Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent

Integrin alpha5beta1, the principal fibronectin receptor, is an important survival factor, playing a key role in angiogenesis. Angiogenesis is critical for tumor growth, and anti-angiogenic therapies have met clinical success. To validate the therapeutic potential of an anti-alpha5beta1 strategy, we generated volociximab (M200) a chimeric human IgG4 version of the alpha5beta1 function-blocking murine antibody IIA1; and F200, the Fab derivative. Volociximab, F200 and IIA1 showed similar activity by ELISA (EC50= 0.2nM), Biacore (Kd= 0.1-0.4nM) and inhibition of fibronectin binding (IC50= 2-3nM). The inhibitory potential of alpha5beta1 antibodies was compared to HuMV833, an anti-VEGF antibody. Both volociximab and HuMV833 inhibited HUVEC proliferation (IC50 of volociximab = 0.2-0.5nM; IC50 of HuMV833 = 45nM). However, IIA1, volociximab and F200 were also potent inhibitors of an in vitro model of angiogenesis (HUVEC tube formation assay), unlike HuMV833. Additionally, volociximab inhibited in vitro tube formation induced by VEGF and/or bFGF, suggesting a mechanism of action independent of growth factor stimulus. In fact, inhibition of alpha5beta1 function by volociximab induced apoptosis of actively proliferating, but not resting, endothelial cells. Volociximab does not cross-react with rodent alpha5beta1, therefore in vivo validation of an anti-alpha5beta1 approach was conducted in a cynomolgus model of choroidal revascularization. Volociximab and F200 were potent inhibitors of neovessel formation in this model. These data demonstrate that volociximab has therapeutic potential in diseases in which new vessel formation is a component of the pathology.     

Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer

Genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumor suppressor gene are common in sporadic conventional renal cell carcinoma (cRCC). Further insight into the clinical significance of these changes may lead to increased biological understanding and identification of subgroups of patients differing prognostically or who may benefit from specific targeted treatments. We have comprehensively examined the VHL status in tissue samples from 115 patients undergoing nephrectomy, including 96 with sporadic cRCC. In patients with cRCC, loss of heterozygosity was found in 78.4%, mutation in 71%, and promoter methylation in 20.4% of samples. Multiplex ligation-dependent probe amplification identified intragenic copy number changes in several samples including two which were otherwise thought to be VHL-noninvolved. Overall, evidence of biallelic inactivation was found in 74.2% of patients with cRCC. Many of the mutations were novel and approximately two-thirds were potentially truncating. Examination of these and other published findings confirmed mutation hotspots affecting codons 117 and 164, and revealed a common region of mutation in codons 60 to 78. Gender-specific differences in methylation and mutation were seen, although not quite achieving statistical significance (P = 0.068 and 0.11), and a possible association between methylation and polymorphism was identified. No significant differences were seen between VHL subgroups with regard to clinicopathologic features including stage, grade, tumor size, cancer-free and overall survival, with the exception of a significant association between loss of heterozygosity and grade, although a possible trend for survival differences based on mutation location was apparent.     

Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes

Familial renal cell carcinoma (RCC) is genetically heterogeneous. Genetic predisposition to clear cell RCC (CCRCC) is a major feature of von Hippel-Lindau (VHL) disease (MIM 193300) and has rarely been associated with chromosome 3 translocations. In addition, familial papillary (non-clear cell) RCC may result from germline mutations in the MET proto-oncogene (MIM 164860). However, rare kindreds with familial CCRCC (FCRC) not linked to the VHL tumour suppressor gene have been described suggesting that further familial RCC susceptibility genes exist. To investigate the genetic epidemiology of FCRC, we undertook a clinical and molecular study of FCRC in nine kindreds with two or more cases of CCRCC in first degree relatives. FCRC was characterised by an earlier age at onset (mean 47.1 years, 52% of cases <50 years of age) than sporadic cases. These findings differ from the only previous report of two FCRC kindreds and have important implications for renal surveillance in FCRC. The molecular basis of CCRCC susceptibility was investigated in nine FCRC kindreds and seven isolated cases with features of possible genetic susceptibility to CCRCC (four bilateral CCRCC aged <50 years and three with unilateral CCRCC aged <30 years). No germline mutations were detected in the VHL or MET genes, suggesting that FCRC is not allelic with VHL disease or HPRC. As binding of the VHL gene product to the CUL2 protein is important for pVHL function, we then searched for germline CUL2 mutations. Although CUL2 polymorphisms were identified, no pathogenic mutations were detected. These findings further define the clinical features of FCRC and exclude a major role for mutations in VHL, MET, or CUL2 in this disorder.


Keywords: familial clear cell renal carcinoma; VHL; MET; CUL2     

Graphene as a Buffer Layer for Silicon Carbide-on-Insulator Structures

We report an innovative technique for growing the silicon carbide-on-insulator (SiCOI) structure by utilizing polycrystalline single layer graphene (SLG) as a buffer layer. The epitaxial growth was carried out using a hot-mesh chemical vapor deposition (HM-CVD) technique. Cubic SiC (3C-SiC) thin film in (111) domain was realized at relatively low substrate temperature of 750 °C. 3C-SiC energy bandgap of 2.2 eV was confirmed. The Si-O absorption band observed in the grown film can be caused by the out-diffusion of the oxygen atom from SiO₂ substrate or oxygen doping during the cleaning process. Further experimental works by optimizing the cleaning process, growth parameters of the present growth method, or by using other growth methods, as well, are expected to realize a high quality SiCOI structure, thereby opening up the way for a breakthrough in the development of advanced ULSIs with multifunctionalities.     

临床护士信息安全素养评价指标体系的构建研究

目的 构建临床护士信息安全素养评价指标体系,为临床护士信息安全培训及考核评价提供参考。方法 以知信行理论为指导,通过文献研究、现场调研的方法初步拟定指标体系并编制专家函询问卷,邀请全国20名专家进行2轮德尔菲法专家函询,采用层次分析法确定各指标权重。结果 2轮函询问卷有效回收率均为100%,专家权威系数分别为0.945、0.950,肯德尔和谐系数分别为0.179、0.193(均P<0.05)。最终确定的临床护士信息安全素养评价指标体系包括信息安全知识、信息安全意识及信息安全行为3项一级指标、12项二级指标、59项三级指标。结论 构建的临床护士信息安全素养评价指标体系内容全面、科学可靠,可为临床护士信息安全培训及考核评价提供客观的量化依据。     

脑垂体后叶素用于预防产后出血疗效观察

目的 探讨脑垂体后叶素注射液用于减少产后出血量的效果和安全性.方法 在本院住院分娩的产妇中,选择足月妊娠、阴道分娩的头位初产妇100例,有产后出血高危因素,随机分成A、B两组,A组需无使用垂体后叶素禁忌证,A组50例在分娩第二产程胎肩娩出后即静滴垂体后叶素12u;B组50例胎肩娩出后即静滴催产素20u,用容积法和称重法分别测量两组产妇产后2 h内出血量和产后24h出血总量.结果 (1)A组产后2h和24h总出血量分别为295.4mL和382.7mL;B组产后2h和24h总出血量分别为396.2mL和471.4mL.A组和B组比较,A组产后2h和24h总出血量均显著低于B组(P<0.05).(2)A组发生产后出血3例,产后出血发生率为6.0%,B组发生产后出血11例,产后出血发生率为22.0%.A组未发生明显的不良作用.结论 垂体后叶素注射液用于第三产程预防产后出血,能显著减少产后出血量,安全可靠,疗效优于催产素.     

Longitudinal health-related quality of life analysis in childhood cancer survivors after proton beam therapy

International Journal of Clinical Oncology - Whilst proton beam therapy (PBT) for children with cancer is expected to reduce their comorbidities, to date only a limited number of studies have been...