VEGF和TIMP—1表达与乳腺癌浸润、淋巴结转移关系的探讨

目的 研究乳腺癌组织中血管内皮生长因子（VEGF）和金属蛋白酶组织抑制因子（TIMP－1）的表达变化与乳腺癌生物学行为及淋巴结转移的关系。方法 应用S－P免疫组化方法检测85例乳腺癌组织VEGF、TIMP－1及细胞增值核抗原Ki－67的表达情况。结果 VEGF阳性染色率为88％，VEGF阳性表达与肿瘤浸润、淋巴结转移、TNM分期及Ki－67指数呈正相关（x^＝7．31，P＜0．05，x^＝4．59，P＜0．05，x^＝10．71，P＜0．01，x^＝7．04，P＜0．05）。TIMP－1阳性染色率为79％，TIMP－1阳性表达与肿瘤浸润、淋巴结转移及TNM分期呈负相关（x^＝12．81，P＜0．01，x^＝4．94，P＜0．05，x^＝9．9，P＜0．05）。VEGF和TIMP－1联合表达与乳腺癌浸润转移及Ki－67指数显著相关（x^＝13．09，P＜0．01，x^＝16．64，P＜0．001，x^＝8．63，P＜0．05）。结论 VEGF高表达和TIMP－1低表达在乳腺癌浸润、淋巴结转移及细胞增殖中起重要作用。     

乳腺癌组织中VEGF-C的表达及其与临床病理指标的关系

目的：探讨血管内皮生长因子-C（vascular endothelial growth factor C，VEGF-C）在乳腺癌组织的表达情况及与临床病理指标的关系。方法：应用免疫组织化学方法检测69例乳腺癌和10例乳腺纤维腺瘤组织的VEGF-C表达情况，并分析其表达与临床病理特征的关系。结果：69例乳腺癌组织中VEGF-C阳性表达72．46％（50／69），10例乳腺纤维腺瘤表达为30％，两者差异有统计学意义（Hc=10．173，P〈0．01）。VEGF-C在乳腺癌中的表达与其组织学分级有关（χ^2=12．026，P〈0．01），组织学分化Ⅲ级的VEGF-C阳性表达率为92．86％，高于组织学分化Ⅰ级（37．5％，P〈0．01）、Ⅱ级（63．64％，P〈0．05），Ⅰ级与Ⅱ级比较差异无统计学意义（P〉0．05）；有腋淋巴结癌转移组与无转移组的VEGF-C阳性表达率分别为87．10％和60．53％，差异有统计学意义（P〈0．05）；而与月经状态、肿瘤大小、病理类型、TNM分期、ER／PR状态和预后无关（均P〉0．05）。结论：乳腺癌组织中VEGF-C的表达明显增加，其表达水平显著高于乳腺纤维腺瘤，并且与肿瘤组织学分级、区域淋巴结转移有关。     

血管内皮生长因子在乳腺癌中的表达及意义

目的：探讨血管内皮生长因子（VEGF）在乳腺癌中的表达及其临床意义。方法：应用免疫组织化学法检测74例乳腺癌组织中VEGF的表达。分析其与乳腺癌临床病理特征及预后的关系。结果：VEGF的阳性表达率为64．9％。VEGF的表达与肿瘤大小（P〈0．05）、临床分期（P〈0．05）、腋淋巴结转移（P〈0．05）有关。VEGF表达阴性和阳性两组5年总生存率（overall survival，OS）和无瘤生存率（disease free survival，DFS）差异有显著性（P〈0．05）。结论：VEGF阳性表达提示乳腺癌预后不良。VEGF可为判断乳腺癌预后的有效指标。     

可溶性耐药相关钙结合蛋白在乳腺癌组织中的表达及预后

目的：研究可溶性耐药相关钙结合蛋白（Soluble resistiince-related caLcittmbinding protein，Sorcin）在乳腺癌组织中的表达，评估其在乳腺癌预后中的作用。方法：采用免疫组织化学方法（IHC）检测47例手术切除的乳腺癌组织中Sorcin的表达．并分析其与临床、病理特征的关系及对预后的影响。结果：（1）Sorcin在乳腺癌组织中的阳性表达率为85．1％（40／47例），其中高表达27例（57．4％）；（2）Sorcin与月经状况、肿瘤大小、淋巴结转移、组织分级和雌激素受体状况差异均无显著性（P〉0．05），但与孕激素受体状况似有一定关系（P〈0．05）；（3）Kaplan-Meier生存分析结果表明Sorcin表达与无瘤生存期和总生存期差异均无显著性（P〉0．05）；（4）COX多因素分析显示肿瘤大小、淋巴结转移与无瘤生存期及总生存期明显相关（P〈0．05），组织分级也与无瘤生存期明显相关（P〈0．05）。结论：Sorein在乳腺癌组织中具有高表达。但与乳腺癌患者无瘤生存期和总生存期均无关。     

MMP3与TIMP2蛋白在宫颈癌中的表达及意义

目的探讨基质金属蛋白酶子（MMP3）与基质金属蛋白酶抑制因子（TIMP2）蛋白在宫颈癌组织中表达、相互关系及意义。方法采用免疫组化学S-P法检测46例宫颈癌、20例宫颈上皮内瘤变（CIN）和10例宫颈良性病变上皮组织中MMP3及TIMP2的表达情况。结果宫颈癌组织中MMP3表达水平高于CIN及宫颈良性病变上皮（P〈0．05），而TIMP2蛋白表达水平低于CIN及宫颈良性病变上皮（P〈0．05）；MMP3的阳性表达率与宫颈癌分化程度、淋巴结转移有关（P〈0．05），与患者年龄、组织类型及临床分期无关（P〉0．05）；TIMP2的阳性表达率与宫颈癌分化程度及淋巴结转移有关（P〈0．05），与患者年龄、组织类型、临床分期无关（P〉0．05）；结论MMP3与TIMP2的表达程度与宫颈癌的发生发展密切相关，二者的比例失衡可能与宫颈癌的临床分期有关系。     

乳腺癌组织中SPARC和Her-2的表达

目的探讨富含半胱氨酸的酸性分泌蛋白（SPARC）和人表皮生长因子受体（Her-2）在乳腺癌组织中的表达及与临床病理参数的关系。方法应用免疫组织化学方法检测70例乳腺癌和20例乳腺纤维腺瘤中SPARC和Her-2的表达。结果SPARC在乳腺癌间质细胞的高表达率为68．6％（48／70）明显高于肿瘤细胞表达率为37．1％（26／70）（P〈0．05）;间质细胞中乳腺癌的SPARC表达率为68．6％（48／70）明显高于乳腺纤维腺瘤的表达率为40．0％（8／20）（P〈0．05）;在有淋巴结转移、TNM分期为Ⅲ期的乳腺癌中SPARC的表达率升高（P〈0．05）。乳腺癌中SPARC的高表达率与腋窝淋巴结转移相关。Her-2在乳腺癌肿瘤细胞中的高表达率为45．7％（32／70）明显高于乳腺纤维腺瘤表达率的10．0％（2／20）（P〈0．05）。Her-2在淋巴结转移组的表达率较无淋巴结转移组高（P〈0．05）。结论乳腺癌中SPARC、Her-2的高表达与乳腺癌的发生、发展、转移和预后有关。     

血管内皮生长因子及环氧化酶2在乳腺癌中的表达及其相关研究

目的探讨血管内皮生长因子（VEGF）、环氧化酶-2（COX-2）在乳腺癌中的表达及其相关性。方法采用EliVision免疫组织化学技术,检测55例乳腺癌组织标本中VEGF及COX-2的表达。结果55例乳腺癌中VEGF的阳性表达率为78．2％（43／55）,其表达与患者的年龄、肿瘤大小、雌激素受体（ER）、孕激素受体（PR）的表达无关（均P〉0．05）,但与组织学分级及淋巴结转移密切相关（P〈0．05）;COX-2的阳性表达率为50．9％（28／55）,其表达与患者的年龄、肿瘤大小无关（均P〉0．05）,ER、PR阴性组阳性表达率明显高于阳性组（P〈0．05）,但其表达与淋巴结转移无关（P〉0．05）。结论VEGF和COX-2参与了乳腺癌的发生、发展过程,且表达具有相关性,两者可作为判断乳腺癌生物学行为的参考指标。     

HER-2与 Ki-67在直肠癌组织中的表达及临床意义

目的：探讨HER-2与Ki-67在直肠癌组织中的表达及临床意义。方法选取2013年10月至2015年3月接收的80例直肠癌患者,收集切除后的直肠癌组织标本,作为观察组。另外,收集20例健康者肠黏膜组织标本作为对照组。采用免疫组化SP方法对2组标本HER-2与Ki-67的表达进行研究。结果直肠癌组织中的HER-2、Ki67阳性表达率明显高于正常肠黏膜组织,2组比较差异有统计学意义（ P ＜0?．05）;HER-2的表达与直肠癌患者的性别、年龄、淋巴结转移情况、肿瘤部位无明显关联（ P ＞0．05）,而与直肠癌患者Dukes分期、细胞分化程度、浸润深度有明显关联（ P ＜0．05）。 Ki-67表达与直肠癌患者的性别、年龄、肿瘤大小、肿瘤部位、细胞分化程度无显著关联（ P ＞0．05）,而与肿瘤浸润深度、淋巴结转移及Dukes分期有显著关联（ P ＜0．05）。对直肠癌患者组织中HER-2与Ki-67的表达情况进行等级相关分析,发现两者表达呈正相关（ r ＝0．354, P ＜0．01）。结论直肠癌组织中HER-2与Ki-67蛋白的表达在一定程度上与患者的性别、年龄、肿瘤部位、以及淋巴结转移情况无关,与直肠癌组织细胞分化程度、Dukes分期、浸润深度有关。 HER-2和Ki-67表达水平可作为判定直肠癌的生物学指标。     

HER-2、EGFR及P16在宫颈鳞癌中的表达及临床意义

目的探讨人表皮生长因子受体2（HER-2）、表皮生长因子受体（EGFR）及P16基因在正常宫颈组织及宫颈鳞癌中的表达及临床意义。方法采用免疫组化检测15例正常宫颈组织及30例宫颈鳞癌组织中HER-2、EGFR及P16蛋白的表达情况。结果HER-2、EGFR及P16蛋白在宫颈鳞癌组织中的阳性表达率分别为66．67％、60．00％和73．33％。HER-2阳性表达与组织学分级和淋巴结转移有关（P〈0．05）;EGFR阳性表达与淋巴结转移有关（P〈0．01）;P16阳性表达与组织学分级和浸润深度有关（P〈0．05,P〈0．01）;HER-2和EGFR蛋白表达呈正相关（r=0．6000,P=0．0201）。结论联合检测宫颈鳞癌组织中HER-2、EGFR及P16蛋白的表达能更清楚地了解宫颈鳞癌的生物学行为,对宫颈癌的诊断、指导治疗及预后评估有重要的临床意义。     

乳腺癌组织中VEGF的表达与CD44v6、MMP一2的相关性研究

目的检测血管内皮生长因子（VEGF）与CD44v6、MMP-2在乳腺癌中的表达情况,探讨它们之间的关系。方法采用免疫组化SP法检测92例乳腺浸润性癌中VEGF、CD44v6、MMP-2的表达情况,并与正常乳腺组织进行比较。结果VEGF在正常乳腺组织和乳腺癌中的阳性表达率分别为6．7％（3／45）和90．2％（83／92）,且VEGF在淋巴结转移组中的阳性表达率（53／55）明显高于无淋巴结转移组（P〈0．05）。CD44v6在正常乳腺组织及乳腺癌中的阳性表达率分别为8．9％（4／45）和85．9％（79／92）,而且CD44v6在淋巴结转移组中的阳性表达率（51／55）明显高于无淋巴结转移组（P〈0．05）。MMP-2蛋白在正常乳腺组织及乳腺癌中的阳性表达率分别为4．4％（2／45）、87．0％％（80／92）,而且MMP-2在淋巴结转移组中的阳性表达率（52／55）明显高于无淋巴结转移组（P〈0．05）。VEGF与CD44v6、MMP-2的表达均存在正相关关系（P〈0．05）。结论VEGF、CD44v6、MMP-2在乳腺癌组织中高表达,且均与淋巴结转移有关,它们可能在乳腺癌的远处转移中起协同作用。     

2-吡啶甲醇及2-吡啶甲醛的合成

以 2 -甲基吡啶为原料、过氧化氢为氧化剂制备 2 -吡啶甲醇和 2 -吡啶甲醛,工艺方法经济、安全     

2-苯基-1-丁醇与2-二甲氨基-2-苯基丁腈的合成

目的为马来酸曲美布汀的重要中间体2-二甲氨基-2-苯基-1-丁醇的合成奠定基础。方法苯乙腈与溴乙烷进行烃化反应得2-苯基-1-丁腈,所得产物经水解得2-苯基-1-丁酸,然后通过硼氢化钠-碘体系还原得2-苯基-1-丁醇;苯乙腈与N-溴代丁二酰亚胺进行卤代反应得溴代苯乙腈,所得产物与二甲胺进行烃化反应得2-二甲氨基苯乙腈,然后与溴乙烷进行烃化反应得2-二甲氨基-2-苯基丁腈。结果合成了2-苯基-1-丁醇和2-二甲氨基-2-苯基丁腈,总收率为分别为51%和59.4%。目标产物的结构经核磁共振氢谱、质谱确证。结论本合成方法原料易得,操作简单,收率较高,适合于工业化生产。     

Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.     

Metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine

The metabolism and metabolic effects of 2-azahypoxanthine and 2-azaadenosine were studied to elucidate the biochemical basis for their known cytotoxicities. 2-Azaadenosine is a known substrate for adenosine kinase. That 2-azahypoxanthine is a substrate for hypoxanthine (guanine) phosphoribosyltransferase is shown by the observations that, in cell-free fractions from HEp-2 cells supplemented with 5-phosphoribosyl-1-pyrophosphate, 2-azahypoxanthine inhibited the conversion of hypoxanthine to IMP but not the conversion of adenine to AMP, and hypoxanthine, but not adenine, inhibited the conversion of 2-azahypoxanthine to 2-azaIMP. [8-14C]2-Azahypoxanthine was synthesized from [8-14C]hypoxanthine via [2-14C]-4-amino-5-imidazolecarboxamide. In HEp-2 cells in culture, the principal metabolite of [8-14C]-2-azahypoxanthine was 2-azaATP; there was no detectable 14C in deoxynucleotides or in DNA or RNA fractions. 2-Azaadenosine was much more toxic than 2-azahypoxanthine, and, when used in the presence of an adenosine deaminase inhibitor, 2'-deoxycoformycin, was converted in HEp-2 cells to 2-azaATP in amounts that exceeded those of ATP in control cells. The pool of ATP was reduced by as much as 75% as 2-azaATP accumulated. In a short-term experiment (4 hr), 2-azaadenosine selectively reduced the pools of adenine nucleotides, whereas 2-azahypoxanthine reduced the pools of guanine nucleotides selectively. Both 2-azahypoxanthine and 2-azaadenosine inhibited the incorporation of formate into purine nucleotides and were without effect on the conversion of thymidine and uridine to nucleotides. 2-Azahypoxanthine inhibited the incorporation of thymidine into macro-molecules but not that of uridine or leucine; 2-azaadenosine inhibited the incorporation of all three of these precursors non-selectively. 2-AzaIMP inhibited IMP dehydrogenase competitively with IMP (Ki = 66 microM). The difference in effects of 2-azahypoxanthine and 2-azaadenosine perhaps may be due to the production, from 2-azahypoxanthine but not from 2-azaadenosine + 2'-deoxycoformycin, of 2-azaIMP, which inhibits synthesis of guanine nucleotides and thereby results in inhibition of DNA synthesis. Specific sites of action for 2-azaadenosine are yet undefined.     

Molecular modeling of 2-alkyloxy- and 2-aralkyloxy-adenosine A1- and A2-agonists

The C2-region of adenosine A1- and A2-receptors by a molecular modeling technique has been extended and applied to a series of 2-substituted adenosines reported by Olsson, et al. The similarity and dissimilarity of the structure maps obtained by molecular modeling have been used as a basis for the mapping of the analysed receptor domain. The proposed model of the C2-region of the A1-receptor consists of a narrow and sterically limited area that interacts well electrostatically with small and electron rich moieties. Olsson's provisional model of the C2-region of the A2-receptor has been extended with two subsites, as well as with a forbidden area near the C2-position of the purine ring. The conformational analysis performed in the study does not support the hypothesis of Olsson et al. that adenosine C2 substituents may partly occupy the same receptor domain as the N6 substituents of the A1-receptor. The occupation of the cycloalkyl subsite increases the receptor selectivity while the occupation of the other subsite by aryl rings, fixed at a parallel position to the purine system, highly enhances the receptor affinity.     

Synthesis and antiviral evaluation of carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine

Carbocyclic analogues of 2'-azido- and 2'-amino-2'-deoxycytidine, compounds 8 and 9, were synthesized by an eight-step synthesis from (+/-)-(1 alpha,2 alpha,3 beta,5 beta)-3-amino-5-(hydroxymethyl)-1,2- cyclopentanediol (1), which was prepared from cyclopentadiene via an eight-step route. These compounds were tested in vitro against herpes simplex virus type 1 (HSV-1). The 2'-amino analogue was found to show moderate antiviral activity, with an ED50 of 50 microM. However, the 2'-azido analogue was not active at a concentration up to 400 microM.     

2-Fluoroformycin and 2-aminoformycin. Synthesis and biological activity

Syntheses of 2-fluoroformycin [7-amino-5-fluoro-3-(beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine] (2b) and 2-aminoformycin [5,7-diamino-3-(beta-D-ribofuranosyl)pyrazolo[4,3-d]pyrimidine] (2c) are described. Cytotoxicity data are given for 2b and 2c alone as well as with added pentostatin. Kinetic parameters for adenosine deaminase are also provided. 2-Fluoroformycin, although a much poorer substrate for adenosine deaminase than formycin A, is not nearly as cytotoxic to cells in culture.