胰腺癌组织中Syk的表达及意义

目的探讨胰腺癌组织中脾酪氨酸激酶（Syk）的表达情况及意义。方法用免疫组化法和RT-PCR检测40例胰腺癌组织、9例慢性胰腺炎、8例正常胰腺组织中的Syk蛋白及其mRNA,形态计量学图象分析法测定微淋巴管密度（MLVD）。结果Syk蛋白在胰腺癌、慢性胰腺炎和正常胰腺组织中阳性率分别为27.5%、77.8%和100%;Syk蛋白与胰腺癌TNM分期、分化程度和淋巴结转移有关（P〈0.05）。Syk mRNA在胰腺癌中呈低表达（P〈0.01）。胰腺癌组织中微淋巴管密度（MLVD）在TNM分期III-IV期组显著高于I-II期组（P〈0.05）,淋巴结转移阳性组显著高于阴性组（P〈0.01）。Syk蛋白阴性表达者的MLVD显著高于阳性组（P〈0.01）。结论Syk在胰腺癌中表达减低或缺失,与胰腺癌的发展显著相关。     

脾酪氨酸激酶蛋白在食管鳞癌组织中的表达及临床意义

目的观察脾酪氨酸激酶（Syk）蛋白在食管鳞癌组织中的表达,探讨其与食管鳞癌发生、发展的关系。方法用免疫组化法检测48例食管鳞癌患者的癌组织及其癌旁组织中的Syk蛋白表达;分析不同TNM分期及淋巴结转移情况下食管鳞癌组织中的Syk蛋白表达。结果食管鳞癌组织Syk蛋白表达阳性率显著低于癌旁组织（χ^2=51.24,P〈0.05）;Syk蛋白表达与肿瘤TNM分期及淋巴结转移相关（P〈0.05）。结论食管鳞癌组织中Syk蛋白表达缺失与其发生及淋巴结转移倾向有关。     

从药代学和药效学的观点看什么是理想的吸入性激素

吸入性激素（ICS）是支气管哮喘（简称哮喘）长期治疗的一线药物。糖皮质激素（简称激素）是目前最有效的哮喘抗炎药物，但因为全身性不良反应使其长期应用受限。但ICS治疗哮喘的疗效仍不甚理想，全球哮喘防治创议（GINA）中推荐ICS单独使用仅适用于轻度持续哮喘。研究ICS的药代学和药效学规律对认识ICS治疗哮喘的有效性和安全性，指导临床用药和开发新型ICS极为重要。     

支气管哮喘临床研究中应当重视的一些问题

支气管哮喘（简称哮喘）临床研究近年来受到普遍重视，检索Medline 2000至2005年6月哮喘类献共计22000余篇，其中临床研究类献约占1／4（5000余篇）。尤为值得一提的是，上个世纪中期以来进行了多项国际多中心临床研究，如关于哮喘防治现状调查的欧洲哮喘临床管理调查研究（AIRE）、亚太地区哮喘临床管理调查研究（AIRIEP），哮喘联合治疗临床试验（OPTIMA）、布地奈德治疗基础上加用福莫特罗的疗效评估（FACET）、     

mTOR信号通路抑制剂和DNA甲基转移酶抑制剂对人胃癌细胞株Syk表达的影响

背景：哺乳动物雷帕霉素靶蛋白（roTOR）信号途径和DNA甲基化均参与肿瘤的发生、发展。脾酪氨酸激酶（Syk）是一种候选抑癌基因,与肿瘤发生有关。目的：研究mTOR信号通路抑制剂和DNA甲基转移酶抑制剂对人胃癌细胞株Syk表达的调控作用。方法：分别单独或联合应用mTOR抑制剂雷帕霉素（RAPA）、DNA甲基转移酶抑制剂5-氮杂-2’-脱氧胞苷（5-Aza—dC）、磷脂酰肌醇-3-激酶／丝苏氨酸蛋白激酶（P13K／Akt）抑制剂LY294002干预人胃癌细胞株MKN45和SGC7901,以细胞计数法检测细胞增殖能力,实时定量PCR法检测Syk表达情况,亚硫酸氢盐修饰后测序法检测DNA甲基化改变。结果：单独应用5-Aza—dC对细胞增殖抑制不明显,与RAPA、LY294002联合则显著抑制细胞增殖。单独应用5-Aza-dC可通过抑制DNA甲基化上调胃癌细胞的Syk表达,联合应用5-Aza—dc、RAPA和LY294002则显著上调Syk表达,但未进一步抑制DNA甲基化。结论：抑制mTOR信号通路可间接增强DNA甲基转移酶抑制剂上调Syk表达,从而抑制胃癌细胞生长。     

脾酪氨酸激酶蛋白在胃癌组织中的表达及意义

目的观察脾酪氨酸激酶（Syk）蛋白在胃癌组织中的表达,探讨其与胃癌发生、发展的关系。方法采用免疫组化法检测38例胃癌患者的癌组织及16例癌旁组织中Syk蛋白表达,并分析不同组织学类型、TNM分期、淋巴结转移、浆膜浸润、远处转移等胃癌组织中Syk蛋白的表达情况。结果胃癌组织中Syk蛋白表达阳性率显著低于癌旁组织（P〈0.01）;Syk蛋白表达与肿瘤TNM分期、淋巴结转移、浆膜浸润及远处转移相关（P均〈0.05）。结论胃癌组织中Syk蛋白表达缺失与其发生恶性生物学倾向有关。     

Syk和VEGF-C在胰腺癌组织中的表达及临床意义

目的进一步探讨胰腺癌发生、发展机制。方法收集4JD例胰腺癌、9例慢性胰腺炎、8例正常胰腺组织标本，应用免疫组织化学方法和RT—PCR检测脾酪氨酸激酶（Syk）和血管内皮生长因子-C（VEGF—C）表达情况，分析两者表达与胰腺癌临床病理特征的相关性。结果Syk和VEGF—C在胰腺癌组织中的表达显著低于在正常胰腺组织中的表达（P〈0．01、0．05），并与胰腺癌TNM分期、分化程度和淋巴结转移有关（P〈0．05），两者表达具有显著相关性（P=0．019）。结论Syk、VEGF-C在胰腺癌发生、发展中可能具有协同作用。     

胆囊癌组织中脾酪氨酸激酶的表达变化及意义

目的观察胆囊癌组织中脾酪氨酸激酶（Syk）的表达变化,并探讨其临床意义。方法采用免疫组化SP法检测55例胆囊癌组织、10例正常胆囊组织及10例慢性胆囊炎组织中的Syk蛋白。结果 10例正常胆囊组织、8例慢性胆囊炎组织及18例胆囊癌组织中Syk蛋白阳性表达。Syk蛋白在胆囊癌组织中的阳性表达率与前两者相比P均〈0.05。Syk在胆囊癌组织中的表达与性别、年龄、肿瘤部位、大小、分化程度及有无淋巴结转移无关（P均〉0.05）,而与临床分期有关（P〈0.05）。结论胆囊癌组织中Syk蛋白表达下调,且其与胆囊癌的临床分期有关。     

支气管哮喘三种病理改变的分子生物学机制研究进展

支气管哮喘（哮喘）作为一种常见病，近年来其发病率和病死率都有上升趋势。现代分子生物学的发展，使人们对哮喘的各种病理改变的分子生物学特性有了较深的研究，从而对哮喘的治疗提供了新思路。     

难控制支气管哮喘

糖皮质激素（以下简称激素）是目前治疗支气管哮喘（以下简称哮喘）最有效的药物，也是哮喘长期治疗的一线药物。多数哮喘患者，尤其是轻、中度患者对激素治疗的反应良好。但有少数中、重度哮喘患者对激素治疗的反应较差，这部分患者被称为难治或激素抵抗性哮喘。     

支气管哮喘精准治疗的研究进展

支气管哮喘(哮喘)是一种以慢性气道炎症为特征的异质性疾病,是全世界最普遍的慢性病之一,控制不佳可引起巨大医疗负担。尽管大多数哮喘患者能被吸入糖皮质激素和/或支气管扩张剂有效控制,但部分重症哮喘患者在常规疗法下仍难达理想的控制状态。为更有效地治疗重症哮喘,分子水平的靶向药物受到越来越多的重视。本综述旨在通过讨论目前在哮喘精准治疗方面的研究进展,探讨靶向治疗药物在重症哮喘治疗中的应用价值。     

Inhibition of spleen tyrosine kinase prevents mast cell activation and airway hyperresponsiveness

RATIONALE: Spleen tyrosine kinase (Syk) is important for Fc and B-cell receptor-mediated signaling. OBJECTIVE: To determine the activity of a specific Syk inhibitor (R406) on mast cell activation in vitro and on the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation in vivo. METHODS: AHR and inflammation were induced after 10 d of allergen (ovalbumin [OVA]) exposure exclusively via the airways and in the absence of adjuvant. This approach was previously established to be IgE, FcepsilonRI, and mast cell dependent. Alternatively, mice were passively sensitized with OVA-specific IgE, followed by limited airway challenge. In vitro, the inhibitor was added to cultures of IgE-sensitized bone marrow-derived mast cells (BMMCs) before cross-linking with allergen. RESULTS: The inhibitor prevented OVA-induced degranulation of passively IgE-sensitized murine BMMCs and inhibited the production of interleukin (IL)-13, tumor necrosis factor alpha, IL-2, and IL-6 in these sensitized BMMCs. When administered in vivo, R406 inhibited AHR, which developed in BALB/c mice exposed to aerosolized 1% OVA for 10 consecutive d (20 min/d), as well as pulmonary eosinophilia and goblet cell metaplasia. A similar inhibition of AHR was demonstrated in mice passively sensitized with OVA-specific IgE and exposed to limited airway challenge. CONCLUSION: This study delineates a functional role for Syk in the development of mast cell- and IgE-mediated AHR and airway inflammation, and these results indicate that inhibition of Syk may be a target in the treatment of allergic asthma.     

Which Biomarkers Are Effective for Identifying Th2-Driven Inflammation in Asthma?

Recognition of asthma as a heterogeneous disease revealed different potential molecular targets and urged the development of targeted, customized treatment modalities. Evidence was provided for different inflammatory subsets of asthma and more recently, further refined to T helper (Th)2-high and Th2-low subphenotypes with different responsiveness to standard and targeted pharmacotherapy. Given these differences in immunology and pathophysiology, proof of concept studies of novel treatment modalities for asthma should be performed in adequate, well-defined phenotypes. In this review, we describe both existing and novel biomarkers of Th2-inflammation in asthma that can be applied to classify asthma subphenotypes in clinical studies and for treatment monitoring.     

Platelet signalling networks: pathway perturbation demonstrates differential sensitivity of ADP secretion and fibrinogen binding

Platelet signalling responses to single agonists have been identified previously. However, a model of the total platelet signalling network is still lacking. In order to gain insights into this network, we explored the effects of a range of platelet-function inhibitors in two independent assays of platelet function, namely fibrinogen binding and ADP secretion. In this study, we targeted the intracellular signalling molecules targeted intracellular signalling molecules, Syk and PI3K and targeted intracellular signalling molecules, Syk and PI3K, the prostaglandin synthesis enzyme cyclooxygenase, surface receptors for TxA(2) and ADP (P2Y1 and P2Y12) and the integrin cell adhesion molecule, αIIbβ3. We demonstrate that the platelet responses of fibrinogen binding and secretion can be differentially affected by the individual inhibitors permitting the generation of a model delineating novel regulatory links in the platelet signalling network. Importantly, the model illustrates the interconnections among portions that are traditionally studied as separate modules, promoting a more integrated view of the platelet.     

哮喘治疗百年回顾:从经典辉煌到靶向选择

当前哮喘患病率在全球范围内仍呈逐年增加的趋势。在过去的一百年,伴随着吸入性糖皮质激素的问世、联合治疗尤其是吸入性糖皮质激素和长效支气管扩张剂联合治疗概念的提出、以哮喘总体控制为目标管理模式的建立,哮喘的治疗进入经典辉煌的抗炎药物治疗时期。我国哮喘的总体控制水平得到了一定程度的提高,但仍有部分重症哮喘患者依然达不到良好控制状态。重症哮喘造成了巨大的社会和经济负担。近年来,基于炎症表型和生物标志物的重症哮喘个体化治疗取得了诸多突破性进展,对未来哮喘治疗的方向产生了极其深远的影响,使更多哮喘患者从中获益。哮喘治疗正在从“经典”走向“精准”。     

重症哮喘新疗法的研究进展

长期吸入糖皮质激素(ICS)是治疗持续性哮喘最主要的方式。然而,在治疗重症哮喘时其疗效是有限的。目前,几种新疗法已被批准用于治疗重症哮喘,本文对其进行了归纳总结,包括长效抗胆碱药物(LAMAs)、支气管热成型术、靶向治疗药物、生物制剂以及免疫抑制剂等,以期为临床医师提供参考。     

Asthma: one hundred years of treatment and onward

There have been four types of drug treatment of asthma that have been used over the past 100 years. Belladonna alkaloids, derived from the thorn-apple plant were used in 1905, and chemically synthesized entities in this class are still in use today. Western medicine began to use adrenergic stimulants approximately 100 years ago, but they were likely used in Asian medicine long before that. Systemic treatment with corticosteroids was introduced into the treatment of asthma in the mid-20th century; inhaled corticosteroids have been in use for over 35 years. The last 40 years have also seen the development of the first targeted asthma treatments: cromones, antileukotrienes, and anti-IgE. As we learn more of the biology of asthma, we anticipate that more effective targeted asthma treatments will be developed.     

Management of chronic asthma in adults in diverse regions of the world.

Asthma is a chronic inflammatory disease of the lungs associated with significant morbidity and mortality worldwide. Adoption of current treatment guidelines that propose inhaled corticosteroids (ICS) as the foundation for asthma treatment should control most patients with chronic asthma. Rapid-acting inhaled beta (beta) 2-agonists are best reserved for acute symptom relief. Long-acting beta-2-agonists in combination with ICS are the most effective asthma treatment currently available when asthma is not controlled on low-dose ICS alone; however, they are not universally available due to cost. Slow-release theophylline may be an alternative cost-effective add-on therapy to ICS in resource-poor areas, although its potential for toxicity has limited its use over the last decade. New targeted anti-inflammatory therapies lack the broad anti-inflammatory activity of ICS and are unaffordable in most settings. Implementation of guidelines for asthma care is an unresolved challenge, and major gaps in asthma care are consistent across the globe. Review of asthma management worldwide shows that control of the disease in relation to the Global Initiative for Asthma (GINA) goals of asthma treatment is not achieved in a large proportion of patients, despite the widespread availability of guidelines and even with access to effective treatment in resource-rich settings. Many resource-poor countries have the additional challenge of lack of access to basic asthma treatment such as ICS. The challenge is to provide global access to core asthma medications, particularly ICS, at affordable prices, to improve implementation of treatment guidelines and to encourage better health care provider and patient education.     

上皮源性细胞因子与支气管哮喘

支气管哮喘(简称哮喘)是全球最常见的慢性气道炎症性疾病之一.慢性气道炎症是哮喘的内在发病机制,炎症细胞在气道的局部聚集、炎症介质和细胞因子的释放促使气道炎症发生.上皮源性细胞因子是免疫活性细胞的效应因子,其免疫调节功能在哮喘发病机制中处于中心地位.在人类肺组织及免疫细胞中,细胞因子的表达增高,从而导致肺部变态反应性疾病的发生.近年来利用哮喘发病机制中细胞因子作为靶点进行靶向治疗哮喘已成为未来哮喘治疗研究的主要热点.本文主要就上皮源性细胞因子中IL-25、IL-33及胸腺基质淋巴细胞生成素的结构和功能进行介绍,并对其与哮喘的关系作一简单综述.     

Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates

Our understanding of the molecular control of many disease pathologies requires the identification of direct substrates targeted by specific protein kinases. Here we describe an integrated proteomic strategy, termed kinase assay linked with phosphoproteomics, which combines a sensitive kinase reaction with endogenous kinase-dependent phosphoproteomics to identify direct substrates of protein kinases. The unique in vitro kinase reaction is carried out in a highly efficient manner using a pool of peptides derived directly from cellular kinase substrates and then dephosphorylated as substrate candidates. The resulting newly phosphorylated peptides are then isolated and identified by mass spectrometry. A further comparison of these in vitro phosphorylated peptides with phosphopeptides derived from endogenous proteins isolated from cells in which the kinase is either active or inhibited reveals new candidate protein substrates. The kinase assay linked with phosphoproteomics strategy was applied to identify unique substrates of spleen tyrosine kinase (Syk), a protein-tyrosine kinase with duel properties of an oncogene and a tumor suppressor in distinctive cell types. We identified 64 and 23 direct substrates of Syk specific to B cells and breast cancer cells, respectively. Both known and unique substrates, including multiple centrosomal substrates for Syk, were identified, supporting a unique mechanism that Syk negatively affects cell division through its centrosomal kinase activity.