Bangwei Cao

Oncogenic Features of PHF8 Histone Demethylase in Esophageal Squamous Cell Carcinoma

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. It has been reported that histone demethylases are involved in the carcinogenesis of certain types of tumors. Here, we studied the role of one of the histone lysine demethylases, plant homeodomain finger protein 8 (PHF8), in the carcinogenesis of esophageal squamous cell carcinoma (ESCC). Using short hairpin RNA via lentiviral infection, we established stable ESCC cell lines with constitutive downregulation of PHF8 expression. Knockdown of PHF8 in ESCC cells resulted in inhibition of cell proliferation and an increase of apoptosis. Moreover, there were reductions of both anchorage-dependent and -independent colony formation. In vitro migration and invasion assays showed that knockdown of PHF8 led to a reduction in the number of migratory and invasive cells. Furthermore, downregulation of PHF8 attenuated the tumorigenicity of ESCC cells in vivo. Taken together, our study revealed the oncogenic features of PHF8 in ESCC, suggesting that PHF8 may be a potential diagnostic marker and therapeutic target for ESCC.

Efficacy and Safety of Gemcitabine-Fluorouracil Combination Therapy in the Management of Advanced Pancreatic Cancer: A Meta-Analysis of Randomized Controlled Trials

Background Gemcitabine (GEM) is the standard first-line chemotherapy that provides limited clinical benefits for patients with locally advanced/metastatic pancreatic adenocarcinoma (LA/MPC). However, the fluorouracil derivatives (CAP and S-1) show promising efficacy in these patients. This study compared the efficacy and safety of GEM with GEM plus fluorouracil drugs in the treatment of LA/MPC. Methods Pubmed, EMBASE and Cochrane Library databases were searched for relevant randomized controlled trials published on or before January 2014. The Cochrane Collaborations tool was used to assess the risk of bias in randomized trials. The primary end point was overall survival (OS); the secondary end points were one-year survival rate, objective response rate (ORR) and toxicity rates (TRs). Results A total of 8 randomized controlled trials involving 2,126 patients were included in the systematic evaluation. The results showed that OS was significantly improved (HR 0.83, P<0.01; HR 0.87, P = 0.03; HR 0.80, P = 0.01; respectively) and ORR was significantly increased (OR 0.51, P<0.01; OR 0.66, P = 0.03; OR 0.35, P<0.01; respectively) in the GEM+5-FU/CAP/S-1, GEM+CAP and GEM+S-1 groups compared to the GEM alone group. In addition, the one-year survival rate was significantly increased (OR 0.78 P = 0.01; OR 0.47, P = 0.04; respectively) in the GEM+5-FU/CAP/S-1 and GEM+S-1 groups compared to the GEM alone group. The frequency of grade 3/4 TRs were higher in GEM+5-FU/CAP/S-1 group, the significant increase of grade 3/4 neutropenia, thrombocytopenia and diarrhea were observed. Conclusions GEM combined with fluorouracil drugs significantly improved OS and increased one-year survival rate and ORR compared to GEM alone in LA/MPC patients. GEM combined with fluorouracil drugs may be considered as an acceptable alternative treatment for LA/MPC patients.

Efficacy and Safety of Bevacizumab Combined with Chemotherapy for Managing Metastatic Breast Cancer: A Meta-Analysis of Randomized Controlled Trials.

Although the FDA revoked metastatic breast cancer (MBC) from bevacizumab (BEV) indication in 2011, BEV combined with paclitaxel has been written in the breast cancer NCCN guidelines. This systematic assessment was performed to evaluate the efficacy and safety of BEV + chemotherapy (CHE) for managing MBC. PubMed and EMBASE were searched for original articles written in English and published before July, 2015. Progression-free survival was significantly improved in the CHE + BEV arms compared to the CHE arms in overall group and in human epidermal growth factor receptor 2-negative group (HR 0.75, 95% CI: 0.68–0.84, P < 0.001; HR 0.75, 95% CI: 0.69–0.82, P < 0.001). There were no significant improvement in overall survival in the CHE + BEV arms compared to the CHE arms. Significantly more grade 3 febrile neutropenia, hypertension, proteinuria, and cardiac events were observed in the CHE + BEV arm, which are controllable and reversible. Severe bleeding occurred more in the BEV + taxane arms and in patients with brain metastases. Therefore, CHE + BEV significantly increases progression-free survival in patients with MBC, it should be considered as a treatment option for these patients under the premise of reasonable selection of target population and combined CHE drugs.

The Efficacy of Synchronous Combination of Chemotherapy and EGFR TKIs for the First-Line Treatment of NSCLC: A Systematic Analysis.

Background The combination of chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) currently has become the hotspot issue in the treatment of non-small lung cancer (NSCLC). This systematic review was conducted to compare the efficacy and safety of the synchronous combination of these two treatments with EGFR TKIs or chemotherapy alone in advanced NSCLC. Methods EMBASE, PubMed, the Central Registry of Controlled Trials in the Cochrane Library (CENTRAL), Chinese biomedical literature database (CNKI) and meeting summaries were searched. The Phase II/III randomized controlled trials were selected by which patients with advanced NSCLC were randomized to receive a combination of EGFR TKIs and chemotherapy by synchronous mode vs. EGFR TKIs or chemotherapy alone. Results A total of six randomized controlled trials (RCTs) including 4675 patients were enrolled in the systematic review. The meta-analysis demonstrated that the synchronous combination group of chemotherapy and EGFR TKIs did not reach satisfactory results; there was no significant difference in overall survival (OS), time to progression (TTP) and objective response rate (ORR), compared with monotherapy (OS: HR = 1.05, 95%CI = 0.98–1.12; TTP: HR = 0.94, 95%CI = 0.89–1.00; ORR: RR = 1.07, 95%CI = 0.98–1.17), and no significant difference in OS and progression-free survival (PFS), compared with EGFR TKIs alone (OS: HR = 1.10, 95% CI = 0.83–1.46; PFS: HR = 0.86, 95% CI = 0.67–1.10). The patients who received synchronous combined therapy presented with increased incidences of grade 3/4 anemia (RR = 1.40, 95% CI = 1.10–1.79) and rash (RR = 7.43, 95% CI = 4.56–12.09), compared with chemotherapy, grade 3/4 anemia (RR = 6.71, 95% CI = 1.25–35.93) and fatigue (RR = 9.60, 95% CI = 2.28–40.86) compared with EGFR TKI monotherapy. Conclusions The synchronous combination of chemotherapy and TKIs is not superior to chemotherapy or EGFR TKIs alone for the first-line treatment of NSCLC.

Isolation and Identification of miRNAs in exosomes derived from serum of colon cancer patients

Objective: To isolate exosomes from the serum of colon cancer patients and identify RNAs in the small vesicles. Methods: ExoQuick-TC™ Exosome Precipitation Solution was used for exosome isolation and the shapes of exosomes were observed under a transmission electron microscope. Mass spectrometry was used to identify the classification of miRNAs encapsulated in exosomes, and the expression levels of miRNA-21,-133a, and -181b in exosomes were detected by RT-PCR. Results: Exosomes isolated from serum of colon cancer patients were circular-or oval-shaped and vary in size with a diameter of 40-100 nm. Mass spectrometry shows that the main RNAs in exosomes are small RNAs; the levels of these small RNAs in exosomes are significantly higher compared with fresh serum. There is still a tiny amount of small RNAs in exosome-free serum, but the amounts are significantly lower than that in exosomes. No more RNAs were detected in the repeated freezing and thawing serum, but there were still some RNAs detectable in the exosomes extracted from these serums. MiRNA-21, -133a and -181b can be detected in exosomes, and the level of miRNA-21 is associated with early diagnosis of colon cancer. Conclusion: This study proves that commercial kits for exosome separation are more convenient and time-saving and that mass spectrometry is capable of identifying the miRNAs in exosomes. Compared with direct extraction of miRNAs from the serum, the method of isolating exosomes from the serum firstly and then extracting miRNAs from the exosomes can enhance the stability and integrity of their inner miRNAs. Also, we demonstrate that the exosomal miRNA-21 expression is associated with the early diagnosis of colon cancer.

Decreased expression of claudin-3 is associated with a poor prognosis and EMT in completely resected squamous cell lung carcinoma

The deregulation of claudin-3 has been reported to correlate with the invasion and metastasis of various cancers, but little is known about its expression level and the prognostic value in squamous cell lung carcinoma (SqCC). The purpose of this study is to determine the expression levels and the prognostic value of claudin-3 in completely resected SqCC tissues, and the potential underlying mechanism. The protein expression of claudin-3, E-cadherin, β-catenin, and vimentin in the tumor tissues from 103 patients with surgically resected SqCC was examined using immunohistochemistry, western blots, as well as semi-quantitative estimation. The claudin-3 protein level was significantly associated with E-cadherin, β-catenin, and vimentin protein expression. A decreased claudin-3 protein level was significantly correlated with TNM stage, lymph node metastasis, and disease recurrence. Similarly, downregulation of E-cadherin was significantly correlated with lymph node metastasis and disease recurrence. Decreased β-catenin expression also had a significant correlation with disease recurrence. Univariate analyses indicated that the T stage, lymph node metastasis, the TNM stage, and the expression of claudin-3, β-catenin, and vimentin were significant predictors for overall survival (OS). Moreover, multivariate analyses demonstrated that the TNM stage and protein levels of claudin-3, β-catenin, and vimentin were independent predictors for OS of SqCC patients. Claudin-3 plays an important role in the epithelial–mesenchymal transition of SqCC and might be used as a potential prognostic factor for SqCC.

Meta-analysis comparing maintenance strategies with continuous therapy and complete chemotherapy-free interval strategies in the treatment of metastatic colorectal cancer.

There is as yet no consensus as to the best choice among the three treatment options (maintenance, complete chemotherapy-free intervals [CFIs], and continuous) for metastatic colorectal cancer (CRC). We performed a meta-analysis of six trials (N = 2, 454 patients) to compare the safety and efficacy of those three treatment strategies. Maintenance appeared to offer an advantage over CFI with respect to progression-free survival (PFS) (hazard ratio [HR]: 0.53, 95% confidence interval [CI], 0.40–0.69). PFS and overall survival (OS) were comparable between the maintenance and continuous strategies (HR: 1.18, 95% CI, 0.96–1.46; HR: 1.05, 95% CI, 0.98–1.27, respectively), as was OS between the maintenance and CFI strategies (HR: 0.84; 95% CI, 0.70–1.00). The incidence of grade 3/4 toxicity, including neutropenia, neuropathy, hand-foot syndrome and fatigue, was lower with maintenance than with continuous therapy. A maintenance regimen utilizing bevacizumab-based doublets appeared to confer a slight advantage over bevacizumab monotherapy with respect to PFS (P = 0.011). Maintenance appeared to reduce cumulative grade 3/4 toxicity as compared to the continuous strategy, while showing comparable efficacy. Bevacizumab-based doublets appeared to be of particular value in patients with metastatic CRC.

Prognostic significance of HER3 in patients with malignant solid tumors

Human epidermal growth factor receptor 3 (HER3) is closely involved in tumor progression and is an important target of therapy. To evaluate the prognostic significance of HER3 in malignant solid tumors, we searched the PUBMED, EMBASE and CNKI databases for relevant studies written in English or Chinese up to December 2015. Fifteen studies comprising 2964 patients were identified. The HER3+ rate ranged from 9.0-75.1 % in malignant solid tumors: 30.3-75.1 % in breast cancers, 51.1-74.5 % in colorectal cancers, 13.7-59.0 % in gastric cancers, and 54.5-74.4 % in cervical cancers. For patients with a malignant solid tumor, the death risk was higher for those with a HER3+ tumor than for those with a HER3- tumor (HR 1.60, 95% CI: 1.27 - 2.02, P < 0.001). Subgroup analysis revealed this was also the case for patients with digestive or gastric cancer (HR 1.78, P < 0.001; HR 2.18, P < 0.001). By contrast, HER3 had no prognostic significance in colorectal or breast cancer (HR 1.52, P = 0.296; HR 1.23, P = 0.108). HER3+ is thus associated with poor survival in overall and in gastric cancer. The prognostic significance of HER3+ in other tumors is uncertain and deserves further study.Human epidermal growth factor receptor 3 (HER3) is closely involved in tumor progression and is an important target of therapy. To evaluate the prognostic significance of HER3 in malignant solid tumors, we searched the PUBMED, EMBASE and CNKI databases for relevant studies written in English or Chinese up to December 2015. Fifteen studies comprising 2964 patients were identified. The HER3+ rate ranged from 9.0-75.1 % in malignant solid tumors: 30.3-75.1 % in breast cancers, 51.1-74.5 % in colorectal cancers, 13.7-59.0 % in gastric cancers, and 54.5-74.4 % in cervical cancers. For patients with a malignant solid tumor, the death risk was higher for those with a HER3+ tumor than for those with a HER3− tumor (HR 1.60, 95% CI: 1.27 - 2.02, P < 0.001). Subgroup analysis revealed this was also the case for patients with digestive or gastric cancer (HR 1.78, P < 0.001; HR 2.18, P < 0.001). By contrast, HER3 had no prognostic significance in colorectal or breast cancer (HR 1.52, P = 0.296; HR 1.23, P = 0.108). HER3+ is thus associated with poor survival in overall and in gastric cancer. The prognostic significance of HER3+ in other tumors is uncertain and deserves further study.

A Meta-Analysis and Systematic Review on the Association between Human Papillomavirus (Types 16 and 18) Infection and Esophageal Cancer Worldwide.

Background Esophageal cancer is a common and aggressive malignant tumor. This study aimed to investigate the association between human papillomavirus (HPV) Types 16 and 18 and esophageal carcinoma (EC) in the world population by conducting a meta-analysis. Materials and Methods Computerized bibliographic and manual searches were performed to identify all eligible literatures between 1982 and 2014. PUBMED (http://www.ncbi.nlm.nih.gov/pubmed/) and CNKI (http://www.cnki.net/) were the primary sources of case-control studies, and key words used include human papillomavirus, HPV, esophageal, esophagus, cancer, carcinoma, and tumor. All searches were performed by reviewing articles and abstracts cited in the published systematic reviews and case-control studies. Prospective studies that reported relative risk (RR) estimates with 95% CIs for the association between HPV and EC were included. Results Thirty-three randomized studies were identified, and the main features of these trials were included in this systematic review. HPV infection rate in the EC group was 46.5%, while HPV infection rate in the control group was 26.2% (OR = 1.62; 95% CI, 1.33–1.98). In China, the merger OR value was 1.62 (95% CI: 1.26–2.07); while in the Asian region, the merger OR value was 1.63 (95% CI: 1.29–2.04). There were statistical differences in HPV testing due to different detection methods such as PCR, IHC and ISH. In the PCR detection group, the merger OR value was 1.61 (95% CI: 1.33–1.95). Conclusions These results indicate that HPV infection and the incidence of EC are closely associated.

Tetrahydropalmatine attenuates irradiation induced lung injuries in rats

AIMS The lung is a major organ targeted by irradiation (R) in cancer radiotherapy of the thoracic region. Irradiation induced lung injury (RILI) is a common major obstacle in thoracic cancer radiotherapy. Tetrahydropalmatine (THP) has been shown to have a protective effect against oxidative stress. This study was designed to investigate the potential radioprotective effect of THP against RILI and to elucidate the underlying mechanisms. MATERIALS AND METHODS Sprague-Dawley rats were treated with THP and R. THP was delivered 1h before R. Using TUNEL staining to explore the effectiveness of THP displayed on R induced pulmonary cells apoptosis. Lung histopathologic findings, bronchoalveolar lavage fluid (BALF) levels of total cell counts, protein and inflammatory cytokines, fibrotic factors (hydroxyproline content), apoptotic mediators (caspase-3 and cytochrome c) and malondialdehyde (MDA) were also evaluated after R. KEY FINDINGS THP significantly ameliorates the deleterious effects of R. Further studies showed that THP decreased lung injury by inhibiting the pulmonary cells apoptosis; reduced lung inflammation by decreasing BALF cells recruitment and lowering BALF protein levels; reduced pulmonary fibrosis by decreasing collagen content of lung tissues. THP also ameliorated oxidative modification of rat lungs as evidenced by levels of lipid peroxidation. BALF cytokine analysis, moreover, pointed to a mitigation of the chronic inflammatory profile of irradiated lungs as a result of the protective effect of THP treatment. SIGNIFICANCE THP can effectively attenuate RILI through anti-apoptosis, anti-fibrosis and anti-inflammation mechanisms.