The clinical utility of multimodal MR image-guided needle biopsy in cerebral gliomas.

PURPOSE: Our aim was to evaluate the diagnostic value of multimodal Magnetic Resonance (MR) Image in the stereotactic biopsy of cerebral gliomas, and investigate its implications. MATERIALS AND METHODS: Twenty-four patients with cerebral gliomas underwent (1)H Magnetic Resonance Spectroscopy ((1)H-MRS)- and intraoperative Magnetic Resonance Imaging (iMRI)-supported stereotactic biopsy, and 23 patients underwent only the preoperative MRI-guided biopsy. The diagnostic yield, morbidity and mortality rates were analyzed. In addition, 20 patients underwent subsequent tumor resection, thus the diagnostic accuracy of the biopsy was further evaluated. RESULTS: The diagnostic accuracies of biopsies evaluated by tumor resection in the trial groups were better than control groups (92.3% and 42.9%, respectively, p = 0.031). The diagnostic yield in the trial groups was better than the control groups, but the difference was not statistically significant (100% and 82.6%, respectively, p = 0.05). The morbidity and mortality rates were similar in both groups. CONCLUSIONS: Multimodal MR image-guided glioma biopsy is practical and valuable. This technique can increase the diagnostic accuracy in the stereotactic biopsy of cerebral gliomas. Besides, it is likely to increase the diagnostic yield but requires further validation.

The Clinical Utility of Matrix Metalloproteinase 9 in Evaluating Pathological Grade and Prognosis of Glioma Patients: A Meta-Analysis.

In the recent years, matrix metalloproteinase 9 (MMP-9) has been focused on as an indicator of glioma grade and prognosis, especially in China. However, all results resulted in many conflicts. So, it is necessary to conduct a meta-analysis to secure a convincing correlation between MMP-9 and grade and prognosis. Eligible studies were included via multiple searches, and then odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were estimated. Funnel plots were available for evaluation of publication bias. In addition, heterogeneity and sensitivity were also analyzed. In the present meta-analysis, 23 articles were allowed for inclusion with total 1,635 patients. Coincidentally, all studies were conducted in Chinese populations. High MMP-9 expression in gliomas was closely associated with high WHO grade (III+IV) (n = 22, OR = 5.25, 95% CI = 4.09-6.73; p = 0.000), while MMP-9 expression did not correlate to age (n = 4, OR = 1.02, 95 % CI = 0.67-1.54; p = 0.929) and gender (n = 5, OR = 0.91, 95% CI = 0.63-1.33; p = 0.632). Besides, overall survival analysis from two articles revealed MMP-9 expression significantly predicted 5-year-OS (HR = 6.44, 95% CI = 3.88-10.70; p = 0.000) in glioma patients. No heterogeneity and publication bias were observed across all studies. To conclude, this meta-analysis suggests MMP-9 is potently associated with high grade and poor 5 years prognosis, and MMP-9 test of glioma tissues should be established in department of pathology as a routine in clinical practice.

The impact of survivin on prognosis and clinicopathology of glioma patients: a systematic meta-analysis.

Up to now, survivin has been recommended as a prognostic and diagnostic indicator in glioma patients. However, there are still many controversies. Here, a meta-analysis was conducted to draw a more definitive conclusion on the correlation of survivin with overall survival (OS), age, gender, and WHO grade. Eligible studies were available through careful assessment, and then pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated. Funnel plots were introduced to evaluate the publication bias. Additionally, heterogeneity and sensitivity were also evaluated. In the present meta-analysis, 15 eligible studies with a total of 1,089 patients were incorporated. Survivin expression in gliomas correlated with 2-year OS (n = 8; HR 0.17, 95% CI 0.11-0.26) and 5-year OS (n = 7; HR 0.12, 95% CI 0.07-0.22) in patients. In addition, a fixed-effect model revealed a significant association between survivin and age (male/+; OR 2.10, 95% CI 1.44-3.05) and survivin and WHO grade (I+II/+; OR 0.27, 95% CI 0.19-0.38). No heterogeneity was observed across all studies. According to Begg's and Egger's test and funnel plot, no publication bias was reported. Taken together, our meta-analysis suggests that survivin expression is associated with poor survival, older age, and higher WHO grade and could be suggested as a useful prognostic and diagnostic biomarker, or an effective therapy target.

The Clinical Implications of Chemokine Receptor CXCR4 in Grade and Prognosis of Glioma Patients: A Meta-Analysis.

Chemokine receptor CXCR4 has been identified to affect glioma progression by dominating cancer cell survival, proliferation, and migration in vitro recently. However, the implications and utilities of CXCR4 in clinical grade and prognosis were rarely reported. Thus, it is essential to carry out a meta-analysis to draw a convincing conclusion. The relevant articles were included through careful assessment, and then, odds ratios (ORs), standard mean differences (SMDs), and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were estimated. Heterogeneity and funnel plots evaluation were conducted. In this meta-analysis, all 13 eligible studies involving 785 patients were included and conducted in China. Ten studies revealed altered CXCR4 expression in glioma tissues was closely associated with high WHO grade (III + IV) (n = 10, OR 5.46, 95% CI 3.81-7.84; p = 0.000); besides, six studies also demonstrated CXCR4 expression intensity extremely correlated to high grade (n = 6, SMD -2.45, 95% CI -2.78, -2.12; p = 0.000). Most importantly, three articles identified that CXCR4 expression significantly correlated to 3-year overall survival (OS) (HR 7.32, 95 % CI 4.16-12.90; p = 0.000) in glioma patients. No heterogeneity and publication bias were observed across all studies. Taken together, this meta-analysis suggests CXCR4 expression in gliomas can be recommended as evidence of WHO grade and indeed predict 3-year overall survival. We also provided a scientific rationale for clinically pathological detection of CXCR4 that is required for treatment of glioma patients.

The Clinical Implications of Transforming Growth Factor Beta in Pathological Grade and Prognosis of Glioma Patients: A Meta-Analysis.

The transforming growth factor beta (TGF-ß) pathway plays a key role in oncogenesis of advanced cancers. However, the effects of TGF-ß pathway on gliomas are still controversial. So, it is essential to conduct a meta-analysis to determine their correlations. Eligible studies were included, and then odds ratios (ORs), standard mean differences (SMDs), and hazard ratios (HRs) with 95 % confidence intervals (95% CIs) were estimated. Funnel plots were available for evaluation of publication bias. In this meta-analysis, all 14 eligible studies involving 875 patients were included and conducted in China. Six studies with dichotomous data revealed altered TGF-ß expression in glioma tissues was closely associated with high WHO grade (III + IV) (OR 4.39, 95% CI 2.90-6.63; p = 0.000), meanwhile, seven studies with continuous data also demonstrated TGF-ß expression intensity extremely related to high grade (SMD -2.44, 95% CI -2.71, -2.16; p = 0.000). To our interest, TGF-ß expression was associated with old age (OR 0.59, 95% CI 0.36-0.93; p = 0.025) rather than gender (OR 1.04, 95% CI 0.64-1.67; p = 0.884). Besides, TGF-ß expression significantly correlated to 3-year-OS (n = 2; HR 2.53, 95% CI 1.18-5.41; p = 0.017) rather than 5-year-OS (n = 1; HR 1.04, 95% CI 0.66-1.64; p = 0.872) in glioma patients. No heterogeneity and publication bias were observed across all studies. Taken together, the present meta-analysis testifies TGF-ß is potently associated with high grade and poor 3 years prognosis, and TGF-ß test combined with survivin [1 Mol Neurobiol] and MMP9 [2 Mol Neurobiol] in glioma tissues should be clinically recommended as criteria of glioma grade in department of pathology.

CXCR4 Signaling Induced Epithelial-Mesenchymal Transition by PI3K/AKT and ERK Pathways in Glioblastoma.

Stromal cell-derived factor 1 (SDF-1) and its receptor, CXCR4, play an important role in tumor progression. Epithelial-mesenchymal transition (EMT) process is linked to disease pathophysiology. This study aimed to investigate the roles and underlying mechanisms of SDF-1/CXCR4 axis in EMT process of glioblastoma. In the present study, CXCR4 activation and inhibition in U87 were induced with exogenous SDF-1 and with CXCR4 small interfering RNA (siRNA), respectively. CXCR4 downstream signal molecules AKT, ERK, and EMT biomarkers (vementin, snail, N-cadherin, and E-cadherin) were tested using the Western blot. Our results showed that SDF-1 can induce AKT and ERK phosphorylation in a dose-dependent manner, and endogenous CXCR4 can be blocked thoroughly by CXCR4 siRNA in U87. Notably SDF-1 alone treatment can induce the upregulation of vementin, snail, and N-cadherin of U87; besides, the downregulation of E-cadherin also occurred. On the contrary, CXCR4 siRNA significantly prohibited SDF-1-induced AKT and ERK phosphorylation, at the same time, EMT biomarker changes were not observed. Function analysis revealed that CXCR4 siRNA obviously interfered with U87 cell migration and proliferation, according to wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the SDF-1/CXCR4 axis in glioblastoma, and then involved in the tumor cell invasion and proliferation via activation of PI3K/AKT and ERK pathway. Our study lays a new foundation for the treatment of glioblastoma through antagonizing CXCR4.

The Downregulation of MicroRNA-146a Modulates TGF-ß Signaling Pathways Activity in Glioblastoma.

Transforming growth factor-ß (TGF-ß) is considered to be one of the main factors responsible for glioblastoma tumorigenesis. MicroRNAs have recently been shown to regulate cell proliferation, differentiation, and apoptosis. However, the involvement of miRNA-146a in TGF-ß1-induced glioblastoma development remains largely unknown. Here, miRNA-164a transfection was used to overexpress miRNA-164a in U87, and then real-time quantitative PCR and Western blot were applied to detect the gene transcription and protein expression. In addition, MTT and wound healing assay were also used to observe cell proliferation and migration. Our data revealed that miRNA-146a was downregulated by TGF-ß1 treatment, but upregulated by miRNA-164a transfection. MiRNA-146a overexpression significantly reduced SMAD4 protein expression instead of p-SMAD2. Besides, miRNA-146a overexpression also decreased the messenger RNA (mRNA) and protein expression of epidermal growth factor receptor (EGFR) and MMP9 as well as the p-ERK1/2 level. Furthermore, the upregulation of miRNA-146a suppressed TGF-ß1-mediated U87 proliferation and migration. These results demonstrate that miRNA-146a acts as a novel regulator to modulate the activity and transduction of TGF-ß signaling pathways in glioblastoma, and the downregulation of miRNA-146a is required for overexpression of EGFR and MMP9, which can be considered an efficiently therapeutic target and a better understanding of glioblastoma pathogenesis.

The impact of statins therapy on disease activity and inflammatory factor in patients with rheumatoid arthritis: a meta-analysis.

OBJECTIVES: Statin is the most widely used as HMG-CoA reductase inhibitor, and contributes to clinically significant vascular risk reduction. However, the role of statins in the rheumatoid arthritis (RA) immunomodulation is debatable. This meta-analysis aimed to determine the efficacy of statins therapy in RA patients. METHODS: A structured literature search was undertaken to identify randomised controlled trials (RCTs) conducted in RA patients receiving either statins or control. A meta-analysis on standardised mean difference (SMD) with a 95% confidence interval (95%CI) was conducted. RESULTS: We included 15 studies with a total of 992 patients (487 patients allocated to statins therapy). Our data revealed statins can attenuate disease activity markedly. Overall, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) declined significantly during the treatment (n=12, SMD: -2.222, 95%CI: -2.404, -2.040, p=0.000; n=14, SMD: -3.014, 95%CI: -3.207, -2.821, p=0.000), among which ESR and CRP decreased obviously at 12 months (n=5, SMD: -2.874, 95%CI: -3.224, -2.523, p=0.000; n=7, SMD: -3.970, 95%CI: -4.300, -3.641, p=0.000; respectively). As expected, the tender joint count (TJC) and swollen joint count (SJC) also fell (n=9, SMD: -2.005, 95% CI: -2.216, -1.794; p=0.000; n=10, SMD: -1.76, 95%CI: -1.948, -1.577; p=0.000; respectively). Besides, morning stiffness was attenuated (n=5, SMD: -1.242, 95%CI: -1.474, -1.011, p=0.000), and showed no significant differences between 12 months and 24 months (p=0.205). Notably, statins indeed potently down-regulate inflammatory factors TNF-α (n=7, SMD: -4.290, 95%CI: -4.659, -3.922; p=0.000), IL-1 (n=4, SMD: -1.324, 95%CI: -1.646, -1.003; p=0.000), and IL-6 (n=10, SMD: -1.652, 95%CI: -1.822, -1.482; p=0.000). No publication bias was observed across all studies based on the Begg and Egger test. CONCLUSIONS: This meta-analysis demonstrates the pleiotropic effects of statins on ameliorating RA activity and mediating clinically apparent anti-inflammatory effects in the context of RA autoimmune inflammation, which make it recommended as a potent treatment for RA patients.

Nuclear Protein C23 on the Cell Surface Plays an Important Role in Activation of CXCR4 Signaling in Glioblastoma.

The chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1 (SDF-1) plays an important role in tumor progression and are associated with angiogenesis. Meanwhile, the implications of C23 in multiple signaling pathways have been also investigated. However, the effects of C23 on CXCR4 pathway in glioblastoma are not fully characterized. In the present study, C23 and CXCR4 of U87 cell line were inhibited by anti-C23 and anti-CXCR4 antibodies, respectively; and then C23 and CXCR4 siRNAs were used to knock down endogenous C23 and CXCR4, respectively. In addition, MTT assay was also introduced. Our data showed that either anti-C23 or anti-CXCR4 antibodies efficaciously repressed the phosphorylation levels of ERK (p < 0.000) and AKT (p < 0.000) compared with SDF-1 alone and control. As expected, either C23 or CXCR4 siRNAs indeed resulted in C23 and CXCR4 knockdown and further suppressed the expression of p-ERK and p-AKT. Most importantly, immunoprecipitation revealed C23 interacted with CXCR4 once U87 was exposed to SDF-1 treatment. In addition, MTT assay identified that C23 or CXCR4 siRNAs could obviously decreased cell proliferation capacity (p = 0.002). In conclusion, our results suggest that C23 plays a crucial role in activation of SDF-1-induced ERK and PI3K/AKT pathways via interacting with CXCR4. Furthermore, C23 could be recommended as an important element in glioblastoma development and a new target for glioblastoma treatment.

Nucleolin promotes TGF-ß signaling initiation via TGF-ß receptor I in glioblastoma.

The transforming growth factor ß (TGF-ß) pathway plays a key role in oncogenesis of advanced cancers, involving the non-Smad and Smad pathways. Meanwhile, nucleolin on the cell surface has been also reported to affect activation of signaling pathways. However, the effect of cell surface nucleolin on TGF-ß pathway in glioblastoma is not still understood. Here, using antibodies of nucleolin and TGF-ß receptor I (TßR-I), we observed blocking of either nucleolin or TßR-I inhibited the phosphorylation of CrkL, Erk1/2, and Smad2. Using nucleolin siRNA, nucleolin knockdown was also identified to suppress the expression of p-CrkL, p-Erk1/2, and p-Smad2. Furthermore, immunoprecipitation revealed the interaction between cell surface nucleolin and TßR-I on the U87 cell membrane. In addition, U87 cell wound-healing, soft-agar and MTT assay also showed si-nucleolin could obviously impair wound closure (p < 0.001), colony formation (p < 0.001) and cell growth (p < 0.001). In conclusion, nucleolin promotes and regulates the TGF-ß pathway by interacting with TßR-I and is required for initiation and activation of TGF-ß signaling. Thus, nucleolin could be a key factor in glioblastoma pathogenesis and considered a therapeutic target, which may also mediate more signaling pathways.

Cell surface protein C23 affects EGF-EGFR induced activation of ERK and PI3K-AKT pathways.

The epidermal growth factor (EGF) pathway has been reported as canonical causes in cancer development. Meanwhile, the involvement of C23 in multiple signaling pathways has been also investigated (Lv et al., 2014). However, the effect of C23 on EGF pathway in glioblastoma is not fully characterized. In the present study, C23 and the epidermal growth factor receptor (EGFR) of U251 cell line were inhibited by C23 and EGFR antibodies, respectively; and then C23 and EGFR siRNAs were used to knock down endogenous C23 and EGFR, respectively. In addition, soft-agar and MTT assay were also introduced. Compared with control, either C23 or EGFR antibodies efficiently repressed the phosphorylation levels of ERK1/2 (p<0.000) and AKT (p<0.000). Similarly, either C23 or EGFR siRNAs indeed resulted in C23 and EGFR knockdown, and further suppressed the expression of p-ERK1/2 and p-AKT. Most importantly, immunoprecipitation revealed C23 interacted with EGFR once U251 was exposed to EGF treatment. In addition, the MTT and soft-agar assay also identified that C23 or EGFR siRNAs could obviously affected cell growth (p=0.004) and invasiveness, as cell viability and colony formation decreased markedly. Our results suggest that C23 plays a crucial role in activation of EGF-induced ERK and PI3K-AKT pathways via interacting with EGFR; furthermore, C23 could be indicative of an important factor in glioblastoma development and a useful target for glioblastoma treatment.

The association of Crk-like adapter protein with poor prognosis in glioma patients.

Glioma is the most common of brain tumors that greatly affects patient survival. In our precious study, Crk-like adapter protein (CrkL) was identified as a key regulator in glioblastoma development [1]. Here, we aimed to investigate the correlation of CrkL with patient prognosis as well as pathological indicators. Immunohistochemistry was available to evaluate CrkL expression in 49 gliomas of distinct malignancy grade, and positive stained sites were analyzed. CrkL protein was detected in cell lines by Western blot as well. We observed CrkL protein stained in 59.2 % (29 out of 49) of all glioma tissues, including 41.4 % of low-grade (I + II) gliomas, and 85.0 % of high-grade (III + IV) gliomas. Of four grades, grade IV exhibited the highest CrkL level. CrkL protein was also identified in cell lines NHA, U87, U251, T98G, and A172 by Western blot. On the other hand, CrkL expression was significantly associated with the patient's age and WHO grade, and patients with high CrkL expression had a significantly shorter median survival time (17 months) than those (median survival time 52 months) with low CrkL expression (p<0.001). According to Cox regression, CrkL can be suggested as an independent prognostic factor. In conclusion, CrkL is differently expressed in different grades of gliomas, and correlated to WHO grade. CrkL also independently indicates poor prognosis in old glioma patients, which can further be recommended as an effective prognostic biomarker or therapeutic target.

The association of CXCR4 expression with prognosis and clinicopathological indicators in colorectal carcinoma patients: a meta-analysis.

AIMS: The clinical relevance of expression of chemokine receptor 4 (CXCR4) in colorectal carcinoma (CRC) remains controversial; our aim was to identify the precise relationship of CXCR4 to prognosis and clinicopathological features. METHODS AND RESULTS: A meta-analysis was performed. Original data included the hazard ratios (HRs) of recurrence-free survival (RFS), overall survival (OS) and odds ratio (OR) in CRC patients. We pooled HR/OR with 95% confidence intervals (CIs) to estimate the hazard. A total of 20 published studies (including 2253 patients) were eligible. RFS and OS were related significantly to CXCR4 expression, with HRs 1.62 (95% CI 1.24-2.11; P < 0.0001) and 1.68 (95% CI 1.31-2.14; P < 0.0001), respectively. In addition, a significant association was revealed between positive CXCR4 expression and age (less than median age: OR 0.78, 95% CI 0.62-0.98; P = 0.03), stage (I and II: OR 0.46, 95% CI 0.32-0.66; P < 0.0001), grade (well/moderately differentiated: OR 0.74, 95% CI 0.56-0.98; P = 0.04), location (colon: OR: 0.73, 95% CI 0.57-0.95; P = 0.02), lymph node invasion (present: OR2.14, 95% CI 1.36-3.37; P = 0.001),and distant metastasis (present: OR 2.40; 95% CI 1.36-4.23; P = 0.003). Heterogeneity was observed among the included studies with regard to stage (I(2) = 58 %), lymph node invasiveness (I(2) = 74%) and distant metastasis (I(2) = 56%). No publication bias was observed. CONCLUSIONS: Chemokine receptor 4 expression indicates poorer prognosis in older patients and advanced stage or poor differentiation in CRC, and also serves as an indicator of lymph node and distal organ metastasis. Surprisingly, high CXCR4 expression may indicate that the location of the tumour is the rectum. Thus, CXCR4 could help to predict outcome and guide clinical therapy.