Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths with 750,000 newly diagnosed cases each year. Surgery, radiotherapy, and chemotherapy constitute the main treatment modalities for HCC, but liver cirrhosis and damage often occur. Molecular targeted drugs have been recently developed to treat HCC. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) autocrine signaling is closely related to the growth, progression, and metastasis of HCC, making the VEGF/VEGFR axis an ideal target for the development of molecular targeted agents. Here, we report the effects of the novel anti-VEGF humanized monoclonal antibody BD0801 on the growth of HCC cells in vitro and in vivo as well as the underlying mechanisms. BD0801 significantly inhibited the proliferation of HepG2, SMMC-7721, and Bel7402 cells in vitro, accompanied with an induction of apoptosis and cell cycle arrest at the G1 phase. BD0801 potently suppressed AKT, Erk1/2, and retinoblastoma (Rb) phosphorylation, while increasing p21 and decreasing cyclin D1 protein levels. BD0801 significantly inhibited growth in mouse tumor xenografts and induced cell apoptosis of HepG2 and SMMC-7721 tumor xenografts. Furthermore, BD0801 effectively reduced the vascular density and tumor tissue microvessel density (MVD). Similarly, BD0801 decreased AKT, Erk1/2, and Rb phosphorylation and cyclin D1 expression whereas it increased p21 protein expression in mouse HCC tumor xenografts. Importantly, BD0801 showed a better effect than Bevacizumab (Bev) on the inhibition of cell growth and induction of apoptosis in HCC cells in vitro and in vivo. These findings suggest that BD0801 is a potent anti-VEGF monoclonal antibody for the treatment of HCC.
Increased plasma levels of C-reactive protein (CRP) are closely associated with cardiovascular diseases, but whether CRP is directly involved in the pathogenesis of atherosclerosis is still under debate. Many controversial and contradictory results using transgenic mice and rabbits have been published but it is also unclear whether CRP lowering can be used for the treatment of atherosclerosis. In the current study, we examined the effects of the rabbit CRP antisense oligonucleotides (ASO) on the development of atherosclerosis in WHHL rabbits. CRP ASO treatment led to a significant reduction of plasma CRP levels; however, both aortic and coronary atherosclerotic lesions were not significantly changed compared to those of control WHHL rabbits. These results suggest that inhibition of plasma CRP does not affect the development of atherosclerosis in WHHL rabbits.
Background. As a parameter integrating platelet (P), neutrophil (N), and lymphocyte (L) levels, the systemic immune-inflammation index (SII) has been used as a prognostic marker for patient survival in various types of solid malignant tumors. However, there is no in-depth study in non-small-cell lung cancer (NSCLC) patients with brain metastases after stereotactic radiotherapy. Therefore, we performed a retrospective analysis to determine the clinical and prognostic value of the SII in NSCLC patients with brain metastases who underwent stereotactic radiotherapy. Materials and Methods. We enrolled 124 NSCLC patients with brain metastases treated with stereotactic radiotherapy in our hospital between May 2015 and June 2018. We obtained all baseline blood samples within one week prior to stereotactic radiotherapy. The SII was calculated by the following formula: neutrophil counts × platelet counts / lymphocyte counts . The optimal cutoff value of the SII for predicting prognosis was assessed by receiver operating characteristic (ROC) curves with the maximum log-rank values. The discriminative ability of predicting prognosis was calculated and compared using the Kaplan–Meier method and log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were combined to evaluate the prognostic impact of the blood index on overall survival (OS) and progression-free survival (PFS). Only those parameters that proved to be associated with statistically significant differences in clinical outcomes were compared in multivariate analysis using a multiple Cox proportional hazard regression model to identify independent prognostic factors. Results. Of the total enrolled patients, 53.2% and 46.8% have high SII and low SII, respectively. In this study, Kaplan–Meier curve analysis revealed that the median PFS was 9 months (range: 2–22 months) and the median OS was 18 months (range: 4–37 months). Applying an optimal cutoff of 480 (SII), the median PFS was better in the low SII group patients (11.5 vs. 9 months), and the median OS was significantly longer in the low SII group patients (20 vs. 18 months). A SII > 480 was significantly associated with worse OS (HR: 2.196; 95% CI 1.259–3.832; P = 0.006 ) and PFS (HR: 2.471; 95% CI 1.488–4.104; P < 0.001 ) according to univariate analysis. In multivariate analysis, only age (HR: 2.159; 95% CI 1.205–3.869; P = 0.010 ), KPS (HR: 1.887; 95% CI 1.114–3.198; P = 0.018 ), and SII (HR: 1.938; 95% CI 1.046–3.589; P = 0.035 ) were independently correlated with OS, and SII (HR: 2.224; 95% CI 1.298–3.810; P = 0.004 ) was an independent prognostic predictor of PFS, whereas we found that other inflammation-based indices lost their independent value. Conclusions. The SII, which is an integrated blood parameter based on platelet, neutrophil, and lymphocyte counts, may be an independent prognostic indicator and may be useful for the identification of NSCLC patients with brain metastases after stereotactic radiotherapy at high risk for recurrence.
Background We previously found that (via inhibition of the VEGF/VEGFR signaling pathway) ckgroundSevacizumab (Sev), an anti-VEGF monoclonal antibody, was proven to have a superior inhibitory effect than bevacizumab (Bev) on the growth of hepatocellular carcinoma (HCC) cells. This study aimed to explore the anti-proliferation and anti-angiogenic effects of Sev on HCC cells in combination with oxaliplatin (OXA) or 5-fluorouracil (5-Fu). Methods In vitro HCC/endothelial cell growth in different concentration drug was analyzed by MTT assay, DAPI and flow cytometry assay. Cell scratch test, transwell assay, tube formation assay, zebrafish assay, and CAM assay were used to investigate anti-angiogenesis effect of drugs. VEGF mRNA relative expression changes of zebrafish embryos were detected by RT-PCR.A fluorescence imaging system was applied to observe the growth of transplantation tumor and blood vessels in HCC mouse xenografts. Tissue H-E staining and TEM detection were used to detect the tumor cell apoptosis. MVD was detected by immunohistochemical analysis of CD31. ELISA and western-blots were used to detect the cell VEGF/VEGFR pathway and its downstream target activity both in vitro and in vivo. Results In vitro results showed that the combination of Sev with OXA/5-Fu can synergistically inhibit the proliferation of HCC and endothelial cells. Compared with the corresponding monotherapy group, combination therapy showed a stronger effect on inducing apoptosis and cell cycle arrest. In vivo findings revealed that Sev in combination with chemotherapy can synergistically inhibit tumor growth by inducing cell apoptosis in nude mice with HCC xenografts. In addition, the wound healing and transwell migration assays demonstrated that Sev can inhibit the migration of endothelial cell lines in combination with chemotherapy. In vitro tube formation test, zebrafish and chicken embryonic-angiogenic assay, immunohistochemistry, and in vivo fluorescence imaging consistently verified that Sev and OXA/5-Fu can synergistically inhibit the growth of blood vessels, and the underlying mechanism may be associated with inhibition of the VEGF/VEGFR signaling pathway. Conclusions The combination of Sev and chemotherapy is associated with the inhibition of HCC growth and tumor angiogenesis, which may provide a significant biological rationale for evaluating the efficacy of Sev and OXA/5-Fu combination therapy on HCC.
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