EGFR-TKI治疗T790M突变非小细胞肺癌患者有效时间较短

表皮生长因子受体抑制剂（epidermal growth factor receptorinhibitor,EGFR）T790M突变是酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）治疗后常见的耐药机制之一,对T790M突变的患者,EGFR—TKI的疗效如何呢？     

EGFR突变阳性晚期非小细胞肺癌患者厄洛替尼治疗前的EGFR T790M突变和BRCA1 mRNA表达

厄洛替尼治疗表皮生长因子受体（EGFR）突变阳性晚期非小细胞肺癌（non—small cell lung cancer,NSCLC）患者的中位无进展生存期（progression—free survival,PFS）长达14个月,最近发表在（（Clin Cancer Res）的一项研究认为,PFS还可能受到治疗前EGFR T790M突变以及DNA修复基因通路分子表达水平的影响,     

T790M的起源、遗传易感性和体内自然选择

3背景·研究一：酪氨酸激酶抑制剂（tyrosine kinase inhibitors．TKI）在部分非小细胞肺癌non-small cell lung cancer．NSCLC）患者,尤其是非吸烟者、妇女和患腺癌伴有支气管肺泡分化者中取得了较好的疗效。以往研究认为,表皮生长因子受体（epidermal growth factor receptor。EGFR）T790M突变是在应用TKI治疗后出现的继发突变。然而在另一些研究中发现,从未给予TKI治疗的NSCLC患者中,也可发现T790M突变。     

抑制STAT3增强对吉非替尼耐药的非小细胞肺癌药物敏感性的研究

目的:探讨非小细胞肺癌(NSCLC)中表皮生长因子受体T790M突变导致的吉非替尼耐药与信号转导及转录激活因子3(STAT3)的相关性。方法:不同浓度STAT3特异性抑制剂JSI-124处理NSCLC H1975细胞和PC9细胞后,CCK-8法检测细胞抑制率,Western blot法检测蛋白水平表达,RT-PCR法检测相关基因mRNA水平的表达。结果:NSCLC中EGFR T790M突变的H1975细胞中STAT3的表达明显高于PC9细胞(P0.01);JSI-124可剂量和时间依赖性地抑制H1975突变细胞中STAT3的活性,并能增强其对吉非替尼的敏感性。且此现象未在对吉非替尼敏感的PC9细胞中观察到。结论:STAT3因子与表皮生长因子受体T790M突变导致的吉非替尼耐药机制相关,抑制STAT3活性可逆转吉非替尼耐药。     

肺癌对表皮生长因子受体抑制剂(EGFR TKI)抵抗作用

表皮生长因子受体抑制剂(EGFR TKI)在非小细胞肺癌(NSCLC)治疗中发挥了重要的作用,可它的缓解率只有9％～19％,缓解维持时间只有6-8个月,提示存在原发性与获得性耐药。原因包括1．EGFR突变：一般认为EGFR基因20外显子的突变,尤其是T790M再突变与EGFR TKI耐药相关。在我们研究的80例NSCLC患者中,未检测到20外显子突变。在4例应用EGFR TKI治疗缓解后进     

伴T790M突变的晚期非小细胞肺癌患者的治疗及耐药机制研究进展

表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors,EGFR-TKIs)已被列为晚期非小细胞肺癌患者的一线用药。第一代和第二代TKIs在为患者带来临床益处的同时,也不可避免的导致了耐药,其中最为常见的机制是T790M突变,见于50%～60%对一二代TKIs耐药的患者。奥希替尼,作为唯一一个获得认证的针对EGFR-T790M突变的第三代TKIs,可以有效克服该种突变导致的耐药,临床上已有大量数据支持该结论。然而,耐药总是难以避免,其耐药机制大致分为EGFR依赖型和EGFR非依赖型两类。本文就EGFR-T790M突变的治疗以及奥希替尼耐药机制简要进行综述,以期对未来临床治疗和基础研究提供思路。     

EGFR-TKI第三代药物临床研究进展

肺癌位居于全世界癌症发病率的首位,其中又以非小细胞肺癌(NSCLC)所占比例最高(约80%),在肺癌治疗中,靶向治疗以其高效、低毒、高选择性的绝对优势占有不可忽视的地位。近年来,随着分子靶向药物在临床的推广应用,第一代可逆性表皮生长因子受体(EGFR)-酪氨酸激酶抑制剂(TKIs),如吉非替尼、厄洛替尼,用药后约50%的患者出现T790M耐药突变,而第二代不可逆性TKIs并未改善上述耐药问题。因此,针对EGFR基因敏感突变及T790m耐药突变的不可逆性EGFR-TKIs第三代靶向药成为研究热点。目前EGFR-TKI第三代药物AZD9291、CO1686、HM61713已进入临床研究,该文对EGFR-TKIs第三代药物的临床研究进展进行综述,为NSCLC临床治疗提供参考。     

非小细胞肺癌表皮生长因子受体P848L突变及其功能研究

目的:检测一组中国非小细胞肺癌(non-small-cell lung cancer,NSCLC)患者的表皮生长因子受体(epidermal growth factor receptor,EGFR)突变情况,探讨检出的1例EGFR突变类型P848L的功能特征。方法:收集55例手术或活检确诊的NSCLC标本,抽提细胞DNA,对EGFR的1~27号外显子进行筛查以检出突变情况;利用EGFR野生型全长基因载体,通过定点诱变技术构建出P848L突变型,进一步构建出P848L突变与T790M突变的双重突变体,分别转入293T细胞,观察细胞EGFR磷酸化活性及EGFR靶向抑制剂吉非替尼对其磷酸化的抑制作用。结果:共发现8例NSCLC携带EGFR突变,均为腺癌患者,占非吸烟腺癌患者的34.78%(8/23);其中1例NSCLC患者携带P848L突变体的细胞对吉非替尼的抑制反应与野生型相近,低于经典型突变体;当引入T790M形成双重突变后,对吉非替尼的反应性显著下降。结论: EGFR激活突变在非吸烟的肺腺癌患者具有较高的发生率,而在鳞状细胞癌等类型未发现;P848L突变不能增强吉非替尼对EGFR受体酪氨酸磷酸化的抑制效应,在携带P848L突变的EGFR基因上,引进耐药的T790M突变,能完全抑制其对吉非替尼的敏感性。     

EGFR C797S突变与奥希替尼耐药的相关性

表皮生长因子受体(EGFR)C797S突变被证实是奥希替尼最常见的耐药机制之一,耐药表现为单纯C797S突变、C797S/T790M顺式突变和C797S/T790M反式突变.目前已有较多关于克服EGFR C797S突变相关奥希替尼耐药的策略,在不断探索中取得了较好的疗效.对于单纯C797S突变可采用一代EGFR酪氨酸激酶抑制剂(EGFR-TKI)治疗,C797S/T790M顺式突变可采用布加替尼联合西妥昔单抗的方案治疗,C797S/T790M反式突变可采用EGFR一代联合三代药物治疗.除此之外,免疫治疗也可能成为该类患者的选择.     

表皮生长因子受体酪氨酸激酶抑制剂致间质性肺炎5例临床分析

吉非替尼是一种表皮生长因子受体酪氨酸激酶抑制剂（EGFR—TKI）,是苯胺喹唑类小分子化合物,可与表皮生长因子受体（EGFR）胞内区的酪氨酸激酶结合,竞争性抑制酪氨酸激酶磷酸化,从而阻断肿瘤细胞信号,抑制肿瘤细胞的生长、转移,主要用于局部晚期或远处转移的非小细胞肺癌（NSCLC）患者的治疗。     

Value of D-Dimers in patients with acute aortic dissection

Objective: To evaluatel the value of D-dimers in patients with acute aortic dissection (AAD). Methods: This study consisted of 16 patients with AAD and 27 non-AAD patients. Serum D-dimets were measured by Sta-Liatest D-DI immunoturbidimetric assay. Results: D-dimer level was higher (P ＜ 0.001) in patients with AAD(7.91 ± 5.52 μg/ml) than that in non- AAD group(1.57±1.24 μg/ml). D-dimer was positive (＞0.4 μg/ml) in all patients with AAD and in 10 control group patients (37%). Among patients with acute AAD, D-dimers tended to be higher in Stanford A than in Stanford B (8.67 ± 4.31 μg/ml vs. 3.24±1.27 μg/ml, P ＜0.01). D-dimer values tended to be higher in more extended disease(3.84 ± 1.65 μg/ml, 8.57 ± 3.58 μg/ml and 11.87 ± 5.69 μg/ml in thoracic aorta, thoracic and abdominal aorta, thoracic and abdominal aorta and iliacal arteries, respectively, P ＜ 0.05 for both 8.57 ± 3.58 and 11.87 ± 5.69 vs. 3.84 ± 1.65 ). Including the control group into the analysis, we found a sensitivity of 100%, a negative predictive value of 100%, and a specificity of 66% and a positive predictive value of 64% for D-dimer in diagnosis of AAD in our patients with suspected AAD. Conclusion: D-dimer was elevated in patients with AAD. A negative D-dimer test result could be useful in excluding AAD.     

Research of combined liver-kidney transplantation model in rats

Objective： To set up a simple and reliable rat model of combined liver-kidney transplantation. Methods： SD rats served as both donors and recipients. 4℃ sodium lactate Ringer＇s was infused from portal veins to donated livers,and from abdominal aorta to donated kidneys, respectively. Anastomosis of the portal vein and the inferior vena cava （IVC） inferior to the right kidney between the graft and the recipient was performed by a double cuff method, then the superior hepatic vena cava with suture. A patch of donated renal artery was anastomosed to the recipient abdominal aorta. The urethra and bile duct were reconstructed with a simple inside bracket. Results： Among 65 cases of combined liver-kidney transplantation, the success rate in the late 40 cases was 77.5%. The function of the grafted liver and kidney remained normal. Conclusion： This rat model of combined liver-kidney transplantation can be established in common laboratory conditions with high success rate and meet the needs of renal transplantation experiment.     

BLOOD PRESSURE CHANGE WITH AGE IN SALT-SENSITIVE TEENAGERS

Objective To observe blood pressure change with age in salt-sensitive teenagers whose salt sensitivity were determined by repeated testing.Methods Salt sensitivity was determined through intravenous infusion of normal saline combined with volume-depletion by oral diuretic furosemide in 55 teenagers. After five years, salt sensitivity was re-examined and subject blood pressure was followed up. Blood pressure changes in salt-sensitive teenagers were compared to that of non-salt sensitive teenagers over five years.Results After 5 years, the repetition rate of salt sensitivity determined by intravenous saline loading is 92.7%. In teenagers with salt sensitivity on the baseline, both the systolic blood pressure increments and increment rates were much higher than non-salt sensitive teenagers (12.7±12.1 mmHg vs. 2.8±5.2 mmHg, P＜ 0.01; 12.2%± 12.0% vs. 2.5% ±4.4%, P＜ 0.001,respectively). There was a similar trend for diastolic blood pressure (8.4 ± 6.4 mmHg vs. 3.7 ± 6.4 mmHg, P = 0.052; 13.2% ±10.6 % vs. 6.8%± 10.1%, P = 0.053, respectively).Conclusions Salt sensitivity determined by intravenous saline loading showed good reproducibility. Blood pressure increments with age were much higher in salt-sensitive teenagers than non-salt sensitive teenagers, especially in terms of systolic blood pressure.     

安心颗粒对急诊经皮冠状动脉介入术后生活质量影响的研究

目的：评价使用安心颗粒对急诊经皮冠状动脉介入术（PPCI）术后生活质量的影响.方法：将160例接受PPCI的急性ST段抬高型心肌梗死患者随机分为安心颗粒组（术前顿服安心颗粒8.8g,术后安心颗粒4.4 g/次,每日2次）和对照组（仅接受基础药物治疗）.所有患者均服用阿司匹林、氯吡格雷和阿托伐他汀.分别在入院时、出院前1d、出院后180 d时,应用心肌梗死多维度量表（MIDAS）、中文版SF-36评价量表对患者生活质量评分.并观察术后30 d以内的出血并发症、血小板减少症发生情况.结果：入院时和出院前1d,两组患者的心肌梗死MIDAS、SF-36量表评分比较无差异（P＞0.05）;出院后180 d时,与对照组比较,安心颗粒组MIDAS、SF-36评分明显减低（P＜0.05）;组内与入院时比较,两组出院前1d、出院后180 d时,MIDAS、SF-36评分均降低（P＜0.05）.两组患者在随访期间均无大量出血、少量出血、重度和极重度血小板减少症发生,安心颗粒组有4例、对照组有7例发生不明显出血（P＞0.05）.两组发生轻度血小板减少症的患者数比较无差异（P＞0.05）.结论：PPCI使用安心颗粒,能改善急性ST段抬高型心肌梗死患者的生活质量,且不增加出血风险.     

The comparative studies of the influences of Urapidil and Nicardipine on sino-atrial node function, atrio-ventricular node function and hemodynamics

Objective:To investigate the influences of urapidil and nicardipine on rabbit sinus function,atrio-ventricular node function and hemodynamics.Methods:Thirty-two Angora's rabbits were selected and randomly divided into four groups.U1 group:urapidil 0.25 mg/kg;U2 group:urapidil 0.5 mg/kg;N1 group:nicardipine 10 μg/kg;N2 group:nicardipine 20 μg/kg.All these medicine were administrated within 30 seconds.Measurements were taken before and after the administration of urapidil or nicardipine for the following data:mean blood pressure(MAP),heart rate(HR),sino-atrial conduction time(SACT),maximal sinoatrial recovery time(SNRTmax)corrected sinus node recovery time(CSNRT),index of sinus node recovery time(SNRTI),Wenckebach A-V conduction frequency (WB),and P-R interval.Results:Significant MAP and HR changes were identified in all of the four groups before and after administration of both urapidil and nicardipine.No significant changes could be found in the rest of the parameters.Intergroup analysis showed that SACT and CSNRT of N1 and N2 groups were shorter than those of the U2 group(P＜0.01);the MAP decreased(P＜0.01)and the HR increased drastically(P＜0.01).Conclusions:Neither urapidil(0.25 mg/kg,0.5 mg/kg)nor nicardipine(10μg/kg,20μg/kg)has any significant influence on rabbit sinus function or rabbit atrio-ventricular node function.Nicardipine could be a better choice than urapidil for parafunctional sinus node patients.     

Expression of OPGmRNA and ODFmRNA in the patients of hip fracture due to osteoporosis

Objective：To investigate the gene expression of osteoprotegerin（OPG） and osteoclast differentiation factor（ODF） in the bone tissue of patients with hip fracture due to osteoporosis. Methods：OPGmRNA and ODFmRNA in the bone tissue in 50 cases of osteoporosis sufferers（over 50 years old） with hip fracture（Observer Group） and 30 cases of hip facture sufferers with no osteoporosis（Control group） were analyzed with the Semi-Quantitative RT-PCR method. Results：The mRNA expressed of ODF, OPG were both high in the patients with hip fracture. In the control group, the expression of OPG mRNA was observed, while the expression of ODF mRNA was very slight. Conclusion：Aged patients contained all signals including OPG, ODF that are essential for inducing osteoclastogenesis and promoting bone resorption.     

The clinicopathological and immuohistochemical analysis of solid-pseudopapillary tumor of the pancreas： report of 9 cases

Objective：To investigate the clinical features, pathological characteristics and immunophenotype of solid-pseudopapillary tumor of the pancreas（SPTP）. Methods：Nine surgically treated cases of SPTP were retrospectively reviewed. Hematoxylin and Eosin（HE） staining and immunohistochemical staining were used to analyze all cases, and the general clinical data was collected. Results：Six patients were asymptomatic except for a palpable mass. Two patients complained of vague-epigastric pain. One patient appeared jaundice. The tumor was encapsulated and solid tissues alternately with cystic tissues. Histologically, the histological structure of solid portion was pseudopapillary with a fibrovascular core. Tumor cells were uniform and medium-sized which were arranged in sheets ets or nests or pseudopapillary patterns. Immunohistochemical studies demonstrated that SPTP proved positive in vimentin（9/9 cases）, AAT（9/9 cases）, NSE（9/9 cases）, ACT（7/9 cases）, CK20（2/9 cases）, CgA（1/9 cases）, S-100（3/gcases）, PR（4/gcases）, Syn（3/9 cases） and CD56（5/9cases）, negative in CEA and ER. Conclusion：SPTP is a tumor predominantly occurring in young women frequently without special symptoms. This tumor has various characteristical histological patterns with different immunophenotype.     

Dynamic Changes in Serum Estradiol and Progesterone levels in Patients of Premenstrual Syndrome with Adverse Flow of Liver-qi

Objective:To probe into the influence of changes of ovarian hormones on the pathogenesis of the specific sub-type premenstrual syndrome(PMS)and reveal partial microcosmic mechanisms of adverse flow of liver-qi.Methods:Estradiol(E2)and progesterone(P)levels in serum were determined at different phases of menstrual cycle by radioimmunoassay.Results:In the group of PMS with adverse flow of liver-qi.the secretive peak value Of E2 and P at the follicular phase significantly decreased,and the secretive peak value at the luteal phase did not come into being.Conclusions:Low E2 and P secretive peak at the follicular phase and absence of secretive peak at the luteal phase is one of the microcosmic mechanisms of PMS with adverse flow of liver-qi.One of the pathophysiologic mechanisms of specific sub-type PMS is probably the continuous low level of E2and P.     

Real-time Three-dimensional Echocardiography in Assessment of Left Ventricular and Right Ventricular Volumes

Real-time three-dimensional echocardiography (RT3DE)is a new ultrasound technique that enables dynamic threedimensional visualization and quantification of the heart in real time. Investigation of feasibility and methodology of RT3DE in determining left ventricular (LV) and right ventricular (RV) volumes, RT3DE was performed in 35 normal adults using Philips SONOS 7500 system with a 2-4 MHz matrix array transducer. The 60°×60° "pyramid" volume database was obtained and analyzed on a TomTec echo workstation. Both LV and RV volumes were calculated with four 3DE methods (i.e. apical 2, 4, 8, and 16-plane) through manually tracing ventricular endocardial borders in end diastole and end systole. Stroke volumes were then calculated. LV volume was also measured by 2DE Simpson's rule using GE VIVID 7 ultrasound machine.     

SCREENING FOR A 21-CHROMOSOME ABNORMALITY IN PREIMPLANTED EMBRYOS OF ELDERLY WOMEN

Increasing maternal age is the only etiological factor unequivocally linked to Down's syndrome in humans. The occurrence rate of newborns with Down's syndrome is about 1/220 in women over 35 years old. However, the occurrence rate in embryos fertilized in vitro, of the elder woman is unclear. Using FISH we screened the number of chromosome 21 in preimplanted embryos of 5 elderly women (average age, 38.4 years) to study the feasibility and necessity of screening trisomy 21 in embryos in patients over 35 years old at the in vitro fertilization (IVF) center.