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Chemoresistance has limited clinical treatment of cancer patients. This study aimed to research the regulatory function of circ_0003998 in 5-Fluorouracil (5-FU) resistance. Circ_0003998, microRNA-513a-5p (miR-513a-5p) and AMPK-Related Protein Kinase 5 (ARK5) levels were assayed via the quantitative reverse transcription-PCR. Colony formation ability was assessed by colony formation assay. Flow cytometry was performed for cell cycle and cell apoptosis analysis. Caspase-3 activity was detected using a caspase-3 activity assay. Target analysis was conducted via RNA pull-down assay, a dual-luciferase reporter assay, and an RNA immunoprecipitation assay. In-vivo assay was performed by establishing a xenograft model in mice. Circ_0003998 was upregulated in 5-FU-resistant hepatocellular carcinoma (HCC) tissues and cells. Circ_0003998 downregulation repressed 5-FU resistance and cancer progression in 5-FU-resistant HCC cells. Circ_0003998 interacted with miR-513a-5p. Inhibition of miR-513a-5p reversed the regulation of sh-circ_0003998 in 5-FU resistance. ARK5 was a target of miR-513a-5p, and ARK5 was regulated by circ_0003998 via targeting miR-513a-5p. Circ_0003998 regulated 5-FU resistance partly by upregulating ARK5 expression. 5-FU sensitivity was enhanced after circ_0003998 level reduction in vivo. These findings unraveled that circ_0003998 elevated 5-FU resistance in HCC by sponging miR-513a-5p to upregulate the level of ARK5, indicating that circ_0003998 might be used as a target to improve 5-FU therapy for HCC.

Phosphatidylinositol 3-kinase (PI3K)/AKT signaling is a crucial pathway for cell survival and proliferation, which are regulated by several growth factors and activated receptors. Upregulated PI3K/AKT signaling molecules were reported in several cancers and they are associated with altered cellular functions, leading to oncogenesis. Here, we have examined the implications of elevated PI3K/AKT expression in the apoptosis resistance of human hepatocellular carcinoma (HCC) Huh7 cells. We showed that PI3K/AKT signaling is significantly upregulated in Huh7 cells by quantitative polymerase chain reaction and protein expression analysis. Also, perversely upregulated PI3K/AKT signaling Huh7 cells are highly resistant to treatment with chemotherapy drugs (docetaxel and sorafenib) and acquired apoptosis resistance through downregulation of tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome ten). Hence, we have investigated the effect of PTEN overexpression on apoptosis induction in Huh7 cells. We showed that PTEN overexpressed Huh7 cells became more sensitive toward the aforesaid drugs and induced apoptotic cell death due to intracellular reactive oxygen species (ROS) generation. Concurrently, the overexpression of PTEN leads to the activation of mitochondria facilitated intrinsic apoptosis, evidenced by upregulated cytochrome C, caspase 3, and caspase 9. Collectively, our data suggest that the aberrant expression of PI3K/AKT signaling contributes to apoptosis resistance in HCC.

Esophageal squamous cell carcinoma (ESCC) is malignant cancer with a high mortality rate. Cisplatin is one of the most potent chemotherapy agents used in the treatment of ESCC. However, chemoresistance and severe adverse effects of cisplatin become major obstacles to clinical utility. The combination treatment with molecule-targeted drugs and chemotherapy agents is a promising treatment strategy for cancer to improve antineoplastic responses. VX-680 is a potent inhibitor of Aurora kinases. This study was performed to investigate if VX-680 and cisplatin can synergistically inhibit the malignant behavior of ESCC cells. The results obtained from 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide assay and combination index analysis demonstrated that the combination of VX-680 and cisplatin synergistically enhanced cytotoxic effects in ESCC cells. 2-(4-Amidinophenyl)-6-indolecarbamidine dihydrochloride staining and western blot analysis suggested that VX-680 increased cisplatin-mediated cell apoptosis. Further analysis revealed that VX-680 combined with cisplatin could attenuate cell migration and angiogenesis confirmed by wound-healing assay and tube formation assay. Subsequently, VX-680 and cisplatin combined treatment significantly promoted cell-cell cohesion, and reduced cell-extracellular matrix interaction, as analyzed by the cell dissociation assay and cell-matrix attachment assay. In addition, the combination of VX-680 and cisplatin markedly decreased the expressions of matrix metalloproteinases-2 (MMP-2), vascular endothelial growth factor (VEGF), p-extracellular signal-regulated protein kinase and p-RAC-α serine/threonine-protein kinase compared to VX-680 or cisplatin only treatment. Altogether, these findings strongly suggest that the combination of VX-680 and cisplatin could exert a synergistic antitumor effect in ESCC cells and this combination might represent a promising therapeutic strategy against ESCC.

Background and Aims Programmed cell death-1 (PD-1) plays an important role in downregulating T lymphocytes but the mechanisms are still poorly understood. This study aimed to explore the role of PD-1 in CD8+ T lymphocyte dysfunction in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). Methods Thirty patients with HBV-ACLF and 30 healthy controls (HCs) were recruited. The differences in the numbers and functions of CD8+ T lymphocytes, PD-1 and glucose transporter-1 (Glut1) expression from the peripheral blood of patients with HBV-ACLF and HCs were analyzed. In vitro, the CD8+ T lymphocytes from HCs were cultured (HC group) and the CD8+ T lymphocytes from ACLF patients were cultured with PD-L1-IgG (ACLF+PD-1 group) or IgG (ACLF group). The numbers and functions of CD8+ T lymphocytes, PD-1 expression, glycogen uptake capacity, and Glut1, hexokinase-2 (HK2), and pyruvate kinase (PKM2) expression were analyzed among the HC group, ACLF group and ACLF+ PD-1group. Results The absolute numbers of CD8+ T lymphocytes in the peripheral blood from patients with HBV-ACLF were lower than in the HCs (p

Liver cancer will continue to be a major disease threatening the lives and health of our people in the next few decades. In recent years, with the development of early diagnosis and treatment of liver cancer, precise liver resection, and the development of targeted and immunotherapeutic drugs, the survival rate of liver cancer patients has been improved. Nevertheless, due to the high heterogeneity of liver cancer, patients with liver cancer in the same clinical stage still have great differences in response to treatment and prognosis. New staging and classification indicators are urgently needed to facilitate accurate diagnosis and treatment of liver cancer, so as to further improve the survival rate of patients. The continuous progress and development of multi-omics technology, single-cell technology, tumor molecular visualization technology and medical artificial intelligence, etc., make the molecular classification of liver cancer more and more approaching the true nature of tumor biological characteristics, thus contributing to the accurate diagnosis and treatment of liver cancer.

The carbon catabolite repressor 4-negative on TATA (CCR4-NOT) complex, abbreviated CNOT, has deadenylation and 3'-5' exonuclease activity, mediates deadenylation in the degradation of RNA, initiates the exonuclease degradation pathway, and participates in tumor gene regulation. CNOT proteins comprise a family of global transcriptional regulators that are evolutionarily conserved in eukaryotic cells. Several subunit types of the CNOT complex have been discovered; however, little is known about the role of different subunits in tumorigenesis and development. We observed overexpression of CNOT1-11 in liver cancer and correlations with clinicopathological characteristics. The expression of some CNOTs subunits was associated with histological grades, lymph node metastasis, and tumor stages in patients with hepatocellular carcinoma (HCC). Our data suggested that some CNOTs can be used as predictors of poor prognosis in HCC patients. At the same time, we conducted an analysis of CNOTs mutations in HCC patients. Moreover, we selected CNOT6, CNOT10, and CNOT11 for protein interaction network analysis and Gene Ontology enrichment analysis to investigate their related biological processes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Finally, the results of western blot and quantitative reverse transcription-PCR (qRT-PCR) experiments were consistent with the database findings. Results of this study suggest that CNOT6, CNOT10, and CNOT11, acting as regulators of transcription, may play an important role in the development of HCC and may serve as biological markers in the diagnosis and prognosis of HCC.

The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34(+) HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (mitoROS) during ex vivo culturing. Using single-cell RNA-Seq analysis of the mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the adhesion GPCR G1–positive (ADGRG1(+)) population of CD34(+)CD133(+) CB cells upon ex vivo expansion stress. Gene set enrichment analysis revealed that HSC signature genes including MSI2 and MLLT3 were enriched in CD34(+)CD133(+)ADGRG1(+) CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culturing, which can be a reliable target for drug screening of agonists of HSC expansion.

Background Overexpression of STIL centriolar assembly protein (STIL) has been observed in a variety of cancers. However, the functional significance of STIL in hepatocellular carcinoma remains unknow. Results STIL expression were abnormal in HCC tissues, and HCC patients with increased STIL expression had poor prognosis. In addition, increased STIL expression was correlated with T stage, pathologic stage, histologic grade, AFP, age, tumor status. STIL was an independent predictor of poor prognosis in HCC patients, as verified with a nomogram based on a Cox regression model. STIL was involved in HCC progression by modulating the cell cycle, DNA replication, oocyte meiosis, etc. Correlation analysis indicated TUBG1 mRNA expression was correlated with immune infiltrates. Conclusion STIL plays a vital role in HCC progression and prognosis; it may, therefore, serve as an effective biomarker for the prediction of patient survival.

Background Circular RNAs (circRNAs) function as vital regulators in multifarious cancers, including hepatocellular carcinoma (HCC). However, the roles of circRNA Wolf-Hirschhorn syndrome candidate gene-1 (circWHSC1) in HCC are barely known. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted for the levels of circWHSC1, miR-142-3p, miR-421, miR-665 and homeobox A1 (HOXA1) mRNA. Cell Counting Kit-8 (CCK-8) assay, colony formation assay and 5'-ethynyl-2'-deoxyuridine (EdU) assay were used to evaluate cell proliferation ability. Transwell assay was adopted for cell migration and invasion. Western blot assay was employed for protein levels. RNA pull-down assay, dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were executed to verify the interaction between miR-142-3p and circWHSC1 or HOXA1. Murine xenograft model assay was conducted for the role of circWHSC1 in vivo. The morphology of exosomes was observed by transmission electron microscopy (TEM). Results CircWHSC1 was elevated in HCC tissues and cells, and high level of circWHSC1 was associated with worse overall survival of HCC patients. Knockdown of circWHSC1 suppressed HCC cell proliferation and metastasis in vitro and restrained tumorigenesis in vivo. CircWHSC1 functioned as the sponge for miR-142-3p, which directly targeted HOXA1. Inhibition of miR-142-3p ameliorated the effects of circWHSC1 knockdown on HCC cell proliferation and metastasis. Moreover, miR-142-3p overexpression restrained the growth and motility of HCC cells, with HOXA1 elevation reversing the impacts. Additionally, circWHSC1 was increased in HCC patients' serum and might be a diagnostic indicator for HCC. Conclusion CircWHSC1 played a tumour-promoting role in HCC by elevating HOXA1 through sponging miR-142-3p.

Hepatocellular carcinoma is a highly malignant and lethal tumor. In addition to surgery, immunotherapy is currently a more effective treatment for hepatocellular carcinoma. The tumor immune microenvironment (TIME) largely determines the efficacy of cancer immunotherapy. Based on the universal targeting of TIME modulators in clinical treatment, TIME modulators are promising targets for tumor immunotherapy. We investigated the effect of a double gene expression vector (recombinant galactose-terminal glycol-poly-L-lysine coupled MIP-3α-FL) on dendritic cells (DCs) regulation within the TIME of mice with liver cancer. H22 cells were transfected with a recombinant MIP-3α-FL plasmid to induce DCs differentiation and chemotaxis. The effects of transfection were investigated by flow cytometry following the modified Boyden’s method. Cytokine-induced killer (CIK) cells co-culture revealed changes in the antigen presentation ability of DCs. Further, tumor-bearing mice were injected with the recombinant double gene vector via the tail vein. We compared the survival time, tumor volume, weight of the mice, as well as the number and phenotype of tumor-infiltrating DCs (TIDCs) between groups. The supernatant of transfected H22 cells promoted the phenotypic maturation of DCs, enhancing their chemotaxis. Further, treated DCs promoted the cytokine secretion and killing ability of CIK cells. The survival time of mice injected with the double gene vector was significantly prolonged, while their tumor weight and volume were relatively reduced. Flow cytometry revealed that the number of TIDCs (as well as CD80 and CD86 expression) in the MouseMIP-3α-FL group, were significantly higher than in the control group. The combination of MIP-3α and FL can significantly promote DCs aggregation, maturation, and enhance their antigen presentation ability. The coupling of the double gene vector with glycosylated polylysine can improve the precise targeting of the liver and inhibit tumor growth in vivo, providing a novel approach for immune therapy in liver cancer.

Background: Although DNA topoisomerase II-alpha (TOP2A) has been reported to be associated with tumour pathological processes, systematic research in hepatocellular carcinoma (HCC) prognosis remains scarce. Therefore, this study aimed to investigate the role of differential TOP2A expression in HCC.Results: Our findings revealed that TOP2A was significantly overexpressed in patients with HCC. Higher TOP2A expression is an independent risk factor for survival and prognosis. Subsequently, GO and KEGG pathway analyses showed TOP2A was mainly enriched in cell cycle, DNA replication, immunity, and metabolic-related pathway. We then conducted an integrated analysis of TOP2A, it showed specific relationship between TOP2A and immune-infiltrating cells in HCC. Furthermore, the latent function of query drugs in HCC was explored by integrating drug‑target, drug‑pathway and drug‑protein interactions.Conclusions: Mechanistically, we suggest that overexpression of TOP2A in patients with liver cancer can trigger an anti-tumour immune response by modulating the effective immune response and lymphocyte infiltration. Our findings suggest that TOP2A may play essential biological roles in HCC progression and represent potentially important candidate target in HCC therapy.

Ex vivo expansion of human cord blood (CB) hematopoietic stem cells (HSCs) is one approach to overcome limited numbers of HSCs in single CB units. However, there is still no worldwide acceptable HSC ex vivo expansion system. A main reason is that we still have very limited knowldege regarding mechanisms underlying maintenance and expansion of CB HSCs. Here we report that retinoid X receptor (RXR) activity is of significance for CB HSC ex vivo expansion. RXR antagonist HX531 significantly promoted ex vivo expansion of CB HSCs and progenitor cells (HPCs). RXR agonist Bexarotene notably suppressed ex vivo expansion of CB HSCs. Activation of RXR by Bexarotene significantly blocked expansion of phenotypic HSCs and HPCs and expressed increased functional HPCs as assessed by colony formation induced by UM171 and SR1. In vivo transplantation experiments in immune-deficient mice demonstrated that HX531 expanded CB HSCs possess long-term reconstituting capacities, and Bexarotene treatment inhibited expansion of functional CB HSCs. RNA-seq analysis revealed that RXR regulates expression of FBP1 (a negative regulator of glucose metabolism) and many genes involved in differentation. ECAR analysis showed that HX531 significantly promoted glycolytic activity of CB CD34(+) HSCs and HPCs. Our studies suggest that RXR is a negative regulator of ex vivo expansion of CB HSCs and HPCs.

The carbon catabolite repressor 4-negative on TATA (CCR4-NOT) complex, abbreviated CNOT, has deadenylation and 3'-5' exonuclease activity, mediates deadenylation in the degradation of RNA, initiates the exonuclease degradation pathway, and participates in tumor gene regulation. CNOT proteins comprise a family of global transcriptional regulators that are evolutionarily conserved in eukaryotic cells. Several subunit types of the CNOT complex have been discovered; however, little is known about the role of different subunits in tumorigenesis and development. We observed overexpression of

This paper is dedicated to illustrate the frequency dependence of breakdown strength of epoxy resin insulation used in solid state transformer. The experimental protocol was developed to measure the breakdown voltage of epoxy resin film, including the high frequency power supply (up to 20 kV), measurement and detection units. The frequency of the output high voltage can be reached to 10 kHz. Weibull distribution statistics analysis was employed to discuss the influence of frequency on breakdown characteristics of epoxy resin. The dielectric breakdown strength indicates a reduction with the increase in the frequency of the electric stress. Moreover, the data dispersion of breakdown strength presents slight increase at high frequency. High frequency voltage with harmonics of electric stress caused the reduction of breakdown strength of epoxy resin. It is accepted that partial discharge and increase of dielectric loss led to the reduction of breakdown. Furthermore, the space charge, trapping and polarization should be considered underlying the breakdown mechanism.

Purpose There is growing awareness of critical roles of circular RNA (circRNA) in tumor growth and development. This study aimed to discover new cancer-promoting circRNAs and to study their potential roles in the pathogenesis of hepatocellular carcinoma (HCC). Methods The expression profiles and clinical data of HCC-related circRNA, miRNA, and mRNA were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. A model of the circRNA-miRNA-mRNA network was established based on analysis and interaction prediction. The main biological functions of the targeted mRNA were predicted by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the protein-protein interaction (PPI) network was constructed to reveal important hub genes. The online tool OncomiR and GEPIA were used to analyze the correlation between miRNA and mRNA and clinicopathological features, and the Kaplan-Meier curve was constructed to reveal the relationship between mRNA and patient prognosis. Results Differential analysis indicated that twenty highly expressed circRNA in GEO microarray datasets GSE78520, GSE94508, and GSE97332. Ten miRNAs were targeted by 20 circRNAs. These miRNAs are expressed at lower levels in the TCGA liver hepatocellular carcinoma (LIHC) expression profile, and most of the functions of these genes are closely related to pathological staging. These 10 miRNAs predicted a total of 7310 downstream mRNAs, of which 169 mRNAs were more abundant than normal tissues in the TCGA LIHC expression profile. GO analysis, KEGG analysis, and protein-protein interaction network analysis showed that E2F1, H2AFX, TOP2A, and RAD51 are central genes of the competitive endogenous RNA (ceRNA) network, and are mainly involved in biological mechanisms such as cell cycle, cancer-related pathways, and blood vessel morphogenesis. In addition, E2F1, H2AFX, TOP2A, and RAD51 are also closely related to the pathological stage and survival of patients. Conclusions The analysis allowed the construction of a competitive endogenous RNA network associated with cancer-promoting circRNAs. Genes involved in this network may provide potential therapeutic targets for the diagnosis and treatment of HCC.

Multidrug resistance (MDR) is an important issue in current cancer treatments. In human cancer, drug resistance is primarily associated with the overexpression of multidrug resistance gene 1 (MDR1). Therefore, the human MDR1 gene promoter may be a target for anti‑MDR drug screening. Numerous methods to prevent MDR have been investigated. However, they have been proven to be clinically ineffective. Therefore, the aim of the present study was to investigate whether downregulation of nucleophosmin (NPM) demonstrates any effects on the reversal of MDR in hepatocellular carcinoma (HCC) cells. In the present study, two in vitro MDR HCC cell lines, HepG2/Adriamycin (ADM) and SMMC7721/ADM, were established and the level of MDR was measured. The results demonstrated that NPM downregulation markedly reversed the effects of MDR in the model used. In addition, NPM downregulation reduced P-glycoprotein expression, as well as MDR1 expression. These results suggested that downregulation of NPM may be a novel and effective method of reversing the effects of MDR, and may be a potential adjuvant for tumor chemotherapy.

Background The involvement of circular RNAs (circRNAs) in chemoresistance of tumors has been identified. Herein, this study aims to investigate the role and the underlying mechanism of circ_0003998 in doxorubicin (DOX) resistance in hepatocellular carcinoma (HCC). Methods The expression of circ_0003998 and microRNA (miR)-218-5p and eukaryotic translation initiation factor 5A-2 (EIF5A2) mRNA was detected using quantitative real-time polymerase chain reaction. Cell viability, migration and invasion were analyzed using cell counting kit-8, colony formation and transwell assay, respectively. The levels of matrix metallopeptidase 9 (MMP-9), E-cadherin, Vimentin, N-cadherin and EIF5A2 protein were detected using western blot. The interaction between miR-218-5p and circ_0003998 or EIF5A2 was confirmed by dual-luciferase reporter assay. In vivo experiments were performed using murine xenograft models. Results Circ_0003998 was elevated in HCC tissues, DOX-resistant tissues and cells, and circ_0003998 knockdown promoted DOX-sensitivity in HCC by inhibiting resistant cell viability, migration, invasion and EMT in vitro and enhanced DOX cytotoxicity in vivo. Bioinformatics analysis revealed circ_0003998 inhibited miR-218-5p expression, which was clarified to be a target of circ_0003998, and circ_0003998 knockdown sensitized HCC cell to DOX by sponging miR-218-5p. EIF5A2 was a target of miR-218-5p, and miR-218-5p mitigated DOX resistance in HCC cells through modulating EIF5A2 expression. Additionally, circ_0003998 served as a competing endogenous RNA for miR-218-5p to regulate EIF5A2 expression. Conclusion Circ_0003998 knockdown sensitized HCC cell to DOX by regulating miR-218-5p/EIF5A2 axis, indicating new markers of poor response to DOX and potential therapeutic strategies for the chemotherapy of HCC.

A major obstacle to effective cancer immunotherapy is the tumor immune microenvironment. Natural killer (NK) cell resistance has been suggested as a primary cause of poor prognosis in hepatocellular carcinoma (HCC), which seemingly correlates with CNOT7 overexpression. CNOT7, a cytoplasmic mRNA deadenylase that is highly expressed in HCC, may regulate cytokine transforming growth factor‐β1 (TGF‐β1) secretion by controlling nuclear factor‐κB subunit p65 trafficking. CNOT7 depletion suppresses TGF‐β1 secretion in HCC and promotes interferon‐γ (IFN‐γ) secretion by NK cells, and we previously demonstrated that CNOT7 depletion reversed IFN‐γ resistance in HCC cells. Therefore, we hypothesized that CNOT7 depletion might reverse NK cell resistance by influencing the tumor immune microenvironment of HCC. To test this hypothesis, we examined the correlation between CNOT7, STAT1, TGF‐β1 and IFN‐γ expression with hepatitis B virus‐related cirrhosis and HCC with hepatitis B virus‐related cirrhosis. We found that modulation of CNOT7 expression alters TGF‐β1 secretion in HCC and IFN‐γ secretion in NK cells. We also examined the effects of NK cells in HepG2 cells with CNOT7 knockdown, which showed that NK cell surface CD107a expression is up‐regulated and caspase‐3 expression is significantly enhanced in CNOT7‐deficient HepG2 cells. Overall, our results show that knockdown of CNOT7 expression reverses NK cell resistance in HCC cells. Therefore, CNOT7 depletion has potential as a new adjuvant therapy in immunotherapy for HCC., Natural killer (NK) cell resistance is a primary cause of poor prognosis in hepatocellular carcinoma (HCC), which correlates with CNOT7 overexpression. Tumor‐derived transforming growth factor‐β1 created a strong inhibitory network and impaired NK cells. CNOT7 depletion could suppress transforming growth factor‐β1 secretion by controlling nuclear factor‐κB subunit p65 trafficking in HCC. We found that CNOT7 depletion may reverse NK cell resistance in HCC cells.

Pancreatic cancer is characterized by the absence of early specific clinical symptoms, accompanied with rapid metastasis and invasion. It is one of the most prevalent types of cancer and more importantly, one of the most common types of malignant cancer with the highest mortality rate of all cancer types. The heparanase (HPA)/syndecan-1 (SDC1) axis has been reported to promote tumor growth, invasion, metastasis and angiogenesis in a variety of cancer types; however, studies into the role and mechanism of the HPA/SDC1 axis in pancreatic cancer are limited. The present study aimed to investigate the biological function and clinical significance of the HPA/SDC1 axis in pancreatic cancer. The results demonstrated that HPA is elevated in pancreatic cancer tissues and cell lines, and that its high expression was associated with poor prognosis. HPA was revealed to mediate an increase in fibroblast growth factor 2 (FGF2) expression by upregulating the expression of SDC1. Conversely, silencing HPA mediated the suppression of FGF2 expression. Furthermore, upregulated FGF2 was observed to increase the expression of downstream Palladin proteins by activating the PI3K/Akt signaling pathway and also lead to the activation of epithelial-mesenchymal transition (EMT). Subsequently, EMT was found to promote the migration and invasion of pancreatic cancer cells. In summary, the HPA/SDC1 axis was revealed to serve an important role in the regulation of FGF2, and was found to promote the invasion and metastasis of pancreatic cancer cells. These findings indicated that the HPA/SDC1 axis may be used as an effective therapeutic target for pancreatic cancer.

This study aimed to identify significant biomarkers related to the prognosis of liver cancer using long noncoding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) analysis. Differentially expressed mRNA and lncRNAs between liver cancer and paracancerous tissues were screened, and the functions of these mRNAs were predicted by gene ontology and pathway enrichment analyses. A ceRNA network consisting of differentially expressed mRNAs and lncRNAs was constructed. LncRNA FENDRR and lncRNA HAND2-AS1 were hub nodes in the ceRNA network. A risk score assessment model consisting of eight genes (PDE2A, ESR1, FBLN5, ALDH8A1, AKR1D1, EHHADH, ADRA1A, and GNE) associated with prognosis were developed. Multivariate Cox regression suggested that both pathologic_T and risk group could be regarded as independent prognostic factors. Furthermore, a nomogram model consisting of pathologic_T and risk group showed a good prediction ability for predicting the survival rate of liver cancer patients. The nomogram model consisting of pathologic_T and a risk score assessment model could be regarded as an independent factor for predicting prognosis of liver cancer.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. γδ T cells have been revealed to be promising candidates for immunotherapy in patients with HCC. However, the use of these cells in clinical practice has been demonstrated to be challenging. In the present study, γδ T cells isolated from the peripheral blood of patients with HCC (n=83) and healthy donors (n=15) were characterized. Flow cytometry was used to analyze the proportion, phenotype, tumor-killing capacity and cytokine secretion of regulatory T cells (Tregs) and γδ T17 cells in peripheral blood samples prior to and following amplification. Interleukin (IL)-17A levels in the supernatant was analyzed using an ELISA on days 3, 7, 10 and 14. The in vitro cytotoxicity of γδ T cells was measured using an MTT assay. It was revealed that zoledronate with IL-2 may efficiently expand γδ T cells sourced from the peripheral blood of patients with HCC. The amplification capacity of γδ T cells was associated with the clinicopathological characteristics of patients (clinical stage, levels of AFP and albumin, duration of disease, size and number of tumors, numbers of Tregs and γδ T17 cells, and levels of IL-17A). The proportion of γδ T cells positive for interferon-γ, tumor necrosis factor-α, granzyme B, perforin, and lysosome-associated membrane protein 1 was almost unchanged prior to and following amplification. Following amplification, the in vitro cytotoxicity of γδ T cells also remained unchanged. γδ T17 cells, Tregs and IL-17A levels were not altered during amplification. In summary, following in vitro amplification, circulating γδ T cells were revealed to possess features that may make them suitable for immunotherapy for HCC without increasing immunosuppressive factors. However, immunotherapy should be individualized according to the clinicopathological features of patients.

Academic relations originated from academic activities are of particular temporal features. The academic activities which happen more recently, last longer period and have more occurrence will be more possible to form valuable academic relationships and more meaningful to be analyzed. For the characteristics of the accumulated time and vague boundaries of valid time with academic cooperation, the strategy of time extension and duration accumulation is introduced into the algorithm of progressive partition association rules mining. In the proposed method, the time attribute of academic activities transaction records are mapped and extended on time series, and the duration period is marked according to time partition. Through progressive partition processing, the academic association rules mining with continuous time accumulation is realized. This paper presents basic principle and realization process in details, and takes information about research projects and co-published papers as cases to mine academic relationships. The experimental comparison and results analysis show the effectiveness of the proposed algorithm.