Expressions of STAT3 and SMAD4 in esophageal squamous cell carcinomas

目的 探讨食管鳞癌组织中信号转导和转录活化因子3(STAT3)、胰腺癌缺失因子4(SMAD4)的表达及其临床意义.方法 采用免疫组化技术检测60例食管鳞癌组织(A组)、28例食管上皮内瘤变组织(B组)和20例食管鳞癌癌旁组织(C组)中STAT3和SMAD4的表达情况.结果 A组STAT3的阳性表达率高于C组(P＜0.05).STAT3的表达与食管鳞癌病理分级呈正相关(P＜0.05).A组和B组SMAD4的阳性表达率低于C组(P＜0.05).SMAD4的表达与淋巴结转移和TNM分期呈负相关(P＜0.05).结论 联合检测STAT3和SMAD4的表达对判断食管鳞癌的预后有一定的指导意义.     

食管鳞癌组织中STAT3与SMAD4的表达

目的探讨食管鳞癌组织中信号转导和转录活化因子3(STAT3)、胰腺癌缺失因子4(SMAD4)的表达及其临床意义。方法采用免疫组化技术检测60例食管鳞癌组织(A组)、28例食管上皮内瘤变组织(B组)和20例食管鳞癌癌旁组织(C组)中STAT3和SMAD4的表达情况。结果A组STAT3的阳性表达率高于C组(P<0.05)。STAT3的表达与食管鳞癌病理分级呈正相关(P<0.05)。A组和B组SMAD4的阳性表达率低于C组(P<0.05)。SMAD4的表达与淋巴结转移和TNM分期呈负相关(P<0.05)。结论联合检测STAT3和SMAD4的表达对判断食管鳞癌的预后有一定的指导意义。     

Chemogenomic Analysis Identifies Macbecin II as a Compound Specific for SMAD4-Negative Colon Cancer Cells

The tumor suppressor gene, SMAD4, is mutated in approximately 30% of colon cancers. To identify compounds with enhanced potency on cells with a SMAD4-negative context, we combined genomic and cheminformatic analyses of publicly available data relating to the colon cancer cell lines within the NCI60 panel. Two groups of cell lines were identified with either wild-type or negative SMAD4 status. A cheminformatic analysis of the NCI60 screening data was carried out, which led to the identification of 14 compounds that preferentially inhibited cell growth of the SMAD4-negative cell lines. Using cell viability assays, the effect of these compounds was validated on four colon cancer cell lines: HCT-116 and HCT-15 (SMAD4-expressing), and HT-29 and COLO-205 (SMAD4-negative). Our data identified Macbecin II, a hydroquinone ansamycin antibiotic, as having increased potency in the SMAD4-negative cells compared to SMAD4 wild-type cells. In addition, we showed that silencing of SMAD4 using siRNA in HCT-116 enhanced Macbecin II potency. Our results demonstrate that Macbecin II is specifically active in colon cancer cells having a SMAD4-negative background and thus is a potential candidate for further investigation in a drug discovery perspective.     

PTEN mRNA、SMAD4 mRNA在肝外胆管癌中的表达及临床意义

目的 通过检测第10号染色体磷酸酶和张力蛋白同源丢失基因（PTEN）mRNA和TGF的细胞内信号转导蛋白家族（SMAD）mRNA在肝外胆管癌中的表达,研究它们在肝外胆管癌发生发展过程中的表达特点、相互关系以及对早期诊断及预后判断的临床价值。方法 应用原位杂交染色法检测42例肝外胆管癌中PTEN mRNA、SMAD4 mRNA的表达,并以同期20例慢性胆管炎作对照。结果 （1）PTEN mRNA、SMAD4 mRNA基因阳性表达率分别为57．14％（24／42）、61．90％（26／42）,均显著低于对照组（均为100％）。（2）经统计学分析,PTEN mRNA、SMAD4 mRNA的表达都分别与肝外胆管癌的临床病理分期及预后显著相关（P〈0．05）;与肝外胆管癌的组织学分级显著相关（P〈0．05）;SMAD4 mRNA的表达还与肝外胆管癌是否发生浸润转移显著相关（P〈0．05）。（3）PTEN mRNA与SMAD4 mRNA在肝外胆管癌中的表达呈正相关。结论 PTEN、SMAIN基因在肝外胆管癌的发生发展过程中可能起重要作用。联合检测PTEN mRNA、SMAIN mRNA在肝外胆管癌中表达有助于反映肝外胆管癌生物学特性、为预后判断提供参考指标,并为探索肝外胆管癌早期诊断和干预性基因治疗提供相关的实验依据。     

哮喘高危儿脐血哮喘基因和IgE检测的意义

目的探讨哮喘高危儿脐血哮喘基因以及IgE水平及其对于儿童哮喘预测及治疗的意义。方法选择2011年1月~2012年1月在本院住院并接受治疗的哮喘高危患儿80例作为观察组,同时选择80例健康同龄儿童作为对照组,采用免疫荧光法检测小儿脐血中的IgE、IL-13以及IL-18水平,并进行病原学检查。结果哮喘患儿脐血中的IgE、IL-13以及IL-18水平均显著高于对照组（P〈0.05）。结论儿童哮喘的发病机制与IgE、IL-13以及IL-18水平密切相关。     

Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD

Type 4 cyclic nucleotide phosphodiesterases (PDE4s) are metallo-hydrolases which specifically hydrolyze cAMP to AMP in various cells types. The catalytic core is a bimetallic ion center composed of a tightly bound Zn(2+) and a loosely bound Mg(2+), which plays a dictating role in eliciting cAMP binding and catalysis activation. An invariant glutamine positioned opposite to the ion center serves as the substrate recognition determinant and synergizes the transient Mg-oxo-phosphate interaction in the substrate complex. The Mg(2+) binding is activated by a PKA-mediated serine phosphorylation and modulated through protein-protein interactions, thus, providing efficient mechanisms in the temporal regulation of cAMP signaling. Several PDE4 inhibitors including roflumilast, cilomilast and rolipram also rely on the interaction with the glutamine and metallic ion center for binding, with their affinity enhanced dramatically by the presence of the Mg(2+) ion. Recent studies have provided new insights into the role of this enzyme in inflammatory settings, CFTR regulation, long term potentiation, and its importance in immune surveillance. The major inflammatory cytokines which are modulated with PDE4 inhibitors include TNFalpha, IL-2, IFNgamma, IL-12, GM-CSF and LTB(4). The role of PDE4 inhibitors in modulating cytokines, lipid mediators and in mucociliary clearance, along with clinical efficacy in asthma and/or COPD demonstrated with roflumilast and cilomilast, suggest a broad anti-inflammatory spectrum for these compounds. Presently, the major impediment to approval of these novel therapies has been the mechanism based gastrointestinal adverse events which has limited the dosing and the ultimate efficacy with these novel therapeutic agents.     

Anti-IL-4/-13 based therapy in asthma

It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibition of IL-4, IL-5 and IL-13. However, early clinical trials with these biologics in patients with asthma were for the most part disappointing even though they were highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anti-cytokine-based biologic therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review is an update of the evidence demonstrating the effectiveness or otherwise of the targeting of the T_H2 cytokines IL-4 and IL-13 with biologics in patients with asthma.     

The potential of PDE4 inhibitors in asthma or COPD

At least 11 families of distinct phosphodiesterase (PDE) isoenzymes are known to regulate the function of many cells secondary to altering the intracellular levels of second messengers including cyclic 3'5-monophosphate (cyclic AMP) and cyclic 3'5 guanosine monophosphate (cyclic GMP). While there is a wide distribution of these enzymes throughout the body, it is of interest that inflammatory cells thought to participate in the pathogenesis of inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD), preferentially express PDE4. This finding has stimulated the search for highly selective inhibitors of these enzymes. Unfortunately, PDE4 inhibitors tend to be associated with a number of unwanted side effects including headache and emesis. However, attempts have been made through rational drug design to synthesize compounds that demonstrate improved side effect profile. Such drugs offer an exciting opportunity to selectively downregulate inflammatory cell function as a novel therapeutic approach in the treatment of airway disease.     

支气管哮喘患儿尿白细胞三烯E4、血白细胞介素-4水平变化的研究

目的通过检测哮喘患儿尿白三烯E4、血白介素-4水平变化,探讨尿白三烯E4用于研究哮喘病情变化的意义。方法年龄3~14岁儿童,23例急性发作期、临床缓解期哮喘患儿及21例健康体检儿童采用竞争性酶联免疫吸附分析法检测尿LTE4、血IL-4水平。结果哮喘患儿急性发作期尿LTE4及血清IL-4水平均高于临床缓解期且差异有统计学意义（P〈0.05）;临床缓解期尿LTE4及血清IL-4水平均较健康体检儿童高（P〈0.05）;哮喘患儿尿LTE4水平与血清IL-4水平正相关（r=0.819,P〈0.01）。结论 CysLTs参与哮喘急性期和临床缓解期的炎症反应过程,是哮喘的重要发病机理之一;尿LTE4与哮喘的病情变化相关,有助于哮喘病情监测。     

支气管哮喘患者焦虑抑郁情绪及相关因素分析

目的：探讨支气管哮喘患者的焦虑抑郁情绪出现情况及其相关因素。方法：采用焦虑自评表（SAS）、抑郁自评表（SDS）对96例支气管哮喘（简称哮喘）患者进行测评,并与96例健康者测评结果进行比较;同时哮喘患者在健康教育指导下规范治疗后复诊并再次进行SAS、SDS测评,按有否焦虑抑郁情绪判断标准排序并进行统计学处理。结果：哮喘患者SAS和SDS评分高于健康对照组;治疗前SAS和SDS评分高于治疗后。哮喘患者与健康组间焦虑和抑郁评分差异有显著性（P〈0.01）,治疗前后焦虑抑郁评分差异有显著性（P〈0.01）。结论：焦虑抑郁情绪与哮喘发作和治疗相关,要减轻和消除哮喘患者的焦虑抑郁情绪,不但要积极有效地控制疾病,还要进行健康教育和心理指导。     

118例儿童哮喘住院患者临床用药分析

目的:掌握我院住院哮喘儿童治疗用药现状.方法:对我院2004-2005年118例儿童哮喘住院病人用药进行分析.结果:118例急性发作期患儿81例吸入速效β2受体激动剂,109例给予吸入激素,对57例重度患儿给予全身激素平喘,97例患儿给予抗感染治疗.结论:我院哮喘治疗基本遵循了全球哮喘防治创议方案中关于哮喘急性发作的处理原则,但在一定程度上存在抗生素的不合理应用.     

白介素-13基因多态性与哮喘的相关性研究

目的探讨白介素-13(IL-13)基因多态性与哮喘的相关性。方法用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)方法检测96例汉族哮喘儿童及96名汉族健康儿童IL-13基因内含子区+1923位点的基因型和等位基因频率,分析此位点单核苷酸多态性与哮喘的易感性、血浆总IgE(TIgE)、IL-13水平的相关性。结果+1923位点等位基因C、T频率在两组间分布具有显著性差异(P<0.01),等位基因T与哮喘关联,OR(T/C)=1.87,95%CI=1.25～2.80,P<0.01。两组基因型(TT、CT、CC)频率的分布亦有显著性差异(P<0.01),哮喘组中TT、CT基因型人群外周血IL-13及TIgE水平与同组及对照组CC基因组比较有显著性差异(P<0.01)。结论 IL-13基因+1923位点多态性是影响哮喘的重要候选基因,T等位基因与哮喘关联,并可能通过增强IL-13基因的表达影响血浆总IgE水平。     

儿童哮喘相关危险因素分析

目的分析儿童哮喘的相关危险因素。方法回顾性分析2010年3月~2012年3月本院诊断的0~14岁哮喘儿童100例（病例组）的临床资料,并选择同期健康儿童100例作为对照组。对其进行哮喘相关危险因素的问卷调查,并对结果进行统计学分析。结果单因素显示,急性呼吸道感染史、家族哮喘史、感到压抑沮丧、剧烈运动、母乳喂养、家庭装修与儿童哮喘相关（P〈0.05）;多因素Logistic分析显示,急性呼吸道感染史、感到压抑沮丧、剧烈运动、家庭装修是诱发儿童哮喘的危险因素,母乳喂养是保护因素。结论为防止儿童哮喘应提倡母乳喂养,注意避免相关危险因素的发生,提高父母及医生的预防意识。     

天津市支气管哮喘病人血管紧张素转移酶基因多态性研究

目的　探讨血管紧张素转移酶 (ACE)基因插入 (insertion,I)与缺失 (deletion,D)多态性与支气管哮喘易感性的关系。方法　采用聚合酶链反应 (PCR)方法检测 18例哮喘患者 ,15名正常健康对照者的 ACE基因型。结果　哮喘组 ACE基因中 DD基因型频率和 D等位基因频率分别为 6 1%和 72 % ,而正常对照组为 2 0 %和37% ,两组比较差异有统计学意义 (P<0 .0 5 )。结论　提示 ACE基因 DD等位基因型与哮喘的遗传易感性相关 ,可能是哮喘的危险因素之一。     

支气管哮喘患儿血液脂氧素A4与白三烯C4水平的变化

目的 了解不同严重程度支气管哮喘(哮喘)患儿血液脂氧素A4(LXA4)、白三烯C4(LTC4)水平的变化.方法 应用ELISA方法测定106例急性发作期轻、中、重度哮喘患儿血液LXA4、LTC4含量,并与40例正常健康儿童作对照.结果 轻、中、重度哮喘患儿血液LXA4水平显著高于对照组(P<0.01),中、重度哮喘患儿血液LXA4水平亦显著高于轻度哮喘患儿(P<0.01),重度哮喘患儿血液LXA4水平显著低于中度哮喘患JL(P<0.01).轻、中、重度哮喘患儿血液LTC4水平逐渐升高,均显著高于对照组(P<0.01).结论 重度哮喘患儿血液LXA4水平低于中度哮喘患儿,说明体内白三烯的天然生理拮抗物质LXA4不足是哮喘加重的原因之一.     

儿童哮喘发作与耳鼻咽喉科疾病相互关系的探讨

目的分析87例儿童哮喘发作与其合并耳鼻咽喉疾病的关系。方法回顾性分析我院儿科自2005年10月至2007年10月哮喘儿童中,87例合并有耳鼻咽喉科疾病的儿童,已经过哮喘的规范吸入治疗仍发作者,观察在继续哮喘吸入治疗的基础上进行耳鼻咽喉合并症的治疗前后的临床疗效,分析哮喘发作与其合并耳鼻咽喉疾病的相关性。结果经过哮喘规范吸入治疗儿童哮喘,仍有发作者与其合并过敏性鼻炎、鼻窦炎、扁桃体炎等疾病明显相关。结论合并有耳鼻咽喉疾病的哮喘患儿,要达到理想的哮喘控制目标必须同时治疗其耳鼻咽喉合并症。     

支气管哮喘患者外周血单个核细胞Toll样受体2基因表达与血清白细胞介素4和白细胞介素12的相关性分析

目的：观察支气管哮喘（简称哮喘）控制期、未控制期患者及正常对照人群中外周血单个核细胞Toll样受体2（TLR2）mRNA表达及血清白细胞介素4（IL-4）、IL-12水平,并探讨上述指标间有无相关性。方法根据全球哮喘防治创议（GINA）2006哮喘控制水平分级标准,选取门诊急诊哮喘控制期及未控制期患者各20例,选取体检健康者20名作为正常对照组。采用逆转录聚合酶链反应（ RT-PCR）法检测各组对象外周血单个核细胞TLR2 mRNA表达。用酶联免疫吸附测定（ ELISA）双抗体夹心法检测各组对象血清IL-4、IL-12水平。结果哮喘患者外周血单个核细胞 TLR2 mRNA 的表达水平高于正常对照组[（0．963±0．132）比（0．632±0．172）],差异有统计学意义（P＜0．01）。哮喘控制期与未控制期患者外周血单个核细胞TLR2 mRNA的表达水平差异无统计学意义[（0．936±0．117）比（0．991±0．147）]（ P＞0．05）。哮喘患者外周血IL-4水平高于正常对照组[（34．0±8．2）ng/L比（9．8±2．7）ng/L],差异有统计学意义（t＝13．87,P＜0．01）,未控制组患者外周血IL-4水平高于哮喘控制组[（42．5±5．4）ng/L比（29．4±4．2）ng/L]（t ＝8．53,P＜0．01）。哮喘患者外周血 IL-12水平低于正常对照组[（29．4±3．9）ng/L 比（55．8±6．1）ng/L]（t＝20．54,P＜0．01）,哮喘控制组与未控制组患者外周血IL-12水平差异无统计学意义[（28．7±4．5）ng/L比（30．1±3．0）ng/L]（t＝-1．16,P＞0．05）。哮喘患者外周血单个核细胞TLR2 mRNA表达与外周血IL-4水平呈正相关（r＝0．532,P＜0．01）,与外周血IL-12无明显相关（r＝-0．05,P＞0．05）。结论哮喘患者外周血单核细胞TLR2 mRNA的表达水平高于正常对照,外周血IL-4水平高于正常对照,未控制期外周血IL-4水平高于控制期,外周血IL-12水平低于正常对照。哮喘患者外周?