AIM: To investigate the safety/efficacy of Boceprevirbased triple therapy in hepatitis C virus(HCV)-G1 menopausal women who were historic relapsers, partial-responders and null-responders. METHODS: In this single-assi...AIM: To investigate the safety/efficacy of Boceprevirbased triple therapy in hepatitis C virus(HCV)-G1 menopausal women who were historic relapsers, partial-responders and null-responders. METHODS: In this single-assignment, unblinded study, we treated fifty-six menopausal women with HCV-G1, 46% F3-F4, and previous PEG-α/RBV failure(7% null, 41% non-responder, and 52% relapser) with 4 wk lead-in with PEG-IFNα2b/RBV followed by PEGIFNα2b/RBV+Boceprevir for 32 wk, with an additional 12 wk of PEG-IFN-α-2b/RBV if patients were HCV-RNApositive by week 8. In previous null-responders, 44 wk of triple therapy was used. The primary objective of retreatment was to verify whether a sustained virological response(SVR)(HCV RNA undetectable at 24 wk of follow-up) rate of at least 20% could be obtained. The secondary objective was the evaluation of the percent of patients with negative HCV RNA at week 4(RVR), 8(RVR BOC), 12(EVR), or at the end-of-treatment(ETR) that reached SVR. To assess the relationship between SVR and clinical and biochemical parameters, multiple logistic regression analysis was used.RESULTS: After lead-in, only two patients had RVR; HCV-RNA was unchanged in all but 62% who had ≤1 log10 decrease. After Boceprevir, HCV RNA became undetectable at week 8 in 32/56(57.1%) and at week 12 in 41/56(73.2%). Of these, 53.8% and 52.0%, respectively, achieved SVR. Overall, SVR was obtained in 25/56(44.6%). SVR was achieved in 55% previous relapsers vs. 41% non-responders(P = 0.250), in 44% F0-F2 vs 54% F3-F4(P = 0.488), and in 11/19(57.9%) of patients with cirrhosis. At univariate analysis for baseline predictors of SVR, only previous response to antiviral therapy(OR = 2.662, 95%CI: 0.957-6.881, P = 0.043), was related with SVR. When considering "on treatment" factors, 1 log10 HCV RNA decline at week 4(3.733, 95%CI: 1.676-12.658, P = 0.034) and achievement of RVR BOC(7.347, 95%CI: 2.156-25.035, P = 0.001) were significantly related with the SVR, although RVR BOC only(6.794, 95%CI: 1.596-21.644, P = 0.010) maintained significance at multivariate logistic regression analysis. Anemia and neutropenia were managed with Erythropoietin and Filgrastim supplementation, respectively. Only six patients discontinued therapy. CONCLUSION: Boceprevir obtained high SVR response independent of previous response, RVR or baseline fibrosis or cirrhosis. RVR BOC was the only independent predictor of SVR.展开更多
目的探索酮还原酶家族1成员C3(aldo-keto reductase family 1 member C3,AKR1C3)对乳腺癌恶性细胞生物学行为的干预作用及对程序性细胞死亡蛋白/程序性死亡-配体1(programmed cell death protein1/programmed death-ligand1,PD-1/PD-L)...目的探索酮还原酶家族1成员C3(aldo-keto reductase family 1 member C3,AKR1C3)对乳腺癌恶性细胞生物学行为的干预作用及对程序性细胞死亡蛋白/程序性死亡-配体1(programmed cell death protein1/programmed death-ligand1,PD-1/PD-L)通路的影响。方法把MCF-7人乳腺癌细胞中NC组和AKR1C3组分别转染空质粒和AKR1C3质粒,采用MTT法检测转染后24 h、48 h、72 h细胞活力;采用流式细胞技术测定各组细胞的存活率以及早期、晚期凋亡比例;通过Transwell实验对各组细胞的迁移和侵袭能力进行检测;通过Western blot检测各组细胞PD-1、PD-L1、蛋白激酶B(protein kinase b,AKT)蛋白表达水平。使用C57BL/6小鼠构建荷瘤模型,将采用人乳腺癌MCF-7细胞转染NC质粒和AKR1C3质粒进行细胞荷瘤,每3 d测量瘤体积,持续21 d,绘制两组小鼠肿瘤生长曲线,并于实验终点测量肿瘤质量。结果相较于NC组,AKR1C3组细胞活力降低(P<0.05),并且具有时间依赖效应(P<0.05),迁移和侵袭能力降低(P<0.05),早期凋亡和晚期凋亡比例升高(P<0.05),PD-1、PD-L1、AKT蛋白表达水平降低(P<0.05)。动物实验表明,AKR1C3组小鼠肿瘤体积降低,肿瘤质量下降(P<0.05)。结论AKR1C3可以抑制人乳腺癌细胞恶性生物学行为,抑制PD-1/PDL1信号通路蛋白表达。展开更多
文摘AIM: To investigate the safety/efficacy of Boceprevirbased triple therapy in hepatitis C virus(HCV)-G1 menopausal women who were historic relapsers, partial-responders and null-responders. METHODS: In this single-assignment, unblinded study, we treated fifty-six menopausal women with HCV-G1, 46% F3-F4, and previous PEG-α/RBV failure(7% null, 41% non-responder, and 52% relapser) with 4 wk lead-in with PEG-IFNα2b/RBV followed by PEGIFNα2b/RBV+Boceprevir for 32 wk, with an additional 12 wk of PEG-IFN-α-2b/RBV if patients were HCV-RNApositive by week 8. In previous null-responders, 44 wk of triple therapy was used. The primary objective of retreatment was to verify whether a sustained virological response(SVR)(HCV RNA undetectable at 24 wk of follow-up) rate of at least 20% could be obtained. The secondary objective was the evaluation of the percent of patients with negative HCV RNA at week 4(RVR), 8(RVR BOC), 12(EVR), or at the end-of-treatment(ETR) that reached SVR. To assess the relationship between SVR and clinical and biochemical parameters, multiple logistic regression analysis was used.RESULTS: After lead-in, only two patients had RVR; HCV-RNA was unchanged in all but 62% who had ≤1 log10 decrease. After Boceprevir, HCV RNA became undetectable at week 8 in 32/56(57.1%) and at week 12 in 41/56(73.2%). Of these, 53.8% and 52.0%, respectively, achieved SVR. Overall, SVR was obtained in 25/56(44.6%). SVR was achieved in 55% previous relapsers vs. 41% non-responders(P = 0.250), in 44% F0-F2 vs 54% F3-F4(P = 0.488), and in 11/19(57.9%) of patients with cirrhosis. At univariate analysis for baseline predictors of SVR, only previous response to antiviral therapy(OR = 2.662, 95%CI: 0.957-6.881, P = 0.043), was related with SVR. When considering "on treatment" factors, 1 log10 HCV RNA decline at week 4(3.733, 95%CI: 1.676-12.658, P = 0.034) and achievement of RVR BOC(7.347, 95%CI: 2.156-25.035, P = 0.001) were significantly related with the SVR, although RVR BOC only(6.794, 95%CI: 1.596-21.644, P = 0.010) maintained significance at multivariate logistic regression analysis. Anemia and neutropenia were managed with Erythropoietin and Filgrastim supplementation, respectively. Only six patients discontinued therapy. CONCLUSION: Boceprevir obtained high SVR response independent of previous response, RVR or baseline fibrosis or cirrhosis. RVR BOC was the only independent predictor of SVR.
