Huanliang Liu

PTEN Loss Increases PD-L1 Protein Expression and Affects the Correlation between PD-L1 Expression and Clinical Parameters in Colorectal Cancer

Background Programmed death ligand-1 (PD-L1) has been identified as a factor associated with poor prognosis in a range of cancers, and was reported to be mainly induced by PTEN loss in gliomas. However, the clinical effect of PD-L1 and its regulation by PTEN has not yet been determined in colorectal cancer (CRC). In the present study, we verified the regulation of PTEN on PD-L1 and further determined the effect of PTEN on the correlation between PD-L1 expression and clinical parameters in CRC. Methods/Results RNA interference approach was used to down-regulate PTEN expression in SW480, SW620 and HCT116 cells. It was showed that PD-L1 protein, but not mRNA, was significantly increased in cells transfected with siRNA PTEN compared with the negative control. Moreover, the capacity of PTEN to regulate PD-L1 expression was not obviously affected by IFN-γ, the main inducer of PD-L1. Tissue microarray immunohistochemistry was used to detect PD-L1 and PTEN in 404 CRC patient samples. Overexpression of PD-L1 was significantly correlated with distant metastasis (P<0.001), TNM stage (P<0.01), metastatic progression (P<0.01) and PTEN expression (P<0.001). Univariate analysis revealed that patients with high PD-L1 expression had a poor overall survival (P<0.001). However, multivariate analysis did not support PD-L1 as an independent prognostic factor (Pu200a=u200a0.548). Univariate (P<0.001) and multivariate survival (P<0.001) analysis of 310 located CRC patients revealed that high level of PD-L1 expression was associated with increased risks of metastatic progression. Furthermore, the clinical effect of PD-L1 on CRC was not statistically significant in a subset of 39 patients with no PTEN expression (distant metastasis: Pu200a=u200a0.102; TNM stage: Pu200a=u200a0.634, overall survival: Pu200a=u200a0.482). Conclusions PD-L1 can be used to identify CRC patients with high risk of metastasis and poor prognosis. This clinical manifestation may be partly associated with PTEN expression.

Postoperative Adjuvant Chemotherapy for Stage II Colorectal Cancer: A Systematic Review of 12 Randomized Controlled Trials

BackgroundThe impact of postoperative adjuvant chemotherapy on the oncological outcomes for stage II colorectal cancer remains controversial.MethodsThe literature was searched for studies published between 1985 and 2010 in which patients with stage II colorectal cancer were randomly assigned to receive either surgery combined with postoperative adjuvant chemotherapy or surgery alone. End points included 5-year overall survival, 5-year disease-free survival, recurrence, and mortality.ResultsA significant improvement in 5-year overall survival was associated with surgery combined with postoperative adjuvant chemotherapy for stage II colon cancer (hazard ratio, 0.81; 95% confidence interval (CI), 0.71–0.91) and for stage II rectal cancer (hazard ratio, 0.72; 95% CI, 0.61–0.86). The 5-year disease-free survival also favored the group of surgery combined with postoperative adjuvant chemotherapy for stage II colon cancer (hazard ratio, 0.86; 95% CI, 0.75–0.98) and for stage II rectal cancer (hazard ratio, 0.34; 95% CI, 0.22–0.51). For stage II colon cancer, a significant reduction in risk of recurrence was found in favor of postoperative adjuvant chemotherapy (risk ratio, 0.82; 95% CI, 0.71–0.95).ConclusionsPostoperative adjuvant chemotherapy for stage II colorectal cancer appears to be associated with improved 5-year overall survival and 5-year disease-free survival, and reduction in risk of recurrence.

Clinical outcomes of active specific immunotherapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review

BackgroundTo evaluate the objective clinical outcomes of active specific immunotherapy (ASI) in advanced colorectal cancer (advanced CRC) and suspected minimal residual colorectal cancer (suspected minimal residual CRC).MethodsA search was conducted on Medline and Pub Med from January 1998 to January 2010 for original studies on ASI in colorectal cancer (CRC). All articles included in this study were assessed with the application of predetermined selection criteria and were divided into two groups: ASI in advanced CRC and ASI in suspected minimal residual CRC. For ASI in suspected minimal residual CRC, a meta-analysis was executed with results regarding the overall survival (OS) and disease-free survival (DFS). Regarding ASI in advanced colorectal cancer, a system review was performed with clinical outcomes.Results1375 colorectal carcinoma patients with minimal residual disease have been enrolled in Meta-analysis. A significantly improved OS and DFS was noted for suspected minimal residual CRC patients utilizing ASI (For OS: HR = 0.76, P = 0.007; For DFS: HR = 0.76, P = 0.03). For ASI in stage II suspected minimal residual CRC, OS approached significance when compared with control (HR = 0.71, P = 0.09); however, the difference in DFS of ASI for the stage II suspected minimal residual CRC reached statistical significance (HR = 0.66, P = 0.02). For ASI in stage III suspected minimal residual CRC compared with control, The difference in both OS and DFS achieved statistical significance (For OS: HR = 0.76, P = 0.02; For DFS: HR = 0.81, P = 0.03). 656 advanced colorectal patients have been evaluated on ASI in advanced CRC. Eleven for CRs and PRs was reported, corresponding to an overall response rate of 1.68%. No serious adverse events have been observed in 2031 patients.ConclusionsIt is unlikely that ASI will provide a standard complementary therapeutic approach for advanced CRC in the near future. However, the clinical responses to ASI in patients with suspected minimal residual CRC have been encouraging, and it has become clear that immunotherapy works best in situations of patients with suspected minimal residual CRC.

Mutations of p53 and K-ras correlate TF expression in human colorectal carcinomas: TF downregulation as a marker of poor prognosis

BackgroundTissue factor (TF) is emphasized as the promising target in the future targeted therapy strategy for colorectal cancer (CRC). Recent evidence showed that TF expression is under the control of K-ras and p53. However, a comprehensive evaluation of TF expression, K-ras status, and p53 mutation has not been systematically analyzed. The aims of this study were to identify the percentages of positive TF in CRC patients; analyze the associations of TF expression, K-ras status, and p53 mutation; and evaluate the prognostic value of TF in CRC patients.MethodsNinety-six CRC samples were tested for TF expression, p53 mutation, and K-ras status by semiquantitative immunohistochemistry, Western blotting analysis, direct sequencing, and real-time quantitative PCR. Associations were sought with TF expression and clinical outcomes.ResultsTF expression was related to clinical stages, tumor differentiation, and tumor size. The positive proportions of TF expression on tumor cells and tumor vascular endothelial cells were 70% and 53% respectively in CRC patients. The positive proportion of TF co-expression on both cancer cells and tumor vascular endothelial cells was 40%, compared to an 83% total TF positive proportion in CRC patients. TF expression on CRC appeared to be increased with K-ras and/or p53 mutation(s). Disease-free survival and overall survival were significantly reduced in CRC patients with high TF expression.ConclusionsTF may participate in both K-ras and p53 mutations involved in colorectal carcinogenesis and could be considered as a prognostic indicator for patients CRC.

Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri

The production of fungal metabolites can be remarkably influenced by various cultivation parameters. To explore the biosynthetic potentials of the marine fungus, Neosartorya pseudofischeri, which was isolated from the inner tissue of starfish Acanthaster planci, glycerol-peptone-yeast extract (GlyPY) and glucose-peptone-yeast extract (GluPY) media were used to culture this fungus. When cultured in GlyPY medium, this fungus produced two novel diketopiperazines, neosartins A and B (1 and 2), together with six biogenetically-related known diketopiperazines,1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxopyrazino[1,2-a]indole (3), 1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole (4), 1,2,3,4-tetrahydro-2-methyl-1,3,4-trioxopyrazino[1,2-a] indole (5), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio)gliotoxin (11), didehydrobisdethiobis(methylthio)gliotoxin (12) and N-methyl-1H-indole-2-carboxamide (6). However, a novel tetracyclic-fused alkaloid, neosartin C (14), a meroterpenoid, pyripyropene A (15), gliotoxin (7) and five known gliotoxin analogues, acetylgliotoxin (8), reduced gliotoxin (9), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio) gliotoxin (11) and bis-N-norgliovictin (13), were obtained when grown in glucose-containing medium (GluPY medium). This is the first report of compounds 3, 4, 6, 9, 10 and 12 as naturally occurring. Their structures were determined mainly by MS, 1D and 2D NMR data. The possible biosynthetic pathways of gliotoxin-related analogues and neosartin C were proposed. The antibacterial activity of compounds 2–14 and the cytotoxic activity of compounds 4, 5 and 7–13 were evaluated. Their structure-activity relationships are also preliminarily discussed.

Tissue metabolomic fingerprinting reveals metabolic disorders associated with human gastric cancer morbidity

The principal way to improve the outcome of gastric cancer (GC) is to predict carcinogenesis and metastasis at an early stage. The aims of the present study were to test the hypothesis that distinct metabolic profiles are reflected in GC tissues and to further explore potential biomarkers for GC diagnosis. Gas chromatography/mass spectrometry (GC/MS) was utilized to analyze tissue metabolites from 30 GC patients. A diagnostic model for GC was constructed using orthogonal partial least squares discriminant analysis (OPLS-DA), and the metabolomic data were analyzed using the non-parametric Wilcoxon rank sum test to identify the metabolic tissue biomarkers for GC. Over 100 signals were routinely detected in one single total ion current (TIC) chromatogram, and the OPLS-DA model generated from the metabolic profile of the tissues adequately discriminated the GC tissues from the normal mucosae. Among the low-molecular-weight endogenous metabolites, a total of 41 compounds, such as amino acids, organic acids, carbohydrates, fatty acids and steroids, were detected, and 15 differential metabolites were identified with significant difference (p<0.05). A total of 20 variables were noted which contributed to a great extent in the discriminating OPLS-DA model (VIP value >1.0), among which 12 metabolites were identified using both VIP values (VIP >1) and the Wilcoxon test (p<0.05). In conclusion, the identification of the metabolites associated with GC morbidity potentially revealed perturbations of glycolysis, fatty acid β-oxidation, cholesterol and amino acid metabolism. These results suggest that tissue metabolic profiles have great potential in detecting GC and may aid in understanding its underlying mechanisms.

Gambogic acid inhibits growth, induces apoptosis, and overcomes drug resistance in human colorectal cancer cells

The emergence of chemoresistance is a major limitation of colorectal cancer (CRC) therapies and novel biologically based therapies are urgently needed. Natural products represent a novel potential anticancer therapy. Gambogic acid (GA), a small molecule derived from Garcinia hanburyi Hook. f., has been demonstrated to be highly cytotoxic to several types of cancer cells and have low toxicity to the hematopoietic system. However, the potential role of GA in colorectal cancer and its ability to overcome the chemotherapeutic resistance in CRC cells have not been well studied. In the present study, we showed that GA directly inhibited proliferation and induced apoptosis in both 5-fluorouracil (5-FU) sensitive and 5-FU resistant colorectal cancer cells; induced apoptosis via activating JNK signaling pathway. The data, therefore, suggested an alternative strategy to overcome 5-FU resistance in CRC and that GA could be a promising medicinal compound for colorectal cancer therapy.

Outcomes of post-cataract surgery endophthalmitis referred to a tertiary center from local hospitals in the south of China

BackgroundEndophthalmitis after cataract surgery is an uncommon but devastating complication. Prophylactic intracameral injection of cefuroxime 1xa0mg at the end of surgery decreases the incidence five-fold. The visual outcome can be good (53% of cases having a visual acuity [VA] of better than 20/40) if treatment is initiated rapidly and follows the Endophthalmitis Vitrectomy Study (EVS) guidelines; but even with the best treatment, some patients end up with a poor visual outcome. Previous studies on postoperative endophthalmitis mainly focus on the cases performed in metropolitan tertiary hospitals; however, little information is available on the cases performed in local hospitals in rural areas.MethodsWe retrospectively reviewed the medical records of patients with acute endophthalmitis following cataract surgery, which were performed in local hospitals and later treated at the Zhongshan Ophthalmic Center between 1 January 1998 and 31 December 2009. Details of each case, including the interval from symptoms to presentation, initial treatment in local hospitals, microorganisms isolated, treatment, and visual outcome, were recorded. Cross-tabulations were conducted in order to identify the prognostic factors of final visual outcome.ResultsForty-six patients referred from 36 local hospitals and later treated at the Zhongshan Ophthalmic Center were reviewed over the audit period. Most of these cases occurred in April. Gram-positive bacteria were the predominant etiology, with fungal infection accounting for 15%. Even though 54% of patients had symptoms within 3xa0days post-cataract surgery, they did not present to a tertiary center until a mean of 10xa0days. The main initial treatment in local hospitals is systemic antibiotics, instead of the intravitreal injection of antibiotics. A high proportion of cases (27/46) received immediate pars plana vitrectomy (PPV) in the tertiary center, and the antibiotic used for intravitreal injection was mainly tobramycin. The final visual outcome was poor, with only three cases having a VA ≥20/40.ConclusionA relatively high rate of fungal endophthalmitis suggests that sterilization patterns in local hospitals should be further revised. A delayed presentation, inappropriate treatment procedures, poor presenting VA, and causative organism virulence may account for the unfavorable visual outcome in this study.

AQP9-induced cell cycle arrest is associated with RAS activation and improves chemotherapy treatment efficacy in colorectal cancer

Aquaporin-9 (AQP9) expression is associated with arsenic sensitivity in leukemia cells. However, the role of AQP9 in regulating tumor sensitivity to adjuvant chemotherapy in colorectal cancer (CRC) has not been elucidated. In this study, we demonstrated that AQP9 can serve as an independent predictive marker for adjuvant chemotherapy in CRC. Patients with high AQP9 expression had higher rate of disease-free survival (DFS) than those with low AQP9 expression. Upregulation of AQP9 was associated with enhanced chemosensitivity to 5-fluorouracil (5-FU) both in vitro and in vivo. Overexpression of AQP9 resulted in an increased intracellular level of 5-FU in CRC cells, hence leading to a higher percentage of apoptosis after 5-FU treatment. Moreover, AQP9 is positively associated with RAS activation and other downstream signaling molecules in CRC. AQP9 overexpression resulted in p21 upregulation and induced S-phase arrest. Taken together, AQP9 enhances the cytotoxic response to 5-FU in CRC cells by simultaneously inducing S-phase arrest via activation of RAS signaling and facilitating drug uptake. Our results suggest that AQP9 might be a novel predictor for the benefit of 5-FU-based chemotherapy in CRC. The identification of AQP9-induced tumor sensitivity to 5-FU highlights the role of AQP9 in regulating chemosensitivity in CRC.

Multi-microarray identifies lower AQP9 expression in adjuvant chemotherapy nonresponders with stage III colorectal cancer

Approximately 25% of stage III colorectal cancer patients do not benefit from standard adjuvant chemotherapies. To identify biomarkers for nonresponders, fresh-frozen tissues of 19 nonresponders and 16 responders were analyzed with gene expression and microRNA arrays. Fifty-nine genes and 17 miRNAs were differentially expressed by at least two folds. AQP9, SATB2, and WIF1 were simultaneously lower expressed in the nonresponders and modulated by the differentially expressed miRNAs. RT-PCR validated the differential expression of AQP9 (p=0.035). In conclusion, lower AQP9 gene expression is related with non-response to adjuvant chemotherapy, showing potential as predictive marker and therapeutic target.