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Background: Few studies comprehensively compared the performance of transient elastography (TE) and two-dimensional shear wave elastography(2D-SWE) to diagnose the stage of liver fibrosis in children and adolescents. We assessed the diagnostic performance of these non-invasive imaging techniques from published studies. Methods: To evaluate the diagnostic performance of TE and 2D-SWE, we searched the PubMed, Embase, Web of Science, and Cochrane Library databases until November 13, 2021, for studies that diagnosed liver fibrosis in children and adolescents. Pooled sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratios, and area under the receiver operating characteristic curve were estimated using the bivariate model. We also performed a subgroup analysis of various research characteristics. Results: Twenty-seven studies with 1956 patients were included in the analysis. The sensitivity and specificity of TE and 2D-SWE for detecting liver fibrosis in all stages were greater than 0.82. For the detection of significant fibrosis, advanced fibrosis and cirrhosis, the summary AUC was 0.90 (95% CI: 0.87-0.92), 0.95 (95% CI: 0.93-0.96) and 0.95 (95% CI: 0.93-0.97) for TE, and the summary AUC was 0.92 (95% CI: 0.89-0.94), 0.94 (95% CI: 0.92-0.96) and 0.96 (95% CI: 0.94-0.97) for 2D-SWE, respectively. Both imaging methods detected significant heterogeneity. Conclusions: TE and 2D-SWE can provide accurate non-invasive staging of liver fibrosis in children or adolescents and are a promising technology, particularly for advanced liver fibrosis and cirrhosis, with a high potential to replace liver biopsy.

Background. High expression of copper metabolizing MURR1 domain (COMMD3) is significantly correlated with poor prognosis in hepatocellular carcinoma (HCC) patients. Here, we explored the mechanism by which COMMD3 affects HCC angiogenesis through the HIF1α/VEGF/NF-κB signaling pathway. Methods. SK-Hep1 and Hep-3B cell lines were transfected by COMMD3 overexpression and RNA interference lentivirus and verified using RT-qPCR and western blotting techniques. Using RNA sequencing, we analyzed differentially expressed genes in COMMD3-overexpressed and COMMD3-knockdown HCC cells. Altogether, colony formation assay, wound healing assay, transwell cell invasion assay, flow cytometry apoptosis experiments, HUVEC tube formation detection, phalloidin staining assay, western blotting, immunohistochemical staining, and a nude mouse xenograft model were used for experimental verification. Results. Lentivirus COMMD3 overexpression and knockdown were successfully established in HCC cells. COMMD3 overexpression significantly promoted the proliferation, angiogenesis, migration, and invasion capacities of HCC cells with no obvious effect on apoptosis versus controls while COMMD3 knockdown showed the opposite trend. The expression and protein levels of COMMD3 as well as HIF1α, VEGF, and NF-κB were increased in COMMD3-overexpressing HCC cells versus control cells, while they were reduced after COMMD3 knockdown. In addition, RNA-seq indicated that COMMD3 is an indispensable gene for HCC angiogenesis through HIF1α and NF-κB signaling pathways. Conclusion. This study showed that low expression of COMMD3 can inhibit HCC angiogenesis by suppressing the HIF1α/VEGF/NF-κB pathway. This implicates COMMD3 as a potential biomarker for improving the therapeutic outcome of HCC.

Background. Hepatocellular carcinoma (HCC) is the main form of primary liver cancer and is one of the most prevalent and life-threatening malignancies globally. Hypoxia activates hypoxia-inducible factor-1α (HIF-1α), which is the key factor in promoting angiogenesis in HCC. Currently, there are few studies on the effects of HIF-1α-targeted gene therapy combined with traditional Chinese herbal extracts. Objective. We investigated the effects of HIF-1α RNA interference (RNAi) combined with asparagus polysaccharide (ASP) on HCC in vitro and in vivo. Methods. CCK-8, wound-healing, transwell, and human umbilical vein endothelial cell tube formation assays were performed to evaluate the proliferation, migration, invasion, and angiogenesis of HCC cells in vitro. In addition, western blotting, qPCR, and immunohistochemistry were performed to detect the expression of HIF-1α, vascular endothelial growth factor, AKT, p-AKT, ERK, p-ERK, and CD34 in HCC cells. Results. The combination of HIF-1α RNAi and ASP significantly inhibited the proliferation, migration, invasion, and angiogenesis of SK-Hep1 and Hep-3B cells compared with the use of HIF-1α RNAi or ASP alone. In addition, this combined treatment was shown to exert these effects by regulating the PI3K and MAPK signaling pathways. These results were observed both in vitro and in vivo. Conclusion. Our study indicates that HIF-1α RNAi combined with ASP inhibits angiogenesis in HCC via the PI3K and MAPK signaling pathways. Thus, we suggest that this combination may be an effective method for the comprehensive treatment of HCC, which may provide new ideas for the treatment of other malignant tumors.

Aim: Although there are so many treatment strategies used for hepatocellular carcinoma (HCC), the overall survival (OS) of HCC patients still remains very low. In our previous studies, asparagus polysaccharide (ASP) has been demonstrated to suppress proliferation, migration, invasion and angiogenesis of HCC cells under normoxic conditions in vitro. However, the inhibitory effects of ASP on the hypoxia-induced migration, invasion and angiogenesis of HCC cells still remain largely unexplored. Materials and methods: Cell Counting Kit-8 (CCK-8) assay, transwell assay, and tube formation assay were used to determine the effects of ASP on hypoxia-induced proliferation, migration, invasion and angiogenesis of HCC cells. ELISA, Western blotting analysis and immunofluorescence assay were used to confirm the effects of ASP on the expressions of HIF-1α and VEGF at the protein level. Moreover, effects of ASP on signaling pathway-related proteins were investigated by Western blotting analysis. Immunohistochemistry (IHC) assay was applied to test the effects of ASP on angiogenesis-associated proteins of tumor cells. Results: We showed that ASP effectively suppressed hypoxia-induced proliferation, migration, invasion and angiogenesis of SK-Hep1 and Hep-3B cells in a dose-dependent manner. In addition, the inhibitory effect of ASP might be partly attributed to down-regulation of HIF1α and VEGF proteins in SK-Hep1 and Hep-3B cells under hypoxic conditions. Moreover, signaling pathway study indicated that ASP significantly down-regulated the hypoxia-induced expressions of p-AKT, p-mTOR and p-ERK, while it had little effects on AKT, mTOR and ERK. Besides, SK-Hep1 xenograft tumor models in nude mice further confirmed that the inhibitory effect of ASP on xenograft tumors might be exerted partly via down-regulation of HIF1α and VEGF through blocking MAPK and PI3K signaling pathways. Conclusions: Our findings suggested that ASP suppressed the hypoxia-induced migration, invasion and angiogenesis of HCC cells partly through regulating HIF-1α/VEGF expression via MAPK and PI3K signaling pathways.

The Copper Metabolism MURR1 Domain (COMMD) family proteins are known to play roles in promoting or inhibiting the proliferation, migration and invasion of tumor cells. However, the role of COMMD3 in hepatocellular carcinoma are still unclear. By investigating the TCGA datasets, we found that the mRNA expression of COMMD3 was significantly upregulated in hepatocellular carcinoma tissue compared with normal liver tissue, which was further supported by Oncomine dataset, Western blot, qRT-PCR, and IHC analysis. Moreover, Kaplan-Meier survival analysis showed that the high expression of COMMD3 was associated with poor overall survival (OS) and disease-free survival (DFS). Consistently, the clinic-pathological analysis found that the overexpression of COMMD3 was correlated with advanced TNM stage, advanced T stage and vascular invasion. By performing multivariate analysis, we found that the expression of COMMD3 was an independent influencing factor on OS and DFS. Furthermore, we knocked down COMMD3 in HCC cells via RNA interference. The results showed that silencing COMMD3 could inhibit the migration, invasion, and angiogenesis of HCC cells. Finally, we established xenograft tumor model in nude mice, and the knockdown of COMMD3 suppressed tumor growth and angiogenesis. In summary, our study showed that the high expression of COMMD3 was correlated with poor prognosis in HCC patients and contributed to migration, invasion and angiogenesis of HCC cells.

OBJECTIVETo identify the effect of traditional Chinese medicine (TCM) on postoperative patients with stage II-III colorectal cancer (CRC) and to explore the core herb combination and its mechanism.METHODSFor this observational cohort study, patients diagnosed between January 2006 and September 2016 were enrolled from two hospitals, data was followed up from January 2019 to November 2020 and was analyzed in December 2020. The primary outcome, disease-free survival (DFS), was compared for those patients who received or did not receive TCM, and the secondary outcome was the hazard ratio (HR). The relevance principle was used to obtain the candidate herb combinations, and the core combination was evaluated through assessment of efficacy and representativeness. Then, the interactions among herbs and CRC were visualized by Cytoscape. Furthermore, related biological processes and signalling pathways were obtained by enrichment and KEGG analyses.RESULTSA total of 707 patients were finally included. In general, TCM decreased the metastatic recurrence associated with stage II-III CRC (HR: 0.61, log-rank P＜0.05). Among those patients in the TCM group, the core combination was Baizhu → Yinchen, Chenpi, and Fuling (C), and its antitumor mechanism was most likely related to 30 core targets, which were associated with 327 biological processes and 111 KEGG pathways. The most closely associated pathways were the PI3K-Akt, MAPK and HIF-1 pathways.CONCLUSIONSOn the whole, a combination of four herbs, Baizhu → Yinchen, Chenpi, and Fuling, could reduce metastatic recurrence in postoperative patients with stage II-III CRC, and the mechanism might be related to the PI3K-Akt, MAPK and HIF-1 pathways.

Background HIF1α mRNA expression in hepatocellular carcinoma (HCC) tissues and its relationship with the prognosis in HCC patients is still unclear. We performed this study to investigate the expression of HIF1α mRNA and its correlation with the prognosis in HCC patients. Materials and methods GSE14520 and Oncomine database were used to analyse the differential expression of HIF1α mRNA among HCC tissues and corresponding peritumour tissues or normal liver tissues. The relationship between HIF1α mRNA expression and the clinicopathological features and survival in HCC patients was analysed using the GSE14520 dataset. CCK-8 assay, wound-healing assay, transwell invasion assay, tube formation assay, and subcutaneous xenograft tumour assays using nude mice were used to confirm the function of HIF1α. Results Expression of HIF1α mRNA was significantly upregulated in HCC tissues (P

Background HIF1α mRNA expression in hepatocellular carcinoma (HCC) tissues and its relationship with the prognosis in HCC patients is still unclear. We performed this study to investigate the expression of HIF1α mRNA and its correlation with the prognosis in HCC patients. Materials and methods GSE14520 and Oncomine database were used to analyse the differential expression of HIF1α mRNA among HCC tissues and corresponding peritumour tissues or normal liver tissues. The relationship between HIF1α mRNA expression and the clinicopathological features and survival in HCC patients was analysed using the GSE14520 dataset. CCK-8 assay, wound-healing assay, transwell invasion assay, tube formation assay, and subcutaneous xenograft tumour assays using nude mice were used to confirm the function of HIF1α. Results Expression of HIF1α mRNA was significantly upregulated in HCC tissues (P

Background. Recent several studies have showed that the nanog overexpression leads to poor prognosis in some kinds of cancer including hepatocellular carcinoma and gastrointestinal luminal cancer. However, the correlations between prognosis and clinic-pathological features and nanog overexpression in lung cancer are still not well-known. Thus, we performed a meta-analysis to evaluate the role of nanog in lung cancer.Methods. An electronic retrieval for related studies was conducted in PubMed, Cochrane Library, Web of Science, EMBASE databases, Chinese CNKI, and the Chinese Wan Fang database up to May 2018. The relationships between nanog overexpression and overall survival (OS) and disease-free survival (DFS) as well as clinic-pathological features in lung cancer were investigated. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by STATA12.Results.11 studies containing 1422 patients were identified in our meta-analysis. The overexpression of nanog showed decreased OS (HR = 1.83, 95% CI = 1.49-2.25,P≤ 0.001) and DFS (HR = 1.86, 95% CI = 1.2-2.9,P= 0.006). Moreover, overexpression of nanog was significantly related to differentiation (OR = 4.17, 95% CI = 2.17-6.43,P≤ 0.001), lymph node metastasis (OR = 1.76, 95% CI = 1.06-2.91,P= 0.028) and tumor size (OR = 1.93, 95% CI = 1.17-3.20,P= 0.010), and no correlation with T stage, TNM, stage, and gender.Conclusions.Our results suggested that nanog overexpression, a hazard factor of differentiation, lymph node metastasis, and tumor size, may predicate decreased OS and DFS for lung cancer.

Background Hepatocellular carcinoma (HCC) is the main form of primary liver cancer and is one of the most prevalent and life-threatening malignancies globally. Hypoxia activates hypoxia-inducible factor-1α (HIF-1α), which is the key factor in promoting angiogenesis in HCC. Currently, there are few studies on the effects of HIF-1α-targeted gene therapy combined with traditional Chinese herbal extracts. Objective We investigated the effects of HIF-1α RNA interference (RNAi) combined with asparagus polysaccharide (ASP) on HCC in vitro and in vivo. Methods CCK-8, wound-healing, transwell, and human umbilical vein endothelial cell tube formation assays were performed to evaluate the proliferation, migration, invasion, and angiogenesis of HCC cells in vitro. In addition, western blotting, qPCR, and immunohistochemistry were performed to detect the expression of HIF-1α, vascular endothelial growth factor, AKT, p-AKT, ERK, p-ERK, and CD34 in HCC cells. Results The combination of HIF-1α RNAi and ASP significantly inhibited the proliferation, migration, invasion, and angiogenesis of SK-Hep1 and Hep-3B cells compared with the use of HIF-1α RNAi or ASP alone. In addition, this combined treatment was shown to exert these effects by regulating the PI3K and MAPK signaling pathways. These results were observed both in vitro and in vivo. Conclusion Our study indicates that HIF-1α RNAi combined with ASP inhibits angiogenesis in HCC via the PI3K and MAPK signaling pathways. Thus, we suggest that this combination may be an effective method for the comprehensive treatment of HCC, which may provide new ideas for the treatment of other malignant tumors.

Background Epithelial cell adhesion molecule (EpCAM) is one of the most commonly used markers of cancer stem cells (CSCs). However, the diagnostic and prognostic significance of EpCAM in lung cancer remains largely undetermined. In the present study, we systematically summarized and elucidated the correlation between EpCAM overexpression and lung cancer through a meta-analysis. Methods Six databases (PubMed, Web of Science, Cochrane Library, and Embase, CnKI and Wanfang Database) were systematically searched. Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) criteria were adopted to assess the qualities of the included studies. Relevant data were extracted for meta-analysis using the Stata12.0 software. Unadjusted mixed odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were estimated to evaluate the correlation between EpCAM overexpression and lung cancer. The sensitivity and specificity of the included studies were used to construct the summary receiver operator characteristic (SROC) curve and calculate the area under the SROC curve (AUC). Results A total of 14 studies consisting of 2,658 lung cancer patients were included following the PICOS principle. We found that the EpCAM expression was significantly higher in lung cancer patients compared with normal controls, including patients with benign pulmonary diseases (OR =63.71, 95% CI, 14.59-278.21, P=0.003) and healthy individuals (OR =520.08, 95% CI, 16.38-16,510.80, P=0.002), and its overexpression was negatively associated with the TNM stage (III + IV) (OR =0.41, 95% CI, 0.21-0.82, P=0.073. The combined sensitivity and specificity of EpCAM overexpression in the diagnosis of lung cancer were 0.79 (95% CI, 0.59-0.90) and 0.98 (95% CI, 0.95-0.99), respectively, and the SROC-AUC was 0.98 (95% CI, 0.97-0.99). Multivariate analysis of 322 lung cancer patients showed that there was no significant correlation between the EpCAM overexpression and prognosis of lung cancer (HR =2.28, 95% CI, 0.80-6.51, P=0.002). Deeks' funnel plot analysis showed the existence of publication bias (P=0.000). Conclusions Our present findings suggested that EpCAM overexpression was not sensitive enough to predict the prognosis of lung cancer. Moreover, it was also a potential diagnostic indicator for lung cancer and correlated with TNM staging of lung cancer.

Marketing mix models (MMMs) are statistical models for measuring the effectiveness of various marketing activities such as promotion, media advertisement, etc. In this research, we propose a comprehensive marketing mix model that captures the hierarchical structure and the carryover, shape and scale effects of certain marketing activities, as well as sign restrictions on certain coefficients that are consistent with common business sense. In contrast to commonly adopted approaches in practice, which estimate parameters in a multi-stage process, the proposed approach estimates all the unknown parameters/coefficients simultaneously using a constrained maximum likelihood approach and solved with the Hamiltonian Monte Carlo algorithm. We present results on real datasets to illustrate the use of the proposed solution algorithm.

To evaluate the survival benefits that lymph node dissection (LND) brought to clinically node-negative upper tract urothelial carcinoma (UTUC) patients. Non-metastatic node-negative UTUC patients were identified from the Surveillance, Epidemiology and End Results database. N0 patients were naturally divided as cN0-pNx group (clinically diagnosed as N0 without LND performed) and cNx-pN0 group (pathologically diagnosed as node-negative no matter what clinical node status they have). Of the 2731 patients included, 2240 and 491 cases were cN0-pNx and cNx-pN0, respectively. The overall survival (OS) of cNx-pN0 patients was significantly better than that of cNx-pN0 patients (p = 0.022). After propensity score matching, the survival of cNx-pN0 patients was still significantly better than cN0-pNx group. Besides, multivariate analyses showed cNx-pN0 (received LND) was an independent favorable prognostic factor for OS and CSS compared with cN0-pNx (no LND). Survival advantages of pN0 group were more significant in ≥ T2 patients and patients with tumor size ≤ 5 cm. Even in N0 patients who received adjuvant treatment, LND still brought obvious survival improvement (HRos = 0.565, p = 0.013; HRcss = 0.607, p = 0.046). LND could improve survival outcomes in patients with clinically node-negative UTUC, especially for those with muscle-invasive diseases (T2–4 stages) or smaller tumor size (≤ 5 cm). Adjuvant treatment after nephroureterectomy is incapable of replacing the therapeutic role of LND.

Objective To evaluate the prognostic value of lymph node (LN) involvement for patients with chromophobe renal cell carcinoma (chRCC) and ascertain the minimum number of LNs that need to be pathologically examined to reliably diagnose a patient with node negative chRCC. Methods From 2004 to 2014, non-metastatic chRCC patients receiving radical nephrectomy together with lymphadenectomy were identified from the Surveillance, Epidemiology and End Results (SEER) database. The primary outcome was overall survival (OS). Results Two hundred and forty-six patients received lymph node dissection during the surgery. Of the patients, 24 (10%) had pathologically confirmed positive LN. Multivariate Cox regression model showed that positive LN was an independent unfavorable predictor for OS (HR = 2.83, 95%CI = 1.14-6.98, P = 0.024). More importantly, LN(-) patients with at least three LNs dissected had significantly better OS compared with when 1-2 LNs were examined (P = 0.048). Multivariate analysis confirmed that in LN(-) patients, the examination of three or more LNs could independently predict better OS compared with patients with only 1-2 LNs dissected (HR≥3LNs = 0.362, 95% CI = 0.135-0.972, P = 0.044). Additionally, the likelihood of finding at least one positive LN was significantly higher on dissection of ≥3 LNs compared with examination of 1-2 LNs (15% vs 5%, P = 0.018). Decision curve analysis found a better clinical validity of the '3 LNs examined'-based classification compared with the traditional LN(-)/LN(+) classification. Conclusion The proportion of positive LNs in chRCC was far from neglectable and LN metastasis could independently predict unfavorable OS. We recommended a minimum of three LNs should be pathologically examined in order to reliably determine node negative.

Objectives: To develop reliable nomograms to estimate individualized overall survival (OS) and cancer specific survival (CSS) for patients with primary small cell carcinoma of the bladder (SCCB) and compare the predictive value with the AJCC stages. Patients and Methods: 582 eligible SCCB patients identified in the Surveillance, Epidemiology, and End Results (SEER) dataset were randomly divided into training (n=482) and validation (n=100) cohorts. Akaike information criterion was used to select the clinically important variables in multivariate Cox models when establishing nomograms. The performance of nomograms was bootstrapped validated internally and externally using the concordance index (C-index) with 95% confidence interval (95% CI) and calibration curves and was compared with that of the AJCC stages using C-index, Kaplan-Meier curves and decision curve analysis (DCA). Results: Two nomograms shared common indicators including age, tumor size, T stage, lymph node ratio, metastases, chemotherapy, radiation and radical cystectomy, while marriage and gender were only incorporated in the OS nomogram. The C-indices of nomograms for OS and CSS were 0.736 (95%CI 0.711-0.761) and 0.731(95%CI 0.704-0.758), respectively, indicating considerable predictive accuracy. Calibration curves showed consistency between the nomograms and the actual observation. The results remained reproducible when nomograms were applied to the validation cohort. Additionally, comparisons between C-indices, Kaplan-Meier curves and DCA proved that the nomograms obtained obvious superiority over the AJCC stages with wide practical threshold probabilities. Conclusions: We proposed the first two nomograms for individualized prediction of OS and CSS in SCCB patients with satisfactory predictive accuracy, good robustness and wide applicability.

Fan Dong,1,* Yifan Shen,1,* Fengbin Gao,2 Tianyuan Xu,2 Xianjin Wang,1 Xiaohua Zhang,1 Shan Zhong,1 Minguang Zhang,1 Shanwen Chen,1 Zhoujun Shen1 1Department of Urology, Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, 2Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China *These authors contributed equally to this work Background: We aimed to evaluate the prognostic value of site-specific metastases in patients with metastatic bladder cancer and analyze the roles that surgeries play in the treatment of this malignancy.Materials and methods: A population-based retrospective study using Surveillance, Epidemiology and End Results dataset was performed and metastatic bladder cancer patients were classified according to the sites of metastases (bone, brain, liver, lung and distant lymph nodes). Kaplan–Meier analysis with log-rank test was used for survival comparisons. Multivariate Cox regression model was employed to analyze the effect of distant metastatic sites on overall survival (OS) and cancer-specific survival (CSS).Results: A total of 1862 patients with metastatic bladder cancer from 2010 to 2014 were identified. Bone, lung and distant lymph nodes were the most common metastatic sites. Patients with bone, brain, liver and lung involvement had worse OS and CSS compared to patients without the corresponding sites of metastases. Multivariate analysis showed that bone, brain, liver and lung metastases were independent prognostic factors for both OS and CSS, while distant node metastasis was not. Moreover, patients with a single metastatic site had more favorable OS (p

Background Fibronectin (FN) is associated with tumorigenesis and progression in bladder cancer, however, the underlying mechanisms causing this remain largely unknown. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A) has been shown to play important regulatory roles in cancer proliferation. Here, we investigated whether FN regulates CIP2A expression to promote bladder cancer cell proliferation. Methods The correlations of stromal FN with CIP2A and proliferating cell nuclear antigen (PCNA) expression were analyzed in a cohort bladder cancer patients. The roles of FN and CIP2A in regulating bladder cancer cell proliferation were evaluated in cell and animal models. Cycloheximide treatment was used to determine the effects of CIP2A on β-catenin stabilization. The CIP2A-β-catenin interaction was confirmed by immunofluorescence staining and co-immunoprcipitation. Results In this study, we found that stromal FN expression correlated positively with the levels of CIP2A and PCNA in bladder cancer tissues. Meanwhile, in human bladder cancer cell lines (T24 and J82), exogenous FN significantly promoted cell proliferation, however, CIP2A depletion inhibited this process. Furthermore, the interaction between CIP2A and β-catenin enhanced the stabilization of β-catenin, which was involved in FN-induced cell proliferation. In vivo, CIP2A depletion repressed FN-accelerated subcutaneous xenograft growth rates. Conclusions These data reveal that CIP2A is a crucial mediator of FN-induced bladder cancer cell proliferation via enhancing the stabilization of β-catenin. Promisingly, FN and CIP2A could serve as potential therapeutic targets for bladder cancer treatment. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0539-8) contains supplementary material, which is available to authorized users.

Hepatocellular carcinoma (HCC) has become a leading cause of cancer-associated mortality worldwide and is thus of great concern. Although various chemotherapeutic drugs are currently used for the treatment of HCC, severe side effects associated with these treatments have prompted interest in novel therapies, including the use of certain biological macromolecules such as polysaccharides. Several studies have shown that polysaccharides have anticancer and antiproliferative effects on HCC. Vascular endothelial growth factor, transforming growth factor β, epidermal growth factor and fibroblast growth factor may be effective targets for polysaccharides and may modulate tumor growth and immunity through increasing the expression levels of cytokines. The present review focuses on the ways in which growth factors contribute to the development of HCC, and on the anti-growth factor activities of natural and synthetic polysaccharides, as well as their effect on proinflammatory cytokines.

Hypoxia-inducible factor-1α (HIF-1α) plays a key role by triggering the transcriptional activation of a number of genes involved in migration, invasion, and angiogenesis in hepatocellular carcinoma (HCC). Thus, suppressing tumour growth by targeting the HIF-1α/VEGF signalling pathway represents a promising strategy for the treatment of HCC. In our previous studies, we found that asparagus polysaccharide (ASP) suppressed the proliferation and promoted the apoptosis of HCC cells both in vivo and in vitro. To further explore the potential mechanisms of the antitumor effects of ASP in HCC, we investigated effects of ASP on the migration, invasion, and angiogenesis of HCC cells (SK-Hep1 and Hep-3B) using an in vitro experimental model. First, we found that ASP effectively suppressed the proliferation of the SK-Hep1 and Hep-3B cells but did not cause significant cytotoxicity in normal liver cells (L-O2). Then, we found that ASP inhibited the migration and invasion of the SK-Hep1 and Hep-3B cells and HCC cells-induced angiogenesis of human umbilical vein endothelial cells in a concentration-dependent manner. Mechanistic studies revealed that the inhibition of migration, invasion, and angiogenesis by ASP in the SK-Hep1 and Hep-3B cells might occur via the downregulation of HIF-1α/VEGF signalling pathway. Finally, our results also showed that the inhibition of HIF-1α by ASP may be mediated through the downregulation of the phosphorylation levels of AKT, mTOR, and ERK. In conclusion, our results suggest that ASP suppresses the migration, invasion, and angiogenesis of HCC cells partly via inhibiting the HIF-1α/VEGF signalling pathway.

Clear cell renal cell carcinoma (ccRCC) has been associated with one of the highest mortality rates among all cancers. Fatty acid binding proteins (FABPs) are 14‑15 kDa proteins that are highly abundant in the cytosol of most tissues. FABP5, a member of the FABP family, has been observed to promote tumor cell growth in numerous cancer types. In order to investigate the function of FABP5 in ccRCC cells in the present study, RNA sequencing data from The Cancer Genome Atlas were analyzed to determine the expression levels of FABP5 in ccRCC patient samples. Survival and Cox regression analyses were performed to measure the association between FABP5 expression and clinicopathological features of patients with ccRCC. Subsequent in vitro experiments downregulated or overexpressed FABP5 in Caki‑1 and 786O ccRCC cells using lentiviral vectors to evaluate cell proliferation ability, and a xenograft transplantation model was established to examine the effect of FABP5 on tumorigenesis in vivo. The results demonstrated that FABP5 expression was significantly upregulated in samples from patients with ccRCC when compared with normal tissue samples. High FABP5 expression was also significantly correlated with tumor and metastasis classifications and predicted poor survival in patients with ccRCC. In ccRCC cells, silencing of FABP5 significantly inhibited cell proliferation, while overexpression of FABP5 promoted cell proliferation when compared to the respective controls. In addition, treatment with the phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K)/AKT inhibitor, LY294002, attenuated the pro‑proliferative effects of exogenous FABP5 expression in Caki‑1 and 786O cells. This indicated that the PI3K/AKT signaling pathway may be partially involved in the FABP5‑mediated increase in ccRCC cell proliferation. Furthermore, FABP5 was observed to regulate tumor growth in nude mice in vivo. In conclusion, the results of the present study suggest that FABP5 may exert a pro‑proliferative role in ccRCC and may be associated with malignant progression and tumorigenesis.

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats.

Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is an urgent need for the development of novel therapies for this deadly disease. It has been proven that asparagus polysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notable antitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvant for liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form, asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE) therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesis and promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functions and showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparagus polysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancer TACE therapy.

Prostate cancer (PCa) is the second most frequently diagnosed cancer in males worldwide and resulted in ~258,000 cases of cancer-associated mortality in 2008. The present study visually determined the pathology scores of PCa specimens by taking into account five characteristics, including the hardness, color, plumpness, transparency and uniformity of specimens. The current study also aimed to identify the association between pathology scores and prostate specific antigen (PSA) levels, in order to reduce the complications caused by punctures and elevate the specimen positive rates. A total of 1,608 specimens from 268 patients were analyzed by one sonographer, one urologist and one pathologist. A standard pathological examination was performed on the PCa biopsy specimens and specimen scores were recorded under double-blinded conditions. A receiver operator characteristic curve identified a linear correlation between the visually determined score and PSA levels (r=0.255; P

Hypoxia could enhance radioresistance in prostate cancer cells through up-regulating HIF-1α, which could be inhibited by statins in several cancer cells. However, this effect of statins in prostate cancer remains unclear. In the present study, we aim to investigate the effect of atorvastatin on HIF-1α expression and radiosensitivity in prostate cancer cells. The hypoxia-induced human prostate cancer PC3 cells were generated by incubating with 5% O2 for 24 h. The cell viability and apoptosis were respectively analyzed by cell counting kit-8 (CCK-8) assay and flow cytometry. The HIF-1α protein expression was assessed by Western blotting. HIF-1α expression in PC3 cells was significantly increased after incubating with 5% O2 for 24 h. The viability of hypoxia-induced PC3 cells was inhibited by a higher dose of irradiation than control cells. The viability of hypoxia-induced PC3 cells were inhibited by astorvastatin with a higher concentration than control cells. Astorvastatin reduced the HIF-1α protein expression in hypoxia-induced PC3 cells, and induced apoptosis of both control and hypoxia-induced cells with and without irradiation. Atorvastatin could enhance radiosensitivity in hypoxia-induced prostate cancer cells, which may be related with inhibition of HIF-1α protein.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in the world whose chemoprevention became increasingly important in HCC treatment. Although the anticancer effects of asparagus constituents have been investigated in several cancers, its effects on hepatocellular carcinoma have not been fully studied. In this study, we investigated the anticancer effects of the deproteinized asparagus polysaccharide on the hepatocellular carcinoma cells using the in vitro and in vivo experimental model. Our data showed that deproteinized asparagus polysaccharide might act as an effective inhibitor on cell growth in vitro and in vivo and exert potent selective cytotoxicity against human hepatocellular carcinoma Hep3B and HepG2 cells. Further study showed that it could potently induce cell apoptosis and G2/M cell cycle arrest in the more sensitive Hep3B and HepG2 cell lines. Moreover, deproteinized asparagus polysaccharide potentiated the effects of mitomycin both in vitro and in vivo. Mechanistic studies revealed that deproteinized asparagus polysaccharide might exert its activity through an apoptosis-associated pathway by modulating the expression of Bax, Bcl-2, and caspase-3. In conclusion, deproteinized asparagus polysaccharide exhibited significant anticancer activity against hepatocellular carcinoma cells and could sensitize the tumoricidal effects of mitomycin, indicating that it is a potential therapeutic agent (or chemosensitizer) for liver cancer therapy.

What’s known on the subject? and What does the study add? Vasoactive intestinal polypeptide (VIP) is an important erectile neurotransmitter, and our previous study found that the mRNA expression of VIP was independent of androgens. The present study further investigated the vivo effect of VIP on erection. We found that not only the expression of VIP was independent of androgens, but also the effect of VIP on erection was independent of androgens. In fact, we found that VIP played a more significant role on erection in castrated rats than in normal rats. OBJECTIVE • To investigate the regulatory role of androgen in VIP-mediated erectile effect. Androgen is essential for physiological erection. Vasoactive intestinal polypeptide (VIP) is an important erectile neurotransmitter. While previous studies demonstrated that VIP expression in the penis was androgen-independent, it remains controversial whether androgen has any effect on VIP-mediated erection. MATERIALS AND METHODS • Male SD rats were divided into a control group, a castration group, and a castration-with-testosterone-replacement group. Four weeks later, each group was subdivided into low and high-dose VIP subgroups and subjected to intracavernous injection of 0.5 and 2 µg VIP, respectively. • Erectile function was tested by recording intracavernosal pressure (ICP) and mean arterial blood pressure (MAP) before and after VIP injection. • The expressions of the VIP-receptor (VPAC2), G-protein stimulatory and inhibitory alpha subunits (Gs-α, Gi-α), and PDE3A in rat corpus cavernosum (CC) was qualified by real-time PCR and Western blot analysis. RESULTS • Castration reduced erectile function while testosterone restored it. VIP improved erectile function in a dose-dependent manner. • High-dose VIP significantly enhanced erectile function in castrated rats and there was no difference of ICP/MAP among three groups after injection of high-dose VIP. • Low-dose VIP also resulted in a higher improvement of erectile function in castrated rats, although the ICP/MAP was lower in these rats than in the other two groups. VPAC2 and Gs-α were up-regulated while Gi-α and PDE3A were down-regulated in CC of castrated rats. CONCLUSION • VIP improves erectile function much more significantly in hypogonadal condition, mainly due to the higher expression of VPAC2, Gs-α, and lower expression of Gi-α and PDE3A in CC of castrated rats. Androgen may negatively regulate the erectile effect of VIP.

The aim of this study was to determine the changes and underlying mechanisms of erectile organ structure and function in castrated rats. In addition, the regulatory effects of an androgen on autophagy and apoptosis in corpus cavernosum smooth muscle cells (CCSMCs), especially the regulatory effect of androgen on the BECN 1–Bcl-2 interaction, were investigated. Male Sprague–Dawley rats were divided into three groups (30/group): control group, castration group, and castration with testosterone supplementation group. The erectile function was examined both in vivo and in vitro, by electric stimulation of the cavernous nerve and corpus cavernosum strip bath test, respectively. Transmission electron microscopy, TUNEL assay, Masson’s trichrome staining, immunohistochemistry, and western blotting were performed to determine the levels of autophagy and apoptosis, and the structural changes in corpus cavernosum. Compared with control group, the castration group showed (1) lower erectile function: lower intracavernosal pressure/mean arterial pressure ratio, lower systolic and diastolic capability of corporal strips, and reduced expressions of eNOS and nNOS; (2) greater fibrosis: decreased smooth muscle/collagen ratio, lower expression of α-SMA, and higher expression of TGF-β1; (3) inhibited autophagy: decreased autophagosomes, lower expressions of BECN1 and LC3-II; and (4) enhanced apoptosis: higher apoptotic index and decreased Bcl-2/Bax ratio. Testosterone supplementation partially improved the effects of castration. Castration attenuates erectile function and induces corporeal fibrosis by inhibiting autophagy and promoting apoptosis of CCSMCs in rats. Therefore, our study highlights the important role of androgens in maintaining the integrity of the structure and function of corpus cavernosum in rats through counter-regulation of autophagy and apoptosis, mainly by regulating BECN 1–Bcl-2 interaction.

Objective To critically review the currently available evidence of studies comparing robot-assisted radical cystectomy (RARC) with open radical cystectomy (ORC). Methods A comprehensive review of the literature from Pubmed, Web of Science and Scopus was performed in April 2014. All relevant studies comparing RARC with ORC were included for further screening. A pooled meta-analysis of all comparative studies was performed and publication bias was assessed by a funnel plot. Results Nineteen studies were included for the analysis, including a total of 1779 patients (787 patients in the RARC group and 992 patients in the ORC group). Although RARC was associated with longer operative time (p

A variety of murine models of experimental prostatitis that mimic the phenotype of human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been developed. However, there is still a lack of explicit diagnosis criteria about those animal model. Our study is to establish histopathological classification criteria, which will be conducive to evaluate the animal models. We firstly established a rat model of experimental autoimmune prostatitis that is considered a valid model for CP/CPPS. For modelling, male Sprague–Dawley rats were immunized with autologous prostate tissue homogenate supernatant emulsified with complete Freund’s adjuvant by subcutaneous injection into abdominal flank and simultaneously immunized with pertussis–diphtheria–tetanus vaccine by intraperitoneal injection. Three immunizations were administered semimonthly. At the 45th day, animals were killed, and prostate tissues were examined for morphology. Histologically, the prostate tissues were characterized by lymphoproliferation, atrophy of acini, and chronic inflammatory cells infiltration in the stromal connective tissue around the acini or ducts. Finally, we built histopathological classification criteria incorporating inflammation locations (mesenchyme, glands, periglandular tissues), ranges (focal, multifocal, diffuse), and grades (grade I–IV). To verify the effectiveness and practicability of the histopathological classification criteria, we conducted the treatment study with one of the alpha blockers, tamsulosin. The histopathological classification criteria of rat model of CP/CPPS will serve for further research of the pathogenesis and treatment strategies of the disease.

Objective To investigate the role of 188Re in human sodium iodide symporter (hNIS) theranostic gene-mediated human glioma imaging and therapy in model mice. Methods The human glioma cell line U87 was transfected with recombinant lentivirus encoding the hNIS gene under the control of cytomegalovirus promoter (U87-hNIS). The uptake and efflux of 188Re were determined after incubating the cells with 188Re. 188Re uptake experiments in the presence of various concentrations of sodium perchlorate were carried out. In vitro cell killing tests with 188Re were performed. U87-hNIS mediated 188Re distribution, imaging and therapy in nude mice were also tested. Results U87-hNIS cell line was successfully established. The uptake of 188Re in U87-hNIS cells increased up to 26-fold compared to control cells, but was released rapidly with a half-life of approximately 4 minutes. Sodium perchlorate reduced hNIS-mediated 188Re uptake to levels of control cell lines. U87-hNIS cells were selectively killed following exposure to 188Re, with a survival of 21.4%, while control cells had a survival of 92.1%. Unlike in vitro studies, U87-hNIS tumor showed a markedly increased 188Re retention even 48 hours after 188Re injection. In the therapy study, there was a significant difference in tumor size between U87-hNIS mice (317±67 mm3) and control mice (861±153 mm3) treated with 188Re for 4 weeks (P

Objective To validate the European Organization for Research and Treatment of Cancer (EORTC) model and the Spanish Urological Club for Oncological Treatment (CUETO) model in Chinese patients with nonmuscle-invasive bladder cancer (NMIBC). Materials and Methods A retrospective study was performed of 363 Chinese patients with NMIBC treated at our hospital from January 2003 to September 2010. Most of these patients had undergone intravesical chemotherapy after transurethral resection of the bladder tumor. The scores for recurrence and progression were calculated using the 2 models. Next, all the patients were divided into 4 risk groups according to their scores. The Kaplan-Meier method was used to estimate the probabilities of recurrence and progression according to both models. Discrimination was assessed using the concordance index. Results The EORTC model successfully stratified our patients into 4 groups with statistically significant different probabilities of recurrence. For progression, only the intermediate- and high-risk groups could be reasonably distinguished using the EORTC model. The CUETO model stratified neither the recurrence nor the progression risks. The concordance index using the EORTC and CUETO model was 0.711 and 0.663 for recurrence and 0.768 and 0.741 for progression, respectively. Conclusion Compared with the CUETO risk tables, the EORTC model showed more value in predicting recurrence and progression in Chinese patients with NMIBC, most of whom received intravesical chemotherapy after transurethral resection of the bladder tumor. Prospective multicenter studies should be performed of large cohorts to construct an ideal prognostic model for Chinese patients with NMIBC.

OBJECTIVES To identify the predictive factors for survival and recurrence of patients with muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) after bladder-conserving therapies and to determine the efficacy of partial cystectomy plus chemotherapy and radiotherapy in the treatment of MIBC. METHODS From 2002 through 2007, 100 patients with MIBC (pT2 74%, pT3-4 26%) underwent partial cystectomy (PC). Subjects who had stage pT3-4 disease received adjuvant chemotherapy and radiotherapy. Univariate and multivariate analyses were performed to determine the predictive factors. RESULTS At median follow-up of 31.5 months (range 6-66 months), 46% patients experienced superficial local recurrence and 14% developed muscle-invasive local recurrence. At the end of follow-up, 24 patients died of bladder cancer, and 71 patients (71%) survived with intact bladders. The 5-year bladder-intact survival rate was 63%. The 5-year cancer-specific survival (CSS) rate was 68%. By multivariate analysis, the presence of more than 3 tumors (P = .002, RR 2.718, 95% CI 1.455-5.079) and nonpapillary growth patterns (P = .005, RR 4.537, 95% CI 1.573-13.081) were predictive factors for local cancer recurrence; the presence of more than 3 tumors (P = .002, RR 4.109, 95% CI 1.676-10.072), lymphovascular invasion (P = .001, RR 6.098, 95% CI 2.038-18.246), and partial cystectomy plus ureteral reimplantation (PC plus UR) (P = .011, RR 0.129, 95% CI .027-0.627) were significantly associated with 5-year CSS, and PC plus UR promoted survival. CONCLUSIONS PC plus chemotherapy and radiotherapy is a rational alternative to radical cystectomy for the treatment of MIBC. Lymphovascular invasion and the presence of more than 3 tumors predict poor outcomes in MIBC after bladder-sparing therapy.

Objective To assess the activity of mTOR and downstream effector proteins in the mTOR pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) inhibitor (PP242) compared with that of mTOR complex 1 (mTORC1) inhibitor (rapamycin) using a xenograft tumor model. Methods Pheochromocytoma PC12 cell were xenografted into nude mice. Animals were treated with PP242 and rapamycin. Mean tumor volume was compared across groups. Terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling staining was used to detect apoptosis. Immunoblot analysis was performed to assess mTORC1/2 activity using p-Akt, p-S6, and p-4E-BP1. The expression of the antiapoptotic protein Bcl-2, pro-apoptotic protein Bax, and the mediator of angiogenesis vascular endothelial growth factor were also investigated. Results The mean tumor volume of PP242 was significantly lower than in other groups. The terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling results showed that PP242 markedly increased cell apoptosis compared with other groups. Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated p-Akt. We also observed that only PP242, but not rapamycin, significantly reduced Bcl-2 expression and markedly increased Bax expression. Rapamycin decreased vascular endothelial growth factor expression, but not nearly as striking as seen in the PP242 group. Conclusion Our study showed that PP242 showed strong antitumor activity in a pheochromocytoma PC12 cell tumor model. Based on our study, dual mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for malignant pheochromocytomas or paragangliomas.