An age-and sex-matched postoperative therapy should be required in thyroid papillary carcinoma.

Background and purpose: Thyroid papillary carcinoma (PTC) had a high possibility of recurrence after surgery, and thyroid stimulating hormone (TSH) suppression and radioactive iodine (131I) were used for postoperative therapy. This study explored the potential mechanism of lymph node metastasis (LNM) and aimed to develop differentiated treatments for PTC. Method: This study explored the risk factors of lymph node metastasis in PTC by analyzing the clinical information of 2073 cases. The Cancer Genome Atlas Thyroid Cancer (TCGA-THCA) and the Gene Expression Omnibus (GEO) databases of gene expression were analyzed to identify the interrelationships between gene expression to phenotype. Results: Analyzing clinical data, we found that male gender, younger age, larger tumor size, and extra-thyroidal extension (ETE) were risk significant risk factors for lymph node metastasis(P<0.05). Conversely, thyroid function parameters such as TSH, FT3, FT4, TSH/FT3, and TSH/FT4 didn't correlate with LNM(P>0.05), and TSH levels were observed to be higher in females(P<0.05). Gene expression analysis revealed that SLC5A5 was down-regulated in males, younger individuals, and those with lymph node metastasis, and a lower level of SLC5A5 was associated with a worse disease-free survival(P<0.05). Additionally, our examination of single-cell RNA sequencing (scRNA-seq) data indicated that SLC5A5 expression was reduced in tumors and lymph node metastasis samples, correlating positively with the expression of TSHR. Conclusion: The impact of TSH on PTC behavior remained unclear, while the capacity for absorbing 131I in dependence on SLC5A5 showed variations across different genders and ages. We conclude that postoperative treatment of PTC should take into account the differences caused by gender and age.

The Sex and Age-Associated Infiltration of B Cells May Result in the Dimorphic Behaviors Observed in Papillary Thyroid Carcinomas.

Background and Purpose: Sex and age show a dimorphism role in the pathogenesis, lymph node metastasis, and prognostic outcomes of papillary thyroid carcinoma. This investigation endeavors to elucidate the mechanisms underlying these disparities. Methods: The clinicopathological characteristics and risk factors of lymph node metastasis were explored by analyzing the 2261 patients. The gene expression information of 497 samples from The Cancer Genome Atlas Thyroid Cancer database was used to explore the differentially expressed genes in different phenotypes. What's more, the single-cell RNA sequencing data obtained from the Gene Expression Omnibus database was used to explore the gene expression in specific cells. Results: Multivariate logistic regression analysis showed that in male patients, a larger tumor size, extrathyroidal extension, younger age, and the presence of calcification emerged as significant predictors for lymph node metastasis (LNM)(p < 0.05). Conversely, female patients exhibited a different profile, with larger tumor size, extrathyroidal extension, younger age, calcification, and bilateral tumors being identified as key risk factors (p < 0.05). Further stratification by age demonstrated distinct patterns: among the younger cohort, a larger tumor size, extrathyroidal extension, male gender, calcification, multifocality, and the presence of Hashimoto's thyroiditis held statistical significance (p < 0.05). In contrast, the older subgroup was characterized by a larger tumor size, extrathyroidal extension, male gender, calcification, bilateral tumors, and unclear margins as salient indicators of risk (p < 0.05). In the bulk gene analysis, there were two sex-age-related differentially expressed genes with a contrary trend in tissue sources and LNM status: TCL1A and CR2. The analysis of single-cell RNA sequencing showed that the infiltration of TCL1A- and CR2-related B cells varied in different clinical subtypes. Conclusion: Lymph node metastasis of papillary thyroid carcinoma in different sexes and ages may have distinct patterns, and the ages-sex-related B cell infiltration might explain the dimorphism biological behavior.

Long non­coding RNAs in gallbladder cancer: From mechanisms to therapeutic opportunities (Review).

Due to the lack of specific symptoms, characteristic diagnostic markers and effective comprehensive treatment, gallbladder cancer (GBC) is currently considered one of the most malignant abdominal tumors. With the rapid development of biological technologies, long non­coding RNAs (lncRNAs), once regarded as transcriptional junk, have been demonstrated to participate in almost the whole process of the central dogma of molecular biology. The central dogma deals with the transfer of sequential information at the level of individual residues. LncRNAs have an effect on multiple cancer types. However, evidence of dysregulated lncRNA functions in GBC is limited. In the present review, the regulatory mechanisms of lncRNA function on gene expression were examined, including epigenetic modification, transcriptional regulation and post­translational modulation. These mechanisms are strongly associated with tumor development and metastasis. Next, it was summarized how lncRNAs affect GBC diverse malignant phenotypes through various mechanisms. Moreover, predictions of lncRNA interactions with other functional molecules in malignancies were made using several valuable databases, including crosstalk between lncRNA and DNA, mRNA, microRNA, and protein. Additionally, several potential therapeutic methods targeting pathological lncRNAs in tumors were identified. Finally, perspectives about lncRNA research and applications in GBC were presented in the current study, including viewpoints of coding potential of lncRNAs and feasible usage of micropeptides encoded by lncRNAs; roles of lncRNAs in tumor cell metabolic reprogramming and tumor microenvironment; and function of lncRNAs as possible biomarkers and therapeutic targets for improving GBC diagnosis, treatment and prognosis.

PEX13 is a potential immunotherapeutic indicator and prognostic biomarker for various tumors including PAAD.

The peroxisome serves a significant role in the occurrence and development of cancers. Specifically, the peroxisomal biogenesis factor 13 (PEX13) is crucial to the occurrence of peroxisomes. However, the biological function of PEX13 in cancers remains unclear. To address this, various portals and databases such as The Cancer Genome Atlas Program, The Genotype-Tissue Expression project, the Gene Expression Profiling Interactive Analysis 2, cBioPortal, the Genomic Identification of Significant Targets In Cancer 2.0, Tumor Immune Estimation Resource 2, SangerBox, LinkedOmics, DAVID and STRING were applied to extract and analyze PEX13 data in tumors. The correlations between PEX13 and prognosis, genetic alterations, PEX13-related gene enrichment analysis, weighted gene co-expression network analysis (WGCNA), protein interaction, long non-coding (lnc)RNA/circular (circ)RNA-micro (mi)RNA network and tumor immunity were explored in various tumors. The lncRNA-miRNA-PEX13 and circRNA-miRNA-PEX13 regulatory networks were identified via miRabel, miRDB, TargetScan and ENCORI portals and Cytoscape tool. In vitro assays were applied to verify the biological functions of PEX13 in pancreatic adenocarcinoma (PAAD) cells. The findings revealed that PEX13 is upregulated in various tumors and high PEX13 mRNA expression is associated with poor prognosis in patients with multiple cancers. Genetic alterations in PEX13 such as amplification, mutation and deep deletion have been found in multiple cancers. PEX13-related genes were associated with T cell receptor, signaling pathway and hippo signaling pathway through 'biological process' subontology of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Through WGCNA analysis, it was discovered that PEX13 hub genes were mainly enriched in the Rap1, ErbB and AMPK signaling pathways in PAAD. Immune analysis showed that PEX13 was significantly related to tumor infiltration immune cells, immune checkpoint genes, microsatellite instability, TMB and tumor purity in a variety of tumors. Cell Counting Kit-8, wound healing, Transwell and colony formation assays displayed that PEX13 knockdown could suppress PAAD cell proliferation, migration, invasion, and colony formation in vitro, respectively. Overall, PEX13 is a potential predictor of immunotherapeutic and prognostic biomarkers in various malignant tumors, including ACC, KICH, LGG, LIHC and PAAD.

The role of molecular subtypes and immune infiltration characteristics based on disulfidptosis-associated genes in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer which accounts for about 40% of all lung cancers. Early detection, risk stratification and treatment are important for improving outcomes for LUAD. Recent studies have found that abnormal accumulation of cystine and other disulfide occurs in the cell under glucose starvation, which induces disulfide stress and increases the content of disulfide bond in actin cytoskeleton, resulting in cell death, which is defined as disulfidptosis. Because the study of disulfidptosis is in its infancy, its role in disease progression is still unclear. In this study, we detected the expression and mutation of disulfidptosis genes in LUAD using a public database. Clustering analysis based on disulfidptosis gene was performed and differential genes of disulfidptosis subtype were analyzed. 7 differential genes of disulfidptosis subtype were used to construct a prognostic risk model, and the causes of prognostic differences were investigated by immune-infiltration analysis, immune checkpoint analysis, and drug sensitivity analysis. qPCR was used to verify the expression of 7 key genes in lung cancer cell line (A549) and normal bronchial epithelial cell line (BEAS-2B). Since G6PD had the highest risk factor of lung cancer, we further verified the protein expression of G6PD in lung cancer cells by western blot, and confirmed through colony formation experiment that interference with G6PD was able to significantly inhibit the proliferation ability of lung cancer cells. Our results provide evidence for the role of disulfidptosis in LUAD and provide new ideas for individualized precision therapy of LUAD.

Construction of a pancreatic cancer prediction model for oxidative stress-related lncRNA.

Long non-coding RNAs (lncRNAs) may play a role in oxidative stress by altering the tumor microenvironment, thereby affecting pancreatic cancer progression. There is currently limited information on oxidative stress-related lncRNAs as novel prognostic markers of pancreatic cancer. Gene expression and clinical data of patients with pancreatic cancer were downloaded from The Cancer Genome Atlas (TCGA-PAAD) and the International Cancer Genome Consortium (ICGC-PACA) database. A weighted gene co-expression network analysis (WGCNA) was constructed to identify genes that were differentially expressed between normal and tumor samples. Based on the TCGA-PAAD cohort, a prediction model was established using lasso regression and Cox regression. The TCGA-PAAD and ICGC-PACA cohorts were used for internal and external validation, respectively. Furthermore, a nomogram based on clinical characteristics was used to predict mortality of patients. Differences in mutational status and tumor-infiltrating immune cells between risk subgroups were also explored and model-based lncRNAs were analyzed for potential immune-related therapeutic drugs. A prediction model for 6-lncRNA was established using lasso regression and Cox regression. Kaplan-Meier survival curves and receiver operating characteristic (ROC) curves indicated that patients with lower risk scores had a better prognosis. Combined with Cox regression analysis of clinical features, risk score was an independent factor predicting overall survival of patients with pancreatic cancer in both the TCGA-PAAD and ICGC-PACA cohorts. Mutation status and immune-related analysis indicated that the high-risk group had a significantly higher gene mutation rate and a higher possibility of immune escape, respectively. Furthermore, the model genes showed a strong correlation with immune-related therapeutic drugs. A pancreatic cancer prediction model based on oxidative stress-related lncRNA was established, which may be used as a biomarker related to the prognosis of pancreatic cancer to evaluate the prognosis of pancreatic cancer patients.

Cellular senescence-related long noncoding ribonucleic acids: Predicting prognosis in hepatocellular carcinoma.

BACKGROUND: Due to their inherent role in cell function, long non-coding ribonucleic acids (lncRNAs) mediate changes in the microenvironment, and thereby participate in the development of cellular senescence. AIMS: This study aimed to identify cellular senescence-related lncRNAs that could predict the prognosis of liver cancer. METHODS AND RESULTS: Gene expression and clinical data were downloaded from the UCSC Xena platform, ICGC, and TCGA databases. Cox regression and LASSO regression were used to establish a cellular senescence-related lncRNA model. ROC curves and Kaplan-Meier survival curves were then constructed to predict patient prognosis. Cox regression analysis and clinical characteristics were used to evaluate the capability of the model. Tumor mutational burden and tumor-infiltrating immune cell analyses were subsequently performed in the risk subgroups and the samples in the entire cohort were reclustered. Finally, potential small molecule immune-targeted drugs were identified based on the model. The cellular senescence-related prognostic model that was constructed based on AGAP11 and FAM182B. Along with the results of Cox regression and Lasso regression, the risk score was found to be an independent factor for predicting overall survival in cohorts. In the subgroup analysis, the prognosis of the low-risk group in each cohort was significantly higher than that of the high-risk group; the area under temporal ROC curves and clinical ROC curves were all greater than 0.65, respectively. C-index shows that the risk scores are greater than 0.6, showing the stability of the model. The high-risk group demonstrated lower tumor microenvironment and higher tumor mutational burden scores, further verifying the reliability of the model grouping results. Analysis of tumor-infiltrating immune cells indicated that CD8+ and γδ T cells were more abundant among patients in the low-risk group; cluster reorganization indicated that the two groups had different prognoses and proportions of immune cells. The p value of potential drugs predicted based on the expression of model lncRNAs were all less than .05, demonstrating the potential of model lncRNAs as therapeutic targets to some extent. CONCLUSION: A prognostic model based on cellular senescence-associated lncRNAs was established and this may be used as a potential biomarker for the prognosis assessment of liver cancer patients.

Clinical evaluation of percutaneous endovascular radiofrequency ablation for portal vein tumor thrombus: experience in 120 patients.

BACKGROUND: Portal vein tumor thrombosis (PVTT) secondary to primary liver carcinoma (PLC) is commonly associated with poor prognosis and poses great challenge. This study was to evaluate the efficacy and safety of percutaneous endovascular radiofrequency ablation (RFA) in treatment of PVTT. METHODS: Consecutive patients who were performed endovascular RFA because of PVTT in single-institution in recent 8 years were retrospectively reviewed, compared with patients who underwent only sequential transcatheter arterial chemoembolization (TACE) during the contemporary period. Patency of portal vein, complications, and overall survival (OS) were investigated. RESULTS: One hundred and 20 patients who underwent endovascular RFA and 96 patients who underwent only sequential TACE were included. No severe complications happened in both groups. Except the higher rates of severe fever and moderate pain in the study group, no difference was found in the incidence of side effects and complications. The effective rate in the study group was (78.3%, 94/120) significantly higher than the comparison group (35.4%, 34/96). The median survival time and 1-3 years cumulative survival rates in the study group were 15.7 months and 42.5%, 21.7%, 2.5%, respectively, and 11.3 months, 21.9%, 9.4%, 0 correspondingly in the comparison group, without significant difference. Type of PVTT and Child-Pugh classification of liver function were independent risk factors, and OS was significantly improved by endovascular RFA and subsequent therapy. CONCLUSION: Endovascular RFA is technically safe and feasible for unresectable PLC and PVTT to improve the prognosis and quality of life.

Novel insight into the functions of N6­methyladenosine modified lncRNAs in cancers (Review).

Emerging evidence has suggested that N6­methyladenosine (m6A) modification, a typical RNA methylation modification, controls the fate of modified transcripts and is involved in the pathogenesis of various human diseases, such as metabolic disorders, nephropathology, osteoarthritis and malignant tumours. Long noncoding RNAs (lncRNAs), transcripts of >200 nt in length, have also been indicated to be involved in various diseases by participating in processes such as epigenetic modifications, transcriptional alternations and posttranslational regulation. Recent studies revealed that lncRNAs were widely modified by m6A, which has a critical role in various cellular processes that are associated with numerous disorders, particularly human cancers. The present review first examined functions of m6A modification of lncRNAs, including changing the lncRNA structure, mediating transcriptional regulation, affecting mRNA precursor splicing, and regulating lncRNA stability and translation. Furthermore, the regulatory mechanisms of m6A­modified lncRNAs in cancers were summarized and the up­to­date detection methods and prediction tools for identifying m6A sites on lncRNAs were presented. In addition, viewpoints on potential future directions in the field were discussed, including more accurate detection methods, roles of lncRNAs­encoded micropeptides in cancers, the relationship between m6A­modified lncRNAs and the tumour microenvironment, and m6A­modified lncRNAs as potential biomarkers and therapeutic targets in human cancer.

N(6)-methyladenosine-mediated miR-380-3p maturation and upregulation promotes cancer aggressiveness in pancreatic cancer.

N(6)-methyladenosine (m6A)-modified microRNAs (miRNAs) are relevant to cancer progression. Also, although the involvement of miR-380-3p in regulating cancer progression in bladder cancer and neuroblastoma has been preliminarily explored, its role in other types of cancer, such as pancreatic cancer (PC), has not been studied. Thus, this study aimed to investigate the role of miR-380-3p in regulating PC progression. Here, through performing Real-Time qPCR, we evidenced that miR-380-3p was significantly upregulated in the clinical pancreatic cancer tissues and cells compared to their normal counterparts. Interestingly, miR-380-3p was enriched with m6A modifications, and elimination of m6A modifications by deleting METTL3 and METTL14 synergistically suppressed miR-380-3p expressions in PC cells. Next, the gain and loss-of-function experiments verified that knockdown of miR-380-3p suppressed cell proliferation, epithelial-mesenchymal transition (EMT), and tumorigenesis in PC cells in vitro and in vivo, whereas miR-380-3p overexpression had opposite effects. Furthermore, the underlying mechanisms were uncovered, and our data suggested that miR-380-3p targeted the 3' untranslated regions (3'UTRs) of PTEN for its inhibition and degradation, resulting in the activation of the downstream Akt signal pathway. Moreover, the rescuing experiments validated that both PTEN overexpression and Akt pathway inhibitor LY294002 abrogated the promoting effects of miR-380-3p overexpression on cancer aggressiveness in PC cells. Collectively, this study firstly investigated the role of the m6A-associated miR-380-3p/PTEN/Akt pathway in regulating PC progression, which provided novel therapeutic and diagnostic biomarkers for this cancer.

Design and synthesis of ludartin derivatives as potential anticancer agents against hepatocellular carcinoma.

Our previous study demonstrated that guaiane-type sesquiterpenoid ludartin showed potent antihepatoma activity against two human hepatocellular carcinoma cell lines, HepG2 and Huh7, with IC50 values of 32.7 and 34.3 µM, respectively. In this study, 34 ludartin derivatives were designed, synthesized and evaluated for their cytotoxic activities against HepG2 and Huh7 cell lines using an MTT assay in vitro. As a result, 17 compounds increased the activity against HepG2 cells, and 20 compounds enhanced the activity against Huh7 cells; 14 derivatives 2, 4-7, 9, 11, 17, 24, 28-30 and 32-33 were superior to ludartin on both HepG2 and Huh7 cells. In particular, dimeric derivative 33 as the most active compound showed 20-fold and 17-fold enhancement of cytotoxicity against HepG2 and Huh7 cells compared to that of ludartin. These results suggested that compound 33 could serve as a promising lead compound against liver cancer. Graphical abstract.

Identification of molecular heterogeneity of hepatocellular carcinoma based on immune gene expression signatures.

Although various molecular subtypes of hepatocellular carcinoma (HCC) have been investigated, most of these studies identify HCC subtype based on genomic profiling. Few studies have investigated the classification based on immune signatures, and none have classified HCC based on Immune activation and immunosuppressive. We performed immune gene expression of tumor tissue in 374 HCC patients from The Cancer Genome Atlas (TCGA) database and used unsupervised consensus clustering to stratify tumors. We then used HCC patients from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) as replication datasets. Based on the expression of 782 immune-related genes, HCC was stratified into four distinct immune subtypes. Tumors in one cluster (high immune activation; high-IA) indicate a higher level of Immune activation, which was characterized by higher anti-tumor immunity, higher pro-tumor immune-suppressive cell types, higher fractions of CD8+ T cells and M0 Macrophages compared with other subtypes. The high-IA also presents higher cancer-related hallmark signatures, such as epithelial-mesenchymal transition (EMT), angiogenesis, and apoptosis. We also found subpopulations of regulatory and exhaustion T lymphocyte were characterized by an opposite trend in high-IA, though samples in high-IA response to immunotherapy with better survival. The comparison of the immune profile in tumor and normal tissue indicates the activation of immune responses which only occurred in high-IA patients, while we conducted comparison of cirrhosis and non-cirrhosis tumor immune signatures, immune response activation was almost occurred in high-IA, but some of immune responses occurred in low-IA (low immune activation).

Emerging role of RNA modification N6-methyladenosine in immune evasion.

The innate and adaptive immune cells have complex signaling pathways for sensing and initiating immune responses against disease. These pathways are interrupted at different levels to occur immune evasion, including by N6-methyladenosine (m6A) modification. In this review, we discuss studies revealing the immune evasion mechanism by m6A modification, which underlies the retouching of these signaling networks and the rapid tolerance of innate and adaptive immune molecules during disease. We also focus on the functions of m6A in main chemokines regulation, and their roles in promotive and suppressive immune cell recruitment. We then discuss some of the current challenges in the field and describe future directions for the immunological mechanisms of m6A modification.

Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy.

Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.

Comparable prevalence of distant metastasis and survival of different primary site for LN + pancreatic tumor.

BACKGROUND: Few studies have delved into the prevalence of distant metastasis (DM +) and survival for patients with lymph node metastases (LN +) by primary site. We aimed to detect differences in distant metastasis and prognosis between pancreatic head and bodytail tumors for LN + patients. METHODS: Patients with chemotherapy, histologically diagnosed, primary site between 2004 and 2016 were included from the SEER (Surveillance, Epidemiology, and End Results) database. Pancreatic head tumors were compared with pancreatic bodytail tumors using the odds ratio (OR) for rates of distant metastasis, hazard ratios (HR) for overall survival (OS) and cancer-specific survival (CSS). The competing risk model and propensity score matching (PSM) were performed to further explore. RESULTS: Of 5726 LN + patients identified from the SEER database, pancreatic head tumors account for 85.2% (4877 of 5726) and 14.8% (849 of 5726) were pancreatic bodytail tumors. The incidence of DM was lower in pancreatic head than in pancreatic bodytail tumors (OR, 0.29; 95% CI 0.23-0.37; P < 0.001). The multivariate Cox regression show pancreatic head tumors have a significantly shorter survival rate relative to pancreatic bodytail (HR, 1.12; 95% CI 1.03-1.22; P = 0.008), but the primary site was not a significant independent risk factor for prognosis by log-rank test (P = 0.39) and multivariate competing risk model [subdistribution HR (SHR), 1.08; 95% CI 0.98-1.19; P = 0.087].We then examined our conclusion by 1:1 propensity score matching, and the result reflected pancreatic head tumors have a lower risk of DM compared with pancreatic bodytail tumors (OR, 0.22; 95% CI 0.15-0.34; P < 0.001), but the primary site of pancreatic tumors was not associated with LN + patient survival based on univariate Cox regression (HR, 1.04; 95% CI 0.93-1.17; P = 0.435) and competing risk analysis (SHR, 1.01; 95% CI 0.89-1.12; P = 0.947). CONCLUSIONS: LN + pancreatic head tumors were significantly lower risk of DM relative to pancreatic bodytail tumors. Survival outcome in LN + pancreatic tumors didn't exist significant differences split by primary site, which indicates that the prognosis of LN + patients with chemotherapy isn't associated with the primary site of metastasis, but with the occurrence of metastasis.

Aspirin use and pancreatic cancer risk: A systematic review of observational studies.

OBJECTIVES: Although there is evidence that aspirin might be able to prevent pancreatic cancer, the findings have been inconsistent. In this paper, we conducted a meta-analysis of observational studies to examine the relationship between aspirin use and the risk of pancreatic cancer. METHODS: We identified potential studies by searching the MEDLINE, EMBASE, and Wangfang (Chinese database) database (from 1967 to March 2017) and by reviewing the bibliography of relevant publications. Random effects model was used to calculate odds ratio (OR) and 95% confidence interval. The Cochran Q statistic (significance level at P < .1) was used to assess heterogeneity in this study. The author adopted weighted regression method of Egger to assessed publication bias. RESULTS: A total of 12 studies involving 4748 pancreatic cancer cases, were included in the meta-analysis. The study reflected that there was no signification association between aspirin use and mortality risk of pancreatic cancer. Aspirin use might reduce the incidence of pancreatic cancer. Specifically, there was a high signification association between frequent aspirin use and reduced pancreatic cancer incidence, without heterogeneity. In addition, there was a high signification association between duration of aspirin use more than 5 years and reduced pancreatic cancer incidence, without obvious heterogeneity among the original studies. CONCLUSIONS: In summary, this meta-analysis suggested that the aspirin use might be negatively related to the incidence risk of pancreatic cancer. Specifically, the frequency and duration of aspirin use might play an important role in decreasing the incidence of pancreatic cancer.

Downregulation of miR-21 inhibits the malignant phenotype of pancreatic cancer cells by targeting VHL.

BACKGROUND: MicroRNA (miR)-21 is overexpressed in numerous types of malignancy and participates in the development of cancer. However, the basic mechanism of the influence of miR-21 on the malignant phenotype of pancreatic cancer remains unclear. PURPOSE: The present study aimed to investigate the role of miR-21 in pancreatic cancer development and explore its molecular mechanism. PATIENTS AND METHODS: The tissue samples were collected at the Second Hospital of Tianjin Medical University (Tianjin, China) between January 2013 and December 2015. The expression of VHL in tissue samples was evaluated by IHC staining. The expression of miR-21 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). MiR-21 target gene was detected by real-time PCR, Western blot and the luciferase reporter assay. Cell viability, cell proliferation, cell migration and invasion were evaluated by the MTT assays, the colony formation assays and the transwell assays. The nude mouse tumor xenograft model was performed to detect the effect of miR-21 on tumor growth in vivo. RESULTS: Von Hippel-Lindau tumor suppressor (VHL) was downregulated in pancreatic cancer tissues compared with pancreatic non-tumor tissues. VHL was identified as a novel direct target of miR-21, by which it is negatively regulated. In PANC-1 cells, inhibition of miR-21 and upregulation of VHL significantly suppressed cell proliferation, migration and invasion. Knockdown of miR-21 inhibited the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway, while inhibiting the expression of matrix metallopeptidase (MMP)-2 and MMP-9. Silencing of miR-21 inhibited tumor growth in vivo. CONCLUSION: Knockdown miR-21 increased the expression of VHL, and thus modulated the HIF-1α/VEGF pathway and the expression of MMP-2 and MMP-9, which led to the inhibition of the proliferation, migration and invasion of pancreatic cancer cells. All of these results suggest that the miR-21/VHL interaction may be a novel potential target for pancreatic cancer prevention and therapy.

Comprehensive analysis of five long noncoding RNAs expression as competing endogenous RNAs in regulating hepatoma carcinoma.

Liver cancer is the most common cancer and is the epitome of a recalcitrant cancer. Increasing evidence shown that long noncoding RNAs (lncRNA) were associated with cancer-related death and could function as a competing endogenous RNA (ceRNA). To explore regulatory roles and potential prognostic biomarkers of lncRNA for liver cancer, RNA-sequencing expression data were downloaded from the TCGA database and GEO database. A total of 357 patients were randomly divided into a discovery group and a validation group, of which 313 patients can obtain clinical data. In discovery phrase, 58 lncRNAs, 16 miRNAs, and 34 mRNAs were screened to construct the ceRNA network based on 252 patients employed from discovery group. Univariate and multivariate Cox hazard regression analysis model revealed that five lncRNAs (AATK-AS1, C10orf91, LINC00162, LINC00200, and LINC00501) from 58 lncRNAs were formulated to predict the overall survival (OS). We used the value of gene expression and regression coefficients to construct a risk score based on the five lncRNAs. Next, we validated our model in the GSE116174 dataset (n = 64) and the validation group (n = 94) from TCGA database. Subgroup analysis suggest that the five lncRNAs played critical parts in early stage in cancer from both discovery and validation groups. The five lncRNAs were also found to be associated with immune cells infiltration including CD4+ memory activated, NK cells activated and mast cells activated, then the results were also validated according to the validation group. Furthermore, KEGG pathway enrichment analysis showed that these nine coexpressed modules using the method of WGCNA, and many of these pathways are associated with the development and progression of disease. At last, the transcription factor binding sites (TFBS) of the five lncRNAs were predicted, which help us to understand the potential mechanism that the TFBS adjusted the ceRNA network. In summary, the ceRNA regulatory network may contribute to a better understanding of liver cancer mechanism and provide potential prognostic biomarkers and therapeutic targets.

Efficacy of endoscopic ultrasound-guided and endoscopic retrograde cholangiopancreatography-guided biliary drainage for malignant biliary obstruction: a systematic review and meta-analysis.

INTRODUCTION: Endoscopic ultrasound-guided (EUS) biliary drainage was used as an alternative method for patients who failed endoscopic retrograde cholangiopancreatography (ERCP). In recent years, an increasing number of patients was treated with EUS-biliary drainage (BD), but lack of data was available to value the efficacy and safety between EUS and ERCP. Therefore, a review was needed to evaluate the similarities and differences between the two methods and explored whether EUS-guided biliary drainage could be considered as first-line treatment. EVIDENCE ACQUISITION: We searched the Pubmed/Medline, Embase, Web of science, Google scholar, the Cochrane Library and Clinical trials of electronic databases till October 2018 for all English language. Primary outcomes to comparison included technical success, clinical success and adverse events. Secondary outcomes consisted of stent dysfunction requiring reintervention and procedure duration, Data from selected studies were collected to calculate the odds ratios (OR) and standard mean difference (SMD). EVIDENCE SINTHESIS: We searched 469 studies and at last identified 4 eligible trials. These included a total of 428 patients, 215 in the EUS group and 213 in the ERCP group. There was no difference in technical success (OR, 0.95; 95% CI: 0.45-2.02; I2=0%), clinical success (OR, 0.87; 95% CI: 0.42-1.79; I2=0%) and adverse events between 2 procedures (OR, 0.76; 95% CI: 0.29-2.00; I2=55%) but EUS-BD consisted of lower rate of reintervention (OR, 0.30; 95% CI: 0.14-0.63; I2=0%),and fewer procedure-related adverse events in pancreatitis and cholangitis (OR, 0.14; 95% CI: 0.04-0.51; I2=0%).There was no difference in length of procedure duration, with a pooled standard mean difference of 0.26 (95% CI: -0.15 to 0.66). CONCLUSIONS: EUS-BD and ERCP-BD in terms of relief of malignant biliary obstruction presented the similarity rate of technical success, clinical success and there is no significant difference in adverse events of two procedures. EUS-BD could be used as a substitute for ERCP-BD, even considered as first-line treatment.

FOXO3a expression and its diagnostic value in pancreatic ductal adenocarcinoma.

FOXO3a (FKHRL1) is an important regulator of cell apoptosis, proliferation, metabolic state and longevity. FOXO3a expression can be measured and has been regarded as a tumor suppressor factor in many cancers. However, the expression and role of FOXO3a in PDAC have not been defined. We evaluated the expression of FOXO3a in PDAC and the relationship of its expression with clinicopathological features and patient outcomes. We found that compared with normal tissues, the expression of FOXO3a was significantly higher in tumor tissues (P<0.001). FOXO3a expression correlates significantly with tumor differentiation and with the primary location of the tumor (P<0.001 and P=0.005, respectively). In a univariate analysis, we found that FOXO3a expression has a strong relationship with survival (P=0.013). In addition, Kaplan-Meier survival curves indicated that a low expression of FOXO3a in tumor tissues has a significantly shorter OS compared with patients with high expression of FOXO3a (P=0.013). In conclusion, the expression of FOXO3a is significantly higher in PDAC compared with normal pancreatic tissues and has a low expression or negative staining in poorly differentiated PDAC, which seems to indicate that FOXO3a expression in tumor tissues may be related to the pathological progression stage and may be used as a diagnostic indicator with early tumors.