A roadmap for successful applications of clinical proteomics

Despite over 30,000 publications on proteomics in the last decade, and the accumulation of extensive interesting information on the human proteome in diverse observations, the clinical translation of proteomics to-date has had major setbacks. I review here a roadmap for improving the success rate of clinical proteomics. The roadmap includes steps for improvements that need to be made in analytical tools, discovery, validation, clinical application, and post-clinical application appraisal. It is likely that most if not all of the components that are necessary for clinical success are either readily available, or should be possible to put in place with more rigorous research standards and concerted efforts of the research community, clinicians, and health agencies. Enthusiasm for the clinical impact of proteomics may need to be tempered currently until robust evidence can be obtained, but some clinical successes should eventually be feasible.     

Urine proteomics in kidney and urogenital diseases: Moving towards clinical applications

To date, multiple biomarker discovery studies in urine have been conducted. Nevertheless, the rate of progression of these biomarkers to qualification and even more clinical application is extremely low. The scope of this article is to provide an overview of main clinically relevant proteomic findings from urine focusing on kidney diseases, bladder and prostate cancers. In addition, approaches for promoting the use of urine in clinical proteomics including potential means to facilitate the validation of existing promising findings (biomarker candidates identified from previous studies) and to increase the chances for success for the identification of new biomarkers are discussed.     

Combining laser capture microdissection and proteomics: methodologies and clinical applications

Laser capture microdissection (LCM) has become an important tool for biomedical research. Various molecular biology techniques have been combined with LCM to reveal molecular profiles at an unprecedented tissue resolution. Proteomics is among those techniques that have proved fruitful in combination with LCM. This review provides an overview of the various proteomic techniques that have been developed for analyzing cells obtained using LCM. Methods for analyzing microdissected cells for various proteomic techniques are described and compared. In addition, various applications based on LCM and proteomics are discussed.     

Quantitative proteomics for identification of cancer biomarkers

Quantitative proteomics can be used for the identification of cancer biomarkers that could be used for early detection, serve as therapeutic targets, or monitor response to treatment. Several quantitative proteomics tools are currently available to study differential expression of proteins in samples ranging from cancer cell lines to tissues to body fluids. 2-DE, which was classically used for proteomic profiling, has been coupled to fluorescence labeling for differential proteomics. Isotope labeling methods such as stable isotope labeling with amino acids in cell culture (SILAC), isotope-coded affinity tagging (ICAT), isobaric tags for relative and absolute quantitation (iTRAQ), and (18) O labeling have all been used in quantitative approaches for identification of cancer biomarkers. In addition, heavy isotope labeled peptides can be used to obtain absolute quantitative data. Most recently, label-free methods for quantitative proteomics, which have the potential of replacing isotope-labeling strategies, are becoming popular. Other emerging technologies such as protein microarrays have the potential for providing additional opportunities for biomarker identification. This review highlights commonly used methods for quantitative proteomic analysis and their advantages and limitations for cancer biomarker analysis.     

Mixed computation: potential applications and problems for study

Mixed computation is processing of an incomplete information. Its product are a partially processed information and a so-called residual program destined to complete in sequel the processing of the remaining information. Many kinds of practical work with programs are nothing more but obtaining a residual program. We demonstrate, as an example, the application of mixed computation to compilation. Under computational approach mixed computation generalizes the operational semantics of a language by inclusion of steps which generate residual program instructions. Under transformational approach the residual program is obtained as a result of a series of so-called basic transformations of the program text. We argue that the transformational approach is more fundamental, for it allows to describe mixed computation in all its variety and moreover, to relate mixed computation to other kinds of program manipulation: execution, optimization, macroprocessing, synthesis. Such an integrated approach leads us to a transformational machine concept.     

An innovative degraded adhesion model for multibody applications in the railway field

The simulation of the braking maneuver of a railway vehicle under degraded adhesion conditions is very important concerning the safety of railway operation. However, the implementation of a realistic friction law is comparatively difficult because of the complex and nonlinear behavior of the wheel-rail contact. Particularly under degraded adhesion conditions, very high creepages occur, which cause sliding in the contact. This sliding produces a high dissipation of energy, which has a cleaning effect on the rolling surfaces, and thereby strengthens the influence of the adhesion. In this work, this energetic criterion has been studied. The authors suggest implementing an innovative friction law to the simulation of railway multibody models with 3D multi-point contact detection algorithms. As a benchmark case, the braking of a coach equipped with a Wheel Slide Protection (WSP) system is simulated. The results are compared with experimental data available from previous testing activities by Trenitalia. The new friction law provides to match the experimental reference results and to carry out simulated braking tests, including the working WSP system, which comply with the current regulations (Railway applications, braking, wheel slide protection, UNI EN 15595, 2009).     

分子模拟在木素研究中的应用

分子模拟作为近年发展起来的一门综合性的计算化学技术,越来越受到油田化学、催化剂研制、高分子设计及化学工程等领域的广泛重视。它与实验技术一起成为研究木素分子结构、性质及生物合成机理的有效工具。文章介绍包含分子力学法、分子动力学法和量子力学法在内3种常用的分子模拟方法并综述其在木素研究中的应用,同时指出分子模拟的不足及其发展方向。     

Vascular proteomics and the discovery process of clinical biomarkers: The case of TWEAK

In the last years, big efforts are devoted to the search of novel biomarkers. Proteomic approaches in healthy and pathological samples may help us to discern differential protein expression patterns. These identified proteins include potential culprits in pathological pathways and/or clinical biomarkers to identify individuals at risk. However, extensively validation must be carried out before their implementation into the clinical practice. Biomarkers need to discriminate between health and disease, detect preclinical disease stages, have impact on survival prediction, and add predictive value beyond traditional risk factors and global risk algorithms. Now, we summarize the data of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK), a new cardiovascular biomarker identified by proteomic analysis. Decreased sTWEAK concentrations have been shown in patients with carotid atherosclerosis, coronary artery disease, congestive heart failure, peripheral artery disease, or chronic kidney disease (CKD). sTWEAK predicted adverse outcomes in patients with heart failure, myocardial infarction, and CKD. Finally, different drug regimens were able to modify sTWEAK plasma levels in patients with CKD. Although sTWEAK seems so far to fulfill the requisites in the development of a new biomarker, more large-scale studies are warranted to consolidate its usefulness.     

Mobile asynchronous communication: Exploring the potential for converged applications

Trends in technological development show that devices of personal communication and information management are converging and penetrating to new user segments. Therefore, it is a question of interest how the convergence of applications should be managed. This article explores the current use of email and SMS, focussing on the differences in the ways they are used and understood among their users. It is argued that, since the systems are different and have been in use for some time, established practices in using them as well as systems applied to understanding them are different. Based on analysis of interview data, it is conluded that this is the case, and that the future converged systems should not be considered as replacements of the current ones, but rather that the systems need to supplement each other. For example, the need for a quick and dirty instant asynchronous media such as SMS seems to remain, and therefore it cannot be replaced simply by implementing email to mobile phones. The need for email and SMS seems to be different, and thus the development should be towards a better understanding of these needs rather than simple technological convergence.     

新型生物传感器在蛋白质组学研究中应用进展

微技术和毫微技术的进展,使新技术的广泛领域包括具有毫微大小的机械设计成为可能．这类设计的新型传感器及其分析是蛋白质组学研究中的重要分析仪器和分析方法之一。文章讨论了新型生物传感器的类型,各种不同类型的生物传感器及非传感器生物检测技术对蛋白质敏感的检出限度和分析时间。综述了新型生物传感器在蛋白质分析鉴定、蛋白质组学研究中的应用进展。     

Programmable applications: exploring the potential for language/interface symbiosis

Abstract

Programmable applications are software systems that seek to combine the learnability and accessibility of direct manipulation interfaces with the expressive power and range of programming languages. In this paper we explore techniques for creatively integrating language and interface constructs within programmable applications. Using SchemePaint—a programmable graphics application—as a source of examples, we demonstrate how an interface and language can combine symbolically and thereby provide powerful modes of expression within applications.     

Programmable applications: exploring the potential for language/interface symbiosis

Programmable applications are software systems that seek to combine the learnability and accessibility of direct manipulation interfaces with the expressive power and range of programming languages. In this paper we explore techniques for creatively integrating language and interface constructs within programmable applications. Using SchemePaint—a programmable graphics application—as a source of examples, we demonstrate how an interface and language can combine symbolically and thereby provide powerful modes of expression within applications.     

Social science applications: A caveat for the operations research analyst

There is a growing sense of general discontent with the uncertainty, lack of understanding and absence of agreement in human services programs. Although operations research should have an impact on this situation by structuring the system for evaluation and decision-making, there has been limited application in these programs. This paper attempts to define and describe the gap in progress between the application of computers and operations research to the social sciences and the state of social programs, and attempts to define the limitations, trends and potentials for computer applications and operations research to reduce these gaps. The operations research analyst is cautioned in the judicious use of sophisticated methodology in social programs. Three social programs—child welfare services, vocational rehabilitation services and learning to read—illustrate problems and questions not characteristic of the physical sciences, but which the operations research analyst will confront in the human service fields. Suggestions are made to guide him in adapting to them successfully. These include: adopting a broader, less methodological analysis style; refocusing university training to incorporate a social science orientation in operations research curricula and a better subject matter understanding; and developing an instructional unit on the pathology of failure—that is, the clinical study of failures in the application of computers and operations research to the social sciences—in order to learn from them and to avoid similar future applications.     

Revisiting the Warburg effect in cancer cells with proteomics. The emergence of new approaches to diagnosis, prognosis and therapy

Most cancer cells exhibit elevated levels of glycolysis and this metabolic pathway seems to be related to a greater glucose uptake. This phenomenon, known as the Warburg effect, is considered one of the most fundamental metabolic alterations during malignant transformation. Originally, Warburg hypothesised that the aerobic glycolysis of cancer cells could be just an aspect of a more complex metabolic adaptation. However, this intriguing discovery was partially misinterpreted and disregarded over time. In recent years, the peculiarities of cancer cell metabolism have been re-evaluated in light of new metabolic data that seem to confirm and to widen the original concept of the Warburg effect. In fact, biochemical, molecular, and, above all, proteomic studies on the multifaceted roles of glycolytic enzymes in cancer cells in general, and in cancer stem cells in particular, seem to suggest more complex functional adaptations. These adaptations result in significantly altered protein expression patterns, and they have fundamental implications for diagnosis, prognosis and therapy. Revisiting the Warburg effect in cancer cells with a proteomic approach could deepen our knowledge of cancer cell metabolism and of cancer cell biology in general. Moreover, by identifying useful diagnostic, prognostic and therapeutic targets, it could significantly impact clinical practice.     

Single-cell compressibility quantification for assessing metastatic potential of cancer cells through multi-frequency acoustophoresis

Analyzing cancer cell compressibility with single-cell resolution is of high interest in understanding cancer metastasis as well as in other cell biology applications. Here, a multi-frequency acoustophoretic cell alignment technique to precisely control cell positions in 3D space was developed, and combined with our recently developed numerical acoustophoresis model, which allowed extracting the compressibility of cells with high accuracy. This technology was applied to measure the compressibility of different head and neck cancer (HNC) cell lines that have different metastatic potential. This method can be a simple, non-contact, accurate, and low-cost solution for studying cell biomechanics and utilizing such biomechanical properties in evaluating the metastatic potential of cancer cells.