Targeted cancer therapy

Disruption of the normal regulation of cell-cycle progression and division lies at the heart of the events leading to cancer. Complex networks of regulatory factors, the tumour microenvironment and stress signals, such as those resulting from damaged DNA, dictate whether cancer cells proliferate or die. Recent progress in understanding the molecular changes that underlie cancer development offer the prospect of specifically targeting malfunctioning molecules and pathways to achieve more effective and rational cancer therapy.     

蛋白酶抑制剂在肿瘤治疗中的作用研究

蛋白酶及其抑制剂是非常重要的信号分子,涉及多个关键的人体生理代谢途径,在体内受到严格的调控.蛋白酶抑制剂活性的紊乱可导致多种疾病,诸如心血管和炎症疾病、癌症和神经系统障碍等.已知蛋白酶在肿瘤细胞侵袭和转移过程中扮演着重要的角色.细胞外基质和基底膜重塑是癌细胞侵袭转移过程中的关键环节,这个过程需多个蛋白水解酶的表达和激活.蛋白酶抑制剂的应用在一定程度上可减少由蛋白酶水解引起的肿瘤细胞的侵袭和转移,且它的抑制作用具有不同程度的特异性,可以减缓肿瘤恶性发展的进程.文章对蛋白酶及其抑制剂的靶向治疗药物及临床应用研究进展进行了综述.     

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.     

傅里叶红外光谱法在肿瘤分析中的应用

综述了傅里叶红外光谱(FTIR)在鉴定癌症中的应用研究进展.目前,对其诊断主要是依靠病理学诊断,但是病理学诊断不仅过程烦琐,而且常受人为因素影响.傅里叶红外光谱及其相关技术的迅速发展,使其越来越广泛用于蛋白质,核酸等生物大分子的结构研究上,同时已开始更深入地应用于研究细胞和组织等更加复杂的体系.研究结果表明,FTIR可以从分子水平上揭示肿瘤组织的特性,极有可能发展成为一种可定量化地鉴定肿瘤的手段.     

内质网靶向生物活性小分子探针研究进展

内质网是真核细胞中重要的细胞器，参与多种生理过程．各种外界诱因会引发内质网应激，使细胞产生各种生物活性分子，从而导致细胞生理活性变化，引起癌症等多种疾病．生物活性物种，如活性氧、活性氮、活性硫等，具有较高的氧化还原活性和生物活性，在众多生理病理过程中起着关键作用．荧光探针技术是检测这些生物活性物种的一种较理想的手段，具有光学性质优异、定位效果突出、可以进行多功能实时原位监测等特点．因而，借助荧光成像技术监测活性物种在内质网中的变化过程，对攻克某些代谢疾病和癌症具有极大的推动作用．本文综述了近几年来可以靶向于内质网、特异性检测活性物种的荧光探针，在对其结构进行介绍的基础上，展示了其功能性和生物应用前景，并进一步阐述了定位和检测机制，最后对该类探针的未来发展进行了展望．      

Xenogeneic homologous genes, molecular evolution and cancer therapy

Cancer is one of the main causes for death of human beings to date, and cancer biotherapy (mainlyimmunotherapy and gene therapy) has become the most promising approach after surgical therapy, radiotherapy andchemotherapy. However, there are still many limitations on cancer immunotherapy and gene therapy; therefore great ef-fort is being made to develop new strategies. It has been known that, in the process of evolution, a number of genes, theso-called xenogeneic homologous genes, are well-conserved and show the structural and/or functional similarity betweenvarious species to some degree. The nucleotide changes between various xenogeneic homologous genes are derived frommutation, and most of them are neutral mutations. Considering that the subtle differences in xenogeneic homologousgenes can break immune tolerance, enhance the immunogenicity and induce autologous immune response so as to elimi-nate tumor cells, we expect that a strategy of inducing autoimmune response using the property of xenogeneic homologousgenes will become a new therapy for cancer. Moreover, this therapy can also be used in the treatment of other diseases,such as autoimmune diseases and AIDS. This article will discuss the xenogeneic homologous genes, molecular evolutionand cancer therapy.     

Aneuploidy and cancer

In contrast to normal cells, aneuploidy--alterations in the number of chromosomes--is consistently observed in virtually all cancers. A growing body of evidence suggests that aneuploidy is often caused by a particular type of genetic instability, called chromosomal instability, which may reflect defects in mitotic segregation in cancer cells. A better understanding of the molecular mechanisms leading to aneuploidy holds promise for the development of cancer drugs that target this process.     

肿瘤主动靶向磁性纳米粒子研究现状及其在肿瘤热疗中的应用

 磁性纳米粒子已广泛应用于肿瘤的成像和治疗,但限制其临床应用的重大障碍是纳米粒子在肿瘤部位不能达到足够的浓度。主动靶向磁性纳米粒子是磁性纳米粒子表面偶联特定的靶向配体,靶向性结合特定的肿瘤细胞。靶向配体的选择是提高主动靶向性的关键。主动靶向性提高了磁性纳米粒子在肿瘤组织内的浓度,减少对正常组织的毒性,从而使其在肿瘤成像与治疗成为可能。磁感应热疗利用磁介质在外加交变磁场的作用下感应发热,是一种新型的具有前景的肿瘤治疗手段。依靠磁性纳米粒子主动靶向性,磁感应热疗将更好地实现细胞内热疗,提高肿瘤治疗的疗效。     

一种新的MDM2-p53信号通路抑制剂的发现研究

本研究以研发新型小分子MDM2抑制剂为目的,建立了以分子对接为基础的虚拟筛选流程.利用虚拟筛选流程对SPECS化合物库的分子进行类药性筛选、分子对接粗筛、二次筛选以及排序挑选,并通过细胞实验验证这些分子激活p53并抑制肿瘤细胞生长的活性.结果表明M12能够激活p53及其下游信号通路,抑制肿瘤细胞周期并促进肿瘤细胞凋亡.M12与已知MDM2-p53抑制剂结构完全不同,是一种潜在的癌症治疗候选药物.     

Recovery of learning and memory is associated with chromatin remodelling

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia.     

Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases

The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.     

Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease

Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.     

Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis

The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.     

Design of effective immunotherapy for human autoimmunity

A better understanding of the molecules involved in immune responses has identified many potential targets for the treatment of autoimmune diseases. But although successful therapies have been found for immune disorders in animal studies, few have passed the much harder test of treating human diseases. So far, non-antigen-specific approaches, such as the blocking of tumour-necrosis factor, are achieving some success but the same is not true for antigen-specific approaches. Future therapies will probably include both non-antigen-specific strategies that target cytokines (cell-cell signalling molecules) or block the molecules that stimulate immune responses, and antigen-specific therapies that induce tolerance to self antigens.     

当前慢病防控困境迫切呼唤新医学和菌心说

 进入21 世纪以来,国际社会所面临的慢病防控形势愈发严峻,不仅对于肥胖、糖尿病、高血压、肿瘤等慢病仍然缺乏良策,而且新药研发速度也并没有随着人类基因组计划的完成得到提高,进而导致欧美以及中国医疗改革举步维艰,反过来提示当代医疗模式可能存在一定问题。结合国际上的研究进展,针对这些问题进行系统分析以及基于大量志愿者进行科学研究的基础上,提出“慢病的菌源性学说”,倾向于认为人体慢病主要是由于多种因素所导致的人体共生微生物菌群紊乱造成的,同时证明可通过纠正胃肠道菌群紊乱显著改善包括便秘、肥胖、糖尿病等在内的慢病症状。在此基础上,还进一步提出“心理活动的菌源性学说”,认为人类的心理活动除了与大脑密切相关之外,还与人体共生菌群密切相关,甚至不排除人类心理活动有可能是微生物菌群通过人体大脑控制下的机体行为所展示出来的一种表现。进而提出新医学理论和菌心说学说,认为人菌平衡是健康的标志,而人菌失衡是慢病的根源,而且人菌失衡的关键在于人体和菌群之间的碳源竞争。菌心说学说认为相对于人体的躯体和大脑而言,由人体共生微生物菌群所构成的“心脑菌脑”有可能是人类心理活动的核心、中心和重心,而人体则有可能是被设计为菌群微生态系统提供生存与发展作用的场所和工具。基于这一观点,不仅可望实现慢病防控与健康管理领域的新突破,而且还有可能实现对人类心理活动以及精神意识活动的物质基础的认知与升华,对于重新认识人类以及人类社会将有可能带来前所未有的新突破。     

物性参数对纳米流体强化换热的影响

对铜-氩纳米流体在矩形槽通道内流动和换热情况进行了数值模拟,对基础流体和不同体积分数的纳米流体在不同Re下的换热情况进行研究,分析了纳米流体热物性的改变对强化换热的影响.研究表明:相对于基础流体而言纳米流体由于具有较好的导热性能而强化换热,并且纳米流体体积分数越大,其导热性能越好,从而换热能力也越大.对于相同体积分数的纳米流体,其换热系数提高的程度与流体的速度有关系,流速越小,换热系数提高得越大,而随着流速的逐渐增大换热系数提高的程度逐渐下降.     

卵巢癌转移相关基因及其信号传导途径

卵巢癌转移是一个复杂的过程。这些过程与粘附、降解、运动等行为密切相关,涉及到很多分子的变化,包括相关黏附分子、蛋白水解酶、趋化因子、血管内皮细胞生长因子（VEGF）等。随着研究的深入,对卵巢癌转移相关的基因及其信号传导途径有了更多的了解,这些成果也为临床实践提供了机会。