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Klein J.,University of Manchester | Eales J.,University of Manchester | Zurbig P.,Mosaiques Diagnostics | Vlahou A.,Academy of Athens | And 3 more authors.
Proteomics | Year: 2013

In this study, we have developed Proteasix, an open-source peptide-centric tool that can be used to predict in silico the proteases involved in naturally occurring peptide generation. We developed a curated cleavage site (CS) database, containing 3500 entries about human protease/CS combinations. On top of this database, we built a tool, Proteasix, which allows CS retrieval and protease associations from a list of peptides. To establish the proof of concept of the approach, we used a list of 1388 peptides identified from human urine samples, and compared the prediction to the analysis of 1003 randomly generated amino acid sequences. Metalloprotease activity was predominantly involved in urinary peptide generation, and more particularly to peptides associated with extracellular matrix remodelling, compared to proteins from other origins. In comparison, random sequences returned almost no results, highlighting the specificity of the prediction. This study provides a tool that can facilitate linking of identified protein fragments to predicted protease activity, and therefore into presumed mechanisms of disease. Experiments are needed to confirm the in silico hypotheses; nevertheless, this approach may be of great help to better understand molecular mechanisms of disease, and define new biomarkers, and therapeutic targets. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Borchers S.,Hannover Medical School | Provasi E.,Cancer Immunotherapy and Gene Therapy Program | Silvani A.,MolMed | Radrizzani M.,MolMed | And 13 more authors.
Human Gene Therapy | Year: 2011

Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34 + cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission. © 2011, Mary Ann Liebert, Inc. Source


Mermelekas G.,Academy of Athens | Makridakis M.,Academy of Athens | Koeck T.,Mosaiques Diagnostics | Vlahou A.,Academy of Athens
Expert Review of Proteomics | Year: 2013

Quantitative determination of reactive oxygen species and reactive nitrogen species in body fluids, tissues or cells has always been problematic due to their high chemical reactivity and the resulting short half-life. This high reactivity may involve reversible and/or irreversible protein modifications, in particular the covalent oxidative modification of specific amino acid residues. Thus, the occurrence of reactive oxygen species and reactive nitrogen species can be monitored indirectly from the identification of specific protein-chemical footprints. In combination with classical gel-based proteomics or liquid chromatography labeling or label-free techniques, mass spectrometry has emerged as a powerful tool to identify these protein modifications in biological samples. In this review, we present the main methodological approaches for gel-based proteomics and quantitative mass spectrometry applied to oxidative protein modifications, mainly Cys. Representative examples from their application in identifying respective biomarkers in diseases related to oxidative stress are also presented. © 2013 Informa UK, Ltd. Source


Lindhardt M.,Steno Diabetes Center | Persson F.,Steno Diabetes Center | Currie G.,University of Glasgow | Pontillo C.,Mosaiques Diagnostics | And 13 more authors.
BMJ Open | Year: 2016

Introduction: Diabetes mellitus affects 9% of the European population and accounts for 15% of healthcare expenditure, in particular, due to excess costs related to complications. Clinical trials aiming for earlier prevention of diabetic nephropathy by renin angiotensin system blocking treatment in normoalbumuric patients have given mixed results. This might reflect that the large fraction of normoalbuminuric patients are not at risk of progression, thereby reducing power in previous studies. A specific risk classifier based on urinary proteomics (chronic kidney disease (CKD)273) has been shown to identify normoalbuminuric diabetic patients who later progressed to overt kidney disease, and may hold the potential for selection of high-risk patients for early intervention. Combining the ability of CKD273 to identify patients at highest risk of progression with prescription of preventive aldosterone blockade only to this high-risk population will increase power. We aim to confirm performance of CKD273 in a prospective multicentre clinical trial and test the ability of spironolactone to delay progression of early diabetic nephropathy. Methods and analysis: Investigator-initiated, prospective multicentre clinical trial, with randomised double-masked placebo-controlled intervention and a prospective observational study. We aim to include 3280 type 2 diabetic participants with normoalbuminuria. The CKD273 classifier will be assessed in all participants. Participants with high-risk pattern are randomised to treatment with spironolactone 25 mg once daily, or placebo, whereas, those with low-risk pattern will be observed without intervention other than standard of care. Treatment or observational period is 3 years. The primary endpoint is development of confirmed microalbuminuria in 2 of 3 first morning voids urine samples. Ethics and dissemination: The study will be conducted under International Conference on Harmonisation - Good clinical practice (ICH-GCP) requirements, ethical principles of Declaration of Helsinki and national laws. This first new biomarker-directed intervention trial aiming at primary prevention of diabetic nephropathy may pave the way for personalised medicine approaches in treatment of diabetes complications. Trial registration number: NCT02040441; Preresults. Source


Stepczynska A.,Mosaiques Diagnostics | Schanstra J.P.,French Institute of Health and Medical Research | Schanstra J.P.,University Paul Sabatier | Mischak H.,Mosaiques Diagnostics | Mischak H.,University of Glasgow
Bioanalysis | Year: 2016

The recent advancements in clinical proteomics enabled identification of biomarker panels for a large range of diseases. A number of CE-MS-identified biomarker panels were verified and implemented in clinical studies. Despite multiple challenges, accumulating evidence supports the value and the need for proteome-based biomarker panels. In this perspective, we provide an overview of clinical studies indicating the added value of CE-MS biomarker panels over traditional diagnostics and monitoring methods. We outline apparent advantages of applying novel proteomic biomarker panels for disease diagnosis, prognosis, staging, drug development and patient management. Facing the plethora of benefits associated with the use of CE-MS biomarker panels, we envision their implementation into the medical practice in the near future. © 2016 Future Science Ltd. Source

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