胃癌中p21WAF1/CIP1、细胞周期素D1、p53表达的相关性

目的　探讨p2 1WAF1/CIP1、细胞周期素D1(cyclinD1)、p5 3在胃癌中表达之间的相关性。 方法　应用原位杂交技术检测p2 1WAF1/CIP1mRNA、细胞周期素D1mRNA及免疫组化技术检测p5 3蛋白在胃癌中的表达。结果　p2 1WAF1/CIP1mRNA在癌组织及癌旁正常粘膜中阳性表达率各为 93.15 % (6 8/73)及76 .71% (5 6 /73) ,二者相比具有显著差异 (P <0 .0 5 )。CyclinD1mRNA在癌组织及癌旁正常粘膜中阳性表达率各为 5 4 .79% (40 /73)及 30 .16 % (2 2 /73) ,二者具有显著差异 (P <0 .0 5 )。p5 3蛋白在胃癌中的阳性表达率为 32 .87% (2 4 /73) ,p5 3过表达者 ,其 p2 1WAF1/CIP1mRNA表达较p5 3阴性者为低 ,二者存在显著差异 (P <0 .0 5 )。p2 1WAF1/CIP1表达与细胞周期素D1表达呈负相关。结论　p2 1WAF1/CIP1、CyclinD1、p5 3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。     

p21WAF1/CIP1和p53蛋白表达在胃癌发生发展过程中的研究

目的研究p21WAF1/CIP1和p53蛋白在胃癌发生发展过程中的作用及表达的临床病理意义.方法采用免疫组化SP法对正常胃粘膜、萎缩性胃炎伴肠上皮化生、萎缩性胃炎伴不典型增生组织各20例和78例胃癌组织标本进行p21WAF1/CIP1和p53蛋白检测.结果胃癌组织中p53蛋白阳性表达率高于正常胃粘膜、萎缩性胃炎伴肠上皮化生和不典型增生组(P＜0.05),而p21WAF1/CIP1蛋白阳性表达低于正常胃粘膜、萎缩性胃炎伴肠上皮化生组(P＜0.01)p21WAF1/CIP1、p53蛋白表达与胃癌的分化程度相关(P＜0.05);有淋巴结转移组p21WAF1/CIP1蛋白表达率低于无淋巴结转移组(P＜0.05),而有淋巴结转移组p53蛋白表达率高于无淋巴结转移组(P＜0.05);p53蛋白表达与胃癌浸润深度有关.结论p53蛋白高表达与p21WAF1/CIP1蛋白失表达可能参与胃癌的发生发展过程;检测p53和p21WAF1/CIP1蛋白作为反映胃癌病理学特点的参考指标可能有一定意义;p21WAF1/CIP1蛋白表达在胃癌可能存在非p53诱导表达途径.     

细胞周期蛋白D1和p21WAF1/CIP1在喉癌癌变过程中表达及其意义

目的研究喉癌变过程中细胞周期蛋白(cyclin)D1和p21WAF1/CIP1表达及其临床病理学意义.方法用免疫组化检测20例正常黏膜、40例不典型增生病变和60例喉癌组织中cyclinD1和p21WAF1/CIP1的表达.结果①cyclin D1和p21WAF1/CIP1阳性表达定位于细胞核.②在喉癌癌变过程中,喉正常黏膜、不典型增生病变和喉癌中cyclin D1阳性表达率分别为5.0%(1/20),30,0%(12/40),53.3%(32/60)(P＜0.001);p21WAF1/CIP1阳性表达率分别为95.0%(19/20),75.0%(30/40)和63.3%(38/60)(P＜0.05).③p21WAF1/CIP1在高、中和低分化的喉癌中阳性表达率分别为76.2%(16/21),65.5%(19/29)和30.0%(3/10)(P＜0.05);p21WAF1/CIP1阳性表达与肿瘤细胞的分化有关.④cyclin D1和p21WAF1/CIP1阳性表达显著相关.结论①喉癌癌变过程中cyclin D1阳性表达率呈逐渐升高的趋势,而p21WAF1/CIP1阳性表达率呈呈逐渐降低的趋势.②cyclin D1异常表达是喉癌发生中早期分子事件.③p21WAF1/CIP1表达与喉癌细胞分化程度有关.④cyclin D1和p21WAF1/CIP1阳性表达显著相关.     

cyclin D1、p53 蛋自在胃癌组织中的表达

目的研究cyclin D1、p53蛋白在胃癌组织中的表达及两者的相关性.方法采用原位杂交技术及免疫组化技术,分别检测73例胃癌组织中cyclin D1 mRNA及p53蛋白的表达.结果cyclin D1在胃癌组织及癌旁组织中的阳性表达率分别为54.79%(40/73)及28.77%(21/73),两者有显著性差异.cyclin D1 mRNA表达强度与肿瘤分化、浸润深度、淋巴结转移及病理分期无关(P＞0.05),p53蛋白在胃癌组织中的阳性表达率为32.88%(24/73),cyclin D1表达强度与p53表达无关(P＞0.05).结论cyclin D1及p53蛋白的过表达在胃癌的发生发展过程中均起重要作用.     

p21WAF1/CIP1介导肿瘤化疗耐药机制的研究进展

<正>p21WAF1/CIP1是由细胞增殖抑制基因WAF1(wide type p53 activated factor 1)编码的21kDa的蛋白,属于Cip/Kip家族。作为1种细胞周期蛋白激酶(Cds)抑制剂,p21WAF1/CIP1与肿瘤的分化、浸润深度、增生和转移有关,具有判断肿瘤分化程度和预后的价值[1-4],与肿瘤化疗耐药机制的产生密切相关。1 p21WAF1/CIP1介导化疗耐药的作用机制1.1 p21WAF1/CIP1介导细胞周期G1停滞机制p21WAF1/CIP1是细胞周期依赖性激酶抑制蛋白(CDKs)家族中重要的调节因子,其调节细胞周期的作用途径分为p53依赖型途径和p53非依赖型途径[1-2]。     

原发性肝细胞癌组织中p53和p21WAF/CIP1及MDM2蛋白的表达及其临床意义

目的探讨p53、p21WAF/CIP1及MDM2蛋白在原发性肝细胞癌(hepatocellular carcinoma, HCC)组织中的表达及其临床病理意义.方法选取115例HCC及其相应的癌旁肝组织构建组织芯片,应用免疫组织化学方法检测p53、p21WAF/CIP1及MDM2蛋白的表达,采用统计学分析它们的表达及其与临床病理参数之间的关系.结果p53、p21WAF/CIP1及MDM2在HCC组织中的阳性表达率分别为83.5%(96/115)、36.5%(42/115)和48.7%(56/115),同癌旁组织相比,p53、p21WAF/CIP1及MDM2的表达均明显增高,P＜0.05.两两相关分析比较, p53表达分别与p21WAF/CIP1和MDM2表达有关;p53、p21WAF/CIP1及MDM2的阳性表达率与患者性别、年龄、肿瘤大小、肿瘤数量、HBsAg、病理分级、血清AFP浓度和患者生存时间均无关,P均＞0.05.结论p53、p21WAF/CIP1及MDM2在HCC组织中呈增高表达并具有一定的相关性,提示它们可能在HCC的发生发展中发挥重要的作用.     

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。     

细胞周期G1/S转换调控因子在喉癌癌变过程中的表达

目的 :探讨喉癌癌变过程中p2 1WAF1/CIP1、p53和cyclinDl表达的临床病理学意义。方法 :用免疫组化检测 2 0例正常粘膜、4 0例不典型增生病变和 60例喉癌组织中p2 1WAF1/CIP1、p53和cyclinDl 表达。结果 :①p2 1WAF1/CIP1、p53和cyclinDl 阳性表达定位于细胞核 ;②在喉癌癌变过程中 ,喉正常粘膜、不典型增生病变和喉癌中p2 1WAF1/CIP1阳性表达率分别为 95 0 % ( 19/2 0 ) ,75 0 % ( 30 /40 )和 63 3% ( 38/60 ) (P <0 0 5) ;p53阳性表达率分别为 :0 %、30 0 % ( 12 /40 )和 61 7% ( 37/60 ) (P <0 0 0 1) ;cyclinDl 阳性表达率分别为 5 0 % ( 1/2 0 )、30 0 % ( 12 /40 )、53 3% ( 32 /60 ) (P <0 0 0 1) ;③p2 1WAF1/CIP1在高、中和低分化的喉癌中阳性表达率分别为 76 2 % ( 16/2 1)、65 5% ( 19/2 9)和 30 0 % ( 3/10 ) (P <0 0 5) ;④cyclinDl 和p2 1WAF1/CIP1阳性表达显著相关 ,p2 1WAF1/CIP1和p53表达无相关性。结论 :①喉癌癌变过程中p53和cyclinDl 阳性表达率呈逐渐升高的趋势 ,而p2 1WAF1/CIP1阳性表达率呈逐渐降低的趋势 ;②p53和cy clinDl 异常表达是喉癌发生中早期分子事件 ;③p2 1WAF1/CIP1表达与喉癌细胞分化程度有关 ;④细胞周期调控因子p2 1WAF1/CIP1、p53和cyclinDl 相互调控机制     

胃癌及癌前病变中p16、p21WAF1、CDK4、cyclin D1蛋白的表达及其意义

目的探讨胃癌及癌前病变中p16、p21WAF1、CDK4和cyclinD1蛋白的表达、相互关系及其意义。方法应用免疫组化SP法检测胃癌、不典型增生、慢性浅表性胃炎及正常胃组织中p16、p21WAF1、CDK4和cyclinD1蛋白的表达情况。结果胃癌中p16和p21WAF1蛋白表达率分别为52.7％、30.9％,显著低于慢性浅表性胃炎和不典型增生（P<0.01）,而CDK4和cyclinD1蛋白表达率分别为61.8％、47.3％,均明显高于正常胃组织和慢性浅表性胃炎,差异有显著性（P<0.01）,但胃癌和不典型增生组织中CDK4和cyclinD1蛋白表达率之间差异无显著性（P>0.05）。胃癌中p16与cyclinD1蛋白表达呈负相关关系（P<0.05）,而CDK4与cyclinD1呈正相关关系（P<0.01）。结论胃癌发生机制涉及p16、p21WAF1、CDK4和cyclinD1调节通路中多个基因的异常,且与胃癌Lauren分型、浸润深度、淋巴结转移有关。CDK4和cyclinD1蛋白高表达可能是胃癌发生过程中的早期分子事件。     

NS-398调节HepG2细胞组蛋白乙酰化和p21WAF1/CIP1表达

背景与目的:研究非甾体药物NS-398对人肝癌细胞株HepG2细胞组蛋白H3乙酰化水平的调节作用及对细胞周期素依赖性激酶抑制p21WAF1/CIP1表达的影响.材料与方法:用不同浓度(100、200、300、400μmol/L)的NS-398处理HepG2细胞,以四甲基偶氮唑蓝(MTT)法测定肿瘤细胞增殖抑制率,流式细胞仪(FCM)检测细胞周期的改变及凋亡百分率的变化,应用NS-398分别作用HepG2细胞4、8、12、24、48 h,非药物作用组作为对照,提取细胞的总RNA和总蛋白,采用RT-PCR技术检测p21WAF1/CIP1 mRNA表达情况,并用免疫印迹技术(Western blot)观察组蛋白H3的乙酰化水平变化及p21WAF1/CIP1蛋白的表达水平.结果:NS-398抑制HepG2细胞增殖,且呈剂量依赖性,并诱导其凋亡.且呈浓度依赖性改变细胞周期的分布,一方面增高G0/G1期细胞比例,另一方面降低S期和G2/M期细胞比例,与对照组相比差异具有统计学意义(P＜0.05).NS-398对组蛋白H3乙酰化作用随时间改变而变化,可引起组蛋白H3的乙酰化.NS-398对p21WAF1/CIP1 mRNA和p21WAF1/CIP1蛋白表达的影响呈时间依赖性.结论:NS-398明显上调HepG2细胞组蛋白H3的乙酰化水平,促进细胞周期依赖性激酶抑制剂p21WAF1/CIP1的表达.     

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.     

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     

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。     

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.     

PD-1/PD-L1/2通路在多发性骨髓瘤中的研究进展

多发性骨髓瘤（MM）是一种浆细胞恶性克隆增殖性疾病，近年来，蛋白酶体抑制剂、免疫调节剂在多发性骨髓瘤中的应用明显延长了患者的生存期并提高了生存质量，但因疾病的异质性、易复发及耐药性，目前仍无法治愈。免疫检查点抑制剂如Pembrolizumab、Nivolumab、Pidilizumab、Atezolizumab及Durvalumab等为MM带来了曙光。本文通过回顾近年来国内外的相关文献，综述MM的免疫发病机制、PD-1/PD-L1/2相关的免疫通路及免疫治疗的现状，希望为MM的免疫治疗提供参考。