骨髓增生异常综合征患者p15INK4B基因甲基化与疾病进展的Meta分析

目的 分析骨髓增生异常综合征(MDS)患者p15INK4B基因甲基化与疾病进展的关系.方法 搜索Cochrane Library、Medline、PubMed、Embase、OVID、Springlink、CBMdisc、VIP、万方和CNKI数据库(1979 to 2012),查找报道MDS患者及sAML(MDS转化的白血病)患者p15INK4B基因甲基化发生率的文献,使用RevMan 5.0对数据进行统计分析.结果 共有20篇文献检测了MDS患者p15INK4B基因甲基化状态,并报道了患者骨髓原始细胞数;其中9篇文献包括sAML患者(共690名患者).p15INK4B基因甲基化状态在骨髓原始细胞5％～19％组中高于原始细胞＜5％组(RR=0.41,95％CI:0.33～0.50),sAML组高于MDS原始细胞5％～19％组(RR=0.51,95％CI:0.41～0.64).4篇文献报道了MDS患者疾病的进展(包括179名患者).p15INK4B基因甲基化阳性组疾病进展率高于甲基化阴性组(RR=3.09,95％CI:2.04～4.68).结论 p15INK4B基因甲基化与MDS患者疾病进展及白血病转化密切相关.     

亚砷酸、维甲酸联合小剂量化疗治疗骨髓增生异常综合征的临床疗效

目的分析亚砷酸联合维甲酸(ATRA)及小剂量化疗治疗骨髓增生异常综合征(MDS)的临床疗效。方法收集21例MDS患者，应用亚砷酸联合ATRA及小剂量化疗，观察其有效率及副作用的发生情况。结果治疗后，总有效率达76．2％，长期随访治疗8例，均保持持续缓解状态。未发现严重毒副作用。结论亚砷酸联合ATRA及小剂量化疗治疗MDS安全、有效。     

三氧化二砷联合维甲酸治疗骨髓增生异常综合征

目的：探讨三氧化二砷联合维甲酸(ATRA)治疗MDS的疗效。方法：31例MDS患者均采用三氧化二砷联合维甲酸等治疗。结果：RA RAS组有效率87．1％,RAEB RAEB-T组有效率42．9％。结论：三氧化二砷是一种治疗MDS的有效药物,尤其是在RA的治疗中有显著效果。     

DNA甲基化与骨髓增生异常综合征研究进展

随着肿瘤表观遗传学的深入研究,DNA甲基化异常在血液肿瘤的发生和转化中起着重要作用。近来研究显示p15基因、降钙素基因、紧密连接蛋白-1基因等高度甲基化与骨髓增生异常综合征的发生发展具有重要关系。5-氮杂胞苷和5-2′-脱氧胞嘧啶等在骨髓增生异常综合征患者的治疗中已经取得一定效果。去甲基化治疗有望成为骨髓增生异常综合征治疗的有效方案之一。     

骨髓增生异常综合征患者Dickkopf-3基因启动子区甲基化状态研究

目的 了解骨髓增生异常综合征(MDS)患者WNT/β-catenin信号转导通路中拮抗基因Dickkopf-3(Dkk3)的甲基化状态,初步探索其甲基化状态与MDS发生及疾病进展的关系.方法 应用甲基化特异性PCR(MSP)法对43例MDS患者的骨髓或外周血Dkk3基因启动子区甲基化状况进行检测,并以70例门诊普通患者的外周血检测结果作为对照,同时对患者进行随访.结果 43例MDS患者中检出7例(16.3％)Dkk3甲基化,其中5例(11.6％)为半甲基化状态,2例(4.7％)为完全甲基化状态,70例正常对照中1例(1.4％)为Dkk3甲基化,组间DKK3甲基化率差异有统计学意义(x2=8.93,P=0.005).7例Dkk3甲基化的样本中,2例来自骨髓,5例来自外周血,其中难治性贫血(RA)2例,难治性细胞减少伴多系异常(RCMD)1例,难治性贫血伴原始细胞增多(RAEB)4例.单因素分析示不同性别、染色体核型、样本来源(骨髓/外周血)、危险度(WHO分类的预后评分系统≤2分及＞2分)及老年组与非老年组间甲基化率差异均无统计学意义(均P＞0.05).在35例长期随访患者中,9例患者转化为急性髓系白血病(AML)(6例DKK3甲基化者中3例,29例DKK3非甲基化者中6例),疾病进展组与稳定组间甲基化率差异无统计学意义(P＞0.05);死亡12例中3例为Dkk3甲基化阳性,但甲基化与非甲基化组间生存率差异无统计学意义(P＞0.05).结论 MDS患者中Dkk3基因存在较高的甲基化修饰,这可能是MDS发病的分子机制之一.本组患者例数较少,尚未发现甲基化与临床预后间的相关性.     

CAG预激方案治疗骨髓增生异常综合征RAEB-T的疗效观察

 目的 探讨Acla+Ara-C+G-CSF联合应用,即CAG方案治疗骨髓增生异常综合征（MDS）的临床效果。方法 Ara-C 10 mg·m-2·12 h-1,皮下注射,第1~14天;Ａcla 7 mg·m-2·d-1,静脉滴注,第1 ~ 8天;G-CSF 200 μg·m-2·d-1,皮下注射。共治疗骨髓增生异常综合征29例。结果： 29例患者中,CR13例,PR 8例,NR 8例,CR率为44.8 %,有效率为72.4 %。全组均未见严重毒副反应。结论 CAG方案治疗MDS疗效肯定,缓解率较高,可作为部分MDS的治疗手段。     

亚砷酸治疗骨髓增生异常综合征18例临床观察

目的：探讨亚砷酸治疗骨髓增生异常综合征(MDS)临床疗效。方法：MDS患者18例,亚砷酸10mg加入5％萄糖注射液250mL静脉滴注,1次／d。28d为1疗程,疗程结束后7d～14d复查骨髓象及血象。结果：经1疗程治疗后,大多数病例有所好转,总有效率83．3％。结论：亚砷酸治疗骨髓增生异常综合征疗效肯定,可作为部分骨髓增生异常综合征的治疗手段。     

骨髓增生异常综合征DNA甲基化及其治疗机制的进展

骨髓增生异常综合征（myelodysp lasticsyndrome,MDS）仍为血液病学较难攻克的一大主题。近年由于DNA甲基化研究的进展及DNA去甲基化药物的开发、使用,为MDS的治疗提供了更多可能的靶点。全文就近年DNA甲基化及去甲基化治疗相关机制的研究进展作一介绍。     

骨髓增生异常综合征的治疗进展

骨髓增生异常综合征是一组造血干细胞克隆性疾病,因病态造血导致进行性、难治性血细胞减少为特征,临床主要表现为贫血、感染和出血。少数有进展为急性白血病的危险。目前仍缺乏有效的根治疗法,本文重点讨论MDS的现有治疗和相关的支持治疗。     

p15INK4B基因转染联合TGF-β1对人食管鳞癌的抑制作用

目的：探讨p15^INK4B基因转染与TGF-β1联合应用对人食管鳞癌细胞系EC109细胞增殖和凋亡的影响。方法：脂质体介导将pCDNA3．1（＋）-p15转染EC109细胞，稳定筛选后加入10ng／ml的TGF-β1。PCR检测外源P15基因，Western blot检测转染细胞P15蛋白的变化。用MTT、集落形成实验、流式细胞仪和透射电镜检测p15转染TGF-β1对EC109增殖和凋亡的影响。结果：联合应用与二者单独应用相比。明显抑制EC109生长速度．集落形成率显著降低（P〈0．01）。发生G1／S阻滞。G1期比例显著升高（P〈0．05），S期比例明显降低（P〈0．05）。凋亡率明显升高（P〈0．01）。透射电镜发现二者联合应用诱导EC109发生明显的细胞凋亡。结论：p15基因转染与TGF-β1联合应用可以进一步增强对食管鳞癌EC109细胞的抑制作用并诱导其凋亡。     

p14ARF, p15INK4b and p16INK4a methylation status in chronic myelogenous leukemia

The INK4 family of proteins p15^INK4b, p14^ARF and p16^INK4a function as cell cycle inhibitors where they are involved in the inhibition of G1 phase progression. Methylation of the p15^INK4b promoter never seems to occur in solid tumors but is a major gene silencing mechanism in hematological malignancies. p14^ARF and p16^INK4a promoter methylation often occurs in solid tumors but also in leukemias and lymphomas. In chronic myelogenous leukemia (CML), only a few reports have been published regarding INK4 methylation and the results of the literature are discordant. Thus clearly, more works on large series have to be performed independently.     

慢性乙型肝炎病毒感染与p16INK4A基因启动子甲基化关系的研究

目的探讨慢性乙型肝炎病毒(HBV)感染对p16INK4A基因启动子甲基化的影响及其在HBV相关肝细胞癌(HCC)形成中的作用。方法选取23例HBV相关HCC癌及癌旁组织、25例慢性乙型肝炎肝穿刺组织,采用甲基化特异性PCR(MSP)检测p16INK4A基因启动子的甲基化状态;免疫组化EnVision二步法测定肝组织内HBsAg、HBcAg、HBeAg和HBx蛋白的表达;荧光实时定量PCR检测肝组织HBV DNA含量;PCR扩增和直接测序检测HBV x基因变异。结果癌组织p16INK4A基因启动子甲基化阳性率(47.83%)明显高于癌旁组织(17.39%),慢性乙型肝炎患者p16INK4A基因启动子甲基化阳性率(36.00%)与癌组织、癌旁组织差异无统计学意义。在癌旁组织和慢性乙型肝炎, p16INK4A基因启动子甲基化者HBx蛋白表达中位数分别为3.000和0.250,明显高于非甲基化者(0.500和0.000),但在癌组织中,HBx蛋白的表达与p16INK4A基因启动子甲基化状态无关。HBsAg、HBcAg、组织HBV DNA含量和x基因突变均与p16INK4A基因启动子甲基化状态无关。结论在癌前病变中,p16INK4A基因启动子甲基化与HBx蛋白高表达有关,HBx蛋白可能通过诱导p16INK4A基因启动子甲基化而使该抑癌基因失活,在HBV相关HCC形成中起重要作用。     

丙戊酸钠联合全反式维甲酸治疗骨髓增生异常综合征22例

 目的　探讨丙戊酸钠联合全反式维甲酸治疗骨髓增生异常综合征（MDS）的有效性和安全性。方法　入组患者22例,其中：难治性贫血（RA） 4例,环形铁粒幼细胞性难治性贫血（RARS）1例,RA并多系发育异常（RCMD）10例,难治性血细胞减少症伴有多系发育异常和环状铁粒幼细胞（RCMD-RS）1例,RA伴原始细胞增多-1（RAEB-1）3例,RA伴原始细胞增多-2（RAEB-2）3例。患者入组后给予丙戊酸钠0.2 g／次,3次／d起,1周后加量至0.4 g／次,3次／d;丙戊酸钠使用1周后开始联用全反式维甲酸,10 mg／次,3次／d,每2周连用1周。治疗持续至少3个月,出现严重的不良反应或疾病明显进展时停用,治疗后每4周复查一次骨髓,评价疗效。结果　22例患者治疗有效6例,有效率27.3 %,平均8周开始显效,其中无完全缓解病例,2例患者部分缓解,4例血液学改善,9例治疗期间病情稳定,7例治疗失败。部分患者有轻微的药物不良反应。结论　丙戊酸钠联合全反式维甲酸治疗MDS治疗有效,不良反应轻微,可以耐受。     

小剂量地西他滨联合阿糖胞苷治疗骨髓增生异常综合征临床观察

目的：探讨小剂量地西他滨联合阿糖胞苷治疗骨髓增生异常综合征（MDS）的临床疗效和安全性。方法收集2012年1月至2015年1月接受小剂量地西他滨联合阿糖胞苷方案治疗的15例MDS 患者临床资料,评价其疗效和不良反应。结果15例患者中完全缓解4例,部分缓解5例,稳定、进展和无效6例,总有效率为60.0%（9／15）。总感染率为40.0%（6／15）,其中肺部感染率为26.7%（4／15）,Ⅲ～Ⅳ度骨髓抑制率为73.3%（11／15）。患者经积极抗感染、刺激造血及输血等支持治疗后感染得到控制。15例患者均无严重肝损害,未出现化疗相关死亡。结论小剂量地西他滨单药联合阿糖胞苷方案治疗 MDS 有一定疗效,可延缓疾病进展,患者能耐受化疗不良反应,无化疗相关死亡。     

Lack of Increased P15INK4B Protein Expression in Basal Cell Carcinomas

Background: The basal cell carcinoma (BCC) is the most common non-melanoma skin cancer (NMSK). BCCmight develop because of the faulty cell cycle arrest. P15INK4b is a tumor suppressor gene, involved in cell cyclearrest and inactivated in most human cancers. The role of p15INK4b protein expression in the genesis of BCC is asyet unknown. In a previous study we showed the absence of p15INK4b expression in the majority of tissue microarraycores of cutaneous squamous cell carcinoma (SCCs), another type of non-melanoma skin cancer, indicating thatp15INK4b could possibly be involved in the pathogenesis of cutaneous SCC. The aim of this study was to investigatep15INK4b protein expression in BCCs. Materials and Method: Protein expression of p15INK4b in 35 cases of BCCtissue arrays and 19 cases of normal human skin tissue was studied using an immunohistochemical approach.Results: The expression of p15INK4b was not significantly different in the BCC cases as compared with normalhuman skin (p=0.356; p>0.05). In addition, there were no significant relationship between clinicopathologicvariables of patients (age and sex) and p15INK4b protein expression. Conclusions: Our finding may indicate thatp15INK4b protein expression does not play a role in the genesis of BCC.     

Inactivation of the p15INK4B and p16INK4 Genes in Hematologic Malignancies

The recently discovered p15^INK4B and p16^INK4 genes encoding cell cycle regulating proteins, map to a region on chromosome 9p21 that is commonly deleted in a variety of malignant diseases. The p16^INK4 gene has now been shown to be a tumor suppressor gene. It is frequently inactivated in cancer and is possibly the second most often mutated gene in human malignant disease after p53. The role of the p15^INK4B and p16^INK4 genes in hematologic malignancies has been the subject of intense investigation since their discovery. In this review we address the function and possible role in tumorigenesis of the p15^INK4B and p16^INK4 genes and discuss their significance as prognostic markers in hematologic malignancies.     

Loss of p15INK4b Expression in Colorectal Cancer is Linked to Ethnic Origin

Colorectal cancers remain to be a common cause of cancer-related death. Early-onset cases as well as those ofvarious ethnic origins have aggressive clinical features, the basis of which requires further exploration. The aimof this work was to examine the expression patterns of p15INK4b and SMAD4 in colorectal carcinoma of differentethnic origins. Fifty-five sporadic colorectal carcinoma of Egyptian origin, 25 of which were early onset, and54 cancers of Finnish origin were immunohistochemically stained with antibodies against p15INK4b and SMAD4proteins. Data were compared to the methylation status of the p15INK4b gene promotor. p15INK4b was totally lostor deficient (lost in ≥50% of tumor cell) in 47/55 (85%) tumors of Egyptian origin as compared to 6/50 (12%)tumors of Finnish origin (p=7e-15). In the Egyptian cases with p15INK4b loss and available p15INK4b promotormethylation status, 89% of cases which lost p15INK4b expression were associated with p15INK4b gene promotorhypermethylation. SMAD4 was lost or deficient in 25/54 (46%) tumors of Egyptian origin and 28/48 (58%)tumors of Finnish origin. 22/54 (41%) Egyptian tumors showed combined loss/deficiency of both p15INK4b andSMAD4, while p15INK4b was selectively lost/deficient with positive SMAD4 expression in 24/54 (44%) tumors.Loss of p15INK4b was associated with older age at presentation (>50 years) in the Egyptian tumors (p=0.04). Thesedata show for the first time that p15INK4b loss of expression marks a subset of colorectal cancers and ethnic originmay play a role in this selection. In a substantial number of cases, the loss was independent of SMAD4 butrather associated with p15INK4b gene promotor hypermethylation and old age which could be related to differentenvironmental exposures.