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MALDI-MS-Based Profiling of Serum Proteome: Detection of Changes Related to Progression of Cancer and Response to Anticancer Treatment  [PDF]
Monika Pietrowska,Piotr Wid?ak
International Journal of Proteomics , 2012, DOI: 10.1155/2012/926427
Abstract: Mass spectrometry-based analyses of the low-molecular-weight fraction of serum proteome allow identifying proteome profiles (signatures) that are potentially useful in detection and classification of cancer. Several published studies have shown that multipeptide signatures selected in numerical tests have potential values for diagnostics of different types of cancer. However due to apparent problems with standardization of methodological details, both experimental and computational, none of the proposed peptide signatures analyzed directly by MALDI/SELDI-ToF spectrometry has been approved for routine diagnostics. Noteworthy, several components of proposed cancer signatures, especially those characteristic for advanced cancer, were identified as fragments of blood proteins involved in the acute phase and inflammatory response. This indicated that among cancer biomarker candidates to be possibly identified by serum proteome profiling were rather those reflecting overall influence of a disease (and the therapy) upon the human organism, than products of cancer-specific genes. Current paper focuses on changes in serum proteome that are related to response of patient’s organism to progressing malignancy and toxicity of anticancer treatment. In addition, several methodological issues that affect robustness and interlaboratory reproducibility of MS-based serum proteome profiling are discussed. 1. Cancer Markers and Clinical Proteomics Biological factors (e.g., proteins), whose status and/or quantity reflect the risk of a disease, severity of an illness, or the effects of therapy are called markers or biomarkers. In oncology, appropriately selected sets of markers can provide information about carcinogenic triggers to which the organism was exposed, detect early changes (hyperplasia, dysplasia) that appear prior to the occurrence of overt forms of cancer, as well as monitor efficacy and toxicity of the treatment. Such factors (i.e., potential biomarkers) are present in tumor tissues or body fluids, and encompass a wide variety of molecules, including transcription factors, cell-surface receptors, and secreted proteins. Several protein tumor markers have been used for decades in the traditional oncology for detection of cancer, for example, prostate cancer antigen (PSA) or cancer antigen 125?kD (CA125). In fact, effective tumor markers are in great demand since they have the potential to reduce cancer mortality rates by facilitating diagnosis of cancers at early stages and helping to plan tailored treatment. Cancer biomarkers can be divided into prognostic and
Proteome-Wide Analysis and Diel Proteomic Profiling of the Cyanobacterium Arthrospira platensis PCC 8005  [PDF]
Sabine Matallana-Surget, Jérémy Derock, Baptiste Leroy, Hanène Badri, Frédéric Deschoenmaeker, Ruddy Wattiez
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099076
Abstract: The filamentous cyanobacterium Arthrospira platensis has a long history of use as a food supply and it has been used by the European Space Agency in the MELiSSA project, an artificial microecosystem which supports life during long-term manned space missions. This study assesses progress in the field of cyanobacterial shotgun proteomics and light/dark diurnal cycles by focusing on Arthrospira platensis. Several fractionation workflows including gel-free and gel-based protein/peptide fractionation procedures were used and combined with LC-MS/MS analysis, enabling the overall identification of 1306 proteins, which represents 21% coverage of the theoretical proteome. A total of 30 proteins were found to be significantly differentially regulated under light/dark growth transition. Interestingly, most of the proteins showing differential abundance were related to photosynthesis, the Calvin cycle and translation processes. A novel aspect and major achievement of this work is the successful improvement of the cyanobacterial proteome coverage using a 3D LC-MS/MS approach, based on an immobilized metal affinity chromatography, a suitable tool that enabled us to eliminate the most abundant protein, the allophycocyanin. We also demonstrated that cell growth follows a light/dark cycle in A. platensis. This preliminary proteomic study has highlighted new characteristics of the Arthrospira platensis proteome in terms of diurnal regulation.
Proteome Profiling—Pitfalls and Progress
Paul A. Haynes,John R. Yates III
Comparative and Functional Genomics , 2000, DOI: 10.1002/1097-0061(20000630)17:2<81::aid-yea22>3.0.co;2-z
Abstract: In this review we examine the current state of analytical methods in proteomics. The conventional methodology using two-dimensional electrophoresis gels and mass spectrometry is discussed, with particular reference to the advantages and shortcomings thereof. Two recently published methods which offer an alternative approach are presented and discussed, with emphasis on how they can provide information not available via two-dimensional gel electrophoresis. These two methods are the isotope-coded affinity tags approach of Gygi et al. and the two-dimensional liquid chromatography–tandem mass spectrometry approach as presented by Link et al. We conclude that both of these new techniques represent significant advances in analytical methodology for proteome analysis. Furthermore, we believe that in the future biological research will continue to be enhanced by the continuation of such developments in proteomic analytical technology.
In-Depth Profiling of the Peripheral Blood Mononuclear Cells Proteome for Clinical Blood Proteomics  [PDF]
Sa?a Kon?arevi?,Christopher L??ner,Karsten Kuhn,Thorsten Prinz,Ian Pike,Hans-Dieter Zucht
International Journal of Proteomics , 2014, DOI: 10.1155/2014/129259
Abstract: Peripheral blood mononuclear cells (PBMCs) are an easy accessible cellular part of the blood organ and, along with platelets, represent the only site of active gene expression in blood. These cells undergo immunophenotypic changes in various diseases and represent a peripheral source of monitoring gene expression and posttranslational modifications relevant to many diseases. Little is known about the source of many blood proteins and we hypothesise that release from PBMCs through active and passive mechanisms may account for a substantial part of the plasma proteome. The use of state-of-the-art proteomic profiling methods in PBMCs will enable minimally invasive monitoring of disease progression or response to treatment and discovery of biomarkers. To achieve this goal, detailed mapping of the PBMC proteome using a sensitive, robust, and quantitative methodological setup is required. We have applied an indepth gel-free proteomics approach using tandem mass tags (TMT), unfractionated and SCX fractionated PBMC samples, and LC-MS/MS with various modulations. This study represents a benchmark in deciphering the PBMC proteome as we provide a deep insight by identifying 4129 proteins and 25503 peptides. The identified proteome defines the scope that enables PBMCs to be characterised as cellular major biomarker pool within the blood organ. 1. Introduction Peripheral blood mononuclear cells (PBMCs) constitute the cellular part of the blood organ containing all blood cells with a round nucleus. PBMCs are mainly comprised of monocytes, T cells, B cells, natural killer (NK) cells, and dendritic cells. Thus, the PBMCs contain different cell types that play important roles in the immune system monitoring immune-relevant events and respond in an inflammatory manner [1]. In recent years PBMCs have received growing attention as surrogate markers of several diseases. For example, in vitro data describe the response in PBMCs upon contact with diseased cells [2]. PBMCs can be obtained relatively easy from routinely collected blood samples, and therefore they provide direct access to physiologically relevant (immune) proteins without the well-known analytical difficulties of native human plasma originating from the presence of highly abundant proteins [3]. So far, most Omics studies utilising PBMCs were transcriptional profiling experiments in the context of inflammatory (e.g., preeclampsia, rheumatoid arthritis, and chronic pancreatitis) and malignant (e.g., chronic lymphocytic leukaemia and renal cell carcinoma) diseases [4–8]. Although these studies revealed a number of
Exosomal Proteome Profiling: A Potential Multi-Marker Cellular Phenotyping Tool to Characterize Hypoxia-Induced Radiation Resistance in Breast Cancer  [PDF]
Stefani N. Thomas,Zhongping Liao,David Clark,Yangyi Chen,Ramin Samadani,Li Mao,David K. Ann,Janet E. Baulch,Paul Shapiro,Austin J. Yang
Proteomes , 2013, DOI: 10.3390/proteomes1020087
Abstract: Radiation and drug resistance are significant challenges in the treatment of locally advanced, recurrent and metastatic breast cancer that contribute to mortality. Clinically, radiotherapy requires oxygen to generate cytotoxic free radicals that cause DNA damage and allow that damage to become fixed in the genome rather than repaired. However, approximately 40% of all breast cancers have hypoxic tumor microenvironments that render cancer cells significantly more resistant to irradiation. Hypoxic stimuli trigger changes in the cell death/survival pathway that lead to increased cellular radiation resistance. As a result, the development of noninvasive strategies to assess tumor hypoxia in breast cancer has recently received considerable attention. Exosomes are secreted nanovesicles that have roles in paracrine signaling during breast tumor progression, including tumor-stromal interactions, activation of proliferative pathways and immunosuppression. The recent development of protocols to isolate and purify exosomes, as well as advances in mass spectrometry-based proteomics have facilitated the comprehensive analysis of exosome content and function. Using these tools, studies have demonstrated that the proteome profiles of tumor-derived exosomes are indicative of the oxygenation status of patient tumors. They have also demonstrated that exosome signaling pathways are potentially targetable drivers of hypoxia-dependent intercellular signaling during tumorigenesis. This article provides an overview of how proteomic tools can be effectively used to characterize exosomes and elucidate fundamental signaling pathways and survival mechanisms underlying hypoxia-mediated radiation resistance in breast cancer.
Epigenomics and Genome Wide Methylation Profiling  [cached]
PS Samarakoon
Sri Lanka Journal of Bio-Medical Informatics , 2010, DOI: doi: 10.4038/sljbmi.v1i1.1486
Abstract: Epigenetics is the study of the changes in gene expression that are heritable and do not involve a change in the DNA sequence. DNA methylation is one of the key epigenetic mechanisms that is clearly understood. DNA methylation plays a major role in transcriptional silencing in X inactivation, genomic imprinting and tumor or cancer formation. Today the field of epigenetics has evolved to epigenomics and the focus of DNA methylation analysis has shifted to genome wide methylation analysis. With the increasing interest in the field of epigenomics, initiatives such as the NIH Roadmap Epigenomics Program were established aiming to transform biomedical research by developing new technologies and resources for comprehensive epigenomic studies. Because of high productivity and high accuracy, "high throughput DNA methylation profiling" techniques are at the heart of these initiatives. Methylation profiling is performed on chemically treated DNA fragments using bead array platforms and DNA sequences resulting from high throughput sequencing (HTS). Bead array platforms use sets of probes for the identification of the methylation status and computer algorithms identify the methylation status by mapping DNA sequences to the reference genome.
Proteome Profiling of Neuroblastoma-Derived Exosomes Reveal the Expression of Proteins Potentially Involved in Tumor Progression  [PDF]
Danilo Marimpietri, Andrea Petretto, Lizzia Raffaghello, Annalisa Pezzolo, Cristina Gagliani, Carlo Tacchetti, Pierluigi Mauri, Giovanni Melioli, Vito Pistoia
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075054
Abstract: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, with grim prognosis in a half of patients. Exosomes are nanometer-sized membrane vesicles derived from the multivesicular bodies (MVBs) of the endocytic pathway and released by normal and neoplastic cells. Tumor-derived exosomes have been shown in different model systems to carry molecules that promote cancer growth and dissemination. In this respect, we have here performed the first characterization and proteomic analysis of exosomes isolated from human NB cell lines by filtration and ultracentrifugation. Electron microscopy demonstrated that NB-derived exosomes exhibited the characteristic cup-shaped morphology. Dynamic light scattering studies showed a bell-shaped curve and a polydispersity factor consistent with those of exosomes. Zeta potential values suggested a good nanoparticle stability. We performed proteomic analysis of NB-derived exosomes by two dimension liquid chromatography separation and mass spectrometry analyses using the multidimensional protein identification technology strategy. We found that the large majority of the proteins identified in NB derived exosomes are present in Exocarta database including tetraspanins, fibronectin, heat shock proteins, MVB proteins, cytoskeleton-related proteins, prominin-1 (CD133), basigin (CD147) and B7-H3 (CD276). Expression of the CD9, CD63 and CD81 tetraspanins, fibronectin, CD133, CD147 and CD276 was validated by flow cytometry. Noteworthy, flow cytometric analysis showed that NB-derived exosomes expressed the GD2 disialoganglioside, the most specific marker of NB. In conclusion, this study shows that NB-derived exosomes express a discrete set of molecules involved in defense response, cell differentiation, cell proliferation and regulation of other important biological process. Thus, NB-derived exosomes may play an important role in the modulation of tumor microenvironment and represent potential tumor biomarkers.
Proteome Profiling in Murine Models of Multiple Sclerosis: Identification of Stage Specific Markers and Culprits for Tissue Damage  [PDF]
Ralf A. Linker,Peter Brechlin,Sarah Jesse,Petra Steinacker,D. H. Lee,Abdul R. Asif,Olaf Jahn,Hayrettin Tumani,Ralf Gold,Markus Otto
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007624
Abstract: The identification of new biomarkers is of high interest for the prediction of the disease course and also for the identification of pathomechanisms in multiple sclerosis (MS). To specify markers of the chronic disease phase, we performed proteome profiling during the later phase of myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE, day 35 after immunization) as a model disease mimicking many aspects of secondary progressive MS. In comparison to healthy controls, high resolution 2 dimensional gel electrophoresis revealed a number of regulated proteins, among them glial fibrilary acidic protein (GFAP). Phase specific up-regulation of GFAP in chronic EAE was confirmed by western blotting and immunohistochemistry. Protein levels of GFAP were also increased in the cerebrospinal fluid of MS patients with specificity for the secondary progressive disease phase. In a next step, proteome profiling of an EAE model with enhanced degenerative mechanisms revealed regulation of alpha-internexin, syntaxin binding protein 1, annexin V and glutamate decarboxylase in the ciliary neurotrophic factor (CNTF) knockout mouse. The identification of these proteins implicate an increased apoptosis and enhanced axonal disintegration and correlate well the described pattern of tissue injury in CNTF ?/? mice which involve oligodendrocyte (OL) apoptosis and axonal injury.
Quantitative Proteome Profiling of C. burnetii under Tetracycline Stress Conditions  [PDF]
Iosif Vranakis, Pieter-Jan De Bock, Anastasia Papadioti, Yannis Tselentis, Kris Gevaert, Georgios Tsiotis, Anna Psaroulaki
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033599
Abstract: The recommended antibiotic regimen against Coxiella burnetii, the etiological agent of Q fever, is based on a semi-synthetic, second-generation tetracycline, doxycycline. Here, we report on the comparison of the proteomes of a C. burnetii reference strain either cultured under control conditions or under tetracycline stress conditions. Using the MS-driven combined fractional diagonal chromatography proteomics technique, out of the 531 proteins identified, 5 and 19 proteins were found significantly up- and down-regulated respectively, under tetracycline stress. Although the predicted cellular functions of these regulated proteins did not point to known tetracycline resistance mechanisms, our data clearly reveal the plasticity of the proteome of C. burnetii to battle tetracycline stress. Finally, we raise several plausible hypotheses that could further lead to more focused experiments on studying tetracycline resistance in C. burnetii and thus reduced treatment failures of Q fever.
Regular Patterns for Proteome-Wide Distribution of Protein Abundance across Species  [PDF]
Fan Zhong, Dong Yang, Yunwei Hao, Chengzhao Lin, Ying Jiang, Wantao Ying, Songfeng Wu, Yunping Zhu, Siqi Liu, Pengyuan Yang, Xiaohong Qian, Fuchu He
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032423
Abstract: A proteome of the bio-entity, including cell, tissue, organ, and organism, consists of proteins of diverse abundance. The principle that determines the abundance of different proteins in a proteome is of fundamental significance for an understanding of the building blocks of the bio-entity. Here, we report three regular patterns in the proteome-wide distribution of protein abundance across species such as human, mouse, fly, worm, yeast, and bacteria: in most cases, protein abundance is positively correlated with the protein's origination time or sequence conservation during evolution; it is negatively correlated with the protein's domain number and positively correlated with domain coverage in protein structure, and the correlations became stronger during the course of evolution; protein abundance can be further stratified by the function of the protein, whereby proteins that act on material conversion and transportation (mass category) are more abundant than those that act on information modulation (information category). Thus, protein abundance is intrinsically related to the protein's inherent characters of evolution, structure, and function.
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