Low values of 5-hydroxymethylcytosine (5hmC), the "sixth base," are associated with anaplasia in human brain tumors

5-Methylcytosine (5 mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5-Hydroxymethylcytosine (5 hmC) is generated from 5 mC by the action of the TET (Ten-Eleven-Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5 mC. We have used immunohistochemistry (IHC) and isotope-based liquid chromatography mass spectrometry (LC-MS) to investigate the presence and distribution of 5 hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5 hmC positive cells in the cortex and 32.4% 5 hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC-MS also showed highest values in cortical areas (1.17% 5 hmC/dG [deoxyguanosine]), in the cerebral WM we measured around 0.70% 5 hmC/dG. levels were related to tumor differentiation, ranging from lowest values of 0.078% 5 hmC/dG in GBMs (WHO Grade IV) to 0.24% 5 hmC/dG in WHO Grade II diffuse astrocytomas. 5 hmC measurements were unrelated to 5 mC values. We find that the number of 5 hmC positive cells and the amount of 5 hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia.     

TE T2基因阳性急性髓细胞白血病38例分析

目的：分析TET2基因阳性急性髓细胞白血病（AML）患者的临床及实验室特点,探讨可能影响治疗效果的因素。方法：收集38例TET2基因突变阳性AML患者的临床及实验室资料,并回顾性分析其中可能影响治疗效果的因素,TET2基因检测采用实时定量PCR方法。结果：38例患者中21例接受化疗,获得完全缓解（CR）12例（57．14％）,未缓解（NR）5例（23．81％）,疾病进展（PD）4例（19．05％）。应用不同化疗方案治疗后缓解率不同,应用去甲基化治疗的4例第一个疗程治疗后均达到完全缓解,未应用去甲基化治疗的17例中CR 8例（47．06％）、NR 5例（29．41％）、PD 4例（23．53％）。白血病细胞免疫表型CD34阴性、CD13阴性、CD33阳性者化疗后CR率更高,差异具有统计学意义（P＜0．05）。TET2基因阳性AML患者的CR率与年龄、性别、发病时白细胞计数、血红蛋白、血小板计数、白血病细胞免疫表型（CD56、CD9、HLA－DR）、是否伴有其他预后基因及复杂染色体核型无明显相关性。结论：TET2基因阳性AML患者的CR率与化疗方案及白血病细胞免疫表型CD34、CD13及CD33相关。去甲基化治疗可提高TET2基因阳性AML患者的CR率。影响TET2基因阳性AML患者疗效及长期生存的因素尚需进一步探讨。     

胸腺上皮性肿瘤中TTF1、Ki-67的表达与WHO分型的关系及临床意义

目的 观察TTF1及Ki-67在胸腺上皮性肿瘤(Thymic epithelial tumors,TET)中的表达情况,探讨其与WHO分型的关系及二者的相关性。方法 收集59例TET标本,其中诊断一致的51例,不一致8例。应用免疫组化技术检测TTF1及Ki-67在诊断一致的 51例TET及30例胸腺增生组织中的表达情况,并分析其与临床病理参数之间的关系。结果 在诊断不一致的8例TET中,4例与AB型有关。在诊断一致的51例TET中,TTF1及Ki-67在TET中的表达均显著高于胸腺增生组(P＜0.05)。TTF1仅在AB型胸腺瘤中表达(11/15),其表达与WHO分型有关。Ki-67标记指数从A型到胸腺癌逐渐增加,且在A型与胸腺癌的表达范围不重叠,其表达与WHO分型及MasaoKa分期均有关。同时TTF1及Ki-67在TET中的表达没有相关性。结论 TTF1是AB型胸腺瘤相对特异性的标记;Ki-67不仅对A型与胸腺癌中的区分有帮助,同时具有很好的指示预后的价值。     

Role of genotype-based approach in the clinical management of adult acute myeloid leukemia with normal cytogenetics

Acute myeloid leukemia (AML) is the most common form of acute leukemia affecting adults. Although it is a complex disease driven by numerous genetic and epigenetic abnormalities, nearly 50% of patients exhibit a normal karyotype (CN-AML) with an intermediate cytogenetic risk. However, a widespread genomic analysis has recently shown the recurrence of genomic aberrations in this category (mutations of FLT3, CEBPA, NPM1, RUNX1, TET2, IDH1/2, DNMT3A, ASXL1, MLL and WT1) thus revealing its marked genomic heterogeneity. In this perspective, a global gene expression analysis of AML patients provides an independent prognostic marker to categorize each patient into clinic-pathologic subgroups based on its molecular genetic defects. Consistently such classification, taking into account the uniqueness of each AML patient, furnishes an individualized treatment approach leading a step closer to personalized medicine. Overall the genome-wide analysis of AML patients, by providing novel insights into biology of this tumor, furnishes accurate prognostic markers as well as useful tools for selecting the most appropriate treatment option. Moreover it provides novel therapeutic targets useful to enhance efficacy of the current anti-AML therapeutics. Here we describe the prognostic relevance of such new genetic data and discuss how this approach can be used to improve survival and treatment of AML patients.     

延胡索与白芷组分配伍对延胡索乙素在大鼠肝微粒体中酶促反应动力学的影响

目的研究延胡索总生物碱(TA)中延胡索乙素(TET)在肝微粒体中的酶促反应动力学,并比较白芷有效组分白芷香豆素(Cou)、挥发油(VO)与TA配伍后对TET酶促反应动力学的影响。方法超速离心法制备大鼠肝微粒体,采用高效液相色谱法测定孵育液中TET原形药物的浓度。比较TA、TA-Cou、TA-VO、TA-Cou-VO配伍各组中TET的酶促反应动力学,推导出药物米氏常数(Km)和最大反应速度(Vmax);并计算TET肝内清除率(CLint)。结果 TA配伍组中的TET在大鼠肝微粒体内代谢反应的Vmax、Km和CLint分别为0.12μmol/(L.min.mg)、5.40μmol/L、0.022 L/(min.mg);TA-Cou组分别为0.27μmol/(L.min.mg)、40.18μmol/L、0.006 L/(min.mg);TA-VO组分别为0.57μmol/(L.min.mg)、22.60μmol/L、0.025 L/(min.mg);TA-Cou-VO组分别为0.84μmol/(L.min.mg)、23.25μmol/L、0.036 L/(min.mg)。结论 TA配伍白芷有效组分可降低TA中TET在肝内的CLint。     

Predominant DNMT and TET mediate effects of allergen on the human bronchial epithelium in a controlled air pollution exposure study

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