酪氨酸激酶受体RON与E-cadherin在子宫内膜异位症上的表达及意义

目的探讨酪氨酸激酶受体RON及上皮型钙粘蛋白(E-cadherin)在子宫内膜异位症(endometriosis,EMs)上的表达及意义。方法选择2017年7~12月深圳市龙岗区人民医院收治的42例EMs患者,术中分别留取新鲜异位内膜组织和在位内膜组织,随机选取子宫切除或诊断性刮宫治疗的非EMs患者42例,术中留取其正常子宫内膜组织。采用逆转录聚合酶链反应(RT-PCR)检测子宫内膜组织中RON mRNA的表达,采用免疫组织化学方法检测对应42例石蜡组织中RON蛋白和E-cadherin的表达,并分析RON蛋白和E-cadherin的相关性。结果EMs异位内膜组织RON mRNA及RON蛋白阳性表达率显著高于在位内膜组织及正常子宫内膜组织(P<0.001),在位内膜组织及正常内膜组织中E-cadherin阳性表达率显著高于异位内膜组织(P<0.001),且异位内膜组织中RON mRNA及RON蛋白的表达与临床分期有关(P<0.001)。在同一标本中RON蛋白和E-cadherin表达呈负相关关系(r=-0.497,P<0.05)。结论RON的过度表达与EMs的发生发展密切相关,联合检测RON和E-cadherin的异常对判断EMs的发生发展有一定的参考价值,RON可能成为诊断治疗EMs的新靶点。     

Tryptophan depletion effects on EEG and MEG responses suggest serotonergic modulation of auditory involuntary attention in humans

Involuntary attention shifting, i.e., detecting and orienting to unexpected stimulus changes, may be altered at low brain serotonin (5-hydroxytryptamine; 5-HT) levels. This was studied in 13 healthy subjects (21–30 years old; 6 females) by using a dietary challenge, acute tryptophan depletion (ATD), which decreases 5-HT synthesis in the brain. Five hours after ingestion of either ATD or control mixture (randomized, double-blinded, crossover design), brain responses indexing involuntary attention were measured with simultaneous 64-channel electroencephalography (EEG) and 122-channel magnetoencephalography (MEG). During the measurement, the subjects were instructed to discriminate equiprobable 200- and 400-ms tones by pressing one of two buttons rapidly. Occasionally, the frequency of the tones changed (10% increase/decrease), causing involuntary attention shifting. ATD significantly lowered plasma tryptophan concentrations (total tryptophan decreased by 75%, free tryptophan decreased by 35%). As compared to the control condition, ATD reduced the amplitude of the deviant-tone N2 wave, including the overlapping mismatch negativity (MMN) and N2b subcomponents, which are suggested to reflect change detection in the brain. The EEG results were accompanied by a significant increase in the peak latency of the magnetic counterpart of MMN. However, no ATD effects were observed in P3 to task-irrelevant frequency change. Reaction time (RT) to deviants per se was not significantly affected, but RT in trials succeeding the deviant-frequency tones was increased by ATD, which suggested impaired reorienting to the task-relevant activity. In conclusion, the results suggest that decreased level of central 5-HT function after ATD may decrease involuntary attention shifting to task-irrelevant sound changes and thus modulate resource allocation to the task-relevant activity.     

The time-course of auditory and visual distraction effects in a new crossmodal paradigm

Vision often dominates audition when attentive processes are involved (e.g., the ventriloquist effect), yet little is known about the relative potential of the two modalities to initiate a “break through of the unattended”. The present study was designed to systematically compare the capacity of task-irrelevant auditory and visual events to withdraw attention from the other modality. Sequences of auditory and visual stimuli were presented with different amounts of temporal offset to determine the presence, strength, and time-course of attentional orienting and reorienting as well as their impact on task-related processing. One of the streams was task-relevant, while crossmodal distraction caused by unexpected events in the other stream was measured by impairments of behavioral task performance and by the N2, P3a, and reorienting negativity (RON) components of the event-related potential (ERP). Unexpected events in the visual modality proved to be somewhat more salient than those in the auditory modality, yet crossmodal interference caused by auditory stimuli was more pronounced. The visual modality was relatively constrained in terms of a critical time-range within which distraction effects could be elicited, while the impact of auditory stimuli on task-related processing extended over a longer time-range. These results are discussed in terms of functional differences between the auditory and visual modalities. Further applications of the new crossmodal protocol are deemed promising in view of the considerable size of the obtained distraction effects.     

RON基因在肿瘤中的研究及其靶向治疗进展

RON（recepteur d′origine nantais）是属于MET原癌基因家族的一种酪氨酸激酶受体（RTKs）,主要在上皮细胞中表达,基因编码的酪氨酸激酶受体,与肿瘤侵袭转移密切相关,它具有调节细胞扩散、转移、微管形成和保护细胞免于凋亡的功能[1],一旦其过表达或激活,即成为一种攻击力很强的癌基因。RON在病理学上对肿瘤进展的影响使以RON的靶向治疗成为可能。     

酪氨酸激酶受体RON在胰腺癌中的表达及意义

目的:研究酪氨酸激酶RON(recepteur d'origine nantais)在胰腺癌组织中的表达及其意义.方法:收集胰腺癌组织及相关癌旁组织31例.正常胰腺组织8例,采用免疫组织化学技术检测组织中RON的表达.结果:RON在正常胰腺组织、癌旁组织、胰腺癌组织中均见阳性表达,胰腺癌及癌旁中的表达强度高于正常胰腺组织,胰腺癌RON的表达强度强于癌旁组织(P＜0.05).RON表达与患者年龄、肿瘤大小、组织学类型和肿瘤部位等均无关,与胰腺癌临床分期、分化程度及淋巴结转移相关(P＜0.05).结论:RON表达量的增多与胰腺癌的发生、发展有关.     

受体酪氨酸激酶RON与肿瘤

RON的激活与人体内某些上皮源性肿瘤的发生存在密切关系.在体内,RON基因主要表达于上皮细胞及食管、胃、小肠、肾脏、宫颈、皮肤、膀胱等组织和器官,在肺泡、甲状腺、心脏、平滑肌、成纤维细胞、内皮细胞中几乎没有表达.RON在其配体巨噬细胞刺激蛋白的刺激下,激活后具有调节上皮细胞扩散、转移、微管形成等功能.同时,RON本身也可以诱导细胞发生上皮一间质转化,引起细胞扩散和浸润.研究RON在肿瘤发生中的作用可以为其作为靶向药物干预治疗提供可靠的依据.     

Electrophysiological and behavioral evidence of gender differences in the modulation of distraction by the emotional context

Gender differences in brain activity while processing emotional stimuli have been demonstrated by neuroimaging and electrophysiological studies. However, the possible differential effects of emotion on attentional mechanisms between women and men are less understood. The present study aims to elucidate any gender differences in the modulation of unexpected auditory stimulus processing using an emotional context elicited by aversive images. Fourteen men and fourteen women performed a well-established auditory-visual distraction paradigm in which distraction was elicited by novel stimuli within a neutral or negative emotional context induced by images from the IAPS. Response time increased after unexpected novel sounds as a behavioral effect of distraction, and this increase was larger for women, but not for men, within the negative emotional context. Novelty-P3 was also modulated by the emotional context for women but not for men. These results reveal stronger novelty processing in women than in men during a threatening situation.     

Expression and mutational status of RON in neoplastic lesions of the breast: analysis of MSP/RON signaling in ductal carcinoma in situ and invasive ductal carcinoma

Recepteur d'origine nantais (RON) is a receptor tyrosine kinase closely related to MET and involved in tumorigenesis. We investigated the roles of aberrations in RON and its ligand, macrophage-stimulating protein (MSP), in invasive ductal carcinoma (IDC, n = 81), ductal carcinoma in situ (DCIS, n = 26), and in benign lesions (n = 20) of mammary gland. Expression of RON and MSP was evaluated by immunohistochemistry and the mutational status of a region containing the proteolytic cleavage site in exon 1 and each exon of the kinase domain (exon 14-20) of RON was screened by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis. The proportion of cases positive for RON expression was significantly different between malignant [86% (92/107)] and benign [40% (8/20)] lesions. RON expression was positive in both IDC and DCIS [90% (73/81) and 73% (19/26), respectively], whereas MSP expression was present in 54% (44/81) of IDC and absent in DCIS. RON expression correlated significantly with the histological grade of DCIS. No mutations were detected in the examined regions of RON in breast cancer samples as confirmed by PCR-SSCP. The findings suggest the involvement of RON expression in the development of breast cancer, and that an autocrine/paracrine loop of RON seems to affect tumor invasiveness.     

RNAi沉默RON基因对人结肠癌HT-29细胞侵袭和耐药性的抑制作用

目的:探讨RNAi沉默酪氨酸激酶受体RON(recepteur d'origine nantais)基因对人结肠癌HT-29细胞侵袭和对抗肿瘤药物敏感性的影响.方法:构建RON基因的RNAi慢病毒载体Lv-RON-siRNA.Real-time PCR和Western blotting检测RON基因的沉默效率及RON蛋白表达水平;Transwell侵袭实验和ATP-TCA(ATP-tumor chemosensitivity assay)检测RON基因对HT-29细胞侵袭和对药物敏感性的影响.结果:慢病毒载体Lv-RON-siRNA感染HT-29细胞对RON基因的沉默效果达到70％.Lv-RON-siRNA感染后,HT-29细胞侵袭力较对照组明显降低(0.97±0.072 vs 1.29±0.076,P＜0.05).Lv-RON-siRNA感染后,HT-29细胞对5-氟尿嘧啶(5-fluorouraci,5-FU)的IC90值和IC50值分别为(14.28 ±1.34)、(8.93±1.20) μg/ml,顺铂(cisplatin,DDP)的IC90值和IC50值分别为(1.91±0.22)、(0.64±0.07) μg/ml,均明显低于对照组(P＜0.01).结论:沉默RON基因表达能抑制HT-29细胞的侵袭力,提高细胞对5-FU和DDP的敏感性.     

RON confers lapatinib resistance in HER2-positive breast cancer cells

Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d’Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib sensitivity in these cells by inhibiting PI3K/AKT activation. Our results demonstrate for the first time the important role of RON in mediating lapatinib resistance and suggest that RON-targeted therapy may become a novel, promising therapeutic strategy after the failure of lapatinib treatment in patients with HER2-positive breast cancer.