恶性肿瘤中IGFBP-rP1的抑癌基因作用机制及其可能的临床实用价值

胰岛素样生长因子结合蛋白相关蛋白1(IGFBP-rP1)是近年来恶性肿瘤的研究热点.本文主要综述IGFBP-rP1在恶性肿瘤中的抑癌基因作用机制及可能的临床实用价值.IGFBP-rP1在恶性肿瘤中的作用广泛涉及细胞的增殖、衰老、凋亡、分化、血管生成等多方面,研究指出IGFBP-rP1可缩短细胞增殖周期并影响非停泊性生长从而抑制增殖,降低致瘤能力;调节BRAF-MEKERK信号通路及pRB、HSP60等相关蛋白的表达从而影响衰老及凋亡;主要通过IGF依赖方式抑制血管生成;而且IGFBP-rP1表达下降跟肿瘤细胞分化程度降低有关.研究显示IGFBP-rP1有一定的临床实用价值,如其表达量跟恶性肿瘤的进展相关,低表达提示某些化疗药物抵抗,可提示预后.而在恶性肿瘤中特异性地上调IGFBP-rP1,可抑制肿瘤增殖及血管生成、诱导细胞衰老凋亡、提高肿瘤分化程度及化疗敏感性,具有治疗意义,但研究者们还在努力探究,争取早日找到一种临床有效的靶向IGFBP-rP1的基因治疗方法.     

肝癌复发转移的临床与实验研究进展与展望

90年代以来肝癌已成为我国第二位癌症杀手，为此肝癌的防治至关重要。至今，外科仍然是肝癌获得根治的最好疗法，但复发和转移是进一步改善预后的障碍，近年复发和转移的研究已成为包括肝癌在内所有实体瘤的研究热点。本文复习相关文献，并重点叙述我所的有关工作。临床方面，对亚临床期复发的再切除是进一步提高疗效的有效途径，但复发的预防则困难得多，化疗/免疫/栓塞治疗可能有助。实验研究方面，已建成裸鼠人肝癌高转移模型，研究了与侵袭性相关的分子水平变化（如c-erb-B2、p16、p21、p53、mdm2、VEGF、TGFa、EGF受体、MMP-2、ICAM-1等与侵袭性呈正相关，而nm23-H1、TIMP-2、整合素a5、Kai-1等则与侵袭性呈负相关），并探索了使用反义H-ras、抗HBx/抗CD3的双功能抗体、TNF与TK基因的基因治疗，BB94（基质金属蛋白酶抑制剂）、TNP-470（抗血管生成）等的干预治疗。预期生物治疗、基于分子生物学发现所设计的新疗法、综合干预等可能重要，而针对肿瘤血管的控制对肝癌可能有特殊意义。     

21世纪的新药发现:从基因到药物

随着人类基因线计划的实施将会发现越来越多的功能基因。从中了解到的生物信息对我们了解发病机制将提供很大的帮助,同时可进行广泛的人群遗传相关性和基因治疗研究,并可能发现新的药物作用靶,其取得的研究进展对疾病治疗的合理用药及新药的研究开发将产生深远的影响,未来将会看到更多的新药出现,但一定是随着新基因的发现而开始的。     

基因治疗研究的现状

在巨大的经济效益诱惑下，美国生物医学界在近五年内掀起了一般基因治疗热。这股热浪多少也辐射到了国内。本文评估了美国生物医学科学界的基因治疗现状。认为基因治疗仍处在实验室研究阶段，并未达到临床治疗水平。基因治疗仍需重视其基础研究，现阶段应避免过分强调其临床应用价值。     

肿瘤血管生成抑制剂的研究现状及我国的发展战略探讨

肿瘤血管生成抑制剂是一类能破坏或抑制血管生成,有效地阻止肿瘤的生长和转移的药物。按作用机制可分为五大类：（１）抑制基底膜降解;（２）直接抑制内皮细胞增殖;（３）抑制血管生长因子活化;（４）抑制内皮细胞特异性整合素／生存信号;（５）其它非特异性作用机制的药物。本文主要介绍了肿瘤血管生成抑制剂的研究现状,并对我国在肿瘤血管生成抑制剂研究方面可采取的战略进行了探讨。     

辛伐他汀联合用药研究进展

动脉粥样硬化是心脑血管疾病的主要病理学基础,他汀类药物是抗动脉粥样硬化的基石.辛伐他汀降低总胆固醇（TC）和低密度脂蛋白胆固醇（LDL-C）作用明显,同时也降低甘油三酯（TG）和升高高密度脂蛋白（HDL）水平,是目前临床上应用最广泛的降脂药之一.诸多专家学者对辛伐他汀的联合用药也进行了广泛深入的研究,认为其不仅在抗动脉粥样硬化领域具有确切的疗效,而且在不稳定性心绞痛、冠心病的二级预防、高血压、早期糖尿病肾病以及骨质疏松等疾病中的治疗也具有重要的意义.     

线粒体学与生物医学新前沿

近来大量研究证明,线粒体除了合成ATP能量之外还有多种极为重要新的细胞功能,包括生成活性氧,调节氧化还原电势和信号转导,调控基因表达和细胞凋亡等,并在生物的生长、发育、衰老、疾病、死亡以及生物进化等方面都有重要意义,成为当前生命科学和分子医学中一个新生长点和前沿。     

过氧亚硝酸盐的化学特性与化学发光反应

过氧亚硝酸盐(ONOO)是一氧化氮衍生物，由一氧化氮和超氧阴离子反应生成，它是很强的生物氧化剂，具有高的反应活性和不稳定性。本文评述了过氧亚硝酸盐的形成、生物地位、分解、测定，重点介绍过氧亚硝酸盐化学发光研究以及与二氧化碳的反应，并对其发展前景进行展望。引用参考文献152篇。     

Graves病患者IL-6、IL-10、IFN-γ水平的变化及临床意义

目的 通过检测GD患者外周血血清中IL-6、IL-10、IFN-γ三种细胞因子水平于治疗前后的变化及关系,探讨其与甲状腺功能变化的相关性及临床意义.方法 取GD患者共32例.缓解期患者组共33例为确诊的GD患者,接受系统抗甲状腺药物治疗,临床症状缓解,甲状腺功能恢复正常者定为缓解组.以上两组患者均无其它自身免疫性疾病和感染性疾病.另取正常健康人40倒.均无甲状腺疾病史及甲状腺疾病家族史定为正常对照组.取所有受试者静脉血测定FT3、FT4、TSH、TMAb、TGAb、IL-6、IL-10、IFN-γ值.结果 IL-6:GD组较缓解组显著增高(P<0.01),缓解组与对照组无明显差异(P>0.05)IL-10:GD组与缓解组较对照组显著增高(P<0.01),GD组与缓解组无明显差异(P>0.05)IFN-γ:GD组与缓解组较对照组显著增高(P<0.01),GD组与缓解组无明显差异.结论 IFN-γ可诱导甲状腺细胞Ⅱ型抗原的表达,进而增强这些细胞的免疫原性.IFN-γ单独或与TNF-α联合作用可促进甲状腺细胞表达胞间粘附分子Ⅱ(ICAM-Ⅱ)及HLA-Ⅱ类抗原.并且TNF-α可增强IFN-γ对TEC的MHC-Ⅱ分子抗原的高效表达,而表达的异常则可使自身免疫反应得以发生及进行性发展.随治疗过程的进展,IFN-γ仍处于较高水平.高于正常对照组,反映了免疫治疗过程的滞后性.     

小麦转基因研究现状及展望

自二十世纪八十年代开始研究转基因植物以来，小麦作为世界主要粮食来源，其转基因遗传改良受到科学家的广泛关注。目前国内外已有近200例外源基因，主要是抗除草剂类基因、抗病虫基因、品质基因、抗旱耐盐等抗逆基因、雄性不育类基因等，通过基因枪法、农杆菌介导法、花粉管通道法等技术转入小麦的报道。从转单基因到进行多基因组装，从改良各种生物胁迫和非生物胁迫的抗逆性，到改良品质、高产等生理和农艺性状，是未来转基因小麦的研究方向。本文就近二十几年来转基因小麦研究进展及存在问题进行了全面系统的综述和探讨。     

Tumor necrosis factor as an antineoplastic agent: pitfalls and promises

The discovery and cloning of the cytokine tumor necrosis factor α (TNF) gave rise to new hopes for a significant victory in the war against cancer. Preclinical in vitro studies in cell cultures and in vivo studies in animal models demonstrated the antitumor capacities of TNF. Although clinical studies were largely made possible by the availability of recombinant TNF, phase I and II clinical trials showed very quickly that the systemic administration of TNF induced severe side effects mainly due to its pleiotropic action on immunocompetent cells. The clinical manifestations of the side effects were similar to those observed during a severe infection and inflammation. Very recently, lessons from these clinical studies yielded refined approaches whereby the toxicity of TNF is limited through local administration, a combination with other therapeutic regimens and targeted gene therapy. These new approaches are slated for larger clinical trials and in the near future might demonstrate the limited but powerful usefulness of TNF as an antineoplastic agent for different types of cancer. Received 7 September 1998; received after revision 15 October 1998; accepted 15 October 1998     

Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer’s disease

Deposition of amyloid β-protein (Aβ) in the brain is an early and invariant neuropathological feature of Alzheimer’s disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Aβ in the brain. Here, we review four anti-amyloidogenic strategies: (i) reduction of Aβ production, which has mainly been approached with secretase inhibition, (ii) promotion of the Aβ degrading catabolic pathway, including an Aβ degrading enzyme, neprilysin, (iii) immunotherapy for Aβ and (iv) inhibition of Aβ aggregation. We have reported that AD patients have a favorable molecular environment for Aβ aggregation and that various compounds, such as polyphenols, interfere with Aβ aggregation and destabilize preformed Aβ fibrils. Received 21 December 2005; received after revision 14 February 2006; accepted 29 March 2006     

Molecular mechanisms involved in dendritic cell dysfunction in cancer

Dendritic cells (DC) play a pivotal role in the tumor microenvironment (TME). As the primary antigen-presenting cells in the tumor, DCs modulate anti-tumor responses by regulating the magnitude and duration of infiltrating cytotoxic T lymphocyte responses. Unfortunately, due to the immunosuppressive nature of the TME, as well as the inherent plasticity of DCs, tumor DCs are often dysfunctional, a phenomenon that contributes to immune evasion. Recent progresses in our understanding of tumor DC biology have revealed potential molecular targets that allow us to improve tumor DC immunogenicity and cancer immunotherapy. Here, we review the molecular mechanisms that drive tumor DC dysfunction. We discuss recent advances in our understanding of tumor DC ontogeny, tumor DC subset heterogeneity, and factors in the tumor microenvironment that affect DC recruitment, differentiation, and function. Finally, we describe potential strategies to optimize tumor DC function in the context of cancer therapy.     

Inhibition of SRC family kinases facilitates anti-CTLA4 immunotherapy in head and neck squamous cell carcinoma

The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs’ inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8⁺ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3^Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.     

The development of gene therapy for diseases of the lung

The development of a successful gene therapy has many stages, including preclinical testing in animal models and proof of principle clinical studies. A variety of diseases affect the lung, which are candidates for gene therapy; this review will mainly focus on the diseases that have attracted the most attention and have therefore yielded the most progress, namely lung cancer and the monogenic disorder cystic fibrosis. Knowledge gained from clinical studies could eventually be applied to more complex lung conditions such as acute respiratory distress syndrome and asthma. In addition, increased gene transfer efficiencies could be obtained by appropriate selection of the gene transfer vector and mode of delivery.Received 8 August 2003; received after revision 10 September 2003; accepted 17 September 2003     

What's new in the field of cancer vaccines?

The observation that in some cases tumors undergo spontaneous regression concomitantly with autoimmune manifestations has been interpreted as an indication of the involvement of the immune system in tumor rejection. This raised the conceptual possibility that the immune system could be used against the tumor. However, since tumor cells are poorly immunogenic by themselves, early attempts to develop immune-based approaches for cancer therapy saw the use of tumor cells transduced with genes coding for cytokines or costimulatory molecules to enhance in vivo immunity. The identification of cytotoxic T lymphocyte (CTL)-defined tumor associated antigens has allowed the development of new strategies for cancer immunotherapy. Novel adjuvants have been identified, and different modes of antigen delivery were devised which aim at inducing efficient CTL responses in patients. This review will discuss some of what is currently considered as relevant aspects of antitumor immunization.Received 19 July 2002; received after revision 11 December 2002; accepted 13 December 2002     

Generation of cellular immune responses to antigenic tumor peptides

Tumor immunotherapy is currently receiving close scrutiny. However, with the identification of tumor antigens and their production by recombinant means, the use of cytokines and knowledge of major histocompatibility complex (MHC) class I and class II presentation has provided ample reagents for use and clear indications of how they should be used. At this time, much attention is focused on using peptides to be presented by MHC class I molecules to both induce and be targets for CD8+ cytolytic T cells. Many peptides generated endogenously or given exogenously can enter the class I pathway, but a number of other methods of entering this pathway are also known and are discussed in detail herein. While the review concentrates on inducing cytotoxic T cells (CTLs), it is becoming increasingly apparent that other modes of immunotherapy would be desirable, such as class II presentation to induce increased helper activity (for CTL), but also activating macrophages to be effective against tumor cells.