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Michael J. Dunn

This double issue of Proteomics Clinical Applications contains the 2013 collection of review articles covering the application of proteomics technologies in various areas of biomedical and clinical proteomics. We firmly believe that such an annual collection of review articles is an excellent way for both relative newcomers and experts to keep abreast of the major advances in the field of clinical proteomics and we hope that you will find this year's collection of review articles interesting and helpful.

Technology

  1. Top of page
  2. Technology
  3. Cancer
  4. Neurodegenerative Disease
  5. Cardiovascular Disease
  6. Diabetes
  7. Pharmacology
  8. Microbiology

The search for novel biomarkers that can provide new insights into molecular dysfunction in disease and that have the potential to be of benefit in disease diagnosis, prognosis and therapy continues to be a major challenge. The application of proteomics to this endeavor has to date largely depended on the analysis of body fluids and tissue specimens by 2-DE and/or mass spectrometry. In their review, Hoheisel and colleagues describe how technical advances in antibody microarrays now provide an alternative tool for biomarker discovery. Such analysis is now robust and reproducible, highly sensitive down to the level of single-molecule detection and permits simultaneous analysis of multiple parameters on many molecules. To date most antibody microarray studies have focused on body fluids, but recent advances make the analysis of tissue proteomes possible.

Cancer

  1. Top of page
  2. Technology
  3. Cancer
  4. Neurodegenerative Disease
  5. Cardiovascular Disease
  6. Diabetes
  7. Pharmacology
  8. Microbiology

Cancer is characterized by changes in the levels and activities of important cellular proteins, including oncogenes and tumor suppressors, which result in the altered metabolism, proliferation, and metastasis seen in cancer cells. Characterization of these changes can result in advances in the detection and treatment of the disease. The review by Cole and colleagues focuses on breast cancer. Using human epidermal growth factor receptor 2 (HER2) as an example, they describe efforts to improve the quantitation and reliability of cancer biomarkers by using standards and reference materials.

Colorectal cancer (CRC) arises from the normal colon epithelium through the accumulation of genetic mutations and epigenetic alterations. An understanding of molecular changes in disease progression will provide novel insights into tumor behavior and in addition may result in the discovery of biomarkers for diagnosis, for monitoring treatment responsiveness, or for predicting disease outcomes. In their review, Wang and colleagues summarize the results from recent studies using tissue or serum samples from CRC patients and discuss the opportunities and challenges in translating these findings from the research setting to clinical practice. This theme is continued by Molloy and colleagues, who review the application of proteomic techniques of quantitative mass spectrometry to biomarker discovery and molecular pathway profiling in CRC.

Lung cancer is a major cancer worldwide and in which the overall survival rate remains poor. Over the past decade, efforts have focused on the discovery of protein biomarkers for early detection and monitoring of lung cancer progression during treatment. Recent studies have focused on the analysis of fluid-based specimens, rather than tissue samples or cell lines. Such specimens are relatively easy to collect and can be repeatedly sampled during the disease progression. In their review, Li and colleagues focus on recent advances of glycoproteomics, particularly in the identification of potential protein biomarkers using so-called fluid-based specimens in lung cancer. They summarize current strategies, achievements and perspectives for the discovery of tumor-associated glycoprotein biomarkers in lung cancer and their potential clinical applications.

Sarcomas range from curable tumors to those causing death via metastasis and recurrence. Kondo and colleagues describe their experience and discuss critical points in the proteomic discovery of novel biomarkers that are urgently needed in order to assess the degree of malignancy, predict prognosis, and evaluate possible therapies. A major challenge for such studies is the relative rarity of sarcomas, making biomarker validation more challenging than in other malignancies.

Glioblastomas are the most frequent adult primary brain tumors that remain fatal despite major clinical efforts. In their article, Thirant and colleagues discuss the interactions of glioblastoma stem-like cells (GSCs) that possess tumor initiating and therapeutic resistance properties with endothelial cells. This has made tumor vasculature a promising target in spite of disappointing results from anti-VEGF therapeutic trials. They go on to review recent findings of novel GSC secreted molecules with pro-angiogenic properties (Semaphorin 3A, HDGF) that have the potential to provide a path to the design of a concerted attack on glioblastoma vasculature that could overcome the development of resistance to single-targeted therapies while avoiding problems of toxicity.

Neurodegenerative Disease

  1. Top of page
  2. Technology
  3. Cancer
  4. Neurodegenerative Disease
  5. Cardiovascular Disease
  6. Diabetes
  7. Pharmacology
  8. Microbiology

Multiple sclerosis is an inflammatory-mediated demyelinating disorder most prevalent in young Caucasian adults. The review by Dagley and colleagues focuses on novel candidate biomarkers discovered by quantitative proteomic analysis of relevant disease-affected tissues in both the human disease and in an animal model, experimental autoimmune encephalomyelitis. The role of targeted mass spectrometry approaches for biomarker validation studies, such as multiple reaction monitoring (MRM) is also discussed.

Proteomics has a wide range of applications, including determination of differences in the proteome in terms of expression and post-translational protein modifications. Using proteomic techniques, apolipoprotein A-I (ApoA-I) has been found at decreased levels in subjects with a variety of neurodegenerative disorders, including in the serum and cerebrospinal fluid (CSF) of Alzheimer's disease, Parkinson's disease and Down's syndrome. In their article, Butterfield and colleagues discuss the consequences of oxidation of ApoA-I in neurodegeneration. They conclude that current evidence suggests that ApoA-I is a promising diagnostic marker, as well as a potential target, for therapeutic strategies in neurodegenerative disorders.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of motor neurons leading to death. The pathomechanism of the disease is only partially understood and therapeutic strategies based on mechanistic insights are largely ineffective. In their review, Krueger and colleagues describe how proteomic analysis of body fluids such as CSF, serum, plasma and even urine is being used to discover biomarkers that show significantly altered levels in ALS. They discuss how these biomarkers can be exploited to monitor disease progression and for the development of novel therapeutic strategies.

Amyloidosis is characterized by the deposition of inappropriately folded proteins as fibrils of beta-pleated sheets. At least 28 different proteins have been identified as causative agents of amyloidosis in humans, 14 of which are responsible for systemic forms. Correct identification of the amyloidogenic proteins in each patient is crucial for clinical management, in order to avoid misdiagnosis, inappropriate treatment and to assess the prognosis. In their review, Mauri and colleagues describe how mass spectrometry-based proteomics is now being used to improve unequivocal diagnosis and typing of amyloid deposits.

Cardiovascular Disease

  1. Top of page
  2. Technology
  3. Cancer
  4. Neurodegenerative Disease
  5. Cardiovascular Disease
  6. Diabetes
  7. Pharmacology
  8. Microbiology

Platelets in the circulation are triggered by vascular damage to activate, aggregate and form a thrombus that prevents excessive blood loss. Platelet activation is stringently regulated by intracellular signaling cascades, which when activated inappropriately lead to myocardial infarction and stroke. Proteomic studies of platelet dysfunction have identified a number of novel regulatory proteins of potential therapeutic value. Global analysis of platelet proteomes may enhance the outcome of these studies by arranging this information in a contextual manner that recapitulates established signaling complexes and predicts novel regulatory processes. The review by Wright and colleagues highlights advances in platelet proteomics data mining approaches that complement the emerging systems biology field. They also highlight nucleated cell types as key examples that can inform platelet research. They postulate that therapeutic translation of these modern approaches to understanding platelet regulatory mechanisms will enable the development of novel anti-thrombotic strategies.

Diabetes

  1. Top of page
  2. Technology
  3. Cancer
  4. Neurodegenerative Disease
  5. Cardiovascular Disease
  6. Diabetes
  7. Pharmacology
  8. Microbiology

Glycation, a non-enzymatic reaction between reducing sugars and proteins, is a proteome wide phenomenon, predominantly observed in diabetes due to hyperglycemia. The glycated proteomes of various tissues including plasma, kidney, lens and brain are implicated in the pathogenesis of a number of diseases including diabetic complications, neurodegenerative diseases, cancer and aging. In their review, Kulkarni and colleagues discuss strategies to characterize protein glycation, its functional implications in different diseases and intervention strategies to protect against its deleterious effects.

Pharmacology

  1. Top of page
  2. Technology
  3. Cancer
  4. Neurodegenerative Disease
  5. Cardiovascular Disease
  6. Diabetes
  7. Pharmacology
  8. Microbiology

The emerging field of chemo- and pharmacoproteomics addresses the mechanisms of action of bioactive molecules in a systems pharmacology context. In contrast to traditional approaches to drug discovery, pharmacoproteomics integrates the mechanism of a drug's action, its side effects including toxicity and the discovery of new drug targets in a single approach. Target profiling is accomplished using either active site-labeling probes or immobilized drugs. This enrichment strategy greatly reduces the complexity of the proteome to be analyzed by quantitative mass spectrometry. Recent advances in proteomic technology have enabled “global” proteomic profiling studies of drug-induced changes in protein expression levels and/or post-translational modifications. The review by Hess describes how these approaches have contributed significantly to the identification of novel drug targets and their mechanisms of action.

The identification of essential proteins, i.e. those proteins indispensable to cellular life, can further understanding of the minimal requirements for cell survival. Moreover, essential proteins are also candidate drug-targets in the development of novel therapies of disease such as cancer or infectious disease caused by emerging pathogens. However, it is expensive and time-consuming to experimentally identify essential proteins. Computational approaches for detecting essential proteins are therefore useful complements to limited experimental methods. In their article, Wang and colleagues review state-of-the-art methods for computational detection of essential proteins, and discuss challenges for future research in this field.

Microbiology

  1. Top of page
  2. Technology
  3. Cancer
  4. Neurodegenerative Disease
  5. Cardiovascular Disease
  6. Diabetes
  7. Pharmacology
  8. Microbiology

Coxiella burnetii, is an obligate intracellular pathogen, and is the causative agent of Q fever. The recent (2007–2009) Netherlands Q fever outbreak has stimulated research activity into this bacterium. Proteomic studies, in particular have generated a vast amount of information concerning several aspects of the bacterium such as virulence factors, detection/diagnostic and immunogenic biomarkers, inter/intra-species variation, resistance to antibiotics and secreted effector proteins with significant clinical impact. The review article by Tsiotis and colleagues focuses on advances in the field of C. burnetii proteomics using mass spectrometry, and speculates on how these new proteomic findings may suggest future directions for the improvement of Q fever diagnosis and therapy.

I hope that you will find the collection of review articles in the Proteomics Clinical Applications Reviews 2013 issue to be interesting and stimulating. Please remember that the PROTEOMICS Reviews 2013 is also published this month (Issue 4, Volume 13). You should certainly not miss this issue in order to keep up to date with the wider field of techniques and applications of proteomics! Finally, we are already planning the next collection of review articles that will be published in February 2014 as the Proteomics Clinical Applications Reviews 2014 (Issue 2, Volume 8). A Call for Reviews for that issue also appears in this current issue of Proteomics Clinical Applications.

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Michael J. Dunn

Editor-in-Chief