Molecular Modeling Studies of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Combining Molecular Docking and 3D-QSAR Methods

The vascular endothelial growth factor （VEGF） and its receptor tyrosine kinases VEGFR-2 or kinase insertdomain receptor （KDR） have emerged as attractive targets for the design of novel anticancer agents. In the present work, molecular docking method combined with three dimensional quantitative structure-activity relationships （comparative molecular field analysis （CoMFA） and comparative molecular similarity indice analysis （CoMSIA）） to analyze the possible interactions between KDR and those derivatives which acted as selective inhibitors. The CoMFA and CoMSIA models gave a cross-validated coefficient Q2 of 0.713 and 0.549, non-cross-validated R2 values of 0.974 and 0.878, and predicted R2 values of 0.966 and 0.823, respectively. The 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. The information obtained from 3D-QSAR and docking studies were very helpful to design novel selective inhibitors of KDR with desired activity and good chemical property.

A case-control study about the association between vascular endothelial growth inhibitor gene polymorphisms and breast cancer risk in female patients in Northeast China

Objective： The inhibition of the neovascularization in tumors is a potential therapeutic target of cancer. Vascular endothelial growth inhibitor （VEGI） is a member of the TNF superfamily which has the ability to suppress the formation of new vessels in tumors. In order to study the association between VEGI gene polymorphisms and breast cancer risk, a case-control study was conducted in Chinese Han women in Northeast China. Methods： Our study involved 708 female breast cancer patients and 685 healthy volunteers. Four SNPs of VEGI gene were analyzed through the polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） method. The association between VEGI gene polymorphisms and breast cancer risk was analyzed in our study. The relation between VEGI gene variants and clinical features of breast cancer including lymph node （LN） metastasis, esl^ogen receptor （ER）, progestrogen receptor （PR）, tumor protein 53 （1953）, human epidermal growth factor receptor 2 （Her-2） and triple negative （ER-/PR-/Her-2-） status was analyzed as well. Results： We found that the CT genotype and T allele of rs6478106 were more frequent in patients than in controls. There was also a statistical difference in the distribution of Crs6478106Grs4263839 haplotype between patients and controls. In addition, SNP rs6478106 and rs4979462 were related with the Her-2 status. Conclusions： Our results suggest that VEGI gene variants may be related to the breast cancer risk and the clinical features of breast cancer in Chinese Han women in Northeast China.

Effects of endostatin on expression of vascular endothelial growth factor and its receptors and neovascularization in colonic carcinoma implanted in nude mice

AIM:To investigate the antiangiogenic effects of endostatin on colonic carcinoma cell line implanted in nude mice and its mechanism. METHODS:Nude mice underwent subcutaneous injection with LS-174t colonic carcinoma cell line to generate carcinoma and were randomly separated into two groups.Mice received injection of vehicle or endostatin every day for two weeks. After the tumor was harvested,the tumor volumes were determined,and the expressions of CD34,VEGF and FIk-1 were examined by immunohistochemical method. RESULTS:Tumor volume was significantly inhibited in the endostatin group(84.17%)and tumor weight was significantly inhibited in the endostatin group(0.197±0.049) compared to the control group(1.198±0.105)(F=22.56, P=0.001),microvessel density(MVD)was significantly decreased in the treated group(31.857±3.515)compared to the control group(100.143±4.290)(F=151.62,P<0.001). Furthermore,the expression of FIk-1 was significantly inhibited in the treated group(34.29%) ompared to the control group(8.57%)(X^2=13.745,P=0.001).However no significant decrease was observed in the expression of vascular endothelial growth factor(VEGF)between these two groups(X^2=0.119,P=0.730). CONCLUSION:Endostatin can inhibit tumor growth and angiogenesis by blocking Vegf/FIk-1 pathway.This experiment provides the theory basis for developing a new anti-carcinoma drug through studying the properties of anti-angiogenesis inhibitors.

Anti-cancer effect of iNOS inhibitor and its correlation with angiogenesis in gastric cancer

AIM: To observe the anti-cancer effect of iNOS selective inhibitor (aminoguanidine, AG) and investigate the relationship between iNOS inhibitor and angiogenesis, infiltration or metastasis in MFC gastric cancer xenografts.METHODS: Fifty athymic mice xenograft models were established by inoculating gastric cancer cell MFC subcutaneously. Twenty-four hours later, 0.9% sodium chloride solution, mitomycin, low dosage AG, high dosage AG, mitomycin and AG were administered by intraperitoneal injection respectively. Thus these mice were divided into five groups of 10 each randomly: control group, MMC group,AGL group, AGH group, MMC+AGH group. Two weeks later the mice were killed, and the tumor weight, inhibitory rate were evaluated. Greiss assay was used to detect the nitric oxide levels in plasma. HE and immunohistochemistry staining were used to examine microvessel density (MVD)and the expression of iNOS, VEGF, and PCNA. Apoptosis was detected by using TUNEL assay.RESULTS: The inhibitory rates in MMC+AGH group and AGH group were 52.9% and 47.1% respectively, which is significant statistically compared with that of control group (0). In treatment groups, the cell proliferation index (PI)was lower and apoptosis index was higher than those of control group. Microvessel density, iNOS, and VEGF in MMC+ AGH group were 8.8±2.6, 2.4±1.1, and 2.1±1.4respectively, which is significant statistically compared with those of control group (68.3±10.6, 11.3±1.3, and 10.3±1.6). The NO level in plasma of MMC+ AGH and AGH group were 12.7±2.1 and 12.9±2.0 μmol/L. Compared with that of control group (46.6±2.3 μmol/L), the difference is statistically significant.CONCLUSION: AG has anticancer effect on gastric cancer,and it has positive synergistic effect with chemotherapeutic drugs. It may play important inhibitory roles in angiogenesis of gastric cancer. The anticancer effect of iNOS inhibitors may include inducing cell apoptosis, suppressing cell proliferation and reducing angiogenesis.

Roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy

AIMTo investigate the role of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in proliferative diabetic retinopathy (PDR) and to discuss the correlations among t-PA, PAI and vascular endothelial growth factor (VEGF) expressions.

Transarterial administration of integrin inhibitor loaded nanoparticles combined with transarterial chemoembolization for treating hepatocellular carcinoma in a rat model

AIM: To compare the effect of transarterial chemoembolization(TACE) plus GRGDSP(Gly-Arg-Gly-Asp-SerPro, integrin-inhibitor) loaded nanoparticles with TACE alone or TACE + GRGDSP in a rat model of liver tumor. METHODS: Morris hepatoma 3924 A tumors were implanted in the livers of 30 ACI rats. The ACI rats were divided randomly into three groups(10 animals each). Tumor volume before treatment(V1) was examined by magnetic resonance imaging(MRI), and then, after laparotomy and placement of a PE-10 catheter into the hepatic artery, the following interventional protocols were performed: TACE(mitomycin C + lipiodol + degradable starch microspheres) + GRGDSP loaded nanoparticles for group A; TACE + GRGDSP for group B(control group 1); TACE alone for group C(control group 2). Tumor volume(V2) was assessed by MRI and the mean ratio of the post-treatment to pretreatment tumor volumes(V2/V1) was calculated. Immunohistochemical analysis was performed to assess the quantification of matrix metalloprotein 9(MMP-9) and vascular endothelial growth factor(VEGF) positive tumor cells in each treatment group.RESULTS: The mean tumor growth ratios(V2/V1) were 1.3649 ± 0.1194 in group A, 2.0770 ± 0.1595 in group B, and 3.2148 ± 0.1075 in group C. Compared with groups B and C, group A showed a significant reduction in tumor volume. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C. The angiogenesis of tumor was evaluated using anti-VEGF antibodies, and the metastasis of tumor was assessed using antiMMP-9 antibody. MMP-9 and VEGF were expressed in all specimens. The immunoexpression of these proteins was confirmed by the presence of red cytoplasmic staining in tumor cells. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C.CONCLUSION: Transarterial administration of integrin inhibitor loaded nanoparticles combined with TACE evidently retards tumor growth and intrahepatic metastases compared with TACE alone or TACE plus integrin inhibitor in an animal model of hepatocellular carcinoma.

Tyrosine kinase inhibitors:Multi-targeted or single-targeted?

Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor families.Both multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor environment.In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist.Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor.Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal cells.Considering these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized therapy.The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the tumor.This strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.

Flk-1 specific kinase inhibitor SU5416 blocked angiogenesis of Lewis carcinoma in mouse and prolonged the survival

Objective: To reveal the mechanism and effect of SU5416 in the treatment of mouse Lewis cancer in vivo. Methods: Lewis cell was transplanted into groin of C57/B6 mouse by subcutaneous injection, then SU5416 was administrated intraperitoneally to investigate the impact of SU5416 on tumor angiogenesis and growth in vivo. 32 mice were treated with SU5416 at two different doses every day until the end-point. As a control, 8 mice received no treatment and 8 mice were treated with vehicle (DMSO) only after implantation. Results: Median survival in the treated group was statistically longer compared to that in the control groups (P < 0.05) and no significant systemic adverse was observed. Histological analysis of the treated tumors showed an increase in necroses and reduced in angiogenesis compared to the control tumors. Furthermore, the percent of apoptotic cells increased in the treated tumors by FCM, the expressions of VEGF and KDR had no change after SU5416 administration by western blot. Conclusion: SU5416 may be useful therapeutics drug that specifically inhibits the enzymatic activity of KDR kinase and could down regulate the tumor angiogenesis.

Effect of a novel tyrosine kinase inhibitor nintedanib on bFGF and VEGF concentrations in a rabbit retinal vein occlusion model

AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.METHODS:After a laser induced rabbit retinal vein occlusion(RVO)model was made,0.5 mg of nintedanib was injected intravitreally in the left eye on the third day while the right eye was as a control.Intracameral samples were taken on the day before laser treatment and days 1,3,7,14,21,and 28 after treatment.Enzyme-linked immunosorbent assay(ELISA)was used to test the bFGF and VEGF-A concentrations in the aqueous humor.RESULTS:Both bFGF and VEGF-A rose significantly on the third day after laser treatment in both eyes.In the control eye the bFGF concentration peaked on the 14th day while the VEGF-A concentration dropped rapidly soon after the third day.After nintadanib injection in the study eye,both bFGF and VEGF-A showed a significant reduction on the 4th day(7th day after laser treatment)when compared to the control eye,and kept on low level in the following several weeks.CONCLUSION:Intravitreal injection of nintedanib can inhibit the expression of bFGF and VEGF in the process of RVO model to a certain extent,which is expected to become a new method for the treatment of retinal vascular diseases or fibrotic diseases.

虎黄烧伤搽剂联合常规疗法治疗Wagner 1-2级糖尿病足临床观察

目的探讨虎黄烧伤搽剂联合常规疗法治疗Wagner 1-2级糖尿病足的临床疗效。方法选取重庆医科大学附属大足医院2022年1月至2023年6月收治的Wagner 1-2级糖尿病足患者94例,按随机数字表法分为对照组和观察组,各47例。两组患者均予常规降糖药物,并以蚕食清创法清除坏死组织;观察组患者加用虎黄烧伤搽剂治疗。两组均连续治疗28 d。结果观察组疗效优于对照组(P<0.05);观察组糖尿病足感染率为2.13%,显著低于对照组的14.89%(P<0.05)。与对照组比较,观察组患者治疗第7,14,28天创面面积显著缩小,创面愈合时间显著缩短,创面组织中血管内皮生长因子(VEGF)、表皮生长因子(EGF)、基质金属蛋白酶抑制剂-1(TIMP-1)、转化生长因子-β(TGF-β)水平均显著升高,基质金属蛋白酶-9(MMP-9)水平显著降低(P<0.05)。结论虎黄烧伤搽剂联合常规疗法治疗Wagner 1-2级糖尿病足,可进一步上调创面组织中VEGF,EGF,TIMP-1,TGF-β水平,降低MMP-9水平,加速创面愈合。

血管内皮生长因子及其受体抑制剂相关性高血压病理生理机制及临床诊疗的研究进展

肿瘤治疗相关心血管毒性(CTR-CVT)逐渐成为影响肿瘤幸存者预后的关键因素。以血管内皮生长因子(VEGF)为靶点研发的VEGF及其受体抑制剂(VEGFIs)作为新型抗肿瘤药物现已广泛应用于临床,可延长肿瘤患者的生存周期,改善患者预后,但VEGFIs诱导的高血压作为其最常见的CTR-CVT,可能会限制和影响其应用并引起严重心血管疾病(CVD)。对应用VEGFIs治疗的肿瘤患者应密切监测血压,早期评估,优化管理,使患者获得最佳的抗肿瘤疗效和最低的CTRCVT风险。现就VEGFIs相关性高血压的临床表现、发病机制、诊断和治疗策略进行综述,旨在为临床医生更好地管理和应对VEGFIs相关性高血压提供参考。

血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6在结核性胸膜炎胸膜纤维化患者中的变化及临床意义

目的探讨血清和胸腔积液纤溶酶原激活剂抑制物-1(PAI-1)、转化生长因子-β(TGF-β)、血管内皮生长因子(VEGF)、白细胞介素-6(IL-6)在结核性胸膜炎胸膜纤维化患者中的变化及临床意义。方法选取2020年7月至2023年7月该院收治的103例结核性胸膜炎胸膜纤维化患者作为研究对象,治疗2周后,根据糖皮质激素治疗疗效将其分为显效组、非显效组。比较两组治疗前及治疗1、2周后血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平。采用Spearman相关分析血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平与疗效的相关性。治疗2周后血清PAI-1、TGF-β、VEGF、IL-6水平与胸腔积液中该指标水平之间进行Pearson相关分析。绘制受试者工作特征曲线分析治疗1、2周后血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平对结核性胸膜炎胸膜纤维化患者疗效的预测价值。结果两组治疗1、2周后血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平低于治疗前,显效组治疗1、2周后血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平低于非显效组,差异有统计学意义(P<0.05)。治疗1、2周后血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平与疗效呈负相关(P<0.05)。治疗2周后血清PAI-1、TGF-β、VEGF、IL-6水平和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平呈正相关(r=0.761、0.783、0.812、0.741,均P<0.05)。治疗1、2周后血清和胸腔积液各指标联合检测的曲线下面积(AUC)大于其单独指标的AUC(P<0.05)。结论结核性胸膜炎胸膜纤维化患者血清和胸腔积液PAI-1、TGF-β、VEGF、IL-6水平与疗效有关,血清及胸腔积液PAI-1、TGF-β、VEGF、IL-6联合检测的预测价值较好,能够为临床干预提供参考依据。

自拟健脾除积方联合免疫检查点抑制剂治疗对晚期非小细胞肺癌患者的临床疗效及对其外周血管生长因子的影响

目的 探究自拟健脾除积方联合免疫检查点抑制剂治疗对晚期非小细胞肺癌患者的临床疗效及对其外周血管生长因子的影响。方法 选取2021年6月—2022年12月期间河北省沧州中西医结合医院收治的晚期非小细胞肺癌患者70例,按随机数字表法分为对照组和治疗组,每组各35例。对照组给予常规化疗方法,采用信迪利单抗联合含铂双药治疗,治疗组在对照组的基础上加用自拟健脾除积方治疗。每21 d(3周)为一个治疗周期,两组患者连续接受2个疗程的药物治疗,观察比较两组患者临床疗效、不良反应情况,治疗前后中医临床证候评分、KPS评分、血管生长因子(Vascular endothelial growth factor,VEGF)水平。结果 治疗后治疗组总有效率88.57%(31/35)明显高于对照组65.71%(23/35),差异有统计学意义(P<0.05)。治疗后两组患者中医证候评分均较治疗前降低,功能状态疗效KPS评分均较治疗前升高,差异有统计学意义(P<0.05);且治疗组中医证候评分明显低于对照组,功能状态疗效KPS评分明显高于对照组,差异有统计学意义(P<0.01)。治疗后两组患者血清VEGF水平均较治疗前降低,差异有统计学意义(P<0.05);且治疗组血清VEGF水平明显低于对照组,差异有统计学意义(P<0.05)。两组患者不良反应分级比较,差异无统计学意义(P>0.05)。治疗组白细胞计数降低、恶心/呕吐发生率明显低于对照组,差异有统计学意义(P<0.05)。结论 自拟健脾除积方联合免疫检查点抑制剂治疗晚期非小细胞肺可提高临床治疗效果,改善中医证候评分,提高生活质量,降低外周血血管生长因子含量,且具有相当的安全性,值得推荐使用。

养血散寒通脉方治疗血虚寒凝型子宫内膜异位症的临床研究

【目的】观察养血散寒通脉方(由当归四逆加吴茱萸生姜汤加减而成)治疗血虚寒凝型子宫内膜异位症(EMS)的临床疗效。【方法】将120例血虚寒凝型EMS患者随机分为研究组和对照组,每组各60例。研究组给予养血散寒通脉方治疗,对照组给予少腹逐瘀颗粒治疗,疗程为3个月,并于疗程结束后随访1年。观察2组患者治疗前后各种疼痛评分[包括经期腹痛视觉模拟量表(VAS)评分和痛经、非经期盆腔痛、性交痛、盆腔压痛、骶韧带结节触痛分级评分]、卵巢子宫内膜异位囊肿大小及血清糖类抗原125(CA125)、血管内皮生长因子(VEGF)、可溶性细胞间黏附分子1(SICAM-1)、基质金属蛋白酶9(MMP-9)、组织金属蛋白酶抑制因子2(TIMP-2)水平的变化情况,并观察2组患者的临床疗效、安全性、复发情况及妊娠情况。【结果】(1)研究过程中,研究组脱落3例,对照组脱落5例,最终共112例患者纳入统计分析,其中研究组57例,对照组55例。(2)治疗3个月后,研究组的总有效率为92.98%(53/57),对照组为85.45%(47/55),组间比较,研究组的疗效明显优于对照组(P<0.05)。(3)治疗后,2组患者的各种疼痛评分(包括经期腹痛VAS评分和痛经、非经期盆腔痛、性交痛、盆腔压痛、骶韧带结节触痛分级评分)均较治疗前明显下降(P<0.05),且研究组的下降幅度均明显优于对照组(P<0.05)。(4)治疗后,2组患者的卵巢子宫内膜异位囊肿均略有缩小,但组内治疗前后及治疗后组间比较,差异均无统计学意义(P>0.05)。(5)治疗后,2组患者血清CA125、VEGF、SICAM-1、MMP-9水平均较治疗前下降(P<0.05),血清TIMP-2水平均较治疗前升高(P<0.05),且研究组对血清CA125、VEGF、SICAM-1、MMP-9水平的下降幅度及对血清TIMP-2水平的升高幅度均明显优于对照组(P<0.05)。(6)随访1年,研究组的复发率为30.19%(16/53),明显低于对照组的68.09%(32/47),组间比较,差异有统计学意义(P<0.05)。研究组21例有生育要求,其中14例妊娠,妊娠率为66.67%(14/21);对照组20例有生育要求,其中4例妊娠,妊娠率为20.00%(4/20);组间比较,研究组的妊娠率明显高于对照组,差异有统计学意义(P<0.05)。(7)治疗期间,2组患者均无明显不良反应发生,且患者的血、尿、大便常规及心电图、肝肾功能等安全性指标均无异常变化。【结论】养血散寒通脉方治疗血虚寒凝型EMS患者疗效确切,能够显著缓解患者各种疼痛症状,改善妊娠结局,有效调节血清CA125、VEGF、SICAM-1、MMP-9、TIMP-2水平。

达格列净对2型糖尿病非增殖期视网膜病变的影响

目的:探讨达格列净对2型糖尿病非增殖期视网膜病变(non-proliferative diabetic retinopathy,NPDR)的影响。方法:选取2021年10月—2023年6月湖南师范大学附属湘东医院收治的88例2型糖尿病NPDR患者。随机将其分为观察组及对照组,各44例。两组均给予常规降糖治疗,观察组加用达格列净治疗。比较两组治疗前后血糖指标及相关指标。分析血管内皮生长因子(vascular endothelial growth factor,VEGF)与血糖波动指标的相关性。结果:治疗后,两组空腹血糖(fasting blood glucose,FBG)、餐后2 h血糖(2 h postprandial blood glucose,2 h PBG)、糖化血红蛋白(glycosylated hemoglobin,HbA1c)、血糖水平标准差(standard deviation of blood glucose,SDBG)、餐后血糖波动幅度(postprandial glucose excursion,PPGE)、最大血糖波动幅度(large amplitude glycemic excursion,LAGE)均下降,观察组SDBG、PPGE、LAGE均低于对照组,差异有统计学意义(P<0.05)。治疗后,两组VEGF、黄斑中心凹厚度均下降,最佳矫正视力(best-corrected visual acuity,BCVA)升高,观察组VEGF、黄斑中心凹厚度均低于对照组,BCVA高于对照组,差异有统计学意义(P<0.05)。Pearson相关性分析结果显示:VEGF与SDBG、PPGE、LAGE均呈正相关(P<0.05)。结论:达格列净能够改善血糖波动,降低VEGF水平,对2型糖尿病NPDR有保护作用。

血清TIMP-1、VEGF水平对自然分娩初产妇产后压力性尿失禁严重程度的预测价值

目的探讨自然分娩初产妇血清基质金属蛋白酶组织抑制因子-1(tissue inhibitor of metall oproteinase-1,TIMP-1)、血管内皮生长因子(vascular endothelial growth factor,VEGF)水平对产后压力性尿失禁(post partum stress urinary incontinence,PSUI)严重程度的预测价值。方法选取2019年12月至2023年7月220例PSUI自然分娩初产妇为病例组,根据尿垫试验结果分为轻度组158例和中重度组62例。另纳入同期220例无PSUI的自然分娩初产妇作为对照组。采用ELISA法检测入组者血清TIMP-1、VEGF水平;采用Pearson法分析PSUI患者血清TIMP-1与VEGF的相关性;采用多因素Logistic回归分析PSUI患者疾病严重程度的影响因素;采用受试者工作特征曲线分析血清TIMP-1、VEGF对PSUI患者疾病严重程度的预测价值。结果病例组血清TIMP-1水平显著低于对照组,血清VEGF水平显著高于对照组(P<0.01)。中重度组血清TIMP-1水平显著低于轻度组,血清VEGF水平、年龄≥35岁比例、新生儿体质量显著高于轻度组(P<0.05,P<0.01)。PSUI患者血清TIMP-1与VEGF呈负相关(r=-0.671,P<0.05)。TIMP-1是PSUI患者疾病程度加重的保护因素(P<0.01),VEGF是PSUI患者疾病程度加重的危险因素(P<0.01)。TIMP-1、VEGF单独及联合预测PSUI患者疾病严重程度的曲线下面积(area under curve,AUC)分别为0.857、0.808、0.901,其中联合预测的AUC高于二者单独预测(P<0.01)。结论PSUI患者血清TIMP-1低表达,VEGF高表达,且TIMP-1、VEGF与病情程度密切相关,二者联合在预测PSUI患者疾病严重程度方面有较高的价值。

血管生成抑制蛋白1、血清沉默信息调节因子1、血栓素-B_(2)在2型糖尿病肾病中的水平变化及与白蛋白尿进展的关系分析

目的:探究血管生成抑制蛋白1(VASH-1)、血清沉默信息调节因子1(Sirt1)与血栓素-B2(TXB2)在2型糖尿病肾病中的水平变化及与白蛋白尿进展的关系。方法:选取198例2型糖尿病肾病患者纳入研究组,另选100例无肾脏损害的2型糖尿病患者为对照组,对患者进行随访,检测记录患者的血清VASH-1、Sirt1、TXB2水平,并根据患者是否发生白蛋白尿分层研究,分析VASH-1、Sirt1、TXB2水平与患者白蛋白尿进展的关系。结果:与对照组比较,研究组患者的血清VASH-1、Sirt1水平降低,TXB2水平升高(均P<0.05)。与进展组患者相比较,维持组患者的血清VASH-1、Sirt1水平升高,TXB2水平降低(均P<0.05)。进展组和维持组患者的空腹血糖(FPG)、餐后2h血糖(2hPG)、空腹胰岛素(FINS)、糖化血红蛋白(HbA1c)、胰岛素抵抗指数(HOMA-IR)水平比较差异无统计学意义(均P>0.05)。以研究组患者是否发生白蛋白尿进展为因变量,以患者的血清VASH-1、Sirt1、TXB2水平为自变量,进行多因素Logistic回归分析,可知血清VASH-1、Sirt1、TXB2水平均会对患者发生白蛋白尿进展产生影响(均P<0.05)。采用ROC曲线探究2型糖尿病肾病患者血清VASH-1、Sirt1、TXB2水平对白蛋白尿进展的预测价值,其AUC值分别为0.943、0.758、0.894(均P<0.05)。结论:2型糖尿病肾病患者的血清VASH-1和Sirt1的水平下降,TXB2的水平上升,其水平变化与白蛋白尿的进展有关,对糖尿病肾病患者发生白蛋白尿进展具有一定预测价值。

Efficacy of Ciji Hua'ai Baosheng formula on the expressions of vascular endothelial growth factor,kinase insert domain-containing receptor and basic fibroblast growth factor in mouse models of H22 hepatocellular carcinoma

OBJECTIVE: To investigate the efficacy of Ciji Hua'ai Baosheng formula(CHBF) on microvessel density(MVD) and vascular endothelial growth factor(VEGF), kinase insert domain-containing receptor(KDR) and basic fibroblast growth factor(b FGF) expression in serum and tumor tissue of mice receiving chemotherapy for the treatment of H22 hepatocellular carcinoma.METHODS: Sixty Kunming mice were injected subcutaneously with H22 hepatoma carcinoma cell suspensions into the right anterior armpit. Seven days later, all transplanted tumor were formed and the mice were intraperitoneally injected 200 mg/kg cytoxan(CTX) to establish the models of tumor-bearing mouse chemotherapy, then they were randomly divided into model group, continuing CTX chemotherapy group(CTX group), and three CHBF(117, 58.5 and 29.25 g/kg) groups. After ten days of treatments, histology was observed, contents of VEGF, KDR and b FGF in serum and tumor tissue were measured by enzyme-linked immunosorbent assay(ELISA), VEGF and b FGF protein expression and MVD tagged by CD34 were detected by immunohistochemisty.RESULTS: MVD in CHBF(117, 58.5 g/kg) and CTX groups was significantly lower than that in model group(P < 0.01); expressions of VEGF, KDR and b FGF in serum and tumor tissue in CHBF(117 g/kg)group were less than those in model group(P <0.05; P < 0.01); the expressions of MVD, VEGF and b FGF in tumor tissue of CHBF(117 g/kg) groupwere also less than those in CTX group(P < 0.05;P < 0.01).CONCLUSION: CHBF can effectively reduce the expression of VEGF, KDR and b FGF in serum and tumor tissue, and decrease MVD and delay tumor progression.

不同剂量抗血管内皮生长因子药物治疗ROP的研究进展

随着对血管内皮生长因子(VEGF)在早产儿视网膜病变(ROP)发病机制中作用的研究不断深入。国内外陆续开展了各种抗VEGF药物1/2成人剂量玻璃体腔注射治疗ROP试验并初步取得显著疗效。然而,进一步的研究表明抗VEGF药物可以通过玻璃体腔进入全身血液循环,暂时降低患儿的血清VEGF水平,从而给处于快速生长发育期的早产儿带来潜在的全身不良反应。目前,国内外专家开始重点关注1/2成人剂量治疗ROP的全身不良反应风险,并相继开展了各种低剂量抗VEGF药物治疗ROP的相关研究。目前,大部分研究为小样本回顾性研究,缺乏大样本多中心的前瞻性研究,各剂量抗VEGF药物治疗ROP均属探索阶段。本文就各剂量抗VEGF药物治疗ROP的疗效及问题进行综述,为ROP的治疗提供参考。

肿瘤靶向药物相关皮肤不良反应及发生机制

近年来,肿瘤靶向药物快速发展,成为目前肿瘤治疗的重要选择之一。肿瘤靶向药物在发挥抗肿瘤作用的同时,可能损害正常组织功能,其中皮肤相关不良反应最为常见。部分皮肤不良反应严重影响患者的生活质量,导致其治疗依从性下降,最终影响患者的长期生存。因此,正确认识肿瘤靶向药物相关皮肤不良反应及发生机制,有助于指引未来基于机制的诊断与治疗,从而改善患者生活质量。