Autophagy: from basic science to clinical application

Autophagy is a cellular pathway involved in protein and organelle degradation, which is likely to represent an innate adaptation to starvation. In times of nutrient deficiency, the cell can self-digest and recycle some nonessential components through nonselective autophagy, thus sustaining minimal growth requirements until a food source becomes available. Over recent years, autophagy has been implicated in an increasing number of clinical scenarios, notably infectious diseases, cancer, neurodegenerative diseases, and autoimmunity. The recent identification of the importance of autophagy genes in the genetic susceptibility to Crohn's disease suggests that a selective autophagic response may play a crucial role in the pathogenesis of common complex immune-mediated diseases. In this review, we discuss the autophagic mechanisms, their molecular regulation, and summarize their clinical relevance. This progress has led to great interest in the therapeutic potential of manipulation of both selective and nonselective autophagy in established disease.     

Hyperinsulinism in infancy: from basic science to clinical disease

Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered ion channel function, cell biology, and clinical disease been defined. Hyperinsulinism in infancy (HI) is a rare, potentially lethal condition of the newborn and early childhood. The causes of HI are varied and numerous, but in almost all cases they share a common target protein, the ATP-sensitive K+ channel. From gene defects in ion channel subunits to defects in beta-cell metabolism and anaplerosis, this review describes the relationship between pathogenesis and clinical medicine. Until recently, HI was generally considered an orphan disease, but as parallel defects in ion channels, enzymes, and metabolic pathways also give rise to diabetes and impaired insulin release, the HI paradigm has wider implications for more common disorders of the endocrine pancreas and the molecular physiology of ion transport.     

转化医学:从基础科研到临床应用

转化医学模式是指将医学基础研究成果迅速有效的转化为可在临床实际应用药物或器械的一类新兴科研思路.本文介绍了转化医学产生的背景、意义、模式、及其主要研究内容.在研究国内外成功转化医学模式经验的基础上,本文针对转化医学涉及的三个重要组成部分提出合理建议,旨在积极提高我国预防治疗疾病解决能力和基础科研转化效率等关键问题.     

转化医学:从基础科研到临床应用

转化医学模式是指将医学基础研究成果迅速有效的转化为可在临床实际应用药物或器械的一类新兴科研思路.本文介绍了转化医学产生的背景、意义、模式、及其主要研究内容.在研究国内外成功转化医学模式经验的基础上,本文针对转化医学涉及的三个重要组成部分提出合理建议,旨在积极提高我国预防治疗疾病解决能力和基础科研转化效率等关键问题.     

转化医学:从基础科研到临床应用

转化医学模式是指将医学基础研究成果迅速有效的转化为可在临床实际应用药物或器械的一类新兴科研思路.本文介绍了转化医学产生的背景、意义、模式、及其主要研究内容.在研究国内外成功转化医学模式经验的基础上,本文针对转化医学涉及的三个重要组成部分提出合理建议,旨在积极提高我国预防治疗疾病解决能力和基础科研转化效率等关键问题.     

Vaccination with heat shock protein-peptide complexes: from basic science to clinical applications

There are currently over 150 medical centers worldwide enrolling patients in randomized, controlled Phase III clinical trials testing autologous cancer-derived heat-shock protein (HSP)-peptide complexes for the treatment of renal cell carcinoma and melanoma. In addition, autologous HSP-peptide complexes have been or are being tested in Phase I and II trials of chronic myelogenous leukemia, lymphoma and pancreatic, gastric and colorectal cancers. The door has more recently opened to clinical testing of off-the-shelf HSP-based treatments for infectious diseases. This review recounts the long history of basic research on HSPs in immune response. A keen understanding of how these ancient molecules orchestrate the immune response to cancer and infections has been gained, providing a clear rationale for translating this knowledge into clinical medicine.     

Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application

The intestinal epithelium is faced with the complex task of providing a barrier while also allowing nutrient and water absorption. The frequency with which these processes are disrupted in disease can be taken as evidence of their importance. It is therefore of interest to define the mechanisms of altered intestinal barrier and transport function and develop means to correct disease-associated defects. Over the past 10 years, some of the molecular events underlying physiological epithelial barrier regulation have been described. Remarkably, recent advances have shown that activation of the same mechanisms is central to barrier dysfunction in both in vitro and in vivo models of disease. Although the contribution of barrier dysfunction to pathogenesis of chronic disease remains incompletely understood, it is now clear that cytoskeletal regulation of barrier function is both an important pathogenic process and that targeted inhibition of myosin light chain kinase, which affects this cytoskeleton-dependent tight junction dysfunction, is an attractive candidate for therapeutic intervention.     

The genetic approach to the Epstein-Barr virus: from basic virology to gene therapy.

The Epstein-Barr virus (EBV) infects humans and the genome of this infectious agent has been detected in several tumour types, ranging from lymphomas to carcinomas. The analysis of the functions of the numerous viral proteins encoded by EBV has been impeded by the large size of the viral genome, which renders the construction of viral mutants difficult. To overcome these limitations, several genetic systems have been developed that allow the modification of the viral genome. Two different approaches, depending on the host cell type in which the viral mutants are generated, have been used in the past. Traditionally, mutants were constructed in EBV infected eukaryotic cells, but more recently, approaches that make use of a recombinant EBV cloned in Escherichia coli have been proposed. The phenotype associated with the inactivation or modification of nearly 20 of the 100 EBV viral genes has been reported in the literature. In most of the reported cases, the EBV latent genes that mediate the ability of EBV to immortalize infected cells were the targets of the genetic analysis, but some virus mutants in which genes involved in DNA lytic replication or infection were disrupted have also been reported. The ability to modify the viral genome also opens the way to the construction of viral strains with medical relevance. A cell line infected by a virus that lacks the EBV packaging sequences can be used as a helper cell line for the encapsidation of EBV based viral vectors. This cell line will allow the evaluation of EBV as a gene transfer system with applications in gene therapy. Finally, genetically modified non-pathogenic strains will provide a basis for the design of an attenuated EBV live vaccine.     

骨组织工程由基础研究向临床应用过渡

大块骨缺损的修复是临床面临的棘手难题,采用传统的自体骨或同种异体骨移植及生物材料填充,由于存在种种弊端,均不理想,严重限制了其临床应用。组织工程技术的兴起为解决这一难题带来了希望,成为当前的研究热点。然而,大块组织工程骨血管化等关键性技术难题至今未找到理想的解决办法。采用常规的思路对大块骨缺损进行修复遇到了巨大的挑战。为使骨组织工程走向临床应用,提出并建立"体内灌注诱导成骨微循环系统"。     

用于神经系统基因治疗的病毒载体

近几年来 ,基因治疗 ( gene therapy)研究进展迅速。基因治疗是以基因转移方法将具有表达功能的基因导入到相关的细胞和组织中 ,使转录或翻译的产物发挥治疗作用的一种治疗方法。进行基因治疗时应根据宿主细胞病变基因表达水平的异常状况 ,而采取不同的基因治疗策略。目的是提高或补足表达水平低下的基因 ,降低表达水平过高的基因 ,或将在正常状况下不存在、不表达的基因进行封闭或将之破坏。目前基因治疗有四种基本策略 :基因置换 ( genereplacement)、基因修正 ( gene correction)、基因修饰 ( geneaugmentation)和基因失活 ( gene inacti…     

Thymosin alpha 1 in the treatment of cancer: from basic research to clinical application

Many studies have explored the effects of immunotherapy, alone or in combination with conventional therapies, on both experimental and human cancers. Evidence has been provided that combined treatments with thymosin alpha 1 (T alpha 1) and low doses of interferon (IFN) or interleukin (IL)-2 are highly effective in restoring several immune responses depressed by tumor growth and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to increase the anti-tumor effect of chemotherapy while markedly reducing the general toxicity of the treatment. The advantages of using this combined chemo-immunotherapeutic approach in experimental and human cancers are reviewed in this issue.