甲氧胺联合手霉素对白血病U937细胞凋亡的影响

背景与目的:DNA损伤修复对细胞生存很重要。我们既往的研究发现手霉素可诱导肿瘤细胞出现DNA损害反应。因此,碱基切除修复抑制剂甲氧胺(methoxyamine)有可能增强手霉素(manumycin)的抗肿瘤作用。为此,本实验研究甲氧胺对手霉素诱导白血病细胞凋亡的影响,探讨联合甲氧胺和手霉素诱导白血病细胞凋亡过程中线粒体凋亡途径的变化。方法:不同浓度手霉素和甲氧胺处理U937细胞48h后,MTT细胞毒性测定U937细胞存活率,软琼脂法检测细胞的克隆形成。应用流式细胞术检测细胞凋亡。免疫印迹技术检测细胞色素C、Caspase-9、聚腺苷核糖聚合酶(poly-adenosyl ribose polymerase,PARP)的表达。中位效应方法评价两药的相互作用。结果:甲氧胺使手霉素的剂量反应曲线向左边移动,结合指数(CI)<1(P<0.05)。1μmol/L手霉素、5mmol/L甲氧胺和联合两药处理U937细胞,相对于对照组的克隆形成分别是0.3641±0.0463,0.7541±0.0379,0.0473±0.0024(联合用药组与对照组、手霉素组或甲氧胺组相比,P<0.05);进一步发现,联合两药协同诱导细胞凋亡,引起Annexin V荧光值增加,阳性细胞增加,分别是(2.34±0.30)%、(8.80±0.95)%、(2.21±0.19)%、(13.37±0.91)%,联合用药组与对照组、手霉素组或甲氧胺组相比,差异有统计学意义(P<0.05)。联合甲氧胺和手霉素增强细胞色素C从线粒体释放到细胞浆,Caspase-9激活,PARP特异性裂解。结论:甲氧胺增强手霉素通过线粒体凋亡途径诱导U937细胞凋亡,提示甲氧胺联合FTIs和DNA修复抑制剂治疗白血病的可能性。     

消化道肿瘤组织中P-gp、凋亡抑制蛋白表达与体外化疗药敏性的关系及其意义

背景与目的:p-糖蛋白(P-gp)介导的经典耐药途径和细胞凋亡抑制是肿瘤多药耐药(MDR)研究最多的两种机制,肿瘤细胞多种MDR相关基因/蛋白共同表达、相互作用而出现多态性耐药.本研究通过分析肿瘤P-gP和凋亡抑制蛋白p53、Survivin、bcl-2表达与化疗药敏性的关系,探讨消化道肿瘤组织MDR相关因子表达能否反映肿瘤的化疗耐药性.方法:84例胃癌、大肠癌标本进行MTT法体外化疗药物敏感性实验,免疫组化染色检测组织中P-gp、p53、Survivin、bcl-2的表达,分析4种多药耐药相关因子表达与9种药物对肿瘤细胞抑制率的关系.结果:肿瘤组织中P-gp、p53、Survivin、bcl-2表达率分别为96.4%、64.3%、89.3%、60.7%;P-gp与bcl-2表达、Survivin与bcl-2表达具有正相关性(r=0.5072,r=0.3027,P<0.05).在肿瘤组织耐药因子表达程度与药物对肿瘤细胞抑制率的关系中,P-gp强表达组PIN、OXA、DDP对肿瘤细胞的抑制率明显低于弱表达组(P<0.05);p53强表达与PTX、DDP对肿瘤细胞的抑制率明显降低有关(P<0.05);Survivin强表达时,VCR、DDP对肿瘤细胞的抑制率明显降低(P<0.05).但OXA对肿瘤细胞的抑制率明显增加(P<0.01);bcl-2强表达时,5-FU、VCR、EADM、OXA对肿瘤细胞的抑制率明显低于弱表达组(P<0.05).结论:消化道肿瘤P-gp、p53、Survivin、bcl-2表达程度仅与其对部分化疗药物的耐药性有关.评价消化道肿瘤组织某种耐药因子表达与化疗药物耐药性的关系必须考虑多种因素调节的影响.     

Successful management of pelvic recurrence of MSI-High endometrial cancer by total pelvic exenteration followed by administration of pembrolizumab: A case report

Surgery can be curative treatment for pelvic locoregional recurrence of endometrial cancer; however, a cure is contingent on complete resection. Here, we report the case of a patient in whom recurrent endometrial tumor remained in the pelvis after resection; long-term control was achieved with postoperative administration of pembrolizumab.The patient had recurrent endometrial cancer of stage IA and was treated with chemotherapy and radiation, but tumor persisted in the pelvic cavity. We therefore attempted total pelvic exenteration, but the tumor was adherent to the pelvic wall and complete resection could not be achieved. However, postoperative administration of pembrolizumab controlled the residual tumor for more than two years without regrowth. We believe that since the resected tumor was MSI-High, the residual tumor responded well to pembrolizumab. It is not known whether cytoreductive surgery contributes to a long-term response to pembrolizumab, but at least in our patient, pembrolizumab appeared to be a very effective drug therapy for MSI-High endometrial cancer that was refractory to chemotherapy and radiotherapy.     

细菌外排泵抑制剂

细菌外排泵与细菌耐药有关,为解决细菌耐药性问题,近年来外排泵抑制剂的研究受到关注。细菌外排泵抑制剂在结构上有差异,其共同特点是能抑制细菌对药物的外排从而恢复耐药菌对抗菌药物的敏感性。本文综述了近年来细菌外排泵NorA、Mex、Tet(B)和AcrAB-TolC抑制剂的研究进展情况。所发现的外排泵抑制剂在结构上有差异,其共同特点是能抑制细菌对药物的外排从而恢复耐药菌对抗菌药物的敏感性。植物是细菌外排泵抑制剂的来源之一,开发中草药资源对解决耐药菌感染问题具有实际意义。     

c-Met和TIMP-2在喉癌中的表达及其意义

目的检测c-Met、TIMP-2蛋白在喉鳞状细胞癌（简称喉癌）及癌旁组织中的表达水平,研究两者表达与临床、病理参数的关系,探讨两者在喉癌侵袭、转移过程中的作用及其两者的相互关系。方法选取喉癌患者41例,另选癌旁组织15例作为对照,采用免疫组织化学方法（SP法）检测c-Met、TIMP-2的表达。结果c-Met、TIMP-2蛋白在喉癌组织中的阳性率分别为56．1％（23／41）及63．4％（26／41）。c-Met蛋白在癌旁组织中的阳性率为13．3％（2／15）,TIMP-2蛋白在癌旁组织为阴性。结论c-Met与喉癌颈淋巴结转移及病理分级有关;TIMP-2与喉癌的颈淋巴结转移有关;c-Met与TIMP-2在喉癌中的表达无相关性。     

Cutaneous polyarteritis nodosa in pediatric patients successfully treated with TNF‐α inhibitor and methotrexate: Case series and literature review

Cutaneous polyarteritis nodosa (CPAN) is a rare necrotizing vasculitis affecting small‐ to medium‐sized arteries. Reported treatments include oral corticosteroids alone or in combination with non‐steroidal antiinflammatory drugs, intravenous immunoglobulins, cyclophosphamide, azathioprine, colchicine, or dapsone. However, some patients with CPAN do not respond to such treatments and continue to experience exacerbations over prolonged periods. This series provides support for the use of TNF‐α inhibitors in the treatment of recalcitrant CPAN in pediatric patients.     

Targeting human MutT homolog 1 (MTH1) for cancer eradication: current progress and perspectives

Since accelerated metabolism produces much higher levels of reactive oxygen species (ROS) in cancer cells compared to ROS levels found in normal cells, human MutT homolog 1 (MTH1), which sanitizes oxidized nucleotide pools, was recently demonstrated to be crucial for the survival of cancer cells, but not required for the proliferation of normal cells. Therefore, dozens of MTH1 inhibitors have been developed with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells. While several inhibitors were indeed confirmed to be effective, some inhibitors failed to kill cancer cells, complicating MTH1 as a viable target for cancer eradication. In this review, we summarize the current status of developing MTH1 inhibitors as drug candidates, classify the MTH1 inhibitors based on their structures, and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH1.