NS-398对Tca8113细胞体外增殖的抑制作用

目的:探讨环氧合酶-2抑制剂NS-398对Tca8113细胞的生长抑制作用。方法:应用四甲基偶氮唑蓝(MTT)快速比色法,观察NS-398对Tca8113细胞生长的抑制作用,检测NS-398与Tca8113细胞间的时-效关系和量-效关系;通过流式细胞仪(FCM)研究NS-398对Tca8113细胞周期的影响和作用,采用SAS8.1统计软件包进行数据处理,均数比较采用t检验和重复测量方差分析。结果:含0、25、50、75、100、125、150、200μmol/LNS-398的Tca8113细胞培养液,在分别培养48、72、96、120h后,随着作用时间的延长和药物浓度的增加,抑制作用也增强。NS-398在浓度150μmol/L作用96h后,抑制作用明显(药物浓度:P<0.05;时间:P<0.001),NS-398可引起Tca8113细胞G0/G1期细胞的大量增加,S期和G2/M期细胞比例数减少,阻滞细胞生长于G0/G1期(P<0.001)。结论:NS-398可抑制Tca8113细胞的增殖,并具有时间和浓度依赖性;这种作用可能与阻止细胞周期进展有关,NS-398可能在口腔鳞癌治疗中发挥重要作用。     

Subdivision of MRSA CC398 isolates using MALDI-TOF MS

Outbreak investigations demand a fast and discriminative typing method. MALDI-TOF MS has been shown to be a rapid, easy and inexpensive method of subtyping MRSA.The aim of the present study is to explore whether it is possible to subdivide isolates of MRSA CC398, commonly livestock associated, using an enhanced version of the MALDI-TOF MS typing method that we previously described (Østergaard et al, 2015). We included MALDI-TOF spectra from 378 isolates of MRSA belonging to CC398, of which 322 were epidemiologically independent. We identified 17 peaks as discriminatorily useful and could therefore reliably subdivide the isolates into 23 subtypes, including a distinct type corresponding to a strain from an unusual and initially undiscovered hospital outbreak. Whole genome sequencing was carried out for 193 of the isolates and compared with both the spa type and an antibiogram of these strains. The proposed MALDI-TOF subdivision method for MRSA CC398 was found to be more discriminative than both spa typing and resistotyping, and had a high negative predictive value for ruling out a close genetic relationship between pairs of strains with different MALDI-TOF types. We conclude that the MALDI-TOF-based typing method can be used for rapid and inexpensive routine subdivision of MRSA belonging to CC398.     

食管肿瘤干细胞抗辐射特性的实验研究

目的 :探讨食管肿瘤干细胞的抗辐射特性。方法 :采用无血清培养基培养人食管癌细胞ECA109,分离食管肿瘤干细胞,MTT法检测不同浓度环氧化酶-2选择性抑制剂NS398(2.5、5.0、10.0、20.0、40.0、80.0μmol/L)对细胞增殖的抑制作用,克隆形成实验检测亲本细胞和细胞球的增敏效应,成球实验分析NS398联合X线照射对细胞成球能力的影响,Western blot检测细胞β-catenin蛋白的表达水平。结果:NS398对亲本细胞和细胞球的增殖抑制作用均具有时间、浓度依赖性。20μmol/L NS398作用后,亲本细胞Do、Dq和SF2值均减小(P<0.05),放射增敏比(sensitization enhancement ratio,SER)为1.17;20μmol/L NS398作用后,细胞球Do、SF2减小(P<0.05),SER为1.12。照射使ECA109细胞成球率增加(P<0.05)。NS398联合X线照射组与单纯照射组相比,细胞成球率显著降低(t=7.01,P<0.01),亲本细胞和细胞球β-catenin的表达水平均降低(t=10.15,P<0.01;t=3.225,P<0.05)。结论 :细胞球的增敏效应小于亲本细胞,具有抗辐射特性,其机制可能与抑制细胞β-catenin蛋白表达有关。     

Overactive bladder treatments in early phase clinical trials

‘Overactive bladder’ (OAB) is a syndrome that is characterised by symptoms of urgency, with or without urge urinary incontinence, usually with frequency and nocturia . It is a highly prevalent condition affecting 17% of the general population, with a significant negative effect on quality of life, impairing several areas with physical, social, emotional and sexual limitations. The prevalence of OAB increases with age in both men and women . The pathophysiology is multifactorial and not yet fully understood. Non-surgical treatment is the mainstay of therapy for OAB. The available options include biofeedback, electrical stimulation, bladder training, pharmacotherapy or a combination of these options. Nevertheless pharmacotherapy is still the treatment of choice for OAB symptoms . The pharmacological treatment of OAB is generally directed towards the central or the peripheral neural control pathways or the detrusor muscle . The antimuscarinic drugs are the most commonly used. In the US, approved antimuscarinics include oxybutynin, tolterodine, trospium chloride, solifenacin and darifenacin. Although this class of drugs has been shown to be more effective than placebo in specific meta-analyses , it has been reported that ≤ 80% of the patients discontinue the treatment within 6 months, mainly for the low drug compliance due to the high incidence of side effects . Therefore, there is a strong need to identify drugs with novel mechanisms of action, which could provide equal or even better efficacy and overall greater acceptability than antimuscarinic drugs. At present, several other specific molecular targets identified within detrusor muscle and/or neural systems are under investigation for the development of more specific treatments of OAB. This article provides an up-to date review of drugs that are in investigational preclinical and early stage (Phase I and II) clinical trials for the treatment of OAB.     

NS-398对HepG2细胞增殖的抑制作用及机制探讨

目的探讨氮-2,环己氧-4,硝基苯—甲基磺胺（NS-398）对肝癌细胞株HepG2细胞的生长抑制作用及其机制。方法分别用100、200、300、400μmol/L的NS-398处理HepG2细胞,用MTT法测算肿瘤细胞抑制率,流式细胞仪检测细胞周期及细胞凋亡率,用免疫组化和Westernblot检测细胞的血管生长因子（VEGF）。结果NS-398呈剂量依赖性的方式抑制HepG2细胞增殖,并诱导其凋亡,随着NS-398浓度增大,S期细胞明显减少,有G1期细胞累积现象,其24h半数有效剂量（IC50）为300μmol/L。NS-398浓度为200μmol/L以上时HepG2细胞VEGF的表达与对照组相比,P〈0.01。结论NS-398对肝癌细胞增殖有抑制作用,并诱导其凋亡,可能与G1阻滞以及VEGF的表达受抑制有关。     

Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity

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NS-398对人食管癌细胞放射增敏机制的研究

目的探讨人食管癌放射抗拒细胞株侧群细胞（sP细胞）表达的变化。方法将人食管癌细胞株分为两组：对照组、实验组,对照组分别给予0、2、4、6、8Gy的X射线放射治疗诱导抗拒细胞株;实验组给予NS-398联合上述剂量的X线照射。流式细胞技术检测各组细胞中sP细胞的表达情况,统计分析sP细胞表达的差异。结果随着放射剂量的增加,SP细胞的表达增加,给予NS-398作用后,sP细胞的表达下降。结论sP细胞增加人食管癌细胞的放射抗拒性,抑制sP细胞的表达,能够降低人食管癌细胞的放射抗拒性。     

NS398通过环氧化酶-2依赖途径诱导肾癌细胞786-O凋亡

目的探讨环氧化酶-2(COX-2)抑制剂NS398对肾癌细胞786-O增殖和凋亡的影响及其机制。方法同浓度NS398作用体外培养786-O细胞后,采用噻唑蓝(MTT)法检测24、48、72、96h后肾癌细胞786-O的增殖活性。30、180μmol/L的NS398作用786-O细胞72h后,RT-PCR法检测COX-2 mRNA表达;免疫细胞化学检测COX-2蛋白表达;酶联免疫吸附测定法(ELISA)检测前列腺素E2(PGE2)释放水平;流式细胞仪检测细胞凋亡情况。结果NS398可以抑制786-O细胞的增殖,呈时间和剂量依赖型。RT-PCR法和免疫细胞化学检测显示NS398作用后能降低COX-2 mRNA和蛋白表达。ELISA检测显示NS398作用后PGE2释放水平呈下调趋势;流式细胞仪检测表明,30、180μmol/L NS398处理组凋亡率分别为(14.3±1.4)%、(31.5±2.1)%,与对照组凋亡率(2.1±0.4)%比较,凋亡率显著上升(P<0.05)。结论NS398可能通过COX-2依赖性途径抑制肾癌细胞增殖和诱导其凋亡。     

Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition

A recent gene expression classification of hepatocellular carcinoma (HCC) includes a poor survival subclass termed S2 representing about one‐third of all HCC in clinical series. S2 cells express E‐cadherin and c‐myc and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between S2 and non‐S2 HCC, this study investigated whether molecular subclasses of HCC predict sensitivity to FGFR inhibition. S2 cell lines were significantly more sensitive (p < 0.001) to the FGFR inhibitors BGJ398 and AZD4547. BGJ398 decreased MAPK signaling in S2 but not in non‐S2 cell lines. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 44% or more in all five S2 cell lines (p < 0.05 for each cell line), a significantly greater decrease than seen with knockdown of FGFR1‐3 with siRNA transfection. FGFR4 knockdown decreased MAPK signaling in S2 cell lines, but little effect was seen with knockdown of FGFR1‐3. In conclusion, the S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4‐MAPK signaling plays an important role in driving proliferation of a molecular subclass of HCC. This classification system may help to identify those patients who are most likely to benefit from inhibition of this pathway.