乳腺癌ER、PR及C-erbB-2癌基因蛋白表达与腋窝淋巴结转移的相关性研究

目的：了解乳腺癌组织ER、PR及C-erbB-2癌基因蛋白表达与腋窝淋巴结转移之间的相关性。方法：用免疫组化SP法测定91例乳腺癌及20例乳腺良性病变组织ER、PR及C-erbB-2癌基因蛋白表达。结果：C-erbB-2癌基因蛋白与淋巴结转移存在正相关；ER、PR表达与C-erbB-2癌基因蛋白表达存在负相关；ER、PR表达与淋巴结转移可能无直接相关；但是可能影响C-erbB-2癌基因蛋白阴性者的淋巴结转移。结论：C-erbB-2癌基因蛋白阳性者易出现淋巴结转移;C-erbB-2的表达情况能影响ER、PR受体表达与淋巴结转移的相关性。     

ER、PR、C-erbB-2、E-Cad、p53、Ki-67在乳腺癌组织中的表达及意义

目的 探讨ER、PR、C-erbB-2、E-Cad、p53、Ki-67在乳腺癌组织中的表达及其与临床病理的关系.方法 采用免疫组织化学SP法检测80例乳腺癌患者癌组织中ER、PR、C-erbB-2、E-Cad、p53、Ki-67的蛋白表达,并结合临床和病历资料进行分析.结果 ER、PR、C-erbB-2、E-Cad、p53、Ki-67在乳腺癌中的阳性表达率依次为60.0％、57.5％、45.0％、80.0％、48.8％、82.5％;除C-erbB-2与淋巴结转移存在明显相关性外,其他五项指标与患者年龄、淋巴结转移、肿块大小和病理分级无显著相关性.结论 ER、PR、C-erbB-2、E-Cad、p53、Ki-67在乳腺癌中的表达有一定相关性,联合检测对乳腺癌的治疗及预后评估有一定的价值.     

CD44_V6 C-erbB-2雌激素受体与孕激素受体在乳腺癌中的表达及其意义

目的　探讨CD4 4 V6、C erbB 2、雌激素受体 (ER)、孕激素受体 (PR)的表达与乳腺癌临床病理生物学行为的关系及其临床意义 ,评价其各自在临床中的作用。方法　采用CD4 4 V6、C erbB 2、ER、PR单克隆抗体对 12 6例原发性乳腺癌组织进行SP免疫组织化学检测 ,并对检测结果进行统计学分析。结果　CD4 4 V6阳性表达率与患者年龄、肿瘤大小、腋淋巴结转移情况、TNM分期及组织学分级无显著相关性 ,而与组织学类型相关 ,单纯癌、硬癌和髓样癌阳性表达率明显高于黏液腺癌和浸润性小叶癌 ;C erbB 2阳性表达率与患者年龄、肿瘤大小、TNM分期、组织学分级及组织学类型无显著相关 ,而与腋淋巴结转移情况相关 ;ER和PR阳性表达率与患者年龄、肿瘤大小、腋淋巴结转移情况、TNM分期、组织学分级及组织学类型无相关性。结论　CD4 4 V6作为判断乳腺癌预后的指标不够理想 ,C erbB 2可作为判断乳腺癌预后的一个指标 ,ER和PR测定的意义在于指导临床治疗方案的选择。     

分析乳腺癌组织中ER、PR、PCNA及C-erbB-2表达的意义

目的 为了给临床选择乳腺癌术后辅助治疗方案提供参考依据,探讨乳腺癌预后因素的判断指标。方法 对198例乳腺癌组织蜡块,采用SABC法标记PCNA、C-erbB-2,亲和组化法标记ER、PR,分析其与年龄、病理类型、发病时月经状况、肿瘤大小及淋巴结转移数诸因素的相关性。结果 PCNA的表达与病理类型、淋巴结转移数及发病时月经状况有显著相关(P<0.05);C-erbB-2的表达亦与淋巴结转移及月经状况有显著相关(P<0.05)。ER、PR的表达均与月经状况显著相关(ER:P=0.000,PR:P=0.004)。C-erbB-2高表达与ER呈负相关(r=0.2337,P=0.001)。结论 PCNA高表达预后不良的标记,C-erbB-2高表达可为辅助治疗方案的选择提供依据。     

乳腺癌C-erbB-2表达与临床病理特征相关性分析

目的研究乳腺癌C—erbB-2、ER、PR的表达情况,C—erbB-2及激素受体与乳腺癌分级的相关性以及C-erbB-2的表达与激素受体相关性的确切程度。方法应用免疫组化法、荧光Fish法检测163例浸润性乳腺癌组织中C．erbB-2、ER、PR的表达,统计分析C—erbB-2与ER、PR的表达及组织学分级的相关性。结果163例浸润性乳腺癌组织中C-erbB-2、ER、PR表达率分别为21．5％、64．4％、44．2％,5例黏液癌、3例小管癌、1例微乳头状癌均100．0％,ER不表达;C—erbB-2在Ⅰ级乳腺癌中不表达,Ⅱ级为22．3％,Ⅲ级为27,0％。ER的表达与组织学分级呈负相关。ER、PR阳性表达率在C．erbB-2阳性的病例中明显下降。C-erbB-2阳性的病例中有少部分ER、PR阳性表达。结论浸润性乳腺癌中只有少部分表达C—erbB-2。组织学级别可以提示ER的表达,级别高者ER的表达率低,而Ⅰ级癌大多会表达ER。C-erbB-2的过表达及扩增主要在Ⅱ．Ⅲ级癌中。C—erbB一2与ER、PR的表达呈明显的负相关性。     

ER、PR、c—erbB—2在乳腺癌中的表达及意义

目的 探讨雌激素受体（ER），孕激素受体（PR）及c-erbB-2的表达与浸润性乳腺癌的在关系。方法 应用S－P免疫组化法检测68例乳腺浸润性导管癌中ER，PR及c-erbB-2蛋白表达。结果 乳腺癌中c-erbB-2阳性率在淋巴结转移组75．8％，无淋巴结转移组40％，P＜0．01，该基因蛋白与乳腺癌淋巴结转移明显相关，c-erbB-2阳性者预后差，与肿瘤体积，组织学分级，ER无关，PR与c-erbB-2过表达正相关。结论 c-erbB-2是评价乳腺癌预后的良好指标，合并ER，PR检测有助于指导治疗。     

240例乳腺癌组织中p53、C-erbB-2表达的临床分析

目的 探讨乳腺癌组织中p53、C-erbB-2表达及临床意义.方法 对免疫组织化学染色SP法检测240例乳腺癌组织石腊切片上p53、C-erbB-2的表达结果进行回顾性分析.结果 p53和C-erbB-2阳性表达率分别为53.3%和63.3%;阳性产物主要位于细胞核中,p53和C-erbB-2的表达与肿瘤组织分级、淋巴结转移呈显著相关(P＜0.05),与PR、ER无显著相关.结论 p53和C-erbB-2与乳腺癌的发生发展密切相关,可作为判断肿瘤浸润转移、指导治疗和估计预后的参考指标.特别是p53的表达水平及淋巴结转移是判断乳腺癌预后的独立有效指标.     

C-erbB-2在乳腺浸润性导管癌中的表达及意义

目的:探讨C-erbB-2蛋白在乳腺浸润性导管癌中的表达与淋巴结转移的关系。方法:采用免疫组织化学方法(SP法)检测60例乳腺浸润性导管癌组织中C-erbB-2蛋白、雌激素受体(ER)和孕激素受体(PR)的表达,分析其与临床病理指标的关系。结果:60例乳腺癌组织中C-erbB-2蛋白阳性表达占45.00%(27/60),阳性表达率与肿瘤直径、淋巴结转移、组织学分级比较差异有统计学意义,并与ER、PR呈负相关(P<0.05)。结论:C-erbB-2蛋白与乳腺浸润性导管癌侵袭和转移密切相关,可作为判断乳腺癌预后的一个重要指标。     

PS2、COX2、CerbB2在乳腺癌中表达的研究

目的研究ER、PR与PS2、COX2、CerbB2在乳腺癌组织中的表达,探讨与病理类型、淋巴转移、内分泌治疗及预后的关系。方法采用免疫组化SP检测54例乳腺癌组织中COX2、CerbB2、PS2、ER、PR的表达。结果COX2、CerbB2在乳腺癌组织的表达的阳性率与肿瘤的大小、发病年龄肿瘤分级及淋巴转移有关,（P〈0.05）,在高分化癌中低表达,在低分化癌中高表达,在淋巴结转移组织中两者都高表达。PS2在ER、PR阳性的癌组织中高表达,与肿瘤的大小、发病年龄、淋巴结转移无明显的关系,但与肿瘤的分化程度有关,在高分化癌中高表达,在低分化癌中低表达。结论PS2、ER、PR三项指标全阳性可预测乳腺癌患者辅助内分泌治疗疗效的可靠指标;COX2、CerbB2可作为判断预后的指标。     

ER、PR、c-erbB-2在乳腺癌中的表达及意义

目的　探讨雌激素受体 (ER)、孕激素受体 (PR)及c -erbB -2的表达与浸润性乳腺癌的在关系。方法　应用S -P免疫组化法检测 6 8例乳腺浸润性导管癌中ER、PR及c-erbB -2蛋白表达。结果　乳腺癌中c -erbB -2阳性率在淋巴结转移组 75 .8%,无淋巴结转移组 40 %,P <0 .0 1,该基因蛋白与乳腺癌淋巴结转移明显相关 ,c -erbB -2阳性者预后差 ,与肿瘤体积、组织学分级、ER无关 ,PR与c -erbB -2过表达正相关。结论　c -erbB -2是评价乳腺癌预后的良好指标 ,合并ER、PR检测有助于指导治疗。     

Carcinogenicity and nephrotoxicity of 2-amino-, 1-amino- 2-methyl-, and 2-methyl-1-nitro-anthraquinone

2-Aminoanthraquinone (AA), l-amino-2-methylanthraquinone (l-Am-2-MeA), and 2-methyl-l-nitroanthraquinone (2-Me-1-Na) were tested for carcinogenicity in Fischer 344 rats and B6C3F₁ mice. In rats, all the 3 chemicals increased the incidence of hepatocellular neoplasms. Renal neoplasms were increased with 1-Am-2-MeA, and 2-Me-1-NA increased the incidence of subcutaneous fibromas in a dose-related manner. In mice, incidences of hepatocellular carcinomas were increased with feeding of AA, and 2-Me-l-NA increased the incidence of subcutaneous hemangiosarcomas. 1-Am-2-MeA did not appear to be carcinogenic in the mouse. Nephrotoxicity was associated with feeding of AA to female rats and 1-Am-2-MeA to mice.     

TRAIL、MMP-2及TIMP-2在大肠癌中的表达及意义的研究

目的研究肿瘤坏死因子相关凋亡诱导配体（TRAIL）、MMP-2、TIMP-2在大肠癌中的表达及意义,探讨TRAIL诱导肿瘤细胞凋亡的可能机制,MMP-2及TIMP-2在肿瘤的侵袭和转移中的重要的作用及相互关系,寻求提高TRAIL对肿瘤细胞敏感性的可能途径。方法采用SP法检测102例大肠癌及其癌旁5cm组织、25例正常大肠黏膜组织中TRAIL、MMP-2及TIMP-2蛋白的表达水平。结果 TRAIL在大肠癌、癌旁组织及正常大肠黏膜组织中的表达呈明显递增趋势（P〈0.01）;MMP-2在大肠癌、癌旁组织及正常大肠黏膜组织中的表达呈明显递减趋势（P〈0.01）;TIMP-2在大肠癌、癌旁组织及正常大肠黏膜组织中的表达无统计学意义（P〉0.05）。TRAIL在中、低分化癌中的表达明显低于高分化癌中的表达（P=0.003）。结论 TRAIL、MMP-2及TIMP-2可能与大肠癌的发生、发展、侵袭及转移密切相关;MMP-2与TIMP-2在癌组织中表达失衡在肿瘤的侵袭及转移中可能起重要作用。通过改善MMP-2与MMP-2在癌组织中表达的失衡,可能提高TRAIL对肿瘤细胞的特异性杀伤效率及改善肿瘤患者的预后。     

Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram,fluoxetine, fluvoxamine and paroxetine

Objectives: The purpose of this pharmacokinetic study was to investigate the dose-dependent inhibition of model substrates for CYP2D6, CYP2C19 and CYP1A2 by four marketed selective serotonin reuptake inhibitors (SSRIs): citalopram, fluoxetine, fluvoxamine and paroxetine. Methods: The study was carried out as an in vivo single-dose study including 24 young, healthy men. All volunteers had been identified as sparteine- and mephenytoin-extensive metabolisers. The volunteers received in randomised order, at weekly intervals, increasing single oral doses of one of the four SSRIs, followed 3 h later by sparteine (CYP2D6), mephenytoin (CYP2C19) and caffeine (CYP1A2) tests. Fluoxetine was given at 3-week intervals because of the long half-life of fluoxetine and its metabolite norfluoxetine. Citalopram, fluoxetine and paroxetine were given in doses of 10, 20, 40 and 80 mg and fluvoxamine was given in doses of 25, 50, 100 and 200 mg. Results: With increasing doses, there was a statistically significant increase in the sparteine metabolic ratio (MR) (P < 0.01, Page’s test for trend) for all four SSRIs. The increase was modest after intake of citalopram and fluvoxamine, while the increase was more pronounced after fluoxetine intake, although no volunteers changed phenotype from extensive metabolisers to poor metabolisers. Three of the six volunteers changed phenotype from extensive metabolisers to poor metabolisers after intake of 40 or 80 mg paroxetine. There was a statistically significant increase in the mephenytoin S/R ratio (P < 0.01, Page’s test for trend) with increasing doses of fluoxetine and fluvoxamine, but not after citalopram and paroxetine. However, no volunteers changed phenotype from extensive to poor metabolisers of S-mephenytoin. After intake of fluvoxamine, the urinary excretion of the metabolites related to N3 demethylation of caffeine were below the limit of quantification, whereas there were no significant changes in the urinary caffeine metabolic ratios after intake of the other three SSRIs. Conclusion: This investigation confirms that paroxetine and fluoxetine are potent inhibitors of CYP2D6, that fluvoxamine and fluoxetine are moderate inhibitors of CYP2C19 and that fluvoxamine is a potent inhibitor of CYP1A2 in humans in vivo. The clinical prediction of interaction from single-dose experiments may have to take the degree of accumulation during steady-state after multiple doses into account. Received: 11 December 1995/Accepted in revised form: 29 February 1996     

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Objective The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese.Methods and results The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7–18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; ² test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n = 45) (95% CI: 10.8–19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6–5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3–5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7–11.4%) and 5.3% (95% CI: 3.7–7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0–9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses.Conclusion The frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.     

血清TLR2、PGE2、IL-6对自发性早产的预测价值研究

目的　探讨血清TOLL样受体2（TLR2）、前列腺素E2（PGE2）、白细胞介素-6（IL-6）对自发性早产（SPB）的预测价值。方法　收集2019年3月至2020年3月于济南市妇幼保健院产检具有早产高危因素的孕妇289例,其中有21例SPB、263例足月产、3例治疗性早产、1例晚期流产、1例失访,最终纳入284例。研究组21例（SPB）,分娩孕周（34.08±2.16）周;对照组263例（足月产）,分娩孕周（39.25±1.11）周。比较两组临床资料,行TLR2、PGE2及IL-6检测。计量资料符合正态分布,以均值±标准差（x±s）描述,采用独立样本t检验,计数资料比较采用χ²检验,采用多因素logistic回归模型分析SPB的独立预测因子,应用受试者工作特征曲线（ROC）评估血清TLR2、PGE2及IL-6对SPB的预测价值。结果　研究组血清TLR2、PGE2、IL-6水平均高于对照组（t=8.971、5.813、5.228,均P<0.05）。logistic回归分析显示,TLR2、PGE2和IL-6的比值比分别为1.590、1.714、1.501,是SPB的独立预测因子（均P<0.05）。ROC分析显示,TLR2、PGE2和IL-6预测SPB的曲线下面积分别为0.895、0.807和0.900,以IL-6的预测价值最大（灵敏度为90.48%,特异度为77.78%）。结论　血清TLR2、PGE2、IL-6均是SPB的独立预测因子,以IL-6的预测价值较高。     

Synthesis and antimycobacterial activity of pyridylmethylsulfanyl and naphthylmethylsulfanyl derivatives of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbothioamide/-2-carbonitrile

A set of four types of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbonitrile/-2-carbothioamide substituted with 1-naphthylmethylsulfanyl or pyridylmethylsulfanyl was prepared to modify the structure of benzylsulfanyl derivatives of the above-mentioned heterocycles. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration (MIC). The MIC values fall into a range of 2 to >1000 micromol/L. Introduction of a pyridyl moiety into the molecule mostly decreased the activity. A naphthyl moiety did not influence the activity in comparison with a phenyl. The most active substances were 4-(3-pyridylmethylsulfanyl)pyridine-2-carbothioamide (7b) (MIC = 2 - >62.5 micromol/L) and 4-(1-naphthylmethylsulfanyl)pyridine-2-carbothioamide (7d) (MIC = 2 - >32 micromol/L).     

Synthesis and Anti-proliferative Activity of 2-Hydroxy-l,2-dihydroacronycine Glycosides

Purpose. Combination of the acronycine pharmacophore with various sugar units appeared of interest, since numerous anticancer agents possess a sugar moiety, which strongly influence both their bioavailability and their selective toxicity towards tumor cells. Methods. A series of 2-hydroxy-1,2-dihydroacronycine glycosides were synthetized, by condensation of the racemic aglycone with appropriate glycoside donors. Their effect on the inhibition of L1210 cell proliferation were evaluated. Results. Compounds 6a, 6b, 11a, 11b, and 12a, 12b, including a halogenated sugar moiety displayed activities of the same order of magnitude as acronycine itself. Compounds 7a, 7b, and 8a, 8b, bearing a 2,3,6-trideoxy-3-azido-L-lyxo- and L-arabino-hexopyranose unit respectively, were significantly more potent than acronycine in inhibiting cell proliferation. Conclusions. The activity of 2-hydroxy-1,2-dihydroacronycine glycosides seems to be related to the lipophilicity of the sugar unit.     

Prostaglandin E2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFkappaB activity

BACKGROUND AND PURPOSE: Recombinant cyclooxygenase-2 (COX-2) oxygenates 2-arachidonoylglycerol (2-AG) in vitro. We examined whether prostaglandin E2 glycerol ester (PGE2-G), a COX-2 metabolite of 2-AG, occurs endogenously and affects nociception and immune responses. EXPERIMENTAL APPROACH: Using mass spectrometric techniques, we examined whether PGE2-G occurs in vivo and if its levels are altered by inhibition of COX-2, monoacylglycerol (MAG) lipase or inflammation induced by carrageenan. We also examined the effects of PGE2-G on nociception in rats and NFkappaB activity in RAW264.7 cells. KEY RESULTS: PGE2-G occurs endogenously in rat. Its levels were decreased by inhibition of COX-2 and MAG lipase but were unaffected by carrageenan. Intraplantar administration of PGE2-G induced mechanical allodynia and thermal hyperalgesia. In RAW264.7 cells, PGE2-G and PGE2 produced similar, dose-related changes in NFkappaB activity. PGE2-G was quickly metabolized into PGE2. While the effects of PGE2 on thermal hyperalgesia and NFkappaB activity were completely blocked by a cocktail of antagonists for prostanoid receptors, the same cocktail of antagonists only partially antagonized the actions of PGE2-G. CONCLUSIONS AND IMPLICATIONS: Thermal hyperalgesia and immunomodulation induced by PGE2-G were only partially mediated by PGE2, which is formed by metabolism of PGE2-G. PGE2-G may function through a unique receptor previously postulated to mediate its effects. Taken together, these findings demonstrate that 2-AG is oxygenated in vivo by COX-2 producing PGE2-G, which plays a role in pain and immunomodulation. COX-2 could act as an enzymatic switch by converting 2-AG from an antinociceptive mediator to a pro-nociceptive prostanoid.