Combined Strategies Enable Highly Selective Light Olefins and para-Xylene Production on Single Catalyst Bed.

Achieving multiple high-value-added chemical production through novel reaction processes and shape-selective catalytic strategy is the key to realizing efficient low-carbon catalytic processes. In this work, a methanol-toluene coreaction system was developed, and combined control strategies of reaction pathway guidance and shape-selective catalysis were applied for the successful production of light olefins and para-xylene on single HZSM-5 catalyst bed. Cofeeding toluene additionally provides reactive and flowing aromatic hydrocarbon pool species that change the dominant reaction pathway in the complex network of the methanol reaction on HZSM-5 and promote the formation of ethylene. For the first time, the key reaction intermediates methylmethylenecyclodiene are directly captured and identified by experimental and theoretical techniques. This helps to propose the catalytic cycle for the dominant generation of ethylene and, more importantly, enriches the methanol-to-hydrocarbons (MTH) chemistry and hydrocarbon pool mechanism. Furthermore, 0.4HZSM-5@S-1-CLD, an optimized HZSM-5 catalyst modified by the silicalite-1 epitaxial growth followed by silanization approach, realizes highly selective production of light olefins (especially ethylene) and para-xylene, while excellent reactant activity is maintained. This highly efficient coreaction route gives an important leading significance in synthesizing the raw materials for the polyolefin and polyester industries. The establishment of the combined control strategies provides a model for the joint production of multiple target chemicals in complex catalytic processes.

Evaluation of an artificial intelligence-based clinical trial matching system in Chinese patients with hepatocellular carcinoma: a retrospective study.

BACKGROUND: Artificial intelligence (AI)-assisted clinical trial screening is a promising prospect, although previous matching systems were developed in English, and relevant studies have only been conducted in Western countries. Therefore, we evaluated an AI-based clinical trial matching system (CTMS) that extracts medical data from the electronic health record system and matches them to clinical trials automatically. METHODS: This study included 1,053 consecutive inpatients primarily diagnosed with hepatocellular carcinoma who were referred to the liver tumor center of an academic medical center in China between January and December 2019. The eligibility criteria extracted from two clinical trials, patient attributes, and gold standard were decided manually. We evaluated the performance of the CTMS against the established gold standard by measuring the accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and run time required. RESULTS: The manual reviewers demonstrated acceptable interrater reliability (Cohen's kappa 0.65-0.88). The performance results for the CTMS were as follows: accuracy, 92.9-98.0%; sensitivity, 51.9-83.5%; specificity, 99.0-99.1%; PPV, 75.7-85.1%; and NPV, 97.4-98.9%. The time required for eligibility determination by the CTMS and manual reviewers was 2 and 150 h, respectively. CONCLUSIONS: We found that the CTMS is particularly reliable in excluding ineligible patients in a significantly reduced amount of time. The CTMS excluded ineligible patients for clinical trials with good performance, reducing 98.7% of the work time. Thus, such AI-based systems with natural language processing and machine learning have potential utility in Chinese clinical trials.

Circ_MAPK9 promotes STAT3 and LDHA expression by silencing miR-642b-3p and affects the progression of hepatocellular carcinoma.

BACKGROUND: Aberrant expression and activation of circular RNAs (circRNAs) are closely associated with various cancers. The role of circ_MAPK9 (hsa_circ_0001566) in cancer progression remains unknown. This study aims to investigate the function, mechanism and clinical significance of circ_MAPK9 in hepatocellular carcinoma (HCC). METHODS: Circ_MAPK9 expression on the microarray of tumor from clinical HCC patients was detected by in situ hybridization (ISH). Circ_MAPK9 knockdown was achieved with siRNAs in SMMC-7721 and SK-Hep1 HCC cell lines. The biological function of circ_MAPK9 was verified in vitro by CCK8 test, colony formation assay, transwell assay, PI-Annexin V staining, and in vivo by xenograft tumor in nude mice. Fluorescent in situ hybridization (FISH), subcellular fractionation assay, a dual-luciferase reporter assay and rescue experiments were employed for further mechanistic investigation. RESULTS: The expression of circ_MAPK9 was significantly up-regulated in HCC tissues and cells, which was found to be associated with poor prognosis. Patients with high expression of circ_MAPK9 had a shorter overall survival and disease-free survival in comparison to those with low circ_MAPK9 expression. Functional assays showed that circ_MAPK9 knockdown suppressed cellular proliferation, migration, invasion and tumor growth in vivo, and promoted apoptosis in HCC cells. Moreover, we found that circ_MAPK9 knockdown could inhibit aerobic glycolysis by decreasing the production of adenosine triphosphate (ATP) and lactic acid, which was mediated by lactate dehydrogenase (LDHA). Mechanistically, circ_MAPK9 functioned as ceRNA via sponging miR-642b-3p and alleviated the inhibitory effect of miR-642b-3p on its target signal transducer and activator of transcription 3 (STAT3) and LDHA, thereby leading to STAT3 activation and LDHA expression. CONCLUSIONS: Circ_MAPK9, as an oncogene, promotes HCC growth and metastasis through miR-642b-3p/STAT3-LDHA axis. Circ_MAPK9 could serve as a potential biomarker for HCC poor prognosis and diagnosis.

Effectiveness of dyadic interventions among cancer dyads: An overview of systematic reviews and meta-analyses.

AIMS AND OBJECTIVE: To summarize evidence from systematic reviews (SRs)/meta-analyses (MAs) regarding the impact of dyadic interventions delivered to both members of a cancer dyad, including a cancer patient and caregiver (e.g. family caregiver, intimate partner). DESIGN: This overview of SRs was conducted in accordance with the preferred reporting items for overviews of reviews statement. METHODS: A comprehensive search of multiple databases, including PubMed, Cochrane Library, Embase, CINAHL, Web of Science, China National Knowledge Infrastructure and Wan Fang. The methodological and reporting quality of SRs and MAs was assessed using the Assessing the Methodological Quality of Systematic Reviews 2. The quality of the included SRs/MAs was evaluated using the Grades of Recommendations, Assessment, Development and Evaluation approach. RESULTS: Eighteen SRs/MAs undertook quantitative synthesis to assess the impact of dyadic interventions on cancer dyads. Both the credibility of the SRs/MAs and the evidence quality of the outcome measures were below satisfactory standards. Prior SRs/MAs revealed several limitations such as lack of pre-published protocols or research objectives, failure to report excluded studies and insufficient details on funding sources for individual studies. CONCLUSIONS: Dyadic interventions may prove advantageous for the physical health and dyadic adjustment of cancer dyads. Nevertheless, the reported results of dyadic interventions on the psychological health of patient-caregiver dyads affected by cancer are inconsistent. Thus, rigorous and comprehensive studies are requisite to establish reliable evidence for conclusive determinations. RELEVANCE TO CLINICAL PRACTICE: The findings of this overview can guide healthcare practitioners when considering the use of dyadic interventions for cancer dyads. Moreover, these findings have the potential to enhance the integration of these approaches into clinical practice. PATIENT OR PUBLIC CONTRIBUTION: Our paper presents an overview of systematic reviews, and therefore, such specific details may not be relevant to our study.

Spleen-dedicated stiffness measurement performed well to rule out high-risk varices in HBV-related hepatocellular carcinoma: Screening for high-risk varices in HCC.

BACKGROUND: Esophagogastroduodenoscopy (EGD) is required to screen for high-risk varices (HRV) in patients with hepatocellular carcinoma (HCC), especially since overall survival rates have dramatically improved with new systemic therapies. AIM: To assess the Baveno VI and Baveno VII algorithms' ability to rule out HRV in hepatitis B virus (HBV)-related HCC METHODS: We prospectively enrolled consecutive patients with HBV related, compensated cirrhosis and newly diagnosed HCC who underwent liver stiffness measurement, spleen stiffness measurement (SSM) using a 100-Hz shear wave frequency, and EGD. RESULTS: From September 2021 to August 2023, we enrolled 219 patients with HCC, with 107 (48.9%) Barcelona Clinic Liver Cancer (BCLC) A, 28 (12.8%) BCLC B and 84 (38.3%) BCLC C, respectively. HRV prevalence was 28.8% (63/219). Baveno VI criteria safely (HRV missing rate, 3.2%) avoided 27.4% unnecessary EGDs, while the Baveno VII algorithm avoided 49.3% with HRV missing rate at 7.9% (5/63). The SSM ≤40 kPa avoided 47.5% of EGDs safely (HRV missing rate, 4.8%), significantly better than the Baveno VI criteria (p < 0.001) and comparable to the Baveno VII algorithm (p = 0.390). The SSM ≤40 kPa safely avoided EGDs in patient subgroups within Milan criteria, with portal vein tumour thrombosis or BCLC B/C or candidates for systemic therapy. CONCLUSIONS: We validated that the SSM ≤40 kPa using a 100-Hz probe could safely eliminate more unnecessary EGDs than the Baveno VI criteria in patients with HBV-related HCC. However, the efficacy of the Baveno VII algorithm in patients with HCC requires further investigation.

CT images-based 3D convolutional neural network to predict early recurrence of solitary hepatocellular carcinoma after radical hepatectomy.

PURPOSE The high rate of recurrence of hepatocellular carcinoma (HCC) after radical hepatectomy is an important factor that affects the long-term survival of patients. This study aimed to develop a computed tomography (CT) images-based 3-dimensional (3D) convolutional neural network (CNN) for the preoperative prediction of early recurrence (ER) (≤2 years) after radical hepatectomy in patients with solitary HCC and to compare the effects of segmentation sampling (SS) and non-segmentation sampling (NSS) on the prediction performance of 3D-CNN. METHODS Contrast-enhanced CT images of 220 HCC patients were used in this study (training group=178 and test group=42). We used SS and NSS to select the volume-of-interest to train SS-3D-CNN and NSS-3D-CNN separately. The prediction accuracy was evaluated using the test group. Finally, gradient-weighted class activation mappings (Grad-CAMs) were plotted to analyze the difference of prediction logic between the SS-3D-CNN and NSS-3D-CNN. RESULTS The areas under the receiver operating characteristic curves (AUCs) of the SS-3D-CNN and NSS3D-CNN in the training group were 0.824 (95% CI: 0.764-0.885) and 0.868 (95% CI: 0.815-0.921). The AUC of the SS-3D-CNN and NSS-3D-CNN in the test group were 0.789 (95% CI: 0.637-0.941) and 0.560 (95% CI: 0.378-0.742). The SS-3D-CNN could stratify patients into low- and high-risk groups, with significant differences in recurrence-free survival (RFS) (P < .001). But NSS-3D-CNN could not effectively stratify them in the test group. According to the Grad-CAMs, compared with SS-3D-CNN, NSS-3D-CNN was obviously interfered by the nearby tissues. CONCLUSION SS-3D-CNN may be of clinical use for identifying high-risk patients and formulating individualized treatment and follow-up strategies. SS is better than NSS in improving the performance of 3D-CNN in our study.

Design and application of improved sparrow search algorithm based on sine cosine and firefly perturbation.

Swarm intelligence algorithms are relatively simple and highly applicable algorithms, especially for solving optimization problems with high reentrancy, high stochasticity, large scale, multi-objective and multi-constraint characteristics. The sparrow search algorithm (SSA) is a kind of swarm intelligence algorithm with strong search capability, but SSA has the drawback of easily falling into local optimum in the iterative process. Therefore, a sine cosine and firefly perturbed sparrow search algorithm (SFSSA) is proposed for addressing this deficiency. Firstly, the Tent chaos mapping is invoked in the initialization population stage to improve the population diversity; secondly, the positive cosine algorithm incorporating random inertia weights is introduced in the discoverer position update, so as to improve the probability of the algorithm jumping out of the local optimum and speed up the convergence; finally, the firefly perturbation is used to firefly perturb the sparrows, and all sparrows are updated with the optimal sparrows using the firefly perturbation method to improve their search-ability. Thirteen benchmark test functions were chosen to evaluate SFSSA, and the results were compared to those computed by existing swarm intelligence algorithms, as well as the proposed method was submitted to the Wilcoxon rank sum test. Furthermore, the aforesaid methods were evaluated in the CEC 2017 test functions to further validate the optimization efficiency of the algorithm when the optimal solution is not zero. The findings show that SFSSA is more favorable in terms of algorithm performance, and the method's searchability is boosted. Finally, the suggested algorithm is used to the locating problem of emergency material distribution centers to further validate the feasibility and efficacy of SFSSA.

Sarcopenia among older patients with cancer: A scoping review of the literature.

INTRODUCTION: In the older patients with cancer, the combination of aging and cancer makes sarcopenia more likely to occur. However, previous studies paid less attention to the sarcopenia of older patients with cancer. To address these gaps, we conducted a scoped review of the prevalence, measurement, prognostic value, and clinical interventions of sarcopenia in this population. MATERIALS AND METHODS: A comprehensive search of PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Embase, China National Knowledge Infrastructure (CNKI) and Wangfang electronic databases was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews. Two independent reviewers screened all abstracts and full-text studies for inclusion. RESULTS: We identified 10,850 studies, and 39 met the inclusion criteria. Two reviewers extracted data on study characteristics, study design, measuring tools and main outcomes. This review included works from 11 countries. All studies were quantitative and most used a cross-sectional (n = 17) or retrospective (n = 16) design. The prevalence of sarcopenia in elderly cancer survivors ranged from 18.5% to 83%, and skeletal muscle mass index (SMI) by computed tomography (CT) scan at lumbar 3 (L3) was the most commonly used way to define sarcopenia. Meanwhile, pre-therapeutic sarcopenia was significantly related to postoperative complications, lower overall survival and impaired physical function. DISCUSSION: This review emphasizes sarcopenia is highly prevalent in older patients with cancer, which leads to poor outcomes and urgently needs attention from nutritionists, surgeons, oncologists, psychologists and nurses.

Magnesium isoglycyrrhizinate attenuates acute alcohol-induced hepatic steatosis in a zebrafish model by regulating lipid metabolism and ER stress.

BACKGROUND: Alcoholism is a well-known risk factor for liver injury and is one of the major causes of hepatic steatosis worldwide. Although many drugs have been reported to have protective effects against acute alcohol-induced hepatotoxicity, there is limited available treatment for alcoholic liver disease (ALD), indicating an urgent need for effective therapeutic options. Herein, we first reported the protective effects of magnesium isoglycyrrhizinate (MgIG) on acute alcohol-induced hepatic steatosis and its related mechanisms in a zebrafish model. METHODS: Alcohol was administered directly to embryo medium at 5 days post-fertilization (dpf) for up to 32 h. MgIG was given to the larvae 2 h before the administration of alcohol and then cotreated with alcohol starting at 5 dpf. Oil red O staining was used to determine the incidence of steatosis, and pathological features of the liver were assessed by hematoxylin-eosin staining. Biological indexes, total cholesterol (TC) and triacylglycerol (TG) were detected in the livers of zebrafish larvae. Morphological changes in the livers of zebrafish larvae were observed using liver-specific EGFP transgenic zebrafish (Tg(lfabp10a:eGFP)). The expression levels of critical molecules related to endoplasmic reticulum (ER) stress and lipid metabolism were detected by qRT-PCR, whole-mount in situ hybridization and western blotting. RESULTS: Alcohol-treated larvae developed hepatomegaly and steatosis after 32 h of exposure. We found that MgIG improved hepatomegaly and reduced the incidence of steatosis in a dose-dependent manner by oil red O staining and diminished deposits of alcohol-induced fat droplets by histologic analysis. Moreover, MgIG significantly decreased the levels of TC and TG in the livers of zebrafish larvae. Furthermore, the expression levels of critical genes involved in ER stress (atf6, irela, bip, chop) and the key enzymes regulating lipid metabolism (acc1, fasn, hmgcs1 and hmgcra) were significantly higher in the alcohol-treated group than in the control group. However, in the MgIG plus alcohol-treated group, the expression of these genes was markedly decreased compared with that in the alcohol-treated group. Whole-mount in situ hybridization and western blotting also showed that MgIG had an effect on the expression levels of critical genes and proteins involved in lipid metabolism and ER stress. Our results revealed that MgIG could markedly regulate these genes and protect the liver from ER stress and lipid metabolism disorders. CONCLUSIONS: Our study is the first to demonstrate that MgIG could protect the liver from acute alcohol stimulation by ameliorating the disorder of lipid metabolism and regulating ER stress in zebrafish larvae.

Efficacy and safety of lenvatinib monotreatment and lenvatinib-based combination therapy for patients with unresectable hepatocellular carcinoma: a retrospective, real-world study in China.

BACKGROUND: Lenvatinib and lenvatinib-based combination treatments are widely used in patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice, but their curative effect and safety need further study in the real world. METHODS: This was a retrospective study involving patients with uHCC receiving lenvatinib monotherapy and lenvatinib-based combination treatment between Nov, 2018 and Sep, 2020 in Nanfang Hospital. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS). Treatment-related adverse events (TRAEs) were recorded and graded. Efficacy and safety of monotherapy and combination therapy were compared. Stratified analysis was performed according to systemic line of treatment and medication regimen for combination therapy. RESULTS: For lenvatinib monotherapy (n = 39), OS and PFS were 80 weeks and 24.3 weeks, respectively. For combination treatment (n = 72), median OS and PFS were 99 weeks and 45.6 weeks, respectively. OS, PFS, and TTP for patients in the combination treatment cohort were significantly longer compared to those of patients in the monotreatment cohort (OS: P = 0.04, PFS: P = 0.003; TTP, P = 0.005). The incidence of TRAEs could be controlled both in the monotherapy cohort and the combination treatment cohort. In the monotherapy cohort, OS and PFS were significantly decreased in the second-line treatment group compared with the first-line treatment group, while no differences were observed in the combination cohort. The efficacy of triple therapy (lenvatinib plus PD-1 antibody plus TACE or HAIF) was similar to lenvatinib plus PD-1 antibody or lenvatinib plus TACE or HAIF. CONCLUSIONS: Our real-world study showed that lenvatinib monotherapy and lenvatinib-based combination therapy were well tolerated, with encouraging efficacies in patients with uHCC. Lenvatinib-based combination therapy showed a better curative effect compared with lenvatinib single-agent therapy. In patients who have failed first-line TKI treatment, lenvatinib-based combination therapy may be a better choice than lenvatinib single-agent therapy. Lenvatinib-based triple therapy may not have an advantage over dual therapy.

Berberine Sensitizes Human Hepatoma Cells to Regorafenib via Modulating Expression of Circular RNAs.

Regorafenib resistance is a key limiting factor in the treatment of advanced hepatocellular carcinoma (HCC). Increasing evidence has demonstrated that Berberine (BBR) can synergistically enhance the therapeutic effect of various chemotherapeutic agents. However, the contribution of BBR on regorafenib therapy remains unclear. The purpose of this study was to explore the combined treatment effect of berberine and regorafenib in HCC. We found that BBR enhanced the cytotoxicity of regorafenib in HCC cells. Compared with regorafenib alone, the combined treatment of BBR and regorafenib significantly inhibited the proliferation of HCC cells and induced cellular apoptosis. Meanwhile, the combined treatment group with BBR (10mg/kg/day) and regorafenib (5mg/kg/day) had a dramatic inhibitory effect on the growth of HCC xenograft tumors in nude mice. The increased apoptosis of xenograft tumors was seen in the combined treatment group. Moreover, a comprehensive circular RNA sequencing was performed to identify differentially expressed circRNAs in HCC cells after exposure to 100µM BBR and 5µM regorafenib. The volcano plot and scatter plot analyses revealed that there were 58 up-regulated and 19 down-regulated differentially expressed circRNAs between the combination treatment and control groups. Among them, the expression of hsa_circ_0032029 and hsa_circ_0008928 were up-regulated in HCC cells after treatment with 100µM BBR and 5µM regorafenib. Taken together, this study demonstrated that BBR enhanced the anti-HCC effect of regorafenib both in vitro and in vivo. The synergistic anti-tumor effect of BBR and regorafenib might be related to the up-regulation of hsa_circ_0032029 and hsa_circ_0008928 in HCC cells.

LncRNA-Gm9795 promotes inflammation in non-alcoholic steatohepatitis via NF-[Formula: see text]B/JNK pathway by endoplasmic reticulum stress.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a key stage in leading development of non-alcoholic simple fatty liver (NAFL) into cirrhosis and even liver cancer. This study aimed at exploring the lncRNAs expression profile in NASH and the biological function of a novel LncRNA-gm9795. METHODS: Microarray analysis was performed to compare the expression profiles of lncRNAs in the liver of NASH, NAFLD and normal mice (5 mice for each group). Methionine-choline-deficient Medium (MCD) with Lipopolysaccharide (LPS) or palmitic acid (PA)were used to built NASH cell models. The role and mechanism of LncRNA-gm9795 in NASH were explored by knocking down or over-expressing its expression. RESULTS: A total of 381 lncRNAs were found to be not only highly expressed in NAFLD, but also is going to go even higher in NASH. A novel LncRNA-gm9795 was significantly highly expressed in liver tissues of NASH animal models and NASH cell models. By staining with Nile red, we found that gm9795 did not affect the fat accumulation of NASH. However, gm9795 in NASH cell models significantly promoted the expression of TNF [Formula: see text], IL-6, IL-1[Formula: see text], the important inflammatory mediators in NASH. At the same time, we found that gm9795 upregulated the key molecules in endoplasmic reticulum stress (ERS), while NF-[Formula: see text]B/JNK pathways were also activated. When ERS activator Thapsigargin (TG) was introduced in cells with Ggm9757 si-RNA, NF-[Formula: see text]B and JNK pathways were activated. Conversely, ERS inhibitor Tauroursodeoxycholic acid (TUDCA) inhibited NF-kB and JNK pathways in cells with gm9795 overexpression plasmid. CONCLUSION: LncRNA-gm9795 promotes inflammatory response in NASH through NF-kB and JNK pathways by ERS, which might provide theoretical basis for revealing the pathogenesis of NASH and discovering new therapeutic targets.

Caffeine enhances the anti-tumor effect of 5-fluorouracil via increasing the production of reactive oxygen species in hepatocellular carcinoma.

The development of drug resistance affecting the prognosis of patients with hepatocellular carcinoma (HCC) leads to low survival rate of HCC patients. Caffeine is reported to have a function of protecting the liver and anti-tumor activity. Therefore, caffeine may be an ideal enhancer for HCC chemotherapy regimens. Our study showed that the combination of caffeine and 5-FU significantly inhibited the proliferation of HCC cells in vivo and in vitro comparing with caffeine or 5-FU monotherapy. The CI values of caffeine (0.5 mM) combined with 5-FU (25, 50 µM) were all less than 1, confirming that the utilization of drug combination has a synergistic inhibitory effect on the proliferation of HCC cells. Meanwhile, results of Western blot and TUNEL assays demonstrated that the apoptotic level of HCC cells in the combined group was significantly increased. The protein expression level of cleaved PARP was up-regulated, while the protein level of Bcl-2 and Bcl-xL was down-regulated. In addition, we found that ROS levels were increased in the 1 mM caffeine and 25 µM 5-FU combination group comparing with the control or single drug group. Taken together, this is the first study to demonstrate that the combination of caffeine and 5-FU inhibits HCC cells proliferation and promotes cellular apoptosis by regulating intracellular ROS production. The present data provides a basis for the application of caffeine combined with 5-FU as a novel chemotherapy regimen for HCC.

Long Noncoding RNA Expression Signatures of Colon Cancer Based on the ceRNA Network and Their Prognostic Value.

BACKGROUND: The specific functional roles of long noncoding RNAs (lncRNAs) as ceRNAs in colon cancer and their potential implications for colon cancer prognosis remain unclear. In the present study, a genome-wide analysis was performed to investigate the potential lncRNA-mediated ceRNA interplay in colon cancer based on the "ceRNA hypothesis." The prognostic value of the lncRNAs was evaluated. METHODS: A dysregulated lncRNA-associated ceRNA network was constructed based on the miRNA, lncRNA, and mRNA expression profiles in combination with the miRNA regulatory network by using an integrative computational method. Molecular biological techniques, including qPCR and gene knockdown techniques, were used to verify candidate targets in colon cancer. Survival analysis was performed to identify the candidate lncRNAs with prognostic value. RESULTS: Our network analysis uncovered several novel lncRNAs as functional ceRNAs through crosstalk with miRNAs. The QRT-PCR assays of patient tissues as well as gene knockdown colon cancer cells confirmed the expression of top lncRNAs and their correlation with target genes in the ceRNA network. Functional enrichment analysis predicted that differentially expressed lncRNAs might participate in broad biological functions associated with tumor progression. Moreover, these lncRNAs may be involved in a range of cellular pathways, including the apoptosis, PI3K-AKT, and EGFR signaling pathways. The survival analysis showed that the expression level of several lncRNAs in the network was correlated with the prognosis of patients with colon cancer. CONCLUSIONS: This study uncovered a dysregulated lncRNA-associated ceRNA network in colon cancer. The function of the identified lncRNAs in colon cancer was preliminarily explored, and their potential prognostic value was evaluated. Our study demonstrated that lncRNAs could potentially serve as important regulators in the development and progression of colon cancer. Candidate prognostic lncRNA biomarkers in colon cancer were identified.

The Down-Regulation of SUZ12 Accelerates the Migration and Invasion of Liver Cancer Cells via Activating ERK1/2 Pathway.

The suppressor of zest 12 (SUZ12), an essential subunit of the transcription polycomb repressive complex 2 (PRC2), has been found to be involved in HBV X-induced oncogenic transformation in hepatocellular carcinoma (HCC). However, the specific function of SUZ12 has not yet been determined in the pathogenesis of migration and invasion of HBV-associated HCC. Here, our results showed that SUZ12 was significantly down-regulated in HBV-related HCC tissues compared with adjacent non-tumor tissues by immunohistochemical and Western blot assays. The 5-years survival rate was worse in patients with low expression level of SUZ12. SUZ12 silencing increased the migration and invasion of HCC cells, and its overexpression impaired HCC cells migration and invasion. Knockdown of SUZ12 activated ERK1/2 pathway and increased MMP9 (matrix metallopeptidase 9) and MMP2 (matrix metallopeptidase 2) expression, whereas SUZ12 overexpression had opposite effects. Specific ERK1/2 inhibitor (SCH772984) significantly decreased HCC cells migration and invasion caused by SUZ12 shRNA. Thus, the liver cancer-down-regulated SUZ12 accelerated the invasion and metastasis of HCC cells. These effects might be associated with deregulation of SUZ12 activating ERK1/2, MMP2 and MMP9 in HCC cells.

Identification of candidate diagnostic and prognostic biomarkers for pancreatic carcinoma.

BACKGROUND: Pancreatic carcinoma (PC) is one of the most aggressive cancers affecting human health. It is essential to identify candidate biomarkers for the diagnosis and prognosis of PC. The present study aimed to investigate the diagnosis and prognosis biomarkers of PC. METHODS: Differentially expressed genes (DEGs) were identified from the mRNA expression profiles of GSE62452, GSE28735 and GSE16515. Functional analysis and the protein-protein interaction network analysis was performed to explore the biological function of the identified DEGs. Diagnosis markers for PC were identified using ROC curve analysis. Prognosis markers were identified via survival analysis of TCGA data. The protein expression pattern of the identified genes was verified in clinical tissue samples. A retrospective clinical study was performed to evaluate the correlation between the expression of candidate proteins and survival time of patients. Moreover, comprehensive analysis of the combination of multiple genes/proteins for the prognosis prediction of PC was performed using both TCGA data and clinical data. In vitro studies were undertaken to elaborate the potential roles of these biomarkers in clonability and invasion of PC cells. FINDINGS: In total, 389 DEGs were identified. These genes were mainly associated with pancreatic secretion, protein digestion and absorption, cytochrome P450 drug metabolism, and energy metabolism pathway. The top 10 genes were filtered out following Fisher's exact test. ROC curve analysis demonstrated that TMPRSS4, SERPINB5, SLC6A14, SCEL, and TNS4 could be used as biomarkers for the diagnosis of PC. Survival analysis of TCGA data and clinical data suggested that TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can be potential biomarkers for the prognosis of PC. Comprehensive analysis show that a combination of identified genes/proteins can predict the prognosis of PC. Mechanistically, the identified genes attributes to clonability and invasiveness of PC cells. INTERPRETATION: We synthesized several sets of public data and preliminarily clarified pathways and functions of PC. Candidate molecular markers were identified for diagnosis and prognosis prediction of PC including a novel gene, TMC7. Moreover, we found that the combination of TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can serve as a promising indicator of the prognosis of PC patients. The candidate proteins may attribute to clonability and invasiveness of PC cells. This research provides a novel insight into molecular mechanisms as well as diagnostic and prognostic markers of PC. FUND: National Natural Science Foundation of China [No. 81602646 &81802339], Natural Science Foundation of Guangdong Province [No. 2016A030310254] and China Postdoctoral Science Foundation [No. 2016M600648].

Berberine, a natural plant alkaloid, synergistically sensitizes human liver cancer cells to sorafenib.

Sorafenib resistance is one of the major factors affecting the prognosis of patients with hepatocellular carcinoma (HCC). Increasing evidence has indicated that certain traditional medicines can enhance the sensitivity of cancer cells to sorafenib. Berberine, an isoquinoline alkaloid, has been demonstrated to possess antitumor properties against various malignancies. However, the synergistic effect of the combination of berberine and sorafenib in HCC remains unknown. The aim of the present study was to determine the effects of berberine and sorafenib combination on the growth of liver cancer cells. Initially, it was observed that the combination of sorafenib and berberine exerted a synergistic inhibitory effect on the proliferation of SMMC­7721 and HepG2 cells in a dose­ and time­dependent manner by an MTS assay. Edu staining and colony formation assays also revealed that the combination of 100 µM berberine and 4 µM sorafenib exhibited a significant anti­proliferation effect on SMMC­7721 and HepG2 cells. Furthermore, western blotting assay indicated that the expressions levels of cleaved poly(ADP­ribose) polymerase and cleaved caspase­3 increased, while those of the anti­apoptotic protein B­cell lymphoma 2 and vascular endothelial growth factor decreased. To the best of our knowledge, this is the first study to demonstrate that berberine sensitized liver cancer cells to sorafenib treatment. These results suggest that berberine combined with sorafenib is able to inhibit the proliferation of liver cancer cells and induce apoptosis, which provides evidence for further clinical investigation in HCC patients with sorafenib resistance.

Increased mediator complex subunit 15 expression is associated with poor prognosis in hepatocellular carcinoma.

Mediator complex subunit 15 (MED15) is a coactivator involved in the regulated transcription of RNA polymerase II-dependent genes and serves an oncogenic role in numerous types of cancer. However, the expression and function of MED15 in hepatocellular carcinoma (HCC) remain unknown. In the present study, the aim was to investigate the expression and clinical significance of MED15 in HCC. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical analysis revealed that MED15 mRNA and protein levels were significantly upregulated in HCC tissues compared with those in the corresponding adjacent non-tumor liver tissues. Furthermore, analyzing data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and GSE14520 datasets revealed a significant correlation between MED15 expression and the tumor size (P=0.033), Barcelona Clinic Liver Cancer stage (P=0.031), α-fetoprotein levels (P=0.002) and metastasis risk (P=0.001). Furthermore, patients with high MED15 expression levels had a shorter survival time compared with those with low MED15 expression levels (P<0.05). Univariate and multivariate analyses further revealed that MED15 may be an independent prognostic factor for the overall survival of HCC patients (hazard ratio, 1.762; 95% confidence interval, 1.077-2.882; P<0.05). In addition, MED15 expression was positively associated with hypoxia-inducible factor 1α expression in the TCGA-LIHC and GSE14520 datasets (P<0.01). In conclusion, the data reported in the present study indicated that MED15 is overexpressed in HCC and may represent a novel prognostic biomarker for patients with HCC.

Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation.

Advanced oxidation protein products (AOPPs) are recognized as novel markers of oxidative stress and contribute to various medical conditions, which are associated with secondary osteoporosis. However, little is currently known regarding the role of AOPPs in the development of secondary osteoporosis. As the commander cells of bone remodeling, osteocytes are involved in the pathogenesis of osteoporosis. The present study aimed to determine the cytotoxic mechanisms of AOPPs on osteocytic MLO­Y4 cells. The results demonstrated that treatment with AOPPs significantly triggered apoptosis of MLO­Y4 cells, in a dose­ and time­dependent manner. Furthermore, exposure to AOPPs induced phosphorylation of c­Jun N­terminal kinases (JNK) and p38 mitogen­activated protein kinases (MAPK). Conversely, N­acetylcysteine inhibited the activation of JNK and p38 MAPK, thus suggesting that the AOPPs­induced activation of JNK/p38 MAPK is reactive oxygen species (ROS)­dependent. In addition, SB203580 and SP600125 suppressed apoptosis, but did not affect ROS production, following AOPPs treatment. Notably, AOPPs also induced a significant upregulation in the expression levels of sclerostin and receptor activator of nuclear factor kappa­B ligand (RANKL) in a JNK/p38 MAPK-dependent manner. These findings provide novel insights into the molecular mechanisms underlying AOPPs­mediated cell death, and suggest that modulation of apoptotic pathways via the MAPK signaling cascade may be considered a therapeutic strategy for the prevention and treatment of secondary osteoporosis.

[Establishment of a diet-induced obesity model in zebrafish larvae].

OBJECTIVE: To establish a diet-induced obesity model in zebrafish larvae. METHODS: At 7 days post-fertilization (dpf), 200 zebrafish larvae with normal development were randomly allocated to two groups with the feeding quantity of 30 mg per day (normal feeding group) or 180 mg per day (overfed group) for 20 days. The weight, length, BMI, triglyceride (TG) and total cholesterol (TCH) of each group were measured. Whole-mount Oil Red O staining, frozen Oil Red O staining and hematoxylin-eosin (HE) staining were used to estimate the rate of hepatic steatosis and liver histology of the zebrafish. The dynamic change of hepatic lipid droplets and distribution of adipose tissue were observed with Nile Red staining in overfed zebrafish in vivo. RESULTS: The weight, length, BMI and TG of overfed zebrafish were significantly increased compared with those in normal feeding group. Whole-mount Oil Red O staining showed that the percent of hepatic steatosis in overfed group (89.4%) was markedly higher than that in normal feeding group (20.7%). Macrovesicular steatosis was observed in the liver of the overfed larvae. Nile Red staining visualized hepatic lipid droplets and the distribution of larval adipose tissue, which increased with feeding time in the overfed zebrafish. Starving larvae showed depletion of fat and hepatic lipid, and adipose tissue was induced after refeeding. CONCLUSIONS: We successfully established an diet-induced obesity model in zebrafish larva, in which Nile Red staining allows in vivo observation of the adipocytes and hepatic lipid droplets.