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SPARC和LN在三阴性乳腺癌中的表达及临床意义
的开题报告
三阴性乳腺癌是指不表达雌激素受体、孕激素受体和人表皮生长因子受体2（HER2）的乳腺癌，它的生物学特点和临床表现独特，对化疗和放疗敏感，但易发生局部复发和转移，预后不良。
因此，研究三阴性乳腺癌的分子机制和临床特征，对于制定个体化治疗方案，改善患者预后具有重要意义。
SPARC是一种紧贴基质蛋白质，可以影响细胞外基质的形态，在许多肿瘤中表达水平下调，与肿瘤转移和预后有关。
然而，SPARC在三阴性乳腺癌中的表达和临床意义仍存争议。
LN是一种与淋巴结转移相关的蛋白质，也被用于预测癌症转移和预后，但其在三阴性乳腺癌中的作用尚未确定。
因此，本文将评估SPARC和LN在三阴性乳腺癌中的表达及其与临床特征和预后的关系。
我们将分别研究这两种蛋白质在三阴性乳腺癌组织和正常乳腺组织中的表达，以及在三阴性乳腺癌患者中的表达情况。
然后，我们将分析SPARC和LN的表达与临床病理特征和生存率之间的关联。
我们将通过回顾和整合现有的研究数据来探讨SPARC和LN在三阴性乳腺癌中的角色，并提出未来研究的方向和可能的临床应用。
这将有助于深入理解三阴性乳腺癌的分子机制和治疗策略，并为患者提供更好的个体化治疗方案。
阿托伐他丁钙片药品名称:通用名称：阿托伐他汀钙片英文名称：Lipitor (Atorvastatin Calcium Tablets)商品名称：立普妥成份:阿托伐他汀钙。
适应症:直胆固醇血症:原发性高胆固醇血症患者，包括家族性高胆固醇血症（杂合子型）或混合性高脂血症（相当于Fredrickson分类法的Ⅱa和Ⅱb型）患者，如果饮食治疗和其它非药物治疗疗效不满意，应用本品可治疗其总胆固醇升高、低密度脂蛋白胆固醇升高、载脂蛋白B升高和甘油三酯升高。
在纯合子家族性高胆固醇血症患者，阿托伐他汀钙可与其它降脂疗法（如LDL血浆透析法）合用或单独使用（当无其它治疗手段时），以降低总胆固醇和低密度脂蛋白胆固醇。
冠心病：冠心病或冠心病等危症（如：糖尿病，症状性动脉粥样硬化性疾病等）合并高胆固醇血症或混合型血脂异常的患者，本品适用于：降低非致死性心肌梗死的风险、降低致死性和非致死性卒中的风险、降低血管重建术的风险、降低因充血性心力衰竭而住院的风险、降低心绞痛的风险。
规格:(1)10mg(2)20mg(3)40mg用法用量:病人在开始本品治疗前，应进行标准的低胆固醇饮食控制，在整个治疗期间也应维持合理膳食。
应根据低密度脂蛋白胆固醇基线水平、治疗目标和患者的治疗效果进行剂量的个体化调整。
常用的起始剂量为10mg每日一次。
剂量调整时间间隔应为4周或更长。
本品最大剂量为80mg每日一次。
阿托伐他汀每日用量可在一天内的任何时间一次服用，并不受进餐影响。
对于心血管事件的低危患者治疗目标是LDL-C＜4.14 mmol/L(或＜160mg/dL)和总胆固醇＜6.22 mmol/L(或＜240mg/dL)，中危患者治疗目标是LDL-C＜3.37mmol/L(或＜130mg/dL)和总胆固醇＜5.18mmol/L(或＜200mg/dL)，高危患者治疗目标是LDL-C＜2.59mmol/L(或＜100mg/dL)和总胆固醇＜4.14mmol/L(或＜160mg/dL)，极高危患者治疗目标是LDL-C＜2.07mmol/L(或＜80mg/dL)和总胆固醇＜3.11mmol/L(或＜120mg/dL)。
症状性颅内动脉粥样硬化性狭窄血管内治疗中国专家共识（全文）动脉粥样硬化性颅内外血管狭窄是导致缺血性卒中/短暂性脑缺血发作的主要原因及病理改变，众多研究证实中国患者以颅内动脉狭窄为主。
最近我国大样本观察研究发现颅内动脉早期狭窄≥70％是卒中复发的高危因素，而且随着合并危险因素的增多，复发风险也明显增加。
所以，目前的问题是：如何准确评估风险？如何更好的管理血压、血脂和血糖等危险因素？如何给予抗栓治疗方案？支架治疗和药物治疗该如何选择以及效果如何？为此，《中华内科杂志》编委会组织专家对症状性动脉粥样硬化性颅内血管狭窄血管内治疗最新进展进行回顾，力求针对目前临床治疗方面较为混乱的认识提出一些思路和建议，供国内同行参考。
美国10％缺血性卒中患者是由颅内动脉粥样硬化性疾病所致，在中国这一比例超过30％。
研究显示对于狭窄≥70％的患者，症状性狭窄的动脉供应区1年卒中复发率高达23％。
近期一项关于中国颅内动脉狭窄或闭塞性疾病的研究（CICAS）显示中国缺血性卒中及短暂性脑缺血发作（TIA）患者中颅内动脉狭窄或闭塞的发生率为46.6％（其中19.6％患者合并颈动脉颅外段狭窄），研究同时显示伴随颅内动脉狭窄的患者入院时病情较重且住院时间更长，且1年卒中复发率伴随狭窄程度增加而升高（无狭窄患者为3.34％，50％——69％狭窄患者为3.82％，70％——99％狭窄患者为5.16％，完全闭塞患者为7.40％）。
因此探索颅内动脉粥样硬化性狭窄的治疗方法及对该人群实施有效的二级预防策略显得尤为重要。
一、药物治疗关于颅内动脉粥样硬化性狭窄的药物治疗一直存在争议，WASID研究显示应用华法林及阿司匹林治疗后患者狭窄血管供应区1年缺血性卒中的发生率分别为11％及12％，显示了单纯药物治疗对疾病控制效果并不理想。
研究同时发现华法林治疗组不良事件的发生率显著增高，即针对颅内动脉粥样硬化性狭窄患者的二级预防抗凝治疗并无优势，因此药物治疗的焦点指向了抗血小板治疗。
阿托伐他汀钙片治疗脑卒中并脑微出血的临床效果脑卒中是一种常见且严重的神经系统疾病，可引起脑组织缺血、坏死和出血。
脑卒中通常分为缺血性和出血性，其中缺血性脑卒中是最常见的类型，约占70%至80%。
脑微出血虽然比脑出血少见，但它也被认为是脑卒中的一种形式。
在脑卒中治疗中，降低胆固醇水平被认为是一种可能有益的策略，因为高胆固醇是脑卒中的风险因素之一。
阿托伐他汀是一种降低胆固醇水平的药物，已被广泛用于治疗冠心病和高血脂症。
在本篇文章中，我们将讨论阿托伐他汀钙片治疗脑卒中并脑微出血的临床效果。
一、阿托伐他汀的作用机制阿托伐他汀是一种可逆性的3-羟基-3-甲基戊二酸（HMG-CoA）还原酶抑制剂，通过抑制HMG-CoA还原酶的合成而降低胆固醇水平。
此外，阿托伐他汀还能通过抑制氧化应激和炎症反应来发挥神经保护作用。
这些作用有利于降低脑卒中风险和改善脑卒中后的神经功能。
二、阿托伐他汀的临床研究阿托伐他汀已在多项临床研究中用于治疗不同类型的脑卒中。
以下是对几项重要研究的简要介绍：1. SPARCL研究SPARCL（Stroke Prevention by Aggressive Reduction in Cholesterol Levels）研究是一项比较试验，旨在评估阿托伐他汀对中风患者的预防效果。
共有4,731名患者参与了该研究，但仅限于缺血性脑卒中患者，均接受了阿托伐他汀（80毫克/天）或安慰剂治疗。
该研究发现，接受阿托伐他汀治疗的组患者中风和心血管事件的发生率显著降低，但同时也发现了与阿托伐他汀有关的不良反应，如肌肉疼痛和病理性骨折。
SPARCL-Asia研究是一项针对亚洲人的中风预防试验。
在该研究中，1,472名亚洲患者接受了阿托伐他汀或安慰剂治疗，并进行了长达5年的随访。
研究结果显示，接受阿托伐他汀治疗组的中风和心血管事件发生率显著降低，但与此同时，与阿托伐他汀有关的严重不良事件也增加了。
目前，针对阿托伐他汀治疗脑微出血的研究还相对较少。
万方数据 万方数据SPARCL研究是强化调脂治疗的循证基石作者：高旭光， GAO Xu-guang作者单位：北京大学人民医院神经内科,100044刊名：中国现代神经疾病杂志英文刊名：CHINESE JOURNAL OF CONTEMPORARY NEUROLOGY AND NEUROSURGERY年，卷(期)：2009,9(1)1.Amareneo P;Labreuehe J;Lavallee P Statins in stroke prevention and carotidatherosclerosis:systematic review and up-to-date recta-analysis[外文期刊] 2004(12)2.Coliviechi F;Bassi A;Santini M Discontinuation of statin therapy and clinical outcome after isehemic stroke[外文期刊] 2007(10)3.Rodriguez-Yanez M;Davalos A;Castillo J Withdrawal from statins:implications for secondary stroke prevention and acute treatment[外文期刊] 20084.他汀类药物预防缺血性卒中/短暂性脑缺血发作专家组他汀类药物预防缺血性卒中/短暂性脑缺血发作的专家建议[期刊论文]-中华内科杂志 2007(1)5.Amarenco P;Goldstein LB;Szarek M Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient isehemic attack:the Stroke Prevention by Ag-gressive Reduction in Cholesterol Levels (SPARCL) trial[外文期刊] 20076.Amarenco P;Bogousslavsky J;Callahan A 3rd High-dose atorvastatin after stroke or transient ischemie attack[外文期刊] 2006(6)1.李焰生.LI Yan-sheng SPARCL试验解读[期刊论文]-中国卒中杂志2007,2(4)2.叶平.张明华正确认识阿托伐他汀增加出血性卒中风险：SPARCL研究再分析的解读[会议论文]-20083.杨志兰.伍丽萍.宦丽群综合治疗支气管哮喘慢性持续期和缓解期32例[期刊论文]-实用临床医学2009,10(9)4.胡大一预防脑卒中他汀治疗的新证据(SPARCL试验)[期刊论文]-中国医药导刊2006,8(6)5.欧阳辉.刘高纯.郭勇普鲁卡因治疗老年咯血伴心脑血管疾病患者的效果观察[期刊论文]-中国临床新医学2009,2(11)6.诸骏仁ALLHAT试验引起的混淆和教训[期刊论文]-中华心血管病杂志2003,31(12)7.敬运龙.Jing Yunling复方丹参注射液在儿科的临床应用和不良反应[期刊论文]-现代中西医结合杂志2009,18(23)8.顾萍.缪东培.GU Pin.MIAO Dong-pei他汀类药物防治脑卒中的进展[期刊论文]-医学研究生学报2005,18(3)9.韩俊峰溶栓治疗对缺血性心脑血管疾病疗效分析[期刊论文]-医药论坛杂志2008,29(7)10.顼志敏合理应用调脂药物,重视减少不良反应[期刊论文]-中国临床医生杂志2007,35(9)本文链接：/Periodical_xdsjjbzz200901004.aspx。
SPARC在成人急性白血病细胞中的表达及意义的开题报告【研究背景】急性白血病（acute leukemia）是一种白血细胞克隆增生性疾病，分为两种类型：急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）和急性髓系白血病（acute myeloid leukemia, AML）。
它们的共同特点是克隆细胞的异常增生和分化阻滞，导致正常造血失调。
尽管白血病的致病机制现在已经比较清楚，但是目前尚无根治的方法，治疗主要依靠化疗、放射治疗、干细胞移植等手段。
SPARC（Secreted Protein, Acidic and Rich in Cysteine）是一种富含半胱氨酸、酸性的外分泌蛋白，可以作为一种细胞外矩阵蛋白，存在于多种组织和细胞类型中。
SPARC已经被证明在多种癌症中具有重要的作用，包括乳腺癌、胃癌、宫颈癌等。
最近的研究表明，SPARC在白血病中也可能发挥重要作用，特别是在急性髓系白血病中，但是目前的研究还很有限，仍需要进一步的探索。
【研究目的】本研究旨在探讨SPARC在成人急性白血病细胞中的表达情况及其在白血病中的意义。
【研究内容】1. 收集约100例成人急性白血病患者的骨髓或外周血样本，包括ALL和AML患者。
2. 采用免疫荧光染色和Western blot分析等技术，检测SPARC在白血病细胞中的表达情况。
3. 分析SPARC的表达与患者临床特征之间的关系。
4. 探讨SPARC对白血病细胞增殖、细胞周期和凋亡的影响。
【预期结果】本研究预计可为深入了解SPARC在成人急性白血病中的作用提供新证据，为进一步探索SPARC与白血病的关系提供理论依据，为开发新的白血病治疗方法提供新的思路。
Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels(SPARCL)Trial by Stroke Subtypes Pierre Amarenco,MD;Oscar Benavente,MD;Larry B.Goldstein,MD;Alfred Callahan III,MD;Henrik Sillesen,MD,DMSc;Michael G.Hennerici,MD,PhD;Steve Gilbert,PhD;Amy E.Rudolph,PhD;Lisa Simunovic,MS;Justin A.Zivin,MD,PhD;K.Michael A.Welch,MB,ChB,FRCP;on behalf of the SPARCL InvestigatorsBackground and Purpose—The SPARCL trial showed that atorvastatin80mg/d reduces the risk of stroke and other cardiovascular events in patients with recent stroke or transient ischemic attack(TIA).We tested the hypothesis that the benefit of treatment varies according to index event stroke subtype.Methods—Subjects with stroke or TIA without known coronary heart disease were randomized to atorvastatin80mg/d or placebo.The SPARCL primary end point was fatal or nonfatal stroke.Secondary end points included major cardiovascular events(MCVE;stroke plus major coronary events).Cox regression models testing for an interaction with treatment assignment were used to explore potential differences in efficacy based on stroke subtype. Results—For subjects randomized to atorvastatin versus placebo,a primary end point occurred in13.1%versus18.6%of those classified as having large vessel disease(LVD,15.8%of4,731participants),in13.1%versus15.5%of those with small vessel disease(SVD,29.8%),in11.2%versus12.7%of those with ischemic stroke of unknown cause(21.5%), in7.6%versus8.8%of those with TIA(30.9%),and in22.2%versus8.3%of those with hemorrhagic stroke(HS,2%) at baseline.There was no difference in the efficacy of treatment for either the primary end point(LVD hazard ratio[HR]0.70, 95%confidence interval[CI]0.49to1.02,TIA HR0.81,CI0.57to1.17,SVD HR0.85,CI0.64to1.12,unknown cause HR0.87,CI0.61to1.24,HS HR3.24,CI1.01to10.4;P for heterogeneityϭ0.421),or MCVEs(P for heterogeneityϭ0.360)based on subtype of the index event.As compared to subjects with LVD strokes,those with SVD had similar MCVE rates(19.2%versus18.5%over the course of the trial),and similar overall reductions in stroke and MCVEs. Conclusions—Atorvastatin80mg/d is similarly efficacious in preventing strokes and other cardiovascular events, irrespective of baseline ischemic stroke subtype.(Stroke.2009;40:1405-1409.)Key Words:strokeⅢtransient ischemic attackⅢstatins,cholesterolS troke is a heterogeneous condition with a number of possible etiologies.1Whereas myocardial infarction(MI) is almost always attributable to atherothrombotic disease,brain infarction stems from a host of conditions(eg,rheumatic heart disease,arterial dissection,elastic tissue disease,intracranial small vessel disease,atherosclerotic carotid stenosis,etc).Stroke subtyping systems,such as the Trial of ORG10172in Acute Stroke Treatment(TOAST)classification,help classify patients into the most likely cause category.2Patients with different underlying stroke pathophysiologies may variably respond to specific preventive treatment strategies.For example,athero-thrombotic stroke is best prevented by antiplatelet agents whereas cardioembolic stroke attributable to atrial fibrillation is best prevented by vitamin K antagonists.3Statin outcome trials in subjects with established coronary artery disease,hypertension,diabetes,or at high vascular risk have shown a consistent17%to21%relative reduction in the risk of incident stroke.4These trials predominantly included subjects with established atherothrombotic disease or coro-nary heart disease risk equivalents.It is not known whether the strokes prevented in these trials were mostly of athero-thrombotic origin or from other etiologies.Trials using progression of carotid atherosclerosis as an end point have consistently shown that statins can slow the progres-sion of carotid atherosclerosis with a meta-analysis of these trials indicating that the greater the reduction in low-density lipopro-tein cholesterol(LDL-C),the slower the progression.5It was hypothesized that patients with transient ischemic attack(TIA), ischemic stroke related to atherothrombotic disease,small vessel disease or to undetermined cause,and those with hemorrhagic stroke would benefit from statin therapy similar to those withReceived August7,2008;final revision received September20,2008;accepted October7,2008.From INSERM U-698and Denis Diderot University(P.A.),Paris,France;the University of Texas Health Science Center(O.B.),San Antonio;Duke University(L.B.G.),Durham,North Carolina;Vanderbilt University(A.C.),Nashville,Tenn;University of Copenhagen(H.S.),Denmark;University of Heidelberg(M.G.H.),Mannheim,Germany;Rho Inc(S.G.),Newton,Mass;Pfizer Inc(A.E.R.,L.S.),New York;University of San Diego(J.A.Z.),Calif; and Rosalind Franklin University(K.M.A.W.),Chicago,Ill.Correspondence to Dr Amarenco,INSERM U-698and Denis Diderot University-Paris VII,Department of Neurology and Stroke Centre,Bichat University Hospital,46,rue Henri Huchard,75018,Paris,France.E-mail pierre.amarenco@bch.aphp.fr©2009American Heart Association,Inc.Stroke is available at DOI:10.1161/STROKEAHA.108.534107coronary heart disease because of the many risk factors that are shared between these conditions.6,7The Stroke Prevention by Aggressive Reduction of Cho-lesterol Levels(SPARCL)trial randomized4731subjects with recent stroke or TIA and no known coronary heart disease,and showed that treatment with atorvastatin80mg/d reduced the risk of recurrent stroke.8In a secondary analysis, it was found that the subjects who benefited most had the greatest reductions in LDL-C(ie,Ͼ50%LDL-C decrease from baseline).9The aim of this post hoc analysis of the SPARCL trial was to explore whether the benefit of treatment varied based on the baseline stroke subtype.Subjects and MethodsThe SPARCL methodology has been described in detail previous-ly.7,8The study was approved by the local research committee or institutional review board at each participating center(15of205 centers excluded otherwise suitable subjects with an LDL-C Ͼ4.1mmol/L[160mg/dL]as required by their institutional review boards)and subjects gave written informed consent.Study Hypothesis and Patient PopulationThe primary hypothesis of the SPARCL trial was that treatment with atorvastatin80mg/d would reduce the combined risk of fatal and nonfatal stroke in patients with a recent stroke or TIA.Eligible subjects were men and women aged older than18years who had an ischemic or hemorrhagic stroke,or TIA(all diagnosed by a neurol-ogist within30days of the event)1to6months before randomiza-tion.The protocol did not specifically exclude patients with hemor-rhagic stroke.Stroke was defined as focal clinical signs of central nervous system dysfunction of vascular origin lastingՆ24hours. TIA was defined as an acute loss of cerebral or ocular function lastingϽ24hours and presumed to be of atherosclerotic origin. Subjects had to be ambulatory(Modified Rankin scoreՅ3;score can range from0to6with higher scores indicating more severe disability or death)and have a LDL-C levelՆ2.6andՅ4.9mmol/L(Ն100 andՅ190mg/dL).7Patients were excluded if they had atrial fibrillation,sinus node dysfunction,mechanical prosthetic heart valves,clinically significant mitral stenosis,coronary heart disease, subarachnoid hemorrhage or stroke resulting from revascularization procedure,or trauma.7Subjects were enrolled between September 1998and March2001.Type of Entry EventsInvestigators classified the index event as a TIA or as one of the stroke subtypes based on their clinical judgment without independent adjudication.Strokes were classified as hemorrhagic stroke,small vessel disease stroke,large artery disease stroke,ischemic stroke of unknown cause with more than one cause,unknown cause with complete work-up,or unknown cause with incomplete work-up.For the purposes of this analysis,ischemic stroke of unknown cause was considered as one group.Study ProtocolBetween1and6months after stroke(within30days of the initial screening visit),eligible subjects were randomized to double-blind therapy with either atorvastatin80mg/d or placebo.Nonstudy statins were not permitted.Those subjects who began a nonstudy statin or withdrew from randomized treatment were included in the intention to treat analysis.8All subjects were counseled to follow the National Cholesterol Education Program(NCEP)Step1(or similar)diet, throughout the study.Visits were scheduled at1,3,and6months, and every6months thereafter.Surviving patients had last study visits between March and June2005.Efficacy OutcomesThe SPARCL primary outcome was the time from randomization to the first occurrence of a nonfatal or fatal stroke.There were7 prespecified secondary composite outcomes including stroke or TIA; major cardiovascular event(MCVE;stroke,cardiac death,nonfatal MI or resuscitated cardiac arrest);and all-cause mortality.8End points were adjudicated by an independent committee whose mem-bers were unaware of treatment assignment.Lipid Level Analysis and Safety Assessments Clinical laboratory assessments were performed at1,3,and6 months,and every6months thereafter,with measurement of blood samples in the same central laboratory.Measurements included LDL-C assessment.If LDL-C wasϽ1.0mmol/L(Ͻ40mg/dL),the investigator was informed of the result and could lower the dosage of study drug from80to40mg/d.A second randomly chosen investigator for a placebo patient was similarly notified,and LDL-C levels were retested for both patients to maintain the blind.Drug safety was assessed by an evaluation of the type,frequency,severity, and duration of any reported adverse event,and by vital signs, physical examinations,and laboratory tests.Statistical AnalysisWe used the primary end point(fatal and nonfatal stroke)and the MCVE secondary end point for this post hoc analysis.Our main purpose was to search for heterogeneity between entry event sub-groups.Potential differences in efficacy based on type of entry event were assessed by testing for an interaction with treatment assignment using Cox regression models.Hazard ratios(HR)relative to large vessel disease group were calculated from Cox regression models adjusted for treatment,time since entry event,sex,and baseline age (prespecified adjustments).A probability valueϽ0.05was consid-ered significant.SAS software was used for the analyses.ResultsAmong4731participants,4728had information regarding entry event subtype with15.8%classified as having large vessel disease(nϭ749),29.8%small vessel disease(nϭ1409),21.5% ischemic stroke of unknown cause(nϭ1017),30.9%TIA (nϭ1460),and2%hemorrhagic stroke(nϭ93).Table1shows the baseline characteristics by entry event for those randomized to atorvastatin and placebo.Treatment Effect Across Entry EventStroke SubtypesFigure1shows that atorvastatin treatment was similarly effica-cious in reducing the primary end point(fatal and nonfatal stroke)for all entry event stroke subtypes with no heterogeneity (P for heterogeneityϭ0.421).Although there was no overall heterogeneity between subtypes,the patients with a baseline hemorrhagic stroke and randomized to atorvastatin were quali-tatively different and were more than3times more likely to have a recurrent stroke compared with similar patients randomized to placebo.A test for heterogeneity comparing the outcomes of subjects with hemorrhagic and ischemic stroke at baseline was significant(Pϭ0.0482).10For MCVEs a similar reduction was observed in the atorvastatin compared with the placebo groups for all entry event subgroups with no heterogeneity between groups(P for heterogeneityϭ0.360).The rates of adverse events such as liver enzyme elevation 3times above the upper normal limit,creatine kinase eleva-tion,myalgia,myopathy,or rhabdomyolisis were similar across entry event stroke subtypes in both active and placebo1406Stroke April2009arms.Only liver enzymes were significantly elevated in the atorvastatin arm compared with placebo.Risk of Primary and Secondary End Points in Entry Event Stroke SubtypesTable 2shows percentages of outcome events according to entry stroke subtype.As shown in Figure 2,relative to the group that had a large vessel disease stroke at baseline,the TIA and unknown cause groups had lower absolute rates of outcome strokes,with the small vessel disease and hemorrhagic stroke groups having similar absolute rates;TIA,hemorrhagic stroke,small vessel disease,and unknown cause groups had similar absolute MCVE rates.Mortality rates were similar across all entry event subgroups.The analyses were also carried out with adjustment for blood pressure,diabetes,and mRS at baseline and the results did not differ substantially (data not shown).DiscussionWe found no heterogeneity in the treatment effect for the primary end point (fatal and nonfatal stroke)across baseline ischemic stroke subtypes.This means that atorvastatin 80mg/d was similarly efficacious in subjects randomized with aTable 1.Baseline CharacteristicsLarge Vessel Hemorrhagic Transient Ischemic Attack Small Vessel UnknownAtorvastatin (n ϭ367)Placebo (n ϭ382)Atorvastatin (n ϭ45)Placebo (n ϭ48)Atorvastatin (n ϭ708)Placebo (n ϭ752)Atorvastatin (n ϭ708)Placebo (n ϭ701)Atorvastatin (n ϭ535)Placebo (n ϭ482)Characteristic Age,y62.0(0.6)63.3(0.6)62.1(2.0)63.6(1.7)63.5(0.4)62.2(0.4)63.8(0.4)63.7(0.4)62.0(0.5)60.6(0.5)Male sex,n (%)237(64.6)242(63.4)27(60.0)33(68.8)403(56.9)421(56.0)421(59.5)420(59.9)338(63.2)279(57.9)Systolic blood pressure,mm Hg 138.3(1.0)138.8(0.9)142.6(3.5)140.4(2.2)136.7(0.7)137.9(0.7)141.8(0.7)140.2(0.7)138.4(0.8)136.2(0.9)Diastolic blood pressure,mm Hg81.8(0.6)81.1(0.5)85.2(1.9)85.5(1.5)80.8(0.4)80.8(0.4)82.9(0.4)82.3(0.4)82.4(0.4)80.9(0.5)Body mass index,kg/m 227.3(0.2)27.3(0.2)26.1(0.7)26.8(0.5)27.4(0.2)27.6(0.2)27.8(0.2)27.6(0.2)27.6(0.2)27.1(0.2)Time since entry event,d 86.0(2.5)86.0(2.5)95.8(6.8)94.7(7.3)85.9(1.8)84.1(1.7)87.0(1.9)81.0(1.8)89.1(2.0)86.6(2.1)Risk factors,n (%)Current smoker 70(19.1)89(23.3)7(15.6)5(10.4)135(19.1)136(18.1)146(20.6)133(19.0)93(17.4)93(19.3)Former smoker164(44.7)166(43.5)20(44.4)21(43.8)298(42.1)284(37.8)257(36.3)267(38.1)223(41.7)179(37.1)Systemic hypertension 227(61.9)251(65.7)33(73.3)39(81.3)403(56.9)420(55.9)497(70.2)496(70.8)315(58.9)246(51.0)History of diabetes mellitus 86(23.4)83(21.7)3(6.7)4(8.3)78(11.0)97(12.9)158(22.3)136(19.4)70(13.1)79(16.4)Any prior statin therapy,n (%)8(2.2)15(3.9)1(2.2)2(4.2)19(2.7)18(2.4)15(2.1)15(2.1)14(2.6)13(2.7)Lipids,mg/dL LDL-C 132.3(1.4)133.2(1.2)129.8(4.3)135.3(3.2)133.3(0.9)132.8(0.9)132.4(0.9)135.0(1.0)132.9(1.0)133.3(1.1)HDL-C48.4(0.7)48.0(0.7)51.5(2.1)48.5(1.4)51.5(0.5)51.7(0.5)49.6(0.5)48.8(0.5)49.9(0.6)50.7(0.7)Total cholesterol 209.5(1.6)210.3(1.4)207.9(4.9)209.4(3.9)213.3(1.1)213.5(1.0)210.4(1.1)212.2(1.1)211.6(1.3)212.0(1.4)Triglycerides 143.9(3.6)145.7(3.8)135.0(13.4)128.0(8.0)143.2(2.7)145.7(2.6)143.2(2.6)142.5(2.4)146.1(6.5)141.4(3.4)Apolipoprotein A1146.0(1.4)145.3(1.5)151.5(3.9)144.1(3.3)152.8(1.1)154.1(1.1)148.6(1.0)147.9(1.0)147.4(1.2)149.2(1.3)Apolipoprotein B132.6(1.2)134.1(1.1)129.0(3.6)132.6(2.7)133.7(0.8)133.6(0.8)133.3(0.8)135.5(0.9)132.8(0.9)132.7(1.1)LDL-C indicates low-density lipoprotein cholesterol;HDL-C,high-density lipoproteincholesterol.Figure 1.Risk of recurrent stroke by entry event stroke subtypes,relative to large ves-sel disease entry event group.HR indicates hazard ratio;CI,confidence interval;TIA,tran-sient ischemic attack.Amarenco et alStroke Subtypes in SPARCL 1407TIA or ischemic stroke,regardless of the ischemic stroke subtype.We also found that atorvastatin treatment similarly reduced MCVE end points in all ischemic stroke subgroups.Therefore,we failed to confirm the hypothesis that the benefit of treatment varies based on the ischemic stroke subtype at baseline.It should be noted that the distribution of stroke subtypes at baseline may not mirror that encountered inclinical practice.This is in part attributable to the SPARCL selection criteria in which subjects with high risk sources of cardiogenic embolism and those with coronary heart disease were excluded.We do not have data to permit us to determine the likely pathophysiologies of TIAs,which were considered as a separate category in the analyses.As we previously reported,we found subjects with a hemorrhagic stroke as the qualifying event had no reduction or an increase in outcome strokes with treatment,10and in the present analysis,that they had no reduction in MCVEs.It is notable that the small vessel disease subgroup had an absolute recurrent stroke rate similar to the large vessel disease subgroup (14.3%and 15.9%,respectively).A population-based study has shown that the long-term 5-year recurrent stroke risk was similar across entry stroke subtypes,including patients with lacunar stroke.11Moreover,small vessel disease entry event group in SPARCL had an 18.5%rate of outcome MCVE,whereas the corresponding rate in the large vessel disease group was 19.2%.This similarity be-tween the 2subgroups was unexpected,although it is consis-tent with a recent autopsy study showing that 79%of patients with small vessel disease and no history of coronary heart disease had coronary plaque with 37%having a coronary stenosis Ͼ50%(as compared with 77%and 33%of those with atherothrombotic strokes).12A systematic review showed that the risk of early mortality and stroke recurrence were higher in subjects with nonlacunar than lacunar infarc-tion,whereas the long-term risk was similar,including that of fatal or nonfatal MI.13The present data clearly show that subjects with small vessel disease had a long-term risk of MCVE similar to other ischemic stroke subtypes,and there-fore should benefit from the same intensive preventive strategies,including statin therapy.Indeed,the effect of atorvastatin in reducing MCVEs in SPARCL was similar in those with small vessel and large vessel disease at baseline.Overall benefits on ischemic stroke and cardiac outcome events in the small vessel disease subgroup largely offset the risk of hemorrhagic stroke that we have already reported.10Patients randomized with a TIA had a significantly lower rate of outcome stroke,MCVEs,and deaths as compared to the otherTable 2.Primary and Secondary Efficacy Event Counts by Entry EventsAtorvastatin (n ϭ2363)Placebo (n ϭ2365)Stroke265(11.2)311(13.2)Large vessel 48(13.1)71(18.6)TIA54(7.6)66(8.8)Hemorrhagic 10(22.2)4(8.3)Small vessel 93(13.1)109(15.5)Unknown 60(11.2)61(12.7)Stroke or TIA 375(15.9)476(20.1)Large vessel 59(16.1)95(24.9)TIA106(15.0)151(20.1)Hemorrhagic 11(24.4)7(14.6)Small vessel 124(17.5)138(19.78)Unknown75(14.0)85(17.6)Major cardiovascular event 334(14.1)407(17.2)Large vessel 58(15.8)86(22.5)TIA71(10.0)93(12.4)Hemorrhagic 11(24.4)6(12.5)Small vessel 120(16.9)141(20.1)Unknown 74(13.8)81(16.8)All deaths215(9.1)211(8.9)Large vessel 31(8.4)44(11.5)TIA53(7.5)53(7.0)Hemorrhagic 7(15.6)5(10.4)Small vessel 77(10.9)64(9.1)Unknown47(8.8)45(9.3)Values in bold are total No.of patients (%)in each treatment group and overall experiencing each end-point.Values not in bold give corresponding values for each entry event subgroup.TIA indicates transient ischemicattack.Figure 2.Treatment effect by entry event stroke subtypes:primary end point (fatal or nonfatal stroke)and secondary end points.HR indicates hazard ratio;CI,con-fidence interval;TIA,transient ischemic attack.1408Stroke April 2009subgroups.The5-year stroke event rate was8.2%in the group randomized after a TIA versus15.9%in those with a large vessel disease stroke.The observed event rate in subjects with TIA was even lower than the3-month event rate that has been reported in patients with a TIA and no predefined therapeutic intervention.14 The low event rate observed in patients randomized with a TIA in SPARCL is likely due to the fact that patients were enrolled a mean of3months after the TIA event(ie,after the highest period for stroke risk),to the exclusion of patients with atrial fibrillation or with an indication for carotid endarterectomy and to an early and continued risk factor control,even prior random-ization,which has been reported to result in an80%reduction in the3-month stroke event rate.15,16SPARCL subjects,random-ized after a TIA,however,still had a beneficial effect of atorvastatin therapy for both stroke and MCVEs similar to subjects who had an ischemic stroke.This analysis is limited by its post hoc design and the SPARCL trial was not powered for subgroup analyses.We calculated a power of51%to detect the risk reduction of16% that was observed for the primary SPARCL end point between all entry event stroke subtypes.The power to detect a risk reduction of16%was reduced to20%for the SVD group and to only6%for the hemorrhagic stroke group.Therefore,we cannot exclude the possibility that a larger study might find a significant difference among ischemic stroke subtypes.Stroke subtype assignment was based on investigator judgment and was not standardized or adjudicated.Neuroimaging data to verify cere-bral abnormalities(eg,extent of white matter abnormalities, cerebral microbleeds,or multiple lacunes)which might have confounded or explained some of the associations that we found were not recorded.As a result,this analysis should be viewed as exploratory.With these caveats,the analyses show that atorva-statin80mg/d is similarly efficacious in preventing strokes and other MCVEs,regardless of baseline ischemic stroke subtype.Sources of FundingThis study was sponsored by Pfizer Inc.Employees of Pfizer contrib-uted to the design and conduct of the study,the collection,management, analysis,and interpretation of the data,and review of the manuscript.No content development support was provided,but assistance in preparing the figures and formatting the manuscript for submission was provided by Envision Pharma and funded by Pfizer Inc.DisclosuresThis study was sponsored by Pfizer Inc,who were involved in the design and conduct of the study;collection,management,and analysis of the data;and review of the manuscript.Pierre Amarenco has received grants from Pfizer for other research or activities not reported in this research exceeding$10000/year and honoraria from Pfizer in excess of$10000/year during the course of this study. Oscar Benavente has received honoraria from Pfizer during the course of this study.The honoraria did not exceed$10000/year. Larry Goldstein has received honoraria from Pfizer during the course of this study.The honoraria did not exceed$10000/year.Alfred Callahan has received honoraria from Pfizer in excess of$10000 during the course of this study.Henrik Sillesen has received grants from Pfizer for other research or activities not reported in this research/article in excess of$10000/year and honoraria exceeding $10000/year during the course of this study.Michael Hennerici has received grants from Pfizer for other research or activities not reported in this research/article and honoraria from Pfizer during the course of the study.Neither the grants nor the honoraria exceeded $10000/year.Steve Gilbert is employed by Rho Inc,a company that provides statistical consultation for Pfizer.Amy Rudolph and LisaSimunovic are employees of Pfizer and have an equity or ownership interest in the sponsor of the study.Justin Zivin has received honoraria from Pfizer during the course of this study.The honoraria did not exceed $10000/year.K.Michael Welch has received honoraria from Pfizer during the course of the study in excess of$10000/year.Statistical analysis was performed by Steve Gilbert(employed by Rho Inc,a company that provides statistical consultation for Pfizer).References1.Mohr JP,Albers GW,Amarenco P,Babikian VL,Biller J,Brey RL,Coull B,Easton JD,Gomez CR,Helgason CM,Kase CS,Pullicino PM,Turpie AG.American Heart Association Prevention Conference.IV Prevention andRehabilitation of Stroke.Etiology of stroke.Stroke.1997;28:1501–1506.2.Goldstein LB,Jones MR,Matchar DB,Edwards LJ,Hoff J,Chilukuri V,Armstrong SB,Horner RD.Improving the reliability of stroke subgroupclassification using the Trial of ORG10172in Acute Stroke Treatment(TOAST)criteria.Stroke.2001;32:1091–1098.3.Albers GW,Amarenco P,Easton JD,Sacco RL,Teal P.Antithrombotic andthrombolytic therapy for ischemic stroke:the Seventh ACCP Conference onAntithrombotic and Thrombolytic Therapy.Chest.2004;126(3Suppl):483S–512S.4.Baigent C,Keech A,Kearney PM,Blackwell L,Buck G,Pollicino C,Kirby A,Sourjina T,Peto R,Collins R,Simes R;Cholesterol TreatmentTrialists’(CTT)Collaborators.Efficacy and safety of cholesterol-lowering treatment:prospective meta-analysis of data from90,056par-ticipants in14randomised trials of ncet.2005;366:1267–1278.5.Amarenco P,Labreuche J,Lavalle´e P,Touboul PJ.Statin in strokeprevention and carotid atherosclerosis:systematic review and meta-anal-ysis.Stroke.2004;35:2902–2909.6.Sacco RL,Benjamin EJ,Broderick JP,Dyken M,Easton JD,Feinberg WM,Goldstein LB,Gorelick PB,Howard G,Kittner SJ,Manolio TA,WhisnantJP,Wolf PA.American Heart Association Prevention Conference.IV Preventionand Rehabilitation of Stroke.Risk factors.Stroke.1997;28:1507–1517.7.Amarenco P,Bogousslavsky J,Callahan AS,Goldstein L,Hennerici M,Sillsen H,Welch MA,Zivin J;SPARCL Investigators.Design and baselinecharacteristics of the Stroke Prevention by Aggressive Reduction in Choles-terol Levels(SPARCL)study.Cerebrovasc Dis.2003;16:389–395.8.Amarenco P,Bogousslavsky J,Callahan A III,Goldstein LB,HennericiM,Rudolph AE,Sillesen H,Simunovic L,Szarek M,Welch KM,ZivinJA;Stroke Prevention by Aggressive Reduction in Cholesterol Levels(SPARCL)Investigators.High-dose atorvastatin after stroke or transientischemic attack.N Engl J Med.2006;355:549–559.9.Amarenco P,Goldstein LB,Szarek M,Sillesen H,Rudolph AE,CallahanA3rd,Hennerici M,Simunovic L,Zivin JA,Welch KM;SPARCLInvestigators.Effects of intense low-density lipoprotein cholesterolreduction in patients with stroke or transient ischemic attack:the StrokePrevention by Aggressive Reduction in Cholesterol Levels(SPARCL)trial.Stroke.2007;38:3198–3204.10.Goldstein LB,Amarenco P,Szarek M,Callahan A3rd,Hennerici M,SillesenH,Zivin JA,Welch KM;SPARCL Investigators.Secondary analysis ofhemorrhagic stroke in the Stroke Prevention by Aggressive Reduction inCholesterol Levels(SPARCL)Study.Neurology.2008;70:2364–237011.11.Petty GW,Brown RD Jr,Whisnant JP,Sicks JD,O’Fallon WM,WiebersDO.Ischemic stroke subtypes:a population-based study of functionaloutcome,survival,and recurrence.Stroke.2000;31:1062–1068.12.Gongora-Rivera F,Labreuche J,Jaramillo A,Steg PG,Hauw JJ,Amarenco P.Autopsy prevalence of coronary atherosclerosis in patientswith fatal stroke.Stroke.2007;38:1203–1210.13.Jackson C,Sudlow paring risks of death and recurrent vascular eventsbetween lacunar and non-lacunar infarction.Brain.2005;128:2507–2517.14.Johnston SC,Gress DR,Browner WS,Sidney S.Short-term prognosis afteremergency department diagnosis of TIA.JAMA.2000;284:2901–2906.valle´e PC,Meseguer E,Abboud H,Cabrejo L,Olivot JM,Simon O,Mazighi M,Nifle C,Niclot P,Lapergue B,Klein IF,Brochet E,Steg PG,Lese`che G,Labreuche J,Touboul PJ,Amarenco P.A transient ischaemicattack clinic with round-the-clock access(SOS-TIA):feasibility andncet Neurol.2007;6:953–960.16.Rothwell PM,Giles MF,Chandrateva A,Marquardt L,Geraghty O,Redgrave JN,Lovelock CE,Binney LE,Bull LM,Cuthbertson FC,WelchSJ,Bosch 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SPARC在恶性血液病中的研究进展SPARC（secreted protein，acidic and rich in cysteine），是一种富含半胱氨酸（Cys）的小分子糖蛋白。
定位于人类5号染色体的q31.4-q32，全长25.9kb。
具有多种生物学功能，参与并影响多个下游信号通路，导致细胞生理深刻地变化。
在恶性血液病中，SPARC mRNA及蛋白的表达量发生显著变化，可能参与疾病的发生发展。
本文主要阐述SPARC在恶性血液病中的研究进展。
标签：SPARC；MDS；AML；CML；MMSPARC（secreted protein，acidic and rich in cysteine），又称作骨连接蛋白（osteon ecfin）、基底膜40蛋白（BM40），是一种富含半胱氨酸（Cys）的小分子糖蛋白。
最早是由Termine[1]等人于1981 年鉴定出的一种骨主要的非胶原成分。
目前已经证明其在胰腺癌、卵巢癌和结直肠癌中扮演抑制肿瘤细胞恶性生物学行为的作用；而在黑色素瘤、胶质瘤、前列腺癌和乳腺癌中则展现促进作用[2]。
本文主要阐述SPARC在恶性血液病中的研究进展。
1.SPARC简介1.1 SPARC的基因组构SPARC基因定位于人类5号染色体的q31.4-q32，全长25.9kb，前面第一个非编码外显子后接一个10.6kb的内含子，后面是包括整个3’端非翻译区域的10个外显子。
这个基因组成在脊椎动物中高度保守。
从外显子1至内含子1300bp 的CpG岛为SPARC启动子，在许多癌症中，DNMT3a与之结合，并使其甲基化。
一些cAMP共有序列定位于启动子区域和第一个内含子（区域），已经证明：cAMP可以激活SPARC的表达。
SPARC的mRNA非常稳定，半衰期超过24小时。
然而，它可被绑定在高度保守的3’端非翻译区的miR-29 microRNA诱导退化。
1.2 SPARC的蛋白质结构SPARC 分为3 个独立的模块结构。
