MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. In addition to its known receptor-mediated biological activities, MIF possesses a catalytic site of unknown function between subunits of a homotrimer. Each subunit contributes three β-strands to adjacent subunits to form a core seven-stranded β-sheet for each monomer. MIF monomers, dimers, or trimers have been reported, but the active form that binds and activates the MIF receptor (CD74) is still a matter of debate. A cysteine mutant (N110C) that covalently locks MIF into a trimer by forming a disulfide with Cys-80 of an adjacent subunit is used to study this issue. Partial catalytic activity and receptor binding to CD74 are retained by N110C (locked trimer), but there is no cellular signaling. Wild-type MIF-induced cellular signaling, in vivo lung neutrophil accumulation, and alveolar permeability are inhibited with a fivefold excess of N110C. NMR and size-exclusion chromatography with light scattering reveal that N110C can form a higher-order oligomer in equilibrium with a single locked trimer. The X-ray structure confirms a local conformational change that disrupts the subunit interface and results in global changes responsible for the oligomeric form. The structure also confirms these changes are consistent for the partial catalytic and receptor binding activities. The absence of any potential monomer and the retention of partial catalytic and receptor binding activities despite changes in conformation (and dynamics) in the mutant support an endogenous MIF trimer that binds and activates CD74 at nanomolar concentrations. This conclusion has implications for therapeutic development.     

氨溴特罗口服液治疗儿童咳嗽变异性哮喘疗效观察

目的观察氨溴特罗口服液治疗儿童咳嗽变异性哮喘的疗效。方法将150例咳嗽变异性哮喘患儿随机分为对照组和观察组,每组75例,对照组口服孟鲁司特钠及舒喘灵片,观察组口服孟鲁司特钠及氨溴特罗口服液,比较两组疗效。结果观察组咳嗽消失时间明显短于对照组（P〈0．05）;观察组总有效率（89．3％）高于对照组（76％）,两组比较差异有统计学意义（x2=4．6526,P〈0．05）;对照组不良反应发生率高于对照组（x2=4．7535,P〈0．05）。结论氨溴特罗口服液在儿童咳嗽变异性哮喘治疗中疗效显著,且不良反应少,值得临床推广。     

咳嗽变异性哮喘疗效评价标准的文献调研及内容分析

本研究对中医药治疗咳嗽变异性哮喘的研究文献进行了调查分析,一共收集到近8年的482篇临床研究文献,疗效评价标准以自拟为主,78篇采用了中医病证诊断疗效标准,疗效评价标准依据的指标以咳嗽为主,另有14篇采用证候积分的方法,认为以后需要进一步规范相关标准和指标。     

A recessive variant of XRCC4 predisposes to non-BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization

XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4^A247S mutant, thus compensating for the impaired localization of XRCC4^A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.     

补气祛风汤联合酮替芬治疗咳嗽变异性哮喘随机平行对照研究

[目的]观察补气祛风汤联合酮替芬治疗咳嗽变异性哮喘疗效。[方法]使用随机平行对照方法,将150例门诊及住院患者按抽签法简单随机分为两组。对照组75例氨茶碱,0.1g/次,3次/d。治疗组75例酮替芬,1mg/次,2次/d;补气祛风汤(太子参9g,黄芪10g,防风4g,白术6g,苏叶、浙贝各8g,桑皮6g,地龙8g,蝉蜕7g,野荞麦15g,桃仁4g,枇杷叶8g,甘草4g),1剂/d,水煎200m L,早晚口服。连续治疗30d为1疗程。观测临床症状、咳嗽、不良反应。连续治疗2疗程,判定疗效。[结果]治疗组显效35例,有效38例,无效2例,总有效率97.33%。对照组显效22例,有效27例,无效26例,总有效率65.33%。治疗组疗效优于对照组(P0.05)。[结论]补气祛风汤联合酮替芬治疗咳嗽变异性哮喘效果显著,值得推广。     

天灸治疗儿童咳嗽变异性哮喘的效果观察

目的 分析天灸治疗儿童咳嗽变异性哮喘的临床疗效.方法 选择2009年4月至2012年4月于我院门诊治疗的92例儿童咳嗽变异性哮喘患者作为研究对象,均经临床确诊.根据不同治疗方式,将所有患者随机均分为使用安慰剂的对照组及使用天灸治疗的观察组,各46例.比较两组患者的治疗效果.结果 观察组的治疗效果明显优于对照组,差异有统计学意义（97.83％ vs.89.13％,x2=2.947,P＜0.05）.结论 天灸治疗儿童咳嗽变异性哮喘可以有效改善患者气道功能,提高治疗效果.     

孟鲁司特钠配伍万托林雾化吸入治疗小儿咳嗽变异性哮喘的疗效观察

目的探讨孟鲁司特钠联合硫酸沙丁胺醇气雾剂(万托林)雾化吸入在治疗小儿咳嗽变异性哮喘方面的临床疗效,以及对患儿肺通气功能的影响。方法将78例咳嗽变异性哮喘患儿随机均分为两组,研究组39例给予孟鲁司特钠口服联合硫酸沙丁胺醇气雾剂雾化吸入治疗,对照组39例给予硫酸沙丁胺酸气雾剂雾化吸入治疗,均治疗1个月。疗程结束后,观察两组临床疗效,同时评价最大呼气峰流速(PEF)改善情况。结果研究组治疗的总有效率为97.44%,显著高于对照组的79.49%(P<0.05)。研究组患儿治疗后的最大呼气峰流速为(1.57±0.54)L/min,明显优于对照组的(1.39±0.48)L/min(P<0.05)。结论孟鲁司特钠联合硫酸沙丁胺醇气雾剂雾化吸入在治疗小儿咳嗽变异性哮喘方面临床疗效确切,安全可靠,能显著改善患儿肺通气功能。