| Part ⅠAssociation of polymorphisms of the TGFB1, ENG, ACVRL1 gene with sporadic arteriovenous malformationsObjective:Sporadic brain arteriovenous malformations (BAVMs), one of the major reasons of intracranial hemorrhage (ICH), comprise abnormal snarl of abnormal vessels directly shunting blood from the arterial to venous circulation without capillary beds. However, the etiology of BAVMs is still unknown.TGFB1 signaling pathway may have impact on angiogenesis andfunction of vessel. TGFB receptor complexes were need to exert the biological effects of TGFB1. Endoglin encoded by ENG and encoding serine/threonine protein kinase receptor R3 encoded by ACVRL1 were important partsof TGFB receptors. In TGFB signal path, there is a synergistic effect between ENG and ACVRL1. And the occurrence of sporadic AVM may be affected by them.But scarce study was carried out based on Chinese Han patients with sporadic BAVMs. So in this study we genotyped TGFB1 rs2241716、rs8105161,ENG rsl998923、rs4837192、rs1330684,ACVRL1 rs706819、rs2293094 rs11169953polymorphisms to gain further insight in the association of TGFB1、ENG and ACVRL1 polymorphisms and sporadic BAVMs.Methods:A total of 50 Chinese Han ethnic patients with BAVM were recruited from the department of Neurosurgery at Provincial Hospital affiliated to Shandong University in Jinan from July 2014 to June 2016 and Liaocheng Pepole’s Hospital in Liaocheng from March 2015 to June 2016. As controls we used 120 healthy Chinese Han volunteers.After extracting the DNA of subjects, PCR using amplification of the target genes were amplificated by PCR and application ligase detection reaction (ligase detection reaction, LDR) technology for detecting gene polymorphism. Genotyping of polymorphisms were carried out using the polymerase chain reaction-ligase detection reactions (PCR-LDR) method.Results:1. Allele and Genotypes of TGFB1There was no significantly different between AVM group and control group in the frequencies of rs2241716 genotypes and rs8105161 genotypes (x2=3.88,P=0.14; X2=0.99,P=0.32,respetively). And no different were observedbetween the allele frequency too (x2=0.99,P=0.32; x2=5.78,P=0.056, respectively).2. Allele and Genotypes of ACVRL1There was no significantly different between AVM group and control group in the frequencies of rs2071219 genotypes (X2=0.52,P=0.77). And no different were observed between the allele frequency too (X2=0.46,P=0.5). A/A, A/G, G/G genotype frequencies of rs706819 existed significant differences between the two groups(X2=9.4,P=0.009). But no differences was found in allele frequency(X2=0.03,P=0.86).Heterozygote model (A/A VS A/G) analysis found that A/A genotypes had an protective effect of the emergence of AVM (X2=6.42,P=0.01,OR=0.167,95%CI=(0.036-0.768)).G/G genotype was not detected in AVM patients and control group. There were significant differences between the AVM group and control group in the frequencies of A/A and A/G genotypes(x2=10.52,P=0.005). A and G allele frequencies also presented significant differences between the two groups(x2=8.65,P=0.003,OR=2.28,95%CI=(1.31-3.98)). Frequencies of T/T, C/T, C/C genotype in rs11169953 had significantly different between the AVM group and control group(x2=6.07,P=0.045). C and T allele frequencies also had significant differences between the two groups(X2=1.88,P=0.01,OR=1.88,95%CI=(1.16-3.05)). Recessivemodel had an influence on the AVM(x2=5.23,P=0.022,OR=2.9,95%CI=(1.132-7.428)).Haplotype analysis of rs706819, rs2293094 and rs 11169953 showed that GGT haplotype could reduce the risk of AVM (X2=13.808,P=0.0002,OR=0.279,95%CI=(0.138-0.565)) and GAC haplotype could increase the risk of AVM(x2=8.21,P=0.004,OR=2.17,95%CI=(1.27-3.7)).3. Allele and Genotypes of ENGA/A genotype of rs11545664was not detected in AVM patients and control group.There were no significant differences of A/G, G/Gfrequencies between the two groups(x2==2.91,P=0.08). Frequencies of A and G allele between the two groups also had no significant differences(x2=0.42,P=0.1).C/C genotype of rs1998923 was not detected in AVM patients and control group. There were no significant differences of C/T, T/Tfrequencies between the two groups(x2=0.72,P=0.38). Frequencies of C and T allele between the two groups also had no significant differences (x2=0.77,P=0.43). G/G genotype of rs4837192was not detected in AVM patients and control group.There were no significant differences of A/G, A/A frequencies between the two groups(x2=0.028,P=0.87). Frequencies of G and A allele between the two groups also had no significant differences(x2=0.02,P=0.88).There were no significant differences of G/G, A/G, A/A frequencies between the two groups (x2=2.51,P=0.29). No significant difference between G and A allele frequencies was found too (X2=0.0008,P=0.93).4. Relationship between the SNP sites and clinical characteristics of the AVMNo relationships were found between the SNPs and status of rupture, the location of AVM by logistic regression analysis(P>0.05).Conclusion:This study found that ACVRL1 gene rs706819, rs2293094 and rs11169953 correlated with the AVM in Chinese Han population. And GGT haplotype of rs706819, rs2293094 and rs11169953 may reduce the risk of AVM. GAC haplotypes may increase the risk of AVM.Part Ⅱ Effect of bevacizumab for treatment of newly diagnosed glioblastoma:a meta-analysis on clinical trialsObjective:Glioblastoma (GBM) is the most malignant histological type of glioma. The typical treatment generally involves maximum safe resection, followed by radiochemotherapy. However, the prognosis for these patients remains poor.GBM is a highly angiogenic tumor due to the production by the autocrine and paracrine pathways of large amounts of vascular endothelial growth factor (VEGF), a signal protein produced by cells. An abnormally elevated level of VEGF may promote angiogenesis, increase vascular permeability and stimulate tumor progression. Bevacizumab (BV) is a humanized recombinant monoclonal antibody against VEGF-A that blocks the binding of VEGF to its receptors on the surface of endothelial cells. Although several clinical trials have been performed to evaluate the therapeutic effect of bevacizumab in newly diagnosed GBM, the treatment effect of bevacizumab for glioblastoma is still unclear.Therefore, to better assess the benefit of addition of bevacizumab to radiotherapy-temozolomide as treatment of newly diagnosed glioblastoma and to analyze whether a combination of bevacizumab and radiotherapy-temozolomide presents additional serious side effects for the patients, a meta-analysis was performed.Methods:Data were extracted from publications in PubMed, Embase, and The Cochrane Library, with the last search performed May 1,2016.Overall survival (OS), progression free survival (PFS), and toxicity profiles data were obtained.Results:6 clinical trials including 2,181 subjects were used for this meta-analysis. Bevacizumab was associated with significant improvement of PFS compared with treatment using temozolomide together with radiotherapy treatment, with a hazard ratio (HR) of 0.709 (95% confidence interval(CI) of 0.645-0.779; P<0.001). OS was not improved based on the pooled HRs 0.977 (95% CI 0.886-1.078; P=0.624). Data from 3 clinical trials for a total of 1,443 subjects were used for meta-analysis. MGMT methylatedand unmethylated patients showed improved PFS in the BV group (pooled HRs,0.769,95% CIs 0.604-0.978, P=0.032; 0.675,95%CIs 0.466-0.979, P=0.038). For patients with either type of GBM, BV did not improve the OS based on the pooled HRs 1.132 (95% CIs 0.876-1.462; P=0.345) for methylated and 1.018(95% CIs 0.879-1.179; P=0.345)for unmethylated.During the adjuvant treatment period, the patients in the BV group had a higher risk of developing neutropenia (relative risk (RR) of 2,95%CI 1.18-3.391,P= 0.01). The highest incidence of non-hematologic adverse reactions was thromboembolism(rate 12.9%,95%CI 10.6%-15.2%).Conclusion:The grade 3 or higher toxicities in the bevacizumab group were more common but controllable and reversible. And bevacizumab therapy may significantly improve the progression free survival of newly diagnosed glioblastoma. |
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