Xinwei Zhang

The role of miRNA-29 family in cancer

The miRNA-29 family of microRNAs (miRNAs), including miR-29a, miR-29b and miR-29c, was recently reported to be aberrantly expressed in multiple cancers. Increasing evidence shows that the abnormal expression of miR-29 family is associated with tumorigenesis and cancer progression, making miR-29s a well-analyzed group of miRNAs in cancer research. Here, in this review we aim to provide an overview of the role of miR-29 family in the pathophysiologic changes of cancer cells and the epigenetic and immune regulation through the biological function of miR-29s.

Diagnostic and prognostic value of circulating miR-21 for cancer: A systematic review and meta-analysis

BACKGROUND MicroRNAs (miRNAs) have been reported to be aberrantly expressed in patients with cancer. Many studies have shown that circulating miRNAs could play potential roles as diagnostic and prognostic biomarkers of cancers. The aim of this meta-analysis is to summarize the role of circulating miR-21 as a biomarker in patients with a variety of carcinomas. MATERIAL AND METHODS Eligible studies were identified and assessed for quality through multiple search strategies. For diagnostic meta-analysis, the sensitivity, specificity, and other measures of miR-21 in the diagnosis of cancer were pooled using bivariate random-effects approach models. For prognostic meta-analysis, pooled hazard ratios (HRs) of circulating miR-21 for survival were calculated. RESULTS A total of 36 studies dealing with various carcinomas were included for the systemic review. Among them, 23 studies were finally enrolled in the global meta-analysis (17 studies for diagnosis and 6 studies for prognosis). For diagnostic meta-analysis, the overall pooled results for sensitivity, specificity, positive likelihood ratio (LRP), negative likelihood ratios (LRN) and diagnostic odds ratio (DOR) were 75.7% (95% CI: 67.1%-82.6%), 79.3% (95% CI: 74.2%-83.5%), 3.65 (95% CI: 2.83-4.70), 0.31 (95% CI: 0.22-0.43), and 11.88 (95% CI: 6.99-20.19), respectively. For prognostic meta-analysis, the pooled HR of higher miR-21 expression in circulation was 2.37 (95% CI: 1.83-3.06, P<0.001), which could significantly predict poorer survival in general carcinomas. Importantly, subgroup analysis suggested that higher expression of miR-21 correlated with worse overall survival (OS) significantly in carcinomas of digestion system (HR, 5.77 [95% CI: 2.65-12.52]). CONCLUSIONS Our findings suggest that circulating miR-21 may not suitable to be a diagnostic biomarker, but it has a prognostic value in patients with cancer.

Maintenance therapy with autologous cytokine-induced killer cells in patients with advanced epithelial ovarian cancer after first-line treatment.

Cytokine-induced killer (CIK) cells have shown cytolytic ability against ovarian cancer cells in vitro and in vivo. This study was aimed to evaluate the clinical efficacy of maintenance therapy of CIK cells in patients with advanced epithelial ovarian cancer after first-line treatment. A paired study was performed in patients with stages IIB–IV epithelial ovarian cancer after cytoreductive surgery followed by 6–8 courses of carboplatin/paclitaxel chemotherapy. A total of 92 patients who achieved complete remission after first-line treatment were enrolled in this study. Forty-six patients in the treatment group received CIK cells transfusion monthly, whereas the other 46 patients in the control group received observation with follow-up. Progression-free survival (PFS), overall survival (OS), and toxicity were evaluated. Our results showed that median PFS was 37.7 months in the treatment group and 22.2 months in the control group (P=0.004). However, although median OS in the treatment group (61.5 mo) was longer than that in the control group (55.9 mo), there was no significant difference (P=0.289). The subgroup analysis revealed that the survival advantage of PFS from immunotherapy was independent of the extent of debulking surgery and pathologic stage. After 2 courses of CIK cells transfusion, the proportion of CD4+CD25+CD127− regular T cells in the peripheral blood significantly decreased (P=0.006). No grades III and IV adverse reaction were found during CIK cells infusion. Maintenance therapy with CIK cells improved the PFS in patients with advanced ovarian cancer after first-line treatment with slight side effects. However, the benefits with respect to OS are still pending.

Can the dual-functional capability of CIK cells be used to improve antitumor effects?

Cytokine-induced killer (CIK) cells, which display both potent anti-tumor ability of T lymphocytes and non-major histocompatibility complex (MHC) restricted killing tumor cells capacity of natural killer (NK) cells are capable of recognizing and lysing a broad array of tumor targets. They have begun to be used in clinical care with good prospects for treatment success. CIK cells are a heterogeneous cell population that contain CD3(+)CD56(+) cells, CD3(-)CD56(+) natural killer (NK) cells and CD3(+)CD56(-) T cells on which much attention has been focused. This review will summarize the connections and differences among CD3(+)CD56(+)CIK cells, CD3(-)CD56(+) NK cells and CD3(+)CD56(-) T cells in the following aspects: the main cell surface molecule, killing mechanism, and clinical applications so that treatment with CIK cells can be optimized and further to enhance the antitumor effect.

Identification of a three-miRNA signature as a blood-borne diagnostic marker for early diagnosis of lung adenocarcinoma.

Background The subtypes of NSCLC have unique characteristics of pathogenic mechanism and responses to targeted therapies. Thus, non-invasive markers for diagnosis of different subtypes of NSCLC at early stage are needed. Results Based on the results from the screening and validation process, 3 miRNAs (miR-532, miR-628-3p and miR-425-3p) were found to display significantly different expression levels in early-stage lung adenocarcinoma, as compared to those in healthy controls. ROC analysis showed that the miRNA–based biomarker could distinguish lung adenocarcinoma from healthy controls with high AUC (0.974), sensitivity (91.5%), and specificity (97.8%). Importantly, these three miRNAs could also distinguish lung adenocarcinoma from lung benigh diseases and other subtypes of lung cancer. Methods Two hundreds and one early-stage lung adenocarcinoma cases and one hundreds seventy eight age- and sex-matched healthy controls were recruited to this study. We screened the differentially expressed plasma miRNAs using TaqMan Low Density Arrays (TLDA) followed by three-phase qRT-PCR validation. A risk score model was established to evaluate the diagnostic value of the plasma miRNA profiling system. Conclusions Taken together, these findings suggest that the 3 miRNA–based biomarker might serve as a novel non-invasive approach for diagnosis of early-stage lung adenocarcinoma.

Profiling the dynamic expression of checkpoint molecules on cytokine-induced killer cells from non-small-cell lung cancer patients

Immune checkpoints associate with dysfunctional T cells, which have a reduced ability to clear pathogens or cancer cells. T-cell checkpoint blockade may improve patient survival. However, checkpoint molecules on cytokine-induced killer (CIK) cell, a non-specific adoptive immunotherapy, remain unknown. In present study, we detected the dynamic expression of eight major checkpoint molecules (CTLA-4, PD-1, PD-L1, TIM-3, CEACAM-1, LAG-3, TIGIT and BTLA) on CIK cells from NSCLC patients. The majority of these molecules, except BTLA, were sharply elevated during the early stage of CIK cell culture. Thereafter, PD-1 and TIGIT expressions decreased gradually towards the initial level (day 0). Moreover, CTLA-4 faded away during the later stage of CIK culture. LAG-3 expression decreased but was still significantly higher than the initial level. Of note, PD-L1 remained stably upregulated during CIK culture compared with PD-1, indicating that PD-L1 might act as an inhibitory molecule on CIK cells instead of PD-1. Furthermore, TIM-3 and CEACAM1 were strongly expressed simultaneously during long-term CIK culture and showed a significant and mutually positive correlation. BTLA displayed a distinct pattern, and its expression gradually decreased throughout the CIK culture. These observations suggested that CIK cells might be partly exhausted before clinical transfusion, characterized by the high expression of PD-L1, LAG-3, TIM-3, and CEACAM-1 and the low expression of TIGIT, BTLA, PD-1, and CTLA-4 compared with initial culture. Our results imply that implementing combined treatment on CIK cells before transfusion via antibodies targeting PD-L1, LAG-3, TIM-3, and CEACAM-1 might improve the efficiency of CIK therapy for NSCLC patients.

Prevalence of Type 2 diabetes and pre-diabetes among overweight or obese children in Tianjin, China.

To determine the prevalence of Type 2 diabetes and pre‐diabetes and their risk factors among overweight or obese school children aged 7–18 years in Tianjin, China.

Plasma miR-324-3p and miR-1285 as diagnostic and prognostic biomarkers for early stage lung squamous cell carcinoma

Background Specific biomarkers for early detection and outcome prediction of lung squamous cell carcinoma (LSCC) are still lacking. This study assessed the differentially expressed miRNAs as potential biomarkers for early stage LSCC. Results Base on the results of multi-phase study, we found that miR-324-3p was significantly up-regulated, whereas mir-1285 was significantly down-regulated in plasma of stage I LSCC patients compared to healthy controls. ROC analysis showed that AUC of miR-324-3p and miR-1285 were 0.79 and 0.85, respectively. The combination of these two miRNAs could further improve the diagnostic accuracy (AUC = 0.89). The multivariate analysis revealed that plasma miR-324-3p level was an independent prognostic predictor for early stage LSCC. Methods 395 patients and 195 healthy controls were enrolled in this study. We screened the differentially expressed plasma miRNAs using TaqMan Low Density Arrays (TLDA) followed by three-phase qRT-PCR validation. We also evaluated the association of candidate miRNAs with overall survival of early stage LSCC patients. Finally, the target genes of the candidate miRNAs were analyzed using public available databases and bioinformatics methods. Conclusions The current study suggests that plasma miR-324-3p and miR-1285 levels could serve as LSCC early detection markers while miR-324-3p may serve as a prognostic marker for LSCC patients.

Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis

Objective A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients. Methods Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated. Results Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs. Conclusion K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.

Clinical Implication of MicroRNA for Lung Cancer

MicroRNAs (miRNAs) are a class of endogenous small noncoding regulatory RNAs, which are new regulators of gene expression. They interfere with multiple biological processes involved in tumorigenesis such as cell proliferation, cell cycle, apoptosis, angiogenesis, invasion, and metastasis. A large body of evidence shows that the aberrant expression of miRNAs in cancer patients provides numerous underlying merits as diagnostic, clinical pathological, prognostic markers, and as promising therapeutic targets of lung cancer, providing an insight into the clinical application for lung cancer. Here, we focus on specific miRNAs as biomarkers in lung cancer and briefly introduce the biological function and modification of miRNAs.