蛋白质组学技术对狼疮性肾炎中医证型的研究前景

蛋白质组学是继基因组学后提出的新学科,它是以组织或细胞的全部蛋白质为研究对象,以蛋白质表达的整体水平为研究特点,为生命科学的研究提供了新的视角。蛋白质组学技术应用于中医证候学研究有理论上的支持和技术基础作为保障,在寻找辨证客观化依据,揭示中医＂证＂本质等方面显示出广阔的应用前景。蛋白质组学在狼疮性肾炎中医领域的研究,促进了对其本质认识的深入,提高了临床诊断和治疗水平。现参阅近年来中外文献资料,对蛋白质组学在狼疮性肾炎中医证型的研究前景做一简要概述。     

蛋白质组学在肝癌研究中的应用

蛋白质组学以细胞组织或器官表达的所有蛋白质为研究对象,通过双向凝胶电泳生物质谱技术及生物信息学等方法,达到分离、鉴定、分析蛋白质的目的.在我国肝癌死亡率高,位居第二,预后差.以蛋白质组学的方法,通过比较肿瘤与正常肝组织之间蛋白质组的表达差异,发现新的肝癌肿瘤标志物,寻找与肝癌发生、发展、转移的相关蛋白,为肝癌治疗提供新的靶点.     

Effects of formaldehyde inhalation on lung of rats

To analyze protein changes in the lung of Wistar rats exposed to gaseous formaldehyde (FA) at 32-37 mg/m^3 for 4 h/day for 15 days using proteomics technique. Methods Lung samples were solubilized and separated by two-dimensional electrophoresis (2-DE), and gel patterns were scanned and analyzed for detection of differently expressed protein spots. These protein spots were identified by MALDI-TOF-MS and NCBInr protein database searching. Results Four proteins were altered significantly in 32-37 mg/m3 FA group, with 3 proteins up-regulated, 1 protein down-regulated. The 4 proteins were identified as aldose reductase, LIM protein, glyceraldehyde-3-phosphate dehydrogenase, and chloride intracellular channel 3. Conclusion The four proteins are related to cell proliferation induced by FA and defense reaction of anti-oxidation. Proteomics is a powerful tool in research of environmental health, and has prospects in search for protein markers for disease diagnosis and monitoring.     

Phosphoproteomics Analysis of Endometrium in Women with or without Endometriosis

Background:

The molecular mechanisms underlying the endometriosis are still not completely understood. In order to test the hypothesis that the approaches in phosphoproteomics might contribute to the identification of key biomarkers to assess disease pathogenesis and drug targets, we carried out a phosphoproteomics analysis of human endometrium.

Methods:

A large-scale differential phosphoproteome analysis, using peptide enrichment of titanium dioxide purify and sequential elution from immobilized metal affinity chromatography with linear trap quadrupole-tandem mass spectrometry, was performed in endometrium tissues from 8 women with or without endometriosis.

Results:

The phosphorylation profiling of endometrium from endometriosis patients had been obtained, and found that identified 516 proteins were modified at phosphorylation level during endometriosis. Gene ontology annotation analysis showed that these proteins were enriched in cellular processes of binding and catalytic activity. Further pathway analysis showed that ribosome pathway and focal adhesion pathway were the top two pathways, which might be deregulated during the development of endometriosis.

Conclusions:

That large-scale phosphoproteome quantification has been successfully identified in endometrium tissues of women with or without endometriosis will provide new insights to understand the molecular mechanisms of the development of endometriosis.     

Harmonized patient-reported data elements in the electronic health record: supporting meaningful use by primary care action on health behaviors and key psychosocial factors

Background

Electronic health records (EHR) have the potential to improve patient care through efficient access to complete patient health information. This potential may not be reached because many of the most important determinants of health outcome are rarely included. Successful health promotion and disease prevention requires patient-reported data reflecting health behaviors and psychosocial issues. Furthermore, there is a need to harmonize this information across different EHR systems.

Methods

To fill this gap a three-phased process was used to conceptualize, identify and recommend patient-reported data elements on health behaviors and psychosocial factors for the EHR. Expert panels (n=13) identified candidate measures (phase 1) that were reviewed and rated by a wide range of health professionals (n=93) using the grid-enabled measures wiki social media platform (phase 2). Recommendations were finalized through a town hall meeting with key stakeholders including patients, providers, researchers, policy makers, and representatives from healthcare settings (phase 3).

Results

Nine key elements from three areas emerged as the initial critical patient-reported elements to incorporate systematically into EHR—health behaviors (eg, exercise), psychosocial issues (eg, distress), and patient-centered factors (eg, demographics). Recommendations were also made regarding the frequency of collection ranging from a single assessment (eg, demographic characteristics), to annual assessment (eg, health behaviors), or more frequent (eg, patient goals).

Conclusions

There was strong stakeholder support for this initiative reflecting the perceived value of incorporating patient-reported elements into EHR. The next steps will include testing the feasibility of incorporating these elements into the EHR across diverse primary care settings.     

Pemphigoid: clinical, histologic, immunopathologic, and therapeutic considerations

Autoimmune blistering diseases are generally distinct entities characterized by relatively consistent clinical, histologic, and immunopathologic findings. These disorders may cause impaired adhesion of epidermis to epidermal basement membrane (eg, the pemphigoid group of disorders [bullous, gestational, and mucous membrane]) or impaired adhesion of epidermal cells to each other (eg, the pemphigus group of disorders). Recent studies have shown that these disorders are characterized by autoantibodies that often display pathogenic (ie, blister-forming) activity in passive transfer models. Interestingly, the autoantigens targeted by these patients' autoantibodies represent important structural proteins that promote cell matrix (eg, pemphigoid) or cell-to-cell (eg, pemphigus) adhesion in skin. Autoimmune blistering diseases are characterized by substantial morbidity (pruritus, pain, disfigurement), and in some instances, mortality (secondary to loss of epidermal barrier function). Treatment with systemic immunosuppressives has reduced morbidity and mortality in patients with these diseases. JAMA. 2000;284:350-356     

可溶性耐药相关钙结合蛋白在MPP+诱导的SH-SY5Y细胞帕金森病模型中的表达及意义

目的:观察1-甲基-4-苯基吡啶离子(MPP+)诱导的SH-SY5Y细胞帕金森病(PD)模型中可溶性抗药性相关钙结合蛋白(sorcin)表达的变化,寻求参与PD多巴胺能神经元细胞神经变性的蛋白质改变,为阐明PD的发病机制提供理论依据.方法:应用1.0 mmol·L-1 MPP+处理未分化的SH-SY5Y细胞24 h,在...     

蛋白质组学及其在消化系统疾病中的应用

蛋白质组学是以生物体系整体蛋白质为研究对象,其研究以双向凝胶电泳和质谱技术为核心,旨在研究蛋白质表达谱和蛋白质与蛋白质之间相互作用的新领域,已被广泛应用于疾病的相关研究。本文综述了最近几年来蛋白质组学及其在消化系统疾病方面的进展,其研究结果将对生物标记物和药靶的寻找,以及致病机理的阐述具有重要意义,亦为消化系统疾病的探讨提供了新的思路和方法。     

人前列腺癌细胞骨转移潜能差异表达蛋白的研究

目的 研究人前列腺癌不同骨转移潜能细胞株的差异表达蛋白质图谱,筛选前列腺癌骨转移相关蛋白并探讨其功能.方法 应用蛋白质组学和免疫印迹等.方法比较和筛选来源相同但具有不同骨转移潜能的前列腺癌细胞株(PC-3/骨转移亚克隆T3B/淋巴结转移亚克隆P2-4)的蛋白质表达差异.构建高迁移率族蛋白1(HMGB1)的真核表达载体Pgenesil-1/HMGB1siRNA转染至高骨转移潜能的T3B细胞中,通过动物实验观察HMGB1对前列腺癌细胞骨转移的影响.结果 蛋白质组学技术获得6个有意义的蛋白质,分别参与细胞骨架构成、转录调控、磷酸化过程和物质代谢等功能.成功构建siRNA表达载体Pgenesil-1/HMGB1siRNA,转染后可使T3B细胞HMGB1的蛋白表达水平显著降低(P<0.05).动物实验显示,抑制HMGB1表达可明显降低T3B细胞的骨转移能力(P<0.05).结论 高骨转移潜能的前列腺癌细胞株中存在与前列腺癌骨转移相关的蛋白质,HMGB1与前列腺癌骨转移密切相关.应用siRNA干扰技术能有效地抑制HMGB1基因的表达,同时也能有效抑制前列癌细胞的骨转移能力.     

Allergic reactions to drugs and biologic agents

In summary, the term adverse drug reaction is used to designate any type of undesirable and unintended response to a drug and can be broadly classified on the basis of either the presence or absence of an immune mechanism. Allergic reactions (immune) constitute only 5% to 10% of adverse drug reactions. Drug intolerance (nonimmune) constitutes the rest of these reactions. Many of these latter reactions are mild and self-limited, and many drug intolerances cannot be exactly characterized. Of those reactions in which an immune mechanism has been indicated or reactions that clinically appear to be "allergiclike," a limited number of in vivo (eg, skin tests) or in vitro (eg, RAST, IgE-ELISA, other antibody, or cell-mediated assays) tests have proved helpful in the diagnosis. Best studied are adverse reactions to aspirin, penicillin, insulin, and RCM. The principal treatment of all adverse drug reactions is to avoid the drug that has been specifically identified as being responsible for the previous reaction. In cases where avoidance is not possible, desensitization is an alternative (eg, penicillin and insulin). Prophylactic treatment of patients who had previously demonstrated a drug intolerance reaction (eg, systemic RCM reaction) with medication--particularly type I activation--may be helpful in some patients.     

"毒损脑络"与出血性中风的现代生物学基础

从毒损脑络理论假说出发认识出血性中风(intracerebral hemorrhage,ICH)成为学界的一种新思路。微血管破坏受损是ICH的核心病变和基本动因,也是探求ICH后"病络"的生物学基础的一个切入点。络脉是以解剖为基础的结构功能统一体,与微循环、神经内分泌系统等存在密切联系。在ICH中,毒损脑络、络脉瘀阻、饮停络阻是ICH发病的关键病机,在现代生物学中它们与微循环调控、血管调节功能、血脑屏障等病理生理过程紧密相关。这种探讨将我们对ICH"病络"的认识带入了微观的层次,与现代科学的结合有了一个很好的切入点,具有十分重要的现实意义。     

Bovine somatotropin supplementation of dairy cows. Is the milk safe?

Complex, biologically active proteins (eg, enzymes and hormones) can be manufactured safely and cost-effectively through applications of biotechnology. Some of these proteins (eg, human insulin, human somatotropin, rennet for cheese manufacture) are currently approved for medical or food processing applications. Bovine somatotropin (bST) for lactating dairy cattle is another product that can be produced via biotechnology and may allow dairy farmers to produce milk at a lower cost. In 1985, based on an evaluation of toxicological data, the Food and Drug Administration concluded that milk and meat from bST-supplemented cows was safe and wholesome. The Food and Drug Administration has authorized the use of milk and meat from bST-supplemented cows in the commercial food supply. Its evaluation of the impact of bST supplementation on the long-term health of dairy cattle is near completion, and bST may be approved for commercial use in early 1991.     

Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases

Lorenz C. Hofbauer, MD; Michael Schoppet, MD

JAMA. 2004;292:490-495.

Bone resorption by osteoclasts is coupled with bone formation by osteoblasts, and this balanced process continuously remodels and adapts the skeleton. The receptor activator of nuclear factor B ligand (RANKL) has been identified as an essential cytokine for the formation and activation of osteoclasts. The effects of RANKL are physiologically counterbalanced by the decoy receptor osteoprotegerin (OPG). Estrogen deficiency, glucocorticoid exposure, T-cell activation (eg, rheumatoid arthritis), and skeletal malignancies (eg, myeloma, metastases) enhance the ratio of RANKL to OPG and, thus, promote osteoclastogenesis, accelerate bone resorption, and induce bone loss. Moreover, alterations of the OPG/RANKL/RANK system have been implicated in vascular diseases. RANKL blockade (using OPG or RANK fusion proteins or RANKL antibodies) has prevented bone loss caused by osteoporosis, chronic inflammatory disorders, and malignant tumors in animal models and may emerge as a therapy in humans based on studies in postmenopausal osteoporosis, myeloma bone disease, and osteolytic metastases. This review summarizes the clinical implications of the OPG/RANKL/RANK system for bone and vascular diseases.

     

蛋白质组学技术和基因芯片在白血病研究中的应用

白血病是造血系统的恶性肿瘤。白血病的治疗和发病机制研究已取得显著成果,蛋白质组学与基因芯片技术在白血病的发生机制与治疗效果检测方面取得重大进展。蛋白质组学是指应用各种技术手段来研究蛋白质组的一门新兴科学,目的在于归类蛋白质整体分布,鉴定并分析感兴趣的个别蛋白质,最终阐明它们的关系与功能。基因芯片(microarray)技术也称为基因微阵列,高通量特点使其在基因表达分析、疾病诊断和治疗、新药发现等众多领域得到广泛应用。     

肿瘤蛋白质组学在信号传导通路、肿瘤标志物等方面的研究

肿瘤是一个多因素的疾病 ,在其的发生、发展过程中 ,分子生物学事件的复杂性日益受到人们的重视。随着基因组全序列测定的完成 ,蛋白质组学的研究得到了广泛的关注。应用蛋白质组学的方法 ,可以对细胞生长、分化过程中的蛋白质与细胞信号传导通路上的蛋白质之间的相互作用进行更为深入的研究 ,因而有希望发现控制肿瘤生物学行为的诸多蛋白质和信号分子。     

人高致病性禽流感病毒的分子生物学研究进展

禽流感是由甲型禽流感病毒引起的急性传染病,近年来这种向来只威胁家禽生命的病毒已经打破种属障碍直接导致人类死亡。尤其是高致病性禽流感病毒H5N1亚型的出现,严重威胁人类健康。关于H5N1的形态,基因结构及编码蛋白质的功能研究已取得了较大进展,病毒致病性的研究也发展迅速。加强对人禽流感分子生物学的研究,对防控大流行有重要的意义。     

BET蛋白与脑认知功能关系的研究进展

溴结构域和超末端结构域(BET)蛋白能识别乙酰化组蛋白并与之结合,同时与染色质调节因子相互作用或招募转录起始复合物,从而启动基因转录。近几年,BET蛋白抑制剂的合成推进了BET蛋白相关表观遗传学研究。本文综述BET蛋白的结构和功能、BET蛋白抑制剂、BET蛋白在学习和记忆中的作用、BET蛋白在老年痴呆症中的作用以及BET蛋白在药物成瘾中的作用。     

Comparing and evaluating terminology services application programming interfaces: RxNav, UMLSKS and LexBIG

To facilitate the integration of terminologies into applications, various terminology services application programming interfaces (API) have been developed in the recent past. In this study, three publicly available terminology services API, RxNav, UMLSKS and LexBIG, are compared and functionally evaluated with respect to the retrieval of information from one biomedical terminology, RxNorm, to which all three services provide access. A list of queries is established covering a wide spectrum of terminology services functionalities such as finding RxNorm concepts by their name, or navigating different types of relationships. Test data were generated from the RxNorm dataset to evaluate the implementation of the functionalities in the three API. The results revealed issues with various aspects of the API implementation (eg, handling of obsolete terms by LexBIG) and documentation (eg, navigational paths used in RxNav) that were subsequently addressed by the development teams of the three API investigated. Knowledge about such discrepancies helps inform the choice of an API for a given use case.The evolution of terminologies, across the spectrum of detailed nomenclatures and sophisticated classifications, has accelerated dramatically this decade,¹ and terminologies play a crucial role in applications including knowledge management, data integration and decision support.² To facilitate the integration of terminologies into applications, various terminology services application programming interfaces (API) have been developed in the recent past. In the biomedical domain, for example, such API for terminology services are a key component of the architecture of the cancer biomedical informatics grid (caBIG) developed under the auspices of the National Cancer Institute (NCI).³In practice, these API are tuned to efficiently and effectively provide a host of functional characteristics ranging from retrieving concept attributes such as definitions and synonyms, to navigating relationships between concepts (eg, finding sub or super-concepts of a given concept) and accessing information combinatorially (eg, list the immediate parent concepts of all concepts that have a term that contains the word infarction). In addition, the API provide various degrees of fault resilience (to ensure high availability of service), security (to prevent unauthorized alteration and/or disruption of content) and federation (to maintain linkages among components of a large terminology, or cross-references among related terminologies).As is true of interfaces in general, terminology service API integrated in biomedical applications have an impact on the overall quality of these applications. For example, the inability of a drug terminology API to serve the latest available data or to identify links between drug entities may cause a clinical decision support system (CDSS) relying on terminological information to make wrong inferences. For example, the following scenario illustrates the practical consequences on health care of suboptimal terminology services: A drug terminology service fails to identify the link between a brand name and its ingredients (eg, between Hamarin and allopurinol), which is used by the CDSS to identify drug–drug interactions among ingredients (eg, between allopurinol and warfarin). The CDSS, having failed to identify the proper interactions based on the information from the drug terminology service, fails to send an alert to the physician, and adverse events (eg, increased anticoagulation) occur in a patient as a consequence of the interaction between drugs (eg, metabolism of warfarin inhibited by allopurinol). Although hypothetical, this scenario illustrates the possible impact of terminology services on health care and motivates our investigation of terminology services.In some cases, multiple terminology services API deliver overlapping capabilities and mechanisms for querying the same information, thereby making it important to evaluate the consistency and accuracy of the functionalities provided. The goal of this study is to perform a functional evaluation of three publicly available terminology services API, RxNav, UMLSKS and LexBIG, with respect to the retrieval of information from one biomedical terminology, RxNorm, to which all three services provide access.     

蛋白质组学在中枢神经系统退行性疾病的研究进展

中枢神经系统(CNS)退行性疾病的病因病理非常复杂,因此对它们的诊断和治疗缺乏有效的方法。蛋白质组学研究主要是对生理与病理状态下的体液、组织或细胞中的蛋白质组分进行大通量的综合分析,并识别蛋白质表达的动态特征,这不仅可从蛋白质水平上揭示疾病的本质,还有助于全面探讨其病理机制,建立诊断标准,发现药物治疗靶点。蛋白质组学为CNS退行性疾病的研究提供了有效的方法和手段。目前针对CNS退行性疾病的蛋白质组学研究还是有限的,但是这些研究为理解CNS退行性疾病作出了重大的贡献。     

Incorporating molecular and functional context into the analysis and prioritization of human variants associated with cancer

Background and objective

With recent breakthroughs in high-throughput sequencing, identifying deleterious mutations is one of the key challenges for personalized medicine. At the gene and protein level, it has proven difficult to determine the impact of previously unknown variants. A statistical method has been developed to assess the significance of disease mutation clusters on protein domains by incorporating domain functional annotations to assist in the functional characterization of novel variants.

Methods

Disease mutations aggregated from multiple databases were mapped to domains, and were classified as either cancer- or non-cancer-related. The statistical method for identifying significantly disease-associated domain positions was applied to both sets of mutations and to randomly generated mutation sets for comparison. To leverage the known function of protein domain regions, the method optionally distributes significant scores to associated functional feature positions.

Results

Most disease mutations are localized within protein domains and display a tendency to cluster at individual domain positions. The method identified significant disease mutation hotspots in both the cancer and non-cancer datasets. The domain significance scores (DS-scores) for cancer form a bimodal distribution with hotspots in oncogenes forming a second peak at higher DS-scores than non-cancer, and hotspots in tumor suppressors have scores more similar to non-cancers. In addition, on an independent mutation benchmarking set, the DS-score method identified mutations known to alter protein function with very high precision.

Conclusion

By aggregating mutations with known disease association at the domain level, the method was able to discover domain positions enriched with multiple occurrences of deleterious mutations while incorporating relevant functional annotations. The method can be incorporated into translational bioinformatics tools to characterize rare and novel variants within large-scale sequencing studies.