肿瘤细胞中的表观遗传编码紊乱

不改变基因的DNA编码,通过改变DNA双链与组蛋白间紧密度来决定基因是否转录表达,这称为表观遗传编码机制。表观遗传编码的生理作用是通过组蛋白修饰和DNA甲基化,调控细胞在适当的时间、空间位置表达适当的基因,从而控制细胞的增殖状况和分化方向。在细胞发育过程中,细胞内DNA甲基化水平增龄性增高,基因转录活性逐渐降低,使细胞从幼稚增殖进入成熟分化。肿瘤细胞中出现表观遗传编码紊乱,致细胞增殖失控,不能进入分化成熟阶段。基因启动子出现甲基化重排,阻碍转录因子与启动子结合,导致基因转录丧失正常调控,合成成熟功能蛋白受阻。利用表观遗传机制(如,RNA干涉)可成为肿瘤治疗的新方法。     

Tumor genes and their proteins in cytologic and surgical specimens: Relevance and detection systems

Oncogenesis is the consequence of a series of genetic alterations that allow unrestrained cellular growth, tissue invasion, and eventual metastases. Tumor-related genes can be classified into functional categories. Proto-oncogenes/oncogenes have a stimulatory role in cell growth, and the inactivation of cancer-suppressor genes/antioncogenes results in the loss of cell cycle regulation. More recently, three other groups of tumor-related genes have been recognized. They include the antiapoptosis genes which protect from programmed cell death, the antimetastasis genes, and multidrug resistance genes. Besides aiding in tumor diagnosis, the detection of such tumor-associated genes and their products allows the identification of individuals with an inherited predisposition to neoplastic growths, and the overexpression of many of these oncogene products has been shown to be a potential marker of tumor behavior and a predictor of treatment outcome and response. The ability to utilize DNA and RNA probes for nucleic acid hybridization and polymerase chain reaction procedures in cell and tissue preparations of solid tumors and lymphoid proliferations expands and complements the information provided by immunohistochemical techniques. These probes allow direct visualization and correlation of specific genes and their protein products with cytomorphologic features, and form a powerful addition to the armamentarium of the cytopathologist and surgical pathologist. © 1995 Wiley-Liss, Inc.     

Interleukin-10 inhibits IgE-mediated nitric oxide synthase induction and cytokine synthesis in normal human keratinocytes

Human keratinocytes (HK) generate nitric oxide (NO) and proinflammatory mediators following activation with either IgE/anti-IgE immune complexes or a combination of lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Recently, interleukin-10 (IL-10) has been shown to down-regulate various inflammatory responses and to be secreted by lymphocytes and dendritic cells during skin inflammatory reactions. We show here that IL-10 down-regulates the production of tumor necrosis factor (TNF)-α and IL-6 by activated HK. Also, induction of inducible nitric oxide synthase (iNOS) expression in HK by IgE/anti-IgE or LPS/IFN-γ is significantly reduced by the addition of IL-10. This effect is dose dependent and correlates with reduction of iNOS mRNA production and enzyme level. Therefore, IL-10 down-regulates NO-mediated HK inflammatory responses and may thus participate in the regulation of the skin immune network.     

负性刺激分子PD-L对T细胞介导小鼠L929肿瘤细胞免疫效应的影响

目的：探讨负性刺激分子在肿瘤细胞逃避免疫效应中的作用.方法：以L929细胞为靶细胞,体内致敏C57BL/6小鼠,注入PD-L1、PD-L2抗体阻断,并设立未致敏对照组.分离小鼠脾细胞,体外采用3H-TdR掺入法、荧光标记双染色FCM以及PI染色FCM法分别检测淋巴细胞增殖反应、活化诱导的细胞凋亡以及脾细胞及其培养上清对肿瘤细胞的杀伤效应.结果：L929细胞表达PD-L1,而不表达PD-L2.体内与体外联合应用PD-L1抗体,能显著增强L929肿瘤细胞诱导的致敏组小鼠脾细胞的增殖活性和特异性杀伤效应,并可抑制活化诱导的T细胞凋亡;PD-L1抗体亦可增加L929细胞诱导的未致敏组小鼠脾细胞的增殖活性和促进其脾细胞培养上清对L929细胞的杀伤效应.结论：PD-L1抗体可通过阻断PD1/PDL途径促进初始T细胞和致敏T细胞介导的抗瘤效应.     

Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice

To compare the function of the tumor necrosis factor (TNF) and lymphotoxin (LT)α/β systems in the mature immune system, these two pathways were blocked with soluble receptor-immunoglobulin (R-Ig) fusion proteins in normal adult mice. Inhibition of LTα/β signaling using LTβR-Ig or a blocking monoclonal antibody against murine LTβ had profound effects. The spleen lacked discrete B cell follicles and the marginal zone was altered. Less marked changes were detected in lymph nodes. LTα/β inhibition also prevented germinal center formation in the spleen and impaired Ig production in response to sheep red blood cells (SRBC) immunization. These results show that the LTα/β system is required for the maintenance of splenic architecture and normal immune responses, and not simply for the development of peripheral immune organs during ontogeny. In contrast, inhibition of the TNF/LTα pathway with TNF-R55-Ig did not affect the splenic architecture or the anti-SRBC response. Splenic defects and impaired antibody responses are seen in TNF-deficient mice, suggesting that TNF is important during development. Therefore relative to TNF, the LT system has the dominant influence on splenic organization and anti-SRBC Ig formation in the adult mouse.     

人肿瘤细胞TH2类细胞因子的逆转与NK抗性变化的研究

目的研究促使人肿瘤细胞中ＴＨ２类细胞因子表达向ＴＨ０型的逆转及逆转后的肿瘤细胞对ＮＫ抗性的变化。方法首先用ＭＴＴ方法对悬浮培养的肿瘤细胞株ＤＢ大淋巴细胞瘤、Ｋａｒｐａｓ淋巴瘤、Ｍｉｃｈａｅｌ淋巴瘤、Ｒａｊｉ、ＨＬ６０和Ｋ５６２进行了ＮＫ杀伤敏感性的筛选。选择ＮＫ不敏感的Ｋａｒｐａｓ淋巴瘤和ＨＬ６０，用ｒｈＩＦＮγ、ｒｈＩＬ－１２和抗ＩＬ－１０ＭｃＡｂ经不同组合对其进行由ＴＨ２类细胞因子表达向ＴＨ１类细胞因子表达的促逆转研究，并观察促逆转后的肿瘤细胞对ＮＫ抗性的变化。结果ＲＴ－ＰＣＲ结果表明，经上述不同细胞因子组合诱导后，Ｋａｒｐａｓ淋巴瘤细胞均从表达ＴＨ２类细胞因子为主向ＴＨ０型逆转，并且各组逆转后的肿瘤细胞对ＮＫ的抗性均有不同程度的减弱。结论ＴＨ１类细胞因子（如ＩＦＮγ）、ＴＨ２类细胞因子拮抗剂（如ＩＬ－１０单抗）和ＩＬ－１２不同程度地促进肿瘤细胞表达的细胞因子由ＴＨ２型向ＴＨ０／ＴＨ１型逆转。促逆转后可以改善肿瘤细胞对机体杀伤作用的敏感性，提高抗肿瘤免疫能力     

纳米粒子应用于电化学癌症早期检测技术的研究进展

利用纳米电化学传感技术进行癌症的早期检测是将来生物医学领域的一个重要发展方向.简要介绍了肿瘤早期检测用标志物的概念和电化学检测这些标志物的原理,对纳米粒子应用于电化学癌症早期检测技术的研究进展进行了详细的评述,最后对该领域的应用前景进行了展望.     

TP73-AS1在肿瘤中的表达及调控作用

<正>随着高通量测序技术的发展,成千上万种长链非编码RNA(long non-coding RNA,lncRNA)进入人们的视野。lncRNA是一类长度超过200个核苷酸并缺少开放阅读框的不具备蛋白质编码功能的RNA~([1-2])。研究发现lncRNA参与诸多生物学进程的关键步骤,包括染色质重塑、基因转录、转录后调节和蛋白质翻译等~([3-5])。LncRNA机制的不断被阐明,也为肿瘤的研究提供了新的可能。LncRNA在多种肿瘤的增殖、迁移侵袭和抗凋亡     

Natural mechanisms protecting against cancer

Carcinogenesis is a multistage process. At each step of this process, there are natural mechanisms protecting against development of cancer. The majority of cancers in humans is induced by carcinogenic factors present in our environment including our food. However, some natural substances present in our diet or synthesized in our cells are able to block, trap or decompose reactive oxygen species (ROS) participating in carcinogenesis. Carcinogens can also be removed from our cells. If DNA damage occurs, it is repaired in most of the cases. Unrepaired DNA alterations can be fixed as mutations in proliferating cells only and mutations of very few strategic genes can induce tumor formation, the most relevant are those activating proto-oncogenes and inactivating tumor suppressor genes. A series of mutations and/or epigenetic changes is required to drive transformation of a normal cell into malignant tumor. The apparently unrestricted growth has to be accompanied by a mechanism preserving telomeres which otherwise shorten with succeeding cell divisions leading to growth arrest. Tumor can not develop beyond the size of 1–2 mm in diameter without the induction of angiogenesis which is regulated by natural inhibitors. To invade the surrounding tissues epithelial tumor cells have to lose some adhesion molecules keeping them attached to each other and to produce enzymes able to dissolve the elements of the basement membrane. On the other hand, acquisition of other adhesion molecules enables interaction of circulating tumor cells with endothelial cells facilitating extravasation and metastasis. One of the last barriers protecting against cancer is the activity of the immune system. Both innate and adaptive immunity participates in anti-tumor effects including the activity of natural killer (NK) cells, natural killer T cells, macrophages, neutrophils and eosinophils, complement, various cytokines, specific antibodies, and specific T cytotoxic cells. Upon activation neutrophils and macrophages are able to kill tumor cells but they can also release ROS, angiogenic and immunosuppressive substances. Many cytokines belonging to different families display anti-tumor activity but their role in natural anti-tumor defense remains largely to be established.     

不同来源的TIL临床应用研究

以５１例晚期肿瘤患者作为研究对象，对其不同来源的肿瘤浸润淋巴细胞（ＴＩＬ）进行治疗研究，发现肿瘤组织来源的ＴＩＬ其有效率及一年生存率明显高于胸腹水及转移淋巴结的ＴＡＬ；其中肿瘤组织的ＴＩＬ，胸腹水、转移淋巴结的ＴＡＬ有效率分别为８０．９％、４０．０％、４６．６％；三者治疗肿瘤患者的一年生存率分别为８１．０％、４６．７％、６０．０％；另外发现胸腹水ＴＡＬ对实质性肿块治疗疗效较低，为４０％，其中静脉滴