Identification of the CD8+ T-cell Related Signature for Predicting the Prognosis of Gastric Cancer Based on Integrated Analysis of Bulk and Single-cell RNA Sequencing Data.

The infiltration of CD8+ T cells in the tumor microenvironment is associated with better survival and immunotherapy response. However, their roles in gastric cancer have not been explored so far. In here, the profiles of GC gene expression were collected from The Cancer Genome Atlas database. Single-cell transcriptomic data originated from GSE134520. Cell clustering, annotation, and CD8+ T-cell differential genes were from the TISCH database. We determined 896 CD8+ T-cell differential genes by scRNA-seq analysis. After integrating immune-related genes, 174 overlapping genes were obtained and a novel risk model was subsequently built. The performance of CD8+ T-cell-associated gene signature was assessed in the training and external validation sets. The gene signature showed independent risk factors of overall survival for GC. A quantitative nomogram was built to enhance the clinical efficacy of this signature. Furthermore, low-risk individuals showed higher mutation status, higher immune checkpoint expression, low Tumour Immune Dysfunction and Exclusion (TIDE) scores, and higher IPS-PD-1 combined IPS-CTLA4 scores, indicating a greater response to immunotherapy. In addition, analysis of IMvigor210 immunotherapy cohort demonstrated that low-risk individuals had a favorable response to prognosis and immunotherapy. In conclusion, we generated a CD8+ T-cell-related signature that can serve as a promising tool for personalized prognosis prediction and guiding decisions regarding immunotherapy in GC patients.

TAB182 aggravates progression of esophageal squamous cell carcinoma by enhancing ß-catenin nuclear translocation through FHL2 dependent manner.

TAB182 (also named TNKS1BP1), a binding protein of tankyrase 1, has been found to participate in DNA repair. Our previous study has revealed the involvement of TAB182 in the radioresistance of esophageal squamous cell carcinoma (ESCC) cells. However, whether TAB182 contributes to the ESCC tumorigenesis and progression remains unclear. In this study, we found that highly expressed TAB182 is closely associated with a poor prognosis of patients with ESCC. TAB182 silencing reduced ESCC cell proliferation and invasion in vitro, tumorigenicity and metastasis in vivo. RNA-seq and IP-MS analysis revealed that TAB182 could affect the ß-catenin signaling pathway via interacting with ß-catenin. Furthermore, TAB182 prevented ß-catenin to be phosphorylated by GSK3ß and recruited four and a half of LIM-only protein 2 (FHL2), which thereby promoted ß-catenin nucleus translocation to result in activation of the downstream targets transcription in ESCC cells. Our findings demonstrate that TAB182 enhances tumorigenesis of esophageal cancer by promoting the activation of the ß-catenin signaling pathway, which provides new insights into the molecular mechanisms by which TAB182 accelerates progression of ESCC.

Integrated analysis of senescence-associated genes in pancreatic ductal adenocarcinoma.

Background: Cellular senescence plays a critical role in the occurrence and development, and immune modulation of cancer. This research primarily investigated the role of senescence-associated genes (SAGs) in the survival and tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). Methods: From the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database, the gene expression profiles and clinical data of PDAC samples were downloaded. SAGs in the TCGA cohort were used to build a novel prognostic model and validated in the ICGC cohort. The relationship of signature with the immune landscape, tumor mutational burden (TMB), as well as the sensitivity of different therapies, was explored. Moreover, a nomogram was developed to predict the overall survival of PDAC patients. Results: A prognostic signature was constructed on basis of three SAGs, and patients in the low-risk score group had a longer survival time. The accuracy of the signature to distinguish different score groups was confirmed through principal component analysis (PCA) and the Receiver operator curves curve. The mRNA expression of the three signature genes was also verified in normal pancreatic and PDAC cell lines by RT-qPCR. The signature could independently predict the prognosis of PDAC patients and had broad applicability. Meanwhile, the nomogram predicted that 1- and 3-years survival rates were in good agreement with the observed overall survival rates. Low-risk patients had lower tumor mutational burden, and low-TMB patients had a better prognosis. Low- and high-risk patients exhibit distinct immune cell infiltration and immune checkpoint changes. By further analyzing the risk score, patients in the low-risk group were more responsive to immunotherapy and a variety of commonly used chemotherapeutic drugs. Conclusion: The prognostic signature can well predict the prognosis and assess the possibility of immunotherapy in personalized PDAC treatment.

Prognostic signature based on m6A-related lncRNAs to predict overall survival in pancreatic ductal adenocarcinoma.

A growing body of evidence indicates that N6-methyladenosine (m6A) and long non-coding RNAs (lncRNAs) play crucial roles in the progression of PDAC and the treatment response of patients with pancreatic ductal adenocarcinoma (PDAC). In this study, we identified m6A-related lncRNAs to reveal their association with PDAC in prognosis and tumor immune environment. A prognostic signature based on 9 m6A-related lncRNAs was established, and the high-risk patients exhibited a significantly worse prognosis than low-risk patients. The predictive capacity was confirmed by receiver operating characteristic (ROC) curve analysis and an independent validation cohort. Correlation analyses revealed that m6A-related lncRNA signature was significantly associated with the number of somatic mutations, immunocyte infiltration, immune function, immune checkpoints, tumor microenvironment (TME) score, and sensitivity to chemotherapeutic drugs. Consequently, we constructed a highly accurate nomogram for improving clinical applicability of signature and exhibited superior predictive accuracy than both the signature and tumor stage. In conclusion, our proposed m6A-related lncRNA signature is a potential indicator predictive of prognosis and immunotherapeutic responses in PDAC patients.

Multiomic Analysis of Methylation and Transcriptome Reveals a Novel Signature in Esophageal Cancer.

BACKGROUND: Epigenetic alterations have been shown to lead to human carcinogenesis. The aim of this study was to perform an integrative analysis to develop an epigenetic signature to predict overall survival (OS) of esophageal cancer. METHODS: DNA methylation and messenger RNA expression data of esophageal cancer samples were downloaded from The Cancer Genome Atlas database and were incorporated and analyzed using an R package MethylMix. Functional enrichment analysis of the methylation-related differentially expressed genes (DEGs) was performed. Epigenetic signature and nomogram associated with the OS of esophageal cancer were established by the multivariate Cox model. RESULTS: A total of 71 methylation-related DEGs were identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that these genes were involved in the biological process related to the initiation and progression of esophageal cancer. Two-gene (FAM24B and FAM200A) risk signature for OS was developed by multivariate Cox analysis, of which had high accuracy. The signature is independent of clinicopathological variables and indicated better predictive power than other clinicopathological variables. Moreover, we developed a novel prognostic nomogram based on risk score and 3 clinicopathological factors. CONCLUSIONS: Our study indicated possible methylation-related DEGs and established an epigenetic signature, which may provide novel insights for understanding the pathogenesis of esophageal cancer.

Integrated analysis of circular RNA-associated ceRNA network in pancreatic ductal adenocarcinoma.

Circular RNAs (circRNAs) have displayed dysregulated expression in several types of cancer. However, the functions of the majority of circRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unknown. The present study aimed to investigate the expression, functions and molecular mechanisms of circRNAs in PDAC. The circRNAs, mRNAs and the microRNA (miRNAs) expression profiles were obtained from three Gene Expression Omnibus microarray datasets, and a circRNA-miRNA-mRNA and circRNA-miRNA-hubgene network was established. The interactions between proteins were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins database, and hubgenes were identified using the MCODE plugin. A total of eight differentially expressed circRNAs (DEcircRNAs), 44 differentially expressed miRNAs (DEmiRNAs), and 2,052 differentially expressed mRNAs (DEmRNAs) were identified. The present study successfully constructed a circRNA-miRNA-mRNA competing endogenous RNA (ceRNA) network based on four circRNAs, six miRNAs and 111 mRNAs in PDAC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways analyses indicated that DEmRNAs may participate in the pathogenesis and progression of PDAC. The protein-protein interaction network and module analysis identified six hubgenes (THBS1, FN1, TIMP3, TGFB2, ITGA1 and ITGA3). Furthermore, the circRNA-miRNA-hubgene regulatory modules were constructed based on the three DEcircRNAs, one DEmiRNAs and five DEmRNAs. In conclusion, the results of the present study improve the current understanding of the pathogenesis of PDAC.

Efficacy of afatinib in a HER2 amplification-positive endometrioid adenocarcinoma patient- a case report.

Afatinib has improved the prognosis of epidermal growth factor receptor-positive advanced non-small cell lung cancer and has been explored in the treatment of human epidermal growth factor receptor 2 (HER2)-amplified breast cancer. However, its clinical efficacy in HER2-amplified endometrial cancer has not been reported. Herein, we present the clinical benefit of afatinib in a case of stage IIIC endometrioid adenocarcinoma refractory to multiple lines of chemotherapy and eventually developed pulmonary, abdominal and pelvic metastasis. Upon referral to our clinic, capture-based targeted sequencing was performed on both blood and tumor samples and revealed HER2 amplification. The patient was administered with afatinib and achieved partial response (PR) after two months of treatment, reflected by a significant reduction in pulmonary lesions and serum levels of tumor markers including carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, 125, 15-3 and cytokeratin 19 fragment antigen 21-1 (CY211). The patient passed away after 3 months of afatinib treatment due to suspected complications of severe intestinal obstruction. Our report demonstrates the efficacy of afatinib in a heavily pre-treated HER2-amplified endometrial cancer patient with multi-organ metastasis. This case also highlights the need to include comprehensive mutational profiling in the standard management of endometrial cancer patients for treatment guidance.

Comprehensive analysis of long noncoding RNA-associated competing endogenous RNA network in cholangiocarcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) as a competing endogenous RNA (ceRNA) to regulate the expression of target genes, which can largely influence on tumorigenesis and tumor progression. However, the role of lncRNA-mediated ceRNAs in cholangiocarcinoma (CCA) remains unknown. This study aimed to develop novel lncRNAs as well as their action mechanisms in CCA. METHODS: The expression profiles of lncRNAs, miRNAs, and mRNAs of 36 CCA tissues and 9 non-tumor bile duct tissues were obtained from The Cancer Genome Atlas (TCGA) database. The differentially expressed RNAs werre identified using the DESeq package in R. The ceRNA network was constructed in CCA based on bioinformatics generated from miRcode, miRTarBase, miRDB, and TargetScan. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using "DAVID 6.8" and R packages "Clusterprofile". Survival analysis was performed based on Kaplan-Meier curve analysis. RESULTS: We identified a total of 1411 differentially expressed lncRNAs, 3494 mRNAs, and 64 miRNAs between CCA and matched normal tissues. By combining the data predicted by databases with intersection RNAs, a lncRNA-miRNA-mRNA ceRNA network consisting of 116 lncRNAs, 14 miRNAs and 59 mRNAs was established. According to the survival analysis, we detected 11 DElncRNA to have a significant impact on the overall survival in patients with CCA (P < 0.05). CONCLUSIONS: Our study identified novel lncRNAs associated with CCA progression and prognosis and provided data to further understand lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of CCA.

Development and validation of a nomogram for predicting survival in patients with gastrointestinal stromal tumours.

BACKGROUND: This study aimed to develop and validate nomograms for predicting long-term overall survival (OS) and cancer-specific survival (CSS) in gastrointestinal stromal tumours (GISTs). METHODS: Patients diagnosed with GISTs between 2004 and 2015 were selected for the study from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were randomly separated into the training set and the validation set. Multivariate analysis was used on the training set to obtain independent prognostic factors to build nomograms for predicting 3- and 5-year OS and CSS. The discrimination and calibration plots were used to evaluate the predictive accuracy of the nomograms. RESULTS: Data for a total of 5622 patients with GISTs were collected from the SEER database. Nomograms were established based on variables that were significantly associated with OS and CSS identified by the Cox regression model. The nomograms for predicting OS and CSS displayed better discrimination power than did the SEER stage and Tumour-Node-Metastasis (TNM) staging systems (7th edition) in the training set and validation set. Calibration plots of the nomograms indicated that OS and CSS closely corresponded to actual observation. CONCLUSIONS: The nomograms were able to more accurately predict 3- and 5-year OS and CSS of patients with GISTs than were existing models.

Development and Validation of a Nomogram for Predicting Overall Survival in Pancreatic NeuroendocrineTumors.

BACKGROUND: The objective of current study was to develop and validate a nomogram to predict overall survival in pancreatic neuroendocrine tumors (PNETs). METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for patients with PNETs between 2004 and 2015. Patients were randomly separated into the training set and the validation set. Cox regression model was used in training set to obtain independent prognostic factors to develop a nomogram for predicting overall survival (OS). The discrimination and calibration plots were used to evaluate the predictive accuracy of the nomogram. RESULTS: A total of 3142 patients with PNETs were collected from the SEER database. Sex, age, marital status, primary site, TNM stage, tumor grade, and therapy were associated with OS in the multivariate models. A nomogram was constructed based on these variables. The nomogram for predicting OS displayed better discrimination power than the Tumor-Node-Metastasis (TNM) stage systems 7th edition in the training set and validation set. The calibration curve indicated that the nomogram was able to accurately predict 3- and 5-year OS. CONCLUSIONS: The nomogram which could predict 3- and 5-year OS were established in this study. Our nomogram showed a good performance, suggesting that it could be served as an effective tool for prognostic evaluation of patients with PNETs.

A nomogram to predict overall survival for biliary tract cancer.

BACKGROUND: The aim of the study was to develop and validate a nomogram to predict overall survival (OS) in biliary tract cancer (BTC). PATIENTS AND METHODS: Patients diagnosed with BTC between 2004 and 2014 were selected for the study from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to 2 sets, the training set (n = 8,869) and the validation set (n = 8,766), for the purposes of validation. The prognostic effects of each variable were examined using univariate and multivariate analyses. Cox regression models and a nomogram were developed based on significant prognostic factors. The predictive and discriminatory capacity of the nomogram was evaluated by Harrell's concordance index (C-index) and calibration plots. RESULTS: Data of 17,635 patients with BTC were collected from the SEER database. Age; race; tumor site; tumor grade; T, N, and M stage; marital status; and therapy were associated with survival in the multivariate models. All these factors were integrated to construct the nomogram. The nomogram for predicting OS displayed better discrimination power than the tumor-node-metastasis (TNM) stage system 6th edition in the training set and validation set. The calibration curve indicated that the nomogram was able to accurately predict 3- and 5-year OS. CONCLUSION: This predictive model has the potential to provide an individualized risk estimate of survival in patients with BTC.

Survival rates are higher in married patients with biliary tract cancer: a population-based study.

Marital status has been identified as a prognostic factor in multiple malignancies. In this study, we assessed the prognostic value of marital status in 24,035 patients from the Surveillance, Epidemiology, and End Results database diagnosed with biliary tract cancer (BTC) between 2004 and 2014. Widowed patients were more likely to be women, elderly (> 60 years), have gallbladder cancer, and have localized SEER Stage disease than all other patients. Marital status was identified as an independent prognostic factor in both univariate and multivariate analyses, and cause-specific survival (CSS) rates were higher in married patients than unmarried patients. In addition, CSS rates were higher in ampulla of Vater cancer patients than in gallbladder cancer or cholangiocarcinoma patients. Further analysis revealed that CSS rates were lowest in widowed patients at each TNM stage and for all tumor sites. These results suggest marital status is a prognostic factor for clinical outcomes in patients with BTC, and widowed patients are at greater risk of cancer-specific mortality.

Nomogram for predicting survival in patients with pancreatic cancer.

BACKGROUND: The purpose of this study was to develop a nomogram to predict cancer-specific survival (CSS) in pancreatic cancer (PC). PATIENTS AND METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) database to analyze 53,028 patients diagnosed with PC from 2004 to 2014 and randomly divided them into the training (n=26,583) cohort and validation (n=26,445) cohort. Univariate and multivariate analyses were used to select independent prognostic factors. We used significant prognostic factors for constructing a nomogram based on Cox regression analyses. Validation of the nomogram was assessed by discrimination and calibration. RESULTS: According to the multivariate models of training cohort, a nomogram that combined age, race, tumor location, marital status, tumor size, TNM stage, tumor grade, and surgery was constructed for predicting CSS. The internally validated and externally validated C-indexes were 0.741 and 0.734, respectively. The calibration curves showed that the nomogram was able to predict 1-, 3-, and 5-year CSS accurately. CONCLUSION: A nomogram effectively predicts survival in patients with PC. This prognostic model may be considered for use in clinical practice.

Changes of Th1/Th2 cytokines in patients with primary hepatocellular carcinoma after ultrasound-guided ablation.

Liver cancer is a malignancy of the digestive system and has a high morbidity and mortality rate. Local intervention has become a viable option in identifying liver treatment. The aim of the present study was to analyze the changes of Th1/Th2 cytokines in patients with primary hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA) treatment. 26 patients with stage III-IV liver cancers and 25 healthy controls were selected to participate in the study. HCC patients were initiated with RFA treatment and the serum levels of alpha fetoprotein (AFP) and Th1/Th2 cytokines were valued. We found that with the level of AFP decreased, the levels of Th1 cytokines including interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were significantly increased after treatment with RFA (P<0.05). Meanwhile, the levels of Th2 cytokines consist of interleukin-4 (IL-4), IL-6 and IL-10 were decreased markedly on the contrary, and the differences were statistically significant (P<0.05). In conclusion, the levels of Th1/Th2 cytokines were correlated with the change of AFP in patients of HCC after treatment with RFA, which might be an important guiding significance for the prognosis of HCC.