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ABSTRACT: Mass spectrometry imaging (MSI) generates large volumetric data sets consisting of mass to charge ratio (m/z), ion current, and x,y coordinate location.. These datasets usually serve limited purposes centered on measuring the distribution of a small set of ions with known m/ z. Such earmarked queries consider only a fraction of the full mass spectrum captured, and there are few tools to assist the exploration of the remaining volume of unknown data in terms of demonstrating similarity or discordance in tissue compartment distribution patterns. Here we present a novel, interactive approach to extract information from MSI data that relies on pre-calculated data structures to perform queries of large data sets with a typical laptop. We have devised methods to query the full volume to find new m/z values of potential interest based on similarity to biological structures, or to the spatial distribution of known ions. We describe these query methods in detail and provide examples demonstrating the power of the methods to "discover" m/z values of ions that have such potentially interesting correlations. The "discovered" ions may be further correlated with either positional locations or the coincident distribution of other ions, using successive queries. Finally, we show it is possible to gain insight to the fragmentation pattern of the parent molecule from such correlations. The ability to discover new ions of interest in the unknown bulk of an MSI dataset offers the potential to further our understanding of biological and physiological processes related to health and disease.
Analytical Chemistry 03/2013; · 5.86 Impact Factor
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ABSTRACT: Healthcare systems today are undergoing major restructuring. From the patient’s perspective, expectations focusing on high quality treatments for most common diseases – such as cancer, cardiovascular diseases, neurodegenerative diseases, diabetes, and others – have gone unmet in most countries throughout the world. Today, a number of protein expression and analysis platforms is available, which can generate large-scale maps of proteins related to healthy and diseased states. These mass spectrometry-based technologies are used on a daily basis by thousands of research laboratories around the world. The major interest is focused on discovery and validation of novel biomarkers in various diseases, as well as on targeted proteomics where quantification of multiple protein biomarkers is achieved. We present these technological developments in relation to disease diagnosis and treatment and provide two examples where significant progress has been made.
02/2013: pages 169-185; , ISBN: 978-94-007-5811-7
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Charlotte Welinder,
Göran Jönsson,
Christian Ingvar,
Lotta Lundgren,
Håkan Olsson,
Thomas Breslin,
Akos Végvári,
Thomas Laurell,
Melinda Rezeli,
Bo Jansson,
Bo Baldetorp, György Marko-Varga
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ABSTRACT: BACKGROUND: The objectives and goals of the Southern Swedish Malignant Melanoma (SSMM) are to develop, build and utilize cutting edge biobanks and OMICS platforms to better understand disease pathology and drug mechanisms. The SSMM research team is a truly cross-functional group with members from oncology, surgery, bioinformatics, proteomics, and genomics initiatives. Within the research team there are members who daily diagnose patients with suspect melanomas, do follow-ups on malignant melanoma patients and remove primary or metastatic lesions by surgery. This inter-disciplinary clinical patient care ensures a competence build as well as a best practice procedure where the patient benefits. METHODS: Clinical materials from patients before, during and after treatments with clinical end points are being collected. Tissue samples as well as bio-fluid samples such as blood fractions, plasma, serum and whole blood will be archived in 384-high density sample tube formats. Standardized approaches for patient selections, patient sampling, sample-processing and analysis platforms with dedicated protein assays and genomics platforms that will hold value for the research community are used. The patient biobank archives are fully automated with novel ultralow temperature biobank storage units and used as clinical resources. RESULTS: An IT-infrastructure using a laboratory information management system (LIMS) has been established, that is the key interface for the research teams in order to share and explore data generated within the project. The cross-site data repository in Lund forms the basis for sample processing, together with biological samples in southern Sweden, including blood fractions and tumor tissues. Clinical registries are associated with the biobank materials, including pathology reports on disease diagnosis on the malignant melanoma (MM) patients. CONCLUSIONS: We provide data on the developments of protein profiling and targeted protein assays on isolated melanoma tumors, as well as reference blood standards that is used by the team members in the respective laboratories. These pilot data show biobank access and feasibility of performing quantitative proteomics in MM biobank repositories collected in southern Sweden. The scientific outcomes further strengthen the build of healthcare benefit in the complex challenges of malignant melanoma pathophysiology that is addressed by the novel personalized medicines entering the market.
Clinical and translational medicine. 02/2013; 2(1):7.
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Carol L Nilsson,
Frode Berven,
Frode Selheim,
Huiling Liu,
Joseph R Moskal,
Roger A Kroes,
Erik P Sulman,
Charles A Conrad,
Frederick F Lang,
Per E Andrén, [......],
Akos Végvári,
Karin Sjödin,
Charlotte Welinder,
Thomas Laurell,
Thomas E Fehniger,
Henrik Lindberg,
Melinda Rezeli,
Goutham Edula,
Sophia Hober, György Marko-Varga
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ABSTRACT: A first research development progress report of the Chromosome 19 Consortium with members from Sweden, Norway, Spain, United States, China and India, a part of the Chromosome-centric Human Proteome Project (C-HPP) global initiative, is presented ( http://www.c-hpp.org ). From the chromosome 19 peptide-targeted library constituting 6159 peptides, a pilot study was conducted using a subset with 125 isotope-labeled peptides. We applied an annotation strategy with triple quadrupole, ESI-Qtrap, and MALDI mass spectrometry platforms, comparing the quality of data within and in between these instrumental set-ups. LC-MS conditions were outlined by multiplex assay developments, followed by MRM assay developments. SRM was applied to biobank samples, quantifying kallikrein 3 (prostate specific antigen) in plasma from prostate cancer patients. The antibody production has been initiated for more than 1200 genes from the entire chromosome 19, and the progress developments are presented. We developed a dedicated transcript microarray to serve as the mRNA identifier by screening cancer cell lines. NAPPA protein arrays were built to align with the transcript data with the Chromosome 19 NAPPA chip, dedicated to 90 proteins, as the first development delivery. We have introduced an IT-infrastructure utilizing a LIMS system that serves as the key interface for the research teams to share and explore data generated within the project. The cross-site data repository will form the basis for sample processing, including biological samples as well as patient samples from national Biobanks.
Journal of Proteome Research 12/2012; · 5.11 Impact Factor
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ABSTRACT: The antibody microarrays have become widespread, but their use for quantitative analyses in clinical samples has not yet been established. We investigated an immunoassay based on nanoporous silicon antibody microarrays for quantification of total prostate-specific-antigen (PSA) in 80 clinical plasma samples, and provide quantitative data from a duplex microarray assay that simultaneously quantifies free and total PSA in plasma. To further develop the assay the porous silicon chips was placed into a standard 96-well microtiter plate for higher throughput analysis. The samples analyzed by this quantitative microarray were 80 plasma samples obtained from men undergoing clinical PSA testing (dynamic range: 0.14-44ng/ml, LOD: 0.14ng/ml). The second dataset, measuring free PSA (dynamic range: 0.40-74.9ng/ml, LOD: 0.47ng/ml) and total PSA (dynamic range: 0.87-295ng/ml, LOD: 0.76ng/ml), was also obtained from the clinical routine. The reference for the quantification was a commercially available assay, the ProStatus PSA Free/Total DELFIA. In an analysis of 80 plasma samples the microarray platform performs well across the range of total PSA levels. This assay might have the potential to substitute for the large-scale microtiter plate format in diagnostic applications. The duplex assay paves the way for a future quantitative multiplex assay, which analyzes several prostate cancer biomarkers simultaneously.
Clinica chimica acta; international journal of clinical chemistry 08/2012; 414C:76-84. · 2.54 Impact Factor
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08/2012: pages 309-319;
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ABSTRACT: Biobanks are a major resource to access and measure biological constituents that can be used to monitor the status of health and disease, both in unique individual samples and within populations. Most "omic" activities rely on access to these collections of stored samples to provide the basis for establishing the ranges and frequencies of expression. Furthermore, information about the relative abundance and form of protein constituents found in stored samples provides an important historical index for comparative studies of inherited, epidemic, and developing disease. Standardizations of sample quality, form, and analysis are an important unmet need and requirement for gaining the full benefit from collected samples. Coupled to this standard is the provision of annotation describing clinical status and metadata of measurements of clinical phenotype that characterizes the sample. Today we have not yet achieved consensus on how to collect, manage, and build biobank archives in order to reach goals where these efforts are translated into value for the patient. Several initiatives (OBBR, ISBER, BBMRI) that disseminate best practice examples for biobanking are expected to play an important role in ensuring the need to preserve the sample integrity of biosamples stored for periods that reach one or several decades. These developments will be of great value and importance to programs such as the Chromosome Human Protein Project (C-HPP) that will associate protein expression in healthy and disease states with genetic foci along of each of the human chromosomes.
Journal of Proteome Research 05/2012; · 5.11 Impact Factor
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ABSTRACT: OBJECTIVE: The aim of this study is a novel automated sample-processing concept for future proteomics and clinical research, performing patient studies from resulting blood fractions in various disease areas. Another aim is biobank storage of small sample volumes, where each sample aliquot can be used for a dedicated clinical analysis and end-point measurement in order to preserve sample integrity and value over time. METHODS: 96 and 384 format sample storage tube systems were utilized for preservation and archiving of clinical patient samples. Automated sample processing and aliquoting were achieved using robotic liquid handling instrumentation, followed by biomarker assay quantitations. Sample workflow was documented and tracked by Nautilus LIMS. RESULTS: Validation by repetitive processing and analysis confirmed the reliability of automated high density 384 format aliquoting. This high density scaling allows for reproducible aliquoting of 70-μL volumes of blood. Plasma with EDTA, Li-heparin, and citrate, as anti-coagulants, fractioned along with the buffy coat (leukocytes) and the erythrocyte fraction. Large scale processing of 11,000 sample aliquots resulted in a 99.8% process fulfillment. CONCLUSION: Our results demonstrate that robust results can be generated from an automated sample processing strategy, isolating plasma, buffy coat, erythrocytes, serum and whole blood, proven by quantitation of 23 common markers used in everyday healthcare around the world. This article is part of a Special Issue entitled: Integrated omics.
Journal of proteomics 05/2012; · 5.07 Impact Factor
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ABSTRACT: The objective of this study was to examine the effects of heparan sulfate (HS) on factors involved in the remodeling of connective
tissue observed in patients with fibrotic respiratory disorders such as asthma. A suitable working model is to stimulate human
fetal lung fibroblasts in vitro with structurally different forms of HS. Highly sulfated and iduronic acid (IdoUA)-rich HS
specifically decreased cell proliferaton, production of jyaluronan (HA), transforming growth factor (TGF)-β1, and TFF-β-induced α-smooth muscle actin but did not affect the overall proteoglycan production in the cells. These repressed
factors are suggested to play a critical role in the early stages of remodeling and myofibroblast activation. Low sulfated
and IdoUA-poor HS did not display any effects on these factors. Furthermore, analysis of the protein expression pattern by
two-dimensional gel electrophoresis revealed a 70% increased expression of annexin II, which has previously been shown to
have a high affinity for both heparin and HS. Heat-shock protein 27 and arsenite translocating factor, both involved in actin
organization and polymerization, were also increased in the HS-stimulated cells. Thus, the reduced expression of HA and TGF-β1, both important in the development of fibrosis, seems to be mediated by pecific changes in protein expression of the fibroblast.
The observed inhibition of cell proliferation, HA, and TGF-β1 allows speculation of highly sulfated HS as a antifibrotic candidate in the early stage of remodeling.
Clinical Proteomics 04/2012; 1(3):271-284.
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ABSTRACT: Wettability is a fundamental property of a solid surface, which plays important roles in many industrial applications. The
possibility to create well-controlled nonwetting states on silicon surfaces without photolithography-based processing can
bring many advantages in the biotechnology and microfluidics areas. In this paper, superhydrophobic properties of macroporous–nanoporous
structured silicon are reported. The superhydrophobic porous silicon layers are prepared by electrochemical etching of bulk
crystalline silicon wafers. Altered anodization conditions provide surfaces with varying pore morphologies, yielding different
wetting properties, ranging from highly wetting (nanoporous morphologies) to water-repellent surfaces (macroporous morphologies).
Subsequent surface modification with a fluorocarbon coupling agent can further improve nonwetting properties and stabilize
the surface for a long term. Contact angles as high as 176° were achieved on macroporous silicon and superhydrophobicity was
maintained for several months without degradation. The porous surfaces have proven to be a very attractive substrate for protein
microarrays. Fluorescence-based assay of immunoglobulin G in plasma is reported with a limit of detection of 1pM, a spot
size of 50μm, and an array density of 15,625 spots per square centimeter. Macroporous surfaces have also been developed for
matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) applications, where the intrinsic
hydrophobic surface properties confine the deposited sample to MALDI spots of less than 200μm with well-defined MALDI crystals,
providing a high-sensitivity readout. Furthermore, a superhydrophobic MALDI-TOF MS target anchor chip composed of nonporous
anchor points surrounded by superhydrophobic porous areas for sample deposition and on anchor point confinement is reported.
Such anchor chips allowed localized crystallization of large sample volumes (5μL) improving the hydrophobic spot confinement
strategy in terms of final MALDI crystal localization and readout sensitivity.
Nanobiotechnology 04/2012; 4(1):18-27.
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ABSTRACT: Objectives: Prostate specific antigen (PSA) is a widely used and clinically valuable marker for prostate disease. In order to enable the development of new PSA assays and progress the understanding of the biology of PSA we have analyzed PSA in seminal plasma.
Design and Methods: PSA in seminal plasma from men attending a fertility clinic and healthy controls was analyzed using SDS-PAGE, Western blotting and mass spectrometry.
Results: Using mass spectrometry, different forms of PSA could be identified in 1-9 bands seen on SDS-PAGE analysis of the respective sample. However, a majority of these molecular forms of PSA were not observed on Western blots. Enzymatic activity of PSA isoforms was demonstrated by sequencing data in zymogram gels. Multivariate analysis of clinical data revealed well-separated patient groups.
Conclusions: We demonstrated that PSA in seminal plasma occurs in several isoforms, yet not all were detectable using an antibody based clinical routine method. The heterogeneity of PSA expression might be of clinical significance, by an improved patient phenotyping.
Clinical Biochemistry 02/2012; · 2.08 Impact Factor
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ABSTRACT: An overview on targeted personalized medicine is given describing the developments in Japan of lung cancer patients. These new targeted therapies with novel personalized medicine drugs require new implementations, in order to follow and monitor drug efficacy and outcome. Examples from IRESSA (Gefitinib) and TARCEVA (Erlotinib) treatments used in medication of lung cancer patients are presented. Lung cancer is one of the most common causes of cancer mortality in the world. The importance of both the quantification of disease progression, where diagnostic-related biomarkers are being implemented, in addition to the actual measurement of disease-specific mechanisms relating to pathway signalling activation of disease-progressive protein targets is summarised. An outline is also presented, describing changes and adaptations in Japan, meeting the rising costs and challenges. Today, urgent implementation of programs to address these needs has led to a rebuilding of the entire approach of medical evaluation and clinical care.
International journal of proteomics. 01/2012; 2012:921901.
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ABSTRACT: BACKGROUND: For many common global diseases, such as cancer, diabetes, neurodegenerative and cardiovascular diseases there is an unmet need for diagnosing early indications of disease that could enable medical intervention and early treatment. The treatment of these diseases will require detailed knowledge of targeted pathways involved in disease pathogenesis but also the mode of drug actions at the biological location on these targets. Translational medicine is a new area of research where expert from different disciplines involved in basic science and clinical disciplines meet and join forces. Mode-of-drug-action mechanisms elucidation is key in the characterization of drugs that can relate to both efficacy and safety. METHODS: Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used providing evidence into the fate (destinations and distributions) of administered drugs within tumor regions of lung compartments. RESULTS: We hereby present a pulmonary study in which we have isolated lung tissue after inhaled drug administration and then localized the drug within airway wall compartments. The histology also provides evidence of drug binding to smooth muscle cell microenvironments. We also identified lung tissue regions with tumor cell invasion in these COPD patients. CONCLUSIONS: The ultimate goal is to identify bridging comprehension that forms a knowledge base that can be used by society to develop a better treatment and medicine for patients. Our results demonstrated that robust imaging data could be generated confirming drug localization in pulmonary regions of COPD patients with tumor pathology. TRIAL REGISTRATION: Tallinn Medical Research Ethical Committee decision #1724, 18.06.2009.
Clinical and translational medicine. 01/2012; 1(1):8.
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ABSTRACT: Prostate specific antigen (PSA) is a widely used and clinically valuable marker for prostate disease. In order to enable the development of new PSA assays and progress the understanding of the biology of PSA we have analyzed PSA in seminal plasma.
PSA in seminal plasma from men attending a fertility clinic and healthy controls was analyzed using SDS-PAGE, Western blotting and mass spectrometry.
Using mass spectrometry, different forms of PSA could be identified in 1-9 bands seen on SDS-PAGE analysis of the respective sample. However, a majority of these molecular forms of PSA were not observed on Western blots. Enzymatic activity of PSA isoforms was demonstrated by sequencing data in zymogram gels. Multivariate analysis of clinical data revealed well-separated patient groups.
We demonstrated that PSA in seminal plasma occurs in several isoforms, yet not all were detectable using an antibody based clinical routine method. The heterogeneity of PSA expression might be of clinical significance, by an improved patient phenotyping.
Clinical biochemistry 12/2011; 45(4-5):331-8. · 2.02 Impact Factor
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ABSTRACT: Drug therapy is often directed to specific organ and tissue compartments where the mode of action of the compound affects specifically targeted biological processes. However, the direct measurement of drug uptake in terms of a time kinetic and concentrations attained at the local sites has not been readily available as a clinical index for most drugs. A proof-of-principle study was conducted to test the utility of applying matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) to demonstrate the qualitative distribution pattern of a locally administered drug within tissue sites of targeted action. Here we have measured the occurrence of an inhaled bronchodilator, the muscarinic receptor antagonist ipratropium, within human bronchial biopsies obtained by fiber optic bronchoscopy shortly after dosing exposure. Cryo-preserved biopsy samples from five subjects being evaluated for airway obstruction or potential tumor development were prepared as thin frozen sections. Samples coated with a MALDI matrix were analyzed by a MALDI LTQ Orbitrap XL mass spectrometer at large (100 μm) and small (30 μm) raster sizes. Our results demonstrate that ipratropium is rapidly absorbed into the airway wall. Ipratropium parent ion (m/z 332.332) and daughter ions (m/z 166.2 and 290.2) were coincidently partitioned within submucosal spaces containing targeted airway smooth muscle in four out of five subjects. The signal intensity of ipratropium fragment ions provided estimates that local drug concentrations between 3 and 80 nM were achieved within the airway wall. To our knowledge, this is the first reported study in applying MALDI-MSI to demonstrate the localization of a drug administered at therapeutic levels. The study highlights the potential benefit of MALDI-MSI to provide important measurements of drug efficacy in clinical settings.
Analytical Chemistry 09/2011; 83(21):8329-36. · 5.86 Impact Factor
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ABSTRACT: Prostate specific antigen (PSA), as a widely used clinical biomarker in prostate cancer diagnostics, exists in multiple molecular forms. However, all of these forms might not be recognized in a given sample by the standard immunoassays. Therefore, we have investigated PSA isoforms, separated by size, using mass spectrometric analyses. The objective of these developments was to identify and specify the various forms of PSA. To optimize successful identification of different PSA forms, we have developed a bioinformatic strategy, consisting of high resolution MALDI-MS PMF and sequencing MS/MS data searches. To improve sequence-based identification, the recently introduced Proteios software environment was employed, allowing the combination of multiple database search engines in an automated manner. We could unambiguously identify PSA in clinical samples by all detectable tryptic peptides, which were found to be common in several isoforms.
Journal of proteomics 06/2011; 75(1):202-10. · 5.07 Impact Factor
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ABSTRACT: As a proof-of-principle study, a multiple reaction monitoring (MRM) assay was developed for quantitation of proteotypic peptides, representing seven plasma proteins associated with inflammation (complement components and C-reactive protein). The assay development and the sample analysis were performed on a linear ion trap mass spectrometer. We were able to quantify 5 of the 7 target proteins in depleted plasma digests with reasonable reproducibility over a 2 orders of magnitude linear range (RSD≤25%). The assay panel was utilized for the analysis of a small multiple sclerosis sample cohort with 10 diseased and 8 control patients.
Journal of proteomics 06/2011; 75(1):211-20. · 5.07 Impact Factor
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ABSTRACT: Lung cancer is a common cause of cancer mortality in the world, largely due to the risk factor of tobacco smoking. The drug therapy at the molecular level includes targeting the epidermal growth factor receptor (EGFR) tyrosine kinase activity by using inhibitors, such as erlotinib (Tarceva) and gefitinib (Iressa). The heterogeneity of disease phenotypes and the somatic mutations presented in patient populations have a great impact on the efficacy of treatments using targeted personalized medicine. In this study, we report on basic physical and chemical properties of erlotinib and gefitinib in three different lung cancer tumor phenotypes, using MALDI instrumentation in imaging mode, providing spatial localization of drugs without chemical labeling. Erlotinib and gefitinib were analyzed in i) planocellular lung carcinoma, ii) adenocarcinoma and iii) large cell lung carcinoma following their deposition on the tissue surfaces by piezo-dispensing, using a controlled procedure. The importance of high-resolution sampling was crucial in order to accurately localize the EGFR tyrosine kinase inhibitors deposited in heterogeneous cancer tissue compartments. This is the first report on personalized drug characterization with localizations at a lateral resolution of 30μm, which allowed us to map these compounds at attomolar concentrations within the lung tumor tissue microenvironments.
Journal of proteomics 03/2011; 74(7):982-92. · 5.07 Impact Factor
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György Marko-Varga
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ABSTRACT: ABSTRACT: The ever increasing social cost that society pays for illness and disease are currently steadily increasing in many countries in the world today. These changes in society becomes a major financial burden that activates politicians and health care organizations in order to find new solutions. Biobanks are becoming the new powerful modality within the field of modern Life Science, that is expected to be important in the proactive awareness of patient health status. Biobanks are also expected to promote the developments of targeted treatments with personalized indicator assays, for effective use of Personalized Medicine treatments in the near future.
Journal of clinical bioinformatics. 01/2011; 1(1):14.
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Fredrik Nyberg,
Atsushi Ogiwara,
Chris G Harbron,
Takao Kawakami,
Keiko Nagasaka,
Sachiko Takami,
Kazuya Wada,
Hsiao-Kun Tu,
Makiko Otsuji,
Yutaka Kyono, [......],
Marie C South,
Tim Higenbottam,
Masahiro Fukuoka,
Koichiro Nakata,
Yuichiro Ohe,
Shoji Kudoh,
Ib Groth Clausen,
Toshihide Nishimura, György Marko-Varga,
Harubumi Kato
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ABSTRACT: Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10(-25)), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control.
PLoS ONE 01/2011; 6(7):e22062. · 4.09 Impact Factor
