Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

BACKGROUND Hepatic arterial infusion chemotherapy(HAIC)has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma(uHCC).HAIC-based treatment showed great potential for treating uHCC.However,large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking.AIM To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors,programmed cell death of protein 1(PD-1)and its ligand(PD-L1)blockers(triple therapy)under real-world conditions.METHODS Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis.Study-level pooled analyses of hazard ratios(HRs)and odds ratios(ORs)were performed.This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades(AIPB)at Sun Yat-sen University Cancer Center from January 2018 to April 2023.Propensity score matching(PSM)was performed to balance the bias between the groups.The Kaplan-Meier method and cox regression were used to analyse the survival data,and the log-rank test was used to compare the suvival time between the groups.RESULTS A total of 13 randomized controlled trials were included.HAIC alone and in combination with sorafenib were found to be effective treatments(P values for ORs:HAIC,0.95;for HRs:HAIC+sorafenib,0.04).After PSM,176 HCC patients were included in the analysis.The triple therapy group(n=88)had a longer median overall survival than the AIPB group(n=88)(31.6 months vs 14.6 months,P<0.001)and a greater incidence of adverse events(94.3%vs 75.4%,P<0.001).CONCLUSION This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC.Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor+chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers

BACKGROUND The combination of programmed cell death protein-1(PD-1)inhibitor and che-motherapy is approved as a standard first-or second-line treatment in patients with advanced oesophageal or gastric cancer.However,it is unclear whether this combination is superior to chemotherapy alone.AIM To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer,gastroesophageal junction(GEJ)cancer,or oesophageal carcinoma.METHODS We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer.We employed either random or fixed models to analyze the outcomes of each clinical trial,en-compassing data on overall survival(OS),progression-free survival(PFS),objective response rate,and adverse events(AEs).RESULTS Nine phase 3 clinical trials(7016 advanced oesophageal and gastric cancer patients)met the inclusion criteria.Our meta-analysis demonstrated that the pooled PD-1 inhibitor+chemotherapy group had a significantly longer OS than the chemotherapy-alone group[hazard ratio(HR)=0.76,95%confidence interval(CI):0.71-0.81];the pooled PFS result was consistent with that of OS(HR=0.67,95%CI:0.61-0.74).The count of patients achieving an objective response in the PD-1 inhibitor+chemotherapy group surpassed that of the chemotherapy-alone group[odds ratio(OR)=1.86,95%CI:1.59-2.18].AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group,regardless of whether≥grade 3 only(OR=1.30,95%CI:1.07-1.57)or all AE grades(OR=1.88,95%CI:1.39-2.54)were examined.We performed a subgroup analysis based on the programmed death-ligand 1(PD-L1)combined positive score(CPS)and noted extended OS and PFS durations within the CPS≥1,CPS≥5,and CPS≥10 subgroups of the PD-1 inhibitor+chemotherapy group.CONCLUSION In contrast to chemotherapy alone,the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer,GEJ tumor,or oesophageal cancer.This holds true particularly for individuals with PD-L1 CPS scores of≥5 and≥10.

Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

Present and prospect of transarterial chemoembolization combined with tyrosine kinase inhibitor and PD-1 inhibitor for unresectable hepatocellular carcinoma

In this editorial,we comment on the article(World J Gastrointest Oncol 2024;16:1236-1247),which is a retrospective study of transarterial chemoembolization(TACE)combined with multi-targeted tyrosine kinase inhibitor(TKI)and programmed cell death protein-1(PD-1)inhibitor for the treatment of unresectable hepatocellular carcinoma(HCC).Herein,we focus specifically on the mechanisms of this triple therapy,administration sequence and selection of each medication,and implications for future clinical trials.Based on the interaction mechanisms between medications,the triple therapy of TACE+TKI+PD-1 is proposed to complement the deficiency of each monotherapy,and achieve synergistic antitumor effects.Although this triple therapy has been evaluated by several retrospective trials,it is still controversial whether the triple therapy achieves better clinical benefits,due to the flawed study design and heterogeneity in medications.In addition,the administration sequence,which may greatly affect the clinical benefit,needs to be fully considered at clinical decision-making for obtaining better prognosis.We hope that this editorial could contribute to the design and optimization of future trials.

PD-1/PD-L1抑制剂联合抗血管内皮生长因子药物免疫治疗晚期肝癌的研究进展

肝细胞癌(hepatocellular carcinoma,HCC)是全球高发的恶性肿瘤。程序性死亡蛋白-1(programmed death protein-1,PD-1)/程序性死亡蛋白配体-1(programmed death protein ligand-1,PD-L1)抑制剂可通过阻断T细胞负调节信号,抑制肿瘤细胞免疫逃逸途径,重新激活抗肿瘤免疫应答过程,成为晚期HCC治疗的新手段。然而,长期临床结果显示,采用PD-1/PD-L1抑制剂单药治疗晚期HCC的病人仍存在较高的复发率和转移率。免疫联合疗法是目前针对晚期HCC患者的新的治疗策略,其中PD-1/PD-L1抑制剂联合抗血管内皮生长因子(vascular endothelial growth factor,VEGF)药物在晚期HCC治疗中显示出了良好的疗效和安全性。PD-1/PD-L1抑制剂联合抗VEGF药物可通过参与癌症免疫循环途径抑制肝癌细胞的生长。该文就PD-1/PD-L1抑制剂联合抗VEGF药物在晚期HCC治疗中的临床研究作一综述。

程序性死亡受体1/程序性死亡受体配体1抑制剂联合抗血管生成药物治疗晚期肝细胞癌的临床研究进展

靶免联合治疗在晚期肝细胞癌中发挥着越来越重要的作用,其中程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)抑制剂联合抗血管生成药物治疗晚期肝细胞患者具有良好的疗效和可接受的毒性。抗血管生成药物不仅可以使肿瘤血管系统正常化,还可以介导免疫微环境,增强PD-1/PD-L1抑制剂的疗效。本文总结了PD-1/PD-L1抑制剂联合抗血管生成药物治疗晚期肝细胞癌的一线治疗方案,概述联合治疗的作用机制,回顾和分析这些一线治疗方案的临床研究以及差异性,并对其真实世界研究进行探讨,为后续晚期肝细胞癌的治疗策略提供新的方向和思路。

2型糖尿病患者血清VASH-1、TIMP-1水平与视网膜病变的关系

目的探讨2型糖尿病(T2DM)患者血清血管生成抑制蛋白-1(VASH-1)、金属蛋白酶组织抑制物1(TIMP-1)与糖尿病视网膜病变的关系。方法选取2020年1月至2021年1月陕西省商洛眼科医院收治的79例T2DM患者作为研究对象。根据眼底荧光血管造影结果将患者分为无视网膜病变组、视网膜病变组。另选取40例同期健康体检者作为对照组。采用酶联免疫吸附试验检测血清VASH-1、TIMP-1水平。绘制受试者工作特征(ROC)曲线评估血清VASH-1、TIMP-1水平对T2DM患者发生视网膜病变的预测价值。采用多因素Logistic回归分析T2DM患者发生视网膜病变的危险因素。结果无视网膜病变组纳入45例患者、视网膜病变组纳入34例患者。无视网膜病变组与视网膜病变组FPG、2 h PG、HbA1c、UACR水平均高于对照组,且视网膜病变组均高于无视网膜病变组,差异均有统计学意义(P<0.05)。视网膜病变组T2DM病程长于无视网膜病变组,差异有统计学意义(P<0.05)。无视网膜病变组与视网膜病变组血清VASH-1水平均高于对照组,TIMP-1水平均低于对照组,且视网膜病变组血清VASH-1水平高于无视网膜病变组,视网膜病变组血清TIMP-1水平低于无视网膜病变组,差异均有统计学意义(P<0.05)。ROC曲线分析结果显示,血清VASH-1、TIMP-1预测T2DM患者发生视网膜病变的曲线下面积分别为0.807、0.847。多因素Logistic回归分析结果显示,病程长、血清VASH-1高水平、TIMP-1低水平为T2DM患者发生视网膜病变的危险因素(P<0.05)。结论发生视网膜病变的T2DM患者血清VASH-1水平升高、TIMP-1水平降低。血清VASH-1、TIMP-1为T2DM患者发生视网膜病变的影响因素,二者有望作为临床诊治T2DM患者发生视网膜病变的生物标志物。

Evaluate the Expression of uPA,PAI-1 in Human Gastric Cancer and its Correlation with the Angiogenesis by the Application of Tissue Microarray

OBJECTIVE To investigate the expression of urokinase-type plasminogen （uPA）, its inhibitor-1 （PAI-1） mRNA and its protein in human gastric cancer and to find out the relationship among the tumor differentiation, angiogenesis, and other clinical pathologic factors. METHODS In situ hybridization （ISH） was used to get the uPA, PAI-lmRNA in 110 cases with human gastric cancer in 2-tissue microarray （TMA）. Immunohistochemical staining （S-P method） for uPA, PAI-1 protein and CD34 were performed in the 110 cases in 2 TMA. RESULTS The expression of the uPA, PAI-lmRNA and their protein happened in the cytoplasm of gastric cancer cells were induced by the poor differentiation of the GC, and the expression of uPA had an increasing trend while the expression of the PAI-1 had a decreasing trend. The microvessel density （MVD） had a positive correlation with the clinical stages and the significant relationship with the lymph node metastasis （P 〈 0.05）. The MVD in uPA positive group was significantly higher than those in uPA negative group （P 〈 0.05）. The expression of PAI-1 has no correlation neither with the clinical stages nor the lymph node metastasis. CONCLUSION The uPA play an important role in invasion and metastasis of GC through promoting angiogenesis. Interdicting the secretion and function of the uPA may allow the target therapy against the tumor invasion. As a new high-throughput technology, the tissue microarray is a valuable way to be used in clinical treatment.

Effect of Pin1 Inhibitor Juglone on Proliferation,Migration and Angiogenic Ability of Breast Cancer Cell Line MCF7Adr

Summary： This study aimed to evaluate the effects of Pinl inhibitor Juglone on proliferation, migration and the angiogenic ability of breast cancer cell line MCF7Adr. MCF7Adr ceils were cultured and sepa- rately treated with Pinl inhibitor Juglone （treatment group） and DMEM without drug （control group）. The cell cycle was examined by flow cytometry. Cell migration was measured by wound-healing assay. Cyclin E protein content was detected by Western blotting. The angiogenesis factor vascular endothelial growth factor （VEGF） in cell media was determined by enzyme linked immunosorbent assay. The re- suits showed that the percentage of cells in GJM phase in treatment group was significantly higher than that in control group （25.5% vs. 10.1%, P〈0.05）, and that in G0/G1 phase and S stage in treatment group was significantly lower than that in control group （40.5% vs. 48.2%, and 33.7% vs. 41.7%, P〈0：05）. Cyclin E protein content in treatment group was significantly lower than that in control group （39.2±7.4 vs. 100±23.1, P〈0.05）. （A0-A24）/A0 value in treatment group was significantly lower than that in control group （23.9±3.8 vs. 100±14.4, P〈0.05）. VEGF-A, -B, and -C contents in cell media of treatment group were significantly lower than those in control group （P〈0.05）. It was suggested that Pinl inhibitor Juglone can effectively inhibit the proliferation, migration and the angiogenic ability of MCF7Adr cells, and can be used as an alternative drug therapy for breast cancer.

Mitochondrial division inhibitor 1 protects cortical neurons from excitotoxicity:a mechanistic pathway

Mitochondrial division inhibitor 1（Mdivi-1） is a selective cell-permeable inhibitor of dynamin-related protein-1（Drp1） and mitochondrial division.To investigate the effect of Mdivi-1 on cells treated with glutamate,cerebral cortex neurons isolated from neonatal rats were treated with 10 m M glutamate for 24 hours.Normal cultured cells and dimethyl sulfoxide-cultured cells were considered as controls.Apoptotic cells were detected by flow cytometry.Changes in mitochondrial morphology were examined by electron microscopy.Drp1,Bax,and casp ase-3 expression was evaluated by western blot assays and immunocytochemistry.Mitochondrial membrane potential was detected using the JC-1 probe.Twenty-four hours after 10 m M glutamate treatment,Drp1,Bax and caspase-3 expression was upregulated,Drp1 and Bax were translocated to mitochondria,mitochondrial membrane potential was decreased and the rate of apoptosis was increased.These effects were inhibited by treatment with 50 μM Mdivi-1 for 2 hours.This finding indicates that Mdivi-1 is a candidate neuroprotective drug that can potentially mitigate against neuronal injury caused by glutamate-induced excitotoxicity.

Combined immune checkpoint inhibitors of CTLA4 and PD-1 for hepatic melanoma of unknown primary origin: A case report

BACKGROUND Melanoma is uncommonly found in lymph nodes,subcutaneous tissue,or visceral organs without a primary lesion,where it is identified as metastatic melanoma with unknown primary(MUP).Hepatic MUP is extremely rare and has a poor prognosis.There is limited information on its pathogenesis,clinical and imaging features,and pathological findings.There are no guidelines for the use of immune checkpoint inhibitors(ICIs)in hepatic MUP,and the treatment outcome has rarely been reported.CASE SUMMARY A 42-year-old woman presented to our hospital with hepatic tumors found incidentally during a routine check-up.Contrast-enhanced abdominal computerized tomography showed multiple mass lesions in the liver.Pathological results revealed melanoma,which was confirmed by immunohistochemical staining for HMB-45(+),Melan-A(+),S-100(+),and SOX10(+).There was no evidence of primary cutaneous,ocular,gastrointestinal,or anal lesion on a comprehensive examination.The patient was diagnosed with hepatic MUP.She received combined antibodies against cytotoxic T-lymphocyte-associated antigen 4(CTLA-4,ipilimumab)and programmed death protein-1(PD-1,nivolumab).She died of hepatic failure 9 mo after hepatic MUP was diagnosed.This the first case of hepatic MUP treated with combined ipilimumab and nivolumab,who showed better outcome than previous cases.CONCLUSIONCombined ICIs of PD-1 and CTLA-4 may be considered as the first-line therapyfor patients with hepatic MUP.

Effects of epinephrine on angiogenesis-related gene expressions in cultured rat cardiomyocytes

Epinephrine is often used for the treatment of patients with heart failure, low cardiac output and cardiac arrest. It can acutely improve hemodynamic parameters; however, it does not seem to improve longer term clinical outcomes. Therefore, we hypothesized that epinephrine may induce unfavorable changes in gene expression of cardiomyocyte. Thus, we investigated effects of epinephrine exposure on the mediation or modulation of gene expression of cultured cardiomyocytes at a genome-wide scale. Our investigation revealed that exposure of cardiomyocytes to epinephrine in an in vitro environment can up-regulate the expression ofangiopoietin-2 gene （~ 2.1 times）, and down-regulate the gene expression of neuregulin 1 （-3.7 times）, plasminogen activator inhibitor-1 （-2.4 times） and SPARC-related modular calcium-binding protein-2 （-4.5 times）. These changes suggest that epinephrine exposure may induce inhibition of angiogenesis-related gene expressions in cultured rat cardiomyocytes. The precise clinical significance of these changes in gene expression, which was induced by epinephrine exposure, warrants further experimental and clinical investigations.

Refractory lymphoma treated with chimeric antigen receptor T cells combined with programmed cell death-1 inhibitor:A case report

BACKGROUND Diffuse large B-cell lymphoma(DLBCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHL.Primary testicular(PT)lymphoma is an uncommon extranodal disease representing approximately 1%-2%of lymphoma.Approximately 30%–40%of patients are refractory to frontline therapy or relapse after complete remission.Refractory DLBCL responds poorly to other lines of chemotherapy,and experiences short-term survival.CASE SUMMARY We present a 41-year-old male patient who was diagnosed with PT-DLBCL.Further disease progression was observed after multiline chemotherapy.Chimeric antigen receptor T cells(CAR-T)therapy salvaged the patient.Unfortunately,a new mass was observed in the right adrenal area after six months.The patient was administered programmed cell death protein-1(PD-1)inhibitor therapy and maintained progression-free survival at more than 17 mo of follow-up.CONCLUSION Our findings support the potential benefit of CAR-T combined with PD-1 inhibitor therapies in this type of relapsed and refractory PT-DLBCL.

血管生成抑制蛋白1与肿瘤血管及内镜下的表现关系分析

目的:探讨血管生成抑制蛋白1(VASH1)在食管癌肿瘤血管中的表达与内镜下表现的关系。方法:选取存档石蜡包埋食管癌组织标本120例和正常食管组织标本50例,免疫组织化学SP法检测其VASH1的表达,分析VASH1在食管癌组织和正常食管组织中的形态差异,分析不同IPCL分型VASH1表达情况,以及不同肿瘤分化状态下VASH1表达与MVD的关系。结果:VASH1、血管内皮生长因子(VEGF)在食管癌组织中的阳性表达率分别为54. 17%(65/120)、59. 17%(71/120),在正常组织中的阳性表达率分别为8. 0%(4/50)、16. 0%(8/50),VASH1、VEGF在食管癌组织中的阳性表达率高于正常组织(P <0. 01);食管癌组织中,VEGF与VASH1表达呈显著正相关关系,影响食管癌预后效果的独立危险因素有浸润深度、淋巴结转移、VASH1及VEGF表达水平等(P <0. 05～P <0. 01);上皮乳头内毛细血管襻Ⅴ型病人占比最高为54. 79%,Ⅳ型为56. 82%,差异无统计学意义(P> 0. 05); VASH1阴性、低表达、高表达病人的MVD值差异有统计学意义(P <0. 01),随着VASH1表达增加,病人MVD值增高,VASH1表达与血管形成呈正相关关系(P <0. 01)。结论:VASH1可能与食管癌的发展、肿瘤细胞生成密切相关,且对预测食管癌的预后具有一定的意义。

PD-1单抗治疗晚期HER-2阴性胃癌的临床观察

目的探讨程序性死亡受体-1(PD-1)单抗单药及联合化疗和/或抗血管生成药物治疗晚期人类表皮生长因子受体2(HER-2)阴性胃癌的疗效及安全性。方法回顾性分析2019年1月至2020年12月80例经组织病理学确诊的晚期HER-2阴性胃腺癌患者的临床资料。80例患者中9例仅接受PD-1单抗治疗,20例接受PD-1单抗联合化疗,23例接受PD-1单抗联合抗血管生成治疗,28例接受PD-1单抗联合化疗及抗血管生成治疗。分析接受不同治疗方案和治疗线数患者的近期疗效、远期疗效和不良反应。结果80例患者中无CR病例,获PR 15例、SD 34例、PD 31例,有效率(RR)为18.8%,疾病控制率(DCR)为61.2%。中位随访7个月,中位无进展生存期(PFS)为3.0(95%CI:2.8~3.2)个月,其中二线治疗(n=40)的DCR为77.5%,中位PFS为4.0(95%CI:2.9~5.1)个月,优于三线治疗(n=26)的46.2%和3.0(95%CI:2.3~3.7)个月,以及四线及多线治疗(n=14)的42.8%和2.2(95%CI:1.3~3.1)个月(P=0.005)。PD-1单抗联合化疗及抗血管生成治疗组(n=28)的中位PFS为4.0(95%CI:1.7~6.3)个月,仅接受单药PD-1单抗治疗组的中位PFS为3.0(95%CI:0.9~5.1)个月,联合化疗组为3.0(95%CI:2.6~3.4)个月,联合抗血管生成治疗组为3.0(95%CI:2.1~3.9)个月,差异有统计学意义(P=0.027)。全组主要不良反应包括贫血、乏力、转氨酶升高、纳差、中性粒细胞减少,以1~2级为主,3例患者因3~4级不良反应终止治疗。结论PD-1单抗联合治疗用于晚期HER-2阴性胃癌疗效确切,安全性良好,且越早线使用患者获益越明显。PD-1单抗联合化疗及抗血管生成治疗模式值得临床进一步探索。

基质金属蛋白酶组织抑制剂1基因转染对肾小管上皮细胞PTEN表达的影响

目的观察正反义人TIMP-1转染和酶抑制剂干预HKC细胞对PTEN、VEGF/Flk-1的表达的影响,为研究TIMP-1对肾脏器官衰老的影响机制提供参考。方法将正义和反义人TIMP-1基因转染至人近端肾小管上皮细胞(HKC),同时用与正义转染组细胞酶抑制活性相当的MMP-2/MMP-9抑制剂(MMP-2/MMP-9 InhibitorⅢ,100μmol/L)干预24 h,RT-PCR;间接免疫荧光法检测各组细胞PTEN、VEGF和Flk-1的表达。结果研究显示,与未转染和空载体转染组相比,正义TIMP-1转染组中PTEN表达上调(P<0.05),明胶酶活性降低(P<0.05),VEGF和Flk-1表达下调(P<0.05),而反义TIMP-1转染组则相反(P<0.05);MMP-2/MMP-9 inhibitorⅢ100μmol/L(酶抑制剂组)组PTEN、VEGF和Flk-1表达与未转染和空载体转染组相比无显著差异。结论肾脏器官衰老过程中高表达的TIMP-1,通过上调PTEN(非MMP依赖途径),进而下凋VEGF、Flk-1表达,提示PTEN在TIMP-1介导肾脏衰老微血管生成障碍中起重要作用,为揭示TIMP-1参与肾脏器官衰老分子机制提供了新的理论依据。

X连锁凋亡抑制蛋白相关因子-1抑制肝癌裸鼠移植瘤生长的研究

目的研究X连锁凋亡抑制蛋白相关因子-1(XAF1)基因对人肝癌裸鼠移植瘤生长的抑制作用。方法建立人肝癌细胞株SMMC7721裸鼠荷瘤模型,每组5只裸鼠分别在瘤内分3点注射相同感染滴度的重组腺病毒Ad5/F35-XAF1、Ad5/F35-Null对照空病毒及等体积的磷酸缓冲液(PBS),隔天注射1次,疗程2周。每3天测量各组裸鼠移植瘤的体积,观察Ad5/F35-XAF1组移植瘤的生长与其他两组的差异。原位末端标记TUNEL法检测移植瘤细胞的凋亡,免疫组织化学法检测移植瘤中XAF1蛋白表达和微血管密度(MVD)。结果与PBS组和Ad5/F35-Null组比较,瘤内注射Ad5/F35-XAF1组裸鼠移植瘤体积、质量和MVD显著减小(P<0.05或P<0.01),而移植瘤细胞的凋亡指数和XAF1蛋白的表达率均明显增高(P<0.01)。结论腺病毒介导XAF1基因可抑制人肝癌裸鼠移植瘤的生长,可能与该基因诱导肝癌细胞凋亡和抑制肿瘤血管形成有关。

雷公藤内酯醇对血管内皮细胞t-PA、PAI-1蛋白表达的影响

目的研究雷公藤内酯醇(triptolid,T10)对血管内皮细胞移行活性及组织型纤溶酶原激活物(tissue-typeplasminogenactivator,t-PA)和纤溶酶原激活物抑制物-1(plas-minogenactivatorinhibitor-1,PAI-1)蛋白表达的影响,探讨T10对新生血管生成的抑制作用。方法体外培养传3代人脐静脉内皮细胞(humanumbilicalveinendothelialcells,HUVECs),加入不同浓度的T10(5μg·L-1、10μg·L-1、20μg·L-1、30μg·L-1)、地塞米松(300mg·L-1),观察HUVECs移行活性;免疫组织化学染色检测HUVECs中t-PA和PAI-1蛋白表达量。结果T10能明显抑制HUVECs移行活性,使HUVECs移行数量、移行距离明显减少和缩短;T10能明显抑制HUVECs中t-PA和PAI-1蛋白表达,使t-PA和PAI-1蛋白表达棕黄色阳性染色减少,与对照组相比差异具有显著性(P<0.01)。结论T10能明显抑制血管内皮细胞移行,抑制内皮细胞t-PA和PAI-1蛋白表达,从而有效抑制新生血管生成与生长。

胃癌中uPA、PAI-1表达及其与血管生成的关系

目的观察胃癌组织中uPA、PAI-1mRNA及蛋白的表达,并探讨它们与肿瘤分化、血管生成及临床病理因素之间的关系。方法用原位杂交及免疫组化S-P法检测110例胃癌组织中uPA、PAI-1的表达,根据CD34阳性的血管内皮细胞计数肿瘤组织微血管密度(MVD)。结果(1)胃癌组织中uPA mRNA和蛋白、PAI-1 mRNA和蛋白阳性表达定位于胞质;uPA的表达随分化程度的降低有逐渐升高的趋势,PAI-1的表达随分化程度的降低有逐渐降低的趋势。(2)110例uPA mRNA及蛋白表达阳性组MVD值显著高于阴性组,差异均具有显著性(P值均<0.05)。(3)uPA mRNA及蛋白的表达与临床分期呈正相关(P<0.05),PAI-1的表达与临床分期和淋巴结转移无相关性。(4)uPA mRNA/蛋白与PAI-1 mRNA/蛋白的表达无相关性。结论uPA与促进胃癌的血管生成密切相关,阻断uPA的分泌和作用途径有望对胃癌浸润转移起抑制作用;胃癌组织中PAI-1可能担当重要的调节剂或者是肿瘤细胞防止自身降解的保护剂而不是这个系统的单纯抑制剂。

子宫内膜腺癌组织中Vasohibin-1与MVD的表达及其相关关系的研究

目的:探讨血管生成抑制蛋白-1(Vasohibin-1)、微血管密度(micro vessel density,MVD)在子宫内膜腺癌组织中的表达及两者之间的相关关系。方法:应用SP法检测Vasohibin-1在23例正常子宫内膜组织、28例子宫内膜非典型增生组织及69例子宫内膜腺癌组织中的表达情况;并应用CD34抗体标记上述组织中血管内皮细胞,测定MVD值,分析两者在子宫内膜腺癌的相关关系。结果:Vasohibin-1在子宫内膜腺癌组织中的阳性表达率显著高于子宫内膜不典型增生组织与正常增殖期子宫内膜组织(P<0.05)。子宫内膜腺癌组织中MVD测定值显著高于子宫内膜不典型增生与正常增殖期子宫内膜(P<0.01)。Vaoshibin-1在子宫内膜腺癌组织中的表达与手术病理分期、肌层浸润、淋巴结转移、年龄差异均无统计学意义(P>0.05)。在子宫内膜腺癌组织中,Vasohibin-1的表达与MVD值呈正相关(r=0.337,P<0.05)。结论:在子宫内膜腺癌中存在Vasohibin-1、MVD的高表达,且两者在子宫内膜腺癌的发生、发展中可能起协同作用。