photothermal conversion performance for tumor near-infrared (NIR) phototherapy. Upon photoirradiation, these NPs generate heat, accelerate the release of iron ions, and effectively catalyze the Fenton reaction, resulting in cell apoptosis and ferroptosis. Additionally, AgFeS2 promotes the release of tumor-specific antigens and triggers an immune response via immunogenic cell death (ICD), thereby providing unique synergistic mechanisms for cancer therapy. The present study demonstrates the great potential of iron-based ternary chalcogenide as a new therapeutic platform for a combination of photothermal therapy, ferrotherapy, and immunotherapy for the suppression of TNBC.

The association of immune cell infiltration and prognostic value of tertiary lymphoid structures in gastric cancer.

Tertiary lymphoid structures (TLS) are lymphoid aggregates in tumor tissues and their potential significance in clinical applications has not been fully elucidated in gastric cancer. We evaluated TLS and tumor-infiltrating immune cells using H&E and immunohistochemistry staining in the recruited patients with gastric cancer. The prognostic value of TLS was evaluated by Kaplan-Meier analysis and further validated using gene expression profiling. The alterations in gene mutation, copy number variance, and DNA methylation across the TLS signature subtypes were analyzed based on the Cancer Genome Atlas cohort. High TLS density was associated with improved overall survival and disease-free survival. A combination of TLS density and TNM stage obtained higher prognostic accuracy than the TNM stage alone. Tumors with high TLS density showed significantly higher infiltration of CD3+, CD8+, and CD20+ cells but lower infiltration of CD68+ cells. Transcriptomics analysis demonstrated that high TLS signature status was positively associated with the activation of inflammation-related and immune-related pathways. Multi-omics data showed a distinct landscape of somatic mutations, copy number variants, and DNA methylation across TLS signature subtypes. Our results indicated that TLS might link with enhanced immune responses, and represent an independent and beneficial predictor of resected gastric cancer. Multi-omics analysis further revealed key tumor-associated molecular alterations across TLS signature subtypes, which might help explore the potential mechanism of the interaction between TLS formation and cancer cells.

Trim47 overexpression correlates with poor prognosis in gastric cancer.

Trim47 is a member of the tripartite motif (TRIM) family that participates in many pathophysiological processes. However, the expression pattern and biological functions of Trim47 in gastric cancer (GC) remain unclear. The present study aimed to further explore the clinicopathological significance and potential prognostic role of Trim47 expression in GC. Therefore, in this study, Trim47 mRNA level was investigated in the Cancer Genome Atlas (TCGA) and Oncomine database in GC. We detected Trim47 mRNA and protein expression levels in GC and paired adjacent normal tissues. Kaplan-Meier method and Cox proportional hazard regression models were performed to analyze the survival of patients and prognostic factors. A gene set enrichment analysis (GSEA) was performed to determine the mechanism of Trim47 in GC. Our results indicated that Trim47 mRNA expression in GC tissues was significantly higher than adjacent normal tissues, as was Trim47 protein expression. Trim47 overexpression in GC tissues was significantly associated with tumor differentiation, T stage, N stage, M stage, and TNM stage. Kaplan-Meier analyses showed that high Trim47 expression was associated with worse overall survival (OS) and disease-free survival (DFS) in GC patients. Multivariate analysis confirmed that Trim47 expression was an independent prognostic factor for GC patients. Bioinformatics analysis and western blot indicated Trim47 might regulate GC through NF-κB, EMT, hypoxia, and apoptosis signaling pathway in GC. Our results show that Trim47 has the potential to serve as a novel prognostic biomarker in GC patients.

The role of DNMT1/hsa-miR-124-3p/BCAT1 pathway in regulating growth and invasion of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer with high aggressiveness and poor prognosis. There is an urgent need for understanding the molecular mechanism underlying the development and progression of ESCC. METHODS: ESCC tissues and corresponding non-neoplastic tissues were collected. The expression and function of miR-124-3p and BCAT1 in two cell lines KYSE-150 and Eca109 were determined. RESULTS: We show downregulation of miR-124-3p expression in ESCC tissues, which is highly correlated with proliferation and migration of ESCC cell lines KYSE-150 and Eca109. miR-124-3p show high correlation with TNM stage and differentiation grade. Furthermore, miR-124-3p directly targets mRNA 3'UTR region of BCAT1, which results in upregulation of BCAT1 expression as observed in ESCC tissues and cell lines. Also, our data indicates that BCAT1 high expression is strongly linked to the disease-free survival, tumor size, pathologic stage, T classification and differentiation grade. On the other hand, we clarified the upstream mechanism regulating miR-124-3p expression in ESCC, which involves in the hypermethylation-silencing regulation mediated by DNA methyltransferase 1(DNMT1), which is of high expression in ESCC tissues and cell lines in the present study. In addition, DNMT1 knockdown or inhibition of DNMT1 function contributes to downregulation of miR-124-3p and BCAT1 expression. CONCLUSIONS: Our study thus clarifies a new mechanism that DNMT1/miR-124/BCAT1 axis regulates the development and progression of ESCC.

Predictive ability of prognostic nutritional index in surgically resected gastrointestinal stromal tumors: a propensity score matching analysis.

BACKGROUND: Recent findings have shown that inflammation indices are associated with prognosis in various malignancies. However, the usefulness of inflammation indices including platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and prognostic nutritional index for gastrointestinal stromal tumors (GISTs) remains controversial. METHODS: We retrospectively reviewed 340 primary localized GIST patients who had received surgical resection between 2005 and 2015 to investigate the effect of platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio and prognostic nutritional index on prognosis. 206 patients were selected by propensity score matching to control selection biases. RESULTS: Kaplan-Meier analysis and the log rank test demonstrated that high prognostic nutritional index (≥43.9) was significantly correlated with better recurrence-free survival (RFS) (P<0.001). Among the three inflammatory indices, only preoperative high prognostic nutritional index was an independent prognostic factor for survival [hazard ratio (HR) 0.509; 95% confidence interval (CI) 0.266-0.872; P = 0.031] in multivariate analysis. After propensity score matching, elevated prognostic nutritional index was still a predictor for RFS (HR = 0.498; 95% CI 0.253-0.971; P = 0.042) in the multivariate analyses. In addition, prognostic nutritional index was a significant prognostic factor for GISTs within the National Institutes of Health (NIH) high and very low/low-risk categories. Incorporation prognostic nutritional index into the NIH risk criteria improved the prognostic stratification (c-index, 0.725 vs. 0.686, p = 0.039). CONCLUSIONS: High prognostic nutritional index is a predictor of improved survival for surgically resected GISTs and incorporation prognostic nutritional index into NIH risk criteria improves the predictive accuracy.

Impact of pre-existing type-2 diabetes on patient outcomes after radical resection for gastric cancer: a retrospective cohort study.

BACKGROUND: The aim of this study was to evaluate the impact of pre-existing type-2 diabetes on postoperative recovery and prognosis in gastric cancer (GC) patients who underwent radical gastrectomy. RESEARCH DESIGN AND METHODS: From June 2001 to June 2011, a total of 1,014 eligible patients were enrolled. Among them, 67 patients were diagnosed with type-2 diabetes. The clinicopathologic features and prognostic data were compared between patients with type-2 diabetes (the DM group) and without diabetes (the non-DM group). RESULTS: Median survival was 68.3 months. The 5-year overall survival in the DM group was similar to that in the non-DM group (52.1 vs. 53.0 %, p = 0.411). Propensity score matching analysis demonstrated that the hazard ratio of death in the DM group was 1.191 (95 % confidential index 0.693-2.072; p = 0.531) compared to the-non DM group. Incidence of postoperative complications was higher in the DM group than in the non-DM group (17.9 vs. 8.1 %, p = 0.006). The DM remission rate was 46 % among patients who received Roux-en-Y reconstruction, and 13 % among patients who received Billroth II anastomosis (p = 0.009). The 5-year overall survival rate was 62.1 % for patients with cured or improved DM and 23.4 % for patients with worse or same DM status (p = 0.003). CONCLUSION: Type-2 diabetes can be cured by radical gastrectomy plus Roux-en-Y reconstruction in some GC patients. Pre-existing diabetes is associated with increased postoperative complications and decreased survival when it becomes worse after curative dissection for GC.

Bridging Machine Learning and Thermodynamics for Accurate pK a Prediction.

Integrating scientific principles into machine learning models to enhance their predictive performance and generalizability is a central challenge in the development of AI for Science. Herein, we introduce Uni-pK a, a novel framework that successfully incorporates thermodynamic principles into machine learning modeling, achieving high-precision predictions of acid dissociation constants (pK a), a crucial task in the rational design of drugs and catalysts, as well as a modeling challenge in computational physical chemistry for small organic molecules. Uni-pK a utilizes a comprehensive free energy model to represent molecular protonation equilibria accurately. It features a structure enumerator that reconstructs molecular configurations from pK a data, coupled with a neural network that functions as a free energy predictor, ensuring high-throughput, data-driven prediction while preserving thermodynamic consistency. Employing a pretraining-finetuning strategy with both predicted and experimental pK a data, Uni-pK a not only achieves state-of-the-art accuracy in chemoinformatics but also shows comparable precision to quantum mechanics-based methods.

DDR1 Drives Malignant Progression of Gastric Cancer by Suppressing HIF-1α Ubiquitination and Degradation.

The extracellular matrix (ECM) has been demonstrated to be dysregulated and crucial for malignant progression in gastric cancer (GC), but the mechanism is not well understood. Here, that discoidin domain receptor 1 (DDR1), a principal ECM receptor, is recognized as a key driver of GC progression is reported. Mechanistically, DDR1 directly interacts with the PAS domain of hypoxia-inducible factor-1α (HIF-1α), suppresses its ubiquitination and subsequently strengthens its transcriptional regulation of angiogenesis. Additionally, DDR1 upregulation in GC cells promotes actin cytoskeleton reorganization by activating HIF-1α/ Ras Homolog Family Member A (RhoA)/Rho-associated protein kinase 1 (ROCK1) signaling, which in turn enhances the metastatic capacity. Pharmacological inhibition of DDR1 suppresses GC progression and angiogenesis in patient-derived xenograft (PDX) and organoid models. Taken together, this work first indicates the effects of the DDR1-HIF-1α axis on GC progression and reveals the related mechanisms, providing experimental evidence for DDR1 as a therapeutic target for GC.

Immune checkpoint reprogramming via sequential nucleic acid delivery strategy optimizes systemic immune responses for gastrointestinal cancer immunotherapy.

Monoclonal antibodies targeting immune checkpoints have been widely applied in gastrointestinal cancer immunotherapy. However, systemic administration of various monoclonal antibodies does not often result in sustained effects in reversing the immunosuppressive tumor microenvironment (TME), which may be due to the spatiotemporal dynamic changes of immune checkpoints. Herein, we reported a novel immune checkpoint reprogramming strategy for gastrointestinal cancer immunotherapy. It was achieved by the sequential delivery of siPD-L1 (siRNA for programmed cell death ligand 1) and pOX40L (plasmid for OX40 ligand), which were complexed with two cationic polymer brush-grafted carbon nanotubes (dense short (DS) and dense long (DL)) designed based on the structural characteristics of nucleic acids and brush architectures. Upon administrating DL/pOX40L for the first three dosages, then followed by DS/siPD-L1 for the next three dosages to the TME, it upregulated the stimulatory checkpoint OX40L on dendritic cells (DCs) and downregulated inhibitory checkpoint PD-L1 on tumor cells and DCs in a sequential reprogramming manner. Compared with other combination treatments, this sequential strategy drastically boosted the DCs maturation, and CD8+ cytotoxic T lymphocytes infiltration in tumor site. Furthermore, it could augment the local antitumor response and improve the T cell infiltration in tumor-draining lymph nodes to reverse the peripheral immunosuppression. Our study demonstrated that sequential nucleic acid delivery strategy via personalized nanoplatforms effectively reversed the immunosuppression status in both tumor microenvironment and peripheral immune landscape, which significantly enhanced the systemic antitumor immune responses and established an optimal immunotherapy strategy against gastrointestinal cancer.

Evaluation of skeletonization of the hepatoduodenal ligament for the lower third gastric cancer by propensity score analysis.

BACKGROUND/AIMS: Effects and indications of no. 12b and 12p nodes dissection for gastric cancer are not determined yet. Here we retrospectively evaluated the effect of no. 12b and 12p nodes dissection for treatment of lower third gastric cancer (LTGC). METHODOLOGY: Between 2001 and 2010, 110 LTGC patients with no. 12b and 12p nodes dissection (SHDL group) and 138 patients without no. 12b and 12p nodes dissection (non-SHDL group) were enrolled in this study. Clinicopathological features and prognostic data were compared between the two groups. RESULTS: The nodal metastatic rate was 8.2% of no. 12b and 10.9% of no. 12p. The 5-year survival rate was 62.9% in the SHDL group and 51.4% in the non-SHDL group (p = 0.16). Multivariate analysis with and without propensity score adjustment showed that SHDL was a significantly prognostic factor. The hazard ratio for death after D2 surgery plus SHDL was 0.457 (95% CI: 0.25 to 0.821; p = 0.0085) compared to D2 surgery alone. More patients in the non-SHDL group had only lymph node recurrence compared to the SHDL group (4.3% vs. 0%, p = 0.035). CONCLUSIONS: Skeletonization of the hepatoduodenal ligament is associated with superior outcomes for LTGC patients especially for those with involved local hepatoduodenal nodes.

[Meta-analysis of adjuvant chemotherapy on prognosis for gastric cancer patients after D2 dissection].

OBJECTIVE: To evaluate efficacy of adjuvant chemotherapy after D2 dissection on survival for patients with gastric cancer. METHODS: Randomized clinical trials (RCT) that compared adjuvant chemotherapy after D2 dissection with D2 dissection alone for gastric cancer were searched with Pubmed, Cochrane, Embase and CBM databases. Eligible trials published between 1990 and 2012 were included in the study. The quality of RCTs was assessed by the Jadad scale. Data synthesis and statistical analysis were performed by RevMan 5.1 software. RESULT: Eight RCTs with 3633 patients were included in this study. Among them, 1824 patients received adjuvant chemotherapy and 1809 patients didn't. Adjuvant chemotherapy was associated with a significant benefit in terms of overall survival (RR = 0.76, 95% CI: 0.69-0.84), disease free survival (RR = 0.72, 95%CI: 0.66-0.80) and recurrence rate (RR = 0.69, 95% CI: 0.62-0.77). CONCLUSION: Adjuvant chemotherapy was associated with survival benefit for gastric cancer after D2 dissection.

The Effect of Multidisciplinary Team Discussion Intervention on the Prognosis of Advanced Colorectal Cancer.

Purpose: The effects of multidisciplinary team discussion intervention on the treatment and prognosis of advanced colorectal cancer are still controversial. Large sample size studies to evaluate the efficacy in patients with advanced colorectal cancer are lacking. Materials and Methods: We statistically analyzed the data of surgical patients diagnosed with advanced colorectal cancer from 2008 to 2014 by retrospective analysis. Patients were divided into two groups according to whether or not they received multidisciplinary team discussion intervention. After at least 3 years of follow up, differences between two groups were compared with respect to treatment process and patient prognosis. Results: The time to treatment in intervention group was shorter (9.6 ± 4.2 days vs 10.7 ± 5.6 days; p= 0.002). There were no significant differences in recurrence and metastasis rate between the two groups. Multivariate survival analysis suggested that multidisciplinary team discussion intervention reduced the risk of death (HR = 0.677; p = 0.006). And it had significant interaction with tumor invasion and tumor stage, and especially had beneficial effects in the tumor stage IV subgroup (p=0.005) and tumor invasion T4 subgroup (p<0.001). Conclusion: Multidisciplinary team discussion intervention accelerated the treatment process and reduced the death risk of patients with advanced colorectal cancer, especially improved the overall survival of stage IV and invasion T4 patients. The clinical characteristics of tumor invasion and tumor stage must be the primary considerations when judging whether patients need to conduct multidisciplinary team discussions.

STIP1 knockdown suppresses colorectal cancer cell proliferation, migration and invasion by inhibiting STAT3 pathway.

Stress-induced phosphoprotein 1 (STIP1) plays an important role in cancer tumorigenesis and progression. However, the role of STIP1 in colorectal cancer (CRC) remains unclear. This study aimed to explore clinical significance, biological function and potential molecular mechanism of STIP1 in CRC. Immunohistochemistry (IHC) and Western bolt were performed to detect STIP1 protein level in CRC and adjacent normal tissues. DLD1 and HCT116 cell lines were treated with shSTIP1, cell proliferation was detected by CCK8 and colony formation assays, and cell migration and invasion were detected by wound healing and transwell assays. Moreover, western blot and immunofluorescence assays were performed to explore the potential molecular mechanism of STIP1 in the progression of CRC. We found that STIP1 expression in CRC tissues was significantly higher than in adjacent normal tissues. High STIP1 expression was associated with poor overall survival (OS) in CRC patients. Furthermore, secreted STIP1 promoted CRC cell proliferation and invasion through STAT3 signaling pathway, while STIP1 knockdown inhibited the proliferation, migration and invasion of CRC cells. Mechanistically, STIP1 knockdown suppressed the activation of STAT3 signaling pathway in CRC. In conclusion, STIP1 knockdown suppresses CRC cell proliferation, migration and invasion by inhibiting the activation of STAT3 signaling, and STIP1 is a potential target for CRC therapy.

Identification of Stemness Characteristics Associated With the Immune Microenvironment and Prognosis in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is a highly heterogeneous disease. In recent years, the prognostic value of the mRNA expression-based stemness index (mRNAsi) across cancers has been reported. We intended to identify stemness index-associated genes (SI-genes) for clinical characteristic, gene mutation status, immune response, and tumor microenvironment evaluation as well as risk stratification and survival prediction. METHODS: The correlations between the mRNAsi and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were evaluated. Weighted gene correlation network analysis (WGCNA) was performed to identify SI-genes from differentially expressed genes (DEGs) in The Cancer Genome Atlas (TCGA). Single-sample gene set enrichment analysis (ssGSEA) was employed to calculate the sample SI-gene-based ssGSEA score according to the SI-genes. Then, the correlations between the ssGSEA score and GC prognosis, clinical characteristics, gene mutation status, immune cell infiltration and tumor microenvironment were analyzed. Finally, the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm was used to construct a prognostic signature with prognostic SI-genes. The ssGSEA score and prognostic signature were validated using the Gene Expression Omnibus (GEO) database. RESULTS: The mRNAsi could predict overall survival (OS), clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Fourteen positive SI-genes and 178 negative SI-genes were screened out using WGCNA. The ssGSEA score, similar to the mRNAsi, was found to be closely related to OS, clinical characteristics, the gene mutation status, immune cell infiltration, and the tumor microenvironment composition. Finally, a prognostic signature based on 18 prognostic SI-genes was verified to more accurately predict GC 1-year, 3-year, and 5-year OS than traditional clinical prediction models. CONCLUSION: The ssGSEA score and prognostic signature based on 18 prognostic SI-genes are of great value for immune response evaluation, risk stratification and survival prediction in GC and suggest that stemness features are crucial drivers of GC progression.

Identification of an Immune-Related Long Noncoding RNA Pairs Model to Predict Survival and Immune Features in Gastric Cancer.

Background: Gastric cancer (GC) remains one of the most malignant tumors around the world, and an accurate model that reliably predicts survival and therapeutic efficacy is urgently needed. As a novel predictor for prognosis in a variety of cancers, immune-related long noncoding RNA pairs (IRlncRNAPs) have been reported to predict tumor prognosis. Herein, we integrated an IRlncRNAPs model to predict the clinical outcome, immune features, and chemotherapeutic efficacy of GC. Methods: Based on the GC data obtained from The Cancer Genome Atlas (TCGA) database and the Immunology Database and Analysis Portal (ImmPort), differentially expressed immune-related long noncoding RNAs (DEIRlncRNAs) were identified. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression analysis were used to select the most appropriate overall survival (OS)-related IRlncRNAPs to develop a prognostic signature. The riskScore of each sample was calculated by comparing the long noncoding RNA expression level in each IRlncRNAP. Based on the riskScore for each patient, GC patients were divided into high- and low-risk groups. Then, the correlation of the signature and riskScore with OS, clinical features, immune cell infiltration, immune-related gene (IRG) expression and chemotherapeutic efficacy in GC was analyzed. Results: A total of 107 DEIRlncRNAs were identified which formed 4297 IRlncRNAPs. Fifteen OS-related IRlncRNAPs were selected to develop a prognostic model. GC patients could be accurately classified into high- and low-risk groups according to the riskScore of the prognostic model. The 1-, 2-, 3-, and 5-year receiver operating characteristic (ROC) curves for the riskScore were drawn and the area under the curve (AUC) values were found to be 0.788, 0.810, 0.825, and 0.868, respectively, demonstrating a high sensitivity and accuracy of this prognostic signature. Moreover, the immune-related riskScore was an independent risk factor. Patients showed a poorer outcome within the high-risk group. In addition, the riskScore was found to be significantly correlated with the clinical features, immune infiltration status, IRG expression, and chemotherapeutic efficacy in GC. Conclusion: The prognostic model of IRlncRNAPs offers great promise in predicting the prognosis, immune infiltration status, and chemotherapeutic efficacy in GC, which might be helpful for the selection of chemo- and immuno-therapy of GC.

Cross-Talk of Focal Adhesion-Related Gene Defines Prognosis and the Immune Microenvironment in Gastric Cancer.

Background: Focal adhesion, as the intermediary between tumor cells and extracellular matrix communication, plays a variety of roles in tumor invasion, migration, and drug resistance. However, the potential role of focal adhesion-related genes in the microenvironment, immune cell infiltration, and drug sensitivity of gastric cancer (GC) has not yet been revealed. Methods: The genetic and transcriptional perspectives of focal adhesion-related genes were systematically analyzed. From a genetic perspective, the focal adhesion index (FAI) was constructed based on 18 prognosis-related focus adhesion-related genes to evaluate the immune microenvironment and drug sensitivity. Then three prognosis-related genes were used for consistent clustering to identify GC subtypes. Finally, use FLT1, EGF, COL5A2, and M2 macrophages to develop risk signatures, and establish a nomogram together with clinicopathological characteristics. Results: Mutations in the focal adhesion-related gene affect the survival time and clinical characteristics of GC patients. FAI has been associated with a shorter survival time, immune signaling pathways, M2 macrophage infiltration, epithelial-mesenchymal transition (EMT) signaling, and diffuse type of GC. FAI recognizes ALK, cell cycle, and BMX signaling pathways inhibitors as sensitive agents for the treatment of GC. FLT1, EGF, and COL5A2 may distinguish GC subtypes. The established risk signature is of great significance to the prognostic evaluation of GC based on FLT1, EGF, and COL5A2 and M2 macrophage expression. Conclusion: The focal adhesion-related gene is a potential biomarker for the evaluation of the immune microenvironment and prognosis. This work emphasizes the potential impact of the focal adhesion pathway in GC therapy and highlights its guiding role in prognostic evaluation.

Gender Differences in Gastric Cancer Survival: 99,922 Cases Based on the SEER Database.

OBJECTIVES: To evaluate gender differences in initial presentation, pathology and outcomes with GC (GC). METHODS: The 1973-2013 Surveillance Epidemiology and End Results (SEER) 17-registry database was analysed for renal tumours from 1973 to 2013 coded as primary site "stomach". After various exclusions, a final study group of 99,922 cases with complete data was obtained. Demographic variables analysed included age, sex, marital status and race. Tumour variables included size, stage at diagnosis, grade, primary site, treatment and histology. Primary outcome variables included overall survival (OS) and cancer-specific survival (CSS). RESULTS: Overall, 96,501 gastric cancer patients were identified. Of those, 34,862 (36.2%) were women. For woman, log-rank test showed that OS and CSS were significantly longer in man (p < 0.0001). In Cox regression analysis, woman was associated with a significantly improved OS [(HR of death in 1973 to 2003 = 0.87, 95% CI = 0.85-0.89, P < 0.001) (HR of death in 2004 to 2013 = 0.94, 95% CI = 0.91-0.97, P < 0.001)] and cancer-specific survival [(HR of death in 1973 to 2003 = 0.90, 95% CI = 0.87-0.92, P < 0.001) (HR of death in 2004 to 2013 = 0.90, 95% CI = 0.87-0.93, P < 0.001)]. When performing a Kaplan-Meier curve analysis after propensity score matching, gender persisted to be a significant survival of woman for OS and CSS. CONCLUSIONS: Men present with larger, higher stage, higher grade GC than women. OS and CSS are better in women, which is significantly different.

The prognostic roles of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in gastrointestinal stromal tumours: a meta-analysis.

BACKGROUND: The platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) have been found to be associated with prognosis in several solid tumours. However, the prognostic roles of PLR and NLR in gastrointestinal stromal tumours (GISTs) remain controversial. The aim of this meta-analysis was to assess the prognostic roles of PLR and NLR in GISTs. METHODS: We searched MEDLINE, EMBASE and the Cochrane Library for relevant articles. A systematic review was performed to calculate pooled hazard ratios (HRs) for disease-free survival (DFS) and overall survival (OS) by fixed-effects/random-effects models. RESULTS: Fourteen studies containing 3,151 subjects were finally enrolled in this meta-analysis. Eight studies including 2,560 patients investigated the prognostic effect of PLR, and thirteen studies with 2,751 subjects explored the prognostic effect of NLR. Both elevated PLR (HR: 1.29, 95% CI: 1.10-1.52, P=0.002) and NLR (HR: 1.37, 95% CI: 1.15-1.63, P=0.0005) were significantly associated with decreased DFS. The pooled HR for PLR was not significantly different from that for NLR. High PLR and NLR correlated with increased tumour sizes, more advanced tumour stages and mitotic index (>5/50 HPF). In addition, elevated PLR was related to adjuvant tyrosine kinase inhibitor (TKI) therapy. CONCLUSIONS: Elevated preoperative PLR and NLR are associated with poor outcomes in patients with GISTs.

Long non-coding RNA H19 promotes colorectal cancer metastasis via binding to hnRNPA2B1.

BACKGROUND: Long non-coding RNA H19 was demonstrated to be significantly correlated with tumor metastasis. However, the specific functions of H19 in colorectal cancer (CRC) metastasis and the underlying mechanism are still largely unclear. METHODS: Use public database to screen the potential lncRNA crucial for metastasis in colorectal cancer. The expression of H19 in clinical CRC specimens was detected by qRT-PCR. The effect of H19 on the metastasis of CRC cells was investigated by transwell, wound healing assays, CCK-8 assays and animal studies. The potential proteins binding to H19 were identified by LC-MS and verified by RNA immunoprecipitation (RIP). The expression of indicated RNA and proteins were measured by qRT-PCR or western blot. RESULTS: We found the expression of lncRNA H19 was significantly upregulated in primary tumor and metastatic tissues, correlated with poor prognosis in CRC. Ectopic H19 expression promoted the metastasis of colorectal cancer cells in vitro and in vivo, and induced epithelial-to-mesenchymal transition (EMT). Mechanistically, H19 directly bound to hnRNPA2B1. Knockdown of hnRNPA2B1 attenuated the H19-induce migration and invasion in CRC cells. Furthermore, H19 stabilized and upregulated the expression of Raf-1 by facilitated the interaction between hnRNPA2B1 and Raf-1 mRNA, resulting in activation of Raf-ERK signaling. CONCLUSIONS: Our findings demonstrate the role of H19/hnRNPA2B1/EMT axis in regulation CRC metastasis, suggested H19 could be a potential biomarker to predict prognosis as well as a therapeutic strategy for CRC.

FYN promotes gastric cancer metastasis by activating STAT3-mediated epithelial-mesenchymal transition.

Gastric cancer is one of the most lethal cancers worldwide. FYN, a gene that is differentially expressed in gastric cancer, is considered a critical metastasis regulator in several solid tumors, but its role in gastric cancer is still unclear. This study aimed to evaluate the role of FYN and test whether FYN promotes migration and invasion of gastric cancer cells in vitro and in vivo via STAT3 signaling. FYN was overexpressed in gastric cancer and positively correlated with metastasis. FYN knockdown significantly decreased cancer cell migration and invasion, whereas FYN overexpression increased cancer migration and invasion. Genetic inhibition of FYN decreased the number of metastatic lung nodules in vivo. Several epithelial-mesenchymal transition markers were positively correlated with FYN expression, indicative of FYN involvement in this transition. Furthermore, gene set enrichment analysis of a Cancer Genome Atlas dataset revealed that the STAT3 signaling pathway was positively correlated with FYN expression. STAT3 inhibition reversed the FYN-mediated epithelial-mesenchymal transition and suppressed metastasis. In conclusion, FYN promotes gastric cancer metastasis possibly by activating STAT3-mediated epithelial mesenchymal transition and may be a novel therapeutic target for gastric cancer.