Differentiation-induced ML-1 cells as targets for transformation by a chemical carcinogen

The capacity for continuous proliferation (immortalization) of ML-1 human myeloblastic leukemia cells derives from their sensitivity to growth factors and their insensitivity to differentiation factors (DF) at the limiting concentrations at which these are present in the culture medium. Upon increasing the concentration of DF, or after treatment with DNA-specific anticancer agents, the cells exit the proliferation program and differentiate to monocyte/macrophage-like cells (Y. Honma, C. Honma, and A. Bloch, Cancer Res., 46: 6311-6315, 1986). The study reported here shows that when ML-1 cells, induced to differentiate with DF contained in mitogen-stimulated human leukocyte-conditioned medium (CM) are treated with the carcinogen N-nitroso-N-methylurea, their differentiation program is interrupted and proliferation is resumed at a stably increased rate of growth (doubling time, 25.1 versus 31.3 h). This "step-up" transformation is brought about by only a narrow concentration range of carcinogen, acting at a restricted time interval following differentiation induction. The step-up transformed cells are more sensitive to growth factor signals and less sensitive to DF signals than are untreated ML-1 cells. When retreated with a higher concentration of DF and the same concentration of N-nitroso-N-methylurea, the transformed cells undergo a further decrease in doubling time to 21 h. Differentiation-uninduced ML-1 cells do not respond to treatment with N-nitroso-N-methylurea, indicating that differentiation-induced cells, at an early stage of the maturation process, may be the targets for the carcinogen-mediated transformation.     

企业职工社会心理调查的方法学研究

作者自行设计一种问卷对某企业职工进行社会心理调查。问卷由 A、B两表构成。A 表列出42个问题,包含可能影响该企业职工社会心理的三大类11项因素,要求从该企业中随机抽取的被调查者针对问题回答“是”或“否”。其后附开放式问题一个,被调查者可自由作答,以补封闭式提问的不足。B 表按心理投射机制设计,以解除被调查者的疑虑。测试结果表明,此问卷的信度和效度令人满意。     

Outbreaks of smallpox due to variolation in China, 1962-1965

In 1985, previously unknown outbreaks of smallpox were uncovered which had occurred in Shanxi Province and Nei Monggol Autonomous Region in northern China during 1962-1965, several years after smallpox transmission was thought to have been interrupted. During field investigation, the authors learned that most of the cases were known to local health officials but had not been officially reported to national authorities. All were among persons who had been variolated or were their close contacts. Variolation is an ancient method of protection against naturally acquired smallpox that was officially proscribed in the early 1950s but was renewed in remote areas when smallpox vaccination activities were interrupted during the three-year famine of 1959-1962, following the "great leap forward" program of 1958. It was found that the variolators in Shanxi Province and Nei Monggol Autonomous Region inoculated persons with the use of powdered smallpox scabs mixed with human milk, and that they obtained fresh supplies of scabs every 6-12 months by variolating relatives and friends. The health authorities responded by capturing the variolators, confiscating their variolation material and equipment, and vaccinating the population. The last known cases occurred in 1965, and the practice of variolation is now believed to be extinct.     

Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts

D-54 MG, a human glioma-derived continuous cell line growing as subcutaneous or intracranial xenografts in athymic mice, was found to be sensitive to the effects of D,L-buthionine-(SR)-sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase. Intraperitoneal administration of one dose of buthionine sulfoximine (BSO, 5 mmol/kg) resulted in depletion of total intracellular glutathione to 57 and 47% of control 12 hr, and 73 and 23% of control 24 hr, after BSO in subcutaneous and intracranial xenografts respectively. Concurrent measurement of total glutathione in the contralateral (non-tumor-containing) cerebral hemisphere in mice bearing intracranial D-54 xenografts demonstrated insignificant depletion of glutathione. Multiple doses of BSO, at 12-hr intervals, resulted in further depletion to 27% (s.c.) and 16.5% (i.c.) of control 12 hr following the final dose of BSO. Quantitative analysis of BSO delivery to xenograft and contralateral brain tissue revealed transfer constants, K1, of 15.8-24.1 x 10(-3) and 2.4 x 10(-3) ml.g-1.min-1 for xenograft and "normal" brain respectively. This highly selective depletion of glutathione in neoplastic tissue versus surrounding non-neoplastic host tissue may have therapeutic implications for the rational use of chemotherapeutic and radiotherapeutic intervention.     

Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerases, DNA primase, and ribonucleotide reductase

Recently, 2-halogenated deoxyadenosine analogs (F, Cl, and Br) have been shown to have antitumor activity. These analogs are phosphorylated by cells and are believed to exert their cytotoxic action at the nucleoside triphosphate level. In this work the interaction of these nucleoside triphosphate analogs with potential targets, such as DNA polymerase alpha, beta, and gamma, DNA primase, and ribonucleotide reductase was examined in detail. All of these compounds competitively inhibited the incorporation of dAMP into DNA by DNA polymerase alpha, beta, or gamma. F-dATP was able to completely substitute for dATP using DNA polymerase alpha and gamma, but not with DNA polymerase beta. Cl-dATP and Br-dATP substituted poorly for dATP using DNA polymerase alpha and beta. Extension of a 32P-labeled primer by DNA polymerase alpha, beta, or gamma on a single-stranded M13 template showed that these compounds were incorporated into the 3' end of the growing DNA chain and that elongation beyond the incorporated analogs was significantly retarded for Cl-dATP and Br-dATP using either DNA polymerase alpha or beta. DNA primase using poly(dC) as template was inhibited by these compounds at a concentration 4 to 5 times greater than that required for 2-F-araATP. The 2-halogenated dATP analogs were potent inhibitors of ADP reduction by ribonucleotide reductase. In conclusion, the cytotoxic action of 2-Cl-deoxyadenosine and 2-Br-deoxyadenosine may partially be mediated through the mechanism of "self-potentiation," by depression of the deoxynucleoside triphosphate pools due to inhibition of ribonucleotide reductase, which would facilitate their incorporation into DNA and result in the inhibition of DNA synthesis.     

KMT2C通过c-Myc/CDK4信号通路调控胃癌细胞的生长与增殖

摘要:目的 探究赖氨酸特异性甲基转移酶2C(lysine specific methyltransferase 2C,KMT2C)在胃癌发生发展中的 作用及机制。方法 通过 TCGA 数据库分析 KMT2C在胃癌与癌旁的表达差异。采用 Western blot检测 KMT2C在胃 癌与癌旁临床样本中的表达差异。通过 Kaplan-Meier Plotter数据库分析 KMT2C 对胃癌患者预后的影响。采用细胞 实验(克隆形成、EdU 及 CCK-8检测)及皮下瘤负荷模型检测 KMT2C 在体内外对胃癌细胞增殖能力的影响。结果 KMT2C在胃癌中高表达。胃癌患者中 KMT2C高表达组相对于 KMT2C低表达组预后较差。敲减 KMT2C在体内外 均有抑制胃癌 细 胞 增 殖 的 作 用。基 因 集 富 集 分 析 (GSEA)发 现 KMT2C 影 响 c-Myc信 号 通 路。敲 减 KMT2C 后, H3K4me1蛋白表达水平降低,同时,CDK4的 mRNA 与蛋白表达水平降低。KMT2C与c-Myc核内结合促进了c-Myc 与 CDK4的启动子区域的结合。结论 KMT2C通过影响c-Myc/CDK4信号通路促进胃癌细胞增殖。     

Evidence for the interaction between antacid and gastric mucosa using an "artificial stomach" model including gastric mucosa.

In light of evidence that certain aluminum-based antacids adhere to the gastric mucosa, we modified our previously described "artificial stomach" (AS) model by including a piece of hog stomach and compared the antacid activity of six aluminum-containing antacid products in the model with and without gastric mucosa. The activity of three of these, Maalox, Riopan and Supralox, was not significantly different in the two systems. In contrast, the activity of the other three, Aludrox, Phosphalugel and Simeco, was significantly greater with mucosa. Antacid activity of one product from each set (Supralox, Phosphalugel) was evaluated in two in vivo methods in human volunteers. For both antacids, results in vivo were similar to those obtained with the AS-containing mucosa. Without mucosa, in vivo and in vitro results were dissimilar for Phosphalugel, thus validating the modified AS. The difference between the two sets of antacids can be explained by 1) the fact that the Al:Mg ratio in the set affected by mucosa is greater than that of unaffected antacids, and 2) a weaker antacid load than in unaffected Supralox. We suggest that in an acid milieu, aluminum ions in antacids like Aludrox, Phosphalugel and Simeco are bound to sialic acid residues in mucus glycoproteins, thus retarding the transit of these antacids through both the AS and the real stomach and prolonging their activity in both situations. When the Al:Mg ratio is low or when the amount of antacid salts is large, aluminum ions tend to be buried in complexes, giving them less chance to interact with gastric mucus, so they transit the stomach more quickly.     

Comparative study on healing process between vascularized and non-vascularized autogenous bone grafts]

This study made a histological comparison (light microscope and transmission electron microscope) between vascularized bone graft (VBG) and non-vascularized bone graft (NVBG) in mandible of dog.The study showed:the healing process of VBG was the same as that of bone fracture.The "creeping substitution" process of NVBG was imbued with the inflammation induced by dead bone.There was no significat difference on the bone union between VBG and NVBG perhaps for the recipient region was better vascularized.     

“90增血剂”对特发性血小板减少性紫裥患者的T细胞亚群的作用

作者根据现代免疫学观点,自1989年起采用自制中药“90增血剂”治疗ITP46例。期间,应用间接免疫荧光技术检测了患者外周血T淋巴细胞亚群,结果表明病例组全T细胞(CD_3)、T辅助/诱导细胞(CD_4)降低,T抑制/细胞毒细胞(CD_8)增高,CD_4/CD_8比值明显降低。治疗后,患者T亚群恢复常态,血小板数上升,骨髓产板型巨核细胞数增加,临床总有效率达91.2%,明显优于激素组(71.4%)。提示中药具有显著的疗效和良好的免疫调节作用。同时,动态观察ITP患者T细胞亚群的变化,对帮助临床判断治疗反应和预后有很大意义。