Neurotrophic factor receptor RET: structure,cell biology,and inherited diseases

RET (REarranged during Transfection) is a transmembrane receptor tyrosine kinase that is activated by a complex consisting of a soluble glial cell line‐derived neurotrophic factor (GDNF) family ligand (GFL) and a glycosyl phosphatidylinositol‐anchored co‐receptor, GDNF family receptors α (GFRα). RET signalling is crucial for the development of the enteric nervous system. RET also regulates the development of sympathetic, parasympathetic, motor, and sensory neurons, and is necessary for the postnatal maintenance of dopaminergic neurons. The effect of GFLs on sensory, motor, and dopaminergic neurons has raised clinical interest towards these ligands. Outside the nervous system, RET is crucial for development of the kidney and plays a key role in spermatogenesis. Inactivating mutations in RET cause the Hirschsprung's disease characterized by megacolon aganglionosis. In contrast, activating mutations give rise to different types of cancer, multiple endocrine neoplasia type 2A and type 2B, familial medullary thyroid carcinoma, and papillary thyroid carcinoma. The multiple disease phenotypes correlate with differences in the molecular and cell biological functions of different oncogenic RET proteins. In this review we summarize how the different domains of the RET protein contribute to its normal function and how mutations in these domains affect the function of the receptor.     

Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: mechanisms and therapeutic opportunities

Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filaments of the sarcomere. Understanding the structural and functional role of cMyBP-C in the heart is clinically relevant since cMyBP-C gene mutations are a widely recognized cause of hypertrophic cardiomyopathy (HCM), which affects 0.2% of the general population. Nonsense and frameshift mutations are common in cMyBP-C and their expressions are regulated by three quality control systems, the nonsense-mediated mRNA decay, ubiquitin-proteasome system, and autophagy, which contribute to minimize the production of potential poison mutant proteins. This review discusses the structural and regulatory functions of cMyBP-C, the molecular mechanisms involved in cMyBP-C-related HCM, as well as potential causative therapies for HCM.     

miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma

Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC. We developed two complementary in vitro models based on RET/PTC1 oncogene, starting from the hypothesis that miRNAs modulated by a driving PTC-oncogene are likely to have a role in thyroid neoplastic processes. Through this strategy, we identified a panel of deregulated miRNAs. Among these we focused on miR-199a-3p and showed its under-expression in PTC specimens and cell lines. We demonstrated that miR-199a-3p restoration in PTC cells reduces MET and mTOR protein levels, impairs migration and proliferation and, more interesting, induces lethality through an unusual form of cell death similar to methuosis, caused by macropinocytosis dysregulation. Silencing MET or mTOR, both involved in survival pathways, does not recapitulate miR-199a-3p-induced cell lethality, thus suggesting that the cooperative regulation of multiple gene targets is necessary. Integrated analysis of miR-199a-3p targets unveils interesting networks including HGF and macropinocytosis pathways. Overall our results indicate miR-199a-3p as a tumor suppressor miRNA in PTC.     

甲状腺乳头状癌VEGF、MMP-9及COX-2蛋白表达与淋巴道转移和血管生成的相关性

 目的 通过检测血管内皮细胞生长因子(VEGF)、基质金属蛋白酶-9(MMP -9)、环氧化酶-2(COX-2)在 甲状腺乳头状癌（PTC）细胞中的表达情况,探讨它们与PTC颈淋巴结转移的关系。 方法 采用免疫组织化学SP法检测74例PTC(有淋巴结转移者39例,无淋巴结转移者35例)中VEGF、 MMP-9、COX-2的表达,并对CD34表达阳性血管进行MVD计数。 结果 VEGF、MMP-9、COX-2的表达与MVD值在淋巴结转移组与无转移组之间的差异均具有统计学意义 (P<0.05),与PTC淋巴结转移呈正相关;VEGF、MMP-9、COX-2的表达与MVD值正相关 (P<0.05) ,VGEF、MMP-9阳性表达率与肿瘤大小密切相关（P<0.05）。 结论 甲状腺乳头状癌VEGF、MMP-9、COX-2蛋白表达与其淋巴道转移和MVD有关,检测这几种蛋白表 达将有助于判断甲状腺乳头状癌的转移潜能、血管生成能力及预后。     

中央区淋巴结清扫在cN0期甲状腺乳头状癌中的应用

目的 观察不同临床特点cN0期甲状腺乳头状癌患者的中央区淋巴结转移情况,探讨预防性中央区淋巴结清扫术的应用指征及手术范围。方法 回顾性分析2015年3月至2016年12月期间我院收治的93例甲状腺乳头状癌患者的病历及病理资料。分析患者性别、年龄、肿瘤大小、是否为多灶癌、肿瘤是否累及被膜等因素与中央区淋巴结转移率的关系。所有病例均行甲状腺全切除或近全切除术+患侧中央区淋巴结清扫术,并将患侧中央区标本送冰冻及石蜡病理检查,后再行对侧中央区淋巴结清扫术。观察中央区淋巴结转移情况及患侧中央区淋巴结冰冻与石蜡病理检查符合情况。结果 本组病例男性18例,女性75例;平均年龄41±13.9岁。T165例,T218例,T310例,T40例;单侧多灶癌8例;肿瘤突破甲状腺包膜9例。本组中央区淋巴结转移率为46.2%（43/93）,18.2%（17/93）为双侧中央区淋巴结转移。性别、肿瘤位置、年龄、肿瘤直径、T分期等因素与CLN转移差异无统计学意义。患侧中央区淋巴结冰冻病理检查的敏感性、特异性、准确性分别为86.0%、100%、93.5%。结论 对cN0期甲状腺乳头状癌应常规行患侧中央区淋巴结清扫术;术中冰冻检查能准确预测患侧中央区淋巴结转移状态;术中应常规行冰冻切片检查,如患侧中央区淋巴结转移时,建议行双侧中央区淋巴结清扫术。     

不同影像学检查方法对梗阻性黄疸诊断价值的比较研究

目的探讨梗阻性黄疸病人的病因及评价超声、腹部CT（CT）、核磁胰胆管成像（MRCP）、经内镜逆行胰胆管造影（ERCP）和经皮经肝胆道造影（PTC）五种检查方法对梗阻性黄疸的诊断价值。方法选择2003年1月-2009年l1月在我院住院确诊为梗阻性黄疸的患者,比较分析各种检查方法对梗阻部位及梗阻病因的准确率。结果确诊为梗阻性黄疸的患者为473例,B超、腹部CT、MRCP、ERCP及PTC对患者梗阻部位的显示率分别为59.6%（257/431）,80.9%（106/131）,88.8%（326/367）,84.2%（64/76）,100%（31/31）,而梗阻的原因有：Mirrizi综合征、胆道感染、胆道蛔虫、胆囊癌、胆总管结石、胆总管囊肿、肝内外胆管细胞癌、壶腹癌、十二指肠乳头癌、十二指肠乳头憩室、十二指肠乳头炎、术后胆管狭窄、胃癌术后肝门淋巴结转移、胰头癌、肿块性胰腺炎。结论各种诊断方法各有其优缺点,MRCP在梗阻性黄疸的诊断上具有较大的价值,但必要时仍需进行其它检查方法加以鉴别诊断。     

ERCP和PTC介入治疗肝移植术后胆道并发症的作用比较

目的比较ERCP和PTC介入治疗肝移植术后胆道并发症的作用和疗效。方法回顾性分析2004年8月至2006年8月44例接受介入治疗的肝移植术后胆道并发症患者临床资料，比较ERCP和PTC介入治疗在肝移植术后胆道并发症中的疗效和并发症。结果首选ERCP介入治疗31例，3例操作失败（9．6％）；PTC介入治疗16例，均操作成功。胆道吻合口狭窄和非胆道吻合口狭窄ERCP和PTC介入治疗的治愈率分别为73．3％、77．7％和23．1％、14．3％，差异无统计学意义（P〉0．05）。两种介入治疗术后并发症的发生率差异无统计学意义（P〉0．05）。结论ERCP和PTC介入治疗肝移植术后胆道并发症的疗效和并发症的发生率相当，可以将PTC介入技术作为治疗肝移植术后胆道并发症的首选措施。     

甲状腺肿瘤相关基因研究进展

甲状腺肿瘤是临床常见疾病,其良、恶性诊断缺乏特异性标志物,该疾病的发生与多种基因事件相关,包括BRAF、Ret/PTC、Ras、erBb-2、p53、p16、PTEN、CK19和DDIT3、ARG92、ITM1、C1orf24等基因.不同基因型的改变与甲状腺肿瘤的病理类型存在一定相关性.     

甲状腺乳头状癌微血管密度与VEGF、PD-ECGF表达的研究

目的　研究甲状腺乳头状癌 (PTC)的血管生成及VEGF、PD ECGF的表达 ,并探讨其临床意义。方法　运用免疫组化方法检测 4 3例PTC ,10例甲状腺腺瘤和 10例正常甲状腺组织的MVD值和VEGF、PD ECGF的表达。结果　①PTC的MVD值和VEGF、PD ECGF的表达明显高于正常甲状腺组织 (P <0 .0 5 ) ;PTC的MVD值和VEGF的表达明显高于甲状腺腺瘤 (P <0 .0 5 ) ;甲状腺腺瘤的MVD值和VEGF、PD ECGF的表达明显高于正常甲状腺组织 (P <0 .0 5 )。②PTC的淋巴结转移状况与MVD值及VEGF的表达成正相关 (P <0 .0 5 )。结论　血管生成在PTC的发生、发展中占有重要的地位。