环氧合酶-_2在胃粘膜病变中的表达与意义

目的观察环氧合酶-2（cyclooxygenase-2,COX-2）在汉族和藏族不同人群胃粘膜中的表达。方法采用ABC免疫组化法检测200例,其中藏族和汉族各100例,胃癌手术患者癌组织及慢性萎缩性胃炎（CAG）患者10例,以及18例胃黏膜异型增生（IM）和10个正常胃粘膜组织（NM）中COX-2的表达。结果藏汉族胃癌中COX-2的阳性率均为88.0%,慢性萎缩性胃炎中藏汉族COX-2的表达分别为44.4%和38.9%,胃黏膜异型增生中藏汉族COX-2表达分别为30.0%和20.0%。正常胃粘膜、慢性萎缩性胃炎胃粘膜异型增生和胃癌中COX-2的表达呈递增趋势（P〈0.05）。但在藏汉族之间COX-2的表达无显著性差异,表达程度与胃癌肿瘤细胞的分化程度和有无淋巴结转移有关（P〈0.05）。结论 COX-2可作为高原地区胃癌的预警分子。     

COX-2活性变化对HP感染胃癌变中p27kipl蛋白表达的影响

目的 通过研究幽门螺旋杆菌（HP）感染胃癌变过程中不同病理组织类型的环氧化酶2（COX-2）和p27^kipl蛋白表达,探讨HP致癌的分子生物学机制。方法 经胃镜和病理诊断明确的HP感染患者的不同胃粘膜组织标本共200例。包括慢性浅表性胃炎（CSG）、肠上皮化生（IM）、不典型增生（AH）、胃癌（G（A）各50例,分别以ABC和SP法测定COX-2和p27^kipl蛋白表达情况。结果 COX-2随癌变过程CSG→IM→AH→GCA的阳性率和表达强度不断提高,分别为12％、42％、52％、74％,GCA组与其它组相比,差异显著（P〈0．05）。而p27^kipl随癌变过程,CSG-IM-AH-GCA表达率逐步下降,分别为86％、46％、34％和26％,COX-2和p27^kipl表达呈显著负相关。结论 COX-2是HP感染胃癌变过程的早期事件,并参与了胃癌变的全过程,COX-2抑制了p27^kipl的蛋白表达。     

胃癌及其癌前病变中的Wnt5a表达研究

目的观察在胃癌及癌前病变中Wnt5a mRNA及其蛋白的表达变化。方法采用核酸原位杂交和免疫组织化学方法检测浅表性胃炎组、萎缩性胃炎组、肠化生组、不典型增生组、胃癌组（每组20例）的Wnt5a mRNA和Wnt5a蛋白的表达变化。结果 Wnt5a mRNA阳性细胞浆出现棕黄色颗粒,Wnt5a蛋白阳性细胞浆或细胞核膜出现棕黄色颗粒,浅表性胃炎组、萎缩性胃炎组、肠化生组、不典型增生组及胃癌组的Wnt5a mRNA、蛋白阳性率均分别为30%、40%、45%、65%及85%,其中胃癌组高于浅表性胃炎组、萎缩性胃炎组及肠化生组（均P＜0.05）。浅表性胃炎组、萎缩性胃炎组及肠化生组,不典型增生组与胃癌组差异无统计学意义（均P＞0.05）。结论 Wnt5a的过表达可能在胃癌的发生、发展中起一定的作用。     

三叶因子Ⅰ在胃癌及癌前病变中的表达及意义

目的探讨三叶因子Ⅰ（TFF1）在胃正常黏膜、癌前病变、胃癌中的表达及临床病理意义。方法应用免疫组织化学S—P法检测20例胃正常黏膜、20例萎缩性胃炎伴肠化生、20例不典型增生、15例早期胃癌、45例进展期胃癌组织中TFF1的表达。结果TFF1在胃正常粘膜、萎缩性胃炎伴肠化生、不典型增生、早期胃癌、进展期胃癌阳性表达率分别为100．0％、80．0％、75．0％、26．7％、57．8％，其表达进展期胃癌高于早期胃癌（P〈0．05）；与肿瘤细胞分化程度有关，分化愈低，表达愈强，分化愈高，表达愈弱（P〈0．05）。结论TFF1在癌前病变和胃癌中表达呈下降趋势，与胃癌的发生、发展有关。     

四种常用的幽门螺旋杆菌染色方法的比较

<正>胃癌是最常见的消化系统恶性肿瘤之一,居消化系统恶性肿瘤之首,生存率低,预后差。幽门螺杆菌(HP)已被列为"有充分证据的人类致癌物",主要引起人的胃癌。HP相关性胃癌的发生过程包括:浅表性胃炎、萎缩性胃炎、肠化生、异性增生、胃腺癌。HP也可以引起其他的胃黏膜病变,包括急性胃炎、慢性胃炎、溃疡病及胃黏膜相关淋巴瘤~([1])。因此早期发现HP感染并积极的除菌,对预防胃癌及上述疾病有重大     

胃癌和胃癌前病变COX-2表达与Hp感染的相关性研究

目的：探讨诱生型环氧合酶（COX-2）在胃癌和胃癌前病变中的表达及其与幽门螺杆菌（Hp）的相关性。方法选取本院2010年3月～2013年3月收治的30例胃癌患者（A组）、60例萎缩性胃炎患者（B组）、30例浅表性胃炎患者（C组）,使用免疫组织化学法对3组患者的胃黏膜COX-2水平进行检测。结果 B组肠上皮化生（IM）患者的Hp阳性检出率最高,异型增生（Dys）与A组的Hp阳性检出率、COX-2阳性检出率次之。 A、B组的Hp阳性检出率均显著高于C组患者,差异均有统计学意义（P〈0.05）;在GCa、Dys、IM中均可检测到COX-2蛋白表达,3组差异均无统计学意义（P〉0.05）;COX-2阳性在Hp阳性胃黏膜病变中的检出率显著高于Hp阴性胃黏膜病变（P〈0.05）。结论 Hp感染可促进胃癌细胞的COX-2表达,COX-2表达过度、Hp感染都是胃癌发生的重要因素。     

胃癌前状态577例随诊分析

目的探讨胃癌前状态的转归．提高早期胃癌的诊断率。方法对577例胃癌前状态在3个月至11年期间进行胃镜及病理随诊分析。结果胃溃疡、胃息肉治愈率分别为54．3％、89．3％，慢性萎缩性胃炎、胃粘膜肠化生、胃粘膜异型增生逆转率分别为15．5％、14．3％、14．3％．提示胃癌前状态是一可逆转的病理过程。胃溃疡、胃息肉、慢性萎缩性胃炎、胃粘膜肠化生、胃粘膜异型增生的癌变率分别为2．9％、3．6％、2．6％、2．6％、11．9％．提示胃癌前状态与胃癌关系密切。结论对胃癌前状态定期行胃镜及病理随诊，是提高早期胃癌检出率的重要途径。     

幽门螺杆菌与C反应蛋白在胃癌前病变发展过程中的相关性分析

目前,世界卫生组织国际癌症研究机构(IARC)将幽门螺杆菌(H.Pylori)纳入第一类致癌原[1],H.Pylori启动慢性胃炎,其持续感染可引起和促发萎缩性胃炎和胃粘膜肠化生的发生、发展,直至胃粘膜异型增生,最终发展成胃癌,而C-反应蛋白(CRP)是一种非特异性但敏感的急性时相蛋白,近年来其在诊断胃肠道恶性肿瘤方面的意义逐渐受到重视[2]。本研究采用病例对照的     

不同胃病组织中多种相关基因表达和幽门螺杆菌感染的研究

目的:探讨不同胃病组织中C-myc、p16、p53、K-ras和C-erbB-2基因表达与幽门螺杆菌(HP)感染的临床意义.方法:同顾性分析胃镜检奁活检标本162例,观察胃黏膜的炎症、上皮化生、上皮内瘤变变化及HP(HP IgG).应用免疫组化SP法检测C-myc、p16、p53、K-ras和C-erb B-2基因的表达.结果:在不同胃病组织中,C-myc、P16、P53基因的表达差异均有显著性.而K-ras和C-erbB-2基因表达差异无显著性.肠上皮化生和上皮内瘤变检出率依非萎缩性胃炎、萎缩性胃炎和胃溃疡顺序逐渐增加.HP感染率以胃癌最高,而在胃溃疡、非萎缩性胃炎和萎缩性胃炎组织中检出率较低.结论:胃癌组织中癌基因表达显著高于非癌变胃病,HP感染与胃癌发生有关.     

整合素β1和β3在胃癌及癌前病变组织的表达及临床意义

目的 探讨整合素β1和β3在胃癌及癌前病变中的表达及其生物学行为的关系,为揭示胃癌发生和发展机制、进一步鉴定胃癌早期诊断的标志物和未来胃癌的药物研发提供理论依据.方法 采用SP免疫组化方法检测整合素β1和β3在45例胃癌及24例非典型增生、20例慢性萎缩性胃炎伴肠上皮化生和25例慢性浅表性胃炎中的表达情况.结果 (1...     

The Effects of Etimicin and Gentamicin on Renal Endoplasmic Reticulum ~(45)Ca~(2 )-Uptake and Ca~(2 )-Mg~(2 )-ATPase Activity

目的：研究爱大霉素和庆大霉素对大鼠肾皮质内质网４５Ｃａ２＋摄取以及对内质网膜上Ｃａ２＋Ｍｇ２＋ＡＴＰａｓｅ活性的影响。方法：４５Ｃａ２＋示踪技术和孔雀蓝分光光度法。结果：爱大霉素和庆大霉素在大于或等于３．４×１０４ｍｏｌ·Ｌ１时，能抑制内质网４５Ｃａ２＋摄取（抑制率分别大于或等于１７．４％和２５．５％）；在３．４×１０２ｍｏｌ·Ｌ１时，对内质网膜上Ｃａ２＋Ｍｇ２＋ＡＴＰａｓｅ活性有抑制作用（抑制率分别为２４．１７％和２９．１９％）。结论：爱大霉素和庆大霉素在较高浓度时可使胞浆钙升高，这可能与其产生肾毒性有关     

Switching Shiga Toxin (Stx) Type from Stx2d to Stx2a but Not Stx2c Alters Virulence of Stx-Producing Escherichia coli (STEC) Strain B2F1 in Streptomycin (Str)-Treated Mice

Shiga toxin (Stx)-producing Escherichia coli (STEC) strain B2F1 produces Stx type 2d, a toxin that becomes more toxic towards Vero cells in the presence of intestinal mucus. STEC that make Stx2d are more pathogenic to streptomycin (Str)-treated mice than most STEC that produce Stx2a or Stx2c. However, purified Stx2d is only 2- or 7-fold more toxic by the intraperitoneal route than Stx2a or Stx2c, respectively. We hypothesized, therefore, that the toxicity differences among Stx2a, Stx2c, and Stx2d occur at the level of delivery from the intestine. To evaluate that hypothesis, we altered the toxin type produced by stx_2d+ mouse virulent O91:H21 clinical isolate B2F1 to Stx2a or Stx2c. Because B2F1 encodes two copies of stx_2d, we did these studies in a derivative of B2F1 in which stx_2d1 was deleted. Although the strains were equivalently virulent to the Str-treated mice at the 10¹⁰ dose, the B2F1 strain that produced Stx2a was attenuated relative to the ones that produced Stx2d or Stx2c when administered at 10³ CFU/mouse. We next compared the oral toxicities of purified Stx2a, Stx2c, and Stx2d. We found that purified Stx2d is more toxic than Stx2a or Stx2c upon oral administration at 4 µg/mouse. Taken together, these studies suggest that Stx2 toxins are most potent when delivered directly from the bacterium. Furthermore, because Stx2d and Stx2c have the identical amino acid composition in the toxin B subunit, our results indicate that the virulence difference between Stx2a and Stx2d and Stx2c resides in the B or binding subunit of the toxins.     

Effects of cytochrome P450 3A (CYP3A) and the drug transporters P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) on the pharmacokinetics of lopinavir

Background and purpose:

Lopinavir is extensively metabolized by cytochrome P450 3A (CYP3A) and is considered to be a substrate for the drug transporters ABCB1 (P-glycoprotein) and ABCC2 (MRP2). Here, we have assessed the individual and combined effects of CYP3A, ABCB1 and ABCC2 on the pharmacokinetics of lopinavir and the relative importance of intestinal and hepatic metabolism. We also evaluated whether ritonavir increases lopinavir oral bioavailability by inhibition of CYP3A, ABCB1 and/or ABCC2.

Experimental approach:

Lopinavir transport was measured in Madin-Darby canine kidney cells expressing ABCB1 or ABCC2. Oral lopinavir kinetics (+/− ritonavir) was studied in mice with genetic deletions of Cyp3a, Abcb1a/b and/or Abcc2, or in transgenic mice expressing human CYP3A4 exclusively in the liver and/or intestine.

Key results:

Lopinavir was transported by ABCB1 but not by ABCC2 in vitro. Lopinavir area under the plasma concentration – time curve (AUC)_oral was increased in Abcb1a/b^−/− mice (approximately ninefold vs. wild-type) but not in Abcc2^−/− mice. Increased lopinavir AUC_oral (>2000-fold) was observed in cytochrome P450 3A knockout (Cyp3a^−/−) mice compared with wild-type mice. No difference in AUC_oral between Cyp3a^−/− and Cyp3a/Abcb1a/b/Abcc2^−/− mice was observed. CYP3A4 activity in intestine or liver, separately, reduced lopinavir AUC_oral (>100-fold), compared with Cyp3a^−/− mice. Ritonavir markedly increased lopinavir AUC_oral in all CYP3A-containing mouse strains.

Conclusions and implications:

CYP3A was the major determinant of lopinavir pharmacokinetics, far more than Abcb1a/b. Both intestinal and hepatic CYP3A activity contributed importantly to low oral bioavailability of lopinavir. Ritonavir increased lopinavir bioavailability primarily by inhibiting CYP3A. Effects of Abcb1a/b were only detectable in the presence of CYP3A, suggesting saturation of Abcb1a/b in the absence of CYP3A activity.     

应用大鼠中期肝癌试验研究DEN和2-AFF的促癌作用

目的　应用大鼠中期肝癌试验研究二乙基亚硝胺(DEN)和 2 乙酰氨基芴 (2 AAF)的促癌作用。方法　♂SD大鼠单次ip 2 0 0mg·kg-1DEN启动 ,2wk后每天在饮水中加入 10、33、10 0 ppmDEN ,或以 2 2、6 6、 2 2mg·kg-12 AAF灌胃 ,连续 6wk。第 3周全部大鼠切除 2 /3肝 (partialhepatectomy) ,第 8周末处死 ,以免疫组化方法检测肝脏胎盘型谷胱甘肽S 转移酶 (GST P) ,以GST P阳性灶数量 /面积相对于仅DEN启动的对照组的增加 ,评价化合物的致癌性。结果　DEN和 2 AAF均引起肝GST P阳性灶数量和面积增加 ,并且显示剂量效应关系。结论　DEN和 2 AAF均具有促癌作用 ,大鼠中期肝癌试验是研究受试物促癌作用的简便、经济、有效的方法。     

2,2’-二氟-6,6’-双(二苯基膦)联苯的合成

２，２’－二氟－６，６’－双（二苯基膦）联苯是一种极具吸引力的、缺电子的过渡金属催化剂的配体。本文用三步反应合成了这个配体（总收率为５３％）。比原文献报道的四步反应及４９％总收率的方法有了改进。其结构为ＩＲ，ＭＳ及ＮＭＲＩ所证实。     

山豆根碱对大鼠血小板摄取~（45）Ca~（2＋）的影响

用４５Ｃａ２＋摄入法测定了大鼠血小板摄取细胞外Ｃ２＋，观察山豆根碱对血小板摄取Ｃａ２＋的影响、结果表明，静息血小板可迅速摄取细胞外Ｃａ２＋，呈时间和浓度依赖性；ＡＤＰ促进血小板摄取Ｃａ２＋；山豆根碱以浓度依赖方式抑制静息的和ＡＤＰ诱导的血小板摄取细胞外Ｃａ２＋。这提示山豆根碱抑制血小板聚集的作用机制之一与阻止细胞外Ｃａ２＋内流入血小板，降低血小板胞浆内Ｃａ２＋浓度有关。     

A further attempt to characterize the α2-adrenoceptor blocking properties of (imidazolyl-2)-2-benzodioxane 1–4 (170 150) in pithed rats

(Imidazolyl-2)-2-benzodioxane 1–4 (170 150) has been shown to possess α₂-adrenoceptor blocking properties. The present investigation attempted to further characterize the α₂-adrenoceptor blocking effect of 170 150. In pithed rats, 170 150 did not change the pressor effects of cirazoline a selective α₁-adrenoceptor stimulant. On the other hand, 170 150 significantly and competitively antagonized the effects of B-HT 933, B-HT 920 and clonidine, showing that it has a potent action on α₂-adrenoceptors since these three drugs act preferentially on α₂-adrenoceptors.     

Brain uptake and CNS levels of 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)urea (HECNU)

The uptake of ¹⁴C-labeled 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea (HECNU) into the brain was investigated in the rat after intracarotid injection according to the method of OLDENDORF, as well as in cisternal cerebrospinal fluid obtained by suboccipital puncture after i.v. injection of the drug.The brain uptake index was 31.9 ± 2.9%. Cerebrospinal fluid/blood quotients after i.v. injection were 0.82 at 10 min and 1.10 at 60 min. The results of both methods clearly show that HECNU, in spite of its hydrophilic property, easily penetrates the blood-brain barrier.     

New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP

The metabolism of di(2-ethylhexyl)phthalate (DEHP) in humans was studied after three doses of 0.35 mg (4.7 g/kg), 2.15 mg (28.7 g/kg) and 48.5 mg (650 g/kg) of D4-ring-labelled DEHP were administered orally to a male volunteer. Two new metabolites, mono(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP) were monitored for 44 h in urine and for 8 h in serum for the high-dose case, in addition to the three metabolites previously analysed: mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP). For the medium- and low-dose cases, 24 h urine samples were analysed. Up to 12 h after the dose, 5OH-MEHP was the major urinary metabolite, after 12 h it was 5cx-MEPP, and after 24 h it was 2cx-MMHP. The elimination half-lives of 5cx-MEHP and 2cx-MMHP were between 15 and 24 h. After 24 h 67.0% (range: 65.8–70.5%) of the DEHP dose was excreted in urine, comprising 5OH-MEHP (23.3%), 5cx-MEPP (18.5%), 5oxo-MEHP (15.0%), MEHP (5.9%) and 2cx-MMHP (4.2%). An additional 3.8% of the DEHP dose was excreted on the second day, comprising 2cx-MMHP (1.6%), 5cx-MEPP (1.2%), 5OH-MEHP (0.6%) and 5oxo-MEHP (0.4%). In total about 75% of the administered DEHP dose was excreted in urine after two days. Therefore, in contrast to previous studies, most of the orally administered DEHP is systemically absorbed and excreted in urine. No dose dependency in metabolism and excretion was observed. The secondary metabolites of DEHP are superior biomonitoring markers compared to any other parameters, such as MEHP in urine or blood. 5OH-MEHP and 5oxo-MEHP in urine reflect short-term and 5cx-MEHP and 2cx-MMHP long-term exposure. All secondary metabolites are unsusceptible to contamination. Furthermore, there are strong hints that the secondary oxidised DEHP metabolites—not DEHP or MEHP—are the ultimate developmental toxicants.     

Poly(2-Ethyl-2-Oxazoline) as an Alternative to Poly(Vinylpyrrolidone) in Solid Dispersions for Solubility and Dissolution Rate Enhancement of Drugs

Poly(2-ethyl-2-oxazoline) (PEOX), a biocompatible polymer considered as pseudopolypeptide, was introduced as a potential alternative to the commonly used polymer, poly(vinylpyrrolidone) (PVP) for the preparation of solid dispersion with a poorly soluble drug. Glipizide (GPZ), a Biopharmaceutical Classification System class II model drug, was selected for solubility and dissolution rate study. GPZ-polymer solid dispersions and physical mixtures were characterized and investigated by X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, and FTIR spectroscopy. The impact of polymers on crystal nucleation kinetics was studied, and PEOX exhibited strong inhibitory effect compared with PVP. Solubility and dissolution behavior of the prepared solid dispersions and their physical blends were in vitro examined and evaluated. A significant enhancement in GPZ solubility was obtained with PEOX compared with the pure drug and solid dispersion with PVP. A big improvement in the intrinsic dissolution rate (45 times) and dissolved amount of GPZ (58 times) was achieved with PEOX in fasted state simulated intestinal fluid, against comparable enhancement observed with PEOX and PVP in phosphate buffer at pH 6.8. Lower molecular weight of PEOX-5K (5000 g/mol) was found to be superior to higher molecular weight PEOX-50K (50,000 g/mol) in the improvement of dissolution behavior. The findings of this study with GPZ as a model drug introduce lower molecular weight PEOX as a promising polymeric carrier toward better oral bioavailability of poorly soluble drugs.