稳定型冠心病患者未干预血脂谱的横断面研究

目的评价冠心病患者未干预情况下的血脂谱,探讨冠心病的预测因素。方法入选1772例临床怀疑冠心病并且未服用调脂药的患者进行冠状动脉造影检查,其中1057例被诊断为冠心病,715例无冠心病。分析并比较两组患者的血脂谱。分析血脂水平和冠心病的相关性。结果冠心病患者的血脂谱如下:甘油三酯1.78mmol/L(1.29~2.43 mmol/L)、总胆固醇(TC)4.92±0.99 mmol/L、高密度脂蛋白胆固醇(HDLC)1.09±0.29 mmol/L、低密度脂蛋白胆固醇(LDLC)3.22±0.91 mmol/L。冠心病患者中LDLC和非HDLC都能达标者(LDLC1.81 mmol/L+非HDLC2.59 mmol/L)仅占2.46%。在50~59岁、60~69岁、≥70岁亚组中,男性患者TC、HDLC、载脂蛋白A1(Apo A1)和Apo B水平显著低于女性(均P0.05)。Apo B/Apo A1是冠心病的最强预测因子。结论未服用调脂药的冠心病患者中血脂水平升高,其中大部分都存在轻度或中度血脂异常,血脂达标率很低,而且女性血脂异常程度更严重。非HDLC、Apo B、LDLC/HDLC和Apo B/Apo A1与冠心病相关性好,可以预测冠心病风险。     

非高密度脂蛋白胆固醇与冠状动脉病变严重程度的相关性

目的观察冠状动脉粥样硬化性心脏病(CHD)患者非高密度脂蛋白胆固醇与冠状动脉病变严重程度的相关性,及其预测严重冠状动脉狭窄的能力。方法收集843例CHD患者,根据冠状动脉造影结果将患者分为单支、双支、三支病变组,用Gensini积分评估患者冠状动脉病变狭窄严重程度并按积分四分位数分成Q1～Q4组共4组,分别比较各组间血脂参数差异。用Spearman相关系数分析患者低密度脂蛋白胆固醇(LDLC)、非高密度脂蛋白胆固醇(non-HDLC)、总胆固醇/高密度脂蛋白胆固醇(TC/HDLC)、甘油三酯/高密度脂蛋白胆固醇(TG/HDLC)与Gensini积分的关系。采用受试者工作特征曲线(ROC)和多因素Logistic回归评价LDLC、non-HDLC、TC/HDLC、TG/HDLC预测严重冠状动脉狭窄的能力。结果患者LDLC、non-HDLC、TC/HDLC水平随Gensini积分增高显著增加(P均0.05),Q4组TG/HDLC显著高于Q1和Q2组(P均0.05)。LDLC、non-HDLC、TC/HDLC水平随冠状动脉病变支数增加显著增加(P均0.05),TG/HDLC在各组间差异无显著性。non-HDLC与Gensini积分(r=0.315,P0.01)相关性高于LDLC(r=0.252,P0.01)、TC/HDLC(r=0.242,P0.01)、TG/HDLC(r=0.123,P0.01)。non-HDLC预测高Gensini积分的ROC曲线下面积是0.729(95%Cl 0.691～0.767,P0.01),分别大于LDLC的0.694(95%Cl 0.653～0.734,P0.01)、TC/HDLC的0.681(95%Cl 0.640～0.721,P0.01)、TG/HDLC的0.564(95%Cl 0.521～0.607,P0.01)。用多因素Logistic回归校正冠心病危险因素后,non-HDLC(OR=2.472, 95%Cl 1.962～3.115)预测严重冠状动脉病变的能力轻微优于LDLC(OR=2.265, 95%Cl 1.785-2.875)、TC/HDLC(OR=1.796, 95%Cl 1.483～2.175)、TG/HDLC(OR=1.022, 95%Cl 0.927～1.127)。结论 non-HDLC在预测严重冠状动脉病变方面优于LDLC、TC/HDLC、TG/HDLC,有助于对CHD患者的危险分层。     

急性冠状动脉综合征患者non-HDLC/HDLC比值与颈动脉斑块的关系

目的探讨急性冠状动脉综合征(ACS)患者non-HDLC/HDLC比值与颈动脉斑块之间的关系。方法选择95例ACS患者、30例稳定型心绞痛(SAP)患者及49例无冠心病者,按照颈动脉超声检查结果将颈动脉斑块分为软斑块、纤维斑块和钙化斑块三种类型。酶法测定血清低密度脂蛋白胆固醇(LDLC)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDLC)水平,并计算non-HDLC/HDLC比值。结果与无冠心病组和SAP组比较,ACS组non-HDLC/HDLC比值升高(P0.05或P0.01);与无冠心病组比较,ACS组HDLC水平降低(P0.05);与SAP组比较,ACS组non-HDLC水平升高(P0.05)。与无冠心病组比较,ACS组颈动脉斑块发生率升高(P0.001);与无冠心病组和SAP组比较,ACS组软斑块发生率升高,纤维斑块发生率降低(P0.05或P0.01)。ACS患者钙化斑块组、纤维斑块组和软斑块组non-HDLC水平、non-HDLC/HDLC比值依次升高,且钙化斑块组与软斑块组间non-HDLC水平、non-HDLC/HDLC比较差异显著(P0.05或P0.01)。non-HDLC水平、non-HDLC/HDLC比值对ACS患者颈动脉软斑块诊断的ROC曲线下面积分别为0.722±0.060(95%CI为0.604~0.841,P0.01)、0.669±0.062(95%CI为0.548~0.790,P0.01)。结论 non-HDLC/HDLC比值升高是ACS患者发生软斑块的危险因素。non-HDLC/HDLC比值可作为ACS患者颈动脉软斑块的预测指标。     

调脂胶囊对小鼠血脂异常的预防作用

目的观察调脂胶囊对血脂异常的作用。方法随机将小鼠分为正常组、模型组、血脂康胶囊组、调脂胶囊高、低剂量治疗组。调脂胶囊高、低剂量组分别按16、8g/kg剂量(按体表面积折算,分别约相当于成人临床推荐日口服剂量的28.8、14.4倍),每天灌胃一次;血脂康胶囊组按8g/kg剂量灌胃血脂康胶囊;正常组和模型组灌胃等体积蒸馏水,各组自由饮水。共30d。观察不同时间点的小鼠血清血脂、体重及动脉硬化指数(AI)。结果随着时间的延长,调脂胶囊高、低剂量组均能够阻止血清总胆固醇(TC)和体重进一步升高的趋势,与模型组相比具有显著差异(P0.05)。饲喂高脂饲料30d后,模型组小鼠血清TC、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)水平与正常对照组比较差异显著(P0.01),形成血脂异常动物模型。调脂胶囊高、低剂量组小鼠血清TG、LDL-C与模型组比较均显著降低(P0.01,P0.05),调脂胶囊高剂量组小鼠血清HDL-C升高明显(P0.05)。与血脂康胶囊组比较,调脂胶囊高剂量组升高HDL-C的作用差异有显著性(P0.05)。高脂模型组与正常组比较AI显著升高,HDL-C/TC值显著降低(P0.05),调脂胶囊组AI显著低于高脂饲料组(P0.01)。调脂胶囊高、低剂量组,血脂康胶囊组均能显著升高HDL-C/TC值,且调脂胶囊高剂量组更为明显(P0.05)。结论调脂胶囊在预防血脂异常的发生、抗动脉粥样硬化、减轻体重方面效果显著,是一个理想的调血脂新药。     

瑞舒伐他汀对高脂饲养大鼠心肌脂联素及其受体表达的影响

目的　探讨瑞舒伐他汀对高脂饲养大鼠心肌脂联素及其受体mRNA和蛋白表达的影响。方法　8周龄Wistar大鼠48只,随机分为对照组、高脂饲养组、高脂饲养＋瑞舒伐他汀组,20周后,全自动生化分析仪测定血清甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDLC）、高密度脂蛋白胆固醇（HDLC）、血糖,ELISA测定血清脂联素,RT-qPCR和　Western　blot测定心肌组织脂联素及其受体　mRNA和蛋白的表达。结果　与对照组相比,高脂饲养组大鼠血清TG、TC、LDLC、血糖、脂联素升高（P＜0.01）,HDLC降低（P＜0.01）。与高脂饲养组相比,高脂饲养＋瑞舒伐他汀组血清TG、TC、LDLC、脂联素降低（P＜0.05）,　HDLC升高（P＜0.01）,血糖无明显差异（P＞0.05）。与对照组相比,高脂饲养组心肌脂联素mRNA和蛋白表达升高（P＜0.01）,心肌脂联素受体mRNA和蛋白表达降低（P＜0.05）。与高脂饲养组相比,高脂饲养＋瑞舒伐他汀组心肌脂联素mRNA和蛋白表达降低（P＜0.05）,心肌脂联素受体1　mRNA和蛋白表达升高（P＜0.05）,心肌脂联素受体2　mRNA和蛋白表达无明显差异（P＞0.05）。结论　高脂饲养大鼠过程中,可出现血清脂联素升高,心肌脂联素mRNA和蛋白表达上调,心肌脂联素受体mRNA和蛋白表达下调,瑞舒伐他汀可以部分逆转这些作用。     

类风湿关节炎患者血脂紊乱特点及与疾病活动的关系

目的探讨类风湿性关节炎(RA)患者血脂紊乱特点及与疾病活动的相关性。方法选择RA患者62例作为研究对象(RA组),年龄、性别匹配的健康体检者46例为对照组。根据疾病是否处于活动期,将RA组分为活动期RA组和非活动期RA组。记录一般情况及传统心血管病危险因素,计算体质指数,测量收缩压、舒张压,检测血清中甘油三酯、总胆固醇(TC)、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇(HDLC)、高敏C反应蛋白(hsCRP)及红细胞沉降率(ESR)。比较各组血脂、hs-CRP、ESR差异。用Pearson直线相关分析法分析RA患者血脂与hs-CRP、ESR的相关性。结果 RA组体质指数显著高于对照组(P0.05)。血清TC水平活动期RA组、非活动期RA组显著高于对照组(P0.05);血清HDLC水平活动期RA组显著低于非活动期RA组、对照组(P0.01),非活动期RA组显著低于对照组(P0.01);TC/HDLC比值活动期RA组显著高于非活动期RA组、对照组(P0.01),非活动期RA组显著高于对照组(P0.05)。RA患者血清HDLC水平与hs-CRP、ESR呈负相关(r=-0.532,P=0.000;r=-0.508,P=0.000),TC/HDLC与hs-CRP、ESR呈正相关(r=0.321,P=0.001;r=0.246,P=0.030)。结论 RA患者血脂代谢紊乱以HDLC降低为主,活动期RA患者血清HDLC水平显著降低,并与RA疾病活动密切相关。     

非HDLC/HDLC与2型糖尿病患者早期颈动脉斑块的相关性

目的评价非高密度脂蛋白胆固醇/高密度脂蛋白胆固醇(非HDLC/HDLC)等血脂指标与2型糖尿病患者早期颈动脉斑块发生的相关性。方法回顾性分析1021例无心脑血管疾病病史的2型糖尿病患者。B超判断颈动脉斑块及测量斑块面积。比较颈动脉斑块组与无斑块组的基本资料、糖尿病病程、糖化血红蛋白、非HDLC/HDLC等血脂比值指标。分析不同血脂指标与颈动脉斑块的相关性。受试者作业特征曲线(ROC)分析非HDLC/HDLC等血脂指标对颈动脉斑块的预测价值。在斑块组,评价非HDLC/HDLC等血脂指标与斑块面积的相关性。结果斑块组男性比率、年龄、糖尿病病程、收缩压、非HDLC、非HDL/HDLC、总胆固醇(TC)/HDLC和LDLC/HDLC显著高于无斑块组,但斑块组的HDLC水平显著低于无斑块组,上述差异有统计学意义(P<0.05)。Logistc回归分析示调整混杂因素后非HDLC水平、非HDLC/HDLC、TC/HDLC和LDLC/HDLC分别是颈动脉斑块的独立危险因素(P<0.05)。LDLC水平在调整混杂因素后与颈动脉斑块无相关性。将非HDLC/HDLC与其他血脂指标的ROC曲线下面积进行比较:非HDLC/HDLC高于LDLC/HDLC、TC/HDLC,但差异接近有统计学意义(P值分别为0.052和0.058)。非HDLC/HDLC显著高于非HDLC和LDLC(P均<0.001)。在斑块组,多元回归分析显示非HDLC/HDLC和LDLC/HDLC是斑块面积的独立影响因子(P<0.05),而非HDLC和TC/HDLC在调整混杂因素后与斑块面积无相关性。结论非HDLC/HDLC是评估2型糖尿病患者早期颈动脉斑块的良好血脂指标。     

载脂蛋白C3基因rs5128多态性与不同体质指数冠心病患者血脂水平及冠状动脉狭窄程度的相关性

目的探讨中国汉族人群载脂蛋白C3(ApoC3)基因rs5128多态性与不同体质指数(BMI)冠心病(CHD)患者血脂水平及冠状动脉狭窄程度的相关性。方法根据BMI将312例CHD患者分为正常体重组(205例)和超重/肥胖组(107例)。收集所有患者的生理生化资料和冠状动脉造影数据,采用Gensini评分法评价CHD患者的冠状动脉狭窄程度。提取外周血白细胞DNA并应用聚合酶链反应-限制性片段长度多态性法对ApoC3rs5128多态性分型。结果超重/肥胖组体重、BMI、高血压患病率、甘油三酯(TG)、脂蛋白a、TG/高密度脂蛋白胆固醇(HDLC)、总胆固醇(TC)/HDLC、低密度脂蛋白胆固醇(LDLC)/HDLC和载脂蛋白B100(ApoB100)/载脂蛋白AI(ApoAⅠ)水平高于正常体重组,HDLC和ApoAⅠ水平低于正常体重组(P0.05)。在正常体重组中,G等位基因携带者高血压患病率显著高于CC基因型患者(P0.05);在超重/肥胖组中,G等位基因携带者TG和TG/HDLC水平显著高于CC基因型患者(P0.05)。在正常体重组和超重/肥胖组中,rs5128多态性基因型和等位基因频率在不同冠状动脉狭窄程度亚组中的分布差异无统计学意义(P0.05)。结论在超重/肥胖CHD患者中,rs5128多态性G等位基因与血浆TG和TG/HDLC水平升高显著相关,但与冠状动脉狭窄程度无明显关联。     

高密度脂蛋白颗粒大小与青年冠心病无症状性心肌缺血的关系

目的 探讨高密度脂蛋白(HDL)颗粒大小与青年冠心病无症状性心肌缺血(SMI)的相关性。方法 共纳入469例青年冠心病患者,其中无症状性心肌缺血组194例(SMI组,n=194),有症状性心肌缺血组275例(non-SMI组,n=275)。收集患者的一般资料,检测血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLC)、高密度脂蛋白胆固醇(HDLC)、载脂蛋白A1(ApoA1)水平及相关生化指标。计算HDL颗粒大小的量化指标HDLC/ApoA1,以及相关脂质参数TC/HDLC、non-HDLC、TG/HDLC、LDLC/HDLC。应用多因素Logistic回归分析明确HDL颗粒大小(HDLC/ApoA1)与青年冠心病SMI发生的关系。结果 与non-SMI组比较,SMI组患者血清TC、尿酸、LDLC、LDLC/HDLC、TC/HDLC、non-HDL水平偏低,HDLC、ApoA1、HDLC/ApoA1值更大(均P＜0.05)。相关分析结果显示,HDL颗粒大小(HDLC/ApoA1)与Gensini积分呈负相关(r=－0.405,P＜0.05)。多因素分析显示,HDL颗粒大小(HDLC/ApoA1)是青年冠心病患者SMI的独立预测因子(OR=0.697,95%CI:0.233~0.910,P=0.007)。受试者工作特征曲线显示,以0.36为HDL颗粒大小(HDLC/ApoA1)临界值预测青年冠心病SMI发生的灵敏度为92.1%,特异度为75.5%。结论 HDL颗粒大小(HDLC/ApoA1)与青年冠心病SMI患者冠状动脉病变严重程度呈负相关,对青年冠心病SMI具有较强的预测价值。     

荷叶胶囊对人体血脂异常的调脂作用研究

目的:探讨荷叶水提物对人体血脂异常的调脂作用。方法:从郴州市各类人员体检检出的高脂血症者中,选择符合高血脂诊断标准的自愿者,共90人。随机分成3组,每组30人,即荷叶胶囊组(A组),洛伐他汀组(B组)和对照组(C组)。A组服用荷叶水提物制作的胶囊,4粒/次,3次/d;B组服用洛伐他订,20mg/次,1次/d,C组给予安慰剂;各组均进行健康教育和膳食指导,调脂40天。采用日本产全自动生化分析仪(OLYMPUS-640)测定调脂前、后的血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)水平。结果:A组调脂后血清TC、TG、LDL-C水平明显下降,HDI-C水平明显升高,与调脂前比较有显著差异(P<0.001.<0.001,<0.002,<0.01);B组调脂后TC、TG、LDL-C水平亦明显下降(P<0.001,<0.05,<0,001),与A组无显著差异(P>0.05),但升高HDL-C效果不明显(P>0.05);C组调脂前、后血清TC、TG、LDL-C和HDL-C水平无显著差异(P>0.05),且调脂后的血脂水平明显高于A、B组(P<0.01)。结论;荷叶水提物对人体具较好的调脂作用,且无毒,未发现副作用。     

Quadruple,sequential, and concomitant first-line therapies for H. pylori eradication: a prospective,randomized study

BackgroundCurrent Italian guidelines recommend 10-day bismuth-based or bismuth-free (sequential and concomitant) regimens for first-line H. pylori eradication. However, comparison among these regimens is lacking in our country.AimTo perform a ‘head-to-head’ comparison among these three therapies as first-line treatment for H. pylori eradication in clinical practice.MethodsThis was a prospective, open-label randomized study enrolling consecutive patients diagnosed with H. pylori infection never previously treated. Patients were randomized to receive one of the following 10-day therapies: (a) Bismuth-based therapy: esomeprazole 20 mg b.i.d and Pylera 3 tablets q.i.d; (b) Concomitant therapy: esomeprazole 20 mg plus amoxicyllin 1,000 mg, clarithromycin 500 mg and tinidazole 500 mg (all b.i.d.), and (c) Sequential therapy: esomeprazole 20 mg plus amoxicyllin 1,000 mg for 5 days followed by esomeprazole 20 mg plus clarithromycin 500 mg and tinidazole 500 mg for 5 days (all b.i.d). H. pylori eradication was assessed by using UBT 4-6 weeks after the end of therapy.ResultsOverall, 187 patients were enrolled. The eradication rates achieved with Pylera, concomitant and sequential were 85.2%, 95.2%, and 93.6%, respectively, at intention to treat, and 94.5%, 96.7%, and 95.1% at per protocol analyses, without a statistically significant difference. The incidence of severe side-effects was higher with the bismuth-based therapy than with the two bismuth-free regimens (9.8% vs 1.6%; p = 0.046).ConclusionsBismuth-based and bismuth-free therapies are equally effective for first-line H. pylori eradication. However, bismuth therapy was more frequently interrupted for side-effects than bismuth-free therapies.     

Mutant KRAS is a druggable target for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial–mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.Pancreatic cancer is an aggressive disease that develops in a relatively symptom-free manner and in most cases, is already advanced at the time of diagnosis (1). It has one of the highest fatality rates of all cancers and is one of the leading causes of cancer-related deaths in the Western world (1, 2). Pancreatic ductal adenocarcinoma (PDA) is the most common pancreatic neoplasm, responsible for 95% of pancreatic cancer cases (3). Genetic alterations in the KRAS signaling pathway are involved in over 90% of pancreatic cancer cases (4–6). KRAS mutations were shown to be an early event in the development of pancreatic cancer (5, 7, 8).The most common KRAS mutation of the human pancreas adenocarcinoma is a gain-of-function substitution mutation of glycine at codon 12 to aspartate (G12D) (5, 9–11). Moreover, PDA cancer cell growth was shown to be dependent on the activity of the mutated KRAS (5, 11) and accordingly, silencing KRAS has proven effective in controlling pancreatic cell line proliferation (12). Here, we aimed to harness the advantages of siRNA technology as a therapeutic modality for pancreatic cancer.Parenteral controlled drug delivery systems are used to improve and advance the therapeutic effects of drug treatments by providing optimized local drug concentrations over prolonged periods of time, reduction of side effects, and cost reduction (13). A prominent method of controlling the release rate of a drug in a pharmaceutical dosage is to embed the active agent within a polymeric matrix (14, 15). The polymer must be biocompatible, and in the case of parenteral administration, preferably biodegradable, to avoid the need to remove empty remnants.In the present study, we exploited the slow-release characteristics of the biodegradable polymer matrix, which we named local drug eluter (LODER) for the treatment of solid tumors.     

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

Oncogenic mutations in the BRAF kinase occur in 6–8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF^V600E, but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF^V600E NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF^V600E coupled with expression of an aberrant form of BRAF^V600E that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun–mediated EGFR ligand expression. BRAF^V600E cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF–EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.The discovery of genetic alterations that drive tumor growth in a wide variety of tumor types and the development of targeted therapies acting against these oncogenic drivers have revolutionized the management of many cancer patients (1). Paradigmatic examples of the successful use of oncogene-targeted therapy include the identification and treatment of patients who have EGF receptor (EGFR)-mutant and ALK fusion-positive lung cancer with the tyrosine kinase inhibitors erlotinib and crizotinib, respectively, and of patients who have BRAF^V600E-melanoma with the selective BRAF kinase inhibitor vemurafenib. The clinical success of driver oncogene-targeted therapy arises because of tumor cell oncogene dependence that is established during tumorigenesis, but the mechanistic basis of this dependence remains incompletely understood. Filling this knowledge gap is critical, because the clinical success of driver oncogene-targeted therapies is limited by the almost inevitable escape from oncogene dependence and drug resistance that occur in patients with solid tumors, including lung cancer, the leading cause of cancer mortality worldwide (2, 3). The identification of the signaling events driving resistance provides insights into the molecular mechanisms underlying oncogene dependence and a rationale for mechanism-based polytherapy strategies to subvert resistance in patients (2, 4, 5).The BRAF gene is mutated in ∼7% of human cancers, including melanoma, colorectal, papillary thyroid, and NSCLC (6, 7). The BRAF^V600E variant is the most frequent mutant allele and has been used to match patients genetically to BRAF-inhibitor therapy. The clinical success and approval of the BRAF inhibitors vemurafenib and dabrafenib in BRAF^V600E melanoma have provided a rationale for testing BRAF inhibition in nonmelanoma patients whose tumors harbor BRAF mutations (8–10). The success of such efforts has been limited, with either BRAF-inhibitor treatment or downstream MAPK blockade failing to produce the desired clinical activity in patients with colorectal and thyroid cancers harboring BRAF^V600E; in both cases the failure is caused by intrinsic resistance (11–13). These observations indicate that tumor cell oncogene dependence is context specific and underscore the need to define the molecular events that regulate oncogene dependence in each tumor type to optimize clinical responses.Somatic mutations in BRAF (both V600E and non-V600E variants) are found in 6–8% of NSCLCs, accounting for more than 90,000 deaths annually worldwide. BRAF-mutant NSCLCs frequently harbor the V600E allele (∼55%); additional highly recurrent activating BRAF variants reported in NSCLC include G469A (∼35%) and D594G (∼10%) (14–17). The sensitivity of NSCLC cells across the spectrum of BRAF mutant alleles to BRAF-inhibitor treatment has not been characterized. Despite this uncertainty regarding allelotype specificity, the clinical efficacy of BRAF-inhibitor treatment in BRAF^V600E-melanoma has prompted a clinical trial testing the efficacy of BRAF-inhibitor treatment in patients with BRAF^V600E NSCLC. Given the emerging biological and clinical importance of mutant BRAF and the success (and limitations) of other oncogene-targeted therapies, including EGFR and ALK kinase inhibitors, in NSCLC patients, we sought to define the molecular basis of BRAF oncogene dependence in NSCLC. We investigated and uncovered critical events driving response and resistance to BRAF-inhibitor treatment in models of human BRAF-mutant NSCLC. Our findings provide insight into the regulation of BRAF oncogene dependence and reveal rational strategies for immediate clinical use to enhance patients’ responses to BRAF inhibitors.     

Eradication of Helicobacter pylori infection

Eradication of Helicobacter pylori infection has become an important issue recently, because this bacterial species cluster can cause many gastrointestinal diseases. Elevated antibiotic resistance is related to an increasing failure rate of H. pylori eradication. Standard triple therapy is still the first-line therapy; however, according to the Maastricht IV Consensus Report, it should be abandoned in areas of high clarithromycin resistance. Alternative first-line therapies include bismuth-containing quadruple therapy, sequential, concomitant, and hybrid therapies. Quinolone-based triple therapy may be considered as first-line therapy in areas of clarithromycin resistance >15–20% and quinolone resistance <10%. Unique second-line therapy is still unclear, and bismuth-containing quadruple therapy or levofloxacin-based triple therapy can be used as rescue treatment. Third-line therapy should be under culture guidance to select the most effective regimens (such as levofloxacin-based, rifabutin-based, or furazolidone-based therapies). Antibiotics resistance, patient compliance, and CYP 2C19 genotypes could influence the outcome. Clinicians should use antibiotics according to local reports.     

Treating IPF—all or nothing? A PRO‐CON debate

The Idiopathic Pulmonary Fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis. It is distinct from other idiopathic interstitial pneumonias by its histopathological pattern of usual interstitial pneumonia which is characterized by accumulation of fibroblasts, extracellular matrix and honeycombing. Inflammation is only scarce in true IPF. The use of anti-inflammatory therapy is still part of guidelines for IPF management, although not specifically recommended, because convincing evidence showing beneficial effects of this approach is lacking. This review provides a summary of important arguments PRO and CON using anti-inflammatory and anti-oxidant therapy for patients with IPF in form of a debate with a concluding statement of both positions at the end.     

Endoscopic alcohol injection therapy of giant gastric leiomyomas: an alternative method to surgery

Leiomyomas are the most common benign mesenchymal tumours of the upper gastrointestinal tract. They rarely cause symptoms when they are smaller than 5 cm in diameter. Observation with repeated endoscopies is recommended in asymptomatic patients with small lesions. Surgical resection remains the main therapy option for symptomatic and complicated patients. The treatment of esophageal leiomyoma has been enhanced by improvements in diagnostic and therapeutic endoscopic techniques; however, the same cannot be said for gastric leiomyoma management. The present article describes the management of two cases involving giant gastric leiomyomas that were  successfully treated using endoscopic injection of alcohol. To the authors' knowledge, the present study is the first report of the treatment of such hemorrhagic gastric tumours using this alternative and low-cost technique. Endoscopic local ethanol injection may be the treatment of choice in carefully selected patients with hemorrhagic leiomyomas of the upper gastrointestinal tract.     

The Steroid-Sparing Effect of Long-Term Plasmapheresis in Pemphigus: An Update

Abstract: Glucocorticoids and immunosuppressive agents can induce remission in most pemphigus patients, but mortality remains at 5 to 15% as a result of side effects. We reviewed the adjunctive effect of long-term plasmapheresis in 8 pemphigus patients. Four cases had been resistant to conventional therapy. One or 2 large-volume plasmapheresis treatments were given monthly over 5 to 141 months. All patients, were in clinical remission within 2 months. Relapses seldom occurred: the patients stayed in remission 90% (40–94) (median, ranges) of the period. In all cases the daily dose of glucocorticoid was reduced. The prednisone level could be decreased from 38 (15–80) mg/day to 7.5 (2.5–35) mg/day (p = 0.002). The overall level of other immunosuppressive agents remained unchanged, except in 1 patient for whom cyclosporine was introduced. This indicates that long-term plasmapheresis could have a steroid-sparing effect and clinical efficacy in pemphigus.—     

胰腺癌治疗进展

胰腺癌是高度恶性的消化系统肿瘤，约90%起源于腺管上皮的导管腺癌，其发病率和死亡率近几年明显上升，5年生存率<6%，是预后最差的恶性肿瘤之一。该病早期确诊率较低，手术死亡率较高。男女发病率之比约为(1.5～2)∶1，其治疗方案由单一手术治疗转为多学科综合治疗。近几年内外科治疗方案并无太多新的突破，分子靶向治疗的热度逐年上升，其重要性也越来越引起专家的重视，部分治疗靶点已经应用于临床，并取得可喜的治疗效果。     

四联疗法与序贯疗法在幽门螺杆菌根除补救治疗中的疗效比较

[目的]比较四联疗法与序贯疗法在幽门螺杆菌(Hp)根除补救治疗中的疗效及安全性,旨在寻找一种有效、安全、经济的补救治疗方案。[方法]将首次根除Hp治疗失败的90例慢性胃炎患者,随机分为四联疗法组和序贯疗法组,每组45例。四联疗法组患者治疗方案为埃索美拉唑、枸橼酸铋钾、阿莫西林、莫西沙星,疗程14d。序贯疗法组患者治疗方案为前5d给予埃索美拉唑、阿莫西林;后5d给予埃索美拉唑、克拉霉素、奥硝唑。所有患者在疗程结束停药4周后行14 C尿素呼气试验检测Hp。比较2组患者治疗前后的不良反应。[结果]四联疗法组Hp根除率(91.1%)显著高于序贯疗法组(75.6%),差异有统计学意义(P<0.05)。2组不良反应均很轻微,组间不良反应发生率比较差异无统计学意义(P>0.05)。[结论]对于Hp补救治疗,四联疗法较序贯疗法疗效更好,且不良反应小,患者依从性好,值得在临床上推广。     

肥胖症的药物治疗现状与展望

肥胖是一个严重的公众健康问题，人们迫切希望能有安全、有效的减肥药物。目前用于减肥的药物主要有两类：即西布曲明和赛尼可，前者主要抑制食物的摄取，后者抑制脂肪的吸收。由于对复杂的体重调节机制的认识越来越深入，很多新的减肥药物正在研制过程之中。目前正在研究的具有较大潜力的减肥药物共有30余种，其中研究较多的有瘦素、黑皮质素受体激动剂、神经肽Y拮抗剂、β3肾上腺素能受体激动剂、胰高血糖素样肽－1激动剂以及激活或增加解偶联蛋白表达的药物。