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Plenary Speakers

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Stephen R Pennington
Code / Date
PL-1 / Mar 28 (Thu) 10:40-11:20
Speaker
Stephen R Pennington   CV
Affiliation
University College Dublin
Title
Development and Delivery Advanced Protein Biomarker Tests for an Era of Precision Medicine
Career
Professor Stephen R Pennington is currently the President of HUPO. He received his PhD degree in the Department of Biochemistry, University of Cambridge and was a lecturer in Department of Human Anatomy and Cell Biology, University of Liverpool. Since 2003, he is a professor of Proteomics in the UCD Conway Institute, School of Medicine, University College Dublin. Dr. Pennington spent much of his research career using mass spectrometry to measure and characterize proteins. Dr. Pennington has given over 200 invited presentations at international events, published over 80 scientific papers as well as editing and contributing to several books including editing one of the first books on Proteomics. He is on the editorial board of several journals including in a more senior capacity for 'Proteomics' and the 'Journal of Proteomics'. He is a committee member of European Proteomics. His research is focused on bringing protein biomarker research endeavours to clinical utility and value. His research group is currently actively engaged in 'Biomarker Discovery and Development'.
Abstract

The last two decades of proteomics research has resulted in the discovery of hundreds (if not thousands) of new candidate protein biomarkers including those intended for the diagnosis, prognosis and monitoring disease progression. However, the number of new protein biomarker tests that have been developed to the stage of being used routinely in a clinical setting is disappointingly low. There are many reasons for this lack of success.
By enabling rapid assay development and candidate biomarker evaluation, SRM/MRM on triple quadrupole mass spectrometers holds huge potential as a platform for the development of specific and sensitive 'biomarker signatures' comprising multiple proteins. However, once such prototype signatures are developed can they be clinically validated and then delivered to a clinical test environment on mass spectrometers? The answer to this question will likely be dependent on the implementation of robust and reliable workflows with methods that are easy, quick and inexpensive and may be automated. Such methods may also enable those proficient in SRM/MRM of small molecules to apply their expertise and experience to analysis of protein signatures and so accelerate the delivery of protein biomarkers tests to the patient benefit.
This presentation will address the key issues around the development of protein signatures in areas of significant unmet clinical need and potential strategies for the delivery and implementation of multiplexed protein biomarkers in a diagnostic setting.

 

David E. James
Code / Date
PL-2 / Mar 28 (Thu) 17:00-17:40
Speaker
David E. James   CV
Affiliation
University of Sydney
Title
Global redox proteome and phosphoproteome analysis reveals novel mode of Akt regulation
Career
Dr. James has brought stellar research credentials to the fields of metabolism and proteome research including insulin resistance, multi-omics research, protein and mechanisms, diabetes, and obesity. He has authored over 200 research papers and 25 invited reviews. He has also won several awards including the Glaxo Wellcome Medal for Medical Research and the Kellion medal for outstanding contributions to diabetes research. He currently holds the Leonard P Ullmann Chair in Molecular Systems Biology and the Domain Leader for Biology at the Charles Perkins Centre at the University of Sydney. After earning a Ph.D in Biochemistry/Physiology from Garvan Institute/University of New South Wales in 1985, he was at the Boston University (1985-1988), held an Assistant Professor at the Washington University (1988-1993), Associate Director and National Health and Medical Research Council (NHMRC) Principal Research Fellow at the University of Queensland (1993-2001), and acted as a Director and NHMRC Senior Principal Research Fellow at the Garvan Institute of Medical Research (2002-2014).
Abstract

A major knowledge gap in cell signalling is defining the crosstalk between multiple types of post-translational modification (PTM). Here, we take a multi-omic approach (redox proteome, phosphoproteome and total proteome) to delineate signalling networks in adipocytes modulated by reactive oxygen species and protein phosphorylation. Our integrative analysis of these datasets revealed widespread and complex crosstalk between oxidative stress-induced cysteine oxidation and phosphorylation-based signalling. In particular, we observe that oxidation of key regulatory nodes including Akt, mTOR and AMPK influences the fidelity of signalling via these nodes rather than their absolute activity, providing an underappreciated interplay between these modifications. Mechanistic analysis of the redox regulation of Akt identified that two cysteine residues in the pleckstrin homology domain of Akt (C60 and C77) are likely reversibly oxidised and this regulates recruitment of Akt to PIP3 at the plasma membrane via reconfiguration of the PH domain structure. Overall, these multi-omics datasets provide insight into how redox signalling driven by oxidative stress interacts with protein phosphorylation and should serve as a useful resource for dissecting oxidative stress-induced PTMs and understanding their contribution to a variety of diseases.

 

Harald Mischak
Code / Date
PL-3 / Mar 29 (Fri) 10:40-11:20
Speaker
Harald Mischak   CV
Affiliation
Mosaiques Diagnostics
Title
Application of proteomics in clinical diagnosis and patient management: from discovery to actual routine implementation
Career
Dr. Harald Mischak is currently a professor in University of Glasgow, UK and has been engaging researches in the field of clinical proteomics. He is also a founder of Mosaiques Diagnostics in Germany. His expertise is to discover peptide markers and develop multi-marker panel for disease diagnosis and precision medicine. Particularly, he has developed and has been implementing the CKD273, a prognostic enrichment biomarker panel composed of 273 urinary peptides, to be used in combination with current measures (i.e., albuminuria, serum creatinine) in early phase clinical trials in diabetic kidney disease (DKD) to identify patients with early stage disease who may be more likely to progress. Notably, the CKD273 is thus far the firstly FDA-approved multi-peptide marker panel.
Abstract

Clinical proteomics, the application of proteome analysis to serve a clinical purpose, represents a major field in the area of proteome research. The aim of clinical proteomics is the improvement if clinical care based on information on the proteome, in general to identify and subsequently apply biomarkers, and/or suggest relevant therapeutic targets. These two major areas have different requirements on specimens to be employed, on technology, and also on data evaluation, which will be presented.
While substantial efforts especially in biomarker discovery, but also in the identification of therapeutic targets are evident based on the large number of publications, only a few approaches actually resulted in clinical application yet. In this presentation key issues and major challenges in clinical proteomics will be presented and discussed. Among those are a) the definition of a clinical need and a context-of-use, b) selection of appropriate samples, sample preparation and analytical platform, c) application of appropriate statistics, d) demonstration of a benefit in a well powered clinical study and e) obtaining regulatory approval and reimbursement, to enable actual implementation. Based on successful examples in clinical proteomics, details on the above issues will be presented and discussed.
For several conditions and diseases, clinical proteomics has delivered and is already being applied today. Most of the successful developments are based on multi-marker panels, and demonstrated value in large (including at least several hundred patients) studies. The results from these studies are expected to initiate a change in disease assessment: from diagnosis based on damages occurred and therapy aiming to prevent deterioration, towards diagnosis based on molecular mechanisms, prior to clinical symptoms, and towards correcting molecular changes, thereby preventing onset of disease. This also opens the path towards personalized precision medicine, where intervention is guided by molecular mechanisms, not morphological changes.
Concluding on the current state of the art in clinical proteomics, it is evident that all tools required to apply clinical proteomics are available today. Especially in the area of proteomic biomarkers, a change on objectives appears essential, from additional discovery studies towards studies properly testing the plethora of potential biomarkers that have been described, to demonstrate practical value of clinical proteomics. All elements required, potential biomarkers, technologies and bio-banked samples are available, hence the move from discovery towards validation and application is not only urgently necessary, but also possible based on resources available today.

 

Jong Shin Yoo
Code / Date
PL-4 / Mar 29 (Fri) 17:00-17:40
Speaker
Jong Shin Yoo   CV
Affiliation
Korea Basic Science Institute
Title
Glycoproteomics and Clinical Applications by Mass Spectrometry
Career
Dr. Jong Shin Yoo is a principal investigator of the Biomedical Omics Research Group at Korea Basic Science Institute and an adjunct professor in the Graduate School of Analytical Science and Technology at Chungnam National University in Daejeon, Korea. His research is focused on glycoproteomics based on tandem mass spectrometry including the development of analytical method to characterize the N- and O–linked glycoproteins as cancer biomarkers. He is also interested in the integration of proteomics and genomics data to study the mechanisms of cancer metastasis and its clinical applications.
Abstract

Protein glycosylation is one of the most important posttranslational modifications in a protein, which plays roles in biological systems via various processes such as adhesion, signaling through cellular recognition, and response to abnormal biological states. Analysis of the difference in protein glycosylation between patients with the disease and healthy subjects provides a better understanding of disease progression. For example, the comparative analyses of aberrant glycosylation can be useful in clinical practice for diagnosing cancers. Glycopeptides can be used as analytes to obtain information about glycoforms and exact glycosylated sites on glycoproteins. The analysis of glycopeptides provides site-specific information about glycoproteins with multiple glycosylation sites. These glycoproteomic studies include platforms to enrich glycoproteins from protein mixtures followed by quantitative analysis to determine which proteins are glycosylated, the glycosylation sites, the glycan structures, as well as the abundance of the glycoproteins in disease progression. Mass spectrometry (MS) is widely used to discover protein biomarkers for their clinical applications. A significant advantage of MS is its ability to directly identify and quantify glycoproteins. Analytical advances in mass spectrometry have now facilitated LC-MS/MS-based glycoproteomics studies that are identifying hundreds of unique intact glycopeptides from a single experiment in clinical laboratories In this study, we have developed LC-MS/MS-based high throughput method for intact N-and O-glycopeptides analysis, named GlycoProteomeAnalyzer (GPA) for analysis of N-and O-glycosylation in proteomic scale. It combines tandem mass spectrometry with a database search and algorithmic suite for accurate annotation of the large volumes of MS/MS spectral data from complementary fragmentation modes such as CID, HCD, and ETD. It shows promise for confident identification and automated quantification of tryptic glycopeptides of glycoproteins in human serum, plasma, uirine and tissue samples. In order to target those glycopeptides as cancer biomarkers, parallel reaction monitoring (PRM) is used for relative quantification of glycopeptides. A direct monitoring method of site-specific glycopeptides in serological proteins to distinguish between healthy and cancer patients was also developed using LC-MS/MS-based PRM with immunoprecipitation. All transitions from each precursor ion of glycopeptide are simultaneously monitored with high resolution and mass accuracy in a full scan MS/MS spectrum simultaneously. Our method was applied to evaluate glycopeptides as a tool for differentiation between early hepatocellular carcinoma and cirrhosis using human serum.

 

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