CyclinA、PTEN、Survivin和p27与食管癌相关性的研究进展

细胞周期蛋白A（CyclinA）是细胞周期正性调控因子,表达高低与肿瘤的发生及进展状态关系密切。第10号染色体同源丢失性磷酸酶一张力蛋白基因（PTEN）是迄今发现的第一个具有双特异性磷酸酶活性的抑癌基因,在调节细胞的增殖和凋亡、细胞的粘连和转移等方面发挥重要作用。生存素（Survivin）是凋亡抑制蛋白（inhibitor of apoptosis protein,lAP）家族中的新成员,在多种肿瘤中Survivin的表达增加与肿瘤侵袭能力的增加和患者生存时间的缩短相关联。p27是一种重要的细胞周期蛋白激酶抑制蛋白（cyclin depend-ent kinase inhibitor,CKI）家族成员,其主要功能是作为细胞周期素依赖性蛋白激酶（cyclin dependent kinase,CDK）抑制因子参与细胞周期调控。本文就CyclinA,PTEN,Survivn和p27与食管癌的相关性研究进展作一综述。     

INK4a／ARF抑癌基因

细胞增殖失控和细胞凋亡障碍是癌变的根本原因,而大多数肿瘤细胞都是通过干扰 Rb（ retinoblastoma,Rb）蛋白和 p53的功能,导致细胞周期调节紊乱和凋亡反应阻抑的。 INK4a/ARF（ inhibitor of CDK4/ alternative reading frame）基因可同时调控这两条控制细胞增殖和凋亡的通路,它编码两种蛋白： p16INK4a,一种细胞周期素依赖蛋白激酶抑制蛋白 (CKI),可以上调 Rb蛋白的活性; p19ARF,可以阻抑 mdm2抑制 p53的活性（ mdm2：小鼠双微 -2, murine double minute-2）。这种同一基因—两个产物—两条途径的方式,在哺乳动物中相当罕见,为探索肿瘤的发生提供了一种新的思路。 1 p16INK4a的发现与结构 细胞周期是由细胞周期素（ cyclin）、细胞周期素依赖蛋白激酶 (CDK) 和细胞周期素依赖蛋白激酶抑制蛋白 (CKI)来进行调控的。 CKI分为两类： INK4（ inhibitor of CDK4）和 KIP家族,其中 INK4a和 INK4b位于染色体 9p21。 1992年, Cannon-Albright[1]在研究黑色素瘤的易感基因时,发现 9p21有一个抑癌基因所在位点; 1993年, Xiong Y[2]在用 DNA肿瘤病毒 SV40转化的二倍体成纤维细胞中 ,发现了一个与 CDK4紧密结合的 16 kDa的多肽 (p16);同年, Serrano[3]用酵母双杂合蛋白相关性筛选法,把两个融合蛋白 CAL4ad和 GALR4db与 p16基因表达蛋白进行筛选,发现 p16的 cDNA编码的蛋白与 CAL4ad 相同,命名为 p16INK4a蛋白; 1994年, Kamb[4]利用染色体步移法（ chromosal walk）的物理图和序列标记位点图 (sequence tagged sites,STSs),研究肺癌、乳腺癌、膀胱癌等多种细胞系,发现 9p21存在一个与 p16 cDNA序列相同的多肿瘤抑制基因,命名为 MTS1(multiple tumor suppressor 1),以后由 HUGO正式命名为 CDKN2(cyclin dependent kinase inhibitor 2)。     

食管鳞状细胞癌组织中Cyclin A、PTEN和p27kip1蛋白表达及临床意义

目的 探讨细胞周期蛋白A（Cyclin A）、第10号染色体同源缺失性磷酸酶 张力蛋白基因（PTEN）和p27kip1蛋白在食管鳞状细胞癌（ESCC） 组织中的表达及其临床意义。方法 采用免疫组化En Vision二步法检测68例食管鳞癌组织和25例癌旁正常组织中Cyclin A、PTEN和p27kip1的表达,并分析其与临床病理特征及预后的关系。结果 食管鳞癌组织中Cyclin A、PTEN和p27kip1阳性表达率分别为60.3％、35.3％和41.2％,与癌旁正常组织比较差异有统计学意义（P＜0.05）。3种蛋白表达均与肿瘤大小、淋巴结转移和组织学分级有关（P＜0.05）,其中Cyclin A与年龄有关。经Kaplan Meier法生存比较, Cyclin A阳性表达者较阴性表达者的总生存期短,而PTEN和p27kip1阴性表达者较其阳性表达者的总生存期长。结论 Cyclin A、PTEN和p27kip1的表达与食管鳞癌的发生发展、转移和预后的关系密切相关,联合检测有望成为评估食管鳞状细胞癌生物学行为及预后的有效指标。     

乳腺癌中p27表达及其临床意义

真核细胞增殖过程中，细胞周期素和CDK复合物调控分裂周期的转变。p27基因定位于RP13，它的表达产物p27蛋白是细胞周期的负向调控因子，p27蛋白可以通过抑制细胞周期素依赖性蛋白激酶来抑制细胞周期，阻止肿瘤形成。     

p27、cyclin D1与恶性肿瘤

细胞周期调控紊乱是恶性肿瘤发生、发展的主要原因之一,其中,蛋白p27与cyclin D1在细胞周期调控中发挥了重要作用.p27与cyclinD1是细胞周期正负调控因子.p27蛋白在多数肿瘤中低表达或不表达,而cyclinD1蛋白多呈高表达,它们与恶性肿瘤的发生、发展关系密切.目前细胞周期及其调控机制与肿瘤的关系已成为研究热点.     

抑癌基因P27在急性白血病中作用的研究进展

P27是近年发现的一种抑癌基因,是细胞周期蛋白依赖性激酶抑制剂（cyclindependent kinase inhibitor,CDKIs）家族成员之一。作为细胞周期负调控因子,P27蛋白具有参与细胞周期调控、诱导凋亡、促进细胞分化等多种生物学功能。许多实体瘤存在着P27基因的缺失、突变和低表达,P27的表达水平与急性白血病的发生、发展、治疗、预后密切相关。P27可应用于急性白血病的靶向治疗,通过提高P27蛋白表达水平可治疗白血病。P27基因DNA甲基化研究尚处于初始阶段,急性白血病P27 甲基化与基因表达的关系尚未明确,P27基因甲基化的改变能否作为白血病临床早期诊断及治疗的一个重要靶标,有待于深入探讨。     

Cip/Kip家族的独特成员——p57Kip2的研究进展

p57Kip2属于细胞周期依赖激酶抑制因子(cyclin dependent kinases inhibitor,CDKI)Cip/Kip家族的成员之一,CKI能竞争性地与细胞周期蛋白依赖性激酶(cyclin dependent kinase,CDK)结合抑制其活性,从而调整细胞周期。与家族其它成员相比,p57Kip2在结构和功能有其特殊性。p57Kip2通过多种机制参与肿瘤的发生、侵袭和转移过程,Cip/Kip蛋白能在不同水平抑制Rho/ROCK/LIM/coffilin信号通路而参与肿瘤的形成、侵袭和转移,但在不同的细胞定位和调控下,p57Kip2在肿瘤的侵袭和转移中扮演双重角色。p57Kip2在细胞分化、凋亡上也具有重要作用,p57Kip2的表达异常使细胞不分化和过度增殖而形成肿瘤,p57Kip2在细胞凋亡中的作用也许可以作为肿瘤治疗的靶点。多功能的p57Kip2通过印记丢失、杂合性缺失、启动子甲基化、组蛋白去乙酰化和microRNA的调控等参与肿瘤形成的多个过程。本文就p57Kip2在以上几个方面的研究进展做一综述。     

肿瘤细胞p27kip1蛋白错位分布和低表达的分子机制

p27kip1(p27)蛋白是一种调控细胞周期并抑制细胞分裂的重要因子,p27是细胞周期依赖性激酶抑制因子(CDKI),参与细胞周期的负性调控,在细胞增殖、分化和凋亡等活动中扮演重要角色,p27被认为是人类多种肿瘤独立的预后因子和未来可能的肿瘤治疗靶点。在多种肿瘤细胞内存在p27蛋白低水平表达,p27蛋白的功能异常与多种肿瘤的发生密切相关。除了低丰度表达以外,在多种肿瘤细胞中p27蛋白主要分布在细胞核外,导致p27在肿瘤细胞内错位分布和低丰度表达的分子机制并不清楚。p27蛋白是一种功能广泛的细胞周期调节因子,除了可以和已知几乎所有的细胞周期素(cyclin)和细胞周期激酶(CDK)结合以外,还可以和包括CRM1、Nup50、Jab1和Skp2等在内的细胞核内外多种分子相互作用。推断p27发挥其抑制细胞增殖、促进细胞凋亡等生物学作用是受到以上多种相互作用的蛋白因子调控,这些因子在细胞周期不同的结合顺序和状态是发挥其广泛的生物学效应的分子基础,p27与适当的底物结合后,才能在适当的时间到达适当的细胞内位置并且发挥其生物学活性。因此认为,在肿瘤细胞p27存在和正常细胞不同的相互作用蛋白谱,并且由此决定了p27蛋白错位分布和低表达的可能机制,但是确切调控机制仍需进一步阐明。     

Survivin在乳腺癌中作用的研究进展

生存素（Survivin）属于凋亡抑制蛋白（inhibitor of apoptosis protein,IAP）家族中的新成员,是新近发现的最强的凋亡相关因子。Survivin不仅能够抑制caspase的活性从而抑制细胞的程序性死亡（programmed cell death,PCD）,同时也能部分抑制Bax和Fas的活性从而调节细胞的有丝分裂[1]。Survivin通过其凋亡抑制作用参与包括乳腺癌、胰腺癌、肾癌和膀胱癌等常见肿瘤的发生和发展过程。现今,Survivin与乳腺癌的关系是学者研究的热点,本文就Survivin在乳腺癌中作用的研究进展做一综述。     

雷帕霉素对人淋巴瘤Raji细胞株增殖影响及其机制的探讨

目的:探讨雷帕霉素(宜欣可)对人淋巴瘤细胞株Raji细胞体外增殖及细胞周期的影响,并分析其分子作用机制.方法:采用MTT法检测不同浓度(0、1、5、10、20、40、50和100 nmol/L)雷帕霉素作用不同时间(24、48和72 h)对Raji细胞增殖的影响.用流式细胞仪测定雷帕霉素对Raji细胞周期分布和凋亡的影响.应用蛋白质印迹法检测雷帕霉素对Raji细胞周期蛋白Cyclin D1、Cyclin E、Cyclin A和p27及凋亡蛋白抑制因子Survivin蛋白表达的影响.结果:雷帕霉素浓度＞5 nmol/L对Raji细胞增殖有明显的抑制作用(P＜0.05).且呈现明显的剂量-效应和时间-效应依赖关系.雷帕霉素处理后,可明显抑制Raji细胞周期发展(P＜0.05),随着药物浓度的加大、作用时间的延长,处于G0/G1期细胞逐渐增多,S期和G2/M期细胞则逐渐减少.但Raji细胞没有发生明显的凋亡现象(P＞0.05).50 nmol/L雷帕霉素处理后,Raji细胞的Cyclin D1、Cyclin E、p27表达水平没有明显变化(P＞0.05),但Cyclin A和Survivin表达水平被明显抑制(P＜0.05).结论:雷帕霉素通过阻滞细胞周期发展抑制Raji细胞增殖,其作用机制可能与下调细胞Cyclin A和Survivin表达有关.     

Selenium, lycopene, alpha-tocopherol, beta-carotene, retinol, and subsequent bladder cancer

To examine the association between serum nutrients and the development of bladder cancer we measured selenium, alpha-tocopherol, lycopene, beta-carotene, retinol, and retinol-binding protein in serum collected from 25,802 persons in Washington County, MD, in 1974. Serum samples were kept frozen at -70 degrees C. In the subsequent 12-year period, 35 cases of bladder cancer developed among participants. Comparisons of serum levels in 1974 among cases and two matched controls for each case showed that selenium was significantly lower among cases than controls (P = 0.03), lycopene was lower among cases at a borderline level of significance (P = 0.07), and alpha-tocopherol was nonsignificantly lower (P = 0.13). For selenium there was a nearly linear increase in risk with decreasing serum levels (P = 0.03). When examined by tertiles, the odds ratio associated with the lowest tertile of selenium compared to the highest tertile was 2.06. Serum levels of retinol, retinol-binding protein, and beta-carotene were similar among cases and controls. These results support a role for selenium in the prevention of bladder cancer.     

Susceptibility of Ureaplasma urealyticum to Tetracycline,Doxycycline, Erythromycin,Roxithromycin, Clarithromycin,Azithromycin, Levofloxacin and Moxifloxacin

Abstract

The in vitro activity of tetracycline, doxycycline, erythromycin, roxithromycin, clarithromycin, azithromycin, levofloxacin and moxifloxacin was tested against 63 clinical isolates of Ureaplasma urealyticum. The minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) were determined by the broth microdilution method in A7 medium. The miC50 and miC90 of the tested agents after 24 h of incubation were as follows: Tetracycline, 0.5 and 2.0 μg/ml; doxycycline, 0.125 and 0.25 μg/ml; erythromycin, 2.0 and 8.0 μg/ml; roxithromycin, 2.0 and 4.0 μg/ml; clarithromycin, 0.25 and 1.0 μg/ml; azithromycin, 2.0 and 4.0 μg/ml; levofloxacin, 1.0 and 2.0 μg/ml; and moxifloxacin, 0.5 and 0.5 μg/ml, respectively. The MIC values after 24 h and 48 h incubation differed by no more than one dilution for all the agents with the exception of doxycycline (two dilution difference for MIC₉₀). Overall, moxifloxacin was the most active agent in vitro against U. Urealyticum, with the narrowest difference between MIC and MBC values, followed closely by levofloxacin. Clarithromycin was the most active macrolide.     

80岁以上合并肠梗阻的结直肠癌患者的外科治疗

目的 探讨80岁以上合并肠梗阻的结直肠癌患者的外科治疗策略。方法 回顾性分析中国医学科学院结直肠外科2007年1月—2018年12月行结直肠癌手术且术前合并肠梗阻的77例80岁以上患者的临床病理资料,按照手术方式分为根治组（n=58）与非根治组（n=19）,比较两组患者临床病理特征、围手术期相关指标和预后。采用Kaplan-Meier法进行生存分析,Log rank检验进行生存时间比较;应用Cox比例风险模型进行多因素分析,对影响预后的因素进行分析。结果 根治组TNM分期为Ⅳ期患者的比例明显低于非根治组（8.6% vs. 57.9%, P<0.001）。根治组患者的5年生存率明显高于非根治组（65.5% vs. 26.3%, P<0.001）。单因素分析显示TNM分期和是否行根治性手术与合并肠梗阻的老年结直肠癌患者预后相关。多因素分析表明是否行根治性手术是影响80岁以上合并肠梗阻的结直肠癌患者预后的独立因素。结论 是否行根治性手术是影响80岁以上合并肠梗阻的结直肠癌患者预后的独立因素。     

Cholesterol, weight, height, Quetelet's index, and colon cancer recurrence

The association of low serum cholesterol with colon cancer mortality suggests that low serum cholesterol promotes colon cancer recurrence. We compared cumulative 5-year recurrence-free rates of 279 colon cancer patients in relation to serum cholesterol, weight, height, and Quetelet's index. The median value for each variable was used to divide patients into those above the median, or at the median and below. Patients with median and lower serum cholesterol exhibited an 11% lower disease-free rate at 5 years. Patients above median weight were at significantly increased risk of recurrence in both sexes (76 vs 54%, z = 3.0026, p = 0.003). Progressively decreasing weight was noted with advancing stage in males but not in females. Women above median Quetelet's index were also at significantly greater risk of recurrence (74 vs 52%, z = 2.6109, p = 0.009). Patients above median height were at insignificantly increased risk of recurrence. This study indicates that body weight is a significant prognostic factor for patients with colon cancer.     

Fat, fiber, fruits, vegetables, and risk of colorectal adenomas

A case-control study was conducted at the National Naval Medical Center (Maryland, USA) from 1994 to 1996 to investigate the possible association between dietary factors and colorectal adenomas. Cases (n = 239) were subjects diagnosed with adenomas (146 new and 93 recurrent) by sigmoidoscopy or colonoscopy. Those with no evidence of adenomas found by sigmoidoscopy were recruited as controls (n = 228). Dietary variables, assessed by a 100-item food frequency questionnaire, were analyzed by the logistic regression model, which was adjusted for age, gender and total energy intake. Variables of fat intake were further adjusted for red meat intake. An increased risk of 7% [odds ratio (OR): 1.07; 95% confidence interval (95% CI): 0.94-1.22] per 5% energy/day from total fat was observed. Every additional 5% unit of oleic acid intake/day significantly increased the adenoma risk by 115% (OR: 2.15; 95% CI: 1.05-4.39). Red meat fat increased the risk by 20% (OR: 1.20; 95% CI: 0.71-2.04), and white meat fat decreased the risk by 67% (OR: 0.33; 95% CI: 0.19-0.95) for every additional 5% unit of respective intake/day. Risk decreased by 41% (OR: 0.59; 95% CI: 0.41-0.86) for every additional 5% unit of fiber intake/day. Vegetable [OR per 100 g of vegetable intake/day: 0.83, 95% CI: 0.67-1.04] and fruit (OR per 100 g of fruit intake/day: 0.92, 95% CI: 0.82-1.03) intake showed an inverse association, and the results are suggestive of an association with the risk for adenomas. In conclusion, a strong positive association between oleic acid intake and colorectal adenoma risk was observed. This is likely to be an indicator of "unhealthy" food (meat, dairy, margarine, mayonnaise, sweet baked food) consumption in this population. Increased intake of dietary fiber was associated with a moderately decreased risk of adenomas.