P21WAF1/CLP1在甲状腺癌组织的表达及临床意义

[目的]探讨p21WAF/CLP与p53基因在甲状腺癌中的表达与病理类型和分化程度的关系。[方法］应用免疫组化技术检测甲状腺癌组织中的抑癌基因p2lWAF/CLPl及p53基因的表达。统计学采用x2检验。[结果]甲状腺腺瘤(TT),甲状腺乳头状癌(PTC)、滤泡状癌(FTC)、未分化癌(UDC)组织p21蛋白阳性率分别为66.7％、62 5％、58.3％、50.0％,各组之间无显著差别(P＞0.05);高分化癌(WDC)、低分化癌(PDC)、UDC组织p21蛋白阳性率分别为67.7％、46.2％、50.0％,各组之间无显著差别(P＞0.05);PTC、FTC、UDC组织p53蛋白阳性率分别为31.3％、25.0％、64.3％,UDC与PTC、FTC之间存在显著差别(P＜0 05);WDC、PDC、UDC组织p53蛋白阳性率分别为l6.1％、61.5％、64.3％,WDC的阳性率明显低于PDC、UDC(P＜0.05);p53蛋白阳性的癌组织p21蛋白阳性率为40.9％(9/22),p53蛋白阴性的癌组织p21蛋白阳性率为69.4％(25/36),两者之间存在显者差异(P＜0 05)。[结论］甲状腺癌中p21WAF/CLP的表达与其病理类型和分化程度无关,而p53基因的表达与甲状腺癌病理类型和分化程度有关,p2WAFl/CLPl作为一新的抑癌基因,其表达相当程度上依赖于p53蛋白。     

p21~(WAF1/CIP1)在甲状腺癌组织的表达及临床意义

[目的]探讨 p21WAF1/CIP1与 p53基因在甲状腺癌中的表达与病理类型和分化程度的关系。[方法]应用免疫组化技术检测甲状腺癌组织中的抑癌基因 p21WAF1/CIP1及 p53基因的表达。统计学采用 χ2 检验。[结果]甲状腺腺瘤(TT) ,甲状腺乳头状癌(PTC)、滤泡状癌(FTC)、未分化癌(UDC)组织 p21蛋白阳性率分别为66 7%、62 5 %、58 3 %、50 0% ,各组之间无显著差别(P>0 05) ;高分化癌(WDC)、低分化癌(PDC)、UDC组织p21蛋白阳性率分别为67 7 %、46 2 %、50 0 % ,各组之间无显著差别(P>0 05) ;PTC、FTC、UDC组织 p53蛋白阳性率分别为31 3%、25 0 %、64 3 % ,UDC与PTC、FTC之间存在显著差别(P<0 05) ;WDC、PDC、UDC组织 p53蛋白阳性率分别为16 1 %、61 5 %、64 3 % ,WDC的阳性率明显低于PDC、UDC(P<0 05) ;p53蛋白阳性的癌组织 p21蛋白阳性率为40 9%(9/22) ,p53蛋白阴性的癌组织 p21蛋白阳性率为69 4%(25/36) ,两者之间存在显者差异(P<0 05)。[结论]甲状腺癌中 p21WAF1/CIP1的表达与其病理类型和分化程度无关 ,而 p53基因的表达与甲状腺癌病理类型和分化程度有关 ,p21WAF1/CIP1作为一新的抑癌基因 ,其表达相当程度上依赖于 p53蛋白。     

P53、P21^WAF1和CDK1在卵巢上皮性癌组织中的表达及意义

背景与目的：P53、P21^WAF1,和CDK1是细胞周期中G2／M期DNA损伤检验点“P53通路”的关键因子,本研究拟探讨P53、P21^WAF1和CDKl在卵巢上皮性癌组织中的表达及意义。方法：应用免疫组织化学技术检测20例正常卵巢组织、20例卵巢良性上皮性肿瘤组织、76例卵巢上皮性癌组织中P53、P21^WAF1、CDK1蛋白的表达,并分析卵巢上皮性癌组织中P53、P21^WAF1、CDK1蛋白表达与其临床病理特征的关系以及各蛋白表达之间的相关性。结果：P53、P21^WAF1和CDK1蛋白在卵巢上皮性癌中的阳性率与正常卵巢组织和良性卵巢肿瘤相比其差异均有统计学意义（P〈0．05）,而在正常卵巢组织与良性卵巢肿瘤之间其阳性率差异均无统计学意义（P〉0．05）。在卵巢上皮性癌中,临床分期越晚、组织分化越差,P53蛋白表达越高;随着临床分期的增加,P21^WAF1蛋白表达逐渐降低;CDK1蛋白的表达与各临床病理特征无相关性。卵巢上皮性癌中P53蛋白和P21^WAF1蛋白的表达与CDK1蛋白的表达呈负相关（r=0．388,P=0．001;r=-0．282,P=0．014）,P53蛋白与CDK1蛋白表达呈正相关（r=0．263,P=0．022）。结论：1〉53蛋白与卵巢上皮性癌的恶性程度相关,P53和P21^WAF1蛋白可能与卵巢上皮性癌的恶性进展有关。检测CDK1可能有助于卵巢癌的早期诊断。     

Survivin蛋白在乳腺浸润性导管癌的表达及与p21WAF1、p53的关系

目的研究survivin蛋白在乳腺癌的表达及与p21^WAF1、p53的关系。方法免疫组化二步法（Envision）检测5例乳腺导管内癌及68例浸润性导管癌中单克隆抗体survivin、p21^WAF1、p53蛋白的表达。结果survivin蛋白表达位于细胞浆内;在乳腺导管内癌表达率为40.00％（2／5）,在乳腺浸润性导管癌表达率为64、71％（44／68）,两者差异无统计学意义（P=0.261）;survivin蛋白表达率在组织学Ⅱ～Ⅲ级乳腺癌中明显高于Ⅰ级（P=0．037）,p21^WAF1蛋白表达率为57．53％、p53蛋白表达率为52．05％,三种蛋白表达无相关性。结论survivin蛋白在乳腺癌发生的早期即起作用并持续于乳腺癌的浸润转移过程中,其表达可作为乳腺癌组织分化的参考指标。     

p53蛋白在大肠癌中过度表达与组织学类型及分级的关系

目的：探讨大肠癌的发生与组织学的类型及分化程度的关系。方法：用免疫组织化学及常规病理学方法检测55例大肠癌中抑癌基因p53蛋白的过度表达。结果：p53蛋白的过度表达在大肠癌中为8％,而在正常组织及良性肿瘤中为无表达,按Turbull分期,不同分期大肠癌中p53蛋白过度表达阳性率不同,早期癌（Ⅰ－Ⅱ期）中为32．1％。（9／28）,晚期癌（Ⅲ－Ⅳ期）中为48．1％（13／27）（P＜0．015）,p53蛋白过度表达在不同组织类型中阳性率不同,如粘液腺癌为41．6％,明显低于管状腺癌的66．6％和乳头状腺癌的53．3％的阳性率。其粘液腺癌与管状腺癌的差异显（P＜0．05）,p53蛋白的过度表达在不同分化程度的大肠癌中阳性率亦不同,高分化癌为37．5％;而低分化癌为75．4％,（P＜0．05）。结论：p53蛋白过度表达可能发生于大肠癌病理过程的晚期阶段,可作为大肠癌有参考价值的预后指标之一。     

脑胶质瘤组织p14^ARF、p53和p21^WAF1的表达及其意义

目的：探讨p14^ARF、p53和p21^WAF1蛋白在不同级别脑胶质瘤组织中的表达及其在胶质瘤发生、发展中的生物学意义。方法：应用免疫组化SP法检测Ⅱ级和Ⅳ级胶质瘤组织中p14^ARF、p53和p21^WAF1蛋白的表达,并分析其与胶质瘤组织学分级之间的关系。结果：Ⅱ级和Ⅳ级胶质瘤中,p53蛋白的阳性表达率分别为28．00％（7／25）及60．87％（14／23）（P=0．022）,其阳性表达率随胶质瘤恶性程度的增加而升高,Spearman等级相关分析显示,p53的表达与胶质瘤分级呈正相关（P〈0．05）;p21^WAF1的阳性表达率分别为76．00％（19／25）及39．13％（9／23）（P=0．010）,P14^ARF的阳性表达率分别为76．00％（19／25）及34．78％（8／23）（P=0．004）,二者阳性表达率均随胶质瘤恶性程度的增加而降低,Spearman等级相关分析显示,p21^WAF1、p14^ARF的表达与胶质瘤分级呈负相关（P〈0．05）。结论 胶质瘤组织中,p53呈不同程度的过表达,且随胶质瘤恶性程度的增加而表达水平升高;p21^WAF1、p14^ARF随胶质瘤恶性程度的增加表达水平降低。突变型p53蛋白的过表达以及p21^WAF1、p14^ARF蛋白的低表达,可促进胶质瘤的发生、发展。     

抑癌基因p53在大肠癌中的表达及其意义

用免疫组织化学方法检测55例大肠癌中抑癌基因p53蛋白的过度表达，以探讨大肠癌的发生与组织学的类型及分化程度的关系。结果显示：p53蛋白的过度表达在大肠癌中为53．8％，而在正常及良性肿瘤中为阴性。按Turbull氏分期，不同分期大肠癌中p53蛋白过度表达阳性率不同，早期癌（Ⅰ－Ⅱ）中为32．1％（9／28）；晚期癌（Ⅲ－Ⅳ）中为48．1％（13／27），差异明显（P＜0．015），p53蛋白过度表达在不同组织类型中阳性率不同，粘液腺癌中阳性率（41．6％）明显低于管状腺癌（66．6％）和乳头状腺癌（53．3％）的阳性率。其粘液腺癌与管状腺癌的差别较显著（P＜0．05）。p53蛋白的过度表达在不同分化程度的大肠癌中阳性率不同，高分化癌中为37．5％，而低分化癌中为75．4％，差异显著（P＜0．05）。提示：p53蛋白过度表达可能发生于大肠癌病理过程的较晚阶段，作为大肠癌的预后指标可能有参考价值。     

鼻咽癌p53 p21 WAF1和MDM2蛋白异常表达的临床意义

目的：探讨p53、p21^WAF1、MDM2蛋白在原发鼻咽癌（NPC）异常表达的临床意义。方法：采用LSAB法检测69例原发NPC组织中p53、p21^WAF1和MDM2蛋白的表达状况。结果：1）p53、p21^WAF1和MDM2蛋白在原发NPC组织的阳性表达率分别为79．7％、84．1％、和82．6％；高表达率分别为50．7％、46．4％和31．9％。2）p53蛋白的高表达率随TNM分期的升高而增多，P＝0．042。3）p53或MDM2蛋白高表达者的复发间期显著短于相应蛋白低表达／阴性者，分别P＝0．038和P＝0．002。4）p53和MDM2蛋白同时高表达者、MDM2蛋白高表达同时p21^WAF1蛋白低表达／阴性者的复发间期明显短于对照组，分别P＜0．001；p21^WAF1蛋白高表达同时p53蛋白低表达／阴性者、p53和MDM2蛋白同时低表达／阴性者的复发间期显著长于对照组，分别P＝0．002和P＝0．014。5）p53和MDM2蛋白高表达同时p21^WAF1蛋白低表达／阴性者的复发间期明显短于对照组，P＜0．001；p53和MDM2蛋白低表达阴性同时p21^WAF1蛋白高表达者的复发间期明显长于对照组，P＝0．002。结论：p53或MDM2蛋白高表达提示有促进NPC复发的作用，p21^WAF1蛋白高表达提示有抑制NPC复发的作用。单独检测p53或MDM2蛋白在原发NPC组织的表达情况可以和为预测NPC复发倾向和临床预后的参考指标；如同时检测p53、MDM2和p21^WAF1蛋白的两项或三项指标，预测意义更理想。     

甲状腺癌组织端粒酶激活与p16基因失活的研究

目的：探讨甲状腺癌细胞增殖、分化与端粒酶激活及抑癌基因p16失活（缺失突变）之间可能存在的联系。方法：应用TRAP、多重PCR、免疫组化法检测42例甲状腺癌与16例癌旁组织端粒酶活性、p16基因外显子2缺失、p16蛋白表达。结果：甲状腺癌组端粒酶活性90．48％，高于癌旁组织（P（0．01）；甲状腺癌p16基因外显子2纯合缺失率28．57％。相应癌旁组未检出（P〈0．01）；甲状腺癌p16蛋白表达缺失率40．48％，高于癌旁组（P〈0．05）；甲状腺癌p16蛋白表达缺失率高于p16基因外显子2缺失率。结论：端粒酶激活与p16基因失活以及p16蛋白表达下调可能是甲状腺癌变过程中的重要分子事件．甲状腺癌中p16基因失活可能是端粒酶激活的一种途径。     

c-erbB-2、ras、p53基因产物在大肠癌及癌前病变中的表达

目的：探讨c－erbB－2、ras、p53基因的表达与大肠癌发生发展的关系以及其对大肠癌早期诊断、预后判断的价值。方法：对45例大肠癌及36例癌旁非腺瘤型不典型增生、17例大肠腺瘤，用免疫组化方法检测基因产物的表达。结果：p53在大肠癌的阳性表达率为57．8％，p53蛋白高表达的癌旁非腺瘤型不典型增生及大肠腺瘤均为中度或高度不典型增生。p53蛋白表达与大肠癌的组织分化程度、淋巴结转移有关（P＜0．05）。p21、p185蛋白表达与大肠癌组织学分型、癌组织浸润程度、淋巴结转移无关，而与癌组织分化程度有关（P＜0．05）。结论：p53蛋白表达可能是大肠病变恶性倾向的一个独立标志。p53、p21、p185蛋白对大肠癌的发生、发展起重要作用。     

胃癌中p21WAF1/CIP1、细胞周期素D1、p53表达的相关性

目的探讨p21WAF1/CIP1、细胞周期素D1(cyclin D1)、p53在胃癌中表达之间的相关性.方法应用原位杂交技术检测p21WAF1/CIP1 mRNA、细胞周期素D1 mRNA及免疫组化技术检测p53蛋白在胃癌中的表达.结果 p21WAF1/CIP1 mRNA在癌组织及癌旁正常粘膜中阳性表达率各为93.15%(68/73)及76.71%(56/73),二者相比具有显著差异(P<0.05).Cyclin D1 mRNA在癌组织及癌旁正常粘膜中阳性表达率各为54.79%(40/73)及30.16%(22/73),二者具有显著差异(P<0.05).p53蛋白在胃癌中的阳性表达率为32.87%(24/73), p53过表达者,其p21WAF1/CIP1 mRNA表达较p53阴性者为低,二者存在显著差异(P<0.05).p21WAF1/CIP1表达与细胞周期素D1表达呈负相关.结论 p21WAF1/CIP1、Cyclin D1、p53的异常表达及它们之间可能存在的相互作用,对于胃癌的发生发展具有重要意义.     

Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1

It is clear that FANCJ, also known as BACH1 or BRIP1, is an essential tumor suppressor gene based on the identification of clinically relevant mutations not only in breast cancer, but also the childhood cancer syndrome, Fanconi anemia. This conclusion is further supported by the direct and functional interaction between FANCJ and the hereditary breast cancer-associated gene product BRCA1. In the absence of the FANCJ DNA helicase or its interaction with BRCA1, cells have defects in several aspects of the DNA damage response. In particular, the BRCA1-FANCJ interaction is essential for promoting error-free repair, checkpoint control and for limiting DNA damage tolerance. As the number of FANCJ clinical mutations and affected patients accumulate, it will be critical to understand whether the associated tumors resemble BRCA-associated tumors. If so, FANCJ patients could also benefit from new therapies that selectively sensitize DNA repair-defective tumors and spare healthy cells. In this article, we summarize the breast cancer-associated FANCJ mutations and discuss functional outcomes for DNA repair and tumor suppression.     

Anti-PD1/PDL1 induced psoriasis

BackgroundImmune checkpoint inhibitors are novel agents approved for the treatment of late-stage malignancies. Despite its important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects known as immune-related adverse events. Skin toxicities are the most frequent immune-related adverse events during anti-PD1 blockade therapies. Among them, rare cases of psoriasis exacerbation have been reported.MethodsWe present the clinical characteristics of exacerbated psoriasis in 5 patients under anti-PD1/PDL1 therapy.ResultsA total of 5 patients were overall included (4 males, 1 female mean age 65.8 years). Among them, 3 were diagnosed with nonsmall cell lung cancer, 1 with papillary urothelial carcinoma, and 1 with squamous cell carcinoma of the tonsil. Of all, 3 patients were treated with anti-PD1 (1 with pembrolizumab, 2 with nivolumab), whereas the remaining 2 with anti-PDL1 (durvalumab). Only 1 out of 5 patients had active psoriatic lesions at the time of treatment initiation, 2 shared a past history of psoriasis, and 1 reported a strong related family history (3/5 siblings). Four out of 5 patients experienced guttate lesions, though the most severe exacerbation was noted in the durvalumab group. Four out of 5 patients managed to continue treatment after close dermatologic monitoring, whereas 1 patient under durvalumab was forced to treatment delays owing to the severity of the skin reactions. Skin rashes appeared in all patients after the fourth cycle of immunotherapy.ConclusionsBoth anti-PD1 and anti-PDL1 therapies can lead to psoriasis exacerbation although more severe flares were noted in patients treated with durvalumab. Not only personal but also related family history of psoriasis are significant risk factors and need to be outlined before treatment initiation. If such related history exists, strict skin surveillance can lead to the early diagnosis and treatment of any psoriatic exacerbations that could otherwise severely affect quality of life or even compromise therapeutic protocols and final prognosis.     

PD-1/PD-L1抑制剂的困境与sPD-1/sPD-L1的标志物潜能

PD-1和PD-L1免疫检查点抑制剂是肿瘤治疗的又一个里程碑,但缺乏灵敏度和特异度高的标志物来筛选对免疫检查点抑制剂敏感的患者,导致在部分癌种和患者中有效率低;而且由于毒副作用和耐药性的存在,进一步限制了其临床应用。可溶性PD-1(sPD-1)和可溶性PD-L1(sPD-L1)是PD-1和PD-L1的溶解形式,已在多种肿瘤中被证实与肿瘤的临床病理特征、分期、疾病的严重程度、治疗敏感性及预后密切相关,可能成为免疫治疗的标志物。全文就PD-1/PD-L1抑制剂的作用机制和其在临床应用中的困境及sPD-1和sPD-L1的标志物潜能进行综述。     

脑肿瘤中Pten／MMAC1／Tep1蛋白的表达

目的：探讨Ｐｔｅｎ／ＭＭＡＣ１／Ｔｅｐ１蛋白在不同分化程度的脑肿瘤组织中的表达。方法：应用免疫组化技术检测３０例脑胶质细胞瘤和１５例脑膜瘤Ｐｔｅｎ／ＭＭＡＣ１／Ｔｅｐ１蛋白表达。结果：脑胶质细胞瘤组织中Ｐｔｅｎ／ＭＭＡＣ１／Ｔｅｐ１蛋白表达阳性率为５３．３３％,脑膜瘤组织中Ｐｔｅｎ／ＭＭＡＣ１／ｅｐ１蛋白表达阳性率为９３．３３％,两者差异有显著性（Ｐ〈０．０１）。结论Ｐｔｅｎ／ＭＭＡＣ１／Ｔｅｐ１     

Plastin 1 drives metastasis of colorectal cancer through the IQGAP1/Rac1/ERK pathway

Tumor metastasis is the dominant cause of death in colorectal cancer (CRC) patients, and it often involves dysregulation of various cytoskeletal proteins. Plastin 1 (PLS1) is an actin‐bundling protein that has been implicated in the structure of intestinal epithelial microvilli; however, its role in CRC metastasis has not yet been determined. In this study, we demonstrated that PLS1 is highly expressed in 33.3% (45/135) of CRC patients and is correlated with lymph node metastasis and poor survival. In in vitro and in vivo experiments, PLS1 induced the migration and invasion of CRC cells and the metastases to the liver and lung in mice. Moreover, the expressions of key factors for CRC metastases, matrix metalloproteinase (MMP) 9 and 2, were enhanced by PLS1, which was dependent on phosphorylating ERK1/2 activated by IQGAP1/Rac1 signaling. The connection between these signals and PLS1 was further confirmed in CRC tissues of patients and the metastatic nodules from a mouse model. These findings suggest that PLS1 promotes CRC metastasis through the IQGAP1/Rac1/ERK pathway. Targeting PLS1 may provide a potential approach to inhibit the metastasis of CRC cells.     

Mutational analysis of the p21/WAF1/CIP1/SDI1 coding region in human tumor cell lines

p21/WAF1/CIP1/SDI1 is an important cell-cycle mediator with tumor suppressor gene capabilities, and its inactivation could potentially lead to tumor progression. Because tumor suppressor genes are commonly inactivated by somatic and germline mutations, we analyzed a variety of human tumor cell lines for p21 mutations. We used single-strand conformational analysis and direct sequencing to identify possible mutations in the p21 coding region. Two base-alterations were observed in 41 immortalized human tumor cell lines. A previously reported polymorphism that results in a serine-to-arginine amino-acid substitution at codon 31 was found in 24% (10 of 41) of the tumor cell lines but was also found in 10% (six of 62) of normal parental DNAs tested and 7% (three of 43) of normal DNAs from patients with primary endometrial tumors. Another nucleotide substitution found at codon 80 resulted in the replacement of threonine with methionine. Codon 80 changes were found in 7% (three of 41) of the tumor cell lines (all endometrial) and in 2% (one of 62) of the normal parental DNAs. (This article is a US Government work and, as such, is in the public domain in the United States of America.)     

Prognostic impact of p21/waf1/cip1 in colorectal cancer

In addition to the tumor suppressor gene p53, Cyclin Dependent Kinases (CDK) are well known to influence the cell cycle in normal human tissues and various neoplasias as well. The purpose of our present study was to evaluate the expression of the CDK-inhibitor p21/waf1/cip1 in colorectal cancer with special emphasis on the prognostic impact. Between 1985 and 1991, 294 patients (median age, 65 years) underwent surgical operative therapy for colorectal cancer. Formalin-fixed and paraffin-embedded tumor specimens were investigated. For immunohistochemistry the Catalysed Reporter Deposition (CARD) technique was performed. The survival probability was calculated and possible prognostic risk factors were tested using multivariate analysis. The p21/ waf1/cip1 staining pattern was positive in 197 (67%) specimens and negative in 97 (33%) samples. No significant correlation could been calculated between p21/waf1/cip1 expression and other variables such as age, sex, WHO-Classification, localisation, grading, TNM-classification or UICC-stage. Patients with a positive staining reaction had a significantly better survival (p < 0.0052). Moreover, p21/waf1/cip1 was shown to be an independent prognostic parameter by multivariate analysis (p < 0.022). In contrast with these findings, the p53 tumor status had no impact on survival. P21/ waf1/cip1 appears to be an independent prognostic parameter in colorectal cancer and is associated with a favorable survival. This feature may be related to a cell cycle arrest in the G1 phase induced by p21/waf1/cip1, resulting in lower tumor cell proliferative activity.