Stratification analysis of morphometric indices of populations of cancer cells with the phenotype of drug resistance

A new method of stratification analysis of general populations is proposed that is based on the approximation of inverse empirical distribution functions. With the help of the methods developed, it is shown that the number of modal classes in a heterogeneous population equals the number of segments of a linear regression spline. The proposed method is used for the investigation of populations of cancer cells that are sensitive or resistant to cisplatin. __________ Translated from Kibernetika i Sistemnyi Analiz, No. 6, pp. 158–167, November–December 2005.     

“鲜人参膏”对顺铂致肾损伤小鼠的保护作用及机制

研究了人参加工品"鲜人参膏"(Fresh Ginseng Paste,FGP)对顺铂(Cisplatin,CDDP)致急性肾损伤小鼠的保护作用,并探讨其潜在的作用机制。检测小鼠血清中尿素氮(BUN)和肌酐(CRE)水平,评价肾功能变化;检测肾组织中超氧化物歧化酶(SOD)和还原型谷胱甘肽(GSH)活性及丙二醛(MDA)含量,评价氧化应激水平;并通过HE、TUNEL、Hoechst 33258和免疫组织化学染色法观察肾组织病理学变化,同时采用蛋白质印迹法(Western blot)分析细胞凋亡情况。结果显示:与正常组比,CDDP组血清CRE含量增加了96.97μmol/L,BUN含量增加了16.71 mmol/L,肾组织中MDA升高了1.29μmol/mg,GSH含量降低了5.74μmol/g,SOD活性降低了49.94 U/mg protein(p0.05)。与CDDP组比,FGP各剂量组均可降低血清CRE、BUN及肾组织中的MDA含量,增强肾脏GSH、SOD活性(p0.05);此外,肾组织糖原沉积明显减少,肾小管上皮细胞凋亡明显被抑制(p0.05),同时改善了肾组织坏死和凋亡程度。Western blot分析表明,FGP能够明显抑制Bax和cleaved caspase-3等凋亡蛋白的过表达和降低Bcl-2的蛋白水平。FGP对CDDP诱导小鼠肾损伤具有明显的保护作用,其机制可能与改善氧化应激及抗细胞凋亡有关。     

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鞍?部分为细胞代谢途径相关酶。结论热休克蛋白90和磷酸丙糖异构酶可能参与了NS-398和顺铂对肺腺癌细胞增殖的协同抑制作用。Different proteome of human lung adenocarcinoma cells treated with NS-398 and cisplatinLI Yepen     

Aged garlic extract ameliorates the oxidative stress,histomorphological, and ultrastructural changes of cisplatin‐induced nephrotoxicity in adult male rats

Aim: Aged garlic extract (AGE) is a natural dietary substance having different antioxidant free‐radical‐scavenger compounds that ameliorates the toxicity of the oxidative stress. This study aimed to investigate the effect of AGE on cisplatin (CP)‐induced nephrotoxicity in rats. Materials and Methods: Twenty‐four, adult male Wistar albino rats were randomly divided into four groups namely control, AGE‐treated (a single oral dose of 250 mg/kg/day for 21 days), CP‐treated (a single intraperitoneal dose of 7.5 mg/kg on Day 16), and AGE + CP‐treated (AGE at a dose of 250 mg/kg/once daily for 21 days and a single dose of CP of 7.5 mg/kg intraperitoneally on Day 16). Body weight and absolute and relative kidney weights of each rat were calculated. Serum creatinine, uric acid, and urea levels were determined. Level of malondialdehyde and reduced glutathione and activity of superoxide dismutase and catalase of renal tissues were measured. Renal specimens from each rat were prepared for both light and electron microscopic examinations. Results: Interstitial cell infiltration, hemorrhage, glomerular atrophy, necrosis, and tubular degeneration were observed after CP treatment. Superoxide dismutase and catalase activities and glutathione level were significantly decreased and malondialdehyde level was significantly increased in CP‐treated rats compared with AGE + CP‐treated animals. A remarkable improvement in the histopathological and ultrastructural changes induced by CP in renal tissues was observed in AGE + CP‐treated rats. Conclusion: AGE exhibited antioxidant effect that could ameliorate the nephrotoxic effects of CP. Microsc. Res. Tech. 78:452–461, 2015. © 2015 Wiley Periodicals, Inc.     

18F-FLT MicroPET评估顺铂对A549肺癌早期疗效反应的研究

目前实体瘤疗效评价标准存在诸多不足,为了对抗肿瘤药的早期药效进行更精准的评价,给肺癌A549模型鼠以灌胃方式灌注顺铂进行治疗,并于给药前后分别进行¹⁸F-FLT MicroPET显像,根据瘤组织的放射性摄取值变化评价顺铂对肺癌A549模型鼠的早期疗效,同时采用传统抗肿瘤药药效评价方法作对比,结合病理切片进一步验证实验结果。结果显示,给药第2天,MicroPET显像可见治疗组肿瘤的放射性摄取由(4.91±0.71)%ID·g^-1降至(3.87±0.61)%ID·g^-1,降幅达21.28%;而治疗组和空白组的肿瘤体积在给药后9 d才出现显著性差异（P<0.01）。以上结果表明,¹⁸F-FLT MicroPET显像较传统的肿瘤体积测量能更早、更精准地评价顺铂的抗肿瘤药效。     

放疗联合化疗治疗中晚期子宫颈癌的疗效

目的探讨顺铂注射液与顺铂注射液联合多西他赛注射液化疗方案联合放疗治疗中晚期子宫颈癌的临床疗效。方法将60例中晚期子宫颈癌患者按随机数字表法分为2组：A组（顺铂联合放疗组）和B组（顺铂和多西他赛联合放疗组）,每组30例。2组患者均采用放疗治疗,包括体外照射和腔内后装治疗。在此基础上,A组采用顺铂注射液40 mg.m-2加入0.9%氯化钠注射液500 mL中静脉滴注,1次.周-1,治疗6周期。B组采用顺铂注射液70 mg.m-2加入0.9%氯化钠注射液500 mL中静脉滴注,第1天;多西他赛注射液70 mg.m-2加入0.9%氯化钠注射液500 mL中静脉滴注,第1天,3周后重复1次。共治疗3个疗程。结果 2组患者总有效率比较差异无统计学意义（P〉0.05）。2组患者生存率、复发率、无进展生存率比较差异均有统计学意义（均P〈0.05）,2组患者远处转移率比较差异无统计学意义（P〉0.05）,2组患者消化道反应、骨髓抑制、肾功能损害、变态反应发生率比较差异均无统计学意义（均P〉0.05）。结论采用顺铂注射液和多西他赛注射液化疗方案联合放疗可提高中晚期子宫颈癌患者的生存率,不良反应少,可作为一种中晚期子宫颈癌患者同步放、化疗最佳方案的选择。     

Platinum on Nanodiamond: A Promising Prodrug Conjugated with Stealth Polyglycerol,Targeting Peptide and Acid‐Responsive Antitumor Drug

In the field of nanomedicine, nanoparticles with various functions are required for in vivo applications such as biomedical imaging and drug delivery. Therefore, chemical functionalization of nanoparticles has been extensively investigated. Herein, nanodiamond (ND) coated with polyglycerol (PG) and its derivatives is reported to impart good solubility in a physiological environment, a stealth nature to avoid nonspecific uptake, a targeting property to be taken up by a specific cell, and an acid‐responsive drug release property to kill cancer cells. ND is first grafted with PG and the resulting ND‐PG has a high solubility in physiological media. Since a large number of hydroxyl groups in PG provide scaffolds for further surface functionalization, the targeting RGD peptide and Pt‐based drug are immobilized to give ND‐PG‐RGD, ND‐PG‐Pt and ND‐PG‐RGD‐Pt. The ND with intrinsic fluorescence is also functionalized by PG and RGD to confirm cellular uptake and intracellular localization fluorescently. The results of the cell experiments indicate that PG coating shielded fND from the uptake by HeLa and U87MG cells. In contrast, fND‐PG‐RGD is taken up by U87MG, not HeLa cells, exhibiting high targeting efficacy. When ND‐PG‐RGD‐Pt is applied, U87MG is selectively killed against HeLa. The multi‐functional ND is a promising prodrug in targeting chemotherapy.     

Inhibition of TIGAR Increases Exogenous p53 and Cisplatin Combination Sensitivity in Lung Cancer Cells by Regulating Glycolytic Flux

The metabolism and apoptosis of tumor cells are important factors that increase their sensitivity to chemotherapeutic drugs. p53 and cisplatin not only induce tumor cell apoptosis, but also regulate the tumor cell metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) can inhibit glycolysis and promote more glucose metabolism in the pentose phosphate pathway. We speculate that the regulation of the TIGAR by the combination therapy of p53 and cisplatin plays an important role in increasing the sensitivity of tumor cells to cisplatin. In this study, we found that the combined treatment of p53 and cisplatin was able to inhibit the mitochondrial function, promote mitochondrial pathway-induced apoptosis, and increase the sensitivity. Furthermore, the expression of the TIGAR was inhibited after a combined p53 and cisplatin treatment, the features of the TIGAR that regulate the pentose phosphate pathway were inhibited, the glucose flux shifted towards glycolysis, and the localization of the complex of the TIGAR and Hexokinase 2 (HK2) on the mitochondria was also reduced. Therefore, the combined treatment of p53 and cisplatin may modulate a glycolytic flux through the TIGAR, altering the cellular metabolic patterns while increasing apoptosis. Taken together, our findings reveal that the TIGAR may serve as a potential therapeutic target to increase the sensitivity of lung cancer A549 cells to cisplatin.