hESC-Derived Epicardial Cells Promote Repair of Infarcted Hearts in Mouse and Swine.

Myocardial infarction (MI) causes excessive damage to the myocardium, including the epicardium. However, whether pluripotent stem cell-derived epicardial cells (EPs) can be a therapeutic approach for infarcted hearts remains unclear. Here, the authors report that intramyocardial injection of human embryonic stem cell-derived EPs (hEPs) at the acute phase of MI ameliorates functional worsening and scar formation in mouse hearts, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis. Mechanistically, hEPs suppress MI-induced infiltration and cytokine-release of inflammatory cells and promote reparative macrophage polarization. These effects are blocked by a type I interferon (IFN-I) receptor agonist RO8191. Moreover, intelectin 1 (ITLN1), abundantly secreted by hEPs, interacts with IFN-ß and mimics the effects of hEP-conditioned medium in suppression of IFN-ß-stimulated responses in macrophages and promotion of reparative macrophage polarization, whereas ITLN1 downregulation in hEPs cancels beneficial effects of hEPs in anti-inflammation, IFN-I response inhibition, and cardiac repair. Further, similar beneficial effects of hEPs are observed in a clinically relevant porcine model of reperfused MI, with no increases in the risk of hepatic, renal, and cardiac toxicity. Collectively, this study reveals hEPs as an inflammatory modulator in promoting infarct healing via a paracrine mechanism and provides a new therapeutic approach for infarcted hearts.

Indocyanine Green Retention Test as a Predictor of Postoperative Complications in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma.

Background: Accurate preoperative estimation of liver function reserve is the key to the safety of hepatectomy. Recently, indocyanine green retention test at 15 minutes (ICG-R15) has been widely used to estimate hepatic function reserve in different liver diseases. The purpose of this research was to investigate the clinical value of ICG-R15 in predicting postoperative major complications and severe posthepatectomy liver failure (PHLF) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) subjected to hepatectomy. Methods: A total of 354 HBV-associated HCC patients who underwent hepatectomy were enrolled. The Child-Pugh, model for end-stage liver disease (MELD), albumin-bilirubin (ALBI) and ICG-R15 for assessing postoperative complications risk were compared using receiver operating characteristic (ROC) curve and decision curve analysis (DCA). Results: Postoperative major complications developed in 32 patients (9.1%) and severe PHLF developed in 57 (16.1%) patients. Multivariate analyses revealed that ICG-R15 were independent factors for predicting postoperative major complications and severe PHLF. ROC curve analyses and DCA plots showed that the predictive abilities of ICG-R15 for postoperative major complications and severe PHLF risk was significantly greater than Child-Pugh, MELD, and ALBI scores. Similar results were obtained by stratifying different background subgroups. Then, patients were divided into three different risk cohorts, emphasizing the significantly discrepancy between the incidence of postoperative major complications and severe PHLF. Conclusion: Compared with Child-Pugh, MELD and ALBI scores, ICG-R15 revealed significantly advantages in predicting postoperative major complications and severe PHLF in HBV-related HCC patients subjected to liver resection.

Preoperative fibrinogen-to-albumin ratio predicts the prognosis of patients with hepatocellular carcinoma subjected to hepatectomy.

BACKGROUND: Systemic inflammatory response (SIR) plays a crucial role in every step of tumorigenesis and development. More recently, the fibrinogen-to-albumin ratio (FAR), an inflammation-based model, was suggested as a prognostic maker for various cancer patients. This research aimed to estimate the prognostic abilities of FAR, neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet- lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) in patients with hepatocellular carcinoma (HCC) subjected to curative hepatectomy. METHODS: A total of 1,502 cases who underwent hepatectomy for HCC were included. The predictive performances of FAR, NLR, MLR, PLR and SII were assessed with regards to overall survival (OS) and disease-free survival (DFS). The area under the time-dependent receiver operating characteristic curve was used to compare prognostic performances. RESULTS: Data revealed that FAR had higher predictive accuracy than other inflammation-based models and alpha-fetoprotein (AFP) in assessing OS and DFS. Indeed, the OS and DFS of patients with high FAR (> 8.9), differentiated by the optimal cut-off value of FAR, were remarkably reduced (p < 0.05 for OS and DFS). Multivariate Cox regression analyses identified that AFP, FAR, clinically significant portal hypertension, tumor size, Barcelona Clinical Liver Cancer staging system, major resection and blood loss were independent indicators for predicting OS and DFS. Furthermore, these patients could be classified according to their FAR into significantly different subgroups, regardless of AFP levels (p < 0.05 for DFS and OS). Similar results were obtained in other inflammation-based prognostic models. CONCLUSIONS: Compared with NLR, MLR, PLR, SII and AFP, FAR showed significant advantages in predicting survival of HCC patients subjected to liver resection.

Air pollution, residents' happiness, and environmental regulation: evidence from China.

This study investigates the impact of air pollution on residents' subjective happiness, using data from the China General Social Survey for 2013, 2015, and 2017, regional air pollution, and socioeconomic indicators. We find that air pollution has a negative effect on residents' subjective happiness. Specifically, the average marginal effect of the logarithm of SO2 emissions on happiness is -0.0099 and significant at the 1% level; namely, a one-unit increase in [Formula: see text] will reduce the likelihood of residents feeling happy by 0.99%. This negative effect is greater for those who have children, are old, or have a higher level of education. We also empirically test two mechanisms by which air pollution affects subjective happiness-depressed mood and leisure activities outside the home-and demonstrate that environmental regulation can moderate the negative impact of air pollution on happiness, but the moderating effects are nonlinear. Environmental governance investments are more effective at the low level, pollutant discharge fees are more effective at the medium level, and complaints about environmental pollution are more effective at the high level. As well as enriching theoretical insights into the relationship between air pollution and happiness, this study provides a valuable reference for developing more suitable policies in relation to environmental management and national happiness.

Myosin light chain 2 marks differentiating ventricular cardiomyocytes derived from human embryonic stem cells.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have great value for studies of human cardiac development, drug discovery, disease modeling, and cell therapy. However, the mixed cardiomyocyte subtypes (ventricular-, atrial-, and nodal-like myocytes) and the maturation heterogeneity of hPSC-CMs restrain their application in vitro and in vivo. Myosin light chain 2 (MYL2, encoding the ventricular/cardiac muscle isoform MLC2v protein) is regarded as a ventricular-specific marker of cardiac myocardium; however, its restricted localization to ventricles during human heart development has been questioned. Consequently, it is currently unclear whether MYL2 definitively marks ventricular hESC-CMs. Here, by using a MYL2-Venus hESC reporter line, we characterized a time-dependent increase of the MYL2-Venus positive (MLC2v-Venus+) hESC-CMs during differentiation. We also compared the molecular, cellular, and functional properties between the MLC2v-Venus+ and MYL2-Venus negative (MLC2v-Venus-) hESC-CMs. At early differentiation stages of hESC-CMs, we reported that both MLC2v-Venus- and MLC2v-Venus+ CMs displayed ventricular-like traits but the ventricular-like cells from MLC2v-Venus+ hESC-CMs displayed more developed action potential (AP) properties than that from MLC2v-Venus- hESC-CMs. Meanwhile, about a half MLC2v-Venus- hESC-CM population displayed atrial-like AP properties, and a half showed ventricular-like AP properties, whereas only ~ 20% of the MLC2v-Venus- hESC-CMs expressed the atrial marker nuclear receptor subfamily 2 group F member 2 (NR2F2, also named as COUPTFII). At late time points, almost all MLC2v-Venus+ hESC-CMs exhibited ventricular-like AP properties. Further analysis demonstrates that the MLC2v-Venus+ hESC-CMs had enhanced Ca2+ transients upon increase of the MLC2v level during cultivation. Concomitantly, the MLC2v-Venus+ hESC-CMs showed more defined sarcomeric structures and better mitochondrial function than those in the MLC2v-Venus- hESC-CMs. Moreover, the MLC2v-Venus+ hESC-CMs were more sensitive to hypoxic stimulus than the MLC2v-Venus- hESC-CMs. These results provide new insights into the development of human ventricular myocytes and reveal a direct correlation between the expression profile of MLC2v and ventricular hESC-CM development. Our findings that MLC2v is predominantly a ventricular marker in developmentally immature hESC-CMs have implications for human development, drug screening, and disease modeling, and this marker should prove useful in overcoming issues associated with hESC-CM heterogeneity.

CFH I62V as a Putative Genetic Marker for Posner-Schlossman Syndrome.

Objective: Posner-Schlossman syndrome (PSS), also known as glaucomatocyclitic crisis, is an ocular condition characterized by recurrent attacks of anterior uveitis and raised intraocular pressure. Previous studies by our team and others have identified the genetic association of complement pathway genes with uveitis and glaucoma. This study aimed to investigate the complement genes in PSS patients with the view of elucidating the genetic background of the disease. Methods: A total of 331 subjects (56 PSS patients and 275 controls) were recruited for this study. We selected 27 variants in six complement pathway genes (SERPING1, C2, CFB, CFH, C3, and C5) and detected them using TaqMan single nucleotide polymorphism (SNP) Genotyping Assays. Univariate SNP association analysis, haplotype-based association analysis, gene-gene interaction analysis among complement genes, and genotype-phenotype correlation analysis were performed. Results: Among the 27 variants of six complement pathway genes, the functional variant I62V (rs800292) at the CFH gene was found to be significantly associated with PSS; there was a significant increase in the frequency of A allele and AA homozygosity in PSS patients than in controls (P = 1.79 × 10-4; odds ratio (OR) 2.18, 95% CI: 1.44-3.29; P = 4.65 × 10-4; OR 3.66, 95% CI: 1.70-7.85, respectively). The additive effect of CFH-rs800292 and SERPING1-rs3824988 was identified with an OR of 12.50 (95% CI: 2.16-72.28). Genotype-phenotype analysis indicated that the rs800292 AA genotype was associated with a higher intraocular pressure and higher frequency of recurrence. Unlike a high proportion of human leukocyte antigen (HLA)-B27 positivity in anterior uveitis, only 3 in 56 (5.36%) PSS patients were HLA-B27 positive. In addition, one haplotype block (GC) in the SERPING1 gene showed a nominal association with PSS with an increased risk of 2.04 (P = 0.01; 95% CI: 1.18-3.53), but the P-value could not withstand the Bonferroni correction (Pcorr > 0.05). Conclusion: This study revealed a genetic association of a CFH variant with PSS as well as its clinical parameters, implying that the alternative complement pathway might play an important role in the pathogenesis of PSS. Further studies to enrich the understanding of the genetic background of PSS and the role of the complement system in ocular inflammation are warranted.

Dioscin Reduces Vascular Damage in the Retina of db/db Mice by Inhibiting the VEGFA Signaling Pathway.

Diabetic retinopathy (DR) is a complication of diabetes that has a serious impact on the quality of life of patients. VEGFA is necessary in the physiological state to maintain endothelial activity and physical properties of blood vessels. VEGFA plays an important role in the promotion of neovascularization; therefore, inhibition of VEGFA can degrade the structure of blood vessels and reduce neovascularization. In the present study, HERB, a high-throughput experimental and reference-oriented database of herbal medicines, was used for compound mining targeting VEGFA. The compounds most likely to interact with VEGFA were screened by molecular docking. Next, the compounds were used to verify whether it could inhibit the activity of the VEGF signaling pathway in vitro and neovascularization in vivo. In vitro, we found that dioscin could inhibit the activation of the VEGFA-VEGFR2 signaling pathway and cell proliferation of human retinal microvascular endothelial cells in a high-glucose (HG) environment. A more important dioscin intervention inhibits the expression of pro-angiogenic factors in the retinas of db/db mice. In conclusion, our study indicates that dioscin reduces the vascular damage and the expression of pro-angiogenic factors in the retina of db/db mice and implies an important and potential application of dioscin for treatment of DR in clinics.

[Naringenin promotes osteogenic differentiation of BMSCs via SDF-1α/CXCR4 signaling axis].

PURPOSE: To explore the influence of naringenin on osteogenic differentiation of bone mesenchymal stem cells(BMSCs), and the role of SDF-1α/CXCR4 signaling axis in the osteogenic differentiation by naringenin. METHODS: BMSCs of the rats were isolated,cultured and tested. CCK-8 assay was used to explore the proliferation ability of BMSCs in different concentrations of naringenin, and alkaline phosphatase(ALP) activity was detected. RT-qPCR was used to detect the mRNA expression of ALP, OCN, CXCR4 and SDF-1α in different groups. The expressions of CXCR4 and SDF-1α protein in BMSCs during osteogenic differentiation in different experimental groups were detected by ELISA. SPSS 21.0 software package was used for statistical analysis of the data. RESULTS: The results of cell identification showed that the cultured cells were BMSCs. At 1 d and 3 d, all concentrations of naringenin had no significant effect on the proliferation of BMSCs; and at 5 d, 50 µg/mL of naringenin promoted proliferation of BMSCs；furthermore, at 7 d, all concentrations of naringenin promoted proliferation of BMSCs(P＜0.05). ALP activity value gradually increased in each concentration over time. From the RT-qPCR experiment, the mRNA expression of ALP, OCN, CXCR4 and SDF-1α in the naringenin group and the osteogenic induction group was significantly increased compared with the medium group(P＜0.05). ELISA assay showed that the protein expressions of CXCR4 and SDF-1α increased gradually in the four groups as time went on and the expression of two proteins was the highest in 100 µg/mL naringenin group. CONCLUSIONS: Naringenin can promote the proliferation and osteogenic differentiation of BMSCs. SDF-1α/CXCR4 signaling axis is involved in the osteogenic differentiation of BMSCs by naringenin,particularly in the early stage of BMSCs osteogenic differentiation.

Global transcriptomic study of circRNAs expression profile in sorafenib resistant hepatocellular carcinoma cells.

The anti-angiogenic drugs represented by sorafenib over the years have always been the first-line treatment of hepatocellular carcinoma (HCC), but the drug resistance has always been a "bottleneck" in curative effect. Recently, aberrant expression of circular RNA (circRNA) is considered to play a crucial role in many types of cancers. However, the genome-wide expression pattern of circRNAs in sorafenib-resistant HCC cells remains unknown. Herein, we identified 1717 differentially expressed circRNAs with 559 up-regulated and 1158 down-regulated (fold change > 2, P < 0.05) in sorafenib-resistant (HUH7-S) HCC cells along with 582 differentially expressed circRNAs with 272 up-regulated and 310 down-regulated (fold change > 2, P < 0.05) in sorafenib-resistant (HepG2-S) HCC cells, compared to parental sorafenib-sensitive (HUH7, HepG2) HCC cells by high-throughput sequencing. In addition, GO (Gene Ontology) term enrichment analysis results revealed an enrichment for binding and catalytic activity and for biological regulation of metabolic processes in both the Huh7-S and HepG2-S cell lines compared to parental cell lines. Moreover, KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway analysis of the differentially expressed genes were significantly related to pathways in cancer. Among them, hsa_circ_0006294 and hsa_circ_0035944 expression were consistently down-regulated in resistant HCC cells. Taken together, our data demonstrate, using a global transcriptomic network, that the circRNA expression profile is significantly altered in sorafenib-resistant HCC cells and that the differentially expressed circRNAs may play important functions in HCC sorafenib resistance and HCC progression.

Three-year follow-up of Coats disease treated with conbercept and 532-nm laser photocoagulation.

BACKGROUND: Coats disease is an idiopathic exudative outer retinopathy caused by abnormal retinal vascular development. AIM: To evaluate the long-term outcomes of intravitreal conbercept injection with laser photocoagulation as a treatment for Coats disease in adults. METHODS: This retrospective case series study included patients diagnosed with Coats disease and treated with intravitreal conbercept injection and 532-nm laser photocoagulation at the Ophthalmology Department of Shenzhen People's Hospital between January 2016 and January 2017. Best-corrected visual acuity (BCVA) measurements, noncontact tonometry, ophthalmoscopy, fundus photography, fundus fluorescein angiography and optical coherence tomography were performed before treatment and at 1 wk, 1 mo, 3 mo, 6 mo, 9 mo, 12 mo, 24 mo and 36 mo after therapy. Best-corrected visual acuity was measured using the early treatment of diabetic retinopathy study chart. RESULTS: The study included eight eyes of 8 patients (7 men) aged 36.10 ± 6.65 years. The average BCVA of the affected eye before treatment was 51.17 ± 15.15 letters (range, 28-70 letters), and the average central macular thickness was 303.30 ± 107.87 µm (range, 221-673 µm). Four eyes were injected once, three were injected twice, and one was injected three times. Average follow-up duration was 37.33 ± 2.26 mo. Average BCVA of the affected eye was 51.17 ± 15.15 letters before treatment and was increased by 13.50 ± 3.20, 16.25 ± 7.73, 18.25 ± 8.96, 18.03 ± 5.27, 18.63 ± 3.35, 19.75 ± 6.96, 18.05 ± 5.36 and 17.88 ± 3.45 letters at 1 wk, 1 mo, 3 mo, 6 mo, 9 mo, 12 mo, 24 mo and 36 mo after treatment, respectively (P < 0.01). The patients showed varying degrees of subretinal fluid resorption after treatment. None of the patients had serious complications such as increased intraocular pressure, development/progression of cataracts, endophthalmitis or retinal detachment. CONCLUSION: Intravitreal injection of conbercept combined with 532-nm laser photocoagulation may be a feasible treatment for Coats disease in adult patients.

A Potential Antitumor Effect of Dendritic Cells Fused with Cancer Stem Cells in Hepatocellular Carcinoma.

HCC stem cells were reported as posttreatment residual tumor cells that play a pivotal role in tumor relapse. Fusing dendritic cells (DCs) with tumor cells represents an ideal approach to effectively activate the antitumor immunity in vivo. DC/HCC stem cell vaccine provides a potential strategy to generate polyclonal immune response to multiple tumor stem cell antigens including those yet to be unidentified. To assess the potential capacity of DC/HCC stem cell vaccines against HCC, CD90+HepG2 cells were sorted from the HCC cell line HepG2. DC and CD90+HepG2 and DC and HepG2 fused cells were induced by polyethylene glycol (PEG). The influence of fusion cells on proliferation and immunological function transformation of lymphocytes was assessed by FCM and ELISA assay, respectively. The cytotoxicity assay of specific fusion cell-induced CTLs against HepG2 was conducted by CytoTox 96 Non-Radioactive Cytotoxicity Assay kit in vitro. At last, the prevention of HCC formation in vivo was described in a mouse model. The results of FCM analysis showed that the proportion of CD90+HepG2 cells in the spheral CD90+HepG2 enriched by suspension sphere culture was ranging from 98.7% to 99.5%, and 57.1% CD90+HepG2/DC fused cells were successfully constructed. The fusion cells expressed a higher level of costimulatory molecules CD80, CD83, CD86, and MHC-I and MHC-II molecules HLA-ABC and HLA-DR than did immature DCs (P < 0.05). And the functional analysis of fusion cell-induced CTLs also illustrated that CD90+HepG2/DC fusion cells showed a greater capacity to activate proliferation of lymphocytes in vitro (P < 0.05). The CD90+HepG2/DC-activated CTLs had a specific killing ability against CD90+HepG2 cells in vivo. These results suggested that CD90+HepG2/DC fusion cells could efficiently stimulate T lymphocytes to generate specific CTLs targeting CD90+HepG2 cells. It might be a promising strategy of immunotherapy for HCC.

[Efficiency of Inducing CIK from Cryopreserved PBMNC by Using Immune Cell SR].

OBJECTIVE: To investigate the efficiency of inducing CIK from peripheral blood mononuclear cells(PBMNC) by using immune cell serum replacement(immune cell SR), so as to provide a new strategy for the industrialized production of immune cells. METHODS: The PBMNC of healthy volunteers were collected, and these cells were thawed after short-term cryopreservation and cultured to induce CIK cells. The cells viability was measured by trypan blue exclusion, the phenotypes were analyzed by flow cytometry, and the cytotoxicity was determined by Calcein-AM/PI double staining. RESULTS: In cryopreserved PBMNC, the control group cells failed to normally proliferate. Cell proliferation ratio was low in 2% SR group in comparison with the fresh group, and the difference was significant (P<0.05), however, differences were not statistically significant between 5% SR and fresh group or between 10% AP and fresh group. CD3+, CD3+CD8+ and CD3+CD56+ cell subsets were not significantly different before and after cryopreservation (P>0.05). After being cultured, CD3+, CD3+CD4+, CD3+CD8+, CD3+CD56+ and CD3-CD56+ subsets and the cytotoxicity in vitro were not significantly different among all group(P>0.05). CONCLUSION: 5% SR without the protein of animal origin can be safely used as a substitute for autologous plasma in CIK induced from cryopreserved PBMNC by culture, thus providing a basis for the application of cryopreservation technique of immune cells to cell therapy.

Bone morphogenetic protein and activin membrane-bound inhibitor overexpression inhibits gastric tumor cell invasion via the transforming growth factor-ß/epithelial-mesenchymal transition signaling pathway.

Gastric carcinoma is one of the most common human malignancies and remains the second leading cause of cancer-associated mortality worldwide. Gastric carcinoma is characterized by early-stage metastasis and is typically diagnosed in the advanced stage. Previous results have indicated that bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) overexpression has been demonstrated to inhibit growth and metastasis of gastric cancer cells. However, the molecular mechanisms of the BAMBI-mediated signaling pathway in the progression of gastric cancer are poorly understood. In the present study, to assess whether BAMBI overexpression inhibited the growth and aggressiveness of gastric carcinoma cells through regulation of transforming growth factor (TGF)-ß/epithelial-mesenchymal transition (EMT) signaling pathway, the growth and metastasis of gastric carcinoma cells were analyzed following BAMBI overexpression and knockdown in vitro and in vivo. Molecular changes in the TGF-ß/EMT signaling pathway were studied in gastric carcinoma cells following BAMBI overexpression and knockdown. DNA methylation of the gene regions encoding the TGF-ß/EMT signaling pathway was investigated in gastric carcinoma cells. Tumor growth in tumor-bearing mice was analyzed after mice were subjected to endogenous overexpression of BAMBI. Results indicated that BAMBI overexpression significantly inhibited gastric carcinoma cell growth and aggressiveness, whereas knockdown of BAMBI significantly promoted its growth and metastasis compared with the control (P<0.01). The TGF-ß/EMT signaling pathway was downregulated in BAMBI-overexpressed gastric carcinoma cells; however, signaling was promoted following BAMBI knockdown. In addition, it was observed that BAMBI overexpression significantly downregulated the DNA methylation of the gene regions encoding the TGF-ß/EMT signaling pathway (P<0.01). Furthermore, RNA interference-mediated BAMBI overexpression also promoted apoptosis in gastric cancer cells and significantly inhibited growth of gastric tumors in murine xenografts (P<0.01). In conclusion, the present findings suggest that BAMBI overexpression inhibited the TGF-ß/EMT signaling pathway and suppressed the invasiveness of gastric tumors, suggesting BAMBI may be a potential target for the treatment of gastric carcinoma via regulation of the TGF-ß/EMT signaling pathway.

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common types of malignancy with high morbidity and mortality rates worldwide. This biologically heterogeneous disease results in diverse therapeutic responses, thus, novel prognostic biomarkers are required to improve CRC treatment. Estrogen-related receptor α (ERRα) is a nuclear orphan receptor, which is associated with estrogen receptor α. The present study aimed to investigate the expression of ERRα in patients with CRC, and explore the association between ERRα expression and clinicopathological factors, local recurrence and prognosis. In the present study, ERRα expression was detected in 15 fresh CRC tissues using quantitative real-time polymerase chain reaction (RT-qPCR) and in 128 paraffin-embedded CRC tissues using immunohistochemistry. The associations between ERRα expression and prognosis of CRC patients were evaluated by univariate, and multivariate (Cox proportional hazards model) analysis. RT-qPCR demonstrated that the mRNA expression of ERRα in CRC tissues was significantly higher compared with that in matched normal tissues. Immunohistochemistry revealed that ERRα high expression was detected in the nuclei of cancer cells from 39.1% (50/128) of CRC tissues. ERRα expression based on immunohistochemical staining was significantly associated with tumor differentiation, tumor invasion, lymph node status and Dukes stage (all P<0.05). Furthermore, patients with high ERRα expression were significantly associated with an increased risk of recurrence and poor prognosis, compared with patients with low ERRα expression. ERRα expression was identified as an independent prognostic factor for patients with CRC. In conclusion, ERRα serves important roles in the progression of CRC and is a potential prognostic factor for patients with CRC.

GP73 level determines chemotherapeutic resistance in human hepatocellular carcinoma cells.

Objective GP73 is a new hepatocellular carcinoma (HCC) marker, which is highly expressed in hepatocellular carcinoma and closely relates to prognosis. This study was to investigate the effects of GP73 on cellular proliferation, apoptosis, oxaliplatin (OXA) resistance and secretory clusterin (sCLU) of HCC cells. Materials and Methods Western blot and immunofluorescence was used to detect the expression of GP73 in 8 types of commonly used HCC cell lines. Drug resistance was induced by increasing concentration gradient method. The drug-resistant human HCC cell lines underwent GP73 overexpression or inhibition. Flow cytometry were used to detect the proliferation and apoptosis of HCC cell lines. The changes of sCLU were detected by enzyme-linked immunosorbent assay (ELISA). Results The expression of GP73 in MHC-97H cells was the highest and in Hep3B cells the lowest. The expression of GP73 was found further elevated in OXA-resistant MHC-97H cells. After the knockdown of GP73 in OXA-resistant 97H cells, the IC50 of OXA decreased and the ability of cell proliferation decreased significantly. After over-expression of GP73 in OXA-resistant Hep3B cells, the IC50 of OXA increased and the cell proliferation ability increased, showing that GP73 is critical for OXA resistant in HCC cell lines; No significant change of sCLU level in GP73 overexpressed Hep3B and GP73 blocked MHCC-97H were identified. Conclusion The expression level of GP73 is critical for the resistance of OXA in HCC cell lines.

CHEK2 SNPs predict better prognosis in HBV-related hepatocellular carcinoma patients.

OBJECTIVE: Checkpoint kinase 2 gene (CHEK2) is an important mediator of the DNA damage response pathway. Single nucleotide polymorphisms (SNPs) have been shown to influence the developing risk and clinical characteristics in various types of human malignancies. The values of CHEK2 SNPs in HBV-related hepatocellular carcinoma patients (HCC) were unknown and discussed here. METHODS: The expression and prognostic prediction role of CHEK2 were searched and analyzed in HBV-related HCC patients by GEO database. SNPs in CHEK2 were genotyped by SNP selection tools, and further assessed their associations with clinical outcomes of 339 HBV-related HCC patients. RESULTS: Patients with a higher CHEK2 gene expression predicted a worse relapse free survival (RFS). Moreover, those with a variant alleles CC/TT of SNPs rs1547014 and rs738722 had a significantly better prognosis when compared to the patients with CT genotype (P<0.015 for rs1547014, P=0.001 for rs738722), and CC/TT genotype combined with AFP≤400 ng/ml also predicted the best prognosis in HBV-related HCC patients. In stratified analysis, the protective effect of rs1547014 and rs738722 CC/TT genotype was more evident in patients with adverse strata, comparing the patients with favorable strata. CONCLUSION: CHEK2 SNPs rs1547014 and rs738722 probably be potential prognostic bio-markers in HBV-related HCC patients.

APE1 overexpression is associated with poor survival in patients with solid tumors: a meta-analysis.

APE1 is known as a key mediator of DNA damage repair pathways, and its clinical significance in different types of cancer is well studied. Herein, we performed a meta-analysis to determine the association of APE1 expression and survival in different types of solid cancer. We searched all eligible publications in PubMed, Web of Science and Embase platforms from inception to January 2017 and found 15 relevant manuscripts. Overall survival (OS), 12- and 36-month survival rates, and hazard ratios (HRs) were extracted and analyzed. Heterogeneity and publication bias were also assessed. A subgroup analysis of the different subcellular locations of APE1 was also conducted. Patients with higher APE1 levels demonstrated lower 12- and 36-month survival rates than those with low APE1 levels (HR 2.00, 95% CI 1.33-3.00, P = 0.0009; HR 1.84, 95% CI 1.19-2.84, P = 0.006). Importantly, the pooled analysis showed that high levels of APE1 predict shorter OS (HR 1.44, 95% CI 1.13-1.83, P = 0.003). Subgroup analysis revealed that both nuclear and cytoplasmic expression levels of APE1 are important indicators of poor prognosis in solid tumors.

High expression of RBM8A predicts poor patient prognosis and promotes tumor progression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a huge threat for human health worldwide. As a complicated tumor, the molecular basis for HCC development especially metastasis requires exploration. Although RNA binding motif (RBM) proteins are closely related to various cancers, the clinical importance and underlying mechanisms of RBM8A in HCC remain elusive. In this study, we found that RBM8A was highly expressed in HCC tumor tissues compared to normal liver tissues. Overexpression of RBM8A was associated with HbsAg and Edmondson pathological grading. Moreover, Kaplan-Meier survival analysis showed that high expression of RBM8A was related to the poor overall survival and progression-free survival of patients with HCC. Gain- and loss-of-function experiments further demonstrated that RBM8A promoted tumor cell migration and invasion in HCC via activation of epithelial-mesenchymal transition signaling pathway. It is also noteworthy that RBM8A is required for tumor cell proliferation and anti-apoptosis in HCC. Altogether, our results revealed a close relationship between RBM8A and HCC prognosis as well as a critical tumor-promoting function of RBM8A in HCC progression, suggesting that RBM8A might be a potential bio-marker and drug target in HCC therapy.

The clinical significance and biological function of large tumour suppressor 2 in hepatocellular carcinoma.

OBJECTIVES: Present evidence has suggested that large tumour suppressor 2 (LATS2) is abnormally expressed in most human cancer. However, the clinical and prognostic value in hepatocellular carcinoma (HCC) is still unknown. MATERIALS AND METHODS: Large tumour suppressor 2 mRNA and protein expression levels in HCC tissues and cell lines were detected by qRT-PCR, immunohistochemistry or Western blot. The correlation between LATS2 expression and clinicopathological factors was analysed through immunohistochemistry. The function of LATS2 on HCC cell growth and mobility was explored through MTT, colony formation, Transwell migration and invasion assays. The molecular mechanism of LATS2 was screened and confirmed by qRT-PCR and Western blot. RESULTS AND CONCLUSION: In this study, LATS2 mRNA and protein expressions were decreased in HCC tissues and cell lines compared with normal hepatic tissues and hepatic cell line. Low LATS2 expression was oppositely corrected with tumour stage, vascular invasion and metastasis. The univariate and multivariate analyses suggested that low LATS2 expression was an independent poor prognostic factor for HCC patients. The in vitro experiments showed that LATS2 regulated HCC cells migration and invasion, but had no effect on HCC cells proliferation. Meanwhile, LATS2 modulated metastasis-associated genes expression including E-cadherin, vimentin, snail, slug, MMP2 and MMP9. In conclusion, LATS2 is a prognostic biomarker and a tumour metastasis suppressor in HCC.