口腔微生物稳态与口腔鳞癌患者顺铂敏感性的相关性分析

目的 探讨口腔鳞癌（oral squamous cell carcinoma,OSCC）患者口腔内微生物与顺铂敏感性之间的相关性。方法 采集29例OSCC患者化疗前唾液样本,根据RECIST 1.1评价标准将患者分为顺铂耐药组（无效）和顺铂敏感组（有效）,采用16S rRNA基因测序,分析OSCC患者口腔微生物物种组成、群落多样性及丰度、样本间差异。采用SPSS 19.0软件包对数据进行统计学处理,LEfSe分析2组样本间物种差异。结果 与顺铂化疗敏感组相比,顺铂耐药组唾液样本中微生物多样性和丰度显著增加。在属水平上,顺铂耐药组患者口腔内奇异菌属、红蝽菌、微单胞菌、尤里优杆菌以及梭杆菌与顺铂敏感组相比存在显著差异。结论 顺铂耐药组与敏感组OSCC患者口腔内微生物结构和组成存在显著差异,提示微生物可能成为OSCC患者顺铂化疗前筛选的生物标志物。     

Hesperidin protects testicular and spermatological damages induced by cisplatin in rats

The clinic usage of cisplatin, an anticancer drug, is limited due to it has many side effects in many systems and organs. In this context, it was aimed to investigate the protective effect of hesperidin, a citrus flavonoid, on testicular and spermatological damages induced by cisplatin in rats. The rats were randomly divided into four groups. The first group was kept as a control. In the second groups, cisplatin was given at the single dose of 7 mg kg^?1 intraperitoneally. In the third group, hesperidin was orally administered at the dose of 50 mg/kg day^?1 for 14 days. In the fourth group, cisplatin and hesperidin were given together at the same doses. Cisplatin treatment caused significant reductions enzymatic (SOD, CAT and GPx) and nonenzymatic (GSH) antioxidants and significant induction level of TBARS. In addition, cisplatin treatment caused decreased sperm motility, epididymal sperm concentration, increased abnormal sperm rate and histopathological damage. In contrast, hesperidin treatment significantly attenuated the harmful effects. In conclusion, this study clearly demonstrated that hesperidin has protective effects on cisplatin‐induced reproductive system toxicity depending on its antioxidant properties. Thus, it is thought that hesperidin may be useful against cisplatin toxicity in patients with cancer in terms of reproductive system.     

猪肝内顺铂还原铁粉混悬液增强体外微波热效应

目的 检测微波治疗仪辐射猪肝内顺铂还原铁粉混悬液的热反应和顺铂组织含量.方法 将顺铂含量为9.52 g/L,铁颗粒含量为95.53 g/L的混悬液1.0ml注射入小家猪肝脏内,用医用微波治疗仪对该注射点进行局部微波加热.用红外热像仪测定加热10、20 min时的温度和发热体最大直径,用高效液相色谱仪(HPLC)检测加热20 min、24h顺铂组织含量.将注射同等剂量顺铂者作为对照.结果 采用微波治疗仪辐射猪肝脏内顺铂还原铁粉混悬液10～20 min,低能级组(30 W)、高能级组(60 W)和对照组(60 W)局部温度分别可以达到43～ 46、45 ～ 52和39～40℃;大于45℃发热体最大直径分别为(2.28 ±0.29)、(2.89±0.32) cm和无;顺铂组织含量分别为(2.16 ±0.17)、(2.15 ±0.13)和(2.22 ±0.35) g/L,24 h以后分别为(1.52 ±0.10)、(1.67 ±0.16)和(0.61±0.14) g/L(P＜0.01).结论 医用微波治疗仪体外辐射可以在10～20 min内将含有还原铁粉顺铂混悬液的肝组织快速升温至42 ～ 52℃,且局部具有较高的抗癌药物组织含量,发热体直径明显大于对照组.     

Improved cisplatin delivery in cervical cancer cells by utilizing folate-grafted non-aggregated gelatin nanoparticles

PurposeCisplatin is highly effective in the treatment of cervical cancer. However, in therapeutic doses, cisplatin induces several adverse effects due to undesirable tissue distribution. Therefore, it is worth targeting cisplatin in cervical cancer cells by implicating non-aggregated ligand-modified nanotherapeutics.Methods and resultsHere, we report the preparation of non-aggregated folic acid-conjugated gelatin nanoparticles of cisplatin (Cis-GNs-FA) by two-step desolvation method with mean particle size of 210.6 ± 9.6 nm and 140.5 ± 10.9 nm for Cis-GNs to improve the drug delivery in cervical cancer, HeLa cells. FTIR and DSC spectra confirmed the presence and stability of cisplatin in gelatin matrix. Furthermore, amorphization of cisplatin in nanoparticles was ascertained by PXRD. Drug release followed a first-order release kinetic at both pH ∼ 5.6 (cervical cancer pH) and pH ∼ 7.4. In addition, a significant (P < 0.05) decrease in IC₅₀ value (8.3 μM) and enhanced apoptosis were observed in HeLa cells treated with Cis-GNs-FA as compared to Cis-GNs (15.1 μM) and cisplatin solution (40.2 μM). In contrast, A549 lung cancer cells did not discriminate between Cis-GNs-FA and Cis-GNs due to the absence of folate receptors-α (FR-α). Consistently, higher cellular uptake, 80.54 ± 7.60% was promoted by Cis-GNs-FA significantly (two-way ANOVA, P < 0.05) greater than 51.68 ± 9.78%, by Cis-GNs. This was also illustrated by CLSM images, which indicated that Cis-GNs-FA preferably accumulated in the cytoplasm of HeLa cells nearby nucleus by following receptor-mediated endocytosis pathway as compared to Cis-GNs.ConclusionTherefore, Cis-GNs-FA warrants further in-depth in vitro and in vivo investigations to scale up the technology for clinical translation.     

榄香烯口服乳联合TP方案在食管癌中的疗效观察

目的：探讨榄香烯口服乳联合TP方案在食管癌的疗效和毒副作用。方法选择110例进展期食管癌患者,分为治疗组（榄香烯口服乳+TP方案）和对照组（TP方案）,21 d为1个化疗周期,榄香烯口服乳连服6周为1个疗程,化疗2个周期后进行疗效、生活质量和副作用的评价,并随访生存期。结果治疗组和对照组的有效率分别为90.9%和74.5%,差异具有统计学意义（P<0.05）;治疗组和对照组的中位生存期分别为9.7个月和7.3个月（P<0.05）;主要不良反应和Karnofsky评分的差异无统计学意义（P>0.05）。结论榄香烯口服乳联合TP方案对进展期食管癌具有较好疗效,且毒副作用较少。     

Metastatic Bladder Cancer: Role of Chemotherapy and New Agents

The M-VAC chemotherapy regimen has been widely used in locally advanced as well as in metastatic disease. Since only a proportion of patients with advanced disease will survive, there is a dire need to identify patients who will respond to chemotherapy and to identify new agents, targets and strategies to improve treatment outcome. Approaches to the management of advanced urothelial cancer include: intensifying the dose intensity, doublet and triplet combination chemotherapy, sequential regimens, reducing toxicity in unfit or elderly patients, and the use of biologic targeted therapies and promising new chemotherapeutic agents. These include MTA, the epothilones, topoisomerase inhibitors and vinflunine which act upon folate metabolism or upon different phases of the cell cycle. New agents that are coming into clinical trials include farnesyl transferase inhibitors, several growth factors receptor inhibitors, anti-sense therapy and COX-2 inhibitors. Significant progress has been made in understanding the molecular biology of cancer. Numerous novel agents, many of which are in clinical trials, have been developed to target various processes of tumor progression. The rationale behind application of these molecularly targeted therapies is to overcome resistance to cytotoxic therapies. Bladder cancer represents a unique model for targeted therapy. As our understanding increases, integration of newer biologic agents will condition future trials, and our ability to target bladder and urothelial cancers will be enhanced.     

顺铂联合雷帕霉素或3-甲基腺嘌呤对肺腺癌A549细胞抑制作用的研究

目的观察非小细胞肺癌(non small cell lung cancer,NSCLC)中肺腺癌A549细胞在顺铂(cisplatin,CP)联合雷帕霉素(rapamycin,RAPA)或3-甲基腺嘌呤(3-methyladenine,3-MA)作用下的结果,为提高顺铂的化疗效果提供理论依据。方法 2013年3月至2014年6月期间,通过对人肺腺癌细胞株A549(由河北医科大学第四医院科研中心提供)经四甲基偶氮唑盐3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT)实验检测顺铂、雷帕霉素和3-MA对A549细胞的增殖抑制率,计算出各药物的50%细胞抑制浓度(50%inhibitory concentration,IC50),并以此作为实验浓度。实验分为4组:对照组(无药物干预)、顺铂组(加15μmol/L的顺铂)、顺铂+雷帕霉素组(加10nmol/L的雷帕霉素1h后再加15μmol/L的顺铂)、顺铂+3-MA组(加3μmol/L的3-MA 1h后再加15μmol/L的顺铂),将对数生长期的肺癌A549细胞以每孔1.0×10^6/ml密度接种于6孔培养板中,待细胞长至孔底面积约70%~80%后分别加入稀释好的药物,分别培养24、48、72h。肺癌A549细胞的生长迁移情况用细胞划痕实验检测,mTOR、LC3-Ⅱ及Bax mRNA和蛋白的表达情况用RT-PCR(逆转录-聚合酶链反应)、Western blot(蛋白质印迹)法检测。数据处理采用SPSS 17.0统计软件进行分析。结果顺铂IC50:15μmol/L;雷帕霉素IC50:10nmol/L;3-MA IC50:3μmol/L。划痕实验显示24h顺铂+雷帕霉素组细胞迁移能力最弱,48h和72h顺铂+3-MA组细胞迁移能力最弱。RT-PCR显示顺铂+雷帕霉素组LC3-ⅡmRNA的2-△△Ct值(24h:1.686±0.069;48h:1.803±0.083;72h:1.836±0.056)与顺铂组(24h:1.489±0.031;48h:1.325±0.007;72h:1.428±0.080)相比表达量均明显上升(24hF=149.780,P<0.01;48hF=111.599,P<0.01;72hF=167.855,P<0.01);而顺铂+3-MA组的Bax mRNA的2-△△Ct值(48h:1.864±0.104;72h:1.935±0.068),与顺铂组(48h:1.346±0.080,72h:1.462±0.029)相比,表达量均明显上升(48hF=52.853,72hF=202.118;P值均<0.01)。Western blot显示顺铂+雷帕霉素组LC3-Ⅱ蛋白(48h:0.556±0.010;72h:0.571±0.009)与顺铂组(48h:0.426±0.0107;72h:0.492±0.009)相比表达量均显著上升(48hF=372.056,72hF=930.500;P值均<0.01);而顺铂+3-MA组的Bax蛋白(48h:0.897±0.022;72h:0.916±0.005),与顺铂组(48h:0.463±0.011;72h:0.581±0.007)相比,表达量均显著上升(48hF=1100.412,72hF=5715.778;P值均<0.01)。结论顺铂联合雷帕霉素或3-MA较单独使用顺铂能更好的抑制A549细胞的生长,长时间用药时顺铂联合3-MA作用最强。     

培美曲塞联合顺铂治疗肺腺癌临床疗效的Meta分析

目的评价培美曲塞联合顺铂治疗肺腺癌的临床疗效,为临床选择肺腺癌一线化疗方案提供循证证据。方法遵循Cochrane系统评价手册中随机对照试验检索策略,检索2005—2012年中国知网文献数据库中公开发表的关于培美曲塞联合顺铂治疗肺腺癌临床疗效的随机对照试验,对照组采用多西他赛联合顺铂方案,试验组采用培美曲塞联合顺铂方案。采用Jadad量表评价纳入文献的方法学质量,RevMan 5.0软件包进行数据分析。结果最终纳入8篇文献,Jadad量表评分均≥3分。Meta分析结果显示,试验组总有效率高于对照组〔OR=1.50,95%CI(1.01,2.21),P=0.04〕。结论培美曲塞联合顺铂方案治疗肺腺癌的总有效率高于多西他赛联合顺铂方案,可作为肺腺癌一线化疗方案。     

Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study

BackgroundThe RAF–MEK–ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations. A phase II randomized trial was designed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer.MethodsLocally advanced or metastatic pancreatic adenocarcinoma patients were randomized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400 mg bid (arm A) or without sorafenib (arm B).ResultsOne hundred and fourteen patients were enrolled; of these, 43 (74.6%) patients progressed in arm A and 44 (82.4%) in arm B. Median progression-free survival was 4.3 months (95% CI: 2.7–6.5) and 4.5 months (95% CI: 2.5–5.2), respectively (HR = 0.92; 95% CI: 0.62–1.35). Median overall survival was 7.5 (95% CI: 5.6–9.7) and 8.3 months (95% CI: 6.2–8.7), respectively (HR = 0.95; 95% CI: 0.62–1.48). Response rates were 3.4% in arm A and 3.6% in arm B.ConclusionsSorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients, and therefore should not be assessed in phase III trials.     

Involvement of neutrophil gelatinase-associated lipocalin and osteopontin in renal tubular regeneration and interstitial fibrosis after cisplatin-induced renal failure

The kidney has a capacity to recover from ischemic or toxic insults that result in cell death, and timely tissue repair of affected renal tubules may arrest progression of injury, leading to regression of injury and paving the way for recovery. To investigate the roles of neutrophil gelatinase-associated lipocalin (NGAL/lcn2) and osteopontin (OPN/spp1) during renal regeneration, the expression patterns of NGAL and OPN in the cisplatin-induced rat renal failure model were examined. NGAL expression was increased from day 1 after injection; it was seen mainly in the completely regenerating proximal tubules of the cortico-medullary junction on days 3–35; however, the expression was not seen in abnormally dilated or atrophied renal tubules surrounded by fibrotic lesions. On the other hand, OPN expression was increased from day 5 and the increased expression developed exclusively in the abnormal renal tubules. NGAL expression level well correlated with the proliferating activity in the regenerating renal epithelial cells, whereas OPN significantly correlated with the α-smooth muscle actin-positive myofibroblast appearance, expression of transforming growth factor (TGF)-β1, and the number of CD68-positive macrophages. Interestingly, rat renal epithelial cell line (NRK-52E) treated with TGF-β1 decreased NGAL expression, but increased OPN expression in a dose-dependent manner. Because increases of TGF-β1, myofibroblasts and macrophages contribute to progressive interstitial renal fibrosis, OPN may be involved in the pathogenesis of fibrosis; on the contrary, NGAL may play a role in tubular regeneration after injury. Expression analysis of NGAL and OPN would be useful to investigate the tubule damage in renal-toxicity.