姜黄素和芦荟胶冻干粉及PTC的抗放射作用研究

〔目的〕 通过对受γ射线外照射小鼠骨髓、小肠和睾丸形态、肝组织化学发光、外周血象的改变,比较姜黄素、芦荟胶冻干粉和ＰＴＣ三种药物的抗放射线效果,并探讨其作用机理。〔方法〕 放射源为＾６０Ｃｏ,剂量率１４６．２０ｃＧｙ／ｍｉｎ,哈身照射２００ｃＧｙ。照后６ｈ眼球取血,测外周血象;活杀小鼠取肝脏制匀浆,做化学发光测定;取股骨、小肠和睾丸固定于甲醛溶液、包埋、切片行ＨＥ染色,在光学显微镜下计数凋亡细胞。〔结果〕 （１）外周血淋巴细胞绝对值姜黄素组、ＰＴＣ组显著高于照射对照组（Ｐ〈０．０５）,白细胞各组间无显著差异;（２０化学发光值测定显示,姜黄素组、姜黄素组、ＰＴＣ组显著高于照射对照组（Ｐ〈０．０５）;（３）姜黄素组、ＰＴＣ组和芦荟组小鼠骨髓、小肠和睾丸凋亡细胞数明显低于照射对照组（Ｐ〈０．０１）。〔结论〕 三种药物     

DNA双链断裂感应分子ATM能与PTC1相互作用

目的：研究DNA双链断裂感应分子ATM与原癌基因ret重排活化蛋白PTC1的相互作用。方法：用Flag抗体Western印迹检测，ATM免疫共沉淀真核细胞内过表达的PTC1；RET抗体检测ATM免疫共沉淀真核细胞内过表达的c-ret;用HA／myc抗体Western印迹检测，HA－ret TK myc-LZPR免疫共沉淀蛋白复合物；荧光蛋白标记的亚细胞定位。结果：PTC1可以与ATM激酶相互作用，此作用不依赖于电离辐射，且不被PI3K家族特异性抑制剂沃氏蓝霉素（wortmannin)所抑制，而野生型RET蛋白则不能同ATM结合；缺失体实验进一步证明两者的结合区段为ATM的LZPR结构域与PTC1的酪氨酸激酶结构域，构建PTC1绿色荧光蛋白表达质粒的亚细胞定位实验显示，PTC1以弥散形式分布于细胞质内。结论：胞浆蛋白PTC1可能借债某种途径使ATM在DNA损伤反应发生后重新定位，介导了细胞的恶性转化机制。     

PTC与PTBD在恶性梗阻性黄疸诊断治疗上的应用

本文报告对肿瘤性黄疸病人行PTC86例,PTBD30例的临床体会。指出PTC方法简单、成功率高、合并症少。PTBD治疗梗阻黄疸作用分为术前减黄和姑息外引流两方面。尤其是不需X线设备,床旁体表定位下的PTBD17例,15例成功,更为简便、合并症少,对梗阻性黄疸有治疗价值。作者建议,对肿瘤性黄疸病人采用以下诊治步骤:B超→ERCP→床旁PTBD→经管造影,决定治疗方案为进一步手术治疗或永久带管外引流,提供有力依据。     

N990炭黑/低密度聚乙烯复合材料的电性能

采用熔融复合方法制备了N990炭黑/低密度聚乙烯(LDPE)复合材料,研究了其微观结构和电性能。结果表明:N990炭黑在复合材料中分布较均匀,对LDPE具有诱导结晶作用。复合材料的渗流阈值为20%,临界电阻率指数为9.2,PTC强度都大于4个数量级。复合材料在熔点之下,电阻率的对数值与相对体积存在线性关系。     

KAI1在甲状腺乳头状癌中的表达及其临床意义

目的:研究肿瘤转移抑制基因KAI1在甲状腺乳头状癌(PTC)细胞膜和细胞浆中的表达有无差异;KAI1在PTC中表达情况的临床意义。方法:Western blot法分别检测:KAI1蛋白在30例PTC原发灶标本、7例淋巴结转移灶标本、13例癌旁组织标本和13例良性病变标本细胞膜和细胞浆中的表达;KAI1在30例PTC原发灶中总蛋白表达情况。结果:KAI1蛋白在PTC标本胞膜上表达明显低于胞浆中;而在癌旁组织、淋巴结转移标本和良性病变中表达无差异。KAI1蛋白在PTC中的表达阳性率与有无淋巴结转移有明显相关,无淋巴结转移者阳转移性率明显高于有淋巴结转移者;而KAI1表达阳性率与肿瘤原发灶大小及患者年龄无关、与TNM分期负相关。结论:KAI1蛋白在肿瘤组织中表达没有定位于细胞膜可能是其失去对肿瘤进展和转移抑制的原因。KAI1蛋白的低表达对PTC的临床进程明显相关,可作为判断临床演进、淋巴转移的指标和潜在的治疗靶向。     

RET/PTC fusion gene rearrangements in Japanese thyroid carcinomas

The activation of RET proto-oncogene through chromosomal translocation is reported as being unique to papillary thyroid carcinomas. However, the reported prevalence of RET/PTC activation in papillary carcinoma was variable, and the clinical relevance of RET/PTC rearrangements in papillary carcinomas is still controversial. To investigate the roles of RET rearrangement in the carcinogenesis of papillary thyroid carcinoma, we have studied RET activation and p53 overexpression in various thyroid lesions of the Japanese population by immunohistochemical technique. RET activation and p53 overexpression were studied in 40 papillary carcinomas, 6 poorly differentiated carcinomas, 4 undifferentiated carcinomas, 2 medullary carcinomas, 2 follicular carcinomas and 19 follicular adenomas. RET activation was observed in 12 out of 40 papillary carcinomas, while no immunoreactivity of RET was detected in other lesions. P53 overexpression was observed in only 1 of 40 papillary carcinomas, but in 2 poorly differentiated carcinomas and 4 undifferentiated carcinomas. The prevalence of RET/PTC activation in papillary carcinoma among the Japanese population was higher than in previous reports. Immunohistochemical technique is proved to be a useful tool to detect RFT/PTC activation in thyroid tumors. RET rearrangements are restricted to a well-differentiated papillary carcinoma, suggesting that RET/PTC positive papillary carcinomas do not progress to undifferentiated carcinoma.This work was presented at the 6th Research Workshop on Head and Neck Cancer, 11 October 2002, McLean, VA.     

Apoptotic cell death induction and angiogenesis inhibition in large established medullary thyroid carcinoma xenografts by Ret inhibitor RPI-1

Recent evidence indicates that the success of molecular targeted therapies may depend on the identification of drug targets which are essential for the survival of subsets of tumors. RET oncogenes that have been implicated in the development of thyroid carcinomas are emerging as potential therapeutic targets. In the present study, we investigated the efficacy and the cellular bases of antitumor activity of the indolinone Ret tyrosine kinase inhibitor RPI-1 against large established s.c. TT tumor xenograft, a human medullary thyroid carcinoma (MTC) harboring oncogenic MEN-2A-type RET mutation. Oral treatment with RPI-1 caused growth arrest or regression in 81% treated tumors. Following treatment suspension, tumor inhibition was maintained (51%, P < 0.05, 100 days) and cures were achieved in 2/11 mice. In treated tumors, Ret was tyrosine dephosphorylated. Moreover, compared to control tumors, a significant increase in apoptotic cells (210%, P < 0.0001), loss of cellularity (47%, P < 0.0001) and reduction of microvessel density (36%, P < 0.0005) were detected. In vivo effects of RPI-1 were reflected in activation of BAD, cleavage of caspases, apoptotic DNA fragmentation and inhibition of VEGF production observed in in vitro RPI-1-treated TT cells. These findings thus indicate that RPI-1 antitumor effect on the MTC was characterized by apoptosis induction and angiogenesis inhibition. The results, consistent with a dependence on RET oncogene activation for maintenance and survival of MEN2A-type MTC, provide further preclinical rationale for a pharmacological RET-targeted intervention in thyroid cancer.     

Imaging,genetic testing,and biomarker assessment of follicular cell-derived thyroid cancer

Abstract

Thyroid carcinoma is the most common endocrine malignancy worldwide, and its incidence continues to increase. As such the approach to a recently identified thyroid nodule is important to understand. The relevant imaging, examination, and need for fine-needle aspiration biopsy (FNA) are discussed. In approximately 25% of nodules, the diagnosis cannot be established with FNA-based cytology, and surgical excision is necessary for definitive diagnosis. Recent advances in genetic and molecular testing may increase the diagnostic accuracy of FNA in managing thyroid nodules.     

The anti-mitotic agents PTC-028 and PTC596 display potent activity in pre-clinical models of multiple myeloma but challenge the role of BMI-1 as an essential tumour gene

Future progress in the treatment of multiple myeloma (MM) requires both the characterisation of key drivers of the disease and novel, innovative approaches to tackle these vulnerabilities. The present study focussed on the pre-clinical evaluation of a novel drug class, BMI-1 modulators, in MM. We demonstrate potent activity of PTC-028 and PTC596 in a comprehensive set of in vitro and in vivo models, including models of drug resistance and stromal support. Treatment of MM cells with PTC-028 and PTC596 downregulated BMI-1 protein levels, which was found to correlate with drug activity. Surprisingly, BMI-1 was dispensable for the activity of BMI-1 modulators and MM cell growth. Our data rather point to mitotic arrest accompanied by myeloid cell leukaemia-1 (MCL-1) loss as key anti-MM mechanisms and reveal impaired MYC and AKT signalling activity due to BMI-1 modulator treatment. Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI-1 as an essential MM gene and confirm BMI-1 modulators as potent anti-mitotic agents with encouraging pre-clinical activity that supports their rapid translation into clinical trials.