Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms

We hypothesized that elucidating the interactome of epidermal growth factor receptor (EGFR) forms that are mutated in lung cancer, via global analysis of protein–protein interactions, phosphorylation, and systematically perturbing the ensuing network nodes, should offer a new, more systems‐level perspective of the molecular etiology. Here, we describe an EGFR interactome of 263 proteins and offer a 14‐protein core network critical to the viability of multiple EGFR‐mutated lung cancer cells. Cells with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) had differential dependence of the core network proteins based on the underlying molecular mechanisms of resistance. Of the 14 proteins, 9 are shown to be specifically associated with survival of EGFR‐mutated lung cancer cell lines. This included EGFR, GRB2, MK12, SHC1, ARAF, CD11B, ARHG5, GLU2B, and CD11A. With the use of a drug network associated with the core network proteins, we identified two compounds, midostaurin and lestaurtinib, that could overcome drug resistance through direct EGFR inhibition when combined with erlotinib. Our results, enabled by interactome mapping, suggest new targets and combination therapies that could circumvent EGFR TKI resistance.     

A multi-step directional generalized gradient vector flow snake for target tumor segmentation in US-guided high-intensity focused ultrasound ablation

Getting precise locations of target tumors can help to ensure ablation of cancerous tissues and avoid unwanted destruction of healthy tissues in high-intensity focused ultrasound (HIFU) treatment system. Because of speckle noise and spurious boundaries in ultrasound images, traditional image segmentation methods are not suitable for achieving the precise locations of target tumors in HIFU ablation. In this paper, a multi-step directional generalized gradient vector flow snake model is introduced for target tumor segmentation. In the first step, the traditional generalized gradient vector flow (GGVF) snake is used to obtain an approximate contour of the tumor. According to the approximate contour, a new distance map is generated. Subsequently, a new directional edge map is created by calculating a scalar product of the gradients of the distance map and the initial image. In this process, the gradient directional information and the magnitude information of the distance map are used to attenuate unwanted edges and highlight the real edges in the new directional edge map. Finally, a refined GGVF field is derived from a diffusion operation of the gradient vectors of the directional edge map. The GGVF field is used to refine the tumor's contour, by directing the approximate contour to edges with the desired gradient directionality. Based on the newly developed snake model, the influences of the spurious boundaries and the speckle noise are significantly reduced in the ultrasound image segmentation. Experimental results indicate that this technique is greatly useful for target tumor segmentation in HIFU treatment system     

成人烟雾病合并后循环病变的相关因素分析

目的:探讨成人型烟雾病合并后循环病变发生的相关危险因素,以期指导临床诊治.方法:回顾性分析2009年3月～2010年1月于解放军307医院神经外科就诊并住院的成人烟雾病患者418例,根据是否合并后循环病变(大脑后动脉病变为主)分为合并后循环病变组130例,未合并后循环病变组为288例.分别记录患者的的性别、年龄、籍贯、临床表现类型、铃木分期、既往病史(高血压、高脂血症、高血糖)、不良生活习惯(吸烟、饮酒),是否有烟雾病家族史.对其进行组间对比及logistic回归法进行变量分析.结果:阳性家族史是成人烟雾病患者合并后循环病变的独立危险因素(OR=3.898,95％CI:1.103～13.776,P=0.035),而其余观察指标均无明显相关性(P＞0.05);相对于只存在前循环病变的患者,成人烟雾病合并后循环病变的患者较易出现卒中及头痛,脑出血相对较少;此类患者于31-40岁组出现小高峰.结论:阳性家族史是成人烟雾病患者合并后循环病变的独立危险因素,患者的临床表现较重,治疗后仍可出现反复卒中.     

抗环瓜氨酸肽抗体联合类风湿因子在检测类风湿关节炎中的临床价值

目的：探讨抗环瓜氨酸肽抗体（抗CCP抗体）以及类风湿因子（RV）检测对类风湿关节炎（RA）诊断的意义。方法：采用酶联免疫吸附试验（ELISA）检测355份人血清的抗CCP抗体,同时采用使用贝克曼库尔特Image800双光镜免疫浊度分析仪定量监测类风湿因子（RF）,其中包括门诊及住院RA患者135例,非RA组170例,正常对照组来自本院的健康体检人员50例。结果：抗-CCP检测在RA组与非RA组（和正常对照组）之间的检测结果有统计学差异（P〈0．05）。RF检测在RA组与非RA组（和正常对照组）之间的检测结果有统计学差异（P〈0．05）。在135例RA病人中,抗CCP抗体的阻性率为70．4％,在非RA病人中的阳性率为3．5％,抗CCP抗体对RA的敏感性和特异性分别为70．4％、96．5％。RF的阳性率为63．7％,在非RA病人中的阳性率为14．1％,RF对RA的敏感性和特异性分别为63．7％、81．1％。联合应用抗CCP抗体与RF进行诊断,串联时敏感性为59．3％,特异性为97．1％。并联时敏感性为74．8％,特异性为85.3％。结论：抗CCP抗体和RF对RA具有较好的敏感性和很高的特异性,二者联合检测可提高对RA早期诊断的准确性。     

肺炎链球菌粘附和毒力因子A研究进展

肺炎链球菌（Streptococcus pneumoniae,SP）普遍定植于呼吸道,是人类重要的侵袭性病原菌之一,是社区获得性肺炎、中耳炎、脑膜炎、菌血症、鼻窦炎的主要病原菌。肺炎链球菌粘附和毒力因子A（pneumococcal adherence and virulence factor A,PavA）是肺炎链球菌早期感染和侵袭过程中关键的毒力因子。体外试验表明,缺失PavA的肺炎链球菌的突变株其粘附和侵入上皮细胞和内皮细胞的能力明显下降。作为一种保护性抗原,其诱导的细胞和体液免疫可以有效的抵抗肺炎链球菌的感染,是肺炎链球菌新一代疫苗的候选蛋白。但是,PavA在肺炎链球菌与人肺上皮细胞交互对话中作用机制的研究尚属空白,本文就肺炎链球菌粘附和毒力因子A得最新研究进展作一综述。     

吐鲁番市胃食管反流病发生相关危险因素分析（附280例报道）

目的：探讨280例胃食管反流病（GERD）的分布特点及危险因素。方法：对临床诊断和胃镜确诊的280例GERD患者进行临床和风险因子相关性分析。结果：不论汉族还是维族,男性患者比例均明显高于女性;汉族患者高发年龄段早于维族患者（z=-2．939,P=0．003,）;汉族和维族患者占反流性食管炎和Barrett食管比例分别为42．4％、81_3％及56．5％、18．8％,其中汉族患者Barrett食管比例较高（X2=14．358,P=0．000）;肥胖、习惯性便秘、重体力活动者、饮食习惯不良在维族患者中的比例较高（P〈0．001）。结论：GERD与性别、年龄密切相关,男性多于女性,汉族患者发病年龄高峰旱于维族患者;汉族患者Barrett食管发生比例高于维族患者;肥胖、习惯性便秘、重体力活动、饮食习惯不良可能是GERD尤其是维族人群GERD的危险因素。     

介入治疗成人非创伤性股骨头缺血性坏死的疗效分析

目的：分析介入治疗对于成人非创伤性股骨头缺血性坏死的疗效。方法：采用介入方法治疗95例共117髋非创伤性股骨头缺血性坏死。对比介入治疗前后DSA造影分型结果及血供异常例数。结果：117患髋中,Ia型的31病髋中,11髋（35．48％）介入治疗后动脉主干再通;Ib型的27髋中,24髋（88．89％）介入治疗后分支再通;II型的11髋中,5髋（45．45％）实质期股骨头缺损面积缩小;III型的10髋中,8髋（80．00％）静脉期见股骨头浓密染色明显减轻;Ⅳ型的33髋中,28髋（84．85％）可见动脉主干再通、分支增粗、实质期股骨头缺损面积缩小和静脉期股骨头染色减轻等。治疗前117病髋异常率为95．73％。经过介入治疗后,异常率为30．77％。治疗后异常率明显低于治疗前异常率（P〈0．01）。结论：介入治疗可有效改善非创伤性股骨头缺血性坏死血供异常,增加股骨头血供,具有操作简单、创伤小、疗效确切等优点。关键阗：股骨头缺血性坏死;介入治疗;数字减影血管造影     

变应性鼻炎与IRF5的单核苷酸多态性关系

目的:探讨变应性鼻炎与干扰素调节因子5(IRFS)的单核苷酸多态性(SNP)的相关性.方法:采用聚合酶链(PCR)和限制性片段长度多态性(RFL P)方法在新加坡华人中检测110例变应性鼻炎患者及101健康对照组IRF5位点上的3个单核苷酸多态性(rs4728142,rs11770589,rs2280714)计算基因型和等位基因频率.结果:IRF5基因的3个位点的基因型和等位基因频率在变应性鼻组和对照组间差异无统计学意义.结论:新加坡华人IRF5 rs4728142,rsl1770589,rs2280714多态性与变应性鼻炎无明显相关性.     

Clinical significance of serum transforming growth factor-β1 in lung cancer

Background: Transforming growth factor-β1 (TGF-β1) plays a critical role in human cancer development. Present study aimed to explore the clinical significance of serum TGF-β1 levels in patients with lung cancer and analyze the relationship between TGF-β1 and existing tumor markers for lung cancer. Methods: Serum was collected from 118 patients with lung cancer and 40 healthy volunteers. Serum TGF-β1 levels were measured by enzyme-linked immunosorbent assay (ELISA), and the association with various clinical characteristics was analyzed. The diagnostic value of TGF-β1 was assessed alone and in combination with existing tumor markers for lung cancer. Results: Serum TGF-β1 levels were significantly higher in patients with lung cancer compared to healthy volunteers [0.6 × 10⁵ (0.4 × 10⁵, 0.9 × 10⁵) pg/ml vs 0.5 × 10⁵ (0.3 × 10⁵, 0.7 × 10⁵) pg/ml, P = 0.040]. Although there was a positive correlation between serum TGF-β1 levels and advanced stages, the significant difference was not found between early stages and advanced stages (P = 0.116). The ability of serum TGF-β1 to discriminate lung cancer at a cutoff value of 79,168 pg/ml exhibited sensitivity of 30.6% and specificity of 97.5%. Serum TGF-β1 levels were correlated to cytokeratin fragment 21-1 (CYFRA21-1; R = 0.308, P = 0.020) and neuron-specific enolase (NSE; R = 0.558, P = 0.003). The diagnostic accuracy rates for the existing lung-tumor markers, as SCC, CYFRA21-1, and NSE, were increased from 20.0%, 34.6%, and 45.9% to 48.9%, 51.7%, and 54.5%, respectively by the inclusion of serum TGF-β1 levels. Conclusion: Quantification of serum TGF-β1 levels by ELISA may provide a novel complementary tool for the clinical diagnosis of lung cancer.