BACKGROUND & AIMS: OBJECTIVE:Statins are a group of medications that reduce cholesterol synthesis by inhibiting the activity of HMG-CoA reductase, a key enzyme in the mevalonate pathway. The clinical use of statins to lower excess cholesterol levels has revolutionized the cardiovascular field and increased the survival of millions, but some patients have adverse side effects. A growing body of data suggests that some of the beneficial and adverse effects of statins, including their anti-inflammatory, anti-tumorigenic, and myopathic activities, are cholesterol-independent. However, the underlying mechanisms for these effects of statins are not well defined. METHODS:Because Caenorhabditis elegans (C. elegans) lacks the cholesterol synthesis branch of the mevalonate pathway, this organism is a powerful system to unveil the cholesterol-independent effects of statins. We used genetic and biochemical approaches in C. elegans and cultured macrophage-derived murine cells to study the cellular response to statins. RESULTS:We found that statins activate a conserved p38-MAPK (p38) cascade and that the protein geranylgeranylation branch of the mevalonate pathway links the effect of statins to the activation of this p38 pathway. We propose that the blockade of geranylgeranylation impairs the function of specific small GTPases we identified as upstream regulators of the p38 pathway. Statin-mediated p38 activation in C. elegans results in the regulation of programs of innate immunity, stress, and metabolism. In agreement with this regulation, knockout of the p38 pathway results in the hypersensitivity of C. elegans to statins. Treating cultured mammalian cells with clinical doses of statins results in the activation of the same p38 pathway, which upregulates the COX-2 protein, a major regulator of innate immunity in mammals. CONCLUSIONS:Statins activate an evolutionarily conserved p38 pathway to regulate metabolism and innate immunity. Our results highlight the cytoprotective role of p38 activation under statin treatment in vivo and propose that this activation underlies many of the critical cholesterol-independent effects of statins.

背景与目标：

BACKGROUND & AIMS: Two in vitro and one in vivo assay were performed to study the endothelial pleiotropic actions of "tissue type" angiotensin converting enzyme inhibitors (ACE-Is) such as perindopril and quinapril, their active forms, that is, quinaprilat and peridoprilat, or of statins belonging to natural (lovastatin), semisynthetic (simvastatin), and synthetic enantiomeric (atorvastatin, cerivastatin) classes. Cytoplasmic [Ca2+]i levels in cultured bovine aortic endothelial cells and endothelium-dependent nitric oxide-mediated coronary vasodilatation in the Langendorff preparation of guinea pig heart constituted our in vitro assays. The in vivo assay consisted of study of PGI2-mediated thrombolytic response in arterial blood of rats after intravenous administration of drugs. In this last assay, perindopril and quinapril proved to be, by two orders of magnitude, more potent PGI2-dependent thrombolytics than the most potent statin (atorvastatin). However, in both in vitro assays we found a higher endothelial efficacy of statins as compared to ACE-Is. In particular, those statins that contain the lactone ring in their molecules (lovastatin, simvastatin) were the most potent coronary vasodilators. In summary, the in vivo profile of action of ACE-Is and statins contrasted with their reversed order of potency in vitro. We hypothesize that the endocrine-like function of the pulmonary circulation [28-31] may be responsible for the in vivo bradykinin-triggered, PGI2-mediated thrombolysis by ACE-Is, whereas the pleiotropic action of statins, possibly involving inhibition of prenylation [14-19], is diffused throughout many vascular beds.

背景与目标： 进行了两种体外和一种体内测定，以研究 “组织型” 血管紧张素转换酶抑制剂 (ACE-Is) (例如培哚普利和奎那普利) 的内皮多效性作用，它们的活性形式，即奎那普利拉和哌啶拉，或属于他汀类药物的内皮多效性作用天然 (洛伐他汀)，半合成 (辛伐他汀) 和合成对映体 (阿托伐他汀，西立伐他汀) 类。在豚鼠心脏的Langendorff制剂中，培养的牛主动脉内皮细胞中的细胞质 [Ca2] i水平和内皮依赖性一氧化氮介导的冠状动脉血管舒张作用构成了我们的体外测定。体内测定包括研究静脉给药后大鼠动脉血中的PGI2-mediated溶栓反应。在最后的测定中，培哚普利和喹普利被证明比最有效的他汀类药物 (阿托伐他汀) 具有两个数量级的PGI2-dependent溶栓药。然而，在两种体外测定中，我们发现他汀类药物与ACE-Is相比具有更高的内皮功效。特别是，那些在分子中含有内酯环的他汀类药物 (洛伐他汀，辛伐他汀) 是最有效的冠状动脉血管扩张剂。总而言之，ACE-Is和他汀类药物的体内作用曲线与它们在体外的效力顺序相反。我们假设肺循环的内分泌样功能 [28-31] 可能是体内缓激肽触发的，PGI2-mediated ACE-Is溶栓的原因，而他汀类药物的多效性作用，可能涉及抑制异戊二烯化 [14-19]，扩散到许多血管床。

BACKGROUND & AIMS: OBJECTIVE:To analyze the possible beneficial effects of statins on the disease activity of patients with rheumatoid arthritis (RA) using a database from a large observational cohort study. METHODS:We studied a total of 7512 patients enrolled in a single-institute based prospective observational cohort of RA patients (IORRA); their information was collected biannually. In this study, cross-sectional data of 4152 patients (female 83.3%, average age 58.4 yrs) in October 2003 were analyzed (Mann-Whitney U-test). RESULTS:Among 4152 patients with RA, 279 (6.7%) were taking statins; patients taking statins had lower C-reactive protein (0.85 vs 1.24 mg/dl, respectively) and lower swollen joint counts (1.80 vs 2.55), but more frequently used corticosteroids (2.88 vs 2.40 mg/day) compared to patients not taking statins. Serum cholesterol level was closely related to the use of corticosteroids. Thus, an adjustment with the dose of corticosteroid was conducted; even taking account of the effects of steroids, RA disease activity indicated by patient's assessment for pain, physician's assessment, and swollen joint counts was significantly lower in patients with statins compared to those without. CONCLUSION:This study indicates that statins have beneficial effects in reducing RA disease activity in the daily practice of rheumatology.

背景与目标：

BACKGROUND & AIMS: :Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in patients over the age of 65 years in industrialized countries. Epidemiologic studies suggest that high dietary fat intake is a risk factor for the development and progression of both vascular and retinal disease. These, and other associations, suggest a hypothesis linking elevated cholesterol and AMD progression. It follows, therefore, that cholesterol-lowering medications, such as statins, may influence the onset and progression of AMD. However, the findings have been inconclusive as to whether statins play a role in AMD. Due to the significant public health implications of a potential inhibitory effect of statins on the onset and progression of AMD, it is important to continually evaluate emerging findings germane to this question.

背景与目标： : 年龄相关性黄斑变性 (AMD) 是工业化国家65岁以上患者不可逆的中枢视力丧失的主要原因。流行病学研究表明，高饮食脂肪摄入量是血管和视网膜疾病发生和发展的危险因素。这些以及其他关联表明，胆固醇升高与AMD进展相关的假说。因此，降胆固醇药物，如他汀类药物，可能会影响AMD的发病和进展。然而，对于他汀类药物是否在AMD中发挥作用，研究结果尚无定论。由于他汀类药物对AMD发病和进展的潜在抑制作用对公共健康的重大影响，因此不断评估与该问题密切相关的新兴发现非常重要。

BACKGROUND & AIMS: :Hypertension and hyperlipidemia, two powerful risk factors of cardiovascular disease (CVD), often coexist. Therefore, treatment should consider the beneficial properties of drugs used to treat either condition. Statins, the mainstay of lipid-lowering therapy, result in a significant clinical benefit both in primary and secondary CVD prevention. In addition to their hypolipidemic capacity, other properties may contribute to statin-induced benefits. Clinical and experimental evidence indicates that statins may modulate blood pressure (BP). The mechanisms by which statins reduce BP seem to be largely independent of their lipid effects. Although small, reductions in BP are possibly clinically relevant. Large landmark studies confirm that statins can reduce CVD risk in hypertensive patients. These findings suggest that statins could be prescribed as an adjunct in treating hypertension with dyslipidemia or even in patients with "normal" cholesterol levels. Whether the effect of statins on BP is accompanied by an additional decrease in clinical outcomes needs to be investigated in long-term, large-scale trials.

背景与目标： 高血压和高脂血症是心血管疾病 (CVD) 的两个重要危险因素，通常并存。因此，治疗应考虑用于治疗任何一种疾病的药物的有益特性。他汀类药物是降脂治疗的主要手段，在原发性和继发性CVD预防中均具有显着的临床益处。除了降血脂能力外，其他特性可能有助于他汀类药物诱导的益处。临床和实验证据表明，他汀类药物可能调节血压 (BP)。他汀类药物降低血压的机制似乎在很大程度上与其脂质作用无关。尽管血压降低幅度很小，但可能与临床相关。大型标志性研究证实，他汀类药物可以降低高血压患者的CVD风险。这些发现表明，他汀类药物可以作为治疗血脂异常的高血压甚至胆固醇水平正常的患者的辅助药物。他汀类药物对血压的影响是否伴随着临床结局的额外降低，需要在长期的大规模试验中进行研究。

BACKGROUND & AIMS: BACKGROUND:There is an increasing body of evidence to support the benefits of reducing low-density lipoprotein cholesterol (LDL-C) levels and this has been reflected in a lowering of LDL-C goals recommended by international guidelines. Therefore, there is a growing need for effective lipid-modifying therapies to optimise the achievement of these more stringent LDL-C goals. OBJECTIVE:A meta-analysis of data pooled from five studies participating in the DISCOVERY (DIrect Statin COmparison of LDL-C Values: an Evaluation of Rosuvastatin therapY) Programme was performed to compare the effect of rosuvastatin treatment with other statins in real-life clinical practice. RESULTS:These studies included 6743 patients with hypercholesterolaemia from different ethnicities, countries and cultural environments. The meta-analysis showed that significantly more patients receiving rosuvastatin 10 mg achieved the 2003 European LDL-C goals compared with those who received atorvastatin 10 mg or simvastatin 20 mg (p < 0.001 for both comparisons). A significantly greater proportion of patients receiving rosuvastatin 10 mg also achieved the 2003 European total cholesterol goal compared with those on atorvastatin 10 mg (p < 0.001). CONCLUSIONS:The meta-analysis showed that rosuvastatin was more effective than comparator statins at lowering LDL-C levels and enabling patients to achieve lipid goals at recommended start doses. In addition, all statins studied were well tolerated and confirmed that rosuvastatin had a similar safety profile to other statins.

背景与目标：

BACKGROUND & AIMS: :Background Whether use of high-intensity statins is more important than achieving low-density lipoprotein cholesterol ( LDL -C) target remains controversial in patients with coronary artery disease. We sought to investigate the association between statin intensity and long-term clinical outcomes in patients achieving treatment target for LDL -C after percutaneous coronary intervention. Methods and Results Between February 2003 and December 2014, 1746 patients who underwent percutaneous coronary intervention and achieved treatment target for LDL -C (<70 mg/dL or >50% reduction from baseline level) were studied. We classified patients into 2 groups according to an intensity of statin prescribed after index percutaneous coronary intervention: high-intensity statin group (atorvastatin 40 or 80 mg, and rosuvastatin 20 mg, 372 patients) and non-high-intensity statin group (the other statin treatment, 1374 patients). The primary outcome was a composite of cardiac death, myocardial infarction, or stroke. Difference in time-averaged LDL -C during follow-up was significant, but small, between the high-intensity statin group and non-high-intensity statin group (59±13 versus 61±12 mg/dL; P=0.04). At 5 years, patients receiving high-intensity statins had a significantly lower incidence of the primary outcome than those treated with non-high-intensity statins (4.1% versus 9.9%; hazard ratio, 0.42; 95% confidence interval, 0.23-0.79; P<0.01). Results were consistent after propensity-score matching (4.2% versus 11.2%; hazard ratio, 0.36; 95% confidence interval, 0.19-0.69; P<0.01) and across various subgroups. Conclusions Among patients achieving treatment target for LDL -C after percutaneous coronary intervention, high-intensity statins were associated with a lower risk of major adverse cardiovascular events than non-high-intensity statins despite a small difference in achieved LDL -C level.

背景与目标： 背景: 在冠心病患者中，使用高强度他汀类药物是否比实现低密度脂蛋白胆固醇 (ldl-c) 目标更重要仍存在争议。我们试图调查在经皮冠状动脉介入治疗后达到ldl-c治疗目标的患者中，他汀类药物强度与长期临床结局之间的关系。方法和结果在2003年2月和2014年12月中，对1746例接受经皮冠状动脉介入治疗并达到ldl-c治疗目标 (低于基线水平 <70 mg/dL或> 50%) 的患者进行了研究。我们根据经皮冠状动脉介入治疗后规定的他汀的强度将患者分为2组: 高强度他汀组 (阿托伐他汀40或80 mg，瑞舒伐他汀20 mg，372例患者) 和非高强度他汀组 (其他他汀治疗，1374例患者)。主要结局是心源性死亡、心肌梗死或卒中的复合结局.在高强度他汀组和非高强度他汀组之间，随访期间的时间平均ldl-c差异是显着的，但很小 (59 ± 13对61 ± 12 mg/dL; P = 0.04)。在5年时，接受高强度他汀类药物治疗的患者的主要结局发生率明显低于非高强度他汀类药物治疗的患者 (4.1% 与9.9%; 风险比，0.42; 95% 置信区间，0.23-0.79; P<0.01)。在倾向评分匹配 (4.2% 与11.2%; 风险比，0.36; 95% 置信区间，0.19-0.69; P<0.01) 和不同亚组之间的结果一致。结论在经皮冠状动脉介入治疗后达到ldl-c治疗目标的患者中，高强度他汀类药物的主要不良心血管事件风险低于非高强度他汀类药物，尽管ldl-c水平差异很小。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are a well-known class of drug with beneficial therapeutic effects in cardiovascular disease and lipid disorders and have potential use against cancer. However, the bioavailability of statins is hampered due to low aqueous solubility and rapid metabolism. To improve pharmacokinetic profiles of statins, development of drug delivery systems is promising. Hence, the use of liposomes for selective delivery of statins to a selected site or for bioavailability enhancement is an effective strategy to increase statin therapeutic effects. Moreover, liposomal delivery can reduce the required dose of statins especially in terms of antitumor effects. Liposomes, because of their unique properties and biphasic and amphiphilic nature, have attracted much interest and can be considered as a suitable choice for delivery of both hydrophilic and lipophilic statins. In this review article, we focus on liposomes and evaluate the effects of different liposomal delivery systems, based on differences in size, phospholipid composition, circulation half-life, and cholesterol content, on statin function.

背景与目标： : 他汀类药物是3-羟基-3-甲基戊二酰辅酶a还原酶的抑制剂，是一类著名的药物，在心血管疾病和脂质疾病中具有有益的治疗作用，并且具有潜在的抗癌用途。然而，由于低水溶性和快速代谢，他汀类药物的生物利用度受到阻碍。为了改善他汀类药物的药代动力学特征，药物递送系统的开发是有希望的。因此，使用脂质体将他汀类药物选择性递送至选定部位或增强生物利用度是增加他汀类药物治疗效果的有效策略。此外，脂质体递送可以减少他汀类药物的所需剂量，尤其是在抗肿瘤作用方面。脂质体由于其独特的特性以及双相和两亲性而引起了人们的极大兴趣，可以被认为是递送亲水性和亲脂性他汀类药物的合适选择。在这篇综述文章中，我们专注于脂质体，并基于大小，磷脂组成，循环半衰期和胆固醇含量的差异，评估不同脂质体递送系统对他汀类药物功能的影响。

BACKGROUND & AIMS: :Although elderly patients represent a rapidly growing population often requiring multiple drug treatment, the evidence of effectiveness is limited for many interventions and therapies in this age group. Only during the last 30 years has a requirement to incorporate evidence into the treatment of older subjects become part of the pre- and postmarketing regulatory process in Europe and the United States. Recently, elderly patients have been shown to benefit comparably from several treatments. These studies have supported the validity of an increasingly interventional approach to disorders common in late life. However, an important issue is the applicability of the growing body of clinical trials to 'real life' patients. This is particularly true in very old (i.e. >80 years) patients and those with significant comorbidities. We review the current evidence and controversies related to the effectiveness and safety of several therapeutic strategies in cardiovascular disease (i.e. statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-adrenoceptor blockers, and thrombolytic agents) and bone health (i.e. vitamin D and bisphosphonates).

背景与目标： : 尽管老年患者是一个快速增长的人群，经常需要多种药物治疗，但该年龄段的许多干预措施和疗法的有效性证据有限。只有在过去的30年中，才需要将证据纳入老年受试者的治疗中，这成为欧洲和美国上市前和上市后监管过程的一部分。最近，老年患者已被证明从几种治疗中受益。这些研究支持了对晚年常见疾病的日益介入的方法的有效性。然而，一个重要的问题是越来越多的临床试验对 “现实生活” 患者的适用性。在非常老 (即> 80岁) 的患者和有严重合并症的患者中尤其如此。我们回顾了与心血管疾病 (即他汀类药物，血管紧张素转化酶抑制剂，血管紧张素受体阻滞剂，β-肾上腺素受体阻滞剂和血栓溶解剂) 和骨骼健康 (即维生素d和双膦酸盐) 的有效性和安全性相关的当前证据和争议。

BACKGROUND & AIMS: BACKGROUND:Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate the potential role of statins as immunomodulators in MS, the authors studied their immunologic effects in vitro and compared them to interferon (IFN)beta-1b.

METHODS:Peripheral blood mononuclear cells (PBMC) obtained from untreated or IFN beta-1-treated patients with relapsing-remitting MS or from healthy donors (HD) and T cells were stimulated with concanavalin A, phytohemagglutinin, or antibody to CD3 in the presence of lovastatin, simvastatin, mevastatin, IFN beta-1b, or statins plus IFN beta-1b. The authors analyzed proliferative activity of T cells and B cells, cytokine production and release, activity of matrix metalloproteinases (MMP), and surface expression of activation markers, adhesion molecules, and chemokine receptors on both T and B cells.

RESULTS:All three statins inhibited proliferation of stimulated PBMC in a dose-dependent manner, with simvastatin being the most potent, followed by lovastatin and mevastatin. IFN beta-1b showed a similar effect; statins and IFN beta-1b together added their inhibitory potentials. Furthermore, statins reduced the expression of activation-induced adhesion molecules on T cells, modified the T helper 1/T helper 2 cytokine balance, reduced MMP-9, and downregulated chemokine receptors on both B and T cells. Besides strong anti-inflammatory properties, statins also exhibited some proinflammatory effects.

CONCLUSIONS:Statins are effective immunomodulators in vitro that merit evaluation as treatment for MS.

背景与目标： 背景: 最近的数据表明他汀类药物可能是有效的免疫调节剂。为了评估他汀类药物在MS中作为免疫调节剂的潜在作用，作者研究了它们在体外的免疫作用，并将其与干扰素 (IFN)beta-1b进行了比较。
方法 : 在洛伐他汀，辛伐他汀，美伐他汀，干扰素beta-1b，或他汀类药物加IFN beta-1b。作者分析了T细胞和b细胞的增殖活性，细胞因子的产生和释放，基质金属蛋白酶 (MMP) 的活性以及活化标志物，粘附分子的表面表达，T细胞和b细胞上的趋化因子受体。结果: 三种他汀类药物均以剂量依赖性方式抑制受刺激的PBMC的增殖，辛伐他汀最有效，其次是洛伐他汀和美伐他汀。IFN beta-1b显示出相似的效果; 他汀类药物和干扰素beta-1b共同增加了它们的抑制潜力。此外，他汀类药物降低了活化诱导的T细胞粘附分子的表达，改善了T辅助1/T辅助2细胞因子平衡，降低了MMP-9，并下调了B和T细胞的趋化因子受体。除了强大的抗炎特性，他汀类药物还表现出一些促炎作用。
结论 : 他汀类药物是体外有效的免疫调节剂，值得评估作为MS的治疗方法。

BACKGROUND & AIMS: OBJECTIVE:Dysregulation of the blood-brain barrier (BBB) and transendothelial migration of immune cells are among the earliest central nervous system changes partaking in lesion formation in both multiple sclerosis (MS) and its early clinical form, the clinically isolated syndrome. Evidence for the anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors within the central nervous system arose from studies demonstrating that statins improve clinical signs in the animal model of MS and reduce the number of gadolinium-enhancing lesions in MS. METHODS:We sought to describe the impact of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor treatment on the physiology and immunology of human BBB-derived endothelial cells (ECs). RESULTS:We demonstrate that lovastatin and simvastatin induce a 50 to 60% reduction in the diffusion rates of bovine serum albumin and [(14)C]-sucrose across human BBB-ECs in vitro through abrogation of isoprenylation processes, but independent of the expression of the tight junction molecules occludin, VE-cadherin, JAM-1, zonula occluden-1, and zonula occluden-2. Simvastatin and lovastatin were equipotent in reducing BBB permeability in vitro, with median effective concentration (EC(50)) of 9.5 x 10(-8) and 1.0 x 10(-7)M, respectively. We further demonstrate that lovastatin and simvastatin treatment of BBB-ECs significantly restricts the migration of clinically isolated syndrome-derived and MS-derived monocytes and lymphocytes across the human BBB in vitro, through a specific reduction in the secretion of the chemokines monocyte chemotactic protein-1/CCL2 and interferon-gamma-inducible protein-10/CXCL10 by BBB-ECs. INTERPRETATION:Our data parallel the previously reported magnetic resonance imaging-based radiological findings and suggest an effect of statins that could be beneficial in early MS, restricting the diffusion of molecular tracers and the migration of immune cells across the human BBB.

背景与目标：

BACKGROUND & AIMS: :Age-related macular degeneration (AMD) is a leading cause of blindness worldwide for which preventative therapies are few. Evidence suggesting shared common risk factors and mirrored pathophysiology between cardiovascular disease and AMD led to the hypothesis that hydroxymethylglutaryl-CoA reductase inhibitors (statins) could be helpful in preventing AMD. For over a decade, observational studies have repeatedly investigated this hypothesis with conflicting conclusions. Although many reports conclude that statin use has no effect on the risk of AMD, no randomized controlled trial has yet been completed. Furthermore, relatively few studies factor characteristics of statin use into their analysis. A few studies have observed an incompletely explained protective effect against drusen, a funduscopic finding associated with AMD. Although there is insufficient evidence for a preventive effect of statins on dry AMD, there does seem to be stronger evidence against any effect on the development of exudative AMD. Overall, we find that there is insufficient evidence to conclude whether statin use is helpful in preventing AMD.

背景与目标： : 年龄相关性黄斑变性 (AMD) 是世界范围内失明的主要原因，预防疗法很少。有证据表明心血管疾病和AMD之间存在共同的危险因素和镜像的病理生理学，导致了以下假设: 羟甲基戊二酰辅酶a还原酶抑制剂 (他汀类药物) 可能有助于预防AMD。十多年来，观察性研究反复研究了这一假设，结论相互矛盾。尽管许多报告得出结论，他汀类药物的使用对AMD的风险没有影响，但尚未完成随机对照试验。此外，在分析中使用他汀类药物的因素特征的研究相对较少。一些研究已经观察到对玻璃疣的保护作用不完全解释，玻璃疣是与AMD相关的眼底镜发现。尽管没有足够的证据证明他汀类药物对干性AMD的预防作用，但似乎确实有更有力的证据证明对渗出性AMD的发展有任何影响。总体而言，我们发现没有足够的证据来断定他汀类药物的使用是否有助于预防AMD。

BACKGROUND & AIMS: :Lipophilic statins purportedly exert anti-tumoral effects on breast cancer by decreasing proliferation and increasing apoptosis. HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, is the target of statins. However, data on statin-induced effects on HMGCR activity in cancer are limited. Thus, this pre-operative study investigated statin-induced effects on tumor proliferation and HMGCR expression while analyzing HMGCR as a predictive marker for statin response in breast cancer treatment. The study was designed as a window-of-opportunity trial and included 50 patients with primary invasive breast cancer. High-dose atorvastatin (i.e., 80 mg/day) was prescribed to patients for 2 weeks before surgery. Pre- and post-statin paired tumor samples were analyzed for Ki67 and HMGCR immunohistochemical expression. Changes in the Ki67 expression and HMGCR activity following statin treatment were the primary and secondary endpoints, respectively. Up-regulation of HMGCR following atorvastatin treatment was observed in 68 % of the paired samples with evaluable HMGCR expression (P = 0.0005). The average relative decrease in Ki67 expression following atorvastatin treatment was 7.6 % (P = 0.39) in all paired samples, whereas the corresponding decrease in Ki67 expression in tumors expressing HMGCR in the pre-treatment sample was 24 % (P = 0.02). Furthermore, post-treatment Ki67 expression was inversely correlated to post-treatment HMGCR expression (rs = -0.42; P = 0.03). Findings from this study suggest that HMGCR is targeted by statins in breast cancer cells in vivo, and that statins may have an anti-proliferative effect in HMGCR-positive tumors. Future studies are needed to evaluate HMGCR as a predictive marker for the selection of breast cancer patients who may benefit from statin treatment.

背景与目标： 亲脂性他汀类药物据称通过减少增殖和增加细胞凋亡对乳腺癌发挥抗肿瘤作用。HMG-CoA还原酶 (HMGCR) 是甲羟戊酸途径的限速酶，是他汀类药物的靶标。然而，关于他汀类药物对癌症中HMGCR活性的影响的数据有限。因此，这项术前研究调查了他汀类药物对肿瘤增殖和HMGCR表达的影响，同时分析了HMGCR作为他汀类药物在乳腺癌治疗中反应的预测指标。该研究被设计为机会之窗试验，包括50名原发性浸润性乳腺癌患者。大剂量阿托伐他汀 (即80 mg/天) 在手术前给患者服用2周。分析他汀类药物配对前后的肿瘤样本的Ki67和HMGCR免疫组织化学表达。他汀类药物治疗后Ki67表达和HMGCR活性的变化分别是主要终点和次要终点。在68% 具有可评估的HMGCR表达的配对样品中观察到阿托伐他汀治疗后HMGCR的上调 (P = 0.0005)。在所有配对样品中，阿托伐他汀治疗后Ki67表达的平均相对降低为7.6% (P = 0.39)，而在治疗前样品中表达HMGCR的肿瘤中Ki67表达的相应降低为24% (P = 0.02)。此外，治疗后Ki67表达与治疗后HMGCR表达呈负相关 (rs = -0.42; P = 0.03)。这项研究的结果表明，HMGCR在体内被他汀类药物靶向于乳腺癌细胞，并且他汀类药物可能在HMGCR阳性肿瘤中具有抗增殖作用。需要进一步的研究来评估HMGCR作为选择可能从他汀类药物治疗中受益的乳腺癌患者的预测指标。

BACKGROUND & AIMS: :We investigated the effect of statins and statins plus ezetimibe in 65 FH heterozygotes carrying LDLR-defective or LDLR-negative mutations as well as the effect of ezetimibe monotherapy in 50 hypercholesterolemic (HCH) patients intolerant to statins. PCSK9 and NPC1L1 genes were analysed to assess the role of genetic variants in response to therapy. In FH patients combined therapy reduced LDL-C by 57%, irrespective of the type of LDLR mutation. The additional decrease of plasma LDL-C induced by ezetimibe showed wide inter-individual variability (from -39% to -4.7%) and was negatively correlated with percent LDL-C decrease due to statin alone (r=-0.713, P<0.001). The variable response to statins was not due to PCSK9 gene variants associated with statin hyper-sensitivity. The highest response to ezetimibe was observed in a carrier of R174H substitution in NPC1L1, which had been found to be associated with high cholesterol absorption. In HCH patients, ezetimibe monotherapy induced a variable decrease of plasma LDL-C (from -47.7% to -13.4%). To investigate this variability, we sequenced NPC1L1 gene in patients with the highest and the lowest response to ezetimibe. This analysis showed a higher prevalence of the G allele of the c.816 C>G polymorphism (L272L) in hyper-responders, an observation confirmed also in FH patients hyper-responders to ezetimibe. In both FH and HCH patients, the G allele carriers tended to have a higher LDL-C reduction in response to ezetimibe. These observations suggest that in FH heterozygotes LDL-C reduction following combined therapy reflects a complex interplay between hepatic synthesis and intestinal absorption of cholesterol.

背景与目标： : 我们研究了他汀类药物和他汀类药物加依泽替米布在65例携带LDLR缺陷或LDLR阴性突变的FH杂合子中的作用，以及依泽替米布单药治疗对50例不耐受他汀类药物的高胆固醇血症 (HCH) 患者的作用。分析PCSK9和NPC1L1基因以评估遗传变异在治疗反应中的作用。在FH患者中，联合治疗使ldl-c降低了57%，而与LDLR突变的类型无关。依泽替米布诱导的血浆ldl-c的额外降低显示出广泛的个体间变异性 (从-39% 到-4.7%)，并且与单独使用他汀类药物导致的ldl-c降低百分比呈负相关 (r =-0.713，P<0.001)。对他汀类药物的可变反应不是由于与他汀类药物超敏相关的PCSK9基因变异所致。在NPC1L1的R174H取代载体中观察到对依折麦布的最高响应，已发现这与高胆固醇吸收有关。在HCH患者中，依折替米布单药治疗引起血浆ldl-c的可变降低 (从-47.7% 到-13.4%)。为了研究这种变异性，我们对对依折替米布反应最高和最低的患者进行了NPC1L1基因测序。该分析表明，在高反应者中c.816 C>G多态性 (L272L) 的G等位基因的患病率更高，在FH患者中对依折替米布的高反应中也证实了这一观察结果。在FH和HCH患者中，G等位基因携带者对依折替米布的反应往往具有更高的ldl-c降低。这些观察结果表明，在FH杂合子中，联合治疗后ldl-c的降低反映了肝脏合成与肠道胆固醇吸收之间的复杂相互作用。