Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein- negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.     

犬自体肺组织瓣修补食管壁部分缺损的可行性

目的:分析犬自体肺组织瓣修补食管壁部分缺损的可行性。方法:实验于2003-01/2004-11在中国医科大学附属第二医院动物实验室完成。选用健康成年杂种犬20只,按随机数字表法分为2组,即支架组和无支架组,每组10只。20只实验犬经右胸第5肋间进胸,于胸内中段食管处胸内食管侧壁制成长4cm,环1/2~2/3周径全层缺损。于相应部位选择适当的肺组织,制成带蒂类舌状肺组织瓣。两组均将肺组织瓣覆盖并缝合固定于食管缺损处,支架组于食管缺损内衬自扩性记忆合金支架(管腔直径2.0cm、长6.0cm)并固定。术后抗炎及营养支持治疗。观察实验犬术后情况,并于术后2,4,6,8,10和12周定期处死实验犬行组织学观察。结果:无支架组实验犬存活7只,其中1只犬存活>24个月;支架组存活6只。①实验犬术后一般情况:存活犬于术后均能正常经口进食,早期有进食后呕吐,再吃下呕吐食物的现象,以支架组明显。②组织学观察结果:术后2周,无支架组均可见替代物表面有胶原及炎性渗出物,边缘见1~2层鳞状上皮细胞;支架组除有无支架组基本表现外,可见支架固定良好,光镜下见网架压迫处有较多中性粒细胞浸润。4~6周,两组均可见替代物表面有新生的3~5层复层鳞状上皮细胞;支架组见支架已基本陷入黏膜层内。8~10周,两组均可见管腔表面有6~8层新生复层鳞状上皮细胞;支架组网架边缘瘢痕组织增生,支架完全被包裹,炎症较重的局部有细胞爬行中断现象或新生细胞层数较薄,多为一两层。结论:应用自体肺组织瓣修补食管壁部分缺损是可行的,但支架组支架对食管修补处组织刺激大,炎性反应重,瘢痕重,因此如何选择合适的支撑物是今后替代节段性食管缺损面临的重要问题。     

骨髓间质干细胞移植治疗大鼠急性心肌梗死的病理学观察

目的:观察急性心肌梗死大鼠行骨髓间质干细胞移植后受损心肌组织的病理形态学变化。方法:实验于2004-01/2005-06在上海胸科医院完成。选取健康成年雌性SD大鼠40只,随机数字表法分为骨髓间质干细胞注射组、模型对照组,20只/组。①两组大鼠均建立心肌梗死模型。造模0.5h后,骨髓间质干细胞注射组于结扎点下方缺血区域组织注射Dill标记的骨髓间质干细胞3×106个,模型对照组心肌缺血区域注射100μL生理盐水。②造模后4～6周处死两组大鼠,取出心脏,剪除双侧心房及右心室,沿左心室长轴由心尖到底部做3mm厚切片,镜下观察心肌梗死区域病理组织学表现。③选择心肌梗死表现明显的蜡块切片,行酸性复红染色,用LeicaQWin多媒体彩色病理图文分析软件进行图像分析,自动测量出切片中心肌梗死组织占总面积的百分比。免疫组化检测梗死心肌血管内皮生长因子和FactorⅧ蛋白因子的表达情况。结果:40只大鼠均进入结果分析。①梗死心肌的病理形态学观察:光镜下两组均可见大小不等的心肌梗死灶,梗死心肌区域细胞肿胀坏死,严重缺血坏死区出现心肌溶解。但骨髓间质干细胞注射组上述改变明显弱于模型对照组,其心肌梗死中层可见条索状的梗死灶及纤维瘢痕灶,并且有残存的心肌呈岛状散在分布,纤维瘢痕区域心肌细胞、微血管和毛细血管数量均明显增加,侧支循环丰富。另外,骨髓间质干细胞移植组于造模初期4只大鼠心内膜面有灶性软骨生成,向心室腔突起。②梗死心肌面积百分率的检测:骨髓间质干细胞注射组梗死心肌面积百分率明显低于模型对照组[(3.69±0.48)%,(19.20±1.77)%,t=7.621～10.820,P=0.001]。③梗死心肌血管内皮生长因子和FactorⅧ免疫组化检测:骨髓间质干细胞注射组血管内皮生长因子、FactorⅧ呈阳性表达,模型对照组未检测到血管内皮生长因子和FactorⅧ。结论:骨髓间质干细胞在大鼠心脏内可以转化为血管内皮细胞或分泌血管内皮生长因子,是治疗缺血性心血管疾病理想的细胞来源。心内膜面有灶性软骨生成可能是由于注射细胞时进针太深,警示注意骨髓间质干细胞移植的副反应。