慢性乙型肝炎病毒携带者血清GP73水平与肝组织病理学变化的关系研究*

目的 探讨慢性乙型肝炎病毒携带者血清高尔基体蛋白73（GP73）水平与肝组织病理学变化的关系。方法 2014年1月~2016年12月我院诊治的慢性HBV携带者150例、慢性乙型肝炎患者150例和乙型肝炎肝硬化患者150例,另选同期健康人50例,采用ELISA法检测GP73水平,对150例慢性HBV携带者进行肝穿刺活检,采用Metavir评分对肝组织炎症和纤维化进行评价。结果 慢性HBV携带者血清GP73水平为（46.5±7.8） ng/ml,慢性乙型肝炎组为（90.2±10.9） ng/ml,乙型肝炎肝硬化组为（231.6±20.1） ng/ml,均显著高于健康人组的（36.7±6.6） ng/ml,差异有统计学意义（P<0.05）,肝硬化患者血清GP73水平也显著高于慢性乙型肝炎或HBV携带者（P<0.05）;经肝组织检查,150例慢性HBV携带者肝内炎症活动度分级和纤维化分期表现为G₀~G₁ 105例,G₂ 30例,G₃~G₄ 15例,其血清GP73水平分别为（45.2±12.8）ng/ml、（63.8±15.0）ng/ml和（83.7±20.1）ng/ml,S₀~S₁ 98例,S₂ 3₀例,S₃~S₄ 22例,其血清GP73水平分别为（45.1±16.8）ng/ml、（67.3±16.4）ng/ml和（72.0±18.4）ng/ml,肝组织炎症活动度分级和纤维化分期严重的患者血清GP73水平显著升高,与分级或分期轻的人群比,差异有统计学意义（F=16.8,F=19.2,P均<0.05）;Logistic回归分析发现血清GP73水平升高是慢性HBV携带者肝组织显著炎症（OR=1.1,95 % CI:1.0~1.1,P<0.05）和显著肝纤维化（OR=2.1,95% CI:0.8~1.2,P<0.05）的高危因素。结论 检测血清GP73水平可能有助于对慢性HBV携带者肝组织炎症分级和纤维化分期的判断,能否作为预测慢性HBV携带者肝组织炎症分级和纤维化分期的潜在标志物,还需要扩大验证。     

慢加急性乙型肝炎肝衰竭患者血清IL-10和GP73水平检测及其临床意义

目的 探讨HBV相关慢加急性肝衰竭（HBV-ACLF）患者血清IL-10和GP73水平变化及其临床意义。方法 在56例HBV-ACLF患者、32例慢性乙型肝炎（CHB）患者和20例健康人,采用酶联免疫吸附法检测基线血清IL-10和GP73水平。随访HBV-ACLF患者3个月,进行重复检测。结果 基线时HBV-ACLF组血清IL-10水平为（32.4±14.8） pg/ml,显著高于CHB组的（15.2±6.3） pg/ml或健康人的（6.1±1.9） pg/ml （P<0.05）; HBV-ACLF组血清GP73 水平为（283.4±95.4） ng/ml,显著高于CHB组的（129.7±58.1） ng/ml或健康人的（45.5±16.2） ng/ml （P<0.05）;33例生存的HBV-ACLF患者基线血清IL-10 水平为（34.6±15.3） pg/ml,显著高于23例死亡患者的（30.1±14.3） pg/ml（P<0.05）,但生存组与死亡组血清GP73水平差异无统计学意义【（279.7±94.6） ng/ml 对（287.2±96.2） ng/ml,P=0.36】;治疗2周时,HBV-ACLF生存组血清IL-10水平为（30.1±14.0） pg/ml,仍显著高于死亡组的（24.9±11.2） pg/ml（P<0.05）,但不同于基线时,治疗2周时生存与死亡患者血清GP73水平出现了统计学差异【（258.7±85.9） ng/ml对（331.2±107.5） ng/ml,P<0.05】。结论 HBV-ACLF患者血清IL-10 水平高者可能预后相对较好,而动态观察血清GP73水平变化可能对预测HBV-ACLF患者的短期预后也有一定的价值。     

乙型肝炎肝硬化患者血清B7-H3和IL-18水平变化及其临床意义探讨

目的 通过检测乙型肝炎肝硬化患者血清B7-H3和白细胞介素-18（IL-18）水平,探讨它们水平变化与疾病进展的相关性。方法 2015年4月~2017年3月纳入113例乙型肝炎肝硬化患者,其中代偿期肝硬化患者33例,失代偿期肝硬化患者80例,和健康志愿者20名。采用ELISA法检测血清B7-H3和IL-18水平,采用直线相关分析肝硬化患者血清B7-H3与IL-18水平间的相关性。结果 80例失代偿期肝硬化患者血清B7-H3水平为（62.29±22.17） ng/ml,显著高于33例代偿期肝硬化患者的（32.27±10.29） ng/ml（P<0.05）或20例健康人的（11.35±4.48） ng/ml（P<0.05）,代偿期肝硬化患者血清B7-H3水平也显著高于健康人（P<0.05）;失代偿期肝硬化患者血清IL-18水平为（585.63±121.28） pg/ml,显著高于代偿期肝硬化患者的（396.29±86.91） pg/ml（P<0.05）或健康人的（155.31±76.93） pg/ml（P<0.05）,代偿期肝硬化患者血清IL-18水平也显著高于健康人（P<0.05）;肝硬化患者血清B7-H3水平与IL-18水平间呈显著正相关（r=0.4111,P<0.01）;26例Child-Pugh C级患者血清B7-H3水平为（76.53±22.76） ng/ml,显著高于33例Child-Pugh A级患者的（23.27±9.84） ng/ml或54例Child-Pugh B级患者的（52.21±13.94） ng/ml（P<0.05）,Child-Pugh C患者IL-18水平为（594.13±112.21） pg/ml,显著高于Child-Pugh B级患者的（408.06±92.41） pg/ml或Child-Pugh A级患者的（243.82±57.03） pg/ml（P<0.05）,Child-Pugh B级患者血清IL-18水平也显著高于Child-Pugh A级（P<0.05）。结论 乙型肝炎肝硬化患者血清B7-H3和IL-18水平升高,两者呈正相关,提示B7-H3可能是乙型肝炎肝硬化患者一个预后不良因子,通过与IL-18的协同作用,引起体内免疫功能紊乱,加重了肝细胞损伤,从而促进了疾病的发生和发展。     

慢性乙型肝炎患者血清血管生成素样蛋白2和高尔基体蛋白73水平变化及其诊断显著肝纤维化的效能分析*

目的 评价血清血管生成素样蛋白2(ANGPTL2)和高尔基体蛋白73（GP73）诊断慢性乙型肝炎（CHB）患者肝纤维化程度的价值。方法 2015年3月~2017年10月我院收治的117例CHB患者,采用ELISA法检测血清ANGPTL2和GP73水平,采用受试者工作特征曲线（ROC）下面积（AUC）评价血清ANGPTL2和GP73诊断CHB患者肝纤维化和肝硬化的效能。结果 15例CHBS3~S4期患者血清ANGPTL2和GP73水平分别为（9.1±2.4）ng/ml和（84.9±15.2） ng/ml,显著高于78例S1~S2期[分别为（6.7±2.3） ng/ml和（65.1±14.8） ng/ml,P<0.05]或24例S0期患者[分别为（4.4±1.4） ng/ml和（53.7±14.3） ng/ml,P<0.05];以肝组织纤维化大于等于S3为严重肝纤维化,分别以血清ANGPTL2水平等于8.6 ng/mL和9.6 ng/ml或血清GP73水平等于75.6 ng/ml和103.5 ng/ml为诊断严重肝纤维化和肝硬化的截断点, 结果ANGPTL2诊断慢性乙型肝炎患者严重肝纤维化和肝硬化的AUC与GP73比,差异无统计学意义（Z=1.872,P=0.061;Z=0.328,P=0.743）;ANGPTL2与GP73联合诊断慢性乙型肝炎患者严重肝纤维化的效能显著高于单指标诊断,即AUC联合检测>AUCANGPTL2（Z=3.310,P=0.001）或AUC联合检测>AUCGP73（Z=2.004,P=0.045）,血清ANGPTL2与GP73联合诊断乙型肝炎肝硬化的效能与单指标诊断的效能比,差异无统计学意义（Z=1.471,P=0.141;Z=1.575,P=0.115）;采用血清ANGPTL2与GP73联合诊断肝纤维化的效能与基于4因子模型（FIB-4）或天门冬氨酸氨基转移酶/血小板指数（APRI）比,差异无统计学意义（Z=0.869,P=0.386;Z=0.492,P=0.623）;血清ANGPTL2与GP73联合诊断肝硬化的效能与FIB-4或APRI比,差异也无统计学意义（Z=1.834,P=0.067;Z=0.610,P=0.512）。结论 慢性乙型肝炎患者血清ANGPTL2和GP73水平有一些变化规律,应用两者诊断肝纤维化分期有一些有意义的苗头,值得进一步探讨。     

肝源性糖尿病患者肝组织干扰素诱导蛋白-10表达变化*

目的 观察肝源性糖尿病患者肝组织和血清干扰素诱导蛋白-10（IP-10）水平变化,并分析其在肝源性糖尿病发病过程中的可能作用。方法 2016年3月~2018年5月我院诊治的乙型肝炎肝硬化并发肝源性糖尿病患者70例和不伴有糖尿病的乙型肝炎肝硬化患者70例,采用ELISA法检测血清IP-10水平,采用PCR法和免疫组化法分别检测肝组织IP-10 mRNA水平和蛋白表达。结果 伴有糖尿病的肝硬化血清IP-10水平为（236.59±28.30） pg/mL,显著高于不伴有糖尿病的肝硬化患者【（205.31±26.92） pg/mL,P<0.001】;糖尿病患者肝组织IP-10 mRNA水平为（0.59±0.91） lg copies/ml,显著高于肝硬化患者【（0.21±0.66） lg copies/ml,P<0.05】,差异具有统计学意义;糖尿病患者肝组织IP-10表达阳性率为31.4%,显著高于肝硬化患者的12.9%,差异具有统计学意义（x2=7.002,P<0.05）。结论 乙型肝炎肝硬化并发肝源性糖尿病患者血清和肝组织IP-10水平显著升高,其意义还有待于进一步探讨。     

慢性乙型肝炎患者临床和肝组织病理学特点及影响肝纤维化因素分析*

目的 分析HBeAg阴性与阳性慢性乙型肝炎（CHB）患者临床和肝组织病理学特点,探讨影响CHB患者发生明显肝纤维化的危险因素。方法 回顾性分析250例CHB患者血清HBV DNA水平、Fibroscan检测肝脏硬度（stiffness）值和肝穿刺组织病理学特点,应用多因素Logistic回归模型分析影响CHB患者发生明显肝纤维化的独立危险因素。结果 160例HBeAg阴性患者血清HBV DNA ≥1×10⁵ copies/ml者所占比例显著低于HBeAg阳性组（66.9%对99.4%,P<0.05）;HBeAg阴性组血清ALT和AST水平显著低于HBeAg阳性组（P<0.05）;血清HBeAg阴性组与阳性组肝组织炎症分级和纤维化分期总体分布差异无统计学意义（P>0.05）;多因素Logistic回归分析结果显示年龄≥40岁、HBV DNA水平高、PTA低和Stiffness水平高为CHB患者存在明显肝纤维化的独立危险因素。结论 血清HBeAg阴性与阳性CHB患者存在一些临床和肝组织病理学特征的差异,血清HBeAg阴性患者可能存在更为严重的临床和预后问题,需要给予特别的关注和管理。     

慢性乙型肝炎和肝硬化患者血清TLR4、TGF-β1和IL-17水平及其临床意义*

目的 分析慢性乙型肝炎（CHB）和乙型肝炎肝硬化患者血清Toll样受体4（TLR4）、转化生长因子-β1（TGF-β1）和白细胞介素-17（IL-17）水平变化及其临床意义。方法 2015年6月~2017年4月本院收治的112例CHB、52例乙型肝炎肝硬化患者和选择的33例健康人,采用ELISA法检验血清IL-17、TLR4、TGF-β1水平,常规进行肝活检。结果 慢性乙型肝炎、肝硬化和健康人血清IL-17水平分别为（264.42±32.53） pg/ml、（271.54±33.71） pg/ml和（64.18±5.52） ng/ml,血清TLR4水平分别为（5.81±0.83） pg/ml、（37.41±6.05） pg/ml和（1.07±0.13）ng/ml,血清TGF-β1水平分别为（3.67±0.42） pg/ml、（7.82±1.07） pg/ml和（1.61±0.07） ng/ml,差异明显（P<0.05）;19例Child-Pugh B级血清IL-17、TLR4和TGF-β1水平分别为（231.38±28.67） pg/ml、（18.61±2.87） pg/ml和（5.76±0.52） ng/ml,16例C级患者分别为（301.72±32.72） pg/ml、（39.47±6.82） pg/ml和（9.42±1.27） ng/ml,均明显高于17例Child-Pugh A级患者【分别为（204.53±26.57） pg/ml、（4.72±0.71） pg/ml和（3.18±0.34） ng/ml,P<0.05】;肝活检组织学检查发现S0 8例、S1 42例、S2 43例、S3 19例、S4 52例,血清IL-17、TLR4、TGF-β1水平随着肝组织纤维化分期严重而升高。结论 乙型肝炎肝硬化患者血清TLR4、TGF-β1和IL-17水平升高,对诊断和指导治疗可能有帮助。     

慢性乙型肝炎患者血清脂肪细胞因子水平变化及其临床意义*

目的 研究慢性乙型肝炎（CHB）患者血清脂肪细胞因子水平及其临床意义。方法 2014年11月~2018年4月我院收治的154例CHB患者和同期来我院体检的健康人154例,采用ELISA法检测血清内脏脂肪素、瘦素、脂联素和网膜素水平。所有患者接受肝活检,将肝组织炎症活动度评分为G3或G4者,判定为肝组织严重炎症活动,将肝纤维化S3期和S4期视为严重肝纤维化或肝硬化。结果 CHB患者血清内脏脂肪素、瘦素和脂联素水平健康人比较,差异无统计学意义（P>0.05）,而CHB患者血清网膜素水平为（361.0±132.4） μg/L,显著高于健康人的（300.9±110.5） μg/L（P<0.05）;89例肝组织严重炎症活动与65例轻度炎症活动患者血清内脏脂肪素、瘦素、脂联素和网膜素水平比较差异无统计学意义（P>0.05）;96例肝组织严重纤维化患者与58例轻度纤维化患者血清内脏脂肪素、瘦素和脂联素水平比较差异无统计学意义（P>0.05）,而肝组织严重纤维化患者血清网膜素水平为（397.8±150.4） μg/L,显著高于肝组织轻度纤维化患者的（316.7±118.5） μg/L（P<0.05）。结论 CHB患者血清网膜素水平显著升高,且肝组织严重纤维化患者血清网膜素水平显著升高,或许可以用来帮助评估肝内病变。     

恩替卡韦联合双歧杆菌乳杆菌三联活菌片治疗失代偿期乙型肝炎肝硬化临床疗效观察

目的 探讨恩替卡韦联合双歧杆菌乳杆菌三联活菌片治疗失代偿期乙型肝炎肝硬化患者的临床疗效。方法 2015年3月~2017年8月我院收治的120例失代偿期乙型肝炎肝硬化患者被随机分为对照组60例和观察组60例,分别给予恩替卡韦分散片或恩替卡韦联合双歧杆菌乳杆菌三联活菌片治疗,观察24 w。结果 在治疗12 w时,观察组血清TBIL为（16.3±4.2） μmol/L,显著低于对照组的（26.3±5.2） μmol/L（P<0.05）,观察组血清ALB为（32.5±4.2）g/L,显著高于对照组的（30.2±5.3） g/L（P<0.05）;在治疗24 w时,观察组血清ALB为（37.8±2.3） g/L,显著高于对照组的（34.4±4.2） g/L（P<0.05）;观察组血清LN和C- IV分别为（65.2±15.1）ng/ml和（85.5±8.5） ng/ml,显著低于对照组的【（75.3±10.3） ng/ml和（96.2±10.3） ng/ml,P<0.05】;观察组血清HBV DNA水平为（1.0±0.1） lg copies/ml,与对照组的（1.7±0.3） lg copies/ml比,无显著性差异（P>0.05）,血清HBV DNA转阴率为100.0%,与对照组的90.0%比,无显著性差异（P>0.05）;在治疗12 w和24 w,观察组发生自发性细菌性腹膜炎（SBP）5例（8.3%）和2例（3.3%）,显著低于对照组的10例（16.7%）和8例（13.3%,P<0.05）;在治疗24 w末,观察组死亡3例（5%）,而对照组死亡10例（16.7%,P<0.05）。结论 恩替卡韦联合双歧杆菌乳杆菌三联活菌治疗失代偿期乙型肝炎肝硬化患者能短期改善肝功能指标,降低血清肝纤维化指标水平,减少并发症的发生。     

轮状病毒感染腹泻患儿肝损害状况调查

目的 了解轮状病毒感染致急性腹泻患儿肝损害发生状况。方法 2013年5月~2015年9月我院收治幼儿腹泻160例,采用金标法检测血清RV抗原,采用ELISA法检测肿瘤坏死因子（TNF）-α、IL-6和IL-10水平。结果 本组诊断RV感染70例,非RV感染90例;在RV感染患儿,肝损害发生率为24.3%,明显高于非RV感染组的6.7%（P<0.05）;32例1岁以上RV感染者肝损伤发生率为6.0%,显著低于38例1岁以下患儿的15.8%（P<0.05）;在RV感染组,53例肝功能检查正常者血清IL-6、IL-10和TNF-α水平分别为（4.47±1.38） pg/ml、（101.85±17.46） pg/ml、（24.53±5.37） pg/ml,明显低于17例肝功能损害者【分别为（5.83±2.06）pg/ml、（119.53±20.48） pg/ml、（29.38±6.43） pg/ml,P<0.05】。结论 RV感染腹泻患儿往往会出现肝损害,尤其是1岁以下患儿,应注意防护。     

Fibrinolytic characteristics and their significance in malignant, tuberculous and cirrhotic pleural and ascitic fluids

The fibrinolytic characteristics and clinical pathological significance of pleural and ascitic fluid were studied in patients with malignant tumour, tuberculosis or liver cirrhosis. Urokinase plasminogen activator (uPA) and urokinase plaminogen activator receptor (uPAR) levels were measured by enzyme-linked immunoadsorbent assay and tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), plasminogen (Plg), plasmin (Pl) and alpha(2) plasmin inhibitor (alpha(2)PI) by colorimetric assay. uPA and uPAR levels were higher in malignant tumour and tuberculosis compared with liver cirrhosis, whereas tPA levels were significantly higher in liver cirrhosis and malignant tumour than in tuberculosis patients. Tuberculosis patients showed statistically higher PAI-1, Plg and Pl concentrations than malignant tumour patients, which, in turn, were higher than those in liver cirrhosis patients. alpha(2)PI levels were markedly higher in malignant tumour and liver cirrhosis than in tuberculosis. In the malignant tumour group, only uPA level was significantly different between the samples that contained cancer cells and those that did not. We found significant differences between the fibrinolytic characteristics in pleural and ascitic fluid in patients with malignant tumour, tuberculosis and liver cirrhosis. The analysis of several fibrinolytic parameters could help to determine the quality of pleural and ascitic fluid, and also to further understand the pathological processes of these diseases.     

血清suPAR水平与慢性心力衰竭患者预后的关系研究

目的探讨血清可溶性尿激酶型纤溶酶原激活物受体(suPAR)与慢性心力衰竭(CHF)患者预后的关系。方法选取2016年1月至2017年12月期间于解放军联勤保障部队第九0九医院心血管内科收治的120例CHF患者作为CHF组(n=120),另选取同期来院进行体检的120例健康体检者作为对照组(n=120)。分析对照组及CHF组血清suPAR的表达情况,探讨其与炎症因子如肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)和心功能指标如左室舒张末期内径(LVEDD)、左室射血分数(LVEF)的相关性,并随访两组研究对象12个月,分析血清suPAR对CHF患者预后的评估价值。结果CHF组的血清suPAR、TNF-α、IL-6、N末端脑钠肽前体(NT-proBNP)水平以及LVEDD均明显高于对照组(P<0.05),LVEF明显低于对照组(P<0.05)。CHF患者中,NYHA分级Ⅳ级、Ⅲ级、Ⅱ级患者的血清suPAR、TNF-α、IL-6、NT-proBNP水平以及LVEDD逐渐降低,LVEF逐渐升高,两两比较差异均有统计学意义(P<0.05)。CHF患者中,血清suPAR水平与TNF-ɑ、IL-6、LVEDD、NT-proBNP均呈正相关,与LVEF呈负相关(P<0.05)。随访12个月,共28例患者发生心脏事件。预后不良组患者的血清suPAR、TNF-α、IL-6、NT-proBNP水平以及LVEDD均明显高于预后良好组,LVEF明显低于预后良好组(P<0.05)。多因素Logistic回归分析显示:suPAR水平过高及LVEF过低均是CHF患者发生心脏事件的独立危险因素(P<0.05)。受试者操作特征曲线(ROC)分析显示:血清suPAR对CHF患者预后有较高的评估价值,曲线下面积为0.798,敏感度和特异性为75.00%和77.21%。结论血清suPAR在CHF患者中表达明显上升,且是CHF患者发生心脏事件的独立危险因素,对患者的预后评估具有较高的应用价值。     

Plasminogen activation in human acute leukaemias

Plasminogen activation is implicated in solid tumour growth, invasion and metatastic spread. However, little is known about its role in leukaemia. We investigated the production by leukaemic cells of plasminogen activators [urokinase (uPA) and tissue-type PA (tPA)], cell surface receptor for uPA (uPAR) and PA inhibitors (PAI-1 and PAI-2). Leukaemic cells from 37 patients [26 with acute myeloid leukaemia (AML) and 11 with acute lymphoid leukaemia (ALL)] were analysed for mRNA content and enzymatic activities. High levels of uPA mRNA were found in M1, M2, M3 and M4-M5 AMLs, whereas tPA mRNA was not detected in any of the analysed cases. uPAR mRNA was confined to subtypes M4-M5. PAI-1 mRNA was detected in M3 and M4-M5. PAI-2 mRNA was found predominantly in M2 and M4-M5. SDS-PAGE/zymography analyses of cell extracts and supernatants after 24 and 48 h of culture confirmed the production of active uPA by AML cells (mainly M4-M5). but not by ALL. The finding of uPA, uPAR, PAI-1 and PAI-2 synthesized by leukaemic cells suggests that plasminogen activation may contribute to the invasive behaviour of these cells, the fibrinolytic imbalance observed in leukaemic patients and the differentiation and proliferation of M4-M5 by interaction of uPA with uPAR.     

Cardiovascular risk prediction in the general population with use of suPAR,CRP, and Framingham Risk Score

Background

The inflammatory biomarkers soluble urokinase plasminogen activator receptor (suPAR) and C-reactive protein (CRP) independently predict cardiovascular disease (CVD). The prognostic implications of suPAR and CRP combined with Framingham Risk Score (FRS) have not been determined.

Methods

From 1993 to 1994, baseline levels of suPAR and CRP were obtained from 2315 generally healthy Danish individuals (mean [SD] age: 53.9 [10.6] years) who were followed for the composite outcome of ischemic heart disease, stroke and CVD mortality.

Results

During a median follow-up of 12.7 years, 302 events were recorded. After adjusting for FRS, women with suPAR levels in the highest tertile had a 1.74-fold (95% confidence interval [CI]: 1.08–2.81, p = 0.027) and men a 2.09-fold (95% CI: 1.37–3.18, p < 0.001) increase in risk compared to the lowest tertile. Including suPAR and CRP together resulted in stronger risk prediction with a 3.30-fold (95% CI: 1.36–7.99, p < 0.01) increase for women and a 3.53-fold (1.78–7.02, p < 0.001) increase for men when both biomarkers were in the highest compared to the lowest tertile. The combined extreme tertiles of suPAR and CRP reallocated individuals predicted to an intermediate 10-year risk of CVD of 10–20% based on FRS, to low (< 10%) or high (> 20%) risk categories, respectively. This was reflected in a significant improvement of C statistics for men (p = 0.034) and borderline significant for women (p = 0.054), while the integrated discrimination improvement was highly significant (P ≤ 0.001) for both genders.

Conclusions

suPAR provides prognostic information of CVD risk beyond FRS and improves risk prediction substantially when combined with CRP in this setting.     

Chromosomal localization of the human urokinase plasminogen activator receptor and plasminogen activator inhibitor type-2 genes: Implications in colorectal cancer

Abstract Activation of the proenzyme of urokinase (uPA) on the surface of cancer cells has been implicated in the initiation of focal proteolytic mechanisms that permit invasion and metastasis by colon cancers. The activity of uPA on the cell surface appears to be a function of the number of uPA-specific receptors (uPAR) and the extent of inhibition of uPA by plasminogen activator inhibitors (PAI). The mapping of the genes coding for uPAR, and for PAI-2, was performed to determine whether their chromosomal localization suggested their involvement in the genetic alterations associated with cancer cell DNA.
This study confirms the localization of the human urokinase plasminogen activator receptor gene to chromosome 19q and, using in situ hybridization, provides a precise localization to chromosome 19q13.2. In addition, our results confirm the previous allocation of the human plasminogen activator inhibitor-2 gene to a location 18q21.3 → 18q21.1, a location that corresponds to the commonest (>70%) somatic deletions found in colorectal carcinomas. The mapping of the uPAR and PAI-2 genes enables the elucidation of their possible involvement in the genetic alterations that determine the invasive and metastatic phenotypes in colorectal cancer.     

单核细胞尿激酶型纤溶酶原激活物受体表达水平与冠状动脉粥样硬化斑块稳定性的关系

目的探讨不同临床类型的冠状动脉粥样硬化性心脏病患者外周血单核细胞尿激酶型纤溶酶原激活物受体(uPAR)表达水平的差异及其在治疗前后的变化,并观察该指标与术后心血管事件的相关性。方法连续入选经冠状动脉造影证实的冠心病患者136例,其中包括急性冠脉综合征(ACS)85例、稳定型心绞痛(SAP)51例,另选20例健康志愿者作为对照。留取全血标本,用流式细胞仪检测各组患者外周血单核细胞uPAR的表达水平。观察ACS组经皮冠状动脉介入(PCI)治疗24,48h,3个月后外周血单核细胞uPAR表达水平的变化。随访ACS组患者2年,记录主要心血管事件的发生情况。结果 ACS组uPAR表达水平较SAP组及健康志愿者组均显著升高(P0.01),ACS组PCI术后3个月的uPAR表达水平较术前有显著下降(P0.01)。85例ACS患者平均随访(20.46±2.45)个月,术后发生主要心血管事件24例,事件组单核细胞uPAR表达水平显著高于无事件组(P0.01)。应用多因素logistic回归分析发现,单核细胞上uPAR的表达水平与术后主要心血管事件显著相关(P0.01)。结论 ACS患者单核细胞uPAR的表达水平较SAP患者显著升高,ACS患者uPAR的表达水平与主要心血管事件具有明显相关性,单核细胞uPAR的表达水平是冠心病临床病情严重程度的一个敏感指标,对于判断动脉粥样斑块的稳定性以及心血管疾病的预后有重要价值。     

Relationship between Serum Soluble Urokinase Plasminogen Activator Receptor Level and Steroid Responsiveness in FSGS

Background and objectives

Soluble urokinase plasminogen activator receptor (suPAR) was initially proposed as a pathogenic and predictive biomarker of primary FSGS, but the findings were controversial. This study aimed to clarify the clinical implications of suPAR.

Design, setting, participants, & measurements

The study enrolled 109 patients with biopsy-proven primary FSGS who were administered prednisone between January 2011 and May 2013 and followed up for 6–24 months (median duration of follow-up, 12 months). Ninety-six healthy volunteers, 20 patients with minimal-change disease (MCD), and 22 patients with membranous nephropathy (MN) served as controls. Serum suPAR levels were measured using ELISA.

Results

suPAR levels in patients with FSGS (median, 3512 [interquartile range (IQR), 2232–4231] pg/ml) were significantly higher than in healthy controls (median, 1823 [IQR, 1563–2212] pg/ml; P<0.001), patients with MCD (median, 1678 [IQR, 1476–2182] pg/ml; P<0.001), and patients with MN (median, 1668 [IQR, 1327–2127] pg/ml; P<0.001). With 3000 pg/ml used as a threshold, suPAR levels were elevated in 48.6% of patients with FSGS, in contrast to 5% of patients with MCD and 4.5% of those with MN. suPAR levels were independently associated with steroid response in patients with FSGS (odds ratio, 85.02; P=0.001). Patients who were sensitive to steroids had significantly higher suPAR levels than nonsensitive patients (median, 3426 [IQR, 2670–5655] pg/ml versus 2523 [IQR, 1977–3460] pg/ml; P=0.001). A suPAR level of 3400 pg/ml was chosen as the optimal cutoff value for steroid response. At the 6-month follow-up in 84 patients with FSGS, suPAR levels were significantly decreased in those with suPAR level ≥3400 pg/ml (median, 4553 [IQR, 3771–6120] pg/ml versus 3149 [IQR, 2278–3953]; P=0.002) but were unchanged in patients with suPAR level <3400 pg/ml (median, 2359 [IQR, 2023–2842] pg/ml versus 2490 [IQR, 1916–3623] pg/ml; P=0.09).

Conclusions

suPAR is specifically elevated in some patients with FSGS, which differs from the finding in patients with MCD and MN. A suPAR assay may help predict steroid response in patients with primary FSGS.     

Hypofibrinolysis in patients with hypercoagulability: The roles of urokinase and of plasminogen activator inhibitor

The prevalence of abnormalities of fibrinolysis in patients with venous thromboembolism is as yet unknown. Defined abnormalities include congenital dysfunction and deficiency of plasminogen, and probably impaired plasminogen activation secondary to elevated levels of plasminogen activator inhibitor type 1 (PAI-1) or to impaired release of tissue plasminogen activator (tPA). In this preliminary study, we analyzed plasma samples from 21 patients for whom an investigation for possible thrombophilia was requested. Twenty of the patients had venous thromboembolism, and one had arterial thrombosis at an early age. Two patients had deficiency of protein C or protein S, but no other recognized biochemical disturbances related to thrombophilia were identified. Patient samples and plasma from 25 normal controls were assayed for tPA activity, PAI-1 activity, and urokinase (uPA) activity and antigen. tPA activity and antigen were not significantly different in patients than in controls. PAI-1 activity was significantly greater in patients (P < 0.0001). uPA activity was not different in the two groups. However, uPA antigen was significantly reduced in patients compared to controls (P = 0.001). These data suggest that hypofibrinolysis leading to a risk of thrombosis may be caused not only by elevated PAI-1 activity but also by reduced total uPA concentration. © 1993 Wiley-Liss, Inc.     

Urokinase type plasminogen activator receptor expression in colorectal neoplasms

Background—The urokinase type plasminogenactivator receptor (uPAR) may play a critical role in cancer invasionand metastasis.
Aims—To study the involvement of uPAR incolorectal carcinogenesis.
Methods—The cellular expression and localisationof uPAR were investigated in colorectal adenomas and invasivecarcinomas by in situ hybridisation, immunohistochemistry, and northernand western blot analyses.
Results—uPAR mRNA expression was found mainly inthe cytoplasm of dysplastic epithelial cells of 30% of adenomas withmild (19%), moderate (21%), and severe (47%) dysplasia, and in that of carcinomatous cells of 85% of invasive carcinomas: Dukes' stages A(72%), B (93%), and C (91%). Some stromal cells in the adjacent neoplastic epithelium were faintly positive. Immunoreactivity for uPARwas detected in dysplastic epithelial cells of 14% of adenomas and incarcinomatous cells of 49% of invasive carcinomas. uPAR mRNA andprotein concentrations were significantly higher in severe than in mildor moderate dysplasia (p<0.05); they were notably higher in Dukes'stage A than in severe dysplasia (p<0.05), and significantly higher inDukes' stage B than in stage A (p<0.05), but those in stage B werenot different from those in stage C or in metastatic colorectalcarcinomas of the liver.
Conclusions—Colorectal adenoma uPAR, expressedessentially in dysplastic epithelial cells, was upregulated withincreasing severity of atypia, and increased notably during thecritical transition from severe dysplasic adenoma to invasivecarcinoma. These findings implicate uPAR expression in the invasive andmetastatic processes of colorectal cancer.

Keywords:urokinase type plasminogen activator receptor; colorectal adenoma; colorectal cancer; adenoma-carcinoma sequence